bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2022‒03‒27
101 papers selected by
Yasmin Elkabani
Egyptian Foundation for Research and Community Development
  1. Platelet-Biomimetic Nanoparticles for in vivo Targeted Photodynamic Therapy of Breast Cancer.
  2. Nanostructured Lipid Carriers for The Delivery of Natural Bioactive Compounds.
  3. Curcumin nanofibers: A novel approach to enhance the anticancer potential and bioavailability of curcuminoids.
  4. Isoquinolines alkaloids and cancer metabolism: Pathways and targets to novel chemotherapy.
  5. Nano-based targeted drug delivery for lung cancer: therapeutic avenues and challenges.
  6. Contribution of Nanoscience Research in Antioxidants Delivery Used in Nutricosmetic Sector.
  7. Combinatorial Effects of the Natural Products Arctigenin, Chlorogenic Acid, and Cinnamaldehyde Commit Oxidation Assassination on Breast Cancer Cells.
  8. Combining PEGylated mito-atovaquone with MCT and Krebs cycle redox inhibitors as a potential strategy to abrogate tumor cell proliferation.
  9. Lactate metabolism in rheumatoid arthritis: Pathogenic mechanisms and therapeutic intervention with natural compounds.
  10. Advances in indole-containing alkaloids as potential anticancer agents by regulating autophagy.
  11. Research Progress of Cell Membrane Biomimetic Nanoparticles for Tumor Therapy.
  12. The Role of Epigenetic Modifications in Human Cancers and the Use of Natural Compounds as Epidrugs: Mechanistic Pathways and Pharmacodynamic Actions.
  13. Brain Targeting, Antioxidant Polymeric Nanoparticles for Stroke Drug Delivery and Therapy.
  14. An injectable thermosensitive hydrogel loaded with a theranostic nanoprobe for synergistic chemo-photothermal therapy for multidrug-resistant hepatocellular carcinoma.
  15. Anti-Inflammatory and Active Biological Properties of the Plant-Derived Bioactive Compounds Luteolin and Luteolin 7-Glucoside.
  16. Graphene quantum dots mediated magnetic chitosan drug delivery nanosystems for targeting synergistic photothermal-chemotherapy of hepatocellular carcinoma.
  17. A Platelet Intelligent Vehicle with Navigation for Cancer Photothermal-Chemotherapy.
  18. Nobiletin as an inducer of programmed cell death in cancer: a review.
  19. Site-Specific Displacement-Driven Activation of Supramolecular Photosensitizing Nanoassemblies for Antitumoral Photodynamic Therapy.
  20. Antimicrobial Potential of Curcumin: Therapeutic Potential and Challenges to Clinical Applications.
  21. Lymph-Directed Self-Immolative Nitric Oxide Prodrug for Inhibition of Intractable Metastatic Cancer.
  22. Reactive Oxygen Species and Folate Receptor-Targeted Nanophotosensitizers Composed of Folic Acid-Conjugated and Poly(ethylene glycol)-Chlorin e6 Tetramer Having Diselenide Linkages for Targeted Photodynamic Treatment of Cancer Cells.
  23. Repurposing Lovastatin Cytotoxicity against the Tongue Carcinoma HSC3 Cell Line Using a Eucalyptus Oil-Based Nanoemulgel Carrier.
  24. Dietary Polyphenols as Therapeutic Intervention for Alzheimer's Disease: A Mechanistic Insight.
  25. Liposome Nanoparticles as a Novel Drug Delivery System for Therapeutic and Diagnostic Applications.
  26. Smart Injectable Chitosan Hydrogels Loaded with 5-Fluorouracil for the Treatment of Breast Cancer.
  27. A Therapeutic Journey of Pyridine-Based Heterocyclic Compounds as Potent Anticancer Agents: A Review (From 2017 to 2021).
  28. Well-Defined Polyethylene Glycol Microscale Hydrogel Blocks Containing Gold Nanorods for Dual Photothermal and Chemotherapeutic Therapy.
  29. An In Vivo Inflammatory Loop Potentiates KRAS Blockade.
  30. Advances in the Novel Nanotechnology for the Targeted Tumor Therapy by the Transdermal Drug Delivery.
  31. Nanocarriers Based on Gold Nanoparticles for Epigallocatechin Gallate Delivery in Cancer Cells.
  32. Cannabis as a potential compound against various malignancies, legal aspects, advancement by exploiting nanotechnology and clinical trials.
  33. Elucidation of the Interactions of Reactive Oxygen Species and Antioxidants in Model Membranes Mimicking Cancer Cells and Normal Cells.
  34. pH-Sensitive Peptide Hydrogels as a Combination Drug Delivery System for Cancer Treatment.
  35. Hallmarks of Metabolic Reprogramming and Their Role in Viral Pathogenesis.
  36. Lipid Nanoparticles as a Promising Drug Delivery Carrier for Topical Ocular Therapy-An Overview on Recent Advances.
  37. Targeting tumor innervation: premises, promises, and challenges.
  38. A non-dividing cell population with high pyruvate dehydrogenase kinase activity regulates metabolic heterogeneity and tumorigenesis in the intestine.
  39. Redox dyshomeostasis strategy for tumor therapy based on nanomaterials chemistry.
  40. Selective Photo-Assisted Eradication of Triple-Negative Breast Cancer Cells through Aptamer Decoration of Doped Conjugated Polymer Nanoparticles.
  41. Polyacrylic Acid Nanoplatforms: Antimicrobial, Tissue Engineering, and Cancer Theranostic Applications.
  42. Formulation Strategies for Improving the Stability and Bioavailability of Vitamin D-Fortified Beverages: A Review.
  43. Nanocarrier cancer therapeutics with functional stimuli-responsive mechanisms.
  44. Emerging nanoformulation strategies for phytocompounds and applications from drug delivery to phototherapy to imaging.
  45. Development, Therapeutic Evaluation and Theranostic Applications of Cubosomes on Cancers: An Updated Review.
  46. Natural Polyphenols for the Preservation of Meat and Dairy Products.
  47. Expression of HK2, PKM2, and PFKM Is Associated with Metastasis and Late Disease Onset in Breast Cancer Patients.
  48. Folate-Decorated Cross-Linked Cytochrome c Nanoparticles for Active Targeting of Non-Small Cell Lung Carcinoma (NSCLC).
  49. Novel Hydrogels for Topical Applications: An Updated Comprehensive Review Based on Source.
  50. Bioactive Composite Nanoparticles for Effective Microenvironment Regulation, Neuroprotection, and Cell Differentiation.
  51. Sequential Drug Delivery in Targeted Cancer Therapy.
  52. Natural Compounds as Promising Adjuvant Agents in The Treatment of Gliomas.
  53. Short-Term Fasting Synergizes with Solid Cancer Therapy by Boosting Antitumor Immunity.
  54. Broad-Spectrum Theranostics and Biomedical Application of Functionalized Nanomaterials.
  55. Multifunctional Patented Nanotherapeutics for Cancer Intervention: 2010-onwards.
  56. Development of Lomustine and n-Propyl Gallate Co-Encapsulated Liposomes for Targeting Glioblastoma Multiforme via Intranasal Administration.
  57. The emerging role of deubiquitylating enzymes as therapeutic targets in cancer metabolism.
  58. Two Beats One: Osteosarcoma Therapy with Light-Activated and Chemo-Releasing Keratin Nanoformulation in a Preclinical Mouse Model.
  59. Design and Development of Levodopa Loaded Polymeric Nanoparticles for Intranasal Delivery.
  60. Targeted Delivery of Chemotherapeutic Agents for Osteosarcoma Treatment.
  61. Recent Development of Prodrugs of Gemcitabine.
  62. Nanomicelle-Microsphere Composite as a Drug Carrier to Improve Lung-Targeting Specificity for Lung Cancer.
  63. Genesis and Mechanism of Some Cancer Types and an Overview on the Role of Diet and Nutrition in Cancer Prevention.
  64. An integrated metabonomics study to reveal the inhibitory effect and metabolism regulation of taurine on breast cancer.
  65. Bioactive compounds in kombucha: A review of substrate effect and fermentation conditions.
  66. Pharmacological Modulation of Apoptosis and Autophagy in the Treatment of Pancreatic Cancer.
  67. Cubosomes as an emerging platform for drug delivery: a review of the state of the art.
  68. Applications of Antimicrobial Photodynamic Therapy against Bacterial Biofilms.
  69. PLGA-Gold Nanocomposite: Preparation and Biomedical Applications.
  70. Sonodynamic Therapy Using Dacarbazine-Loaded AuSiO2 Nanoparticles for Melanoma Treatment: An In-Vitro Study on the B16F10 Murine Melanoma Cell Line.
  71. Facile Solvent-Free Preparation of Antioxidant Idebenone-Loaded Nanoparticles for Efficient Wound Healing.
  72. Hexachlorophene, a selective SHP2 inhibitor, suppresses proliferation and metastasis of KRAS-mutant NSCLC cells by inhibiting RAS/MEK/ERK and PI3K/AKT signaling pathways.
  73. Polysaccharide-Zein Composite Nanoparticles for Enhancing Cellular Uptake and Oral Bioavailability of Curcumin: Characterization, Anti-colorectal Cancer Effect, and Pharmacokinetics.
  74. Hidden in Plants-A Review of the Anticancer Potential of the Solanaceae Family in In Vitro and In Vivo Studies.
  75. Elderberries-A Source of Bioactive Compounds with Antiviral Action.
  76. Targeting ferroptosis as a vulnerability in cancer.
  77. Antioxidants of Fruit Extracts as Antimicrobial Agents against Pathogenic Bacteria.
  78. Liposomal cyanine dyes with enhanced nonradiative transition for the synergistic phototherapy of tumors.
  79. The effect of Elettaria cardamomum (cardamom) on the metabolic syndrome: Narrative review.
  80. Surface-Modified Bilosomes Nanogel Bearing a Natural Plant Alkaloid for Safe Management of Rheumatoid Arthritis Inflammation.
  81. Preparation and in vitro evaluation of thermosensitive liposomes targeting for ovarian cancer.
  82. The Natural Cryoprotectant Honey for Fertility Cryopreservation.
  83. Ketogenic HMG-CoA lyase and its product β-hydroxybutyrate promote pancreatic cancer progression.
  84. pH-Responsive Nanoparticles for Delivery of Paclitaxel to the Injury Site for Inhibiting Vascular Restenosis.
  85. Engineering naphthalimide-cyanine integrated near-infrared dye into ROS-responsive nanohybrids for tumor PDT/PTT/chemotherapy.
  86. Benefits of Black Cohosh (Cimicifuga racemosa) for Women Health: An Up-Close and In-Depth Review.
  87. Liposomes as Tools to Improve Therapeutic Enzyme Performance.
  88. Preparation, characterization and evaluation of capsaicin-loaded indica rice starch nanoparticles.
  89. Applications of Focused Ultrasound in the Treatment of Genitourinary Cancers.
  90. Ginsenoside Rk1 regulates glutamine metabolism in hepatocellular carcinoma through inhibition of the ERK/c-Myc pathway.
  91. Potential enhancement of metformin hydrochloride in solidified reverse micellar solution-based PEGylated lipid nanoparticles targeting therapeutic efficacy in diabetes treatment.
  92. Current Understanding of Modes of Action of Multicomponent Bioactive Phytochemicals: Potential for Nutraceuticals and Antimicrobials.
  93. Honeybee Venom Synergistically Enhances the Cytotoxic Effect of CNS Drugs in HT-29 Colon and MCF-7 Breast Cancer Cell Lines.
  94. Chitosan/PVA Hetero-Composite Hydrogel Containing Antimicrobials, Perfluorocarbon Nanoemulsions, and Growth Factor-Loaded Nanoparticles as a Multifunctional Dressing for Diabetic Wound Healing: Synthesis, Characterization, and In Vitro/In Vivo Evaluation.
  95. Medical Cannabis in Pediatric Oncology: Friend or Foe?
  96. The Effect of Photodynamic Therapy on Oral-Premalignant Lesions: A Systematic Review.
  97. Laurus nobilis L. Essential Oil-Loaded PLGA as a Nanoformulation Candidate for Cancer Treatment.
  98. Co-treatment of betulin and gefitinib is effective against EGFR wild-type/KRAS-mutant non-small cell lung cancer by inducing ferroptosis.
  99. Chitosan-Tripolyphosphate Nanoparticles Prepared by Ionic Gelation Improve the Antioxidant Activities of Astaxanthin in the In Vitro and In Vivo Model.
  100. Synthesis and characterization of photosensitive gelatin-based hydrogels for photodynamic therapy in HeLa-CCL2 cell line.
  101. Investigation on the in vitro anti-Trichophyton activity of photosensitizers.
  1. J Biomater Sci Polym Ed. 2022 Mar 23. 1-11
    Platelet-Biomimetic Nanoparticles for in vivo Targeted Photodynamic Therapy of Breast Cancer.
    Yangyang Song, Xue Tan, Yanan Gao.
      Nanocarrier-based photodynamic therapy (PDT) has emerged as a promising treatment in cancer therapy. However, the PDT therapeutic efficacy is limited by the lack of specificity, limited intracellular cytotoxic reactive oxygen species (ROS) generation, and the immunosuppressive tumor microenvironment. Herein, a platelet membrane (Pm) decorated and chlorin e6 loaded liposome (Pm/Lps/Ce6) is developed to improve specific tumor-targeting capability and antitumor responses. Pm/Lps/Ce6 could efficiently improve the cellular internalization of Ce6. Under 660-nm laser irradiation, enough ROS was produced to suppress the growth of tumor cells in vitro. In vivo, the Pm decoration increased cellular uptake of the Ce6 loaded liposome in cancer cells by the tumor-targeting and immune escape capacity and produced a satisfactory inhibitory effect on breast cancer. Our study provides a biomimetic strategy via the biological properties of Pm to improve the antitumor performance of photodynamic therapy for treating breast cancer.
    Keywords:  breast cancer; drug delivery; liposome; photodynamic therapy; platelet membrane
    DOI:  https://doi.org/10.1080/09205063.2022.2056942
  2. Curr Drug Deliv. 2022 Mar 24.
    Nanostructured Lipid Carriers for The Delivery of Natural Bioactive Compounds.
    Nur Amira Mohd Shamsuddin, Mohd Hanif Zulfakar.
      Natural products contain bioactive compounds that are produced naturally via synthetic or semisynthetic processes. These bioactive compounds play significant biological roles, especially for growth as well as in defence mechanisms against pathogens. Bioactive compounds in natural products have been extensively studied in recent decades for their pharmacological activity such as anti-cancer, wound healing, anti-microbial, anti-inflammatory, and anti-oxidative properties. However, their pharmaceutical significance has always been hindered by their low bioavailability, and instability with variations of pH, temperature, and exposure to light. Nanotechnology paves the way for the development of drug delivery systems by enhancing therapeutic efficacy. Nanostructured lipid carriers, a lipid-based drug delivery system, are recently being studied to improve the biocompatibility, biodegradability, bioavailability, solubility, permeability, and shelf life of bioactive compounds in the pharmaceutical industry. The ideal component and preparation method for bioactive compounds in nanostructured lipid carrier development is necessary for their physicochemical properties and therapeutic efficiency. Therefore, this review seeks to highlight recent developments, preparation, and application of nanostructured lipid carriers as carriers for natural bioactive compounds in improving their therapeutic potential in drug delivery systems.
    Keywords:  Bioactive compounds; Development; Nanostructured lipid carriers; Physicochemical properties; Preparation; Therapeutic potential
    DOI:  https://doi.org/10.2174/1567201819666220324094234
  3. Curr Med Chem. 2022 Mar 22.
    Curcumin nanofibers: A novel approach to enhance the anticancer potential and bioavailability of curcuminoids.
    Mahshid Ataei, Basil D Roufogalis, Muhammed Majeed, Muhammad Ajmal Shah, Amirhossein Sahebkar.
      Development of novel treatment methods for cancer are needed given limitations of current treatment methods, including side effects and chemotherapeutic resistance, providing new hope for cancer patients. Cancer is the second leading cause of global mortality. Curcumin, the active ingredient of turmeric, has been used since ancient times for various therapeutic purposes. Several studies have identified its activity against cancer. Despite the established anticancer activity of curcumin, its low aqueous solubility and bioavailability are barriers to its effectiveness. In an attempt to solve this problem, many studies have formulated curcumin nanofiber preparations using a variety of methods. Electrospinning is a simple and affordable method in the production of nanofibers. Studies have shown increased curcumin bioavailability in nanofibers resulting from their high surface/ volume ratio and porosity. We have undertaken a detailed review of studies on the anticancer effects of curcumin nanofibers. Curcumin acts by inhibition of various biological cancer pathways, including NF-κB, mTOR, complex I, cytokines, expression of p-p65, Ki67, and angiogenesis-associated genes. It also induces apoptosis through activation of caspase pathways and ROS production in cancer cells. Curcumin-loaded PLA50/PVP50/Cur15 nanofibers were investigated in breast cancer, one of the most studied cancers, and was shown to have significant effects on the widely used HeLa-cell line. Most of the studies that were undertaken have been performed in cell lines in vitro, while relatively few animal studies have been reported. More preclinical and clinical studies are needed to evaluate the effectiveness of curcumin nanofiber anticancer activity. Amongst studies undertaken a variety of curcumin nanofibers of various formulations were shown to suppress a variety of cancer types. Overall, curcumin nanofibers were found to be more efficient than free curcumin. Therefore, curcumin nanofibers provide cancer treatment that offers great potential for effective cancer management. Further studies with curcumin nanofibers both in vitro and in vivo have the potential to benefit cancer management.
    Keywords:  cancer; curcumin; electrospinning; nanofiber
    DOI:  https://doi.org/10.2174/0929867329666220322110348
  4. Chem Biol Drug Des. 2022 Mar 24.
    Isoquinolines alkaloids and cancer metabolism: Pathways and targets to novel chemotherapy.
    Angélica Lauria do Nascimento Mello, Patricia Zancan.
      Cancer is one of the main causes of death in the world. This is a complex disease where the development of resistance to chemotherapy is frequent driving the search for new anticancer compounds. In this sense, isoquinolines have gained attention in the past few years. This review aims to highlight the new advances related to the use of isoquinolines compounds against cancer cells and we point out targets for their anti-tumor action. Isoquinolines are compounds found in plants that are important for their protection. In cancer, many representatives of this class of compounds have demonstrated their efficacy against cancer by acting on cancer metabolism, such as: triggering cell death, reducing pro-survival protein expression, inducing ROS production, inhibiting pro-survival cell signaling pathways, among other effects. The mechanisms triggered by isoquinolines in cancer cells represent robust anti-cancer strategies, which support that this class of compounds are strong candidates for cancer treatment.
    Keywords:  MAPK; NFκB; PI3K; cancer metabolism; cell death; isoquinolines
    DOI:  https://doi.org/10.1111/cbdd.14043
  5. Nanomedicine (Lond). 2022 Mar 21.
    Nano-based targeted drug delivery for lung cancer: therapeutic avenues and challenges.
    Devaraj Ezhilarasan, Thangavelu Lakshmi, Sreekanth Kumar Mallineni.
      Most anticancer drugs often fail in clinical trials due to poor solubility, poor bioavailability, lack of targeted delivery and several off-target effects. Polymeric nanoparticles such as poly(lactide), poly(lactic-co-glycolic acid), ALB-loading paclitaxel (Abraxane® ABI-007), lomustine-loaded chitosan, gelatin (decorated with EGF receptor-targeted biotinylated EGF) and so on offer controlled and sustained drug release properties, biocompatibility and promising anticancer effects. EGF, folic acid, transferrin, sigma and urokinase plasminogen activator receptors-targeting nano preparations improve bioavailability and accumulate drugs on the lung tumor cell surface. However, route of administration, size, pharmacokinetic properties, immune clearance and so on hamper nanomedicines' clinical uses. This review focuses on the benefits, avenues and challenges of nanoparticle-based drug-delivery systems for lung cancer treatment.
    Keywords:  doxorubicin; liposomes; lung cancer; paclitaxel; polymeric nanoparticles
    DOI:  https://doi.org/10.2217/nnm-2021-0364
  6. Antioxidants (Basel). 2022 Mar 16. pii: 563. [Epub ahead of print]11(3):
    Contribution of Nanoscience Research in Antioxidants Delivery Used in Nutricosmetic Sector.
    Irene Dini.
      Nanoscience applications in the food and cosmetic industry offer many potential benefits for consumers and society. Nanotechnologies permit the manipulation of matter at the nanoscale level, resulting in new properties and characteristics useful in food and cosmetic production, processing, packaging, and storage. Nanotechnology protects sensitive bioactive compounds, improves their bioavailability and water solubility, guarantees their release at a site of action, avoids contact with other constituents, and masks unpleasant taste. Biopolymeric nanoparticles, nanofibers, nanoemulsions, nanocapsules, and colloids are delivery systems used to produce food supplements and cosmetics. There are no barriers to nanoscience applications in food supplements and cosmetic industries, although the toxicity of nano-sized delivery systems is not clear. The physicochemical and toxicological characterization of nanoscale delivery systems used by the nutricosmeceutic industry is reviewed in this work.
    Keywords:  edible nanocoating; nanoceutic; nanocosmeceuticals; nanoemulsion; nanotechnology; nutraceutic; nutricosmetic; phytochemical delivery; polymeric nanoparticles
    DOI:  https://doi.org/10.3390/antiox11030563
  7. Antioxidants (Basel). 2022 Mar 20. pii: 591. [Epub ahead of print]11(3):
    Combinatorial Effects of the Natural Products Arctigenin, Chlorogenic Acid, and Cinnamaldehyde Commit Oxidation Assassination on Breast Cancer Cells.
    Caroline Schuster, Nicholas Wolpert, Naima Moustaid-Moussa, Lauren S Gollahon.
      Major obstacles in current breast cancer treatment efficacy include the ability of breast cancer cells to develop resistance to chemotherapeutic drugs and the off-target cytotoxicity of these drugs on normal cells, leading to debilitating side effects. One major difference between cancer and normal cells is their metabolism, as cancer cells acquire glycolytic and mitochondrial metabolism alterations throughout tumorigenesis. In this study, we sought to exploit this metabolic difference by investigating alternative breast cancer treatment options based on the application of phytochemicals. Herein, we investigated three phytochemicals, namely cinnamaldehyde (CA), chlorogenic acid (CGA), and arctigenin (Arc), regarding their anti-breast-cancer properties. These phytochemicals were administered alone or in combination to MCF-7, MDA-MB-231, and HCC1419 breast cancer or normal MCF-10A and MCF-12F breast cells. Overall, our results indicated that the combination treatments showed stronger inhibitory effects on breast cancer cells versus single treatments. However, only treatments with CA (35 μM), CGA (250 μg/mL), and the combination of CA + CGA (35 μM + 250 μg/mL) showed no significant cytotoxic effects on normal mammary epithelial cells, suggesting that Arc was the driver of normal cell cytotoxicity in all other treatments. CA + CGA and, to a lesser extent, CGA alone effectively induced breast cancer cell death accompanied by decreases in mitochondrial membrane potential, increased mitochondrial superoxide, reduced mitochondrial and glycolytic ATP production, and led to significant changes in cellular and mitochondrial morphology. Altogether, the combination of CA + CGA was determined as the best anti-breast-cancer treatment strategy due to its strong anti-breast-cancer effects without strong adverse effects on normal mammary epithelial cells. This study provides evidence that targeting the mitochondria may be an effective anticancer treatment, and that using phytochemicals or combinations thereof offers new approaches in treating breast cancer that significantly reduce off-target effects on normal cells.
    Keywords:  ROS; arctigenin; breast cancer; cancer metabolism; chlorogenic acid; cinnamaldehyde; mitochondria
    DOI:  https://doi.org/10.3390/antiox11030591
  8. Sci Rep. 2022 Mar 24. 12(1): 5143
    Combining PEGylated mito-atovaquone with MCT and Krebs cycle redox inhibitors as a potential strategy to abrogate tumor cell proliferation.
    Gang Cheng, Micael Hardy, Ming You, Balaraman Kalyanaraman.
      Glycolytic and mitochondrial oxidative metabolism, which are two major energy sources in tumors, are potential targets in cancer treatment. Metabolic reprogramming from glycolysis to mitochondrial oxidative metabolism and vice versa is an adaptive strategy with which tumor cells obtain energy to survive and thrive under the compromised conditions of glycolysis and mitochondrial respiration. Developing highly potent, nontoxic, and tumor-selective oxidative phosphorylation (OXPHOS) inhibitors may help advance therapeutic targeting of mitochondrial drugs in cancer. The FDA-approved antimalarial drug atovaquone (ATO), a mitochondrial complex III inhibitor, was repurposed in cancer treatment. Here, we developed a new class of PEGylated mitochondria-targeted ATO (Mito-(PEG)n-ATO). Depending on the PEGylation chain length (n), Mito-PEG-ATO analogs inhibit both mitochondrial complex I- and complex III-induced oxygen consumption in human pancreatic (MiaPaCa-2) and brain (U87MG) cancer cells. Mito-PEG5-ATO is one of the most potent antiproliferative mitochondria-targeted compounds (IC50 = 38 nM) in MiaPaCa-2 cells, and is more effective than other inhibitors of OXPHOS in MiaPaCa-2 and U87MG cells. Furthermore, we show that the combined use of the most potent OXPHOS-targeted inhibitors (Mito-PEG5-ATO) and inhibitors of monocarboxylate transporters (MCT-1 and MCT-4), Krebs cycle redox metabolism, or glutaminolysis will synergistically abrogate tumor cell proliferation. Potential clinical benefits of these combinatorial therapies are discussed.
    DOI:  https://doi.org/10.1038/s41598-022-08984-6
  9. Phytomedicine. 2022 Mar 15. pii: S0944-7113(22)00126-X. [Epub ahead of print]100 154048
    Lactate metabolism in rheumatoid arthritis: Pathogenic mechanisms and therapeutic intervention with natural compounds.
    Ouyang Yi, Ye Lin, Mingyue Hu, Shengtao Hu, Zhaoli Su, Jin Liao, Bin Liu, Liang Liu, Xiong Cai.
      BACKGROUND: Rheumatoid arthritis (RA) is a common chronic and systemic autoimmune disease characterized by persistent inflammation and hyperplasia of the synovial membrane, the degradation of cartilage, and the erosion of bones in diarthrodial joints. The inflamed joints of patients with RA have been recognized to be a site of hypoxic microenvironment which results in an imbalance of lactate metabolism and the accumulation of lactate. Lactate is no longer considered solely a metabolic waste product of glycolysis, but also a combustion aid in the progression of RA from the early stages of inflammation to the late stages of bone destruction.PURPOSE: To review the pathogenic mechanisms of lactate metabolism in RA and investigate the potential of natural compounds for treating RA linked to the regulation of imbalance in lactate metabolism.
    METHODS: Research advances in our understanding of lactate metabolism in the pathogenesis of RA and novel pharmacological approaches of natural compounds by targeting lactate metabolic signaling were comprehensively reviewed and deeply discussed.
    RESULTS: Lactate produced by RA synovial fibroblasts (RASFs) acts on targeted cells such as T cells, macrophages, dendritic cells and osteoclasts, and affects their differentiation, activation and function to accelerate the development of RA. Many natural compounds show therapeutic potential for RA by regulating glycolytic rate-limiting enzymes to limit lactate production, and affecting monocarboxylate transporter and acetyl-CoA carboxylase to inhibit lactate transport and conversion.
    CONCLUSION: Regulation of imbalance in lactate metabolism offers novel therapeutic approaches for RA, and natural compounds capable of targeting lactate metabolic signaling constitute potential candidates for development of drugs RA.
    Keywords:  Hypoxic microenvironment; Lactate metabolism; Natural compounds; Rheumatoid arthritis; Synovial fibroblasts
    DOI:  https://doi.org/10.1016/j.phymed.2022.154048
  10. Biomed Pharmacother. 2022 Mar 19. pii: S0753-3322(22)00215-3. [Epub ahead of print]149 112827
    Advances in indole-containing alkaloids as potential anticancer agents by regulating autophagy.
    Meng-Lan Luo, Wei Huang, Hong-Ping Zhu, Cheng Peng, Qian Zhao, Bo Han.
      Cancer is a leading cause of death worldwide, and cancer development is often associated with disturbances in the autophagy process. Autophagy is a catabolic process involved in many physiological processes, crucial for cell growth and survival. It is an intracellular lysosomal/vacuolar degradation system. In this system, inner cytoplasmic cell membrane is degraded by lysosomal hydrolases, and the products are released back into the cytoplasm. Indole alkaloids are natural products extensively found in nature and have been proven to possess various pharmacological activities. In recent years, pharmacological studies have demonstrated another potential of indole alkaloids, autophagy regulation. The regulation may contribute to the efficacy of indole alkaloids in preventing and treating cancer. This review summarizes the current understanding of indole alkaloids' effect on tumor cells and autophagy. Then, we focus on mechanisms by which indole alkaloids can target the autophagy process associated with cancer, including the PI3K/Akt/mTOR signaling pathway, MAPK signaling pathway, ROS signaling pathway, Beclin-1, and so on. Literature has been surveyed primarily from 2009 to Nov. 2021, and some semisynthetic or fully synthetic indole derivatives are also discussed.
    Keywords:  Autophagy-related; Cancer therapy; Cell death; Cell survival; Indole; Signaling pathway
    DOI:  https://doi.org/10.1016/j.biopha.2022.112827
  11. Nanoscale Res Lett. 2022 Mar 22. 17(1): 36
    Research Progress of Cell Membrane Biomimetic Nanoparticles for Tumor Therapy.
    Xuefen Zhao, Chao Yan.
      Nanoparticles have unique properties and high design flexibility, which are thought to be safe, site-specific, and efficient drug delivery systems. However, nanoparticles as exogenous materials can provide recognition and be eliminated by the body's immune system, which considerably restricts their applications. To overcome these drawbacks, natural cell membrane coating method has attracted great attention in the field of drug delivery systems, which can prolong nanoparticles blood circulation time and avoiding the capture as well as elimination by the body immune system. Biomimetic nanoparticles via a top-down approach can avoid the laborious group modified engineering and keep the integrity of cell membrane structure and membrane antigens, which can be endowed with unique properties, such as immune escape, longer blood circulation time, targeting delivery and controlling drugs sustain-release. At the present research, erythrocyte membrane, cancer cell membrane, platelet membrane, lymphocyte membrane and hybrid membrane have been successfully coated into the surface of nanoparticles to achieve biological camouflage. Thus, integrating various kinds of cell membranes and nanoparticles into one system, the biomimetic nanoparticles can inherit unique biofunction and drug delivery properties to exhibit tumor targeting-delivery and antitumor outcomes. In this article, we will discuss the prospects and challenges of some basic cell membrane cloaking nanoparticles as a drug delivery system for cancer therapy.
    Keywords:  Biomimetic nanoparticles; Cell membrane; Tumor therapy
    DOI:  https://doi.org/10.1186/s11671-022-03673-9
  12. Biomolecules. 2022 Feb 25. pii: 367. [Epub ahead of print]12(3):
    The Role of Epigenetic Modifications in Human Cancers and the Use of Natural Compounds as Epidrugs: Mechanistic Pathways and Pharmacodynamic Actions.
    Abdelhakim Bouyahya, Hamza Mechchate, Loubna Oumeslakht, Ikrame Zeouk, Sara Aboulaghras, Abdelaali Balahbib, Gokhan Zengin, Mohammad Amjad Kamal, Monica Gallo, Domenico Montesano, Nasreddine El Omari.
      Cancer is a complex disease resulting from the genetic and epigenetic disruption of normal cells. The mechanistic understanding of the pathways involved in tumor transformation has implicated a priori predominance of epigenetic perturbations and a posteriori genetic instability. In this work, we aimed to explain the mechanistic involvement of epigenetic pathways in the cancer process, as well as the abilities of natural bioactive compounds isolated from medicinal plants (flavonoids, phenolic acids, stilbenes, and ketones) to specifically target the epigenome of tumor cells. The molecular events leading to transformation, angiogenesis, and dissemination are often complex, stochastic, and take turns. On the other hand, the decisive advances in genomics, epigenomics, transcriptomics, and proteomics have allowed, in recent years, for the mechanistic decryption of the molecular pathways of the cancerization process. This could explain the possibility of specifically targeting this or that mechanism leading to cancerization. With the plasticity and flexibility of epigenetic modifications, some studies have started the pharmacological screening of natural substances against different epigenetic pathways (DNA methylation, histone acetylation, histone methylation, and chromatin remodeling) to restore the cellular memory lost during tumor transformation. These substances can inhibit DNMTs, modify chromatin remodeling, and adjust histone modifications in favor of pre-established cell identity by the differentiation program. Epidrugs are molecules that target the epigenome program and can therefore restore cell memory in cancerous diseases. Natural products isolated from medicinal plants such as flavonoids and phenolic acids have shown their ability to exhibit several actions on epigenetic modifiers, such as the inhibition of DNMT, HMT, and HAT. The mechanisms of these substances are specific and pleiotropic and can sometimes be stochastic, and their use as anticancer epidrugs is currently a remarkable avenue in the fight against human cancers.
    Keywords:  DNMT; HDAC; cancer; cancer therapy; epidrugs; pharmacodynamic
    DOI:  https://doi.org/10.3390/biom12030367
  13. Small. 2022 Mar 20. e2107126
    Brain Targeting, Antioxidant Polymeric Nanoparticles for Stroke Drug Delivery and Therapy.
    Haoan Wu, Bin Peng, Farrah S Mohammed, Xingchun Gao, Zhenpeng Qin, Kevin N Sheth, Jiangbing Zhou, Zhaozhong Jiang.
      Ischemic stroke is a leading cause of death and disability and remains without effective treatment options. Improved treatment of stroke requires efficient delivery of multimodal therapy to ischemic brain tissue with high specificity. Here, this article reports the development of multifunctional polymeric nanoparticles (NPs) for both stroke treatment and drug delivery. The NPs are synthesized using an reactive oxygen species (ROS)-reactive poly (2,2'-thiodiethylene 3,3'-thiodipropionate) (PTT) polymer and engineered for brain penetration through both thrombin-triggered shrinkability and AMD3100-mediated targeted delivery. It is found that the resulting AMD3100-conjugated, shrinkable PTT NPs, or ASPTT NPs, efficiently accumulate in the ischemic brain tissue after intravenous administration and function as antioxidant agents for effective stroke treatment. This work shows ASPTT NPs are capable of efficient encapsulation and delivery of glyburide to achieve anti-edema and antioxidant combination therapy, resulting in therapeutic benefits significantly greater than those by either the NPs or glyburide alone. Due to their high efficiency in brain penetration and excellent antioxidant bioactivity, ASPTT NPs have the potential to be utilized to deliver various therapeutic agents to the brain for effective stroke treatment.
    Keywords:  anti-edema; antioxidants; blood-brain barrier; shrinkable nanoparticles; stroke
    DOI:  https://doi.org/10.1002/smll.202107126
  14. J Mater Chem B. 2022 Mar 22.
    An injectable thermosensitive hydrogel loaded with a theranostic nanoprobe for synergistic chemo-photothermal therapy for multidrug-resistant hepatocellular carcinoma.
    Shanzhou Huang, Zuyi Ma, Chengjun Sun, Qi Zhou, Zhenchong Li, Shujie Wang, Qian Yan, Chunsheng Liu, Baohua Hou, Chuanzhao Zhang.
      Multi-drug resistance (MDR) is a complicated cellular defense mechanism for tumor cells to resist chemotherapy drugs, which is also the main cause of chemotherapy failure. In this study, a local injectable hydrogel delivery system was used to construct an on-demand sustained-release platform with the advantages of chemotherapy, photothermal therapy (PTT), and magnetic resonance imaging (MRI). It could achieve synergistic chemo-photothermal therapy and real-time evaluation of the therapeutic effects (via MRI) for MDR hepatocellular carcinoma (HCC). Furthermore, after a single administration, the prepared hydrogel with a theranostic nanoprobe could release the therapeutic agents on demand for up to 14 d. Firstly, doxorubicin (DOX) and gold-manganese oxide (Au-MnO) nanoparticles (NPs) were incorporated into liposome-based self-assembled micelles, then loaded into the thermosensitive hydrogel (F127) to form DOX@Au-MnO-L NPs/F127 hydrogel (DAML/H). The prepared NP complex showed a spherical morphology with a narrow size distribution. The prepared hydrogel drug delivery system had injectable properties and stable photothermal conversion. Both the DOX@Au-MnO-L NPs and DAML/H showed controlled drug release under near infrared (NIR) laser irradiation. The in vitro MRI studies indicated that the prepared DAML/H had a high relaxation rate (14.38 mM-1 s-1) and good MRI scanning sensitivity conditions. The in vitro and in vivo results suggested the synergistic chemo-photothermal therapy of DAML/H with NIR irradiation (808 nm, 1 W cm-2, 10 min) improved the antitumor efficacy for MDR HCC. The in vivo retention experiment of Au in tumors indicated that the prepared hydrogel drug delivery system (DAML/H) had a good ability to retain Au in the tumor for a long time (at least 14 d). The western blotting results revealed that DAML/H with laser treatment could effectively downregulate P-glycoprotein (P-gp), p53 and antiapoptotic protein (Bcl-2), whereas the expression level of proapoptotic protein (Bax) and caspase-3 were increased. Therefore, DAML/H could serve as a promising synergistic chemo-photothermal therapy for MDR HCC, and a single administration might achieve long-term (14 d), on-demand, sustained-release treatment of tumors.
    DOI:  https://doi.org/10.1039/d2tb00044j
  15. Nutrients. 2022 Mar 09. pii: 1155. [Epub ahead of print]14(6):
    Anti-Inflammatory and Active Biological Properties of the Plant-Derived Bioactive Compounds Luteolin and Luteolin 7-Glucoside.
    Sabrina Caporali, Alessandro De Stefano, Cinzia Calabrese, Alfredo Giovannelli, Massimo Pieri, Isabella Savini, Manfredi Tesauro, Sergio Bernardini, Marilena Minieri, Alessandro Terrinoni.
      Flavonoids are interesting molecules synthetized by plants. They can be found abundantly in seeds and fruits, determining the color, flavor, and other organoleptic characteristics, as well as contributing to important nutritional aspects. Beyond these characteristics, due to their biochemical properties and characteristics, they can be considered bioactive compounds. Several interesting studies have demonstrated their biological activity in different cellular and physiological processes in high-order organisms including humans. The flavonoid molecular structure confers the capability of reacting with and neutralizing reactive oxygen species (ROS), behaving as scavengers in all processes generating this class of molecules, such as UV irradiation, a process widely present in plant physiology. Importantly, the recent scientific literature has demonstrated that flavonoids, in human physiology, are active compounds acting not only as scavengers but also with the important role of counteracting the inflammation process. Among the wide variety of flavonoid molecules, significant results have been shown by investigating the role of the flavones luteolin and luteolin-7-O-glucoside (LUT-7G). For these compounds, experimental results demonstrated an interesting anti-inflammatory action, both in vitro and in vivo, in the interaction with JAK/STAT3, NF-κB, and other pathways described in this review. We also describe the effects in metabolic pathways connected with inflammation, such as cellular glycolysis, diabetes, lipid peroxidation, and effects in cancer cells. Moreover, the inhibition of inflammatory pathway in endothelial tissue, as well as the NLRP3 inflammasome assembly, demonstrates a key role in the progression of such phenomena. Since these micronutrient molecules can be obtained from food, their biochemical properties open new perspectives with respect to the long-term health status of healthy individuals, as well as their use as a coadjutant treatment in specific diseases.
    Keywords:  endothelial inflammation; flavones; flavonoids; glucose metabolism; inflammation; luteolin; luteolin-7-O-glucoside (LUT-7G)
    DOI:  https://doi.org/10.3390/nu14061155
  16. Cancer Biol Ther. 2022 Dec 31. 23(1): 281-293
    Graphene quantum dots mediated magnetic chitosan drug delivery nanosystems for targeting synergistic photothermal-chemotherapy of hepatocellular carcinoma.
    Lili Chen, Wenzhong Hong, Siliang Duan, Yiping Li, Jian Wang, Jianmeng Zhu.
      Conventional clinical monotherapies for advanced hepatocellular carcinoma (HCC) have numerous limitations. Integrated oncology approaches can improve cancer treatment efficacy, and photothermal-chemotherapy drug delivery nanosystems (DDS) based on nanotechnology and biotechnology have piqued the interest of researchers. This study developed an aptamer-modified graphene quantum dots (GQDs)/magnetic chitosan DDS for photothermal-chemotherapy of HCC. The HCC aptamer and the EPR effect of nanoparticles, in particular, enable active and passive targeting of DDS to HCC. GQDs functioned as photosensitizers, effectively moderating photothermal therapy and inhibiting drug release during blood circulation. Magnetic chitosan demonstrated excellent drug encapsulation, acid sensitivity, and tumor imaging capabilities. Proper assembly of the units mentioned above enables precise combined therapy of HCC. This study indicates that DDS can significantly inhibit tumor growth while also extending the survival duration of tumor-bearing mice. The DDS (DOX-Fe3O4@CGA) shows strong synergistic tumor treatment potential, allowing for the exploration and development of novel HCC therapies.
    Keywords:  Hepatocellular carcinoma; combined therapy; drug delivery nanosystems; graphene quantum dot; magnetic chitosan
    DOI:  https://doi.org/10.1080/15384047.2022.2054249
  17. ACS Nano. 2022 Mar 24.
    A Platelet Intelligent Vehicle with Navigation for Cancer Photothermal-Chemotherapy.
    Yan Zhang, Yuanchao Sun, Xia Dong, Qiang-Song Wang, Dunwan Zhu, Lin Mei, Husheng Yan, Feng Lv.
      Controllable and visible delivery of therapeutic agents is critical for tumor precise therapy. Tumor targeting and deep penetration of therapeutic agents are still challenging issues for controllable delivery. Visible drug delivery with imaging navigation can optimize the treatment window for personalized medicine. Herein, a biomimetic platelet intelligent vehicle with navigation (IRDNP-PLT) was developed to achieve controllable and visible delivery with a navigation system, a driving system, and a loading system. The platelets acted as engines and drug repositories to exert the target driving and delivery functions. The fluorescent photothermal agent IR-820 was introduced in the platform to offer an imaging navigation for the intelligent platelet vehicle in addition to photothermal therapy. The nanodrug-loaded platelets enabled efficient drug loading and controlled release of the therapeutic payload by encapsulating photothermal-/pH-sensitive chemotherapeutic nanoparticles (PDA@Dox NPs). In in vivo experiments on 4T1 tumor-bearing mice models, IRDNP-PLT performed well in tumor targeting and showed excellent therapeutic efficacy and tumor recurrence prevention ability. The intelligent platelet vehicle achieved the functions of tumor targeting and deep penetration, fluorescence imaging guidance, photocontrolled drug release, and chemo-photothermal combination therapy, suggesting the advancement for tumor precise delivery and efficient therapy.
    Keywords:  cancer recurrence; imaging-navigation; photothermal-chemotherapy; platelet; tumor-targeted
    DOI:  https://doi.org/10.1021/acsnano.2c00453
  18. Apoptosis. 2022 Mar 21.
    Nobiletin as an inducer of programmed cell death in cancer: a review.
    Jun Huang, Zaoshang Chang, Quzhe Lu, Xuedong Chen, Masoud Najafi.
      Cancer resistance to therapy is a big issue in cancer therapy. Tumours may develop some mechanisms to reduce the induction of cell death, thus stimulating tumour growth. Cancer cells may show a low expression and activity of tumour suppressor genes and a low response to anti-tumour immunity. These mutations can increase the resistance of cancer cells to programmed cell death mechanisms such as apoptosis, ferroptosis, pyroptosis, autophagic cell death, and some others. The upregulation of some mediators and transcription factors such as Akt, nuclear factor of κB, signal transducer and activator of transcription 3, Bcl-2, and others can inhibit cell death in cancer cells. Using adjuvants to induce the killing of cancer cells is an interesting strategy in cancer therapy. Nobiletin (NOB) is a herbal-derived agent with fascinating anti-cancer properties. It has been shown to induce the generation of endogenous ROS by cancer cells, leading to damage to critical macromolecules and finally cell death. NOB may induce the activity of p53 and pro-apoptosis mediators, and also inhibit the expression and nuclear translocation of anti-apoptosis mediators. In addition, NOB may induce cancer cell killing by modulating other mechanisms that are involved in programmed cell death mechanisms. This review aims to discuss the cellular and molecular mechanisms of the programmed cell death in cancer by NOB via modulating different types of cell death in cancer.
    Keywords:  Apoptosis; Autophagy; Cancer; Cell death; NOB; Pyroptosis
    DOI:  https://doi.org/10.1007/s10495-022-01721-4
  19. ACS Appl Mater Interfaces. 2022 Mar 25.
    Site-Specific Displacement-Driven Activation of Supramolecular Photosensitizing Nanoassemblies for Antitumoral Photodynamic Therapy.
    Evelyn Y Xue, Caixia Yang, Wing-Ping Fong, Dennis K P Ng.
      The delivery and activation of photosensitizers in a specific manner is crucial in photodynamic therapy. For an antitumoral application, it can confine the photodynamic action on the cancer cells, thereby enhancing the treatment efficacy and reducing the side effects. We report herein a novel supramolecular photosensitizing nanosystem that can be specifically activated in cancer cells and tumors that overexpress epidermal growth factor receptor (EGFR). It involves the self-assembly of the amphiphilic host-guest complex of a β-cyclodextrin-conjugated phthalocyanine-based photosensitizer (Pc-CD) and a ferrocene-substituted poly(ethylene glycol) (Mn = 2000) (Fc-PEG) in aqueous media. The resulting nanosystem Pc-CD@Fc-PEG with a hydrodynamic diameter of 124-147 nm could not emit fluorescence and generate reactive oxygen species due to the self-quenching effect and the ferrocene-based quencher. Upon interactions with molecules of adamantane substituted with an EGFR-targeting peptide (Ad-QRH*) in water and in EGFR-positive HT29 and A431 cells, the ferrocene guest species were displaced, resulting in disassembly of the nanoparticles and restoration of these photoactivities. The half-maximal inhibitory concentration values were down to 1.24 μM (for HT29 cells). The nanosystem Pc-CD@Fc-PEG could also be activated in an Ad-QRH*-treated HT29 tumor in nude mice, leading to increased intratumoral fluorescence intensity and effective eradication of the tumor upon laser irradiation. The results showed that this two-step supramolecular approach can actualize site-specific photosensitization and minimize nonspecific phototoxicity in a general photodynamic treatment.
    Keywords:  cyclodextrin; host−guest complexes; photodynamic therapy; photosensitizers; phthalocyanines
    DOI:  https://doi.org/10.1021/acsami.1c23740
  20. Antibiotics (Basel). 2022 Feb 28. pii: 322. [Epub ahead of print]11(3):
    Antimicrobial Potential of Curcumin: Therapeutic Potential and Challenges to Clinical Applications.
    Yaseen Hussain, Waqas Alam, Hammad Ullah, Marco Dacrema, Maria Daglia, Haroon Khan, Carla Renata Arciola.
      Curcumin is a bioactive compound that is extracted from Curcuma longa and that is known for its antimicrobial properties. Curcuminoids are the main constituents of curcumin that exhibit antioxidant properties. It has a broad spectrum of antibacterial actions against a wide range of bacteria, even those resistant to antibiotics. Curcumin has been shown to be effective against the microorganisms that are responsible for surgical infections and implant-related bone infections, primarily Staphylococcus aureus and Escherichia coli. The efficacy of curcumin against Helicobacter pylori and Mycobacterium tuberculosis, alone or in combination with other classic antibiotics, is one of its most promising antibacterial effects. Curcumin is known to have antifungal action against numerous fungi that are responsible for a variety of infections, including dermatophytosis. Candidemia and candidiasis caused by Candida species have also been reported to be treated using curcumin. Life-threatening diseases and infections caused by viruses can be counteracted by curcumin, recognizing its antiviral potential. In combination therapy with other phytochemicals, curcumin shows synergistic effects, and this approach appears to be suitable for the eradication of antibiotic-resistant microbes and promising for achieving co-loaded antimicrobial pro-regenerative coatings for orthopedic implant biomaterials. Poor water solubility, low bioavailability, and rapid degradation are the main disadvantages of curcumin. The use of nanotechnologies for the delivery of curcumin could increase the prospects for its clinical application, mainly in orthopedics and other surgical scenarios. Curcumin-loaded nanoparticles revealed antimicrobial properties against S. aureus in periprosthetic joint infections.
    Keywords:  antimicrobial potential; clinical challenges; curcumin; nanocurcumin; nanoparticles; orthopedics
    DOI:  https://doi.org/10.3390/antibiotics11030322
  21. Adv Sci (Weinh). 2022 Mar;9(8): 2101935
    Lymph-Directed Self-Immolative Nitric Oxide Prodrug for Inhibition of Intractable Metastatic Cancer.
    Taejeong Kim, Jeeyeon Suh, Jihoon Kim, Won Jong Kim.
      There has been a significant clinical demand for lymph-directed anti-metastatic therapy as tumor-draining lymph nodes play pivotal roles in cancer metastasis which accounts for more than 90% of tumor-related deaths. Despite the high potential of nitric oxide (NO) in anti-cancer therapy owing to its biocompatibility and tumor cell-specific cytotoxicity, the poor stability and lack of target specificity of present NO donors and delivery systems have limited its clinical applications. Herein, a redox-triggered self-immolative NO prodrug that can be readily conjugated to various materials containing free thiol groups such as albumin, is reported. The prodrug and its conjugates demonstrate smart release of NO donor via intramolecular cyclization under reductive conditions, followed by spontaneously generating NO in physiological conditions. The albumin-prodrug conjugate inhibits tumor metastasis by inducing cytotoxicity preferentially on tumor cells after efficiently draining into lymph nodes. This novel prodrug can contribute to the development of on-demand NO delivery systems for anti-metastatic therapy and other treatments.
    Keywords:  lymph‐directed drug delivery; metastatic cancer therapy; nitric oxide; prodrug; redox chemistry
    DOI:  https://doi.org/10.1002/advs.202101935
  22. Int J Mol Sci. 2022 Mar 14. pii: 3117. [Epub ahead of print]23(6):
    Reactive Oxygen Species and Folate Receptor-Targeted Nanophotosensitizers Composed of Folic Acid-Conjugated and Poly(ethylene glycol)-Chlorin e6 Tetramer Having Diselenide Linkages for Targeted Photodynamic Treatment of Cancer Cells.
    Seong-Won Yang, Young-Il Jeong, Min-Suk Kook, Byung-Hoon Kim.
      Folic acid-conjugated nanophotosensitizers composed of folic acid (FA), poly(ethylene glycol) (PEG) and chlorin e6 (Ce6) tetramer were synthesized using diselenide linkages for reactive oxygen species (ROS)- and folate receptor-specific delivery of photosensitizers. Ce6 was conjugated with 3-[3-(2-carboxyethoxy)-2,2-bis(2-carboxyethoxymethyl)propoxy]propanoic acid (tetra acid, or TA) to make Ce6 tetramer via selenocystamine linkages (TA-sese-Ce6 conjugates). In the carboxylic acid end group of the TA-sese-Ce6 conjugates, FA-PEG was attached again using selenocystamine linkages to make FA-PEG/TA-sese-Ce6 conjugates (abbreviated as FAPEGtaCe6 conjugates). Nanophotosensitizers were fabricated by a dialysis procedure. In the morphological observations, they showed spherical shapes with small diameters of less than 200 nm. Stability of the aqueous FAPEGtaCe6 nanophotosensitizer solution was maintained (i.e., their particle sizes were not significantly changed until 7 days later). When H2O2 was added to the nanophotosensitizer solution, the particle size distribution was changed from a monomodal pattern to a multimodal pattern. In addition, the fluorescence intensity and Ce6 release rate from the nanophotosensitizers were also increased by the addition of H2O2. These results indicated that the nanophotosensitizers had ROS-sensitive properties. In an in vitro cell culture study, an FAPEGtaCe6 nanophotosensitizer treatment against cancer cells increased the Ce6 uptake ratio, ROS generation and light-irradiated cytotoxicity (phototoxicity) compared with Ce6 alone against various cancer cells. When the folic acid was pretreated to block the folate receptors of the Y79 cells and KB cells (folate receptor-overexpressing cells), the intracellular Ce6 uptake, ROS generation and thereby phototoxicity were decreased, while the MCF-7 cells did not significantly respond to blocking of the folate receptors. These results indicated that they could be delivered by a folate receptor-mediated pathway. Furthermore, an in vivo pulmonary metastasis model using Y79 cells showed folate receptor-specific delivery of FAPEGtaCe6 nanophotosensitizers. When folic acid was pre-administered, the fluorescence intensity of the lungs was significantly decreased, indicating that the FAPEGtaCe6 nanophotosensitizers had folate receptor specificity in vitro and in vivo. We suggest that FAPEGtaCe6 nanophotosensitizers are promising candidates for a targeted photodynamic therapy (PDT) approach against cancer cells.
    Keywords:  drug targeting; nanophotosensitizers; photodynamic therapy; reactive oxygen species; retinoblastoma
    DOI:  https://doi.org/10.3390/ijms23063117
  23. Gels. 2022 Mar 12. pii: 176. [Epub ahead of print]8(3):
    Repurposing Lovastatin Cytotoxicity against the Tongue Carcinoma HSC3 Cell Line Using a Eucalyptus Oil-Based Nanoemulgel Carrier.
    Waleed Y Rizg, Khaled M Hosny, Samar S Mahmoud, Ahmed K Kammoun, Abdulmohsin J Alamoudi, Hossam H Tayeb, Haitham A Bukhary, Moutaz Y Badr, Samar S A Murshid, Eman Alfayez, Sarah A Ali, Rayan Y Mushtaq, Walaa A Abualsunun.
      Tongue cancer is one of the most common carcinomas of the head and neck region. The antitumor activities of statins, including lovastatin (LV), and the essential oil of eucalyptus (Eu oil), have been adequately reported. The aim of this study was to develop a nanoemulgel containing LV combined with Eu oil that could then be made into a nanoemulsion and assessed to determine its cytotoxicity against the cell line human chondrosarcoma-3 (HSC3) of carcinoma of the tongue. An I-optimal coordinate-exchange quadratic mixture design was adopted to optimize the investigated nanoemulsions. The droplet size and stability index of the developed formulations were measured to show characteristics of the nanoemulsions. The optimized LV loaded self-nanoemulsifying drug delivery system (LV-Eu-SNEDDS) was loaded into the gelling agent Carbopol 934 to develop the nanoemulgel and evaluated for its rheological properties. The cytotoxic efficiency of the optimized LV-Eu-SNEDDS loaded nanoemulgel was tested for cell viability, and the caspase-3 enzyme test was used against the HSC3 cell line of squamous carcinoma of the tongue. The optimized nanoemulsion had a droplet size of 85 nm and a stability index of 93%. The manufactured nanoemulgel loaded with the optimum LV-Eu-SNEDDS exhibited pseudoplastic flow with thixotropic behavior. The developed optimum LV-Eu-SNEDDS-loaded nanoemulgel had the best half-maximal inhibitory concentration (IC50) and caspase-3 enzyme values of the formulations developed for this study, and these features improved the ability of the nanoemulsion-loaded gel to deliver the drug to the investigated target cells. In addition, the in vitro cell viability studies revealed the synergistic effect between LV and Eu oil in the treatment of tongue cancer. These findings illustrated that the LV-Eu-SNEDDS-loaded gel formulation could be beneficial in the local treatment of tongue cancer.
    Keywords:  essential oils; experimental design; nanosized delivery systems; statins; tongue cancer
    DOI:  https://doi.org/10.3390/gels8030176
  24. Antioxidants (Basel). 2022 Mar 15. pii: 554. [Epub ahead of print]11(3):
    Dietary Polyphenols as Therapeutic Intervention for Alzheimer's Disease: A Mechanistic Insight.
    Syed Nasir Abbas Bukhari.
      Dietary polyphenols encompass a diverse range of secondary metabolites found in nature, such as fruits, vegetables, herbal teas, wine, and cocoa products, etc. Structurally, they are either derivatives or isomers of phenol acid, isoflavonoids and possess hidden health promoting characteristics, such as antioxidative, anti-aging, anti-cancerous and many more. The use of such polyphenols in combating the neuropathological war raging in this generation is currently a hotly debated topic. Lately, Alzheimer's disease (AD) is emerging as the most common neuropathological disease, destroying the livelihoods of millions in one way or another. Any therapeutic intervention to curtail its advancement in the generation to come has been in vain to date. Using dietary polyphenols to construct the barricade around it is going to be an effective strategy, taking into account their hidden potential to counter multifactorial events taking place under such pathology. Besides their strong antioxidant properties, naturally occurring polyphenols are reported to have neuroprotective effects by modulating the Aβ biogenesis pathway in Alzheimer's disease. Thus, in this review, I am focusing on unlocking the hidden secrets of dietary polyphenols and their mechanistic advantages to fight the war with AD and related pathology.
    Keywords:  amyloid; homeostasis; like curcumin; metal chelation; quercetin
    DOI:  https://doi.org/10.3390/antiox11030554
  25. Curr Drug Deliv. 2022 Mar 24.
    Liposome Nanoparticles as a Novel Drug Delivery System for Therapeutic and Diagnostic Applications.
    Yanan Meng, Xia Niu, Guiling Li.
      Liposome nanoparticles (LNPs) as a promising platform in drug delivery, combine the advantages of both liposomes and inorganic/organic nanoparticles into a single system. Both liposomes and nanoparticles have demonstrated the optimized drug efficacy in clinic. LNPs are proven to be a multifunctional system and thus utilized in various research applications (e.g., spatiotemporal control of drug release, hyperthermia, photothermal therapy, and biological imaging). The type of nanoparticles involved in LNPs largely affects the features of LNPs. Besides, diverse nanoparticlesenable liposomes to overcome the defects such as poor stability, few functions and rapid elimination from blood circulation. In this review, multiple nanoparticles materials and further prepared LNPs as well as their structure, physicochemical properties, manipulation and the latest applications in biomedical field are introduced. Future directions in advancing of LNPs are also discussed in the end.
    Keywords:  Liposome nanoparticles; combination therapy; controlled drug release; drug delivery system; imaging; nanostructure
    DOI:  https://doi.org/10.2174/1567201819666220324093821
  26. Pharmaceutics. 2022 Mar 17. pii: 661. [Epub ahead of print]14(3):
    Smart Injectable Chitosan Hydrogels Loaded with 5-Fluorouracil for the Treatment of Breast Cancer.
    Ahmed A H Abdellatif, Ahmed M Mohammed, Imran Saleem, Mansour Alsharidah, Osamah Al Rugaie, Fatma Ahmed, Shaaban K Osman.
      The treatment of breast cancer requires long chemotherapy management, which is accompanied by severe side effects. Localized delivery of anticancer drugs helps to increase the drug concentration at the site of action and overcome such a problem. In the present study, chitosan hydrogel was prepared for local delivery of 5-Fluorouracil. The in vitro release behavior was investigated and the anticancer activity was evaluated against MCF-7 cells using MTT assay. The in vivo studies were investigated via intra-tumoral injection of a 5-FU loaded hydrogel into breast cancer of female rats. The results indicated that the modified hydrogel has excellent physicochemical properties with a sustained in vitro release profile matching a zero-order kinetic for one month. In addition, the hydrogel showed superior inhibition of cell viability compared with the untreated control group. Moreover, the in vivo studies resulted in antitumor activity with minor side effects. The tumor volume and level of tumor markers in blood were inhibited significantly by applying the hydrogel compared with the untreated control group. In conclusion, the designed injectable hydrogels are potential drug delivery systems for the treatment of breast cancer with a controlled drug release profile, which could be suitable for decreasing the side effects of chemotherapy agents.
    Keywords:  5-fluorouracil; MTT assay; chitosan; in vitro release; in vivo antitumor; thermosensitive hydrogel
    DOI:  https://doi.org/10.3390/pharmaceutics14030661
  27. Anticancer Agents Med Chem. 2022 Mar 24.
    A Therapeutic Journey of Pyridine-Based Heterocyclic Compounds as Potent Anticancer Agents: A Review (From 2017 to 2021).
    Munira Alrooqi, Sikandar Khan, Fahad A Alhumaydhi, Saeed A Asiri, Meshal Alshamrani, Mutaib M Mashraqi, Ahmad Alzamami, Asma M Alshahrani, Afaf A Aldahish.
      Pyridine derivatives are the most common and significant heterocyclic compounds, which show their fundamental characteristics to various pharmaceutical agents and natural products. Pyridine derivatives possess several pharmacological properties and a broad degree of structural diversity that is considered most valuable to explore the novel therapeutic agents. These compounds have an extensive range of biological activities such as antifungal, antibacterial, anticancer, anti-obesity, anti-inflammatory, antitubercular, antihypertensive, antineuropathic, antihistaminic, antiviral activities, and antiparasitic. The potent therapeutic properties of pyridine derivatives allow medicinal chemists to synthesize novel and effective chemotherapeutic agents. Consequently, the imperative objective of this comprehensive review is to summarize and investigate the literature regarding recent advancements in pyridine-based heterocycles to treat several kinds of cancer. Furthermore, the performances of pyridine derivatives were compared with some standard drugs including etoposide, sorafenib, cisplatin, and triclosan against different cancer cell lines. We hope this study will support the new thoughts to pursue the most active and less toxic rational designs.
    Keywords:  Antibacterial; Anticancer; Cisplatin; Heterocycles; Pyridine; Therapeutic agents
    DOI:  https://doi.org/10.2174/1871520622666220324102849
  28. Pharmaceutics. 2022 Feb 28. pii: 551. [Epub ahead of print]14(3):
    Well-Defined Polyethylene Glycol Microscale Hydrogel Blocks Containing Gold Nanorods for Dual Photothermal and Chemotherapeutic Therapy.
    Ben Newland, Johannes Starke, Chiara Bastiancich, Diana P N Gonçalves, Laura J Bray, Wenxin Wang, Carsten Werner.
      Local drug delivery offers a means of achieving a high concentration of therapeutic agents directly at the tumor site, whilst minimizing systemic toxicity. For heterogenous cancers such as glioblastoma, multimodal therapeutic approaches hold promise for better efficacy. Herein, we aimed to create a well-defined and reproducible drug delivery system that also incorporates gold nanorods for photothermal therapy. Solvent-assisted micromolding was used to create uniform sacrificial templates in which microscale hydrogels were formed with and without gold nanorods throughout their structure. The microscale hydrogels could be loaded with doxorubicin, releasing it over a period of one week, causing toxicity to glioma cells. Since these microscale hydrogels were designed for direct intratumoral injection, therefore bypassing the blood-brain barrier, the highly potent breast cancer therapeutic doxorubicin was repurposed for use in this study. By contrast, the unloaded hydrogels were well tolerated, without decreasing cell viability. Irradiation with near-infrared light caused heating of the hydrogels, showing that if concentrated at an injection site, these hydrogels maybe able to cause anticancer activity through two separate mechanisms.
    Keywords:  glioblastoma; gold nanorods; microscale hydrogels; photodynamic therapy; polyethylene glycol
    DOI:  https://doi.org/10.3390/pharmaceutics14030551
  29. Biomedicines. 2022 Mar 03. pii: 592. [Epub ahead of print]10(3):
    An In Vivo Inflammatory Loop Potentiates KRAS Blockade.
    Kristina A M Arendt, Giannoula Ntaliarda, Vasileios Armenis, Danai Kati, Christin Henning, Georgia A Giotopoulou, Mario A A Pepe, Laura V Klotz, Anne-Sophie Lamort, Rudolf A Hatz, Sebastian Kobold, Andrea C Schamberger, Georgios T Stathopoulos.
      KRAS (KRAS proto-oncogene, GTPase) inhibitors perform less well than other targeted drugs in vitro and fail clinical trials. To investigate a possible reason for this, we treated human and murine tumor cells with KRAS inhibitors deltarasin (targeting phosphodiesterase-δ), cysmethynil (targeting isoprenylcysteine carboxylmethyltransferase), and AA12 (targeting KRASG12C), and silenced/overexpressed mutant KRAS using custom-designed vectors. We showed that KRAS-mutant tumor cells exclusively respond to KRAS blockade in vivo, because the oncogene co-opts host myeloid cells via a C-C-motif chemokine ligand 2 (CCL2)/interleukin-1 beta (IL-1β)-mediated signaling loop for sustained tumorigenicity. Indeed, KRAS-mutant tumors did not respond to deltarasin in C-C motif chemokine receptor 2 (Ccr2) and Il1b gene-deficient mice, but were deltarasin-sensitive in wild-type and Ccr2-deficient mice adoptively transplanted with wild-type murine bone marrow. A KRAS-dependent pro-inflammatory transcriptome was prominent in human cancers with high KRAS mutation prevalence and poor predicted survival. Our findings support that in vitro cellular systems are suboptimal for anti-KRAS drug screens, as these drugs function to suppress interleukin-1 receptor 1 (IL1R1) expression and myeloid IL-1β-delivered pro-growth effects in vivo. Moreover, the findings support that IL-1β blockade might be suitable for therapy for KRAS-mutant cancers.
    Keywords:  IL-1β; IL1R1; KRAS; KRAS mutation; KRASG12C; deltarasin; inflammation; lung cancer
    DOI:  https://doi.org/10.3390/biomedicines10030592
  30. Anticancer Agents Med Chem. 2022 Mar 21.
    Advances in the Novel Nanotechnology for the Targeted Tumor Therapy by the Transdermal Drug Delivery.
    Yuchen Wang, Guan Jiang.
      Despite modern medicine advances greatly, cancer remains a serious challenge to world health for which effective methods of treatment have hardly been developed yet. However, throughout the recent years, the rapid-developing nanotechnology has provided a new outlook of cancer therapy by transdermal drug delivery. By disrupting the stratum corneum, drugs are delivered through the skin and navigated to the tumor site by drug delivery systems such as nanogels, microneedles, etc. The superiorities include the improvement of drug pharmacokinetics as well as reduced side effects. This paper reviews the reported novel development of transdermal drug delivery systems for targeted cancer therapy. Advanced techniques for penetrating the skin will be discussed as well.
    Keywords:  Transdermal drug delivery; cancer treatment; microneedles; nanogels; nanotechnology
    DOI:  https://doi.org/10.2174/1871520622666220321093000
  31. Pharmaceutics. 2022 Feb 24. pii: 491. [Epub ahead of print]14(3):
    Nanocarriers Based on Gold Nanoparticles for Epigallocatechin Gallate Delivery in Cancer Cells.
    Lídia Cunha, Sílvia Castro Coelho, Maria do Carmo Pereira, Manuel A N Coelho.
      Gold nanoparticles (AuNPs) are inorganic and biocompatible nanovehicles capable of conjugating biomolecules to enhance their efficacy in cancer treatment. The high and reactive surface area provides good advantages for conjugating active compounds. Two approaches were developed in this work to improve the Epigallocatechin-3-gallate (EGCG) antioxidant efficacy. AuNPs were synthesized by reducing gold salt with chitosan. One other nanosystem was developed by functionalizing AuNPs with cysteamine using the Turkevitch method. The physico-chemical characterization of EGCG conjugated in the two nanosystems-based gold nanoparticles was achieved. The in vitro toxic effect induced by the nanoconjugates was evaluated in pancreatic cancer cells, showing that encapsulated EGCG keeps its antioxidant activity and decreasing the BxPC3 cell growth. A significant cell growth inhibition was observed in 50% with EGCG concentrations in the range of 2.2 and 3.7 μM in EGCG-ChAuNPs and EGCG-Cyst-AuNPs nanoconjugates, respectively. The EGCG alone had to be present at 23 μM to induce the same cytotoxicity response. Caspase-3 activity assay demonstrated that the conjugation of EGCG induces an enhancement of BxPC3 apoptosis compared with EGCG alone. In conclusion, AuNPs complexes can be used as delivery carriers to increase EGCG antioxidant activity in cancer tissues.
    Keywords:  antioxidant activity; drug delivery systems; epigallocatechin gallate; gold nanoparticles; pancreatic cancer cells
    DOI:  https://doi.org/10.3390/pharmaceutics14030491
  32. J Drug Target. 2022 Mar 24. 1-49
    Cannabis as a potential compound against various malignancies, legal aspects, advancement by exploiting nanotechnology and clinical trials.
    Nazeer Hasan, Mohammad Imran, Afsana Sheikh, Suma Saad, Gaurav Chaudhary, Gaurav Kumar Jain, Prashant Kesharwani, Farhan J Ahmad.
      Various preclinical and clinical studies exhibited the potential of cannabis against various diseases, including cancer and related pain. Subsequently, many efforts have been made to establish and develop cannabis-related products and make them available as prescription products. Moreover, FDA has already approved some cannabis-related products, and more advancement in this aspect is still going on. However, the approved product of cannabis is in oral dosage form, which exerts various limitations to achieve maximum therapeutic effects. A considerable translation is on a hike to improve bioavailability, and ultimately, the therapeutic efficacy of cannabis by the employment of nanotechnology. Besides the well-known psychotropic effects of cannabis upon the use at high doses, literature has also shown the importance of cannabis and its constituents in minimizing the lethality of cancer in the preclinical models. This review discusses the history of cannabis, its legal aspect, safety profile, the mechanism by which cannabis combats with cancer, and the advancement of clinical therapy by exploiting nanotechnology. A brief discussion related to the role of cannabinoid in various cancers has also been incorporated. Lastly, the information regarding completed and ongoing trials have also been elaborated.
    Keywords:  Anti-cancer agent; Cannabis; Clinical Trials; Drug delivery; Endocannabinoid systems; Nanotechnology
    DOI:  https://doi.org/10.1080/1061186X.2022.2056188
  33. Membranes (Basel). 2022 Mar 01. pii: 286. [Epub ahead of print]12(3):
    Elucidation of the Interactions of Reactive Oxygen Species and Antioxidants in Model Membranes Mimicking Cancer Cells and Normal Cells.
    Geonho Cho, Deborah Lee, Sun Min Kim, Tae-Joon Jeon.
      Photosensitizers (PSs) used in photodynamic therapy (PDT) have been developed to selectively destroy tumor cells. However, PSs recurrently reside on the extracellular matrix or affect normal cells in the vicinity, causing side effects. Additionally, the membrane stability of tumor cells and normal cells in the presence of reactive oxygen species (ROS) has not been studied, and the effects of ROS at the membrane level are unclear. In this work, we elucidate the stabilities of model membranes mimicking tumor cells and normal cells in the presence of ROS. The model membranes are constructed according to the degree of saturation in lipids and the bilayers are prepared either in symmetric or asymmetric form. Interestingly, membranes mimicking normal cells are the most vulnerable to ROS, while membranes mimicking tumor cells remain relatively stable. The instability of normal cell membranes may be one cause of the side effects of PDT. Moreover, we also show that ROS levels are controlled by antioxidants, helping to maintain an appropriate amount of ROS when PDT is applied.
    Keywords:  antioxidant; biomimetic membranes; lipid membranes; photodynamic therapy; reactive oxygen species
    DOI:  https://doi.org/10.3390/membranes12030286
  34. Pharmaceutics. 2022 Mar 16. pii: 652. [Epub ahead of print]14(3):
    pH-Sensitive Peptide Hydrogels as a Combination Drug Delivery System for Cancer Treatment.
    Yuanfen Liu, Yingchun Ran, Yu Ge, Faisal Raza, Shasha Li, Hajra Zafar, Yiqun Wu, Ana Cláudia Paiva-Santos, Chenyang Yu, Meng Sun, Ying Zhu, Fei Li.
      Conventional antitumor chemotherapeutics generally have shortcomings in terms of dissolubility, selectivity and drug action time, and it has been difficult to achieve high antitumor efficacy with single-drug therapy. At present, combination therapy with two or more drugs is widely used in the treatment of cancer, but a shortcoming is that the drugs do not reach the target at the same time, resulting in a reduction in efficacy. Therefore, it is necessary to design a carrier that can release two drugs at the same site. We designed an injectable pH-responsive OE peptide hydrogel as a carrier material for the antitumor drugs gemcitabine (GEM) and paclitaxel (PTX) that can release drugs at the tumor site simultaneously to achieve the antitumor effect. After determining the optimal gelation concentration of the OE polypeptide, we conducted an in vitro release study to prove its pH sensitivity. The release of PTX from the OE hydrogel in the medium at pH 5.8 and pH 7.4 was 96.90% and 38.98% in 7 days. The release of GEM from the OE hydrogel in media with pH of 5.8 and 7.4 was 99.99% and 99.63% in 3 days. Transmission electron microscopy (TEM) and circular dichroism (CD) experiments were used to observe the microstructure of the peptides. The circular dichroism of OE showed a single negative peak shape when under neutral conditions, indicating a β-folded structure, while under acidic conditions, it presented characteristics of a random coil. Rheological experiments were used to investigate the mechanical strength of this peptide hydrogel. Furthermore, the treatment effect of the drug-loaded peptide hydrogel was demonstrated through in vitro and in vivo experiments. The results show that the peptide hydrogels have different structures at different pH values and are highly sensitive to pH. They can reach the tumor site by injection and are induced by the tumor microenvironment to release antitumor drugs slowly and continuously. This biologically functional material has a promising future in drug delivery for combination drugs.
    Keywords:  cancer; combination therapy; drug delivery; hydrogel; peptide
    DOI:  https://doi.org/10.3390/pharmaceutics14030652
  35. Viruses. 2022 Mar 14. pii: 602. [Epub ahead of print]14(3):
    Hallmarks of Metabolic Reprogramming and Their Role in Viral Pathogenesis.
    Charles N S Allen, Sterling P Arjona, Maryline Santerre, Bassel E Sawaya.
      Metabolic reprogramming is a hallmark of cancer and has proven to be critical in viral infections. Metabolic reprogramming provides the cell with energy and biomass for large-scale biosynthesis. Based on studies of the cellular changes that contribute to metabolic reprogramming, seven main hallmarks can be identified: (1) increased glycolysis and lactic acid, (2) increased glutaminolysis, (3) increased pentose phosphate pathway, (4) mitochondrial changes, (5) increased lipid metabolism, (6) changes in amino acid metabolism, and (7) changes in other biosynthetic and bioenergetic pathways. Viruses depend on metabolic reprogramming to increase biomass to fuel viral genome replication and production of new virions. Viruses take advantage of the non-metabolic effects of metabolic reprogramming, creating an anti-apoptotic environment and evading the immune system. Other non-metabolic effects can negatively affect cellular function. Understanding the role metabolic reprogramming plays in viral pathogenesis may provide better therapeutic targets for antivirals.
    Keywords:  Warburg effect; amino acid metabolism; biomass; biosynthetic and bioenergetic pathways; glutaminolysis; glycolysis; lipid metabolism; metabolic reprogramming; mitochondria; pentose phosphate pathway; viral replication; virus
    DOI:  https://doi.org/10.3390/v14030602
  36. Pharmaceutics. 2022 Feb 27. pii: 533. [Epub ahead of print]14(3):
    Lipid Nanoparticles as a Promising Drug Delivery Carrier for Topical Ocular Therapy-An Overview on Recent Advances.
    Shery Jacob, Anroop B Nair, Jigar Shah, Sumeet Gupta, Sai H S Boddu, Nagaraja Sreeharsha, Alex Joseph, Pottathil Shinu, Mohamed A Morsy.
      Due to complicated anatomical and physical properties, targeted drug delivery to ocular tissues continues to be a key challenge for formulation scientists. Various attempts are currently being made to improve the in vivo performance of therapeutic molecules by encapsulating them in various nanocarrier systems or devices and administering them via invasive/non-invasive or minimally invasive drug administration methods. Biocompatible and biodegradable lipid nanoparticles have emerged as a potential alternative to conventional ocular drug delivery systems to overcome various ocular barriers. Lipid-based nanocarrier systems led to major technological advancements and therapeutic advantages during the last few decades of ocular therapy, such as high precorneal residence time, sustained drug release profile, minimum dosing frequency, decreased drug toxicity, targeted site delivery, and, therefore, an improvement in ocular bioavailability. In addition, such formulations can be given as fine dispersion in patient-friendly droppable preparation without causing blurred vision and ocular sensitivity reactions. The unique advantages of lipid nanoparticles, namely, solid lipid nanoparticles, nanostructured lipid carriers, nanoemulsions, and liposomes in intraocular targeted administration of various therapeutic drugs are extensively discussed. Ongoing and completed clinical trials of various liposome-based formulations and various characterization techniques designed for nanoemulsion in ocular delivery are tabulated. This review also describes diverse solid lipid nanoparticle preparation methods, procedures, advantages, and limitations. Functionalization approaches to overcome the drawbacks of lipid nanoparticles, as well as the exploration of new functional additives with the potential to improve the penetration of macromolecular pharmaceuticals, would quickly progress the challenging field of ocular drug delivery systems.
    Keywords:  clinical trials; lipid nanoparticles; liposomes; nanoemulsions; nanostructured lipid carriers; ocular drug delivery; solid-lipid nanoparticles
    DOI:  https://doi.org/10.3390/pharmaceutics14030533
  37. Cell Death Discov. 2022 Mar 25. 8(1): 131
    Targeting tumor innervation: premises, promises, and challenges.
    Xinyu Li, Xueqiang Peng, Shuo Yang, Shibo Wei, Qing Fan, Jingang Liu, Liang Yang, Hangyu Li.
      A high intratumoral nerve density is correlated with poor survival, high metastasis, and high recurrence across multiple solid tumor types. Recent research has revealed that cancer cells release diverse neurotrophic factors and exosomes to promote tumor innervation, in addition, infiltrating nerves can also mediate multiple tumor biological processes via exosomes and neurotransmitters. In this review, through seminal studies establishing tumor innervation, we discuss the communication between peripheral nerves and tumor cells in the tumor microenvironment (TME), and revealed the nerve-tumor regulation mechanisms on oncogenic process, angiogenesis, lymphangiogenesis, and immunity. Finally, we discussed the promising directions of 'old drugs newly used' to target TME communication and clarified a new line to prevent tumor malignant capacity.
    DOI:  https://doi.org/10.1038/s41420-022-00930-9
  38. Nat Commun. 2022 Mar 21. 13(1): 1503
    A non-dividing cell population with high pyruvate dehydrogenase kinase activity regulates metabolic heterogeneity and tumorigenesis in the intestine.
    Carlos Sebastian, Christina Ferrer, Maria Serra, Jee-Eun Choi, Nadia Ducano, Alessia Mira, Manasvi S Shah, Sylwia A Stopka, Andrew J Perciaccante, Claudio Isella, Daniel Moya-Rull, Marianela Vara-Messler, Silvia Giordano, Elena Maldi, Niyati Desai, Diane E Capen, Enzo Medico, Murat Cetinbas, Ruslan I Sadreyev, Dennis Brown, Miguel N Rivera, Anna Sapino, David T Breault, Nathalie Y R Agar, Raul Mostoslavsky.
      Although reprogramming of cellular metabolism is a hallmark of cancer, little is known about how metabolic reprogramming contributes to early stages of transformation. Here, we show that the histone deacetylase SIRT6 regulates tumor initiation during intestinal cancer by controlling glucose metabolism. Loss of SIRT6 results in an increase in the number of intestinal stem cells (ISCs), which translates into enhanced tumor initiating potential in APCmin mice. By tracking down the connection between glucose metabolism and tumor initiation, we find a metabolic compartmentalization within the intestinal epithelium and adenomas, where a rare population of cells exhibit features of Warburg-like metabolism characterized by high pyruvate dehydrogenase kinase (PDK) activity. Our results show that these cells are quiescent cells expressing +4 ISCs and enteroendocrine markers. Active glycolysis in these cells suppresses ROS accumulation and enhances their stem cell and tumorigenic potential. Our studies reveal that aerobic glycolysis represents a heterogeneous feature of cancer, and indicate that this metabolic adaptation can occur in non-dividing cells, suggesting a role for the Warburg effect beyond biomass production in tumors.
    DOI:  https://doi.org/10.1038/s41467-022-29085-y
  39. Chem Sci. 2022 Feb 23. 13(8): 2202-2217
    Redox dyshomeostasis strategy for tumor therapy based on nanomaterials chemistry.
    Yelin Wu, Yanli Li, Guanglei Lv, Wenbo Bu.
      Redox homeostasis, as an innate cellular defense mechanism, not only contributes to malignant transformation and metastasis of tumors, but also seriously restricts reactive oxygen species (ROS)-mediated tumor therapies, such as chemotherapy, radiotherapy, photodynamic therapy (PDT), and chemodynamic therapy (CDT). Therefore, the development of the redox dyshomeostasis (RDH) strategy based on nanomaterials chemistry is of great significance for developing highly efficient tumor therapy. This review will firstly introduce the basic definition and function of cellular redox homeostasis and RDH. Subsequently, the current representative progress of the nanomaterial-based RDH strategy for tumor therapy is evaluated, summarized and discussed. This strategy can be categorized into three groups: (1) regulation of oxidizing species; (2) regulation of reducing species and (3) regulation of both of them. Furthermore, the current limitations and potential future directions for this field will be briefly discussed. We expect that this review could attract positive attention in the chemistry, materials science, and biomedicine fields and further promote their interdisciplinary integration.
    DOI:  https://doi.org/10.1039/d1sc06315d
  40. Pharmaceutics. 2022 Mar 12. pii: 626. [Epub ahead of print]14(3):
    Selective Photo-Assisted Eradication of Triple-Negative Breast Cancer Cells through Aptamer Decoration of Doped Conjugated Polymer Nanoparticles.
    Luis Exequiel Ibarra, Simona Camorani, Lisa Agnello, Emilia Pedone, Luciano Pirone, Carlos Alberto Chesta, Rodrigo Emiliano Palacios, Monica Fedele, Laura Cerchia.
      Photodynamic therapy (PDT) may be an excellent alternative in the treatment of breast cancer, mainly for the most aggressive type with limited targeted therapies such as triple-negative breast cancer (TNBC). We recently generated conjugated polymer nanoparticles (CPNs) as efficient photosensitizers for the photo-eradication of different cancer cells. With the aim of improving the selectivity of PDT with CPNs, the nanoparticle surface conjugation with unique 2'-Fluoropyrimidines-RNA-aptamers that act as effective recognition elements for functional surface signatures of TNBC cells was proposed and designed. A coupling reaction with carbodiimide was used to covalently bind NH2-modified aptamers with CPNs synthetized with two polystyrene-based polymer donors of COOH groups for the amide reaction. The selectivity of recognition for TNBC membrane receptors and PDT efficacy were assayed in TNBC cells and compared with non-TNBC cells by flow cytometry and cell viability assays. Furthermore, in vitro PDT efficacy was assayed in different TNBC cells with significant improvement results using CL4, sTN29 and sTN58 aptamers compared to unconjugated CPNs and SCR non-specific aptamer. In a chemoresistance TNBC cell model, sTN58 was the candidate for improving labelling and PDT efficacy with CPNs. We proposed sTN58, sTN29 and CL4 aptamers as valuable tools for selective TNBC targeting, cell internalization and therapeutic improvements for CPNs in PDT protocols.
    Keywords:  TNBC; aptamer; cancer targeting; chemotherapy resistance; conjugated polymer nanoparticles; photodynamic therapy
    DOI:  https://doi.org/10.3390/pharmaceutics14030626
  41. Polymers (Basel). 2022 Mar 21. pii: 1259. [Epub ahead of print]14(6):
    Polyacrylic Acid Nanoplatforms: Antimicrobial, Tissue Engineering, and Cancer Theranostic Applications.
    Hassan Arkaban, Mahmood Barani, Majid Reza Akbarizadeh, Narendra Pal Singh Chauhan, Sapana Jadoun, Maryam Dehghani Soltani, Payam Zarrintaj.
      Polyacrylic acid (PAA) is a non-toxic, biocompatible, and biodegradable polymer that gained lots of interest in recent years. PAA nano-derivatives can be obtained by chemical modification of carboxyl groups with superior chemical properties in comparison to unmodified PAA. For example, nano-particles produced from PAA derivatives can be used to deliver drugs due to their stability and biocompatibility. PAA and its nanoconjugates could also be regarded as stimuli-responsive platforms that make them ideal for drug delivery and antimicrobial applications. These properties make PAA a good candidate for conventional and novel drug carrier systems. Here, we started with synthesis approaches, structure characteristics, and other architectures of PAA nanoplatforms. Then, different conjugations of PAA/nanostructures and their potential in various fields of nanomedicine such as antimicrobial, anticancer, imaging, biosensor, and tissue engineering were discussed. Finally, biocompatibility and challenges of PAA nanoplatforms were highlighted. This review will provide fundamental knowledge and current information connected to the PAA nanoplatforms and their applications in biological fields for a broad audience of researchers, engineers, and newcomers. In this light, PAA nanoplatforms could have great potential for the research and development of new nano vaccines and nano drugs in the future.
    Keywords:  anticancer; antimicrobial; biosensing; polyacrylic acid (PAA); polymerizations; synthesize
    DOI:  https://doi.org/10.3390/polym14061259
  42. Foods. 2022 Mar 16. pii: 847. [Epub ahead of print]11(6):
    Formulation Strategies for Improving the Stability and Bioavailability of Vitamin D-Fortified Beverages: A Review.
    Elsa F Vieira, Suene Souza.
      Vitamin D is a lipophilic bioactive that plays an important role in bone health. Fortification of beverages, such as milk, fruit juices, teas, and vegetable drinks, could be an efficient strategy to prevent vitamin D deficiency and its associated effects on health. This review summarizes the current understanding of beverage fortification strategies with vitamin D and the resulting effects on the stability, bioaccessibility, and sensory properties of the formulated products. The direct addition technique has been the conventional approach to fortifying beverages. In addition, encapsulation has been pointed out as a desirable delivery approach to increase stability, preserve bioactivity, and enhance the absorption of vitamin D in beverage systems. The literature reports the potential applicability of several methods for encapsulating vitamin D in beverages, including spray drying, micro/nanoemulsions, nanostructured lipid carriers, liposomes, and complexation to polymers. Some of these delivery systems have been assessed regarding vitamin D stability, but there is a lack of kinetic data that allow for the prediction of its stability under industrial processing conditions. Moreover, in some cases, the applicability of some of these delivery systems to real beverages as well as the in vivo efficacy were not evaluated; thus, fortification strategies with a global outreach are lacking.
    Keywords:  bioavailability; delivery systems; stability; vitamin D-fortified beverages
    DOI:  https://doi.org/10.3390/foods11060847
  43. J Nanobiotechnology. 2022 Mar 24. 20(1): 152
    Nanocarrier cancer therapeutics with functional stimuli-responsive mechanisms.
    Neha Kaushik, Shweta B Borkar, Sondavid K Nandanwar, Pritam Kumar Panda, Eun Ha Choi, Nagendra Kumar Kaushik.
      Presently, nanocarriers (NCs) have gained huge attention for their structural ability, good biocompatibility, and biodegradability. The development of effective NCs with stimuli-responsive properties has acquired a huge interest among scientists. When developing drug delivery NCs, the fundamental goal is to tackle the delivery-related problems associated with standard chemotherapy and to carry medicines to the intended sites of action while avoiding undesirable side effects. These nanocarriers were able of delivering drugs to tumors through regulating their pH, temperature, enzyme responsiveness. With the use of nanocarriers, chemotherapeutic drugs could be supplied to tumors more accurately that can equally encapsulate and deliver them. Material carriers for chemotherapeutic medicines are discussed in this review keeping in viewpoint of the structural properties and targeting methods that make these carriers more therapeutically effective, in addition to metabolic pathways triggered by drug-loaded NCs. Largely, the development of NCs countering to endogenous and exogenous stimuli in tumor regions and understanding of mechanisms would encourage the progress for tumor therapy and precision diagnosis in future.
    Keywords:  Cancer therapy; Functional nanocarriers; Smart drug delivery; Stimulus-responsive drug release
    DOI:  https://doi.org/10.1186/s12951-022-01364-2
  44. Bioact Mater. 2022 Aug;14 182-205
    Emerging nanoformulation strategies for phytocompounds and applications from drug delivery to phototherapy to imaging.
    Hwa Seung Han, Song Yi Koo, Ki Young Choi.
      Over thousands of years, natural bioactive compounds derived from plants (bioactive phytocompounds, BPCs) have been used worldwide to address human health issues. Today, they are a significant resource for drug discovery in the development of modern medicines. Although many BPCs have promising biological activities, most of them cannot be effectively utilized in drugs for therapeutic applications because of their inherent limitations of low solubility, structural instability, short half-life, poor bioavailability, and non-specific distribution to organs. Researchers have utilized emerging nanoformulation (NF) technologies to overcome these limitations as they have demonstrated great potential to improve the solubility, stability, and pharmacokinetic and pharmacodynamic characteristics of BPCs. This review exemplifies NF strategies for resolving the issues associated with BPCs and summarizes recent advances in their preclinical and clinical applications for imaging and therapy. This review also highlights how innovative NF technologies play a leading role in next-generation BPC-based drug development for extended therapeutic applications. Finally, this review discusses the opportunities to take BPCs with meaningful clinical impact from bench to bedside and extend the patent life of BPC-based medicines with new formulations or application to new adjacent diseases beyond the primary drug indications.
    Keywords:  Drug delivery; Nanoformulation; Natural products; Phototherapy; Phytocompound
    DOI:  https://doi.org/10.1016/j.bioactmat.2021.11.027
  45. Pharmaceutics. 2022 Mar 09. pii: 600. [Epub ahead of print]14(3):
    Development, Therapeutic Evaluation and Theranostic Applications of Cubosomes on Cancers: An Updated Review.
    Yosif Almoshari.
      Cancer is a group of disorders characterized by aberrant gene function and alterations in gene expression patterns. In 2020, it was anticipated that 19 million new cancer cases would be diagnosed globally, with around 10 million cancer deaths. Late diagnosis and interventions are the leading causes of cancer-related mortality. In addition, the absence of comprehensive cancer therapy adds to the burden. Many lyotropic non-lamellar liquid-crystalline-nanoparticle-mediated formulations have been developed in the last few decades, with promising results in drug delivery, therapeutics, and diagnostics. Cubosomes are nano-structured liquid-crystalline particles made of specific amphiphilic lipids in particular proportions. Their ability to encapsulate lipophilic, hydrophilic, and amphiphilic molecules within their structure makes them one of a kind. They are biocompatible, versatile drug carriers that can deliver medications through various routes of administration. Many preclinical studies on the use of cubosomes in cancer treatment and theranostic applications have been conducted. However, before cubosomes may be employed in clinical practice, significant technical advances must be accomplished. This review summarizes the development of cubosomes and their multifunctional role in cancer treatment based on the most recent reports.
    Keywords:  cancer; cubosomes; lipid; nanoparticles; self-assembly; theranostic
    DOI:  https://doi.org/10.3390/pharmaceutics14030600
  46. Molecules. 2022 Mar 15. pii: 1906. [Epub ahead of print]27(6):
    Natural Polyphenols for the Preservation of Meat and Dairy Products.
    Hammad Ullah, Yaseen Hussain, Cristina Santarcangelo, Alessandra Baldi, Alessandro Di Minno, Haroon Khan, Jianbo Xiao, Maria Daglia.
      Food spoilage makes foods undesirable and unacceptable for human use. The preservation of food is essential for human survival, and different techniques were initially used to limit the growth of spoiling microbes, e.g., drying, heating, salting, or fermentation. Water activity, temperature, redox potential, preservatives, and competitive microorganisms are the most important approaches used in the preservation of food products. Preservative agents are generally classified into antimicrobial, antioxidant, and anti-browning agents. On the other hand, artificial preservatives (sorbate, sulfite, or nitrite) may cause serious health hazards such as hypersensitivity, asthma, neurological damage, hyperactivity, and cancer. Thus, consumers prefer natural food preservatives to synthetic ones, as they are considered safer. Polyphenols have potential uses as biopreservatives in the food industry, because their antimicrobial and antioxidant activities can increase the storage life of food products. The antioxidant capacity of polyphenols is mainly due to the inhibition of free radical formation. Moreover, the antimicrobial activity of plants and herbs is mainly attributed to the presence of phenolic compounds. Thus, incorporation of botanical extracts rich in polyphenols in perishable foods can be considered since no pure polyphenolic compounds are authorized as food preservatives. However, individual polyphenols can be screened in this regard. In conclusion, this review highlights the use of phenolic compounds or botanical extracts rich in polyphenols as preservative agents with special reference to meat and dairy products.
    Keywords:  dairy products; food preservation; food spoilage; meat products; polyphenols
    DOI:  https://doi.org/10.3390/molecules27061906
  47. Genes (Basel). 2022 Mar 20. pii: 549. [Epub ahead of print]13(3):
    Expression of HK2, PKM2, and PFKM Is Associated with Metastasis and Late Disease Onset in Breast Cancer Patients.
    Mehreen Ishfaq, Nabiha Bashir, Syeda Kiran Riaz, Shumaila Manzoor, Jahangir Sarwar Khan, Yamin Bibi, Rokayya Sami, Amani H Aljahani, Saif A Alharthy, Ramla Shahid.
      The reprogramming of energy metabolism is one of the hallmarks of cancer and is crucial for tumor progression. Altered aerobic glycolysis is a well-known characteristic of cancer cell metabolism. In the present study, the expression profiles of key metabolic genes (HK2, PFKM, and PKM2) were assessed in the breast cancer cohort of Pakistan using quantitative polymerase chain reaction (qPCR) and IHC. Expression patterns were correlated with molecular subtypes and clinical parameters in the patients. A significant upregulation of key glycolytic genes was observed in tumor samples in comparison to their adjacent controls (p < 0.0001). The expression of the studied glycolytic genes was significantly increased in late clinical stages, positive nodal involvement, and distant metastasis (p < 0.05). HK2 and PKM2 were found to be upregulated in luminal B, whereas PFKM was overexpressed in the luminal A subtype of breast cancer. The genes were positively correlated with the proliferation marker Ki67 (p < 0.001). Moreover, moderate positive linear correlations between HK2 and PKM2 (r = 0.476), HK2 and PFKM (r = 0.473), and PKM2 and PFKM (r = 0.501) were also observed (p < 0.01). These findings validate that the key regulatory genes in glycolysis can serve as potential biomarkers and/or molecular targets for breast cancer management. However, the clinical significance of these molecules needs to be further validated through in vitro and in vivo experiments.
    Keywords:  HK2; PFKM; PKM2; Warburg effect; aerobic glycolysis; breast cancer
    DOI:  https://doi.org/10.3390/genes13030549
  48. Pharmaceutics. 2022 Feb 24. pii: 490. [Epub ahead of print]14(3):
    Folate-Decorated Cross-Linked Cytochrome c Nanoparticles for Active Targeting of Non-Small Cell Lung Carcinoma (NSCLC).
    Irivette Dominguez-Martinez, Freisa Joaquin-Ovalle, Yancy Ferrer-Acosta, Kai H Griebenow.
      The folate receptor alpha (FR), which is overexpressed in solid tumors including NSCLC, can be utilized for active tumor targeting to afford more effective cancer therapies. In this context, cytochrome c (Cyt c) has drawn attention to cancer research because it is non-toxic, yet, when delivered to the cytoplasm of cancer cells, can kill them by inducing apoptosis. Cyt c nanoparticles (NPs, 169 ± 9 nm) were obtained by solvent precipitation with acetonitrile, and stabilized by reversible homo-bifunctional crosslinking to accomplish a Cyt-c-based drug delivery system that combines stimulus-responsive release and active targeting. Cyt c was released under intracellular redox conditions, due to an S-S bond in the NPs linker, while NPs remained intact without any release under extracellular conditions. The NP surface was decorated with a hydrophilic folic acid-polyethylene glycol (FA-PEG) polymer for active targeting. The FA-decorated NPs specifically recognized and killed cancer cells (IC50 = 47.46 µg/mL) that overexpressed FR, but showed no toxicity against FR-negative cells. Confocal microscopy confirmed the preferential uptake and apoptosis induction of our NPs by FR-positive cancer cells. In vivo experiments using a Lewis lung carcinoma (LLC) mouse model showed visible NP accumulation within the tumor and inhibited the growth of LLC tumors.
    Keywords:  Lewis lung carcinoma; cancer; crosslinker; cytochrome c; drug delivery; folate receptor; triggered release
    DOI:  https://doi.org/10.3390/pharmaceutics14030490
  49. Gels. 2022 Mar 10. pii: 174. [Epub ahead of print]8(3):
    Novel Hydrogels for Topical Applications: An Updated Comprehensive Review Based on Source.
    Yosif Almoshari.
      Active pharmaceutical ingredients (API) or drugs are normally not delivered as pure chemical substances (for the prevention or the treatment of any diseases). APIs are still generally administered in prepared formulations, also known as dosage forms. Topical administration is widely used to deliver therapeutic agents locally because it is convenient and cost-effective. Since earlier civilizations, several types of topical semi-solid dosage forms have been commonly used in healthcare society to treat various skin diseases. A topical drug delivery system is designed primarily to treat local diseases by applying therapeutic agents to surface level parts of the body such as the skin, eyes, nose, and vaginal cavity. Nowadays, novel semi-solids can be used safely in pediatrics, geriatrics, and pregnant women without the possibility of causing any allergy reactions. The novel hydrogels are being used in a wide range of applications. At first, numerous hydrogel research studies were carried out by simply adding various APIs in pure form or dissolved in various solvents to the prepared hydrogel base. However, numerous research articles on novel hydrogels have been published in the last five to ten years. It is expected that novel hydrogels will be capable of controlling the APIs release pattern. Novel hydrogels are made up of novel formulations such as nanoparticles, nanoemulsions, microemulsions, liposomes, self-nano emulsifying drug delivery systems, cubosomes, and so on. This review focus on some novel formulations incorporated in the hydrogel prepared with natural and synthetic polymers.
    Keywords:  hydrogel; natural polymer; novel formulations; synthetic polymer; topical application
    DOI:  https://doi.org/10.3390/gels8030174
  50. ACS Appl Mater Interfaces. 2022 Mar 24.
    Bioactive Composite Nanoparticles for Effective Microenvironment Regulation, Neuroprotection, and Cell Differentiation.
    Qiong Yuan, Benkai Bao, Meiqi Li, Yanli Tang.
      Brain injuries typically result in neural tissue damage and trigger a permanent neurologic deficit. Current methods exhibit limited effects due to the harsh microenvironment of injury regions rich in reactive oxygen species (ROS). Herein, a microenvironment regulation combined with cellular differentiation strategy is designed for repairing injured nerves. We prepare PMNT/F@D-NP nanoparticles comprising a bioactive polythiophene derivative (PMNT) and fullerenol as a multifunctional theranostic nanoplatform. PMNT/F@D-NPs can significantly reduce the accumulation of ROS in the simulated ischemic brain injury trial and inhibit cell apoptosis due to the effective free radical scavenging ability of fullerenol. Interestingly, the bioactive PMNT/F@D-NPs can promote the proliferation and differentiation of neurons, confirmed by immunofluorescence and western blotting studies. This newly developed strategy exhibits a combinatorial therapeutic effect by promoting nerve cell survival and differentiation while improving the microenvironment in the damaged area, which paves the way for the rational design of multifunctional agents for brain injury therapy.
    Keywords:  brain injury; cell proliferation; conjugated polymers; fullerenol; microenvironment regulation
    DOI:  https://doi.org/10.1021/acsami.2c00579
  51. Pharmaceutics. 2022 Mar 05. pii: 573. [Epub ahead of print]14(3):
    Sequential Drug Delivery in Targeted Cancer Therapy.
    Han Yu, Na Ning, Xi Meng, Chuda Chittasupho, Lingling Jiang, Yunqi Zhao.
      Cancer is a major public health problem and one of the leading causes of death. However, traditional cancer therapy may damage normal cells and cause side effects. Many targeted drug delivery platforms have been developed to overcome the limitations of the free form of therapeutics and biological barriers. The commonly used cancer cell surface targets are CD44, matrix metalloproteinase-2, folate receptors, etc. Once the drug enters the cell, active delivery of the drug molecule to its final destination is still preferred. The subcellular targeting strategies include using glucocorticoid receptors for nuclear targeting, negative mitochondrial membrane potential and N-acetylgalactosaminyltransferase for Golgi apparatus targeting, etc. Therefore, the most effective way to deliver therapeutic agents is through a sequential drug delivery system that simultaneously achieves cellular- and subcellular-level targeting. The dual-targeting delivery holds great promise for improving therapeutic effects and overcoming drug resistance. This review classifies sequential drug delivery systems based on final targeted organelles. We summarize different targeting strategies and mechanisms and gave examples of each case.
    Keywords:  cancer treatment; drug delivery; mitochondria targeting; nucleus targeting; sequential targeted
    DOI:  https://doi.org/10.3390/pharmaceutics14030573
  52. Int J Mol Sci. 2022 Mar 20. pii: 3360. [Epub ahead of print]23(6):
    Natural Compounds as Promising Adjuvant Agents in The Treatment of Gliomas.
    Francesca Persano, Giuseppe Gigli, Stefano Leporatti.
      In humans, glioblastoma is the most prevalent primary malignant brain tumor. Usually, glioblastoma has specific characteristics, such as aggressive cell proliferation and rapid invasion of surrounding brain tissue, leading to a poor patient prognosis. The current therapy-which provides a multidisciplinary approach with surgery followed by radiotherapy and chemotherapy with temozolomide-is not very efficient since it faces clinical challenges such as tumor heterogeneity, invasiveness, and chemoresistance. In this respect, natural substances in the diet, integral components in the lifestyle medicine approach, can be seen as potential chemotherapeutics. There are several epidemiological studies that have shown the chemopreventive role of natural dietary compounds in cancer progression and development. These heterogeneous compounds can produce anti-glioblastoma effects through upregulation of apoptosis and autophagy; allowing the promotion of cell cycle arrest; interfering with tumor metabolism; and permitting proliferation, neuroinflammation, chemoresistance, angiogenesis, and metastasis inhibition. Although these beneficial effects are promising, the efficacy of natural compounds in glioblastoma is limited due to their bioavailability and blood-brain barrier permeability. Thereby, further clinical trials are necessary to confirm the in vitro and in vivo anticancer properties of natural compounds. In this article, we overview the role of several natural substances in the treatment of glioblastoma by considering the challenges to be overcome and future prospects.
    Keywords:  brain tumors; curcumin; epigallocatechin gallate; glioblastoma; glioma tumors; natural compounds; resveratrol
    DOI:  https://doi.org/10.3390/ijms23063360
  53. Cancers (Basel). 2022 Mar 09. pii: 1390. [Epub ahead of print]14(6):
    Short-Term Fasting Synergizes with Solid Cancer Therapy by Boosting Antitumor Immunity.
    Nadia de Gruil, Hanno Pijl, Sjoerd H van der Burg, Judith R Kroep.
      Short-term fasting (STF), using a low caloric, low protein fasting mimicking diet (FMD), appears to be a promising strategy to enhance chemotherapy-based cancer efficacy, while potentially alleviating toxicity. Preclinical results suggest that enhanced tumor immunity and decreased growth signaling, via lowering of circulating insulin and insulin growth factor 1 (IGF-1) levels form the potential underlying mechanisms. STF may boost anti-tumor responses by promoting tumor immunogenicity and decreasing local immunosuppression. These findings warrant further studies focused on the combination of STF, not only with chemotherapy, but also with immunotherapy to evaluate the full range of benefits of STF in cancer treatment. Here, we delineate the underlying anticancer mechanisms of fasting. We summarize preclinical evidence of STF boosting antitumor immunity and alleviating immunosuppression, as well as the clinical findings reporting the immunomodulatory effects of STF during various cancer treatments, including immunotherapy.
    Keywords:  cancer immunity; cancer therapy; chemotherapy; fasting mimicking diet; immunomodulation; immunotherapy; short-term fasting
    DOI:  https://doi.org/10.3390/cancers14061390
  54. Polymers (Basel). 2022 Mar 17. pii: 1221. [Epub ahead of print]14(6):
    Broad-Spectrum Theranostics and Biomedical Application of Functionalized Nanomaterials.
    Meshal Alshamrani.
      Nanotechnology is an important branch of science in therapies known as "nanomedicine" and is the junction of various fields such as material science, chemistry, biology, physics, and optics. Nanomaterials are in the range between 1 and 100 nm in size and provide a large surface area to volume ratio; thus, they can be used for various diseases, including cardiovascular diseases, cancer, bacterial infections, and diabetes. Nanoparticles play a crucial role in therapy as they can enhance the accumulation and release of pharmacological agents, improve targeted delivery and ultimately decrease the intensity of drug side effects. In this review, we discussthe types of nanomaterials that have various biomedical applications. Biomolecules that are often conjugated with nanoparticles are proteins, peptides, DNA, and lipids, which can enhance biocompatibility, stability, and solubility. In this review, we focus on bioconjugation and nanoparticles and also discuss different types of nanoparticles including micelles, liposomes, carbon nanotubes, nanospheres, dendrimers, quantum dots, and metallic nanoparticles and their crucial role in various diseases and clinical applications. Additionally, we review the use of nanomaterials for bio-imaging, drug delivery, biosensing tissue engineering, medical devices, and immunoassays. Understandingthe characteristics and properties of nanoparticles and their interactions with the biological system can help us to develop novel strategies for the treatment, prevention, and diagnosis of many diseases including cancer, pulmonary diseases, etc. In this present review, the importance of various kinds of nanoparticles and their biomedical applications are discussed in much detail.
    Keywords:  bioconjugation; biomedical imaging; drug delivery systems; theranostics; tissue engineering
    DOI:  https://doi.org/10.3390/polym14061221
  55. Recent Pat Anticancer Drug Discov. 2022 Mar 22.
    Multifunctional Patented Nanotherapeutics for Cancer Intervention: 2010-onwards.
    Parijat Pandey, Hitesh Chopra, Deepak Kaushik, Ravinder Verma, Deepika Purohit, Jatin Parashar, Vineet Mittal, Habibur Rahman, Saurabh Bhatia, Pradeep Kumar, Tanima Bhattacharya, Priti Tagde, Ahmed Al-Harrasi.
      Even today, cancer is one of the prominent leading causes of death worldwide. However, there are a couple of treatment options available for management, but the adverse effects are more prominent compared to therapeutic effects. Therefore, there is a need to design some midway that may help to bypass the negative effects or lower their severity. Using nanotechnology has addressed many issues, even still many miles needed to cover before reaching the center stage. The nanoformulations thus developed can target distant organs owing to their multifunctionality and targeting potential. Stimuli-responsive nanomedicine is one of the most exploited formulations. They can encapsulate and release the drugs for a higher period. However, they release a burst mechanism. The other nano-formulations contain dendrimers, micelles, and lipid-based nano-formulations that have been developed and evaluated for their efficacy in cancer treatment. This review paper highlights some significant patents granted/applied in various patent offices around the globe to treat cancer using nanotechnology. The Google patent, United States Patent and Trademark Office (USPTO), Escapenet, and many others were used as the search engine for patent search, and data were collected and evaluated. They used these patented technologies for diagnostic and treatment options, enhancing the absorption, distribution, metabolism, and excretion (ADME) profile of therapeutic molecules.
    Keywords:  Nanotechnology; anticancer; dendrimers; hydrogels; liposomes; multifunctional.
    DOI:  https://doi.org/10.2174/1574892817666220322085942
  56. Pharmaceutics. 2022 Mar 12. pii: 631. [Epub ahead of print]14(3):
    Development of Lomustine and n-Propyl Gallate Co-Encapsulated Liposomes for Targeting Glioblastoma Multiforme via Intranasal Administration.
    Gábor Katona, Fakhara Sabir, Bence Sipos, Muhammad Naveed, Zsuzsanna Schelz, István Zupkó, Ildikó Csóka.
      This work aimed to develop lomustine (LOM) and n-propyl gallate (PG)-loaded liposomes suitable for targeting glioblastoma multiforme (GBM) via the auspicious nose-to-brain drug delivery pathway. The therapeutical effect of LOM, as a nitrosourea compound, can be potentiated by PG suitable for enhanced anti-cancer therapy. Nose-to-brain delivery of PG and LOM combined in liposomes can overcome the poor water solubility, absorption properties, and toxicity issues in the systemic circulation. Optimization and characterization of the liposomal carrier with binary drug contents were carried out in order to achieve adequate encapsulation efficiency, loading capacity, drug release, and ex vivo permeation. The optimized liposome co-encapsulated with both drugs showed suitable Z-average (127 ± 6.9 nm), size distribution (polydispersity index of 0.142 ± 0.009), zeta potential (-34 ± 1.7 mV), and high encapsulation efficacy (63.57 ± 1.3% of PG and 73.45 ± 2.2% of LOM, respectively) meeting the acceptance criteria of nose-to-brain transport for both drugs. MTT assays of PG-LOM formulations were also conducted on NIH/3T3 (murine embryonic fibroblast), U87 (glioblastoma), and A2780 (ovarian cancer) cell lines indicating reduced an antiproliferative effect on all types of cells. Our results supported the use of this novel combination of LOM and PG in a liposomal formulation as a promising carrier for glioblastoma targeting via the intranasal route.
    Keywords:  controlled release; glioblastoma multiforme; liposome; lomustine; n-propyl gallate; nasal delivery
    DOI:  https://doi.org/10.3390/pharmaceutics14030631
  57. Cancer Cell Int. 2022 Mar 20. 22(1): 130
    The emerging role of deubiquitylating enzymes as therapeutic targets in cancer metabolism.
    Rongfu Tu, Junpeng Ma, Peng Zhang, Ye Kang, Xiaofan Xiong, Junsheng Zhu, Miao Li, Chengsheng Zhang.
      Cancer cells must rewire cellular metabolism to satisfy the unbridled proliferation, and metabolic reprogramming provides not only the advantage for cancer cell proliferation but also new targets for cancer treatment. However, the plasticity of the metabolic pathways makes them very difficult to target. Deubiquitylating enzymes (DUBs) are proteases that cleave ubiquitin from the substrate proteins and process ubiquitin precursors. While the molecular mechanisms are not fully understood, many DUBs have been shown to be involved in tumorigenesis and progression via controlling the dysregulated cancer metabolism, and consequently recognized as potential drug targets for cancer treatment. In this article, we summarized the significant progress in understanding the key roles of DUBs in cancer cell metabolic rewiring and the opportunities for the application of DUBs inhibitors in cancer treatment, intending to provide potential implications for both research purpose and clinical applications.
    Keywords:  Aerobic glycolysis; Cancer metabolism; Deubiquitylating enzymes; Fatty acid metabolism; Targeted therapy
    DOI:  https://doi.org/10.1186/s12935-022-02524-y
  58. Pharmaceutics. 2022 Mar 19. pii: 677. [Epub ahead of print]14(3):
    Two Beats One: Osteosarcoma Therapy with Light-Activated and Chemo-Releasing Keratin Nanoformulation in a Preclinical Mouse Model.
    Elisa Martella, Barbara Dozza, Claudia Ferroni, Clement Osuru Obeyok, Andrea Guerrini, Daniele Tedesco, Ilse Manet, Giovanna Sotgiu, Marta Columbaro, Marco Ballestri, Lucia Martini, Milena Fini, Enrico Lucarelli, Greta Varchi, Serena Duchi.
      Osteosarcoma treatment is moving towards more effective combination therapies. Nevertheless, these approaches present distinctive challenges that can complicate the clinical translation, such as increased toxicity and multi-drug resistance. Drug co-encapsulation within a nanoparticle formulation can overcome these challenges and improve the therapeutic index. We previously synthetized keratin nanoparticles functionalized with Chlorin-e6 (Ce6) and paclitaxel (PTX) to combine photo (PDT) and chemotherapy (PTX) regimens, and the inhibition of osteosarcoma cells growth in vitro was demonstrated. In the current study, we generated an orthotopic osteosarcoma murine model for the preclinical evaluation of our combination therapy. To achieve maximum reproducibility, we systematically established key parameters, such as the number of cells to generate the tumor, the nanoparticles dose, the design of the light-delivery device, the treatment schedule, and the irradiation settings. A 60% engrafting rate was obtained using 10 million OS cells inoculated intratibial, with the tumor model recapitulating the histological hallmarks of the human counterpart. By scheduling the treatment as two cycles of injections, a 32% tumor reduction was obtained with PTX mono-therapy and a 78% reduction with the combined PTX-PDT therapy. Our findings provide the in vivo proof of concept for the subsequent clinical development of a combination therapy to fight osteosarcoma.
    Keywords:  chemotherapy; drug delivery; keratin nanoparticles; musculoskeletal tumors; orthotopic osteosarcoma murine model; osteosarcoma; photodynamic therapy
    DOI:  https://doi.org/10.3390/pharmaceutics14030677
  59. Pharmaceuticals (Basel). 2022 Mar 18. pii: 370. [Epub ahead of print]15(3):
    Design and Development of Levodopa Loaded Polymeric Nanoparticles for Intranasal Delivery.
    Mohd Zulhelmy Ahmad, Akmal Hidyat Bin Sabri, Qonita Kurnia Anjani, Juan Domínguez-Robles, Normala Abdul Latip, Khuriah Abdul Hamid.
      Intranasal delivery is an alternative administration route to deliver levodopa (L-Dopa) to the brain. This drug delivery route offers high drug permeability across the nasal epithelium and rapid absorption into the central nervous system (CNS) while bypassing first-pass metabolism. In this study, we developed a library of polymeric nanocarrier systems for L-Dopa utilising poly(lactic-co-glycolic acid) (PLGA) and chitosan. A total of three PLGA nanoparticles formulations (P1, P2 and P3) were prepared using a modified water-in-oil-in-water (W/O/W) solvent evaporation technique, while four formulations of chitosan nanoparticles (C1, C2, C3 and C4) were prepared by ionic gelation method with sodium tripolyphosphate (TPP) as a cross-linking agent. Upon characterising nanocarriers developed, it was discovered that C2 demonstrated the best results with regard to droplet size (553 ± 52 nm), polydispersity index (0.522), zeta potential (+46.2 ± 2.3 mV), and encapsulation efficiency (82.38% ± 1.63). Transmission electron microscopy (TEM) and scanning electron microscopy (SEM) further corroborated the particle size analysis highlighting that C2 displayed uniform particle size with spherical morphology. Additionally, X-ray diffraction analysis (XRD) revealed that C2 was in an amorphous state while Fourier transform infrared (FTIR) analysis showed that there were no chemical interactions that might change the chemical structure of L-Dopa within the polymeric nanoparticle matrix. Lastly, an in-vivo intranasal study in male Wistar rats showed that the absorption of L-Dopa when formulated as chitosan nanoparticles was significantly enhanced (p < 0.05) by approximately two-fold compared to unmodified L-Dopa. Therefore, this work illustrates that formulating L-Dopa into chitosan nanoparticles for intranasal delivery is a potentially viable formulation strategy to improve the bioavailability of the drug for the treatment of Parkinson's disease.
    Keywords:  PLGA; bioavailability; chitosan; nanoparticles
    DOI:  https://doi.org/10.3390/ph15030370
  60. Front Oncol. 2022 ;12 843345
    Targeted Delivery of Chemotherapeutic Agents for Osteosarcoma Treatment.
    Duoli Xie, Zhuqian Wang, Jie Li, De-An Guo, Aiping Lu, Chao Liang.
      Since osteosarcoma (OS) is an aggressive bone cancer with unknown molecular pathways of etiology and pathophysiology, improving patient survival has long been a challenge. The conventional therapy is a complex multidisciplinary management that include radiotherapy, chemotherapy which followed by surgery and then post-operative adjuvant chemotherapy. However, they have severe side effects because the majority of the medicines used have just a minor selectivity for malignant tissue. As a result, treating tumor cells specifically without damaging healthy tissue is currently a primary goal in OS therapy. The coupling of chemotherapeutic drugs with targeting ligands is a unique therapy method for OS that, by active targeting, can overcome the aforementioned hurdles. This review focuses on advances in ligands and chemotherapeutic agents employed in targeted delivery to improve the capacity of active targeting and provide some insight into future therapeutic research for OS.
    Keywords:  antibodies; chemotherapeutic agents; ligand-based delivery systems; osteosarcoma; targeted delivery
    DOI:  https://doi.org/10.3389/fonc.2022.843345
  61. Genes (Basel). 2022 Mar 05. pii: 466. [Epub ahead of print]13(3):
    Recent Development of Prodrugs of Gemcitabine.
    Bhoomika Pandit, Maksim Royzen.
      Gemcitabine is a nucleoside analog that has been used widely as an anticancer drug for the treatment of a variety of conditions, including ovarian, bladder, non-small-cell lung, pancreatic, and breast cancer. However, enzymatic deamination, fast systemic clearance, and the emergence of chemoresistance have limited its efficacy. Different prodrug strategies have been explored in recent years, seeking to obtain better pharmacokinetic properties, efficacy, and safety. Different drug delivery strategies have also been employed, seeking to transform gemcitabine into a targeted medicine. This review will provide an overview of the recent developments in gemcitabine prodrugs and their effectiveness in treating cancerous tumors.
    Keywords:  anticancer agent; chemotherapy; drug delivery; gemcitabine; prodrug
    DOI:  https://doi.org/10.3390/genes13030466
  62. Pharmaceutics. 2022 Feb 25. pii: 510. [Epub ahead of print]14(3):
    Nanomicelle-Microsphere Composite as a Drug Carrier to Improve Lung-Targeting Specificity for Lung Cancer.
    Qianqian Zhang, Jianwei Bao, Tijie Duan, Minxing Hu, Yuting He, Junwei Wang, Rongfeng Hu, Jihui Tang.
      Lung cancer is the second-most common cancer and has the highest mortality among all cancer types. Nanoparticle (NP) drug delivery systems have been used to improve the therapeutic effectiveness of lung cancer, but rapid clearance and poor targeting limit their clinical utility. Here, we developed a nanomicelle-microsphere composite, in which doxorubicin (DOX) was loaded with spermine (Spm) modified poly (ethylene glycol)-poly(ε-caprolactone) (PEG-PCL) micelles, and then the nanomicelles were noncovalently adsorbed on the surface of poly (lactic-co-glycolic acid) (PLGA) microspheres. The attachment was confirmed by scanning electron microscopy and confocal microscopy. In vitro cell experiments, MTT assays and intracellular uptake assays were used to demonstrate the cytotoxicity and the cellular uptake of micelles in A549 cells. In vivo biodistribution studies were conducted, an orthotopic lung cancer implantation model based on C57BL/6 mice was established, and then real-time fluorescence imaging analysis was used to study the targeted efficacy of the complex. A nanomicelle-microsphere composite was successively constructed. Moreover, Spm-modified micelles significantly enhanced cytotoxicity and displayed more efficient cellular uptake. Notably, an orthotopic lung cancer implantation model based on C57BL/6 mice was also successively established, and in vivo biodistribution studies confirmed that the complex greatly improved the distribution of DOX in the lungs and displayed notable tumor targeting. These results suggested that the nanomicelle-microsphere composite has potential application prospects in the targeted treatment of lung cancer.
    Keywords:  lung cancer; micelles; microsphere; polyamine transport system; targeted drug delivery system
    DOI:  https://doi.org/10.3390/pharmaceutics14030510
  63. Molecules. 2022 Mar 09. pii: 1794. [Epub ahead of print]27(6):
    Genesis and Mechanism of Some Cancer Types and an Overview on the Role of Diet and Nutrition in Cancer Prevention.
    Nurkhalida Kamal, Muna Abdulsalam Ilowefah, Ayah Rebhi Hilles, Nurul Adlina Anua, Tahani Awin, Hussah Abdullah Alshwyeh, Sahar Khamees Aldosary, Najla Gooda Sahib Jambocus, Areej A Alosaimi, Azizur Rahman, Syed Mahmood, Ahmed Mediani.
      Cancer is a major disease with a high mortality rate worldwide. In many countries, cancer is considered to be the second most common cause of death after cardiovascular disease. The clinical management of cancer continues to be a challenge as conventional treatments, such as chemotherapy and radiation therapy, have limitations due to their toxicity profiles. Unhealthy lifestyle and poor dietary habits are the key risk factors for cancer; having a healthy diet and lifestyle may minimize the risk. Epidemiological studies have shown that a high fruit and vegetable intake in our regular diet can effectively reduce the risk of developing certain types of cancers due to the high contents of antioxidants and phytochemicals. In vitro and in vivo studies have shown that phytochemicals exert significant anticancer effects due to their free radical scavenging capacity potential. There has been extensive research on the protective effects of phytochemicals in different types of cancers. This review attempts to give an overview of the etiology of different types of cancers and assesses the role of phytonutrients in the prevention of cancers, which makes the present review distinct from the others available.
    Keywords:  cancer; diagnosis; diet; nutrition; phytochemicals; therapeutics
    DOI:  https://doi.org/10.3390/molecules27061794
  64. J Pharm Biomed Anal. 2022 Mar 06. pii: S0731-7085(22)00132-7. [Epub ahead of print]214 114711
    An integrated metabonomics study to reveal the inhibitory effect and metabolism regulation of taurine on breast cancer.
    Wanting Chen, Qian Li, Ranran Hou, Huaguo Liang, Yongli Zhang, Yongxia Yang.
      Breast cancer is a common metastatic malignant tumor in women. Taurine has been found to have anti-tumor effects on a variety of cancers. However, to the best of our knowledge, the role of taurine in the metastasis of breast cancer has not been reported. Thus, this study examined the effects of taurine on the growth and lung metastasis of breast cancer. Furthermore, the metabolism of serum, tumor tissue, and lung metastasis tissue were studied in a 4T1 subcutaneously transplanted breast cancer model through the integration of a 1H NMR-based metabonomics approach and histopathological assessments. The results showed that taurine significantly attenuated the tumor growth and lung metastasis, improved the pathological structure of tumor and lung tissue, and improved the metabolic disorders in 4T1 breast cancer mice. Additionally, taurine reversed the changes in serum lactate, creatine, and choline caused by the progression of breast cancer tumors. The levels of leucine/isoleucine, valine, alanine, arginine, methionine, glutamate, histidine, trimethylamine oxide (TMAO), taurine, and glucose in tumor tissues decreased, with an increment in lipids, lactate, and N-acetyl glycoprotein. Also, there was a reversal of leucine/isoleucine, valine, lactate, arginine, N-acetyl glycoprotein, glutamate, histidine, choline, and glycerophosphocholine/phosphocholine (GPC/PC) in the lung tissues. These metabolites changes were involved in the metabolic pathways of glycolysis, choline, amino acid, and lipid, suggesting that taurine exerted anti-breast cancer effects through the regulation of the underlying metabolism. This study provides a scientific basis for the adoption of taurine in the treatment of breast cancer metastasis.
    Keywords:  Breast cancer; Metabonomics; NMR; Taurine
    DOI:  https://doi.org/10.1016/j.jpba.2022.114711
  65. Food Chem. 2022 Mar 15. pii: S0308-8146(22)00681-1. [Epub ahead of print]385 132719
    Bioactive compounds in kombucha: A review of substrate effect and fermentation conditions.
    Bruna Milena Bortolomedi, Camila Souza Paglarini, Fábio Cristiano Angonesi Brod.
      Plant bioactive compounds have been studied mainly for their beneficial antioxidant properties. Kombucha is a fermented beverage traditionally obtained from fermentation of sweetened black or green tea by a characteristic consortium of yeasts and bacteria. The beverage naturally contains bioactive compounds from teas and their synthesis can be increased during fermentation. This review aims to explore the different bioactive compounds found in kombucha from different substrates, as well as the factors that influence on their synthesis and their amount in the final product. The results suggest phenolic compounds are the main bioactive compounds in kombucha. The substrate type contributes the most to increasing the content of bioactive compounds in the final product; fermentation time and type of sugar also increase the amount of these compounds. Further research suggestions include the combination of strategies to increase bioactive compounds in kombucha, quantification and characterization of the isolated compounds.
    Keywords:  Antioxidants; Fermented tea; Functional food; Phenolic compounds
    DOI:  https://doi.org/10.1016/j.foodchem.2022.132719
  66. Mini Rev Med Chem. 2022 Mar 24.
    Pharmacological Modulation of Apoptosis and Autophagy in the Treatment of Pancreatic Cancer.
    Nityaa Selvarajoo, Johnson Stanslas, Mohammad Kaisarul Islam, Sreenivasa Rao Sagineedu, Kok Lian Ho, Jonathan Chee Woei Lim.
      BACKGROUND: Pancreatic cancer is a fatal malignant neoplasm with infrequent signs and symptoms until a progressive stage. In 2020, GLOBOCAN reported that, pancreatic cancer accounts for 4.7% of all cancer deaths. Despite the availability of standard chemotherapy regiments for treatment, the survival benefits are not guaranteed because tumour cells become chemoresistant even due to the development of chemoresistance in tumour cells even with a short treatment course, where apoptosis and autophagy play critical roles.OBJECTIVE: This review compiled essential information on the regulatory mechanisms and roles of apoptosis and autophagy in pancreatic cancer, as well as drug-like molecules that target different pathways in pancreatic cancer eradication, with an aim of providing ideas to the scientific communities to discover novels and specific drug to treat pancreatic cancer, specifically PDAC. highlight these mechanisms which target different pathways in eradicating pancreatic cancer.
    METHOD: Electronic databases that were searched for research articles for this review were Scopus, Science Direct, PubMed, Springer Link, and Google Scholar. The published studies were identified and retrieved using selected keywords. Discussion/ Conclusion: Many small-molecule anticancer agents have been developed to regulate autophagy and apoptosis associated with pancreatic cancer treatment, where most of them target apoptosis directly through EGFR/Ras/Raf/MAPK and PI3K/Akt/mTOR pathways. The cancer drugs that regulate autophagy in treating cancer can be categorized into three groups: i) direct autophagy inducers (e.g., rapamycin), ii) indirect autophagy inducers (e.g., resveratrol), and iii) autophagy inhibitors. Resveratrol persuades both apoptosis and autophagy with cytoprotective effect, while autophagy inhibitors (e.g., 3-methyladenine, chloroquine) can turn off the protective autophagic effect for therapeutic benefits. Several studies showed that autophagy inhibition resulted in a synergistic effect with chemotherapy (e.g., combination of metformin with gemcitabine/5FU) and such drugs possess a unique clinical value in treating pancreatic cancer as well as other autophagy-dependent carcinomas.
    Keywords:  Apoptosis; Autophagy; Autophagy modulators; Cancer drugs.; Chemoresistance; Pancreatic cancer
    DOI:  https://doi.org/10.2174/1389557522666220324123605
  67. J Mater Chem B. 2022 Mar 22.
    Cubosomes as an emerging platform for drug delivery: a review of the state of the art.
    Mohammed A S Abourehab, Mohammad Javed Ansari, Anshul Singh, Ahmed Hassan, Mohamed A Abdelgawad, Prachi Shrivastav, Bassam M Abualsoud, Larissa Souza Amaral, Sheersha Pramanik.
      Lipid-based drug-delivery nanoparticles, including non-lamellar-type, mesophasic nanostructured materials of lyotropic liquid crystals (LLCs), have been a topic of interest for researchers for their applications in the encapsulation of biopharmaceutical drugs as well as their controlled and targeted release. Cubosomes, derived from LLCs, are self-assembled cubic-phase bicontinuous crystalline nanoparticulate colloidal dispersions. Their lipid bilayers are arranged in 3D space such that they have an uninterrupted, regular cubic symmetrical surface, separated by two interconnected aqueous channels. Thus, they have a large surface area involving numerous internal segments, giving them a definitive advantage over lamellar liposomes in facilitating the efficient entrapment and sustained release of active therapeutic substances. This Review focuses on the unique properties of cubosomes, such as their ability to encapsulate hydrophobic, hydrophilic, and amphiphilic bioactive substances, which make them attractive for the encapsulation and release of therapeutic molecules, including large biomolecules. Controlled drug release via functionalization has demonstrated cubosomes as a potential vehicle for various administration routes. Their self-assembling properties make their production uncomplicated, with two major manufacturing methods: the top-down and bottom-up methods. Cubosomes are formed when amphiphilic lipids, such as monoolein, monolinolein, phytantriol, etc., self-assemble into non-lamellar bicontinuous cubic phases in excess water. In this Review, we have endeavored to outline the composition, preparation techniques, drug-encapsulation approaches, and drug-loading and -release mechanisms of cubosomes. Furthermore, the prospective routes for cubosomes, their challenges, and future potentialities are addressed.
    DOI:  https://doi.org/10.1039/d2tb00031h
  68. Int J Mol Sci. 2022 Mar 16. pii: 3209. [Epub ahead of print]23(6):
    Applications of Antimicrobial Photodynamic Therapy against Bacterial Biofilms.
    Sandile Phinda Songca, Yaw Adjei.
      Antimicrobial photodynamic therapy and allied photodynamic antimicrobial chemotherapy have shown remarkable activity against bacterial pathogens in both planktonic and biofilm forms. There has been little or no resistance development against antimicrobial photodynamic therapy. Furthermore, recent developments in therapies that involve antimicrobial photodynamic therapy in combination with photothermal hyperthermia therapy, magnetic hyperthermia therapy, antibiotic chemotherapy and cold atmospheric pressure plasma therapy have shown additive and synergistic enhancement of its efficacy. This paper reviews applications of antimicrobial photodynamic therapy and non-invasive combination therapies often used with it, including sonodynamic therapy and nanozyme enhanced photodynamic therapy. The antimicrobial and antibiofilm mechanisms are discussed. This review proposes that these technologies have a great potential to overcome the bacterial resistance associated with bacterial biofilm formation.
    Keywords:  antibiotic chemotherapy; antimicrobial photodynamic therapy; biofilm; cold atmospheric pressure plasma; extracellular polymeric substance; magnetic hyperthermia therapy; nanozyme enhanced photodynamic therapy; photothermal hyperthermia therapy; planktonic bacteria; sonodynamic therapy
    DOI:  https://doi.org/10.3390/ijms23063209
  69. Pharmaceutics. 2022 Mar 17. pii: 660. [Epub ahead of print]14(3):
    PLGA-Gold Nanocomposite: Preparation and Biomedical Applications.
    Alaaldin M Alkilany, Ousama Rachid, Mahmoud Y Alkawareek, Nashiru Billa, Anis Daou, Catherine J Murphy.
      A composite system consisting of both organic and inorganic nanoparticles is an approach to prepare a new material exhibiting "the best of both worlds". In this review, we highlight the recent advances in the preparation and applications of poly(lactic-co-glycolic acid)-gold nanoparticles (PLGA-GNP). With its current clinically use, PLGA-based nanocarriers have promising pharmaceutical applications and can "extract and utilize" the fascinating optical and photothermal properties of encapsulated GNP. The resulting "golden polymeric nanocarrier" can be tracked, analyzed, and visualized using the encapsulated gold nanoprobes which facilitate a better understanding of the hosting nanocarrier's pharmacokinetics and biological fate. In addition, the "golden polymeric nanocarrier" can reveal superior nanotherapeutics that combine both the photothermal effect of the encapsulated gold nanoparticles and co-loaded chemotherapeutics. To help stimulate more research on the development of nanomaterials with hybrid and exceptional properties, functionalities, and applications, this review provides recent examples with a focus on the available chemistries and the rationale behind encapsulating GNP into PLGA nanocarriers that has the potential to be translated into innovative, clinically applicable nanomedicine.
    Keywords:  PLGA; composite; gold nanoparticles; poly(lactic-co-glycolic acid)
    DOI:  https://doi.org/10.3390/pharmaceutics14030660
  70. Ultrasound Med Biol. 2022 Mar 17. pii: S0301-5629(22)00078-3. [Epub ahead of print]
    Sonodynamic Therapy Using Dacarbazine-Loaded AuSiO2 Nanoparticles for Melanoma Treatment: An In-Vitro Study on the B16F10 Murine Melanoma Cell Line.
    Arman Esmailzadeh, Ahmad Shanei, Neda Attaran, Seyed Hossein Hejazi, Simin Hemati.
      The use of nanoparticles as a sonosensitizer in cancer sonodynamic therapy has been gaining attention because of their great advantages in drug delivery applications. By conjugating chemotherapy agents with nanoparticles, we can develop a drug delivery platform, control drug release and improve the outcome of treatments. The in-vitro study described here evaluates the combination of AuSiO2 nanoparticles and dacarbazine (DTIC@AuSiO2) as a sonosensitizer for sonodynamic therapy of melanoma. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and flow cytometry assays revealed that the viability of B16F10 melanoma cells was significantly inhibited by the increase in apoptosis induction in treatment with DTIC@AuSiO2 nanoparticles under ultrasound exposure compared with treatment with the free DTIC or AuSiO2 nanoparticles. The sonosensitization activity of AuSiO2 nanoparticles and greater uptake of DTIC by tumor cells after loading in DTIC@AuSiO2 nanoparticles inhibited the proliferation of melanoma tumor cells effectively. In conclusion, the DTIC@AuSiO2 nanoparticles established in this study could represent a good drug delivery and sonosensitizer platform for use in melanoma sonodynamic therapy.
    Keywords:  Apoptosis; Core–shell nanoparticle; Dacarbazine; Melanoma; Sonodynamic therapy
    DOI:  https://doi.org/10.1016/j.ultrasmedbio.2022.02.015
  71. Pharmaceutics. 2022 Feb 26. pii: 521. [Epub ahead of print]14(3):
    Facile Solvent-Free Preparation of Antioxidant Idebenone-Loaded Nanoparticles for Efficient Wound Healing.
    HeeSeon Yang, Sohyeon Yu, Jisu Kim, KumJu Baek, Young-Ran Lee, Hye Sun Lee, Won Il Choi, Daekyung Sung.
      The excessive production of reactive oxygen species (ROS) causes harmful effects, including biomolecular damage and inflammation. ROS due to ultraviolet rays, blue light, and fine dust harm the skin, causing urban-related aging. Therefore, a strong antioxidant that relieves oxidative stress in the skin and removes ROS is required. Idebenone (IB) is a powerful antioxidant but is poorly soluble and thus has low solubility in water, resulting in low bioavailability. In this study, IB-loaded nanoparticles (IB@NPs) were synthesized by loading IB without an organic solvent into nanoparticles that can provide high loading efficiency and stability for solubilization. Indeed, the synthesized IB@NPs exhibited long-term stability through dynamic light scattering, methylene blue staining, and redispersion assays, and IB@NPs prepared with a 5 wt% IB loading content were found to be optimal. The antioxidant activity of IB@NPs evaluated using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay was significantly higher than that of unloaded IB. In addition, IB@NPs showed excellent biocompatibility, inhibited oxidative damage to mouse NIH-3T3 fibroblasts, and reduced intracellular ROS generation according to an in vitro DPPH antioxidant assay. Most notably, IB@NPs significantly promoted wound healing in vitro, as demonstrated by scratch assays. Therefore, as carriers with excellent stability, IB@NPs have potential cosmetic and pharmaceutical applications.
    Keywords:  PEG-40 hydrogenated castor oil; antioxidant activity; idebenone; nanoparticle; solubilization; wound healing
    DOI:  https://doi.org/10.3390/pharmaceutics14030521
  72. Toxicol Appl Pharmacol. 2022 Mar 18. pii: S0041-008X(22)00133-8. [Epub ahead of print]441 115988
    Hexachlorophene, a selective SHP2 inhibitor, suppresses proliferation and metastasis of KRAS-mutant NSCLC cells by inhibiting RAS/MEK/ERK and PI3K/AKT signaling pathways.
    Nai-Jie Fu, Rui-Ying Xi, Xiao-Ke Shi, Run-Ze Li, Zhong-Hui Zhang, Ling-Yu Li, Guo-Lin Zhang, Fei Wang.
      Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations account for 35% of the genetic alterations in non-small cell lung cancer (NSCLC). The Src-homology region 2-containing protein tyrosine phosphatase 2 (SHP2), encoded by PTPN11, is closely involved in RAS downstream pathways and development of many tumors by affecting cell proliferation, differentiation, and immunity. Targeting SHP2 with small molecules may be a promising avenue for the treatment of KRAS-mutant (mut) NSCLC. Herein, hexachlorophene (HCP) was identified as a SHP2 inhibitor with an IC50 value of 5.63 ± 0.75 μM through screening of the FDA-approved drug library. HCP specifically inhibited SHP2 rather than other phosphatases. Molecular docking showed that HCP displayed an orientation favorable for nucleophilic attack in the catalytic domain of SHP2. HCP suppressed viability of multiple KRAS-mut and KRAS-wild type cells and induced senescence and apoptosis in KRAS-mut cells. Moreover, HCP reversed epithelial-mesenchymal transition to suppress metastasis in KRAS-mut cells, and inhibited the RAS/MEK/ERK and PI3K/AKT signaling pathways by suppression of SHP2 phosphorylation and formation SHP2/Grb2/Gab1/SOS1 complex. In summary, HCP can act as a specific SHP2 inhibitor to inhibit KRAS-mut NSCLC cell proliferation and metastasis and induce senescence through suppression of the RAF/MEK/ERK and PI3K/AKT pathways. HCP warrants further investigation as a new compound skeleton for the development of selective SHP2 inhibitors for the treatment of NSCLC.
    Keywords:  Hexachlorophene; Inhibitor; Non-small cell lung cancer; RAS; SHP2
    DOI:  https://doi.org/10.1016/j.taap.2022.115988
  73. Front Nutr. 2022 ;9 846282
    Polysaccharide-Zein Composite Nanoparticles for Enhancing Cellular Uptake and Oral Bioavailability of Curcumin: Characterization, Anti-colorectal Cancer Effect, and Pharmacokinetics.
    Lu Liu, Shufang Yang, Feng Chen, Ka-Wing Cheng.
      Curcumin (CUR) has demonstrated promising potential as a therapeutic agent against colorectal cancer (CRC). However, its intrinsic shortcomings, including oxidative instability, sensitivity to gastrointestinal (GI) hydrolytic/enzymatic action, and susceptibility to biotransformation and systemic elimination, have greatly undermined its value for application in clinical settings. The development of carriers, in particular oral formulations, for its efficient delivery has remained an important direction in nutraceutical research. In the present work, CUR-encapsulated nanoparticles were fabricated with zein alone (Zein-CUR) and with zein and a polysaccharide (PS) [gum Arabic (GA), hyaluronic acid (HA) and pectin (PC), respectively] (PS-Zein-CUR). Their physicochemical and biological properties were evaluated in a series of in vitro and in vivo assays. Dynamic light scattering analysis showed an increase in the particle size of the nanoparticles from 129.0 nm (Zein-CUR) to 188.8-346.4 nm (PS-Zein-CUR). The three PS-Zein-CUR formulations had significantly higher (17-22%) CUR encapsulation efficiency (EE) than Zein-CUR. Among them, HA-Zein-CUR exhibited the highest EE and loading capacity. Zeta potential and FTIR spectra indicated the involvement of electrostatic and hydrophobic interactions and hydrogen bonds in the formation of the PS-Zein-CUR. In human CRC cell lines (HCT8, HCT29, and HCT116), the three PS-Zein-CUR and CUR all effectively inhibited cell viability and colony formation (HA-Zein-CUR > PC-Zein-CUR > GA-Zein-CUR/CUR). HA-Zein-CUR and PC-Zein-CUR also resulted in significantly higher cellular uptake of CUR than GA-Zein-CUR and CUR. Simulated GI-digestion assay demonstrated significantly improved controlled-release properties of these two formulations. Further pharmacokinetics and tissue distribution assays in a CRC subcutaneous xenograft model in nude mice corroborated the enhanced pharmacokinetic properties of intragastric administration of HA-Zein-CUR compared with that of free CUR (3 times higher C max and 9.18 times higher plasma AUC). HA-Zein-CUR also led to enhanced delivery and accumulation of CUR in major organs/tissues, in particular CRC tumors and colon. These results together support that HA-Zein-CUR has promising potential as an oral agent for the control of CRC.
    Keywords:  cellular uptake; colorectal cancer; curcumin; pharmacokinetics; polysaccharide-zein composite nanoparticles
    DOI:  https://doi.org/10.3389/fnut.2022.846282
  74. Cancers (Basel). 2022 Mar 11. pii: 1455. [Epub ahead of print]14(6):
    Hidden in Plants-A Review of the Anticancer Potential of the Solanaceae Family in In Vitro and In Vivo Studies.
    Tomasz Kowalczyk, Anna Merecz-Sadowska, Patricia Rijo, Mattia Mori, Sophia Hatziantoniou, Karol Górski, Janusz Szemraj, Janusz Piekarski, Tomasz Śliwiński, Michał Bijak, Przemysław Sitarek.
      Many of the anticancer agents that are currently in use demonstrate severe side effects and encounter increasing resistance from the target cancer cells. Thus, despite significant advances in cancer therapy in recent decades, there is still a need to discover and develop new, alternative anticancer agents. The plant kingdom contains a range of phytochemicals that play important roles in the prevention and treatment of many diseases. The Solanaceae family is widely used in the treatment of various diseases, including cancer, due to its bioactive ingredient content. The purpose of this literature review is to highlight the antitumour activity of Solanaceae extracts-single isolated compounds and nanoparticles with extracts-and their synergistic effect with chemotherapeutic agents in various in vitro and in vivo cancer models. In addition, the biological properties of many plants of the Solanaceae family have not yet been investigated, which represents a challenge and an opportunity for future anticancer therapy.
    Keywords:  Solanaceae; anticancer potential; apoptosis; cytotoxic effect; in vitro and in vivo studies; plant extracts; pure compounds
    DOI:  https://doi.org/10.3390/cancers14061455
  75. Plants (Basel). 2022 Mar 10. pii: 740. [Epub ahead of print]11(6):
    Elderberries-A Source of Bioactive Compounds with Antiviral Action.
    Mirela Lăcrămioara Mocanu, Sonia Amariei.
      In the current context, when more and more unknown pathogens appear, healthy eating and supplementing it with natural products play an increasingly important role in maintaining the health of the body. The European black elder (Sambucus nigra), found in abundance in the spontaneous flora, can provide us, as a raw material, elderberries, which have been known for thousands of years as having nutritional and healing properties. The phytotherapeutic principles found in elderberry fruits give them antiviral, antibacterial and antidiabetic properties, antitumor potential, antioxidant, antidepressant and immune boosting properties, as well as a certain impacts on obesity and metabolic dysfunctions. Polyphenols and lectins give elderberry fruits the ability to inhibit coronaviruses, which is a topic of great interest in our times. This article summarizes the existing data regarding the chemical composition, active principles and biopharmaceutical properties of elderberries, as well as their use.
    Keywords:  Sambucus nigra; antioxidant; antiviral; black elder; phenolic compounds
    DOI:  https://doi.org/10.3390/plants11060740
  76. Nat Rev Cancer. 2022 Mar 25.
    Targeting ferroptosis as a vulnerability in cancer.
    Guang Lei, Li Zhuang, Boyi Gan.
      Ferroptosis is an iron-dependent form of regulated cell death that is triggered by the toxic build-up of lipid peroxides on cellular membranes. In recent years, ferroptosis has garnered enormous interest in cancer research communities, partly because it is a unique cell death modality that is mechanistically and morphologically different from other forms of cell death, such as apoptosis, and therefore holds great potential for cancer therapy. In this Review, we summarize the current understanding of ferroptosis-inducing and ferroptosis defence mechanisms, dissect the roles and mechanisms of ferroptosis in tumour suppression and tumour immunity, conceptualize the diverse vulnerabilities of cancer cells to ferroptosis, and explore therapeutic strategies for targeting ferroptosis in cancer.
    DOI:  https://doi.org/10.1038/s41568-022-00459-0
  77. Antioxidants (Basel). 2022 Mar 21. pii: 602. [Epub ahead of print]11(3):
    Antioxidants of Fruit Extracts as Antimicrobial Agents against Pathogenic Bacteria.
    Sureeporn Suriyaprom, Pascale Mosoni, Sabine Leroy, Thida Kaewkod, Mickaël Desvaux, Yingmanee Tragoolpua.
      Fruit is an essential part of the human diet and is of great interest because of its richness in phytochemicals. Various fruit extracts from citrus, berries and pomegranates have been shown to possess a broad spectrum of medicinal properties. Fruit phytochemicals are of considerable interest because of their antioxidant properties involving different mechanisms of action, which can act against different pathogenic bacteria. The antioxidant capacity of fruit phytochemicals involves different kinds of reactions, such as radical scavenging and chelation or complexation of metal ions. The interaction between fruit phytochemicals and bacteria has different repercussions: it disrupts the cell envelope, disturbs cell-cell communication and gene regulation, and suppresses metabolic and enzymatic activities. Consequently, fruit phytochemicals can directly inhibit bacterial growth or act indirectly by modulating the expression of virulence factors, both of which reduce microbial pathogenicity. The aim of this review was to report our current knowledge on various fruit extracts and their major bioactive compounds, and determine the effectiveness of organic acids, terpenes, polyphenols, and other types of phenolic compounds with antioxidant properties as a source of antimicrobial agents.
    Keywords:  antimicrobial activity mechanisms; antioxidant properties; fruit extracts; organic acids; polyphenols; terpenes
    DOI:  https://doi.org/10.3390/antiox11030602
  78. J Mater Chem B. 2022 Mar 25.
    Liposomal cyanine dyes with enhanced nonradiative transition for the synergistic phototherapy of tumors.
    Yuan Wang, Di Liu, Meng You, Hong Yang, Hengte Ke.
      Organic photosensitizers are of great interest in cancer diagnosis and treatments such as fluorescence imaging, photodynamic therapy (PDT), and photothermal therapy (PTT). However, their poor aqueous solubility, inadequate photostability and unsatisfactory photophysical parameters limit their clinical application. Herein, we report the construction of liposome encapsulating cyanine dye Cypate (Lipo-Cy) with enhanced nonradiative transition for efficient cancer therapy. After being loaded in liposomes, Cypate molecules are spatially confined within the hydrophobic lipid bilayer, thereby causing much better stability, higher photothermal conversion efficiency, and increased singlet oxygen quantum yield than free Cypate via enhanced nonradiative transition through π-π aggregation. Lipo-Cy further enhanced the cellular uptake of Cypate, as well as preferable tumor accumulation and retention, leading to abundant intracellular singlet oxygen and potent hyperthermia at the tumor for effective PTT synergized PDT, even at dosages 10 times less than free Cypate. The Lipo-Cy exhibited superior anticancer efficiency, showing great prospects for clinical translation.
    DOI:  https://doi.org/10.1039/d2tb00176d
  79. Iran J Basic Med Sci. 2021 Nov;24(11): 1462-1469
    The effect of Elettaria cardamomum (cardamom) on the metabolic syndrome: Narrative review.
    Roghayeh Yahyazadeh, Mahboobeh Ghasemzadeh Rahbardar, Bibi Marjan Razavi, Gholamreza Karimi, Hossein Hosseinzadeh.
      Metabolic syndrome (MetS), as a health-threatening factor, consists of various symptoms including insulin resistance, high blood sugar, hypertension, dyslipidemia, inflammation, and abdominal obesity that raise the risk of diabetes mellitus and cardiovascular disease. Cardiovascular diseases are important causes of mortality among the world population. Recently, there has been a growing interest in using phytomedicine and natural compounds in the prevention and treatment of various diseases. The data was gathered by searching various standard electronic databases (Google Scholar, Scopus, Web of Science, and PubMed) for English articles with no time limitations. All in vivo, in vitro, and clinical studies were included. Elettaria cardamomum (cardamom) is a rich source of phenolic compounds, volatile oils, and fixed oils. Cardamom and its pharmacologically effective substances have shown broad-spectrum activities including antihypertensive, anti-oxidant, lipid-modifying, anti-inflammatory, anti-atherosclerotic, anti-thrombotic, hepatoprotective, hypocholesterolemic, anti-obesity, and antidiabetic effects. This review aims to highlight the therapeutic effects of cardamom on MetS and its components including diabetes, hyperlipidemia, obesity, and high blood pressure as well as the underlying mechanisms in the management of MetS. Finally, it can be stated that cardamom has beneficial effects on the treatment of MetS and its complications.
    Keywords:  Anti-inflammatory agents; Anti-oxidants; Elettaria cardamomum; Hypoglycemic agents; Hypolipidemic agents; Metabolic syndrome
    DOI:  https://doi.org/10.22038/IJBMS.2021.54417.12228
  80. Pharmaceutics. 2022 Mar 03. pii: 563. [Epub ahead of print]14(3):
    Surface-Modified Bilosomes Nanogel Bearing a Natural Plant Alkaloid for Safe Management of Rheumatoid Arthritis Inflammation.
    Mohammed H Elkomy, Nabil K Alruwaili, Mohammed Elmowafy, Khaled Shalaby, Ameeduzzafar Zafar, Naveed Ahmad, Izzeddin Alsalahat, Mohammed M Ghoneim, Essam M Eissa, Hussein M Eid.
      Rheumatoid arthritis (RA) is a chronic inflammatory illness affecting the joints. The characteristic of RA is gradual joint deterioration. Current RA treatment alleviates signs such as inflammation and pain and substantially slows the progression of the disease. In this study, we aimed to boost the transdermal delivery of berberine (a natural product) by encapsulating it in chitosan, surface-modified bilosomes nanogel for better management of the inflammation of RA. The chitosan-coated bilosomes loaded with berberine (BER-CTS-BLS) were formulated according to the thin-film hydration approach and optimized for various causal variables, considering the effect of lipid, sodium deoxycholate, and chitosan concentrations on the size of the particles, entrapment, and the surface charge. The optimized BER-CTS-BLS has 202.3 nm mean diameter, 83.8% entrapment, and 30.8 mV surface charge. The optimized BER-CTS-BLS exhibited a delayed-release profile in vitro and increased skin permeability ex vivo. Additionally, histological examination revealed that the formulated BLS had no irritating effects on the skin. Furthermore, the optimized BER-CTS-BLS ability to reduce inflammation was evaluated in rats with carrageenan-induced paw edema. Our results demonstrate that the group treated with topical BER-CTS-BLS gel exhibited a dramatic reduction in rat paw edema swelling percentage to reach 24.4% after 12 h, which was substantially lower than other groups. Collectively, chitosan-coated bilosomes containing berberine have emerged as a promising therapeutic approach to control RA inflammation.
    Keywords:  berberine; bilosomes; carrageenan-induced paw edema; chitosan; inflammation; nanogel; rheumatoid arthritis
    DOI:  https://doi.org/10.3390/pharmaceutics14030563
  81. Curr Drug Deliv. 2022 Mar 21.
    Preparation and in vitro evaluation of thermosensitive liposomes targeting for ovarian cancer.
    Xingming Wang, Fang Wang, Sixie Li, Guangfu Yin, Ximing Pu.
      INTRODUCTION: Liposomes have been widely used in drug delivery systems because the encapsulation of liposomes changes the biological distribution profile and improves the therapeutic indices of various drugs. Thermosensitive liposomes have been proven to be a precise and effective method for cancer therapy in many preclinical studies. However, the lack of specific targeting ability to cancer cells limited their application in safe and efficient chemotherapy.MATERIALS AND METHODS: In the present study, an ovarian targeting ligand namely WSGFPGVWGASVK (WSG) screened by phage display in vivo was grafted on the thermosensitive phospholipids to prepare the liposomes targeting ovarian cancer cells. WSG was first grafted onto the hydrophilic terminal of DSPE-PEG2000 molecules, and then the WSG modified thermosensitive liposomes (WSG-Lipo) were prepared by thin-film hydration method. Doxorubicin hydrochloride (DOX) was used as a model drug to investigate the drug release behavior of liposomes at different temperatures. The specificity of liposomes to SKOV-3 cells was studied by cell uptake in vitro.
    RESULTS: The WSG-Lipo-DOX could release more DOX at 42°C than at 37°C, showing stronger specificity to SKOV-3 cells and thus selectively inhibiting SKOV-3 cells activity in vitro.
    CONCLUSION: The active targeting liposome showed potential in improving the specificity of thermosensitive liposomes and would be applied in the chemotherapy combined with a thermotherapy.
    Keywords:  Cellular specificity; Liposomes; Ovarian cancer; Thermosensitivity; Tumor targeting; controlled drug release
    DOI:  https://doi.org/10.2174/1567201819666220321110812
  82. Bioengineering (Basel). 2022 Feb 22. pii: 88. [Epub ahead of print]9(3):
    The Natural Cryoprotectant Honey for Fertility Cryopreservation.
    Faryal Farooq Cheepa, Huilan Liu, Gang Zhao.
      Honey is a mixture of 25 sugars with other bioactive substances (i.e., organic acids, enzymes, antioxidants, and vitamins) and has been known as a highly nutritious functional food. Traditionally, it has been widely used in medicinal applications to cure various diseases. The effectiveness of honey in different applications has been used for its antimicrobial activity, absorption of hydrops, cleansing, removing odor, assisting granulation, recovery of nutrition, and formation of tissue and epithelium, which proved that honey has dehydrating and preserving properties to make it ideal for the cryopreservation of cells and tissues. Cryopreservation is an advanced preservation technique for tissue, cells, organelles, or other biological specimen storage, performed by cooling the sample at a very low temperature. It is the most common approach to improved preserving fertility (sperm, embryos, and oocytes) in different species that may undergo various life-threatening illnesses and allows for the genetic screening of these cells to test the sample for diseases before use. However, with toxic cryoprotectant (CPA), cryopreservation of fertility has been challenging because of their particular structure and sensitivity to chilling. Honey's unique composition, as well as its dehydrating and preserving properties, qualify it to be used as a natural cryoprotectant. The aim of this study is to emphasize the ability of honey as a natural cryoprotectant in cryopreservation. The articles for this review were searched from Google Scholar, PubMed, Science Direct, Web of Science, and Scopus, using the keywords, honey, cryopreservation, natural cryoprotectant/CPAs, extenders, and fertility. Honey, as a natural cryoprotectant in fertility cryopreservation, yielded satisfactory results, with respect to improved post-thaw quality and viability. It is now proved as a non-toxic and highly efficient natural cryoprotectant in fertility preservation because its increasing viscosity at low temperature can provide a protective barrier to cells by reducing ice formation. Furthermore, its antioxidant property plays a vital role in protecting the cells from thermal damage by reducing the reactive oxygen species (ROS). This review provides a road map for future studies to investigate the potential of honey in the cryopreservation of other cells and tissue and contribute to the scientific research, regarding this remarkable natural product.
    Keywords:  cryopreservation; extenders; fertility; honey; natural cryoprotectant
    DOI:  https://doi.org/10.3390/bioengineering9030088
  83. EMBO J. 2022 Mar 21. e110466
    Ketogenic HMG-CoA lyase and its product β-hydroxybutyrate promote pancreatic cancer progression.
    Victoire Gouirand, Tristan Gicquel, Evan C Lien, Emilie Jaune-Pons, Quentin Da Costa, Pascal Finetti, Elodie Metay, Camille Duluc, Jared R Mayers, Stephane Audebert, Luc Camoin, Laurence Borge, Marion Rubis, Julie Leca, Jeremy Nigri, François Bertucci, Nelson Dusetti, Juan Lucio Iovanna, Richard Tomasini, Ghislain Bidaut, Fabienne Guillaumond, Matthew G Vander Heiden, Sophie Vasseur.
      Pancreatic ductal adenocarcinoma (PDA) tumor cells are deprived of oxygen and nutrients and therefore must adapt their metabolism to ensure proliferation. In some physiological states, cells rely on ketone bodies to satisfy their metabolic needs, especially during nutrient stress. Here, we show that PDA cells can activate ketone body metabolism and that β-hydroxybutyrate (βOHB) is an alternative cell-intrinsic or systemic fuel that can promote PDA growth and progression. PDA cells activate enzymes required for ketogenesis, utilizing various nutrients as carbon sources for ketone body formation. By assessing metabolic gene expression from spontaneously arising PDA tumors in mice, we find HMG-CoA lyase (HMGCL), involved in ketogenesis, to be among the most deregulated metabolic enzymes in PDA compared to normal pancreas. In vitro depletion of HMGCL impedes migration, tumor cell invasiveness, and anchorage-independent tumor sphere compaction. Moreover, disrupting HMGCL drastically decreases PDA tumor growth in vivo, while βOHB stimulates metastatic dissemination to the liver. These findings suggest that βOHB increases PDA aggressiveness and identify HMGCL and ketogenesis as metabolic targets for limiting PDA progression.
    Keywords:  HMGCL; ketone bodies; metastasis; pancreatic cancer; β-hydroxybutyrate
    DOI:  https://doi.org/10.15252/embj.2021110466
  84. Pharmaceutics. 2022 Feb 27. pii: 535. [Epub ahead of print]14(3):
    pH-Responsive Nanoparticles for Delivery of Paclitaxel to the Injury Site for Inhibiting Vascular Restenosis.
    Huiru Zhu, Li Kong, Xu Zhu, Tingting Ran, Xiaojuan Ji.
      A high incidence of restenosis has been reported at the site of inflammation following angioplasty and stent implantation. The anti-proliferative drug paclitaxel (PTX) could help to reduce inflammation and restenosis; however, it has poor water solubility and serious adverse side effects at high doses. Given the presence of metabolic acidosis at the site of inflammation, we hypothesized that nanoparticles that are responsive to low pH could precisely release the loaded drug at the target site. We successfully constructed pH-responsive poly(D, L-lactic-co-glycolic acid) (PLGA) nanoparticles loaded with PTX and NaHCO3 as a pH-sensitive therapeutic agent (PTX-NaHCO3-PLGA NPs). The NPs exhibited remarkable pH sensitivity and a good safety profile both in vitro in rat vascular smooth muscle cells and in vivo in Sprague Dawley rats after tail vein injection. In the rat model, the PTX-NaHCO3-PLGA NPs treatment group showed suppressed intimal proliferation following balloon-induced carotid artery injury compared with that of the saline-treated control. Overall, these results demonstrate that our newly developed pH-responsive nanodrug delivery platform has the potential to effectively inhibit restenosis.
    Keywords:  drug delivery; pH-responsive nanoparticles; paclitaxel; sodium bicarbonate; vascular restenosis
    DOI:  https://doi.org/10.3390/pharmaceutics14030535
  85. Bioact Mater. 2022 Aug;14 42-51
    Engineering naphthalimide-cyanine integrated near-infrared dye into ROS-responsive nanohybrids for tumor PDT/PTT/chemotherapy.
    Tongxia Jin, Di Cheng, Guanyu Jiang, Wenqian Xing, Peiwen Liu, Bin Wang, Weiping Zhu, Haitao Sun, Zhenrong Sun, Yufang Xu, Xuhong Qian.
      Photodynamic (PDT) and photothermal therapies (PTT) are emerging treatments for tumour ablation. Organic dyes such as porphyrin, chlorin, phthalocyanine, boron-dipyrromethene and cyanine are the clinically or preclinically used photosensitizer or photothermal agents. Development of structurally diverse near-infrared dyes with long absorption wavelength is of great significance for PDT and PTT. Herein, we report a novel near-infrared dye ML880 with naphthalimide modified cyanine skeleton. The introduction of naphthalimide moiety results in stronger electron delocalization and larger redshift in emission compared with IR820. Furthermore, ML880 is co-loaded with chemotherapeutic drug into ROS-responsive mesoporous organosilica (RMON) to construct nanomedicine NBD&ML@RMON, which exhibits remarkable tumor inhibition effects through PDT/PTT/chemotherapy in vivo.
    Keywords:  Combination therapy; Drug delivery system; Integration strategy; Near-infrared dye; Phototherapy
    DOI:  https://doi.org/10.1016/j.bioactmat.2021.12.009
  86. Pharmaceuticals (Basel). 2022 Feb 23. pii: 278. [Epub ahead of print]15(3):
    Benefits of Black Cohosh (Cimicifuga racemosa) for Women Health: An Up-Close and In-Depth Review.
    Sradhanjali Mohapatra, Ashif Iqubal, Mohammad Javed Ansari, Bisma Jan, Sultan Zahiruddin, Mohd Aamir Mirza, Sayeed Ahmad, Zeenat Iqbal.
      Women's health is an imminent concern worldwide, but it remains an ignored segment of research in most developing countries, and is yet to take the center stage in even developed nations. Some exclusive female health concerns revolve around both pathological and physiological aspects. These gender-specific maladies include breast, cervical, and ovarian cancers, and physiological concerns such as menopause and osteoporosis, which are often coexistent. Recently, women's health issues, including postmenopausal syndrome, have attracted the attention of researchers and practitioners alike, opening newer pharmaceutical research and clinical avenues. Although not counted as a disease, postmenopausal syndrome (PMS) is a female health phenomenon underpinned by hormonal depletion. Enhanced life expectancy in women has added to their suffering, and pharmacological interventions are needed. Amongst the available treatment modalities, the use of numerous botanicals has emerged as an efficient health management tool for women. Cimicifuga racemosa (CR or Black Cohosh) is a plant/herb which has been traditionally exploited and extensively used by women. This review is an attempt to compile and provide a summary of the importance of CR in complementary and alternative therapies for the improvement of various disorders related to women, such as menopausal syndrome, mammary cancer, and osteoporosis. It aims to systematically highlight the bioactive constituents, pharmacology, pharmacokinetics, therapeutic potentials, quality control processes, chromatographic techniques, and possible mechanisms of action of clinically effective phytomedicine for women's health. Various clinical trials and patents relating to CR and women's health have been collated. Furthermore, the plant and its related products have been considered from a regulatory perspective to reveal its commercial feasibility. The present review summarizes the existing data on CR focusing on women's health, which can help to introduce this traditional phytomedicine to the world and provide some reference for future drug development.
    Keywords:  black cohosh; cimicifuga racemose; clinical trials; commercial products; mechanism of action; menopause; patents; phytomedicines; postmenopausal syndrome; women health
    DOI:  https://doi.org/10.3390/ph15030278
  87. Pharmaceutics. 2022 Feb 27. pii: 531. [Epub ahead of print]14(3):
    Liposomes as Tools to Improve Therapeutic Enzyme Performance.
    Maria Eugénia Meirinhos Cruz, Maria Luísa Corvo, Maria Bárbara Martins, Sandra Simões, Maria Manuela Gaspar.
      The drugs concept has changed during the last few decades, meaning the acceptance of not only low molecular weight entities but also macromolecules as bioagent constituents of pharmaceutics. This has opened a new era for a different class of molecules, namely proteins in general and enzymes in particular. The use of enzymes as therapeutics has posed new challenges in terms of delivery and the need for appropriate carrier systems. In this review, we will focus on enzymes with therapeutic properties and their applications, listing some that reached the pharmaceutical market. Problems associated with their clinical use and nanotechnological strategies to solve some of their drawbacks (i.e., immunogenic reactions and low circulation time) will be addressed. Drug delivery systems will be discussed, with special attention being paid to liposomes, the most well-studied and suitable nanosystem for enzyme delivery in vivo. Examples of liposomal enzymatic formulations under development will be described and successful pre-clinical results of two enzymes, L-Asparaginase and Superoxide dismutase, following their association with liposomes will be extensively discussed.
    Keywords:  drug delivery systems; liposomes; therapeutic enzymes
    DOI:  https://doi.org/10.3390/pharmaceutics14030531
  88. Food Chem. 2022 Mar 12. pii: S0308-8146(22)00654-9. [Epub ahead of print]386 132692
    Preparation, characterization and evaluation of capsaicin-loaded indica rice starch nanoparticles.
    Xiaoqi Tao, Lei Zhan, Yanxia Huang, Pan Li, Baona Liu, Pei Chen.
      Capsaicin (CAP) is an alkaloid with multiple physiological effects, but its application is difficult. In this research, indica rice starch nanoparticles (IRSNPs) based nanocarrier was used to load CAP to obtain capsaicin-loaded indica rice starch nanoparticles (CAP-IRSNPs). The microstructure, characteristics and in vitro release behaviors of CAP-IRSNPs were analyzed. CAP-IRSNPs presented average particle sizes of 617.84 ± 6.38 nm, encapsulation efficiency of 70.05 ± 1.78% and loading capacity of 13.41 ± 0.18%. Fourier-transform infrared spectroscopy confirmed that CAP-IRSNPs might be formed by hydrogen-bonding action. Differential scanning calorimetry and X-ray diffraction showed that IRSNPs influenced the crystallization and melting temperatures of CAP. In in vitro release study, CAP-IRSNPs exhibited a sustained release. The CAP concentration, CAP diffusion from matrix and matrix erosion might be the potentially possible mechanisms for capsaicin release from CAP-IRSNPs. These new results concluded that IRSNPs may be a promising nanocarrier for CAP or other hydrophobic bioactive ingredients.
    Keywords:  Adsorption; Capsaicin; Indica rice; Starch; Starch nanoparticles; Sustained release
    DOI:  https://doi.org/10.1016/j.foodchem.2022.132692
  89. Cancers (Basel). 2022 Mar 17. pii: 1536. [Epub ahead of print]14(6):
    Applications of Focused Ultrasound in the Treatment of Genitourinary Cancers.
    John Panzone, Timothy Byler, Gennady Bratslavsky, Hanan Goldberg.
      Traditional cancer treatments have been associated with substantial morbidity for patients. Focused ultrasound offers a novel modality for the treatment of various forms of cancer which may offer effective oncological control and low morbidity. We performed a review of PubMed articles assessing the current applications of focused ultrasound in the treatment of genitourinary cancers, including prostate, kidney, bladder, penile, and testicular cancer. Current research indicates that high-intensity focused ultrasound (HIFU) focal therapy offers effective short-term oncologic control of localized prostate and kidney cancer with lower associated morbidity than radical surgery. In addition, studies in mice have demonstrated that focused ultrasound treatment increases the accuracy of chemotherapeutic drug delivery, the efficacy of drug uptake, and cytotoxic effects within targeted cancer cells. Ultrasound-based therapy shows promise for the treatment of genitourinary cancers. Further research should continue to investigate focused ultrasound as an alternative cancer treatment option or as a complement to increase the efficacy of conventional treatments such as chemotherapy and radiotherapy.
    Keywords:  cancer; review; treatment; ultrasound
    DOI:  https://doi.org/10.3390/cancers14061536
  90. Food Funct. 2022 Mar 22.
    Ginsenoside Rk1 regulates glutamine metabolism in hepatocellular carcinoma through inhibition of the ERK/c-Myc pathway.
    Haoping Lu, Huayu Yin, Linlin Qu, Xiaoxuan Ma, Rongzhan Fu, Daidi Fan.
      Hepatocellular carcinoma (HCC) is one of the most prevalent and deadly cancers in the world. Recently, suppression of glutamine metabolism has become one of the hottest therapy targets for cancer treatment. There is a growing amount of research that indicates that ginsenosides possess good anti-tumor activity. However, the effect of ginsenoside Rk1 on glutamine metabolism in HCC is unclear. In this study, Rk1 was demonstrated to be effective at inhibiting the proliferation of HCC through the induction of cell cycle arrest and apoptosis. Especially, Rk1 was shown for the first time to inhibit glutamine metabolism in HCC. Rk1 downregulates GLS1 expression, and consequently decreases the GSH production, stimulating ROS accumulation to induce apoptosis. In addition, transcriptomic results showed that the ERK/c-Myc signaling pathway was enriched in HepG2. Rk1 exerts an inhibitory effect on glutamine metabolism in HCC by regulating the ERK/c-Myc signaling pathway, and inducing apoptosis in vitro and in vivo with less toxicity. Therefore, ginsenoside Rk1 could be a promising candidate for the clinical treatment of HCC.
    DOI:  https://doi.org/10.1039/d1fo03728e
  91. Heliyon. 2022 Mar;8(3): e09099
    Potential enhancement of metformin hydrochloride in solidified reverse micellar solution-based PEGylated lipid nanoparticles targeting therapeutic efficacy in diabetes treatment.
    Franklin Chimaobi Kenechukwu, Daniel Okwudili Nnamani, Judith Chekwube Duhu, Bright Ugochukwu Nmesirionye, Mumuni Audu Momoh, Paul Achile Akpa, Anthony Amaechi Attama.
      Metformin hydrochloride (MH) is a widely used oral biguanide antihyperglycemic (antidiabetic) drug with poor bioavailability which necessitates the development of novel drug delivery systems such as PEGylated solid lipid nanoparticles for improving its therapeutic activity. The aim of this study was to formulate, characterize and evaluate in vitro and in vivo pharmacodynamic properties of metformin-loaded PEGylated solid lipid nanoparticles (PEG-SLN) for improved delivery of MH. The lipid matrices (non-PEGylated lipid matrix and PEGylated lipid matrices) used in the formulation of both non-PEGylated (J0) and PEGylated SLNs (J10, J20, J40) were prepared by fusion using beeswax and Phospholipon ® 90H at 7:3 ratio with or without polyethylene glycol (PEG) 4000 (0, 10, 20 and 40% w/w), respectively. Representative lipid matrices (LM and PEG-LM) were loaded with MH by fusion and then characterized by differential scanning calorimetry (DSC) and Fourier transform infrared (FT-IR) spectroscopy. The PEG-SLNs were prepared by high shear hot homogenization using the lipid matrices (5% w/w), drug (MH) (1.0% w/w), sorbitol (4% w/w) (cryoprotectant), Tween ® 80 (2% w/w) (surfactant) and distilled water (q.s to 100% w/w) (vehicle). The non-PEGylated and PEGylated SLNs (J0, J10, J20, J40)) were characterized with respect to encapsulation efficiency (EE%), loading capacity (LC), morphology by scanning electron microscopy (SEM), mean particle size (Zav) and polydispersity indices (PDI) by photon correlation spectroscopy (PCS), compatibility by FT-IR spectroscopy and in vitro drug release in biorelevant medium. Thereafter, in vivo antidiabetic study was carried out in alloxanized rats' model and compared with controls (pure sample of MH and commercial MH- Glucophage®)). Solid state characterizations indicated the amorphous nature of MH in the drug loaded-lipid matrices. The PEG-SLNs were mostly smooth and spherical nanoformulations with Zav and PDI of 350.00 nm and 0.54, respectively, for non-PEGylated SLNs, and in the range of 386.80-783.10 nm and 0.592 to 0.752, respectively, for PEGylated SLNs. The highest EE% and LC were noted in batch J20 and were 99.28% and 16.57, respectively. There was no strong chemical interaction between the drug and excipients used in the preparation of the formulations. The PEGylated SLN (batch J40) exhibited the highest percentage drug released (60%) at 8 h. The PEGylated SLNs showed greater hyperglycemic control than the marketed formulation (Glucophage ®) after 24 h. This study has shown that metformin-loaded PEGylated solid lipid nanoparticles could be employed as a potential approach to improve the delivery of MH in oral diabetic management, thus encouraging further development of the formulations.
    Keywords:  Anti-diabetic activity; Beeswax; Metformin; PEGylated solid lipid nanoparticles; Phospholipon ® 90H; Solidified reverse micellar solution (SRMS)
    DOI:  https://doi.org/10.1016/j.heliyon.2022.e09099
  92. Annu Rev Food Sci Technol. 2022 Mar 25. 13 337-359
    Current Understanding of Modes of Action of Multicomponent Bioactive Phytochemicals: Potential for Nutraceuticals and Antimicrobials.
    Michael Wink.
      Plants produce a diversity of plant secondary metabolites (PSMs), which function as defense chemicals against herbivores and microorganisms but also as signal compounds. An individual plant produces and accumulates mixtures of PSMs with different structural features using different biosynthetic pathways. Almost all PSMs exert one or several biological activities that can be useful for nutrition and health. This review discusses the modes of action of PSMs alone and in combinations. In a mixture, most individual PSMs can modulate different molecular targets; they are thus multitarget drugs. In an extract with many multitarget chemicals, additive and synergistic effects occur. Experiments with the model system Caenorhabditis elegans show that polyphenols and carotenoids can function as powerful antioxidative and longevity-promoting PSMs. PSMs of food plants and spices often exhibit antioxidant, anti-inflammatory, and antimicrobial properties, which can be beneficial for health and the prevention of diseases. Some extracts from food plants and spices with bioactive PSMs have potential for nutraceuticals and antimicrobials.
    Keywords:  Caenorhabditis elegans; antimicrobials; antioxidants; defense compounds; multitarget drugs; nutraceuticals; phytochemicals; plant secondary metabolites; synergism
    DOI:  https://doi.org/10.1146/annurev-food-052720-100326
  93. Pharmaceutics. 2022 Feb 25. pii: 511. [Epub ahead of print]14(3):
    Honeybee Venom Synergistically Enhances the Cytotoxic Effect of CNS Drugs in HT-29 Colon and MCF-7 Breast Cancer Cell Lines.
    Diana Duarte, Soraia I Falcão, Iouraouine El Mehdi, Miguel Vilas-Boas, Nuno Vale.
      5-fluorouracil (5-FU) and doxorubicin (DOX) are potent anti-tumour agents commonly used for colon and breast cancer therapy, respectively. However, their clinical application is limited by their side effects and the development of drug resistance. Honeybee venom is a complex mixture of substances that has been reported to be effective against different cancer cells. Its active compound is melittin, a positively charged amphipathic peptide that interacts with the phospholipids of the cell membrane, forming pores that enable the internalization of small molecules with cytotoxic activities,. and consequently, causing cell death. Some central nervous system (CNS) drugs have recently demonstrated great anti-cancer potential, both in vitro, in vivo and in clinical trials, being promising candidates for drug repurposing in oncology. The present work evaluated the anti-cancer efficacy of honeybee venom in combination with chemotherapeutic or CNS drugs in HT-29 colon and MCF-7 breast cancer cell lines. The chemical characterization of a Portuguese sample of honeybee venom was done by LC-DAD-ESI/MSn analysis. For single treatments, cells were incubated with increasing concentrations of bee venom. For combination treatments, increasing concentrations of bee venom were first combined with the half-maximal inhibitory concentration (IC50) of 5-FU and DOX, in HT-29 and MCF-7 cells, respectively. Cells were also treated with increasing concentrations of bee venom in combination with the IC50 value of four CNS drugs (fluphenazine, fluoxetine, sertraline and thioridazine). Cytotoxicity was evaluated by MTT and SRB assays. The combination index (CI) value was calculated using CompuSyn software, based on the Chou-Talalay method. Synergy scores of different reference models (HSA, Loewe, ZIP and Bliss) were also calculated using SynergyFinder. The results demonstrate that honeybee venom is active against HT-29 colon and MCF-7 breast cancer cells, having better anti-tumour activity in MCF-7 cells. It was found that bee venom combined with 5-FU and fluphenazine in HT-29 cells resulted in less cytotoxic effects compared to the co-treatment of fluoxetine, sertraline and thioridazine plus bee venom, which resulted in less than 15% of viable cells for the whole range of concentrations. The combination of MCF-7 cells with repurposed drugs plus honeybee venom resulted in better anti-cancer efficacies than with DOX, notably for lower concentrations. A combination of fluoxetine and thioridazine plus honeybee venom resulted in less than 40% of viable cells for all ranges of concentrations. These results support that the combination of honeybee venom with repurposed drugs and chemotherapeutic agents can help improve their anti-cancer activity, especially for lower concentrations, in both cell lines. Overall, the present study corroborates the enormous bioactive potential of honeybee venom for colon and breast cancer treatments, both alone and in combination with chemotherapy or repurposed drugs.
    Keywords:  CNS drugs; antineoplastic drugs; breast cancer; colorectal cancer; drug combination; drug repurposing; honeybee venom; melittin
    DOI:  https://doi.org/10.3390/pharmaceutics14030511
  94. Pharmaceutics. 2022 Feb 28. pii: 537. [Epub ahead of print]14(3):
    Chitosan/PVA Hetero-Composite Hydrogel Containing Antimicrobials, Perfluorocarbon Nanoemulsions, and Growth Factor-Loaded Nanoparticles as a Multifunctional Dressing for Diabetic Wound Healing: Synthesis, Characterization, and In Vitro/In Vivo Evaluation.
    Yu-Hsiang Lee, Sheng-Jhe Lin.
      Diabetic foot ulcers remain one of the most difficult-to-treat complications of diabetes and may seriously threaten the life of patients since it frequently results in limb loss due to amputation, suggesting that an effective therapeutic strategy is still urgently needed. In this study, a chitosan-based heterogeneous composite hydrogel encapsulating perfluorocarbon emulsions, epidermal growth factor (EGF)-loaded chitosan nanoparticles, and polyhexamethylene biguanide (PHMB) named PEENPPCH was developed for diabetic wound healing. The PEENPPCH could sustainably release EGF and PHMB in an ion-rich environment to exert antibacterial effects and promote cell growth for wound repair. In addition, the PEENPPCH can provide anti-inflammatory effects functioned by its main constituent of chitosan. Moreover, the PEENPPCH can proactively offer oxygen delivery through the incorporation of perfluorocarbon and, therefore, is able to alleviate hypoxia conditions on diabetic wounds. These functionalities enabled a markedly enhanced wound healing efficacy on diabetic rats treated with the PEENPPCHs, including thorough re-epithelization, a reduced inflammatory response, faster collagen deposition, and advanced collagen maturation resulting in a 95% of wound closure degree after 15 days that was 12.6% (p < 0.05) higher than the value of the group treated with the commercial dressing HeraDerm. Given the aforementioned advantages, together with the known merits of hydrogels, the developed PEENPPCH is anticipated to be a feasible tool for clinical diabetic wound treatment.
    Keywords:  anti-inflammatory; antibacterial; cell growth; diabetic wound healing; hydrogel; nanoparticle; oxygen delivery; perfluorocarbon
    DOI:  https://doi.org/10.3390/pharmaceutics14030537
  95. Pharmaceuticals (Basel). 2022 Mar 16. pii: 359. [Epub ahead of print]15(3):
    Medical Cannabis in Pediatric Oncology: Friend or Foe?
    Megan Malach, Igor Kovalchuk, Olga Kovalchuk.
      The antineoplastic effects of cannabis have been known since 1975. Since the identification of the components of the endogenous cannabinoid system (ECS) in the 1990s, research into the potential of cannabinoids as medicine has exploded, including in anti-cancer research. However, nearly all of this research has been on adults. Physicians and governing bodies remain cautious in recommending the use of cannabis in children, since the ECS develops early in life and data about cannabis exposure in utero show negative outcomes. However, there exist many published cases of use of cannabis in children to treat pediatric epilepsy and chemotherapy-induced nausea and vomiting (CINV) that show both the safety and efficacy of cannabis in pediatric populations. Additionally, promising preclinical evidence showing that cannabis has anti-cancer effects on pediatric cancer warrants further investigation of cannabis' use in pediatric cancer patients, as well as other populations of pediatric patients. This review aims to examine the evidence regarding the potential clinical utility of cannabis as an anti-cancer treatment in children by summarizing what is currently known about uses of medical cannabis in children, particularly regarding its anti-cancer potential.
    Keywords:  CBD; Cannabis sativa; Epidiolex; Marinol; Sativex; THC; cannabinoids; medical cannabis; pediatric cancer
    DOI:  https://doi.org/10.3390/ph15030359
  96. J Clin Exp Dent. 2022 Mar;14(3): e285-e292
    The Effect of Photodynamic Therapy on Oral-Premalignant Lesions: A Systematic Review.
    Ruchika Choudhary, Sujatha S Reddy, Ravleen Nagi, Rakesh Nagaraju, Sreekanth P Kunjumon, Ritu Sen.
      Background: Dentists now have access to a wide range of unique treatment methods as a result of substantial scientific and technological breakthroughs in the field of dentistry. Photodynamic therapy (PDT) is a non-invasive treatment procedure that use photosensitizers, a specific wavelength of light, and the production of singlet oxygen and reactive oxygen species (ROS) to kill undesired eukaryotic cells (such as oral tumors) and harmful microbes. In several disciplines of dentistry, it is seen as a valid therapeutic option. The purpose of this study was to examine the effectiveness and side effects of PDT in the treatment of oral premalignant lesions.Material and Methods: Three search engines (PubMed, ISI Web of Science, and the Cochrane Library) were used to conduct a systematic review using the phrases photodynamic therapy and PDT in combination with other terms. To define our study eligibility criteria, we used the Population, Intervention and Comparison, Outcomes, and Study design technique.
    Results: Initial results were 33. Definitely, 18 studies met our selection criteria.
    Conclusions: Our analysis suggests ALA- PDT as a promising therapeutic modality for OEL lesions which should be treated first with the topical ALA-PDT using either the LED or laser light for successful clinical outcome for OEL lesions. Key words:Photodynamic Therapy, Photosensitizer, Aminolevulinic Acid (ALA), Methylene Blue (MB), Toludine Blue, Oral Leukoplakia, Oral Erythroplakia, Oral Verrucous hyperplasia, Oral Lichen Planus.
    DOI:  https://doi.org/10.4317/jced.59348
  97. Molecules. 2022 Mar 15. pii: 1899. [Epub ahead of print]27(6):
    Laurus nobilis L. Essential Oil-Loaded PLGA as a Nanoformulation Candidate for Cancer Treatment.
    Esin Ercin, Serda Kecel-Gunduz, Bahar Gok, Tugba Aydin, Yasemin Budama-Kilinc, Murat Kartal.
      The aim of this study was to obtain essential oil (LNEO) from the Laurus nobilis L. plant, and to prepare LNEO-loaded poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs) as an approach in cancer treatment. The components of the obtained LNEO were analyzed using GC-MS. The LNEO-NPs were synthesized by the single-emulsion method. The LNEO-NPs were characterized using UV-Vis spectrometry, Dynamic Light Scattering (DLS), Scanning Electron Microscopy (SEM), and a DNA binding assay, which was performed via the UV-Vis titration method. According to the results, the LNEO-NPs had a 211.4 ± 4.031 nm average particle size, 0.068 ± 0.016 PdI, and -7.87 ± 1.15 mV zeta potential. The encapsulation efficiency and loading capacity were calculated as 59.25% and 25.65%, respectively, and the in vitro drug release study showed an LNEO release of 93.97 ± 3.78% over the 72 h period. Moreover, the LNEO was intercalatively bound to CT-DNA. In addition, the mechanism of action of LNEO on a dual PI3K/mTOR inhibitor was predicted, and its antiproliferative activity and mechanism were determined using molecular docking analysis. It was concluded that LNEO-loaded PLGA NPs may be used for cancer treatment as a novel phytotherapeutic agent-based controlled-release system.
    Keywords:  DNA binding; PLGA; controlled release system; laurel essential oil; nanoparticle
    DOI:  https://doi.org/10.3390/molecules27061899
  98. Neoplasma. 2022 Mar 24. pii: 211103N1568. [Epub ahead of print]
    Co-treatment of betulin and gefitinib is effective against EGFR wild-type/KRAS-mutant non-small cell lung cancer by inducing ferroptosis.
    Wei-Ya Yan, Jian Cai, Jiang-Nan Wang, Yong-Sheng Gong, Xue-Bing Ding.
      Clinical trials suggest that non-small-cell lung cancer (NSCLC) patients with KRAS mutations and wild-type EGFR have reduced benefits from gefitinib treatment. Ferroptosis is a new form of cell death that plays an important role in mediating the sensitivity of EGFR-TIKs. Here, we explored the antitumor ability of gefitinib in combination with betulin to overcome drug resistance through ferroptosis in wild-type EGFR/KRAS-mutant NSCLC cells. A549 and H460 cells were treated with gefitinib and betulin, and cell viability, apoptosis, and migration ability were assessed using the CCK-8 assay, flow cytometry, and wound-healing assay, respectively. Several cell death inhibitors were used to study the form of cell death. Ferroptosis-related events were detected by performing reactive oxygen species (ROS) and iron level detection, malondialdehyde (MDA) assay, and glutathione (GSH) assay. EMT-associated proteins and ferroptosis-related proteins were detected by using western blotting. A xenograft model was constructed in vivo to investigate the role of the combination treatment of betulin and gefitinib in NSCLC tumor growth. Gefitinib in combination with betulin exhibited antagonistic effects on cellular viability and induced cell apoptosis. It also induced ROS accumulation, lipid peroxidation, and GSH depletion and induced ferroptosis-related gene expression. Moreover, ferroptosis inhibitors, but not inhibitors of other forms of cell death, abrogated the effect of gefitinib in combination with betulin. Moreover, it also inhibited the tumor growth of NSCLC in vivo. Our findings suggest that gefitinib in combination with betulin is a novel therapeutic approach to overcome gefitinib resistance in EGFR wild-type/KRAS-mutant NSCLC cells by inducing ferroptosis.
    DOI:  https://doi.org/10.4149/neo_2022_211103N1568
  99. Antioxidants (Basel). 2022 Feb 28. pii: 479. [Epub ahead of print]11(3):
    Chitosan-Tripolyphosphate Nanoparticles Prepared by Ionic Gelation Improve the Antioxidant Activities of Astaxanthin in the In Vitro and In Vivo Model.
    Eun Suh Kim, Youjin Baek, Hyun-Jae Yoo, Ji-Soo Lee, Hyeon Gyu Lee.
      The present study aimed to investigate the effects of chitosan (CS)-tripolyphosphate (TPP) nanoparticles (NPs) on the stability, antioxidant activity, and bioavailability of astaxanthin (ASX). ASX-loaded CS-TPP NPs (ACT-NPs) prepared by ionic gelation between CS (0.571 mg/mL) and TPP (0.571 mg/mL) showed 505.2 ± 184.8 nm, 20.4 ± 1.2 mV, 0.348 ± 0.044, and 63.9 ± 3.0% of particle size, zeta potential, polydispersity index and encapsulation efficiency, respectively. An in vitro release study confirmed that the release of ASX in simulated gastric (pH 1.2) and intestinal (pH 6.8) fluid was prolonged within ACT-NPs. The in vitro antioxidant activities of ACT-NPs were significantly improved compared with free ASX (FA) (p < 0.05). Furthermore, the cellular and in vivo antioxidant analysis verified that ACT-NPs could enhance the cytoprotective effects on the BHK-21 cell line and demonstrate sustained release properties, leading to prolonged residence time in the rat plasma. The results suggest that the stability, antioxidant properties, and bioavailability of ASX can be effectively enhanced through encapsulation within CS-TPP NPs.
    Keywords:  antioxidant activity; astaxanthin; bioavailability; chitosan nanoparticle; nanoencapsulation; stability
    DOI:  https://doi.org/10.3390/antiox11030479
  100. Photodiagnosis Photodyn Ther. 2022 Mar 21. pii: S1572-1000(22)00107-7. [Epub ahead of print] 102818
    Synthesis and characterization of photosensitive gelatin-based hydrogels for photodynamic therapy in HeLa-CCL2 cell line.
    Jéssica A R Ambrósio, Bruna C S Pinto, Vitor Luca Moura Marmo, Kennedy Wallace Dos Santos, Milton Beltrame Junior, Juliana G Pinto, Juliana Ferreira-Strixino, Leandro José Raniero, Andreza R Simioni.
      BACKGROUND: Hydrogel systems are increasingly gaining visibility in numerous areas involving biomedicine, tissue engineering, environmental treatments, and drug delivery systems. These systems have a three-dimensional network composition and high-water absorption capacity, are biocompatible, allowing them to become an option as photosensitizer carriers (PS) for applications Photodynamic Therapy (PDT) protocols.METHODS: In this work was to shynthesize a nanohydrogel system (NAHI), encapsulated with chloroaluminium phthalocyanine (ClAlPc), for DDS. NAHI was synthesized using gelatin as based polymer by the chemical cross-linking technique. The drug was encapsulated by immersing the hydrogel in a 1.0 mg.mL-1 ClAlPc solution. The external morphology of NAHI was examined by scanning electron microscopy (SEM). The degree of swelling of the synthesized system was evaluated to determine the water absorption potential. The produced nanohydrogel system was characterized by photochemical, photophysical and photobiologial studies.
    RESULTS: The images from the SEM analysis showed the presence of three-dimensional networks in the formulation. The swelling test demonstrated that the nanohydrogel freeze-drying process increases its water holding capacity. All spectroscopic results showed excellent photophysical parameters of the drug studied when served in the NAHI system. The incorporation efficiency was 70%. The results of trypan blue exclusion test have shown significant reduction (p < 0.05) in the cell viability for all groups treated with PDT, in all concentrations tested. In HeLa cells, PDT mediated by 0,5 mg.mL-1 ClAlPc encapsulated in NAHI showed a decrease in survival close to 95%. In the internalization cell study was possible to observe the internalization of phthalocyanine after one hour of incubation, at 37°C, with the the accumulation of PS in the cytoplasm and inside the nucleus at both concentrations tested.
    CONCLUSIONS: Given the peculiar performance of the selected system, the resulting nanohydrogel is a versatile platform and display potential applications as controlled delivery systems of photosensitizer for photodynamic therapy application.
    Keywords:  Chloroaluminium phthalocyanine; gelatin; hydrogel; photodynamic therapy
    DOI:  https://doi.org/10.1016/j.pdpdt.2022.102818
  101. Photochem Photobiol Sci. 2022 Mar 24.
    Investigation on the in vitro anti-Trichophyton activity of photosensitizers.
    Ana Paula da Silva, Marciana Pierina Uliana, Francisco Eduardo Gontijo Guimarães, Kleber Thiago de Oliveira, Kate Cristina Blanco, Vanderlei Salvador Bagnato, Natalia Mayumi Inada.
      Onychomycosis is the most common disease caused by fungal nail infections, and often caused by dermatophytes. This infection is very resistant to antifungal treatments, and promising Photodynamic Therapy (PDT) mediated treatments has been presented as a multitarget tracking. Optimization of PDT guide for uptake time, concentration of photosensitizers (PS) and the light dose to inactivate Trichophyton mentagrophytes. Curcumin derivatives, porphyrin Chlorin e6 (CHL-E6) and Chlorin-P6-6-N-butylamide-7-methyl-ester (CHL-butyl) were evaluated. PS photobleaching was observed on the hyphae photosensitized over the time, correlating the PS concentration and light dose of antifungal PDT. Porphyrin, Curcumin, Chl-e6 and Chl-butyl concentrations of 2.5 µg/mL, 0.025 µg/mL, 10 µg/mL and 5 µg/mL respectively, under illumination of 10.5 J/cm2 were the best antifungal conditions found in the study. Curcumin, in low concentrations, and chlorin were the PSs with higher activity anti-T. mentagrophytes.
    Keywords:  Chlorin; Curcumin; Onychomycosis; Photodynamic therapy; Porphyrin
    DOI:  https://doi.org/10.1007/s43630-022-00205-3
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