bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2022‒02‒20
117 papers selected by
Yasmin Elkabani
Egyptian Foundation for Research and Community Development
  1. Exploiting macropinocytosis for drug delivery into KRAS mutant cancer.
  2. Advancing Cancer Treatment by Targeting Glutamine Metabolism-A Roadmap.
  3. Application of Selenium Nanoparticles in Localized Drug Targeting for Cancer Therapy.
  4. Homologous targeting nanoparticles for enhanced PDT against osteosarcoma HOS cells and the related molecular mechanisms.
  5. Nanoparticles as phytochemical carriers for cancer treatment: News of the last decade.
  6. Lotus (Nelumbo nucifera Gaertn.) and Its Bioactive Phytocompounds: A Tribute to Cancer Prevention and Intervention.
  7. Nanoparticle Phototherapy in the Era of Cancer Immunotherapy.
  8. Recent Advancements of Stimuli-Responsive Targeted Liposomal Formulations for Cancer Drug Delivery.
  9. The effects of ellagic acid and other pomegranate (Punica granatum L.) derivatives on human gastric cancer AGS cells.
  10. Mitochondrion-targeted supramolecular "nano-boat" simultaneously inhibiting dual energy metabolism for tumor selective and synergistic chemo-radiotherapy.
  11. Targeting Ferroptosis Pathways: A Novel Strategy for Cancer Therapy.
  12. Doxorubicin-loaded graphene oxide nanocomposites in cancer medicine: Stimuli-responsive carriers, co-delivery and suppressing resistance.
  13. Tumor microenvironment-responsive size-switchable drug delivery nanosystems.
  14. Autophagy Contributes to Metabolic Reprogramming and Therapeutic Resistance in Pancreatic Tumors.
  15. Combination therapy based on targeted nano drug co-delivery systems for liver fibrosis treatment: A review.
  16. Nanoparticles in Clinical Translation for Cancer Therapy.
  17. Interactions between Radiation and One-Carbon Metabolism.
  18. Drug delivery systems for cancer treatment: a review of marine-derived polysaccharides.
  19. Concomitant KRAS mutations attenuate sensitivity of non-small cell lung cancer cells to KRAS G12C inhibition.
  20. Research on the synthesis of nanoparticles of betulinic acid and their targeting antitumor activity.
  21. The Apoptosis Paradox in Cancer.
  22. Nuclear Targeted Peptide Combined With Gambogic Acid for Synergistic Treatment of Breast Cancer.
  23. Recent Progress in Understanding the Action of Natural Compounds at Novel Therapeutic Drug Targets for the Treatment of Liver Cancer.
  24. Doxorubicin-Loaded Metal-Organic Framework Nanoparticles as Acid-Activatable Hydroxyl Radical Nanogenerators for Enhanced Chemo/Chemodynamic Synergistic Therapy.
  25. Magnetic Fields and Cancer: Epidemiology, Cellular Biology, and Theranostics.
  26. Cancer as a Metabolic Disorder.
  27. Phenylethyl Isothiocyanate: A Bioactive Agent for Gastrointestinal Health.
  28. Itraconazole for Topical Treatment of Skin Carcinogenesis: Efficacy Enhancement by Lipid Nanocapsule Formulations.
  29. Promoting Apoptosis, a Promising Way to Treat Breast Cancer With Natural Products: A Comprehensive Review.
  30. Pharmacological Effects of Cisplatin Combination with Natural Products in Cancer Chemotherapy.
  31. Macropinocytic dextran facilitates KRAS-targeted delivery while reducing drug-induced tumor immunity depletion in pancreatic cancer.
  32. Fabrication, characterization and in vitro cell exposure study of zein-chitosan nanoparticles for co-delivery of curcumin and berberine.
  33. Withania somnifera (L.) Dunal: Phytochemistry, structure-activity relationship, and anticancer potential.
  34. Nano-Strategies for Enhancing the Bioavailability of Tea Polyphenols: Preparation, Applications, and Challenges.
  35. A "Weird" Mitochondrial Fatty Acid Oxidation as a Metabolic "Secret" of Cancer.
  36. Recent Advances in the Chemistry and Therapeutic Evaluation of Naturally Occurring and Synthetic Withanolides.
  37. Sonodynamic therapy: Rapid progress and new opportunities for non-invasive tumor cell killing with sound.
  38. Reactive Oxygen Species-Responsive Polyether Micelle Nanomaterials for Targeted Treatment of Ulcerative Colitis.
  39. Emerging Roles of COX7RP and Mitochondrial Oxidative Phosphorylation in Breast Cancer.
  40. Targeting cancer stem cells with antibiotics inducing mitochondrial dysfunction as an alternative anticancer therapy.
  41. Synergistic Ferroptosis-Gemcitabine Chemotherapy of the Gemcitabine Loaded Carbonaceous Nanozymes to Enhance the Treatment and Magnetic Resonance Imaging Monitoring of Pancreatic Cancer.
  42. Drug molecules bridge with small gatekeeper to co-block mesoporous silica nanoparticles for drug delivery.
  43. Advances in Management of Bladder Cancer-The Role of Photodynamic Therapy.
  44. An Overview of Epigenetics in Obesity: The Role of Lifestyle and Therapeutic Interventions.
  45. Nanoscale Drug Delivery Systems in Glioblastoma.
  46. A carrier free photodynamic oxidizer for enhanced tumor therapy by redox homeostasis disruption.
  47. Therapeutic targets of neuroprotection and neurorestoration in ischemic stroke: Applications for natural compounds from medicinal herbs.
  48. Role of Polysaccharides Mimetic Components in Targeted Cancer Treatment.
  49. Genistein encapsulated inulin-stearic acid bioconjugate nanoparticles: Formulation development, characterization and anticancer activity.
  50. ROS-Generating Amine-Functionalized Magnetic Nanoparticles Coupled with Carboxymethyl Chitosan for pH-Responsive Release of Doxorubicin.
  51. Drugging the Next Undruggable KRAS Allele-Gly12Asp.
  52. Design of Turmeric Rhizome Extract Nano-Formula for Delivery to Cancer Cells.
  53. Antioxidant, Anti-Obesity, Nutritional and Other Beneficial Effects of Different Chili Pepper: A Review.
  54. Innovating the Synergistic Assets of β-Amino Butyric Acid (BABA) and Selenium Nanoparticles (SeNPs) in Improving the Growth, Nitrogen Metabolism, Biological Activities, and Nutritive Value of Medicago interexta Sprouts.
  55. Forging Forward in Photodynamic Therapy.
  56. New insights into the discovery of drugs for triple-negative breast cancer metastasis.
  57. Mechanistic Insights of Chelator Complexes with Essential Transition Metals: Antioxidant/Pro-Oxidant Activity and Applications in Medicine.
  58. Enhanced Antibacterial Activity of Indocyanine Green-Loaded Graphene Oxide via Synergistic Contact Killing, Photothermal and Photodynamic Therapy.
  59. Co-delivery of doxorubicin and siRNA by all-trans retinoic acid conjugated chitosan-based nanocarriers for multiple synergistic antitumor efficacy.
  60. Goji Berries Supplementation in the Diet of Rabbits and Other Livestock Animals: A Mini-Review of the Current Knowledge.
  61. Targeted Delivery Methods for Anticancer Drugs.
  62. Metabolic Phenotyping in Prostate Cancer Using Multi-Omics Approaches.
  63. Self-Rectifiable and Hypoxia-Assisted Chemo-Photodynamic Nanoinhibitor for Synergistic Cancer Therapy.
  64. Jumonji-C domain-containing protein 5 suppresses proliferation and aerobic glycolysis in pancreatic cancer cells in a c-Myc-dependent manner.
  65. Nano-ultrasonic Contrast Agent for Chemoimmunotherapy of Breast Cancer by Immune Metabolism Reprogramming and Tumor Autophagy.
  66. Allium vegetables: Traditional uses, phytoconstituents, and beneficial effects in inflammation and cancer.
  67. Programmed Stimuli-Responsive Carbon Dot-Nanogel Hybrids for Imaging-Guided Enhanced Tumor Phototherapy.
  68. Indomethacin and Diclofenac Hybrids with Oleanolic Acid Oximes Modulate Key Signaling Pathways in Pancreatic Cancer Cells.
  69. Biomimetic nanoprobe-augmented triple therapy with photothermal, sonodynamic and checkpoint blockade inhibits tumor growth and metastasis.
  70. Bioactive-Based Cosmeceuticals: An Update on Emerging Trends.
  71. Curcumin in Combination with Other Adjunct Therapies for Brain Tumor Treatment: Existing Knowledge and Blueprint for Future Research.
  72. Comparative Study between Curcumin and Nanocurcumin Loaded PLGA on Colon Carcinogenesis Induced Mice.
  73. Improving Gallic Acid and Quercetin Bioavailability by Polymeric Nanoparticle Formulation.
  74. Lipid-Coated CaCO3 Nanoparticles as a Versatile pH-Responsive Drug Delivery Platform to Enable Combined Chemotherapy of Breast Cancer.
  75. Experimental Design and Optimization of Nano-Transfersomal Gel to Enhance the Hypoglycemic Activity of Silymarin.
  76. Stealth Liposomes (PEGylated) Containing an Anticancer Drug Camptothecin: In Vitro Characterization and In Vivo Pharmacokinetic and Tissue Distribution Study.
  77. Berberine-loaded liquid crystalline nanoparticles inhibit non-small cell lung cancer proliferation and migration in vitro.
  78. Breast Cancer Bone Metastasis: A Narrative Review of Emerging Targeted Drug Delivery Systems.
  79. Effect of Low-Level Laser Therapy and Sinensetin (Combination therapy) on Tumor Cells (Hela) and Normal Cells (CHO).
  80. Epigenetic Regulation of Ferroptosis-Associated Genes and Its Implication in Cancer Therapy.
  81. PDGF-BB/PDGFRβ Promotes Epithelial-Mesenchymal Transition by Affecting PI3K/AKT/mTOR-Driven Aerobic Glycolysis in Wilms' tumor G401 Cells.
  82. Ferroptosis in cancer therapy: a novel approach to reversing drug resistance.
  83. Intranasal Delivery of Functionalized Polymeric Nanomaterials to the Brain.
  84. Phytochemical Profile, Biological Properties, and Food Applications of the Medicinal Plant Syzygium cumini.
  85. Mechanistic Basis for the Role of Phytochemicals in Inflammation-Associated Chronic Diseases.
  86. A Nanocrystal Platform Based on Metal-Phenolic Network Wrapping for Drug Solubilization.
  87. Drug repurposing for cancer therapy in the era of precision medicine.
  88. Research progress of natural products for the treatment of ischemic stroke.
  89. Recent Advances in the Surface Functionalization of PLGA-Based Nanomedicines.
  90. Apoptosis Induction, a Sharp Edge of Berberine to Exert Anti-Cancer Effects, Focus on Breast, Lung, and Liver Cancer.
  91. Traditional medicine in China for ischemic stroke: bioactive components, pharmacology, and mechanisms.
  92. Prodrug based on halloysite delivery systems to improve the antitumor ability of methotrexate in leukemia cell lines.
  93. Amplification of ferroptosis with a liposomal nanoreactor cooperates with low-toxicity doxorubicin apoptosis for enhanced tumor chemotherapy.
  94. Bioinspired Multifunctional Black Phosphorus Hydrogel with Antibacterial and Antioxidant Properties: A Stepwise Countermeasure for Diabetic Skin Wound Healing.
  95. Evidence for Improved Cognitive Health with Diet: A Narrative Review.
  96. A Review of Recent Studies on the Antioxidant and Anti-Infectious Properties of Senna Plants.
  97. Natural Products from Physalis alkekengi L. var. franchetii (Mast.) Makino: A Review on Their Structural Analysis, Quality Control, Pharmacology, and Pharmacokinetics.
  98. Melatonin: Regulation of Prion Protein Phase Separation in Cancer Multidrug Resistance.
  99. Remodeling of the tumor/tumor microenvironment ecosystem during KRAS G12C inhibitor clinical resistance in lung cancer.
  100. Safety Profile of Rapamycin Perfluorocarbon Nanoparticles for Preventing Cisplatin-Induced Kidney Injury.
  101. Centella asiatica (L.) Urb. attenuates cardiac hypertrophy and improves heart function through multi-level mechanisms revealed by systems pharmacology.
  102. Introducing a Novel Chemotherapeutic Drug for the Treatment of Lung Adenocarcinoma: Silver Nanoparticles Green-formulated by Cinnamomum verum.
  103. Stimuli-Responsive Drug Delivery Systems for the Diagnosis and Therapy of Lung Cancer.
  104. Intelligent Nanomedicine Approaches Using Medical Gas-Mediated Multi-Therapeutic Modalities Against Cancer.
  105. Functionalized LbL Film for Localized Delivery of STAT3 siRNA and Oxaliplatin Combination to Treat Colon Cancer.
  106. Agro-industrial by-products: Valuable sources of bioactive compounds.
  107. The Fluorescent Effect of Withania Somnifera Chitosan Nanocomposite as an Effective Contrast Agent for Cancer Theragnostic: Experimental Study in Vitro.
  108. Safranal Prevents Liver Cancer Through Inhibiting Oxidative Stress and Alleviating Inflammation.
  109. Curcumin Loaded Nanocarriers with Varying Charges Augmented with Electroporation Designed for Colon Cancer Therapy.
  110. Multifunctional liposome for photoacoustic/ultrasound imaging-guided chemo/photothermal retinoblastoma therapy.
  111. Recent advances in developing polymeric micelles for treating cancer: breakthroughs and bottlenecks in their clinical translation.
  112. Nutritional Impact on Metabolic Homeostasis and Brain Health.
  113. Triblock Copolymer Micelles with Tunable Surface Charge as Drug Nanocarriers: Synthesis and Physico-Chemical Characterization.
  114. Syzygium jambos L. Alston: An Insight Into its Phytochemistry, Traditional Uses, and Pharmacological Properties.
  115. p53 Modulation of Autophagy Signaling in Cancer Therapies: Perspectives Mechanism and Therapeutic Targets.
  116. Western and ketogenic diets in neurological disorders: can you tell the difference?
  117. Pro-oxidant vitamin C mechanistically exploits p66Shc/Rac1GTPase pathway in inducing cytotoxicity.
  1. Theranostics. 2022 ;12(3): 1321-1332
    Exploiting macropinocytosis for drug delivery into KRAS mutant cancer.
    Huiqin Liu, Feng Qian.
      KRAS mutations are one of the most common gene mutations linked to cancer, presenting in approximately 25% of all tumors, especially pancreatic, lung, and colorectal cancers. Mutant KRAS has long been considered an undruggable target, stalling progress in direct KRAS targeting for many years, while targeted drug delivery into KRAS mutant cells utilizing their transformed metabolic behavior might present an alternative opportunity. Macropinocytosis, a nonselective, fluid-phase, endocytic route, was found to be upregulated as a metabolic feature in KRAS-driven tumors and plays a critical role in nutrient acquisition from extracellular fluids. With the observation that a variety of drug delivery systems could be internalized by KRAS mutant cancer cells through macropinocytosis, exploiting macropinocytosis for intracellular delivery of therapeutics into KRAS mutant tumor cells is emerging as a new drug delivery expedition. In this article, we summarized cancer biology studies that examined KRAS mutation-induced macropinocytosis, reviewed recent studies exploiting macropinocytosis enhancement for KRAS mutant cancer cell-selective drug delivery, and discussed the potential opportunities, challenges and pitfalls of this strategy.
    Keywords:  KRAS; Macropinocytosis; drug delivery; pancreatic cancer
    DOI:  https://doi.org/10.7150/thno.67889
  2. Cancers (Basel). 2022 Jan 22. pii: 553. [Epub ahead of print]14(3):
    Advancing Cancer Treatment by Targeting Glutamine Metabolism-A Roadmap.
    Anna Halama, Karsten Suhre.
      Tumor growth and metastasis strongly depend on adapted cell metabolism. Cancer cells adjust their metabolic program to their specific energy needs and in response to an often challenging tumor microenvironment. Glutamine metabolism is one of the metabolic pathways that can be successfully targeted in cancer treatment. The dependence of many hematological and solid tumors on glutamine is associated with mitochondrial glutaminase (GLS) activity that enables channeling of glutamine into the tricarboxylic acid (TCA) cycle, generation of ATP and NADPH, and regulation of glutathione homeostasis and reactive oxygen species (ROS). Small molecules that target glutamine metabolism through inhibition of GLS therefore simultaneously limit energy availability and increase oxidative stress. However, some cancers can reprogram their metabolism to evade this metabolic trap. Therefore, the effectiveness of treatment strategies that rely solely on glutamine inhibition is limited. In this review, we discuss the metabolic and molecular pathways that are linked to dysregulated glutamine metabolism in multiple cancer types. We further summarize and review current clinical trials of glutaminolysis inhibition in cancer patients. Finally, we put into perspective strategies that deploy a combined treatment targeting glutamine metabolism along with other molecular or metabolic pathways and discuss their potential for clinical applications.
    Keywords:  cancer; cancer treatment; drug resistance; glutamine metabolism; glutaminolysis inhibition; metabolism
    DOI:  https://doi.org/10.3390/cancers14030553
  3. Anticancer Agents Med Chem. 2022 Feb 15.
    Application of Selenium Nanoparticles in Localized Drug Targeting for Cancer Therapy.
    Dipak Nath, Loveleen Kaur, Harvinder Singh Sohal, Dharambeer Singh Malhi, Sonali Garg, Deepa Thakur.
      BACKGROUND: Selenium nanoparticles (SeNPs) have gardened their place in the biomedical field and serve as a chemotherapeutic agent for targeted drug delivery due to their capacity to exert distinct mechanisms of action on cancer and normal cells. The principle behind these mechanisms is the generation of Reactive Oxygen Species (ROS) eventually leads to apoptosis via the dysfunction of various pathways. SeNPs, when used in higher concentrations, lead to toxicity; therefore, conjugation and surface functionalization not only improve their toxic nature but also enhance their anticancer activity.OBJECTIVES: The primary goal of this analysis is to provide a thorough and systematic investigation into the use of various SeNPs in localized drug targeting for cancer therapy. This has been achieved by citing examples of numerous SeNPs and their use as a drug targeting agent for cancer therapy.
    METHODS: All relevant data and information about the various SeNPs for drug targeting in cancer therapy were gathered from various databases, including Science Direct, PubMed, Taylor and Francis imprints, American Chemical Society, Springer, Royal Society of Chemistry, and Google scholar.
    RESULTS: SeNPs are explored due to their better biopharmaceutical properties and their cytostatic behavior. Se, as an essential component of the enzyme glutathione peroxidase (GPx) and other seleno-chemical substances, might boost chemotherapeutic efficacy, and protect tissues from cellular damage caused by ROS. SeNPs have the potential to set the stage for developing new strategies to treat malignancy.
    CONCLUSION: This review extensively analyzed the anticancer efficacy and functionalization strategies of SeNPs in drug delivery to cancer cells. In addition, this review highlights the mechanism of action of drug-loaded SeNPs to suppress the proliferation of cancer cells in different cell lines.
    Keywords:  Nanoparticles; ROS; anti-cancer; apoptosis; functionalized Se-NPs; selenium nanoparticles
    DOI:  https://doi.org/10.2174/1871520622666220215122756
  4. J Nanobiotechnology. 2022 Feb 17. 20(1): 83
    Homologous targeting nanoparticles for enhanced PDT against osteosarcoma HOS cells and the related molecular mechanisms.
    Yang Wang, Liang Zhang, Guosheng Zhao, Yuan Zhang, Fangbiao Zhan, Zhiyu Chen, Tao He, Yang Cao, Lan Hao, Zhigang Wang, Zhengxue Quan, Yunsheng Ou.
      BACKGROUND: No prominent advancements in osteosarcoma (OS) treatment have been made in the past 20 years. Although photodynamic therapy (PDT) is an emerging technique for cancer therapy, the lack of targeted photosensitizers for OS treatment severely limits its applications.RESULTS: In this study, we constructed a potential theranostic nanoplatform by using (poly (lactic-co-glycolic) acid (PLGA) nanoparticles (NPs) encapsulating IR780 into the shell (PLGA-IR780 NPs), which were further camouflaged with human OS cell membranes from the HOS cell line (MH-PLGA-IR780 NPs). These constructed NPs showed the capacity for homologous targeting with excellent photoacoustic (PA)/fluorescence (FL) imaging ability. Benefitting from their homologous targeting capacity, MH-PLGA-IR780 NPs obviously promoted cell endocytosis in vitro and tumor accumulation in vivo, which could further improve PDT performance under near-infrared (NIR) irradiation. In addition, to their homologous targeting and PA/FL dual-mode imaging ability, MH-PLGA-IR780 NPs had advantages in penetrating deeper into tumor tissues and in real-time dynamic distribution monitoring in vivo, which laid a foundation for further clinical applications in OS. Moreover, we demonstrated that PDT guided by the constructed NPs could significantly induce HOS cells apoptosis and ferroptosis via excessive accumulation of reactive oxygen species (ROS), and further determined that the potential anticancer molecular mechanism of apoptosis was triggered by the release of cytochrome c-activated mitochondrial apoptosis (endogenous apoptosis), and that ferroptosis caused the activation of nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy and the inactivation of glutathione peroxidase 4 (GPX4), synergistically leading to excessive accumulation of Lipid-ROS and Lipid peroxides (LPOs). Concurrently, MH-PLGA-IR780 NPs-guided PDT also showed an obvious inhibitory effect on tumor growth in vivo.
    CONCLUSION: These results suggest that this homologous targeting-based theranostic nanoplatform provides an effective method to improve PDT performance in OS and contributes a new and promising approach for OS therapy.
    Keywords:  Apoptosis; Ferroptosis; Homologous targeting; OS; PDT
    DOI:  https://doi.org/10.1186/s12951-021-01201-y
  5. Expert Opin Drug Deliv. 2022 Feb 15.
    Nanoparticles as phytochemical carriers for cancer treatment: News of the last decade.
    Catarina Melim, Mariana Magalhães, Ana Cláudia Santos, Elisa Julião Campos, Célia Cabral.
      INTRODUCTION: The development and application of novel therapeutic medicines for the treatment of cancer are of vital importance to improve the disease's outcome and survival rate. One noteworthy treatment approach is the use of biologically active compounds present in natural products. Even though these phytocompounds present anti-inflammatory, antioxidant, and anticancer properties, their use is limited essentially due to poor systemic delivery, low bioavailability, and water solubility concerns. To make full use of the anticancer potential of natural products, these limitations need to be technologically addressed. In this sense, nanotechnology emerges as a promising drug delivery system strategy.AREAS COVERED: In this review, the benefits and potential of nanodelivery systems for natural products encapsulation as promising therapeutic approaches for cancer, which were developed during the last decade, are highlighted.
    EXPERT OPINION: The nanotechnology area has been under extensive research in the medical field given its capacity for improving the therapeutic potential of drugs by increasing their bioavailability and allowing a targeted delivery to the tumor site. Thereby, the nanoencapsulation of phytocompounds can have a direct impact on the recognized therapeutic activity of natural products towards cancer.
    Keywords:  Cancer; Drug Delivery Systems; Nanoparticles; Natural Products; Phytochemicals
    DOI:  https://doi.org/10.1080/17425247.2022.2041599
  6. Cancers (Basel). 2022 Jan 21. pii: 529. [Epub ahead of print]14(3):
    Lotus (Nelumbo nucifera Gaertn.) and Its Bioactive Phytocompounds: A Tribute to Cancer Prevention and Intervention.
    Anupam Bishayee, Palak A Patel, Priya Sharma, Shivani Thoutireddy, Niranjan Das.
      Cancer is one of the major leading causes of death worldwide. Accumulating evidence suggests a strong relationship between specific dietary habits and cancer development. In recent years, a food-based approach for cancer prevention and intervention has been gaining tremendous attention. Among diverse dietary and medicinal plants, lotus (Nelumbo nucifera Gaertn., family Nymphaeaceae), also known as Indian lotus, sacred lotus or Chinese water lily, has the ability to effectively combat this disease. Various parts of N. nucifera have been utilized as a vegetable as well as an herbal medicine for more than 2000 years in the Asian continent. The rhizome and seeds of N. nucifera represent the main edible parts. Different parts of N. nucifera have been traditionally used to manage different disorders, such as fever, inflammation, insomnia, nervous disorders, epilepsy, hypertension, cardiovascular diseases, obesity, and hyperlipidemia. It is believed that numerous bioactive components, including alkaloids, polyphenols, terpenoids, steroids, and glycosides, are responsible for its various biological and pharmacological activities, such as antioxidant, anti-inflammatory, immune-modulatory, antiviral, hepatoprotective, cardioprotective, and hypoglycemic activities. Nevertheless, there is no comprehensive review with an exclusive focus on the anticancer attributes of diverse phytochemicals from different parts of N. nucifera. In this review, we have analyzed the effects of N. nucifera extracts, fractions and pure compounds on various organ-specific cancer cells and tumor models to understand the cancer-preventive and therapeutic potential and underlying cellular and molecular mechanisms of action of this interesting medicinal and dietary plant. In addition, the bioavailability, pharmacokinetics, and possible toxicity of N. nucifera-derived phytochemicals, as well as current limitations, challenges and future research directions, are also presented.
    Keywords:  Nelumbo nucifera; cancer; molecular mechanisms; phytochemicals; prevention; therapeutic benefits
    DOI:  https://doi.org/10.3390/cancers14030529
  7. Trends Chem. 2020 Dec;2(12): 1082-1095
    Nanoparticle Phototherapy in the Era of Cancer Immunotherapy.
    Shiyi Zhou, Dandan Li, Chaebin Lee, Jin Xie.
      Phototherapy, including photodynamic therapy and photothermal therapy, exploits light to activate photo-reactions that kill cancer cells. Recent studies show that phototherapy can not only kill irradiated tumor cells, but also elicit a tumor specific immune response. This phenomenon breaks the limitations of conventional phototherapy, and has reinvigorated phototherapy-related research in the era of cancer immunotherapy. Nanoparticles play essential roles in this new campaign for allowing simultaneous delivery of photo-reactive agents and immune modulators. Some nanoparticles are potent adjuvants on their own and can augment anticancer immunity to fight off tumor relapse and metastasis. In this review, we summarize recent advances on exploiting nanoparticle-based photodynamic therapy and photothermal therapy for cancer immunotherapy, with an emphasis on nanoplatform design and functions.
    Keywords:  Nanoparticles; drug delivery; immunotherapy; photodynamic therapy; photothermal therapy
    DOI:  https://doi.org/10.1016/j.trechm.2020.09.008
  8. Pharm Nanotechnol. 2022 Feb 14.
    Recent Advancements of Stimuli-Responsive Targeted Liposomal Formulations for Cancer Drug Delivery.
    Hamad Alrbyawi, Ishwor Poudel, Manjusha Annaji, Robert D Arnold, Amit K Tiwari, R Jayachandra Babu.
      Liposomes have gained attention as a well-accepted nanocarrier for several chemotherapeutic drugs and are considered a drug delivery system of choice for a wide range of products. These amphipathic spherical vesicles primarily consist of one or more phospholipid bilayers, showing promise for drug delivery of both hydrophilic and hydrophobic components in addition to unique properties such as biocompatibility, biodegradability, low toxicity, and non-immunogenicity. Recent advances in liposomes are mainly centered on chemical and structural modification with the multifunctional approach to target the cancer cells activating the offensive mechanisms within the proximity of the tumors. Stimuli-responsive liposomes are a precisive approach to deliver and release chemotherapeutic drugs in the tumor site in a controlled fashion, thus reducing damage to normal tissues and preventing the side effects of the conventional chemotherapy regimen. The unique characteristics in the tumor microenvironment facilitate applying an endogenous stimulus (pH, redox potential, or enzymatic activity) to trigger the release of the drug, or external stimulus (heat or light) could be applied to tailor the drug release from liposomes. This review focuses on newer developments in stimuli-sensitive liposomal drug delivery systems designed to apply either exogenous (temperature, light, and magnetic field) or endogenous (pH changes, enzymatic triggers, or redox potential) approaches.
    Keywords:  Cancer; Liposomes; Nanovesicular; Stimuli-responsive; Targeted drug delivery; pH-sensitive
    DOI:  https://doi.org/10.2174/2211738510666220214102626
  9. Hum Exp Toxicol. 2022 Jan-Dec;41:41 9603271211064534
    The effects of ellagic acid and other pomegranate (Punica granatum L.) derivatives on human gastric cancer AGS cells.
    Hamid Cheshomi, Ahmad Reza Bahrami, Houshang Rafatpanah, Maryam M Matin.
      Although surgery with or without (neo)adjuvant chemo/radiotherapy, as the standard treatments, can be suitable therapeutic strategies for gastric cancer, side effects and drug resistance are two main treatment obstacles. It has been discovered that pomegranate and its natural derivatives, especially ellagic acid (EA), offer significant anti-cancer effects while causing trivial side effects. In this study, we aimed to explore the anti-cancer effects of EA on a human gastric adenocarcinoma cell line (AGS) as well as in immunocompromised mice bearing human gastric tumors, for the first time. HPLC was used for determining EA in samples. MTT assay, apoptosis and scratch assay, gelatin zymography, and quantitative RT-PCR were used to determine the anti-cancer properties of different concentrations of pomegranate fruit juice, pomegranate peel extract, and EA. Furthermore, the effects of these compounds were investigated on immunosuppressed C57BL/6 mice carrying human gastric cancer tumors. EA could inhibit the proliferation and migration of gastric cancer cells. It also had significant effects on reducing both expression and activity of MMP-2 and MMP-9. Further, it was demonstrated that with alterations in the expression of genes involved in apoptosis and inflammation including P53, BAX, APAF1, BCL2, iNOS, NF-κB, IL-8, and TNF-α, EA treatment led to increased cancer cell death and reduced inflammation. Furthermore, its use in mice bearing gastric tumors resulted in a significant reduction in tumor volume without any obvious side effects. Ellagic acid exhibited anti-cancer effects on gastric adenocarcinoma, and can be considered as a safe anti-cancer agent for further preclinical studies on this cancer.
    Keywords:  Ellagic acid; P53; Punica granatum; apoptosis; gastric cancer; inflammation
    DOI:  https://doi.org/10.1177/09603271211064534
  10. Theranostics. 2022 ;12(3): 1286-1302
    Mitochondrion-targeted supramolecular "nano-boat" simultaneously inhibiting dual energy metabolism for tumor selective and synergistic chemo-radiotherapy.
    Jie Gao, Zhilong Wang, Qingxiang Guo, Huan Tang, Zhongyan Wang, Cuihong Yang, Huirong Fan, Wenxue Zhang, Chunhua Ren, Jianfeng Liu.
      Rationale: Tumor energy metabolism has been a well-appreciated target of cancer therapy; however, the metabolism change of cancer cells between oxidative phosphorylation and glycolysis poses a challenge to the above. In this study, we constructed an innovative mitochondrion-targeted supramolecular "nano-boat" based on peptide self-assembly for tumor combined chemo-radiotherapy by simultaneously inhibiting the dual energy metabolism. Methods: A lipophilic self-assembled peptide and a positively charged cyclen were integrated to fabricate a brand new mitochondrion-targeted nano-platform for the first time. The indices of mitochondrial dysfunction including mitochondrial membrane potential, apoptosis proteins expression and ultrastructure change were evaluated using a JC-1 probe, western blotting and biological transmission electron microscopy, respectively. Energy metabolism assays were conducted on a Seahorse XF24 system by detecting the oxygen consumption rate and the glycolytic proton efflux rate. The radio-sensitization effect was investigated by colony formation, the comet assay, and γ-H2AX staining. Results: The supramolecular "nano-boat" could selectively kill cancer cells by much higher enrichment and reactive oxygen species generation than those in normal cells. In the cancer cells treated with the supramolecular "nano-boat", the dysfunctional morphological changes of the mitochondrial ultrastructure including swelling and pyknosis were evidently observed, and the endogenous mitochondrial apoptosis pathway was effectively triggered by abundant of cytochrome C leaking out. Concurrently, the dual metabolic pathways of glycolysis and oxidative phosphorylation were severely inhibited. More importantly, the supramolecular "nano-boat" displayed an excellent radio-sensitization effect with a sensitization enhancement ratio value as high as 2.58, and hence, in vivo efficiently combining radiotherapy yielded an enhanced chemo-radiotherapy effect. Conclusion: Our study demonstrated that the rationally designed peptide-based "nano-boat" could efficiently induce cancer cell apoptosis by the energy metabolism inhibition involving multiple pathways, which may provide the motivation for designing novel and universal mitochondria-targeted drug delivery systems for cancer therapy.
    Keywords:  cancer metabolism; mitochondrion-targeted; peptide self-assembly; radio-sensitization; selective killing
    DOI:  https://doi.org/10.7150/thno.67543
  11. Curr Cancer Drug Targets. 2022 Feb 11.
    Targeting Ferroptosis Pathways: A Novel Strategy for Cancer Therapy.
    Devangkumar Maru, Akhil Hothi, Chintan Bagariya, Anmol Kumar.
      Ferroptosis is an iron-dependent nonapoptotic kind of regulated cell death resulting from the destruction of redox balance in the cytosol. Unlike apoptosis, ferroptosis is caused by an increase in intracellular iron and lipid peroxides that causes significant damage to the membrane lipid bilayer and mitochondria, which leads to cell death. Increased iron level in the cell promotes ROS production. Ferroptosis inducer molecules increase ROS production and inhibit the antioxidant defence mechanism to facilitate ferroptosis in cancer cells. Inhibition of GPX4, redox-active iron availability, and lipid peroxidation are major contributors to ferroptosis. Ferroptosis is involved in many diseases like heart disease, neurodegenerative disease as well as cancer. Ferroptosis induction recently emerged as an attractive strategy for cancer therapy. In this review, we discuss the regulatory mechanism of ferroptosis, its different hallmarks, including genetic and metabolic regulators and inducers that promote ferroptosis in the cancer cells. Finally, the latest progress and development in ferroptosis research in different cancer with a focus on proposing a novel strategy in cancer therapy, are discussed.
    Keywords:  Ferroptosis; cancer; hallmarks; inducer.; redox imbalance; regulated cell death
    DOI:  https://doi.org/10.2174/1568009622666220211122745
  12. Expert Opin Drug Deliv. 2022 Feb 14.
    Doxorubicin-loaded graphene oxide nanocomposites in cancer medicine: Stimuli-responsive carriers, co-delivery and suppressing resistance.
    Milad Ashrafizadeh, Hamidreza Saebfar, Mohammad Hossein Gholami, Kiavash Hushmandi, Amirhossein Zabolian, Pooria Bikarannejad, Mehrdad Hashemi, Salman Daneshi, Sepideh Mirzaei, Esmaeel Sharifi, Alan Prem Kumar, Haroon Khan, Hamid Heydari Sheikh Hossein, Massoud Vosough, Navid Rabiee, Vijay Thakur Kumar, Pooyan Makvandi, Yogendra Kumar Mishra, Franklin R Tay, Yuzhuo Wang, Ali Zarrabi, Gorka Orive, Ebrahim Mostafavi.
      INTRODUCTION: The application of doxorubicin (DOX) in cancer therapy has been limited due to its drug resistance and poor internalization. Graphene oxide (GO) nanostructures have the capacity for DOX delivery while promoting its cytotoxicity in cancer.AREAS COVERED: The favorable characteristics of GO nanocomposites, preparation method, and application in cancer therapy are described. Then, DOX resistance in cancer is discussed. The GO-mediated photothermal therapy and DOX delivery for cancer suppression are described. Preparation of stimuli-responsive GO nanocomposites, surface functionalization, hybrid nanoparticles, and theranostic applications are emphasized in DOX chemotherapy.
    EXPERT OPINION: Graphene oxide nanoparticle-based photothermal therapy maximizes the anti-cancer activity of DOX against cancer cells. Apart from DOX delivery, GO nanomaterials are capable of loading anti-cancer agents and genetic tools to minimize drug resistance and enhance the cytolytic impact of DOX in cancer eradication. To enhance DOX accumulation in cancer cells, stimuli-responsive (redox-, light-, enzyme- and pH-sensitive) GO nanoparticles have been developed for DOX delivery. Further development of targeted delivery of DOX-loaded GO nanomaterials against cancer cells may be achieved by surface modification of polymers such as polyethylene glycol, hyaluronic acid, and chitosan. Doxorubicin-loaded GO nanoparticles have demonstrated theranostic potential for simultaneous diagnosis and therapy. Hybridization of GO with other nanocarriers such as silica and gold nanoparticles further broadens their potential anti-cancer therapy applications.
    Keywords:  anti-cancer chemotherapy; carbon nanomaterials; doxorubicin; drug resistance; graphene oxide; stimuli-responsive
    DOI:  https://doi.org/10.1080/17425247.2022.2041598
  13. Expert Opin Drug Deliv. 2022 Feb 15.
    Tumor microenvironment-responsive size-switchable drug delivery nanosystems.
    Yue Hu, Shan Gao, Abdur Rauf Khan, Xiaoye Yang, Jianbo Ji, Yanwei Xi, Guangxi Zhai.
      INTRODUCTION: Compared with ordinary chemotherapeutic drugs, the variable-size nanoparticles (NPs) have better therapeutic effects and fewer side effects.AREAS COVERED: This review mainly summarizes the strategies used to construct smart, size-tunable nanocarriers based on characteristic factors of tumor microenvironment (TME) to dramatically increase the penetration and retention of drugs within tumors.
    EXPERT OPINION: Nanosystems with changeable sizes based on the TME have been extensively studied in the past decade, and their permeability and retention have been greatly improved, making them a very promising treatment for tumors.
    Keywords:  nano-drug delivery systems; particle size; size-switchable; tumor microenvironment
    DOI:  https://doi.org/10.1080/17425247.2022.2042512
  14. Cells. 2022 Jan 26. pii: 426. [Epub ahead of print]11(3):
    Autophagy Contributes to Metabolic Reprogramming and Therapeutic Resistance in Pancreatic Tumors.
    Gabriela Reyes-Castellanos, Nadine Abdel Hadi, Alice Carrier.
      Metabolic reprogramming is a feature of cancers for which recent research has been particularly active, providing numerous insights into the mechanisms involved. It occurs across the entire cancer process, from development to resistance to therapies. Established tumors exhibit dependencies for metabolic pathways, constituting vulnerabilities that can be targeted in the clinic. This knowledge is of particular importance for cancers that are refractory to any therapeutic approach, such as Pancreatic Ductal Adenocarcinoma (PDAC). One of the metabolic pathways dysregulated in PDAC is autophagy, a survival process that feeds the tumor with recycled intracellular components, through both cell-autonomous (in tumor cells) and nonautonomous (from the local and distant environment) mechanisms. Autophagy is elevated in established PDAC tumors, contributing to aberrant proliferation and growth even in a nutrient-poor context. Critical elements link autophagy to PDAC including genetic alterations, mitochondrial metabolism, the tumor microenvironment (TME), and the immune system. Moreover, high autophagic activity in PDAC is markedly related to resistance to current therapies. In this context, combining autophagy inhibition with standard chemotherapy, and/or drugs targeting other vulnerabilities such as metabolic pathways or the immune response, is an ongoing clinical strategy for which there is still much to do through translational and multidisciplinary research.
    Keywords:  autophagy; cancer metabolism; mitochondrial metabolism; pancreatic ductal adenocarcinoma; therapeutic resistance
    DOI:  https://doi.org/10.3390/cells11030426
  15. J Drug Target. 2022 Feb 18. 1-22
    Combination therapy based on targeted nano drug co-delivery systems for liver fibrosis treatment: A review.
    Liyue Zhou, Yifan Li, Qiangwei Liang, Jinxia Liu, Yanhua Liu.
      Liver fibrosis is the hallmark of liver disease and occurs prior to the stages of cirrhosis and hepatocellular carcinoma. Any type of liver damage or inflammation can result in fibrosis. Fibrosis does not develop overnight, but rather as a result of the long-term action of injury factors. At present, however, there are no good treatment methods or specific drugs other than removing the pathogenic factors. Drug application is still limited, which means that drugs with good performance in vitro cannot achieve good therapeutic effects in vivo, owing to various factors such as poor drug targeting, large side effects, and strong hydrophobicity. Hepatic stellate cells (HSC) are the primary effector cells in liver fibrosis. The nano-drug delivery system is a new and safe drug delivery system that has many advantages which are widely used in the field of liver fibrosis. Drug resistance and side effects can be reduced when two or more drugs are used in combination drug delivery. Combination therapy of drugs with different targets has emerged as a novel approach to treating liver fibrosis, and the nano co-delivery system enhances the benefits of combination therapy. While nano co-delivery systems can maximize benefits while avoiding drug side effects, this is precisely the advantage of the nano co-delivery system. This review briefly described the pathogenesis and current treatment strategies, the different co-delivery systems of combination drugs in the nano delivery system, and targeting strategies for nano delivery systems on liver fibrosis therapy. Because of their superior performance, nano delivery systems and targeting drug delivery systems have received a lot of attention in the new drug delivery system. The new delivery systems offer a new pathway in the treatment of liver fibrosis, and it is believed that it can be a new treatment for fibrosis in the future. Nano co-delivery system of combination drugs and targeting strategies has proven the effectiveness of anti-fibrosis at the experimental level.
    Keywords:  drug co-delivery; liver fibrosis; polymeric nanoparticles; targeted therapy
    DOI:  https://doi.org/10.1080/1061186X.2022.2044485
  16. Int J Mol Sci. 2022 Feb 01. pii: 1685. [Epub ahead of print]23(3):
    Nanoparticles in Clinical Translation for Cancer Therapy.
    Deepa Mundekkad, William C Cho.
      The advent of cancer therapeutics brought a paradigm shift from conventional therapy to precision medicine. The new therapeutic modalities accomplished through the properties of nanomaterials have extended their scope in cancer therapy beyond conventional drug delivery. Nanoparticles can be channeled in cancer therapy to encapsulate active pharmaceutical ingredients and deliver them to the tumor site in a more efficient manner. This review enumerates various types of nanoparticles that have entered clinical trials for cancer treatment. The obstacles in the journey of nanodrug from clinic to market are reviewed. Furthermore, the latest developments in using nanoparticles in cancer therapy are also highlighted.
    Keywords:  cancer therapy; nanochemotherapy; nanodrugs; nanomedicine; nanoparticles
    DOI:  https://doi.org/10.3390/ijms23031685
  17. Int J Mol Sci. 2022 Feb 08. pii: 1919. [Epub ahead of print]23(3):
    Interactions between Radiation and One-Carbon Metabolism.
    Navyateja Korimerla, Daniel R Wahl.
      Metabolic reprogramming is a hallmark of cancer. Cancer cells rewire one-carbon metabolism, a central metabolic pathway, to turn nutritional inputs into essential biomolecules required for cancer cell growth and maintenance. Radiation therapy, a common cancer therapy, also interacts and alters one-carbon metabolism. This review discusses the interactions between radiation therapy, one-carbon metabolism and its component metabolic pathways.
    Keywords:  cancer therapy; folate cycle; methionine cycle; one-carbon metabolism; radiation therapy
    DOI:  https://doi.org/10.3390/ijms23031919
  18. Curr Pharm Des. 2022 Feb 11.
    Drug delivery systems for cancer treatment: a review of marine-derived polysaccharides.
    Harika Atmaca, Ferdi Oguz, Suleyman Ilhan.
      Cancer is a disease characterized by uncontrolled cell proliferation and the spread of cells to other tissues and remains one of the worldwide problems waiting to be solved. There are various treatment strategies for cancer, such as chemotherapy, surgery, radiotherapy, and immunotherapy, although it varies according to its type and stage. Many chemotherapeutic agents have limited clinical use due to lack of efficacy, off-target toxicity, metabolic instability, or poor pharmacokinetics. One possible solution to this high rate of clinical failure is to design drug delivery systems that deliver drugs in a controlled and specific manner and are not toxic to normal cells. Marine systems contain biodiversity, including components and materials that can be used in biomedical applications and therapy. Biomaterials such as chitin, chitosan, alginate, carrageenan, fucoidan, hyaluronan, agarose, and ulvan obtained from marine organisms have found use in DDSs today. These polysaccharides are biocompatible, non-toxic, biodegradable, and cost-effective, making them ideal raw materials for increasingly complex DDSs with a potentially regulated release. In this review, the contributions of polysaccharides from the marine environment to the development of anticancer drugs in DDSs will be discussed.
    Keywords:  Anti-cancer; and polysaccharides; cancer drugs; drug delivery systems; marine biomaterials; marine biotechnology
    DOI:  https://doi.org/10.2174/1381612828666220211153931
  19. Sci Rep. 2022 Feb 17. 12(1): 2699
    Concomitant KRAS mutations attenuate sensitivity of non-small cell lung cancer cells to KRAS G12C inhibition.
    Tereza Vaclova, Atanu Chakraborty, James Sherwood, Sarah Ross, Danielle Carroll, J Carl Barrett, Julian Downward, Elza C de Bruin.
      The development of covalent inhibitors against KRAS G12C represents a major milestone in treatment of RAS-driven cancers, especially in non-small cell lung cancer (NSCLC), where KRAS G12C is one of the most common oncogenic driver. Here we investigated if additional KRAS mutations co-occur with KRAS G12C (c.34G>T) in NSCLC tumours and if such mutation co-occurrence affects cellular response to G12C-specific inhibitors. Analysis of a large cohort of NSCLC patients whose tumours harboured KRAS mutations revealed co-occurring KRAS mutations in up to 8% of tumours with the KRAS c.34G>T mutation. KRAS c.35G>T was the most frequently co-occurring mutation, and could occur on the same allele (in cis) translating to a single mutant KRAS G12F protein, or on the other allele (in trans), translating to separate G12C and G12V mutant proteins. Introducing KRAS c.35G>T in trans in the KRAS G12C lung cancer model NCI-H358, as well as the co-occurrence in cis in the KRAS G12F lung cancer model NCI-H2291 led to cellular resistance to the G12C-specific inhibitor AZ'8037 due to continuing active MAPK and PI3K cascades in the presence of the inhibitor. Overall, our study provides a comprehensive assessment of co-occurring KRAS mutations in NSCLC and in vitro evidence of the negative impact of co-occurring KRAS mutations on cellular response to G12C inhibitors, highlighting the need for a comprehensive KRAS tumour genotyping for optimal patient selection for treatment with a KRAS G12C inhibitor.
    DOI:  https://doi.org/10.1038/s41598-022-06369-3
  20. J Biomed Mater Res B Appl Biomater. 2022 Feb 18.
    Research on the synthesis of nanoparticles of betulinic acid and their targeting antitumor activity.
    Xuan Chen, Shuting Lu, Fengrong Gong, Xiaoyu Sui, Tingting Liu, Ting Wang.
      Betulinic acid (BA), a natural pentacyclic lupine-type triterpene, has shown its prominent efficiency on the selective antitumor activity. However, its poor water solubility and bioavailability have limited its application. Herein, targeting nanoparticles were prepared to improve BA-based liposome (BL)'s restricted chemotherapeutic efficacy. Multi-layers membranes from the cancer cells were added as highly penetrative targeting ligands to functionalize the BA-based liposomes. In vitro experiments including the MTT assay and the fluorescence imaging of live/dead staining were adopted to prove its great inhibition in the growth of tumor cells. And it manifests that the antitumor efficacy of BL coated with cell membranes (BLCM) achieves nearly 4.3 times as that of BL under the same conditions in the MTT experiments. In addition, the fluorescence imaging stained with DAPI-FITC was applied to prove the targeting positioning effects on the BLCM. In a nutshell, the nanomedicine has good targeting antitumor efficacy and has great potential in being applied for the personalized cancer clinical treatment.
    Keywords:  antitumor; betulinic acid; cancer membrane; targeted therapy
    DOI:  https://doi.org/10.1002/jbm.b.35036
  21. Int J Mol Sci. 2022 Jan 25. pii: 1328. [Epub ahead of print]23(3):
    The Apoptosis Paradox in Cancer.
    Ornella Morana, Will Wood, Christopher D Gregory.
      Cancer growth represents a dysregulated imbalance between cell gain and cell loss, where the rate of proliferating mutant tumour cells exceeds the rate of those that die. Apoptosis, the most renowned form of programmed cell death, operates as a key physiological mechanism that limits cell population expansion, either to maintain tissue homeostasis or to remove potentially harmful cells, such as those that have sustained DNA damage. Paradoxically, high-grade cancers are generally associated with high constitutive levels of apoptosis. In cancer, cell-autonomous apoptosis constitutes a common tumour suppressor mechanism, a property which is exploited in cancer therapy. By contrast, limited apoptosis in the tumour-cell population also has the potential to promote cell survival and resistance to therapy by conditioning the tumour microenvironment (TME)-including phagocytes and viable tumour cells-and engendering pro-oncogenic effects. Notably, the constitutive apoptosis-mediated activation of cells of the innate immune system can help orchestrate a pro-oncogenic TME and may also effect evasion of cancer treatment. Here, we present an overview of the implications of cell death programmes in tumour biology, with particular focus on apoptosis as a process with "double-edged" consequences: on the one hand, being tumour suppressive through deletion of malignant or pre-malignant cells, while, on the other, being tumour progressive through stimulation of reparatory and regenerative responses in the TME.
    Keywords:  apoptosis; cancer; cancer therapy; cell death; extracellular vesicle; immune system; macrophage; regeneration; repair; tumour
    DOI:  https://doi.org/10.3390/ijms23031328
  22. Front Chem. 2021 ;9 821426
    Nuclear Targeted Peptide Combined With Gambogic Acid for Synergistic Treatment of Breast Cancer.
    Wenli Dang, Pan Guo, Xunan Song, Ying Zhang, Nan Li, Changxiang Yu, Bin Xing, Rui Liu, Xintao Jia, Qingqing Zhang, Xiaojiao Feng, Zhidong Liu.
      As a natural compound, gambogic acid (GA) emerged a shining multi-target antitumor activity in a variety of tumors. Whereas its poor solubility and non-specific effect to tumor blocked the clinical application of this drug. Herein, we reported a simple and effective strategy to construct liposome modified with nuclear targeted peptide CB5005N (VQRKRQKLMPC) via polyethylene glycol (PEG) linker to decrease the inherent limitations of GA and promote its anti-tumor activity. In this study, liposomes were prepared by thin film hydration method. The characterization of formulations contained particle size, Zeta potential, morphology and encapsulation efficiency. Further, in vitro cytotoxicity and uptake tests were investigated by 4T1 and MDA-MB-231 cells, and nuclear targeting capability was performed on MDA-MB-231 cells. In addition, the in vivo antitumor effect and biological distribution of formulations were tested in BALB/c female mice. The GA-loaded liposome modified by CB5005N showed small size, good uniformity, better targeting, higher anti-tumor efficiency, better tumor inhibition rate and lower toxicity to normal tissues than other groups. In vitro and in vivo research proved that CB5005N-GA-liposome exhibited excellent anti-tumor activity and significantly reduced toxicities. As a result, CB5005N-GA-liposome nano drug delivery system enhanced the tumor targeting and antitumor effects of GA, which provided a basis for its clinical application.
    Keywords:  anti-tumor; breast cancer; gambogic acid; liposome; nuclear targeted peptide (CB5005N)
    DOI:  https://doi.org/10.3389/fchem.2021.821426
  23. Front Oncol. 2021 ;11 795548
    Recent Progress in Understanding the Action of Natural Compounds at Novel Therapeutic Drug Targets for the Treatment of Liver Cancer.
    Yannan Zheng, Wenhui Zhang, Lin Xu, Hua Zhou, Man Yuan, Hongxi Xu.
      Liver cancer is the third most common cause of cancer-related death following lung and stomach cancers. As a highly lethal disease, liver cancer is diagnosed frequently in less developed countries. Natural compounds extracted from herbs, animals and natural materials have been adopted by traditional Chinese medicine (TCM) practices and reported to be effective in the development of new medications for the treatment of diseases. It is important to focus on the mechanisms of action of natural compounds against hepatocellular carcinoma (HCC), particularly in terms of cell cycle regulation, apoptosis induction, autophagy mediation and cell migration and invasion. In this review, we characterize novel representative natural compounds according to their pharmacologic effects based on recently published studies. The aim of this review is to summarize and explore novel therapeutic drug targets of natural compounds, which could accelerate the discovery of new anticancer drugs.
    Keywords:  HCC; liver cancer; natural compound; signaling pathway; target
    DOI:  https://doi.org/10.3389/fonc.2021.795548
  24. Materials (Basel). 2022 Jan 30. pii: 1096. [Epub ahead of print]15(3):
    Doxorubicin-Loaded Metal-Organic Framework Nanoparticles as Acid-Activatable Hydroxyl Radical Nanogenerators for Enhanced Chemo/Chemodynamic Synergistic Therapy.
    Honghui Li, Ying Zhang, Lingxia Liang, Jiaxing Song, Zixuan Wei, Shuyue Yang, Yunong Ma, Wei R Chen, Cuixia Lu, Liewei Wen.
      Doxorubicin (DOX) is a widely used first-line antitumor agent; however, acquired drug resistance and side effects have become the main challenges to effective cancer therapy. Herein, DOX is loaded into iron-rich metal-organic framework/tannic acid (TA) nanocomplex to form a tumor-targeting and acid-activatable drug delivery system (MOF/TA-DOX, MTD). Under the acidic tumor microenvironment, MTD simultaneously releases DOX and ferrous ion (Fe2+) accompanied by degradation. Apart from the chemotherapeutic effect, DOX elevates the intracellular H2O2 levels through cascade reactions, which will be beneficial to the Fenton reaction between the Fe2+ and H2O2, to persistently produce hydroxyl radicals (•OH). Thus, MTD efficiently mediates chemodynamic therapy (CDT) and remarkably enhances the sensitivity of chemotherapy. More encouragingly, the cancer cell killing efficiency of MTD is up to ~86% even at the ultralow equivalent concentration of DOX (2.26 μg/mL), while the viability of normal cells remained >88% at the same concentration of MTD. Taken together, MTD is expected to serve as drug-delivery nanoplatforms and •OH nanogenerators for improving chemo/chemodynamic synergistic therapy and reducing the toxic side effects.
    Keywords:  chemodynamic therapy; chemotherapy; doxorubicin; hydroxyl radicals; metal–organic framework
    DOI:  https://doi.org/10.3390/ma15031096
  25. Int J Mol Sci. 2022 Jan 25. pii: 1339. [Epub ahead of print]23(3):
    Magnetic Fields and Cancer: Epidemiology, Cellular Biology, and Theranostics.
    Massimo E Maffei.
      Humans are exposed to a complex mix of man-made electric and magnetic fields (MFs) at many different frequencies, at home and at work. Epidemiological studies indicate that there is a positive relationship between residential/domestic and occupational exposure to extremely low frequency electromagnetic fields and some types of cancer, although some other studies indicate no relationship. In this review, after an introduction on the MF definition and a description of natural/anthropogenic sources, the epidemiology of residential/domestic and occupational exposure to MFs and cancer is reviewed, with reference to leukemia, brain, and breast cancer. The in vivo and in vitro effects of MFs on cancer are reviewed considering both human and animal cells, with particular reference to the involvement of reactive oxygen species (ROS). MF application on cancer diagnostic and therapy (theranostic) are also reviewed by describing the use of different magnetic resonance imaging (MRI) applications for the detection of several cancers. Finally, the use of magnetic nanoparticles is described in terms of treatment of cancer by nanomedical applications for the precise delivery of anticancer drugs, nanosurgery by magnetomechanic methods, and selective killing of cancer cells by magnetic hyperthermia. The supplementary tables provide quantitative data and methodologies in epidemiological and cell biology studies. Although scientists do not generally agree that there is a cause-effect relationship between exposure to MF and cancer, MFs might not be the direct cause of cancer but may contribute to produce ROS and generate oxidative stress, which could trigger or enhance the expression of oncogenes.
    Keywords:  MRI; cancer; diagnostics; epidemiology; magnetic field; magnetic nanoparticles; nanomedicine; reactive oxygen species; theranostic; therapy
    DOI:  https://doi.org/10.3390/ijms23031339
  26. Int J Mol Sci. 2022 Jan 21. pii: 1155. [Epub ahead of print]23(3):
    Cancer as a Metabolic Disorder.
    Jones Gyamfi, Jinyoung Kim, Junjeong Choi.
      Cancer has long been considered a genetic disease characterized by a myriad of mutations that drive cancer progression. Recent accumulating evidence indicates that the dysregulated metabolism in cancer cells is more than a hallmark of cancer but may be the underlying cause of the tumor. Most of the well-characterized oncogenes or tumor suppressor genes function to sustain the altered metabolic state in cancer. Here, we review evidence supporting the altered metabolic state in cancer including key alterations in glucose, glutamine, and fatty acid metabolism. Unlike genetic alterations that do not occur in all cancer types, metabolic alterations are more common among cancer subtypes and across cancers. Recognizing cancer as a metabolic disorder could unravel key diagnostic and treatments markers that can impact approaches used in cancer management.
    Keywords:  cancer; fatty acids; glucose; glutamine; metabolism
    DOI:  https://doi.org/10.3390/ijms23031155
  27. Molecules. 2022 Jan 25. pii: 794. [Epub ahead of print]27(3):
    Phenylethyl Isothiocyanate: A Bioactive Agent for Gastrointestinal Health.
    Ezequiel R Coscueta, Ana Sofia Sousa, Celso A Reis, Maria Manuela Pintado.
      The incidence of gastrointestinal pathologies (cancer in particular) has increased progressively, with considerable morbidity and mortality, and a high economic impact on the healthcare system. The dietary intake of natural phytochemicals with certain bioactive properties has shown therapeutic and preventive effects on these pathologies. This includes the cruciferous vegetable derivative phenylethyl isothiocyanate (PEITC), a bioactive compound present in some vegetables, such as watercress. Notably, PEITC has antioxidant, anti-inflammatory, bactericidal, and anticarcinogenic properties. This review summarized the current knowledge on the role of PEITC as a potential natural nutraceutical or an adjuvant against oxidative/inflammatory-related disorders in the gastrointestinal tract. We also discussed the safe and recommended dose of PEITC. In addition, we established a framework to guide the research and development of sustainable methodologies for obtaining and stabilizing this natural molecule for industrial use. With PEITC, there is great potential to develop a viable strategy for preventing cancer and other associated diseases of the gastrointestinal tract. However, this topic still needs more scientific studies to help develop new PEITC products for the nutraceutical, pharmaceutical, or food industries.
    Keywords:  gastrointestinal health; natural anti-cancer; natural anti-inflammatory; natural antioxidant; nutraceutical; watercress
    DOI:  https://doi.org/10.3390/molecules27030794
  28. J Biomed Nanotechnol. 2022 Jan 01. 18(1): 97-111
    Itraconazole for Topical Treatment of Skin Carcinogenesis: Efficacy Enhancement by Lipid Nanocapsule Formulations.
    Nabila A El-Sheridy, Riham M El-Moslemany, Alyaa A Ramadan, Maged W Helmy, Labiba K El-Khordagui.
      Itraconazole (ITC), an antifungal drug with anticancer activity, shows potential for oral treatment of skin cancer. There is clinical need for topical ITC for treating low-risk skin carcinogenesis. Our objective was to develop ITC nanoformulations with enhanced anticancer efficacy. Lipid nanocapsules (LNC), either unmodified (ITC/LNC) or modified with the amphiphiles miltefosine (ITC/MF-LNC) or the lipopeptide biosurfactant surfactin (ITC/SF-LNC) as bioactive additives were developed. LNC formulations showed high ITC entrapment efficiency (>98%), small diameter (42-45 nm) and sustained ITC release. Cytotoxicity studies using malignant SCC 9 cells and normal human fibroblasts (NHF) demonstrated significant enhancement of ITC anticancer activity and selectivity for cancer cells by the LNC formulations and a synergistic ITC-amphiphile interaction improving the combination performance. Treatment of intradermal tumor-bearing mice with the ITC nanoformulation gels compared with ITC and 5-FU gels achieved significant tumor growth inhibition that was remarkably enhanced by ITC/MF-LNC and ITC/SF-LNC as well as recovery of skin architecture. Molecularly, tumoral expression of Ki-67 and cytokeratin proliferative proteins was significantly suppressed by LNC formulations, the suppressive effect on cytokeratins was superior to that of 5-FU. These findings provide new evidence for effective topical treatment of low-risk skin carcinogenesis utilizing multiple approaches that involve drug repurposing, nanotechnology, and bioactive amphiphiles as formulation enhancing additives.
    DOI:  https://doi.org/10.1166/jbn.2022.3217
  29. Front Pharmacol. 2021 ;12 801662
    Promoting Apoptosis, a Promising Way to Treat Breast Cancer With Natural Products: A Comprehensive Review.
    Lie Yuan, Yongqing Cai, Liang Zhang, Sijia Liu, Pan Li, Xiaoli Li.
      Breast cancer is one of the top-ranked malignant carcinomas associated with morbidity and mortality in women worldwide. Chemotherapy is one of the main approaches to breast cancer treatment. Breast cancer initially responds to traditional first- and second-line drugs (aromatase inhibitor, tamoxifen, and carboplatin), but eventually acquires resistance, and certain patients relapse within 5 years. Chemotherapeutic drugs also have obvious toxic effects. In recent years, natural products have been widely used in breast cancer research because of their low side effects, low toxicity, and good efficacy based on their multitarget therapy. Apoptosis, a programmed cell death, occurs as a normal and controlled process that promotes cell growth and death. Inducing apoptosis is an important strategy to control excessive breast cancer cell proliferation. Accumulating evidence has revealed that natural products become increasingly important in breast cancer treatment by suppressing cell apoptosis. In this study, we reviewed current studies on natural product-induced breast cancer cell apoptosis and summarized the proapoptosis mechanisms including mitochondrial, FasL/Fas, PI3K/AKT, reactive oxygen species, and mitogen-activated protein kinase-mediated pathway. We hope that our review can provide direction in the search for candidate drugs derived from natural products to treat breast cancer by promoting cell apoptosis.
    Keywords:  apoptosis; breast cancer; mechanism; monomer; natural products
    DOI:  https://doi.org/10.3389/fphar.2021.801662
  30. Int J Mol Sci. 2022 Jan 28. pii: 1532. [Epub ahead of print]23(3):
    Pharmacological Effects of Cisplatin Combination with Natural Products in Cancer Chemotherapy.
    Shaloam Dasari, Sylvianne Njiki, Ariane Mbemi, Clement G Yedjou, Paul B Tchounwou.
      Cisplatin and other platinum-based drugs, such as carboplatin, ormaplatin, and oxaliplatin, have been widely used to treat a multitude of human cancers. However, a considerable proportion of patients often relapse due to drug resistance and/or toxicity to multiple organs including the liver, kidneys, gastrointestinal tract, and the cardiovascular, hematologic, and nervous systems. In this study, we sought to provide a comprehensive review of the current state of the science highlighting the use of cisplatin in cancer therapy, with a special emphasis on its molecular mechanisms of action, and treatment modalities including the combination therapy with natural products. Hence, we searched the literature using various scientific databases., such as MEDLINE, PubMed, Google Scholar, and relevant sources, to collect and review relevant publications on cisplatin, natural products, combination therapy, uses in cancer treatment, modes of action, and therapeutic strategies. Our search results revealed that new strategic approaches for cancer treatment, including the combination therapy of cisplatin and natural products, have been evaluated with some degree of success. Scientific evidence from both in vitro and in vivo studies demonstrates that many medicinal plants contain bioactive compounds that are promising candidates for the treatment of human diseases, and therefore represent an excellent source for drug discovery. In preclinical studies, it has been demonstrated that natural products not only enhance the therapeutic activity of cisplatin but also attenuate its chemotherapy-induced toxicity. Many experimental studies have also reported that natural products exert their therapeutic action by triggering apoptosis through modulation of mitogen-activated protein kinase (MAPK) and p53 signal transduction pathways and enhancement of cisplatin chemosensitivity. Furthermore, natural products protect against cisplatin-induced organ toxicity by modulating several gene transcription factors and inducing cell death through apoptosis and/or necrosis. In addition, formulations of cisplatin with polymeric, lipid, inorganic, and carbon-based nano-drug delivery systems have been found to delay drug release, prolong half-life, and reduce systemic toxicity while other formulations, such as nanocapsules, nanogels, and hydrogels, have been reported to enhance cell penetration, target cancer cells, and inhibit tumor progression.
    Keywords:  cancer treatment; cisplatin; combination therapy; modes of action; natural products
    DOI:  https://doi.org/10.3390/ijms23031532
  31. Theranostics. 2022 ;12(3): 1061-1073
    Macropinocytic dextran facilitates KRAS-targeted delivery while reducing drug-induced tumor immunity depletion in pancreatic cancer.
    Fang Yuan, Mengnan Sun, Zhengsheng Liu, Huiqin Liu, Weijian Kong, Rui Wang, Feng Qian.
      Background: Pancreatic cancer comprises not only cancer cells but also a collection of cross-talking noncancerous cells within tumor. Therefore, selective delivery of cytotoxic agents towards cancer cells and limiting the collateral damage to tumor suppressive benign cells, such as effector lymphocytes in the tumor microenvironment, is of great value. Methods: Pancreatic cancer cells harbor oncogenic KRAS which induces a constitutively high level of macropinocytosis. Inspired by such uniquity, we sought to explore the targeting potential of dextran, a biomaterial presumed to be endocytosed in the macropinocytosis dependent manner. Cell entry preference, mechanism and subcellular sorting of dextran with different molecular weights were firstly examined. Triptolide (TP), a potent cytotoxin was then set as the model payload for dextran conjugation. KRAS selectivity and the therapeutic effects of dextran-conjugated TP were investigated via both in vitro cellular studies and in vivo tumor model assessment. Results: Dextran, with a specific molecular weight of 70 kDa rather than other weights, was identified as a robust KRAS-responsive intracellular delivery carrier with enhanced entry upon KRAS mutation. The 70 kDa dextran-conjugated TP (DEX-TP) displayed greater efficacy and cellular deposition efficiency towards KRAS mutant cells than KRAS wild-type cells. Treatment with DEX-TP suppressed tumor progression in KRAS mutant pancreatic cancer orthotopic mouse models with reduced toxicity and significantly extended mouse survival time. Furthermore, the conjugate attained a more favorable therapeutic outcome in the tumor immune microenvironment than the free drug, preserving the fraction of T cells and their effector cytokines. Conclusions: In summary, macropinocytic dextran was able to provide drug delivery selectivity towards KRAS mutant cancer cells and reduce tumor immunity depletion caused by the cytotoxic drug in pancreatic cancer.
    Keywords:  KRAS mutation; Pancreatic cancer; dextran; targeted drug delivery; tumor microenvironment
    DOI:  https://doi.org/10.7150/thno.65299
  32. Int J Biol Macromol. 2022 Feb 11. pii: S0141-8130(22)00277-X. [Epub ahead of print]204 576-586
    Fabrication, characterization and in vitro cell exposure study of zein-chitosan nanoparticles for co-delivery of curcumin and berberine.
    Niloofar Ghobadi-Oghaz, Ahmad Asoodeh, Marzieh Mohammadi.
      For the first time, we synthesized the co-delivery nanopolymers using zein protein as the core and chitosan polysaccharide as the shell to deliver curcumin (Cur) and berberine (Ber) in MDA-MB-231 breast cancer cells. It has been shown that Cur and Ber altogether have synergistic effects on multiple cancers. Herein, the curcumin-zein-berberine-chitosan (Cur-Z-Ber-Ch) nanoparticles were fabricated and their organization procedure was reported. Physicochemical properties of synthesized nanoparticles were determined by Fourier transform infrared (FTIR) spectroscopy, XRD and fluorescence spectroscopy analyses. The nanoparticles included relatively small particles (d = 168.24 nm) with +36.76 mV zeta potential. The resulting nanoparticles had high entrapment efficiency (about 75%) for Cur and 60% for Ber. The Cur-Z-Ber-Ch nanoparticles represented ideal redispersibility and storage stability after 4 months. Drug release of the freeze-dried nanoparticles had pH-sensitive characteristic. In vitro cytoxicity assay demonstrated that Cur-Z-Ber-Ch nanoparticles induced elevated cytotoxic effect in MDA-MB-231 and A549 cancer cells. In vitro studies in MDA-MB-231 cells demonstrated that the Cur-Z-Ber-Ch nanoparticles could successfully increase cellular uptake and apoptosis with significant inhibition of IL-8 pro-inflammatory cytokines in comparison to the free Cur + Ber bioactive molecules. These bio-nanoparticles are the co-delivery vehicle for Cur and Ber which could be beneficial for participating them into pharmaceutical products.
    Keywords:  Curcumin-berberine; Nanoparticle; Zein-chitosan
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.02.041
  33. Phytomedicine. 2022 Jan 19. pii: S0944-7113(22)00027-7. [Epub ahead of print]98 153949
    Withania somnifera (L.) Dunal: Phytochemistry, structure-activity relationship, and anticancer potential.
    Devesh Tewari, Vikas Chander, Archana Dhyani, Sanjeev Sahu, Pawan Gupta, Pooja Patni, Lindsay S Kalick, Anupam Bishayee.
      BACKGROUND: Ayurveda is a highly recognized, well-documented, and well-accepted traditional medicine system. This system utilizes many natural products in various forms for therapeutic purposes. Thousands of plants mentioned in the Ayurvedic system are useful in disease mitigation and health preservation. One potential plant of the Ayurvedic system is "Ashwagandha" [Withania somnifera (L.) Dunal], commonly regarded as Indian Ginseng. It possesses various therapeutic activities, such as neuroprotective, hypoglycemic, hepatoprotective, antiarthritic, and anticancer effects.PURPOSE: Here we present a comprehensive insight on the anticancer effects of W. somnifera and mechanistic attributes of its bioactive phytocompounds. This review also provides updated information on the clinical studies pertaining to cancer, safety evaluation and opportunities for chemical modifications of withanolides, a group of specialized phytochemicals of W. somnifera.
    METHODS: The present study was performed in accordance with the guidelines of the Preferred Reporting Items for Systemic Reviews and Meta-Analysis. Various scientific databases, such as PubMed, Science Direct, Scopus, Google Scholar, were explored for related studies published up to May 2021.
    RESULTS: An updated review on the anticancer potential and mechanisms of action of the major bioactive components of W. somnifera, including withanolides, withaferin A and withanone, is presented. Comprehensive information on clinical attributes of W. somnifera and its active components are presented with the structure-activity relationship (SAR) and toxicity evaluation.
    CONCLUSION: The outcome of the work clearly indicates that W. somnifera has a significant potential for cancer therapy. The SAR revealed that various withanolides in general and withaferin A in particular have binding energies against various proteins and tremendous potential to serve as the lead for new chemical entities. Nevertheless, additional studies, particularly well-designed clinical trials are required before therapeutic application of withanolides for cancer treatment.
    Keywords:  Cancer; Indian ginseng; Molecular targets; Therapy; Withaferin A; Withania somnifera; Withanolides
    DOI:  https://doi.org/10.1016/j.phymed.2022.153949
  34. Foods. 2022 Jan 29. pii: 387. [Epub ahead of print]11(3):
    Nano-Strategies for Enhancing the Bioavailability of Tea Polyphenols: Preparation, Applications, and Challenges.
    Li Niu, Ziqiang Li, Wei Fan, Xiaohong Zhong, Miao Peng, Zhonghua Liu.
      Tea polyphenols (TPs) are among the most abundant functional compounds in tea. They exhibit strong antioxidant, anti-inflammatory, and anti-cancer effects. However, their instability and low bioavailability limits their applications. Nanotechnology, which involves the use of nanoscale substances (sizes ranging from 1 to 100 nm) to improve the properties of substances, provides a solution for enhancing the stability and bioavailability of TPs. We reviewed the preparation, performance, effects, and applications of different types of TPs nanocarriers. First, we introduced the preparation of different nanocarriers, including nanoparticles, nanoemulsions, nanomicelles, and nanolipids. Then, we discussed various applications of tea polyphenol-loaded nanocarriers in functional ingredient delivery, food quality improvement, and active food packaging. Finally, the challenges and future development directions of TPs nanocarriers were elucidated. In conclusion, a nano-strategy may be the "key" to break the application barriers of TPs. Therefore, the use of nano-strategies for the safe, stable, and efficient release of TPs is the direction of future research.
    Keywords:  catechin; epigallocatechin gallate; nanoemulsions; nanolipids; nanomicelles; nanoparticles; tea polyphenols
    DOI:  https://doi.org/10.3390/foods11030387
  35. Oxid Med Cell Longev. 2022 ;2022 2339584
    A "Weird" Mitochondrial Fatty Acid Oxidation as a Metabolic "Secret" of Cancer.
    Zhivko Zhelev, Ichio Aoki, Dessislava Lazarova, Tatyana Vlaykova, Tatsuya Higashi, Rumiana Bakalova.
      Cancer metabolism is an extensively studied field since the discovery of the Warburg effect about 100 years ago and continues to be increasingly intriguing and enigmatic so far. It has become clear that glycolysis is not the only abnormally activated metabolic pathway in the cancer cells, but the same is true for the fatty acid synthesis (FAS) and mevalonate pathway. In the last decade, a lot of data have been accumulated on the pronounced mitochondrial fatty acid oxidation (mFAO) in many types of cancer cells. In this article, we discuss how mFAO can escape normal regulation under certain conditions and be overactivated. Such abnormal activation of mitochondrial β-oxidation can also be combined with mutations in certain enzymes of the Krebs cycle that are common in cancer. If overactivated β-oxidation is combined with other common cancer conditions, such as dysfunctions in the electron transport complexes, and/or hypoxia, this may alter the redox state of the mitochondrial matrix. We propose the idea that the altered mitochondrial redox state and/or inhibited Krebs cycle at certain segments may link mitochondrial β-oxidation to the citrate-malate shuttle instead to the Krebs cycle. We call this abnormal metabolic condition "β-oxidation shuttle". It is unconventional mFAO, a separate metabolic pathway, unexplored so far as a source of energy, as well as a source of cataplerosis, leading to biomass accumulation, accelerated oxygen consumption, and ultimately a source of proliferation. It is inefficient as an energy source and must consume significantly more oxygen per mole of ATP produced when combined with acetyl-CoA consuming pathways, such as the FAS and mevalonate pathway.
    DOI:  https://doi.org/10.1155/2022/2339584
  36. Molecules. 2022 Jan 28. pii: 886. [Epub ahead of print]27(3):
    Recent Advances in the Chemistry and Therapeutic Evaluation of Naturally Occurring and Synthetic Withanolides.
    Amandeep Singh, Asif Raza, Shantu Amin, Chendil Damodaran, Arun K Sharma.
      Natural products are a major source of biologically active compounds that make promising lead molecules for developing efficacious drug-like molecules. Natural withanolides are found in many flora and fauna, including plants, algae, and corals, that traditionally have shown multiple health benefits and are known for their anti-cancer, anti-inflammatory, anti-bacterial, anti-leishmaniasis, and many other medicinal properties. Structures of these withanolides possess a few reactive sites that can be exploited to design and synthesize more potent and safe analogs. In this review, we discuss the literature evidence related to the medicinal implications, particularly anticancer properties of natural withanolides and their synthetic analogs, and provide perspectives on the translational potential of these promising compounds.
    Keywords:  anti-bacterial; anti-inflammatory; anti-leishmaniasis; anticancer; withaferin A; withanolides
    DOI:  https://doi.org/10.3390/molecules27030886
  37. Cancer Lett. 2022 Feb 11. pii: S0304-3835(22)00067-2. [Epub ahead of print]532 215592
    Sonodynamic therapy: Rapid progress and new opportunities for non-invasive tumor cell killing with sound.
    Katherine M Nowak, Mark R Schwartz, Victoria R Breza, Richard J Price.
      Solid tumor treatment relies heavily upon chemotherapies, radiation, surgical resection, and/or immunotherapies. Although many alternative non-invasive solid tumor therapies have been proposed through the years and continue to be tested in various contexts, tumor cell eradication remains a daunting task for the current cancer armamentarium. Indeed, solid tumors exhibit physically and biochemically heterogenous microenvironments, allowing them to easily acquire resistance mechanisms. Progress in sonodynamic therapy (SDT), a treatment modality capable of controlling tumor growth while limiting off-target effects and toxicities, has accelerated in recent years. SDT combines "sonosensitizing" agents with the non-invasive application of focused acoustic energy [i.e. focused ultrasound (FUS)] to drive highly localized formation of tumor cell-killing reactive oxygen species (ROS). Sonosensitizers selectively accumulate in tumor cells, after which FUS radiation eliminates the tumor by forcing the tumor cells to undergo cell death. In this article, we comprehensively review recent studies wherein SDT has been applied to treat primary and metastatic tumors. We discuss sonosensitizers, combination therapies with SDT, developments in defining the mechanism of SDT-induced cell cytotoxicity, and the promise SDT offers as a modulator of anti-tumor immunity.
    Keywords:  Focused ultrasound; Immunogenic cell death; Immunotherapy; Photodynamic therapy; Sonosensitizers
    DOI:  https://doi.org/10.1016/j.canlet.2022.215592
  38. J Biomed Nanotechnol. 2022 Jan 01. 18(1): 120-131
    Reactive Oxygen Species-Responsive Polyether Micelle Nanomaterials for Targeted Treatment of Ulcerative Colitis.
    Xin-Xin Zhao, Shan-Bo Ma, Jin-Peng Wen, Da-Tao Hu, Ju-Shan Gao, Qiao Peng, Yu-Chen Zhang, Jin-Qing Wang, Ke Wang, Xiao-Peng Shi.
      As one of the most challenging inflammatory diseases, the incidence of ulcerative colitis (UC) is increasing year by year, but the existing therapeutic drugs are not effective and lack of targeting. Nanomaterials are expected to become promising delivery system due to their good targeting effects. Here, we designed a nanomaterial sensitive to reactive oxygen species, which can be used to treat IBD, especially UC. It is a self-assembled polyether micelle that can be oxidized at the inflammation site where the concentration of reactive oxygen increases, and effectively release the encapsulated budesonide (Bud). Experiments have proved that for DSS-induced colitis, the synthetic drug-loaded nanoparticles have excellent therapeutic effects, can effectively repair intestinal barrier, and significantly improve the damaged colon tissue. At the same time, it has a beneficial regulatory effect on inflammatory factors. Molecular mechanism studies have shown that it achieves its therapeutic effects by activating the peroxisome proliferators-activated receptors-γ (PPAR-γ) pathway and inhibiting the nuclear factor (NF)-κB pathway. This study proves that oral nano-micelles have an important impact on improving the efficacy of UC treatment drugs and have far-reaching significance for the targeted treatment of gastrointestinal diseases.
    DOI:  https://doi.org/10.1166/jbn.2022.3233
  39. Front Cell Dev Biol. 2022 ;10 717881
    Emerging Roles of COX7RP and Mitochondrial Oxidative Phosphorylation in Breast Cancer.
    Shuhei Kamada, Toshihiko Takeiwa, Kazuhiro Ikeda, Kuniko Horie, Satoshi Inoue.
      Metabolic alterations are critical events in cancers, which often contribute to tumor pathophysiology. While aerobic glycolysis is a known characteristic of cancer-related metabolism, recent studies have shed light on mitochondria-related metabolic pathways in cancer biology, including oxidative phosphorylation (OXPHOS), amino acid and lipid metabolism, nucleic acid metabolism, and redox regulation. Breast cancer is the most common cancer in women; thus, elucidation of breast cancer-related metabolic alteration will help to develop cancer drugs for many patients. We here aim to define the contribution of mitochondrial metabolism to breast cancer biology. The relevance of OXPHOS in breast cancer has been recently defined by the discovery of COX7RP, which promotes mitochondrial respiratory supercomplex assembly and glutamine metabolism: the latter is also shown to promote nucleic acid and fatty acid biosynthesis as well as ROS defense regulation. In this context, the estrogen-related receptor (ERR) family nuclear receptors and collaborating coactivators peroxisome proliferator-activated receptor-γ coactivator-1 (PGC-1) are essential transcriptional regulators for both energy production and cancer-related metabolism. Summarizing recent findings of mitochondrial metabolism in breast cancer, this review will aim to provide a clue for the development of alternative clinical management by modulating the activities of responsible molecules involved in disease-specific metabolic alterations.
    Keywords:  ERR; OxPhos; breast cancer; metabolism; mitochondria
    DOI:  https://doi.org/10.3389/fcell.2022.717881
  40. Biochem Pharmacol. 2022 Feb 15. pii: S0006-2952(22)00060-0. [Epub ahead of print] 114966
    Targeting cancer stem cells with antibiotics inducing mitochondrial dysfunction as an alternative anticancer therapy.
    Igor Karp, Alex Lyakhovich.
      Traditional cancer treatments based on chemo- and/or radiotherapy effectively kill only differentiated cancer cells, while metastasis and recurrences are caused by surviving cancer resistant cells (CRC) or a special subpopulation of cancer cells known as cancer stem cells (CSC). Both of these cell types compromise anticancer treatment through various mechanisms, including withdrawal of the anticancer drug through ATP-binding cassette transporters, increased expression of DNA repair genes, or transition to a quiescent phenotype. In contrast to many cancers, where energy consumption is due to glycolysis (Warburg effect), the bioenergetics of CSC and CRC is most often related to oxidative phosphorylation, that is, dependent on mitochondrial function. Therefore, compounds that induce mitochondrial dysfunction (MDF), such as some antibiotics, may represent an alternative approach to anticancer therapy. This review summarizes the major recent works on the use of antibiotics to target tumors via CSC and suggests next steps for developing this approach.
    Keywords:  OXPHOS; antibiotics; anticancer therapy; cancer resistance; cancer stem cells; mitochondrial dysfunction
    DOI:  https://doi.org/10.1016/j.bcp.2022.114966
  41. Acta Biomater. 2022 Feb 10. pii: S1742-7061(22)00082-4. [Epub ahead of print]
    Synergistic Ferroptosis-Gemcitabine Chemotherapy of the Gemcitabine Loaded Carbonaceous Nanozymes to Enhance the Treatment and Magnetic Resonance Imaging Monitoring of Pancreatic Cancer.
    Gaorui Zhang, Nianlu Li, Yafei Qi, Quanqin Zhao, Jinhua Zhan, Dexin Yu.
      Pancreatic adenocarcinoma (PDAC) is one of the deadliest cancers, and it is resistant to most conventional antineoplastic therapies. To address this challenge, gemcitabine (Gem)-loaded carbonaceous nanoparticles (MFC-Gem) as nanozymes and a theranostic platform were fabricated and used for MR-guided ferroptosis-chemo synergetic therapy of PDAC. As a biocompatible carrier, MFC-Gem nanoparticles are regarded as peroxidase-like and glutathione peroxidase-like nanozymes that promote ferroptosis therapy by effectively generating ROS and consuming GSH. Meanwhile, the combination of MnFe2O4 and Gem can markedly enhance synergetic therapy by both ferroptosis and Gem chemotherapy. MFC-Gem has higher magnetic susceptibility and was used for simultaneous magnetic resonance imaging (MRI) monitoring of the PDAC treatment. In conclusion, these salient features unequivocally indicate that this biocompatible nanotheranostic system has cooperative and enhancing chemotherapy effects for anti-PDAC therapy with simultaneous MRI monitoring. STATEMENT OF SIGNIFICANCE: Pancreatic adenocarcinoma (PDAC) is one of the deadliest cancers, and it is resistant to most conventional antineoplastic therapies. To address this challenge, gemcitabine (Gem)-loaded carbonaceous nanoparticles (MFC-Gem) as nanozymes and a theranostic platform were fabricated and used for MR-guided ferroptosis-chemo synergetic therapy of PDAC. i) MFC nanoparticles are regarded as peroxidase-like and glutathione peroxidase-like nanozymes that enhance ferroptosis therapy by effectively generating ROS and consuming GSH. ii) The combination of MnFe2O4 and Gem can markedly enhance synergetic therapy by both ferroptosis and Gem chemotherapy. iii) MFC-Gem has higher magnetic susceptibility and was used for simultaneous magnetic resonance imaging (MRI) monitoring of the PDAC treatment.
    Keywords:  Ferroptosis; Magnetic resonance imaging; Pancreatic cancer; Synergetic therapy; Theranostics
    DOI:  https://doi.org/10.1016/j.actbio.2022.02.006
  42. Colloids Surf B Biointerfaces. 2022 Jan 21. pii: S0927-7765(22)00033-9. [Epub ahead of print]213 112350
    Drug molecules bridge with small gatekeeper to co-block mesoporous silica nanoparticles for drug delivery.
    Rui Li, Cong Feng, Runqian Yang, Xiangfeng Li, Liping Ruan.
      In this study, a filter-like blocking system based on MSN with small gatekeeper 5- mercapto-2 nitrobenzoic acid (MNBA) has developed. The MNBA grafted nanoparticle MSN-SS-MNBA shows excellent blocking performance with negligible leakage when loaded with doxorubicin (DOX), and the release profiles illustrate stimuli-responsive property when triggered by GSH. Viability experiments indicate that MSN-SS-MNBA has obvious inhibition for both Hela cells and HCT116 cells, while showing good biocompatibility for L929 cells, which suggests that the modified MNBA has a synergistic effect on cancer cells-killing. Since the small grafted molecule MNBA cannot block the channels of MSN via self-assembly, a filter-like blocking model that the loaded drug bridged with modified MNBA to fulfill the blocking process is proposed. The novel blocking strategy provides a new possible way for pore blocking, and the small nanovalve can be used as synergistic molecule for cancer therapy.
    Keywords:  Bridge; Drug delivery; GSH responsive; Mesoporous silica nanoparticles; Synergistic effect
    DOI:  https://doi.org/10.1016/j.colsurfb.2022.112350
  43. Molecules. 2022 Jan 23. pii: 731. [Epub ahead of print]27(3):
    Advances in Management of Bladder Cancer-The Role of Photodynamic Therapy.
    Tomasz Kubrak, Michał Karakuła, Marcin Czop, Aleksandra Kawczyk-Krupka, David Aebisher.
      Photodynamic therapy (PDT) is a non-invasive and modern form of therapy. It is used in the treatment of non-oncological diseases and more and more often in the treatment of various types of neoplasms in various locations including bladder cancer. The PDT method consists of local or systemic application of a photosensitizer, i.e., a photosensitive compound that accumulates in pathological tissue. Light of appropriate wavelength is absorbed by the photosensitizer molecules, which in turn transfers energy to oxygen or initiates radical processes that leads to selective destruction of diseased cells. The technique enables the selective destruction of malignant cells, as the photocytotoxicity reactions induced by the photosensitizer take place strictly within the pathological tissue. PDT is known to be well tolerated in a clinical setting in patients. In cited papers herein no new safety issues were identified. The development of anti-cancer PDT therapies has greatly accelerated over the last decade. There was no evidence of increased or cumulative toxic effects with each PDT treatment. Many modifications have been made to enhance the effects. Clinically, bladder cancer remains one of the deadliest urological diseases of the urinary system. The subject of this review is the anti-cancer use of PDT, its benefits and possible modifications that may lead to more effective treatments for bladder cancer. Bladder cancer, if localized, would seem to be a good candidate for PDT therapy since this does not involve the toxicity of systemic chemotherapy and can spare normal tissues from damage if properly carried out. It is clear that PDT deserves more investment in clinical research, especially for plant-based photosensitizers. Natural PS isolated from plants and other biological sources can be considered a green approach to PDT in cancer therapy. Currently, PDT is widely used in the treatment of skin cancer, but numerous studies show the advantages of related therapeutic strategies that can help eliminate various types of cancer, including bladder cancer. PDT for bladder cancer in which photosensitizer is locally activated and generates cytotoxic reactive oxygen species and causing cell death, is a modern treatment. Moreover, PDT is an innovative technique in oncologic urology.
    Keywords:  PDT; bladder cancer; cancers; diagnosis; photodynamic therapy
    DOI:  https://doi.org/10.3390/molecules27030731
  44. Int J Mol Sci. 2022 Jan 25. pii: 1341. [Epub ahead of print]23(3):
    An Overview of Epigenetics in Obesity: The Role of Lifestyle and Therapeutic Interventions.
    Abeer M Mahmoud.
      Obesity has become a global epidemic that has a negative impact on population health and the economy of nations. Genetic predispositions have been demonstrated to have a substantial role in the unbalanced energy metabolism seen in obesity. However, these genetic variations cannot entirely explain the massive growth in obesity over the last few decades. Accumulating evidence suggests that modern lifestyle characteristics such as the intake of energy-dense foods, adopting sedentary behavior, or exposure to environmental factors such as industrial endocrine disruptors all contribute to the rising obesity epidemic. Recent advances in the study of DNA and its alterations have considerably increased our understanding of the function of epigenetics in regulating energy metabolism and expenditure in obesity and metabolic diseases. These epigenetic modifications influence how DNA is transcribed without altering its sequence. They are dynamic, reflecting the interplay between the body and its surroundings. Notably, these epigenetic changes are reversible, making them appealing targets for therapeutic and corrective interventions. In this review, I discuss how these epigenetic modifications contribute to the disordered energy metabolism in obesity and to what degree lifestyle and weight reduction strategies and pharmacological drugs can restore energy balance by restoring normal epigenetic profiles.
    Keywords:  DNA methylation; diet; energy metabolism; epigenetics; histone modifications; lifestyle; microRNAs; obesity; physical activity; weight loss
    DOI:  https://doi.org/10.3390/ijms23031341
  45. Nanoscale Res Lett. 2022 Feb 16. 17(1): 27
    Nanoscale Drug Delivery Systems in Glioblastoma.
    Zihao Liu, Xiaoshuai Ji, Dong He, Rui Zhang, Qian Liu, Tao Xin.
      Glioblastoma is the most aggressive cerebral tumor in adults. However, the current pharmaceuticals in GBM treatment are mainly restricted to few chemotherapeutic drugs and have limited efficacy. Therefore, various nanoscale biomaterials that possess distinct structure and unique property were constructed as vehicles to precisely deliver molecules with potential therapeutic effect. In this review, nanoparticle drug delivery systems including CNTs, GBNs, C-dots, MOFs, Liposomes, MSNs, GNPs, PMs, Dendrimers and Nanogel were exemplified. The advantages and disadvantages of these nanoparticles in GBM treatment were illustrated.
    Keywords:  Biomaterials; Drug delivery systems; Glioblastoma; Nanoparticles
    DOI:  https://doi.org/10.1186/s11671-022-03668-6
  46. Biomater Sci. 2022 Feb 18.
    A carrier free photodynamic oxidizer for enhanced tumor therapy by redox homeostasis disruption.
    Ni Yang, Rong-Rong Zheng, Zi-Ying Chen, Rui-Xin Wang, Lin-Ping Zhao, Xia-Yun Chen, Lei Chen, Lin Xu, Shi-Ying Li, A-Li Chen.
      Abnormal tumor microenvironments play important roles in cancer progression. In general, tumor cells are capable of upregulating glutathione (GSH) levels to maintain aberrant redox homeostasis and cause resistance to oxidative damage. Herein, we develop a photodynamic oxidizer to disrupt the redox homeostasis of tumor cells for enhanced photodynamic tumor therapy. Based on pyropheophorbide-a (Pyro) and naphthazarin (Nap), a carrier free photodynamic oxidizer (named PyroNap) is prepared by the self-assembly technique through hydrophobic interactions. It is confirmed that nanosized PyroNap has high drug contents as well as favorable dispersity and stability. Besides, the photodynamic property of Pyro has obviously improved after self-assembly into the nanomedicine of PyroNap, which facilitates the production of reactive oxygen species (ROS) for robust photodynamic therapy (PDT). More importantly, the Nap induced GSH decrease could disrupt the redox homeostasis of tumor cells to further improve the PDT efficacy on tumor suppression. Consequently, after intravenous administration, PyroNap was able to significantly inhibit tumor growth and cause minimal side effects. This study might shed light on developing translational nanomedicine for tumor precision therapy.
    DOI:  https://doi.org/10.1039/d1bm01876k
  47. Biomed Pharmacother. 2022 Feb 12. pii: S0753-3322(22)00107-X. [Epub ahead of print]148 112719
    Therapeutic targets of neuroprotection and neurorestoration in ischemic stroke: Applications for natural compounds from medicinal herbs.
    Ting Zhu, Lei Wang, Li-Ping Wang, Qi Wan.
      Neuroprotective and neurorestorative therapy represent two major drug intervention strategies for ischemic stroke. Multiple factors such as excitotoxicity, inflammation, angiogenesis, and neurogenesis are the main pathological processes that underlie acute and chronic ischemic brain injury. Furthermore, their intimate interactions mediate blood-brain barrier permeability, increase neurovascular unit structural damage as well as a hemorrhagic transformation during ischemic stroke. We aimed to review the current understandings of the underlying mechanisms of neuroprotection and neurorestoration in ischemic stroke. Notably, traditional Chinese medicine (TCM) has notable advantages in the comprehensive treatment and overall regulation of multi-site and multi-target diseases. Therefore, we reviewed the recent advances in natural compounds from medicinal herbs that possess the bioactivities of simultaneously promoting neuroprotection (e.g., excitotoxicity, oxidative stress, apoptosis, inflammation, and autophagy) and neurorestoration (e.g., angiogenesis, neurogenesis, and axonal sprouting) following brain ischemia injury. These natural compounds were divided into glycosides (astragaloside IV, gastrodin, ginsenoside Rg1 and salidroside), flavonoids (baicalin, icariin, puerarin and breviscapine), phenols (resveratrol, curcumin and salvianolic acid B), and terpenes (ginkgolide B and catalpol). We found that all compounds exhibited anti-brain ischemia activities in vivo and in vitro experiments by promoting neuroprotection and, or neurorestoration. This review tracks and summarizes the progress of the past five years to explore the active compounds and the underlying molecular mechanisms of TCMs that produce pro-neuroprotection and pro-neurorestoration. Additionally, we provide another basis of reference supporting the advantages of TCMs, which could ultimately lead to the development of precise clinical medications for ischemic stroke treatment.
    Keywords:  Ischemic stroke; Neuroprotection; Neurorestoration; Traditional Chinese medicine (TCM)
    DOI:  https://doi.org/10.1016/j.biopha.2022.112719
  48. Curr Drug Targets. 2022 Feb 14.
    Role of Polysaccharides Mimetic Components in Targeted Cancer Treatment.
    Nandan Gupta, Rishabha Malviya.
      Organic or inorganic compounds are synthesized or formulated in a manner that they completely show their therapeutic actions like as a natural polysaccharide in the body. Polysaccharides, the major type of natural polymers, are efficiently biologically active, non-toxic, hydrophilic, and biodegradable and show various properties. In this manuscript, the main focus is on delivering anticancer drugs with the help of mimetic components of polysaccharides. All data collected for this manuscript was from PubMed, Elsevier, Taylor, and Francis Bentham science journals. Most chemotherapeutics are therapeutically toxin to the human body, have a narrow therapeutic index, sluggish pharmaceutical delivery mechanisms, and are poorly soluble in water. The use of mimetic components of polysaccharides leads to the enhancement of the solubility of drugs in the biological environment. The manuscript summarizes the use of mimetic components of polysaccharides along with anticancer agents which are capable to inhibit the growth of cancerous cells in the body which shows lesser adverse effects in the biological system compared to other therapies.
    Keywords:  Cancer; Drug Delivery; Nanoformulations; Polysaccharide; Therapy
    DOI:  https://doi.org/10.2174/1389450123666220214121505
  49. Int J Biol Macromol. 2022 Feb 15. pii: S0141-8130(22)00267-7. [Epub ahead of print]
    Genistein encapsulated inulin-stearic acid bioconjugate nanoparticles: Formulation development, characterization and anticancer activity.
    Ashok Kumar Jangid, Raghu Solanki, Sunita Patel, Deep Pooja, Hitesh Kulhari.
      Achieving controlled and site-specific delivery of hydrophobic drugs in the colon environment is a major challenge. The primary goal of this research was to synthesize inulin-stearic acid (INU-SA) conjugate and to evaluate its potential in the site-specific delivery of genistein (GEN) for the treatment of colon cancer. INU is a hydrophilic polysaccharide biological macromolecule was modified with hydrophobic SA to form amphiphilic conjugate (INU-SA) which can self-assemble into spherical nanoparticles with interesting drug release properties. The hydrophobic GEN was encapsulated into the INU-SA conjugate to prepare GEN loaded nanoparticles (GNP). The prepared GNP possessed nano size (115 nm), good colloidal dispersibility (0.066 PDI), and high drug encapsulation efficiency (92.2%). The release behaviour of GNP indicated the site-specific release of GEN, only 3.4% at gastric pH while 94% at intestinal pH. The prepared GNP showed potential cytotoxicity against HCT 116 human colorectal cancer cells, as demonstrated by antiproliferation and apoptosis assays. The observed half maximum inhibitory concentration (IC50) value of GNP (5.5 μg/mL) was significantly lower than pure GEN (28.2 μg/mL) due to higher cellular internalization of GNP than free GEN. Therefore, this research suggests a way to improve the therapeutic effectiveness of natural biomolecules using modified and biocompatible polysaccharide INU.
    Keywords:  Genistein; HCT 116 cancer cells; Inulin; Inulin-stearic acid conjugate
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.02.031
  50. Int J Nanomedicine. 2022 ;17 589-601
    ROS-Generating Amine-Functionalized Magnetic Nanoparticles Coupled with Carboxymethyl Chitosan for pH-Responsive Release of Doxorubicin.
    Sreekanth Reddy Obireddy, Wing-Fu Lai.
      Purpose: Magnetic nanoparticles have been used in diverse pharmaceutical applications because they can potentially be used to target specific sites. In the present work, a new type of nanocomposites is designed as a carrier of controlled bioactive agent delivery.Methods: Amine-functionalized magnetic nanoparticles (amine-MNPs) are coupled with carboxymethyl chitosan (CMC) to generate the nanocomposites, namely MNPs-CMC, which can be further loaded with doxorubicin (DOX) to produce MNPs-CMC-DOX. The generated nanocomposites are characterized by using various techniques (including FTIR, 1H-NMR, DSC, TGA, SEM, TEM and XRD). In vitro drug release studies are conducted in PBS with different pH values (1.2 and 6.8) at different temperatures (25°C and 37°C). The toxicity of the nanocomposites is tested in MCF-7 and 3T3 cells. The ROS-generating capacity of the nanocomposites is determined in treated cells using 2',7'-dichlorodihydrofluorescein diacetate.
    Results: The structures of MNPs, CMC, and nanocomposites are confirmed by FTIR, XRD, and 1H-NMR data reveals the formation of CMC from chitosan (CS). The size of MNPs is estimated by TEM to be around 25 nm. After conjugation with CMC, the size of the nanocomposites increases to 46-57 nm. Based on the release profiles of MNPs-CMC-DOX, our nanocomposites are pH-responsive. In addition, our nanocomposites show reactive oxygen species (ROS)-generating capacity and cell type-dependent toxicity.
    Conclusion: Our nanocomposites show high potential for use in bioactive agent delivery. Along with their ROS-generating capacity, they warrant further development as pH-responsive carriers for therapeutic applications.
    Keywords:  biocompatibility; controlled release; drug delivery; nanocomposites
    DOI:  https://doi.org/10.2147/IJN.S338897
  51. J Med Chem. 2022 Feb 15.
    Drugging the Next Undruggable KRAS Allele-Gly12Asp.
    Qinheng Zheng, D Matthew Peacock, Kevan M Shokat.
      Since its discovery as the first human oncogene in 1983, the small GTPase KRAS has been a major target of cancer drug discovery. The paper reported in this issue describes a long-awaited small molecule drug candidate of the oncogenic KRAS (G12D) mutant for the treatment of currently incurable pancreatic cancer.
    DOI:  https://doi.org/10.1021/acs.jmedchem.2c00099
  52. Molecules. 2022 Jan 28. pii: 896. [Epub ahead of print]27(3):
    Design of Turmeric Rhizome Extract Nano-Formula for Delivery to Cancer Cells.
    Sakchai Auychaipornlert, Pojawon Prayurnprohm Lawanprasert, Suchada Piriyaprasarth, Pongtip Sithisarn, Supachoke Mangmool.
      Novel turmeric rhizome extract nanoparticles (TE-NPs) were developed from fractions of dried turmeric (Curcuma longa Linn.) rhizome. Phytochemical studies, by using HPLC and TLC, of the fractions obtained from ethanol extraction and solvent-solvent extraction showed that turmeric rhizome ethanol extract (EV) and chloroform fraction (CF) were composed mainly of three curcuminoids and turmeric oil. Hexane fraction (HE) was composed mainly of turmeric oil while ethyl acetate fraction (EA) was composed mainly of three curcuminoids. The optimal TE-NPs formulation with particle size of 159.6 ± 1.7 nm and curcumin content of 357.48 ± 8.39 µM was successfully developed from 47-run D-optimal mixture-process variables experimental design. Three regression models of z-average, d50, and d90 could be developed with a reasonable accuracy of prediction (predicted r2 values were in the range of 0.9120-0.9992). An in vitro cytotoxicity study using MTT assay demonstrated that the optimal TE-NPs remarkably exhibited the higher cytotoxic effect on human hepatoma cells, HepG2, when compared with free curcumin. This study is the first to report nanoparticles prepared from turmeric rhizome extract and their cytotoxic activity to hepatic cancer cells compared with pure curcumin. These nanoparticles might serve as a potential delivery system for cancer therapy.
    Keywords:  HepG2; anticancer; curcumin; nanoparticles; turmeric oil; turmeric rhizome extract
    DOI:  https://doi.org/10.3390/molecules27030896
  53. Molecules. 2022 Jan 28. pii: 898. [Epub ahead of print]27(3):
    Antioxidant, Anti-Obesity, Nutritional and Other Beneficial Effects of Different Chili Pepper: A Review.
    Azrina Azlan, Sharmin Sultana, Chan Suk Huei, Muhammad Rizal Razman.
      Fruits and vegetables are important components of a healthy diet. They are rich sources of vitamins and minerals, dietary fibre and a host of beneficial non-nutrient substances including plant sterols, flavonoids and other antioxidants. It has been reported that reduced intake of fruits and vegetables may increase the risk of non-communicable diseases (NCDs). Chili pepper, is a common and important spice used to enhance taste and nutrition. Over the years, reports have shown its potential as antioxidant and an anti-obesity agent. Obesity is a serious health concern as it may initiate other common chronic diseases. Due to the side effects of synthetic antioxidants and anti-obesity drugs, scientists are now focusing on natural products which produce similar effects to synthetic chemicals. This up-to-date review addresses this research gap and presents, in an accessible format, the nutritional, antioxidant and anti-obesity properties of different chili peppers. This review article serves as a reference guide for use of chili peppers as anti-obesity agents.
    Keywords:  anti-obesity; antioxidant properties; beneficial effects; capsaicin; chili pepper; diet
    DOI:  https://doi.org/10.3390/molecules27030898
  54. Plants (Basel). 2022 Jan 24. pii: 306. [Epub ahead of print]11(3):
    Innovating the Synergistic Assets of β-Amino Butyric Acid (BABA) and Selenium Nanoparticles (SeNPs) in Improving the Growth, Nitrogen Metabolism, Biological Activities, and Nutritive Value of Medicago interexta Sprouts.
    Samy Selim, Nosheen Akhtar, Eman El Azab, Mona Warrad, Hassan H Alhassan, Mohamed Abdel-Mawgoud, Soad K Al Jaouni, Hamada Abdelgawad.
      In view of the wide traditional uses of legume sprouts, several strategies have been approved to improve their growth, bioactivity, and nutritive values. In this regard, the present study aimed at investigating how priming with selenium nanoparticles (SeNPs, 25 mg L-1) enhanced the effects of β-amino butyric acid (BABA, 30 mM) on the growth, physiology, nitrogen metabolism, and bioactive metabolites of Medicago interexta sprouts. The results have shown that the growth and photosynthesis of M. interexta sprouts were enhanced by the treatment with BABA or SeNPs, being higher under combined treatment. Increased photosynthesis provided the precursors for the biosynthesis of primary and secondary metabolites. In this regard, the combined treatment had a more pronounced effect on the bioactive primary metabolites (essential amino acids), secondary metabolites (phenolics, GSH, and ASC), and mineral profiles of the investigated sprouts than that of sole treatments. Increased amino acids were accompanied by increased nitrogen metabolism, i.e., nitrate reductase, glutamate dehydrogenase (GDH), glutamate synthase (GOGAT), glutamine synthase (GS), cysteine synthesis serine acetyltransferase, arginase, threonine synthase, and methionine synthase. Further, the antioxidant capacity (FRAP), the anti-diabetic activities (i.e., α-amylase and α-glucosidase inhibition activities), and the glycemic index of the tested sprouts were more significantly improved by the combined treatment with BABA and SeNPs than by individual treatment. Overall, the combined effect of BABA and SeNPs could be preferable to their individual effects on plant growth and bioactive metabolites.
    Keywords:  BABA; Medicago interexta; SeNPs; anti-diabetic; nutritious metabolites; sprouts
    DOI:  https://doi.org/10.3390/plants11030306
  55. Cancer Res. 2022 Feb 15. 82(4): 534-536
    Forging Forward in Photodynamic Therapy.
    Gwendolyn M Cramer, Keith A Cengel, Theresa M Busch.
      In 1978, a Cancer Research article by Dougherty and colleagues reported the first large-scale clinical trial of photodynamic therapy (PDT) for treatment of 113 cutaneous or subcutaneous lesions associated with ten different kinds of malignancies. In classic applications, PDT depends on excitation of a tissue-localized photosensitizer with wavelengths of visible light to damage malignant or otherwise diseased tissues. Thus, in this landmark article, photosensitizer (hematoporphyrin derivative) dose, drug-light interval, and fractionation scheme were evaluated for their therapeutic efficacy and normal tissue damage. From their observations came early evidence of the mechanisms of PDT's antitumor action, and in the decades since this work, our knowledge of these mechanisms has grown to build an understanding of the multifaceted nature of PDT. These facets are comprised of multiple cell death pathways, together with antivascular and immune stimulatory actions that constitute a PDT reaction. Mechanism-informed PDT protocols support the contribution of PDT to multimodality treatment approaches. Moreover, guided by an understanding of its mechanisms, PDT can be applied to clinical needs in fields beyond oncology. Undoubtedly, there still remains more to learn; new modes of cell death continue to be elucidated with relevance to PDT, and factors that drive PDT innate and adaptive immune responses are not yet fully understood. As research continues to forge a path forward for PDT in the clinic, direction is provided by anchoring new applications in mechanistically grounded protocol design, as was first exemplified in the landmark work conducted by Dougherty and colleagues. See related article by Dougherty and colleagues, Cancer Res 1978;38:2628-35.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-4122
  56. Expert Opin Drug Discov. 2022 Feb 18. 1-12
    New insights into the discovery of drugs for triple-negative breast cancer metastasis.
    Wanessa Fernanda Altei, Bianca Cruz Pachane, Cristiano Souza, Márcia Maria Chiquitelli Marques, Heloisa Selistre-de-Araújo.
      INTRODUCTION: Triple-negative breast cancer (TNBC) is of great concern due to its aggressiveness and lack of targeted therapy. For these reasons, TNBC is one of the main causes of death in women, mainly due to metastases. Tumor dissemination has highlighted a set of possible targets, with extensive research into new single-target drugs, in addition to drug repurposing strategies, being undertaken to discover new classes of potential inhibitors of metastasis.AREAS COVERED: The authors here describe the main proposed targets and the bases of their pharmacological inhibition with different chemical compounds. The authors also discuss the state-of-the-art from the latest clinical trials and highlight other potential targets for metastatic TNBC.
    EXPERT OPINION: In the last decade, oncology research has changed its focus from primary tumors to moving tumor cells, their products, and to the secondary tumor and its surroundings, for the purpose of finding targets to treat metastasis. Consequently, our comprehension of the complexity of the metastatic process has increased drastically, with, furthermore, the discovery of new potential targets. Although promising, the wide range of strategies is still not effective to suppress TNBC metastasis in terms of increasing patient survival or decreasing the number of metastases. Treating or preventing metastasis continues to be a great challenge.
    Keywords:  Breast cancer; liquid biopsy; metastasis; molecular targets; triple-negative breast cancer
    DOI:  https://doi.org/10.1080/17460441.2022.2039619
  57. Int J Mol Sci. 2022 Jan 23. pii: 1247. [Epub ahead of print]23(3):
    Mechanistic Insights of Chelator Complexes with Essential Transition Metals: Antioxidant/Pro-Oxidant Activity and Applications in Medicine.
    Viktor A Timoshnikov, Olga Yu Selyutina, Nikolay E Polyakov, Victoria Didichenko, George J Kontoghiorghes.
      The antioxidant/pro-oxidant activity of drugs and dietary molecules and their role in the maintenance of redox homeostasis, as well as the implications in health and different diseases, have not yet been fully evaluated. In particular, the redox activity and other interactions of drugs with essential redox metal ions, such as iron and copper, need further investigation. These metal ions are ubiquitous in human nutrition but also widely found in dietary supplements and appear to exert major effects on redox homeostasis in health, but also on many diseases of free radical pathology. In this context, the redox mechanistic insights of mainly three prototype groups of drugs, namely alpha-ketohydroxypyridines (alpha-hydroxypyridones), e.g., deferiprone, anthraquinones, e.g., doxorubicin and thiosemicarbazones, e.g., triapine and their metal complexes were examined; details of the mechanisms of their redox activity were reviewed, with emphasis on the biological implications and potential clinical applications, including anticancer activity. Furthermore, the redox properties of these three classes of chelators were compared to those of the iron chelating drugs and also to vitamin C, with an emphasis on their potential clinical interactions and future clinical application prospects in cancer, neurodegenerative and other diseases.
    Keywords:  alpha-ketohydroxypyridines; anthraquinones; antioxidant activity; ascorbic acid; chelators; hydroxypyridones; pro-oxidant activity; reactive oxygen species; thiosemicarbazones; transition metals
    DOI:  https://doi.org/10.3390/ijms23031247
  58. J Biomed Nanotechnol. 2022 Jan 01. 18(1): 185-192
    Enhanced Antibacterial Activity of Indocyanine Green-Loaded Graphene Oxide via Synergistic Contact Killing, Photothermal and Photodynamic Therapy.
    Yuan Chen, Wenlong Huang, Yuanhao Dong, Xiaotong Yu, Anchun Mo, Qiang Peng.
      Methicillin-resistant Staphylococcus aureus (MRSA) has become a serious threat to human's health. Recently, photodynamic/photothermal therapy (PDT/PTT) has emerged as promising strategies against antibiotics-resistant pathogens due to their broad antibacterial spectrum and negligible resistance. In this work, the photosensitizer indocyanine green (ICG) was loaded on graphene oxide (GO) nanosheets with good encapsulation efficiency high to 92.31%. Under near-infrared (NIR) irradiation, the anti-MRSA efficiency of GO (20 μg/ml), ICG (5 μg/ml) and ICG-GO (5 μg/ml-20 μg/ml) was 33.76%, 40.15% and 99.86%, respectively. We further showed that NIR irradiation mildly increased the temperature to 43.1 °C for ICG-GO, and lead to the highest reactive oxygen species (ROS) generation (316.51% and 157.11% compared to ICG alone and GO alone). In conclusion, ICG-GO has a great potential for antibacterial treatment due to its synergistic contact killing, photothermal and photodynamic activity.
    DOI:  https://doi.org/10.1166/jbn.2022.3236
  59. Carbohydr Polym. 2022 May 01. pii: S0144-8617(22)00001-7. [Epub ahead of print]283 119097
    Co-delivery of doxorubicin and siRNA by all-trans retinoic acid conjugated chitosan-based nanocarriers for multiple synergistic antitumor efficacy.
    Chang Liu, Cui Tang, Chunhua Yin.
      To achieve the co-delivery of doxorubicin (DOX) and small interfering RNA (siRNA) targeting B-cell lymphoma 2 (siBcl-2), lactose acid (LA) and all-trans retinoic acid (ATRA) double grafted N,N,N-trimethyl chitosan (TMC) nanoparticles (GTA NPs) were developed. The relative viability of QGY-7703 cells was decreased to 81.3% when the concentration of GTA NPs was 0.1 mg/mL, but no toxicity to normal cells was observed, indicating that the GTA NPs selectively inhibited the proliferation of tumor cells. With DOX loaded into the hydrophobic core and siRNA condensed onto the hydrophilic shell, GTA/DOX/siRNA NPs were prepared. The GTA/DOX/siRNA NPs possessed high cellular uptake via receptor-mediated endocytosis. Owing to multiple cooperative antitumor effects of DOX, siBcl-2, and GTA NPs, GTA/DOX/siRNA NPs had superior in vitro and in vivo antitumor efficiency to other formulations. These findings provide a guideline for the combined applications of multiple synergistic antitumor manners.
    Keywords:  All-trans retinoic acid; B-cell lymphoma 2 siRNA; Chitosan; Doxorubicin; Synergistic antitumor treatment
    DOI:  https://doi.org/10.1016/j.carbpol.2022.119097
  60. Front Vet Sci. 2021 ;8 823589
    Goji Berries Supplementation in the Diet of Rabbits and Other Livestock Animals: A Mini-Review of the Current Knowledge.
    Stella Agradi, Susanna Draghi, Elisa Cotozzolo, Olimpia Barbato, Marta Castrica, Alda Quattrone, Majlind Sulce, Daniele Vigo, Laura Menchetti, Maria Rachele Ceccarini, Egon Andoni, Federica Riva, Maria Laura Marongiu, Giulio Curone, Gabriele Brecchia.
      In the last decades, several nutraceutical substances have received great attention for their potential role in the prevention and treatment of different diseases as well as for their beneficial effects in promoting the health of humans and animals. Goji berries (GBs) are the fruit of Lycium barbarum and other species of Lycium, used in traditional Chinese medicine, and they have recently become very popular in the Occidental world because of their properties, such as anti-aging, antioxidant, anticancer, neuroprotective, cytoprotective, antidiabetic, and anti-inflammatory activities. These effects are essentially evaluated in clinical trials in humans; in experimental animal models, such as mice and rats; and in cell lines in in vitro studies. Only recently has scientific research evaluated the effects of GBs diet supplementation in livestock animals, including rabbits. Although studies in the zootechnical field are still limited and the investigation of the GB mechanisms of action is in an early stage, the results are encouraging. This review includes a survey of the experimental trials that evaluated the effects of the GBs supplementation on reproductive and productive performances, immune system, metabolic homeostasis, and meat quality principally in the rabbit with also some references to other livestock animal species. Evidence supports the idea that GB supplementation could be used in rabbit breeding, although future studies should be conducted to establish the optimal dose to be administered and to assess the sustainability of the use of GBs in the diet of the rabbit.
    Keywords:  Chinese traditional medicine; Lycium barbarum; immune system; meat quality; metabolism; nutraceutical; polysaccharides; reproductive and productive performance
    DOI:  https://doi.org/10.3389/fvets.2021.823589
  61. Cancers (Basel). 2022 Jan 26. pii: 622. [Epub ahead of print]14(3):
    Targeted Delivery Methods for Anticancer Drugs.
    Valery V Veselov, Alexander E Nosyrev, László Jicsinszky, Renad N Alyautdin, Giancarlo Cravotto.
      Several drug-delivery systems have been reported on and often successfully applied in cancer therapy. Cell-targeted delivery can reduce the overall toxicity of cytotoxic drugs and increase their effectiveness and selectivity. Besides traditional liposomal and micellar formulations, various nanocarrier systems have recently become the focus of developmental interest. This review discusses the preparation and targeting techniques as well as the properties of several liposome-, micelle-, solid-lipid nanoparticle-, dendrimer-, gold-, and magnetic-nanoparticle-based delivery systems. Approaches for targeted drug delivery and systems for drug release under a range of stimuli are also discussed.
    Keywords:  dendrimers; metal nanoparticles; nanocarriers; oligo- and polysaccharides; solid-lipid systems; stimuli-responsive
    DOI:  https://doi.org/10.3390/cancers14030622
  62. Cancers (Basel). 2022 Jan 25. pii: 596. [Epub ahead of print]14(3):
    Metabolic Phenotyping in Prostate Cancer Using Multi-Omics Approaches.
    Nuria Gómez-Cebrián, José Luis Poveda, Antonio Pineda-Lucena, Leonor Puchades-Carrasco.
      Prostate cancer (PCa), one of the most frequently diagnosed cancers among men worldwide, is characterized by a diverse biological heterogeneity. It is well known that PCa cells rewire their cellular metabolism to meet the higher demands required for survival, proliferation, and invasion. In this context, a deeper understanding of metabolic reprogramming, an emerging hallmark of cancer, could provide novel opportunities for cancer diagnosis, prognosis, and treatment. In this setting, multi-omics data integration approaches, including genomics, epigenomics, transcriptomics, proteomics, lipidomics, and metabolomics, could offer unprecedented opportunities for uncovering the molecular changes underlying metabolic rewiring in complex diseases, such as PCa. Recent studies, focused on the integrated analysis of multi-omics data derived from PCa patients, have in fact revealed new insights into specific metabolic reprogramming events and vulnerabilities that have the potential to better guide therapy and improve outcomes for patients. This review aims to provide an up-to-date summary of multi-omics studies focused on the characterization of the metabolomic phenotype of PCa, as well as an in-depth analysis of the correlation between changes identified in the multi-omics studies and the metabolic profile of PCa tumors.
    Keywords:  metabolism; metabolomics; multi-omics; prostate cancer
    DOI:  https://doi.org/10.3390/cancers14030596
  63. ACS Appl Mater Interfaces. 2022 Feb 16.
    Self-Rectifiable and Hypoxia-Assisted Chemo-Photodynamic Nanoinhibitor for Synergistic Cancer Therapy.
    Yanan Wang, Jian Huo, Shuang Li, Ran Huang, Daopeng Fan, Hanghang Cheng, Bo Wan, Yongkun Du, Hua He, Gaiping Zhang.
      Photodynamic therapy (PDT) can eradicate cancer cells under light irradiation, mainly because of reactive singlet oxygen (1O2) being transformed from intratumoral oxygen. Nonetheless, the consumption of oxygen during PDT results in serious hypoxic conditions and an elevated hypoxia-inducing factor-1α (HIF-1α) level that hamper further photodynamic efficacy and induce tumor metastasis. To address this problem, we developed hypoxia-assisted NP-co-encapsulating Ce6 (photosensitizer) and YC-1 (HIF-1α inhibitor) as a self-rectifiable nanoinhibitor for synergistic antitumor treatment. PDT-aggravated intracellular hypoxic stress facilitated NP dissociation to release the drug (YC-1), which achieved tumor killing and HIF-1α inhibition to further enhance the therapeutic effect of PDT and prevent tumor metastasis. Besides, in vivo studies revealed that the HC/PI@YC-1 NPs afforded synergistic anticancer efficacy with minimal toxicity. Therefore, this study provides a prospective approach against PDT drawbacks and combination cancer therapy.
    Keywords:  HIF protein inhibitor; hypoxia; photodynamic therapy; self-rectifiable; synergistic anticancer efficacy
    DOI:  https://doi.org/10.1021/acsami.1c23121
  64. Cell Signal. 2022 Feb 14. pii: S0898-6568(22)00042-0. [Epub ahead of print] 110282
    Jumonji-C domain-containing protein 5 suppresses proliferation and aerobic glycolysis in pancreatic cancer cells in a c-Myc-dependent manner.
    Hongcheng Wang, Jianfa Wang, Jiazhe Liu, Yiwei Wang, Guanggai Xia, Xinyu Huang.
      Despite the importance of metabolic reprogramming in cancer cells, the molecular mechanism regulating the tumor metabolic shift is still poorly understood. Deregulation of Jumonji-C domain-containing protein 5 (JMJD5) has been associated with multiple facets of biological processes in cancer cells. However, the role of JMJD5 in pancreatic cancer cells has seldom been discussed and requires further investigation. In the present study, by silencing or overexpressing JMJD5 in pancreatic cancer cells, we examined the impact of JMJD5 on cell proliferation and glucose metabolism. Using a dual luciferase assay, we assessed the effect of JMJD5 on the transcriptional activity of the c-Myc target gene. Analyzing The Cancer Genome Atlas and the Gene Expression Omnibus datasets revealed that low JMJD5 expression was associated with poor prognosis in patients with pancreatic cancer. JMJD5 loss promoted pancreatic cancer cell proliferation and induced a cellular metabolic shift from oxidative phosphorylation to glycolysis. In addition, in vivo experiments confirmed that ectopic JMJD5 expression inhibited cancer cell growth and the expression of glycolytic enzymes, such as lactate dehydrogenase and phosphoglycerate kinase 1. Moreover, JMJD5 negatively regulated c-Myc expression, the main regulator of cancer metabolism, leading to decreased c-Myc-targeted gene expression. Overall, the present study indicated that decreased JMJD5 expression promoted cell proliferation and glycolytic metabolism in pancreatic cancer cells in a c-Myc-dependent manner.
    Keywords:  C-Myc; Glycolysis; JMJD5; Metabolism; Pancreatic cancer
    DOI:  https://doi.org/10.1016/j.cellsig.2022.110282
  65. ACS Nano. 2022 Feb 14.
    Nano-ultrasonic Contrast Agent for Chemoimmunotherapy of Breast Cancer by Immune Metabolism Reprogramming and Tumor Autophagy.
    Xupeng Yang, Meng Zhao, Zhihua Wu, Chuanrong Chen, Yanhua Zhang, Liting Wang, Qianqian Guo, Quan Wang, Shunshun Liang, Suxian Hu, Yourong Duan, Ying Sun.
      The functional status of innate immune cells is a considerable determinant of effective antitumor immune response. However, the triple-negative breast cancer tumor microenvironment with high lactic acid metabolism and high antioxidant levels limits immune cell survival, differentiation, and function. Here, we determine that the tumor microenvironment-responsive nano-ultrasonic contrast agent Pt(IV)/CQ/PFH NPs-DPPA-1 boosts the ratio of mature dendritic cells (mDCs) and proinflammatory macrophages by reprogramming the metabolism of immature DCs (iDCs) and tumor-associated macrophages (TAMs). Specifically, platinum(IV) in cancer cells or iDCs was reduced to cisplatin, which can increase the intracellular content of ROS and therefore enhance the ratio of mDCs and apoptotic tumor cells. Meanwhile, chloroquine (CQ) released from nanoparticles (NPs) minimizes protective autophagy caused by cisplatin in tumor cells and reprograms the metabolism of TAMs to enhance the proportion of proinflammatory macrophages, achieving a superior synergistic effect of chemoimmunotherapy combined with Pt(IV) and anti-PD-L1 peptide (DPPA-1). Furthermore, perfluorohexane (PFH) in NPs realizes monitoring treatment corresponding to ultrasound. Collectively, the nano-ultrasonic contrast agent supports a candidate for monitoring treatment and augmenting antitumor chemoimmunotherapy by suppressing tumor cell autophagy and reprogramming immunocyte metabolism.
    Keywords:  autophagy; chloroquine; immune metabolism reprogramming; nano-ultrasonic contrast agent; platinum(IV)
    DOI:  https://doi.org/10.1021/acsnano.2c00462
  66. Crit Rev Food Sci Nutr. 2022 Feb 16. 1-35
    Allium vegetables: Traditional uses, phytoconstituents, and beneficial effects in inflammation and cancer.
    Ashraful Alam, Abdullah Al Arif Jahan, Md Sazzadul Bari, Labony Khandokar, Md Hasan Mahmud, Muhammed Junaid, Mohammed Salahuddin Chowdhury, Mohammad Forhad Khan, Veronique Seidel, Md Areeful Haque.
      The genus Allium comprises of at least 918 species; the majority grown for dietary and medicinal purposes. This review describes the traditional uses, phytoconstituents, anti-inflammatory and anticancer activity, and safety profile of six main species, namely Allium sativum L. (garlic), Allium cepa L. (onions), Allium ampeloprasum L. (leek), Allium fistulosum L. (scallion), Allium schoenoprasum L. (chives) and Allium tuberosum Rottler (garlic chives). These species contain at least 260 phytoconstituents; mainly volatile compounds-including 63 organosulfur molecules-, saponins, flavonoids, anthocyanins, phenolic compounds, amino acids, organic acids, fatty acids, steroids, vitamins and nucleosides. They have prominent in vitro anti-inflammatory activity, and in vivo replications of such results have been achieved for all except for A. schoenoprasum. They also exert cytotoxicity against different cancer cell lines. Several anticancer phytoconstituents have been characterized from all except for A. fistulosum. Organosulfur constituents, saponins and flavonoid glycosides have demonstrated anti-inflammatory and anticancer activity. Extensive work has been conducted mainly on the anti-inflammatory and anticancer activity of A. sativum and A. cepa. The presence of anti-inflammatory and anticancer constituents in these two species suggests that similar bioactive constituents could be found in other species. This provides future avenues for identifying new Allium-derived anti-inflammatory and anticancer agents.
    Keywords:   Allium vegetables; anti-inflammatory activity; anticancer activity; ethnopharmacology; phytochemistry
    DOI:  https://doi.org/10.1080/10408398.2022.2036094
  67. ACS Appl Mater Interfaces. 2022 Feb 17.
    Programmed Stimuli-Responsive Carbon Dot-Nanogel Hybrids for Imaging-Guided Enhanced Tumor Phototherapy.
    Chen Zhao, Shan Sun, Si Li, A'man Lv, Qiao Chen, Kai Jiang, Zhenqi Jiang, Zhongjun Li, Aiguo Wu, Hengwei Lin.
      For harmonizing the contradiction of nanotheranostic agents between enhanced tumor accumulation and penetration, efficient cell internalization and fast elimination are key tactics for promoting their clinical applications. Herein, programmed stimuli-responsive poly(N-isopropylacrylamide)-carbon dot (PNIPAM-CD) hybrid nanogels are designed to address the abovementioned conflicts. The enlarged particle size of PNIPAM-CDs enables one to effectively improve their accumulation at tumor sites. Once the hybrid nanogels are docked in tumors and exposed to deep-red-light (660 nm) irradiation, heat and reactive oxygen species (ROS) are generated from the CDs, consequently activating photothermal therapy (PTT) and photodynamic therapy (PDT) effects and meanwhile inducing partial degradation of PNIPAM-CDs for deep tissue penetration. Further, enhanced cellular internalization of the functional components can be achieved owing to the pH-responsive charge reversal and temperature-dependent hydrophilic/hydrophobic conversion characteristics of PNIPAM-CDs. Finally, the overexpressed glutathione (GSH) in tumor cells would trigger further cleavage of the partially degraded hybrid nanogels, which is beneficial for their rapid clearance from the body. This work not only proposed a novel strategy to fabricate nanotheranostic agents using just a single functional component (i.e., the versatile CDs) to simplify the preparation process but also achieved effective delivery of agents into tumor cells by overcoming the multiple biological barriers to enhance therapeutic efficacy and decrease side effects.
    Keywords:  carbon dots; nanogel hybrids; stimuli-responsiveness; theranostic agents; tumor phototherapy
    DOI:  https://doi.org/10.1021/acsami.2c00174
  68. Int J Mol Sci. 2022 Jan 22. pii: 1230. [Epub ahead of print]23(3):
    Indomethacin and Diclofenac Hybrids with Oleanolic Acid Oximes Modulate Key Signaling Pathways in Pancreatic Cancer Cells.
    Maria Narożna, Violetta Krajka-Kuźniak, Robert Kleszcz, Wanda Baer-Dubowska.
      Our earlier studies showed that coupling nonsteroidal anti-inflammatory drugs (NSAIDs) with oleanolic acid derivatives increased their anti-inflammatory activity in human hepatoma cells. The aim of this study was to evaluate their effect on the signaling pathways involved in inflammation processes in human pancreatic cancer (PC) cells. Cultured PSN-1 cells were exposed for 24 h (30 µM) to OA oxime (OAO) derivatives substituted with benzyl or morpholide groups and their conjugates with indomethacin (IND) or diclofenac (DCL). The activation of NF-κB and Nrf2 was assessed by the evaluation of the translocation of their active forms into the nucleus and their binding to specific DNA sequences via the ELISA assay. The expression of NF-κB and Nrf2 target genes was evaluated by R-T PCR and Western blot analysis. The conjugation of IND or DCL with OAO derivatives increased cytotoxicity and their effect on the tested signaling pathways. The most effective compound was the DCL hybrid with OAO morpholide (4d). This compound significantly reduced the activation and expression of NF-κB and enhanced the activation and expression of Nrf2. Increased expression of Nrf2 target genes led to reduced ROS production. Moreover, MAPKs and the related pathways were also affected. Therefore, conjugate 4d deserves more comprehensive studies as a potential PC therapeutic agent.
    Keywords:  MAPKs; NF-κB; Nrf2; PSN-1 cells; diclofenac; indomethacin; inflammation; oleanolic acid derivative conjugates; reactive oxygen species
    DOI:  https://doi.org/10.3390/ijms23031230
  69. J Nanobiotechnology. 2022 Feb 15. 20(1): 80
    Biomimetic nanoprobe-augmented triple therapy with photothermal, sonodynamic and checkpoint blockade inhibits tumor growth and metastasis.
    Xiaohong Lin, Tao He, Rui Tang, Qianru Li, Nianhong Wu, Yin Zhou, Hongye He, Li Wan, Ju Huang, Qinqin Jiang, Yixin Zhong, Zhuoyan Xie, Zhongqian Hu, Yang Zhou, Pan Li.
      BACKGROUND: Comprehensive antitumor therapy through integrated multimodal means has drawn increasing attention owing to its high efficiency and metastasis suppression.RESULTS: We describe a synergistic triple protocol combining photothermal and sonodynamic therapy (PTT and SDT), together with immune checkpoint blockade for the inhibition of breast cancer growth and metastases in the 4T1 mouse model. PTT and SDT are synergistically augmented by a novel multimodal imaging nanoprobe integrated with cancer cell membrane-biomimetic nanoparticles (CHINPs) loaded with superparamagnetic iron oxide (SPIO) and hematoporphyrin monomethyl ether (HMME). CHINPs exhibit excellent homologous tumor targeting, and are sequentially triggered by ultrasound and near infrared (NIR) light under the guidance of magnetic resonance, photoacoustic and photothermal imaging, leading to complete in situ tumor eradication and systemic anti-tumor immune activation. Further combination of this approach with immune checkpoint blockade therapy is shown to suppress tumor metastasis.
    CONCLUSION: This work provides proof-of-principle for triple therapy using multimodal imaging-guided PTT/SDT based on biomimetic nanoprobes in combination with immunotherapy to eliminate tumors.
    Keywords:  Cancer cell membrane; Immunotherapy; Multimodal imaging; Photothermal therapy; Sonodynamic therapy
    DOI:  https://doi.org/10.1186/s12951-022-01287-y
  70. Molecules. 2022 Jan 27. pii: 828. [Epub ahead of print]27(3):
    Bioactive-Based Cosmeceuticals: An Update on Emerging Trends.
    Anju Goyal, Aditya Sharma, Jasanpreet Kaur, Sapna Kumari, Madhukar Garg, Rakesh K Sindhu, Md Habibur Rahman, Muhammad Furqan Akhtar, Priti Tagde, Agnieszka Najda, Barbara Banach-Albińska, Katarzyna Masternak, Ibtesam S Alanazi, Hanan R H Mohamed, Attalla F El-Kott, Muddaser Shah, Mousa O Germoush, Hamdan S Al-Malky, Salman H Abukhuwayjah, Ahmed E Altyar, Simona G Bungau, Mohamed M Abdel-Daim.
      Cosmetic-containing herbals are a cosmetic that has or is claimed to have medicinal properties, with bioactive ingredients purported to have medical benefits. There are no legal requirements to prove that these products live up to their claims. The name is a combination of "cosmetics" and "pharmaceuticals". "Nutricosmetics" are related dietary supplements or food or beverage products with additives that are marketed as having medical benefits that affect appearance. Cosmetic-containing herbals are topical cosmetic-pharmaceutical hybrids intended to enhance the health and beauty of the skin. Cosmetic-containing herbals improve appearance by delivering essential nutrients to the skin. Several herbal products, such as cosmetic-containing herbals, are available. The present review highlights the use of natural products in cosmetic-containing herbals, as natural products have many curative effects as well as healing effects on skin and hair growth with minimal to no side effects. A brief description is given on such plants, their used parts, active ingredients, and the therapeutic properties associated with them. Mainly, the utilization of phytoconstituents as cosmetic-containing herbals in the care of skin and hair, such as dryness of skin, acne, eczema, inflammation of the skin, aging, hair growth, and dandruff, along with natural ingredients, such as for hair colorant, are explained in detail in the present review.
    Keywords:  bioactive ingredients; cosmetic-containing herbals; cosmetics
    DOI:  https://doi.org/10.3390/molecules27030828
  71. Int J Mol Cell Med. 2021 ;10(3): 163-181
    Curcumin in Combination with Other Adjunct Therapies for Brain Tumor Treatment: Existing Knowledge and Blueprint for Future Research.
    Kavita Peter, Santosh Kumar Kar, Ragini Gothalwal, Puneet Gandhi.
      Malignant brain tumors proliferate aggressively and have a debilitating outcome. Surgery followed by chemo-radiotherapy has been the standard procedure of care since 2005 but issues of therapeutic toxicity and relapse still remain unaddressed. Repurposing of drugs to develop novel combinations that can augment existing treatment regimens for brain tumors is the need of the hour. Herein, we discuss studies documenting the use of curcumin as an adjuvant to conventional and alternative therapies for brain tumors. Comprehensive analysis of data suggests that curcumin together with available therapies can generate a synergistic action achieved through multiple molecular targeting, which results in simultaneous inhibition of tumor growth, and reduced treatment-induced toxicity as well as resistance. The review also highlights approaches to increase bioavailability and bioaccumulation of drugs when co-delivered with curcumin using nano-cargos. Despite substantial preclinical work on radio-chemo sensitizing effects of curcumin, to date, there is only a single clinical report on brain tumors. Based on available lab evidence, it is proposed that antibody-conjugated nano-curcumin in combination with sub-toxic doses of conventional or repurposed therapeutics should be designed and tested in clinical studies. This will increase tumor targeting, the bioavailability of the drug combination, reduce therapy resistance, and tumor recurrence through modulation of aberrant signaling cascades; thus improving clinical outcomes in brain malignancies.
    Keywords:  Glioblastoma; combination therapy; polyphenol; resistance; sensitization; synergistic
    DOI:  https://doi.org/10.22088/IJMCM.BUMS.10.3.163
  72. Nanomaterials (Basel). 2022 Jan 20. pii: 324. [Epub ahead of print]12(3):
    Comparative Study between Curcumin and Nanocurcumin Loaded PLGA on Colon Carcinogenesis Induced Mice.
    Farida E Elbassiouni, Wafaa M El-Kholy, El-Sayed M Elhabibi, Sarah Albogami, Eman Fayad.
      Colorectal cancer is the third most common cancer. Because curcumin (CUR) has anti-inflammatory and anticancer properties, research has been undertaken to indicate that nanocurcumin compounds can be used to treat a variety of cancers. CUR in nanoform has been found to have a stronger effect than conventional CUR. The purpose of this study was to show that CUR-loaded poly lactic-co-glycolic acid nanoparticles (PLGA) (CUR-loaded PLGA) have anti-inflammatory and anticancer effects on colon carcinogenesis in male dimethyl hydrazine (DMH) mice as a comparative study between the nanoform of curcumin and normal curcumin, focusing on the anticancer effect of nanocurcumin. Mice were separated into six groups: No treatment was given to Group I (negative Group-I). Group II was treated with CUR. Group III was treated with CUR-loaded PLGA. Group IV was treated with DMH. Group V received DMH and curcumin. Group VI received DMH and CUR-loaded PLGA. At the conclusion of the trial, the animals were slain (6 weeks). Inflammatory indicators and vascular endothelial growth factor (VEGF) levels all changed significantly in this study, as the following inflammatory markers as TNF showed percent of change compared to the DMH group. Recovery percentage for Groups V and VI, respectively, were 9.18 and 55.31%. In addition, IL1 was 7.45 and 50.37% for Groups V and VI, respectively. The results of IL6 were 4.86 and 25.79% for Groups V and VI, respectively. The vascular endothelial growth factor (VEGF) recovery percent was 16.98 and 45.12% for Groups V and VI, respectively. Following the effect of DMH on colon mucosa shape, the researchers looked at the effect of CUR-loaded PLGA on colon histology. It was shown that CUR-loaded PLGA affects the cell cycle and PCNA expression. We conclude that nanocurcumin is an important anti-inflammatory and cancer-fighting agent.
    Keywords:  DMH and curcumin encapsulated PLGA; VEGF; colorectal cancer; inflammatory factors
    DOI:  https://doi.org/10.3390/nano12030324
  73. Drug Dev Ind Pharm. 2022 Feb 18. 1-22
    Improving Gallic Acid and Quercetin Bioavailability by Polymeric Nanoparticle Formulation.
    Poounima Patil, Suresh Killedar.
      The anticancer activity and pharmacokinetic properties of encapsulated polyherbal nanoparticles (Gallic acid and quercetin Nanocomposite) and polyherbal extract (Amla and pomegranate fruit peels) in normal and DMH-induced colorectal cancer in rats was examined in this work. In normal and DMH-induced rats, a pharmacokinetic study demonstrated that polyherbal nanoparticles had a typical sustained release profile with a 4-fold increase in bioavailability when compared to polyherbal extract. Based on serum-concentration profiles of polyherbal nanoparticles and polyherbal extract following oral administration, the pharmacokinetic parameters for polyherbal nanoparticles and polyherbal extract were established using a single compartmental approach. This research suggests that encapsulating Gallic acid and quercetin in polymeric nanoparticles improves their oral bioavailability and anti-colon cancer efficacy. Polymeric nanoparticles could be a novel therapeutic possibility for carcinogenesis prevention.
    Keywords:  Colorectal cancer; Gallic acid; Polyherbal extract; Polyherbal nanoparticles; Quercetin
    DOI:  https://doi.org/10.1080/03639045.2022.2043353
  74. ACS Appl Bio Mater. 2022 Feb 18.
    Lipid-Coated CaCO3 Nanoparticles as a Versatile pH-Responsive Drug Delivery Platform to Enable Combined Chemotherapy of Breast Cancer.
    Yuejuan Xu, Chunjie Wang, Fangrong Shen, Ziliang Dong, Yu Hao, Youguo Chen, Zhuang Liu, Liangzhu Feng.
      The development of smart drug delivery nanocarriers for tumor-targeted delivery and controllable release of therapeutic agents is appealing to achieve effective cancer chemotherapy. We herein use CaCO3 nanoparticles as the core to load doxorubicin (DOX) and direct the assembly of amphiphilic oxaliplatin prodrugs (Pt(IV)) in the presence of other commercial lipids. The obtained DOX-Pt(IV)-CaCO3-PEG with excellent physiological stability exhibits instant pH-responsive degradation, thus enabling efficient pH-dependent release of DOX. Via detailed pharmacokinetic study, it is shown that DOX-Pt(IV)-CaCO3-PEG shows significantly improved pharmacokinetic behaviors compared to these free drugs, featured in prolonged blood circulation time and superior tumor homing efficacy. Resultantly, treatment with systemic administration of DOX-Pt(IV)-CaCO3-PEG was the most effective in suppressing the growth of tumors in Balb/c mice. This study highlights that our liposomal CaCO3 is a robust and biocompatible platform for preparing pH-responsive drug delivery systems, due to its multifaceted drug loading capacity, and thus is promising for potential clinical translation.
    Keywords:  combined chemotherapy; lipid-coated CaCO3 nanoparticles; pH responsiveness; tumor-targeted drug delivery; versatile molecule loading
    DOI:  https://doi.org/10.1021/acsabm.1c01234
  75. Polymers (Basel). 2022 Jan 27. pii: 508. [Epub ahead of print]14(3):
    Experimental Design and Optimization of Nano-Transfersomal Gel to Enhance the Hypoglycemic Activity of Silymarin.
    Marwa H Abdallah, Amr S Abu Lila, Seham Mohammed Shawky, Khaled Almansour, Farhan Alshammari, El-Sayed Khafagy, Tarek Saad Makram.
      Current advancements in the research investigations focused at using natural products to generate novel dosage forms with a potential therapeutic impact. Silymarin is a natural product obtained from the herb Silybum marianum that has been shown to have remarkable hypoglycemic activity. Owing to the low enteral absorption, instability in stomach secretion, and poor solubility of Silymarin, it was better to be produced as a topical dosage form. A three-factor, three-level Box Behnken (33 BB) design was constructed to develop 15 formulations using three independent variables (phospholipid concentration, surfactant concentration, and sonication time) and two dependent variables (encapsulation efficiency and in vitro drug release). The optimized formula was added to HPMC gel and the resulting transfersomal gel was investigated for its characteristics, in vitro, ex vivo and hypoglycemic behaviors. The pH of the Silymarin-loaded transfersomal gel was 7.05, the spreadability was 55.35 mm, and the viscosity was 6.27 Pa. Furthermore, Silymarin loaded transfersomal gel had the greatest transdermal flux (92.41 µg/cm2·h), which was much greater than all other formulations. In vivo observations revealed that Silymarin loaded transfersomal gel significantly reduced blood glucose levels, compared to either Silymarin gel or oral Silymarin suspension. The findings show that the developed transfersomal gel could be an effective carrier for Silymarin transdermal delivery.
    Keywords:  Box Behnken Design; Silymarin; hypoglycemic effect; transdermal application; transfersomes
    DOI:  https://doi.org/10.3390/polym14030508
  76. Molecules. 2022 Feb 06. pii: 1086. [Epub ahead of print]27(3):
    Stealth Liposomes (PEGylated) Containing an Anticancer Drug Camptothecin: In Vitro Characterization and In Vivo Pharmacokinetic and Tissue Distribution Study.
    Durgaramani Sivadasan, Muhammad H Sultan, Osama Ali Madkhali, Shahd Hassan Alsabei, Asia Abdullah Alessa.
      Numerous attempts to overcome the poor water solubility of cam ptothecin (CPT) by various nano drug delivery systems are described in various sources in the literature. However, the results of these approaches may be hampered by the incomplete separation of free CPT from the formulations, and this issue has not been investigated in detail. This study aimed to promote the solubility and continuous delivery of CPT by developing long-lasting liposomes using various weights (M.W. 2000 and 5000 Daltons) of the hydrophilic polymer polyethylene glycol (PEG). Conventional and PEGylated liposomes containing CPT were formulated via the lipid film hydration method (solvent evaporation) using a rotary flash evaporator after optimising various formulation parameters. The following physicochemical characteristics were investigated: surface morphology, particle size, encapsulation efficiency, in vitro release, and formulation stability. Different molecular weights of PEG were used to improve the encapsulation efficiency and particle size. The stealth liposomes prepared with PEG5000 were discrete in shape and with a higher encapsulation efficiency (83 ± 0.4%) and a prolonged rate of drug release (32.2% in 9 h) compared with conventional liposomes (64.8 ± 0.8% and 52.4%, respectively) and stealth liposomes containing PEG2000 (79.00 ± 0.4% and 45.3%, respectively). Furthermore, the stealth liposomes prepared with PEG5000 were highly stable at refrigeration temperature. Significant changes were observed using various pharmacokinetic parameters (mean residence time (MRT), half-life, elimination rate, volume of distribution, clearance, and area under the curve) of stealth liposomes containing PEG2000 and PEG5000 compared with conventional liposomes. The stealth liposomes prepared with PEG5000 showed promising results with a slow rate of release over a long period compared with conventional liposomes and liposomes prepared with PEG2000, with altered tissue distribution and pharmacokinetic parameters.
    Keywords:  camptothecin; colorectal cancer; encapsulation efficiency; lipid film hydration; pharmacokinetic study; polyethylene glycol; stealth liposomes
    DOI:  https://doi.org/10.3390/molecules27031086
  77. Environ Sci Pollut Res Int. 2022 Feb 16.
    Berberine-loaded liquid crystalline nanoparticles inhibit non-small cell lung cancer proliferation and migration in vitro.
    Keshav R Paudel, Meenu Mehta, Geena Hew Suet Yin, Lee Li Yen, Vamshikrishna Malyla, Vyoma K Patel, Jithendra Panneerselvam, Thiagarajan Madheswaran, Ronan MacLoughlin, Niraj Kumar Jha, Piyush Kumar Gupta, Sachin Kumar Singh, Gaurav Gupta, Pradeep Kumar, Brian G Oliver, Philip M Hansbro, Dinesh Kumar Chellappan, Kamal Dua.
      Non-small cell lung cancer (NSCLC) is reported to have a high incidence rate and is one of the most prevalent types of cancer contributing towards 85% of all incidences of lung cancer. Berberine is an isoquinoline alkaloid which offers a broad range of therapeutical and pharmacological actions against cancer. However, extremely low water solubility and poor oral bioavailability have largely restricted its therapeutic applications. To overcome these limitations, we formulated berberine-loaded liquid crystalline nanoparticles (LCNs) and investigated their in vitro antiproliferative and antimigratory activity in human lung epithelial cancer cell line (A549). 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), trypan blue staining, and colony forming assays were used to evaluate the anti-proliferative activity, while scratch wound healing assay and a modified Boyden chamber assay were carried out to determine the anti-migratory activity. We also investigated major proteins associated with lung cancer progression. The developed nanoparticles were found to have an average particle size of 181.3 nm with spherical shape, high entrapment efficiency (75.35%) and have shown sustained release behaviour. The most remarkable findings reported with berberine-loaded LCNs were significant suppression of proliferation, inhibition of colony formation, inhibition of invasion or migration via epithelial mesenchymal transition, and proliferation related proteins associated with cancer progression. Our findings suggest that anti-cancer compounds with the problem of poor solubility and bioavailability can be overcome by formulating them into nanotechnology-based delivery systems for better efficacy. Further in-depth investigations into anti-cancer mechanistic research will expand and strengthen the current findings of berberine-LCNs as a potential NSCLC treatment option.
    Keywords:  Berberine; Liquid crystalline nanoparticles; Lung cancer; Migration; Proliferation, Epithelial mesenchymal transition
    DOI:  https://doi.org/10.1007/s11356-022-19158-2
  78. Cells. 2022 Jan 24. pii: 388. [Epub ahead of print]11(3):
    Breast Cancer Bone Metastasis: A Narrative Review of Emerging Targeted Drug Delivery Systems.
    Huimin Shao, Pegah Varamini.
      Bone is one of the most common metastatic sites among breast cancer (BC) patients. Once bone metastasis is developed, patients' survival and quality of life will be significantly declined. At present, there are limited therapeutic options for BC patients with bone metastasis. Different nanotechnology-based delivery systems have been developed aiming to specifically deliver the therapeutic agents to the bone. The conjugation of targeting agents to nanoparticles can enhance the selective delivery of various payloads to the metastatic bone lesion. The current review highlights promising and emerging advanced nanotechnologies designed for targeted delivery of anticancer therapeutics, contrast agents, photodynamic and photothermal materials to the bone to achieve the goal of treatment, diagnosis, and prevention of BC bone metastasis. A better understanding of various properties of these new therapeutic approaches may open up new landscapes in medicine towards improving the quality of life and overall survival of BC patients who experience bone metastasis.
    Keywords:  bone metastasis; breast cancer; nanomedicine; nanotechnology; targeted drug delivery system
    DOI:  https://doi.org/10.3390/cells11030388
  79. J Lasers Med Sci. 2021 ;12 e85
    Effect of Low-Level Laser Therapy and Sinensetin (Combination therapy) on Tumor Cells (Hela) and Normal Cells (CHO).
    Behnam Javaheri, Gholamreza Esmaeeli Djavid, Kazem Parivar, Azadeh Hekmat.
      Introduction: Cervical and ovarian cancers are well-known causes of death among women in developing countries. There are various technologies to treat cancer cells, but the polyphenolic compound is a natural one and has an anti-cancer effect. Sinensetin is one of them and is found in Orthosiphon stamineus and citrus fruits. Since combination therapy is more effective than drug treatment alone, in this study, we investigated combination therapy using sinensetin and low-level laser therapy (LLLT) to enhance treatment. Methods: The cancer cells purchased from Pasteur Institute, Iran, were cultured. The cells were treated with various concentrations of sinensetin (0.1-1-10-50,150 µg/mL for 24 hours), wavelengths of laser therapy (660 nm) and power density (3 J/cm2) for different times)30, 60, and 90 seconds) separately. Furthermore, sensitivity of cells to sinensetin, LLLT and combined therapy was determined by clonogenic assays. To measure DNA damage and repair at individual cell level used comet assay. To examine the intracellular generation of reactive oxygen species used 2',7'-dichlorodihydrofluorescein (DCFH) as an intracellular probe. To analyze data we used SPSS software and comparison between groups was used (ANOVA) and t test statistical analyses were performed using SPSS 17 software. Data are presented as means - standard error of mean. The level of statistical significance was set at a two-tailed P value of 0.05. All tests were performed in triplicate. Results: Our results demonstrated that the doubling time for CHO is more than Hella cells, with 20.7 and 27.7 h for each cell respectively. The pretreatments (first LLLT, then sinensetin) can decrease the viability of both cell lines more than the first treatment (sinensetin + LLLT). In the clonogenic assay, the pretreatment of cells with LLLT and Sinensetin significantly reduced the surviving fraction of both cell lines. MTT results showed that pretreatment with LLLT and Sinensetin can increase cell death compared to Sinensetin and LLLT alone. Production of ROS within the cell was enhanced with LLLT + sinensetin. Conclusion: Our result indicated that combined therapy with LLLT and Sinensetin can treat CHO and Hela cells better than the other groups. Combination treatment with sinensetin-LLLT and the other treatment means, sinensetin and LLLT alone, did not change the cell viability significantly.
    Keywords:  Anti-cancer effect; CHO; Combined therapy; Hella; Low-level laser irradiation (LLLT); Sinensetin
    DOI:  https://doi.org/10.34172/jlms.2021.85
  80. Front Oncol. 2022 ;12 771870
    Epigenetic Regulation of Ferroptosis-Associated Genes and Its Implication in Cancer Therapy.
    Yanzi Pei, Yujie Qian, Hao Wang, Li Tan.
      Ferroptosis is an evolutionarily conserved form of regulated cell death triggered by iron-dependent phospholipid peroxidation. Ferroptosis contributes to the maintenance of tissue homeostasis under physiological conditions while its aberration is tightly connected with lots of pathophysiological processes such as acute tissue injury, chronic degenerative disease, and tumorigenesis. Epigenetic regulation controls chromatin structure and gene expression by writing/reading/erasing the covalent modifications on DNA, histone, and RNA, without altering the DNA sequence. Accumulating evidences suggest that epigenetic regulation is involved in the determination of cellular vulnerability to ferroptosis. Here, we summarize the recent advances on the epigenetic mechanisms that control the expression of ferroptosis-associated genes and thereby the ferroptosis process. Moreover, the potential value of epigenetic drugs in targeting or synergizing ferroptosis during cancer therapy is also discussed.
    Keywords:  DNA methylation; RNA methylation; cancer; epigenetic regulation; ferroptosis; histone modifications
    DOI:  https://doi.org/10.3389/fonc.2022.771870
  81. Cell Biol Int. 2022 Feb 14.
    PDGF-BB/PDGFRβ Promotes Epithelial-Mesenchymal Transition by Affecting PI3K/AKT/mTOR-Driven Aerobic Glycolysis in Wilms' tumor G401 Cells.
    Jia-Qi Guo, Chang-Dong Wang, Hu-Ying Tang, Bo-Tao Sang, Xing Liu, Fa-Ping Yi, Xiang-Mei Wu.
      Wilms' tumor (WT) is the most common pediatric renal malignancy. PDGFRβ belongs to the type III receptor tyrosine kinase family and is known to be involved in tumor metastasis and angiogenesis. Here, we studied the effect and underlying mechanism of PDGFRβ on Wilms' tumor G401 cells. Transwell assay and wound-healing assay were used to detect the effect of PDGFRβ on G401 cells invasion and migration. Western blot and immunofluorescence were used to detect the expression of EMT-related genes. The expression of PI3K/AKT/mTOR pathway proteins was detected by western blot. The relationship between PDGFRβ and aerobic glycolysis was studied by assessing the expression of glycolysis-related enzymes detected by qRT-PCR and western blot. The activity of HK, PK and LDH was detected by corresponding enzyme activity kits. The concentration of lactic acid and glucose was detected by Lactic Acid Assay Kit and Glucose Assay Kit-glucose oxidase method separately. To investigate the mechanism of PDGFRβ in the development of Wilms' tumor, the changes of glucose and lactic acid were analyzed after blocking PI3K pathway, aerobic glycolysis or PDGFRβ. The key enzyme was screened by western blot and glucose metabolism experiment after HK2, PKM2 and PDK1 were inhibited. The results showed that PDGFRβ promoted the EMT process by modulating aerobic glycolysis through PI3K/AKT/mTOR pathway in which PKM2 plays a key role. Therefore, our study of the mechanism of PDGFRβ in G401 cells provides a new target for the treatment of Wilms' tumor. This article is protected by copyright. All rights reserved.
    Keywords:  Aerobic glycolysis; EMT; PDGFRβ; Wilms’ tumor
    DOI:  https://doi.org/10.1002/cbin.11780
  82. Mol Cancer. 2022 02 12. 21(1): 47
    Ferroptosis in cancer therapy: a novel approach to reversing drug resistance.
    Chen Zhang, Xinyin Liu, Shidai Jin, Yi Chen, Renhua Guo.
      Ferroptosis is an intracellular iron-dependent form of cell death that is distinct from apoptosis, necrosis, and autophagy. Extensive studies suggest that ferroptosis plays a pivotal role in tumor suppression, thus providing new opportunities for cancer therapy. The development of resistance to cancer therapy remains a major challenge. A number of preclinical and clinical studies have focused on overcoming drug resistance. Intriguingly, ferroptosis has been correlated with cancer therapy resistance, and inducing ferroptosis has been demonstrated to reverse drug resistance. Herein, we provide a detailed description of the mechanisms of ferroptosis and the therapeutic role of regulating ferroptosis in reversing the resistance of cancer to common therapies, such as chemotherapy, targeted therapy and immunotherapy. We discuss the prospect and challenge of regulating ferroptosis as a therapeutic strategy for reversing cancer therapy resistance and expect that our review could provide some references for further studies.
    Keywords:  Chemotherapy; Drug resistance; Ferroptosis; Immunotherapy; Targeted therapy
    DOI:  https://doi.org/10.1186/s12943-022-01530-y
  83. Adv Healthc Mater. 2022 Feb 14. e2102610
    Intranasal Delivery of Functionalized Polymeric Nanomaterials to the Brain.
    Shuai Zha, Ka-Leung Wong, Angelo H All.
      Intravenous delivery of nanomaterials containing therapeutic agents and various cargos for treating neurological disorders is often constrained by low delivery efficacy due to difficulties in passing the blood-brain barrier (BBB). Nanoparticles (NPs) administered intranasally can move along olfactory and trigeminal nerves so that they do not need to pass through the BBB, allowing non-invasive, direct access to selective neural pathways within the brain. Hence, intranasal administration of NPs can effectively deliver drugs and genes into targeted regions of the brain, holding potential for efficacious disease treatment in the central nervous system (CNS). In this review, we primarily showcase current methods for delivering conjugated NPs to the brain. We then discuss distinctive potential mechanisms of therapeutic nanocomposites delivered via intranasal pathways to the brain. We also review recent progress in developing functional NPs for applications in multimodal bioimaging, drug delivery, diagnostics, and therapeutics. We conclude the review by discussing existing challenges, new directions and future perspectives in intranasal delivery of nanomaterials. This article is protected by copyright. All rights reserved.
    Keywords:  brain delivery; functionalized nanomaterials; intranasal delivery; nanomedicine; polymeric nanomaterials; therapeutic nanocarriers
    DOI:  https://doi.org/10.1002/adhm.202102610
  84. Foods. 2022 Jan 28. pii: 378. [Epub ahead of print]11(3):
    Phytochemical Profile, Biological Properties, and Food Applications of the Medicinal Plant Syzygium cumini.
    Muhammad Qamar, Saeed Akhtar, Tariq Ismail, Muqeet Wahid, Malik Waseem Abbas, Mohammad S Mubarak, Ye Yuan, Ross T Barnard, Zyta M Ziora, Tuba Esatbeyoglu.
      Syzygium cumini, locally known as Jamun in Asia, is a fruit-bearing crop belonging to the Myrtaceae family. This study aims to summarize the most recent literature related to botany, traditional applications, phytochemical ingredients, pharmacological activities, nutrition, and potential food applications of S. cumini. Traditionally, S. cumini has been utilized to combat diabetes and dysentery, and it is given to females with a history of abortions. Anatomical parts of S. cumini exhibit therapeutic potentials including antioxidant, anti-inflammatory, analgesic, antipyretic, antimalarial, anticancer, and antidiabetic activities attributed to the presence of various primary and secondary metabolites such as carbohydrates, proteins, amino acids, alkaloids, flavonoids (i.e., quercetin, myricetin, kaempferol), phenolic acids (gallic acid, caffeic acid, ellagic acid) and anthocyanins (delphinidin-3,5-O-diglucoside, petunidin-3,5-O-diglucoside, malvidin-3,5-O-diglucoside). Different fruit parts of S. cumini have been employed to enhance the nutritional and overall quality of jams, jellies, wines, and fermented products. Today, S. cumini is also used in edible films. So, we believe that S. cumini's anatomical parts, extracts, and isolated compounds can be used in the food industry with applications in food packaging and as food additives. Future research should focus on the isolation and purification of compounds from S. cumini to treat various disorders. More importantly, clinical trials are required to develop low-cost medications with a low therapeutic index.
    Keywords:  antioxidant; cancer; diabetes; hyperlipidemia; inflammation; jamun; nutrition; packaging; radioprotection; value addition
    DOI:  https://doi.org/10.3390/foods11030378
  85. Molecules. 2022 Jan 25. pii: 781. [Epub ahead of print]27(3):
    Mechanistic Basis for the Role of Phytochemicals in Inflammation-Associated Chronic Diseases.
    Brianna Cote, Fawzy Elbarbry, Fiona Bui, Joe W Su, Karen Seo, Arthur Nguyen, Max Lee, Deepa A Rao.
      Chronic inflammatory diseases occur in a large portion of the population and are associated with a poor diet. Key natural products found in fruits and vegetables may assist in lowering inflammation associated with chronic diseases such as obesity, diabetes, cardiovascular diseases, and cancer. This review seeks to examine the roles of several natural products, resveratrol (RES), quercetin (QUE), curcumin (CUR), piperine (PIP), epigallocatechin gallate (EGCG), and gingerol (GIN), in their ability to attenuate inflammatory markers in specific diseases states. Additionally, we will discuss findings in past and ongoing clinical trials, detail possible phytochemical-drug interactions, and provide a brief resource for researchers and healthcare professionals on natural product and supplement regulation as well as names of databases with information on efficacy, indications, and natural product-drug interactions. As diet and over-the-counter supplement use are modifiable factors and patients are interested in using complementary and alternative therapies, understanding the mechanisms by which natural products have demonstrated efficacy and the types of drugs they interact with and knowing where to find information on herbs and supplements is important for practicing healthcare providers and researchers interested in this field.
    Keywords:  complementary and alternative therapies; inflammation associated diseases; natural product drug interactions; natural products
    DOI:  https://doi.org/10.3390/molecules27030781
  86. AAPS PharmSciTech. 2022 Feb 17. 23(3): 76
    A Nanocrystal Platform Based on Metal-Phenolic Network Wrapping for Drug Solubilization.
    Feifei Huang, Xiaohong Jiang, Marwa A Sallam, Xingwang Zhang, Wei He.
      The preparation of drugs into nanocrystals represents a practical pharmaceutical technology to solubilize poorly water-soluble drugs and enhance bioavailability. However, commonly used stabilizers in nanocrystals like polymers and surfactants are frequently inefficient and cannot stabilize nanocrystals for an expected time. This study reports an exquisite platform for nanocrystal production based on a metal-phenolic network (MPN). MPN-wrapped nanocrystal particles (MPN-NPs) were fabricated through an anti-solvent precipitation method using tannic acid and FeIII or AlIII as coupling agents and characterized by dynamic light scattering, transmission electron microscope, ultraviolet and visible spectrophotometry, fourier-transform infrared spectroscopy, and X-ray powder diffraction. In vitro release, cytotoxicity, and stability were mainly studied with MPN-NPs loading paclitaxel. The suitability of MPN as a nanocrystal stabilizer was also investigated for other classical hydrophobic drugs, including simvastatin, andrographolide, atorvastatin calcium, ferulic acid, and famotidine. The results showed that MPN could effectively wrap and stabilize various drug nanocrystals apart from famotidine. The maximum solubilization of MPN towards atorvastatin calcium was up to 1587 folds, and it also exhibited an excellent solubilizing effect on other hydrophobic drugs. We disclosed that the drug was entrapped in MPN in the nanocrystal form, and there were distinct physiochemical interactions between MPN and the payload. Our findings suggested that MPN may be a promising platform for nanocrystal production to address the challenge of low solubility associated with hydrophobic drugs. Graphical abstract.
    Keywords:  Drug release; Hydrophobic drugs; Metal-phenolic network; Nanocrystals; Solubilization
    DOI:  https://doi.org/10.1208/s12249-022-02220-0
  87. Curr Mol Pharmacol. 2022 Feb 14.
    Drug repurposing for cancer therapy in the era of precision medicine.
    Kenneth K W To, William C S Cho.
      Drug repurposing refers to the identification of clinically approved drugs, with the known safety profiles and defined pharmacokinetic properties, to new indications. Despite the advances in oncology research, cancers are still associated with the most unmet medical needs. Drug repurposing has emerged as a useful approach for the search for effective and durable cancer treatment. It may also represent a promising strategy to facilitate precision cancer treatment and to overcome drug resistance. The repurposing of non-cancer drugs for precision oncology effectively extends the inventory of actionable molecular targets and thus increases the number of patients who may benefit from precision cancer treatment. In cancer types where genetic heterogeneity is so high that it is not feasible to identify strong repurposed drug candidates for standard treatment, the precision oncology approach offers individual patients access to novel treatment options. For repurposed candidates with low potency, a combination of multiple repurposed drugs may produce a synergistic therapeutic effect. Precautions should be taken when combining repurposed drugs with anticancer agents to avoid detrimental drug-drug interactions and unwanted side effects. New multifactorial data analysis and artificial intelligence methods are needed to untangle the complex association of molecular signatures influencing specific cancer subtypes to facilitate drug repurposing in precision oncology.
    Keywords:  Drug repurposing; Drug resistance; Precision oncology; Rare cancer; Synergistic drug combination
    DOI:  https://doi.org/10.2174/1874467215666220214104530
  88. J Integr Neurosci. 2022 Jan 28. 21(1): 14
    Research progress of natural products for the treatment of ischemic stroke.
    Jiaxin Li, Tingting Zhao, Hanzi Qiao, Yanling Li, Mengyao Xia, Xiaoyu Wang, Chuanguo Liu, Tingting Zheng, Renjie Chen, Yicheng Xie, Jibiao Wu, Xia Wei, Jun Li, Yu Feng, Peng Sun.
      Stroke is a leading cause of death and disability world-widely. The incidence rate of stroke has been increasing due to the aging population and lifestyle changes. At present, the only drug approved by the US Food and Drug Administration (FDA) for the treatment of ischemic stroke is tissue plasminogen activator (t-PA), but its clinical application is greatly limited because of its narrow time window and bleeding risk. Natural products have a long history of being used in traditional medicine with good safety, making them an important resource for the development of new drugs. Indeed, some natural products can target a variety of pathophysiological processes related to stroke, including oxidative stress, inflammation and neuronal apoptosis. Therefore, the development of high-efficiency, low-toxicity, safe and cheap active substances from natural products is of great significance for improving the treatment alternatives of patients with stroke. This article reviews the neuroprotective effects of 33 natural compounds by searching recent related literature. Among them, puerarin, pinocembrin, quercetin, epigallocatechin-3-gallate (EGCG), and resveratrol have great potential in the clinical treatment of ischemic stroke. This review will provide a powerful reference for screening natural compounds with potential clinical application value in ischemic stroke or synthesizing new neuroprotective agents with natural compounds as lead compounds.
    Keywords:  Ischemic stroke; Mechanism; Natural products
    DOI:  https://doi.org/10.31083/j.jin2101014
  89. Nanomaterials (Basel). 2022 Jan 22. pii: 354. [Epub ahead of print]12(3):
    Recent Advances in the Surface Functionalization of PLGA-Based Nanomedicines.
    Mazen M El-Hammadi, José L Arias.
      Therapeutics are habitually characterized by short plasma half-lives and little affinity for targeted cells. To overcome these challenges, nanoparticulate systems have entered into the disease arena. Poly(d,l-lactide-co-glycolide) (PLGA) is one of the most relevant biocompatible materials to construct drug nanocarriers. Understanding the physical chemistry of this copolymer and current knowledge of its biological fate will help in engineering efficient PLGA-based nanomedicines. Surface modification of the nanoparticle structure has been proposed as a required functionalization to optimize the performance in biological systems and to localize the PLGA colloid into the site of action. In this review, a background is provided on the properties and biodegradation of the copolymer. Methods to formulate PLGA nanoparticles, as well as their in vitro performance and in vivo fate, are briefly discussed. In addition, a special focus is placed on the analysis of current research in the use of surface modification strategies to engineer PLGA nanoparticles, i.e., PEGylation and the use of PEG alternatives, surfactants and lipids to improve in vitro and in vivo stability and to create hydrophilic shells or stealth protection for the nanoparticle. Finally, an update on the use of ligands to decorate the surface of PLGA nanomedicines is included in the review.
    Keywords:  PLGA; active drug targeting; ligand-mediated targeting; nanoparticle; passive drug targeting; stealth coating; surface functionalization
    DOI:  https://doi.org/10.3390/nano12030354
  90. Front Pharmacol. 2022 ;13 803717
    Apoptosis Induction, a Sharp Edge of Berberine to Exert Anti-Cancer Effects, Focus on Breast, Lung, and Liver Cancer.
    Yi Zhu, Na Xie, Yilu Chai, Yisen Nie, Ke Liu, Yufei Liu, Yang Yang, Jinsong Su, Chuantao Zhang.
      Cancer is the leading cause of death and one of the greatest barriers to increased life expectancy worldwide. Currently, chemotherapy with synthetic drugs remains one of the predominant ways for cancer treatment, which may lead to drug resistance and normal organ damage. Increasing researches have suggested that apoptosis, a type of programmed cell death, is a promising way for cancer therapy. Furthermore, natural products are important sources for finding new drugs with high availability, low cost and low toxicity. As a well-known isoquinoline alkaloid, accumulating evidence has revealed that berberine (BBR) exerts potential pro-apoptotic effects on multiple cancers, including breast, lung, liver, gastric, colorectal, pancreatic, and ovarian cancers. The related potential signal pathways are AMP-activated protein kinase, mitogen-activated protein kinase, and protein kinase B pathways. In this review, we provide a timely and comprehensive summary of the detailed molecular mechanisms of BBR in treating three types of cancer (breast, lung and liver cancer) by inducing apoptosis. Furthermore, we also discuss the existing challenges and strategies to improve BBR's bioavailability. Hopefully, this review provides valuable information for the comprehension of BBR in treating three types of cancer and highlight the pro-apoptotic effects of BBR, which would be beneficial for the further development of this natural compound as an effective clinical drug for treating cancers.
    Keywords:  ADMET; anticancer effects; apoptosis induction; berberine; bioavailability
    DOI:  https://doi.org/10.3389/fphar.2022.803717
  91. J Integr Neurosci. 2022 Jan 28. 21(1): 26
    Traditional medicine in China for ischemic stroke: bioactive components, pharmacology, and mechanisms.
    Min Xu, Rui-Xia Wu, Xiao-Li Li, Yi-Shen Zeng, Jia-Yang Liang, Ke Fu, Yuan Liang, Zhang Wang.
      Ischemic stroke is an acute cerebrovascular disease and the third most common cause of death after ischemic heart disease. Increasing attention is being paid to finding effective treatments through traditional medicine. Thus, studying the traditional medicine for the treatment of ischemic stroke is of great importance. Traditional medicine in China includes traditional Chinese medicine (TCM) and other ethnic medicines, which is rich in variety and resources. This review first introduces the treatment mechanisms associated with ischemic stroke, such as antioxidant nitrification, antiexcitotoxic, antiapoptotic, anti-inflammatory, antiplatelet and anticoagulation mechanisms. Then, we calculated the frequency of prescription use for ischemic stroke and summarized the treatments for ischemic stroke by investigating 13 drug monographs and standards. We found 192 prescriptions from the traditional medical system for ischemic stroke, including Angong Niuhuang pill, Qishiwei Zhenzhu Pills, Ginkgo biloba leaf, and other traditional Chinese patent medicines and national medicines. There were 398 kinds of traditional medicine, including 301 kinds of plant-based medicines, 54 kinds of animal-based medicines, 28 kinds of mineral-based medicines, and 15 kinds of other medicines. We introduced the names, families, medicinal components, traditional uses, phytochemical information, and pharmacological activities of the commonly used Chinese patent medicines and TCMs. In addition, some chemicals were introduced. These medicines may be potential candidates for the treatment of ischemic stroke. This work provides a reference for the research and clinical use of new drugs for ischemic stroke.
    Keywords:  Ischemic stroke; Mechanisms; Medicinal materials; Pharmacology; Traditional Chinese patent medicines; Traditional medicine
    DOI:  https://doi.org/10.31083/j.jin2101026
  92. Colloids Surf B Biointerfaces. 2022 Feb 02. pii: S0927-7765(22)00068-6. [Epub ahead of print]213 112385
    Prodrug based on halloysite delivery systems to improve the antitumor ability of methotrexate in leukemia cell lines.
    Marina Massaro, Paola Poma, Giuseppe Cavallaro, Fátima García-Villén, Giuseppe Lazzara, Monica Notarbartolo, Nicola Muratore, Rita Sánchez-Espejo, César Viseras Iborra, Serena Riela.
      The prodrug approach, as well as the development of specific systems able to deliver a chemotherapeutic agent in the target site, decreasing the side effects often associated with its administration, are still a challenging. In this context, both methotrexate drug molecules (MTX) and biotin ligand moieties, whose receptors are overexpressed on the surface of several cancer cells, were loaded on halloysite nanotubes (HNTs) to develop nanomaterial based on multifunctional and "smart" delivery systems. To highlight the crucial role played by biotin, carrier systems based on HNTs and MTX were also synthetized. In detail, several approaches were envisaged: i) a supramolecular interaction between the clay and the drug; ii) a covalent grafting of the drug onto the HNTs external surface and, iii) a combination of both approaches. The nanomaterials obtained were characterized by thermogravimetric analysis, FT-IR, and UV-vis spectroscopies, DLS and ζ-potential measurements and the morphologies were imaged by HAADF/STEM investigations. Kinetic release experiments at different pH conditions were also performed. Finally, as a proof-of-concept application of our pro-drug delivery systems based on HNTs in cancer therapy, the cytotoxic effects were evaluated on acute myeloid leukemia cell lines, HL60 and its multidrug resistance variant, HL60R. The obtained results showed that both the MTX prodrug system and the biotinylated ones played a crucial role in the biological activity and, they are promising agents for the cancer treatments.
    Keywords:  Biotin; Drug delivery systems; Halloysite nanotubes; Leukemia cells; Methotrexate; Prodrug
    DOI:  https://doi.org/10.1016/j.colsurfb.2022.112385
  93. Biomater Sci. 2022 Feb 16.
    Amplification of ferroptosis with a liposomal nanoreactor cooperates with low-toxicity doxorubicin apoptosis for enhanced tumor chemotherapy.
    Peng Ji, Xianglong Wang, Jiabing Yin, Yansheng Yao, Wangqi Du.
      Despite the remarkable tumor inhibition effect of doxorubicin (DOX), its cardiotoxicity severely limits the clinical dosage and further impairs the chemotherapy efficacy. To improve the biosafety and effectiveness of conventional chemotherapy, we propose a strategy to co-deliver DOX and ART to supplement apoptosis with ferroptosis. To this end, ART and DOX were incorporated into ferrous LiMOFs to develop a nanoreactor, utilizing ferrous ions as a catalyst to decompose ART into radicals and thus to induce efficient ferroptosis. Further, DOX can induce another form of death, apoptosis, which in combination enhances tumor inhibition. The synthesized nanoreactor (DOX/ART@LiMOFs) possesses a size of ∼100 nm and maintains a regular crystal structure. The pH-responsive disassociation endows it with acid-sensitive drug-releasing kinetics, and the liposomal bilayers bring about a sustained release feature (up to 12 h). The cellular ROS assay indicated that the supply of ferrous ions dramatically increased the ROS mediated by ART and led to markedly enhanced tumor inhibition in animal tests accompanied by the apoptosis of DOX. Consequently, this work presents an innovative strategy to synchronously induce potent ferroptosis and apoptosis, promoting conventional cancer chemotherapy.
    DOI:  https://doi.org/10.1039/d2bm00079b
  94. Adv Healthc Mater. 2022 Feb 19. e2102791
    Bioinspired Multifunctional Black Phosphorus Hydrogel with Antibacterial and Antioxidant Properties: A Stepwise Countermeasure for Diabetic Skin Wound Healing.
    Qiuyue Ding, Tingfang Sun, Weijie Su, Xirui Jing, Bing Ye, Yanlin Su, Lian Zeng, Yanzhen Qu, Xu Yang, Yuzhou Wu, Zhiqiang Luo, Xiaodong Guo.
      Cutaneous wound healing, especially diabetic wound healing, is a common clinical dilemma. Reactive oxygen species (ROS) and bacterial infection are two major detrimental states that induce oxidative stress and inflammatory responses and impede angiogenesis and wound healing. A derivative of the metabolite itaconate, 4-octyl itaconate (4OI) has attracted increasing research interest in recent years due to its antioxidant and anti-inflammatory properties. In this study, 4-octyl itaconate (4OI)-modified black phosphorus (BP) nanosheets were incorporated into a photosensitive, multifunctional gelatin methacrylamide hydrogel to produce a new photothermal therapy(PTT) and photodynamic therapy (PDT) system with antibacterial and antioxidant properties for diabetic wound regeneration. Under laser irradiation, the 4OI-BP-entrapped hydrogel enables rapid gelation, forming a membrane on wounds, and offers high PTT and PDTefficacy to eliminate bacterial infection. Without laser irradiation, BP acts as a carrier and controls the release of 4OI, with which it synergistically enhances antioxidant activity, thus alleviating excessive ROS damage to endothelial cells, promoting neovascularization, and facilitating faster diabetic wound closure. These findings indicate that 4OI-BP-entrapped multifunctional hydrogel provides a stepwise countermeasure with antibacterial and antioxidant properties for enhanced diabetic wound healing and may lead to novel therapeutic interventions for diabetic ulcers. This article is protected by copyright. All rights reserved.
    Keywords:  4-octyl Itaconate; Black phosphorus; diabetic skin ulcers; photodynamic therapy; photothermal therapy
    DOI:  https://doi.org/10.1002/adhm.202102791
  95. Altern Ther Health Med. 2022 Feb 18. pii: AT6726. [Epub ahead of print]
    Evidence for Improved Cognitive Health with Diet: A Narrative Review.
    Yue Hong, Erika Clark, Kayla Furbish, Nicolette Maggiolo, Emerson West, Louisa Sylvia.
      Background: Despite growing interest in nutrition as a behavioral intervention to improve cognitive health in clinical populations, many providers find it challenging to provide specific nutritional recommendations. We aimed to review and synthesize current empirical research on this topic and provide considerations for healthcare providers working with adults who wish to optimize their cognition via dietary improvements.Methods: We performed a narrative review of research published between January 2009 and May 2021 on 5 popular dietary interventions: the Mediterranean diet, Dietary Approaches to Stop Hypertension (DASH), the Mediterranean-DASH Intervention Diet for Neurodegenerative Delay (MIND), the ketogenic diet and intermittent fasting.
    Results and Conclusions: Of the 5 dietary interventions, the Mediterranean diet has been the most extensively investigated, and there is evidence supporting its cognitive benefits. However, operationalization of the Mediterranean diet varies across studies, rendering the results inconclusive. The DASH diet and the MIND diet have stronger operationalization and showed evidence of cognitive benefits. More longitudinal studies and/or randomized clinical trials should be conducted on these 2 relatively new interventions. Finally, there is limited research with human participants regarding the ketogenic diet and intermittent fasting, which are found to be cognitively protective within stringent parameters. Definitions for these 5 dietary patterns and practice tips and recommendations are provided.
  96. Oxid Med Cell Longev. 2022 ;2022 6025900
    A Review of Recent Studies on the Antioxidant and Anti-Infectious Properties of Senna Plants.
    Mohammed M Alshehri, Cristina Quispe, Jesús Herrera-Bravo, Javad Sharifi-Rad, Sena Tutuncu, Elif Feyza Aydar, Cansu Topkaya, Zehra Mertdinc, Beraat Ozcelik, Mahima Aital, N V Anil Kumar, Natallia Lapava, Jovana Rajkovic, Andrea Ertani, Silvana Nicola, Prabhakar Semwal, Sakshi Painuli, Carlos González-Contreras, Miquel Martorell, Monica Butnariu, Iulia Cristina Bagiu, Radu Vasile Bagiu, Mrunal D Barbhai, Manoj Kumar, Sevgi Durna Daştan, Daniela Calina, William C Cho.
      The use of phytochemicals is gaining interest for the treatment of metabolic syndromes over the synthetic formulation of drugs. Senna is evolving as one of the important plants which have been vastly studied for its beneficial effects. Various parts of Senna species including the root, stem, leaves, and flower are found rich in numerous phytochemicals. In vitro, in vivo, and clinical experiments established that extracts from Senna plants have diverse beneficial effects by acting as a strong antioxidant and antimicrobial agent. In this review, Senna genus is comprehensively discussed in terms of its botanical characteristics, traditional use, geographic presence, and phytochemical profile. The bioactive compound richness contributes to the biological activity of Senna plant extracts. The review emphasizes on the in vivo and in vitro antioxidant and anti-infectious properties of the Senna plant. Preclinical studies confirmed the beneficial effects of the Senna plant extracts and its bioactive components in regard to the health-promoting activities. The safety, side effects, and therapeutic limitations of the Senna plant are also discussed in this review. Additional research is necessary to utilize the phenolic compounds towards its use as an alternative to pharmacological treatments and even as an ingredient in functional foods.
    DOI:  https://doi.org/10.1155/2022/6025900
  97. Molecules. 2022 Jan 21. pii: 695. [Epub ahead of print]27(3):
    Natural Products from Physalis alkekengi L. var. franchetii (Mast.) Makino: A Review on Their Structural Analysis, Quality Control, Pharmacology, and Pharmacokinetics.
    Jing Yang, Yanping Sun, Feng Cao, Bingyou Yang, Haixue Kuang.
      The calyxes and fruits of Physalis alkekengi L. var. franchetii (Mast.) Makino (P. alkekengi), a medicinal and edible plant, are frequently used as heat-clearing and detoxifying agents in thousands of Chinese medicine prescriptions. For thousands of years in China, they have been widely used in clinical practice to treat throat disease, hepatitis, and bacillary dysentery. This systematic review summarizes their structural analysis, quality control, pharmacology, and pharmacokinetics. Furthermore, the possible development trends and perspectives for future research studies on this medicinal plant are discussed. Relevant information on the calyxes and fruits of P. alkekengi was collected from electronic databases, Chinese herbal classics, and Chinese Pharmacopoeia. Moreover, information was collected from ancient documents in China. The components isolated and identified in P. alkekengi include steroids, flavonoids, phenylpropanoids, alkaloids, nucleosides, terpenoids, megastigmane, aliphatic derivatives, organic acids, coumarins, and sucrose esters. Steroids, particularly physalins and flavonoids, are the major characteristic and bioactive ingredients in P. alkekengi. According to the literature, physalins are synthesized by the mevalonate and 2-C-methyl-d-erythritol-4-phosphate pathways, and flavonoids are synthesized by the phenylpropanoid pathway. Since the chemical components and pharmacological effects of P. alkekengi are complex and varied, there are different standards for the evaluation of its quality and efficacy. In most cases, the analysis was performed using high-performance liquid chromatography coupled with ultraviolet detection. A pharmacological study showed that the crude extracts and isolated compounds from P. alkekengi had extensive in vitro and in vivo biological activities (e.g., anti-inflammatory, anti-tumor, immunosuppressive, antibacterial, anti-leishmanial, anti-asthmatic, anti-diabetic, anti-oxidative, anti-malarial, anti-Alzheimer's disease, and vasodilatory). Moreover, the relevant anti-inflammatory and anti-tumor mechanisms were elucidated. The reported activities indicate the great pharmacological potential of P. alkekengi. Similarly, studies on the pharmacokinetics of specific compounds will also contribute to the progress of clinical research in this setting.
    Keywords:  pharmacokinetics; pharmacology; quality control; structural analysis; the calyxes and fruits of P. alkekengi
    DOI:  https://doi.org/10.3390/molecules27030695
  98. Molecules. 2022 Jan 21. pii: 705. [Epub ahead of print]27(3):
    Melatonin: Regulation of Prion Protein Phase Separation in Cancer Multidrug Resistance.
    Doris Loh, Russel J Reiter.
      The unique ability to adapt and thrive in inhospitable, stressful tumor microenvironments (TME) also renders cancer cells resistant to traditional chemotherapeutic treatments and/or novel pharmaceuticals. Cancer cells exhibit extensive metabolic alterations involving hypoxia, accelerated glycolysis, oxidative stress, and increased extracellular ATP that may activate ancient, conserved prion adaptive response strategies that exacerbate multidrug resistance (MDR) by exploiting cellular stress to increase cancer metastatic potential and stemness, balance proliferation and differentiation, and amplify resistance to apoptosis. The regulation of prions in MDR is further complicated by important, putative physiological functions of ligand-binding and signal transduction. Melatonin is capable of both enhancing physiological functions and inhibiting oncogenic properties of prion proteins. Through regulation of phase separation of the prion N-terminal domain which targets and interacts with lipid rafts, melatonin may prevent conformational changes that can result in aggregation and/or conversion to pathological, infectious isoforms. As a cancer therapy adjuvant, melatonin could modulate TME oxidative stress levels and hypoxia, reverse pH gradient changes, reduce lipid peroxidation, and protect lipid raft compositions to suppress prion-mediated, non-Mendelian, heritable, but often reversible epigenetic adaptations that facilitate cancer heterogeneity, stemness, metastasis, and drug resistance. This review examines some of the mechanisms that may balance physiological and pathological effects of prions and prion-like proteins achieved through the synergistic use of melatonin to ameliorate MDR, which remains a challenge in cancer treatment.
    Keywords:  band 3; cancer multidrug resistance; copper; heme iron; hypoxia; liquid–liquid phase separation; melatonin; pH; prions; tumor microenvironment
    DOI:  https://doi.org/10.3390/molecules27030705
  99. J Clin Invest. 2022 02 15. pii: e156891. [Epub ahead of print]132(4):
    Remodeling of the tumor/tumor microenvironment ecosystem during KRAS G12C inhibitor clinical resistance in lung cancer.
    Tadashi Manabe, Trever G Bivona.
      KRAS G12C inhibitors such as sotorasib and adagrasib are often effective in KRAS G12C-driven non-small cell lung cancer (NSCLC) patients. However, acquired resistance limits long-term patient survival. In this issue of the JCI, Tsai et al. present a comprehensive genetic analysis of multiple tumors with acquired sotorasib resistance obtained through an autopsy of a patient with KRAS G12C-mutant NSCLC. This analysis of pre- and posttreatment tumors uncovered cancer cell-intrinsic and -extrinsic features of resistance, including reactivation of KRAS-mediated signaling, reprogramming of metabolism, epithelial-mesenchymal transition, and tumor microenvironment changes. This elegant study demonstrates the multifaceted nature of KRAS G12C inhibitor clinical resistance and potential avenues to overcome resistance.
    DOI:  https://doi.org/10.1172/JCI156891
  100. Nanomaterials (Basel). 2022 Jan 21. pii: 336. [Epub ahead of print]12(3):
    Safety Profile of Rapamycin Perfluorocarbon Nanoparticles for Preventing Cisplatin-Induced Kidney Injury.
    Qingyu Zhou, Justin Doherty, Antonina Akk, Luke E Springer, Ping Fan, Ivan Spasojevic, Ganesh V Halade, Huanghe Yang, Christine T N Pham, Samuel A Wickline, Hua Pan.
      Cancer treatment-induced toxicities may restrict maximal effective dosing for treatment and cancer survivors' quality of life. It is critical to develop novel strategies that mitigate treatment-induced toxicity without affecting the efficacy of anti-cancer therapies. Rapamycin is a macrolide with anti-cancer properties, but its clinical application has been hindered, partly by unfavorable bioavailability, pharmacokinetics, and side effects. As a result, significant efforts have been undertaken to develop a variety of nano-delivery systems for the effective and safe administration of rapamycin. While the efficacy of nanostructures carrying rapamycin has been studied intensively, the pharmacokinetics, biodistribution, and safety remain to be investigated. In this study, we demonstrate the potential for rapamycin perfluorocarbon (PFC) nanoparticles to mitigate cisplatin-induced acute kidney injury with a single preventative dose. Evaluations of pharmacokinetics and biodistribution suggest that the PFC nanoparticle delivery system improves rapamycin pharmacokinetics. The safety of rapamycin PFC nanoparticles was shown both in vitro and in vivo. After a single dose, no disturbance was observed in blood tests or cardiac functional evaluations. Repeated dosing of rapamycin PFC nanoparticles did not affect overall spleen T cell proliferation and responses to stimulation, although it significantly decreased the number of Foxp3+CD4+ T cells and NK1.1+ cells were observed.
    Keywords:  autophagy; biodistribution; cardiac function; immune responses; inflammation; kidney function; perfluorocarbon nanoparticle; pharmacokinetics; rapamycin; spleen
    DOI:  https://doi.org/10.3390/nano12030336
  101. J Ethnopharmacol. 2022 Feb 15. pii: S0378-8741(22)00144-1. [Epub ahead of print] 115106
    Centella asiatica (L.) Urb. attenuates cardiac hypertrophy and improves heart function through multi-level mechanisms revealed by systems pharmacology.
    Bojiao Ding, Weiqing Niu, Siyi Wang, Fan Zhang, Haiqing Wang, Xuetong Chen, Sen Chen, Shuangxin Ma, Wenhui Kang, Mingjuan Wang, Liang Li, Wei Xiao, Zihu Guo, Yonghua Wang.
      ETHNOPHARMACOLOGICAL RELEVANCE: Cardiac hypertrophy (CH) is an incurable heart disease, contributing to an increased risk of heart failure due to the lack of safe and effective strategies. Therefore, searching for new approaches to treat CH is urgent. Centella asiatica (L.) Urb. (CA), a traditional food and medicinal natural plant, has been turned out to be effective in the treatment of cardiovascular disease, but its efficacy and potential mechanisms in alleviating CH have not yet been investigated.AIM OF STUDY: In this study, we aimed to elucidate the multi-level mechanisms underlying the effect of CA against CH.
    STUDY DESIGN AND METHODS: A systems pharmacology approach was employed to screen active ingredients, identify potential targets, construct visual networks and systematically investigate the pathways and mechanisms of CA for CH treatment. The cardiac therapeutic potential and mechanism of action of CA on CH were verified with in vivo and in vitro experiments.
    RESULTS: Firstly, we demonstrated the therapeutic effect of CA on CH and then screened 13 active compounds of CA according to the pharmacokinetic properties. Then, asiatic acid (AA) was identified as the major active molecule of CA for CH treatment. Afterwards, network and functional enrichment analyses showed that CA exerted cardioprotective effects by modulating multiple pathways mainly involved in anti-apoptotic, antioxidant and anti-inflammatory processes. Finally, in vivo, the therapeutic effects of AA and its action on the YAP/PI3K/AKT axis and NF-κB signaling pathway were validated using an isoproterenol-induced CH mouse model. In vitro, AA decreased ROS levels in hydrogen peroxide-treated HL-1 cells.
    CONCLUSION: Overall, the multi-level mechanisms of CA for CH treatment were demonstrated by systems pharmacology approach, which provides a paradigm for systematically deciphering the mechanisms of action of natural plants in the treatment of diseases and offers a new idea for the development of medicinal and food products.
    Keywords:  Asiatic acid; Cardiac hypertrophy; Centella asiatica (L.) Urb.; Molecular mechanisms; Systems pharmacology
    DOI:  https://doi.org/10.1016/j.jep.2022.115106
  102. J Oleo Sci. 2022 Feb 15.
    Introducing a Novel Chemotherapeutic Drug for the Treatment of Lung Adenocarcinoma: Silver Nanoparticles Green-formulated by Cinnamomum verum.
    Jianzhong Zhou, Xiaogang Zheng, Qigui Cai, Chunlin Song.
      In this study we report the green synthesis of nontoxic, stable, and small size silver nanoparticle by Cinnamomum verum with reducing/capping ability without any toxic reducing agents. The in situ prepared AgNPs were characterized by advanced physicochemical techniques like FE-SEM, TEM, and UV-Vis study. It has been established that AgNPs have a spherical shape with a mean diameter from 10 to 45 nm. In the antioxidant test, the IC50 of AgNPs and BHT against DPPH free radicals were 191 and 242 µg/mL, respectively. In the cellular and molecular part of the recent study, the treated cells with AgNPs were assessed by MTT assay for 48 h about the cytotoxicity and anti-human lung adenocarcinoma properties on normal (HUVEC) and lung adenocarcinoma cell lines i.e. PC-14, LC-2/ad, and HLC-1. The IC50 of AgNPs were 259, 291, and 395 µg/mL against PC-14, LC-2/ad, and HLC-1 cell lines, respectively. The viability of malignant lung cell line reduced dose-dependently in the presence of AgNPs.
    Keywords:  Cinnamomum verum; antioxidant; lung cancer; silver nanoparticles
    DOI:  https://doi.org/10.5650/jos.ess21316
  103. Molecules. 2022 Jan 30. pii: 948. [Epub ahead of print]27(3):
    Stimuli-Responsive Drug Delivery Systems for the Diagnosis and Therapy of Lung Cancer.
    Xu Lin, Jiahe Wu, Yupeng Liu, Nengming Lin, Jian Hu, Bo Zhang.
      Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer death worldwide. Numerous drugs have been developed to treat lung cancer patients in recent years, whereas most of these drugs have undesirable adverse effects due to nonspecific distribution in the body. To address this problem, stimuli-responsive drug delivery systems are imparted with unique characteristics and specifically deliver loaded drugs at lung cancer tissues on the basis of internal tumor microenvironment or external stimuli. This review summarized recent studies focusing on the smart carriers that could respond to light, ultrasound, pH, or enzyme, and provided a promising strategy for lung cancer therapy.
    Keywords:  drug delivery; lung cancer; stimuli-responsive
    DOI:  https://doi.org/10.3390/molecules27030948
  104. J Biomed Nanotechnol. 2022 Jan 01. 18(1): 24-49
    Intelligent Nanomedicine Approaches Using Medical Gas-Mediated Multi-Therapeutic Modalities Against Cancer.
    Xuechun Ren, Ying Wang, Liangliang Jia, Xiaoqing Guo, Xinyu He, Zhipeng Zhao, Di Gao, Zhe Yang.
      The emerging area of gas-mediated cancer treatment has received widespread attention in the medical community. Featuring unique physical, chemical, and biological properties, nanomaterials can facilitate the delivery and controllable release of medicinal gases at tumor sites, and also serve as ideal platforms for the integration of other therapeutic modalities with gas therapy to augment cancer therapeutic efficacy. This review presents an overview of anti-cancer mechanisms of several therapeutic gases: nitric oxide (NO), hydrogen sulfide (H₂S), carbon monoxide (CO), oxygen (O₂), and hydrogen (H₂). Controlled release behaviors of gases under different endogenous and exogenous stimuli are also briefly discussed, followed by their synergistic effects with different therapeutic modes. Moreover, the potential challenges and future prospects regarding gas therapy based on nanomaterials are also described, aiming to facilitate the advancement of gas therapeutic nanomedicine in new frontiers for highly efficient cancer treatment.
    DOI:  https://doi.org/10.1166/jbn.2022.3224
  105. ACS Appl Mater Interfaces. 2022 Feb 16.
    Functionalized LbL Film for Localized Delivery of STAT3 siRNA and Oxaliplatin Combination to Treat Colon Cancer.
    Leela Sai Lokesh Janardhanam, Sony Priyanka Bandi, Venkata Vamsi Krishna Venuganti.
      The aim of the study was to develop and evaluate the efficacy of a functionalized layer-by-layer (LbL) assembled film entrapped with oxaliplatin (OX) and signal transducer and activator of transcription 3 (STAT3) siRNA in the localized treatment of colon cancer. The LbL film was prepared by the sequential layering of chitosan (CS) and alginate to attain desired physical and mechanical properties. The film was functionalized by coating folic acid-conjugated CS on one side. On the other side, polycaprolactone was coated as a backing layer to provide directional drug release. OX was entrapped within the layers of the film, while STAT3 siRNA was complexed with CS to form nanoparticles before entrapment in the LbL film. The CS-siRNA nanoparticles were taken up by the colon carcinoma, Caco-2 cells within 3 h and provided concentration-dependent reduction in STAT3 protein expression. The functionalized LbL film (F-LbL film) selectively adhered to the colon cancer tissue in the mice model, whereas the nonfunctionalized film adhered to the normal colon tissue. The combination of OX and STAT3 siRNA provided significantly greater tumor regression, survival rate, and STAT3 protein suppression after localized delivery through oral administration compared with intravenous administration. Taken together, the F-LbL film can selectively bind to colon tumors for localized delivery of drugs to treat colon cancer.
    Keywords:  chitosan-STAT3 siRNA nanoparticles; colon cancer; functionalized layer-by-layer assembled film; localized treatment; oxaliplatin
    DOI:  https://doi.org/10.1021/acsami.1c22166
  106. Food Res Int. 2022 Feb;pii: S0963-9969(21)00771-7. [Epub ahead of print]152 110871
    Agro-industrial by-products: Valuable sources of bioactive compounds.
    Lívia Mateus Reguengo, Mateus Kawata Salgaço, Katia Sivieri, Mário Roberto Maróstica Júnior.
      In a world with eminent scarcity of natural resources and increasing incidence of chronic diseases related to unhealthy eating habits, the search for biologically active and environmentally friendly food products is raising among customers. Agro-industrial by-products have caught special attention from the scientific community for being an available, cost-effective and sustainable source of a wide array of bioactive compounds. Review papers frequently restrain their research to by-products derived from the production of most worldwide consumed crops. Therefore, the aim of this review is to summarize the latest overall research, which focus on the biological potential of agro-industrial by-products and their bioactive compound profile, targeting their application as food ingredients, including not only researches with worldwide consumed crops, but also local foodstuff. A total of 152 research papers, browsed in 2 databases, and involving more than 30 countries were gathered. The richness of bioactive compounds of food by-products from different industries, from fruits to marine products, is ascertained throughout this review. The diversity of food residue being investigated for their nutritional and biological capabilities and the content of specific molecules in each food group are remarkable points. Higher literature reports about fruits by-products may be explained by its wide range of bioactive compounds, especially in Latin American fruits, which includes all flavonoids subclasses, besides betaxanthins, carotenoids and phytosterols. Researchers mainly focus on the quantification of fiber, polyphenols and antioxidant capacity of the investigated by-products, obstructing the investigation of specific biological activities, which are precisely related to the main phytochemicals of the residue matrix, as each molecule has an individual mechanism of action that should be considered when evaluating its biological capabilities. Furthermore, the addition of food by-products has also been advantageous in the production of fortified or enriched bakery, dairy and meat products and functional beverages. All along this literature review, it becomes clearer the high nutritional and nutraceutical value that many by-products possess, besides their attested biological activities, such as antioxidant, anticarcinogenic, antimicrobial, among others.
    Keywords:  Antioxidant capacity; Biological activity; Circular economy; Flavonoids; Food loss and waste; Health benefits; Phenolic acids; Polyphenols; Residue; Sustainability
    DOI:  https://doi.org/10.1016/j.foodres.2021.110871
  107. J Fluoresc. 2022 Feb 15.
    The Fluorescent Effect of Withania Somnifera Chitosan Nanocomposite as an Effective Contrast Agent for Cancer Theragnostic: Experimental Study in Vitro.
    Hala S Abuelmakarem, Mahmoud A Sliem, Jala El-Azab, Mostafa Farghaly, M A Om-Hashem, Wafaa A Ahmed.
      Nanomedicine and fluorescent optical imaging are effective in early cancer detection. The current study synthesized biocompatible nanocomposites from natural biomaterials towards inexpensive and safe cancer theragnostic. Two forms of nanocomposites were synthesized using the ionic gelation method: 1. Chitosan/ Withania Somnifera /tripolyphosphate nanocomposites, 2. Withania Somnifera/Chitosan nanocomposites. The nanocomposites were characterized by dynamic light scattering, zeta potential, and the transmission electron microscope. Fourier transform infrared spectroscopy analyzed the Withania Somnifera root water extract, Chitosan, and the synthesized nanocomposites. The cytotoxicity of the nanocomposites was investigated against the colon cancer cells (Caco2 cells) in the absence and the presence of laser (665 nm, 5 mW) irradiation. MTT assay evaluated the cytotoxicity, and Trypan blue assay assessed the cell viability. Cancerous cells were photographed under the inverted microscope in the presence and the absence of laser irradiation. Results were analyzed statistically using one-way variance (ANOVA) analysis with Bonferroni post-Hoc multiple two-group comparisons. The characterization results ensured the successful synthesis of Withania Somnifera/Chitosan nanocomposites. The results showed an increase in the cytotoxicity against colon carcinoma and a decrease in cell viability in the presence and absence of Near-infrared laser irradiation under the action of nanocomposites. The cytotoxicity of the synthesized nanocomposites increased by exposing the cells to the laser. The shining light of the nanocomposites appeared on the cells photographed under the inverted microscope. The synthesized natural nanocomposites promise systemic cytotoxicity will be efficient in molecular imaging in vivo applications.
    Keywords:  Cancer treatment; Chitosan nanoparticles; Fluorescent nanoparticles; Near infra-red optical imaging; Withania somnifera
    DOI:  https://doi.org/10.1007/s10895-022-02895-5
  108. Front Pharmacol. 2021 ;12 777500
    Safranal Prevents Liver Cancer Through Inhibiting Oxidative Stress and Alleviating Inflammation.
    Youssef Abdalla, Ali Abdalla, Alaaeldin Ahmed Hamza, Amr Amin.
      Despite all efforts, an effective and safe treatment for liver cancer remains elusive. Natural products and their derived biomolecules are potential resources to mine for novel anti-cancer drugs. Chemopreventive effects of safranal, a major bioactive ingredient of the golden spice "saffron", were evaluated in this study against diethylnitrosamine (DEN)-induced liver cancer in rats. Safranal's mechanisms of action were also investigated in the human liver cancer line "HepG2". When administered to DEN-treated rats, safranal significantly inhibited proliferation (Ki-67) and also induced apoptosis (TUNEL and M30 CytoDeath). It also exhibited anti-inflammatory properties where inflammatory markers such as NF-kB, COX2, iNOS, TNF-alpha, and its receptor were significantly inhibited. Safranal's in vivo effects were further supported in HepG2 cells where apoptosis was induced and inflammation was downregulated. In summary, safranal is reported here as a potent chemopreventive agent against hepatocellular carcinoma that may soon be an important ingredient of a broad-spectrum cancer therapy.
    Keywords:  inflammation; liver cancer; oxidative stress; prevention; safranal
    DOI:  https://doi.org/10.3389/fphar.2021.777500
  109. Int J Mol Sci. 2022 Jan 26. pii: 1377. [Epub ahead of print]23(3):
    Curcumin Loaded Nanocarriers with Varying Charges Augmented with Electroporation Designed for Colon Cancer Therapy.
    Julita Kulbacka, Kazimiera A Wilk, Urszula Bazylińska, Magda Dubińska-Magiera, Stanisław Potoczek, Jolanta Saczko.
      (1) Background: The size and surface charge are the most significant parameters of nanocarriers that determine their efficiency and potential application. The poor cell uptake of encapsulated drugs is the main limitation in anticancer treatment. The well-defined properties of nanocarriers will enable to target specific tissue and deliver an active cargo. (2) Methods: In the current study, poly(D,L -lactide) (PLA) nanocarriers loaded with curcumin (CUR) and differing surface charge were evaluated for transport efficacy in combination with electroporation (EP) in dependence on the type of cells. The obtained CUR-loaded nanoparticles with diameters ranging from 195 to 334 nm (derived from dynamic light scattering (DLS)) were characterized by atomic force microscopy (AFM) (morphology and shape) and Doppler electrophoresis (ζ-potential) as well as UV-vis spectroscopy (CUR encapsulation efficiency (about 90%) and photobleaching rate). The drug delivery properties of the obtained PLA nanocarriers enhanced by electroporation were assessed in human colon cancer cells (LoVo), excitable normal rat muscle cells (L6), and free of voltage-gated ion channels cells (CHO-K1). CLSM studies, viability, and ROS release were performed to determine the biological effects of nanocarriers. (3) Results: The highest photodynamic activity indicated anionic nanocarriers (1a) stabilized by C12(COONa)2 surfactant. Nanocarriers were cytotoxic for LoVo cells and less cytotoxic for normal cells. ROS release increased in cancer cells with the increasing electric field intensity, irradiation, and time after EP. Muscle L6 cells were less sensitive to electric pulses. (4) Conclusions: EP stimulation for CUR-PLA nanocarriers transport was considered to improve the regulated and more effective delivery of nanosystems differing in surface charge.
    Keywords:  PLA nanocarriers; colon cancer; curcumin; electroporation; surface charge
    DOI:  https://doi.org/10.3390/ijms23031377
  110. Drug Deliv. 2022 Dec;29(1): 519-533
    Multifunctional liposome for photoacoustic/ultrasound imaging-guided chemo/photothermal retinoblastoma therapy.
    Meng Li, Xintong Bian, Xu Chen, Ningke Fan, Hongmi Zou, Yixi Bao, Yu Zhou.
      Retinoblastoma (RB) is a malignant intraocular neoplasm that occurs in children. Diagnosis and therapy are frequently delayed, often leading to metastasis, which necessitates effective imaging and treatment. In recent years, the use of nanoplatforms allowing both imaging and targeted treatment has attracted much attention. Herein, we report a novel nanoplatform folate-receptor (FR) targeted laser-activatable liposome termed FA-DOX-ICG-PFP@Lip, which is loaded with doxorubicin (DOX)/indocyanine green (ICG) and liquid perfluoropentane (PFP) for photoacoustic/ultrasound (PA/US) dual-modal imaging-guided chemo/photothermal RB therapy. The dual-modal imaging capability, photothermal conversion under laser irradiation, biocompatibility, and antitumor ability of these liposomes were appraised. The multifunctional liposome showed a good tumor targeting ability and was efficacious as a dual-modality contrast agent both in vivo and in vitro. When laser-irradiated, the liposome converted light energy to heat. This action caused immediate destruction of tumor cells, while simultaneously initiating PFP phase transformation to release DOX, resulting in both photothermal and chemotherapeutic antitumor effects. Notably, the FA-DOX-ICG-PFP@Lip showed good biocompatibility and no systemic toxicity was observed after laser irradiation in RB tumor-bearing mice. Hence, the FA-DOX-ICG-PFP@Lip shows great promise for dual-modal imaging-guided chemo/photothermal therapy, and may have significant value for diagnosing and treating RB.
    Keywords:  Nanoplatform; doxorubicin; dual-modal imaging; photothermal therapy; retinoblastoma
    DOI:  https://doi.org/10.1080/10717544.2022.2032876
  111. Drug Discov Today. 2022 Feb 11. pii: S1359-6446(22)00045-9. [Epub ahead of print]
    Recent advances in developing polymeric micelles for treating cancer: breakthroughs and bottlenecks in their clinical translation.
    Jaskiran Kaur, Monica Gulati, Niraj Kumar Jha, John Disouza, Vandana Patravale, Kamal Dua, Sachin Kumar Singh.
      Polymeric micelles (PMs) have been explored pre-clinically for the delivery of chemotherapeutics to treat cancer. Their unique features, such as easy surface functionalization, stimuli-responsiveness, good stability, ability to modify drug release, enhanced permeation and retention effect, and potential to encapsulate more than one type of therapeutic molecules at a time, make them unique carriers for the targeted delivery or for enhancing the bioavailability of chemotherapeutics. PMs can also be used as theranostic nanocarriers for the mapping of drug therapy along with tumor imaging in patients with cancer. This review focuses on the limitations of existing treatment strategies and on innovative approaches employed for the functionalization of PMs for targeting cancer cells. In addition, the bottlenecks associated with the translation of PMs from the laboratory to clinics are also discussed.
    Keywords:  cancer; clinical applications; polymeric micelles; site-specificity; theranostic
    DOI:  https://doi.org/10.1016/j.drudis.2022.02.005
  112. Front Neurosci. 2021 ;15 767405
    Nutritional Impact on Metabolic Homeostasis and Brain Health.
    Lionel Carneiro, Luc Pellerin.
      Aging in modern societies is often associated with various diseases including metabolic and neurodegenerative disorders. In recent years, researchers have shown that both dysfunctions are related to each other. Although the relationship is not fully understood, recent evidence indicate that metabolic control plays a determinant role in neural defects onset. Indeed, energy balance dysregulation affects neuroenergetics by altering energy supply and thus neuronal activity. Consistently, different diets to help control body weight, blood glucose or insulin sensitivity are also effective in improving neurodegenerative disorders, dampening symptoms, or decreasing the risk of disease onset. Moreover, adapted nutritional recommendations improve learning, memory, and mood in healthy subjects as well. Interestingly, adjusted carbohydrate content of meals is the most efficient for both brain function and metabolic regulation improvement. Notably, documented neurological disorders impacted by specific diets suggest that the processes involved are inflammation, mitochondrial function and redox balance as well as ATP production. Interestingly, processes involving inflammation, mitochondrial function and redox balance as well as ATP production are also described in brain regulation of energy homeostasis. Therefore, it is likely that changes in brain function induced by diets can affect brain control of energy homeostasis and other brain functions such as memory, anxiety, social behavior, or motor skills. Moreover, a defect in energy supply could participate to the development of neurodegenerative disorders. Among the possible processes involved, the role of ketone bodies metabolism, neurogenesis and synaptic plasticity, oxidative stress and inflammation or epigenetic regulations as well as gut-brain axis and SCFA have been proposed in the literature. Therefore, the goal of this review is to provide hints about how nutritional studies could help to better understand the tight relationship between metabolic balance, brain activity and aging. Altogether, diets that help maintaining a metabolic balance could be key to both maintain energy homeostasis and prevent neurological disorders, thus contributing to promote healthy aging.
    Keywords:  aging; cognition; metabolism; neurological disorder; nutrient sensing; nutrition
    DOI:  https://doi.org/10.3389/fnins.2021.767405
  113. Nanomaterials (Basel). 2022 Jan 27. pii: 434. [Epub ahead of print]12(3):
    Triblock Copolymer Micelles with Tunable Surface Charge as Drug Nanocarriers: Synthesis and Physico-Chemical Characterization.
    Radostina Kalinova, Ivaylo Dimitrov.
      Polymeric micelles have gained increasing interest as efficient drug delivery systems for cancer treatment and diagnosis. The aim of the present study was to construct and to evaluate novel polymeric nanosized drug carriers with tunable surface charges. Initially, amphiphilic triblock copolymers with predetermined molar mass characteristics were synthesized by applying controlled polymerization techniques. The copolymers self-assembled in aqueous media into core-shell spherical micelles, comprising a biodegradable hydrophobic poly(D,L-lactide) core, positively charged middle layer of poly((2-dimethylamino)ethyl methacrylate), and an outer shell of neutral hydrophilic poly(oligo(ethylene glycol) methyl ether methacrylate), with various densities of the short polyether side chains. The block copolymer micelles with average diameters of about 70 nm and surface charges varying from strongly positive to neutral were characterized and loaded with the model, natural, hydrophobic drug curcumin. Characteristics such as drug loading efficiency, in-vitro drug release profiles, and stability under physiological conditions were evaluated and discussed in terms of nanocarriers' composition. As a result, the most promising candidates for potential application in nanomedicine were identified.
    Keywords:  amphiphilic block copolymers; curcumin; drug delivery; micelles; nanocarriers; stability; synthesis
    DOI:  https://doi.org/10.3390/nano12030434
  114. Front Pharmacol. 2022 ;13 786712
    Syzygium jambos L. Alston: An Insight Into its Phytochemistry, Traditional Uses, and Pharmacological Properties.
    Melvin Adhiambo Ochieng, Widad Ben Bakrim, Gabin Thierry M Bitchagno, Mona F Mahmoud, Mansour Sobeh.
      Medicinal plants have been used since ancient times for human healthcare as drugs, spices, and food additives. The progress in technology and medicine observed, the last decades, has improved the quality of life and healthcare but with worrisome drawbacks. Side effects caused by synthetic drugs for instance originate sometimes irreversible health disorders. Natural substances, in contrast, are biologically and environmentally friendly. Syzygium jambos L. (Alston) also known as rose apple conveys a long history as essential traditional medicine with a broad spectrum of application in various cultures. The plant discloses a diverse group of secondary metabolites and extracts that displayed major susceptibilities towards various health concerns especially stress-related and inflammatory diseases. Despite a rich literature about the plant, the chemistry and biology of S. jambos have not been comprehensively reviewed yet. Accordingly, we present herein a literature survey of rose apple which aims to draw the chemical identity of the plant and establish a consistent discussion on the respective biological application of plant extracts and their corresponding traditional uses. The present work could provide a scientific basis for future studies and necessary information for further investigations of new drug discovery.
    Keywords:  Syzygium jambos; antiinflammatory; antioxidant; medicinal plants; pharmacological activities
    DOI:  https://doi.org/10.3389/fphar.2022.786712
  115. Front Cell Dev Biol. 2022 ;10 761080
    p53 Modulation of Autophagy Signaling in Cancer Therapies: Perspectives Mechanism and Therapeutic Targets.
    Md Ataur Rahman, Moon Nyeo Park, Md Hasanur Rahman, Md Mamunur Rashid, Rokibul Islam, Md Jamal Uddin, Md Abdul Hannan, Bonglee Kim.
      The key tumor suppressor protein p53, additionally known as p53, represents an attractive target for the development and management of anti-cancer therapies. p53 has been implicated as a tumor suppressor protein that has multiple aspects of biological function comprising energy metabolism, cell cycle arrest, apoptosis, growth and differentiation, senescence, oxidative stress, angiogenesis, and cancer biology. Autophagy, a cellular self-defense system, is an evolutionarily conserved catabolic process involved in various physiological processes that maintain cellular homeostasis. Numerous studies have found that p53 modulates autophagy, although the relationship between p53 and autophagy is relatively complex and not well understood. Recently, several experimental studies have been reported that p53 can act both an inhibitor and an activator of autophagy which depend on its cellular localization as well as its mode of action. Emerging evidences have been suggested that the dual role of p53 which suppresses and stimulates autophagy in various cencer cells. It has been found that p53 suppression and activation are important to modulate autophagy for tumor promotion and cancer treatment. On the other hand, activation of autophagy by p53 has been recommended as a protective function of p53. Therefore, elucidation of the new functions of p53 and autophagy could contribute to the development of novel therapeutic approaches in cancer biology. However, the underlying molecular mechanisms of p53 and autophagy shows reciprocal functional interaction that is a major importance for cancer treatment and manegement. Additionally, several synthetic drugs and phytochemicals have been targeted to modulate p53 signaling via regulation of autophagy pathway in cancer cells. This review emphasizes the current perspectives and the role of p53 as the main regulator of autophagy-mediated novel therapeutic approaches against cancer treatment and managements.
    Keywords:  apoptosis; autophagy; p53; phytochemical; synthetic drug; tumor suppressor
    DOI:  https://doi.org/10.3389/fcell.2022.761080
  116. Nutr Rev. 2022 Feb 16. pii: nuac008. [Epub ahead of print]
    Western and ketogenic diets in neurological disorders: can you tell the difference?
    Karl John Habashy, Fatima Ahmad, Stanley Ibeh, Sarah Mantash, Fatima Kobeissy, Hawraa Issa, Ralph Habis, Ali Tfaily, Sanaa Nabha, Hayat Harati, Mohammad Amine Reslan, Yara Yehya, Chloe Barsa, Abdullah Shaito, Kazem Zibara, Ahmed F El-Yazbi, Firas H Kobeissy.
      The prevalence of obesity tripled worldwide between 1975 and 2016, and it is projected that half of the US population will be overweight by 2030. The obesity pandemic is attributed, in part, to the increasing consumption of the high-fat, high-carbohydrate Western diet, which predisposes to the development of the metabolic syndrome and correlates with decreased cognitive performance. In contrast, the high-fat, low-carbohydrate ketogenic diet has potential therapeutic roles and has been used to manage intractable seizures since the early 1920s. The brain accounts for 25% of total body glucose metabolism and, as a result, is especially susceptible to changes in the types of nutrients consumed. Here, we discuss the principles of brain metabolism with a focus on the distinct effects of the Western and ketogenic diets on the progression of neurological diseases such as epilepsy, Parkinson's disease, Alzheimer's disease, and traumatic brain injury, highlighting the need to further explore the potential therapeutic effects of the ketogenic diet and the importance of standardizing dietary formulations to assure the reproducibility of clinical trials.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; aging; epilepsy; high-fat diet; ketogenic diet; neuroinflammation; neurologic disorders; neurometabolism; traumatic brain injury; western diet
    DOI:  https://doi.org/10.1093/nutrit/nuac008
  117. Int J Biol Macromol. 2022 Feb 15. pii: S0141-8130(22)00282-3. [Epub ahead of print]
    Pro-oxidant vitamin C mechanistically exploits p66Shc/Rac1GTPase pathway in inducing cytotoxicity.
    Hilal Ahmad Mir, Roshia Ali, Zahoor Ahmad Wani, Firdous Ahmad Khanday.
      P66Shc is the master regulator of oxidative stress whose pro-oxidant functioning is governed by ser36 phosphorylation. Phosphorylated p66Shc via Rac1GTPase activation modulates ROS levels which in turn influence its pro-oxidative functions. Vitamin C at higher concentrations exhibits cytotoxic activity in various cancers, inducing ROS mediated cell death via pro-apoptotic mechanisms. Here we show a novel role of p66Shc in mediating pro-oxidant activity of vitamin C. Effect of vitamin C on the viability of breast cancer and normal cells was studied. High doses of vitamin C decreased viability of cancerous cells but not normal cells. Docking study displayed significant binding affinity of vitamin C with p66Shc PTB domain. Western blot results suggest that vitamin C not only enhances p66Shc expression but also induces its ser36 phosphorylation. Vitamin C at high doses was also found to activate Rac1, enhance ROS production and induce apoptosis. Interestingly, ser36 phosphorylation mutant transfection and pretreatment with antioxidant N-acetylcysteine results indicate that vitamin C induced Rac1 activation, ROS production and apoptosis is p66Shc ser36 phosphorylation dependent. Overall, results highlight that vitamin C mechanistically explores p66Shc/Rac1 pathway in inducing apoptosis and thus can pave a way to use this pathway as a potential therapeutic target in breast cancers.
    Keywords:  Apoptosis; P66Shc; ROS; Rac1; Vitamin C; cancer
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.02.046
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