bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2022‒11‒13
183 papers selected by
Yasmin Elkabani, Egyptian Foundation for Research and Community Development
  1. Enhancing an Oxidative "Trojan Horse" Action of Vitamin C with Arsenic Trioxide for Effective Suppression of KRAS-Mutant Cancers: A Promising Path at the Bedside.
  2. Wound-Healing Effects of Curcumin and Its Nanoformulations: A Comprehensive Review.
  3. Combined phototherapy with metabolic reprogramming-targeted albumin nanoparticles for treating breast cancer.
  4. Metabolic Pathways, Enzymes, and Metabolites: Opportunities in Cancer Therapy.
  5. In-depth drug delivery to tumoral soft tissues via pH responsive hydrogel.
  6. Effect of Curcumin-Loaded Mesoporous Silica Nanoparticles on the Head and Neck Cancer Cell Line, HN5.
  7. Ferritinophagy, a form of autophagic ferroptosis: New insights into cancer treatment.
  8. Recent Progress in Carrier-Free Nanomedicine for Tumor Phototherapy.
  9. Light at the end of the tunnel: Clinical features and therapeutic prospects of KRAS mutant subtypes in non-small-cell lung cancer.
  10. Metabolism of Selenium, Selenocysteine, and Selenoproteins in Ferroptosis in Solid Tumor Cancers.
  11. Natural products targeting glycolytic signaling pathways-an updated review on anti-cancer therapy.
  12. Caffeine and Its Antioxidant Properties-It Is All about Dose and Source.
  13. Dietary Phenolic Compounds as Anticancer Natural Drugs: Recent Update on Molecular Mechanisms and Clinical Trials.
  14. Metabolic reprogramming mediated PD-L1 depression and hypoxia reversion to reactivate tumor therapy.
  15. Co-Delivery of Paclitaxel Prodrug, Gemcitabine and Porphine by Micelles for Pancreatic Cancer Treatment via Chemo-Photodynamic Combination Therapy.
  16. Peritumoral scaffold neutralizes tumor pH for chemotherapy sensitization and metastasis inhibition.
  17. Advancements in Polymeric Nanocarriers to Mediate Targeted Therapy against Triple-Negative Breast Cancer.
  18. Insight into the Prospects for Tumor Therapy Based on Photodynamic Immunotherapy.
  19. Mitochondrial Role in Oncogenesis and Potential Chemotherapeutic Strategy of Mitochondrial Infusion in Breast Cancer.
  20. Targeting nanoparticle-conjugated microbubbles combined with ultrasound-mediated microbubble destruction for enhanced tumor therapy.
  21. Advanced techniques for performing photodynamic therapy in deep-seated tissues.
  22. HA-DOPE-Modified Honokiol-Loaded Liposomes Targeted Therapy for Osteosarcoma.
  23. Preparation of Paclitaxel-Encapsulated Bio-Functionalized Selenium Nanoparticles and Evaluation of Their Efficacy against Cervical Cancer.
  24. Phytochemicals Targeting Ferroptosis: Therapeutic Opportunities and Prospects for Treating Breast Cancer.
  25. Drug Delivery Systems and Flavonoids: Current Knowledge in Melanoma Treatment and Future Perspectives.
  26. Evaluating anticancer properties of Withaferin A-a potent phytochemical.
  27. Polymeric Iron Chelators for Enhancing 5-Aminolevulinic Acid-Induced Photodynamic Therapy.
  28. Tumor Microenvironment-Based Stimuli-Responsive Nanoparticles for Controlled Release of Drugs in Cancer Therapy.
  29. Dual-Functionalized Nanoliposomes Achieve a Synergistic Chemo-Phototherapeutic Effect.
  30. Role of Iron Oxide (Fe2O3) Nanocomposites in Advanced Biomedical Applications: A State-of-the-Art Review.
  31. Dual-Drug Conjugated Glyco-Nanoassemblies for Tumor-Triggered Targeting and Synergistic Cancer Therapy.
  32. Unsaturated Fatty Acid Liposomes Selectively Regulate Glutathione Peroxidase 4 to Exacerbate Lipid Peroxidation as an Adaptable Liposome Platform for Anti-Tumor Therapy.
  33. Target enzymes in serine-glycine-one-carbon metabolic pathway for cancer therapy.
  34. Cinnamon cassia oil chitosan nanoparticles: Physicochemical properties and anti-breast cancer activity.
  35. The Therapeutic Efficacy of Punica granatum and Its Bioactive Constituents with Special Reference to Photodynamic Therapy.
  36. Combination of polythyleneimine regulating autophagy prodrug and Mdr1 siRNA for tumor multidrug resistance.
  37. Chitosan-Polyphenol Conjugates for Human Health.
  38. Dietary Diindolylmethane Enhances the Therapeutic Effect of Centchroman in Breast Cancer by Inhibiting Neoangiogenesis.
  39. Curcumin Represses Colorectal Cancer Cell Proliferation by Triggering Ferroptosis via PI3K/Akt/mTOR Signaling.
  40. Smart Nanoformulations for Brain Cancer Theranostics: Challenges and Promises.
  41. Redox balance and autophagy regulation in cancer progression and their therapeutic perspective.
  42. Ferulic Acid: A Natural Phenol That Inhibits Neoplastic Events through Modulation of Oncogenic Signaling.
  43. Activation of G protein-coupled receptors by ketone bodies: Clinical implication of the ketogenic diet in metabolic disorders.
  44. Thermosensitive In Situ Gels for Joint Disorders: Pharmaceutical Considerations in Intra-Articular Delivery.
  45. The bromoporphyrins as promising anti-tumor photosensitizers in vitro.
  46. Druggable Metabolic Vulnerabilities Are Exposed and Masked during Progression to Castration Resistant Prostate Cancer.
  47. Development and Evaluation of PLGA Nanoparticle-Loaded Organogel for the Transdermal Delivery of Risperidone.
  48. Natural Products for Esophageal Cancer Therapy: From Traditional Medicine to Modern Drug Discovery.
  49. Perfluorooctylbromide-loaded fucoidan-chlorin e6 nanoparticles for tumor-targeted photodynamic therapy.
  50. Pathological implications of metabolic reprogramming and its therapeutic potential in medulloblastoma.
  51. Tea Polyphenols and Their Preventive Measures against Cancer: Current Trends and Directions.
  52. Journey of Rosmarinic Acid as Biomedicine to Nano-Biomedicine for Treating Cancer: Current Strategies and Future Perspectives.
  53. Beneficial effects of natural flavonoids on neuroinflammation.
  54. Transformable nanoparticles to bypass biological barriers in cancer treatment.
  55. Decrease in Tumor Interstitial Pressure for Enhanced Drug Intratumoral Delivery and Synergistic Tumor Therapy.
  56. Possible Effects and Mechanisms of Dietary Natural Products and Nutrients on Depression and Anxiety: A Narrative Review.
  57. Ligand-modified nanocarriers for oral drug delivery: Challenges, rational design, and applications.
  58. Evidence of the Beneficial Effects of Ursolic Acid against Lung Cancer.
  59. Switchable ROS Scavenger/Generator for MRI-Guided Anti-Inflammation and Anti-Tumor Therapy with Enhanced Therapeutic Efficacy and Reduced Side Effects.
  60. KRAS in NSCLC: State of the Art and Future Perspectives.
  61. Natural bioactive compounds against oxidative stress: dietary polyphenols strike back.
  62. A Comprehensive Review on Nutraceuticals: Therapy Support and Formulation Challenges.
  63. Insight into Fucoidan-Based PEGylated PLGA Nanoparticles Encapsulating Methyl Anthranilic Acid: In Vitro Evaluation and In Vivo Anti-Inflammatory Study.
  64. Reactive oxygen species (ROS), oxygen radicals and antioxidants: Where are we now, where is the field going and where should we go?
  65. Pharmacological Activity, Pharmacokinetics, and Clinical Research Progress of Puerarin.
  66. Role of Natural Products in Developing Novel Anticancer Agents: A Perspective.
  67. Bacterial Metabolism-Initiated Nanocatalytic Tumor Immunotherapy.
  68. Targeted delivery of liposomal chemoimmunotherapy for cancer treatment.
  69. The Warburg effect and mitochondrial oxidative phosphorylation: Friends or foes?
  70. Focusing on the Role of Natural Products in Overcoming Cancer Drug Resistance: An Autophagy-Based Perspective.
  71. Research progress on Walnut oil: Bioactive compounds, health benefits, extraction methods, and medicinal uses.
  72. [Metformin and malignant neoplasms: a possible mechanism of antitumor action and prospects for use in practice].
  73. pH-Sensitive Targeting of Tumors with Chemotherapy-Laden Nanoparticles: Progress and Challenges.
  74. Isolongifolene-loaded chitosan nanoparticles synthesis and characterization for cancer treatment.
  75. Effects of curcumin, a bioactive component of turmeric, on type 2 diabetes mellitus and its complications: an updated review.
  76. Research Progress of Antioxidant Nanomaterials for Acute Pancreatitis.
  77. Microbubble-Nanoparticle Complexes for Ultrasound-Enhanced Cargo Delivery.
  78. Cortex Mori extracts induce apoptosis and inhibit tumor invasion via blockage of the PI3K/AKT signaling in melanoma cells.
  79. Molecular Mechanisms of Action of Eugenol in Cancer: Recent Trends and Advancement.
  80. Wnt/β-Catenin Signaling as a Driver of Stemness and Metabolic Reprogramming in Hepatocellular Carcinoma.
  81. Disulfiram loaded calcium phosphate nanoparticles for enhanced cancer immunotherapy.
  82. Nano-integrated cascade antioxidases opsonized by albumin bypass the blood-brain barrier for treatment of ischemia-reperfusion injury.
  83. Fabrication and analysis of chitosan oligosaccharide based mucoadhesive patch for oromucosal drug delivery.
  84. Curcumin: A dietary phytochemical for boosting exercise performance and recovery.
  85. Curcumin and Its Derivatives Induce Apoptosis in Human Cancer Cells by Mobilizing and Redox Cycling Genomic Copper Ions.
  86. Near infrared-activatable biomimetic nanogels enabling deep tumor drug penetration inhibit orthotopic glioblastoma.
  87. Biophysical Evaluation of Water-Soluble Curcumin Encapsulated in β-Cyclodextrins on Colorectal Cancer Cells.
  88. Uncovering the Anticancer Potential of Polydatin: A Mechanistic Insight.
  89. Folic acid engineered sulforaphane loaded microbeads for targeting breast cancer.
  90. Development and assessment of phospholipid-based luteolin-loaded lipid nanocapsules for skin delivery.
  91. Recent Advances in the Development of Lipid-, Metal-, Carbon-, and Polymer-Based Nanomaterials for Antibacterial Applications.
  92. Prospective challenges for patenting and clinical trials of anticancer compounds from natural products: Coherent review.
  93. Lipid metabolism reprogramming in colorectal cancer.
  94. The fate of flaxseed-lignans after oral administration: A comprehensive review on its bioavailability, pharmacokinetics, and food design strategies for optimal application.
  95. Lactate Oxidase-Instructed Cancer Diagnosis and Therapy.
  96. Advances in the research of nano delivery systems in ischemic stroke.
  97. Physical characterization and safety evaluation of folic acid-conjugated mesoporous silica nanoparticles loaded with Rhodojaponin III.
  98. Fabrication of chitosan-gelatin films incorporated with thymol-loaded alginate microparticles for controlled drug delivery, antibacterial activity and wound healing: In-vitro and in-vivo studies.
  99. Vitamin D in Cancer Prevention: Gaps in Current Knowledge and Room for Hope.
  100. Antiproliferative Effects of Ferulic, Coumaric, and Caffeic Acids in HepG2 Cells by hTERT Downregulation.
  101. Pectin: A Bioactive Food Polysaccharide with Cancer Preventive Potential.
  102. MnO2 coated multi-layer nanoplatform for enhanced sonodynamic therapy and MR imaging of breast cancer.
  103. Self-Healing Hydrogels: Development, Biomedical Applications, and Challenges.
  104. Nanotechnology strategies for hepatocellular carcinoma diagnosis and treatment.
  105. Chitosan-Boric Acid Scaffolds for Doxorubicin Delivery in the Osteosarcoma Treatment.
  106. Sodium Thiosulphate-Loaded Liposomes Control Hydrogen Sulphide Release and Retain Its Biological Properties in Hypoxia-like Environment.
  107. Drug repurposing in cardiovascular inflammation: Successes, failures, and future opportunities.
  108. Medical Device Advances in the Treatment of Glioblastoma.
  109. Recent Advances on Natural Aryl-C-glycoside Scaffolds: Structure, Bioactivities, and Synthesis-A Comprehensive Review.
  110. Enhanced Sensitivity of Tumor Cells to Autophagy Inhibitors Using Fasting-Mimicking Diet and Targeted Lysosomal Delivery Nanoplatform.
  111. Photodynamic Therapy Efficacy of Novel Zinc Phthalocyanine Tetra Sodium 2-Mercaptoacetate Combined with Cannabidiol on Metastatic Melanoma.
  112. Nose-to-brain delivery of octreotide acetate in situ gel for pituitary adenoma: Pharmacological and in vitro cytotoxicity studies.
  113. Ethnopharmacology of Rubus idaeus Linnaeus: A critical review on ethnobotany, processing methods, phytochemicals, pharmacology and quality control.
  114. Folic acid-Chitosan Coated Stylosin Nanostructured Lipid Carriers: Fabrication, In Vitro-In Vivo Assessment in Breast Malignant Cells.
  115. Vitamin D increases the efficacy of cisplatin on bladder cancer cell lines.
  116. A xCT role in tumour-associated ferroptosis shed light on novel therapeutic options.
  117. Molecular Targeting of the Most Functionally Complex Gene in Precision Oncology: p53.
  118. Effects of the ketogenic diet on cognition: a systematic review.
  119. Combining metformin with lactate transport inhibitors as a treatment modality for cancer - recommendation proposal.
  120. MsrB1-regulated GAPDH oxidation plays programmatic roles in shaping metabolic and inflammatory signatures during macrophage activation.
  121. Nano-Encapsulation of Citrus Essential Oils: Methods and Applications of Interest for the Food Sector.
  122. Delivery of Corn-Derived Nanoparticles with Anticancer Activity to Tumor Tissues by Modification with Polyethylene Glycol for Cancer Therapy.
  123. Metabolic Reprogramming in Tumor-Associated Macrophages in the Ovarian Tumor Microenvironment.
  124. Improved uptake and bioavailability of cinnamaldehyde via solid lipid nanoparticles for oral delivery.
  125. Synthesis of Artemether-Loaded Albumin Nanoparticles and Measurement of Their Anti-Cancer Effects.
  126. Losartan Potassium and Verapamil Hydrochloride Compound Transdermal Drug Delivery System: Formulation and Characterization.
  127. Neuroprotective and anti-epileptic potentials of genus Artemisia L.
  128. Melatonin Treatment Triggers Metabolic and Intracellular pH Imbalance in Glioblastoma.
  129. Antibody-Functionalized Nanoformulations for Targeted Therapy of Colorectal Cancer: A Systematic Review.
  130. Size optimization of carfilzomib nanocrystals for systemic delivery to solid tumors.
  131. Cisplatin conjugation with an exopolysaccharide extracted from Lactobacillus gasseri potentiates its efficacy and attenuates its toxicity.
  132. Design, Preparation and Evaluation of Supramolecular Complexes with Curcumin for Enhanced Cytotoxicity in Breast Cancer Cell Lines.
  133. Multi-Target Potential of Berberine as an Antineoplastic and Antimetastatic Agent: A Special Focus on Lung Cancer Treatment.
  134. Interactions between Gut Microbiota and Polyphenols: New Insights into the Treatment of Fatigue.
  135. Numerical and experimental evaluation of ultrasound-assisted convection enhanced delivery to transfer drugs into brain tumors.
  136. Oxygen self-supplied upconversion nanoplatform loading cerium oxide for amplified photodynamic therapy of hypoxic tumors.
  137. Nutraceutical Preventative and Therapeutic Potential in Neuroblastoma: From Pregnancy to Early Childhood.
  138. Highly biocompatible chlorin e6-poly(dopamine) core-shell nanoparticles for enhanced cancer phototherapy.
  139. Potential role of resveratrol and its nano-formulation as anti-cancer agent.
  140. Development of Genistein Drug Delivery Systems Based on Bacterial Nanocellulose for Potential Colorectal Cancer Chemoprevention: Effect of Nanocellulose Surface Modification on Genistein Adsorption.
  141. Breast Cancer with Increased Drug Resistance, Invasion Ability, and Cancer Stem Cell Properties through Metabolism Reprogramming.
  142. Enhancement of curcumin level and hepatoprotective effect in rats through antioxidant activity following modification into nanosized particles.
  143. Medical Treatment of Pediatric Low-Grade Glioma.
  144. Ferroptosis: a double-edged sword mediating immune tolerance of cancer.
  145. Synthesis and Biological Evaluation of PEGylated MWO4 Nanoparticles as Sonodynamic AID Inhibitors in Treating Diffuse Large B-Cell Lymphoma.
  146. Long-Term Fenofibrate Treatment Stimulates the Phenotypic Microevolution of Prostate Cancer Cells In Vitro.
  147. Chondroitin sulfate-based composites: a tour d'horizon of their biomedical applications.
  148. Anti-inflammatory hydrogel dressings and skin wound healing.
  149. Radioiodinated acemetacin loaded niosomes as a dual anticancer therapy.
  150. Fine-tuned magnetic nanobubbles for magnetic hyperthermia treatment of glioma cells.
  151. Recent advances in cold atmospheric plasma (CAP) for breast cancer therapy.
  152. Sequential Delivery of Novel Triple Drug Combination via Crosslinked Alginate/Lactoferrin Nanohybrids for Enhanced Breast Cancer Treatment.
  153. Surface Functionalization of Nanofibers: The Multifaceted Approach for Advanced Biomedical Applications.
  154. Synergetic delivery of artesunate and isosorbide 5-mononitrate with reduction-sensitive polymer nanoparticles for ovarian cancer chemotherapy.
  155. Synergistically Anti-Multiple Myeloma Effects: Flavonoid, Non-Flavonoid Polyphenols, and Bortezomib.
  156. Metformin: a promising antidiabetic medication for cancer treatment.
  157. Chitosan Nanoparticles Loaded Poloxamer 407 Gel for Transungual Delivery of Terbinafine HCl.
  158. Engineered multifunctional nanocarriers for controlled drug delivery in tumor immunotherapy.
  159. Evaluation of the Biodistribution of Arginine, glycine, aspartic acid peptide-modified Nanoliposomes Containing Curcumin in Rats.
  160. Novel Scintillating Nanoparticles for Potential Application in Photodynamic Cancer Therapy.
  161. Neuroprotective Panel of Olive Polyphenols: Mechanisms of Action, Anti-Demyelination, and Anti-Stroke Properties.
  162. Prevalence and patterns of mutations in RAS/RAF/MEK/ERK/MAPK signaling pathway in colorectal cancer in North Africa.
  163. Onosma L. as a source of anticancer agents: phytochemistry to mechanistic insight.
  164. Recent technological strategies for enhancing the stability of lycopene in processing and production.
  165. Mechanism of Progesterone in Treatment of Traumatic Brain Injury Based on Network Pharmacology and Molecular Docking Technology.
  166. Sustained release of drug-loaded nanoparticles from injectable hydrogels enables long-term control of macrophage phenotype.
  167. Curcumin and Its Analogs in Non-Small Cell Lung Cancer Treatment: Challenges and Expectations.
  168. Protective effects and mechanism of puerarin targeting PI3K/Akt signal pathway on neurological diseases.
  169. Silicon nanoparticles for oral administration of molecular hydrogen.
  170. Effect of Germination and Illumination on Melatonin and Its Metabolites, Phenolic Content, and Antioxidant Activity in Mung Bean Sprouts.
  171. Targeting Mitochondrial Metabolism to Reverse Radioresistance: An Alternative to Glucose Metabolism.
  172. Garlic and Its Bioactive Compounds: Implications for Methane Emissions and Ruminant Nutrition.
  173. Getting drugs to the brain: advances and prospects of organic nanoparticle delivery systems for assisting drugs to cross the blood-brain barrier.
  174. Discovery of potential natural dihydroorotate dehydrogenase inhibitors and their synergism with brequinar via integrated molecular docking, dynamic simulations and in vitro approach.
  175. Resveratrol inhibits proliferation and induces apoptosis via the Hippo/YAP pathway in human colon cancer cells.
  176. Crosstalk between Depression and Breast Cancer via Hepatic Epoxide Metabolism: A Central Comorbidity Mechanism.
  177. Targeting Heat Shock Proteins in Malignant Brain Tumors: From Basic Research to Clinical Trials.
  178. An updated and comprehensive review on the ethnomedicinal uses, phytochemistry, pharmacological activity and toxicological profile of Tinospora crispa (L.) Hook. f. & Thomson.
  179. Peptide-Based Supramolecular Hydrogels as Drug Delivery Agents: Recent Advances.
  180. Antitumor effects of lactate transport inhibition on esophageal adenocarcinoma cells.
  181. Extracellular matrix degrading enzyme with stroma-targeting peptides enhance the penetration of liposomes into tumors.
  182. Formulation of Chitosan Microparticles for Enhanced Intranasal Macromolecular Compound Delivery: Factors That Influence Particle Size during Ionic Gelation.
  183. Aloe Vera coated Dextran Sulfate/Chitosan nanoparticles (Aloe Vera @ DS/CS) encapsulating Eucalyptus essential oil with antibacterial potent property.
  1. Cells. 2022 Nov 01. pii: 3454. [Epub ahead of print]11(21):
    Enhancing an Oxidative "Trojan Horse" Action of Vitamin C with Arsenic Trioxide for Effective Suppression of KRAS-Mutant Cancers: A Promising Path at the Bedside.
    Agata N Burska, Bayansulu Ilyassova, Aruzhan Dildabek, Medina Khamijan, Dinara Begimbetova, Ferdinand Molnár, Dos D Sarbassov.
      The turn-on mutations of the KRAS gene, coding a small GTPase coupling growth factor signaling, are contributing to nearly 25% of all human cancers, leading to highly malignant tumors with poor outcomes. Targeting of oncogenic KRAS remains a most challenging task in oncology. Recently, the specific G12C mutant KRAS inhibitors have been developed but with a limited clinical outcome because they acquire drug resistance. Alternatively, exploiting a metabolic breach of KRAS-mutant cancer cells related to a glucose-dependent sensitivity to oxidative stress is becoming a promising indirect cancer targeting approach. Here, we discuss the use of a vitamin C (VC) acting in high dose as an oxidative "Trojan horse" agent for KRAS-mutant cancer cells that can be potentiated with another oxidizing drug arsenic trioxide (ATO) to obtain a potent and selective cytotoxic impact. Moreover, we outline the advantages of VC's non-natural enantiomer, D-VC, because of its distinctive pharmacokinetics and lower toxicity. Thus, the D-VC and ATO combination shows a promising path to treat KRAS-mutant cancers in clinical settings.
    Keywords:  Kirsten rat sarcoma (KRAS) mutant ancers; Warburg effect; arsenic trioxide (ATO); oxidative stress; reactive oxygen species (ROS); suicidal ROS production by mitochondrial (SRPM); vitamin C (VC also known as ascorbic acid)
    DOI:  https://doi.org/10.3390/cells11213454
  2. Pharmaceutics. 2022 Oct 25. pii: 2288. [Epub ahead of print]14(11):
    Wound-Healing Effects of Curcumin and Its Nanoformulations: A Comprehensive Review.
    Amrita Kumari, Neha Raina, Abhishek Wahi, Khang Wen Goh, Pratibha Sharma, Riya Nagpal, Atul Jain, Long Chiau Ming, Madhu Gupta.
      Wound healing is an intricate process of tissue repair or remodeling that occurs in response to injury. Plants and plant-derived bioactive constituents are well explored in the treatment of various types of wounds. Curcumin is a natural polyphenolic substance that has been used since ancient times in Ayurveda for its healing properties, as it reduces inflammation and acts on several healing stages. Several research studies for curcumin delivery at the wound site reported the effectiveness of curcumin in eradicating reactive oxygen species and its ability to enhance the deposition of collagen, granulation tissue formation, and finally, expedite wound contraction. Curcumin has been widely investigated for its wound healing potential but its lower solubility and rapid metabolism, in addition to its shorter plasma half-life, have limited its applications in wound healing. As nanotechnology has proven to be an effective technique to accelerate wound healing by stimulating appropriate mobility through various healing phases, curcumin-loaded nanocarriers are used for targeted delivery at the wound sites. This review highlights the potential of curcumin and its nanoformulations, such as liposomes, nanoparticles, and nano-emulsions, etc. in wound healing. This paper emphasizes the numerous biomedical applications of curcumin which collectively prepare a base for its antibiofilm and wound-healing action.
    Keywords:  Diabetic foot ulcer; FDA regulations; Patents; antibiofilm; antioxidant; drug delivery; nanotechnology; polyphenolic compound; skin; wound healing
    DOI:  https://doi.org/10.3390/pharmaceutics14112288
  3. Biomater Sci. 2022 Nov 09.
    Combined phototherapy with metabolic reprogramming-targeted albumin nanoparticles for treating breast cancer.
    Xuan Thien Le, Junyeong Lee, Nguyen Thi Nguyen, Woo Tak Lee, Eun Seong Lee, Kyung Taek Oh, Han-Gon Choi, Beom Soo Shin, Yu Seok Youn.
      Triple-negative breast cancer (TNBC) is characterized by rapid tumor growth and resistance to cancer therapy, and has a poor prognosis. Accumulating data have revealed that cancer metabolism relies on both the Warburg effect and oxidative phosphorylation (OXPHOS), which are strongly related to the high proliferation and chemoresistance of cancer cells. Phototherapy is considered as a non-invasive method to precisely control drug activity with reduced side effects. Herein, our group introduced an Abraxane-like nanoplatform, named LCIR NPs, which significantly eradicates cancer cells via synergism between metabolic reprogramming and phototherapy effects. Endowed with mitochondria-targeting residues, the nanoparticles efficiently inhibited mitochondrial complexes I and IV as well as hexokinase II, leading to the depletion of intracellular ATP. Consequently, the photodynamic and photothermal effect triggered by NIR irradiation was enhanced due to the alleviation of hypoxia and the thermoresistance mechanism that rely on mitochondrial metabolism. In vivo experiments showed that the tumor size of mice that received the combination treatment was only 50.7 mm3, which was 21 times smaller than that of the untreated group and was much lower than those of other single treatments after 21 days. Additionally, almost no systemic undesired toxicity was detected during the observation period. We believe that the concept of LCIR as presented here offers a potential platform to overcome the resistance to conventional therapies by the incorporation with the energy metabolism inhibition approach.
    DOI:  https://doi.org/10.1039/d2bm01281b
  4. Cancers (Basel). 2022 Oct 27. pii: 5268. [Epub ahead of print]14(21):
    Metabolic Pathways, Enzymes, and Metabolites: Opportunities in Cancer Therapy.
    Rishabh Kumar, Anurag Mishra, Priyanka Gautam, Zainab Feroz, Sivakumar Vijayaraghavalu, Eviania M Likos, Girish C Shukla, Munish Kumar.
      Metabolic reprogramming enables cancer cells to proliferate and produce tumor biomass under a nutrient-deficient microenvironment and the stress of metabolic waste. A cancer cell adeptly undergoes a variety of adaptations in metabolic pathways and differential expression of metabolic enzyme genes. Metabolic adaptation is mainly determined by the physiological demands of the cancer cell of origin and the host tissue. Numerous metabolic regulators that assist cancer cell proliferation include uncontrolled anabolism/catabolism of glucose metabolism, fatty acids, amino acids metabolism, nucleotide metabolism, tumor suppressor genes, microRNAs, and many regulatory enzymes and genes. Using this paradigm, we review the current understanding of metabolic reprogramming in tumors and discuss the new strategies of cancer metabolomics that can be tapped into for cancer therapeutics.
    Keywords:  Warburg effect; amino acid metabolism; cancer metabolism; cancer therapeutics; fatty acid metabolism; glycolysis; microRNA; oncogenes; tumor suppressor genes
    DOI:  https://doi.org/10.3390/cancers14215268
  5. RSC Adv. 2022 Oct 27. 12(48): 31402-31411
    In-depth drug delivery to tumoral soft tissues via pH responsive hydrogel.
    Shumaila Sarwar, Sajid Bashir, Mulazim Hussain Asim, Fakhera Ikram, Arsalan Ahmed, Ume Omema, Anila Asif, Aqif Anwar Chaudhry, Yong Hu, Cem Bulent Ustundag.
      A pH responsive nanoparticle-hydrogel hybrid drug delivery system was investigated for in-depth anticancer drug delivery to solid tumours. It consists of acid susceptible polymer nanoparticles loaded in a chitosan hydrogel. The hybrid formulation was characterized by UV-visible spectroscopy, FTIR, SEM, TEM, particle size analysis, zeta potential measurement and viscosity measurement. Drug encapsulation and nanoparticle loading efficiencies were found to be 48% and 72% respectively which describes the efficient interaction of the chemical entities in this hybrid drug delivery system. The hydrogel exhibited pH responsive behaviour: minimal drug and nanoparticle release at physiological pH but an increase in viscosity under acidic conditions and fast nanoparticle and drug release. The cytotoxicity of the drug loaded hydrogel was investigated against the MCF-7 breast cancer cell line along with the drug and nanoparticles without hydrogel. The drug loaded hydrogel showed a better cytotoxic effect on MCF-7 cancer cells. Thus, drug loaded nanoparticles containing hydrogel could be a better option for maximum drug distribution in tumours.
    DOI:  https://doi.org/10.1039/d2ra05639a
  6. Curr Issues Mol Biol. 2022 Oct 27. 44(11): 5247-5259
    Effect of Curcumin-Loaded Mesoporous Silica Nanoparticles on the Head and Neck Cancer Cell Line, HN5.
    Simin Sharifi, Elaheh Dalir Abdolahinia, Mohammad Ali Ghavimi, Solmaz Maleki Dizaj, Michael Aschner, Luciano Saso, Haroon Khan.
      Curcumin is an active ingredient isolated from Curcuma longa. It has several pharmacological effects, including anticancer, anti-inflammatory, and antioxidant effects. Due to its low bioavailability, chemical structure instability, and easy oxidation, the application of curcumin has been limited. In this study, to overcome these limitations, curcumin-loaded mesoporous silica nanoparticles (Cur-MSN) were prepared, and the anticancerous effect of Cur-MSNs on head and neck cancer cells, HN5, was investigated. Transmission electron microscopy (TEM) revealed rod-shaped mesoporous nanoparticles with average particle size smaller than 100 nm. Higher cytotoxicity of Cur-MSNs was seen in treated cancer cells compared with free curcumin. The expression of Bcl-2 was significantly reduced in the presence of Cur-MSNs compared to the control (untreated HN5 cells) (p < 0.05). A 3.43-fold increase in the Bax/Bcl-2 ratio was seen in Cur-MSNs treated HN5 cells at the IC50. Cur-MSNs increased intracellular reactive oxygen species (ROS) production. Based on these novel results, we suggest that Cur-MSNs offer efficacy for cancer treatment and future studies should further characterize their properties in various experimental cancer models.
    Keywords:  Bax/Bcl-2; anticancer; curcumin; mesoporous silica nanoparticles
    DOI:  https://doi.org/10.3390/cimb44110357
  7. Front Pharmacol. 2022 ;13 1043344
    Ferritinophagy, a form of autophagic ferroptosis: New insights into cancer treatment.
    Kai Sun, Chenyuan Li, Shichong Liao, Xinrui Yao, Yang Ouyang, Yi Liu, Zhong Wang, Zhiyu Li, Feng Yao.
      Ferritinophagy, a form of autophagy, is also an important part of ferroptosis, a type of regulated cell death resulting from abnormal iron metabolism involving the production of reactive oxygen species. As ferroptosis, autophagy and cancer have been revealed, ferritinophagy has attracted increasing attention in cancer development. In this review, we discuss the latest research progress on ferroptosis, autophagy-associated ferroptosis led by ferritinophagy, the regulators of ferritinophagy and promising cancer treatments that target ferritinophagy. Ferritinophagy is at the intersection of ferroptosis and autophagy and plays a significant role in cancer development. The discussed studies provide new insights into the mechanisms of ferritinophagy and promising related treatments for cancer.
    Keywords:  autophagy; cancer; ferritinophagy; ferroptosis; iron
    DOI:  https://doi.org/10.3389/fphar.2022.1043344
  8. Adv Healthc Mater. 2022 Nov 09. e2202307
    Recent Progress in Carrier-Free Nanomedicine for Tumor Phototherapy.
    Ying-Tao Zhong, Yi Cen, Lin Xu, Shi-Ying Li, Hong Cheng.
      Safe and effective strategies are urgently needed to fight against the life-threatening diseases of various cancers. However, traditional therapeutic modalities, such as radiotherapy, chemotherapy and surgery, exhibit suboptimal efficacy for malignant tumors owing to the serious side effect, drug resistance and even relapse. Phototherapies, including photodynamic therapy (PDT) and photothermal therapy (PTT), are emerging therapeutic strategies for localized tumor inhibition, which can produce a large amount of reactive oxygen species (ROS) or elevate the temperature to initiate cell death by non-invasive irradiation. In consideration of the poor bioavailability of phototherapy agents (PTAs), lots of drug delivery systems have been developed to enhance the tumor targeted delivery. Nevertheless, the carriers of drug delivery systems inevitably bring biosafety concerns on account of their metabolism, degradation and accumulation. Of note, carrier-free nanomedicine attracts great attention for clinical translation with synergistic antitumor effect, which is characterized by high drug loading, simplified synthetic method and good biocompatibility. In this review, we summarize the latest advances of phototherapy with various carrier-free nanomedicines, which may provide a new paradigm for the future development of nanomedicine and tumor precision therapy. This article is protected by copyright. All rights reserved.
    Keywords:  carrier-free nanomedicine; self-assembly; tumor phototherapy
    DOI:  https://doi.org/10.1002/adhm.202202307
  9. Front Genet. 2022 ;13 890247
    Light at the end of the tunnel: Clinical features and therapeutic prospects of KRAS mutant subtypes in non-small-cell lung cancer.
    Liyuan Gao, Weizhang Shen.
      Lung cancer is one of the most common causes of cancer-related deaths, and non-small-cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases. Kirsten rat sarcoma virus (KRAS), one of the three subtypes of the RAS family, is the most common oncogene involved in human cancers and encodes the key signaling proteins in tumors. Oncogenic KRAS mutations are considered the initiating factors in 30% of NSCLC cases, accounting for the largest proportion of NSCLC cases associated with driver mutations. Because effective inhibition of the related functions of KRAS with traditional small-molecule inhibitors is difficult, the KRAS protein is called an "undruggable target." However, in recent years, the discovery of a common mutation in the KRAS gene, glycine 12 mutated to cysteine (G12C), has led to the design and synthesis of covalent inhibitors that offer novel strategies for effective targeting of KRAS. In this review, we have summarized the structure, function, and signal transduction pathways of KRAS and discussed the available treatment strategies and potential treatment prospects of KRAS mutation subtypes (especially G12C, G12V, and G12D) in NSCLC, thus providing a reference for selecting KRAS mutation subtypes for the treatment of NSCLC.
    Keywords:  KRAS G12C; KRAS G12D; KRAS G12V; KRAS mutation; non-small-cell lung cancer
    DOI:  https://doi.org/10.3389/fgene.2022.890247
  10. Biomolecules. 2022 Oct 28. pii: 1581. [Epub ahead of print]12(11):
    Metabolism of Selenium, Selenocysteine, and Selenoproteins in Ferroptosis in Solid Tumor Cancers.
    Briana K Shimada, Sydonie Swanson, Pamela Toh, Lucia A Seale.
      A potential target of precision nutrition in cancer therapeutics is the micronutrient selenium (Se). Se is metabolized and incorporated as the amino acid selenocysteine (Sec) into 25 human selenoproteins, including glutathione peroxidases (GPXs) and thioredoxin reductases (TXNRDs), among others. Both the processes of Se and Sec metabolism for the production of selenoproteins and the action of selenoproteins are utilized by cancer cells from solid tumors as a protective mechanism against oxidative damage and to resist ferroptosis, an iron-dependent cell death mechanism. Protection against ferroptosis in cancer cells requires sustained production of the selenoprotein GPX4, which involves increasing the uptake of Se, potentially activating Se metabolic pathways such as the trans-selenation pathway and the TXNRD1-dependent decomposition of inorganic selenocompounds to sustain GPX4 synthesis. Additionally, endoplasmic reticulum-resident selenoproteins also affect apoptotic responses in the presence of selenocompounds. Selenoproteins may also help cancer cells adapting against increased oxidative damage and the challenges of a modified nutrient metabolism that result from the Warburg switch. Finally, cancer cells may also rewire the selenoprotein hierarchy and use Se-related machinery to prioritize selenoproteins that are essential to the adaptations against ferroptosis and oxidative damage. In this review, we discuss both the evidence and the gaps in knowledge on how cancer cells from solid tumors use Se, Sec, selenoproteins, and the Se-related machinery to promote their survival particularly via resistance to ferroptosis.
    Keywords:  cancer; ferroptosis; selenium; selenium metabolism; solid tumors
    DOI:  https://doi.org/10.3390/biom12111581
  11. Front Pharmacol. 2022 ;13 1035882
    Natural products targeting glycolytic signaling pathways-an updated review on anti-cancer therapy.
    Yuting Cui, Chuang Li, Feng Sang, Weiling Cao, Zhuo Qin, Peng Zhang.
      Glycolysis is a complex metabolic process that occurs to convert glucose into pyruvate to produce energy for living cells. Normal cells oxidized pyruvate into adenosine triphosphate and carbon dioxide in the presence of oxygen in mitochondria while cancer cells preferentially metabolize pyruvate to lactate even in the presence of oxygen in order to maintain a slightly acidic micro-environment of PH 6.5 and 6.9, which is beneficial for cancer cell growth and metastasis. Therefore targeting glycolytic signaling pathways provided new strategy for anti-cancer therapy. Natural products are important sources for the treatment of diseases with a variety of pharmacologic activities. Accumulated studies suggested that natural products exhibited remarkable anti-cancer properties both in vitro and in vivo. Plenty of studies suggested natural products like flavonoids, terpenoids and quinones played anti-cancer properties via inhibiting glucose metabolism targets in glycolytic pathways. This study provided an updated overview of natural products controlling glycolytic pathways, which also provide insight into druggable mediators discovery targeting cancer glucose metabolism.
    Keywords:  anti-cancer; glycolysis; hexokinase (HK); natural compounds; phosphofructokinase-1 (PFK-1); pyruvate kinase (PK)
    DOI:  https://doi.org/10.3389/fphar.2022.1035882
  12. Int J Mol Sci. 2022 Oct 28. pii: 13074. [Epub ahead of print]23(21):
    Caffeine and Its Antioxidant Properties-It Is All about Dose and Source.
    Bianca-Eugenia Ősz, George Jîtcă, Ruxandra-Emilia Ștefănescu, Amalia Pușcaș, Amelia Tero-Vescan, Camil-Eugen Vari.
      Caffeine is the most frequently used substance with a central nervous system stimulant effect, but its consumption is most often due to the intake of foods and drinks that contain it (coffee, tea, chocolate, food supplements with plant extracts of Guarana, Mate herba, Cola nuts). Due to its innocuity, caffeine is a safe xanthine alkaloid for human consumption in a wide range of doses, being used for its central nervous stimulating effect, lipolytic and diuresis-enhancing properties, but also as a permitted ergogenic compound in athletes. In addition to the mechanisms that explain the effects of caffeine on the targeted organ, there are many proposed mechanisms by which this substance would have antioxidant effects. As such, its consumption prevents the occurrence/progression of certain neurodegenerative diseases as well as other medical conditions associated with increased levels of reactive oxygen or nitrogen species. However, most studies that have assessed the beneficial effects of caffeine have used pure caffeine. The question, therefore, arises whether the daily intake of caffeine from food or drink has similar benefits, considering that in foods or drinks with a high caffeine content, there are other substances that could interfere with this action, either by potentiating or decreasing its antioxidant capacity. Natural sources of caffeine often combine plant polyphenols (phenol-carboxylic acids, catechins) with known antioxidant effects; however, stimulant drinks and dietary supplements often contain sugars or artificial sweeteners that can significantly reduce the effects of caffeine on oxidative stress. The objective of this review is to clarify the effects of caffeine in modulating oxidative stress and assess these benefits, considering the source and the dose administered.
    Keywords:  caffeine; cocoa; coffee; oxidative stress; sweets; xanthine oxidase
    DOI:  https://doi.org/10.3390/ijms232113074
  13. Foods. 2022 Oct 23. pii: 3323. [Epub ahead of print]11(21):
    Dietary Phenolic Compounds as Anticancer Natural Drugs: Recent Update on Molecular Mechanisms and Clinical Trials.
    Saad Bakrim, Nasreddine El Omari, Naoufal El Hachlafi, Youssef Bakri, Learn-Han Lee, Abdelhakim Bouyahya.
      Given the stochastic complexity of cancer diseases, the development of chemotherapeutic drugs is almost limited by problems of selectivity and side effects. Furthermore, an increasing number of protective approaches have been recently considered as the main way to limit these pathologies. Natural bioactive compounds, and particularly dietary phenolic compounds, showed major protective and therapeutic effects against different types of human cancers. Indeed, phenolic substances have functional groups that allow them to exert several anti-cancer mechanisms, such as the induction of apoptosis, autophagy, cell cycle arrest at different stages, and the inhibition of telomerase. In addition, in vivo studies show that these phenolic compounds also have anti-angiogenic effects via the inhibition of invasion and angiogenesis. Moreover, clinical studies have already highlighted certain phenolic compounds producing clinical effects alone, or in combination with drugs used in chemotherapy. In the present work, we present a major advance in research concerning the mechanisms of action of the different phenolic compounds that are contained in food medicinal plants, as well as evidence from the clinical trials that focus on them.
    Keywords:  apoptosis; cancer; clinical trials; dietary phenolic compounds
    DOI:  https://doi.org/10.3390/foods11213323
  14. J Control Release. 2022 Nov 04. pii: S0168-3659(22)00743-X. [Epub ahead of print]
    Metabolic reprogramming mediated PD-L1 depression and hypoxia reversion to reactivate tumor therapy.
    Zaigang Zhou, Yu Liu, Wei Song, Xin Jiang, Zaian Deng, Wei Xiong, Jianliang Shen.
      As a promising cancer treatment, photodynamic therapy (PDT) still achieved limited clinical success due to the severe hypoxia and programmed death ligand-1 (PD-L1) over-expressed immunosuppression tumor microenvironment. At present, few methods have been proven to solve these two defects simply and effectively by a single drug or nano-system simultaneously. To ameliorate this situation, we designed and constructed MB@Bu@MnO2 nanoparticles with two-step oxygen regulation ability and PD-1/PD-L1 axis cascade-disruption capacity via a biomineralization method. In such a nanosystem, manganese dioxide albumin (MnO2@Alb) was used as the drug carrier, Butformin (Bu) as mitochondria-associated oxidative phosphorylation (OXPHOS) disruption agent with PD-L1 depression and oxygen reversion ability, and methylene blue (MB) as PDT drug with programmed cell death protein 1 (PD-1) inhibition capacity. Owing to the tumor-responsive capacity of MB@Bu@MnO2 nanoparticles, Bu and MB were selectively delivered and released in tumors. Then, the tumor hypoxia was dramatically reversed by Bu inhibited oxygen consumption, and MnO2 improved oxygen generation. Following this, the reactive oxygen species (ROS) generation was enhanced by MB@Bu@MnO2 nanoparticles mediated PDT owing to the reversed tumor hypoxia. Furthermore, the immunosuppression microenvironment was also obviously reversed by MB@Bu@MnO2 nanoparticles enhanced immunogenic cell death (ICD) and PD-1/PD-L1 axis cascade-disruption, which then enhanced T cell infiltration and improved its tumor cell killing ability. Finally, the growth of solid tumors was significantly depressed by MB@Bu@MnO2 nanoparticles mediated PDT. All in all, this well-designed nanosystem could solve the defects of traditional PDT via PD-1/PD-L1 axis dual disruption and reversing tumor hypoxia by two-step oxygen regulation.
    Keywords:  Butformin; Hypoxia; Methylene blue; Mitochondrial oxidative phosphorylation; Photodynamic immunotherapy; Programmed death ligand-1
    DOI:  https://doi.org/10.1016/j.jconrel.2022.11.004
  15. Pharmaceutics. 2022 Oct 25. pii: 2280. [Epub ahead of print]14(11):
    Co-Delivery of Paclitaxel Prodrug, Gemcitabine and Porphine by Micelles for Pancreatic Cancer Treatment via Chemo-Photodynamic Combination Therapy.
    Qiwei Wu, Xiaodong Ma, Wenhui Zhou, Rong Yu, Jessica M Rosenholm, Weizhong Tian, Lirong Zhang, Dongqing Wang, Hongbo Zhang.
      Pancreatic carcinoma is an aggressive subtype of cancer with poor prognosis, known for its refractory nature. To address this challenge, we have established a stable nanoplatform that combines chemotherapy with photodynamic therapy (PDT) to achieve better curative efficacy. First, we designed and synthesized a disulfide-bonded paclitaxel (PTX)-based prodrug, which was further mixed with gemcitabine (GEM) and photosensitizer THPP in an optimized ratio. Subsequently, the mixture was added dropwise into amphiphilic polymer DSPE-PEG water solution to form micelles composed of DSPE-PEG nanoparticles (TPG NPs). The TPG NPs were around 135 nm, and showed great ability of DTT stimulated release of PTX and GEM. Moreover, the TPG NPs can be efficiently uptaken by pancreatic cancer PANC-1 cells and effectively kill them, especially when combined with 650 nm laser irradiation. Finally, the TPG NPs have shown enhanced long-term circulation ability and also exhibited efficient anti-tumor activity in combination with 650 nm laser irradiation in a pancreatic cancer mouse model. In summary, the designed TPG NPs possesses great potential for co-delivery of paclitaxel prodrug, GEM and THPP, which enables combined chemo-photodynamic therapy for cancer treatment. In addition, the stimulated release of PTX prodrug and GEM also allows for better targeting of tumor cells and the increased therapeutic effect against cancer cells. Overall, the TPG NPs can serve as a good candidate for pancreatic cancer treatment.
    Keywords:  combination therapy; pancreatic carcinoma; photodynamic therapy; prodrug
    DOI:  https://doi.org/10.3390/pharmaceutics14112280
  16. J Control Release. 2022 Nov 07. pii: S0168-3659(22)00745-3. [Epub ahead of print]
    Peritumoral scaffold neutralizes tumor pH for chemotherapy sensitization and metastasis inhibition.
    Yue Yan, Junlin Li, Xiaoli Yi, Chendong Liu, Zhou Zhou, Yuan Huang, Lian Li.
      The abnormal metabolism of rapidly growing tumors can create an acidic tumor microenvironment (TME) that renders cancer cells resistant to chemotherapy and further facilitates endothelial-to-mesenchymal transition (EMT) progress to promote metastasis. Here, we developed a combination strategy consisting of (1) peritumorally injected scaffold that alleviates TME acidosis, and (2) intravenously injected nanoparticles that delivers anti-cancer agents to tumor. Concurrent treatment with these two drug delivery systems profoundly delayed the growth of primary tumor and reduced the spontaneous metastasis to lung in an orthotopic breast cancer mouse model. Mechanism studies both in vitro and in vivo further revealed that neutralization of TME pH by the hydrogel scaffold sensitized cancer cells to nanoparticle-based chemotherapy, thereby strengthening the cytotoxicity against tumor growth; In parallel, reversal of tumor acidity downregulated various pro-metastatic proteins intratumorally to block the EMT progress, thereby reducing the metastatic potential of cancer cells. This work provided proof-of-concept demonstration that chemotherapy sensitization and EMT suppression could be synchronized by the modulation of TME pH, which may be potentially beneficial for simultaneous inhibition of tumor growth and cancer metastasis.
    Keywords:  Chemotherapy sensitization; Endothelial-to-mesenchymal transition; Metastasis inhibition; Tumor acidity modulation; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.jconrel.2022.11.006
  17. Pharmaceutics. 2022 Nov 10. pii: 2432. [Epub ahead of print]14(11):
    Advancements in Polymeric Nanocarriers to Mediate Targeted Therapy against Triple-Negative Breast Cancer.
    Mahak Fatima, Afsana Sheikh, Mohammed A S Abourehab, Prashant Kesharwani.
      Triple-negative breast cancer (TNBC) is a destructive disease with a poor prognosis, low survival rate and high rate of metastasis. It comprises 15% of total breast cancers and is marked by deficiency of three important receptor expressions, i.e., progesterone, estrogen, and human epidermal growth factor receptors. This absence of receptors is the foremost cause of current TNBC therapy failure, resulting in poor therapeutic response in patients. Polymeric nanoparticles are gaining much popularity for transporting chemotherapeutics, genes, and small-interfering RNAs. Due to their exclusive properties such as great stability, easy surface modification, stimuli-responsive and controlled drug release, ability to condense more than one therapeutic moiety inside, tumor-specific delivery of payload, enhanced permeation and retention effect, present them as ideal nanocarriers for increasing efficacy, bioavailability and reducing the toxicity of therapeutic agents. They can even be used as theragnostic agents for the diagnosis of TNBC along with its treatment. In this review, we discuss the limitations of already existing TNBC therapies and highlight the novel approach to designing and the functionalization of polymeric nanocarriers for the effective treatment of TNBC.
    Keywords:  cancer-stem cells; drug-delivery system; immunotherapy; nanotechnology; polymeric nanoparticles; triple-negative breast cancer
    DOI:  https://doi.org/10.3390/pharmaceutics14112432
  18. Pharmaceuticals (Basel). 2022 Nov 04. pii: 1359. [Epub ahead of print]15(11):
    Insight into the Prospects for Tumor Therapy Based on Photodynamic Immunotherapy.
    Xiaoxia Cheng, Yiqu Wei, Xiaomei Jiang, Chunli Wang, Mengyu Liu, Jiaxin Yan, Lei Zhang, Yaqi Zhou.
      Malignancy is one of the common diseases with high mortality worldwide and the most important obstacle to improving the overall life expectancy of the population in the 21st century. Currently, single or combined treatments, including surgery, chemotherapy, and radiotherapy, are still the mainstream regimens for tumor treatment, but they all present significant side effects on normal tissues and organs, such as organ hypofunction, energy metabolism disorders, and various concurrent diseases. Based on this, theranostic measures for the highly selective killing of tumor cells have always been a hot area in cancer-related fields, among which photodynamic therapy (PDT) is expected to be an ideal candidate for practical clinical application due to its precise targeting and excellent safety performance, so-called PDT refers to a therapeutic method mainly composed of photosensitizers (PSs), laser light, and reactive oxygen species (ROS). Photoimmunotherapy (PIT), a combination of PDT and immunotherapy, can induce systemic antitumor immune responses and inhibit continuing growth and distant metastasis of residual tumor cells, demonstrating a promising application prospect. This article reviews the types of immune responses that occur in the host after PDT treatment, including innate and adaptive immunity. To further help PIT-related drugs improve their pharmacokinetic properties and bioavailability, we highlight the potential improvement of photodynamic immunotherapy from three aspects: immunostimulatory agents, tumor-associated antigens (TAAs) as well as different immune cells. Finally, we focus on recent advances in various strategies and shed light on their corresponding mechanisms of immune activation and possible clinical applications such as cancer vaccines. Having discovered the inherent potential of PDT and the mechanisms that PDT triggers host immune responses, a variety of immunotherapeutic strategies have been investigated in parallel with approaches to improve PDT efficiency. However, it remains to be further elucidated under what conditions the immune effect induced by PDT can achieve tumor immunosuppression and to what extent PDT-induced antitumor immunity will lead to complete tumor rejection. Currently, PIT presents several outstanding intractable challenges, such as the aggregation ability of PSs locally in tumors, deep tissue penetration ability of laser light, immune escape, and biological toxicity, and it is hoped that these issues raised will help to point out the direction of preclinical research on PIT and accelerate its transition to clinical practice.
    Keywords:  REACTIVE oxygen species; immunity; malignant tumor treatment; photodynamic therapy; photoimmunotherapy
    DOI:  https://doi.org/10.3390/ph15111359
  19. Int J Mol Sci. 2022 Oct 27. pii: 12993. [Epub ahead of print]23(21):
    Mitochondrial Role in Oncogenesis and Potential Chemotherapeutic Strategy of Mitochondrial Infusion in Breast Cancer.
    Prisha S Patel, Christopher Castelow, Disha S Patel, Syamal K Bhattacharya, Cem Kuscu, Canan Kuscu, Liza Makowski, James D Eason, Amandeep Bajwa.
      Triple negative breast cancer (TNBC) is one of the most aggressive cancers diagnosed amongst women with a high rate of treatment failure and a poor prognosis. Mitochondria have been found to be key players in oncogenesis and tumor progression by mechanisms such as altered metabolism, reactive oxygen species (ROS) production and evasion of apoptosis. Therefore, mitochondrial infusion is an area of interest for cancer treatment. Studies in vitro and in vivo demonstrate mitochondrial-mediated reduction in glycolysis, enhancement of oxidative phosphorylation (OXPHOS), reduction in proliferation, and an enhancement of apoptosis as effective anti-tumor therapies. This review focuses on mitochondrial dysregulation and infusion in malignancies, such as TNBC.
    Keywords:  cancer; metabolism; mitochondria; mitotherapy; triple negative breast cancer
    DOI:  https://doi.org/10.3390/ijms232112993
  20. Pharmacol Res. 2022 Nov 02. pii: S1043-6618(22)00478-9. [Epub ahead of print]186 106532
    Targeting nanoparticle-conjugated microbubbles combined with ultrasound-mediated microbubble destruction for enhanced tumor therapy.
    Kuo-Wei Chen, Po-Hung Hsu, Hau-Lun Huang, Hao-Li Liu, Ya-Tin Lin, Che-Yu Hsu, Jui-Hsiang Lin, Yu-Hsin Lin.
      The stress of the abnormal stromal matrix of solid tumors is a major limiting factor that prevents drug penetration. Controlled, accurate, and efficient delivery of theranostic agents into tumor cells is crucial. Combining ultrasound with nanocarrierbased drug delivery systems have become a promising approach for targeted drug delivery in preclinical cancer therapy. In this study, to ensure effective tumor barrier penetration, access to the tumor microenvironment, and local drug release, we designed targeted nanoparticle (NP)-conjugated microbubbles (MBs); ultrasound could then help deliver acoustic energy to release the NPs from the MBs. The ultrasound-targeted MB destruction (UTMD) system of negatively charged NPs was conjugated with positively charged MBs using an ionic gelation method. We demonstrated the transfer of targeted NPs and their entry into gastric cancer cells through ligand-specific recognition, followed by enhanced cell growth inhibition owing to drug delivery-induced apoptosis. Moreover, the UTMD system combining therapeutic and ultrasound image properties can effectively target gastric cancer, thus significantly enhancing antitumor activity, as evident by tumor localization in an orthotopic mouse model of gastric cancer. The combination of ultrasound and NP-based drug delivery systems has become a promising approach for targeted drug delivery in preclinical cancer therapy.
    Keywords:  Antitumor activity; Microbubbles; Nanoparticle; Theranostic agents; Ultrasound-targeted
    DOI:  https://doi.org/10.1016/j.phrs.2022.106532
  21. Biomaterials. 2022 Oct 27. pii: S0142-9612(22)00515-4. [Epub ahead of print]291 121875
    Advanced techniques for performing photodynamic therapy in deep-seated tissues.
    Bowen Sun, Juwita Norasmara Bte Rahmat, Yong Zhang.
      Photodynamic therapy (PDT) is a promising localized cancer treatment modality. It has been used successfully to treat a range of dermatological conditions with comparable efficacy to conventional treatments. However, some drawbacks limit the clinical utility of PDT in treating deep-seated tumors. Notably, the penetration limitation of UV and visible light, commonly applied to activate photosensitizers, makes PDT incompetent in treating deep-seated tumors. Development in light delivery technologies, especially fiber optics, led to improved clinical strategies for accessing deep tissues for irradiation. However, PDT efficacy issues remained partly due to light penetration limitations. In this review, we first summarized the current PDT applications for deep-seated tumor treatment. Then, the most recent progress in advanced techniques to overcome the light penetration limitation in PDT, including using functional nanomaterials that can either self-illuminate or be activated by near-infrared (NIR) light and X-rays as transducers, and implantable light delivery devices were discussed. Finally, current challenges and future opportunities of these technologies were discussed, which we hope may inspire the development of more effective techniques to enhance PDT efficacy against deep-seated tumors.
    Keywords:  Deep-seated tumor; Implantable light source; Light penetration limitation; Nanomaterials; Photodynamic therapy
    DOI:  https://doi.org/10.1016/j.biomaterials.2022.121875
  22. Int J Nanomedicine. 2022 ;17 5137-5151
    HA-DOPE-Modified Honokiol-Loaded Liposomes Targeted Therapy for Osteosarcoma.
    Xiangxiang Zhang, Huaen Chen, Yang Zhang, Qijing Huang, Jianjia Feng, Haoyu Xing, Xiaguo Fu, Xiufang Yan, Yingying Zhang, Qin Xu, Jianming Liang.
      Purpose: Osteosarcoma (OS) is the most common bone cancer with a high risk of metastasis, high growth rate, and poor prognosis. Honokiol (HNK) is a general ingredient of traditional Chinese medicine, with a potential anti-tumor effect. However, HNK is insoluble in water and lacks drug targeting, which limits its clinical application. To improve the OS therapeutic effect of HNK, we used HNK-loaded liposomes modified with hyaluronic acid-phospholipid conjugates (HA-DOPE) to treat OS based on the HA interaction with CD44.Methods: The HNK-loaded liposomes were prepared via thin-film hydration and sonication. HA-DOPE was used to combine the HNK-loaded liposomes (HA-DOPE@Lips/HNK) via sonication and co-extrusion. HA-DOPE@Lips/HNK were characterized with respect to size, zeta potential, polymer dispersity index (PDI), and stability, and transmission electron microscopy was performed. Cellular uptake, cell viability, cell apoptosis, cell cycle, and mitochondrial activity were utilized to evaluate the antitumor effect in vitro. The biodistribution, xenograft tumor growth inhibition, and safety of HA-DOPE@Lips/HNK were evaluated in 143B OS xenograft mice in vivo.
    Results: The particle size, PDI, and zeta potential of HA-DOPE@Lips/HNK were 146.20±0.26 nm, 0.20±0.01, and -38.45±0.98 mV, respectively. The encapsulation rate and drug loading were 80.14±0.32% and 3.78±0.09%, respectively. HA-DOPE@Lips/HNK could inhibit cell proliferation, cause apoptosis, block the cell cycle and disrupt mitochondrial activity. HA-DOPE@Lips/HNK specially delivered the drug into the tumor and inhibited tumor growth, and showed no obvious toxicity to normal tissues.
    Conclusion: HA-DOPE@Lips/HNK could deliver HNK into the tumor site and had a good antitumor ability in vitro and in vivo. In addition, HA-DOPE@Lips/HNK increased the antitumor effects of HNK. Thus, it provides a promising nanocarrier to improve drug delivery in OS therapy.
    Keywords:  honokiol; hyaluronic acid; liposomes; osteosarcoma
    DOI:  https://doi.org/10.2147/IJN.S371934
  23. Molecules. 2022 Oct 27. pii: 7290. [Epub ahead of print]27(21):
    Preparation of Paclitaxel-Encapsulated Bio-Functionalized Selenium Nanoparticles and Evaluation of Their Efficacy against Cervical Cancer.
    Soumya Menon, Santhoshkumar Jayakodi, Kanti Kusum Yadav, Prathap Somu, Mona Isaq, Venkat Kumar Shanmugam, Amballa Chaitanyakumar, Nagaraj Basavegowda.
      The potentiality of nanomedicine in the cancer treatment being widely recognized in the recent years. In the present investigation, the synergistic effects of chitosan-modified selenium nanoparticles loaded with paclitaxel (PTX-chit-SeNPs) were studied. These selenium nanoparticles were tested for drug release analysis at a pH of 7.4 and 5.5, and further characterized using FTIR, DLS, zeta potential, and TEM to confirm their morphology, and the encapsulation of the drug was carried out using UPLC analysis. Quantitative evaluation of anti-cancer properties was performed via MTT analysis, apoptosis, gene expression analysis, cell cycle arrest, and over-production of ROS. The unique combination of phytochemicals from the seed extract, chitosan, paclitaxel, and selenium nanoparticles can be effectively utilized to combat cancerous cells. The production of the nanosystem has been demonstrated to be cost-effective and have unique characteristics, and can be utilized for improving future diagnostic approaches.
    Keywords:  Mucuna pruriens seed extract; anticancer; cervical cancer; chitosan; flow cytometer; paclitaxel; selenium nanoparticles
    DOI:  https://doi.org/10.3390/molecules27217290
  24. Pharmaceuticals (Basel). 2022 Nov 05. pii: 1360. [Epub ahead of print]15(11):
    Phytochemicals Targeting Ferroptosis: Therapeutic Opportunities and Prospects for Treating Breast Cancer.
    Xinyi Zhao, Xueni Wang, Yuzhou Pang.
      Ferroptosis, a recently discovered iron-dependent regulated cell death, has been implicated in the therapeutic responses of various cancers including breast cancer, making it a promising therapeutic target to manage this malignancy. Phytochemicals are conventional sources for medication development. Some phytochemicals have been utilized therapeutically to treat cancers as pharmaceutic agents or dietary supplements. Intriguingly, a considerable number of antitumor drugs derived from phytochemicals have been proven to be targeting ferroptosis, thus producing anticancer effects. In this review, we provide a short overview of the interaction between core ferroptosis modulators and breast cancer, illustrating how ferroptosis affects the destiny of breast cancer cells. We also systematically summarize the regulatory effects of phytochemicals on ferroptosis and emphasize their clinical applications in breast cancer suppression, which may accelerate the development of their therapeutic use in breast cancer.
    Keywords:  breast cancer; curcumin; ferroptosis; phytochemicals; quercetin
    DOI:  https://doi.org/10.3390/ph15111360
  25. Micromachines (Basel). 2022 Oct 27. pii: 1838. [Epub ahead of print]13(11):
    Drug Delivery Systems and Flavonoids: Current Knowledge in Melanoma Treatment and Future Perspectives.
    Catarina Cunha, Ana L Daniel-da-Silva, Helena Oliveira.
      Melanoma is an aggressive form of skin cancer with a high prevalence in the population. An early diagnosis is crucial to cure this disease. Still, when this is not possible, combining potent pharmacological agents and effective drug delivery systems is essential to achieve optimal treatment and improve patients' quality of life. Nanotechnology application in biomedical sciences to encapsulate anticancer drugs, including flavonoids, in order to enhance therapeutic efficacy has attracted particular interest. Flavonoids have shown effectiveness against various types of cancers including in melanoma, but they show low aqueous solubility, low stability and very poor oral bioavailability. The utilization of novel drug delivery systems could increase flavonoid bioavailability, thereby potentiating its antitumor effects in melanoma. This review summarizes the potential of different flavonoids in melanoma treatment and the several nanosystems used to improve their biological activity, considering published information that reported improved biological and pharmacological properties of encapsulated flavonoids.
    Keywords:  drug delivery systems; flavonoids; melanoma; nanocarriers
    DOI:  https://doi.org/10.3390/mi13111838
  26. Front Pharmacol. 2022 ;13 975320
    Evaluating anticancer properties of Withaferin A-a potent phytochemical.
    Maushma Atteeq.
      Withaferin A is a C28 steroidal lactone derived from the plant Withania somnifera, commonly known as Ashwagandha. Withaferin A has received great attention for its anticancer properties noted in cancer cells of various origins. Extracts of Withania somnifera have been used in traditional Ayurvedic and Unani Indian medicine for their various pharmacological benefits. In recent years, Withania somnifera or Ashwagandha extract has become popularized as a health supplement marketed for its stress and anxiety reducing effects. Withaferin A is one of the most studied withanolides extracted from Withania somnifera that has gained great attention for its anticancer, anti-inflammatory, metabolic, and pro-apoptotic effects. Extensive in vivo and in vitro studies have depicted Withaferin A's interactions with key role players in cancerous activity of the cell to exert its pro-apoptotic effects. Withaferin A interactions with NF-κB, STAT, Hsp90, ER-α, p53, and TGF-β have noted inhibition in cancer cell proliferation and cell cycle arrest in G2/M stage, ultimately leading to apoptosis or cell death. This review highlights pro-apoptotic properties of Withaferin A including generation of reactive oxidative species, Par-4 activation, endoplasmic reticulum stress (ER) induction, and p53 activation. Analysis of Withaferin A's involvement in various oncogenic pathways leading to malignant neoplasm and its pharmacologic activity in conjunction with various cancer drugs provides promising evidence in therapeutic potential of Withaferin A as a cancer treatment.
    Keywords:  Ashwagandha; Withaferin A; Withania somnifera; apoptosis; cancer; cancer treatment; withanolides
    DOI:  https://doi.org/10.3389/fphar.2022.975320
  27. Cancer Sci. 2022 Nov 07.
    Polymeric Iron Chelators for Enhancing 5-Aminolevulinic Acid-Induced Photodynamic Therapy.
    Takahiro Nomoto, Kana Komoto, Tomoya Nagano, Takuya Ishii, Haochen Guo, Yuto Honda, Shun-Ichiro Ogura, Masahiro Ishizuka, Nobuhiro Nishiyama.
      5-Aminolevulinic acid (5-ALA) is an amino acid that can be metabolized into a photosensitizer, protoporphyrin IX (PpIX) selectively in a tumor cell, permitting minimally invasive photodynamic diagnosis/therapy. However, some malignant tumor cells have excess intracellular labile iron and facilitate the conversion of PpIX into heme, which compromises the therapeutic potency of 5-ALA. Here, we examined the potential of chelation of such unfavorable intratumoral labile iron in photodynamic therapy (PDT) with 5-ALA hydrochloride, using polymeric iron chelators that we recently developed. The polymeric iron chelator efficiently inactivated the intracellular labile iron in cultured cancer cells and importantly enhanced the accumulation of PpIX, thereby improving the cytotoxicity upon photoirradiation. Even in in vivo study with subcutaneous tumor models, the polymeric iron chelator augmented the intratumoral accumulation of PpIX and the PDT effect. This study suggests that our polymeric iron chelator could be a tool for boosting the effect of 5-ALA-induced PDT by modulating tumor microenvironment.
    Keywords:  aminolevulinic acid; deferoxamine; drug delivery systems; iron; photodynamic therapy
    DOI:  https://doi.org/10.1111/cas.15637
  28. Pharmaceutics. 2022 Oct 31. pii: 2346. [Epub ahead of print]14(11):
    Tumor Microenvironment-Based Stimuli-Responsive Nanoparticles for Controlled Release of Drugs in Cancer Therapy.
    Weixin Zhou, Yujie Jia, Yani Liu, Yan Chen, Pengxuan Zhao.
      With the development of nanomedicine technology, stimuli-responsive nanocarriers play an increasingly important role in antitumor therapy. Compared with the normal physiological environment, the tumor microenvironment (TME) possesses several unique properties, including acidity, high glutathione (GSH) concentration, hypoxia, over-expressed enzymes and excessive reactive oxygen species (ROS), which are closely related to the occurrence and development of tumors. However, on the other hand, these properties could also be harnessed for smart drug delivery systems to release drugs specifically in tumor tissues. Stimuli-responsive nanoparticles (srNPs) can maintain stability at physiological conditions, while they could be triggered rapidly to release drugs by specific stimuli to prolong blood circulation and enhance cancer cellular uptake, thus achieving excellent therapeutic performance and improved biosafety. This review focuses on the design of srNPs based on several stimuli in the TME for the delivery of antitumor drugs. In addition, the challenges and prospects for the development of srNPs are discussed, which can possibly inspire researchers to develop srNPs for clinical applications in the future.
    Keywords:  cancer therapy; nanoparticles; stimuli-responsive; tumor microenvironment
    DOI:  https://doi.org/10.3390/pharmaceutics14112346
  29. Int J Mol Sci. 2022 Oct 24. pii: 12817. [Epub ahead of print]23(21):
    Dual-Functionalized Nanoliposomes Achieve a Synergistic Chemo-Phototherapeutic Effect.
    Ana Lazaro-Carrillo, Beatriz Rodríguez-Amigo, Margarita Mora, Maria Lluïsa Sagristá, Magdalena Cañete, Santi Nonell, Angeles Villanueva.
      The enhancement of photodynamic therapy (PDT) effectiveness by combining it with other treatment modalities and improved drug delivery has become an interesting field in cancer research. We have prepared and characterized nanoliposomes containing the chemotherapeutic drug irinotecan (CPT11lip), the photodynamic agent protoporphyrin IX (PpIXlip), or their combination (CPT11-PpIXlip). The effects of individual and bimodal (chemo-phototherapeutic) treatments on HeLa cells have been studied by a combination of biological and photophysical studies. Bimodal treatments show synergistic cytotoxic effects on HeLa cells at relatively low doses of PpIX/PDT and CPT11. Mechanistic cell inactivation studies revealed mitotic catastrophe, apoptosis, and senescence contributions. The enhanced anticancer activity is due to a sustained generation of reactive oxygen species, which increases the number of double-strand DNA breaks. Bimodal chemo-phototherapeutic liposomes may have a very promising future in oncological therapy, potentially allowing a reduction in the CPT11 concentration required to achieve a therapeutic effect and overcoming resistance to individual cancer treatments.
    Keywords:  bimodal-functionalized nanoliposomes; chemo-phototherapy; double-strand DNA break; irinotecan; photodynamic therapy; protoporphyrin IX; reactive oxygen species; subcellular location; synergistic effect; time-lapse microscopy
    DOI:  https://doi.org/10.3390/ijms232112817
  30. Nanomaterials (Basel). 2022 Nov 02. pii: 3873. [Epub ahead of print]12(21):
    Role of Iron Oxide (Fe2O3) Nanocomposites in Advanced Biomedical Applications: A State-of-the-Art Review.
    Mehrab Pourmadadi, Erfan Rahmani, Amin Shamsabadipour, Shima Mahtabian, Mohammadjavad Ahmadi, Abbas Rahdar, Ana M Díez-Pascual.
      Nanomaterials have demonstrated a wide range of applications and recently, novel biomedical studies are devoted to improving the functionality and effectivity of traditional and unmodified systems, either drug carriers and common scaffolds for tissue engineering or advanced hydrogels for wound healing purposes. In this regard, metal oxide nanoparticles show great potential as versatile tools in biomedical science. In particular, iron oxide nanoparticles with different shape and sizes hold outstanding physiochemical characteristics, such as high specific area and porous structure that make them idoneous nanomaterials to be used in diverse aspects of medicine and biological systems. Moreover, due to the high thermal stability and mechanical strength of Fe2O3, they have been combined with several polymers and employed for various nano-treatments for specific human diseases. This review is focused on summarizing the applications of Fe2O3-based nanocomposites in the biomedical field, including nanocarriers for drug delivery, tissue engineering, and wound healing. Additionally, their structure, magnetic properties, biocompatibility, and toxicity will be discussed.
    Keywords:  drug delivery; iron oxide nanoparticles; nanocarrier; nanomaterials; nanotreatment; tissue engineering; wound dressing
    DOI:  https://doi.org/10.3390/nano12213873
  31. ACS Appl Bio Mater. 2022 Nov 08.
    Dual-Drug Conjugated Glyco-Nanoassemblies for Tumor-Triggered Targeting and Synergistic Cancer Therapy.
    Tugba Gencoglu Katmerlikaya, Aydan Dag, Pınar Sinem Omurtag Ozgen, Busra Cetin Ersen.
      Drug-conjugated nanoassemblies potentiate the efficiency of anticancer drugs through the advantages of high drug-loading capacity and passive/active targeting ability in cancer therapy. This study describes the synthesis of gemcitabine (Gem) and cisplatin (cisPt) dual-drug-functionalized glyco-nanoassemblies (GNs) for anticancer drug delivery systems. It also investigates the pH-triggered drug delivery of the conventional anticancer drug cisPt. A Gem-functionalized well-defined glycoblock copolymer backbone (P(iprFruMA-b-MAc)-Gem), which consists of fructose and methacrylic acid segments, was synthesized via a reversible addition-fragmentation chain transfer (RAFT) polymerization method. Following the hydrolysis of the protecting groups on the backbone copolymer, cisPt functionalization of P(FruMA-b-MAc)-Gem in aqueous media was carried out during the transformation of glycoblock polymers into self-assembled spherical glyco-nanoassemblies (GN3). Monodrug-functionalized glyco-nanoassemblies were also prepared either with Gem (GN1) or cisPt (GN2) to compare the synergetic effect of dual-drug conjugated glyco-nanoassemblies (GN3). The sizes of glyco-nanoassemblies GN1, GN2, and GN3 were found as 5.76 ± 0.64, 59.80 ± 0.13, and 53.80 ± 3.90 nm and dispersity (Đ) values as 0.476, 0.292, and 0.311 by dynamic light scattering (DLS) measurement, respectively. The in vitro studies revealed that the drug-free glyco-nanoassemblies are biocompatible at concentrations higher than 296 μg/mL. The drug-conjugated glyco-nanoassemblies (GN1 and GN2) exhibited in vitro cytotoxicity against human breast cancer cell lines of MDA-MB-231 comparable to free Gem and cisPt, illustrating an efficient drug release into the tumor environment. Additionally, GNs exhibited higher selectivity and preferential cellular internalization in MDA-MB-231 when compared to healthy cell lines of CCD-1079Sk. These dual-drug conjugated GNs can effectively enhance the killing of cancer cells and increase synergistic chemotherapy.
    Keywords:  cellular uptake; cisPt; gemcitabine; glyco-nanoassemblies; synergistic chemotherapy
    DOI:  https://doi.org/10.1021/acsabm.2c00749
  32. Mol Pharm. 2022 Nov 11.
    Unsaturated Fatty Acid Liposomes Selectively Regulate Glutathione Peroxidase 4 to Exacerbate Lipid Peroxidation as an Adaptable Liposome Platform for Anti-Tumor Therapy.
    Huan Huang, Yuling Chen, Na Yin, Gaojie Li, Shanshan Ye, Ling Guo, Min Feng.
      Regulating non-apoptotic cell death of cancer cells provides a promising strategy to overcome apoptosis resistance during cancer treatment. Lipids are essential components to exacerbate several non-apoptotic cell death pathways. In the present study, unsaturated fatty acid (UFA) liposomes prepared with linoleic acid, oleic acid, or α-linolenic acid have the potential to affect lipid metabolism. Notably, UFA liposomes markedly increased cellular reactive oxygen species (ROS) and down-regulated the expression of glutathione peroxidase 4 (GPX4) in tumor cells, resulting in lipid peroxidation, which in turn caused rapid membrane rupture and induced non-apoptotic cell death of tumor cells. Concomitantly, UFA liposomes induced ROS-mediated tumor-associated macrophages toward a tumoricidal phenotype to reverse the immunosuppressive tumor microenvironment. Consequently, UFA liposomes substantially inhibited tumor growth in a melanoma model by promoting lipid peroxidation, inducing non-apoptotic cell death of tumor cells, and increasing infiltration of anti-tumor immune cells at tumor sites. Therefore, UFA liposomes regulate GXP4 to exacerbate lipid peroxidation and provide a versatile liposome platform for enhancing anti-tumor therapy which could be readily extended to the delivery of anticancer agents.
    Keywords:  GPX4; ROS; adaptable liposome platform; linoleic acid; lipid peroxidation
    DOI:  https://doi.org/10.1021/acs.molpharmaceut.2c00642
  33. Int J Cancer. 2022 Nov 08.
    Target enzymes in serine-glycine-one-carbon metabolic pathway for cancer therapy.
    Wei Sun, Erhu Zhao, Hongjuan Cui.
      Cancer cells selectively take up exogenous serine or synthesize serine via the serine synthesis pathway for conversion into intracellular glycine and one-carbon units for nucleotide biosynthesis. In this process, serine-glycine metabolism and the one-carbon cycle play vital roles, which is named serine-glycine-one-carbon metabolism (SGOC). The SGOC pathway is a metabolic network crucial for tumorigenesis with unexpected complexity and clinical importance. Accumulating evidence has demonstrated that metabolic enzymes in SGOC metabolism play key roles in tumorigenesis, metastasis, and resistance to therapies. In this review, we focus on the involvement of serine and glycine in the folate-mediated one-carbon pathway during cancer progression and highlight the pathways through which cancer cells acquire and use one-carbon units. In addition, we discuss the recently elucidated effects of SGOC (folate cycle) metabolic enzymes in the occurrence and development of tumors and their links to drug resistance. Inhibitors of target enzymes in the SGOC pathway display promise as investigational new drug candidates for the treatment of tumors. This article is protected by copyright. All rights reserved.
    Keywords:  cancer therapy; drug resistance; inhibitors; serine-glycine-one-carbon metabolism; target enzymes
    DOI:  https://doi.org/10.1002/ijc.34353
  34. Int J Biol Macromol. 2022 Nov 07. pii: S0141-8130(22)02433-3. [Epub ahead of print]
    Cinnamon cassia oil chitosan nanoparticles: Physicochemical properties and anti-breast cancer activity.
    Xiqiang Xu, Qiuxiang Li, Wei Dong, Guowei Zhao, Yongfeng Lu, Xiaoying Huang, Xinli Liang.
      The aim of this study was to prepare Cinnamomum cassia essential oil (CEO) impregnated chitosan nanoparticles (CS-CEO) and assess its pharmacological activity against breast cancer. Cinnamon oil-loaded chitosan nanoparticles were investigated for their physicochemical properties, stability, and anti-cancer activities both in vitro and in vivo. The prepared CS-CEO nanoparticles have a particle size, zeta-potential, entrapment efficiency and drug loading of (215.40 ± 3.90) nm, (51.70 ± 1.90) mV, (83.37 ± 0.4)% and (26.42 ± 0.65)%, respectively. CS-CEO showed a regular, uniform, and spherical or quasi-spherical structure under a transmission electron microscope. CS-CEO remained stable upon storage at 4 °C. CS-CEO exhibited enhanced in vitro antitumor activity (52 μg/mL) compared to CEO. The mechanism might be related to the up-regulation of Caspase-3 and AIF protein expression. In in vivo experiments, CS-CEO suppressed the growth of 4T1 breast cancer cells transplanted into mice, inhibited tumor cell proliferation, and induced apoptosis by reducing the expression of the Ki-67 protein. These results indicated that CEO encapsulated in chitosan had a higher physical stability and was also more effective against 4T1 breast tumor model, which can be used as a reference for the application of volatile oil components in traditional Chinese medicine.
    Keywords:  Apoptosis; Breast cancer; Chitosan; Cinnamon essential oil; Mitochondrial membrane potential; Nanoparticles
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.10.191
  35. Plants (Basel). 2022 Oct 24. pii: 2820. [Epub ahead of print]11(21):
    The Therapeutic Efficacy of Punica granatum and Its Bioactive Constituents with Special Reference to Photodynamic Therapy.
    Nosipho Thembekile Fakudze, Eric Chekwube Aniogo, Blassan P George, Heidi Abrahamse.
      Punica granatum (P. granatum) is a fruit-bearing tree from the Punicaceae family, indigenous to Iran. This plant has healing qualities that have drawn the interest of the medical community as an alternative treatment for malignancies and non-malignancies. Its healing quality is due to the phytochemicals present in the plant. These include ellagic acid, punicic acid, phenols, and flavonoids. In traditional medicine, P. granatum has been used in treating diseases such as dysentery, bleeding disorders, leprosy, and burns. This review explores the effects of the phytochemical constituents of P. granatum on photodynamic therapy for cancer, chronic inflammation, osteoarthritis, and viral infections. Its antioxidant and antitumor effects play a role in reduced free radical damage and cancer cell proliferation. It was concluded that P. granatum has been used for many disease conditions for a better therapeutic outcome. This paper will give visibility to more studies and expand the knowledge on the potential use of P. granatum in photodynamic cancer treatment.
    Keywords:  P. granatum; anti-osteoarthritis; anticancer; antioxidant
    DOI:  https://doi.org/10.3390/plants11212820
  36. J Nanobiotechnology. 2022 Nov 11. 20(1): 476
    Combination of polythyleneimine regulating autophagy prodrug and Mdr1 siRNA for tumor multidrug resistance.
    Changduo Wang, Zhipeng Li, Ping Xu, Lisa Xu, Shangcong Han, Yong Sun.
      Multidrug resistance (MDR) has been restricting the efficacy of chemotherapy, which mainly include pump resistance and non-pump resistance. In order to fight overall MDR, a novel targeted gene/drug co-deliver nano system is developed, which can suppress the drug efflux pumps and modulate autophagy to overcoming both pump and non-pump resistance. Here, small interfere RNA (siRNA) is incorporated into polymer-drug conjugates (PEI-PTX, PP) which are composed of polyethyleneimine (PEI) and paclitaxel (PTX) via covalent bonds, and hyaluronic acid (HA) is coated on the surface of PP/siRNA to achieve long blood cycle and CD44-targeted delivery. The RNA interference to mdr1 gene is combined with autophagy inhibition by PP, which efficiently facilitate apoptosis of Taxol-resistant lung cancer cells (A549/T). Further study indicates that PEI in PP may play a significant role to block the autophagosome-lysosome fusion process by means of alkalizing lysosomes. Both in vitro and in vivo studies confirm that the nanoassemblies can successfully deliver PTX and siRNA into tumor cells and significantly inhibited A549/T tumor growth. In summary, the polymeric nanoassemblies provide a potential strategy for combating both pump and non-pump resistance via the synergism of RNAi and autophagy modulation.
    Keywords:  Autophagy; MDR; Prodrug; Tumor therapy; siRNA
    DOI:  https://doi.org/10.1186/s12951-022-01689-y
  37. Life (Basel). 2022 Nov 02. pii: 1768. [Epub ahead of print]12(11):
    Chitosan-Polyphenol Conjugates for Human Health.
    Ananya Pattnaik, Sanghamitra Pati, Sangram Keshari Samal.
      Human health deteriorates due to the generation and accumulation of free radicals that induce oxidative stress, damaging proteins, lipids, and nucleic acids; this has become the leading cause of many deadly diseases such as cardiovascular, cancer, neurodegenerative, diabetes, and inflammation. Naturally occurring polyphenols have tremendous therapeutic potential, but their short biological half-life and rapid metabolism limit their use. Recent advancements in polymer science have provided numerous varieties of natural and synthetic polymers. Chitosan is widely used due to its biomimetic properties which include biodegradability, biocompatibility, inherent antimicrobial activity, and antioxidant properties. However, due to low solubility in water and the non-availability of the H-atom donor, the practical use of chitosan as an antioxidant is limited. Therefore, chitosan has been conjugated with polyphenols to overcome the limitations of both chitosan and polyphenol, along with increasing the potential synergistic effects of their combination for therapeutic applications. Though many methods have been evolved to conjugate chitosan with polyphenol through activated ester-modification, enzyme-mediated, and free radical induced are the most widely used strategies. The therapeutic efficiency of chitosan-polyphenol conjugates has been investigated for various disease treatments caused by ROS that have shown favorable outcomes and tremendous results. Hence, the present review focuses on the recent advancement of different strategies of chitosan-polyphenol conjugate formation with their advantages and limitations. Furthermore, the therapeutic applicability of the combinatorial efficiency of chitosan-based conjugates formed using Gallic Acid, Curcumin, Catechin, and Quercetin in human health has been described in detail.
    Keywords:  antioxidant; chitosan; human health; oxidative stress; polyphenol
    DOI:  https://doi.org/10.3390/life12111768
  38. Nutr Cancer. 2022 Nov 12. 1-16
    Dietary Diindolylmethane Enhances the Therapeutic Effect of Centchroman in Breast Cancer by Inhibiting Neoangiogenesis.
    Dhanamjai Penta, Jagadish Natesh, Priya Mondal, Syed Musthapa Meeran.
      Tumor angiogenesis is primarily regulated by vascular endothelial growth factor and its receptor (VEGF-VEGFR) communication, which is involved in cancer cell growth, progression, and metastasis. Diindolylmethane (DIM), a dietary bioactive from cruciferous vegetables, has been extensively studied in preclinical models for breast cancer prevention and treatment. Nevertheless, the possible role of DIM in the angiogenesis and metastasis regulations in triple-negative breast cancer (TNBC) remains elusive. Here, we investigated the potential anti-angiogenic and anti-metastatic role of DIM in combination with centchroman (CC). We observed that the oral administration of the DIM and CC combination suppressed primary tumor growth and tumor-associated vascularization in 4T1 tumors. Further, the DIM and CC combination exhibited a strong inhibitory effect on VEGF-induced angiogenesis in matrigel plugs. The mechanistic study demonstrated that DIM and CC could effectively downregulate VEGFA expression in tumor tissue and strongly interact with VEGFR2 to block its kinase activity. Interestingly, the DIM and CC combination also suppressed the lung metastasis of the highly metastatic 4T1 tumors through the downregulation of FAK/MMP9/2 signaling and reversal of epithelial-to-mesenchymal transition (EMT). Overall, these findings suggest that DIM-based nutraceuticals and functional foods can be developed as adjuvant therapy for treating TNBC.
    DOI:  https://doi.org/10.1080/01635581.2022.2143825
  39. Nutr Cancer. 2022 Nov 08. 1-8
    Curcumin Represses Colorectal Cancer Cell Proliferation by Triggering Ferroptosis via PI3K/Akt/mTOR Signaling.
    Mei Chen, An-Hui Tan, Jing Li.
      Curcumin is known to suppress the progression of colorectal cancer by inhibiting cancer cell proliferation. In this study, we explored the role of ferroptosis in the antiproliferative properties of curcumin. The effect of curcumin on ferroptosis In Vitro was evaluated in HCT-8 cells. Ferroptosis was first blocked by ferrostatin-1 (Fer-1) and the antiproliferative effect of curcumin was evaluated by determining the levels of ferroptotic markers, including glutathione (GSH), SLC7A11, GPX4, iron, malondialdehyde (MDA), and reactive oxygen species (ROS). An agonist and an inhibitor of PI3K were also used to verify the signaling pathway involved in the antiproliferative effects. Curcumin repressed HCT-8 cell proliferation in a dose-dependent manner. Treating HCT-8 cells with curcumin significantly downregulated GSH, SLC7A11, and GPX4, while significantly increasing levels of iron, MDA, and ROS. In addition, curcumin promoted ferroptosis and reduced proliferation of HCT-8 cells by suppressing the PI3K/Akt/mTOR pathway, and these effects were antagonized by Fer-1. The effects of curcumin were antagonized by a PI3K agonist and reinforced by a PI3K inhibitor. Curcumin triggers ferroptosis and suppresses proliferation of colorectal cancer cells by inhibiting the PI3K/Akt/mTOR signaling pathway. These results indicate its potential as a treatment against colorectal cancer.
    DOI:  https://doi.org/10.1080/01635581.2022.2139398
  40. Cancers (Basel). 2022 Nov 01. pii: 5389. [Epub ahead of print]14(21):
    Smart Nanoformulations for Brain Cancer Theranostics: Challenges and Promises.
    Faraz Ahmad, Ressin Varghese, Subhrajita Panda, Siva Ramamoorthy, Mohammad Y Areeshi, Sharmila Fagoonee, Shafiul Haque.
      Despite their low prevalence, brain tumors are among the most lethal cancers. They are extremely difficult to diagnose, monitor and treat. Conventional anti-cancer strategies such as radio- and chemotherapy have largely failed, and to date, the development of even a single effective therapeutic strategy against central nervous system (CNS) tumors has remained elusive. There are several factors responsible for this. Brain cancers are a heterogeneous group of diseases with variable origins, biochemical properties and degrees of invasiveness. High-grade gliomas are amongst the most metastatic and invasive cancers, which is another reason for therapeutic failure in their case. Moreover, crossing the blood brain and the blood brain tumor barriers has been a significant hindrance in the development of efficient CNS therapeutics. Cancer nanomedicine, which encompasses the application of nanotechnology for diagnosis, monitoring and therapy of cancers, is a rapidly evolving field of translational medicine. Nanoformulations, because of their extreme versatility and manipulative potential, are emerging candidates for tumor targeting, penetration and treatment in the brain. Moreover, suitable nanocarriers can be commissioned for theranostics, a combinatorial personalized approach for simultaneous imaging and therapy. This review first details the recent advances in novel bioengineering techniques that provide promising avenues for circumventing the hurdles of delivering the diagnostic/therapeutic agent to the CNS. The authors then describe in detail the tremendous potential of utilizing nanotechnology, particularly nano-theranostics for brain cancer imaging and therapy, and outline the different categories of recently developed next-generation smart nanoformulations that have exceptional potential for making a breakthrough in clinical neuro-oncology therapeutics.
    Keywords:  bioengineering; electro-magnetic nanoparticles; exosomes; focused ultrasound; gliomas; theranostics
    DOI:  https://doi.org/10.3390/cancers14215389
  41. Med Oncol. 2022 Nov 09. 40(1): 12
    Redox balance and autophagy regulation in cancer progression and their therapeutic perspective.
    Sameer Ullah Khan, Kaneez Fatima, Shariqa Aisha, Baseerat Hamza, Fayaz Malik.
      Cellular ROS production participates in various cellular functions but its accumulation decides the cell fate. Malignant cells have higher levels of ROS and active antioxidant machinery, a characteristic hallmark of cancer with an outcome of activation of stress-induced pathways like autophagy. Autophagy is an intracellular catabolic process that produces alternative raw materials to meet the energy demand of cells and is influenced by the cellular redox state thus playing a definite role in cancer cell fate. Since damaged mitochondria are the main source of ROS in the cell, however, cancer cells remove them by upregulating the process of mitophagy which is known to play a decisive role in tumorigenesis and tumor progression. Chemotherapy exploits cell machinery which results in the accumulation of toxic levels of ROS in cells resulting in cell death by activating either of the pathways like apoptosis, necrosis, ferroptosis or autophagy in them. So understanding these redox and autophagy regulations offers a promising method to design and develop new cancer therapies that can be very effective and durable for years. This review will give a summary of the current therapeutic molecules targeting redox regulation and autophagy for the treatment of cancer. Further, it will highlight various challenges in developing anticancer agents due to autophagy and ROS regulation in the cell and insights into the development of future therapies.
    Keywords:  Apoptosis; Autophagy; Glutathione; Mitophagy; Oxidative stress; Reactive oxygen species
    DOI:  https://doi.org/10.1007/s12032-022-01871-0
  42. Molecules. 2022 Nov 07. pii: 7653. [Epub ahead of print]27(21):
    Ferulic Acid: A Natural Phenol That Inhibits Neoplastic Events through Modulation of Oncogenic Signaling.
    Hardeep Singh Tuli, Ajay Kumar, Seema Ramniwas, Renuka Coudhary, Diwakar Aggarwal, Manoj Kumar, Ujjawal Sharma, Nidarshana Chaturvedi Parashar, Shafiul Haque, Katrin Sak.
      Despite the immense therapeutic advances in the field of health sciences, cancer is still to be found among the global leading causes of morbidity and mortality. Ethnomedicinally, natural bioactive compounds isolated from various plant sources have been used for the treatment of several cancer types and have gained notable attention. Ferulic acid, a natural compound derived from various seeds, nuts, leaves, and fruits, exhibits a variety of pharmacological effects in cancer, including its proapoptotic, cell-cycle-arresting, anti-metastatic, and anti-inflammatory activities. This review study presents a thorough overview of the molecular targets and cellular signaling pathways modulated by ferulic acid in diverse malignancies, showing high potential for this phenolic acid to be developed as a candidate agent for novel anticancer therapeutics. In addition, current investigations to develop promising synergistic formulations are also discussed.
    Keywords:  anti-angiogenesis; anti-metastasis; apoptosis and cell cycle arrest; ferulic acid; synergism
    DOI:  https://doi.org/10.3390/molecules27217653
  43. Front Endocrinol (Lausanne). 2022 ;13 972890
    Activation of G protein-coupled receptors by ketone bodies: Clinical implication of the ketogenic diet in metabolic disorders.
    Valentina Spigoni, Gloria Cinquegrani, Nicolas Thomas Iannozzi, Giulia Frigeri, Giulia Maggiolo, Marta Maggi, Vanessa Parello, Alessandra Dei Cas.
      Ketogenesis takes place in hepatocyte mitochondria where acetyl-CoA derived from fatty acid catabolism is converted to ketone bodies (KB), namely β-hydroxybutyrate (β-OHB), acetoacetate and acetone. KB represent important alternative energy sources under metabolic stress conditions. Ketogenic diets (KDs) are low-carbohydrate, fat-rich eating strategies which have been widely proposed as valid nutritional interventions in several metabolic disorders due to its substantial efficacy in weight loss achievement. Carbohydrate restriction during KD forces the use of FFA, which are subsequently transformed into KB in hepatocytes to provide energy, leading to a significant increase in ketone levels known as "nutritional ketosis". The recent discovery of KB as ligands of G protein-coupled receptors (GPCR) - cellular transducers implicated in a wide range of body functions - has aroused a great interest in understanding whether some of the clinical effects associated to KD consumption might be mediated by the ketone/GPCR axis. Specifically, anti-inflammatory effects associated to KD regimen are presumably due to GPR109A-mediated inhibition of NLRP3 inflammasome by β-OHB, whilst lipid profile amelioration by KDs could be ascribed to the actions of acetoacetate <i>via</i> GPR43 and of β-OHB <i>via</i> GPR109A on lipolysis. Thus, this review will focus on the effects of KD-induced nutritional ketosis potentially mediated by specific GPCRs in metabolic and endocrinological disorders. To discriminate the effects of ketone bodies <i>per se</i>, independently of weight loss, only studies comparing ketogenic <i>vs</i> isocaloric non-ketogenic diets will be considered as well as short-term tolerability and safety of KDs.
    Keywords:  GPCR (G protein coupled receptors); ketogenic diet; ketone bodies; metabolic disorder; very low carbohydrate ketogenic diet
    DOI:  https://doi.org/10.3389/fendo.2022.972890
  44. Gels. 2022 Nov 08. pii: 723. [Epub ahead of print]8(11):
    Thermosensitive In Situ Gels for Joint Disorders: Pharmaceutical Considerations in Intra-Articular Delivery.
    Marina Koland, Anoop Narayanan Vadakkepushpakath, Anish John, Arunraj Tharamelveliyil Rajendran, Indu Raghunath.
      The intra-articular administration of conventional drug solutions or dispersions in joint diseases such as osteoarthritis has a relatively short retention time and, therefore, limited therapeutic effect. Thermosensitive polymer solutions that exhibit a sol-gel phase transition near body temperature after injection can prolong drug retention by providing a depot from which the drug release is sustained while relieving inflammation and preventing degradation of the joint complex. Thermosensitive hydrogels have in recent times garnered considerable attention in the intra-articular therapeutics of joint diseases such as osteoarthritis. Among the stimuli-responsive gelling systems, most research has focused on thermosensitive hydrogels. These gels are preferred over other stimuli-sensitive hydrogels since they have well-controlled in situ gelling properties and are also easier to load with drugs. Temperature-sensitive polymers, such as block copolymers or poloxamers, are frequently used to modify their gelation properties, usually in combination with other polymers. They are compatible with most drugs but may pose formulation challenges in terms of their low-response time, highly fragile nature, and low biocompatibility. The stability and biodegradability of implant hydrogels can control the drug release rate and treatment efficacy. This review stresses the application of thermosensitive gels in joint disorders and summarizes recent developments for intra-articular application, including the incorporation of nanoparticles. The hydrogel composition, drug release mechanisms, and the challenges involved in their formulation and storage are also discussed.
    Keywords:  gels, poloxamer; intra-articular; joint disease; thermosensitive
    DOI:  https://doi.org/10.3390/gels8110723
  45. Photochem Photobiol Sci. 2022 Nov 07.
    The bromoporphyrins as promising anti-tumor photosensitizers in vitro.
    Man-Yi Li, Le Mi, Tabbisa Namulinda, Yi-Jia Yan, Xing-Ping Zhou, Zhi-Long Chen.
      The synthesis of ideal photosensitizers (PSs) is considered to be the most significant bottleneck in photodynamic therapy (PDT). To discover novel PSs with excellent photodynamic anti-tumor activities, a series of novel photosensitizers 5,15-diaryl-10,20-dibromoporphyrins (I1-6) were synthesized by a facile method. Compared with hematoporphyrin monomethyl ether (HMME) as the representative porphyrin-based photosensitizers, it is found that not only the longest absorption wavelength of all compounds was red-shifted to therapeutic window (660 nm) of photodynamic therapy, but also the singlet oxygen quantum yields were significantly increased. Furthermore, all compounds exhibited lower dark toxicity (except I2) and stronger phototoxicity (except I4) against Eca-109 tumor cells than HMME. Among them, I3 possessed the highest singlet oxygen quantum yield (ΦΔ = 0.205), the lower dark toxicity and the strongest phototoxicity (IC50 = 3.5 μM) in vitro. The findings indicated the compounds I3 had the potential to become anti-tumor agents for PDT.
    Keywords:  Anti-tumor; Bromoporphyrin; Photodynamic therapy; Photosensitizer
    DOI:  https://doi.org/10.1007/s43630-022-00326-9
  46. Biomolecules. 2022 Oct 28. pii: 1590. [Epub ahead of print]12(11):
    Druggable Metabolic Vulnerabilities Are Exposed and Masked during Progression to Castration Resistant Prostate Cancer.
    Stephen Y C Choi, Caroline Fidalgo Ribeiro, Yuzhuo Wang, Massimo Loda, Stephen R Plymate, Takuma Uo.
      There is an urgent need for exploring new actionable targets other than androgen receptor to improve outcome from lethal castration-resistant prostate cancer. Tumor metabolism has reemerged as a hallmark of cancer that drives and supports oncogenesis. In this regard, it is important to understand the relationship between distinctive metabolic features, androgen receptor signaling, genetic drivers in prostate cancer, and the tumor microenvironment (symbiotic and competitive metabolic interactions) to identify metabolic vulnerabilities. We explore the links between metabolism and gene regulation, and thus the unique metabolic signatures that define the malignant phenotypes at given stages of prostate tumor progression. We also provide an overview of current metabolism-based pharmacological strategies to be developed or repurposed for metabolism-based therapeutics for castration-resistant prostate cancer.
    Keywords:  Warburg’s effect; androgen receptor; cancer metabolism; drug resistance; fatty acids; lactate; prostate cancer
    DOI:  https://doi.org/10.3390/biom12111590
  47. Gels. 2022 Nov 02. pii: 709. [Epub ahead of print]8(11):
    Development and Evaluation of PLGA Nanoparticle-Loaded Organogel for the Transdermal Delivery of Risperidone.
    Naz Dilawar, Tofeeq Ur-Rehman, Kifayat Ullah Shah, Humaira Fatima, Aiyeshah Alhodaib.
      A transdermal delivery approach may circumvent the limitations associated with the oral use of risperidone (RIS), an atypical antipsychotic drug. The current study focuses on the utilization of poloxamer (pluronic) lecithin organogel (PLO), a suitable transdermal vehicle, and a biodegradable nanoparticulate system of PLGA with the potential to deliver RIS in an efficient way. PLGA nanoparticles were fabricated using different ratios of the polymer and surfactant. The optimization was performed principally on the basis of particle size and entrapment efficiency (EE). The developed PLGA nanoparticles were spherical, sized around 109 nm with negative charge (-9.3 mv) and enhanced drug entrapment efficiency (58%). The in vitro drug release study of lyophilized nanoparticles showed a sustained pattern. Statistical analysis confirmed that there was a significant difference (p &lt; 0.05) between the nanoparticle-loaded PLO gel and conventional drug formulations in terms of drug release and ex vivo permeation across rat skin (three-fold). The results confirm enhanced drug release and permeation through the skin at 72 h. Hence, the investigated formulation could be a better alternative to the conventional route for improving patient compliance.
    Keywords:  PLGA nanoparticles; antidepressants; organogel; risperidone nanoparticles; transdermal drug delivery systems
    DOI:  https://doi.org/10.3390/gels8110709
  48. Int J Mol Sci. 2022 Nov 04. pii: 13558. [Epub ahead of print]23(21):
    Natural Products for Esophageal Cancer Therapy: From Traditional Medicine to Modern Drug Discovery.
    Jeongeun An, Soojin An, Min Choi, Ji Hoon Jung, Bonglee Kim.
      Esophageal cancer (EC) is one of the most malignant types of cancer worldwide and has a high incidence and mortality rate in Asian countries. When it comes to treating EC, although primary methods such as chemotherapy and surgery exist, the prognosis remains poor. The purpose of this current research is to review the range of effects that natural products have on cancer by analyzing studies conducted on EC. Fifty-seven studies were categorized into four anti-cancer mechanisms, as well as clinical trials. The studies that were scrutinized in this research were all reported within five years. The majority of the substances reviewed induced apoptosis in EC, acting on a variety of mechanisms. Taken together, this study supports the fact that natural products have the potential to act as a candidate for treating EC.
    Keywords:  angiogenesis; apoptosis; esophageal cancer; herbal medicine; metastasis; natural product; resistance; traditional medicine
    DOI:  https://doi.org/10.3390/ijms232113558
  49. Int J Biol Macromol. 2022 Nov 04. pii: S0141-8130(22)02509-0. [Epub ahead of print]223(Pt A): 77-86
    Perfluorooctylbromide-loaded fucoidan-chlorin e6 nanoparticles for tumor-targeted photodynamic therapy.
    Seongryeong Han, Eunjin Jeong, Seo Young Cheon, Donghyun Lee, Yeeun Lee, Song Yi Lee, Hyun-Jong Cho, Heebeom Koo.
      Efficient delivery of a photosensitizer (PS) and oxygen to tumor tissue is critical for successful photodynamic therapy (PDT). For this purpose, we developed a fucoidan (Fu)-chlorin e6 (Ce6) nanoparticle (NP) containing perfluorooctylbromide (PFOB). Fu, a biopolymer derived from seaweed, made up the hydrophilic shell of the NP and provided specific targeting to tumor cells by P-selectin binding. Conjugation with the hydrophobic Ce6 enabled self-assembly and Ce6-generated cytotoxic reactive oxygen species to kill tumor cells upon laser irradiation. PF supplied oxygen to the hypoxic tumor tissue and increased the efficacy of the PDT. The developed Fu-Ce6-PF-NPs bound specifically to SCC7 tumor cells and killed them via a photodynamic effect on laser irradiation. High accumulation of the NPs in tumor tissue and improved tumor suppression by PDT were observed in SCC7 tumor-bearing mice. The overall data demonstrated the potential of Fu-Ce6-PF-NP as a tumor-targeting drug carrier for effective PDT.
    Keywords:  Fucoidan; Nanoparticle; Perfluorocarbon; Photodynamic therapy; Tumor-targeting
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.10.254
  50. Front Cell Dev Biol. 2022 ;10 1007641
    Pathological implications of metabolic reprogramming and its therapeutic potential in medulloblastoma.
    Veronica Marabitti, Manuela Giansanti, Francesca De Mitri, Francesca Gatto, Angela Mastronuzzi, Francesca Nazio.
      Tumor-specific alterations in metabolism have been recognized to sustain the production of ATP and macromolecules needed for cell growth, division and survival in many cancer types. However, metabolic heterogeneity poses a challenge for the establishment of effective anticancer therapies that exploit metabolic vulnerabilities. Medulloblastoma (MB) is one of the most heterogeneous malignant pediatric brain tumors, divided into four molecular subgroups (Wingless, Sonic Hedgehog, Group 3 and Group 4). Recent progresses in genomics, single-cell sequencing, and novel tumor models have updated the classification and stratification of MB, highlighting the complex intratumoral cellular diversity of this cancer. In this review, we emphasize the mechanisms through which MB cells rewire their metabolism and energy production networks to support and empower rapid growth, survival under stressful conditions, invasion, metastasis, and resistance to therapy. Additionally, we discuss the potential clinical benefits of currently available drugs that could target energy metabolism to suppress MB progression and increase the efficacy of the current MB therapies.
    Keywords:  OXPHOS (oxidative phosphorylation); ROS; glutamine/glutamate (GABA) cycle; metabolism; warburg effect
    DOI:  https://doi.org/10.3389/fcell.2022.1007641
  51. Foods. 2022 Oct 25. pii: 3349. [Epub ahead of print]11(21):
    Tea Polyphenols and Their Preventive Measures against Cancer: Current Trends and Directions.
    Anuva Talukder Trisha, Mynul Hasan Shakil, Suvro Talukdar, Kobun Rovina, Nurul Huda, Wahidu Zzaman.
      Cancer is exerting an immense strain on the population and health systems all over the world. Green tea because of its higher simple catechin content (up to 30% on dry weight basis) is greatly popular as an anti-cancer agent which is found to reduce the risks of cancer as well as a range of other diseases. In addition, several in vitro and in vivo studies have shown that green tea possesses copious health benefits like anti-diabetic, anti-obese, anti-inflammatory, neuro-protective, cardio-protective, etc. This review highlights the anti-carcinogenic effects of green tea catechins integrating the recent information to gain a clear concept. Special emphasis was given to the effectiveness of green tea polyphenols (GTP) in the prevention of cancer. Overall, green tea has been found to be effective to reduce the risks of breast cancer, ovarian cancer, liver cancer, colorectal cancer, skin cancer, prostate cancer, oral cancer, etc. However, sufficient information was not found to support that green tea consumption reduces the risk of lung cancer, esophageal cancer, or stomach cancer. The exciting data integrated into this article will increase interest in future researchers to garner more fruitful information on the relevant topics.
    Keywords:  anti-cancer agent; bioactive compounds; cancer prevention; catechins; health benefits
    DOI:  https://doi.org/10.3390/foods11213349
  52. Pharmaceutics. 2022 Nov 07. pii: 2401. [Epub ahead of print]14(11):
    Journey of Rosmarinic Acid as Biomedicine to Nano-Biomedicine for Treating Cancer: Current Strategies and Future Perspectives.
    Motamarri Venkata Naga Lalitha Chaitanya, Arya Kadukkattil Ramanunny, Malakapogu Ravindra Babu, Monica Gulati, Sukriti Vishwas, Thakur Gurjeet Singh, Dinesh Kumar Chellappan, Jon Adams, Kamal Dua, Sachin Kumar Singh.
      Rosmarinic acid (RA) is a polyphenolic metabolite found in various culinary, dietary sources, and medicinal plants like Coleus scutellarioides (Linn) Benth., Lavandula angustifolia Linn., Mellisa officinalis Linn., Origanum vulgare Linn., Rosmarinus officinalis Linn., Zataria multiflora Boiss. and Zhumeria majdae Rech. F. Apart from its dietary and therapeutic values, RA is an important anticancer phytochemical owing to its multi-targeting anticancer mechanism. These properties provide a scope for RA's therapeutic uses beyond its traditional use as a dietary source. However, its oral bioavailability is limited due to its poor solubility and permeability. This impedes its efficacy in treating cancer. Indeed, in recent years, tremendous efforts have been put towards the development of nanoformulations of RA for treating cancer. However, this research is in its initial stage as bringing a nanoparticle into the market itself is associated with many issues such as stability, toxicity, and scale-up issues. Considering these pitfalls during formulation development and overcoming them would surely provide a new face to RA as a nanomedicine to treat cancer. A literature search was conducted to systematically review the various biological sources, extraction techniques, and anticancer mechanisms through which RA showed multiple therapeutic effects. Various nanocarriers of RA pertaining to its anticancer activity are also discussed in this review.
    Keywords:  cancer; clinical translation; novel drug delivery systems; rosmarinic acid
    DOI:  https://doi.org/10.3390/pharmaceutics14112401
  53. Front Immunol. 2022 ;13 1006434
    Beneficial effects of natural flavonoids on neuroinflammation.
    Yu Chen, Fu Peng, Ziwei Xing, Junren Chen, Cheng Peng, Dan Li.
      Neuroinflammation is the fundamental immune response against multiple factors in the central nervous system and is characterized by the production of inflammatory mediators, activated microglia and astrocytes, and the recruitment of innate and adaptive immune cells to inflammatory sites, that contributes to the pathological process of related brain diseases, such as Alzheimer's disease, Parkinson's disease, depression, and stroke. Flavonoids, as a species of important natural compounds, have been widely revealed to alleviate neuroinflammation by inhibiting the production of pro-inflammatory mediators, elevating the secretion of anti-inflammatory factors, and modulating the polarization of microglia and astrocyte, mainly via suppressing the activation of NLRP3 inflammasome, as well as NF-κB, MAPK, and JAK/STAT pathways, promoting Nrf2, AMPK, BDNF/CREB, Wnt/β-Catenin, PI3k/Akt signals and SIRT1-mediated HMGB1 deacetylation. This review will provide the latest and comprehensive knowledge on the therapeutic benefits and mechanisms of natural flavonoids in neuroinflammation, and the natural flavonoids might be developed into food supplements or lead compounds for neuroinflammation-associated brain disorders.
    Keywords:  astrocytes; brain disorders; microglia; natural flavonoids; neuroinflammation
    DOI:  https://doi.org/10.3389/fimmu.2022.1006434
  54. Nanoscale Adv. 2022 Oct 25. 4(21): 4470-4480
    Transformable nanoparticles to bypass biological barriers in cancer treatment.
    Mythili Ramachandran, Zhao Ma, Kai Lin, Cristabelle De Souza, Yuanpei Li.
      Nanomedicine based drug delivery platforms provide an interesting avenue to explore for the future of cancer treatment. Here we discuss the barriers for drug delivery in cancer therapeutics and how nanomaterials have been designed to bypass these blockades through stimuli responsive transformation in the most recent update. Nanomaterials that address the challenges of each step provide a promising solution for new cancer therapeutics.
    DOI:  https://doi.org/10.1039/d2na00485b
  55. ACS Nano. 2022 Nov 10.
    Decrease in Tumor Interstitial Pressure for Enhanced Drug Intratumoral Delivery and Synergistic Tumor Therapy.
    Yihan Fu, Fei Ye, Xuwu Zhang, Yuchu He, Xiaoyu Li, Yongfu Tang, Jing Wang, Dawei Gao.
      Currently, one of the main reasons for the ineffectiveness of tumor treatment is that the abnormally high tumor interstitial pressure (TIP) hinders the delivery of drugs to the tumor center and promotes intratumoral cell survival and metastasis. Herein, we designed a "nanomotor" by in situ growth of Ag2S nanoparticles on the surface of ultrathin WS2 to fabricate Z-scheme photocatalytic drug AWS@M, which could rapidly enter tumors by splitting water in interstitial liquid to reduce TIP, along with O2 generation. Moreover, the O2 would be further converted to reactive oxygen species (ROS), accompanied by increased local temperature of tumors, and the combination of ROS with thermotherapy could eliminate the deep tumor cells. Therefore, the "nanomotor'' could effectively reduce the TIP levels of cervical cancer and pancreatic cancer (degradation rates of 40.2% and 36.1%, respectively) under 660 nm laser irradiation, further enhance intratumor drug delivery, and inhibit tumor growth (inhibition ratio 95.83% and 87.61%, respectively), and the related mechanism in vivo was explored. This work achieves efficiently photocatalytic water-splitting in tumor interstitial fluid to reduce TIP by the nanomotor, which addresses the bottleneck problem of blocking of intratumor drug delivery, and provides a general strategy for effectively inhibiting tumor growth.
    Keywords:  Z-scheme photocatalytic drug; nanodrug intratumor delivery; transition metal-sulfide compounds; tumor interstitial pressure; tumor therapy
    DOI:  https://doi.org/10.1021/acsnano.2c06356
  56. Antioxidants (Basel). 2022 Oct 28. pii: 2132. [Epub ahead of print]11(11):
    Possible Effects and Mechanisms of Dietary Natural Products and Nutrients on Depression and Anxiety: A Narrative Review.
    Si-Xia Wu, Jiahui Li, Dan-Dan Zhou, Ruo-Gu Xiong, Si-Yu Huang, Adila Saimaiti, Ao Shang, Hua-Bin Li.
      Depression and anxiety are severe public health problems and have attracted more and more attention from researchers of food science and nutrition. Dietary natural products and nutrients, such as fish, coffee, tea, n-3 PUFA, lycopene, and dietary fiber, could play a vital role in the prevention and management of these diseases. The potential mechanisms of action mainly include inhibiting inflammation, ameliorating oxidative stress, modulating the microbiota-gut-brain axis, suppressing hypothalamic-pituitary-adrenal axis hyperactivity, and regulating the levels of monoamine neurotransmitters. In this narrative review, we summarize the most recent advancements regarding the effects of dietary natural products and nutrients on depression and anxiety, and their underlying mechanisms are discussed. We hope that this paper can provide a better understanding of the anti-depressive and anxiolytic action of dietary natural products, and that it is also helpful for developing dietary natural products for functional food, dietary supplements, or auxiliary agents for the prevention and management of these diseases.
    Keywords:  anxiety; depression; dietary natural products; gut microbiota; nutrients
    DOI:  https://doi.org/10.3390/antiox11112132
  57. J Control Release. 2022 Nov 08. pii: S0168-3659(22)00754-4. [Epub ahead of print]
    Ligand-modified nanocarriers for oral drug delivery: Challenges, rational design, and applications.
    Yaqi Zhang, Yaying Wang, Xiang Li, Di Nie, Chang Liu, Yong Gan.
      Ligand-modified nanocarriers (LMNCs) specific to their targets have attracted increasing interest for enhanced oral drug delivery in recent decades. Although the design of LMNCs for enhanced endocytosis and improved exposure of the loaded drugs through the oral route has received abundant attention, it remains unclear how the design influences their transcellular process, especially the key factors affecting their functions. This review discusses the extracellular and cellular barriers to orally administered LMNCs in the gastrointestinal (GI) tract and new discoveries regarding the GI protein corona and the sequential transport barriers that impede the preplanned movements of LMNCs after oral administration. Furthermore, innovative progress in considering key factors (including target selection, ligand properties, and other important factors) in the rational design of LMNCs for oral drug delivery is presented. In particular, some factors that endow LMNCs with efficient transcytosis rather than only endocytosis are highlighted. Finally, the prospects of orally administered LMNCs in disease therapy for the enhanced oral/local bioavailability of active pharmaceutical ingredients, as well as emerging delivery routes, such as lymphatic drug delivery and systemic location-specific drug release based on transcellular oral LMNCs, are discussed.
    Keywords:  Active targeting; Ligand-modified nanocarriers; Local drug delivery; Oral drug delivery; Transcytosis; Transporter
    DOI:  https://doi.org/10.1016/j.jconrel.2022.11.010
  58. Molecules. 2022 Nov 02. pii: 7466. [Epub ahead of print]27(21):
    Evidence of the Beneficial Effects of Ursolic Acid against Lung Cancer.
    Amanda Kornel, Matteo Nadile, Evangelia Tsiani.
      Lung cancer is the leading cause of cancer-related deaths globally. Despite current treatment approaches that include surgery, chemotherapy, radiation and immunotherapies, lung cancer accounted for 1.79 million deaths worldwide in 2020, emphasizing the urgent need to find novel agents and approaches for more effective treatment. Traditionally, chemicals derived from plants, such as paclitaxel and docetaxel, have been used in cancer treatment, and in recent years, research has focused on finding other plant-derived chemicals that can be used in the fight against lung cancer. Ursolic acid is a polyphenol found in high concentrations in cranberries and other fruits and has been demonstrated to have anti-inflammatory, antioxidant and anticancer properties. In this review, we summarize recent research examining the effects of ursolic acid and its derivatives on lung cancer. Data from in vitro cell culture and in vivo animal studies show potent anticancer effects of ursolic acid and indicate the need for clinical studies.
    Keywords:  invasion; lung cancer; metastasis; proliferation; signaling cascades; survival; ursolic acid
    DOI:  https://doi.org/10.3390/molecules27217466
  59. Adv Healthc Mater. 2022 Nov 11. e2202043
    Switchable ROS Scavenger/Generator for MRI-Guided Anti-Inflammation and Anti-Tumor Therapy with Enhanced Therapeutic Efficacy and Reduced Side Effects.
    Muyao Li, Linlin Huo, Jie Zeng, Guifen Zhu, Xiangqing Liu, Xianglong Zhu, Guoming Huang, Yi Wang, Kaiyuan Ni, Zhenghuan Zhao.
      Photodynamic therapy (PDT) is a potent anti-tumor treatment that combines photosensitizer and light to damage tumor tissue. However, photosensitizer that accumulates in both tumor and adjacent normal tissue due to low selective biodistribution, results in an undesirable side effect with limited clinic application. Herein, we report an intelligent nanoplatform that selectively act as reactive oxygen species (ROS) scavenger in normal tissue but ROS generator in tumor microenvironment (TME) to differentially control ROS level in tumor and surrounding normal tissue during PDT. By down-regulating the produced ROS with dampened cytokine wave in normal tissue after PDT, the nanoplatform reduces the inflammatory response of normal tissue in PDT, minimizing the side effect and tumor metastasis in PDT. Alternatively, the nanoplatform switches from ROS scavenger to generator through the GSH-responsive degradation in TME, which effectively improves the PDT efficacy with reduced GSH level and amplified oxidative stress in tumor. Simultaneously, the released Mn ions provide real-time and in situ signal change of magnetic resonance imaging (MRI) to monitor the reversal process of catalysis activity and achieve accurate tumor diagnosis. This TME-responsive ROS scavenger/generator with activable MRI contrast may provide a new dimension for design of next-generation PDT agents with precise diagnosis, high therapeutic efficacy, and low side effect. This article is protected by copyright. All rights reserved.
    Keywords:  Activable MRI; Low side effect; Switchable ROS scavenger/generator; microenvironment; photodynamic therapy
    DOI:  https://doi.org/10.1002/adhm.202202043
  60. Cancers (Basel). 2022 Nov 04. pii: 5430. [Epub ahead of print]14(21):
    KRAS in NSCLC: State of the Art and Future Perspectives.
    Priscilla Cascetta, Arianna Marinello, Chiara Lazzari, Vanesa Gregorc, David Planchard, Roberto Bianco, Nicola Normanno, Alessandro Morabito.
      In NSCLC, KRAS mutations occur in up to 30% of all cases, most frequently at codon 12 and 13. KRAS mutations have been linked to adenocarcinoma histology, positive smoking history, and Caucasian ethnicity, although differences have been described across KRAS mutational variants subtypes. KRAS mutations often concur with other molecular alterations, notably TP53, STK11, and KEAP1, which could play an important role in treatment efficacy and patient outcomes. For many years, KRAS mutations have been considered undruggable mainly due to a high toxicity profile and low specificity of compounds. Sotorasib and adagrasib are novel KRAS inhibitors that recently gained FDA approval for pre-treated KRAS mutant NSCLC patients, and other molecules such as GDC-6036 are currently being investigated with promising results. Despite their approval, the efficacy of these drugs is lower than expected and progression among responders has been reported. Mechanisms of acquired resistance to anti-KRAS molecules typically involves either on target secondary mutations (e.g., G12, G13, Q61H, R68S, H95, Y96C, V8L) or off-target alterations. Ongoing trials are currently evaluating strategies for implementing efficacy and overcoming acquired resistance to these compounds. Finally, the efficacy of immune-checkpoint inhibitors still needs to be completely assessed and responses to anti-PD-1/PD-L1 agents may strongly depend on concomitant mutations.
    Keywords:  AMG 510; KRAS; MRTX849; NSCLC; acquired resistance; adagrasib; immune-checkpoint inhibitors; lung cancer; sotorasib
    DOI:  https://doi.org/10.3390/cancers14215430
  61. Endocr Metab Immune Disord Drug Targets. 2022 Nov 07.
    Natural bioactive compounds against oxidative stress: dietary polyphenols strike back.
    Roberto Arrigoni, Francesco Cammarota, Rosa Porro, Stefania Cantore, Mario Dioguardi, Angela Pia Cazzolla, Francesco De Leonardis, Lorenzo Polimeno, Nicoletta Zerman, Michele Di Cosola, Filiberto Mastrangelo, Luigi Santacroce, Andrea Ballini.
      Oxidative stress is a major cellular and metabolic burden that can really alter cell life and became the base for disease inset and development. Many widespread pathologies can develop starting from an unresolved oxidative stress situation, thus addressing this state is paramount for human health. Our antioxidant enzymes sometimes are not just enough. Fortify our defense and antioxidant and anti-inflammatory system can make a difference for our health: if this attainable with our dietary habits, could be a dream come true. Polyphenols are a fantastic tool indeed into the fight against oxidative stress: they are easy to obtain, with little cost, no side effects, and a multitude of metabolic actions. This perspective review would like to shed a light about polyphenol's metabolic and molecular action respect to oxidative stress to help us to preserve our health.
    Keywords:  Polyphenols; clinical studies; natural compounds anti-inflammatory activity; oxidative stress; polyphenol therapeutic potential; reactive oxygen species (ROS)
    DOI:  https://doi.org/10.2174/1871530323666221107092553
  62. Nutrients. 2022 Nov 03. pii: 4637. [Epub ahead of print]14(21):
    A Comprehensive Review on Nutraceuticals: Therapy Support and Formulation Challenges.
    Vivek Puri, Manju Nagpal, Inderbir Singh, Manjinder Singh, Gitika Arora Dhingra, Kampanart Huanbutta, Divya Dheer, Ameya Sharma, Tanikan Sangnim.
      Nutraceuticals are the nourishing components (hybrid of nutrition and pharmaceuticals) that are biologically active and possess capability for maintaining optimal health and benefits. These products play a significant role in human health care and its endurance, most importantly for the future therapeutic development. Nutraceuticals have received recognition due to their nutritional benefits along with therapeutic effects and safety profile. Nutraceuticals are globally growing in the field of services such as health care promotion, disease reduction, etc. Various drug nutraceutical interactions have also been elaborated with various examples in this review. Several patents on nutraceuticals in agricultural applications and in various diseases have been stated in the last section of review, which confirms the exponential growth of nutraceuticals' market value. Nutraceuticals have been used not only for nutrition but also as a support therapy for the prevention and treatment of various diseases, such as to reduce side effects of cancer chemotherapy and radiotherapy. Diverse novel nanoformulation approaches tend to overcome challenges involved in formulation development of nutraceuticals. Prior information on various interactions with drugs may help in preventing any deleterious effects of nutraceuticals products. Nanotechnology also leads to the generation of micronized dietary products and other nutraceutical supplements with improved health benefits. In this review article, the latest key findings (clinical studies) on nutraceuticals that show the therapeutic action of nutraceutical's bioactive molecules on various diseases have also been discussed.
    Keywords:  cardiovascular diseases; interactions; nutrition; prevention; therapeutics
    DOI:  https://doi.org/10.3390/nu14214637
  63. Mar Drugs. 2022 Nov 04. pii: 694. [Epub ahead of print]20(11):
    Insight into Fucoidan-Based PEGylated PLGA Nanoparticles Encapsulating Methyl Anthranilic Acid: In Vitro Evaluation and In Vivo Anti-Inflammatory Study.
    Dalia H Abdelkader, Engy Elekhnawy, Walaa A Negm, Thanaa A El-Masry, May Almukainzi, Ahmed Zayed, Roland Ulber.
      A potential fucoidan-based PEGylated PLGA nanoparticles (NPs) offering a proper delivery of N-methyl anthranilic acid (MA, a model of hydrophobic anti-inflammatory drug) have been developed via the formation of fucoidan aqueous coating surrounding PEGylated PLGA NPs. The optimum formulation (FuP2) composed of fucoidan:m-PEG-PLGA (1:0.5 w/w) with particle size (365 ± 20.76 nm), zeta potential (-22.30 ± 2.56 mV), % entrapment efficiency (85.45 ± 7.41), drug loading (51.36 ± 4.75 µg/mg of NPs), % initial burst (47.91 ± 5.89), and % cumulative release (102.79 ± 6.89) has been further investigated for the anti-inflammatory in vivo study. This effect of FuP2 was assessed in rats' carrageenan-induced acute inflammation model. The average weight of the paw edema was significantly lowered (p ≤ 0.05) by treatment with FuP2. Moreover, cyclooxygenase-2 and tumor necrosis factor-alpha immunostaining were decreased in FuP2 treated group compared to the other groups. The levels of prostaglandin E2, nitric oxide, and malondialdehyde were significantly reduced (p ≤ 0.05) in the FuP2-treated group. A significant reduction (p ≤ 0.05) in the expression of interleukins (IL-1β and IL-6) with an improvement of the histological findings of the paw tissues was observed in the FuP2-treated group. Thus, fucoidan-based PEGylated PLGA-MA NPs are a promising anti-inflammatory delivery system that can be applied for other similar drugs potentiating their pharmacological and pharmacokinetic properties.
    Keywords:  aqueous coating; cyclooxygenase-2; interleukins; reactive oxygen species; single emulsion solvent evaporation; tumor necrosis factor-alpha
    DOI:  https://doi.org/10.3390/md20110694
  64. Biochem Biophys Res Commun. 2022 Dec 10. pii: S0006-291X(22)01270-0. [Epub ahead of print]633 17-19
    Reactive oxygen species (ROS), oxygen radicals and antioxidants: Where are we now, where is the field going and where should we go?
    Barry Halliwell.
      The field of oxygen free radicals, antioxidants and reactive oxygen species (ROS) has exploded in the past few decades, and BBRC has published several seminal papers. ROS can cause oxidative damage, but also play fundamental roles in living organisms, in such processes as signal transduction and defence against pathogens. ROS underpin every aspect of human biology. Indeed, an endless stream of published papers refers to the biological roles of "ROS". Sadly, much of this work is mechanistically meaningless. To make progress, the detailed molecular mechanisms of action of ROS must be elucidated and appropriate methodology must be used to measure them and the oxidative damage that they can cause, as emphasized in a recent review by Murphy et al. Attention must also switch from clinical studies involving administration of high-dose supplements of vitamins E, C and β-carotene for the treatment or prevention of human disease into other promising diet-derived cytoprotective agents. One of them may be ergothioneine.
    Keywords:  Antioxidant; Oxygen radicals; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.bbrc.2022.08.098
  65. Antioxidants (Basel). 2022 Oct 27. pii: 2121. [Epub ahead of print]11(11):
    Pharmacological Activity, Pharmacokinetics, and Clinical Research Progress of Puerarin.
    Di Wang, Tong Bu, Yangqian Li, Yueyue He, Fan Yang, Liang Zou.
      As a kind of medicine and food homologous plant, kudzu root (Pueraria lobata (Willd.) Ohwi) is called an "official medicine" in Chinese folk medicine. Puerarin is the main active component extracted from kudzu root, and its structural formula is 8-β-D-grapes pyranose-4, 7-dihydroxy isoflavone, with a white needle crystal; it is slightly soluble in water, and its aqueous solution is colorless or light yellow. Puerarin is a natural antioxidant with high health value and has a series of biological activities such as antioxidation, anti-inflammation, anti-tumor effects, immunity improvement, and cardio-cerebrovascular and nerve cell protection. In particular, for the past few years, it has also been extensively used in clinical study. This review focuses on the antioxidant activity of puerarin, the therapy of diverse types of inflammatory diseases, various new drug delivery systems of puerarin, the "structure-activity relationship" of puerarin and its derivatives, and pharmacokinetic and clinical studies, which can provide a new perspective for the puerarin-related drug research and development, clinical application, and further development and utilization.
    Keywords:  anti-inflammation; antioxidation; clinical studies; new drug delivery systems; pharmacokinetic; pharmacological activities; puerarin
    DOI:  https://doi.org/10.3390/antiox11112121
  66. Chem Biodivers. 2022 Nov 08. e202200535
    Role of Natural Products in Developing Novel Anticancer Agents: A Perspective.
    Baji Baba Shaik, Naresh Kumar Katari, Sreekantha Babu Jonnalagadda.
      Cancer is a heterogeneous disease and is one of the significant health issues, especially in public health systems around the world. Natural products and their structural derivatives with outstanding chemical diversity have been investigated for potential anti-cancer agents. Many natural products revealing potential anti-cancer properties such as cytotoxicity, proliferation inhibition, induced apoptosis, retard metastasis, suppressing angiogenesis, and improved chemotherapy have been isolated from various plants and herbs. Several promising lead molecules have been identified recently; a few are in the clinical trial stage. This short communication summarises the role of natural products and their analogs in anti-cancer drug developments, especially plant, marine and microbial-based anti-cancer agents.
    Keywords:  anti-cancer; chemotherapy; cytotoxicity; natural products
    DOI:  https://doi.org/10.1002/cbdv.202200535
  67. Nanomicro Lett. 2022 Nov 11. 14(1): 220
    Bacterial Metabolism-Initiated Nanocatalytic Tumor Immunotherapy.
    Wencheng Wu, Yinying Pu, Shuang Gao, Yucui Shen, Min Zhou, Heliang Yao, Jianlin Shi.
      The low immunogenicity of tumors remains one of the major limitations of cancer immunotherapy. Herein, we report a bacterial metabolism-initiated and photothermal-enhanced nanocatalytic therapy strategy to completely eradicate primary tumor by triggering highly effective antitumor immune responses. Briefly, a microbiotic nanomedicine, designated as Cu2O@ΔSt, has been constructed by conjugating PEGylated Cu2O nanoparticles on the surface of an engineered Salmonella typhimurium strain (ΔSt). Owing to the natural hypoxia tropism of ΔSt, Cu2O@ΔSt could selectively colonize hypoxic solid tumors, thus minimizing the adverse effects of the bacteria on normal tissues. Upon bacterial metabolism within the tumor, Cu2O@ΔSt generates H2S gas and other acidic substances in the tumor microenvironment (TME), which will in situ trigger the sulfidation of Cu2O to form CuS facilitating tumor-specific photothermal therapy (PTT) under local NIR laser irradiation on the one hand. Meanwhile, the dissolved Cu+ ions from Cu2O into the acidified TME enables the nanocatalytic tumor therapy by catalyzing the Fenton-like reaction of decomposing endogenous H2O2 into cytotoxic hydroxyl radicals (·OH) on the other hand. Such a bacterial metabolism-triggered PTT-enhanced nanocatalytic treatment could effectively destroy tumor cells and induce a massive release of tumor antigens and damage-associated molecular patterns, thereby sensitizing tumors to checkpoint blockade (ICB) therapy. The combined nanocatalytic and ICB therapy results in the much-inhibited growth of distant and metastatic tumors, and more importantly, induces a powerful immunological memory effect after the primary tumor ablation.
    Keywords:  Bacterial metabolism; Immunotherapy; In situ nanocatalytic therapy
    DOI:  https://doi.org/10.1007/s40820-022-00951-0
  68. Front Immunol. 2022 ;13 1010021
    Targeted delivery of liposomal chemoimmunotherapy for cancer treatment.
    Yusheng Liu, Joonsu Han, Yang Bo, Rimsha Bhatta, Hua Wang.
      Chemoimmunotherapy that utilizes the immunomodulatory effect of chemotherapeutics has shown great promise for treating poorly immunogenic solid tumors. However, there remains a significant room for improving the synergy between chemotherapy and immunotherapy, including the efficient, concurrent delivery of chemotherapeutics and immunomodulators into tumors. Here, we report the use of metabolic glycan labeling to facilitate cancer-targeted delivery of liposomal chemoimmunotherapy. 4T1 triple-negative breast cancer cells can be metabolically labeled with azido groups for subsequently targeted conjugation of dibenzocycoloctyne (DBCO)-bearing liposomes loaded with doxorubicin and imiquimod (R837) adjuvant <i>via</i> efficient click chemistry. The encased doxorubicin can induce the immunogenic death of cancer cells and upregulate the expression of CD47 and calreticulin on the surface of cancer cells, while R837 can activate dendritic cells for enhanced processing and presentation of tumor antigens. Targeted delivery of liposomes encapsulating doxorubicin and R837 to 4T1 tumors, enabled by metabolic glycan labeling and click chemistry, showed the promise to reshape the immunosuppressive tumor microenvironment of solid tumors. This cancer-targetable liposomal chemoimmunotherapy could provide a new approach to improving conventional chemotherapy.
    Keywords:  chemo-immunotherapy; click chemistry; immunotherapy; liposome; metabolic glycan labeling
    DOI:  https://doi.org/10.3389/fimmu.2022.1010021
  69. Biochim Biophys Acta Bioenerg. 2022 Oct 29. pii: S0005-2728(22)00401-7. [Epub ahead of print]1864(1): 148931
    The Warburg effect and mitochondrial oxidative phosphorylation: Friends or foes?
    M Martins Pinto, P Paumard, C Bouchez, S Ransac, S Duvezin-Caubet, J P Mazat, M Rigoulet, A Devin.
      Cancer cells display an altered energy metabolism, which was proposed to be the root of cancer. This early discovery was done by O. Warburg who conducted one of the first studies of tumor cell energy metabolism. Taking advantage of cancer cells that exhibited various growth rates, he showed that cancer cells display a decreased respiration and an increased glycolysis proportional to the increase in their growth rate, suggesting that they mainly depend on fermentative metabolism for ATP generation. Warburg's results and hypothesis generated controversies that are persistent to this day. It is thus of great importance to understand the mechanisms by which cancer cells can reversibly regulate the two pathways of their energy metabolism as well as the functioning of this metabolism in cell proliferation. In this review, we discuss of the origin of the decrease in cell respiratory rate, whether the Warburg effect is mandatory for an increased cell proliferation rate, the consequences of this effect on two major players of cell energy metabolism that are ATP and NADH, and the role of the microenvironment in the regulation of cellular respiration and metabolism both in cancer cell and in yeast.
    Keywords:  Cancer; Mitochondria; Oxidative phosphorylation; Warburg effect
    DOI:  https://doi.org/10.1016/j.bbabio.2022.148931
  70. Biomolecules. 2022 Oct 26. pii: 1565. [Epub ahead of print]12(11):
    Focusing on the Role of Natural Products in Overcoming Cancer Drug Resistance: An Autophagy-Based Perspective.
    Jiaqi Yao, Chi Ma, Kaixuan Feng, Guang Tan, Qingping Wen.
      Autophagy is a critical cellular adaptive response in tumor formation. Nutritional deficiency and hypoxia exacerbate autophagic flux in established malignancies, promoting tumor cell proliferation, migration, metastasis, and resistance to therapeutic interventions. Pro-survival autophagy inhibition may be a promising treatment option for advanced cancer. Furthermore, excessive or persistent autophagy is cytotoxic, resulting in tumor cell death. Targeted autophagy activation has also shown significant promise in the fight against tumor drug resistance. Several research groups have examined the ability of natural products (NPs) such as alkaloids, terpenoids, polyphenols, and anthraquinones to serve as autophagy inhibitors or activators. The data support the capacity of NPs that promote lethal autophagy or inhibit pro-survival autophagy from being employed against tumor drug resistance. This paper discusses the potential applications of NPs that regulate autophagy in the fight against tumor drug resistance, some limitations of the current studies, and future research needs and priorities.
    Keywords:  autophagy; natural products; resistance; therapy; tumors
    DOI:  https://doi.org/10.3390/biom12111565
  71. J Food Biochem. 2022 Nov 12. e14504
    Research progress on Walnut oil: Bioactive compounds, health benefits, extraction methods, and medicinal uses.
    Huaying Song, Zhufeng Cong, Changlin Wang, Mengyuan He, Congying Liu, Peng Gao.
      Walnut oil is extracted from walnut kernels (Juglans regia Linne) or iron walnut kernels (Juhlans sigillata Dode). The percentage of oil in walnuts is 52%-70%. The main constituents in oil are fatty acids, phenols, sterols, squalene, melatonin, vitamins, and minerals. Many extraction methods such as supercritical carbon dioxide extraction, maceration, modified "bligh and dyer extraction," aqueous enzymatic extraction, ultrasonic extraction, soxhlet extraction, and cold-press extraction methods are reported in the literature. Walnut oil showed anti-inflammatory, antitumor, antioxidant, immunomodulatory, neuroprotective, cardioprotective, antidiabetic, and antihyperlipidemic activities. The reported data in the literature suggest that walnut oil has many health benefits. This review summarizes the extraction methods, bioactive constituents, health benefits, and pharmacological actions of walnut oil. PRACTICAL APPLICATIONS: Walnut oil is a natural vegetable oil of significant importance due to their nutritional, and intelligence-boosting benefits. Several factors, including the processing parameters and the phytochemical profile, affect walnut oil products' flavor and color. In addition, storage environment of walnut oil can also affect walnut oil quality. Apart from the predominant ingredient fatty acids, the chemical composition of walnut oil comprises phenols, sterols, squalene, melatonin, vitamins, and minerals. These bioactive compounds are of potential value owing to their health-promoting benefits, including antioxidant, antitumor, and cholesterol-lowering effects. Many chemical constituents were isolated from walnut oil; however, all the compounds are not explored for their possible medicinal value. Thus, clinical studies, exploration of the therapeutic potential and the molecular mechanisms of all the compounds, and development of convenient dosage forms either for therapeutic or functional food purposes are warranted.
    Keywords:  Walnut oil; chemistry; extraction; health benefits; medicinal value
    DOI:  https://doi.org/10.1111/jfbc.14504
  72. Probl Endokrinol (Mosk). 2022 Jul 14. 68(5): 45-55
    [Metformin and malignant neoplasms: a possible mechanism of antitumor action and prospects for use in practice].
    K O Kuznetsov, E R Safina, D V Gaimakova, Ya S Frolova, I Yu Oganesyan, A G Sadertdinova, K A Nazmieva, A H Islamgulov, A R Karimova, A M Galimova, E V Rizvanova.
      Metformin is a first-line antidiabetic drug for the treatment of type 2 diabetes mellitus (DM2); its molecular target is AMP-activated protein kinase (AMPK), which is involved in many metabolic processes. Metformin not only reduces blood glucose levels and improves insulin sensitivity, but also inhibits lipolysis and reduces cardiovascular risk in patients with DM2. In recent years, it has been proven that metformin slows down the aging process, stimulates hair growth, eliminates cognitive impairment, and also has an antitumor effect. Most basic studies have shown that metformin inhibits the growth of tumor cells and promotes cellular apoptosis, while clinical studies show contradictory results. This discrepancy can be explained by the difference in the concentration of metformin between basic and clinical studies. The maximum daily dose of metformin for patients with DM2 is 2500 mg / day, and the dose used in basic research was much higher. Metformin directly activates the AMPK signaling pathway, inhibits the production of reactive oxygen species, induces the activation of mTORC1, inhibits cyclin D1, which leads to a reduction in the risk of the occurrence and development of malignant neoplasms. In addition, metformin indirectly inhibits tumor growth, proliferation, invasion and metastasis by reducing the concentration of glucose in the blood, insulin resistance, as well as by reducing inflammation and affecting the tumor microenvironment. Glycolysis plays an important role in the energy metabolism of tumors, and metformin is able to have an inhibitory effect on it. Currently, studies of the mechanism of antitumor effects of metformin are becoming more extensive and in-depth, but there are still some contradictions.
    DOI:  https://doi.org/10.14341/probl13097
  73. Pharmaceutics. 2022 Nov 10. pii: 2427. [Epub ahead of print]14(11):
    pH-Sensitive Targeting of Tumors with Chemotherapy-Laden Nanoparticles: Progress and Challenges.
    Zuha Imtiyaz, Jiaxi He, Qixin Leng, Atul K Agrawal, A James Mixson.
      Accumulating chemotherapeutic drugs such as doxorubicin within a tumor while limiting the drug dose to normal tissues is a central goal of drug delivery with nanoparticles. Liposomal products such as Doxil® represent one of the marked successes of nanoparticle-based strategies. To replicate this success for cancer treatment, many approaches with nanoparticles are being explored in order to direct and release chemotherapeutic agents to achieve higher accumulation in tumors. A promising approach has been stimulus-based therapy, such as the release of chemotherapeutic agents from the nanoparticles in the acidic environments of the tumor matrix or the tumor endosomes. Upon reaching the acidic environments of the tumor, the particles, which are made up of pH-dependent polymers, become charged and release the entrapped chemotherapy agents. This review discusses recent advances in and prospects for pH-dependent histidine-based nanoparticles that deliver chemotherapeutic agents to tumors. The strategies used by investigators include an array of histidine-containing peptides and polymers which form micelles, mixed micelles, nanovesicles, polyplexes, and coat particles. To date, several promising histidine-based nanoparticles have been demonstrated to produce marked inhibition of tumor growth, but challenges remain for successful outcomes in clinical trials. The lessons learned from these histidine-containing particles will provide insight in the development of improved pH-dependent polymeric delivery systems for chemotherapy.
    Keywords:  doxorubicin; histidine; imidazole; micelles; nanoparticles; polymers; tumor pH
    DOI:  https://doi.org/10.3390/pharmaceutics14112427
  74. Sci Rep. 2022 Nov 10. 12(1): 19250
    Isolongifolene-loaded chitosan nanoparticles synthesis and characterization for cancer treatment.
    Dharmar Manimaran, Namasivayam Elangovan, Panagal Mani, Kumaran Subramanian, Daoud Ali, Saud Alarifi, Chella Perumal Palanisamy, Hongxia Zhang, Kowsalya Rangasamy, Vasan Palanisamy, Renuka Mani, Kavitha Govarthanan, Wilson Aruni, Rajeshkumar Shanmugam, Guru Prasad Srinivasan, Aruncahllam Kalirajan.
      Recent breakthroughs in the field of nanoparticle-based therapeutic delivery methods have changed the standpoint of cancer therapy by effectively delaying the process of disease development. Nanoparticles have a unique capacity of good penetrating ability than other therapeutic leads used in traditional therapeutics, and also, they have the highest impact on disease management. In the current study isolongifolene-loaded Chitosan nanoparticles have been formulated, synthesized and then characterized by the use of Fourier Transform Infrared Spectroscopy, X-ray Diffraction, Scanning Electron Microscopy and Transmission Electron Microscopy. Further, the characterized chitosan nano formulation was evaluated for hemocompatibility, plasma stability, and in-vitro release. Isolongifolene-loaded chitosan nanoparticles were found to be compatible with plasma and also, they exhibited a constant release pattern. Hence, chitosan-loaded nanoparticles could be employed as an excellent adjuvant in cancer therapeutic, to combat the multi-drug resistance in solid tumors.
    DOI:  https://doi.org/10.1038/s41598-022-23386-4
  75. Food Funct. 2022 Nov 11.
    Effects of curcumin, a bioactive component of turmeric, on type 2 diabetes mellitus and its complications: an updated review.
    Osman Bozkurt, Betül Kocaadam-Bozkurt, Hilal Yildiran.
      Type 2 diabetes mellitus (T2DM) is a substantial issue in public health. Recently, there has been considerable interest in the effectiveness of using herbal supplements for T2DM. Among the herbal supplements, turmeric (Curcuma longa L.) has been attracting an avalanche of attention owing to its main component, curcumin. This review examines the physiological activities and mechanisms of action of curcumin associated with T2DM and its complications. The literature indicates that pro-inflammatory cytokines along with oxidative stress play a very important role in diabetes pathogenesis. Since inflammation is a main cause of disruption of the β cell structure, the anti-diabetic characteristic of curcumin is mainly attributed to its anti-inflammatory as well as anti-oxidant activities. In addition to these activities, curcumin has been developed as a promising prevention/treatment choice for diabetes complications by modulating various critical signal steps owing to the anti-hyperglycemic and anti-hyperlipidemic activities of curcumin. Studies on diabetic humans and animals have revealed that curcumin may have positive effects on oxidative stress and inflammation and may reduce fasting blood glucose levels, increase insulin sensitivity/secretion and regulate the lipid profile. Thus, it may prevent and treat diabetes by affecting various molecular targets.
    DOI:  https://doi.org/10.1039/d2fo02625b
  76. Molecules. 2022 Oct 25. pii: 7238. [Epub ahead of print]27(21):
    Research Progress of Antioxidant Nanomaterials for Acute Pancreatitis.
    Xiaoyi Zheng, Jiulong Zhao, Shige Wang, Lianghao Hu.
      Acute pancreatitis (AP) is a complex inflammatory disease caused by multiple etiologies, the pathogenesis of which has not been fully elucidated. Oxidative stress is important for the regulation of inflammation-related signaling pathways, the recruitment of inflammatory cells, the release of inflammatory factors, and other processes, and plays a key role in the occurrence and development of AP. In recent years, antioxidant therapy that suppresses oxidative stress by scavenging reactive oxygen species has become a research highlight of AP. However, traditional antioxidant drugs have problems such as poor drug stability and low delivery efficiency, which limit their clinical translation and applications. Nanomaterials bring a brand-new opportunity for the antioxidant treatment of AP. This review focuses on the multiple advantages of nanomaterials, including small size, good stability, high permeability, and long retention effect, which can be used not only as effective carriers of traditional antioxidant drugs but also directly as antioxidants. In this review, after first discussing the association between oxidative stress and AP, we focused on summarizing the literature related to antioxidant nanomaterials for the treatment of AP and highlighting the effects of these nanomaterials on the indicators related to oxidative stress in pathological states, aiming to provide references for follow-up research and promote clinical application.
    Keywords:  acute pancreatitis; antioxidant drugs; nanomaterials; oxidative stress; reactive oxygen species
    DOI:  https://doi.org/10.3390/molecules27217238
  77. Pharmaceutics. 2022 Nov 07. pii: 2396. [Epub ahead of print]14(11):
    Microbubble-Nanoparticle Complexes for Ultrasound-Enhanced Cargo Delivery.
    Rachel Chapla, Katherine T Huynh, Carolyn E Schutt.
      Targeted delivery of therapeutics to specific tissues is critically important for reducing systemic toxicity and optimizing therapeutic efficacy, especially in the case of cytotoxic drugs. Many strategies currently exist for targeting systemically administered drugs, and ultrasound-controlled targeting is a rapidly advancing strategy for externally-stimulated drug delivery. In this non-invasive method, ultrasound waves penetrate through tissue and stimulate gas-filled microbubbles, resulting in bubble rupture and biophysical effects that power delivery of attached cargo to surrounding cells. Drug delivery capabilities from ultrasound-sensitive microbubbles are greatly expanded when nanocarrier particles are attached to the bubble surface, and cargo loading is determined by the physicochemical properties of the nanoparticles. This review serves to highlight and discuss current microbubble-nanoparticle complex component materials and designs for ultrasound-mediated drug delivery. Nanocarriers that have been complexed with microbubbles for drug delivery include lipid-based, polymeric, lipid-polymer hybrid, protein, and inorganic nanoparticles. Several schemes exist for linking nanoparticles to microbubbles for efficient nanoparticle delivery, including biotin-avidin bridging, electrostatic bonding, and covalent linkages. When compared to unstimulated delivery, ultrasound-mediated cargo delivery enables enhanced cell uptake and accumulation of cargo in target organs and can result in improved therapeutic outcomes. These ultrasound-responsive delivery complexes can also be designed to facilitate other methods of targeting, including bioactive targeting ligands and responsivity to light or magnetic fields, and multi-level targeting can enhance therapeutic efficacy. Microbubble-nanoparticle complexes present a versatile platform for controlled drug delivery via ultrasound, allowing for enhanced tissue penetration and minimally invasive therapy. Future perspectives for application of this platform are also discussed in this review.
    Keywords:  cavitation; microbubble; nanoparticle; sonoporation; targeted drug delivery; ultrasound
    DOI:  https://doi.org/10.3390/pharmaceutics14112396
  78. Front Pharmacol. 2022 ;13 1007279
    Cortex Mori extracts induce apoptosis and inhibit tumor invasion via blockage of the PI3K/AKT signaling in melanoma cells.
    Xin Hu, Kui Zhang, Guangzhao Pan, Yinggang Wang, Yue Shen, Cheng Peng, Longfei Deng, Hongjuan Cui.
      Melanoma, the most aggressive and deadliest form of skin cancer, has attracted increased attention due to its increasing incidence worldwide. The Cortex Mori (CM) has long been used as a classical traditional Chinese medicine (TCM) to treat various diseases, including cancer. The bioactive components and underlying mechanisms, however, remain largely unknown. The current study aims to investigate the anti-melanoma effects of CM and potential mechanisms through combined network pharmacology and bioinformatic analyses, and validated by in vitro and in vivo experiments. We report here that CM has anti-melanoma activity both in vitro and in vivo. Furthermore, 25 bioactive compounds in CM were found to share 142 melanoma targets, and network pharmacology and enrichment analyses suggested that CM inhibits melanoma through multiple biological processes and signaling pathways, particularly the PI3K-AKT signaling inhibition and activation of apoptotic pathways, which were further confirmed by biochemical and histological examinations. Finally, partial CM-derived bioactive compounds were found to show anti-melanoma effects, validating the anti-melanoma potential of bioactive ingredients of CM. Taken together, these results reveal bioactive components and mechanisms of CM in inhibiting melanoma, providing them as potential anti-cancer natural products for the treatment of melanoma.
    Keywords:  Cortex Mori; anti-cancer natural product; melanoma; molecular docking; network pharmacology
    DOI:  https://doi.org/10.3389/fphar.2022.1007279
  79. Life (Basel). 2022 Nov 06. pii: 1795. [Epub ahead of print]12(11):
    Molecular Mechanisms of Action of Eugenol in Cancer: Recent Trends and Advancement.
    Ipsa Padhy, Paramita Paul, Tripti Sharma, Sabyasachi Banerjee, Arijit Mondal.
      BACKGROUND: Cancer is, at present, among the leading causes of morbidity globally. Despite advances in treatment regimens for cancer, patients suffer from poor prognoses. In this context, the availability of vast natural resources seems to alleviate the shortcomings of cancer chemotherapy. The last decade has seen a breakthrough in the investigations related to the anticancer potential of dietary phytoconstituents. Interestingly, a handsome number of bioactive principles, ranging from phenolic acids, phenylpropanoids, flavonoids, stilbenes, and terpenoids to organosulphur compounds have been screened for their anticancer properties. Among the phenylpropanoids currently under clinical studies for anticancer activity, eugenol is a promising candidate. Eugenol is effective against cancers like breast, cervical, lung, prostate, melanomas, leukemias, osteosarcomas, gliomas, etc., as evident from preclinical investigations.OBJECTIVE: The review aims to focus on cellular and molecular mechanisms of eugenol for cancer prevention and therapy.
    METHODS: Based on predetermined criteria, various scholarly repositories, including PubMed, Scopus, and Science Direct were analyzed for anticancer activities of eugenol.
    RESULTS: Different biochemical investigations reveal eugenol inducing cytotoxicity, inhibiting phases of the cell cycles, programmed cell death, and auto-phagocytosis in studied cancer lines; thus, portraying eugenol as a promising anticancer molecule. A survey of current literature has unveiled the molecular mechanisms intervened by eugenol in exercising its anticancer role.
    CONCLUSION: Based on the critical analysis of the literature, eugenol exhibits vivid signaling pathways to combat cancers of different origins. The reports also depict the advancement of novel nano-drug delivery approaches upgrading the therapeutic profile of eugenol. Therefore, eugenol nanoformulations may have enormous potential for both the treatment and prevention of cancer.
    Keywords:  anticancer; dietary phytochemicals; drug delivery; eugenol; signaling pathways; therapeutic profile
    DOI:  https://doi.org/10.3390/life12111795
  80. Cancers (Basel). 2022 Nov 07. pii: 5468. [Epub ahead of print]14(21):
    Wnt/β-Catenin Signaling as a Driver of Stemness and Metabolic Reprogramming in Hepatocellular Carcinoma.
    Rainbow Wing Hei Leung, Terence Kin Wah Lee.
      Hepatocellular carcinoma (HCC) is a major cause of cancer death worldwide due to its high rates of tumor recurrence and metastasis. Aberrant Wnt/β-catenin signaling has been shown to play a significant role in HCC development, progression and clinical impact on tumor behavior. Accumulating evidence has revealed the critical involvement of Wnt/β-catenin signaling in driving cancer stemness and metabolic reprogramming, which are regarded as emerging cancer hallmarks. In this review, we summarize the regulatory mechanism of Wnt/β-catenin signaling and its role in HCC. Furthermore, we provide an update on the regulatory roles of Wnt/β-catenin signaling in metabolic reprogramming, cancer stemness and drug resistance in HCC. We also provide an update on preclinical and clinical studies targeting Wnt/β-catenin signaling alone or in combination with current therapies for effective cancer therapy. This review provides insights into the current opportunities and challenges of targeting this signaling pathway in HCC.
    Keywords:  Wnt/β-catenin; cancer metabolism; drug resistance; hepatocellular carcinoma; metabolic reprogramming
    DOI:  https://doi.org/10.3390/cancers14215468
  81. Biomaterials. 2022 Oct 27. pii: S0142-9612(22)00520-8. [Epub ahead of print]291 121880
    Disulfiram loaded calcium phosphate nanoparticles for enhanced cancer immunotherapy.
    Qiaofeng Li, Yu Chao, Bo Liu, Zhisheng Xiao, Zhijuan Yang, Yuzhe Wu, Zhuang Liu.
      Considering the huge cost and long test periods required for new drug development, repurposing drugs that have already been applied in the clinic as new cancer treatment candidates represents an attractive alternative. Disulfiram (DSF) was originally used to treat alcoholism and has proven to have anticancer effects with the coadministration of copper ions (Cu2+). However, the limited water-solubility of DSF and systemic toxicity induced by exogenous Cu2+ hinder its practical application. Herein, we constructed pH-responsive lipid-coated calcium phosphate nanoparticles (LCP NPs) co-loaded with Cu2+ and DSF. After intravenous injection, those nanoparticles with long blood half-life preferentially accumulate in tumors, followed by the degradation of nanoparticles in response to the acidic tumor microenvironment, subsequently releasing Cu2+ and DSF to generate cytotoxic metabolite DTC-Copper complex, bis(diethyldithiocarbamate)-copper (CuET) for tumor treatment. In addition to direct cytotoxicity, the active metabolite CuET could effectively induce immunogenic cell death (ICD) of cancer cells to regulate the immunosuppressive tumor microenvironment, contributing to enhanced immune checkpoint blockade (ICB) therapy in triggering systemic immune responses. This work thus demonstrates the great promises of repurposing the old drug DSF as a new ICD inducer with nano-formulation, to achieve improved synergetic tumor-responsive therapy with low side effects.
    Keywords:  Chemotherapy; Disulfiram; Immunogenic cell death; Immunotherapy; Nanomedicine
    DOI:  https://doi.org/10.1016/j.biomaterials.2022.121880
  82. Biomater Sci. 2022 Nov 07.
    Nano-integrated cascade antioxidases opsonized by albumin bypass the blood-brain barrier for treatment of ischemia-reperfusion injury.
    Wuxuan Wang, Zheng Zhang, Yi Liu, Lingqi Kong, Wenyu Li, Wei Hu, Yucai Wang, Xinfeng Liu.
      Potent antioxidative drugs are urgently needed to treat ischemia-reperfusion (I/R) induced reactive oxygen species (ROS)-mediated cerebrovascular and neural injury during ischemia strokes. However, current antioxidative agents have limited application in such disease due to low blood-brain barrier (BBB) penetration. We herein designed a "neutrophil piggybacking" strategy based on albumin opsonized nanoparticles co-encapsulated with antioxidases catalase (CAT) and superoxide dismutase 1 (SOD1). The system utilized the natural potential of neutrophils to target inflamed tissues to deliver antioxidases to injured sites in the brain. In addition, the system was integrated with a selenium (Se)-containing crosslinker to inhibit ferroptosis. We showed that the nanoparticles opsonized in the hybrid form rather than with an albumin-shell structure exhibited enhanced neutrophil targeting and efficient BBB penetration in vitro and in vivo. We further showed that the neutrophil-mediated delivery of antioxidases effectively reduced oxidative damage and apoptosis of neurons in brain tissue in a transient middle cerebral artery occlusion (tMCAO) mouse model. Moreover, the successful delivery of Se with the nanoparticles increased the expression of glutathione peroxidase 4 (GPX4) and effectively inhibited neuronal ferroptosis, achieving a satisfactory neuroprotective effect in I/R injury mice. Our study demonstrated that the rationally designed nanomedicines using the "neutrophil piggybacking" strategy can efficiently penetrate the BBB, greatly expanding the application of nanomedicines in the treatment of central nervous system (CNS) diseases.
    DOI:  https://doi.org/10.1039/d2bm01401g
  83. Drug Dev Ind Pharm. 2022 Nov 12. 1-28
    Fabrication and analysis of chitosan oligosaccharide based mucoadhesive patch for oromucosal drug delivery.
    Ashwini Kumar, Ram Kumar Sahu, Shibu Chameettachal, Falguni Pati, Awanish Kumar.
      OBJECTIVE: Fabrication and analyses of mucoadhesive patches made from chitosan oligosaccharide for the purpose of oromucosal drug delivery.SIGNIFICANCE: The mucosal epithelium in the oral cavity, consisting of buccal and sublingual epithelium, has gained significant attention in the last decade as an alternative anatomical site for systemic drug delivery that could potentially minimize the challenges of solid oral dosage and parenteral delivery. In this study, we have fabricated and tested drug-loaded chitosan oligosaccharide-based patches for the oromucosal drug delivery.
    METHODS: The chitosan oligosaccharide (with and without alginate) based patches were fabricated using the conventional solvent casting method and were analyzed for their swelling capacity, hydrophilicity, anti-cancer activity, in vitro drug release, and in vivo drug release activity. The in-house developed artificial saliva was used for the swelling study.
    RESULTS: Alginate-containing patches showed lesser swelling ability compared to the bare chitosan oligosaccharide-based patches. The former was also found to be more hydrophobic compared to the latter one. Both the unloaded patches restricted the growth of epithelial cancer cells indicating their anti-cancer behavior. In vitro drug release indicated a super case II release pattern while in vivo study demonstrated the release of drug from the patch into the plasma indicating the purpose of the fabricated patch.
    CONCLUSIONS: The chitosan oligosaccharide-based mucoadhesive hydrogel patch fabricated in this study can be highly suitable for possible translational purposes.
    Keywords:  Buccal patch; Chitosan oligosaccharide; Drug delivery; Mucoadhesion; Therapeutic potential
    DOI:  https://doi.org/10.1080/03639045.2022.2146705
  84. Food Sci Nutr. 2022 Nov;10(11): 3531-3543
    Curcumin: A dietary phytochemical for boosting exercise performance and recovery.
    Mohammad Nosrati-Oskouie, Nazanin Sadat Aghili-Moghaddam, Omid Mohammad Tavakoli-Rouzbehani, Tannaz Jamialahmadi, Thomas P Johnston, Amirhossein Sahebkar.
      Curcumin, as the main natural compound in the turmeric plant (Curcuma longa), is a yellowish polyphenol that has been used traditionally in Asian countries as a medicinal herb for various types of disease and pathological conditions caused by inflammation and oxidative stress. In the present review, we conducted a comprehensive literature search for evidence that shows the effect of curcumin on factors influencing exercise performance, including muscle damage, muscle soreness, inflammation, and oxidative stress. During exercise, reactive oxygen species and inflammation are increased. Thus, if there is no balance between endogenous and exogenous antioxidants and increases in oxidative stress and inflammation, which is important for maintaining redox homeostasis in skeletal muscle, it can lead to muscle soreness and muscle damage and ultimately result in reduced exercise performance. Due to the anti-oxidant and anti-inflammatory properties of curcumin, it can increase exercise performance and decrease exercise-induced muscle soreness and muscle damage. It appears that curcumin supplementation can have positive effects on exercise performance and recovery, muscle damage and pain, inflammation, and oxidative stress. However, there is still a need to precisely evaluate factors to more accurately assess/quantify the beneficial therapeutic effects of curcumin with regard to enhancing exercise performance and recovery.
    Keywords:  athletes; curcumin; exercise; metabolism
    DOI:  https://doi.org/10.1002/fsn3.2983
  85. Molecules. 2022 Nov 01. pii: 7410. [Epub ahead of print]27(21):
    Curcumin and Its Derivatives Induce Apoptosis in Human Cancer Cells by Mobilizing and Redox Cycling Genomic Copper Ions.
    Mohammed Ahmed Ismail Alhasawi, Mohammad Aatif, Ghazala Muteeb, Mir Waqas Alam, Mohamed El Oirdi, Mohd Farhan.
      Turmeric spice contains curcuminoids, which are polyphenolic compounds found in the Curcuma longa plant's rhizome. This class of molecules includes curcumin, demethoxycurcumin, and bisdemethoxycurcumin. Using prostate cancer cell lines PC3, LNCaP, DU145, and C42B, we show that curcuminoids inhibit cell proliferation (measured by MTT assay) and induce apoptosis-like cell death (measured by DNA/histone ELISA). A copper chelator (neocuproine) and reactive oxygen species scavengers (thiourea for hydroxyl radical, superoxide dismutase for superoxide anion, and catalase for hydrogen peroxide) significantly inhibit this reaction, thus demonstrating that intracellular copper reacts with curcuminoids in cancer cells to cause DNA damage via ROS generation. We further show that copper-supplemented media sensitize normal breast epithelial cells (MCF-10A) to curcumin-mediated growth inhibition, as determined by decreased cell proliferation. Copper supplementation results in increased expression of copper transporters CTR1 and ATP7A in MCF-10A cells, which is attenuated by the addition of curcumin in the medium. We propose that the copper-mediated, ROS-induced mechanism of selective cell death of cancer cells may in part explain the anticancer effects of curcuminoids.
    Keywords:  ROS; anticancer; copper; curcuminoids; pro-oxidant
    DOI:  https://doi.org/10.3390/molecules27217410
  86. Nat Commun. 2022 Nov 11. 13(1): 6835
    Near infrared-activatable biomimetic nanogels enabling deep tumor drug penetration inhibit orthotopic glioblastoma.
    Dongya Zhang, Sidan Tian, Yanjie Liu, Meng Zheng, Xiangliang Yang, Yan Zou, Bingyang Shi, Liang Luo.
      Glioblastoma multiforme (GBM) is one of the most fatal malignancies due to the existence of blood-brain barrier (BBB) and the difficulty to maintain an effective drug accumulation in deep GBM lesions. Here we present a biomimetic nanogel system that can be precisely activated by near infrared (NIR) irradiation to achieve BBB crossing and deep tumor penetration of drugs. Synthesized by crosslinking pullulan and poly(deca-4,6-diynedioic acid) (PDDA) and loaded with temozolomide and indocyanine green (ICG), the nanogels are inert to endogenous oxidative conditions but can be selectively disintegrated by ICG-generated reactive oxygen species upon NIR irradiation. Camouflaging the nanogels with apolipoprotein E peptide-decorated erythrocyte membrane further allows prolonged blood circulation and active tumor targeting. The precisely controlled NIR irradiation on tumor lesions excites ICG and deforms the cumulated nanogels to trigger burst drug release for facilitated BBB permeation and infiltration into distal tumor cells. These NIR-activatable biomimetic nanogels suppress the tumor growth in orthotopic GBM and GBM stem cells-bearing mouse models with significantly extended survival.
    DOI:  https://doi.org/10.1038/s41467-022-34462-8
  87. Int J Mol Sci. 2022 Oct 25. pii: 12866. [Epub ahead of print]23(21):
    Biophysical Evaluation of Water-Soluble Curcumin Encapsulated in β-Cyclodextrins on Colorectal Cancer Cells.
    Zhi Xuan Low, Michelle Yee Mun Teo, Fariza Juliana Nordin, Firli Rahmah Primula Dewi, Vijayaraj Kumar Palanirajan, Lionel Lian Aun In.
      Curcumin (CUR), a curcuminoid originating from turmeric root, possesses diverse pharmacological applications, including potent anticancer properties. However, the use of this efficacious agent in cancer therapy has been limited due to low water solubility and poor bioavailability. To overcome these problems, a drug delivery system was established as an excipient allowing improved dispersion in aqueous media coupled with enhanced in vitro anticancer effects. Different analyses such as UV-vis spectroscopy, differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), solubility and dissolution assays were determined to monitor the successful encapsulation of CUR within the inner cavity of a β-cyclodextrin (β-CD) complex. The results indicated that water solubility was improved by 205.75-fold compared to pure CUR. Based on cytotoxicity data obtained from MTT assays, the inclusion complex exhibited a greater decrease in cancer cell viability compared to pure CUR. Moreover, cancer cell migration rates were decreased by 75.5% and 38.92%, invasion rates were decreased by 37.7% and 35.7%, while apoptosis rates were increased by 26.3% and 14.2%, and both caused caspase 3 activation toward colorectal cancer cells (SW480 and HCT116 cells). This efficacious formulation that enables improved aqueous dispersion is potentially useful and can be extended for various chemotherapeutic applications. Preliminary toxicity evaluation also indicated that its composition can be safely used in humans for cancer therapy.
    Keywords:  anticancer; colorectal cancer; curcumin; cyclodextrin; encapsulation; inclusion complex; solubility
    DOI:  https://doi.org/10.3390/ijms232112866
  88. Molecules. 2022 Oct 23. pii: 7175. [Epub ahead of print]27(21):
    Uncovering the Anticancer Potential of Polydatin: A Mechanistic Insight.
    Muhammad Ajmal Shah, Ayesha Hamid, Hafiza Ishmal Faheem, Azhar Rasul, Tourki A S Baokbah, Muhammad Haris, Rimsha Yousaf, Uzma Saleem, Shabnoor Iqbal, Maria Silvana Alves, Zahid Khan, Ghulam Hussain, Ifat Alsharfi, Haroon Khan, Philippe Jeandet.
      Polydatin or 3-O-β-d-resveratrol-glucopyranoside (PD), a stilbenoid component of Polygonum cuspicadum (Polygonaceae), has a variety of biological roles. In traditional Chinese medicine, P. cuspicadum extracts are used for the treatment of infections, inflammation, and cardiovascular disorders. Polydatin possesses a broad range of biological activities including antioxidant, anti-inflammatory, anticancer, and hepatoprotective, neuroprotective, and immunostimulatory effects. Currently, a major proportion of the population is victimized with cervical lung cancer, ovarian cancer and breast cancer. PD has been recognized as a potent anticancer agent. PD could effectively inhibit the migration and proliferation of ovarian cancer cells, as well as the expression of the PI3K protein. The malignancy of lung cancer cells was reduced after PD treatments via targeting caspase 3, arresting cancer cells at the S phase and inhibiting NLRP3 inflammasome by downregulation of the NF-κB pathway. This ceases cell cycle, inhibits VEGF, and counteracts ROS in breast cancer. It also prevents cervical cancer by regulating epithelial-to-mesenchymal transition (EMT), apoptosis, and the C-Myc gene. The objective of this review is thus to unveil the polydatin anticancer potential for the treatment of various tumors, as well as to examine the mechanisms of action of this compound.
    Keywords:  3-O-β-d-resveratrol-glucopyranoside; breast cancer; cervical cancer; lung cancer; ovarian cancer; phenol compounds; polydatin
    DOI:  https://doi.org/10.3390/molecules27217175
  89. J Biomater Sci Polym Ed. 2022 Nov 08. 1-20
    Folic acid engineered sulforaphane loaded microbeads for targeting breast cancer.
    Zafar Khan, Abdulsalam Alhalmi, Neha Tyagi, Wasi Uzzaman Khan, Afsana Sheikh, Mohammed A S Abourehab, Kanchan Kohli, Prashant Kesharwani.
      Non-targeted cancer therapy poses a huge risk to the cancer patients' life due to high toxicity offered by chemotherapy. Breast carcinoma is one of such deleterious disease, demanding a highly effectual treatment option which could reduce the toxicity and extend survival rate. Since, folate receptors extensively display themselves on the cancer cell surface, targeting them would help to ameliorate the progression and metastasis. Considering this, we envisaged and developed sulforaphane loaded folate engineered microbeads to target breast cancer cells over-expressing folate receptors. The surface engineered microbeads were optimized and developed using emulsion gelation technique, among which the best developed preparation demonstrated the particle size of 1302 ± 3.98 µm, % EE of 84.1 ± 3.32% and in vitro drug release of 98.1 ± 4.42%@24h. The spherical sized microbead showed controlled release with improved haem-compatibility in comparison to the bare drug. Free radical scavenging activity by ABTS assay showed strong anti-oxidant activity (IC50-20.62 µg/ml) of the targeted microbeads with profound cancer cell suppressing effect ((IC50-17.48 ± 3.5 µM) as observed in MCF-7 cells by MTT assay. Finally, in comparison to lone SFN, the targeted therapy showed enhanced uptake by the intestinal villi indicating a suitable oral targeted therapy against breast carcinoma.
    Keywords:  : Breast Cancer; folate-targeted; microbeads; sulforaphane; targeted drug delivery
    DOI:  https://doi.org/10.1080/09205063.2022.2144692
  90. Int J Pharm. 2022 Nov 06. pii: S0378-5173(22)00930-9. [Epub ahead of print] 122375
    Development and assessment of phospholipid-based luteolin-loaded lipid nanocapsules for skin delivery.
    Mohammed Elmowafy, Khaled Shalaby, Mohammed H Elkomy, Omar Awad Alsaidan, Hesham A M Gomaa, Mohamed A Abdelgawad, Diaa Massoud, Ayman Salama, Khalid M El-Say.
      Luteolin is an excellent flavone possessing several beneficial properties such as antioxidant and anti-inflammatory effects which are interesting for skin delivery. Development of an appropriate skin delivery system could be a promising strategy to improve luteolin cutaneous performance.So, the main aim of this work was to fabricate, characterize and evaluate phospholipid-based luteolin-loaded lipid nanocapsules for skin delivery. The influence of phospholipid/oil ratio, surfactant type and chitosan coating were investigated. The prepared formulations underwent in vitro assessment and the selected formulations were evaluated ex vivo and in vivo. The mean diameters of investigated formulations varied between 174 nm and 628 nm while zeta potential varied between -25.7±4.8 mV and 6.8±1.7 mV. Increasing in phospholipid/oil ratios resulted in decrease in particles size with little effect on zeta potential and drug encapsulation. Cremophor EL showed the lowest particle sizes and the highest drug encapsulation. Chitosan coating shifted zeta potential towards positive values. Structural analyses showed that luteolin is incorporated into lipid core of nanocapsules. Selected formulations (LNC4 and LNC13) exhibited sustained in vitro release and antioxidant activity. LNC13 (chitosan coated) showed higher flux (0.457±0.113 µg/cm2/h), permeability (45.70±11.66 *10-5 cm2/h) and skin retention (121.66 ± 7.6 µg/cm2 after 24h) when compared to LNC4 and suspension. It also showed disordered the integrity of the stratum corneum, increased epidermal thickness and relieving most of inflammatory features in animal model. In conclusion, this study proves that lipid nanocapsules could effectively deliver luteolin into skin and then can be established as a potential system in the pharmaceutical and cosmeceutical horizons.
    Keywords:  Anti-inflammatory; LNCs; Luteolin; Skin penetration
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.122375
  91. Nanomaterials (Basel). 2022 Nov 01. pii: 3855. [Epub ahead of print]12(21):
    Recent Advances in the Development of Lipid-, Metal-, Carbon-, and Polymer-Based Nanomaterials for Antibacterial Applications.
    Ruohua Ren, Chiaxin Lim, Shiqi Li, Yajun Wang, Jiangning Song, Tsung-Wu Lin, Benjamin W Muir, Hsien-Yi Hsu, Hsin-Hui Shen.
      Infections caused by multidrug-resistant (MDR) bacteria are becoming a serious threat to public health worldwide. With an ever-reducing pipeline of last-resort drugs further complicating the current dire situation arising due to antibiotic resistance, there has never been a greater urgency to attempt to discover potential new antibiotics. The use of nanotechnology, encompassing a broad range of organic and inorganic nanomaterials, offers promising solutions. Organic nanomaterials, including lipid-, polymer-, and carbon-based nanomaterials, have inherent antibacterial activity or can act as nanocarriers in delivering antibacterial agents. Nanocarriers, owing to the protection and enhanced bioavailability of the encapsulated drugs, have the ability to enable an increased concentration of a drug to be delivered to an infected site and reduce the associated toxicity elsewhere. On the other hand, inorganic metal-based nanomaterials exhibit multivalent antibacterial mechanisms that combat MDR bacteria effectively and reduce the occurrence of bacterial resistance. These nanomaterials have great potential for the prevention and treatment of MDR bacterial infection. Recent advances in the field of nanotechnology are enabling researchers to utilize nanomaterial building blocks in intriguing ways to create multi-functional nanocomposite materials. These nanocomposite materials, formed by lipid-, polymer-, carbon-, and metal-based nanomaterial building blocks, have opened a new avenue for researchers due to the unprecedented physiochemical properties and enhanced antibacterial activities being observed when compared to their mono-constituent parts. This review covers the latest advances of nanotechnologies used in the design and development of nano- and nanocomposite materials to fight MDR bacteria with different purposes. Our aim is to discuss and summarize these recently established nanomaterials and the respective nanocomposites, their current application, and challenges for use in applications treating MDR bacteria. In addition, we discuss the prospects for antimicrobial nanomaterials and look forward to further develop these materials, emphasizing their potential for clinical translation.
    Keywords:  antimicrobial; drug delivery systems; multidrug-resistant bacteria; nanomaterials; nanoparticles
    DOI:  https://doi.org/10.3390/nano12213855
  92. Recent Pat Anticancer Drug Discov. 2022 Nov 04.
    Prospective challenges for patenting and clinical trials of anticancer compounds from natural products: Coherent review.
    Ankit Sahoo, Ashok Kumar Mandal, Mayank Kumar, Khusbu Dwivedi, Deepika Singh.
      Cancer is a leading cause of morbidity and mortality worldwide. Each year, millions of people worldwide are diagnosed with cancer, and more than half of them die. Various conventional therapies for cancer, including chemotherapy and radiotherapy, have extreme side effects. Therefore, to minimize the global burden of lethal diseases like cancer, an effective and novel drug must be discovered. Its patent should be acquired to secure the novel in medicament. The pharmacological potential of different natural products has made them popular in the healthcare and pharmaceutical industries. Various anticancer compounds are obtained from natural sources such as plants, microbes, and marine and terrestrial animals, including alkaloids, terpenoids, biophenols, enzymes, glycosides, etc. The term "natural products" is defined as the product of secondary or non-essential metabolic processes produced by living organisms (such as plants, invertebrates, and microorganisms). Although more precise definitions of NPs exist, they do not always meet consensus. Others define NPs as small molecules (excluding biomolecules) that emerge from the metabolic reaction. A handful of effective compounds are used currently from natural or analogs moieties, and many more are in clinical studies. There is an excellent need for patenting molecules from natural products as the hit lead molecules are derived, isolated, and synthesized from natural products. However, these naturally occurring products may not be patentable under the law because they come from nature. This review highlights why natural products and compounds are hard to patent, under what patent law criteria we can patent these natural products and compounds, patent procedural guideline sources and why researchers prefer publication rather than a patent. Here, various patent scenarios of natural products and compounds for cancer have been given.
    Keywords:  Natural products; Patent; anticancer compounds; challenges; clinical trial; criteria; marketed product
    DOI:  https://doi.org/10.2174/1574892818666221104113703
  93. J Cell Biochem. 2022 Nov 05.
    Lipid metabolism reprogramming in colorectal cancer.
    Dan Chen, Xuebing Zhou, PengYu Yan, Chunyu Yang, Yuan Li, Longzhe Han, Xiangshan Ren.
      The hallmark feature of metabolic reprogramming is now considered to be widespread in many malignancies, including colorectal cancer (CRC). Of the gastrointestinal tumors, CRC is one of the most common with a high metastasis rate and long insidious period. The incidence and mortality of CRC has increased in recent years. Metabolic reprogramming also has a significant role in the development and progression of CRC, especially lipid metabolic reprogramming. Many studies have reported that lipid metabolism reprogramming is similar to the Warburg effect with typical features affecting tumor biology including proliferation, migration, local invasion, apoptosis, and other biological behaviors of cancer cells. Therefore, studying the role of lipid metabolism in the occurrence and development of CRC will increase our understanding of its pathogenesis, invasion, metastasis, and other processes and provide new directions for the treatment of CRC. In this paper, we mainly describe the molecular mechanism of lipid metabolism reprogramming and its important role in the occurrence and development of CRC. In addition, to provide reference for subsequent research and clinical diagnosis and treatment we also review the treatments of CRC that target lipid metabolism.
    Keywords:  colorectal cancer; lipid metabolism reprogramming; metastasis; proliferation; targeted drugs
    DOI:  https://doi.org/10.1002/jcb.30347
  94. Crit Rev Food Sci Nutr. 2022 Nov 08. 1-19
    The fate of flaxseed-lignans after oral administration: A comprehensive review on its bioavailability, pharmacokinetics, and food design strategies for optimal application.
    Abdul Mueed, Muhammad Ibrahim, Sahar Shibli, Philippe Madjirebaye, Zeyuan Deng, Muhammad Jahangir.
      Lignans are one of the most important and abundant phytochemicals found in flaxseed-diets. These have shown to possess several health-benefits, including anticancer, antioxidant, neuroprotective, cardioprotective, and estrogenic-properties etc. The potential of lignans health-promoting effects are circumscribed due to their poor-bioavailability resulting from their bound structure. Recent studies have demonstrated that various food design strategies can enhance the release of bound-lignans from agro-industrial residues, resulting in a higher bioaccessibility and bioavailability. This review focuses primarily on the bioavailability of flaxseed lignans, key factors affecting it and their pharmacokinetics, different strategies to improve the contents of lignans, their release and delivery. Present study will help to deepen our understanding of the applications of lignans and their dietary-supplements in the prevention and treatment of diseases. Several absorption issues of lignans have been observed such as impaired-bioavailability and variability in pharmacokinetics and pharmacodynamics. Therefore, the development of novel strategies for optimizing lignan bioavailability is critical to ensure its successful application, such as the delivery of lignans to biological targets via "targeted designs." In addition, some detailed examination is required to identify and understand the basis of variation in lignans bioavailability caused by interactions with the gastrointestinal system.
    Keywords:  Flaxseed lignans; bioavailability; composition; pharmacokinetics; solubility and bioaccessibility; structure
    DOI:  https://doi.org/10.1080/10408398.2022.2140643
  95. Adv Mater. 2022 Nov 10. e2207951
    Lactate Oxidase-Instructed Cancer Diagnosis and Therapy.
    Shanshan Jiang, Xin Chen, Jing Lin, Peng Huang.
      Lactate oxidase (LOx) has attracted extensive interest in cancer diagnosis and therapy in recent years owing to its specific catalysis on L-lactate, its catalytic process consumes oxygen (O2 ) and generates a large amount of hydrogen peroxide (H2 O2 ) and pyruvate. Given high levels of lactate in tumor tissues and its tight correlation with tumor growth, metastasis, and recurrence, LOx-based biosensors including H2 O2 -based, O2 -based, pH-sensitive, and electrochemical have been designed for cancer diagnosis, and various LOx-based cancer therapy strategies including lactate depletion based metabolic cancer therapy/immunotherapy, hypoxia activated chemotherapy, H2 O2 based chemodynamic therapy, and multimodal synergistic cancer therapy have also been developed. In this review, the lactate-specific catalytic properties of LOx are introduced, and the recent advances on LOx-instructed cancer diagnostic or therapeutic platforms and corresponding biological applications are summarized. Additionally, the challenges and potential of LOx-based nanomedicines are highlighted. This article is protected by copyright. All rights reserved.
    Keywords:  L-lactate; cancer; diagnosis; lactate oxidase; therapy
    DOI:  https://doi.org/10.1002/adma.202207951
  96. Front Bioeng Biotechnol. 2022 ;10 984424
    Advances in the research of nano delivery systems in ischemic stroke.
    Yi-Xuan Li, Hong-Bo Wang, Jian-Bo Jin, Chun-Lin Yang, Jing-Bo Hu, Jing Li.
      Ischemic stroke is the most common type of cerebrovascular disease with high disability rate and mortality. The blood-brain barrier (BBB) protects the homeostasis of the brain's microenvironment and impedes the penetration of 98% of drugs. Therefore, effective treatment requires the better drug transport across membranes and increased drug distribution. Nanoparticles are a good choice for drugs to cross BBB. The main pathways of nano delivery systems through BBB include passive diffusion, adsorption-mediated endocytosis, receptor-mediated transport, carrier-mediated transport, etc. At present, the materials used in brain-targeted delivery can be divided into natural polymer, synthetic polymers, inorganic materials and phospholipid. In this review, we first introduced several ways of nano delivery systems crossing the BBB, and then summarized their applications in ischemic stroke. Based on their potential and challenges in the treatment of ischemic stroke, new ideas and prospects are proposed for designing feasible and effective nano delivery systems.
    Keywords:  blood-brain barrier; endogenous vesicles; ischemic stroke; nano delivery system; polymer
    DOI:  https://doi.org/10.3389/fbioe.2022.984424
  97. Curr Drug Deliv. 2022 Nov 08.
    Physical characterization and safety evaluation of folic acid-conjugated mesoporous silica nanoparticles loaded with Rhodojaponin III.
    Qingyun Yang, Chuncao Zhao, Jian Yang, Jingyi Zhao, Minchen Liu, Jiquan Zhang.
      BACKGROUND: Rhodojaponin III (RJ-III), a characteristic diterpene of Rhododendron molle G. Don, has a wide range of pharmacological activities including anti-inflammatory, antihypertensive, and analgesic effects. However, further research and development has been limited because of its intense acute toxicity and poor pharmacokinetic profile.OBJECTIVE: In this study, we propose the construction of folic acid-conjugated mesoporous silica nanoparticles (FA-MSNs) as carriers to deliver RJ-III in an attempt to reduce the acute toxicity and improve biomedical applications by prolonging drug release and targeting delivery.
    METHODS: FA-MSNs were synthesized and characterized. RJ-III was then loaded into FA-MSNs (RJ-III@FA-MSNs), and the in vitro drug release profile was assessed. Subsequently, the RJ-III@FA-MSNs' cytotoxicity and targeting efficiency were explored in lipopolysaccharide-activated RAW 264.7 cells, and their acute toxicity was investigated in mice.
    RESULTS: Spherical FA-MSNs were approximately 122 nm in size. Importantly, the RJ-III@FA-MSNs showed prolonged RJ-III release in vitro. Moreover, in lipopolysaccharide-activated RAW 264.7 cells, RJ-III@FA-MSNs not only reduced the cytotoxicity of RJ-III (P < 0.01), but also showed a good targeting effect from the results of cellular uptake. Additionally, the acute toxicity results demonstrated that RJ-III@FA-MSNs improved the LD50 value of RJ-III in mice by intraperitoneal injection 10-fold.
    CONCLUSION: This is the first study to use FA-MSNs as carriers of RJ-III to reduce the acute toxicity of RJ-III. The results confirm the potential for targeted delivery of RJ-III in inflammatory cells to enhance efficacy, as well as providing data for future investigations on anti-inflammatory activity.
    Keywords:  Rhodojaponin-III; cellular uptake; folic acid; mesoporous silica nanoparticles; safety evaluation; sustained release.
    DOI:  https://doi.org/10.2174/1567201820666221108121347
  98. Int J Biol Macromol. 2022 Nov 07. pii: S0141-8130(22)02504-1. [Epub ahead of print]
    Fabrication of chitosan-gelatin films incorporated with thymol-loaded alginate microparticles for controlled drug delivery, antibacterial activity and wound healing: In-vitro and in-vivo studies.
    Azin Rashidy Ahmady, Kavoos Razmjooee, Saeed Saber-Samandari, Davood Toghraie.
      Previously, studies have demonstrated the unique characteristics of chitosan-gelatin films as wound dressings applications. However, their application has been limited due to their inadequacy of antimicrobial and anti-inflammatory characteristics. To improve the intended multifunctional characteristics of chitosan-gelatin film, in this study, we designed a novel composite film with the capability of controlled and prolonged release of thymol as a natural antioxidant and antimicrobial drug. Here, thymol-loaded ALG MPs (Thymol-ALG MPs) were prepared by electrospraying method and incorporated into the chitosan-gelatin film. The composite wound dressings of Thymol-ALG MPs incorporated in chitosan-gelatin film (CS-GEL/Thymol-ALG MPs) were characterized by in vitro and in vivo evaluations. The Thymol-ALG MPs demonstrated spherical and uniform morphology, with high encapsulation efficiency (88.9 ± 1.1 %). The CS-GEL/Thymol-ALG MPs exhibited high antibacterial activity against both Gram-positive and Gram-negative bacteria and no cytotoxicity for the L929 fibroblast cells. The release trend of thymol from CS-GEL/Thymol-ALG MPs and Thymol-ALG MPs followed a pseudo-Fickian diffusion mechanism. This wound dressing effectively accelerates the wound healing process at rats' full-thickness skin excisions. Also, the histological analysis demonstrated that the CS-GEL/Thymol-ALG MPs could significantly enhance epithelialization, collagen deposition, and induce skin regeneration. The present antibacterial composite film has promising characteristics for wound dressings applications.
    Keywords:  Alginate; Antibacterial; Chitosan; Drug delivery; Gelatin; Wound dress
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.10.249
  99. Nutrients. 2022 Oct 27. pii: 4512. [Epub ahead of print]14(21):
    Vitamin D in Cancer Prevention: Gaps in Current Knowledge and Room for Hope.
    Matthias Henn, Victor Martin-Gorgojo, Jose M Martin-Moreno.
      Intensive epigenome and transcriptome analyses have unveiled numerous biological mechanisms, including the regulation of cell differentiation, proliferation, and induced apoptosis in neoplastic cells, as well as the modulation of the antineoplastic action of the immune system, which plausibly explains the observed population-based relationship between low vitamin D status and increased cancer risk. However, large randomized clinical trials involving cholecalciferol supplementation have so far failed to show the potential of such interventions in cancer prevention. In this article, we attempt to reconcile the supposed contradiction of these findings by undertaking a thorough review of the literature, including an assessment of the limitations in the design, conduct, and analysis of the studies conducted thus far. We examine the long-standing dilemma of whether the beneficial effects of vitamin D levels increase significantly above a critical threshold or if the conjecture is valid that an increase in available cholecalciferol translates directly into an increase in calcitriol activity. In addition, we try to shed light on the high interindividual epigenetic and transcriptomic variability in response to cholecalciferol supplementation. Moreover, we critically review the standards of interpretation of the available study results and propose criteria that could allow us to reach sound conclusions in this field. Finally, we advocate for options tailored to individual vitamin D needs, combined with a comprehensive intervention that favors prevention through a healthy environment and responsible health behaviors.
    Keywords:  calcitriol; cancer incidence; cancer mortality; cancer prevention; cancer prognosis; evidence-based medicine; nutritional assessment; nutritional intervention; preventive medicine; vitamin D
    DOI:  https://doi.org/10.3390/nu14214512
  100. Adv Pharmacol Pharm Sci. 2022 ;2022 1850732
    Antiproliferative Effects of Ferulic, Coumaric, and Caffeic Acids in HepG2 Cells by hTERT Downregulation.
    Afsoon Afshari, Mahmoodreza Moein, Afshin Afsari, Zahra Sabahi.
      Objective: Phenolic acids are well-known phytochemicals that are detected in a wide variety of medicinal plants, and their antiproliferative effects on cancer cells are known, but their mechanisms are poorly revealed. In most of cancer cells, telomerase reverse transcriptase (hTERT) is a dominant factor of telomere length regulation. The hTERT expression promotes invasiveness in tumor cells and is a hallmark of cancer. Therefore, in this study, the probable inhibitory effects of caffeic (Caf), coumaric (Cum), and ferulic acids (Fer) are investigated on the hTERT expression pattern in HepG2 cells.Methods: The MTT, apoptosis assays, and real-time PCR analysis were applied to evaluate viability, cytotoxicity, and hTERT gene expression level, respectively.
    Results: All of the studied phenolic acids showed cytotoxic effects on HepG2 cells in a timely manner and presented a time-dependent inhibitory effect on the growth of HepG2 cells. They reduced percentage of viable cells and induced apoptosis. Also, these phenolic acids had significant inhibitory effects on hTERT gene expression.
    Conclusion: These findings suggest that cell viability along with hTERT gene expression in HepG2 cells could be reduced by Cum, Caf, and Fer. As different cancer cells are resistant to conventional chemotherapeutics, this type of results proposes the telomerase as a proper target of cancer therapy development by natural products.
    DOI:  https://doi.org/10.1155/2022/1850732
  101. Molecules. 2022 Oct 31. pii: 7405. [Epub ahead of print]27(21):
    Pectin: A Bioactive Food Polysaccharide with Cancer Preventive Potential.
    Talha Bin Emran, Fahadul Islam, Saikat Mitra, Shyamjit Paul, Nikhil Nath, Zidan Khan, Rajib Das, Deepak Chandran, Rohit Sharma, Clara Mariana Gonçalves Lima, Ahmed Abdullah Al Awadh, Ibrahim Abdullah Almazni, Abdulaziz Hassan Alhasaniah, Raquel P F Guiné.
      Pectin is an acidic heteropolysaccharide found in the cell walls and the primary and middle lamella of land plants. To be authorized as a food additive, industrial pectins must meet strict guidelines set forth by the Food and Agricultural Organization and must contain at least 65% polygalacturonic acid to achieve the E440 level. Fruit pectin derived from oranges or apples is commonly used in the food industry to gel or thicken foods and to stabilize acid-based milk beverages. It is a naturally occurring component and can be ingested by dietary consumption of fruit and vegetables. Preventing long-term chronic diseases like diabetes and heart disease is an important role of dietary carbohydrates. Colon and breast cancer are among the diseases for which data suggest that modified pectin (MP), specifically modified citrus pectin (MCP), has beneficial effects on the development and spread of malignancies, in addition to its benefits as a soluble dietary fiber. Cellular and animal studies and human clinical trials have provided corroborating data. Although pectin has many diverse functional qualities, this review focuses on various modifications used to develop MP and its benefits for cancer prevention, bioavailability, clinical trials, and toxicity studies. This review concludes that pectin has anti-cancer characteristics that have been found to inhibit tumor development and proliferation in a wide variety of cancer cells. Nevertheless, further clinical and basic research is required to confirm the chemopreventive or therapeutic role of specific dietary carbohydrate molecules.
    Keywords:  apoptosis; cancer; food polysaccharide; modified citrus pectin; pectin
    DOI:  https://doi.org/10.3390/molecules27217405
  102. Front Bioeng Biotechnol. 2022 ;10 955127
    MnO2 coated multi-layer nanoplatform for enhanced sonodynamic therapy and MR imaging of breast cancer.
    Yan Xu, Wanlin Tan, Mingyu Chen, Sijie Chen, Kui Tang, Haiqin Liao, Chengcheng Niu.
      Sonodynamic therapy (SDT) is a promising new anti-tumor therapy that inhibits tumor growth by ultrasound activation of sonosensitizers to produce reactive oxygen species (ROS). However, the problems of hypoxia in the microenvironment within solid tumors and the effectiveness of SDT will decrease due to the little accumulation of sonosensitizers at the tumor site, as well as tumor cell tolerance, have limited the development of SDT. To overcome these problems, a core-shell structured nanoparticle (IR780/PLGA@MnO2 NPs) loaded with IR780 and manganese dioxide (MnO2) was developed as a nanocarrier to transport the sonosensitizer IR780 and the generated oxygen into the tumor tissue. The MnO2 shell layer of IR780/PLGA@MnO2 NPs can prevent the premature release of IR780 in the blood and also it can react with acidic and high H2O2, the generated oxygen can relieve tumor tissue hypoxia, and the generated Mn can enhance magnetic resonance imaging (MRI) signal intensity by acting as a contrast agent for MRI. More importantly, the released IR780 can produce ROS to kill tumor cells under ultrasound excitation. This PH-responsive and H2O2-triggered SDT based on the IR780/PLGA@MnO2NPs is an effective platform to inhibit tumor growth with negligible systemic toxicity. This work develops a multifunctional therapeutic integrated nanoplatform for breast cancer treatment, which is expected to be used in the clinic.
    Keywords:  magnetic resonance imaging; manganese dioxide; reactive oxygen species; sonodynamic therapy; tumor hypoxia
    DOI:  https://doi.org/10.3389/fbioe.2022.955127
  103. Polymers (Basel). 2022 Oct 26. pii: 4539. [Epub ahead of print]14(21):
    Self-Healing Hydrogels: Development, Biomedical Applications, and Challenges.
    Md Mahamudul Hasan Rumon, Anwarul Azim Akib, Fahmida Sultana, Md Moniruzzaman, Mahruba Sultana Niloy, Md Salman Shakil, Chanchal Kumar Roy.
      Polymeric hydrogels have drawn considerable attention as a biomedical material for their unique mechanical and chemical properties, which are very similar to natural tissues. Among the conventional hydrogel materials, self-healing hydrogels (SHH) are showing their promise in biomedical applications in tissue engineering, wound healing, and drug delivery. Additionally, their responses can be controlled via external stimuli (e.g., pH, temperature, pressure, or radiation). Identifying a suitable combination of viscous and elastic materials, lipophilicity and biocompatibility are crucial challenges in the development of SHH. Furthermore, the trade-off relation between the healing performance and the mechanical toughness also limits their real-time applications. Additionally, short-term and long-term effects of many SHH in the in vivo model are yet to be reported. This review will discuss the mechanism of various SHH, their recent advancements, and their challenges in tissue engineering, wound healing, and drug delivery.
    Keywords:  drug delivery; hydrogel; mechanical properties; modulus; self-healing; tissue engineering
    DOI:  https://doi.org/10.3390/polym14214539
  104. RSC Adv. 2022 Oct 27. 12(48): 31068-31082
    Nanotechnology strategies for hepatocellular carcinoma diagnosis and treatment.
    WeiLu Jia, YingHui Han, XinYu Mao, WenJing Xu, YeWei Zhang.
      Hepatocellular carcinoma (HCC) is a common malignancy threatening human health, and existing diagnostic and therapeutic techniques are facing great challenges. In the last decade or so, nanotechnology has been developed and improved for tumor diagnosis and treatment. For example, nano-intravenous injections have been approved for malignant perivascular epithelioid cell tumors. This article provides a comprehensive review of the applications of nanotechnology in HCC in recent years: (I) in radiological imaging, magnetic resonance imaging (MRI), fluorescence imaging (FMI) and multimodality imaging. (II) For diagnostic applications in HCC serum markers. (III) As embolic agents in transarterial chemoembolization (TACE) or directly as therapeutic drugs. (IV) For application in photothermal therapy and photodynamic therapy. (V) As carriers of chemotherapeutic drugs, targeted drugs, and natural plant drugs. (VI) For application in gene and immunotherapy. Compared with the traditional methods for diagnosis and treatment of HCC, nanoparticles have high sensitivity, reduce drug toxicity and have a long duration of action, and can also be combined with photothermal and photodynamic multimodal combination therapy. These summaries provide insights for the further development of nanotechnology applications in HCC.
    DOI:  https://doi.org/10.1039/d2ra05127c
  105. Polymers (Basel). 2022 Nov 06. pii: 4753. [Epub ahead of print]14(21):
    Chitosan-Boric Acid Scaffolds for Doxorubicin Delivery in the Osteosarcoma Treatment.
    Luka Dornjak, Marin Kovačić, Karla Ostojić, Ange Angaits, Joanna Szpunar, Inga Urlić, Anamarija Rogina.
      Biologically compatible chitosan-based scaffolds have been considered a promising platform for tissue regeneration, tumor treatment, and targeted drug delivery. Chitosan-based scaffolds can be utilized as pH-sensitive drug carriers with targeted drug delivery resulting in less invasive tumor treatments. Further improvement with bioactive ions, such as borate ions, can result in the dual functionality of chitosan carriers provided by simultaneous antitumor efficacy and tissue regeneration. Here, boric acid-containing crosslinked chitosan scaffolds were prepared as delivery systems of doxorubicin, a chemotherapy drug used in the treatment of osteosarcoma. The encapsulation of boric acid was indicated by FTIR spectroscopy, while the ICP-MS analysis indicated the rapid release of boron in phosphate buffer (pH 6.0) and phosphate-buffered saline solution (pH 7.4). The obtained chitosan-boric acid scaffolds exhibit a highly porous and interconnected structure responsible for high swelling capacity, while enzymatic degradation indicated good scaffolds stability during four weeks of incubation at pH 6.0 and 7.4. Furthermore, the release of doxorubicin investigated in phosphate buffers indicated lower doxorubicin concentrations at pH 7.4 with respect to pH 6.0. Finally, the cytotoxicity of prepared doxorubicin-encapsulated scaffolds was evaluated on human sarcoma cells indicating the scaffolds' potential as cytostatic agents.
    Keywords:  boric acid; chitosan; doxorubicin; osteosarcoma
    DOI:  https://doi.org/10.3390/polym14214753
  106. Antioxidants (Basel). 2022 Oct 24. pii: 2092. [Epub ahead of print]11(11):
    Sodium Thiosulphate-Loaded Liposomes Control Hydrogen Sulphide Release and Retain Its Biological Properties in Hypoxia-like Environment.
    Lissette Sanchez-Aranguren, Milda Grubliauskiene, Hala Shokr, Pavanjeeth Balakrishnan, Keqing Wang, Shakil Ahmad, Mandeep Kaur Marwah.
      Hypoxia, or insufficient oxygen availability is a common feature in the development of a myriad of cardiovascular-related conditions including ischemic disease. Hydrogen sulphide (H2S) donors, such as sodium thiosulphate (STS), are known for their cardioprotective properties. However, H2S due to its gaseous nature, is released and cleared rapidly, limiting its potential translation to clinical settings. For the first time, we developed and characterised liposome formulations encapsulating STS and explored their potential for modulating STS uptake, H2S release and the ability to retain pro-angiogenic and biological signals in a hypoxia-like environment mirroring oxygen insufficiency in vitro. Liposomes were prepared by varying lipid ratios and characterised for size, polydispersity and charge. STS liposomal encapsulation was confirmed by HPLC-UV detection and STS uptake and H2S release was assessed in vitro. To mimic hypoxia, cobalt chloride (CoCl2) was administered in conjunction with formulated and non-formulated STS, to explore pro-angiogenic and metabolic signals. Optimised liposomal formulation observed a liposome diameter of 146.42 ± 7.34 nm, a polydispersity of 0.22 ± 0.19, and charge of 3.02 ± 1.44 mV, resulting in 25% STS encapsulation. Maximum STS uptake (76.96 ± 3.08%) from liposome encapsulated STS was determined at 24 h. Co-exposure with CoCl2 and liposome encapsulated STS resulted in increased vascular endothelial growth factor mRNA as well as protein expression, enhanced wound closure and increased capillary-like formation. Finally, liposomal STS reversed metabolic switch induced by hypoxia by enhancing mitochondrial bioenergetics. These novel findings provide evidence of a feasible controlled-delivery system for STS, thus H2S, using liposome-based nanoparticles. Likewise, data suggests that in scenarios of hypoxia, liposomal STS is a good therapeutic candidate to sustain pro-angiogenic signals and retain metabolic functions that might be impaired by limited oxygen and nutrient availability.
    Keywords:  angiogenesis; controlled-release; drug delivery systems; hydrogen sulphide; liposomes; mitochondrial metabolism
    DOI:  https://doi.org/10.3390/antiox11112092
  107. Front Pharmacol. 2022 ;13 1046406
    Drug repurposing in cardiovascular inflammation: Successes, failures, and future opportunities.
    Laura Chaffey, Annabell Roberti, David R Greaves.
      Drug repurposing is an attractive, pragmatic approach to drug discovery that has yielded success across medical fields over the years. The use of existing medicines for novel indications enables dramatically reduced development costs and timescales compared with de novo drug discovery and is therefore a promising strategy in cardiovascular disease, where new drug approvals lag significantly behind that of other fields. Extensive evidence from pre-clinical and clinical studies show that chronic inflammation is a driver of pathology in cardiovascular disease, and many efforts have been made to target cardiovascular inflammation therapeutically. This approach has been met with significant challenges however, namely off-target effects associated with broad-spectrum immunosuppression, particularly in long-term conditions such as cardiovascular disease. Nevertheless, multiple anti-inflammatory medicines have been assessed for efficacy in cardiovascular clinical trials, with most of these being repurposed from their original indications in autoimmune conditions like rheumatoid arthritis. In this review, we discuss the mixed successes of clinical trials investigating anti-inflammatory drugs in cardiovascular disease, with examples such as anti-cytokine monoclonal antibodies, colchicine, and methotrexate. Looking to the future, we highlight potential new directions for drug repurposing in cardiovascular inflammation, including the emerging concepts of drug re-engineering and chrono-pharmacology.
    Keywords:  cardiovascular disease; chrono-pharmacology; drug delivery; drug reengineering; drug repurposing; inflammation
    DOI:  https://doi.org/10.3389/fphar.2022.1046406
  108. Cancers (Basel). 2022 Oct 29. pii: 5341. [Epub ahead of print]14(21):
    Medical Device Advances in the Treatment of Glioblastoma.
    Cher Ying Foo, Nimrah Munir, Ashwin Kumaria, Qasim Akhtar, Christopher J Bullock, Ashwin Narayanan, Richard Z Fu.
      Despite decades of research and the growing emergence of new treatment modalities, Glioblastoma (GBM) frustratingly remains an incurable brain cancer with largely stagnant 5-year survival outcomes of around 5%. Historically, a significant challenge has been the effective delivery of anti-cancer treatment. This review aims to summarize key innovations in the field of medical devices, developed either to improve the delivery of existing treatments, for example that of chemo-radiotherapy, or provide novel treatments using devices, such as sonodynamic therapy, thermotherapy and electric field therapy. It will highlight current as well as emerging device technologies, non-invasive versus invasive approaches, and by doing so provide a detailed summary of evidence from clinical studies and trials undertaken to date. Potential limitations and current challenges are discussed whilst also highlighting the exciting potential of this developing field. It is hoped that this review will serve as a useful primer for clinicians, scientists, and engineers in the field, united by a shared goal to translate medical device innovations to help improve treatment outcomes for patients with this devastating disease.
    Keywords:  GBM; Glioblastoma; blood-brain barrier (BBB); brachytherapy; convection enhanced delivery (CED); electric field therapy (EFT); laser interstitial therapy (LIT); magnetic hyperthermia; medical device; photodynamic therapy (PDT); sonodynamic; ultrasound
    DOI:  https://doi.org/10.3390/cancers14215341
  109. Molecules. 2022 Nov 01. pii: 7439. [Epub ahead of print]27(21):
    Recent Advances on Natural Aryl-C-glycoside Scaffolds: Structure, Bioactivities, and Synthesis-A Comprehensive Review.
    Chen-Fu Liu.
      Aryl-C-glycosides, of both synthetic and natural origin, are of great significance in medicinal chemistry owing to their unique structures and stability towards enzymatic and chemical hydrolysis as compared to O-glycosides. They are well-known antibiotics and potent enzyme inhibitors and possess a wide range of biological activities such as anticancer, antioxidant, antiviral, hypoglycemic effects, and so on. Currently, a number of aryl-C-glycoside drugs are on sale for the treatment of diabetes and related complications. This review summarizes the findings on aryl-C-glycoside scaffolds over the past 20 years, concerning new structures (over 200 molecules), their bioactivities-including anticancer, anti-inflammatory, antioxidant, antivirus, glycation inhibitory activities and other pharmacological effects-as well as their synthesis.
    Keywords:  aryl-C-glycoside; bioactivity; novel structures; synthesis
    DOI:  https://doi.org/10.3390/molecules27217439
  110. Nano Lett. 2022 Nov 07.
    Enhanced Sensitivity of Tumor Cells to Autophagy Inhibitors Using Fasting-Mimicking Diet and Targeted Lysosomal Delivery Nanoplatform.
    Ruihao Qian, Guoliang Cao, Wen Su, Jie Zhang, Yue Jiang, Haohao Song, Fuhao Jia, Hai Wang.
      Autophagy is one of the key pathways for tumor cell survival and proliferation. Therefore, inhibition of autophagy has been extensively studied for cancer therapy. However, current autophagy inhibitors lack specificity and are ineffective in limiting tumor progression. Herein, we report a nanoplatform for tumor-site-targeted delivery of hydroxychloroquine (HCQ) using insulin-like growth factors 2 receptor (IGF2R)-targeted liposomes (iLipo-H). A fasting-mimicking diet (FMD) is used to increase the autophagy levels in tumor cells, thereby increasing the sensitivity of tumor cells to HCQ. In addition, FMD treatment upregulates the expression of IGF2R in tumor cells, but not normal cells. Consequently, iLipo-H nanoparticles efficiently accumulate at the tumor site under FMD condition. In vivo studies demonstrate that iLipo-H nanoparticles efficiently inhibit 4T1 tumor growth without obvious side effects, especially under FMD condition. This study provides a promising strategy to increase the sensitivity of tumor cells to autophagy inhibitors for effective cancer therapy.
    Keywords:  autophagy; hydroxychloroquine; insulin-like growth factors 2 receptor; targeted delivery
    DOI:  https://doi.org/10.1021/acs.nanolett.2c03890
  111. Pharmaceutics. 2022 Nov 09. pii: 2418. [Epub ahead of print]14(11):
    Photodynamic Therapy Efficacy of Novel Zinc Phthalocyanine Tetra Sodium 2-Mercaptoacetate Combined with Cannabidiol on Metastatic Melanoma.
    Nkune Williams Nkune, Gauta Gold Matlou, Heidi Abrahamse.
      This work reports for the first time on the synthesis, characterization, and photodynamic therapy effect of a novel water-soluble zinc (II) 2(3), 9(10), 16(17), 23(24)-tetrakis-(sodium 2-mercaptoacetate) phthalocyanine (ZnPcTS41), on metastatic melanoma cells (A375) combined with cannabidiol (CBD). The ZnPcTS41 structure was confirmed using FTIR, NMR, MS, and elemental analysis while the electronic absorption spectrum was studied using UV-VIS. The study reports further on the dose-dependent effects of ZnPcTS41 (1-8 µM) and CBD alone (0.3-1.1 µM) at 636 nm with 10 J/cm2 on cellular morphology and viability. The IC50 concentrations of ZnPcTS41 and CBD were found to be 5.3 µM and 0.63 µM, respectively. The cytotoxicity effects of the ZnPcTS41 enhanced with CBD on A375 cells were assessed using MTT cell viability assay, ATP cellular proliferation and inverted light microscopy. Cell death induction was also determined via Annexin V-FITC-PI. The combination of CBD- and ZnPcTS41-mediated PDT resulted in a significant reduction in cell viability (15%***) and an increase in the late apoptotic cell population (25%*). These findings suggest that enhancing PDT with anticancer agents such as CBD could possibly obliterate cancer cells and inhibit tumor recurrence.
    Keywords:  cannabidiol; photodynamic therapy; skin cancer cells; zinc phthalocyanine
    DOI:  https://doi.org/10.3390/pharmaceutics14112418
  112. Int J Pharm. 2022 Nov 06. pii: S0378-5173(22)00927-9. [Epub ahead of print] 122372
    Nose-to-brain delivery of octreotide acetate in situ gel for pituitary adenoma: Pharmacological and in vitro cytotoxicity studies.
    Dnyandev Gadhave, Shubham Khot, Shrikant Tupe, Mahesh Shinde, Amol Tagalpallewar, Bapi Gorain, Chandrakant Kokare.
      Octreotide acetate (OA), a potent octapeptide, is used in the treatment of pituitary adenoma. An approach has been made in the present research to formulate an OA-loaded intranasal in situ gel (OA-ISG) to target pituitary adenoma. To achieve the objective of the present work, OA-ISG was fabricated using cold method, and further optimization was done by 32 factorial design. The optimized formulation was evaluated for gelation temperature, mucoadhesive strength, and % drug release (8 h), and the results were found to be 30.01 ± 0.4 °C, 40.12 ± 0.5 g, and 98.54 ± 0.45%, respectively. Brain availability of OA was determined through gamma scintigraphy, wherein Cmax for technetium (99mTC) labeled intranasal OA-ISG (99mTC-OA-ISG) was found to be 1.041% RA/g, and the findings for 99mTC-OA-Solution (intranasal) and 99mTC-OA-Solution (intravenous) were 0.395% and 0.164% RA/g, respectively. Consequently, a 3-10 fold increase in brain OA concentrations was observed upon intranasal administration (OA-ISG) as compared to others. Additionally, drug targeting index (100.13), targeting efficiency (10013%), and direct transport percentage (2564.1%) corroborate brain targeting of OA via intranasal route. Further, the cytotoxic potential of OA-ISG was screened on human pituitary tumor (GH3) cell lines using MTT assay. The IC50 value was found to be 9.5 μg/mL for OA-ISG, whereas it was 20.1 μg/mL for OA-Solution, thereby confirming the superior results of OA-ISG as compared to OA-Solution. Hence, the developed intranasal OA-ISG can be further explored for establishing its potential clinical safety, and as effective platform for targeted drug delivery to the brain in pituitary adenoma.
    Keywords:  Octreotide acetate; cytotoxicity study; gamma scintigraphy; in situ gel; intranasal administration; pituitary cancer
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.122372
  113. J Ethnopharmacol. 2022 Oct 29. pii: S0378-8741(22)00909-6. [Epub ahead of print]302(Pt A): 115870
    Ethnopharmacology of Rubus idaeus Linnaeus: A critical review on ethnobotany, processing methods, phytochemicals, pharmacology and quality control.
    Yi Tao, Jiaqi Bao, Fei Zhu, Meiling Pan, Qing Liu, Ping Wang.
      ETHNOPHARMACOLOGICAL RELEVANCE: Rubus idaeus Linnaeus (RI) is a Chinese herbal medicine that has been widely used in China for a long time to reinforce the kidney, nourish the liver, improve vision, and arrest polyuria.AIM OF THE STUDY: This work aims to evaluate the recent progress of the chemical composition, pharmacological activity, pharmacokinetics, metabolism, and quality control and of Rubus idaeus, which focuses on the insufficiency of existing research and will shed light on future studies of Rubus idaeus.
    METHODS: Literatures about "Rubus idaeus","Red raspberry" and "Fupenzi"are retrieved by browsing the database, such as Web of Science (http://www.webofknowledge.com/wos), Pubmed (https://pubmed.ncbi.nlm.nih.gov/), CNKI (http://www.cnki.net/), and Wanfang Data (http://www.wanfangdata.com.cn). In addition, related textbooks and digital documents are interrogated to provide a holistic and critical review of the topic. The period of the literature covered from 1981 to 2022.
    RESULTS: Approximately 194 compounds have been isolated from Rubus idaeus, which is rich in phenols, terpenoids, alkaloids, steroids, and fatty acids. Numerous investigations have demonstrated that Rubus idaeus exhibits many pharmacological activities, including hypoglycemic and hypolipidemic, anti-Alzheimer effect, anti-osteoporosis, hepatoprotective, anti-cancer, neuroprotective, anti-bacteria and skin care, etc. However, it is worth noting that most of the research is not associated with the conventional effect, such as reducing urination and treating opacity of the cornea.
    CONCLUSION: The effectiveness of Rubus idaeus has been proved by its long-term clinical application. The research on the pharmacological activity of Rubus idaeus has flourished. In many pharmacological experiments, only the high-dose group can achieve the corresponding efficacy, so the efficacy of Rubus idaeus needs to be further interrogated. Meanwhile, the relationship between pharmacological activity and specific compounds of Rubus idaeus has not been clarified yet. Last but not least, studies involving toxicology and pharmacokinetics are very limited. Knowledge of bioavailability and toxicological behavior of Rubus idaeus can help understand the herb's pharmacodynamic and safety profile.
    Keywords:  2-Hexadecenoic acid(PubChem CID:5282743); 2-Hydroxyquinoline-4-carboxylic acid(PubChem CID:85076); 2α-Hydroxyursolic acid(PubChem CID:11655818); 2’’-O-Galloylhyperin(PubChem CID:6453359); 4-Hydroxy- 3-methoxybenzoic acid(PubChem CID:8468); 4-Hydroxybenzaldehyde(PubChem CID:126); 4-Hydroxybenzoic acid(PubChem CID:135); 4-Hydroxyphenylacetic acid(PubChem CID:127); 8,11,14-Eicosatrienoic acid(PubChem CID:5280581); 9,10-Dihydroxyoctadeca-12,15-dienoic acid(PubChem CID:54242986); 9-Octadecynoic acid (PubChem CID:68167); Arjunic acid(PubChem CID:15385516); Aromadenrin (PubChem CID:122850); Arrest polyuria; Astragalin(PubChem CID:5282102); Brevifolin carboxylic acid(PubChem CID:9838995); Campesterol(PubChem CID:173183); Caproic acid(PubChem CID:8892); Caprylic acid(PubChem CID:379); Casuarictin (PubChem CID:73644); Casuariin(PubChem CID:14035442); Casuarinin(PubChem CID:157395); Catechin(PubChem CID:9064); Daucosterol(PubChem CID: 5742590); Dodecanoic acid(PubChem CID:3893); Dotriacontanoic acid(PubChem CID:19255); Ellagic acid pentoside(PubChem CID:5487461); Ellagic acid(PubChem CID:5281855); Ellagic acid-pentoside(PubChem CID:5487461); Esculetin(PubChem CID:5281416); Esculin(PubChem CID:5281417); Ethyl gallate (PubChem CID:13250); Euscaphic acid(PubChem CID:471426); Ferulic acid(PubChem CID:445858); Fupenzic acid (PubChem CID:12045007); Gallic acid (PubChem CID:370); Gosh-onoside-F2(PubChem CID:13855763); Goshonoside-F1(PubChem CID:13855760); Goshonoside-F3(PubChem CID: 131752349); Goshonoside-F4(PubChem CID:131752350); Goshonoside-F5(PubChem CID: 13855771); Goshonoside-F6(PubChem CID: 131752396); Goshonoside-F7(PubChem CID:131752351); Hexacosyl pcoumarate(PubChem CID:6479500); Hexadecanoic acid(PubChem CID:985); Hyperoside(PubChem CID:5281643); Imperatorin(PubChem CID:10212); Improve vision; Isoquercitrin(PubChem CID:5280804); Kaempferol(PubChem CID:5280 863); Kaempferol-3-O-rhamnoside (PubChem 5835713); Kaempferol-3-O-rutinoside(PubChem CID:5318767); Kaempferol-7-rhamnoside(PubChem CID:25079 965); Lambertianin C (PubChem CID:155903165); Linoleic acid(PubChem CID:5280450); Linolenic acid (PubChem CID: 5280934); Maslinic acid (PubChem CID:73659); Methyl brevifolincarboxylate(PubChem CID:5319518); N-pentadecanoic acid(PubChem CID:13849); Nicotiflorin(PubChem CID:5318767); Nigaichigoside F1(PubChem CID:16118969); Oleanic acid(PubChem CID:10494); Oleic acid(PubChem CID: 445639); Pedunculagin (PubChem CID:442688); Phenols; Phlorizin(PubChem CID: 6072); Quercetin(PubChem CID:5280343); Quercitrin(PubChem CID:5280459); Raspberry ketone(PubChem CID:21648); Resveratrol(PubChem CID:445154); Rubus idaeus Linnaeus; Rubuso-side(PubChem CID: 24721373); Rutin(PubChem CID:5280805); Salicylic acid(PubChem CID:338); Sanguiin H-6(PubChem CID:16130897); Sanguisorbic acid dilactone(PubChem CID:136784551); Sericic acid (PubChem CID:124214); Shikimic acid(PubChem CID:8742); Sitosterol palmitate(PubChem CID:9852570); Stearic acid(PubChem CID: 5281); Stigmast-4-ene-(3β,6α)-diol(PubChem CID:10550610); Stigmast-5-en-3-ol, oleate(PubChem CID:20831071); Tetradecanoic acid(Pub Chem CID:11005); Tiliroside(PubChem CID: 5320686); Tormentic acid(PubChem CID:73193); Undecanoic acid(PubChem CID:8180); Ursolic acid(PubChem CID:64945); Valoneic acid bilactone(PubChem CID:10151874); Vanillic acid(PubChem CID:8468); Vanillin(PubChem CID:1183); cis-Tiliroside(PubChem CID:10175330); n-Heptadecanoic acid(PubChem CID:10465); p-Coumaric acid (PubChem CID:637542); trans-Traumatic acid(PubChem CID: 5283028); α-Linolenic acid (PubChem CID:860); β-Sitosterol(PubChem CID:521199); β-Stigmasterol(PubChem CID:5280794)
    DOI:  https://doi.org/10.1016/j.jep.2022.115870
  114. J Biomater Sci Polym Ed. 2022 Nov 08. 1-15
    Folic acid-Chitosan Coated Stylosin Nanostructured Lipid Carriers: Fabrication, In Vitro-In Vivo Assessment in Breast Malignant Cells.
    Soroush Sadeghi, Masoud Homayouni Tabrizi, Amin Farhadi.
      OBJECTIVE: Synthesis of Targeted Nanostructure Lipid Carriers for stylosin (STY-CFN-NPs) delivery to MCF-7 Cells.MATERIALS AND METHODS: STY-CFN-NPs were formulated via the homogenization and ultra-sonication technique. After evaluating the amount of drug encapsulation and FA binding, the toxicity effect of the STY and STY-CFN-NPs on MCF-7 cells was measured by the MTT method. Cell cycle analysis, AO/PI staining and qPCR to assess the inducing of apoptosis as well as Tubo cancer cell inoculated mouse model for antitumor properties of STY-CFN-NPs were used.
    RESULTS: Significant increases in nanoparticle size and changes in zeta potential were observed after FA-CS coating on nanoparticles. Slow release of the STY within 144 h as well as the acceptable rate for STY encapsulation efficiency (92.4% and FA binding (52.5%) to the STY-CFN-NPs (PS: 66.26 ± 3.02 nm, ZP: 29.54 ± 1.01 mV and PDI: 0.32 ± 0.01) was reported. STY-CFN-NPs exhibited higher toxicity compared to STY suspension and treatment with STY-CFN-NPs was lead to increased apoptotic cells, stopped cells in the SubG1 phase, and also increased Caspase and Bax expression and decreased BCL-2 and BCL-XL expression in In vitro and decreased the size of murine tumors (54.57% in 16 days) in In vivo.
    CONCLUSION: The results showed STY-CFN-NPs have good potential for breast cancer management.
    Keywords:  Breast Malignant Cells; Chitosan; Nanostructured Lipid Carriers; Stylosin
    DOI:  https://doi.org/10.1080/09205063.2022.2145868
  115. Mol Biol Rep. 2022 Nov 12.
    Vitamin D increases the efficacy of cisplatin on bladder cancer cell lines.
    Özge Özgen, Güneş Özen Eroğlu, Özlem Küçükhüseyin, Nilgün Akdeniz, Ceylan Hepokur, Serap Kuruca, İlhan Yaylım.
      BACKGROUND: 1,25(OH)2D3(Calcitriol), which is a broad regulatory molecule, plays a role in changing the efficacy of chemotherapeutic drugs. Cisplatin is one of a current standard chemotherapy regimen for bladder cancer. Increasing the effectiveness of the treatment and reducing the side effects to chemotherapeutics are of great importance in bladder cancer. We aimed to investigate the effect of the combination of cisplatin and calcitriol in order to create a possible advantage in treatment of bladder cancer.METHODS: T24, ECV-304 and HUVEC cell lines were treated with calcitriol and cisplatin individually and in combination. Dose determination and combination treatments of calcitriol and cisplatin were evaluated using the MTT assay for cytotoxicity analysis on the cells. Annexin V-PI staining method was used for apoptosis determination by flow cytometry. Also the P-gp expression levels were determined by flow cytometry.
    RESULTS: The combination treatment increased the anti-proliferative efficacy compared to the efficacy in cisplatin alone in T24 cells and reduced the cytotoxicity in the HUVEC healthy cells compared to cisplatin alone. Combination treatment achieved significantly higher apoptosis rate in T24 cells compared with the rates in treatment of cisplatin alone. However apoptosis decreased in HUVEC cell line. P-gp ratios were increased in HUVEC and decreased in T24 cells with combination treatment compared to the numbers in the control cells. The rate of apoptosis and P-gp levels showed no significant change in ECV-304 cells.
    CONCLUSION: Our study revealed that the combination of calcitriol and cisplatin allows the use of cisplatin at lower doses in T24 bladder cancer cell line.
    Keywords:  Apoptosis; Bladder cancer; Calcitriol; Cisplatin; P-gp; T24 cell line; Vitamin D
    DOI:  https://doi.org/10.1007/s11033-022-08044-2
  116. Explor Target Antitumor Ther. 2022 ;3(5): 570-581
    A xCT role in tumour-associated ferroptosis shed light on novel therapeutic options.
    Daniela Criscuolo, Francesco Morra, Angela Celetti.
      Solute carrier family 7 member 11 (SLC7A11; also known as xCT), a key component of the cystine/glutamate antiporter, is essential for the maintenance of cellular redox status and the regulation of tumor-associated ferroptosis. Accumulating evidence has demonstrated that xCT overexpression, resulting from different oncogenic and tumor suppressor signaling, promotes tumor progression and multidrug resistance partially via suppressing ferroptosis. In addition, recent studies have highlighted the role of xCT in regulating the metabolic flexibility in cancer cells. In this review, the xCT activities in intracellular redox balance and in ferroptotic cell death have been summarized. Moreover, the role of xCT in promoting tumor development, drug resistance, and nutrient dependency in cancer cells has been explored. Finally, different therapeutic strategies, xCT-based, for anti-cancer treatments have been discussed.
    Keywords:  Solute carrier family 7 member 11 (SLC7A11); cancer therapy; coiled-coil domain containing 6 (CCDC6); ferroptosis-regulators; reactive oxygen species (ROS) tolerance
    DOI:  https://doi.org/10.37349/etat.2022.00101
  117. Cancers (Basel). 2022 Oct 22. pii: 5176. [Epub ahead of print]14(21):
    Molecular Targeting of the Most Functionally Complex Gene in Precision Oncology: p53.
    Douglas W Brown, Perrin H Beatty, John D Lewis.
      While chemotherapy is a key treatment strategy for many solid tumors, it is rarely curative, and most tumor cells eventually become resistant. Because of this, there is an unmet need to develop systemic treatments that capitalize on the unique mutational landscape of each patient's tumor. The most frequently mutated protein in cancer, p53, has a role in nearly all cancer subtypes and tumorigenesis stages and therefore is one of the most promising molecular targets for cancer treatment. Unfortunately, drugs targeting p53 have seen little clinical success despite promising preclinical data. Most of these drug compounds target specific aspects of p53 inactivation, such as through inhibiting negative regulation by the mouse double minute (MDM) family of proteins. These treatment strategies fail to address cancer cells' adaptation mechanisms and ignore the impact that p53 loss has on the entire p53 network. However, recent gene therapy successes show that targeting the p53 network and cellular dysfunction caused by p53 inactivation is now possible and may soon translate into successful clinical responses. In this review, we discuss p53 signaling complexities in cancer that have hindered the development and use of p53-targeted drugs. We also describe several current therapeutics reporting promising preclinical and clinical results.
    Keywords:  cancer treatment; genetic therapy; p53; p53 and signaling; solid tumors
    DOI:  https://doi.org/10.3390/cancers14215176
  118. Nutr Neurosci. 2022 Nov 10. 1-21
    Effects of the ketogenic diet on cognition: a systematic review.
    Arun Chinna-Meyyappan, Fabiano Alves Gomes, Elena Koning, Jennifer Fabe, Vitor Breda, Elisa Brietzke.
      INTRODUCTION: Ketogenic diet (KD) therapy has been used as a dietary intervention in drug-resistant epilepsy for several years. Research currently suggests that KD therapy may carry neuroprotective and cognition enhancing effects for individuals with non-epileptic conditions as well as for healthy individuals. Therefore, KD may have potential as a non-invasive, nutritional treatment approach for difficult to manage conditions such as neurodegenerative illnesses or mood disorders. The aim of this review is to summarize the available evidence on ketogenic interventions and the resulting cognitive outcomes.MATERIALS AND METHODS: The paper was based on PRISMA 2020 guidelines. The search was conducted in June 2021 on the following databases: CENTRAL, PubMed, EMBASE, PsycInfo, Web of Science. The search yielded 2014 studies, of which 49 were included.
    RESULTS: There were 22 animal studies assessing murine models and 27 studies on humans. The primary indications in these studies were epileptic conditions, neurodegenerative disorders, cognitive impairment, and healthy populations.
    DISCUSSION: Administration of KD seems to confer cognitive-enhancing effects in areas such as working memory, reference memory and attention. Studies found that KD treatment in animals has the potential to alleviate age-related cognitive decline. Over 80% of the 27 human studies reported a favourable effect of intervention, and none reported a detrimental effect of KD. While these findings suggest that KD may improve the functioning of certain cognitive domains, definitive conclusions were limited by studies with small sample sizes, the absence of controls and randomization, and the lack of objective measures of cognition.
    Keywords:  Ketosis; attention; cognition; executive function; ketogenic diet; low-carbohydrate; nutrition; working memory
    DOI:  https://doi.org/10.1080/1028415X.2022.2143609
  119. Front Oncol. 2022 ;12 1034397
    Combining metformin with lactate transport inhibitors as a treatment modality for cancer - recommendation proposal.
    Don Benjamin, Michael N Hall.
      Highly glycolytic cancer cells excrete lactate to maintain cellular homeostasis. Inhibiting lactate export by pharmacological targeting of plasma membrane lactate transporters is being pursued as an anti-cancer therapy. Work from many laboratories show that the simultaneous inhibition of lactate export and mitochondrial respiration elicits strong synthetic lethality. The mitochondrial inhibitor, metformin, has been the subject of numerous clinical trials as an anti-cancer agent. We propose that, in future clinical trials, metformin be combined with lactate transport inhibitors to exploit this synergistic interaction.
    Keywords:  MCT4; cancer; lactic acid; metformin; monocarboxylate transporter; syrosingopine
    DOI:  https://doi.org/10.3389/fonc.2022.1034397
  120. Cell Rep. 2022 Nov 08. pii: S2211-1247(22)01463-2. [Epub ahead of print]41(6): 111598
    MsrB1-regulated GAPDH oxidation plays programmatic roles in shaping metabolic and inflammatory signatures during macrophage activation.
    Hyun Jung Yoo, Dong Wook Choi, Yeon Jin Roh, Yoon-Mi Lee, Ji-Hong Lim, Soohak Eo, Ho-Jae Lee, Na Young Kim, Seohyun Kim, Sumin Cho, Gyumin Im, Byung Cheon Lee, Ji Hyung Kim.
      Classically activated pro-inflammatory macrophages are generated from naive macrophages by pro-inflammatory cues that dynamically reprogram their fuel metabolism toward glycolysis. This increases their intracellular reactive oxygen species (ROS) levels, which then activate the transcription and release of pro-inflammatory mediators. Our study on mice that lack methionine sulfoxide reductase (Msr)-B1 shows that the resulting partial loss of protein methionine reduction in pro-inflammatory macrophages creates a unique metabolic signature characterized by altered fuel utilization, including glucose and pyruvate. This change also associates with hyper-inflammation that is at least partly due to sustained oxidation of an exposed methionine residue (M44) on glyceraldehyde 3-phosphate dehydrogenase (GAPDH), thereby inducing GAPDH aggregation, inflammasome activation, and subsequent increased interleukin (IL)-1β secretion. Since MsrB1-knockout mice exhibit increased susceptibility to lipopolysaccharide (LPS)-induced sepsis, the MsrB1-GAPDH axis may be a key molecular mechanism by which protein redox homeostasis controls the metabolic profile of macrophages and thereby regulates their functions.
    Keywords:  CP: Metabolism; GAPDH; MsrB1; ROS; inflammasome; macrophage; metabolic reprogramming; sepsis
    DOI:  https://doi.org/10.1016/j.celrep.2022.111598
  121. Polymers (Basel). 2022 Oct 25. pii: 4505. [Epub ahead of print]14(21):
    Nano-Encapsulation of Citrus Essential Oils: Methods and Applications of Interest for the Food Sector.
    Ioana Oprea, Anca Corina Fărcaș, Loredana Florina Leopold, Zoriţa Diaconeasa, Cristina Coman, Sonia Ancuța Socaci.
      Citrus essential oils possess many health-promoting benefits and properties of high interest in the food and agri-food sector. However, their large-scale application is limited by their sensitivity to environmental factors. Nanostructures containing citrus essential oils have been developed to overcome the high volatility and instability of essential oils with respect to temperature, pH, UV light, etc. Nanostructures could provide protection for essential oils and enhancement of their bioavailability and biocompatibility, as well as their biological properties. Nano-encapsulation is a promising method. The present review is mainly focused on methods developed so far for the nano-encapsulation of citrus essential oils, with emphasis on lipid-based (including liposomes, solid lipid nanoparticles, nanostructured lipid particles, and nano- and micro-emulsions) and polymer-based nanostructures. The physico-chemical characteristics of the obtained structures, as well as promising properties reported, with relevance for the food sector are also discussed.
    Keywords:  antimicrobial; antioxidant; citrus essential oils; nano-emulsions; nano-encapsulation; nanoliposomes; polymers
    DOI:  https://doi.org/10.3390/polym14214505
  122. Pharm Res. 2022 Nov 09.
    Delivery of Corn-Derived Nanoparticles with Anticancer Activity to Tumor Tissues by Modification with Polyethylene Glycol for Cancer Therapy.
    Daisuke Sasaki, Kosuke Kusamori, Makiya Nishikawa.
      PURPOSE: We recently reported that intratumoral injection of corn-derived nanoparticles (cNPs) affords anticancer activity in tumor-bearing mice. To increase their applicability in cancer therapy, we examined the tissue distribution of cNPs after intravenous injection in mice, modified their surface with polyethylene glycol (PEG) to improve tumor delivery, and examined tissue distribution and anticancer activity of PEG-cNPs in tumor-bearing mice.METHODS: N-(Carbonyl-methoxypolyethyleneglycol2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE-PEG) was added to cNPs by sonication to obtain PEG-cNPs, and the ratio of DSPE-PEG to cNPs was optimized by evaluating the modification efficiency. cNPs and PEG-cNPs were labeled with fluorescent dyes DiO or DiR, and their tissue distribution was subsequently examined after intravenous administration to mice. Finally, we determined the anticancer activity and toxicity of PEG-cNPs.
    RESULTS: No detectable fluorescence intensity was observed in mouse serum after intravenous DiR-cNP injection. DSPE-PEG was successfully modified into cNPs, and a PEG:cNPs ratio of 50 was determined as optimal for preparing PEG-cNPs, based on their size and zeta potential. DiO-PEG-cNPs exhibited significantly higher serum concentrations and lower liver accumulation than DiO-cNPs. Moreover, DiR-PEG-cNPs accumulated in tumor tissues of colon26 tumor-bearing mice. Repeated intravenous PEG-cNP injections significantly retarded tumor growth, with no significant hepatotoxicity or nephrotoxicity.
    CONCLUSION: Overall, these results indicate that controlling the tissue distribution of cNPs via PEG modification on their surface can be a valuable strategy for developing intravenously injectable cNPs for cancer therapy.
    Keywords:  cancer therapy; corn-derived nanoparticle; polyethylene glycol; surface modification; tumor delivery
    DOI:  https://doi.org/10.1007/s11095-022-03431-7
  123. Cancers (Basel). 2022 Oct 25. pii: 5224. [Epub ahead of print]14(21):
    Metabolic Reprogramming in Tumor-Associated Macrophages in the Ovarian Tumor Microenvironment.
    Sudhir Kumar, Sonam Mittal, Prachi Gupta, Mona Singh, Pradeep Chaluvally-Raghavan, Sunila Pradeep.
      The interaction between tumor cells and macrophages in the tumor microenvironment plays an essential role in metabolic changes in macrophages and reprograms them towards a pro-tumorigenic phenotype. Increasing evidence indicates that macrophage metabolism is a highly complex process and may not be as simple as previously thought. Pro-inflammatory stimuli switch macrophages towards an M1-like phenotype and rely mainly on aerobic glycolysis and fatty acid synthesis, whereas anti-inflammatory stimuli switch macrophages towards an M2-like phenotype. M2-like macrophages depend more on oxidative phosphorylation (OXPHOS) and fatty acid oxidation. However, this metabolically reprogrammed phenotypic switch in macrophages remained a mystery for a while. Therefore, through this review, we tend to describe how macrophage immunometabolism determines macrophage phenotypes and functions in tumor microenvironments (TMEs). Furthermore, we have discussed how metabolic reprogramming in TAM can be used for therapeutic intervention and drug resistance in ovarian cancer.
    Keywords:  extracellular vesicles (EVs); metabolic reprogramming; metabolism; ovarian cancer; tumor microenvironment (TME); tumor-associated macrophages (TAMs)
    DOI:  https://doi.org/10.3390/cancers14215224
  124. Pharm Dev Technol. 2022 Nov 11. 1-33
    Improved uptake and bioavailability of cinnamaldehyde via solid lipid nanoparticles for oral delivery.
    Long Wu, Yun Meng, Yuhang Xu, Xiaoqin Chu.
      Objective: The purpose of this experiment was to explore the effect of Solid lipid nanoparticles (SLNs) on improving the oral absorption and bioavailability of cinnamaldehyde (CA). Methods: CA-SLNs were prepared by high pressure homogenization and characterized by particle size, entrapment efficiency, and morphology, thermal behavior and attenuated total reflection Fourier transform infrared (ATR-FTIR). In vitro characteristics of release, stability experiments, cytotoxicity, uptake and transport across Caco-2 cell monolayer of CA-SLNs were studied as well. In addition, CA-SLNs underwent pharmacokinetic and gastrointestinal mucosal irritation studies in rats. Results: CA-SLNs exhibited a spherical shape with a particle size of 44.57 ± 0.27 nm, zeta potential of -27.66 ± 1.9 mV and entrapment efficiency of 83.63% ± 2.16%. Differential scanning calorimetry (DSC) and ATR-FTIR confirmed that CA was well encapsulated. In vitro release of CA-SLNs displayed that most of the drug (90.77%±5%) was released in the phosphate buffer, and only a small amount of drug (18.55%±5%) was released in the HCl buffer. CA-SLNs were taken up by an energy-dependent, endocytic mechanism mediated by caveolae mediated endocytosis across Caco-2 cells. The CA permeation through Caco-2 cell was facilitated by CA-SLNs. The outcome of the gastrointestinal irritation test demonstrated that CA-SLNs had no irritation to the rats' intestines. Compared with CA dispersions, incorporation of SLNs increased the oral bioavailability of CA more than 1.69-fold. Conclusions: It was concluded that CA-SLNs improved the absorption across Caco-2 cell model and improved the oral administration bioavailability of CA in rats.
    Keywords:  Cinnamaldehyde; cellular uptake; in vivo pharmacokinetics; solid lipid nanoparticles
    DOI:  https://doi.org/10.1080/10837450.2022.2147542
  125. Biomedicines. 2022 Oct 26. pii: 2713. [Epub ahead of print]10(11):
    Synthesis of Artemether-Loaded Albumin Nanoparticles and Measurement of Their Anti-Cancer Effects.
    Zeynab Pirali-Hamedani, Ardeshir Abbasi, Zuhair Mohammad Hassan.
      Colorectal cancer is the third most common cancer in the world. Due to the side effects of common treatments such as chemotherapy and radiotherapy, the use of herbal medicines has received much attention. Artemether (ARM) is an herbal medicine derived from artemisinin, which has many anti-tumor properties. However, factors such as low solubility and short half-life have limited the use of artemether in clinical practice. In this study, we aimed to reduce these limitations by encapsulating artemether in human serum albumin (HSA). The hydrodynamic diameter and the zeta potential value of ARM-ALB nanoparticles (NPs) were 171.3 ± 5.88 nm and -19.1 ± 0.82 mV, respectively. Comparison of the effect of free and encapsulated artemether on CT 26 cell line showed that the use of artemether in capsulated form can reduce the effective concentration of the drug. Additionally, in vivo studies have also shown that albumin-artemether nanoparticles can control tumor growth by increasing the production of cytokine IFN-γ and decreasing the production of IL4. Therefore, ARM-ALB nanoparticles have greater anti-tumor effects than free artemether.
    Keywords:  albumin–artemether nanoparticles; artemether; colorectal cancer
    DOI:  https://doi.org/10.3390/biomedicines10112713
  126. Int J Mol Sci. 2022 Oct 27. pii: 13051. [Epub ahead of print]23(21):
    Losartan Potassium and Verapamil Hydrochloride Compound Transdermal Drug Delivery System: Formulation and Characterization.
    Yu-Si Chen, Yi-Yang Sun, Zi-Chen Qin, Sai-Ya Zhang, Wen-Bo Chen, Yan-Qiang Liu.
      In this study, we developed a sustained-release transdermal delivery system containing losartan potassium (LP) and verapamil hydrochloride (VPH). LP and VPH have low bioavailability and long half-life. Therefore, the development of an optimum administration mode is necessary to overcome these drawbacks and enhance the antihypertensive effect. A transdermal diffusion meter was used to determine the optimal formulation of LP-VPH transdermal drug delivery systems (TDDS). Based on in vitro results, a sustained-release patch was prepared. Physical characteristics, including quality, stickiness, and appearance, were evaluated in vitro, while pharmacokinetics and skin irritation were evaluated in vivo. The results showed that 8.3% polyvinyl alcohol, 74.7% polyvinylpyrrolidone K30, 12% oleic acid-azone, and 5% polyacrylic acid resin II provided an optimized TDDS product for effective administration of LP and VPH. Furthermore, in vitro and in vivo release tests showed that the system continuously released LP and VPH for 24 h. The pharmacokinetic results indicated that although the maximum concentration was lower, both the area under the curve from 0-time and the mean residence time of the prepared patch were significantly higher than those of the oral preparations. Furthermore, the prepared LP-VPH transdermal patch showed good stability and no skin irritation. The developed LP-VPH TDDS showed a sustained-release effect and good characteristics and pharmacokinetics; therefore, it is an ideal formulation.
    Keywords:  losartan potassium; pharmacokinetics; skin irritation; transdermal delivery; verapamil hydrochloride
    DOI:  https://doi.org/10.3390/ijms232113051
  127. Front Pharmacol. 2022 ;13 1021501
    Neuroprotective and anti-epileptic potentials of genus Artemisia L.
    Bayan Sailike, Zhannur Omarova, Janar Jenis, Altynay Adilbayev, Burkitkan Akbay, Sholpan Askarova, Wei-Lin Jin, Tursonjan Tokay.
      The Genus Artemisia L. is one of the largest genera in the Asteraceae family growing wild over in Europe, North America, and Central Asia and has been widely used in folk medicine for the treatment of various ailments. Phytochemical and psychopharmacological studies indicated that the genus Artemisia extracts contain various antioxidant and anti-inflammatory compounds and possess antioxidant, anti-inflammatory, antimicrobial, antimalarial, and antitumor activity. Recently, increasing experimental studies demonstrated that many Artemisia extracts offer a great antiepileptic potential, which was attributed to their bioactive components via various mechanisms of action. However, detailed literature on the antiepileptic properties of the genus Artemisia and its mechanism of action is segregated. In this review, we tried to gather the detailed neuroprotective and antiepileptic properties of the genus Artemisia and its possible underlying mechanisms. In this respect, 63 articles were identified in the PubMed and Google scholars databases, from which 18 studies were examined based on the pharmacological use of the genus Artemisia species in epilepsy. The genus Artemisia extracts have been reported to possess antioxidant, anti-inflammatory, neurotransmitter-modulating, anti-apoptotic, anticonvulsant, and pro-cognitive properties by modulating oxidative stress caused by mitochondrial ROS production and an imbalance of antioxidant enzymes, by protecting mitochondrial membrane potential required for ATP production, by upregulating GABA-A receptor and nACh receptor activities, and by interfering with various anti-inflammatory and anti-apoptotic signaling pathways, such as mitochondrial apoptosis pathway, ERK/CREB/Bcl-2 pathway and Nrf2 pathway. This review provides detailed information about some species of the genus Artemisia as potential antiepileptic agents. Hence, we recommend further investigations on the purification and identification of the most biological effective compounds of Artemisia and the mechanisms of their action to cure epilepsy and other neurological diseases.
    Keywords:  cognitive impairment; epilepsy; excitotoxicity; genus artemisia; neuroinflammation; neuroprotection; oxidative stress
    DOI:  https://doi.org/10.3389/fphar.2022.1021501
  128. Cells. 2022 Nov 02. pii: 3467. [Epub ahead of print]11(21):
    Melatonin Treatment Triggers Metabolic and Intracellular pH Imbalance in Glioblastoma.
    Beatriz I Fernandez-Gil, Andrea Otamendi-Lopez, Alexandra Bechtle, Carla A Vazquez-Ramos, Neda Qosja, Paola Suarez-Meade, Rachel Sarabia-Estrada, Mark E Jentoft, Hugo Guerrero-Cázares, Germaine Escames, Paula Schiapparelli, Alfredo Quiñones-Hinojosa.
      Metabolic rewiring in glioblastoma (GBM) is linked to intra- and extracellular pH regulation. In this study, we sought to characterize the role of melatonin on intracellular pH modulation and metabolic consequences to identify the mechanisms of action underlying melatonin oncostatic effects on GBM tumor initiating cells. GBM tumor initiating cells were treated at different times with melatonin (1.5 and 3.0 mM). We analyzed melatonin's functional effects on GBM proliferation, cell cycle, viability, stemness, and chemo-radiosensitivity. We then assessed the effects of melatonin on GBM metabolism by analyzing the mitochondrial and glycolytic parameters. We also measured the intracellular and extracellular pH. Finally, we tested the effects of melatonin on a mouse subcutaneous xenograft model. We found that melatonin downregulated LDHA and MCT4, decreasing lactate production and inducing a decrease in intracellular pH that was associated with an increase in ROS and ATP depletion. These changes blocked cell cycle progression and induced cellular death and we observed similar results in vivo. Melatonin's cytotoxic effects on GBM were due, at least in part, to intracellular pH modulation, which has emerged as a newly identified mechanism, providing new insights into the oncostatic effect of melatonin on GBM.
    Keywords:  GBM; LDHA; MCT4; OXPHOS; ROS; cancer metabolism; glycolysis; intracellular acidity; lactate
    DOI:  https://doi.org/10.3390/cells11213467
  129. Int J Nanomedicine. 2022 ;17 5065-5080
    Antibody-Functionalized Nanoformulations for Targeted Therapy of Colorectal Cancer: A Systematic Review.
    Ana Cepero, Cristina Luque, Laura Cabeza, Gloria Perazzoli, Francisco Quiñonero, Cristina Mesas, Consolación Melguizo, Jose Prados.
      The failure of chemotherapeutic treatment in colorectal cancer (CRC), the second most mortal cancer worldwide, is associated with several drug limitations, such as non-selective distribution, short half-life, and development of multiple resistances. One of the most promising strategies in CRC therapy is the development of delivery systems based on nanomaterials that can transport antitumor agents to the tumor site more efficiently, increasing accumulation within the tumor and thus the antitumor effect. In addition to taking advantage of the increased permeability and retention effect (EPR) of solid tumors, these nanoformulations can be conjugated with monoclonal antibodies that recognize molecular markers that are specifically over-expressed on CRC cells. Active targeting of nanoformulations reduces the adverse effects associated with the cytotoxic activity of drugs in healthy tissues, which will be of interest for improving the quality of life of cancer patients in the future. This review focuses on in vitro and in vivo studies of drug delivery nanoformulations functionalized with monoclonal antibodies for targeted therapy of CRC.
    Keywords:  5-fluorouracil; colon carcinoma; monoclonal antibody; nanoformulation; targeted therapy
    DOI:  https://doi.org/10.2147/IJN.S368814
  130. J Control Release. 2022 Nov 05. pii: S0168-3659(22)00719-2. [Epub ahead of print]352 637-651
    Size optimization of carfilzomib nanocrystals for systemic delivery to solid tumors.
    Hytham H Gadalla, Seongsoo Lee, Hyungjun Kim, Abigail T Armstrong, Dina Fathalla, Fawzia Habib, Hyunyoung Jeong, Wooin Lee, Yoon Yeo.
      Carfilzomib (CFZ) is a second-generation proteasome inhibitor effective in blood cancer therapy. However, CFZ has shown limited efficacy in solid tumor therapy due to the short half-life and poor tumor distribution. Albumin-coated nanocrystal (NC) formulation was shown to improve the circulation stability of CFZ, but its antitumor efficacy remained suboptimal. We hypothesize that NC size reduction is critical to the formulation safety and efficacy as the small size would decrease the distribution in the reticuloendothelial system (RES) and selectively increase the uptake by tumor cells. We controlled the size of CFZ-NCs by varying the production parameters in the crystallization-in-medium method and compared the size-reduced CFZ-NCs (z-average of 168 nm, NC168) with a larger counterpart (z-average of 325 nm, NC325) as well as the commercial CFZ formulation (CFZ-CD). Both CFZ-NCs showed similar or higher cytotoxicity than CFZ-CD against breast cancer cells. NC168 showed greater uptake by cancer cells, less uptake by macrophages and lower immune cell toxicity than NC325 or CFZ-CD. NC168, but not NC325, showed a similar safety profile to CFZ-CD in vivo. The biodistribution and antitumor efficacy of CFZ-NCs in mice were also size-dependent. NC168 showed greater antitumor efficacy and tumor accumulation but lower RES accumulation than NC325 in 4T1 breast cancer model. These results support that NC formulation with an optimal particle size can improve the therapeutic efficacy of CFZ in solid tumors.
    Keywords:  Biodistribution; Cancer chemotherapy; Nanocrystals; Proteasome inhibitor; Reticuloendothelial uptake; Size optimization
    DOI:  https://doi.org/10.1016/j.jconrel.2022.10.041
  131. Int J Biol Macromol. 2022 Oct 30. pii: S0141-8130(22)02511-9. [Epub ahead of print]
    Cisplatin conjugation with an exopolysaccharide extracted from Lactobacillus gasseri potentiates its efficacy and attenuates its toxicity.
    Nisha Sharma, Shaheen Wasil Kabeer, Inder Pal Singh, Kulbhushan Tikoo.
      The development of newer cisplatin analogs is constantly being investigated owing to its low solubility, poor pharmacokinetics, and dose-related toxicity. In order to address the limitations of current cisplatin therapy, the present study was undertaken. Cisplatin conjugation with an exopolysaccharide extracted from Lactobacillus gasseri (LG-EPS) showed remarkably enhanced and selective anticancer activity by targeting tumor cells overexpressing glucose transporter 1 (GLUT1). The EPS-cisplatin complex exhibited a 600-fold increase in aqueous solubility with a better pharmacokinetic profile (longer half-life) in comparison to cisplatin. Cell viability assay and western blotting demonstrated a strong correlation between the cytotoxicity profile and GLUT1 expressions in different cell lines. The concentration of DNA-bound platinum was also found to be significantly higher in EPS-cisplatin-treated cells. Quercetin, a competitive inhibitor of GLUTs, was shown to prevent this selective uptake of EPS-cisplatin complex. Surprisingly, EPS-cisplatin complex showed an exceptionally safer profile (4 times the maximum tolerated dose of cisplatin) in the acute toxicity study and was also more efficacious against the xenograft mice model. The study suggests that this green glycoconjugation can be an effective and safer strategy to broaden the therapeutic potential of anti-cancer drugs in general and cisplatin in particular.
    Keywords:  Cancer; Cisplatin; Exopolysaccharide; Targeted-therapy; Warburg effect
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.10.256
  132. Pharmaceutics. 2022 Oct 25. pii: 2283. [Epub ahead of print]14(11):
    Design, Preparation and Evaluation of Supramolecular Complexes with Curcumin for Enhanced Cytotoxicity in Breast Cancer Cell Lines.
    Hamdy Abdelkader, Adel Al Fatease, Zeinab Fathalla, Mai E Shoman, Heba A Abou-Taleb, Mohammed A S Abourehab.
      Curcumin is one of the most researched phytochemicals by pharmacologists and formulation scientists to unleash its potential therapeutic benefits and tackle inherent biopharmaceutic problems. In this study, the native β-cyclodextrin (CD) and three derivatives, namely, Captisol (sulfobutyl ether β-CD), hydroxypropyl β-cyclodextrin, and hydroxyethyl β-cyclodextrin were investigated for inclusion complexes with curcumin using two preparation methods (physical mixing and solvent evaporation). The prepared complexes were studied for docking, solubility, FTIR, DSC, XRD, and dissolution rates. The best-fitting curcumin: cyclodextrins (the latter of the two CDs) were evaluated for cytotoxicity using human breast cell lines (MCF-7). Dose-dependent cytotoxicity was recorded as IC50% for curcumin, curcumin: hydroxyethyl β-cyclodextrin, and curcumin: hydroxypropyl β-cyclodextrin were 7.33, 7.28, and 19.05 µg/mL, respectively. These research findings indicate a protective role for the curcumin: hydroxypropyl β-cyclodextrin complex on the direct cell lines of MCF-7.
    Keywords:  MCF-7; curcumin; cyclodextrins; cytotoxicity; hydroxyethyl β-cyclodextrin; solubility
    DOI:  https://doi.org/10.3390/pharmaceutics14112283
  133. Cells. 2022 Oct 31. pii: 3433. [Epub ahead of print]11(21):
    Multi-Target Potential of Berberine as an Antineoplastic and Antimetastatic Agent: A Special Focus on Lung Cancer Treatment.
    Ijeoma Theresa Achi, Paromita Sarbadhikary, Blassan P George, Heidi Abrahamse.
      Despite therapeutic advancements, lung cancer remains the principal cause of cancer mortality in a global scenario. The increased incidence of tumor reoccurrence and progression and the highly metastatic nature of lung cancer are of great concern and hence require the investigation of novel therapies and/or medications. Naturally occurring compounds from plants serve as important resources for novel drugs for cancer therapy. Amongst these phytochemicals, Berberine, an alkaloid, has been extensively explored as a potential natural anticancer therapeutic agent. Several studies have shown the effectiveness of Berberine in inhibiting cancer growth and progression mediated via several different mechanisms, which include cell cycle arrest, inducing cell death by apoptosis and autophagy, inhibiting cell proliferation and invasion, as well as regulating the expression of microRNA, telomerase activity, and the tumor microenvironment, which usually varies for different cancer types. In this review, we aim to provide a better understanding of molecular insights of Berberine and its various derivative-induced antiproliferative and antimetastatic effects against lung cancer. In conclusion, the Berberine imparts its anticancer efficacy against lung cancers via modulation of several signaling pathways involved in cancer cell viability and proliferation, as well as migration, invasion, and metastasis.
    Keywords:  apoptosis; autophagy; berberine; cell proliferation; lung cancer; metastasis; phytochemicals; signaling pathways
    DOI:  https://doi.org/10.3390/cells11213433
  134. Molecules. 2022 Oct 30. pii: 7377. [Epub ahead of print]27(21):
    Interactions between Gut Microbiota and Polyphenols: New Insights into the Treatment of Fatigue.
    Chuanhong Luo, Xichuan Wei, Jiao Song, Xiaorong Xu, Haozhou Huang, Sanhu Fan, Dingkun Zhang, Li Han, Junzhi Lin.
      Fatigue seriously affects people's work efficiency and quality of life and has become a common health problem in modern societies around the world. The pathophysiology of fatigue is complex and not fully clear. To some degree, interactions between gut microbiota and host may be the cause of fatigue progression. Polyphenols such as tannin, tea polyphenols, curcumin, and soybean isoflavones relieve fatigue significantly. Studies have shown that the gut microbiota is able to convert these active compounds into more active metabolites through intestinal fermentation. However, the mechanism of anti-fatigue polyphenols is currently mainly analyzed from the perspective of antioxidant and anti-inflammatory effects, and changes in gut microbiota are rarely considered. This review focuses on gut microecology and systematically summarizes the latest theoretical and research findings on the interaction of gut microbiota, fatigue, and polyphenols. First, we outline the relationship between gut microbiota and fatigue, including changes in the gut microbiota during fatigue and how they interact with the host. Next, we describe the interactions between the gut microbiota and polyphenols in fatigue treatment (regulation of the gut microbiota by polyphenols and metabolism of polyphenols by the gut microbiota), and how the importance of potential active metabolites (such as urolithin) produced by the decomposition of polyphenols by gut microbiota is emerging. Based on the new perspective of gut microbiota, this review provides interesting insights into the mechanism of polyphenols in fatigue treatment and clarifies the potential of polyphenols as targets for anti-fatigue product development, aiming to provide a useful basis for further research and design.
    Keywords:  fatigue; gut microbiota; interaction; polyphenols; urolithin
    DOI:  https://doi.org/10.3390/molecules27217377
  135. Sci Rep. 2022 Nov 11. 12(1): 19299
    Numerical and experimental evaluation of ultrasound-assisted convection enhanced delivery to transfer drugs into brain tumors.
    Ahmad Boroumand, Mehrnoush Mehrarya, Ashkan Ghanbarzadeh-Dagheyan, Mohammad Taghi Ahmadian.
      Central Nervous System (CNS) malignant tumors are a leading cause of death worldwide with a high mortality rate. While numerous strategies have been proposed to treat CNS tumors, the treatment efficacy is still low mainly due to the existence of the Blood-Brain Barrier (BBB). BBB is a natural cellular layer between the circulatory system and brain extracellular fluid, limiting the transfer of drug particles and confining the routine treatment strategies in which drugs are released in the blood. Consequently, direct drug delivery methods have been devised to bypass the BBB. However, the efficiency of these methods is not enough to treat deep and large brain tumors. In the study at hand, the effect of focused ultrasound (FUS) waves on enhancing drug delivery to brain tumors, through ultrasound-assisted convection-enhanced delivery (UCED), has been investigated. First, brain mimicking gels were synthesized to mimic the CNS microenvironment, and the drug solution was injected into them. Second, FUS waves with the resonance frequency of 1.1 MHz were applied to the drug injected zone. Next, a finite element (FE) model was developed to evaluate the pre-existing equation in the literature for describing the drug delivery via acoustic streaming in brain tissue. Experimental results showed that the FUS transducer was able to enhance the drug volume distribution up to 500% relative to convection-enhanced delivery alone (CED). Numerical analysis showed that the FE model could replicate the experimental penetration depths with a mean difference value of less than 21%, and acoustic streaming plays a significant role in UCED. Therefore, the results of this study could open a new way to develop FE models of the brain to better evaluate the UCED and reduce the costs of conducting clinical and animal studies.
    DOI:  https://doi.org/10.1038/s41598-022-23429-w
  136. Biomater Sci. 2022 Nov 11.
    Oxygen self-supplied upconversion nanoplatform loading cerium oxide for amplified photodynamic therapy of hypoxic tumors.
    Yunjian Xu, Kexin Wang, Zhenjiang Chen, Rui Hu, Yihua Zhao, Xiang Li, Junle Qu, Liwei Liu.
      Photodynamic therapy (PDT) has been widely used in preclinical trials for treating various tumors. However, the hypoxic environment of tumors and the limited penetration depth of ultraviolet light severely weaken the PDT effect. To solve the above problems, a near-infrared (NIR) light-triggered oxygen (O2) self-supplied phototherapeutic platform (UCNPs/CeO2/Ce6/BSA) for amplified PDT performance against solid tumors by alleviating tumor hypoxia has been rationally developed. The platform has excellent stability and can continuously decompose H2O2 for sustained O2 supply to synergize 1O2 generation, thus inducing an enhanced mortality rate (59%) of ID8 cells in vitro under hypoxic + H2O2 conditions. The growth of solid tumors was effectively inhibited and the mouse survival rate was dramatically enhanced via a superior PDT therapeutic performance. This reported study facilitated the positive development of multifunctional diagnosis and treatment platforms under long-wavelength excitation for O2 self-supplied tumor treatments.
    DOI:  https://doi.org/10.1039/d2bm01455f
  137. Life (Basel). 2022 Nov 02. pii: 1762. [Epub ahead of print]12(11):
    Nutraceutical Preventative and Therapeutic Potential in Neuroblastoma: From Pregnancy to Early Childhood.
    Maddalena Sbaffone, Marianna Ruggieri, Michela Sebastiano, Andrew Reay Mackay, Veronica Zelli, Antonietta Rosella Farina, Lucia Annamaria Cappabianca.
      Neuroblastoma (NB) is a highly malignant embryonic extracranial solid tumor that arises from sympathoadrenal neuroblasts of neural crest origin. In addition to genetic factors, NB has been linked to maternal exposure to a variety of substances during pregnancy. Recent interest in the potential of nutrients to prevent cancer and reduce malignancy has resulted in the identification of several nutraceuticals including resveratrol, curcumin, and molecular components of garlic, which together with certain vitamins may help to prevent NB development. As NBs arise during fetal development and progress during early childhood, specific NB inhibiting nutraceuticals and vitamins could enhance the preventative influence of maternal nutrition and breast feeding on the development and early progression of NB. In this article, we review NB inhibitory nutraceuticals and vitamins, their mechanisms of action and expound their potential as maternal nutritional supplements to reduce NB development and progression during fetal growth and early childhood, whilst at the same time enhancing maternal, fetal, and infant health.
    Keywords:  neuroblastoma; nutraceuticals; pregnancy; prevention; therapy
    DOI:  https://doi.org/10.3390/life12111762
  138. Nanoscale Adv. 2022 Oct 25. 4(21): 4617-4627
    Highly biocompatible chlorin e6-poly(dopamine) core-shell nanoparticles for enhanced cancer phototherapy.
    Shilin Chen, Yihang Jiang, Miaozhaung Fan, Xinmeng Zhang, Ying Zhang, Ting Chen, Chengbin Yang, Wing-Cheung Law, Zhourui Xu, Gaixia Xu.
      Cancer is a life-threatening disease worldwide. Although several approaches, such as surgery, chemotherapy, and radiotherapy, have been proven effective for many patients in clinics, they usually suffer from drug resistance, severe toxic-side effects, patient discomfort, and sometimes, unsatisfactory efficacies. In recent years, phototherapy, as a less invasive but effective therapeutic method, has brought hope for cancer treatment. However, most reported photo-therapeutic agents are constructed using complex components with non-negligible toxicity risk, thus retarding the start of their clinical trials. To address this issue, herein, biocompatible photothermal/photodynamic dual-mode therapeutic nanoparticles (CBP NPs) were successfully designed and constructed based on the Food and Drug Administration (FDA)-approved ingredients, chlorin e6 (Ce6) and poly(dopamine) (PDA). Upon light irradiation, hyperthermia was induced and reactive oxygen species (ROS) were generated simultaneously by CBP NPs, contributing to synergistic phototherapy toward cancer. The in vitro and in vivo experiments have demonstrated well the antitumor effect of CBP NPs. More importantly, CBP NPs are completely harmless and degradable in vivo. Together, the CBP NPs developed by us are an ideal candidate for the enhanced phototherapy of tumors, which holds great potential for future clinical translation.
    DOI:  https://doi.org/10.1039/d2na00504b
  139. Explor Target Antitumor Ther. 2022 ;3(5): 643-658
    Potential role of resveratrol and its nano-formulation as anti-cancer agent.
    Akshay Kumar, Balak Das Kurmi, Amrinder Singh, Dilpreet Singh.
      The uncontrolled and metastatic nature of cancer makes it worse and more unpredictable. Hence, many therapy and medication are used to control and treat cancer. However, apart from this, many medications cause various side effects. In America, nearly 8% of patients admitted to the hospital are due to side effects. Cancer is more seen in people residing in developed countries related of their lifestyle. There are various phytoconstituents molecules in which resveratrol (RSV) is the best-fitted molecule for cancer due to its significantly less adverse effect on the body. RSV inhibits the initiation and progression of cell proliferation due to the modulation of various pathways like the phosphoinositol 3 kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway. RSV downgraded cell cycle-regulated proteins like cyclin E, cyclin D1, and proliferating cell nuclear antigen (PCNA) and induced the release of cytochrome c from the mitochondria, causing apoptosis or programmed cell death (PCD). A great benefit comes with some challenges, hence, RSV does suffer from poor solubility in water i.e. 0.05 mg/mL. It suffers from poor bioavailability due to being highly metabolized by the liver and intestine. Surprisingly, RSV metabolites also induce the metabolism of RSV. Hence, significantly less amount of RSV presented in the urine in the unchanged form. Due to some challenges like poor bioavailability, less aqueous solubility, and retention time in the body, researchers concluded to make the nanocarriers for better delivery. Adopting the technique of nano-formulations, increased topical penetration by up to 21%, improved nano-encapsulation and consequently improved bioavailability and permeability by many folds. Hence, the present review describes the complete profile of RSV and its nano-formulations for improving anti-cancer activity along with a patent survey.
    Keywords:  Resveratrol; cancer; nano-formulations; solubility; synergism
    DOI:  https://doi.org/10.37349/etat.2022.00105
  140. Molecules. 2022 Oct 24. pii: 7201. [Epub ahead of print]27(21):
    Development of Genistein Drug Delivery Systems Based on Bacterial Nanocellulose for Potential Colorectal Cancer Chemoprevention: Effect of Nanocellulose Surface Modification on Genistein Adsorption.
    Melissa Castaño, Estefanía Martínez, Marlon Osorio, Cristina Castro.
      Genistein is an isoflavone with antioxidant, anti-inflammatory, and anticancer properties. That said, its use in the industry is limited by its low solubility in aqueous systems. In this work, bacterial nanocellulose (BNC) and BNC modified with cetyltrimethylammonium (BNC-CTAB) were evaluated as genistein-encapsulating materials for their controlled release in cancer chemoprevention. Thin films were obtained and characterized by contact angle, AFM, TEM, UV-Vis spectroscopy FTIR, and TGA techniques to verify surface modification and genistein encapsulation. The results show a decrease in hydrophilization degree and an increase in diameter after BNC modification. Furthermore, the affinity of genistein with the encapsulating materials was determined in the context of monolayer and multilayer isotherms, thermodynamic parameters and adsorption kinetics. Spontaneous, endothermic and reversible adsorption processes were found for BNC-GEN and BNC-CTAB-GEN. After two hours, the maximum adsorption capacity corresponded to 4.59 mg GEN∙g-1 BNC and 6.10 mg GEN∙g-1 BNC-CTAB; the latter was a more stable system. Additionally, in vitro release assays performed with simulated gastrointestinal fluids indicated controlled and continuous desorption in gastric and colon fluids, with a release of around 5% and 85%, respectively, for either system. Finally, the IC50 tests made it possible to determine the amounts of films required to achieve therapeutic concentrations for SW480 and SW620 cell lines.
    Keywords:  bacterial nanocellulose; colorectal cancer; controlled drug delivery system; genistein; surface modification
    DOI:  https://doi.org/10.3390/molecules27217201
  141. Int J Mol Sci. 2022 Oct 25. pii: 12875. [Epub ahead of print]23(21):
    Breast Cancer with Increased Drug Resistance, Invasion Ability, and Cancer Stem Cell Properties through Metabolism Reprogramming.
    Kian-Hwee Chong, Yao-Jen Chang, Wei-Hsin Hsu, Ya-Ting Tu, Yi-Ru Chen, Ming-Cheng Lee, Kuo-Wang Tsai.
      Breast cancer is a heterogeneous disease, and the survival rate of patients with breast cancer strongly depends on their stage and clinicopathological features. Chemoradiation therapy is commonly employed to improve the survivability of patients with advanced breast cancer. However, the treatment process is often accompanied by the development of drug resistance, which eventually leads to treatment failure. Metabolism reprogramming has been recognized as a mechanism of breast cancer resistance. In this study, we established a doxorubicin-resistant MCF-7 (MCF-7-D500) cell line through a series of long-term doxorubicin in vitro treatments. Our data revealed that MCF-7-D500 cells exhibited increased multiple-drug resistance, cancer stemness, and invasiveness compared with parental cells. We analyzed the metabolic profiles of MCF-7 and MCF-7-D500 cells through liquid chromatography-mass spectrometry. We observed significant changes in 25 metabolites, of which, 21 exhibited increased levels (&gt;1.5-fold change and p &lt; 0.05) and 4 exhibited decreased levels (&lt;0.75-fold change and p &lt; 0.05) in MCF-7 cells with doxorubicin resistance. These results suggest the involvement of metabolism reprogramming in the development of drug resistance in breast cancer, especially the activation of glycolysis, the tricarboxylic acid (TCA) cycle, and the hexamine biosynthesis pathway (HBP). Furthermore, most of the enzymes involved in glycolysis, the HBP, and the TCA cycle were upregulated in MCF-7-D500 cells and contributed to the poor prognosis of patients with breast cancer. Our findings provide new insights into the regulation of drug resistance in breast cancer, and these drug resistance-related metabolic pathways can serve as targets for the treatment of chemoresistance in breast cancer.
    Keywords:  breast cancer; drug-resistant; glycolysis; hexamine biosynthesis pathway; metabolism; tricarboxylic acid cycle
    DOI:  https://doi.org/10.3390/ijms232112875
  142. Vet World. 2022 Sep;15(9): 2323-2332
    Enhancement of curcumin level and hepatoprotective effect in rats through antioxidant activity following modification into nanosized particles.
    Ni Made Dwi Sandhiutami, Rika Sari Dewi, Sondang Khairani, Raka Nitya Agasti Putri.
      Background and Aim: Developing curcumin into nanosized particles is one of the approaches to overcome the limited use of curcumin. This study aimed to prepare curcumin into nanosized particles to increase the curcumin level in the rat's liver and hepatoprotective effect in rats.Materials and Methods: Curcumin into nanosized particles formulated using ionic gelation method. Rats were divided into four groups (n = 6): Normal, negative, curcumin, and curcumin modified into nanosized particles were treated with 100 mg/kg body weight orally for 14 days. Hepatic curcumin level was investigated using liquid chromatography with tandem mass spectrometry, antioxidant activity by malondialdehyde (MDA), and hepatoprotective effect by aspartate transaminase (AST), alanine transaminase (ALT), and histopathology.
    Results: The curcumin level in the rat's liver in the curcumin group was 12.19 ng/mL, and that in those receiving modified into nanosized curcumin was 209.36 ng/mL. The MDA levels in the normal, negative, curcumin, and curcumin modified into nanosized particles groups were 1.88, 4.87, 3.38, and 1.04 nmol/L, respectively. The AST levels in these groups were 57.12, 130.00, 102.13, and 74.28 IU/L, and the ALT levels were 21.63, 61.97, 39.38, and 28.55 IU/L. The liver histopathology scoring showed that curcumin in nanosized particles was better than curcumin in degeneration of fat, lymphocyte infiltration, and necrosis.
    Conclusion: There was a 17 times increase in curcumin level in the liver of rats treated with curcumin modified into nanosized particles. Curcumin modified into nanosized particles showed more significant improvement as antioxidant and hepatoprotector than curcumin.
    Keywords:  antioxidant; curcumin modified into nanosized particles; hepatoprotective
    DOI:  https://doi.org/10.14202/vetworld.2022.2323-2332
  143. Brain Tumor Res Treat. 2022 Oct;10(4): 221-225
    Medical Treatment of Pediatric Low-Grade Glioma.
    Yeon Jung Lim.
      Low-grade glioma (LGG) is the most common brain tumor in children and has excellent long-term survival. With an excellent survival rate, the choice of treatment involves careful consideration of minimizing late toxicity from surgery, radiation, and chemotherapy. Surgery, radiation therapy, and chemotherapy can be used as monotherapy or in combination, providing different therapeutic ratios and complications. As a result, establishing the selection of ideal therapies has been a controversial area, presenting challenges. Recent advances in understanding molecular characteristics of pediatric LGG affect classification and treatment approaches. This review aims to overview recent developments in medical treatment in pediatric LGG.
    Keywords:  Chemotherapy; Low grade glioma; Pediatric brain tumor; Target therapy
    DOI:  https://doi.org/10.14791/btrt.2022.0039
  144. Cell Death Dis. 2022 Nov 05. 13(11): 925
    Ferroptosis: a double-edged sword mediating immune tolerance of cancer.
    Qin Dang, Ziqi Sun, Yang Wang, Libo Wang, Zaoqu Liu, Xinwei Han.
      The term ferroptosis was put forward in 2012 and has been researched exponentially over the past few years. Ferroptosis is an unconventional pattern of iron-dependent programmed cell death, which belongs to a type of necrosis and is distinguished from apoptosis and autophagy. Actuated by iron-dependent phospholipid peroxidation, ferroptosis is modulated by various cellular metabolic and signaling pathways, including amino acid, lipid, iron, and mitochondrial metabolism. Notably, ferroptosis is associated with numerous diseases and plays a double-edged sword role. Particularly, metastasis-prone or highly-mutated tumor cells are sensitive to ferroptosis. Hence, inducing or prohibiting ferroptosis in tumor cells has vastly promising potential in treating drug-resistant cancers. Immunotolerant cancer cells are not sensitive to the traditional cell death pathway such as apoptosis and necroptosis, while ferroptosis plays a crucial role in mediating tumor and immune cells to antagonize immune tolerance, which has broad prospects in the clinical setting. Herein, we summarized the mechanisms and delineated the regulatory network of ferroptosis, emphasized its dual role in mediating immune tolerance, proposed its significant clinical benefits in the tumor immune microenvironment, and ultimately presented some provocative doubts. This review aims to provide practical guidelines and research directions for the clinical practice of ferroptosis in treating immune-resistant tumors.
    DOI:  https://doi.org/10.1038/s41419-022-05384-6
  145. Molecules. 2022 Oct 22. pii: 7143. [Epub ahead of print]27(21):
    Synthesis and Biological Evaluation of PEGylated MWO4 Nanoparticles as Sonodynamic AID Inhibitors in Treating Diffuse Large B-Cell Lymphoma.
    Junna Jiao, Zhuang Qian, Yurong Wang, Mei Liu, Liye Fan, Mengqing Liu, Zichen Hao, Junrong Jiao, Zhuangwei Lv.
      Sonodynamic therapy (SDT) triggered by ultrasound (US) has attracted increasing attention owing to its ability to overcome critical limitations, including low tissue-penetration depth and phototoxicity in photodynamic therapy (PDT). Biogenic metal oxide nanoparticles (NPs) have been used as anti-cancer drugs due to their biocompatibility properties with most biological systems. Here, sonosensitizer MWO4-PEG NPs (M = Fe Mn Co Ni) were synthesized as inhibitors to activation-induced cytidine deaminase (AID), thus neutralizing the extensive carcinogenesis of AID in diffuse large B-cell lymphoma (DLBCL). The physiological properties of these nanomaterials were examined using transmission electron microscopy (TEM). The inhibition of NPs to AID was primarily identified by the affinity interaction prediction between reactive oxygen species (ROS) and AID through molecular dynamics and molecular docking technology. The cell apoptosis and ROS generation in US-triggered NPs treated DLBCL cells (with high levels of AID) were also detected to indicate the sonosensitivity and toxicity of MWO4-PEG NPs to DLBCL cells. The anti-lymphoma studies using DLBCL and AID-deficient DLBCL cell lines indicated a concentration-dependent profile. The synthesized MWO4-PEG NPs in this study manifested good sonodynamic inhibitory effects to AID and well treatment for AID-positive hematopoietic cancers.
    Keywords:  DLBCL treatment; PEGylated MWO4 nanoparticles; activation-induced cytidine deaminase; inhibitors
    DOI:  https://doi.org/10.3390/molecules27217143
  146. Pharmaceuticals (Basel). 2022 Oct 26. pii: 1320. [Epub ahead of print]15(11):
    Long-Term Fenofibrate Treatment Stimulates the Phenotypic Microevolution of Prostate Cancer Cells In Vitro.
    Karolina W Warzecha, Maciej Pudełek, Jessica Catapano, Zbigniew Madeja, Jarosław Czyż.
      Fenofibrate is a widely used anti-hyperlipidemic agonist of peroxisome proliferator-activated receptor alpha (PPARα). As a metabolic blocker, fenofibrate interferes with cancer promotion/progression via its misbalancing effects on cellular metabolism. However, the consequences of its long-term application for patients with diagnosed drug-resistant cancers are unknown. We addressed this point by tracing the phenotypic microevolution of naïve and drug-resistant prostate cancer PC3_DCX20 cells that underwent a long-term exposition to 10 μM and 50 μM fenofibrate. Their resistance to fenofibrate, metabolic profile and invasive phenotype were estimated in the control conditions and under fenofibrate-induced stress. Apparently, drug efflux systems are not effective against the cytostatic FF action. However, wtPC3 and PC3_DCX20 cells that survived the long-term 50 μM fenofibrate treatment gave rise to lineages that displayed an increased proliferation rate, lower motility in the control conditions and enhanced fenofibrate resistance. Attenuated fenofibrate bioavailability modified the pattern of PC3 microevolution, as illustrated by phenotypic differences between wtPC3/PC3_DCX20 lineages propagated in the presence of 50 μM and 10 μM fenofibrate. Collectively, our observations indicate that fenofibrate acts as a selective factor that affects prostate cancer microevolution. We also pinpoint potential consequences of long-term exposition of prostate cancer patients to metabolic blockers.
    Keywords:  drug resistance; fenofibrate; microevolution; prostate cancer
    DOI:  https://doi.org/10.3390/ph15111320
  147. J Mater Chem B. 2022 Nov 07.
    Chondroitin sulfate-based composites: a tour d'horizon of their biomedical applications.
    Mohammed A S Abourehab, Shreya Baisakhiya, Akanksha Aggarwal, Anshul Singh, Mohamed A Abdelgawad, A Deepak, Mohammad Javed Ansari, Sheersha Pramanik.
      Chondroitin sulfate (CS), a natural anionic mucopolysaccharide, belonging to the glycosaminoglycan family, acts as the primary element of the extracellular matrix (ECM) of diverse organisms. It comprises repeating units of disaccharides possessing β-1,3-linked N-acetyl galactosamine (GalNAc), and β-1,4-linked D-glucuronic acid (GlcA), and exhibits antitumor, anti-inflammatory, anti-coagulant, anti-oxidant, and anti-thrombogenic activities. It is a naturally acquired bio-macromolecule with beneficial properties, such as biocompatibility, biodegradability, and immensely low toxicity, making it the center of attention in developing biomaterials for various biomedical applications. The authors have discussed the structure, unique properties, and extraction source of CS in the initial section of this review. Further, the current investigations on applications of CS-based composites in various biomedical fields, focusing on delivering active pharmaceutical compounds, tissue engineering, and wound healing, are discussed critically. In addition, the manuscript throws light on preclinical and clinical studies associated with CS composites. A short section on Chondroitinase ABC has also been canvassed. Finally, this review emphasizes the current challenges and prospects of CS in various biomedical fields.
    DOI:  https://doi.org/10.1039/d2tb01514e
  148. Clin Transl Med. 2022 Nov;12(11): e1094
    Anti-inflammatory hydrogel dressings and skin wound healing.
    Can Huang, Lanlan Dong, Baohua Zhao, Yifei Lu, Shurun Huang, Zhiqiang Yuan, Gaoxing Luo, Yong Xu, Wei Qian.
      Hydrogels are promising and widely utilized in the biomedical field. In recent years, the anti-inflammatory function of hydrogel dressings has been significantly improved, addressing many clinical challenges presented in ongoing endeavours to promote wound healing. Wound healing is a cascaded and highly complex process, especially in chronic wounds, such as diabetic and severe burn wounds, in which adverse endogenous or exogenous factors can interfere with inflammatory regulation, leading to the disruption of the healing process. Although insufficient wound inflammation is uncommon, excessive inflammatory infiltration is an almost universal feature of chronic wounds, which impedes a histological repair of the wound in a predictable biological step and chronological order. Therefore, resolving excessive inflammation in wound healing is essential. In the past 5 years, extensive research has been conducted on hydrogel dressings to address excessive inflammation in wound healing, specifically by efficiently scavenging excessive free radicals, sequestering chemokines and promoting M1 -to-M2 polarization of macrophages, thereby regulating inflammation and promoting wound healing. In this study, we introduced novel anti-inflammatory hydrogel dressings and demonstrated innovative methods for their preparation and application to achieve enhanced healing. In addition, we summarize the most important properties required for wound healing and discuss our analysis of potential challenges yet to be addressed.
    Keywords:  anti-inflammatory; chemokines; hydrogel dressings; reactive oxygen species (ROS); wound healing
    DOI:  https://doi.org/10.1002/ctm2.1094
  149. Int J Pharm. 2022 Oct 28. pii: S0378-5173(22)00900-0. [Epub ahead of print]628 122345
    Radioiodinated acemetacin loaded niosomes as a dual anticancer therapy.
    Mona A Shewaiter, Adli A Selim, Yasser M Moustafa, Shadeed Gad, Hassan M Rashed.
      A niosomal formula of acemetacin was developed to improve its tumor targeting and radio-kinetic evaluation was performed using 131I. Niosomes were prepared by ether injection method and characterized for particle size (PS), polydispersity index (PDI), zeta potential (ZP), entrapment efficiency (EE%) and in vitro drug release. Factors affecting radiolabeling with 131I were studied and optimized. Radio-kinetic evaluation was done for 131I-ACM optimum niosomal formula by intravenous (I.V) administration to solid tumor bearing mice and compared to I.V 131I-ACM solution as a control. The average droplet size, zeta potential and in vitro release after 24 h for the optimum formula were 315.23 ± 5.37 nm, -9.16 ± 2.91 and 76 %, respectively. The greatest labeling yield of 131I-ACM was 93.1 ± 1.1 %. Radio-kinetic evaluation showed a maximum tumor uptake of 5.431 %ID/g for 131I-ACM niosomal formula and 2.601 %ID/g for 131I-ACM solution at 60 min post I.V. injection. As a conclusion, niosomal formula increased tumor uptake of ACM by passive targeting of the nanosized niosomes. In addition, chemotherapeutic effect of ACM and radiotherapeutic effect of 131I were successfully combined in one treatment regimen using 131I-ACM niosomes which could be used as a hopeful dual anticancer therapy.
    Keywords:  (131)I; Acemetacin; Anticancer; Niosomes; Radiolabeling
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.122345
  150. Biointerphases. 2022 Nov 11. 17(6): 061004
    Fine-tuned magnetic nanobubbles for magnetic hyperthermia treatment of glioma cells.
    Bin Li, Yuexia Han, Yang Liu, Fang Yang.
      Magnetic nanoparticle (MNP) induced magnetic hyperthermia has been demonstrated as a promising technique for the treatment of brain tumor. However, lower heating efficiency resulting from low intratumoral accumulation of magnetic nanomaterials is still one of the significant limitations for their thermotherapeutic efficacy. In this study, we have designed a nanobubble structure with MNPs decorated on the shell, which leads to the improvement of magnetocaloric performance under an alternating magnetic field. First, the phospholipid coupled with MNPs as the shell to be self-assembled magnetic nanobubbles (MNBs) was fabricated by a temperature-regulated repeated compression self-assembly approach. Then, the optimal magnetic heating concentration, electric current parameters for producing the magnetic field, and the number of magnetic heating times were investigated for tuning the better magnetoenergy conversion. Finally, the well-defined geometrical orientation of MNPs on the nanobubble structure enhanced hypothermia effect was investigated. The results demonstrate that the MNBs could promote the endocytosis of magnetic nanoparticles by glioma cells, resulting in better therapeutic effect. Therefore, the controlled assembly of MNPs into well-defined bubble structures could serve as a new hyperthermia agent for tumor therapy.
    DOI:  https://doi.org/10.1116/6.0002110
  151. Cell Biol Int. 2022 Nov 07.
    Recent advances in cold atmospheric plasma (CAP) for breast cancer therapy.
    Supat Chupradit, Gunawan Widjaja, Basman Radhi Majeed, Maria Kuznetsova, Mohammad Javed Ansari, Wanich Suksatan, Abduladheem Turki Jalil, Bahar Ghazi Esfahani.
      The serious problems of conventional breast cancer therapy strategies such as drug resistance, severe side effects, and lack of selectivity prompted the development of various cold atmospheric plasma (CAP) devices. Due to its advanced technology, CAP can produce a unique environment rich in reactive oxygen and nitrogen species (RONS), photons, charged ions, and an electric field, making it a promising revolutionary platform for cancer therapy. Despite substantial technological successes, CAP-based therapeutic systems are encounter with distinct limitations, including low control of the generated RONS, poor knowledge about its anticancer mechanisms, and challenges concerning designing, manufacturing, clinical translation, and commercialization, which must be resolved. The latest developments in CAP-based therapeutic systems for breast cancer treatment are discussed in this review. More significantly, the integration of CAP-based medicine approaches with other breast cancer therapies, including chemo- and nanotherapy is thoroughly addressed.
    Keywords:  breast cancer; cold atmospheric plasma (CAP); plasma medicine; reactive nitrogen species (RNS); reactive oxygen species (ROS)
    DOI:  https://doi.org/10.1002/cbin.11939
  152. Pharmaceutics. 2022 Nov 08. pii: 2404. [Epub ahead of print]14(11):
    Sequential Delivery of Novel Triple Drug Combination via Crosslinked Alginate/Lactoferrin Nanohybrids for Enhanced Breast Cancer Treatment.
    Mai Salah, Marwa A Sallam, Mona A Abdelmoneem, Mohamed Teleb, Kadria A Elkhodairy, Adnan A Bekhit, Asmaa F Khafaga, Ahmed E Noreldin, Ahmed O Elzoghby, Sherine N Khattab.
      While breast cancer remains a global health concern, the elaboration of rationally designed drug combinations coupled with advanced biocompatible delivery systems offers new promising treatment venues. Herein, we repurposed rosuvastatin (RST) based on its selective tumor apoptotic effect and combined it with the antimetabolite pemetrexed (PMT) and the tumor-sensitizing polyphenol honokiol (HK). This synergistic three-drug combination was incorporated into protein polysaccharide nanohybrids fabricated by utilizing sodium alginate (ALG) and lactoferrin (LF), inspired by the stealth property of the former and the cancer cell targeting capability of the latter. ALG was conjugated to PMT and then coupled with LF which was conjugated to RST, forming core shell nanohybrids into which HK was physically loaded, followed by cross linking using genipin. The crosslinked HK-loaded PMT-ALG/LF-RST nanohybrids exhibited a fair drug loading of 7.86, 5.24 and 6.11% for RST, PMT and HK, respectively. It demonstrated an eight-fold decrease in the IC50 compared to the free drug combination, in addition to showing an enhanced cellular uptake by MCF-7 cells. The in vivo antitumor efficacy in a breast cancer-bearing mouse model confirmed the superiority of the triple cocktail-loaded nanohybrids. Conclusively, our rationally designed triple drug-loaded protein/polysaccharide nanohybrids offer a promising, biocompatible approach for an effective breast tumor suppression.
    Keywords:  breast cancer treatment; honokiol; lactoferrin; pemetrexed; protein/polysaccharide nanohybrids; rosuvastatin; sodium alginate
    DOI:  https://doi.org/10.3390/pharmaceutics14112404
  153. Nanomaterials (Basel). 2022 Nov 04. pii: 3899. [Epub ahead of print]12(21):
    Surface Functionalization of Nanofibers: The Multifaceted Approach for Advanced Biomedical Applications.
    Deepak Kulkarni, Shubham Musale, Prabhakar Panzade, Ana Cláudia Paiva-Santos, Pratiksha Sonwane, Monika Madibone, Puja Choundhe, Prabhanjan Giram, Simona Cavalu.
      Nanocarriers are gaining significant importance in the modern era of drug delivery. Nanofiber technology is one of the prime paradigms in nanotechnology for various biomedical and theranostic applications. Nanofibers obtained after successful electrospinning subjected to surface functionalized for drug delivery, biomedical, tissue engineering, biosensing, cell imaging and wound dressing application. Surface functionalization entirely changes physicochemical and biological properties of nanofibers. In physicochemical properties, wettability, melting point, glass transition temperature, and initial decomposition temperature significantly change offer several advantageous for nanofibers. Similarly, biological properties include cell adhesion, biocompatibility, and proliferation, also changes by functionalization of nanofibers. Various natural and synthetic materials polymers, metals, carbon materials, functional groups, proteins, and peptides, are currently used for surface modification of nanofibers. Various research studies across the globe demonstrated the usefulness of surface functionalized nanofibers in tissue engineering, wound healing, skin cancers, melanoma, and disease diagnosis. The delivery of drug through surface functionalized nanofibers results in improved permeation and bioavailability of drug which is important for better targeting of disease and therapeutic efficacy. This review provides a comprehensive insight about various techniques of surface functionalization of nanofibers along with its biomedical applications, toxicity assessment and global patent scenario.
    Keywords:  biomedical applications; electrospinning; nanofibers; surface functionalization
    DOI:  https://doi.org/10.3390/nano12213899
  154. J Nanobiotechnology. 2022 Nov 05. 20(1): 471
    Synergetic delivery of artesunate and isosorbide 5-mononitrate with reduction-sensitive polymer nanoparticles for ovarian cancer chemotherapy.
    Guang Li, Mingjian Ling, Kunyi Yu, Wei Yang, Qiwen Liu, Lijuan He, Xuzi Cai, Min Zhong, Ziyi Mai, Rui Sun, Yuanling Xiao, Zhiqiang Yu, Xuefeng Wang.
      Ovarian cancer is a highly fatal gynecologic malignancy worldwide. Chemotherapy remains the primary modality both for primary and maintenance treatments of ovarian cancer. However, the progress in developing chemotherapeutic agents for ovarian cancer has been slow in the past 20 years. Thus, new and effective chemotherapeutic drugs are urgently needed for ovarian cancer treatment. A reduction-responsive synergetic delivery strategy (PSSP@ART-ISMN) with co-delivery of artesunate and isosorbide 5-mononitrate was investigated in this research study. PSSP@ART-ISMN had various effects on tumor cells, such as (i) inducing the production of reactive oxygen species (ROS), which contributes to mitochondrial damage; (ii) providing nitric oxide and ROS for the tumor cells, which further react to generate highly toxic reactive nitrogen species (RNS) and cause DNA damage; and (iii) arresting cell cycle at the G0/G1 phase and inducing apoptosis. PSSP@ART-ISMN also demonstrated excellent antitumor activity with good biocompatibility in vivo. Taken together, the results of this work provide a potential delivery strategy for chemotherapy in ovarian cancer.
    Keywords:  Artesunate; Cell cycle arrest; DNA damage; Isosorbide 5-mononitrate; Mitochondrial damage; Ovarian cancer
    DOI:  https://doi.org/10.1186/s12951-022-01676-3
  155. Biomolecules. 2022 Nov 07. pii: 1647. [Epub ahead of print]12(11):
    Synergistically Anti-Multiple Myeloma Effects: Flavonoid, Non-Flavonoid Polyphenols, and Bortezomib.
    Kaixi Ding, Wei Jiang, Huanan Jia, Ming Lei.
      Multiple myeloma (MM) is a clonal plasma cell tumor originating from a post-mitotic lymphoid B-cell lineage. Bortezomib(BTZ), a first-generation protease inhibitor, has increased overall survival, progression-free survival, and remission rates in patients with MM since its clinical approval in 2003. However, the use of BTZ is challenged by the malignant features of MM and drug resistance. Polyphenols, classified into flavonoid and non-flavonoid polyphenols, have potential health-promoting activities, including anti-cancer. Previous preclinical studies have demonstrated the anti-MM potential of some dietary polyphenols. Therefore, these dietary polyphenols have the potential to be alternative therapies in anti-MM treatment regimens. This systematic review examines the synergistic effects of flavonoids and non-flavonoid polyphenols on the anti-MM impacts of BTZ. Preclinical studies on flavonoids and non-flavonoid polyphenols-BTZ synergism in MM were collected from PubMed, Web of Science, and Embase published between 2008 and 2020. 19 valid preclinical studies (Published from 2008 to 2020) were included in this systematic review. These studies demonstrated that eight flavonoids (icariin, icariside II, (-)-epigallocatechin-3-gallate, scutellarein, wogonin, morin, formononetin, daidzin), one plant extract rich in flavonoids (Punica granatum juice) and four non-flavonoid polyphenols (silibinin, resveratrol, curcumin, caffeic acid) synergistically enhanced the anti-MM effect of BTZ. These synergistic effects are mediated through the regulation of cellular signaling pathways associated with proliferation, apoptosis, and drug resistance. Given the above, flavonoids and non-flavonoid polyphenols can benefit MM patients by overcoming the challenges faced in BTZ treatment. Despite the positive nature of this preclinical evidence, some additional investigations are still needed before proceeding with clinical studies. For this purpose, we conclude by providing some suggestions for future research directions.
    Keywords:  bortezomib; flavonoids; multiple myeloma; non-flavonoid polyphenols; synergy
    DOI:  https://doi.org/10.3390/biom12111647
  156. Curr Drug Targets. 2022 Nov 04.
    Metformin: a promising antidiabetic medication for cancer treatment.
    Wei Mu, Yunyun Jiang, Guoqiang Liang, Yue Feng, Falin Qu.
      Metformin is a widely used drug in patients with type 2 diabetes mellitus. Metformin inhibits hepatic gluconeogenesis and increases glucose utilization in peripheral tissues. In recent years, several studies have shown that metformin is a potential therapeutic agent against cancer, alone or combined with other anticancer treatments. Metformin mainly activates the AMPK complex and regulates intracellular energy status, inhibiting the mitochondrial respiratory chain complex I and reducing the production of reactive oxygen species. Other anticancer targets of metformin are specific transcription factors inhibiting cell proliferation, promoting apoptosis and reducing drug resistance. In addition, metformin modulates tumor cells response to anticancer treatments, favoring the activity of T cells. In diabetic patients, metformin reduces the occurrence of cancer and improves the prognosis and efficacy of anticancer treatments. In this review, we provided a comprehensive perspective of metformin as an anticancer drug.
    Keywords:  AMPK complex; ICIs.; Metformin; ROS; Sps; anticancer
    DOI:  https://doi.org/10.2174/1389450124666221104094918
  157. Pharmaceutics. 2022 Oct 31. pii: 2353. [Epub ahead of print]14(11):
    Chitosan Nanoparticles Loaded Poloxamer 407 Gel for Transungual Delivery of Terbinafine HCl.
    Kamran Hidayat Ullah, Faisal Rasheed, Iffat Naz, Naveed Ul Haq, Humaira Fatima, Nosheen Kanwal, Tofeeq Ur-Rehman.
      The current study aimed to develop chitosan nanoparticles (CSNP) loaded poloxamer 407 (P407) gel formulation for transungual delivery of terbinafine HCl (TBN). TBN-CSNP were prepared by nanoprecipitation method and optimized by face-centered central composite design (FCCCD). Optimized TBN-CSNP formulation exhibited a spherical shape with hydrodynamic diameter; zeta potential and entrapment efficiency (EE) of 229 ± 5 nm; 37 ± 1.5 mV; and 75 ± 2% respectively. The solid state of TBN and its compatibility with formulation ingredients were confirmed through XRD and FTIR analysis respectively. TBN-CSNP loaded P407 gel exhibited pseudoplastic rheological behavior having a spreadability of 11 ± 2 g·cm/s. The washability study showed that 40 ± 2% of the gel was eroded after washing 12 times. Drug release from TBN-CSNP- and TBN-CSNP-loaded gel was 84 ± 5% and 57 ± 3%, respectively. The cumulative quantity of TBN permeated from TBN-CSNP-loaded P407 gel and TBN-loaded P407 gel was 25 ± 8 and 27 ± 4 µg/cm2, respectively. The nail uptake study showed that 3.6 ± 0.7 and 2.1 ± 0.3 µg of rhodamine was uptaken by the nail following 2 h topical application of TBN-CSNP loaded P407 gel and TBN loaded P407 gel, respectively. Hence, the developed CSNP-based P407 gel formulation can be a potential carrier for transungual delivery of TBN to topically treat onychomycosis.
    Keywords:  chitosan nanoparticles; face-centered central composite design; onychomycosis; poloxamer 407 gel; transungual drug delivery
    DOI:  https://doi.org/10.3390/pharmaceutics14112353
  158. Front Oncol. 2022 ;12 1042125
    Engineered multifunctional nanocarriers for controlled drug delivery in tumor immunotherapy.
    Theodora Katopodi, Savvas Petanidis, Drosos Tsavlis, Doxakis Anestakis, Charalampos Charalampidis, Ioanna Chatziprodromidou, Panagiotis Eskitzis, Paul Zarogoulidis, Christoforos Kosmidis, Dimitris Matthaios, Konstantinos Porpodis.
      The appearance of chemoresistance in cancer is a major issue. The main barriers to conventional tumor chemotherapy are undesirable toxic effects and multidrug resistance. Cancer nanotherapeutics were developed to get around the drawbacks of conventional chemotherapy. Through clinical evaluation of thoughtfully developed nano delivery systems, cancer nanotherapeutics have recently offered unmatched potential to comprehend and combat drug resistance and toxicity. In different design approaches, including passive targeting, active targeting, nanomedicine, and multimodal nanomedicine combination therapy, were successful in treating cancer in this situation. Even though cancer nanotherapy has achieved considerable technological development, tumor biology complexity and heterogeneity and a lack of full knowledge of nano-bio interactions remain important hurdles to future clinical translation and commercialization. The recent developments and advancements in cancer nanotherapeutics utilizing a wide variety of nanomaterial-based platforms to overcome cancer treatment resistance are covered in this article. Additionally, an evaluation of different nanotherapeutics-based approaches to cancer treatment, such as tumor microenvironment targeted techniques, sophisticated delivery methods for the precise targeting of cancer stem cells, as well as an update on clinical studies are discussed. Lastly, the potential for cancer nanotherapeutics to overcome tumor relapse and the therapeutic effects and targeted efficacies of modern nanosystems are analyzed.
    Keywords:  immunotherapy; microneedles; nanocarriers; nanodrugs; nanogel
    DOI:  https://doi.org/10.3389/fonc.2022.1042125
  159. Iran J Biotechnol. 2022 Apr;20(2): e2990
    Evaluation of the Biodistribution of Arginine, glycine, aspartic acid peptide-modified Nanoliposomes Containing Curcumin in Rats.
    Parisa Salehi Najafabadi, Hamdollah Delaviz, Arash Asfaram, Mehrzad Jafari Barmak, Amir Ghanbari, Mohsen Alipour, Parastou Rad, Hassan Bardania.
      Background: Liposomes, as a biological membrane, is successfully used for drug delivery, reduces toxicity in normal cells and improves bio-accessibility of the drug to the target cells. Curcumin, as a bioactive substance with pleiotropic biological activities, is an anti-inflammatory compound and has several anticancer effects in different cancers such as pancreatic and breast cancer.Objectives: This study was conducted to determine the bio-distribution of arginine-glycine-aspartic acid (RGD)-modified nanoliposomes containing curcumin in different tissues of rats.
    Materials and Methods: The amount of curcumin in each tissue was examined by HPLC analysis. The distribution of liposomal Hoechst in the rats was evaluated by using fluorescence spectrophotometry, live animal imaging analyses and histological methods.
    Results: HPLC analysis showed the mean of curcumin in the blood significantly increased in the liposomal curcumin modified with RGD compared to free curcumin. These results were confirmed by fluorescence measurement for RGD modified liposome containing Hoechst dye. There was negligible fluorescent intensity in the blood rats, which received Hoechst alone. Live animal imaging analysis showed the presence of fluorescent color in heart tissue for all groups. It was also detected in kidney tissue for liposomal Hoechst modified with RGD group.
    Conclusions: The present study demonstrated that RGD-modified nano-liposomes can significantly improve drug retention time in the blood of rats.
    Keywords:   Biodistribution; Curcumin; Nanoliposome; RGD; Rats
    DOI:  https://doi.org/10.30498/ijb.2021.272168.2990
  160. Pharmaceutics. 2022 Oct 22. pii: 2258. [Epub ahead of print]14(11):
    Novel Scintillating Nanoparticles for Potential Application in Photodynamic Cancer Therapy.
    Bianca A da Silva, Michael Nazarkovsky, Helmut Isaac Padilla-Chavarría, Edith Alejandra C Mendivelso, Heber L de Mello, Cauê de S C Nogueira, Rafael Dos S Carvalho, Marco Cremona, Volodymyr Zaitsev, Yutao Xing, Rodrigo da C Bisaggio, Luiz A Alves, Jiang Kai.
      The development of X-ray-absorbing scintillating nanoparticles is of high interest for solving the short penetration depth problem of visible and infrared light in photodynamic therapy (PDT). Thus, these nanoparticles are considered a promising treatment for several types of cancer. Herein, gadolinium oxide nanoparticles doped with europium ions (Gd2O3:Eu3+) were obtained by using polyvinyl alcohol as a capping agent. Hybrid silica nanoparticles decorated with europium-doped gadolinium oxide (SiO2-Gd2O3:Eu3+) were also prepared through the impregnation method. The synthesized nanoparticles were structurally characterized and tested to analyze their biocompatibility. X-ray diffraction, scanning electron microscopy, and transmission electron microscopy confirmed the high crystallinity and purity of the Gd2O3:Eu3+ particles and the homogeneous distribution of nanostructured rare earth oxides throughout the fumed silica matrix for SiO2-Gd2O3:Eu3+. Both nanoparticles displayed stable negative ζ-potentials. The photoluminescence properties of the materials were obtained using a Xe lamp as an excitation source, and they exhibited characteristic Eu3+ bands, including at 610 nm, which is the most intense transition band of this ion. Cytotoxicity studies on mouse glioblastoma GL261 cells indicated that these materials appear to be nontoxic from 10 to 500 μg·mL-1 and show a small reduction in viability in non-tumor cell lines. All these findings demonstrate their possible use as alternative materials in PDT.
    Keywords:  cancer; nanoparticles; nanosilica; photodynamic therapy; rare earth oxides
    DOI:  https://doi.org/10.3390/pharmaceutics14112258
  161. Nutrients. 2022 Oct 28. pii: 4533. [Epub ahead of print]14(21):
    Neuroprotective Panel of Olive Polyphenols: Mechanisms of Action, Anti-Demyelination, and Anti-Stroke Properties.
    Tanja Grubić Kezele, Božena Ćurko-Cofek.
      Neurological diseases such as stroke and multiple sclerosis are associated with high morbidity and mortality, long-term disability, and social and economic burden. Therefore, they represent a major challenge for medical treatment. Numerous evidences support the beneficial effects of polyphenols from olive trees, which can alleviate or even prevent demyelination, neurodegeneration, cerebrovascular diseases, and stroke. Polyphenols from olive oils, especially extra virgin olive oil, olive leaves, olive leaf extract, and from other olive tree derivatives, alleviate inflammation and oxidative stress, two major factors in demyelination. In addition, they reduce the risk of stroke due to their multiple anti-stroke effects, such as anti-atherosclerotic, antihypertensive, antioxidant, anti-inflammatory, hypocholesterolemic, hypoglycemic, and anti-thrombotic effects. In addition, olive polyphenols have beneficial effects on the plasma lipid profiles and insulin sensitivity in obese individuals. This review provides an updated version of the beneficial properties and mechanisms of action of olive polyphenols against demyelination in the prevention/mitigation of multiple sclerosis, the most common non-traumatic neurological cause of impairment in younger adults, and against cerebral insult with increasing incidence, that has already reached epidemic proportions.
    Keywords:  cerebrovascular diseases; demyelination; extra virgin olive oil; multiple sclerosis; neuroprotection; olive leaf extract; olive leaves; olive oil; olive polyphenols; stroke
    DOI:  https://doi.org/10.3390/nu14214533
  162. BMC Cancer. 2022 Nov 07. 22(1): 1142
    Prevalence and patterns of mutations in RAS/RAF/MEK/ERK/MAPK signaling pathway in colorectal cancer in North Africa.
    Meryem Jafari, Abdelilah Laraqui, Walid Baba, Soukaina Benmokhtar, Sara El Zaitouni, Abdelmounaim Ait Ali, Ahmed Bounaim, Mountassir Moujahid, Rachid Tanz, Tarik Mahfoud, Yassir Sbitti, Hicham El Annaz, Rachid Abi, Mohamed Rida Tagajdid, Safae El Kochri, Idriss Amine Lahlou, Houda El Hsaini, Lamiae Belayachi, Abdelaziz Benjouad, Mohammed Ichou, Amina En-Nya, Khalid Ennibi.
      BACKGROUND: Our review discuss (i) the findings from analyzed data that have examined KRAS, NRAS and BRAF mutations in patients with colorectal cancer (CRC) in North Africa and to compare its prevalence with that shown in other populations and (ii) the possible role of dietary and lifestyle factors with CRC risk.  METHODS: Using electronic databases, a systematic literature search was performed for the KRAS, NRAS, and BRAF mutations in CRC patients from Morocco, Tunisia, Algeria and Lybia.  RESULTS: Seventeen studies were identified through electronic searches with six studies conducted in Morocco, eight in Tunisia, two in Algeria, and one in Libya. A total of 1843 CRC patients were included 576 (31.3%) in Morocco, 641 (34.8%) in Tunisia, 592 (32.1%) in Algeria, and 34 (1.8%) in Libya. Overall, the average age of patients was 52.7 years old. Patients were predominantly male (56.6%). The mutation rates of KRAS, NRAS and BRAF were 46.4%, 3.2% and 3.5% of all patients, respectively. A broad range of reported KRAS mutation frequencies have been reported in North Africa countries. The KRAS mutation frequency was 23.9% to 51% in Morocco, 23.1% to 68.2% in Tunisia, 31.4% to 50% in Algeria, and 38.2% in Libya. The G12D was the most frequently identified KRAS exon 2 mutations (31.6%), followed by G12V (25.4%), G13D (15.5%), G12C (10.2%), G12A (6.9%), and G12S (6.4%). G12R, G13V, G13C and G13R are less than 5%. There are important differences among North Africa countries. In Morocco and Tunisia, there is a higher prevalence of G12D mutation in KRAS exon 2 (≈50%). The most frequently mutation type in KRAS exon 3 was Q61L (40%). A59T and Q61E mutations were also found. In KRAS exon 4, the most common mutation was A146T (50%), followed by K117N (33.3%), A146P (8.3%) and A146V (8.3%).CONCLUSION: KRAS mutated CRC patients in North Africa have been identified with incidence closer to the European figures. Beside established anti-CRC treatment, better understanding of the causality of CRC can be established by combining epidemiology and genetic/epigenetic on CRC etiology. This approach may be able to significantly reduce the burden of CRC in North Africa.
    Keywords:  And BRAF mutations; Colorectal cancer; KRAS; Lifestyle factors; NRAS; North Africa
    DOI:  https://doi.org/10.1186/s12885-022-10235-w
  163. Explor Target Antitumor Ther. 2022 ;3(5): 719-733
    Onosma L. as a source of anticancer agents: phytochemistry to mechanistic insight.
    Ajay Kumar, Shivani Attri, Sandeep Kaur, Hardeep Singh Tuli, Reena V Saini, Adesh Kumar Saini, Manoj Kumar, Satwinderjeet Kaur.
      Onosma (O.) is a genus of perennial flowering plants in the family Boraginaceae with approximately 250 species widely dispersed in temperate, tropical, and subtropical areas. It is traditionally used to treat rheumatism, fever, asthma, stomach irritation, and inflammatory ailments. The bioactive constituents present in the genus O. include benzoquinones, naphthazarins, alkaloids, phenolic, naphthoquinones, and flavonoids whereas shikonins and onosmins are the most significant. The review compiled contemporary research on O. L., including its distribution, morphology, traditional applications, phytochemistry, ethnopharmacology, and toxicology. This review also highlights a few critical challenges and possible future directions for O. L. research. Modern research has demonstrated a wide range of pharmacological effects of different species of O. L., including anti-diabetic, anticancer, anti-inflammatory, and cardiovascular protective. However, the studies on the O. genus are still not fully explored, therefore, researchers need to discover novel products with their toxicity studies, molecular mechanism, and associated side effects. Future exploration of potent constituents from this genus and clinical trials are required to explore its pharmacological importance.
    Keywords:  Alkaloids; Boraginaceae ethnopharmacological; anti-cancer; anti-inflammatory; naphthoquinones; shikonin
    DOI:  https://doi.org/10.37349/etat.2022.00109
  164. Food Chem. 2022 Nov 01. pii: S0308-8146(22)02761-3. [Epub ahead of print]405(Pt A): 134799
    Recent technological strategies for enhancing the stability of lycopene in processing and production.
    Yanxin Li, Zhe Cui, Liandong Hu.
      Lycopene, a popular antioxidant, exists abundantly in nature in all-E form, but the Z-lycopene has better solubility and absorption characteristics. Lycopene is labile to light, thermal and oxygen. Emerging technological approaches are developed to improve the stability of lycopene during production and processing. This review presents the degradation mechanism of lycopene. A comprehensive evaluation has made by comparing the advantages and disadvantages of different extraction and isomerization methods. Encapsulation of lycopene in different delivery systems can further improve its stability. The process and formulation influence factors, as well as the advantages and disadvantages of lycopene encapsulation delivery systems are summarized. In the future, it is necessary to scientifically design low-cost and high-efficiency lycopene production methods.The stable and high bioavailable lycopene encapsulation systems need to be designed. Further study on the chemical stability mechanism of lycopene, the toxicity of biological materials, the safety of lycopene preparations also need to be evaluated.
    Keywords:  Encapsulation delivery system; Extraction; Isomerization; Lycopene; Lycopene degradation; Stability improvement
    DOI:  https://doi.org/10.1016/j.foodchem.2022.134799
  165. Med Sci Monit. 2022 Nov 07. 28 e937564
    Mechanism of Progesterone in Treatment of Traumatic Brain Injury Based on Network Pharmacology and Molecular Docking Technology.
    Chen Zheng, Jian Gong, Lili Zang, Daiying Song, Xinyue Ran, Juncen Li, Bo Jiang, Jianli Xu, Qihua Wu.
      BACKGROUND Previous studies have confirmed that progesterone has a protective effect on traumatic brain injury (TBI). In this paper, network pharmacology and molecular docking technology were used to further explore the potential mechanism of progesterone in the treatment of TBI. MATERIAL AND METHODS Based on network pharmacology, potential targets of progesterone for TBI were obtained. The network diagram of interactions between target proteins was established to screen the key targets of progesterone for TBI. The DAVID database was used to analyze its biological function and enrichment pathway, and to explore and determine the biological pathway of progesterone in treating TBI. Molecular docking technology was used to simulate the interaction between progesterone and key target proteins. RESULTS Progesterone can treat TBI by anti-inflammatory action, repairing damaged cell membranes, stabilizing the structure of the blood-brain barrier, alleviating brain edema, reducing neuronal apoptosis, and improving neurological function. The molecular mechanism involves the PI3K/Akt signaling pathway, MAPK signaling pathway, and Ras signaling pathway. CONCLUSIONS Progesterone is a potential clinical treatment for TBI. Exploring the potential targets and pathways of TBI therapy through network pharmacology can provide a direction for subsequent research.
    DOI:  https://doi.org/10.12659/MSM.937564
  166. Biomater Sci. 2022 Nov 07.
    Sustained release of drug-loaded nanoparticles from injectable hydrogels enables long-term control of macrophage phenotype.
    Shreya S Soni, Arielle M D'Elia, Abdulrahman Alsasa, Sylvia Cho, Tina Tylek, Erin M O'Brien, Ricardo Whitaker, Kara L Spiller, Christopher B Rodell.
      Injectable hydrogels may be pre-formed through dynamic crosslinks, allowing for injection and subsequent retention in the tissue by shear-thinning and self-healing processes, respectively. These properties enable the site-specific delivery of encapsulated therapeutics; yet, the sustained release of small-molecule drugs and their cell-targeted delivery remains challenging due to their rapid diffusive release and non-specific cellular biodistribution. Herein, we develop an injectable hydrogel system composed of a macrophage-targeted nanoparticle (cyclodextrin nanoparticles, CDNPs) crosslinked by adamantane-modified hyaluronic acid (Ad-HA). The polymer-nanoparticle hydrogel uniquely leverages cyclodextrin's interaction with small molecule drugs to create a spatially discrete drug reservoir and with adamantane to yield dynamic, injectable hydrogels. Through an innovative two-step drug screening approach and examination of 45 immunomodulatory drugs with subsequent in-depth transcriptional profiling of both murine and human macrophages, we identify celastrol as a potent inhibitor of pro-inflammatory (M1-like) behavior that furthermore promotes a reparatory (M2-like) phenotype. Celastrol encapsulation within the polymer-nanoparticle hydrogels permitted shear-thinning injection and sustained release of drug-laden nanoparticles that targeted macrophages to modulate cell behavior for greater than two weeks in vitro. The modular hydrogel system is a promising approach to locally modulate cell-specific phenotype in a range of applications for immunoregenerative medicine.
    DOI:  https://doi.org/10.1039/d2bm01113a
  167. Biomolecules. 2022 Nov 04. pii: 1636. [Epub ahead of print]12(11):
    Curcumin and Its Analogs in Non-Small Cell Lung Cancer Treatment: Challenges and Expectations.
    Chunyin Tang, Jieting Liu, Chunsong Yang, Jun Ma, Xuejiao Chen, Dongwen Liu, Yao Zhou, Wei Zhou, Yunzhu Lin, Xiaohuan Yuan.
      Researchers have made crucial advances in understanding the pathogenesis and therapeutics of non-small cell lung cancer (NSCLC), improving our understanding of lung tumor biology and progression. Although the survival of NSCLC patients has improved due to chemoradiotherapy, targeted therapy, and immunotherapy, overall NSCLC recovery and survival rates remain low. Thus, there is an urgent need for the continued development of novel NSCLC drugs or combination therapies with less toxicity. Although the anticancer effectiveness of curcumin (Cur) and some Cur analogs has been reported in many studies, the results of clinical trials have been inconsistent. Therefore, in this review, we collected the latest related reports about the anti-NSCLC mechanisms of Cur, its analogs, and Cur in combination with other chemotherapeutic agents via the Pubmed database (accessed on 18 June 2022). Furthermore, we speculated on the interplay of Cur and various molecular targets relevant to NSCLC with discovery studio and collected clinical trials of Cur against NSCLC to clarify the role of Cur and its analogs in NSCLC treatment. Despite their challenges, Cur/Cur analogs may serve as promising therapeutic agents or adjuvants for lung carcinoma treatment.
    Keywords:  combined treatment; curcumin; curcumin analogs; non-small cell lung cancer; signaling pathways
    DOI:  https://doi.org/10.3390/biom12111636
  168. Front Pharmacol. 2022 ;13 1022053
    Protective effects and mechanism of puerarin targeting PI3K/Akt signal pathway on neurological diseases.
    Qian Wang, Zi-Nuo Shen, Shu-Jing Zhang, Yan Sun, Feng-Jie Zheng, Yu-Hang Li.
      Neurological diseases impose a tremendous and increasing burden on global health, and there is currently no curative agent. Puerarin, a natural isoflavone extracted from the dried root of Pueraria montana var. Lobata (Willd.) Sanjappa and Predeep, is an active ingredient with anti-inflammatory, antioxidant, anti-apoptotic, and autophagy-regulating effects. It has great potential in the treatment of neurological and other diseases. Phosphatidylinositol 3-kinases/protein kinase B (PI3K/Akt) signal pathway is a crucial signal transduction mechanism that regulates biological processes such as cell regeneration, apoptosis, and cognitive memory in the central nervous system, and is closely related to the pathogenesis of nervous system diseases. Accumulating evidence suggests that the excellent neuroprotective effect of puerarin may be related to the regulation of the PI3K/Akt signal pathway. Here, we summarized the main biological functions and neuroprotective effects of puerarin via activating PI3K/Akt signal pathway in neurological diseases. This paper illustrates that puerarin, as a neuroprotective agent, can protect nerve cells and delay the progression of neurological diseases through the PI3K/Akt signal pathway.
    Keywords:  PI3K/Akt signal pathway; natural products; nerve protection; neurological diseases; puerarin
    DOI:  https://doi.org/10.3389/fphar.2022.1022053
  169. Int J Pharm. 2022 Nov 05. pii: S0378-5173(22)00926-7. [Epub ahead of print] 122371
    Silicon nanoparticles for oral administration of molecular hydrogen.
    Hennie Marie Johnsen, Werner Filtvedt, Marianne Hiorth, Jo Klaveness.
      Medical use of hydrogen gas (H2) has been given increasing attention over the past 15 years with numerous clinical trials for a variety of indications. The biological activity of H2 includes antioxidant properties and thereby the ability to neutralize damaging reactive oxygen species (ROS). Administration of hydrogen as a medical gas is limited by the poor water solubility and by the flammability of H2 in air. Therefore, nanocarriers have been investigated for safer and more efficient administration of hydrogen. Silicon particles are suggested for oral administration with the ability to undergo a redox reaction with water to produce H2in vivo. The purpose of this work was to investigate the hydrogen generating abilities of silicon particles synthesized by centrifugal chemical vapor deposition (cCVD). High hydrogen generation rates up to 1310 ml/g at physiological pH 7.4 (82% yield) were observed. An in vitro model of oral administration showed that pretreatment in artificial gastric juice did not affect hydrogen generation. Thus, the cCVD silicon particles seem to be suitable for in vivo hydrogen generation. A surface carbon coating or addition of surfactants or albumin reduced hydrogen generation. The addition of egg white reduced hydrogen generation but did not block it.
    Keywords:  artificial oral delivery; hydrogen delivery; hydrogen therapy; nanomedicine; nanoparticles; silicon particles
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.122371
  170. Plants (Basel). 2022 Nov 06. pii: 2990. [Epub ahead of print]11(21):
    Effect of Germination and Illumination on Melatonin and Its Metabolites, Phenolic Content, and Antioxidant Activity in Mung Bean Sprouts.
    Pimolwan Siriparu, Panyada Panyatip, Thanawat Pota, Juthamat Ratha, Chawalit Yongram, Tarapong Srisongkram, Bunleu Sungthong, Ploenthip Puthongking.
      Mung bean (Vigna radiata L.) sprouts are increasingly consumed and have become part of a healthy diet. The sprouts are composed of proteins, carbohydrates, and biochemical compounds. During germination, the phytochemical compounds are significantly elevated, especially under stress conditions such as salinity, drought, extreme temperature, and illumination. The present study examined the effects of light and germination time on the bioactive compounds in mung bean sprout extracts. Mung bean seeds were sprouted under different light exposure conditions, and the phytochemical composition and antioxidant activity of sprout extracts were determined compared to seeds. The results show that tryptophan sharply decreased during germination. On the contrary, melatonin, polyphenols, and total phenolic content (TPC) were elevated with increased germination time, correlated with increased antioxidant activity. Sprouts germinated in the dark presented higher levels of melatonin and TPC compared with those germinated under 12 h light exposure (3.6- and 1.5-fold, respectively). In conclusion, germination can enhance valuable phytochemicals and antioxidant activity of mung bean sprouts. Mung bean sprouts may be a good alternative functional food for promoting human health.
    Keywords:  germination; illumination; melatonin; polyphenols; sprouts; tryptophan
    DOI:  https://doi.org/10.3390/plants11212990
  171. Antioxidants (Basel). 2022 Nov 07. pii: 2202. [Epub ahead of print]11(11):
    Targeting Mitochondrial Metabolism to Reverse Radioresistance: An Alternative to Glucose Metabolism.
    Chenbin Bian, Zhuangzhuang Zheng, Jing Su, Huanhuan Wang, Sitong Chang, Ying Xin, Xin Jiang.
      Radiotherapy failure and poor tumor prognosis are primarily attributed to radioresistance. Improving the curative effect of radiotherapy and delaying cancer progression have become difficult problems for clinicians. Glucose metabolism has long been regarded as the main metabolic process by which tumor cells meet their bioenergetic and anabolic needs, with the complex interactions between the mitochondria and tumors being ignored. This misconception was not dispelled until the early 2000s; however, the cellular molecules and signaling pathways involved in radioresistance remain incompletely defined. In addition to being a key metabolic site that regulates tumorigenesis, mitochondria can influence the radiation effects of malignancies by controlling redox reactions, participating in oxidative phosphorylation, producing oncometabolites, and triggering apoptosis. Therefore, the mitochondria are promising targets for the development of novel anticancer drugs. In this review, we summarize the internal relationship and related mechanisms between mitochondrial metabolism and cancer radioresistance, thus exploring the possibility of targeting mitochondrial signaling pathways to reverse radiation insensitivity. We suggest that attention should be paid to the potential value of mitochondria in prolonging the survival of cancer patients.
    Keywords:  apoptosis; oncometabolites; oxidative phosphorylation; radioresistance; reactive oxygen species
    DOI:  https://doi.org/10.3390/antiox11112202
  172. Animals (Basel). 2022 Oct 31. pii: 2998. [Epub ahead of print]12(21):
    Garlic and Its Bioactive Compounds: Implications for Methane Emissions and Ruminant Nutrition.
    Nurul Fitri Sari, Partha Ray, Caroline Rymer, Kirsty E Kliem, Sokratis Stergiadis.
      Methane (CH4) emission from enteric fermentation of ruminant livestock is a source of greenhouse gases (GHG) and has become a significant concern for global warming. Enteric methane emission is also associated with poor feed efficiency. Therefore, research has focused on identifying dietary mitigation strategies to decrease CH4 emissions from ruminants. In recent years, plant-derived bioactive compounds have been investigated for their potential to reduce CH4 emissions from ruminant livestock. The organosulphur compounds of garlic have been observed to decrease CH4 emission and increase propionate concentration in anaerobic fermentations (in vitro) and in the rumen (in vivo). However, the mode of action of CH4 reduction is not completely clear, and the response in vivo is inconsistent. It might be affected by variations in the concentration and effect of individual substances in garlic. The composition of the diet that is being fed to the animal may also contribute to these differences. This review provides a summary of the effect of garlic and its bioactive compounds on CH4 emissions by ruminants. Additionally, this review aims to provide insight into garlic and its bioactive compounds in terms of enteric CH4 mitigation efficacy, consistency in afficacy, possible mode of action, and safety deriving data from both in vivo and in vitro studies.
    Keywords:  garlic; greenhouse gas; organosulphur; plant-derived bioactive compounds; ruminant
    DOI:  https://doi.org/10.3390/ani12212998
  173. J Mater Chem B. 2022 Nov 09.
    Getting drugs to the brain: advances and prospects of organic nanoparticle delivery systems for assisting drugs to cross the blood-brain barrier.
    Qiuxia Tan, Shaojing Zhao, Ting Xu, Qin Wang, Minhuan Lan, Li Yan, Xianfeng Chen.
      The blood-brain barrier (BBB) plays an irreplaceable role in protecting the central nervous system (CNS) from bloodborne pathogens. However, the BBB complicates the treatment of CNS diseases because it prevents almost all therapeutic drugs from getting into the CNS. With the growing understanding of the physiological characteristics of the BBB and the development of nanotechnology, nanomaterial-based drug delivery systems have become promising tools for delivering drugs across the BBB to the CNS. Herein, we systematically summarize the recent progress in organic-nanoparticle delivery systems for treating CNS diseases and evaluate their mechanisms in overcoming the BBB with the aim to provide a comprehensive understanding of the advantages, disadvantages, and challenges of organic nanoparticles in delivering drugs across the BBB. This review may inspire new research ideas and directions for applying nanotechnology to treat CNS diseases.
    DOI:  https://doi.org/10.1039/d2tb01440h
  174. Sci Rep. 2022 Nov 09. 12(1): 19037
    Discovery of potential natural dihydroorotate dehydrogenase inhibitors and their synergism with brequinar via integrated molecular docking, dynamic simulations and in vitro approach.
    Asmaa Khairy, Hala M Hammoda, Ismail Celik, Hala H Zaatout, Reham S Ibrahim.
      The critical function of dihydroorotate dehydrogenase (DHODH) in pyrimidine synthesis attracted a great interest throughout beyond decades. Inhibitors of human DHODH (hDHODH) have validated efficacy for remedy of many immunological diseases. Brequinar and leflunomide are examples of such compounds. However, most of such immunosuppressive medications suffer from a lot of side effects and accompanied by adverse metabolic disturbances and toxicities. So that, immunomodulation utilizing natural products received the attention of many researchers. In this study, computer-aided molecular docking, molecular dynamic (MD) simulations and biochemical testing were utilized to find new pharmacologically active chemical entities from natural sources to combat immunosuppressive diseases. More specifically, Glide docking was used for a structure-based virtual screening of in-house 3D database of compounds retrieved from some traditionally known immunomodulatory plants surveyed from literature. The top five scored plants were found to be Zingiber officinale, Curcuma longa, Glycyrrhiza glabra, Allium sativum and Olea europaea. In vitro hDHODH inhibitory assays illustrated the ability of Allium sativum and silymarin standard hits; specifically, silibinin, to significantly inhibit the hDHODH enzyme. Molecular docking and MD simulations revealed a strong binding of the discovered hits within the active site. Following that, the most promising hits were tested separately with brequinar in a fixed-ratio combination setting to assess their combined effects on hDHODH catalytic inhibition. The binary combination of silibinin and brequinar revealed that in this combination, brequinar could be utilized at a dose 9.33-fold less when compared to its single-use to produce 99% inhibition for hDHODH enzyme. These findings confirmed that this binary mixture is an excellent combination providing better therapeutic effects and lower side effects.
    DOI:  https://doi.org/10.1038/s41598-022-23006-1
  175. Biochem Biophys Res Commun. 2022 Oct 25. pii: S0006-291X(22)01488-7. [Epub ahead of print]636(Pt 1): 197-204
    Resveratrol inhibits proliferation and induces apoptosis via the Hippo/YAP pathway in human colon cancer cells.
    Xiaoying Qin, Honghong Luo, Yixuan Deng, Xintong Yao, Jie Zhang, Baicheng He.
      High malignancy and mortality in colon cancer require clarifying the underlying mechanisms of colon cancer carcinogenesis and exploring new targets or drugs for the clinical treatment of colon cancer. Resveratrol (Res), a natural compound, shows cytotoxicity against various tumors. However, the specific anti-cancer mechanism of Res remains unclear. In the present study, we aimed to explore the anti-cancer activity of Res against colon cancer cells and the possible mechanism. The results showed that Res could inhibit cell proliferation and induce cell cycle arrest and apoptosis in HCT116 cells. Western blotting and Polymerase chain reaction (PCR) showed that Res increased the phosphorylated YAP (pYAP) levels and decreased YAP total protein level and decreased the mRNA expression of the YAP signaling downstream genes CTGF and CYR61. The effects of Res on pYAP were enhanced by YAP inhibitor verteporfin (VP). VP also enhanced the effects of Res on decreasing viability and inducing apoptosis. Furthermore, the molecular docking analysis indicated Res could bind with YAP-TEAD through van der Waals, pi-alkyl, and pi-pi stacked interactions. Our findings suggested that the anti-cancer activity of Res may be mediated via activating Hippo/YAP signaling and partially disturbing the interaction between YAP and TEAD. All this evidence supports that Res may be an efficacious drug for colon cancer treatment.
    Keywords:  Colon cancer; Molecular docking; Proliferation inhibition; Resveratrol; YAP
    DOI:  https://doi.org/10.1016/j.bbrc.2022.10.077
  176. Molecules. 2022 Oct 31. pii: 7269. [Epub ahead of print]27(21):
    Crosstalk between Depression and Breast Cancer via Hepatic Epoxide Metabolism: A Central Comorbidity Mechanism.
    Zhen Ye, Kumar Ganesan, Mingquan Wu, Yu Hu, Yingqi She, Qianqian Tian, Qiaobo Ye, Jianping Chen.
      Breast cancer (BC) is a serious global challenge, and depression is one of the risk factors and comorbidities of BC. Recently, the research on the comorbidity of BC and depression has focused on the dysfunction of the hypothalamic-pituitary-adrenal axis and the persistent stimulation of the inflammatory response. However, the further mechanisms for comorbidity remain unclear. Epoxide metabolism has been shown to have a regulatory function in the comorbid mechanism with scattered reports. Hence, this article reviews the role of epoxide metabolism in depression and BC. The comprehensive review discloses the imbalance in epoxide metabolism and its downstream effect shared by BC and depression, including overexpression of inflammation, upregulation of toxic diols, and disturbed lipid metabolism. These downstream effects are mainly involved in the construction of the breast malignancy microenvironment through liver regulation. This finding provides new clues on the mechanism of BC and depression comorbidity, suggesting in particular a potential relationship between the liver and BC, and provides potential evidence of comorbidity for subsequent studies on the pathological mechanism.
    Keywords:  breast cancer; comorbidity; depression; epoxide metabolism; tumor microenvironment
    DOI:  https://doi.org/10.3390/molecules27217269
  177. Cancers (Basel). 2022 Nov 04. pii: 5435. [Epub ahead of print]14(21):
    Targeting Heat Shock Proteins in Malignant Brain Tumors: From Basic Research to Clinical Trials.
    Aisha Babi, Karashash Menlibayeva, Torekhan Bex, Aidos Doskaliev, Serik Akshulakov, Maxim Shevtsov.
      Heat shock proteins (HSPs) are conservative and ubiquitous proteins that are expressed both in prokaryotic and eukaryotic organisms and play an important role in cellular homeostasis, including the regulation of proteostasis, apoptosis, autophagy, maintenance of signal pathways, protection from various stresses (e.g., hypoxia, ionizing radiation, etc.). Therefore, HSPs are highly expressed in tumor cells, including malignant brain tumors, where they also associate with cancer cell invasion, metastasis, and resistance to radiochemotherapy. In the current review, we aimed to assess the diagnostic and prognostic values of HSPs expression in CNS malignancies as well as the novel treatment approaches to modulate the chaperone levels through the application of inhibitors (as monotherapy or in combination with other treatment modalities). Indeed, for several proteins (i.e., HSP10, HSPB1, DNAJC10, HSPA7, HSP90), a direct correlation between the protein level expression and poor overall survival prognosis for patients was demonstrated that provides a possibility to employ them as prognostic markers in neuro-oncology. Although small molecular inhibitors for HSPs, particularly for HSP27, HSP70, and HSP90 families, were studied in various solid and hematological malignancies demonstrating therapeutic potential, still their potential was not yet fully explored in CNS tumors. Some newly synthesized agents (e.g., HSP40/DNAJ inhibitors) have not yet been evaluated in GBM. Nevertheless, reported preclinical studies provide evidence and rationale for the application of HSPs inhibitors for targeting brain tumors.
    Keywords:  Hsp27; Hsp40; Hsp70; Hsp90; brain tumors; glioblastoma; heat shock proteins; inhibitors; prognostic marker; small HSPs
    DOI:  https://doi.org/10.3390/cancers14215435
  178. Phytochem Rev. 2022 Nov 03. 1-63
    An updated and comprehensive review on the ethnomedicinal uses, phytochemistry, pharmacological activity and toxicological profile of Tinospora crispa (L.) Hook. f. & Thomson.
    Ehfazul Haque, Md Sazzadul Bari, Labony Khandokar, Juhaer Anjum, Ibrahim Jantan, Veronique Seidel, Md Areeful Haque.
      Tinospora crispa (L.) Hook. f. & Thomson (Menispermaceae) is a plant indigenous to Africa and South-East Asia. It is widely used in ethnomedicine to alleviate various diseases including hypertension, diabetes, rheumatism, jaundice, inflammation, fever, fractures, scabies, and urinary disorders. A total of 167 phytoconstituents, belonging to 12 different chemical categories, including alkaloids, flavonoids, terpenoids, and phenolic compounds have thus far been isolated from various parts of T. crispa. Numerous in vitro and in vivo investigations have already established the antidiabetic, anticancer, antiparasitic, antimicrobial, immunomodulatory, hepatoprotective, analgesic, antipyretic, antihyperuricemic, and pesticidal activity of this plant, as well as its effects on the cardiac and the central nervous system. Most pharmacological investigations to date have been carried out on plant extracts and fractions. The exact identity of the phytoconstituents responsible for the observed biological effects and their mode of action at the molecular level are yet to be ascertained. Toxicological studies have demonstrated that T. crispa is relatively safe, although dose-dependent hepatotoxicity is a concern at high doses. This review presents a comprehensive update and analysis on studies related to the ethnomedicinal uses, phytochemistry, pharmacological activity and toxicological profile of T. crispa. It provides some critical insights into the current scientific knowledge on this plant and its future potential in pharmaceutical research.
    Keywords:  Ethnomedicinal uses; Pharmacological activity; Phytoconstituents; Tinospora crispa; Toxicological profile
    DOI:  https://doi.org/10.1007/s11101-022-09843-y
  179. Gels. 2022 Nov 01. pii: 706. [Epub ahead of print]8(11):
    Peptide-Based Supramolecular Hydrogels as Drug Delivery Agents: Recent Advances.
    Carlos B P Oliveira, Valéria Gomes, Paula M T Ferreira, José A Martins, Peter J Jervis.
      Supramolecular peptide hydrogels have many important applications in biomedicine, including drug delivery applications for the sustained release of therapeutic molecules. Targeted and selective drug administration is often preferential to systemic drug delivery, as it can allow reduced doses and can avoid the toxicity and side-effects caused by off-target binding. New discoveries are continually being reported in this rapidly developing field. In this review, we report the latest developments in supramolecular peptide-based hydrogels for drug delivery, focusing primarily on discoveries that have been reported in the last four years (2018-present). We address clinical points, such as peptide self-assembly and drug release, mechanical properties in drug delivery, peptide functionalization, bioadhesive properties and drug delivery enhancement strategies, drug release profiles, and different hydrogel matrices for anticancer drug loading and release.
    Keywords:  biomaterials; cancer therapy; controlled release; drug delivery; hydrogel; peptide; smart materials; stimuli-responsive; supramolecular
    DOI:  https://doi.org/10.3390/gels8110706
  180. J Physiol Biochem. 2022 Nov 07.
    Antitumor effects of lactate transport inhibition on esophageal adenocarcinoma cells.
    Laura Grasa, Eduardo Chueca, Samantha Arechavaleta, María Asunción García-González, María Ángeles Sáenz, Alberto Valero, Carlos Hördnler, Ángel Lanas, Elena Piazuelo.
      As a consequence of altered glucose metabolism, cancer cell intake is increased, producing large amounts of lactate which is pumped out the cytosol by monocarboxylate transporters (MCTs). MCT 1 and MCT4 are frequently overexpressed in tumors, and recently, MCT inhibition has been reported to exert antineoplastic effects. In the present study, MCT1 and MCT4 levels were assessed in esophageal adenocarcinoma (EAC) cells and the effects of the MCT-1 selective inhibitor AZD3965, hypoxia, and a glucose overload were evaluated in vitro. Two EAC cell lines (OE33 and OACM5.1C) were treated with AZD3965 (10-100 nM) under different conditions (normoxia/hypoxia) and also different glucose concentrations, and parameters of cytotoxicity, oxidative stress, intracellular pH (pHi), and lactate levels were evaluated. MCT1 was present in both cell lines whereas MCT4 was expressed in OE33 cells and only in a small proportion of OACM5.1C cells. Glucose addition did not have any effect on apoptosis nor cell proliferation. AZD3965 increased apoptosis and reduced proliferation of OACM5.1C cells, effects which were abrogated when cells were growing in hypoxia. MCT1 inhibition increased intracellular lactate levels in all the cells evaluated, but this increase was higher in cells expressing only MCT1 and did not affect oxidative stress. AZD3965 induced a decrease in pHi of cells displaying low levels of MCT4 and also increased the sodium/hydrogen exchanger 1 (NHE-1) expression on these cells. These data provide in vitro evidence supporting the potential of MCT inhibitors as novel antineoplastic drugs for EAC and highlight the importance of achieving a complete MCT inhibition.
    Keywords:  Apoptosis; Esophageal adenocarcinoma; Intracellular pH; Lactate; MCT; Proliferation
    DOI:  https://doi.org/10.1007/s13105-022-00931-3
  181. J Control Release. 2022 Nov 06. pii: S0168-3659(22)00748-9. [Epub ahead of print]
    Extracellular matrix degrading enzyme with stroma-targeting peptides enhance the penetration of liposomes into tumors.
    Mayumi Ikeda-Imafuku, Yongsheng Gao, Suyog Shaha, Lily Li-Wen Wang, Kyung Soo Park, Mayuka Nakajima, Omokolade Adebowale, Samir Mitragotri.
      Various anti-tumor nanomedicines have been developed based on the enhanced permeability and retention effect. However, the dense extracellular matrix (ECM) in tumors remains a major barrier for the delivery and accumulation of nanoparticles into tumors. While ECM-degrading enzymes, such as collagenase, hyaluronidase, and bromelain, have been used to facilitate the accumulation of nanoparticles, serious side effects arising from the current non-tumor-specific delivery methods limit their clinical applications. Here, we report targeted delivery of bromelain into tumor tissues through its covalent attachment to a hyaluronic acid (HA)-peptide conjugate with tumor ECM targeting ability. The ECM targeting peptide, collagen type IV-binding peptide (C4BP), was chosen from six candidate-peptides based on their ability to bind to frozen sections of triple-negative breast cancer, 4 T1 tumor ex vivo. The HA- C4BP conjugate showed a significant increase in tumor accumulation in 4 T1-bearing mice after intravenous administration compared to unmodified HA. We further demonstrated that the systemic administration of bromelain conjugated C4BP-HA (C4BP-HA-Bro) potentiates the anti-tumor efficacy of liposomal doxorubicin. C4BP-HA-Bro decreased the number and length of collagen fibers and improved the distribution of doxorubicin within the tumor. No infusion reaction was noted after delivery of C4BP-HA-Bro. C4BP-HA thus offers a potential for effective and safe delivery of bromelain for improved intratumoral delivery of therapeutics.
    Keywords:  Bromelain; Cancer stroma; Collagen type IV; EPR effect; Extracellular matrix; Triple-negative breast cancer
    DOI:  https://doi.org/10.1016/j.jconrel.2022.11.007
  182. Gels. 2022 Oct 23. pii: 686. [Epub ahead of print]8(11):
    Formulation of Chitosan Microparticles for Enhanced Intranasal Macromolecular Compound Delivery: Factors That Influence Particle Size during Ionic Gelation.
    Morné Weyers, Bianca Peterson, Josias H Hamman, Jan H Steenekamp.
      Therapeutic macromolecules (e.g., protein and peptide drugs) present bioavailability challenges via extravascular administration. The nasal route presents an alternative non-invasive route for these drugs, although low bioavailability remains challenging. Co-administration of permeation enhancers is a promising formulation approach to improve the delivery of poorly bioavailable drugs. The aim of this study was to prepare and characterize chitosan microparticulate formulations containing a macromolecular model compound (fluorescein isothiocyanate dextran 4400, FD-4) and a bioenhancer (piperine). Ionic gelation was used to produce chitosan microparticle delivery systems with two distinct microparticle sizes, differing one order of magnitude in size (±20 µm and ±200 µm). These two microparticle delivery systems were formulated into thermosensitive gels and their drug delivery performance was evaluated across ovine nasal epithelial tissues. Dissolution studies revealed a biphasic release pattern. Rheometry results demonstrated a sol-to-gel transition of the thermosensitive gel formulation at a temperature of 34 °C. The microparticles incorporating piperine showed a 1.2-fold increase in FD-4 delivery across the excised ovine nasal epithelial tissues as compared to microparticles without piperine. This study therefore contributed to advancements in ionic gelation methods for the formulation of particulate systems to enhance macromolecular nasal drug delivery.
    Keywords:  chitosan; fluorescein isothiocyanate dextran (FD-4); ionic gelation; microparticulate; nasal; thermosensitive gel
    DOI:  https://doi.org/10.3390/gels8110686
  183. J Biomater Sci Polym Ed. 2022 Nov 11. 1-18
    Aloe Vera coated Dextran Sulfate/Chitosan nanoparticles (Aloe Vera @ DS/CS) encapsulating Eucalyptus essential oil with antibacterial potent property.
    Mirhane Mostafa Darwish, Mona S Elneklawi, Ebtesam A Mohamad.
      The goal of this work is to encapsulate Eucalyptus staigeriana essential oil in biopolymer matrices, to optimize the biological effects and the antibacterial properties of this oil. In this study, Eucalyptus extract was encapsulated in Aloe Vera coated Dextran Sulfate/Chitosan nanoparticles to form a hydrogel with potent properties. In this study, Eucalyptus extract was loaded on to Aloe Vera coated Dextran Sulphate/Chitosan nanoparticles to obtain a nano-hydrogel with potent properties. The characterization of nanoparticles was evaluated using transmission and scanning electron microscopes, dynamic light scattering, Fourier transform infrared spectroscopy, differential scanning calorimetry and antibacterial activity. The Eucalyptus staigeriana release profile from the prepared nanoparticles was studied in vitro at a pH of 7.4. The results showed that this nano-carrier controls Eucalyptus release. Aloe Vera coated Dextran Sulfate/Chitosan nanoparticles encapsulated with Eucalyptus staigeriana inhibited the bacteria by 47.27%. These investigations concluded that Eucalyptus staigeriana loaded Aloe Vera coated Dextran Sulfate/Chitosan hydrogel could be used as a powerful dressing material to accelerate wound healing.
    Keywords:  Aloe Vera; Chitosan nanoparticles; Dextran sulfate; Eucalyptus
    DOI:  https://doi.org/10.1080/09205063.2022.2145869
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