bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2022–10–30
151 papers selected by
Yasmin Elkabani, Egyptian Foundation for Research and Community Development
  1. Prodrug and Glucose Oxidase Coloaded Photodynamic Hydrogels for Combinational Therapy of Melanoma.
  2. Searching for the Metabolic Signature of Cancer: A Review from Warburg's Time to Now.
  3. Synthesis and Characterization of Curcumin-Loaded Nanoparticles of Poly(Glycerol Sebacate): A Novel Highly Stable Anticancer System.
  4. Juglone promotes antitumor activity against prostate cancer via suppressing glycolysis and oxidative phosphorylation.
  5. Updates on Responsive Drug Delivery Based on Liposome Vehicles for Cancer Treatment.
  6. Development of Biotechnological Photosensitizers for Photodynamic Therapy: Cancer Research and Treatment-From Benchtop to Clinical Practice.
  7. Solid lipid nanoparticles: a promising tool for insulin delivery.
  8. Epigenetic Reprogramming of the Glucose Metabolic Pathways by the Chromatin Effectors During Cancer.
  9. Identification of Natural Compounds as Inhibitors of Pyruvate Kinase M2 for Cancer Treatment.
  10. Reprogramming Carbohydrate Metabolism in Cancer and Its Role in Regulating the Tumor Microenvironment.
  11. Correlation of Glucose Metabolism with Cancer and Intervention with Traditional Chinese Medicine.
  12. Targeting amino acid metabolism in cancer.
  13. Rosmarinic Acid and Related Dietary Supplements: Potential Applications in the Prevention and Treatment of Cancer.
  14. Advancements in Rectal Drug Delivery Systems: Clinical Trials, and Patents Perspective.
  15. Amino acid metabolism in primary bone sarcomas.
  16. Cinnamaldehyde-modified chitosan hybrid nanoparticles for DOX delivering to produce synergistic anti-tumor effects.
  17. Novel Therapeutic Approach in PEGylated Chitosan Nanoparticles of Apigenin for the Treatment of Cancer via Oral Nanomedicine.
  18. Conquering Cancer Multi-Drug Resistance Using Curcumin and Cisplatin Prodrug-Encapsulated Mesoporous Silica Nanoparticles for Synergistic Chemo- and Photodynamic Therapies.
  19. Natural Products for Liver Cancer Treatment: From Traditional Medicine to Modern Drug Discovery.
  20. Development of Glycyrrhetinic Acid and Folate Modified Cantharidin Loaded Solid Lipid Nanoparticles for Targeting Hepatocellular Carcinoma.
  21. Antidepressant Drug Sertraline against Human Cancer Cells.
  22. Amygdalin: A Review on Its Characteristics, Antioxidant Potential, Gastrointestinal Microbiota Intervention, Anticancer Therapeutic and Mechanisms, Toxicity, and Encapsulation.
  23. Novel archetype in cancer therapeutics: exploring prospective of phytonanocarriers.
  24. Modulation of Macrophages Using Nanoformulations with Curcumin to Treat Inflammatory Diseases: A Concise Review.
  25. Targeting KRAS in PDAC: A New Way to Cure It?
  26. Anti-cancer effect and potential microRNAs targets of ginsenosides against breast cancer.
  27. Combination strategies to target metabolic flexibility in cancer.
  28. Flavonoids for the treatment of breast cancer, present status and future prospective.
  29. Fasting and cancer responses to therapy.
  30. Smart Multistage "Trojan Horse"-Inspired Bovine Serum Albumin-Coated Liposomes for Enhancing Tumor Penetration and Antitumor Efficacy.
  31. A Recent Review on Bio-availability Enhancement of Poorly Water-Soluble Drugs by Using Bioenhancer and Nanoparticulate Drug Delivery System.
  32. Regulators of epigenetic change in ferroptosis‑associated cancer (Review).
  33. Drugging KRAS: current perspectives and state-of-art review.
  34. Role of curcumin and its nanoformulations in the treatment of neurological diseases through the effects on stem cells.
  35. A Comprehensive Review on Nanomedicine: Promising approach for treatment of brain tumor through intranasal administration.
  36. Solid lipid nanoparticles (slns): Advancements in modification strategies toward drug delivery vehicle.
  37. Glycolytic Inhibitors Potentiated the Activity of Paclitaxel and Their Nanoencapsulation Increased Their Delivery in a Lung Cancer Model.
  38. Pharmacological treatment strategies of pterygium: drugs, biologics, and novel natural products.
  39. Co-Delivery of Dihydroartemisinin and Indocyanine Green by Metal-Organic Framework-Based Vehicles for Combination Treatment of Hepatic Carcinoma.
  40. Enhanced skin localization of metronidazole using solid lipid microparticles incorporated into polymeric hydrogels for potential improved of rosacea treatment: An ex vivo proof of concept investigation.
  41. Grape Pomace Polyphenols as a Source of Compounds for Management of Oxidative Stress and Inflammation-A Possible Alternative for Non-Steroidal Anti-Inflammatory Drugs?
  42. Ferroptosis: Shedding Light on Mechanisms and Therapeutic Opportunities in Liver Diseases.
  43. The Use of Photodynamic Therapy in the Treatment of Brain Tumors-A Review of the Literature.
  44. The Credible Role of Curcumin in Oxidative Stress-Mediated Mitochondrial Dysfunction in Mammals.
  45. Polymeric nanoparticles-Promising carriers for cancer therapy.
  46. Epigenetic Small-Molecule Modulators Targeting Metabolic Pathways in Cancer.
  47. Polyphenols and Their Nanoformulations: Protective Effects against Human Diseases.
  48. Organ restricted delivery through stimuli responsive nanocarriers for lung cancer therapy.
  49. Curcumin Hybrid Lipid Polymeric Nanoparticles: Antioxidant Activity, Immune Cellular Response, and Cytotoxicity Evaluation.
  50. PTEN-knockout regulates metabolic rewiring and epigenetic reprogramming in prostate cancer and chemoprevention by triterpenoid ursolic acid.
  51. Antioxidants in brain tumors: current therapeutic significance and future prospects.
  52. TCA-phospholipid-glycolysis targeted triple therapy effectively suppresses ATP production and tumor growth in glioblastoma.
  53. Targeting Asparagine Synthetase in Tumorgenicity Using Patient-Derived Tumor-Initiating Cells.
  54. Precise Design Strategies of Nanotechnologies for Controlled Drug Delivery.
  55. Evaluation of the Effects of Genistein In Vitro as a Chemopreventive Agent for Colorectal Cancer-Strategy to Improve Its Efficiency When Administered Orally.
  56. Apoptin inhibits glycolysis and regulates autophagy by targeting pyruvate kinase M2 (PKM2) in lung cancer A549 cells.
  57. Combination of an autophagy inhibitor with immunoadjuvants and an anti-PD-L1 antibody in multifunctional nanoparticles for enhanced breast cancer immunotherapy.
  58. Engineering of QbD driven and ultrasonically shaped lyotropic liquid crystalline nanoparticles for Apigenin in the management of skin cancer.
  59. Vitamin K Contribution to DNA Damage-Advantage or Disadvantage? A Human Health Response.
  60. Progress of Research in In Situ Smart Hydrogels for Local Antitumor Therapy: A Review.
  61. Alginate-Based Micro- and Nanosystems for Targeted Cancer Therapy.
  62. Metabolic Regulation of Lysine Acetylation: Implications in Cancer.
  63. The Rate of Cisplatin Dosing Affects the Resistance and Metastatic Potential of Triple Negative Breast Cancer Cells, Independent of Hypoxia.
  64. Diclofenac Sensitizes Signet Ring Cell Gastric Carcinoma Cells to Cisplatin by Activating Autophagy and Inhibition of Survival Signal Pathways.
  65. Antioxidative and Anti-Inflammatory Activity of Ascorbic Acid.
  66. Curcumin-Encapsulated Nanomicelles Improve Cellular Uptake and Cytotoxicity in Cisplatin-Resistant Human Oral Cancer Cells.
  67. Non-Canonical Functions of Myeloperoxidase in Immune Regulation, Tissue Inflammation and Cancer.
  68. Regulation of Lipid Metabolism Under Stress and Its Role in Cancer.
  69. Light-Activated Reactive Oxygen Species-Responsive Nanocarriers for Enhanced Photodynamic Immunotherapy of Cancer.
  70. The pathogenesis of liver cancer and the therapeutic potential of bioactive substances.
  71. Sustained Drug Release from Smart Nanoparticles in Cancer Therapy: A Comprehensive Review.
  72. Upregulation of Succinate Dehydrogenase (SDHA) Contributes to Enhanced Bioenergetics of Ovarian Cancer Cells and Higher Sensitivity to Anti-Metabolic Agent Shikonin.
  73. Analyzing the metabolic fate of oral administration drugs: A review and state-of-the-art roadmap.
  74. Pancreatic Cancer Research beyond DNA Mutations.
  75. Disturbance of the Warburg effect by dichloroacetate and niclosamide suppresses the growth of different sub-types of malignant pleural mesothelioma in vitro and in vivo.
  76. Dietary Interventions in Cancer Treatment and Response: A Comprehensive Review.
  77. Ultrasound Responsive Smart Implantable Hydrogels for Targeted Delivery of Drugs: Reviewing Current Practices.
  78. Effect of surface ligand modification on the properties of anti-tumor nanocarrier.
  79. Size-transformable gelatin/nanochitosan/doxorubicin nanoparticles with sequentially triggered drug release for anticancer therapy.
  80. Curcumin Targeting Non-Coding RNAs in Colorectal Cancer: Therapeutic and Biomarker Implications.
  81. Inhibition of Phosphoglycerate Dehydrogenase Radiosensitizes Human Colorectal Cancer Cells under Hypoxic Conditions.
  82. Liposomal Drug Delivery Systems for Cancer Therapy: The Rotterdam Experience.
  83. Natural cell based biomimetic cellular transformers for targeted therapy of digestive system cancer.
  84. Aptamer-Functionalized Nanoparticles Mediate PD-L1 siRNA Delivery for Effective Gene Silencing in Triple-Negative Breast Cancer Cells.
  85. Chemopreventive Effect on Human Colon Adenocarcinoma Cells of Styrylquinolines: Synthesis, Cytotoxicity, Proapoptotic Effect and Molecular Docking Analysis.
  86. New Approach for Preparing Solid Lipid Nanoparticles with Volatile Oil-Loaded Quercetin Using the Phase-Inversion Temperature Method.
  87. Design Optimization and Evaluation of Solid Lipid Nanoparticles of Azelnidipine for the treatment of Hypertension.
  88. Potential benefits of metformin and pioglitazone combination therapy via gut microbiota and metabolites in high-fat diet-fed mice.
  89. A Comprehensive Study of Therapeutic Applications of Chamomile.
  90. Vitamin E in Cancer Treatment: A Review of Clinical Applications in Randomized Control Trials.
  91. CoQ10 and Resveratrol Effects to Ameliorate Aged-Related Mitochondrial Dysfunctions.
  92. Fasting and cancer: from yeast to mammals.
  93. Attenuation by Time-Restricted Feeding of High-Fat and High-Fructose Diet-Induced NASH in Mice Is Related to Per2 and Ferroptosis.
  94. Circular RNAs: Emerging regulators of glucose metabolism in cancer.
  95. Tailoring carrier-free nanocombo of small-molecule prodrug for combinational cancer therapy.
  96. Risk-Assessment-Based Optimization Favours the Development of Albumin Nanoparticles with Proper Characteristics Prior to Drug Loading.
  97. Polyphenols, Saponins and Phytosterols in Lentils and Their Health Benefits: An Overview.
  98. The Activity of Vitamin C Against Ovarian Cancer Cells Is Enhanced by Hyperthermia.
  99. Harnessing the dual role of polysaccharides in treating gastrointestinal diseases: As therapeutics and polymers for drug delivery.
  100. Lipid-Encapsuled Grape Tannins Prevent Oxidative-Stress-Induced Neuronal Cell Death, Intracellular ROS Accumulation and Inflammation.
  101. Molecular Pathways Related to Sulforaphane as Adjuvant Treatment: A Nanomedicine Perspective in Breast Cancer.
  102. Design and optimization of Metformin-Loaded Solid Lipid Nanoparticles for Neuroprotective effects in a rat model of diffuse traumatic brain injury: A biochemical, behavioral, and histological study.
  103. Gefitinib: An Updated Review of its Role in the Cancer Management, its Nanotechnological Interventions, Recent Patents and Clinical Trials.
  104. The Next Generation of KRAS Targeting: Reasons for Excitement and Concern.
  105. Nanoparticles: The future of effective diagnosis and treatment of colorectal cancer?
  106. Improving the Bioaccessibility and Bioavailability of Carotenoids by Means of Nanostructured Delivery Systems: A Comprehensive Review.
  107. Progress in the Surface Functionalization of Selenium Nanoparticles and Their Potential Application in Cancer Therapy.
  108. Modulation of DNA/RNA Methylation Signaling Mediating Metabolic Homeostasis in Cancer.
  109. The Protective Effect of CBD in a Model of In Vitro Ischemia May Be Mediated by Agonism on TRPV2 Channel and Microglia Activation.
  110. Hydroxyzine Induces Cell Death in Triple-Negative Breast Cancer Cells via Mitochondrial Superoxide and Modulation of Jak2/STAT3 Signaling.
  111. Curcumin Nanodiscs Improve Solubility and Serve as Radiological Protectants against Ionizing Radiation Exposures in a Cell-Cycle Dependent Manner.
  112. Sodium Alginate-Natural Microencapsulation Material of Polymeric Microparticles.
  113. Advances in the Study of Hexokinase 2 (HK2) Inhibitors.
  114. Effect of Vitamin D on Bone Regeneration: A Review.
  115. Modulation of the activity of histone lysine methyltransferases and demethylases by curcumin analog in leukaemia cells.
  116. Sahlep (Dactylorhiza osmanica): Phytochemical Analyses by LC-HRMS, Molecular Docking, Antioxidant Activity, and Enzyme Inhibition Profiles.
  117. Pharmacological and Therapeutic Applications of Esculetin.
  118. Designing Deferoxamine-Loaded Flaxseed Gum and Carrageenan-Based Controlled Release Biocomposite Hydrogel Films for Wound Healing.
  119. Natural Products for the Treatment of Drug Addiction: a Narrative review.
  120. The α-Ketoglutarate Dehydrogenase Complex as a Hub of Plasticity in Neurodegeneration and Regeneration.
  121. A Review on Proniosomes: A Propitious Outlook to the Provesicular Drug Delivery System.
  122. Short- and long- term efficacy of Very Low and Low Calorie Ketogenic Diets on metabolic and cardiometabolic risk factors: a narrative review.
  123. Novel Strategies for Cancer Combat: Drug Combination Using Repurposed Drugs Induces Synergistic Growth Inhibition of MCF-7 Breast and HT-29 Colon Cancer Cells.
  124. TRAIL in the Treatment of Cancer: From Soluble Cytokine to Nanosystems.
  125. Iron in Cancer Progression: Does BACH1 Promote Metastasis by Altering Iron Homeostasis?
  126. Vitamin E and Non-Communicable Diseases: A Review.
  127. Role of ginsenoside Rh2 in tumor therapy and tumor microenvironment immunomodulation.
  128. Polycaprolactone based pharmaceutical nanoemulsion loaded with acriflavine: optimization and in vivo burn wound healing activity.
  129. Platelet-promoting drug delivery efficiency for inhibition of tumor growth, metastasis, and recurrence.
  130. Gut Microbiome: The Interplay of an "Invisible Organ" with Herbal Medicine and Its Derived Compounds in Chronic Metabolic Disorders.
  131. Blood-Brain Barrier Transport of Transferrin Receptor-Targeted Nanoparticles.
  132. Co-encapsulation of quercetin and resveratrol in zein/carboxymethyl cellulose nanoparticles: characterization, stability and in vitro digestion.
  133. Novel Metoprolol-Loaded Chitosan-Coated Deformable Liposomes in Thermosensitive In Situ Gels for the Management of Glaucoma: A Repurposing Approach.
  134. Marine Compounds, Mitochondria, and Malignancy: A Therapeutic Nexus.
  135. The role of melatonin in the development of postmenopausal osteoporosis.
  136. New insights into ruthenium(II) metallodendrimers as anticancer drug nanocarriers: from synthesis to preclinic behaviour.
  137. Alpinumisoflavone Impairs Mitochondrial Respiration via Oxidative Stress and MAPK/PI3K Regulation in Hepatocellular Carcinoma Cells.
  138. H2O2/pH Dual-Responsive Biomimetic Nanoenzyme Drugs Delivery System for Enhanced Tumor Photodynamic Therapy.
  139. Ultraviolet Radiation Protective and Anti-Inflammatory Effects of Kaempferia galanga L. Rhizome Oil and Microemulsion: Formulation, Characterization, and Hydrogel Preparation.
  140. Chemical Modification of Curcumin into Its Semi-Synthetic Analogs Bearing Pyrimidinone Moiety as Anticancer Agents.
  141. Enhanced manipulation of tumor microenvironments by nanomotor for synergistic therapy of malignant tumor.
  142. A comparative analysis of low intensity ultrasound effects on living cells: from simulation to experiments.
  143. Hydrogel on a Smart Nanomaterial Interface to Carry Therapeutics for Digitalized Glioma Treatment.
  144. Link between glucose metabolism and epithelial-to-mesenchymal transition drives triple-negative breast cancer migratory heterogeneity.
  145. Anti-inflammatory therapeutics: Conventional concepts and future with nanotechnology.
  146. Gut and breast microbiota as endocrine regulators of hormone receptor-positive breast cancer risk and therapy response.
  147. Preparation of pH-Responsive Hydrogels Based on Chondroitin Sulfate/Alginate for Oral Drug Delivery.
  148. Epigenetic Regulation During Hypoxia and Its Implications in Cancer.
  149. Lysosomes and Their Role in Regulating the Metabolism of Hematopoietic Stem Cells.
  150. Computational pharmacogenomic screen identifies drugs that potentiate the anti-breast cancer activity of statins.
  151. Overview of Physicochemical Properties of Nanoparticles as Drug Carriers for Targeted Cancer Therapy.
  1. ACS Biomater Sci Eng. 2022 Oct 24.
    Prodrug and Glucose Oxidase Coloaded Photodynamic Hydrogels for Combinational Therapy of Melanoma.
    Jianhui Zhou, Changcun Liu, Yue Wang, Mengbin Ding, Ningyue Yu, Dongliang Liu, Qin Zhang, Jingchao Li.
      With the advantages of high safety and selectivity, photodynamic therapy (PDT) has been widely used for cancer treatments, while the anticancer efficacy is often limited because of its relying on oxygen concentrations. Therefore, sole PDT fails to achieve the desired therapeutic effect for hypoxic tumors. To address this issue, we herein report the construction of prodrug and glucose oxidase (GOx) coloaded alginate (ALG) hydrogels for PDT-combined chemotherapy of melanoma. The hydrogels are in situ formed in tumor sites after injection of ALG solution containing semiconducting polymer nanoparticles, hypoxia-responsive prodrug tirapazamine (TPZ), and GOx, which is based on chelation of ALG by endogenous Ca2+. Due to the presence of semiconducting polymer nanoparticles acting as photosensitizers, the hydrogels mediate PDT to produce singlet oxygen (1O2) for directly killing tumor cells, in which oxygen is consumed to create a more hypoxic tumor microenvironment. Moreover, the loaded GOx within hydrogels can deplete oxygen to further aggravate tumor hypoxia. As such, TPZ is effectively activated by hypoxia to cause cancer cell death via chemotherapy. Thus, the hydrogels with laser irradiation achieve a combinational action of PDT with chemotherapy to almost completely eradicate tumors, leading to a much higher therapeutic efficacy relative to sole PDT. This study will provide a promising injectable hydrogel platform for effective treatments of cancer.
    Keywords:  cancer therapy; injectable hydrogels; photodynamic therapy; prodrug; tumor hypoxia
    DOI:  https://doi.org/10.1021/acsbiomaterials.2c00992
  2. Biomolecules. 2022 Oct 02. pii: 1412. [Epub ahead of print]12(10):
    Searching for the Metabolic Signature of Cancer: A Review from Warburg's Time to Now.
    Pierre Jacquet, Angélique Stéphanou.
      This review focuses on the evolving understanding that we have of tumor cell metabolism, particularly glycolytic and oxidative metabolism, and traces back its evolution through time. This understanding has developed since the pioneering work of Otto Warburg, but the understanding of tumor cell metabolism continues to be hampered by misinterpretation of his work. This has contributed to the use of the new concepts of metabolic switch and metabolic reprogramming， that are out of step with reality. The Warburg effect is often considered to be a hallmark of cancer, but is it really? More generally, is there a metabolic signature of cancer? We draw the conclusion that the signature of cancer cannot be reduced to a single factor, but is expressed at the tissue level in terms of the capacity of cells to dynamically explore a vast metabolic landscape in the context of significant environmental heterogeneities.
    Keywords:  Warburg effect; metabolic landscape; metabolic reprogramming; metabolic switch; reverse Warburg
    DOI:  https://doi.org/10.3390/biom12101412
  3. Molecules. 2022 Oct 18. pii: 6997. [Epub ahead of print]27(20):
    Synthesis and Characterization of Curcumin-Loaded Nanoparticles of Poly(Glycerol Sebacate): A Novel Highly Stable Anticancer System.
    Alessio Massironi, Stefania Marzorati, Alessandra Marinelli, Marta Toccaceli, Stefano Gazzotti, Marco Aldo Ortenzi, Daniela Maggioni, Katia Petroni, Luisella Verotta.
      The research for alternative administration methods for anticancer drugs, towards enhanced effectiveness and selectivity, represents a major challenge for the scientific community. In the last decade, polymeric nanostructured delivery systems represented a promising alternative to conventional drug administration since they ensure secure transport to the selected target, providing active compounds protection against elimination, while minimizing drug toxicity to non-target cells. In the present research, poly(glycerol sebacate), a biocompatible polymer, was synthesized and then nanostructured to allow curcumin encapsulation, a naturally occurring polyphenolic phytochemical isolated from the powdered rhizome of Curcuma longa L. Curcumin was selected as an anticancer agent in virtue of its strong chemotherapeutic activity against different cancer types combined with good cytocompatibility within healthy cells. Despite its strong and fascinating biological activity, its possible exploitation as a novel chemotherapeutic has been hampered by its low water solubility, which results in poor absorption and low bioavailability upon oral administration. Hence, its encapsulation within nanoparticles may overcome such issues. Nanoparticles obtained through nanoprecipitation, an easy and scalable technique, were characterized in terms of size and stability over time using dynamic light scattering and transmission electron microscopy, confirming their nanosized dimensions and spherical shape. Finally, biological investigation demonstrated an enhanced cytotoxic effect of curcumin-loaded PGS-NPs on human cervical cancer cells compared to free curcumin.
    Keywords:  curcumin; drug delivery system; human cervical cancer; nanoparticles; poly(glycerol sebacate)
    DOI:  https://doi.org/10.3390/molecules27206997
  4. Phytother Res. 2022 Oct 24.
    Juglone promotes antitumor activity against prostate cancer via suppressing glycolysis and oxidative phosphorylation.
    Cheng Hu, Haiyue Xu, Zehao Li, Dandan Liu, Siqi Zhang, Fang Fang, Liguo Wang.
      The treatments currently used for prostate cancer (PC) do not meet clinical needs, and thus, new therapies with greater effectiveness are urgently required. Metabolic reprogramming of tumor cells is emerging as an exciting field for cancer therapy. Although the Warburg effect is a common feature of glucose metabolism in many cancers, PC cells have a unique metabolic phenotype. Non-neoplastic prostate cells show reduced oxidative phosphorylation (OXPHOS) because large, accumulated zinc inhibits citrate oxidation. During transformation, there are low levels of zinc in PC cells, and the tricarboxylic acid (TCA) cycle is reactivated. However, metastatic PC exhibits the Warburg effect. Due to metabolic differences in prostate tissue, targeting metabolic alterations in PC cells is an attractive therapeutic strategy. In this study, we investigated the effect of juglone on energy metabolism in PC cells. We found that juglone inhibited cell proliferation and induced apoptosis. Mechanistically, we demonstrated that juglone suppressed OXPHOS and glycolysis due to its inhibition of hexokinase (HK), phosphofructokinase (PFK), and pyruvate kinase (PK) activity. Furthermore, downregulation of PFK and PK, but not HK contributed to the inhibition of these enzyme activities. The current study indicates that further development of juglone for PC treatment would be beneficial.
    Keywords:  Warburg effect; glycolysis; juglone; metabolomics; oxidative phosphorylation; prostate cancer
    DOI:  https://doi.org/10.1002/ptr.7631
  5. Pharmaceutics. 2022 Oct 15. pii: 2195. [Epub ahead of print]14(10):
    Updates on Responsive Drug Delivery Based on Liposome Vehicles for Cancer Treatment.
    Maria P Nikolova, Enamala Manoj Kumar, Murthy S Chavali.
      Liposomes are well-known nanoparticles with a non-toxic nature and the ability to incorporate both hydrophilic and hydrophobic drugs simultaneously. As modern drug delivery formulations are produced by emerging technologies, numerous advantages of liposomal drug delivery systems over conventional liposomes or free drug treatment of cancer have been reported. Recently, liposome nanocarriers have exhibited high drug loading capacity, drug protection, improved bioavailability, enhanced intercellular delivery, and better therapeutic effect because of resounding success in targeting delivery. The site targeting of smart responsive liposomes, achieved through changes in their physicochemical and morphological properties, allows for the controlled release of active compounds under certain endogenous or exogenous stimuli. In that way, the multifunctional and stimuli-responsive nanocarriers for the drug delivery of cancer therapeutics enhance the efficacy of treatment prevention and fighting over metastases, while limiting the systemic side effects on healthy tissues and organs. Since liposomes constitute promising nanocarriers for site-targeted and controlled anticancer drug release, this review focuses on the recent progress of smart liposome achievements for anticancer drug delivery applications.
    Keywords:  cancer; drug delivery; internal and external stimuli; liposomes; smart stimulus-responsive
    DOI:  https://doi.org/10.3390/pharmaceutics14102195
  6. Molecules. 2022 Oct 13. pii: 6848. [Epub ahead of print]27(20):
    Development of Biotechnological Photosensitizers for Photodynamic Therapy: Cancer Research and Treatment-From Benchtop to Clinical Practice.
    Mariza Aires-Fernandes, Ramon Botelho Costa, Stéphanie Rochetti do Amaral, Cassamo Ussemane Mussagy, Valéria C Santos-Ebinuma, Fernando Lucas Primo.
      Photodynamic therapy (PDT) is a noninvasive therapeutic approach that has been applied in studies for the treatment of various diseases. In this context, PDT has been suggested as a new therapy or adjuvant therapy to traditional cancer therapy. The mode of action of PDT consists of the generation of singlet oxygen (¹O2) and reactive oxygen species (ROS) through the administration of a compound called photosensitizer (PS), a light source, and molecular oxygen (3O2). This combination generates controlled photochemical reactions (photodynamic mechanisms) that produce ROS, such as singlet oxygen (¹O2), which can induce apoptosis and/or cell death induced by necrosis, degeneration of the tumor vasculature, stimulation of the antitumor immune response, and induction of inflammatory reactions in the illuminated region. However, the traditional compounds used in PDT limit its application. In this context, compounds of biotechnological origin with photosensitizing activity in association with nanotechnology are being used in PDT, aiming at its application in several types of cancer but with less toxicity toward neighboring tissues and better absorption of light for more aggressive types of cancer. In this review, we present studies involving innovatively developed PS that aimed to improve the efficiency of PDT in cancer treatment. Specifically, we focused on the clinical translation and application of PS of natural origin on cancer.
    Keywords:  biotechnological photosensitizers; cancer therapy; malignant tumors; nanobiotechnology; photodynamic therapy
    DOI:  https://doi.org/10.3390/molecules27206848
  7. Expert Opin Drug Deliv. 2022 Oct 26.
    Solid lipid nanoparticles: a promising tool for insulin delivery.
    Fatemeh Mohammadpour, Hossein Kamali, Leila Gholami, Alice P McCloskey, Prashant Kesharwani, Amirhossein Sahebkar.
       INTRODUCTION: Insulin plays a critical role in metabolism modulation including carbohydrate, lipid and protein metabolism. There is room to improve insulin delivery but optimizing the best carrier remains challenging. Traditional and conventional approaches for insulin delivery does not emulate the normal fate of insulin release in the body. Despite extensive research attempts to overcome this and other challenges, the goal of achieving optimal insulin delivery that emulates the natural system remains unresolved.
    AREAS COVERED: Solid Lipid Nanoparticles (SLNs) may provide a solution, because they are nontoxic, biocompatible, and straightforward to formulate. Thus are a promising platform for achieving targeted and controlled delivery of various therapeutic agents. This review aims to provide an overview on the suitability and application of SLNs for insulin delivery. A special emphasis is placed on the biopharmaceutical aspects of insulin loaded SLNs which has not been explored in detail to date.
    EXPERT OPINION: SLNs have proven to be safe and versatile drug delivery systems suitable for insulin delivery and capable of improving the efficacy and pharmacokinetic profile of encapsulated insulin. There is still some work to do to fully explore SLNs' true potential as drug delivery and specifically insulin delivery vehicles suitable for clinical use.
    Keywords:  Diabetes; Drug delivery; Insulin; Solid lipid nanoparticles; Therapeutic agents
    DOI:  https://doi.org/10.1080/17425247.2022.2138328
  8. Subcell Biochem. 2022 ;100 269-336
    Epigenetic Reprogramming of the Glucose Metabolic Pathways by the Chromatin Effectors During Cancer.
    Payel Mondal, Niharika Tiwary, Amrita Sengupta, Sinjini Dhang, Siddhartha Roy, Chandrima Das.
      Glucose metabolism plays a vital role in regulating cellular homeostasis as it acts as the central axis for energy metabolism, alteration in which may lead to serious consequences like metabolic disorders to life-threatening diseases like cancer. Malignant cells, on the other hand, help in tumor progression through abrupt cell proliferation by adapting to the changed metabolic milieu. Metabolic intermediates also vary from normal cells to cancerous ones to help the tumor manifestation. However, metabolic reprogramming is an important phenomenon of cells through which they try to maintain the balance between normal and carcinogenic outcomes. In this process, transcription factors and chromatin modifiers play an essential role to modify the chromatin landscape of important genes related directly or indirectly to metabolism. Our chapter surmises the importance of glucose metabolism and the role of metabolic intermediates in the cell. Also, we summarize the influence of histone effectors in reprogramming the cancer cell metabolism. An interesting aspect of this chapter includes the detailed methods to detect the aberrant metabolic flux, which can be instrumental for the therapeutic regimen of cancer.
    Keywords:  Epigenetic reader; Extracellular flux analysis; Gluconeogenesis; Glucose metabolism; Glycolysis; Hepatocellular carcinoma; Histone modification; Hypoxia; Metabolic intermediates; OXPHOS; TCA cycle; Techniques to measure; Warburg effect
    DOI:  https://doi.org/10.1007/978-3-031-07634-3_9
  9. Molecules. 2022 Oct 21. pii: 7113. [Epub ahead of print]27(20):
    Identification of Natural Compounds as Inhibitors of Pyruvate Kinase M2 for Cancer Treatment.
    Iqra Sarfraz, Azhar Rasul, Farhat Jabeen, Tayyaba Sultana, Şevki Adem.
      The reliance of tumor cells on aerobic glycolysis is one of the emerging hallmarks of cancer. Pyruvate kinase M2 (PKM2), an important enzyme of glycolytic pathway, is highly expressed in a number of cancer cells. Tumor cells heavily depend on PKM2 to fulfill their divergent energetic and biosynthetic requirements, suggesting it as novel drug target for cancer therapies. Based on this context, we performed enzymatic-assay-based screening of the in-house phenolic compounds library for the identification of PKM2 inhibitors. This screening identified silibinin, curcumin, resveratrol, and ellagic acid as potential inhibitors of PKM2 with IC50 values of 0.91 µM, 1.12 µM, 3.07 µM, and 4.20 µM respectively. For the determination of Ki constants and the inhibition type of hit compounds, Lineweaver-Burk graphs were plotted. Silibinin and ellagic acid performed the competitive inhibition of PKM2 with Ki constants of 0.61 µM and 5.06 µM, while curcumin and resveratrol were identified as non-competitive inhibitors of PKM2 with Ki constants of 1.20 µM and 7.34 µM. The in silico screening of phenolic compounds against three binding sites of PKM2 provided insight into the binding pattern and functionally important amino residues of PKM2. Further, the evaluation of cytotoxicity via MTT assay demonstrated ellagic acid as potent inhibitor of cancer cell growth (IC50 = 20 µM). These results present ellagic acid, silibinin, curcumin, and resveratrol as inhibitors of PKM2 to interrogate metabolic reprogramming in cancer cells. This study has also provided the foundation for further research to validate the potential of identified bioactive entities for PKM2 targeted-cancer therapies.
    Keywords:  enzymatic assay; phytochemicals; pyruvate kinase M2; tumor metabolism
    DOI:  https://doi.org/10.3390/molecules27207113
  10. Subcell Biochem. 2022 ;100 3-65
    Reprogramming Carbohydrate Metabolism in Cancer and Its Role in Regulating the Tumor Microenvironment.
    Swagata Adhikari, Deblina Guha, Chitra Mohan, Shravanti Mukherjee, Jessica K Tyler, Chandrima Das.
      Altered metabolism has become an emerging feature of cancer cells impacting their proliferation and metastatic potential in myriad ways. Proliferating heterogeneous tumor cells are surrounded by other resident or infiltrating cells, along with extracellular matrix proteins, and other secretory factors constituting the tumor microenvironment. The diverse cell types of the tumor microenvironment exhibit different molecular signatures that are regulated at their genetic and epigenetic levels. The cancer cells elicit intricate crosstalks with these supporting cells, exchanging essential metabolites which support their anabolic processes and can promote their survival, proliferation, EMT, angiogenesis, metastasis and even therapeutic resistance. In this context, carbohydrate metabolism ensures constant energy supply being a central axis from which other metabolic and biosynthetic pathways including amino acid and lipid metabolism and pentose phosphate pathway are diverged. In contrast to normal cells, increased glycolytic flux is a distinguishing feature of the highly proliferative cancer cells, which supports them to adapt to a hypoxic environment and also protects them from oxidative stress. Such rewired metabolic properties are often a result of epigenetic alterations in the cancer cells, which are mediated by several factors including, DNA, histone and non-histone protein modifications and non-coding RNAs. Conversely, epigenetic landscapes of the cancer cells are also dictated by their diverse metabolomes. Altogether, this metabolic and epigenetic interplay has immense potential for the development of efficient anti-cancer therapeutic strategies. In this book chapter we emphasize upon the significance of reprogrammed carbohydrate metabolism in regulating the tumor microenvironment and cancer progression, with an aim to explore the different metabolic and epigenetic targets for better cancer treatment.
    Keywords:  Acetyl-CoA; Carbohydrate metabolism; DNMTs; Epigenetics; Glycolytic flux; HATs; HDACs; HDM; HMT; Hypoxia; Metabolic reprogramming; Metastasis; OXPHOS; Oncometabolites; SAM; Tumor microenvironment
    DOI:  https://doi.org/10.1007/978-3-031-07634-3_1
  11. Evid Based Complement Alternat Med. 2022 ;2022 2192654
    Correlation of Glucose Metabolism with Cancer and Intervention with Traditional Chinese Medicine.
    Gui-Hua Lai, Fei Wang, Duo-Rui Nie, Shu-Jun Lei, Zhuo-Jun Wu, Jian-Xiong Cao, Lan-Lan Tang.
      Cancer is a complex disease with several distinct characteristics, referred to as "cancer markers" one of which is metabolic reprogramming, which is a common feature that drives cancer progression. Over the last ten years, researchers have focused on the reprogramming of glucose metabolism in cancer. In cancer, the oxidative phosphorylation metabolic pathway is converted into the glycolytic pathway in order to meet the growth requirements of cancer cells, thereby creating a microenvironment that promotes cancer progression. The precise mechanism of glucose metabolism in cancer cells is still unknown, but it is thought to involve the aberrant levels of metabolic enzymes, the influence of the tumor microenvironment (TME), and the activation of tumor-promoting signaling pathways. It is suggested that glucose metabolism is strongly linked to cancer progression because it provides energy to cancer cells and interferes with antitumor drug pharmacodynamics. Therefore, it is critical to unravel the mechanism of glucose metabolism in tumors in order to gain a better understanding of tumorigenesis and to lay the groundwork for future research into the identification of novel diagnostic markers and therapeutic targets for cancer treatment. Traditional Chinese Medicine (TCM) has the characteristics of multiple targets, multiple components, and less toxic side effects and has unique advantages in tumor treatment. In recent years, researchers have found that a variety of Chinese medicine monomers and compound recipes play an antitumor role by interfering with the reprogramming of tumor metabolism. The underlying mechanisms of metabolism reprogramming of tumor cells and the role of TCM in regulating glucose metabolism are reviewed in this study, so as to provide a new idea for antitumor research in Chinese medicine.
    DOI:  https://doi.org/10.1155/2022/2192654
  12. Int Rev Cell Mol Biol. 2022 ;pii: S1937-6448(22)00109-5. [Epub ahead of print]373 37-79
    Targeting amino acid metabolism in cancer.
    Lucie Safrhansova, Katerina Hlozkova, Julia Starkova.
      Metabolic rewiring is a characteristic hallmark of cancer cells. This phenomenon sustains uncontrolled proliferation and resistance to apoptosis by increasing nutrients and energy supply. However, reprogramming comes together with vulnerabilities that can be used against tumor and can be applied in targeted therapy. In the last years, the genetic background of tumors has been identified thoroughly and new therapies targeting those mutations tested. Nevertheless, we propose that targeting the phenotype of cancer cells could be another way of treatment aiming to avoid drug resistance and non-responsiveness of cancer patients. Amino acid metabolism is part of the altered processes in cancer cells. Amino acids are building blocks and also sensors of signaling pathways regulating main biological processes. In this comprehensive review, we described four amino acids (asparagine, arginine, methionine, and cysteine) which have been actively investigated as potential targets for anti-tumor therapy. Asparagine depletion is successfully used for decades in the treatment of acute lymphoblastic leukemia and there is a strong implication to apply it to other types of tumors. Arginine auxotrophic tumors are great candidates for arginine-starvation therapy. Higher requirement for essential amino acids such as methionine and cysteine point out promising targetable weaknesses of cancer cells.
    Keywords:  Amino acid metabolism; Arginine; Asparagine; Cancer; Cysteine; Methionine; Targeted therapy
    DOI:  https://doi.org/10.1016/bs.ircmb.2022.08.001
  13. Biomolecules. 2022 Oct 02. pii: 1410. [Epub ahead of print]12(10):
    Rosmarinic Acid and Related Dietary Supplements: Potential Applications in the Prevention and Treatment of Cancer.
    Jiachao Zhao, Liwei Xu, Di Jin, Yu Xin, Lin Tian, Tan Wang, Daqing Zhao, Zeyu Wang, Jing Wang.
      Cancer constitutes a severe threat to human health and quality of life and is one of the most significant causes of morbidity and mortality worldwide. Natural dietary products have drawn substantial attention in cancer treatment and prevention due to their availability and absence of toxicity. Rosmarinic acid (RA) is known for its excellent antioxidant properties and is safe and effective in preventing and inhibiting tumors. This review summarizes recent publications on culture techniques, extraction processes, and anti-tumor applications of RA-enriched dietary supplements. We discuss techniques to improve RA bioavailability and provide a mechanistic discussion of RA regarding tumor prevention, treatment, and adjuvant therapy. RA exhibits anticancer activity by regulating oxidative stress, chronic inflammation, cell cycle, apoptosis, and metastasis. These data suggest that daily use of RA-enriched dietary supplements can contribute to tumor prevention and treatment. RA has the potential for application in anti-tumor drug development.
    Keywords:  adjuvant therapy; cancer; molecular mechanism; rosmarinic acid; tumorigenesis
    DOI:  https://doi.org/10.3390/biom12101410
  14. Pharmaceutics. 2022 Oct 17. pii: 2210. [Epub ahead of print]14(10):
    Advancements in Rectal Drug Delivery Systems: Clinical Trials, and Patents Perspective.
    Ritu Rathi, Sanshita, Alpesh Kumar, Vivekanand Vishvakarma, Kampanart Huanbutta, Inderbir Singh, Tanikan Sangnim.
      The rectal route is an effective route for the local and systemic delivery of active pharmaceutical ingredients. The environment of the rectum is relatively constant with low enzymatic activity and is favorable for drugs having poor oral absorption, extensive first-pass metabolism, gastric irritation, stability issues in the gastric environment, localized activity, and for drugs that cannot be administered by other routes. The present review addresses the rectal physiology, rectal diseases, and pharmaceutical factors influencing rectal delivery of drugs and discusses different rectal drug delivery systems including suppositories, suspensions, microspheres, nanoparticles, liposomes, tablets, and hydrogels. Clinical trials on various rectal drug delivery systems are presented in tabular form. Applications of different novel drug delivery carriers viz. nanoparticles, liposomes, solid lipid nanoparticles, microspheres, transferosomes, nano-niosomes, and nanomicelles have been discussed and demonstrated for their potential use in rectal administration. Various opportunities and challenges for rectal delivery including recent advancements and patented formulations for rectal drug delivery have also been included.
    Keywords:  clinical trials; novel drug delivery; rectal; rectal diseases; rectal drug delivery
    DOI:  https://doi.org/10.3390/pharmaceutics14102210
  15. Front Oncol. 2022 ;12 1001318
    Amino acid metabolism in primary bone sarcomas.
    Jennifer A Jiménez, Elizabeth R Lawlor, Costas A Lyssiotis.
      Primary bone sarcomas, including osteosarcoma (OS) and Ewing sarcoma (ES), are aggressive tumors with peak incidence in childhood and adolescence. The intense standard treatment for these patients consists of combined surgery and/or radiation and maximal doses of chemotherapy; a regimen that has not seen improvement in decades. Like other tumor types, ES and OS are characterized by dysregulated cellular metabolism and a rewiring of metabolic pathways to support the biosynthetic demands of malignant growth. Not only are cancer cells characterized by Warburg metabolism, or aerobic glycolysis, but emerging work has revealed a dependence on amino acid metabolism. Aside from incorporation into proteins, amino acids serve critical functions in redox balance, energy homeostasis, and epigenetic maintenance. In this review, we summarize current studies describing the amino acid metabolic requirements of primary bone sarcomas, focusing on OS and ES, and compare these dependencies in the normal bone and malignant tumor contexts. We also examine insights that can be gleaned from other cancers to better understand differential metabolic susceptibilities between primary and metastatic tumor microenvironments. Lastly, we discuss potential metabolic vulnerabilities that may be exploited therapeutically and provide better-targeted treatments to improve the current standard of care.
    Keywords:  Ewing sarcoma; amino acid metabolism; osteoblast; osteoclast; sarcoma; tumor metabolism
    DOI:  https://doi.org/10.3389/fonc.2022.1001318
  16. Front Bioeng Biotechnol. 2022 ;10 968065
    Cinnamaldehyde-modified chitosan hybrid nanoparticles for DOX delivering to produce synergistic anti-tumor effects.
    Zuoqin Zhou, Caiyun Wang, Jingqi Bai, Zihan Zeng, Xiaoyu Yang, Bing Wei, Zheng Yang.
      Cancer cells are under oxidative stress associated with the increased generation of reactive oxygen species (ROS). Therefore, increasing the oxidative stress of tumor cells by delivering ROS generators is an effective strategy to induce apoptosis of cancer cells. Herein, we reported a hybrid nanoparticle based on lactobionic acid (LA) modified chitosan and cinnamaldehyde (CA) modified chitosan, which possesses both active tumor-targeting ability and ROS regulation ability, in order to have a synergistic effect with the anti-tumor drug doxorubicin (DOX). LA can improve the tumor-targeting ability and cellular accumulation of these nanoparticles, and CA can induce apoptotic cell death through ROS generation, mitochondrial permeability transition and caspase activation. The particle size and distribution as well as drug release profiles of these nanoparticles were observed. In vitro and in vivo antitumor studies demonstrated that the hybrid nanoparticles show a significant synergistic antitumor effect. Thus, we anticipate that the hybrid nanoparticles have promising potential as an anticancer drug carrier.
    Keywords:  anti-tumor; chitosan; cinnamaldehyde; drug carrier; lactobionic acid
    DOI:  https://doi.org/10.3389/fbioe.2022.968065
  17. Polymers (Basel). 2022 Oct 15. pii: 4344. [Epub ahead of print]14(20):
    Novel Therapeutic Approach in PEGylated Chitosan Nanoparticles of Apigenin for the Treatment of Cancer via Oral Nanomedicine.
    Md Ali Mujtaba, Nawaf M Alotaibi, Sultan M Alshehri, Mohammad Yusuf, Md Khalid Anwer, Mohammad Akhlaquer Rahman, Arshiya Parveen.
      The goal of this study was to optimize and formulate apigenin (APG)-loaded pegylated chitosan nanoparticles (PEGylated-CNPs) via ionic gelation techniques using the Box-Behnken design (BBD). Three individual variables, X1(chitosan: TPP concentration), X2 (PEG-400 concentration), and X3 (sonication time), were investigated for their influence on response variables (Y1-particle size (PS); Y2-drug entrapment efficiency (DEE); and Y3-zeta potential (ZP). The optimized formula of APG-PEGylated CNPs was picked from the statistical design and was then examined for physical, morphological, release characterization, anti-oxidant, and anti-tumor potential. The average PS, PDI, %DEE, and ZP were found to be 139.63 ± 5.67 nm, 0.296 ± 0.014, 79.55 ± 3.12%, and 24.68 ± 1.84 mV, respectively. The optimized APG formulation was chosen and reformulated based on the desirability function. Results of the observed and predicted values of responses through the BBD process were found to be nearly identical. The resulting APG-PEGylated CNPs were spherical and smooth, according to surface morphology studies. The release study revealed that PEGylated-CNPs exhibited biphasic release patterns distinguished by an initial burst release of APG only at early phases accompanied by a delayed release near 24 h. Furthermore, APG-PEGylated CNPs demonstrated statistically increased antioxidant activities and cytotoxicity against MCF-7 cells compared to pure APG. Based on the findings, it is possible to conclude that BBD was efficient in optimizing the PEGylated CNPs formulation and recognizing the impacts of formulation variables. In conclusion, the developed formulation has a significant potential for anticancer therapy.
    Keywords:  Box–Behnken design; antioxidant; apigenin; chitosan; nanoparticles
    DOI:  https://doi.org/10.3390/polym14204344
  18. Nanomaterials (Basel). 2022 Oct 21. pii: 3693. [Epub ahead of print]12(20):
    Conquering Cancer Multi-Drug Resistance Using Curcumin and Cisplatin Prodrug-Encapsulated Mesoporous Silica Nanoparticles for Synergistic Chemo- and Photodynamic Therapies.
    Prabhakar Busa, Ranjith Kumar Kankala, Jin-Pei Deng, Chen-Lun Liu, Chia-Hung Lee.
      Recently, the development of anti-cancer approaches using different physical or chemical pathways has shifted from monotherapy to synergistic therapy, which can enhance therapeutic effects. As a result, enormous efforts have been devoted to developing various delivery systems encapsulated with dual agents for synergistic effects and to combat cancer cells acquired drug resistance. In this study, we show how to make Institute of Bioengineering and Nanotechnology (IBN)-1-based mesoporous silica nanoparticles (MSNs) for multifunctional drug delivery to overcome drug resistance cancer therapy. Initially, curcumin (Cur)-embedded IBN-1 nanocomposites (IBN-1-Cur) are synthesized in a simple one-pot co-condensation and then immobilized with the prodrug of Cisplatin (CP) on the carboxylate-modified surface (IBN-1-Cur-CP) to achieve photodynamic therapy (PDT) and chemotherapy in one platform, respectively, in the fight against multidrug resistance (MDR) of MES-SA/DX5 cancer cells. The Pluronic F127 triblock copolymer, as the structure-directing agent, in nanoparticles acts as a p-glycoprotein (p-gp) inhibitor. These designed hybrid nanocomposites with excellent structural properties are efficiently internalized by the endocytosis and successfully deliver Cur and CP molecules into the cytosol. Furthermore, the presence of Cur photosensitizer in the nanochannels of MSNs resulted in increased levels of cellular reactive oxygen species (ROS) under light irradiation. Thus, IBN-1-Cur-CP showed excellent anti-cancer therapy in the face of MES-SA/DX5 resistance cancer cells, owing to the synergistic effects of chemo- and photodynamic treatment.
    Keywords:  Cisplatin; mesoporous silica nanoparticles; p-glycoprotein; photodynamic therapy; reactive oxygen species
    DOI:  https://doi.org/10.3390/nano12203693
  19. Nutrients. 2022 Oct 12. pii: 4252. [Epub ahead of print]14(20):
    Natural Products for Liver Cancer Treatment: From Traditional Medicine to Modern Drug Discovery.
    Da Bin Kim, Do Kyeong Lee, Chunhoo Cheon, Rosy Iara Maciel A Ribeiro, Bonglee Kim.
      Primary liver cancer was the seventh most diagnosed cancer and the second leading cause of cancer death with about 906,000 cases and 830,000 deaths, respectively, in 2020. Conventional treatment for liver cancer, such as transarterial chemoembolization (TACE) or sorafenib, has limitations in that there is the recurrence of cancer, drug inefficacy, and adverse effects. Traditional medicine and natural products of several regions including Korea, China, Europe, North America, India, and the Middle East have attracted a lot of attention since they have been reported to have anticancer effects with low adverse effects. In this review, several in vivo studies on the effects of natural compounds on liver cancer and clinical trials approving their therapeutic benefits were selected and discussed. As a result of the analysis of these studies, the effects of natural compounds were classified into a few mechanisms: apoptosis, anti-metastasis, and antiangiogenesis. In addition, medications including natural products in clinical trials were observed to exhibit improvements in various liver cancer symptoms and patients' survival rates. This study presents findings suggestive of the anticancer potential of natural products and their properties in relieving related symptoms.
    Keywords:  anti-metastasis; antiangiogenesis; anticancer; apoptosis; hepatic cancer; liver cancer; natural compounds; natural products
    DOI:  https://doi.org/10.3390/nu14204252
  20. Molecules. 2022 Oct 11. pii: 6786. [Epub ahead of print]27(20):
    Development of Glycyrrhetinic Acid and Folate Modified Cantharidin Loaded Solid Lipid Nanoparticles for Targeting Hepatocellular Carcinoma.
    Yilin Xu, Min Wang, Shuangcheng Ning, Zhonglan Yang, Lili Zhou, Xinhua Xia.
      Cantharidin (CTD) is the major component of anticancer drugs obtained from Mylabris Cichorii and has a good inhibitory effect on several cancers, including hepatocellular carcinoma (HCC) and breast cancer. However, due to its toxicity, oral administration can cause various adverse reactions, limiting its clinical application. The aim of this work was to design glycyrrhetinic acid (GA)- and/or folate (FA)-modified solid lipid nanoparticles (SLNs) for the encapsulation of CTD to target HCC. Four CTD-loaded SLNs (cantharidin solid lipid nanoparticles (CSLNs), glycyrrhetinic acid-modified cantharidin solid lipid nanoparticles (GA-CSLNs), folate-modified cantharidin solid lipid nanoparticles (FA-CSLNs), and glycyrrhetinic acid and folate-modified cantharidin solid lipid nanoparticles (GA-FA-CSLNs)) were prepared by the emulsion ultrasonic dispersion method, and their physicochemical parameters were determined (particle size and distribution, morphology, zeta-potential, entrapment efficiency, drug loading, and hemolysis). Additionally, the antitumor activities of the four SLNs were evaluated comprehensively by tests for cytotoxicity, cell migration, cell cycle, apoptosis, cellular uptake, competition suppression assay, and in vivo tumor suppression assay. Four SLNs showed spherical shapes and mean diameters in the range of 75-110 nm with size dispersion (PDI) within the range of 0.19-0.50 and zeta-potential approximately -10 mV. The entrapment efficiency of CTD in SLNs was higher than 95% for all tested formulations, and no hemolysis was observed. Compared to GA-CSLNs or CSLNs, GA-FA-CSLNs and FA-CSLNs showed stronger cytotoxicity on hepatocellular carcinoma cells (HepG2), and the cytotoxicity of GA-FA-CSLNs on hepatocyte cells (L-02) was remarkably reduced compared with other formulations. GA-FA-CSLNs and FA-CSLNs also increased the inhibition of HepG2 cell migration, and FA-CSLNs had the highest apoptosis rate. The cell cycle results indicated that HepG2 cells were arrested mainly in the S phase and G2/M phase. Analysis of competition inhibition experiments showed that GA and FA ligands had targeted effects on HepG2 cells. The in vivo tumor inhibition experiment showed that GA-FA-CSLNs and FA-CSLNs had excellent tumor inhibition ability-their tumor inhibition rates were 96.46% and 89.92%, respectively. Our results indicate that GA-FA-CSLNs and FA-CSLNs have a promising future in the therapeutic intervention of HCC.
    Keywords:  antitumor; cantharidin; folate; glycyrrhetinic acid; liver-targeting; solid lipid nanoparticles
    DOI:  https://doi.org/10.3390/molecules27206786
  21. Biomolecules. 2022 Oct 19. pii: 1513. [Epub ahead of print]12(10):
    Antidepressant Drug Sertraline against Human Cancer Cells.
    Diana Duarte, Nuno Vale.
      The use of FDA-approved drugs for new indications represents a faster and more economical way to find novel therapeutic agents for cancer therapy, compared to the development of new drugs. Repurposing drugs is advantageous in a pharmacological context since these drugs already have extensive data related to their pharmacokinetics, facilitating their approval process for different diseases. Several studies have reported the promising anticancer effects of sertraline, both alone and combined, in different types of cancer cell lines. Here, we performed a literature review on the anticancer potential of sertraline against different human cancer cells, more specifically in lung, colorectal, breast, hepatocellular, leukemia, brain, skin, oral, ovarian, and prostate cancer. Taken together, these findings suggest that sertraline decreases cell viability, proliferation, migration, and invasion, induces apoptosis, and causes cell cycle arrest in different types of cancer cells, besides being an established P-glycoprotein modulator. It was also found that this drug is able to modulate autophagy, cause DNA fragmentation, and induce radical oxygen species (ROS) formation. Moreover, it was found this drug targets important cellular pathways involved in tumorigeneses such as the TNF-MAP4K4-JNK pathway, the antiapoptotic pathway PI3K/Akt/mTOR, and the AMPK/mTOR axis. This drug also interferes with the TCTP/P53 feedback loop and with the cytosolic free Ca2+ levels. Together, these results suggest that sertraline may be a promising compound for further evaluation in novel cancer therapies.
    Keywords:  anticancer activity; antidepressant drugs; human cancer cell lines; sertraline
    DOI:  https://doi.org/10.3390/biom12101513
  22. Biomolecules. 2022 Oct 19. pii: 1514. [Epub ahead of print]12(10):
    Amygdalin: A Review on Its Characteristics, Antioxidant Potential, Gastrointestinal Microbiota Intervention, Anticancer Therapeutic and Mechanisms, Toxicity, and Encapsulation.
    Hassan Barakat, Thamer Aljutaily, Mona S Almujaydil, Reham M Algheshairy, Raghad M Alhomaid, Abdulkarim S Almutairi, Saleh I Alshimali, Ahmed A H Abdellatif.
      Bioactive amygdalin, found in high concentrations in bitter almonds, has been recognized as a symbol of the cyanogenic glycoside chemical organic substance, which was initially developed as a pharmaceutical for treating cancer after being hydrolyzed to hydrogen cyanide (HCN). Regrettably, research has shown that HCN can also damage normal cells, rendering it non-toxic to the human body. Extreme controversy surrounds both in vivo and in vitro studies, making its use risky. This review provides an extensive update on characteristics, antioxidant potential, gastrointestinal microbiota intervention, anticancer therapeutic, mechanisms, toxicity, and encapsulation of amygdalin. Antioxidant, anti-tumor, anti-fibrotic, antiatherosclerosis, anti-inflammatory, immunomodulatory, and analgesic characteristics, and the ability to improve digestive and reproductive systems, neurodegeneration, and cardiac hypertrophy are just some of the benefits of amygdalin. Studies verified the HCN-produced amygdalin to be harmful orally, but only at very high doses. Although intravenous treatment was less effective than the oral method, the oral route has a dose range of 0.6 to 1 g daily. Amygdalin's toxicity depends heavily on the variety of bacteria in the digestive tract. Unfortunately, there is currently no foolproof method for determining the microbial consortium and providing a safe oral dosage for every patient. Amygdalin encapsulation in alginate-chitosan nanoparticles (ACNPs) is a relatively new area of research. Amygdalin has an enhanced cytotoxic effect on malignant cells, and ACNPs can be employed as an active drug-delivery system to release this compound in a regulated, sustained manner without causing any harm to healthy cells or tissues. In conclusion, a large area of research for a substance that might be the next step in cancer therapy is opened up due to unverified and conflicting data.
    Keywords:  amygdalin; anticancer; antioxidant; encapsulation; mechanisms; microbiota intervention; toxicity
    DOI:  https://doi.org/10.3390/biom12101514
  23. 3 Biotech. 2022 Nov;12(11): 324
    Novel archetype in cancer therapeutics: exploring prospective of phytonanocarriers.
    Nisha Yadav, Deependra Singh, Manju Rawat, Neelam Sangwan.
      This paper reports various types of cancer, their incidence, and prevalence all over the globe. Along with the discovery of novel natural drugs for cancer treatment, these present a promising option which are eco-friendly, safe, and provide better acceptability in comparison to synthetic agents that carries multiple side effects. This paper provides an idea about various nanocarriers and phytochemicals, along with how their solubility and bioavailability can be enhanced in nanocarrier system. This report combines the data from various literature available on public domain including PubMed on research articles, reviews, and along with report from various national and international sites. Specialized metabolites (polyphenols, alkaloids, and steroids etc) from medicinal plants are promising alternatives to existing drugs. Studies have suggested that the treatment of cancer using plant products could be an alternative and a safe option. Studies have shown with the several cell lines as well as animal models, that phytomolecules are important in preventing/treating cancer. Phytochemicals often outperform chemical treatments by modulating a diverse array of cellular signaling pathways, promoting cell cycle arrest, apoptosis activation, and metastatic suppression, among others. However, limited water solubility, bioavailability, and cell penetration limit their potential clinical manifestations. The development of plant extract loaded nanostructures, rendering improved specificity and efficacy at lower concentrations could prove effective. Nanocarriers, such as liposomes, nanostructured lipids, polymers, and metal nanoparticles, have been tested for the delivery of plant products with enhanced effects. Recent advances have achieved improvement in the the stability, solubility, bioavailability, circulation time, and target specificity by nanostructure-mediated delivery of phytochemicals. Nanoparticles have been considered and attempted as a novel, targeted, and safe option. Newer approaches such as phyto-nanocarriers with carbohydrates, lignin, and polymers have been considered even more selective and effective modes of drug delivery in biomedical or diagnostic applications.
    Keywords:  Alkaloids; Anticancer; Cancer; Macromolecules; Nanoparticles; Phyto-nanocarriers; Phytochemical; Phytotherapeutics; Polyphenols; Steroids
    DOI:  https://doi.org/10.1007/s13205-022-03372-3
  24. Pharmaceutics. 2022 Oct 20. pii: 2239. [Epub ahead of print]14(10):
    Modulation of Macrophages Using Nanoformulations with Curcumin to Treat Inflammatory Diseases: A Concise Review.
    Huxiao Sun, Mengsi Zhan, Serge Mignani, Dzmitry Shcharbin, Jean-Pierre Majoral, João Rodrigues, Xiangyang Shi, Mingwu Shen.
      Curcumin (Cur), a traditional Chinese medicine extracted from natural plant rhizomes, has become a candidate drug for the treatment of diseases due to its anti-inflammatory, anticancer, antioxidant, and antibacterial activities. However, the poor water solubility and low bioavailability of Cur limit its therapeutic effects for clinical applications. A variety of nanocarriers have been successfully developed to improve the water solubility, in vivo distribution, and pharmacokinetics of Cur, as well as to enhance the ability of Cur to polarize macrophages and relieve macrophage oxidative stress or anti-apoptosis, thus accelerating the therapeutic effects of Cur on inflammatory diseases. Herein, we review the design and development of diverse Cur nanoformulations in recent years and introduce the biomedical applications and potential therapeutic mechanisms of Cur nanoformulations in common inflammatory diseases, such as arthritis, neurodegenerative diseases, respiratory diseases, and ulcerative colitis, by regulating macrophage behaviors. Finally, the perspectives of the design and preparation of future nanocarriers aimed at efficiently exerting the biological activity of Cur are briefly discussed.
    Keywords:  bioavailability; curcumin; drug delivery; inflammation; nanoformulations
    DOI:  https://doi.org/10.3390/pharmaceutics14102239
  25. Cancers (Basel). 2022 Oct 11. pii: 4982. [Epub ahead of print]14(20):
    Targeting KRAS in PDAC: A New Way to Cure It?
    Qianyu He, Zuojia Liu, Jin Wang.
      Pancreatic cancer is one of the most intractable malignant tumors worldwide, and is known for its refractory nature and poor prognosis. The fatality rate of pancreatic cancer can reach over 90%. In pancreatic ductal carcinoma (PDAC), the most common subtype of pancreatic cancer, KRAS is the most predominant mutated gene (more than 80%). In recent decades, KRAS proteins have maintained the reputation of being "undruggable" due to their special molecular structures and biological characteristics, making therapy targeting downstream genes challenging. Fortunately, the heavy rampart formed by KRAS has been broken down in recent years by the advent of KRASG12C inhibitors; the covalent inhibitors bond to the switch-II pocket of the KRASG12C protein. The KRASG12C inhibitor sotorasib has been received by the FDA for the treatment of patients suffering from KRASG12C-driven cancers. Meanwhile, researchers have paid close attention to the development of inhibitors for other KRAS mutations. Due to the high incidence of PDAC, developing KRASG12D/V inhibitors has become the focus of attention. Here, we review the clinical status of PDAC and recent research progress in targeting KRASG12D/V and discuss the potential applications.
    Keywords:  KRAS; PDAC; autophagy; combination therapy; drug resistance
    DOI:  https://doi.org/10.3390/cancers14204982
  26. Front Pharmacol. 2022 ;13 1033017
    Anti-cancer effect and potential microRNAs targets of ginsenosides against breast cancer.
    Meiling Fan, Mengyao Shan, Xintian Lan, Xiaoxue Fang, Dimeng Song, Haoming Luo, Donglu Wu.
      Breast cancer (BC) is one of the most common malignant tumor, the incidence of which has increased worldwide in recent years. Ginsenosides are the main active components of Panax ginseng C. A. Mey., in vitro and in vivo studies have confirmed that ginsenosides have significant anti-cancer activity, including BC. It is reported that ginsenosides can induce BC cells apoptosis, inhibit BC cells proliferation, migration, invasion, as well as autophagy and angiogenesis, thereby suppress the procession of BC. In this review, the therapeutic effects and the molecular mechanisms of ginsenosides on BC will be summarized. And the combination strategy of ginsenosides with other drugs on BC will also be discussed. In addition, epigenetic changes, especially microRNAs (miRNAs) targeted by ginsenosides in the treatment of BC are clarified.
    Keywords:  MicroRNAs; breast cancer; combination therapy; ginsenosides; molecular mechanism
    DOI:  https://doi.org/10.3389/fphar.2022.1033017
  27. Int Rev Cell Mol Biol. 2022 ;pii: S1937-6448(22)00022-3. [Epub ahead of print]373 159-197
    Combination strategies to target metabolic flexibility in cancer.
    Jelena Krstic, Katharina Schindlmaier, Andreas Prokesch.
      Therapeutically interfering with metabolic pathways has great merit to curtail tumor growth because the demand for copious amounts of energy for growth-supporting biomass production is common to all cancer entities. A major impediment to a straight implementation of metabolic cancer therapy is the metabolic flexibility and plasticity of cancer cells (and their microenvironment) resulting in therapy resistance and evasion. Metabolic combination therapies, therefore, are promising as they are designed to target several energetic routes simultaneously and thereby diminish the availability of alternative substrates. Thus, dietary restrictions, specific nutrient limitations, and/or pharmacological interventions impinging on metabolic pathways can be combined to improve cancer treatment efficacy, to overcome therapy resistance, or even act as a preventive measure. Here, we review the most recent developments in metabolic combination therapies particularly highlighting in vivo reports of synergistic effects and available clinical data. We close with identifying the challenges of the field (metabolic tumor heterogeneity, immune cell interactions, inter-patient variabilities) and suggest a "metabo-typing" strategy to tailor evidence-based metabolic combination therapies to the energetic requirements of the tumors and the patient's nutritional habits and status.
    Keywords:  Cancer; Combination therapy; Dietary restriction; Metabolic flexibility
    DOI:  https://doi.org/10.1016/bs.ircmb.2022.03.001
  28. Anticancer Agents Med Chem. 2022 Oct 24.
    Flavonoids for the treatment of breast cancer, present status and future prospective.
    Sonali Sahoo, Priyanka Mohapatra, Sanjeeb Kumar Sahoo.
      Breast Cancer is one of the notorious cancer-affecting women globally. Current therapies available for breast cancer treatment have certain limited efficacy; develop drug resistance and severe adverse effects. Thus, identifying novel therapies for treatment will reduce the devastating effect on cancer survivors. The exhilarating and fast-growing studies on flavonoids have evidenced that it has the potential to inflect various antitumor activity and modulate various signal transduction pathways in carcinogenesis. Flavonoids also have been found to regulate cellular metabolism and oxidative stress, cell cycle progression, angiogenesis and metastasis ultimately preventing the progression of the diseases. As per the reports, a flavonoid-rich diet appears the most potent and promising approach to abate the risk of cancer. Thus, now a day these are the prime target for drug discovery research. Based on existing findings, it can be concluded that beyond the currently employed chemotherapeutics, natural products (like flavonoids) exhibit pleiotropic, multi-target activities and are budding as possible complementary chemopreventive molecules against breast cancer with fewer side effects than conventional therapy. In this review, we comprehensively highlight an outline of the multiple pleiotropic pharmacological effects of various major classes of flavonoids on breast cancer with their specific mechanisms underlying its anticancer effect.
    Keywords:  Apoptosis; Breast cancer; Flavonoids; Tumor microenvironment
    DOI:  https://doi.org/10.2174/1871520623666221024114521
  29. Int Rev Cell Mol Biol. 2022 ;pii: S1937-6448(22)00110-1. [Epub ahead of print]373 107-123
    Fasting and cancer responses to therapy.
    José Manuel Bravo-San Pedro, Federico Pietrocola.
      The therapeutic outcome of multiple anticancer regimens relies upon a fine balance between tumor intrinsic and host-related factors. In this context, qualitative changes in dietary composition as well as alterations in total calorie supply influence essential aspects of cancer biology, spanning from tumor initiation to metastatic spreading. On the one hand, circumstances of nutritional imbalance or excessive calorie intake promote oncogenesis, accelerate tumor progression, and hamper the efficacy of anticancer treatments. On the other hand, approaches based on bulk (e.g., fasting, fasting mimicking diets) or selective (e.g., amino acids) shortage of nutrients are currently in the spotlight for their ability to potentiate the effect of anticancer drugs. While the chemosensitizing effect of fasting has long been attributed to the overdemanding metabolic requirements of neoplastic cells, recent findings suggest that caloric restriction improves the efficacy of chemotherapy and immunotherapy by boosting anticancer immunosurveillance. Here, we provide a critical overview of current preclinical and clinical studies that address the impact of nutritional interventions on the response to cancer therapy, laying particular emphasis on fasting-related interventions.
    Keywords:  Autophagy; Caloric restriction; Immunotherapy; Inflammation; Metabolism; Nutrition; Obesity
    DOI:  https://doi.org/10.1016/bs.ircmb.2022.08.002
  30. Biomacromolecules. 2022 Oct 26.
    Smart Multistage "Trojan Horse"-Inspired Bovine Serum Albumin-Coated Liposomes for Enhancing Tumor Penetration and Antitumor Efficacy.
    Jianqin Yan, Chan Shan, Caili Liang, Jinting Han, Bin He, Yong Sun, Kui Luo, Jing Chang, Xianwen Wang, Yan Liang.
      Poor antitumor drug penetration into tumor tissues is a global challenge in clinical cancer treatment. Here, we reported a smart multistage "Trojan Horse"-inspired bovine serum albumin (BSA)-coated liposome (HBM), including the mimics of capsid and secondary BSA-coated polymeric nanoparticles (NPs) for enhancing tumor penetration and antitumor efficacy. These drug-loaded polymeric NPs possess a capsid-like component, a well-distributed nanostructure (size: 190.1 ± 4.98 nm, PDI: 0.259), and an excellent drug loading content (15.85 ± 1.36%). Meaningfully, after the smart multistage BSA-coated liposome targeted the tumor tissue, the mimics of capsid were "taken off" under the condition of tumor-specific enzymes, releasing "Heart" BSA-modified secondary NPs to increase the ability to penetrate tumor cells for enhancing antitumor efficacy. As expected, the HBM efficiently achieves high drug penetration into PAN02 tumor cells. Moreover, compared to free DOX and HM (HBM without BSA) NPs, DOX/HBM NPs exhibited the strongest tumor penetration and the highest cytotoxicity against PAN02 tumor cells both in vitro (IC50 = 0.141 μg/mL) and in vivo. This smart multistage "Trojan Horse"-inspired BSA-coated liposome should provide a new hathpace for further development of polymeric NPs in clinical treatment.
    DOI:  https://doi.org/10.1021/acs.biomac.2c00984
  31. Curr Pharm Des. 2022 Oct 21.
    A Recent Review on Bio-availability Enhancement of Poorly Water-Soluble Drugs by Using Bioenhancer and Nanoparticulate Drug Delivery System.
    Mohit Kumar, Devesh Kumar, Sumant, Akshay Kumar, Uttam Kumar Mandal.
       BACKGROUND: Intravenous route of drug administration has maximum bioavailability, which shows 100% of the drug reaches blood circulation, whereas the oral administration, of drugs, are readily undergoing pre-systemic metabolism, which means the poor bioavailability of the drug and limited amount of drug reaches the target site.
    INTRODUCTION: Bioenhancers are substances having medicinal entities which enhance the bioavailability and efficacy of the active constituents of drugs. The enhanced bioavailability of drugs may lead to dose reduction, which may further lead to lessening the cost and undesired side effects associated with the drugs.
    METHODS: The solid lipid nanoparticles (SLNs) loaded with ketoprofen made from carnauba wax and beeswax. It was discovered that when the drug-loaded SLNs were mixed with egg-lecithin and Tween-80, as well as when the total surfactant concentration was increased, the average particle size of the drug-loaded SLNs decreased.
    RESULT: The drug-loaded nanoparticles, when given in combination with bio-enhancers such as piperine and quercetin enhanced the effectiveness of the drug. The Area Under Curve (AUC) was increased when the drug was coupled with bio-enhancers. Based on the findings, it can be concluded that piperine and quercetin when used with drug-loaded nanoparticles improve their therapeutic effectiveness.
    CONCLUSION: Bioenhancers are crucial to amplifying the bioavailability of many synthetic drugs. These attributes are useful to reduce the dose of drugs as well as increase the therapeutic efficacy of drugs that has poor bioavailability.
    Keywords:  Bioavailability; Bioenhancer; Nanotechnology; Phytotherapy; Side effects.
    DOI:  https://doi.org/10.2174/1381612829666221021152354
  32. Oncol Rep. 2022 Dec;pii: 215. [Epub ahead of print]48(6):
    Regulators of epigenetic change in ferroptosis‑associated cancer (Review).
    Jiaming Wu, Shuang Zhu, Peng Wang, Jinge Wang, Jingjing Huang, Tong Wang, Lingfeng Guo, Desen Liang, Qinghui Meng, Huayang Pan.
      The occurrence of tumors is associated with the upregulation or downregulation of certain genes. The identification of novel tumor therapies has revealed that regulation of tumor cell death can either promote or suppress the occurrence and development of tumors. Iron‑dependent lipid free oxygen radical accumulation causes tumor cells to die by ferroptosis, a form of regulated cell death. Multiple mechanisms mediate this mode of cell death, including redox homeostasis, iron metabolism, mitochondrial activity, breakdown of amino acids, lipids and sugars and epigenetic regulatory and disease‑associated signaling pathways. The present review discussed epigenetic mechanism of ferroptosis with the aim of providing novel insight for optimization of the effects of antitumor therapy.
    Keywords:  cancer; epigenetic; ferroptosis
    DOI:  https://doi.org/10.3892/or.2022.8430
  33. J Hematol Oncol. 2022 Oct 25. 15(1): 152
    Drugging KRAS: current perspectives and state-of-art review.
    Kaushal Parikh, Giuseppe Banna, Stephen V Liu, Alex Friedlaender, Aakash Desai, Vivek Subbiah, Alfredo Addeo.
      After decades of efforts, we have recently made progress into targeting KRAS mutations in several malignancies. Known as the 'holy grail' of targeted cancer therapies, KRAS is the most frequently mutated oncogene in human malignancies. Under normal conditions, KRAS shuttles between the GDP-bound 'off' state and the GTP-bound 'on' state. Mutant KRAS is constitutively activated and leads to persistent downstream signaling and oncogenesis. In 2013, improved understanding of KRAS biology and newer drug designing technologies led to the crucial discovery of a cysteine drug-binding pocket in GDP-bound mutant KRAS G12C protein. Covalent inhibitors that block mutant KRAS G12C were successfully developed and sotorasib was the first KRAS G12C inhibitor to be approved, with several more in the pipeline. Simultaneously, effects of KRAS mutations on tumour microenvironment were also discovered, partly owing to the universal use of immune checkpoint inhibitors. In this review, we discuss the discovery, biology, and function of KRAS in human malignancies. We also discuss the relationship between KRAS mutations and the tumour microenvironment, and therapeutic strategies to target KRAS. Finally, we review the current clinical evidence and ongoing clinical trials of novel agents targeting KRAS and shine light on resistance pathways known so far.
    DOI:  https://doi.org/10.1186/s13045-022-01375-4
  34. J Drug Target. 2022 Oct 28. 1-34
    Role of curcumin and its nanoformulations in the treatment of neurological diseases through the effects on stem cells.
    Nasim Sabouni, Hadi Zare Marzouni, Sepideh Palizban, Sepideh Meidaninikjeh, Prashant Kesharwani, Tannaz Jamialahmadi, Amirhossein Sahebkar.
      Curcumin from turmeric is a natural phenolic compound with a promising potential to regulate fundamental processes involved in neurological diseases, including inflammation, oxidative stress, protein aggregation, and apoptosis at the molecular level. In this regard, employing nanoformulation can improve curcumin efficiency by reducing its limitations, such as low bioavailability. Besides curcumin, growing data suggest that stem cells are a noteworthy candidate for neurodegenerative disorders therapy due to their anti-inflammatory, anti-oxidative, and neuronal-differentiation properties, which result in neuroprotection. Curcumin and stem cells have similar neurogenic features and can be co-administered in a cell-drug delivery system to achieve better combination therapeutic outcomes for neurological diseases. Based on the evidence, curcumin can induce the neuroprotective activity of stem cells by modulating their related signaling pathways. The present review is about the role of curcumin and its nanoformulations in the improvement of neurological diseases alone and through the effect on different categories of stem cells by discussing the underlying mechanisms to provide a roadmap for future investigations.
    Keywords:  : Curcumin; combination therapy; nanoformulation; neurological disease; neuroprotective; stem cells
    DOI:  https://doi.org/10.1080/1061186X.2022.2141755
  35. Curr Drug Targets. 2022 Oct 19.
    A Comprehensive Review on Nanomedicine: Promising approach for treatment of brain tumor through intranasal administration.
    Shiv Bahadur, Anubhav Prakash.
      Brain tumors have become one of the deadliest cancers; however, their treatment is still limited by conventional approaches. Brain tumors, among other CNS diseases, are the most lethal form of cancer due to ineffective diagnosis and profiling. The major limiting factor in treating brain tumors is the blood-brain barrier (BBB), and the required therapeutic concentration is not achieved. Hence, most drugs are prescribed at higher doses, which have several unwanted side effects. Nanotechnology has emerged as an interesting and promising new approach for treating neurological disorders, including brain tumors, with the potential to overcome concerns related to traditional therapeutic approaches. Moreover, biomimetic nanomaterials have been introduced to successfully cross the blood-brain barrier and be consumed by deep skin cancer for imaging brain tumors using multimodal functional nanostructures for more specific and reliable medical assessment. These nanomedicines can address several challenges by enhancing the bioavailability of therapeutics through controlled pharmacokinetics and pharmacodynamics. Further nasal drug delivery has been considered as an alternative approach for the brain's targeting for the treatment of several CNS diseases. A drug can be directly delivered to the brain by bypassing the BBB through intranasal administration. This review discusses intranasal nanomedicine-based therapies for brain tumor targeting, which can be explored from different perspectives.
    Keywords:  Nanomedicine; blood-brain barrier; brain tumor; intranasal delivery; nanotechnology
    DOI:  https://doi.org/10.2174/1389450124666221019141044
  36. Pharm Nanotechnol. 2022 Oct 26.
    Solid lipid nanoparticles (slns): Advancements in modification strategies toward drug delivery vehicle.
    Galal Mohsen Hussein Al-Sayadi, Abhishek Verma, Yash Choudhary, Pallavi Sandal, Preeti Patel, Dilpreet Singh, G D Gupta, Balak Das Kurmi.
      Solid lipid nanoparticles are at the cornerstone of the swiftly growing area of medical nanotechnology, having several potential functions in drug delivery, research, clinical care, and a variety of other fields. They provide the opportunity of developing novel therapies due to their unique properties, such as small particle size and being prepared from physiological biodegradable lipids. The loading of bioactive molecules into nanocarriers is a novel drug delivery prototype employed for various drug targeting levels. Hence, SLNs hold a great promise for achieving the aim of targeted and controlled drug delivery. For this reason, they have attracted the extensive attention of scientists and researchers. This review is based on recent studies and research, and here we present advantages, disadvantages, and preparation methods, several advanced modifications, targeting strategies, and recent applications of solid lipid nanocarriers in drug delivery systems.
    Keywords:  CNS disorders; Cancer; Cosmetics; Covid vaccine; Solid lipid nanoparticles; Targeting; drug delivery
    DOI:  https://doi.org/10.2174/2211738511666221026163303
  37. Pharmaceutics. 2022 Sep 23. pii: 2021. [Epub ahead of print]14(10):
    Glycolytic Inhibitors Potentiated the Activity of Paclitaxel and Their Nanoencapsulation Increased Their Delivery in a Lung Cancer Model.
    Andrea Cunha, Ana Catarina Rocha, Flávia Barbosa, Ana Baião, Patrícia Silva, Bruno Sarmento, Odília Queirós.
      Antiglycolytic agents inhibit cell metabolism and modify the tumor's microenvironment, affecting chemotherapy resistance mechanisms. In this work, we studied the effect of the glycolytic inhibitors 3-bromopyruvate (3BP), dichloroacetate (DCA) and 2-deoxyglucose (2DG) on cancer cell properties and on the multidrug resistance phenotype, using lung cancer cells as a model. All compounds led to the loss of cell viability, with different effects on the cell metabolism, migration and proliferation, depending on the drug and cell line assayed. DCA was the most promising compound, presenting the highest inhibitory effect on cell metabolism and proliferation. DCA treatment led to decreased glucose consumption and ATP and lactate production in both A549 and NCI-H460 cell lines. Furthermore, the DCA pretreatment sensitized the cancer cells to Paclitaxel (PTX), a conventional chemotherapeutic drug, with a 2.7-fold and a 10-fold decrease in PTX IC50 values in A549 and NCI-H460 cell lines, respectively. To increase the intracellular concentration of DCA, thereby potentiating its effect, DCA-loaded poly(lactic-co-glycolic acid) nanoparticles were produced. At higher DCA concentrations, encapsulation was found to increase its toxicity. These results may help find a new treatment strategy through combined therapy, which could open doors to new treatment approaches.
    Keywords:  2-deoxyglucose; 3-bromopyruvate; Warburg effect; dichloroacetate; nanoparticles; tumor metabolism
    DOI:  https://doi.org/10.3390/pharmaceutics14102021
  38. Drug Discov Today. 2022 Oct 21. pii: S1359-6446(22)00409-3. [Epub ahead of print] 103416
    Pharmacological treatment strategies of pterygium: drugs, biologics, and novel natural products.
    Sanaz Sadig Baheran, Raid G Alany, Sianne Schwikkard, Wisam Muen, Lena Namaan Salman, Nicholas Freestone, Ali A Al-Kinani.
      Pterygium is a fibrovascular tissue growth invading the cornea. Adjunctive treatment post-surgery includes conventional immunosuppressants as well as antiviral drugs. The use of large- and small-molecule antivascular endothelial growth factor (VEGF) agents remains an integral part of pterygium treatment as well as other neovascular conditions of the eye. Naturally occurring polyphenolic compounds have favorable characteristics for treating neovascular and inflammatory eye conditions, including good efficacy, stability, cost-effectiveness, and the versatility of their chemical synthesis. In this review, we discuss pharmacological treatments of pterygium. Natural products, such curcumin, ellagic acid, and chalcones, are reviewed, with emphasis on their potential as future pterygium treatments.
    Keywords:  Pterygium; adjunctive therapy; anti-VEGF; antioxidant; chalcone; curcumin; natural products
    DOI:  https://doi.org/10.1016/j.drudis.2022.103416
  39. Pharmaceutics. 2022 Sep 26. pii: 2047. [Epub ahead of print]14(10):
    Co-Delivery of Dihydroartemisinin and Indocyanine Green by Metal-Organic Framework-Based Vehicles for Combination Treatment of Hepatic Carcinoma.
    Yang Chen, Bin Wang, Wenping Chen, Tao Wang, Min Li, Zucheng Shen, Fang Wang, Jing Jia, Fenglan Li, Xiangyu Huang, Junyang Zhuang, Ning Li.
      Dihydroartemisinin (DHA), a widely used antimalarial agent, has clinical potential for the treatment of hepatic carcinoma. Although chemotherapy is indispensable for tumor therapy, it is generally limited by poor solubility, low efficiency, rapid clearance, and side effects. As an emerging treatment method, photothermal therapy (PTT) has many outstanding properties, but suffers from poor photostability of photosensitizer and incomplete ablation. Multimodal therapies could combine the advantages of different therapy methods to improve antitumor efficiency. Hence, we designed a nano-delivery system (ICG&DHA@ZIF-8) using zeolitic imidazolate framework-8 (ZIF-8) with a high porous rate and pH sensitivity property, to co-load DHA and indocyanine green (ICG). Dynamic light scattering and transmission electron microscopy were used to characterize the prepared nanoparticles. The photothermal conversion and drug release performances of ICG&DHA@ZIF-8 were investigated. In vitro antitumor efficacy and cellular uptake were studied. The mechanism of the combination treatment was studied by reactive oxygen species level detection and western blot assays. In vivo antitumor assays were then studied with the guidance of ex vivo imaging. The results showed that the ICG&DHA@ZIF-8 based combination therapy could efficiently kill hepatic carcinoma cells and suppress tumor growth. This research provides a potential nanodrug for the treatment of hepatic carcinoma.
    Keywords:  ZIF-8; combination therapy; dihydroartemisinin; nanoparticles; phototherapy
    DOI:  https://doi.org/10.3390/pharmaceutics14102047
  40. Int J Pharm. 2022 Oct 21. pii: S0378-5173(22)00882-1. [Epub ahead of print] 122327
    Enhanced skin localization of metronidazole using solid lipid microparticles incorporated into polymeric hydrogels for potential improved of rosacea treatment: An ex vivo proof of concept investigation.
    Sulistiawati, Kadek Saka Dwipayanti, Muhammad Azhar, Latifah Rahman, Ermina Pakki, Achmad Himawan, Andi Dian Permana.
      Metronidazole (MNZ) is a nitroimidazole derivative antibiotic that has been generally used in the treatment of rosacea. However, it has low molecular weight and lipophilicity, limiting the effectiveness of MNZ in the topical treatment of rosacea. This study reports an MNZ-loaded solid lipid microparticle (SLM) gel formulation with sustained drug release effects required in the treatment of rosacea. SLM was formulated using the double emulsification method with five different concentrations of glyceryl monostearate (GMS) as a solid lipid used to encapsulate MNZ. All the MNZ-loaded SLM formulas were extensively characterized by various analytical tools. After optimized MNZ-loaded SLM formulation was obtained, then formulated into gel preparation. To obtain a gel formula with good physical characteristics and drug release in the development of topical therapy, the SLM-loaded gel was further evaluated, covering various parameters such as pH, viscosity, rheology, spreadability, extrudability, skin occlusivity, gel strength, permeation and retention ex vivo, as well as hemolysis tests and antioxidant activity. The evaluation results showed that the SLM formulations had desired properties with optimum encapsulation efficiency. Moreover, the gels prepared from carbomer possessed desired characteristics and were found to be hemocompatible. In addition, the gel formula with a carbomer concentration of 1.25% can provide better drug release with the highest MNZ retention after 24 hours of 2.35 ± 0.05 mg. Notably, the formulation of MNZ into SLM and hydrogel did not affect the antioxidant activity. Thus, it can provide continuous drug release, which could potentially be useful in increasing efficacy in rosacea therapy. The results obtained also showed a significant difference (p < 0.05) compared to the control formula and other formulas. Therefore, this study has proven a new approach to developing drug delivery systems for rosacea treatment.
    Keywords:  Rosacea; hydrogel; metronidazole; solid lipid microparticles
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.122327
  41. Molecules. 2022 Oct 12. pii: 6826. [Epub ahead of print]27(20):
    Grape Pomace Polyphenols as a Source of Compounds for Management of Oxidative Stress and Inflammation-A Possible Alternative for Non-Steroidal Anti-Inflammatory Drugs?
    Veronica Sanda Chedea, Ștefan Octavian Macovei, Ioana Corina Bocșan, Dan Claudiu Măgureanu, Antonia Mihaela Levai, Anca Dana Buzoianu, Raluca Maria Pop.
      Flavonoids, stilbenes, lignans, and phenolic acids, classes of polyphenols found in grape pomace (GP), were investigated as an important alternative source for active substances that could be used in the management of oxidative stress and inflammation. The benefic antioxidant and anti-inflammatory actions of GP are presented in the literature, but they are derived from a large variety of experimental in vitro and in vivo settings. In these in vitro works, the decrease in reactive oxygen species, malondialdehyde, and thiobarbituric acid reactive substances levels and the increase in glutathione levels show the antioxidant effects. The inhibition of nuclear factor kappa B and prostaglandin E2 inflammatory pathways and the decrease of some inflammatory markers such as interleukin-8 (IL-8) demonstrate the anti-inflammatory actions of GP polyphenols. The in vivo studies further confirmed the antioxidant (increase in catalase, superoxide dismutase and glutathione peroxidase levels and a stimulation of endothelial nitric oxide synthase -eNOS gene expression) and anti-inflammatory (inhibition of IL-1𝛼, IL-1β, IL-6, interferon-𝛾, TNF-α and C-reactive protein release) activities. Grape pomace as a whole extract, but also different individual polyphenols that are contained in GP can modulate the endogenous pathway responsible in reducing oxidative stress and chronic inflammation. The present review analyzed the effects of GP in oxidative stress and inflammation, suggesting that it could become a valuable therapeutic candidate capable to reduce the aforementioned pathological processes. Grape pomace extract could become an adjuvant treatment in the attempt to reduce the side effects of the classical anti-inflammatory medication like non-steroidal anti-inflammatory drugs (NSAIDs).
    Keywords:  anti-inflammatory; antioxidant; grape pomace; polyphenols
    DOI:  https://doi.org/10.3390/molecules27206826
  42. Cells. 2022 Oct 20. pii: 3301. [Epub ahead of print]11(20):
    Ferroptosis: Shedding Light on Mechanisms and Therapeutic Opportunities in Liver Diseases.
    Hongmei You, Ling Wang, Fangtian Bu, Hongwu Meng, Cheng Huang, Guoying Fang, Jun Li.
      Cell death is a vital physiological or pathological phenomenon in the development process of the organism. Ferroptosis is a kind of newly-discovered regulated cell death (RCD), which is different from other RCD patterns, such as apoptosis, necrosis and autophagy at the morphological, biochemical and genetic levels. It is a kind of iron-dependent mode of death mediated by lipid peroxides and lipid reactive oxygen species aggregation. Noteworthily, the number of studies focused on ferroptosis has been increasing exponentially since ferroptosis was first found in 2012. The liver is the organ that stores the most iron in the human body. Recently, it was frequently found that there are different degrees of iron metabolism disorder and lipid peroxidation and other ferroptosis characteristics in various liver diseases. Numerous investigators have discovered that the progression of various liver diseases can be affected via the regulation of ferroptosis, which may provide a potential therapeutic strategy for clinical hepatic diseases. This review aims to summarize the mechanism and update research progress of ferroptosis, so as to provide novel promising directions for the treatment of liver diseases.
    Keywords:  ferroptosis; liver diseases; regulated cell death
    DOI:  https://doi.org/10.3390/cells11203301
  43. Molecules. 2022 Oct 13. pii: 6847. [Epub ahead of print]27(20):
    The Use of Photodynamic Therapy in the Treatment of Brain Tumors-A Review of the Literature.
    Dorota Bartusik-Aebisher, Aleksandra Żołyniak, Edyta Barnaś, Agnieszka Machorowska-Pieniążek, Piotr Oleś, Aleksandra Kawczyk-Krupka, David Aebisher.
      The treatment of neoplastic disease of the brain is still a challenge for modern medicine. Therefore, advanced methodologies are needed that can rationally and successfully contribute to the early diagnosis of primary and metastatic tumors growing within the brain. Photodynamic therapy (PDT) seems to be a valuable method of treatment for precancerous and cancerous lesions including brain tumors. The main advantage of PDT is its high efficiency, minimal invasiveness and no serious side effects, compared with chemotherapy and radiotherapy. This review was conducted through a comprehensive search of articles, scientific information databases and the websites of organizations dealing with cancer treatment. Key points from clinical trials conducted by other researchers are also discussed. The common databases such as PubMed, Google Scholar, EBSCO, Scopus, and Elsevier were used. Articles in the English language of reliable credibility were mainly analyzed. The type of publications considered included clinical and preclinical studies, systematic reviews, and case reports. Based on these collected materials, we see that scientists have already demonstrated the potential of PDT application in the field of brain tumors. Therefore, in this review, the treatment of neoplasm of the Central Nervous System (CNS) and the most common tumor, glioblastoma multiforme (GBM), have been explored. In addition, an overview of the general principles of PDT, as well as the mechanism of action of the therapy as a therapeutic platform for brain tumors, is described. The research was carried out in June 2022.
    Keywords:  5-aminolevulinic acid; brain tumor; glioblastoma multiforme; photodynamic therapy
    DOI:  https://doi.org/10.3390/molecules27206847
  44. Biomolecules. 2022 Oct 01. pii: 1405. [Epub ahead of print]12(10):
    The Credible Role of Curcumin in Oxidative Stress-Mediated Mitochondrial Dysfunction in Mammals.
    Muthuswamy Sathyabhama, Loganathan Chandramani Priya Dharshini, Adhimoolam Karthikeyan, Senthil Kalaiselvi, Taesun Min.
      Oxidative stress and mitochondrial dysfunction are associated with the pathogenesis of several human diseases. The excessive generation of reactive oxygen species (ROS) and/or lack of adequate antioxidant defenses causes DNA mutations in mitochondria, damages the mitochondrial respiratory chain, and alters membrane permeability and mitochondrial defense mechanisms. All these alterations are linked to the development of numerous diseases. Curcumin, an active ingredient of turmeric plant rhizomes, exhibits numerous biological activities (i.e., antioxidant, anti-inflammatory, anticancer, and antimicrobial). In recent years, many researchers have shown evidence that curcumin has the ability to reduce the oxidative stress- and mitochondrial dysfunction-associated diseases. In this review, we discuss curcumin's antioxidant mechanism and significance in oxidative stress reduction and suppression of mitochondrial dysfunction in mammals. We also discuss the research gaps and give our opinion on how curcumin research in mammals should proceed moving forward.
    Keywords:  anti-inflammatory; anticancer; antimicrobial; antioxidant; curcumin; mammals; mitochondrial dysfunction; oxidative stress
    DOI:  https://doi.org/10.3390/biom12101405
  45. Front Bioeng Biotechnol. 2022 ;10 1024143
    Polymeric nanoparticles-Promising carriers for cancer therapy.
    Xiao Xiao, Fei Teng, Changkuo Shi, Junyu Chen, Shuqing Wu, Bao Wang, Xiang Meng, Aniekan Essiet Imeh, Wenliang Li.
      Polymeric nanoparticles (NPs) play an important role in controlled cancer drug delivery. Anticancer drugs can be conjugated or encapsulated by polymeric nanocarriers, which are known as polymeric nanomedicine. Polymeric nanomedicine has shown its potential in providing sustained release of drugs with reduced cytotoxicity and modified tumor retention, but until now, few delivery systems loading drugs have been able to meet clinical demands, so more efforts are needed. This research reviews the current state of the cancer drug-loading system by exhibiting a series of published articles that highlight the novelty and functions from a variety of different architectures including micelles, liposomes, dendrimers, polymersomes, hydrogels, and metal-organic frameworks. These may contribute to the development of useful polymeric NPs to achieve different therapeutic purposes.
    Keywords:  cancer drug delivery; nanocarrier; pH-sensitive; polymeric nanoparticle; thermo-sensitive
    DOI:  https://doi.org/10.3389/fbioe.2022.1024143
  46. Subcell Biochem. 2022 ;100 523-555
    Epigenetic Small-Molecule Modulators Targeting Metabolic Pathways in Cancer.
    Dipanwita Das, Nandini Karthik, Reshma Taneja.
      Metabolic deregulation is a key factor in cancer progression. Epigenetic changes and metabolic rewiring are intertwined in cancer. Deregulated epigenetic modifiers cause metabolic aberrations by targeting the expression of metabolic enzymes. Conversely, metabolites and cofactors affect the expression and activity of epigenetic regulators. Small molecules are promising therapeutic approaches to target the epigenetic-metabolomic crosstalk in cancer. Here, we focus on the interplay between metabolic rewiring and epigenetic landscape in the context of tumourigenesis and highlight recent advances in the use of small-molecule drug targets for therapy.
    Keywords:  Cancer; Epigenetics; Metabolism; Signalling pathways; Small molecules
    DOI:  https://doi.org/10.1007/978-3-031-07634-3_16
  47. Life (Basel). 2022 Oct 19. pii: 1639. [Epub ahead of print]12(10):
    Polyphenols and Their Nanoformulations: Protective Effects against Human Diseases.
    Santosh Anand, Ramachandregowda Sowbhagya, Mohammad Azam Ansari, Mohammad A Alzohairy, Mohammad N Alomary, Asiyah I Almalik, Wasim Ahmad, Takshashila Tripathi, Abozer Y Elderdery.
      Polyphenols are the secondary metabolites synthesized by the plants as a part of defense machinery. Owing to their antioxidant, anti-inflammatory, anticancerous, antineoplastic, and immunomodulatory effects, natural polyphenols have been used for a long time to prevent and treat a variety of diseases. As a result, these phytochemicals may be able to act as therapeutic agents in treating cancer and cardiovascular and neurological disorders. The limited bioavailability of polyphenolic molecules is one issue with their utilization. For the purpose of increasing the bioavailability of these chemicals, many formulation forms have been developed, with nanonization standing out among them. The present review outlines the biological potential of nanoformulated plant polyphenolic compounds. It also summarizes the employability of various polyphenols as nanoformulations for cancer and neurological and cardiovascular disease treatment. Nanoencapsulated polyphenols, singular or in combinations, effective both in vitro and in vivo, need more investigation.
    Keywords:  bioavailability; cancer; cardiovascular diseases; human health; nanoformulations; nanonization; neurological diseases; polyphenols
    DOI:  https://doi.org/10.3390/life12101639
  48. Life Sci. 2022 Oct 25. pii: S0024-3205(22)00833-5. [Epub ahead of print] 121133
    Organ restricted delivery through stimuli responsive nanocarriers for lung cancer therapy.
    Yirivinti Hayagreeva Dinakar, Archana Karole, Shabi Parvez, Vikas Jain, Shyam Lal Mudavath.
      Lung Cancer (LC) is the malignant tumor of the lungs which is defined by the unrestricted cell development in the lung tissues which if left untreated may migrate to different regions of the body. LC accounts for 12 % of the total cancer diagnosis and is among the most occurring malignancies in both genders. Radiotherapy, surgery, and chemotherapy are the treatment options for LC. The obstacles faced by chemotherapy include faster elimination, affecting healthy cells, and poor targeting. The application of nanotechnology in drug delivery has gained profound value with the development of various nanoparticulate systems such as nanoparticles, liposomes etc. Some limitations exhibited by the conventional nanocarriers include leakage of the drug, and stability issues. In order to overcome these problems, approaches such as coating of the NPs and use of stimuli responsive nanocarriers have been used. These approaches also aid in boosting pre-existing properties and achieving organ restricted drug delivery. Stimuli responsive DDS (drug delivery systems) are those systems in which the drug is released or delivered via a stimulus. Due to the reason that cancer tissues exhibit characteristic pH, elevated enzyme levels, these sort of smart nanocarriers have found their application in targeting cancer. Various nanocarriers incorporating various molecules have also been formulated and tested against lung cancer. In this review, we have discussed various classes of stimuli responsive nanocarriers such as endogenous stimuli responsive nanocarriers which include pH responsive nanocarriers, enzyme responsive nanocarriers and exogenous stimuli responsive nanocarriers such as thermoresponsive, magnetic responsive, ultrasound responsive, photoresponsive nanocarrier along with their application in targeting lung cancer.
    Keywords:  Liposomes; Lung cancer; Nanoparticles; Organ restricted drug delivery; Stimuli responsive nanocarriers etc.; Tumor targeting
    DOI:  https://doi.org/10.1016/j.lfs.2022.121133
  49. Biomedicines. 2022 Sep 29. pii: 2431. [Epub ahead of print]10(10):
    Curcumin Hybrid Lipid Polymeric Nanoparticles: Antioxidant Activity, Immune Cellular Response, and Cytotoxicity Evaluation.
    María Isabel Quirós-Fallas, Krissia Wilhelm-Romero, Silvia Quesada-Mora, Gabriela Azofeifa-Cordero, Luis Felipe Vargas-Huertas, Diego Alvarado-Corella, Juan José Mora-Román, José Roberto Vega-Baudrit, Mirtha Navarro-Hoyos, Andrea Mariela Araya-Sibaja.
      Poor solubility and short biological half-life present a challenge that needs to be overcome in order to improve the recognized bioactivities of curcumin (CUR), the main phenolic compounds derived from the roots of Curcuma longa. However, drug delivery systems have proven to be an excellent strategy to improve and obtain greater bioavailability. Our previous studies on curcuminoid hybrid nanoparticles have shown promising results by significantly increasing the solubility of desmethoxycurcumin (DMC) and bisdemethoxycurcumin (BDM). In this contribution, we performed a detailed characterization of a CUR as well as in vitro and in vivo studies. The developed method produced CUR loaded nanoparticles with an average size of 49.46 ± 0.80. Moreover, the FT-IR analysis confirmed the encapsulation, and TEM images showed their spherical shape. The NP achieved an encapsulation efficiency greater than 99%. Further, the release studies found that the NPs obtained a significantly higher release than the pure compounds in water. In vivo delayed-type hypersensitivity (DTH) studies showed promising results by enhancing the immune activity response of CUR in NP compared to bulk CUR. Furthermore, we report a significant increase in antioxidant activity for CUR-NP in aqueous solution compared to free CUR. Finally, an important in vitro cytotoxic effect on gastric AGS and colon SW620 adenocarcinoma cell lines was found for CUR-NP while empty carrier nanoparticles are observed to exhibit low cytotoxicity, indicating the potential of these CUR-PLU NPs for further studies to assess their phytotherapeutic applications.
    Keywords:  Immune cellular response; antioxidant activity; curcumin; cytotoxicity; hybrid lipid polymeric nanoparticles; nanoparticle characterization
    DOI:  https://doi.org/10.3390/biomedicines10102431
  50. FASEB J. 2022 Nov;36(11): e22626
    PTEN-knockout regulates metabolic rewiring and epigenetic reprogramming in prostate cancer and chemoprevention by triterpenoid ursolic acid.
    Lujing Wang, Chao Wang, Md Shahid Sarwar, Pochung Chou, Yujue Wang, Xiaoyang Su, Ah-Ng Tony Kong.
      PTEN (phosphatase and tensin homolog deleted on chromosome 10) is one of the most frequently mutated/deleted tumor suppressor genes in many human cancers. Ursolic acid (UA) is a natural triterpenoid possessing antioxidant, anti-inflammatory, and anticancer effects. However, how PTEN impacts metabolic rewiring and how UA modifies PTEN-driven metabolic and epigenetic reprogramming in prostate cancer (PCa) remains unknown. In the current study, we found that UA protects against PTEN knockout (KO)-induced tumorigenesis at different stages of PCa. Epigenomic CpG methyl-seq revealed UA attenuated PTEN KO-induced differentially methylated regions (DMRs) profiles. Transcriptomic RNA-seq showed UA abrogated PTEN KO-induced differentially expressed genes (DEGs) of PCa-related oncogenes' Has3, Cfh, and Msx1 overexpression, indicating UA plays a crucial role in PTEN KO-mediated gene regulation and its potential consequences on cancer interception. Association analysis of DEGs and DMRs identified that the mRNA expression of tumor suppressor gene BDH2, and oncogenes Ephas, Isg15, and Nos2 were correlated with the promoter CpG methylation status in the early-stage comparison groups indicating UA could regulate the oncogenes or tumor suppressor genes by modulating their promoter methylation at an early stage of prostate tumorigenesis. The metabolomic study showed UA attenuated PTEN KO-regulated cancer-associated metabolisms like purine metabolism/metabolites correlating with RNAseq findings, glycolysis/gluconeogenesis metabolism, as well as epigenetic-related metabolites pyruvate and lactate indicating UA plays a critical role in PTEN KO-mediated metabolic and epigenetic reprogramming and its consequences on cancer development. In this context, UA impacts metabolic rewiring causing epigenetic and transcriptomic reprogramming potentially contributing to the overall protection against prostate-specific PTEN KO-mediated PCa.
    Keywords:  PTEN; chemoprevention; epigenetic; metabolomics; prostate cancer; ursolic acid
    DOI:  https://doi.org/10.1096/fj.202201195R
  51. Mol Cancer. 2022 Oct 28. 21(1): 204
    Antioxidants in brain tumors: current therapeutic significance and future prospects.
    Xuchen Qi, Saurabh Kumar Jha, Niraj Kumar Jha, Saikat Dewanjee, Abhijit Dey, Rahul Deka, Pingal Pritam, Kritika Ramgopal, Weiting Liu, Kaijian Hou.
      Brain cancer is regarded among the deadliest forms of cancer worldwide. The distinct tumor microenvironment and inherent characteristics of brain tumor cells virtually render them resistant to the majority of conventional and advanced therapies. Oxidative stress (OS) is a key disruptor of normal brain homeostasis and is involved in carcinogenesis of different forms of brain cancers. Thus, antioxidants may inhibit tumorigenesis by preventing OS induced by various oncogenic factors. Antioxidants are hypothesized to inhibit cancer initiation by endorsing DNA repair and suppressing cancer progression by creating an energy crisis for preneoplastic cells, resulting in antiproliferative effects. These effects are referred to as chemopreventive effects mediated by an antioxidant mechanism. In addition, antioxidants minimize chemotherapy-induced nonspecific organ toxicity and prolong survival. Antioxidants also support the prooxidant chemistry that demonstrate chemotherapeutic potential, particularly at high or pharmacological doses and trigger OS by promoting free radical production, which is essential for activating cell death pathways. A growing body of evidence also revealed the roles of exogenous antioxidants as adjuvants and their ability to reverse chemoresistance. In this review, we explain the influences of different exogenous and endogenous antioxidants on brain cancers with reference to their chemopreventive and chemotherapeutic roles. The role of antioxidants on metabolic reprogramming and their influence on downstream signaling events induced by tumor suppressor gene mutations are critically discussed. Finally, the review hypothesized that both pro- and antioxidant roles are involved in the anticancer mechanisms of the antioxidant molecules by killing neoplastic cells and inhibiting tumor recurrence followed by conventional cancer treatments. The requirements of pro- and antioxidant effects of exogenous antioxidants in brain tumor treatment under different conditions are critically discussed along with the reasons behind the conflicting outcomes in different reports. Finally, we also mention the influencing factors that regulate the pharmacology of the exogenous antioxidants in brain cancer treatment. In conclusion, to achieve consistent clinical outcomes with antioxidant treatments in brain cancers, rigorous mechanistic studies are required with respect to the types, forms, and stages of brain tumors. The concomitant treatment regimens also need adequate consideration.
    Keywords:  Antioxidant; Brain tumor; Chemopreventive role; Chemotherapy; Dietary antioxidants; Gene mutation; Glioblastoma; Glioma; Metabolic reprogramming; Oxidative stress
    DOI:  https://doi.org/10.1186/s12943-022-01668-9
  52. Theranostics. 2022 ;12(16): 7032-7050
    TCA-phospholipid-glycolysis targeted triple therapy effectively suppresses ATP production and tumor growth in glioblastoma.
    Shixue Yang, Jixing Zhao, Xiaoteng Cui, Qi Zhan, Kaikai Yi, Qixue Wang, Menglin Xiao, Yanli Tan, Biao Hong, Chuan Fang, Chunsheng Kang.
      Rationale: Glioblastoma (GBM) displays a complex metabolic reprogramming in cancer cells. Adenosine triphosphate (ATP) is one of the central mediators of cell metabolism and signaling. GBM cells generate ATP by glycolysis and the tricarboxylic acid (TCA) cycle associated with oxidative phosphorylation (OXPHOS) through the breaking-down of pyruvate or fatty acids to meet the growing energy demand of cancer cells. Therefore, it's urgent to develop novel treatments targeting energy metabolism to hinder tumor cell proliferation in GBM. Methods: Non-targeted metabolomic profiling analysis was utilized to evaluate cell metabolic reprogramming using a small molecule inhibitor (SMI) EPIC-0412 treatment. Cellular oxygen consumption rate (OCR) and the total proton efflux rate (PER), as well as ATP concentration, were tracked to study metabolic responses to specifically targeted inhibitors, including EPIC-0412, arachidonyl trifluoromethyl ketone (AACOCF3), and 2 deoxy-D-glucose (2-DG). Cancer cell proliferation was assessed by CCK-8 measurements and colony formation assay. Additionally, flow cytometry, immunoblotting (IB), and immunofluorescence (IF) analyses were performed with GBM cells to understand their tumorigenic properties under treatments. Finally, the anticancer effects of this combination therapy were evaluated in the GBM mouse model by convection-enhanced delivery (CED). Results: We found that SMI EPIC-0412 could effectively perturb the TCA cycle, which participated in the combination therapy of cytosolic phospholipase A2 (cPLA2)-inhibitor AACOCF3, and hexokinase II (HK2)-inhibitor 2-DG to disrupt the GBM energy metabolism for targeted metabolic treatments. ATP production was significantly declined in glioma cells when treated with monotherapy (EPIC-0412 or AACOCF3), dual therapy (EPIC-0412 + AACOCF3), or triple therapy (EPIC-0412 + AACOCF3 +2-DG) regimen. Our experiments revealed that these therapies hindered glioma cell proliferation and growth, leading to the reduction in ATP production and G0/G1 cell cycle arrest. We demonstrated that the combination therapy effectively extended the survival of cerebral tumor-bearing mice. Conclusion: Our findings indicate that the TCA-phospholipid-glycolysis metabolism axis can be blocked by specific inhibitors that significantly disrupt the tumor energy metabolism and suppress tumor proliferation in vitro and in vivo, suggesting that targeting ATP synthesis inhibition in cancer cells might be an attractive therapeutic avenue in GBM management.
    Keywords:  ATP production; convection-enhanced delivery.; energy metabolism; glioblastoma
    DOI:  https://doi.org/10.7150/thno.74197
  53. Cells. 2022 Oct 18. pii: 3273. [Epub ahead of print]11(20):
    Targeting Asparagine Synthetase in Tumorgenicity Using Patient-Derived Tumor-Initiating Cells.
    Gen Nishikawa, Kenji Kawada, Keita Hanada, Hisatsugu Maekawa, Yoshiro Itatani, Hiroyuki Miyoshi, Makoto Mark Taketo, Kazutaka Obama.
      Reprogramming of energy metabolism is regarded as one of the hallmarks of cancer; in particular, oncogenic RAS has been shown to be a critical regulator of cancer metabolism. Recently, asparagine metabolism has been heavily investigated as a novel target for cancer treatment. For example, Knott et al. showed that asparagine bioavailability governs metastasis in a breast cancer model. Gwinn et al. reported the therapeutic vulnerability of asparagine biosynthesis in KRAS-driven non-small cell lung cancer. We previously reported that KRAS-mutated CRC cells can adapt to glutamine depletion through upregulation of asparagine synthetase (ASNS), an enzyme that synthesizes asparagine from aspartate. In our previous study, we assessed the efficacy of asparagine depletion using human cancer cell lines. In the present study, we evaluated the clinical relevance of asparagine depletion using a novel patient-derived spheroid xenograft (PDSX) mouse model. First, we examined ASNS expression in 38 spheroid lines and found that 12 lines (12/37, 32.4%) displayed high ASNS expression, whereas 26 lines (25/37, 67.6%) showed no ASNS expression. Next, to determine the role of asparagine metabolism in tumor growth, we established ASNS-knockdown spheroid lines using lentiviral short hairpin RNA constructs targeting ASNS. An in vitro cell proliferation assay demonstrated a significant decrease in cell proliferation upon asparagine depletion in the ASNS-knockdown spheroid lines, and this was not observed in the control spheroids lines. In addition, we examined asparagine inhibition with the anti-leukemia drug L-asparaginase (L-Asp) and observed a considerable reduction in cell proliferation at a low concentration (0.1 U/mL) in the ASNS-knockdown spheroid lines, whereas it exhibited limited inhibition of control spheroid lines at the same concentration. Finally, we used the PDSX model to assess the effects of asparagine depletion on tumor growth in vivo. The nude mice injected with ASNS-knockdown or control spheroid lines were administered with L-Asp once a day for 28 days. Surprisingly, in mice injected with ASNS-knockdown spheroids, the administration of L-Asp dramatically inhibited tumor engraftment. On the other hands, in mice injected with control spheroids, the administration of L-Asp had no effect on tumor growth inhibition at all. These results suggest that ASNS inhibition could be critical in targeting asparagine metabolism in cancers.
    Keywords:  KRAS-driven cancer; L-asparaginase; asparagine metabolism; asparagine synthetase; patient-derived spheroid; patient-derived spheroid xenograft
    DOI:  https://doi.org/10.3390/cells11203273
  54. J Funct Biomater. 2022 Oct 14. pii: 188. [Epub ahead of print]13(4):
    Precise Design Strategies of Nanotechnologies for Controlled Drug Delivery.
    Shiyi Huang, Xianting Ding.
      Rapid advances in nanotechnologies are driving the revolution in controlled drug delivery. However, heterogeneous barriers, such as blood circulation and cellular barriers, prevent the drug from reaching the cellular target in complex physiologic environments. In this review, we discuss the precise design of nanotechnologies to enhance the efficacy, quality, and durability of drug delivery. For drug delivery in vivo, drugs loaded in nanoplatforms target particular sites in a spatial- and temporal-dependent manner. Advances in stimuli-responsive nanoparticles and carbon-based drug delivery platforms are summarized. For transdermal drug delivery systems, specific strategies including microneedles and hydrogel lead to a sustained release efficacy. Moreover, we highlight the current limitations of clinical translation and an incentive for the future development of nanotechnology-based drug delivery.
    Keywords:  barriers; drug delivery; hydrogel; microneedles; nanoparticles
    DOI:  https://doi.org/10.3390/jfb13040188
  55. Molecules. 2022 Oct 19. pii: 7042. [Epub ahead of print]27(20):
    Evaluation of the Effects of Genistein In Vitro as a Chemopreventive Agent for Colorectal Cancer-Strategy to Improve Its Efficiency When Administered Orally.
    Juan Pablo Rendón, Ana Isabel Cañas, Elizabeth Correa, Vanesa Bedoya-Betancur, Marlon Osorio, Cristina Castro, Tonny W Naranjo.
      Colorectal Cancer (CRC) ranks third in terms of incidence and second in terms of mortality and prevalence worldwide. In relation to chemotherapy treatment, the most used drug is 5-fluorouracil (5-FU); however, the use of this drug generates various toxic effects at the systemic level. For this reason, new therapeutic strategies are currently being sought that can be used as neoadjuvant or adjuvant treatments. Recent research has shown that natural compounds, such as genistein, have chemotherapeutic and anticancer effects, but the mechanisms of action of genistein and its molecular targets in human colon cells have not been fully elucidated. The results reported in relation to non-malignant cell lines are also unclear, which does not allow evidence of the selectivity that this compound may have. Therefore, in this work, genistein was evaluated in vitro in both cancer cell lines SW480 and SW620 and in the non-malignant cell line HaCaT. The results obtained show that genistein has selectivity for the SW480 and SW620 cell lines. In addition, it inhibits cell viability and has an antiproliferative effect in a dose-dependent manner. Increased production of reactive oxygen species (ROS) was also found, suggesting an association with the cell death process through various mechanisms. Finally, the encapsulation strategy that was proposed made it possible to demonstrate that bacterial nanocellulose (BNC) is capable of protecting genistein from the acidic conditions of gastric fluid and also allows the release of the compound in the colonic fluid. This would allow genistein to act locally in the mucosa of the colon where the first stages of CRC occur.
    Keywords:  chemoprevention; colon cancer; encapsulation; genistein
    DOI:  https://doi.org/10.3390/molecules27207042
  56. Curr Cancer Drug Targets. 2022 Oct 25.
    Apoptin inhibits glycolysis and regulates autophagy by targeting pyruvate kinase M2 (PKM2) in lung cancer A549 cells.
    Gaojie Song, Chao Shang, Yilong Zhu, Zhiru Xiu, Yaru Li, Xia Yang, Chenchen Ge, Jicheng Han, Ningyi Jin, Yiquan Li, Xiao Li, Jinbo Fang.
      Pyruvate kinase M2 (PKM2) is a key enzyme in aerobic glycolysis, and which plays an important role in tumor energy metabolism and tumor growth. Ad-apoptin, a recombinant oncolytic adenovirus, that can stably express apoptin in tumor cells and selectively causes cell death in tumor cells. The relationship between the anti-tumor function of apoptin, including apoptosis and autophagy activation, and energy metabolism of tumor cells has not been clarified. In this study, we used the A549 lung cancer cell line to analyze the mechanism of PKM2 involvement apoptin-mediated cell death in tumor cells. PKM2 expression in lung cancer cells was detected by Western blot and qRT-PCR. In the PKM2 knockdown and over-expression experiments, A549 lung cancer cells were treated with Ad-apoptin, and cell viability was determined by the CCK-8 assay and crystal violet staining. Glycolysis was investigated using glucose consumption and lactate production experiments. Moreover, the effects of Ad-apoptin on autophagy and apoptosis were analyzed by immunofluorescence using the Annexin v-mCherry staining and by western blot for c-PARP, p62 and LC3-II proteins. Immunoprecipitation analysis was used to investigate the interaction between apoptin and PKM2. In addition, following PKM2 knockdown and overexpression, the expression levels of p-AMPK, p-mTOR, p-ULK1, and p-4E-BP1 proteins in Ad-apoptin treated tumor cells, were analyzed by western blot to investigate the mechanism of apoptin effect on the energy metabolism of tumor cells. The in vivo antitumor mechanism of apoptin was analyzed by xenograft tumor inhibition experiment in nude mice and immunohistochemistry of tumors' tissue. As a result, apoptin could target PKM2, inhibit glycolysis and cell proliferation in A549 cells, and promote autophagy and apoptosis in A549 cells by regulating the PKM2/AMPK/mTOR pathway. This study confirmed the necessary role of Ad-apoptin in energy metabolism of A549 cells.
    Keywords:  PKM2; apoptin; autophagy; glycolysis; lung cancer
    DOI:  https://doi.org/10.2174/1568009623666221025150239
  57. BMC Med. 2022 Oct 28. 20(1): 411
    Combination of an autophagy inhibitor with immunoadjuvants and an anti-PD-L1 antibody in multifunctional nanoparticles for enhanced breast cancer immunotherapy.
    Yibin Cheng, Caixia Wang, Huihui Wang, Zhiwei Zhang, Xiaopeng Yang, Yanming Dong, Lixin Ma, Jingwen Luo.
       BACKGROUND: The application of combination therapy for cancer treatment is limited due to poor tumor-specific drug delivery and the abscopal effect.
    METHODS: Here, PD-L1- and CD44-responsive multifunctional nanoparticles were developed using a polymer complex of polyethyleneimine and oleic acid (PEI-OA) and loaded with two chemotherapeutic drugs (paclitaxel and chloroquine), an antigen (ovalbumin), an immunopotentiator (CpG), and an immune checkpoint inhibitor (anti-PD-L1 antibody).
    RESULTS: PEI-OA greatly improved the drug loading capacity and encapsulation efficiency of the nanoplatform, while the anti-PD-L1 antibody significantly increased its cellular uptake compared to other treatment formulations. Pharmacodynamic experiments confirmed that the anti-PD-L1 antibody can strongly inhibit primary breast cancer and increase levels of CD4+ and CD8+ T cell at the tumor site. In addition, chloroquine reversed the "immune-cold" environment and improved the anti-tumor effect of both chemotherapeutics and immune checkpoint inhibitors, while it induced strong immune memory and prevented lung metastasis.
    CONCLUSIONS: Our strategy serves as a promising approach to the rational design of nanodelivery systems for simultaneous active targeting, autophagy inhibition, and chemotherapy that can be combined with immune-checkpoint inhibitors for enhanced breast cancer treatment.
    Keywords:  Anti-PD-L1 antibody; Autophagy response; Immuno-chemotherapy; Multifunctional nanoparticles
    DOI:  https://doi.org/10.1186/s12916-022-02614-8
  58. Eur J Pharm Biopharm. 2022 Oct 19. pii: S0939-6411(22)00242-9. [Epub ahead of print]
    Engineering of QbD driven and ultrasonically shaped lyotropic liquid crystalline nanoparticles for Apigenin in the management of skin cancer.
    Ayesha Waheed, Saima Zameer, Niha Sultana, Asad Ali, Mohd Aqil, Yasmin Sultana, Zeenat Iqbal.
      Treatment of skin cancer demands targeted delivery without minimal systemic circulation for maximum therapeutic window. Dermal delivery with nano-formulation offers such advantages. Therefore, present study aims to formulate Lyotropic liquid crystalline nanoparticles (LLC NPs) loaded with Apigenin (API) for dermal delivery using quality by design (QbD) approach for effective permeation resulting in improved bioavailability. Apigenin loaded LLC NPs (API-LLC NPs) were formulated and optimized by applying risk assessment and design of experiments (Box-Behnken Design). The optimized API-LLC NPs showed particle size, PdI and entrapment efficiency of 287.7±9.53 nm, 0.152±0.051 and 80±2.2 % respectively. The optimized API-LLC NPs were characterized for morphology and crystallinity using optical microscopy, TEM, DSC and PXRD. In vitro and ex vivo studies showed sustained release and better permeation profile. CLSM study presented better penetration of API-LLC NPs which were quantitatively confirmed with dermatokinetics. Cytotoxic efficacy assessed on B16F10 cell lines showed a dose-dependent efficacy of API-LLC NPs with an IC50 of 45.74 ± 0.05. In a nutshell, the developed API-LLC NPs exhibit excellent potential for targeting deeper skin layers thereby can be considered a promising topical drug delivery nanocarrier in the treatment and management of skin cancer.
    Keywords:  Apigenin; CLSM; Cytotoxicity; Dermal delivery; Liquid crystalline nanoparticles; Quality by design
    DOI:  https://doi.org/10.1016/j.ejpb.2022.10.015
  59. Nutrients. 2022 Oct 11. pii: 4219. [Epub ahead of print]14(20):
    Vitamin K Contribution to DNA Damage-Advantage or Disadvantage? A Human Health Response.
    Julia Kaźmierczak-Barańska, Bolesław T Karwowski.
      Vitamin K is the common name for a group of compounds recognized as essential for blood clotting. The group comprises phylloquinone (K1)-a 2-methyl-3-phytyl-1,4-naphthoquinone; menaquinone (K2, MK)-a group of compounds with an unsaturated side chain in position 3 of a different number of isoprene units and a 1,4-naphthoquinone group and menadione (K3, MD)-a group of synthetic, water-soluble compounds 2-methyl-1,4-naphthoquinone. However, recent epidemiological studies suggest that vitamin K has various benefits that go beyond blood coagulation processes. A dietary intake of K1 is inversely associated with the risk of pancreatic cancer, K2 has the potential to induce a differentiation in leukemia cells or apoptosis of various types of cancer cells, and K3 has a documented anti-cancer effect. A healthy diet rich in fruit and vegetables ensures an optimal supply of K1 and K2, though consumers often prefer supplements. Interestingly, the synthetic form of vitamin K-menadione-appears in the cell during the metabolism of phylloquinone and is a precursor of MK-4, a form of vitamin K2 inaccessible in food. With this in mind, the purpose of this review is to emphasize the importance of vitamin K as a micronutrient, which not only has a beneficial effect on blood clotting and the skeleton, but also reduces the risk of cancer and other pro-inflammatory diseases. A proper diet should be a basic and common preventive procedure, resulting in a healthier society and reduced burden on healthcare systems.
    Keywords:  ROS; anti-cancer; vitamin K
    DOI:  https://doi.org/10.3390/nu14204219
  60. Pharmaceutics. 2022 Sep 23. pii: 2028. [Epub ahead of print]14(10):
    Progress of Research in In Situ Smart Hydrogels for Local Antitumor Therapy: A Review.
    Juan Zhao, Ling Wang, Haiwei Zhang, Bin Liao, Yongsheng Li.
      Cancer seriously threatens human health. Surgery, radiotherapy and chemotherapy are the three pillars of traditional cancer treatment, with targeted therapy and immunotherapy emerging over recent decades. Standard drug regimens are mostly executed via intravenous injection (IV), especially for chemotherapy agents. However, these treatments pose severe risks, including off-target toxic side effects, low drug accumulation and penetration at the tumor site, repeated administration, etc., leading to inadequate treatment and failure to meet patients' needs. Arising from these challenges, a local regional anticancer strategy has been proposed to enhance therapeutic efficacy and concomitantly reduce systemic toxicity. With the advances in biomaterials and our understanding of the tumor microenvironment, in situ stimulus-responsive hydrogels, also called smart hydrogels, have been extensively investigated for local anticancer therapy due to their injectability, compatibility and responsiveness to various stimuli (pH, enzyme, heat, light, magnetic fields, electric fields etc.). Herein, we focus on the latest progress regarding various stimuli that cause phase transition and drug release from smart hydrogels in local regional anticancer therapy. Additionally, the challenges and future trends of the reviewed in situ smart hydrogels for local drug delivery are summarized and proposed.
    Keywords:  in situ hydrogel; local regional therapy; progress; stimuli responsive
    DOI:  https://doi.org/10.3390/pharmaceutics14102028
  61. Mar Drugs. 2022 Sep 23. pii: 598. [Epub ahead of print]20(10):
    Alginate-Based Micro- and Nanosystems for Targeted Cancer Therapy.
    Siavash Iravani, Rajender S Varma.
      Alginates have been widely explored due to their salient advantages of hydrophilicity, biocompatibility, mucoadhesive features, bioavailability, environmentally-benign properties, and cost-effectiveness. They are applied for designing micro- and nanosystems for controlled and targeted drug delivery and cancer therapy as alginate biopolymers find usage in encapsulating anticancer drugs to improve their bioavailability, sustained release, pharmacokinetics, and bio-clearance. Notably, these nanomaterials can be applied for photothermal, photodynamic, and chemodynamic therapy of cancers/tumors. Future explorations ought to be conducted to find novel alginate-based (nano)systems for targeted cancer therapy using advanced drug delivery techniques with benefits of non-invasiveness, patient compliance, and convenience of drug administration. Thus, some critical parameters such as mucosal permeability, stability in the gastrointestinal tract environment, and drug solubility ought to be considered. In addition, the comprehensive clinical translational studies along with the optimization of synthesis techniques still need to be addressed. Herein, we present an overview of the current state of knowledge and recent developments pertaining to the applications of alginate-based micro- and nanosystems for targeted cancer therapy based on controlled drug delivery, photothermal therapy, and chemodynamic/photodynamic therapy approaches, focusing on important challenges and future directions.
    Keywords:  alginate; alginate-based nanosystems; cancer therapy; drug delivery; nanomaterials
    DOI:  https://doi.org/10.3390/md20100598
  62. Subcell Biochem. 2022 ;100 393-426
    Metabolic Regulation of Lysine Acetylation: Implications in Cancer.
    Siddharth Singh, Parijat Senapati, Tapas K Kundu.
      Lysine acetylation is the second most well-studied post-translational modification after phosphorylation. While phosphorylation regulates signaling cascades, one of the most significant roles of acetylation is regulation of chromatin structure. Acetyl-coenzyme A (acetyl-CoA) serves as the acetyl group donor for acetylation reactions mediated by lysine acetyltransferases (KATs). On the other hand, NAD+ serves as the cofactor for lysine deacetylases (KDACs). Both acetyl-CoA and NAD+ are metabolites integral to energy metabolism, and therefore, their metabolic flux can regulate the activity of KATs and KDACs impacting the epigenome. In this chapter, we review our current understanding of how metabolic pathways regulate lysine acetylation in normal and cancer cells.
    Keywords:  Acetyl-CoA; Acetylation; Epigenome; Metabolic reprogramming; Metabolism; NAD+; Oral cancer
    DOI:  https://doi.org/10.1007/978-3-031-07634-3_12
  63. Pharmaceutics. 2022 Oct 13. pii: 2184. [Epub ahead of print]14(10):
    The Rate of Cisplatin Dosing Affects the Resistance and Metastatic Potential of Triple Negative Breast Cancer Cells, Independent of Hypoxia.
    Omkar Bhatavdekar, Inês Godet, Daniele Gilkes, Stavroula Sofou.
      To best control tumor growth and/or metastasis in triple negative breast cancer (TNBC), it may be useful to understand the effect(s) of chemotherapy delivery (i.e., the rate and pattern of exposure to the drug) on cell sub-populations that have experienced different levels of hypoxia (and/or acidosis). In this spirit, MDA-MB-231 TNBC cells, and their hypoxia-reporter counterparts, were characterized for their sensitivity to cisplatin. When in the form of multicellular spheroids, that capture the diffusion-limited transport that generates hypoxic and acidic subregions within the avascular areas of solid tumors, the effects of the rate and pattern of exposure to cisplatin on cell viability and motility/migration potential were evaluated for each cell sub-population. We demonstrated that cell sensitivity to cisplatin was not dependent on acidosis, but cell resistance increased with exposure to hypoxia. In spheroids, the increase of the rates of cell exposure to cisplatin, at a constant cumulative dose, increased sensitivity to chemotherapy and lowered the cells' metastatic potential, even for cells that had experienced hypoxia. This effect was also shown to be caused by nanocarriers engineered to quickly release cisplatin which deeply penetrated the spheroid interstitium, resulting in the fast and uniform exposure of the TNBC tumors to the agent. This rate and dosing-controlled model may effectively limit growth and/or metastasis, independent of hypoxia. This mode of chemotherapy delivery can be enabled by engineered nanocarriers.
    Keywords:  cisplatin; diffusion; hypoxia; metastatic potential; nanoparticle; rate of drug release; solid tumors; triple negative breast cancer
    DOI:  https://doi.org/10.3390/pharmaceutics14102184
  64. Int J Mol Sci. 2022 Oct 11. pii: 12066. [Epub ahead of print]23(20):
    Diclofenac Sensitizes Signet Ring Cell Gastric Carcinoma Cells to Cisplatin by Activating Autophagy and Inhibition of Survival Signal Pathways.
    Nang Lae Lae Phoo, Amonnat Sukhamwang, Pornngarm Dejkriengkraikul, Supachai Yodkeeree.
      Gastric cancer has one of the highest incidence rates of cancer worldwide while also contributing to increased drug resistance among patients in clinical practice. Herein, we have investigated the role of diclofenac (DCF) on sensitizing cisplatin resistance in signet ring cell gastric carcinoma cells (SRCGC). Non-toxic concentrations of DCF significantly augmented cisplatin-induced cell death in cisplatin-resistant SRCGC cells (KATO/DDP) but not in cisplatin-sensitive SRCGC cells (KATOIII). Consistently, concomitant treatment of DCF and cisplatin significantly enhanced autophagic cell death due to overproduction of intracellular reactive oxygen species (ROS). At the molecular level, the induction of ROS has been associated with a reduction in antioxidant enzymes expression while inhibiting nuclear factor erythroid 2-related factor 2 (Nrf2) activity. Moreover, the combination of DCF and cisplatin also inhibited the expression of survival proteins including Bcl-2, Bcl-xL, cIAP1 and cyclin D1 in KATO/DDP cells when compared with cisplatin alone. This was due, at least in part, to reduce MAPKs, Akt, NF-κB, AP-1 and STAT-3 activation. Taken together, our results suggested that DCF potentiated the anticancer effect of cisplatin in SRCGC via the regeneration of intracellular ROS, which in turn promoted cell death as an autophagy mechanism and potentially modulated the cell survival signal transduction pathway.
    Keywords:  ROS; autophagy; cisplatin; cisplatin resistance; diclofenac; gastric cancer; survival proteins
    DOI:  https://doi.org/10.3390/ijms232012066
  65. Antioxidants (Basel). 2022 Oct 07. pii: 1993. [Epub ahead of print]11(10):
    Antioxidative and Anti-Inflammatory Activity of Ascorbic Acid.
    Agnieszka Gęgotek, Elżbieta Skrzydlewska.
      Ascorbic acid, as a one of the basic exogenous vitamins, occurs in the body in the form of ascorbate, known for its strong antioxidant and anti-inflammatory properties. The presented review shows not only the importance of ascorbate as a free radical scavenger but also summarizes its antioxidant action based on other mechanisms, including the activation of intracellular antioxidant systems and its effect on the NFκB/TNFα pathway and apoptosis. Ascorbate interacts with small-molecule antioxidants, including tocopherol, glutathione, and thioredoxin; it can also stimulate biosynthesis and the activation of antioxidant enzymes, such as superoxide dismutase, catalase, or glutathione peroxidase. Moreover, ascorbate promotes the activity of transcription factors (Nrf2, Ref-1, AP-1), which enables the expression of genes encoding antioxidant proteins. Additionally, it supports the action of other exogenous antioxidants, mainly polyphenols. In this regard, both DNA, proteins, and lipids are protected against oxidation, leading to an inflammatory reaction and even cell death. Although ascorbate has strong antioxidant properties, it can also have pro-oxidant effects in the presence of free transition metals. However, its role in the prevention of DNA mutation, inflammation, and cell apoptosis, especially in relation to cancer cells, is controversial.
    Keywords:  DNA reparation; NFκB; Nrf2; ROS scavenging; antioxidant enzymes; ascorbic acid; intracellular signalization
    DOI:  https://doi.org/10.3390/antiox11101993
  66. J Funct Biomater. 2022 Sep 21. pii: 158. [Epub ahead of print]13(4):
    Curcumin-Encapsulated Nanomicelles Improve Cellular Uptake and Cytotoxicity in Cisplatin-Resistant Human Oral Cancer Cells.
    Vijay M Kumbar, Uday Muddapur, Abdullatif Bin Muhsinah, Saad Ali Alshehri, Mohammed Merae Alshahrani, Ibrahim Abdullah Almazni, Manohar S Kugaji, Kishore Bhat, Malleswara Rao Peram, Mater H Mahnashi, Sameer J Nadaf, Sheetalnath B Rooge, Aejaz Abdullatif Khan, Ibrahim Ahmed Shaikh.
      Oral cancer has a high mortality rate, which is mostly determined by the stage of the disease at the time of admission. Around half of all patients with oral cancer report with advanced illness. Hitherto, chemotherapy is preferred to treat oral cancer, but the emergence of resistance to anti-cancer drugs is likely to occur after a sequence of treatments. Curcumin is renowned for its anticancer potential but its marred water solubility and poor bioavailability limit its use in treating multidrug-resistant cancers. As part of this investigation, we prepared and characterized Curcumin nanomicelles (CUR-NMs) using DSPE-PEG-2000 and evaluated the anticancer properties of cisplatin-resistant cancer cell lines. The prepared CUR-NMs were sphere-shaped and unilamellar in structure, with a size of 32.60 ± 4.2 nm. CUR-NMs exhibited high entrapment efficiency (82.2%), entrapment content (147.96 µg/mL), and a mean zeta potential of -17.5ζ which is considered moderately stable. The cellular uptake and cytotoxicity studies revealed that CUR-NMs had significantly higher cytotoxicity and cellular uptake in cisplatin drug-resistant oral cancer cell lines and parental oral cancer cells compared to plain curcumin (CUR). The DAPI and FACS analysis corroborated a high percentage of apoptotic cells with CUR-NMs (31.14%) compared to neat CUR (19.72%) treatment. Conclusively, CUR-NMs can potentially be used as an alternative carrier system to improve the therapeutic effects of curcumin in the treatment of cisplatin-resistant human oral cancer.
    Keywords:  bioavailability; cisplatin-resistant oral cancer; curcumin nanomicelles; cytotoxicity; pre-cancer
    DOI:  https://doi.org/10.3390/jfb13040158
  67. Int J Mol Sci. 2022 Oct 14. pii: 12250. [Epub ahead of print]23(20):
    Non-Canonical Functions of Myeloperoxidase in Immune Regulation, Tissue Inflammation and Cancer.
    Joey S Lockhart, Ronen Sumagin.
      Myeloperoxidase (MPO) is one of the most abundantly expressed proteins in neutrophils. It serves as a critical component of the antimicrobial defense system, facilitating microbial killing via generation of reactive oxygen species (ROS). Interestingly, emerging evidence indicates that in addition to the well-recognized canonical antimicrobial function of MPO, it can directly or indirectly impact immune cells and tissue responses in homeostatic and disease states. Here, we highlight the emerging non-canonical functions of MPO, including its impact on neutrophil longevity, activation and trafficking in inflammation, its interactions with other immune cells, and how these interactions shape disease outcomes. We further discuss MPO interactions with barrier forming endothelial and epithelial cells, specialized cells of the central nervous system (CNS) and its involvement in cancer progression. Such diverse function and the MPO association with numerous inflammatory disorders make it an attractive target for therapies aimed at resolving inflammation and limiting inflammation-associated tissue damage. However, while considering MPO inhibition as a potential therapy, one must account for the diverse impact of MPO activity on various cellular compartments both in health and disease.
    Keywords:  cancer; cell activation; endothelial cell; inflammation; neutrophil; reactive oxygen species; therapeutic; tissue injury; trafficking
    DOI:  https://doi.org/10.3390/ijms232012250
  68. Subcell Biochem. 2022 ;100 81-113
    Regulation of Lipid Metabolism Under Stress and Its Role in Cancer.
    Rimsha Munir, Nousheen Zaidi.
      Within the tumor microenvironment, cancer cells are often exposed to oxygen and nutrient deficiency, leading to various changes in their lipid composition and metabolism. These alterations have important therapeutic implications as they affect the cancer cells' survival, membrane dynamics, and therapy response. This chapter provides an overview of recent insights into the regulation of lipid metabolism in cancer cells under metabolic stress. We discuss how this metabolic adaptation helps cancer cells thrive in a harsh tumor microenvironment.
    Keywords:  Cancer; De Novo Fatty acid synthesis; Fatty acid synthase; Hypoxia; Lipid metabolism; Lipidomic profiles; Metabolic stress; Nutrient deprivation
    DOI:  https://doi.org/10.1007/978-3-031-07634-3_3
  69. Langmuir. 2022 Oct 23.
    Light-Activated Reactive Oxygen Species-Responsive Nanocarriers for Enhanced Photodynamic Immunotherapy of Cancer.
    Na Peng, Yijing Du, Guang Yu, Chenglan Zhang, Qun Cai, Hu Tang, Yi Liu.
      Exploring polymeric nanoplatforms combined with reactive oxygen species (ROS) responsiveness with mitochondria targeting has emerged as an effective strategy for enhanced photodynamic therapy (PDT). Amphiphilic copolymers were synthesized by reacting acrylamide thioketal (TK) linkers with amino-terminated triphenylphosphonium-polyethylene glycol and dodecylamine for encapsulating chlorin e6 (Ce6) via self-assembly. Then, anionic cladding with tumor targeting deshelled in tumor acidic microenvironments was surface-anchored by electrostatic forces (BioPEGDMA@RM). After sequential targeting to the mitochondria of cancerous cells, BioPEGDMA@RM could be light-activated with Ce6 released upon ROS cleavage of TK linkages. It was found that Ce6-loaded BioPEGDMA@RM exhibited higher cytotoxicity on CT26 cells and performed stronger ability on the production of ROS than that without TK linkers. Moreover, a minimum illumination of 3 and 5 min could be required for achieving the maximum release of Ce6 and high in vitro cytotoxicity for Ce6-loaded BioPEGDMA@RM, respectively. Furthermore, Ce6-loaded BioPEGDMA@RM showed 1.29-fold and 1.21-fold higher tumor inhibition on BALB/c nude mice and Kunming mice and stimulated immunologic reactions with more generation of IFN-γ and TNF-α and activation of CD3+, CD4+, and CD8+ T-lymphocytes and DCs than that of Ce6-loaded nanoparticles without TK bonds. This work provided an academic reference for the development of ROS-responsive drug delivery systems for advanced PDT efficiency.
    DOI:  https://doi.org/10.1021/acs.langmuir.2c01857
  70. Front Pharmacol. 2022 ;13 1029601
    The pathogenesis of liver cancer and the therapeutic potential of bioactive substances.
    Song Gao, Xingyue Jiang, Liang Wang, Shanshan Jiang, Hanyuan Luo, Yan Chen, Cheng Peng.
      Liver cancer is the third most common cause of cancer-related deaths in the world and has become an urgent problem for global public health. Bioactive substances are widely used for the treatment of liver cancer due to their widespread availability and reduced side effects. This review summarizes the main pathogenic factors involved in the development of liver cancer, including metabolic fatty liver disease, viral infection, and alcoholic cirrhosis, and focuses on the mechanism of action of bioactive components such as polysaccharides, alkaloids, phenols, peptides, and active bacteria/fungi. In addition, we also summarize transformation methods, combined therapy and modification of bioactive substances to improve the treatment efficiency against liver cancer, highlighting new ideas in this field.
    Keywords:  bioactive substances; bioavailability; liver cancer; mechanisms of action; pathogenic factors
    DOI:  https://doi.org/10.3389/fphar.2022.1029601
  71. Micromachines (Basel). 2022 Sep 28. pii: 1623. [Epub ahead of print]13(10):
    Sustained Drug Release from Smart Nanoparticles in Cancer Therapy: A Comprehensive Review.
    Xue Bai, Zara L Smith, Yuheng Wang, Sam Butterworth, Annalisa Tirella.
      Although nanomedicine has been highly investigated for cancer treatment over the past decades, only a few nanomedicines are currently approved and in the market; making this field poorly represented in clinical applications. Key research gaps that require optimization to successfully translate the use of nanomedicines have been identified, but not addressed; among these, the lack of control of the release pattern of therapeutics is the most important. To solve these issues with currently used nanomedicines (e.g., burst release, systemic release), different strategies for the design and manufacturing of nanomedicines allowing for better control over the therapeutic release, are currently being investigated. The inclusion of stimuli-responsive properties and prolonged drug release have been identified as effective approaches to include in nanomedicine, and are discussed in this paper. Recently, smart sustained release nanoparticles have been successfully designed to safely and efficiently deliver therapeutics with different kinetic profiles, making them promising for many drug delivery applications and in specific for cancer treatment. In this review, the state-of-the-art of smart sustained release nanoparticles is discussed, focusing on the design strategies and performances of polymeric nanotechnologies. A complete list of nanomedicines currently tested in clinical trials and approved nanomedicines for cancer treatment is presented, critically discussing advantages and limitations with respect to the newly developed nanotechnologies and manufacturing methods. By the presented discussion and the highlight of nanomedicine design criteria and current limitations, this review paper could be of high interest to identify key features for the design of release-controlled nanomedicine for cancer treatment.
    Keywords:  cancer nanomedicine; drug delivery systems; liposomes; microfluidics; polymeric nanoparticles; sustained drug release
    DOI:  https://doi.org/10.3390/mi13101623
  72. Cancers (Basel). 2022 Oct 18. pii: 5097. [Epub ahead of print]14(20):
    Upregulation of Succinate Dehydrogenase (SDHA) Contributes to Enhanced Bioenergetics of Ovarian Cancer Cells and Higher Sensitivity to Anti-Metabolic Agent Shikonin.
    Lin Wang, Magdalena Cybula, Maria Rostworowska, Luyao Wang, Patryk Mucha, Magdalena Bulicz, Magdalena Bieniasz.
      We discovered that the overexpression of mitochondrial enzyme succinate dehydrogenase (SDHA) is particularly prevalent in ovarian carcinoma and promotes highly metabolically active phenotype. Succinate dehydrogenase deficiency has been previously studied in some rare disorders. However, the role of SDHA upregulation and its impact on ovarian cancer metabolism has never been investigated, emphasizing the need for further research. We investigated the functional consequences of SDHA overexpression in ovarian cancer. Using proteomics approaches and biological assays, we interrogated protein content of metabolic pathways, cell proliferation, anchorage-independent growth, mitochondrial respiration, glycolytic function, and ATP production rates in those cells. Lastly, we performed a drug screening to identify agents specifically targeting the SDHA overexpressing tumor cells. We showed that SDHA overexpressing cells are characterized by enhanced energy metabolism, relying on both glycolysis and oxidative phosphorylation to meet their energy needs. In addition, SDHA-high phenotype was associated with cell vulnerability to glucose and glutamine deprivation, which led to a substantial reduction of ATP yield. We also identified an anti-metabolic compound shikonin with a potent efficacy against SDHA overexpressing ovarian cancer cells. Our data underline the unappreciated role of SDHA in reprogramming of ovarian cancer metabolism, which represents a new opportunity for therapeutic intervention.
    Keywords:  SDHA; metabolism; ovarian cancer; patient-derived xenograft; shikonin; succinate dehydrogenase
    DOI:  https://doi.org/10.3390/cancers14205097
  73. Front Pharmacol. 2022 ;13 962718
    Analyzing the metabolic fate of oral administration drugs: A review and state-of-the-art roadmap.
    Liu Liu, Yiming Liu, Xiaojie Zhou, Zhiwei Xu, Yehui Zhang, Liting Ji, Chunlan Hong, Changyu Li.
      The key orally delivered drug metabolism processes are reviewed to aid the assessment of the current in vivo/vitro experimental systems applicability for evaluating drug metabolism and the interaction potential. Orally administration is the most commonly used state-of-the-art road for drug delivery due to its ease of administration, high patient compliance and cost-effectiveness. Roles of gut metabolic enzymes and microbiota in drug metabolism and absorption suggest that the gut is an important site for drug metabolism, while the liver has long been recognized as the principal organ responsible for drugs or other substances metabolism. In this contribution, we explore various experimental models from their development to the application for studying oral drugs metabolism of and summarized advantages and disadvantages. Undoubtedly, understanding the possible metabolic mechanism of drugs in vivo and evaluating the procedure with relevant models is of great significance for screening potential clinical drugs. With the increasing popularity and prevalence of orally delivered drugs, sophisticated experimental models with higher predictive capacity for the metabolism of oral drugs used in current preclinical studies will be needed. Collectively, the review seeks to provide a comprehensive roadmap for researchers in related fields.
    Keywords:  metabolic models; metabolism enzymes; metabolism pathway; model application; oral drugs
    DOI:  https://doi.org/10.3389/fphar.2022.962718
  74. Biomolecules. 2022 Oct 17. pii: 1503. [Epub ahead of print]12(10):
    Pancreatic Cancer Research beyond DNA Mutations.
    Hiromichi Sato, Kazuki Sasaki, Tomoaki Hara, Yoshiko Tsuji, Yasuko Arao, Chihiro Otsuka, Yumiko Hamano, Mirei Ogita, Shogo Kobayashi, Eric di Luccio, Takaaki Hirotsu, Yuichiro Doki, Hidetoshi Eguchi, Taroh Satoh, Shizuka Uchida, Hideshi Ishii.
      Pancreatic ductal adenocarcinoma (PDAC) is caused by genetic mutations in four genes: KRAS proto-oncogene and GTPase (KRAS), tumor protein P53 (TP53), cyclin-dependent kinase inhibitor 2A (CDKN2A), and mothers against decapentaplegic homolog 4 (SMAD4), also called the big 4. The changes in tumors are very complex, making their characterization in the early stages challenging. Therefore, the development of innovative therapeutic approaches is desirable. The key to overcoming PDAC is diagnosing it in the early stages. Therefore, recent studies have investigated the multifaced characteristics of PDAC, which includes cancer cell metabolism, mesenchymal cells including cancer-associated fibroblasts and immune cells, and metagenomics, which extend to characterize various biomolecules including RNAs and volatile organic compounds. Various alterations in the KRAS-dependent as well as KRAS-independent pathways are involved in the refractoriness of PDAC. The optimal combination of these new technologies is expected to help treat intractable pancreatic cancer.
    Keywords:  RNA; cancer metabolism; mutations; pancreatic ductal adenocarcinoma; sequencing
    DOI:  https://doi.org/10.3390/biom12101503
  75. Front Pharmacol. 2022 ;13 1020343
    Disturbance of the Warburg effect by dichloroacetate and niclosamide suppresses the growth of different sub-types of malignant pleural mesothelioma in vitro and in vivo.
    Sze-Kwan Lam, Sheng Yan, Joyce Sze-Man Lam, Yuqian Feng, Mahjabin Khan, Caoyang Chen, Frankie Chi-Fat Ko, James Chung-Man Ho.
      Background: Inhalation of asbestos fibers is the most common cause of malignant pleural mesothelioma (MPM). In 2004, the United States Food and Drug Administration approved a combination of cisplatin with pemetrexed to treat unresectable MPM. Nonetheless novel treatment is urgently needed. The objective of this study is to report the combination effect of dichloroacetate (DCA) or niclosamide (Nic) Nic in MPM. Materials and methods: The effect of a combination of DCA and Nic was studied using a panel of MPM cell lines (H28, MSTO-211H, H226, H2052, and H2452). Cell viability was monitored by MTT assay. Glycolysis, oxidative phosphorylation, glucose, glycogen, pyruvate, lactate, citrate, succinate and ATP levels were determined by corresponding ELISA. Apoptosis, mitochondrial transmembrane potential, cell cycle analysis, hydrogen peroxide and superoxide were investigated by flow cytometry. Cell migration and colony formation were investigated by transwell migration and colony formation assays respectively. The in vivo effect was confirmed using 211H and H226 nude mice xenograft models. Results and conclusion: Cell viability was reduced. Disturbance of glycolysis and/or oxidative phosphorylation resulted in downregulation of glycogen, citrate and succinate. DCA and/or Nic increased apoptosis, mitochondrial transmembrane depolarization, G2/M arrest and reactive oxygen species. Moreover, DCA and/or Nic suppressed cell migration and colony formation. Furthermore, a better initial tumor suppressive effect was induced by the DCA/Nic combination compared with either drug alone in both 211H and H226 xenograft models. In H226 xenografts, DCA/Nic increased median survival of mice compared with single treatment. Single drug and/or a combination disturbed the Warburg effect and activated apoptosis, and inhibition of migration and proliferation in vivo. In conclusion, dichloroacetate and/or niclosamide showed a tumor suppressive effect in MPM in vitro and in vivo, partially mediated by disturbance of glycolysis/oxidative phosphorylation, apoptosis, ROS production, G2/M arrest, and suppression of migration and proliferation.
    Keywords:  apoptosis; dichloroacetate; malignant pleural mesothelioma; niclosamide; warburg effect; xenografts
    DOI:  https://doi.org/10.3389/fphar.2022.1020343
  76. Cancers (Basel). 2022 Oct 20. pii: 5149. [Epub ahead of print]14(20):
    Dietary Interventions in Cancer Treatment and Response: A Comprehensive Review.
    Benjamin D Mercier, Eemon Tizpa, Errol J Philip, Qianhua Feng, Ziyi Huang, Reeny M Thomas, Sumanta K Pal, Tanya B Dorff, Yun R Li.
      Chemotherapy and radiotherapy are first-line treatments in the management of advanced solid tumors. Whereas these treatments are directed at eliminating cancer cells, they cause significant adverse effects that can be detrimental to a patient's quality of life and even life-threatening. Diet is a modifiable risk factor that has been shown to affect cancer risk, recurrence, and treatment toxicity, but little information is known how diet interacts with cancer treatment modalities. Although dietary interventions, such as intermittent fasting and ketogenic diets, have shown promise in pre-clinical studies by reducing the toxicity and increasing the efficacy of chemotherapeutics, there remains a limited number of clinical studies in this space. This review surveys the impact of dietary interventions (caloric restriction, intermittent and short-term fasting, and ketogenic diet) on cancer treatment outcomes in both pre-clinical and clinical studies. Early studies support a complementary role for these dietary interventions in improving patient quality of life across multiple cancer types by reducing toxicity and perhaps a benefit in treatment efficacy. Larger, phase III, randomized clinical trials are ultimately necessary to evaluate the efficacy of these dietary interventions in improving oncologic or quality of life outcomes for patients that are undergoing chemotherapy or radiotherapy.
    Keywords:  caloric restriction; cancer; cancer treatment toxicity; chemotherapy; dietary intervention; fasting; intermittent fasting; ketogenic diet; quality of life; radiation therapy; radiotherapy; time-restricted diet
    DOI:  https://doi.org/10.3390/cancers14205149
  77. Int J Nanomedicine. 2022 ;17 5001-5026
    Ultrasound Responsive Smart Implantable Hydrogels for Targeted Delivery of Drugs: Reviewing Current Practices.
    Yi Sun, Le-Gao Chen, Xiao-Ming Fan, Jian-Liang Pang.
      Over the last two decades, the process of delivering therapeutic drugs to a patient with a controlled release profile has been a significant focus of drug delivery research. Scientists have given tremendous attention to ultrasound-responsive hydrogels for several decades. These smart nanosystems are more applicable than other stimuli-responsive drug delivery vehicles (ie UV-, pH- and thermal-, responsive materials) because they enable more efficient targeted treatment via relatively non-invasive means. Ultrasound (US) is capable of safely transporting energy through opaque and complex media with minimal loss of energy. It is capable of being localized to smaller regions and coupled to systems operating at various time scales. However, the properties enabling the US to propagate effectively in materials also make it very difficult to transform acoustic energy into other forms that may be used. Recent research from a variety of domains has attempted to deal with this issue, proving that ultrasonic effects can be used to control chemical and physical systems with remarkable specificity. By obviating the need for multiple intravenous injections, implantable US responsive hydrogel systems can enhance the quality of life for patients who undergo treatment with a varied dosage regimen. Ideally, the ease of self-dosing in these systems would lead to increased patient compliance with a particular therapy as well. However, excessive literature has been reported based on implanted US responsive hydrogel in various fields, but there is no comprehensive review article showing the strategies to control drug delivery profile. So, this review was aimed at discussing the current strategies for controlling and targeting drug delivery profiles using implantable hydrogel systems.
    Keywords:  acoustic energy; cavitation; localized therapy; on-demand drug delivery; smart hydrogels; ultrasound
    DOI:  https://doi.org/10.2147/IJN.S374247
  78. Colloids Surf B Biointerfaces. 2022 Oct 17. pii: S0927-7765(22)00628-2. [Epub ahead of print]220 112944
    Effect of surface ligand modification on the properties of anti-tumor nanocarrier.
    Na Ying, Xiangde Lin, Meihua Xie, Dongdong Zeng.
      With the continuous increasing number of cancer patients worldwide, there has been great interest in developing the targeted delivery anti-cancer drugs. The drug concentration reaching the tumor site is not enough to achieve a good therapeutic effect if it relies only on passive targeted drug delivery. In a long-lasting effort to improve the anti-cancer effect of drugs, surface ligand modification to nanocarriers has been actively explored to greatly improve the targeting ability, induce apoptosis in tumor cells, and prolong the drug circulation time in blood. This present review provides an overview of the effects of surface ligand modifications on the properties of anti-tumor nanocarriers. The first part presents the targeting mechanisms of nanocarriers. The second part focuses on recent progress in types of surface modification ligands exploited for anti-tumor nanocarriers. And the third part encompasses the effect of surface modifications on the properties of nanocarriers. In addition, the perspective in this field is also discussed.
    Keywords:  Anti-tumor; Ligand; Nanocarrier; Surface-modified; Target
    DOI:  https://doi.org/10.1016/j.colsurfb.2022.112944
  79. Colloids Surf B Biointerfaces. 2022 Oct 13. pii: S0927-7765(22)00611-7. [Epub ahead of print]220 112927
    Size-transformable gelatin/nanochitosan/doxorubicin nanoparticles with sequentially triggered drug release for anticancer therapy.
    Kaichun Li, Dong Zhou, Hengqing Cui, Guoyan Mo, Yu Liu, Kaikai Zheng, Zheng Zhou, Jian Li, Ping Dai, Jing Sun, Yuhong Zhang, Jie Gao.
      The translation of nanoparticles in cancer treatment is limited by their low drug-loading capacity, poor colloidal stability, insufficient tumor penetration, and uncontrolled drug release. Herein, gelatin/nanochitosan/doxorubicin nanoparticles (GND) are developed by crosslinking nanochitosan (NCT) with gelatin for doxorubicin delivery. The hydrophilicity and stability properties of GND allow it to be protected and have a long circulation time in blood. The GND formulation exhibited shedding and triggered release effects as well as improved colloidal stability. When reaching the tumor site, matrix metallopeptidase-2 (MMP-2) from the tumor environment degrades gelatin from 178-nm GND to release smaller 4 nm nanochitosan/doxorubicin (ND) nanoparticles for deep tumor penetration and efficient tumor cell endocytosis. Following endocytosis by tumor cells, the intracellular low pH and MMP-2 further trigger doxorubicin release, resulting in superior inhibitory capacity against cancer cells. Using a mouse tumor-bearing model, the superior anticancer activity and good in vivo biocompatibility of GND were verified. The rational design of tumor-penetrating GND enables MMP-2/pH sequentially triggered intelligent drug delivery, providing a practical approach for anticancer therapy.
    Keywords:  Anticancer therapy; Drug delivery; Nanoparticles; Sequentially triggered drug release; Size-transformable
    DOI:  https://doi.org/10.1016/j.colsurfb.2022.112927
  80. Biomolecules. 2022 Sep 21. pii: 1339. [Epub ahead of print]12(10):
    Curcumin Targeting Non-Coding RNAs in Colorectal Cancer: Therapeutic and Biomarker Implications.
    Jiaying Li, Rundong Chai, Yinxiao Chen, Shuwu Zhao, Yuhong Bian, Xiangling Wang.
      Colorectal cancer is one of the most common gastrointestinal malignancies, with high incidence rates, a low rate of early diagnosis, and complex pathogenesis. In recent years, there has been progress made in its diagnosis and treatment methods, but tumor malignant proliferation and metastasis after treatment still seriously affect the survival and prognosis of patients. Therefore, it is an extremely urgent task of current medicine to find new anti-tumor drugs with high efficiency and safety and low toxicity. Curcumin has shown potent anti-tumor and anti-inflammatory effects and is considered a hot spot in the research and development of anti-tumor drugs due to its advantages of precise efficacy, lower toxic side effects, and less drug resistance. Recent studies have revealed that curcumin has anti-tumor effects exerted on the epigenetic regulation of tumor-promoting/tumor-suppressing gene expression through the alteration of expression levels of non-coding RNAs (e.g., lncRNAs, miRNAs, and circRNAs). Herein, we summarize the interaction between curcumin and non-coding RNAs on the occurrence and development of colorectal cancer. The information complied in this review will serve as a scientific and reliable basis and viewpoint for the clinical application of non-coding RNAs in colorectal cancer.
    Keywords:  anti-tumor; colorectal cancer; curcumin; epigenetic regulation; non-coding RNAs
    DOI:  https://doi.org/10.3390/biom12101339
  81. Cancers (Basel). 2022 Oct 15. pii: 5060. [Epub ahead of print]14(20):
    Inhibition of Phosphoglycerate Dehydrogenase Radiosensitizes Human Colorectal Cancer Cells under Hypoxic Conditions.
    Melissa Van de Gucht, Inès Dufait, Lisa Kerkhove, Cyril Corbet, Sven de Mey, Heng Jiang, Ka Lun Law, Thierry Gevaert, Olivier Feron, Mark De Ridder.
      Augmented de novo serine synthesis activity is increasingly apparent in distinct types of cancers and has mainly sparked interest by investigation of phosphoglycerate dehydrogenase (PHGDH). Overexpression of PHGDH has been associated with higher tumor grade, shorter relapse time and decreased overall survival. It is well known that therapeutic outcomes in cancer patients can be improved by reprogramming metabolic pathways in combination with standard treatment options, for example, radiotherapy. In this study, possible metabolic changes related to radioresponse were explored upon PHGDH inhibition. Additionally, we evaluated whether PHGDH inhibition could improve radioresponse in human colorectal cancer cell lines in both aerobic and radiobiological relevant hypoxic conditions. Dysregulation of reactive oxygen species (ROS) homeostasis and dysfunction in mitochondrial energy metabolism and oxygen consumption rate were indicative of potential radiomodulatory effects. We demonstrated that PHGDH inhibition radiosensitized hypoxic human colorectal cancer cells while leaving intrinsic radiosensitivity unaffected. In a xenograft model, the first hints of additive effects between PHGDH inhibition and radiotherapy were demonstrated. In conclusion, this study is the first to show that modulation of de novo serine biosynthesis enhances radioresponse in hypoxic colorectal cancer cells, mainly mediated by increased levels of intracellular ROS.
    Keywords:  colorectal cancer; hypoxia; radiosensitivity; reactive oxygen species; serine synthesis pathway
    DOI:  https://doi.org/10.3390/cancers14205060
  82. Pharmaceutics. 2022 Oct 11. pii: 2165. [Epub ahead of print]14(10):
    Liposomal Drug Delivery Systems for Cancer Therapy: The Rotterdam Experience.
    Mohamadreza Amin, Ann L B Seynhaeve, Majid Sharifi, Mojtaba Falahati, Timo L M Ten Hagen.
      At the Nanomedicine Innovation Center (NICE) at the Erasmus MC in Rotterdam, we have approached the treatment of cancer by starting with a vision of first establishing a platform that enables us to overcome the low levels of drugs delivered to tumors and the issue of dose-limiting toxicity. Showing that a reduction of the volume of distribution, and a lowering of toxicity and side-effects, accompanied by augmented intratumoral drug delivery, could change outcomes in patients, paved the way to target, not only localized disease, but also systemic and metastasized cancers. In particular, the detailed studies with intravital microscopy we performed at NICE provided us with the necessary insights and affected to a large extent our program on liposome-based cancer therapy. Together with our experience with the loco-regional treatment of cancer, this helped us to develop a program that focused on the subsequent aspects discussed here. We recognized that passive accumulation of nanoparticles was not as effective as previously believed and undertook to improve the local accumulation by changing the tumor pathophysiology and, in particular, the vascular permeability. We added the targeting of liposomes using vascular and tumor directed moieties, to improve cellular drug delivery. To improve payload delivery, we studied the modification of liposomes with phospholipids that help passive drug release and augment cellular accumulation. Second, and importantly, modification of liposomes was undertaken, to enable triggered drug release. The capability for modifying liposomes to respond to a trigger, and the ability to now apply an external trigger (e.g., hyperthermia) and specifically reach the tumor volume, resulted in the current smart drug delivery systems. Our experience at NICE, after a few decades of research on lipid-based nanoparticles, shows that, after the first liposomal formulation registered for clinical application in cancer therapy, further developments quickly followed, while further clinical applications lagged behind. Now we need to focus on and make the next steps towards the clinic, to fulfil the promise that is found there.
    Keywords:  The Netherlands; active targeting; cancer therapy; drug delivery; hyperthermia; intravital microscopy; liposomes; smart drug delivery system; temperature sensitive liposomes; vascular permeabilization; vascular targeting
    DOI:  https://doi.org/10.3390/pharmaceutics14102165
  83. Theranostics. 2022 ;12(16): 7080-7107
    Natural cell based biomimetic cellular transformers for targeted therapy of digestive system cancer.
    Xiaomeng Tang, Dan Li, Yongwei Gu, Yunan Zhao, Aixue Li, Fu Qi, Jiyong Liu.
      Digestive system cancer is the most common cause of cancer death in the world. Although cancer treatment options are increasingly diversified, the mortality rate of malignant cancer of the digestive system remains high. Therefore, it is necessary to explore effective cancer treatment methods. Recently, biomimetic nanoparticle delivery systems based on natural cells that organically integrate the low immunogenicity, high biocompatibility, cancer targeting, and controllable, versatile functionality of smart nanocarrier design with natural cells have been expected to break through the bottleneck of tumor targeted therapy. In this review, we focus on the dynamic changes and complex cellular communications that occur in vivo in natural cells based vehicles. Recent studies on the development of advanced targeted drug delivery systems using the dynamic behaviors such as specific surface protein affinity, morphological changes, and phenotypic polarization of natural cells are summarized. In addition to drug delivery mediated by dynamic behavior, functional "delivery" based on the natural cell themselves is also involved. Aiming to make the best use of the functions of cells, providing clues for the development of advanced drug delivery platforms.
    Keywords:  Biomimetic cellular transformers; Cancer targeting; Digestive system cancer; Natural cell; Transformation
    DOI:  https://doi.org/10.7150/thno.75937
  84. Pharmaceutics. 2022 Oct 18. pii: 2225. [Epub ahead of print]14(10):
    Aptamer-Functionalized Nanoparticles Mediate PD-L1 siRNA Delivery for Effective Gene Silencing in Triple-Negative Breast Cancer Cells.
    Simona Camorani, Silvia Tortorella, Lisa Agnello, Chiara Spanu, Annachiara d'Argenio, Roberto Nilo, Antonella Zannetti, Erica Locatelli, Monica Fedele, Mauro Comes Franchini, Laura Cerchia.
      Small interfering RNA (siRNA) therapies require effective delivery vehicles capable of carrying the siRNA cargo into target cells. To achieve tumor-targeting, a drug delivery system would have to incorporate ligands that specifically bind to receptors expressed on cancer cells to function as portals via receptor-mediated endocytosis. Cell-targeting and internalizing aptamers are the most suitable ligands for functionalization of drug-loaded nanocarriers. Here, we designed a novel aptamer-based platform for the active delivery of siRNA targeting programmed cell death-ligand 1 (PD-L1) to triple-negative breast cancer (TNBC) cells. The generated nanovectors consist of PLGA-based polymeric nanoparticles, which were loaded with PD-L1 siRNA and conjugated on their surface with a new RNA aptamer, specific for TNBC and resistant to nucleases. In vitro results demonstrated that these aptamer-conjugated nanoparticles promote siRNA uptake specifically into TNBC MDA-MB-231 and BT-549 target cells, along with its endosomal release, without recognizing non-TNBC BT-474 breast cancer cells. Their efficiency resulted in an almost complete suppression of PD-L1 expression as early as 90 min of cell treatment. This research provides a rational strategy for optimizing siRNA delivery systems for TNBC treatments.
    Keywords:  PD-L1; PLGA-b-PEG nanoparticles; TNBC; active siRNA delivery; aptamer; endosomal escape
    DOI:  https://doi.org/10.3390/pharmaceutics14102225
  85. Molecules. 2022 Oct 21. pii: 7108. [Epub ahead of print]27(20):
    Chemopreventive Effect on Human Colon Adenocarcinoma Cells of Styrylquinolines: Synthesis, Cytotoxicity, Proapoptotic Effect and Molecular Docking Analysis.
    Vanesa Bedoya-Betancur, Elizabeth Correa, Juan Pablo Rendón, Andrés F Yepes-Pérez, Wilson Cardona-Galeano, Tonny W Naranjo.
      Seven styrylquinolines were synthesized in this study. Two of these styrylquinolines are new and were elucidated by spectroscopic analysis. The chemopreventive potential of these compounds was evaluated against SW480 human colon adenocarcinoma cells, its metastatic derivative SW620, and normal cells (HaCaT). According to the results, compounds 3a and 3d showed antiproliferative activity in SW480 and SW620 cells, but their effect seemed to be caused by different mechanisms of action. Compound 3a induced apoptosis independent of ROS production, as evidenced by increased levels of caspase 3, and had an immunomodulatory effect, positively regulating the production of different immunological markers in malignant cell lines. In contrast, compound 3d generated a pro-oxidant response and inhibited the growth of cancer cells, probably by another type of cell death other than apoptosis. Molecular docking studies indicated that the most active compound, 3a, could efficiently bind to the proapoptotic human caspases-3 protein, a result that could provide valuable information on the biochemical mechanism for the in vitro cytotoxic response of this compound in SW620 colon carcinoma cell lines. The obtained results suggest that these compounds have chemopreventive potential against CRC, but more studies should be carried out to elucidate the molecular mechanisms of action of each of them in depth.
    Keywords:  antiproliferation; apoptosis; cell death; colorectal cancer; inflammation; molecular docking; reactive oxygen species; styrylquinolines
    DOI:  https://doi.org/10.3390/molecules27207108
  86. Pharmaceutics. 2022 Sep 20. pii: 1984. [Epub ahead of print]14(10):
    New Approach for Preparing Solid Lipid Nanoparticles with Volatile Oil-Loaded Quercetin Using the Phase-Inversion Temperature Method.
    Yotsanan Weerapol, Suwisit Manmuan, Nattaya Chaothanaphat, Sontaya Limmatvapirat, Jitnapa Sirirak, Poomipat Tamdee, Sukannika Tubtimsri.
      Quercetin (QCT), a natural flavonoid, is of research interest owing to its pharmacological properties. However, its pharmacokinetic limitations could hinder its widespread therapeutic use. Nanocarriers, especially solid lipid nanoparticles (SLNs), might overcome this constraint. This study aimed to investigate QCT-loaded SLNs prepared via a new approach using a volatile oil. The phase-inversion temperature method was used to incorporate rosemary oil (RMO) into SLNs prepared using solid lipids possessing different chemical structures. Among the solid lipids used in the formulations, trilaurin (TLR) exhibited the smallest particle size and good stability after a temperature cycling test. SLNs prepared with a ratio of RMO to TLR of 1:3 could load QCT with an entrapment efficiency of &gt;60% and drug loading of ~2% w/w. The smallest particle size was achieved using the polyoxyethylene-hydrogenated castor oil RH40, and the particle size depended on the concentration. The drug-release profile of QCT_TLR exhibited prolonged biphasic release for &gt;24 h. QCT_TLR was a safe formulation, as indicated by a cell viability percentage of &gt;75% at &lt;2% v/v. In a computer simulation, the system with RMO enabled smaller sized SLNs than those without RMO. This new discovery shows great promise for producing SLNs via the phase-inversion temperature method with incorporation of volatile oil, particularly for delivering compounds with limited water solubility.
    Keywords:  molecular dynamics study; phase-inversion temperature; quercetin; solid lipid nanoparticles; volatile oil
    DOI:  https://doi.org/10.3390/pharmaceutics14101984
  87. Recent Pat Nanotechnol. 2022 Oct 19.
    Design Optimization and Evaluation of Solid Lipid Nanoparticles of Azelnidipine for the treatment of Hypertension.
    Abhishek Kanugo, Tejas Dugad.
       BACKGROUND: Solid lipid nanoparticles (SLN) are the most promising lipid-based drug delivery utilized for enhancing the solubility, bioavailability, and therapeutic efficacy of poorly water-soluble molecules. Azelnidipine (AZN) is a calcium channel blocker widely recommended for the treatment of high blood pressure but its activity is restricted due to high lipophilicity and poor solubility in the GIT. The current research focused on the development of the SLN of AZN and thereby improving the absorption, bioavailability, and therapeutic efficacy in hypertension which is a leading cause of death worldwide. Recent patents on SLN was available as U.S. Patent,10,973,798B2, U.S. Patent 10,251,960B2, U.S. Patent 2021/0069121A1, U.S. Patent 2022/0151945A1.
    METHODS: SLN was developed by hot melt emulsification and ultrasonication method using glyceryl monostearate (GMS) as solid lipid and Poloxamer 188 as a surfactant for the stabilization of colloidal dispersion.
    RESULTS: Box-Behnken model was utilized which predicted 13 batches in which concentration of GMS (X1), Poloxamer 188 (X2) and sonication time (X3) were considered as independent parameters. The particle size (Y1) and entrapment efficiency (Y2) were dependable parameters and optimized batch F2 showed a particle size of 166.4 nm, polydispersity index of 0.40 and zeta potential of -13.7 mV. The entrapment efficiency was observed at 86.21 %. FTIR spectra confirm the identity and compatibility with the formulation components. The differential scanning calorimetry (DSC) confirmed the absence of melting point and interpreted that AZN was entirely incorporated in the lipid matrix and transformed from crystalline to amorphous form. The ANOVA for the particle size (p-value: 0.0203), % EE (p-value: 0.0271) was found significant. The in-vitro drug release showed a sustained release pattern for about 12 h. The AZN-loaded SLN was lyophilized and intended for oral delivery.
    CONCLUSION: AZN-loaded SLN was developed by the hot melt emulsification method which accelerated the solubility and bioavailability and released in a sustained manner for treating hypertension.
    Keywords:  Azelnidipine; Box-Behnken design; Oral delivery.; Solid lipid nanoparticles; hypertension
    DOI:  https://doi.org/10.2174/1872210517666221019102543
  88. Front Pharmacol. 2022 ;13 1004617
    Potential benefits of metformin and pioglitazone combination therapy via gut microbiota and metabolites in high-fat diet-fed mice.
    Dongmei Wang, Jieying Liu, Ling Zhong, Lu Ding, Qian Zhang, Miao Yu, Ming Li, Xinhua Xiao.
      Metformin and pioglitazone monotherapy have been proven to alter gut microbiota in diabetes and obesity. The present study aimed to investigated whether the combined administration of pioglitazone and metformin achieved superior protective effects on high-fat diet (HFD)-fed obese mice and elucidated its molecular mechanism via the gut microbiota and its metabolites. C57BL/6 males were randomly divided into five groups: the control group, fed a normal control diet; the HFD group, fed an HFD; the metformin monotherapy group, fed an HFD and treated with metformin; the pioglitazone monotherapy group, fed an HFD and treated with pioglitazone; and the combination therapy group, fed an HFD and treated with metformin and pioglitazone combination therapy. The cecal contents were collected for 16S rDNA amplicon sequencing and untargeted metabolomics analysis. The results showed that the combination therapy of metformin and pioglitazone significantly improved insulin sensitivity and glucolipid metabolism in HFD-fed mice. Combination therapy markedly altered gut microbiota by increasing beneficial bacteria, such as Bifidobacterium, Christensenellaceae_R-7_group, Faecalibacterium and Roseburia, and decreasing harmful bacteria, such as Oscillibacter and Eubacterium_xylanophilum_group. Fecal metabolites were significantly changed in the combination therapy group, including a reduction in amino acid metabolism and augmentation of lipid metabolism, such as citrulline, sarcosine, D-glutamine, lipoxin A4, prostaglandin E2, stearidonic acid and lucidenic acid A. These results revealed that combined metformin and pioglitazone therapy had synergistic effects or at least have an additive effect on modifying gut microbiota and metabolites, closely associated with improved glucolipid metabolic parameters in HFD-fed mice, which provides novel evidence and promising targets for metformin and pioglitazone combination therapy in type 2 diabetes.
    Keywords:  combination therapy; gut microbiota; metabolites; metformin; pioglitazone
    DOI:  https://doi.org/10.3389/fphar.2022.1004617
  89. Pharmaceuticals (Basel). 2022 Oct 19. pii: 1284. [Epub ahead of print]15(10):
    A Comprehensive Study of Therapeutic Applications of Chamomile.
    Amit Sah, Punnoth Poonkuzhi Naseef, Mohammed S Kuruniyan, Gaurav K Jain, Foziyah Zakir, Geeta Aggarwal.
      Chamomile has a long history of traditional medicinal uses. The two commonly used varieties with therapeutic applications are German chamomile known as Matricaria chamomilla L. and Roman chamomile or Chamaemelum nobile L. The plant contains many components, namely, flavonoids, terpenoids, and coumarins, which are responsible for its medicinal properties. The review discusses recent developments that help in establishing its role as a therapeutic agent in various areas as an anti-inflammatory, antioxidant, analgesic, antimicrobial, hepatoprotective, anti-allergic, anticancer, and anti-hypertensive agent. Not much is known about its role in the treatment of CNS disorders and metabolic syndromes, which are also discussed. The chemical components responsible for the therapeutic activity and the respective mechanism of action are also elaborated.
    Keywords:  apigenin; bisabalool; chamomile; chamomilla; flavonoid; matricaria
    DOI:  https://doi.org/10.3390/ph15101284
  90. Nutrients. 2022 Oct 16. pii: 4329. [Epub ahead of print]14(20):
    Vitamin E in Cancer Treatment: A Review of Clinical Applications in Randomized Control Trials.
    Jennifer Donnelly, Amanda Appathurai, Hui-Ling Yeoh, Kate Driscoll, Wasek Faisal.
      Vitamin E, along with other vitamins and micronutrients play a range of physiologic roles in the homeostasis of the body. Moreover, they also have postulated therapeutic roles that are often incompletely studied and understood. In this scoping review, we explored the recent randomized control trials (RCTs) of Vitamin E in the context of cancer, to investigate whether Vitamin E has a therapeutic role. We searched major bibliographic electronic databases to identify sixteen RCTs studying the role of Vitamin E in cancer management that have been published in the last ten years. These studies had different methodological qualities, including some that used Vitamin E in combination with other treatments. Furthermore, due to the heterogenous results, it is difficult to make a consensus statement on the effectiveness of Vitamin E in cancer therapeutics. In some cases, there were even suggestion of detriment with Vitamin E supplementation. Therefore, well designed, large, prospective RCTs are needed studying pure isoforms of Vitamin E to establish the safety and efficacy of this dietary supplement.
    Keywords:  Vitamin E; cancer; malignancy; neoplasm; nutrition; randomized controlled trial; scoping review; tocopherol
    DOI:  https://doi.org/10.3390/nu14204329
  91. Nutrients. 2022 Oct 16. pii: 4326. [Epub ahead of print]14(20):
    CoQ10 and Resveratrol Effects to Ameliorate Aged-Related Mitochondrial Dysfunctions.
    Gaia Gherardi, Giovanni Corbioli, Filippo Ruzza, Rosario Rizzuto.
      Mitochondria participate in the maintenance of cellular homeostasis. Firstly, mitochondria regulate energy metabolism through oxidative phosphorylation. In addition, they are involved in cell fate decisions by activating the apoptotic intrinsic pathway. Finally, they work as intracellular signaling hubs as a result of their tight regulation of ion and metabolite concentrations and other critical signaling molecules such as ROS. Aging is a multifactorial process triggered by impairments in different cellular components. Among the various molecular pathways involved, mitochondria are key regulators of longevity. Indeed, mitochondrial deterioration is a critical signature of the aging process. In this scenario, we will focus specifically on the age-related decrease in CoQ levels, an essential component of the electron transport chain (ETC) and an antioxidant, and how CoQ supplementation could benefit the aging process. Generally, any treatment that improves and sustains mitochondrial functionality is a good candidate to counteract age-related mitochondrial dysfunctions. In recent years, heightened attention has been given to natural compounds that modulate mitochondrial function. One of the most famous is resveratrol due to its ability to increase mitochondrial biogenesis and work as an antioxidant agent. This review will discuss recent clinical trials and meta-analyses based on resveratrol and CoQ supplementation, focusing on how these compounds could improve mitochondrial functionality during aging.
    Keywords:  aging; coenzymeQ10; mitochondria; resveratrol
    DOI:  https://doi.org/10.3390/nu14204326
  92. Int Rev Cell Mol Biol. 2022 ;pii: S1937-6448(22)00010-7. [Epub ahead of print]373 81-106
    Fasting and cancer: from yeast to mammals.
    Maira Di Tano, Valter D Longo.
      Fasting and fasting mimicking diets extend lifespan and healthspan in mouse models and decrease risk factors for cancer and other age-related pathologies in humans. Normal cells respond to fasting and the consequent decrease in nutrients by down-regulating proto-oncogene pathways to enter a stress-resistant mode, which protects them from different cancer therapies. In contrast, oncogene mutations and the constitutive activation of pathways including RAS, AKT, and PKA allow cancer cells to disobey fasting-dependent anti-growth signal. Importantly, in different tumor types, fasting potentiates the toxicity of various therapies by increasing reactive oxygen species and oxidative stress, which ultimately leads to DNA damage and cell death. This effect is not limited to chemotherapy, since periodic fasting/FMD cycles potentiate the effects of tyrosine kinase inhibitors, hormone therapy, radiotherapy, and pharmacological doses of vitamin C. In addition, the anticancer effects of fasting/FMD can also be tumor-independent and involve an immunotherapy-like activation of T cell-dependent attack of tumor cells. Supported by a range of pre-clinical studies, clinical trials are beginning to confirm the safety and efficacy of fasting/FMD cycles in improving the potential of different cancer therapies, while decreasing side effects to healthy cells and tissues.
    Keywords:  Cancer; Differential stress resistance; Differential-stress sensitization; Fasting-mimicking diet; Longevity
    DOI:  https://doi.org/10.1016/bs.ircmb.2022.02.005
  93. Oxid Med Cell Longev. 2022 ;2022 8063897
    Attenuation by Time-Restricted Feeding of High-Fat and High-Fructose Diet-Induced NASH in Mice Is Related to Per2 and Ferroptosis.
    Yan-Yun Shu, Wen-Kang Gao, Hui-Kuan Chu, Ling Yang, Xiao-Li Pan, Jin Ye.
      Nonalcoholic steatohepatitis (NASH) is a chronic and progressive disease whose treatment strategies are limited. Although time-restricted feeding (TRF) is beneficial for metabolic diseases without influencing caloric intake, the underlying mechanisms of TRF action in NASH and its efficacy have not yet been demonstrated. We herein showed that TRF effectively alleviated NASH, producing a reduction in liver enzymes and improvements in liver pathology. Regarding the mechanisms by which TRF mitigates NASH, we ascertained that TRF inhibited ferroptosis and the expression of the circadian gene Per2. By adopting a hepatocyte-specific Per2-knockout (Per2△hep) mice model, we clarified the critical role of Per2 in exacerbating NASH. According to the results of our RNA-Seq analysis, the knockout of Per2 ameliorated NASH by inhibiting the onset of ferroptosis; this was manifested by diminished lipid peroxidation levels, decreased mRNA and protein levels for ferroptosis-related genes, and alleviated morphologic changes in mitochondria. Furthermore, using a ferroptosis inhibitor, we showed that ferroptosis significantly aggravated NASH and noted that this was likely achieved by regulation of the expression of peroxisome proliferator activated receptor (PPAR)α. Finally, we discerned that TRF and hepatocyte-specific knockout of Per2 promoted the expression of PPARα. Our results revealed a potential for TRF to effectively alleviate high-fat and high-fructose diet-induced NASH via the inhibition of Per2 and depicted the participation of Per2 in the progression of NASH by promoting ferroptosis, which was ultimately related to the expression of PPARα.
    DOI:  https://doi.org/10.1155/2022/8063897
  94. Cancer Lett. 2022 Oct 22. pii: S0304-3835(22)00465-7. [Epub ahead of print] 215978
    Circular RNAs: Emerging regulators of glucose metabolism in cancer.
    Ze-Rong Cai, Yan Hu, Kun Liao, Hao Li, Dong-Liang Chen, Hua-Qiang Ju.
      Aberrant glucose metabolism is one of the most striking characteristics of metabolic reprogramming in cancer. Thus, clarifying the regulatory mechanism of glucose metabolism is crucial to understanding tumor progression and developing novel therapeutic strategies for cancer patients. Recent developments in circular RNAs have explained the regulatory mechanism of glucose metabolism from a new dimension. In this review, we briefly summarize the recent advances in circRNA research on cancer glucose metabolism and emphasize the different regulatory mechanisms, including acting as miRNA sponges, interacting with proteins and being translated into proteins. Additionally, we discuss the future research directions of circular RNAs in the field of glucose metabolism.
    Keywords:  Warburg effect; circRNA; circRNA translation product; circRNA-protein interaction; miRNA sponge
    DOI:  https://doi.org/10.1016/j.canlet.2022.215978
  95. J Control Release. 2022 Oct 25. pii: S0168-3659(22)00692-7. [Epub ahead of print]352 256-275
    Tailoring carrier-free nanocombo of small-molecule prodrug for combinational cancer therapy.
    Haonan Li, Wenli Zang, Zhen Mi, Junyu Li, Lijuan Wang, Dan Xie, Li Zhao, Dan Wang.
      The outcomes of monotherapy could not satisfy clinical cancer treatment owing to the challenges of tumor heterogeneity, multi-drug resistance, tumor metastasis and relapse. In response, the significance of combinational cancer therapy has been highlighted. Traditional combinational schemes usually utilize "free" drug for multi drug administration, independently. The diverse pharmacokinetics and biodistribution greatly hinder the antitumor effects and cause systematic toxicity. To tackle the hinderance, various nanoparticulate drug delivery systems (Nano-DDSs) have been developed. However, conventional Nano-DDSs encapsulate drugs into carrier materials through noncovalent interactions, resulting in low drug loading, fixed multi drug encapsulation ratio, chemical instability and carrier-associated toxicity. Recently, carrier-free nanocombos based on self-assembling small-molecule prodrugs (SPNCs) have emerged as a versatile Nano-DDSs for multiple drug delivery. Benefited by the self-assembly capability, SPNCs could be facilely fabricated with distinct merits of ultra-high drug loading, adjustable drug ratio and negligible carrier-associated toxicity. Herein, we summarize the latest trends of SPNCs. First, a basic review on self-assembling small-molecule prodrugs is presented. Additionally, facile techniques to prepare SPNCs are introduced. Furthermore, advanced combinational therapies based on SPNCs are spotlighted with special emphasis on synergistic mechanisms. Finally, future prospects and challenges are discussed.
    Keywords:  Carrier-free nanosystem; Combinational cancer therapy; Nanotechnology; Self-assembling prodrug
    DOI:  https://doi.org/10.1016/j.jconrel.2022.10.022
  96. Pharmaceutics. 2022 Sep 24. pii: 2036. [Epub ahead of print]14(10):
    Risk-Assessment-Based Optimization Favours the Development of Albumin Nanoparticles with Proper Characteristics Prior to Drug Loading.
    Gábor Katona, Bence Sipos, Ildikó Csóka.
      Albumin nanocarrier research and development is a challenging area in the field of personalized medicine and in providing advanced therapeutic solutions. Albumin as a biocompatible, nonimmunogenic, and non-toxic protein carrier that can be exploited to conjugate drugs with poor bioavailability to improve on this feature. With many different perspectives and desired target profiles, a systematic structural approach must be used in nanoparticle development. The extended Research and Development (R&D) Quality by Design thinking and methodology proved to be useful in case of specific nanoparticle development processes before. However, the coacervation method is the most frequently applied preparation method for HSA nanoparticles; there is a lack of existing research work which has directly determined the influence of process parameters, control strategy, or design space. With a quality-management-driven strategy, a knowledge space was developed for these versatile nanoparticles and an initial risk assessment was conducted on the quality-affecting factors regarding the coacervation method, followed by an optimization process via Plackett-Burman and Box-Behnken experimental design. As a result of screening the effect of process variables on the fabrication of HSA nanoparticles, an optimized colloidal drug delivery system was engineered with desired nanoparticulate properties.
    Keywords:  Quality by Design; albumin nanoparticle; factorial design; nanomedicine; quality control
    DOI:  https://doi.org/10.3390/pharmaceutics14102036
  97. Pharmaceuticals (Basel). 2022 Oct 03. pii: 1225. [Epub ahead of print]15(10):
    Polyphenols, Saponins and Phytosterols in Lentils and Their Health Benefits: An Overview.
    Ahmed M Mustafa, Doaa Abouelenein, Laura Acquaticci, Laura Alessandroni, Simone Angeloni, Germana Borsetta, Giovanni Caprioli, Franks Kamgang Nzekoue, Gianni Sagratini, Sauro Vittori.
      The lentil (Lens culinaris L.) is one of the most important legumes (family, Fabaceae). It is a natural functional food rich in many bioactive compounds, such as polyphenols, saponins and phytosterols. Several studies have demonstrated that the consumption of lentils is potentially important in reducing the incidence of a number of chronic diseases, due to their bioactive compounds. The most common polyphenols in lentils include phenolic acids, flavan-3-ol, flavonols, anthocyanidins, proanthocyanidins or condensed tannins, and anthocyanins, which play an important role in the prevention of several degenerative diseases in humans, due to their antioxidant activity. Furthermore, lentil polyphenols are reported to have antidiabetic, cardioprotective and anticancer activities. Lentil saponins are triterpene glycosides, mainly soyasaponins I and βg. These saponins have a plasma cholesterol-lowering effect in humans and are important in reducing the risk of many chronic diseases. Moreover, high levels of phytosterols have been reported in lentils, especially in the seed coat, and β-sitosterol, campesterol, and stigmasterol are the most abundant. Beyond their hypocholesterolemic effect, phytosterols in lentils are known for their anti-inflammatory activity. In this review, the current information on the nutritional composition, bioactive compounds including polyphenols, saponins and phytosterols, and their associated health-promoting effects are discussed.
    Keywords:  health-promoting effects; lentils; phytosterols; polyphenols; saponins
    DOI:  https://doi.org/10.3390/ph15101225
  98. Anticancer Res. 2022 Nov;42(11): 5365-5383
    The Activity of Vitamin C Against Ovarian Cancer Cells Is Enhanced by Hyperthermia.
    Alicja Bieńkowska-Tokarczyk, Aneta Manda-Handzlik, Krzysztof Gawrychowski, Urszula Demkow, Maciej Małecki.
       BACKGROUND/AIM: Vitamin C is essential for the proper functioning of the human body and plays a crucial role in many biological processes as a cofactor for enzymes. The anticancer activity of vitamin C has been indicated for years. Hyperthermia used in clinics allows increasing the effectiveness of anticancer therapies and may also be useful in enhancing the action of other substances. The purpose of this study was to enhance the anticancer activity of vitamin C through hyperthermia against ovarian cancer cells.
    MATERIALS AND METHODS: The ovarian cancer cell lines Caov-3, NIH:OVCAR-3, and human fibroblasts CCD-1064Sk were tested in the present study. Vitamin C was used in the following concentrations: 0.24, 2.50 and 5.25 mM. Each of the selected concentrations was combined with the different temperatures (37°C, 40°C and 43°C). Cell survival, adhesion and changes at the molecular level were assessed.
    RESULTS: The obtained results revealed that hyperthermia enhances the anticancer activity of vitamin C. Ovarian cancer cells showed greater sensitivity to vitamin C at elevated temperatures. Cells may have different sensitivity to vitamin C due to the activation of different gene signatures associated with redox reactions and apoptosis, therefore we examined the following genes: BCAP31, BCL2L13, BID, CASP7, FADD and HTRA2. The increase in expression of these genes in cancer cells generated a stronger proapoptotic response.
    CONCLUSION: The present study showed that hyperthermia enhanced the anticancer activity of vitamin C in vitro.
    Keywords:  Vitamin C; anticancer activity; hyperthermia; ovarian cancer
    DOI:  https://doi.org/10.21873/anticanres.16042
  99. Chem Biol Interact. 2022 Oct 25. pii: S0009-2797(22)00443-4. [Epub ahead of print] 110238
    Harnessing the dual role of polysaccharides in treating gastrointestinal diseases: As therapeutics and polymers for drug delivery.
    Leander Corrie, Monica Gulati, Ankit Awasthi, Sukriti Vishwas, Jaskiran Kaur, Rubiya Khursheed, Omji Porwal, Aftab Alam, Shaik Rahana Parveen, Hardeep Singh, Dinesh Kumar Chellappan, Gaurav Gupta, Popat Kumbhar, John Disouza, Vandana Patravale, Jon Adams, Kamal Dua, Sachin Kumar Singh.
      Polysaccharides (PS) represent a broad class of polymer-based compounds that have been extensively researched as therapeutics and excipients for drug delivery. As pharmaceutical carriers, PS have mostly found their use as adsorbents, suspending agents, as well as cross linking agents for various formulations such as liposomes, nanoparticles, nanoemulsions, nano lipid carriers, microspheres etc. This is due to inherent properties of PS such as porosity, steric stability and swellability, insolubility in pH. There have been emerging reports on the use of PS as therapeutic agent due to its anti-inflammatory and anti-oxidative properties for various diseases. In particular, for Crohn's disease, ulcerative colitis and inflammatory bowel disease. However, determining the dosage, treatment duration and effective technology transfer of these therapeutic moieties have not occurred. This is due to the fact that PS are still at a nascent stage of development to a full proof therapy for a particular disease. Recently, a combination of polysaccharide which act as a prebiotic and a probiotic have been used as a combination to treat various intestinal and colorectal (CRC) related diseases. This has proven to be beneficial, has shown good in vivo correlation and is well reported. The present review entails a detailed description on the role of PS used as a therapeutic agent and as a formulation pertaining to gastrointestinal diseases.
    Keywords:  Colon targeted delivery; Colorectal diseases; Microspheres; Nanoparticles
    DOI:  https://doi.org/10.1016/j.cbi.2022.110238
  100. Antioxidants (Basel). 2022 Sep 28. pii: 1928. [Epub ahead of print]11(10):
    Lipid-Encapsuled Grape Tannins Prevent Oxidative-Stress-Induced Neuronal Cell Death, Intracellular ROS Accumulation and Inflammation.
    Hugo S Díaz, Angélica Ríos-Gallardo, Domiziana Ortolani, Esteban Díaz-Jara, María José Flores, Ignacio Vera, Angela Monasterio, Fernando C Ortiz, Natalia Brossard, Fernando Osorio, Rodrigo Del Río.
      The central nervous system (CNS) is particularly vulnerable to oxidative stress and inflammation, which affect neuronal function and survival. Nowadays, there is great interest in the development of antioxidant and anti-inflammatory compounds extracted from natural products, as potential strategies to reduce the oxidative/inflammatory environment within the CNS and then preserve neuronal integrity and brain function. However, an important limitation of natural antioxidant formulations (mainly polyphenols) is their reduced in vivo bioavailability. The biological compatible delivery system containing polyphenols may serve as a novel compound for these antioxidant formulations. Accordingly, in the present study, we used liposomes as carriers for grape tannins, and we tested their ability to prevent neuronal oxidative stress and inflammation. Cultured catecholaminergic neurons (CAD) were used to establish the potential of lipid-encapsulated grape tannins (TLS) to prevent neuronal oxidative stress and inflammation following an oxidative insult. TLS rescued cell survival after H2O2 treatment (59.4 ± 8.8% vs. 90.4 ± 5.6% H2O2 vs. TLS+ H2O2; p &lt; 0.05) and reduced intracellular ROS levels by ~38% (p &lt; 0.05), despite displaying negligible antioxidant activity in solution. Additionally, TLS treatment dramatically reduced proinflammatory cytokines' mRNA expression after H2O2 treatment (TNF-α: 400.3 ± 1.7 vs. 7.9 ± 1.9-fold; IL-1β: 423.4 ± 1.3 vs. 12.7 ± 2.6-fold; p &lt; 0.05; H2O2 vs. TLS+ H2O2, respectively), without affecting pro/antioxidant biomarker expression, suggesting that liposomes efficiently delivered tannins inside neurons and promoted cell survival. In conclusion, we propose that lipid-encapsulated grape tannins could be an efficient tool to promote antioxidant/inflammatory cell defense.
    Keywords:  liposomes; natural products; neuroprotection; oxidative stress; polyphenols
    DOI:  https://doi.org/10.3390/antiox11101928
  101. Medicina (Kaunas). 2022 Oct 01. pii: 1377. [Epub ahead of print]58(10):
    Molecular Pathways Related to Sulforaphane as Adjuvant Treatment: A Nanomedicine Perspective in Breast Cancer.
    María Zenaida Saavedra-Leos, Euclides Jordan-Alejandre, Jonathan Puente-Rivera, Macrina Beatriz Silva-Cázares.
      Because cancer is a multifactorial disease, it is difficult to identify the specific agents responsible for the disease's progression and development, but lifestyle and diet have been shown to play a significant role. Diverse natural compounds are demonstrating efficacy in the development of novel cancer therapies, including sulforaphane (1-isothiocyanate-4-(methylsulfinyl)butane), a compound found in broccoli and other cruciferous vegetables that promotes key biological processes such as apoptosis, cell cycle arrest, autophagy, and suppression of key signalling pathways such as the PI3K/AKT/mTOR pathway in breast cancer cells. However, one of the primary challenges with sulforaphane treatment is its low solubility in water and oral bioavailability. As a consequence, several investigations were conducted using this component complexed in nanoparticles, which resulted in superior outcomes when combined with chemotherapy drugs. In this study, we discuss the properties and benefits of sulforaphane in cancer therapy, as well as its ability to form complexes with nanomolecules and chemotherapeutic agents that synergize the antitumour response in breast cancer cells.
    Keywords:  breast cancer; nanomolecule; sulforaphane
    DOI:  https://doi.org/10.3390/medicina58101377
  102. Eur J Pharm Biopharm. 2022 Oct 25. pii: S0939-6411(22)00244-2. [Epub ahead of print]
    Design and optimization of Metformin-Loaded Solid Lipid Nanoparticles for Neuroprotective effects in a rat model of diffuse traumatic brain injury: A biochemical, behavioral, and histological study.
    Hossein Ebrahimi, Sajjad Kazem Nezhad, Ali Farmoudeh, Amirhossein Babaei, Pedram Ebrahimnezhad, Esmaeil Akbari, Ali Siahposht-Khachaki.
       BACKGROUND AND PURPOSE: Following traumatic brain injury, inflammation, mitochondrial dysfunction, oxidative stress, ischemia, and energy crisis can cause mortality or long-term morbidity. As an activator of AMP-activated protein kinase, metformin reduces the secondary injuries of traumatic brain injury by compensating for the lack of energy in damaged cells. But the blood-brain barrier (BBB) ​​prevents a hydrophilic drug such as metformin from penetrating the brain tissue. Solid lipid nanoparticles (SLN) with their lipid nature can cross the blood-brain barrier and solve this challenge.so This study aimed to investigate the effect of metformin-loaded lipid nanoparticles (NanoMet) for drug delivery to the brain and reduce complications from traumatic brain injury.
    METHOD: Different formulations of NanoMet were designed by Box-Behnken, and after formulation, particle size, zeta potential, and entrapment efficiency were investigated. For in vivo study, Male rats were divided into eight groups, and except for the intact and sham groups, the other groups underwent brain trauma by the Marmarou method. After the intervention, the Veterinary Coma Scale, Vestibular Motor function, BBB integrity, cerebral edema, level of inflammatory cytokines, and histopathology of brain tissue were assessed.
    RESULTS: The optimal formula had a size of 282.2 ± 9.05 nm, a zeta potential of -1.65 ± 0.33 mV, and entrapment efficiency of 60.61± 6.09% Which released the drug in 1400 minutes.Concentrations of 5 and 10 mg/kg of this formula improved the consequences of trauma .
    CONCLUSION: This study showed that nanoparticles could help target drug delivery to the brain and apply the desired result.
    Keywords:  Marmarou method; Metformin; SLN; Solid Lipid Nanoparticle; Traumatic Brain injury
    DOI:  https://doi.org/10.1016/j.ejpb.2022.10.018
  103. Recent Pat Anticancer Drug Discov. 2022 Oct 26.
    Gefitinib: An Updated Review of its Role in the Cancer Management, its Nanotechnological Interventions, Recent Patents and Clinical Trials.
    Pankaj Kumar, Bharti Mangla, Shamama Javed, Waquar Ahsan, Pankaj Musyuni, Aarif Ahsan, Geeta Aggarwal.
       BACKGROUND: Gefitinib, a tyrosine kinase inhibitor, is effectively used in the targeted treatment of malignant conditions. It suppresses the signal transduction cascades leading to cell proliferation in the tumors and is now currently approved in several countries globally as secondline and third-line treatment for non-small cell lung cancer (NSCLC).
    OBJECTIVE: This review is aimed to summarize the journey of gefitinib as an established anticancer drug for the management of various cancers. Moreover, this review will focus on the mechanism of action, established anticancer activities, combination therapy, nanoformulations, as well as recent clinical trials and patents on gefitinib.
    METHODS: The data for this review was collected from scientific databases such as PubMed, Science Direct, Google Scholar, etc. Recent patents on gefitinib granted in the last two years were collected from databases Patentscope, USPTO, Espacenet, InPASS and Google Patents. Data for the recent clinical trials were obtained from the U.S. National Library of Medicine database.
    RESULTS: Recent pre-clinical and clinical studies during the period 2015-2021 demonstrating the efficacy of gefitinib were selected and summarized. Total 31 patents were granted in the year 2020-2021 concerning gefitinib. The efficacy of gefitinib against lung cancer, as well as other cancer types, including breast, prostate, colon, cervix etc., was reviewed.
    CONCLUSION: Gefitinib showed significant advantages in being more effective, safer and more stable, and the associated biopharmaceutical problems are addressed by the application of nanotechnology. The combination therapy using gefitinib and various anticancer molecules of natural and synthetic origin has shown an improved anticancer profile.
    Keywords:  Gefitinib; NSCLC; cancer; clinical trials; nanotechnology; patents
    DOI:  https://doi.org/10.2174/1574892818666221026164940
  104. Mol Cancer Ther. 2022 Oct 24. OF1-OF7
    The Next Generation of KRAS Targeting: Reasons for Excitement and Concern.
    Neal S Akhave, Amadeo B Biter, David S Hong.
      The development of selective KRASG12C inhibitors that directly inhibit KRAS, an oncogene historically thought to be "undruggable," represents a watershed moment in oncology and developmental therapeutics. Now, as KRAS-targeted therapy moves into its second phase, there is significant excitement and anticipation for durable disease control in tumor types where options remain limited, with clinical trials testing combination therapies, indirect pan-RAS/MAP kinase pathway inhibitors, and active-state RAS(on) inhibitors. However, there is also reason for caution regarding the safety and tolerability of expanded RAS inhibition. This is evidenced by the intolerability of some combination therapies with selective KRASG12C inhibitors and foreshadowed by prior failures of combination therapies in other oncogene-driven tumors. Herein, we review the landscape of and outlook for KRAS-targeted therapies. We specifically focus upon strategies to combat resistance to KRAS-targeted therapies, and discuss the possibility of off-target or unanticipated on-target effects that may limit clinical use.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-22-0356
  105. Eur J Pharmacol. 2022 Oct 25. pii: S0014-2999(22)00611-2. [Epub ahead of print] 175350
    Nanoparticles: The future of effective diagnosis and treatment of colorectal cancer?
    Reza Naeimi, Rezvan Najafi, Pejman Molaei, Razieh Amini, Stevan Pecic.
      Colorectal cancer (CRC) is one of the most challenging malignancies in terms of diagnosis and treatment. Conventional diagnostic methods are primarily based on colonoscopy and often lack accuracy, while standard treatment options typically include chemotherapy, which can be unsuccessful due to side effects and (development of) drug resistance. Although new diagnostic methods and timely screening have decreased the death rate from cancer in developed countries in recent years, there still is an urgent need for (novel) therapeutic strategies that render better disease management and clinical outcomes. Nanoparticles (NPs) have emerged as promising candidates for the improvement of diagnosis and treatment by promoting drug targeting, solubility and bioavailability. For example, NPs can reduce toxicity of drugs by increasing solubility and can be engineered to specifically target malignancies, thereby minimizing unwanted side effects. In this review, we evaluated the potential of implementing various NPs for the diagnosis and treatment of CRC.
    Keywords:  Biological availability; Colorectal cancer; Drug delivery systems; Molecular imaging; Nanoparticles
    DOI:  https://doi.org/10.1016/j.ejphar.2022.175350
  106. Antioxidants (Basel). 2022 Sep 28. pii: 1931. [Epub ahead of print]11(10):
    Improving the Bioaccessibility and Bioavailability of Carotenoids by Means of Nanostructured Delivery Systems: A Comprehensive Review.
    Camilla Molteni, Concettina La Motta, Fabio Valoppi.
      Carotenoids are bioactive compounds provided by the diet playing a key role in maintaining human health. Therefore, they should be ingested daily in an adequate amount. However, even a varied and well-balanced diet does not guarantee an adequate intake, as both the bioaccessibility and bioavailability of the compounds significantly affect their absorption. This review summarizes the main results achieved in improving the bioaccessibility and bioavailability of carotenoids by means of nanostructured delivery systems, discussing in detail the available lipid-based and biopolymeric nanocarriers at present, with a focus on their formulation and functional efficiency. Although the toxicity profile of these innovative delivery systems is not fully understood, especially for long-term intake, these systems are an effective and valuable approach to increase the availability of compounds of nutritional interest.
    Keywords:  bioaccessibility; bioavailability; biopolymeric nanocarriers; carotenoids; lipid-based nanocarriers; nanotechnology
    DOI:  https://doi.org/10.3390/antiox11101931
  107. Antioxidants (Basel). 2022 Sep 30. pii: 1965. [Epub ahead of print]11(10):
    Progress in the Surface Functionalization of Selenium Nanoparticles and Their Potential Application in Cancer Therapy.
    Wanwen Chen, Hao Cheng, Wenshui Xia.
      As an essential micronutrient, selenium participates in numerous life processes and plays a key role in human health. In the past decade, selenium nanoparticles (SeNPs) have attracted great attention due to their excellent functionality for potential applications in pharmaceuticals. However, the utilization of SeNPs has been restricted by their instability and low targeting ability. Since the existing reviews mainly focused on the applications of SeNPs, this review highlights the synthesis of SeNPs and the strategies to improve their stability and targeting ability through surface functionalization. In addition, the utilization of functionalized SeNPs for the single and co-delivery of drugs or genes to achieve the combination of therapy are also presented, with the emphasis on the potential mechanism. The current challenges and prospects of functionalized SeNPs are also summarized. This review may provide valuable information for the design of novel functionalized SeNPs and promote their future application in cancer therapy.
    Keywords:  anticancer activity; selenium nanoparticles; stability; surface functionalization; targeting delivery
    DOI:  https://doi.org/10.3390/antiox11101965
  108. Subcell Biochem. 2022 ;100 201-237
    Modulation of DNA/RNA Methylation Signaling Mediating Metabolic Homeostasis in Cancer.
    Pallawi Choubey, Harshdeep Kaur, Kushagra Bansal.
      Nucleic acid methylation is a fundamental epigenetic mechanism that impinges upon several cellular attributes, including metabolism and energy production. The dysregulation of deoxyribonucleic acid (DNA)/ribonucleic acid (RNA) methylation can lead to metabolic rewiring in the cell, which in turn facilitates tumor development. Here, we review the current knowledge on the interplay between DNA/RNA methylation and metabolic programs in cancer cells. We also discuss the mechanistic role of these pathways in tumor development and progression.
    Keywords:  5mC; Cancer; CpG; DNA methylation; RNA methylation; Tumor metabolism; Warburg effect; m6A
    DOI:  https://doi.org/10.1007/978-3-031-07634-3_7
  109. Int J Mol Sci. 2022 Oct 12. pii: 12144. [Epub ahead of print]23(20):
    The Protective Effect of CBD in a Model of In Vitro Ischemia May Be Mediated by Agonism on TRPV2 Channel and Microglia Activation.
    Daniele Lana, Elisa Landucci, Costanza Mazzantini, Giada Magni, Domenico Edoardo Pellegrini-Giampietro, Maria Grazia Giovannini.
      Cannabinoids, used for centuries for recreational and medical purposes, have potential therapeutic value in stroke treatment. Cannabidiol (CBD), a non-psychoactive compound and partial agonist of TRPV2 channels, is efficacious in many neurological disorders. We investigated the effects of CBD or Δ9-tetrahydrocannabinol (THC) in rat organotypic hippocampal slices exposed to oxygen-glucose deprivation (OGD), an in vitro model of ischemia. Neuronal TRPV2 expression decreased after OGD, but it increased in activated, phagocytic microglia. CBD increased TRPV2 expression, decreased microglia phagocytosis, and increased rod microglia after OGD. THC had effects contrary to those of CBD. Our results show that cannabinoids have different effects in ischemia. CBD showed neuroprotective effects, mediated, at least in part, by TRPV2 channels, since the TRPV2 antagonist tranilast blocked them, while THC worsened the neurodegeneration caused by ischemia. In conclusion, our results suggest that different cannabinoid molecules play different roles in the mechanisms of post-ischemic neuronal death. These different effects of cannabinoid observed in our experiments caution against the indiscriminate use of cannabis or cannabinoid preparations for recreational or therapeutic use. It was observed that the positive effects of CBD may be counteracted by the negative effects caused by high levels of THC.
    Keywords:  TRPV2; astrocytes; cannabidiol; confocal microscopy; ischemia; microglia; neuroprotection; organotypic hippocampal slices; rod microglia; Δ-9-tetrahydrocannabinol
    DOI:  https://doi.org/10.3390/ijms232012144
  110. Biomol Ther (Seoul). 2022 Nov 01. 30(6): 585-592
    Hydroxyzine Induces Cell Death in Triple-Negative Breast Cancer Cells via Mitochondrial Superoxide and Modulation of Jak2/STAT3 Signaling.
    Rajina Shakya, Gyu Hwan Park, Sang Hoon Joo, Jung-Hyun Shim, Joon-Seok Choi.
      Treatment of triple-negative breast cancer (TNBC) has been limited due to the lack of molecular targets. In this study, we evaluated the cytotoxicity of hydroxyzine, a histamine H1 receptor antagonist in human triple-negative breast cancer BT-20 and HCC-70 cells. Hydroxyzine inhibited the growth of cells in dose- and time-dependent manners. The annexin V/propidium iodide double staining assay showed that hydroxyzine induced apoptosis. The hydroxyzine-induced apoptosis was accompanied down-regulation of cyclins and CDKs, as well as the generation of reactive oxygen species (ROS) without cell cycle arrest. The effect of hydroxyzine on the induction of ROS and apoptosis on TNBC cells was prevented by pre-treatment with ROS scavengers, N-acetyl cysteine or Mito-TEMPO, a mitochondria-targeted antioxidant, indicating that an increase in the generation of ROS mediated the apoptosis induced by hydroxyzine. Western blot analysis showed that hydroxyzine-induced apoptosis was through down-regulation of the phosphorylation of JAK2 and STAT3 by hydroxyzine treatment. In addition, hydroxyzine induced the phosphorylation of JNK and p38 MAPK. Our results indicate that hydroxyzine induced apoptosis via mitochondrial superoxide generation and the suppression of JAK2/STAT3 signaling.
    Keywords:  Apoptosis; Cell cycle; Hydroxyzine; JAK2/STAT3; Reactive oxygen species; Triple-negative breast cancer
    DOI:  https://doi.org/10.4062/biomolther.2022.121
  111. Nanomaterials (Basel). 2022 Oct 15. pii: 3619. [Epub ahead of print]12(20):
    Curcumin Nanodiscs Improve Solubility and Serve as Radiological Protectants against Ionizing Radiation Exposures in a Cell-Cycle Dependent Manner.
    Angela C Evans, Kelly A Martin, Manoj Saxena, Sandra Bicher, Elizabeth Wheeler, Emilio J Cordova, Christopher D Porada, Graça Almeida-Porada, Takamitsu A Kato, Paul F Wilson, Matthew A Coleman.
      Curcumin, a natural polyphenol derived from the spice turmeric (Curcuma longa), contains antioxidant, anti-inflammatory, and anti-cancer properties. However, curcumin bioavailability is inherently low due to poor water solubility and rapid metabolism. Here, we further refined for use curcumin incorporated into "biomimetic" nanolipoprotein particles (cNLPs) consisting of a phospholipid bilayer surrounded by apolipoprotein A1 and amphipathic polymer scaffolding moieties. Our cNLP formulation improves the water solubility of curcumin over 30-fold and produces nanoparticles with ~350 µg/mL total loading capacity for downstream in vitro and in vivo applications. We found that cNLPs were well tolerated in AG05965/MRC-5 human primary lung fibroblasts compared to cultures treated with curcumin solubilized in DMSO (curDMSO). Pre-treatment with cNLPs of quiescent G0/G1-phase MRC-5 cultures improved cell survival following 137Cs gamma ray irradiations, although this finding was reversed in asynchronously cycling log-phase cell cultures. These findings may be useful for establishing cNLPs as a method to improve curcumin bioavailability for administration as a radioprotective and/or radiomitigative agent against ionizing radiation (IR) exposures in non-cycling cells or as a radiosensitizing agent for actively dividing cell populations, such as tumors.
    Keywords:  curcumin; ionizing radiation; nanodisc; radioprotector; radiosensitizer
    DOI:  https://doi.org/10.3390/nano12203619
  112. Int J Mol Sci. 2022 Oct 11. pii: 12108. [Epub ahead of print]23(20):
    Sodium Alginate-Natural Microencapsulation Material of Polymeric Microparticles.
    Olimpia Daniela Frent, Laura Gratiela Vicas, Narcis Duteanu, Claudia Mona Morgovan, Tunde Jurca, Annamaria Pallag, Mariana Eugenia Muresan, Sanda Monica Filip, Roxana-Liana Lucaciu, Eleonora Marian.
      From the multitude of materials currently available on the market that can be used in the development of microparticles, sodium alginate has become one of the most studied natural anionic polymers that can be included in controlled-release pharmaceutical systems alongside other polymers due to its low cost, low toxicity, biocompatibility, biodegradability and gelatinous die-forming capacity in the presence of Ca2+ ions. In this review, we have shown that through coacervation, the particulate systems for the dispensing of drugs consisting of natural polymers are nontoxic, allowing the repeated administration of medicinal substances and the protection of better the medicinal substances from degradation, which can increase the capture capacity of the drug and extend its release from the pharmaceutical form.
    Keywords:  microencapsulation; microparticles; natural polysaccharide; sodium alginate
    DOI:  https://doi.org/10.3390/ijms232012108
  113. Anticancer Agents Med Chem. 2022 Oct 20.
    Advances in the Study of Hexokinase 2 (HK2) Inhibitors.
    Shaopei Wang, Yan Zhuang, Jindan Xu, Yan Tong, Chunhong Dong, Xiaofei Li.
      Purpose The Warburg effect is an important metabolic feature of tumours, and hexokinase is the first rate-limiting enzyme of the glycolytic pathway during tumour metabolism. Among hexokinase subtypes, hexokinase 2 (HK2) is increasingly proving to be a key target for cancer treatment. This study presents the challenges and potential strategies for developing HK2 inhibitors by systematically summarising the characteristics of HK2 inhibitors reported in the literature and patents. Methods In this study, we analysed the HK2 active site using molecular docking and evaluated the structure, biochemical and physiological function, activity, and action mechanism of reported HK2 inhibitors using databases (Science, SCI finder, CNKI, and WANFANG DATA). Results In total, 6 natural inhibitors of HK2, 9 synthetic inhibitors of HK2, and 3 compounds with patent-pending HK2 inhibitory effects were obtained by searching 87 articles. These inhibitors have poor efficacy and specificity when used alone and have numerous side effects; therefore, there is an urgent need to develop HK2 inhibitors with improved activity and high selectivity. Conclusion: HK2 has received much attention in anticancer drug development, but most previous studies have focused on elucidating the action mechanism of HK2 in carcinogenesis, whereas the development of its small-molecule inhibitors has rarely been reported. In this study, we analysed and illustrated the eutectic structure of small molecules with the catalytic structural domain of HK2 to develop highly selective and low-toxicity HK2 inhibitors.
    Keywords:  Cancer; Energy metabolism; Glycolysis; Hexokinase 2; Inhibitors.; Warburg effect
    DOI:  https://doi.org/10.2174/1871520623666221020092423
  114. Medicina (Kaunas). 2022 Sep 23. pii: 1337. [Epub ahead of print]58(10):
    Effect of Vitamin D on Bone Regeneration: A Review.
    Giorgiana Corina Muresan, Mihaela Hedesiu, Ondine Lucaciu, Sanda Boca, Nausica Petrescu.
      Background and Objectives: Vitamin D (Vit. D) is known for its role in the skeletal system. Vit. D deficiency is also widely researched for its effects on the healing of fractures, bone defects, and osseointegration of implants. In the literature, there are studies that investigated the effects of dietary supplementation with Vit. D to reduce Vit. D deficiency, but increasing the serum level of this vitamin takes time. Therefore, an attempt has been made to combat the effect of Vit. D deficiency through topical applications. The aim of this article was to conduct a review of the existing bibliographic data that investigate the effect of Vit. D on bone regeneration. Materials and Methods: In order to carry out this review, an electronic search was made in several databases and the articles found were selected and analyzed. Results: The in vitro studies' results demonstrated that Vit. D has a high therapeutic potential by enhancing the differentiation of stem cells in osteoblasts. Human and animal studies were conducting using various methods, but most of them revealed that Vit. D has a positive influence on the process of bone regeneration. Conclusions: The overall results of the research showed that, indeed, Vit. D is beneficial for bone regeneration; however, most of the studies imply that a thorough research is still needed for finding the most effective mode of administration and the dose needed in order to achieve the desired effect.
    Keywords:  bone regeneration; new bone formation; osseointegration; osteoporosis; vitamin D
    DOI:  https://doi.org/10.3390/medicina58101337
  115. J Cell Mol Med. 2022 Oct 27.
    Modulation of the activity of histone lysine methyltransferases and demethylases by curcumin analog in leukaemia cells.
    Suhila Sawesi, Sridhar A Malkaram, Zakaria Y Abd Elmageed, Tamer E Fandy.
      Curcumin is a known epigenetic modifier that demonstrated antitumor effect in different types of cancer. The poor solubility and metabolic stability are major drawbacks that limit its development as an antitumor agent. Dimethoxycurcumin (DMC) is a more soluble and stable curcumin analog. In this study, we compared the effect of both drugs on a variety of histone posttranslational modifications and on the activity of histone lysine methyltransferase (HKMTs) and demethylase (HKDMTs) enzymes that target the H3K4, H3K9 and H3K27 epigenetic marks. Mass spectrometry was used to quantitate the changes in 95 histone posttranslational modifications induced by curcumin or DMC. The effect of both drugs on the enzymatic activity of HKMTs and HKDMs was measured using an antibody-based assay. Mass spectrometry analysis showed that curcumin and DMC modulated several histone modifications. Histone changes were not limited to lysine methylation and acetylation but included arginine and glutamine methylation. Only few histone modifications were similarly changed by both drugs. On the contrary, the effect of both drugs on the activity of HKMTs and HKDMs was very similar. Curcumin and DMC inhibited the HKMTs enzymes that target the H3K4, H3K9 and H3K27 marks and increased the activity of the HKDMs enzymes LSD1, JARID and JMJD2. In conclusion, we identified novel enzymatic targets for both curcumin and DMC that support their use and development as epigenetic modifiers in cancer treatment. The multiple targets modulated by both drugs could provide a therapeutic advantage by overcoming drug resistance development.
    Keywords:  histone acetylation; histone lysine demethylases; histone methylation; histone methyltransferase; leukaemia
    DOI:  https://doi.org/10.1111/jcmm.17589
  116. Molecules. 2022 Oct 14. pii: 6907. [Epub ahead of print]27(20):
    Sahlep (Dactylorhiza osmanica): Phytochemical Analyses by LC-HRMS, Molecular Docking, Antioxidant Activity, and Enzyme Inhibition Profiles.
    Hatice Kiziltas, Ahmet Ceyhan Goren, Saleh H Alwasel, İlhami Gulcin.
      Studies have shown an inverse correlation among age-related illnesses like coronary heart disease and cancer and intake of fruit and vegetable. Given the probable health benefits of natural antioxidants from plants, research on them has increased. Dactylorhiza osmanica is consumed as a food and traditional medicine plant in some regions of Turkey, so evaluation of the biological ability of this species is important. In this study, the amount of phenolic content (LC-HRMS), antioxidant activities and enzyme inhibitory properties of an endemic plant, D. osmanica, were investigated. The antioxidant capacities of an ethanol extract of D. osmanica aerial parts (EDOA) and roots (EDOR) were evaluated with various antioxidant methods. Additionally, the enzyme inhibitory effects of EDOA and EDOR were examined against acetylcholinesterase (AChE), α-glycosidase, and α-amylase enzymes, which are associated with common and global Alzheimer's disease and diabetes mellitus. The IC50 values of EDOA against the enzymes were found to be 1.809, 1.098, and 0.726 mg/mL, respectively; and the IC50 values of EDOR against the enzymes were found to be 2.466, 0.442, and 0.415 mg/mL, respectively. Additionally, LC-HRMS analyses revealed p-Coumaric acid as the most plentiful phenolic in both EDOA (541.49 mg/g) and EDOR (559.22 mg/g). Furthermore, the molecular docking interaction of p-coumaric acid, quercitrin, and vanillic acid, which are the most plentiful phenolic compounds in the extracts, with AChE, α-glucosidase, and α-amylase, were evaluated using AutoDock Vina software. The rich phenolic content and the effective antioxidant ability and enzyme inhibition potentials of EDOA and EDOR may support the plant's widespread food and traditional medicinal uses.
    Keywords:  Dactylorhiza osmanica; antioxidant activity; enzyme inhibition; molecular docking; phenolic content; sahlep
    DOI:  https://doi.org/10.3390/molecules27206907
  117. Int J Mol Sci. 2022 Oct 20. pii: 12643. [Epub ahead of print]23(20):
    Pharmacological and Therapeutic Applications of Esculetin.
    Sourbh Suren Garg, Jeena Gupta, Debasis Sahu, Chuan-Ju Liu.
      Esculetin is a coumarin compound, which belongs to the class of benzopyrone enriched in various plants such as Sonchus grandifolius, Aesculus turbinata, etc. Free radicals lead to the development of oxidative stress causing inflammation, arthritis, cancer, diabetes, fatty liver disease, etc. These further reduce the efficacy of anticancer drugs, activate inflammatory signaling pathways, degrade joints and cartilage, and disrupt the glycemic index and normal function of liver enzymes. For instance, the current treatment modalities used in arthritis such as non-steroidal anti-inflammatory drugs, disease-modifying anti-rheumatoid drugs, and lipoxygenase inhibitors present limited efficacy and adverse effects. Thus, there is a constant need to find newer and safer alternatives. Esculetin has an immense antioxidative potential thereby alleviating arthritis, diabetes, malignancies, and hepatic disorders. Structurally, esculetin contains two hydroxyl groups, which enhance its ability to function as an antioxidant by inhibiting oxidative stress in pathological conditions. Leukotriene B4 synthesis, NF-κB and MPAK pathway activation, and inflammatory cytokine production are the main causes of bone and joint deterioration in arthritis, whereas esculetin treatment reverses these factors and relieves the disease condition. In contrast, lipid peroxidation caused by upregulation of TGF-β-mediated expression and dysfunction of antioxidant enzymes is inhibited by esculetin therapy, thus reducing liver fibrosis by acting on the PI3K/FoxO1 pathway. Therefore, targeting NF-κB, pro-inflammatory cytokines, TGF-β and oxidative stress may be a therapeutic strategy to alleviate arthritis and liver fibrosis.
    Keywords:  arthritis; cancer; chromatography; diabetes; esculetin; fatty liver; inflammation; oxidative stress; pharmacokinetic
    DOI:  https://doi.org/10.3390/ijms232012643
  118. Gels. 2022 Oct 14. pii: 652. [Epub ahead of print]8(10):
    Designing Deferoxamine-Loaded Flaxseed Gum and Carrageenan-Based Controlled Release Biocomposite Hydrogel Films for Wound Healing.
    Tayyaba Sadiq, Syed Haroon Khalid, Ikram Ullah Khan, Hira Mahmood, Sajid Asghar.
      In this study, biocomposite hydrogel films made from flaxseed gum (FSG)/kappa carrageenan (CGN) were fabricated, using potassium chloride as a crosslinker and glycerol as a plasticizer. The composite films were loaded with deferoxamine (DFX), an iron chelator that promotes neovascularization and angiogenesis for the healing of wounds. The properties of the biocomposite hydrogel films, including swelling, solubility, water vapor transmission rate, tensile strength, elongation at break, and Young's modulus studies, were tested. The films were characterized by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC). In addition, drug release studies in PBS at pH 7.2 were investigated. In vivo analysis was performed by assessing the wound contraction in a full-thickness excisional wound rat model. Hematoxylin & eosin (H & E) and Masson's trichome staining were performed to evaluate the effect of the films on wound healing progress. The visual and micro-morphological analysis revealed the homogenous structure of the films; however, the elongation at break property decreased within the crosslinked film but increased for the drug-loaded film. The FTIR analysis confirmed the crosslinking due to potassium chloride. A superior resistance towards thermal degradation was confirmed by TGA for the crosslinked and drug-loaded films. Drug release from the optimum film was sustained for up to 24 h. In vivo testing demonstrated 100% wound contraction for the drug-loaded film group compared to 72% for the pure drug solution group. In light of the obtained results, the higher potential of the optimized biocomposite hydrogel film for wound healing applications was corroborated.
    Keywords:  biocompatible; biocomposites; deferoxamine; hydrogel film; wound healing
    DOI:  https://doi.org/10.3390/gels8100652
  119. Chem Biodivers. 2022 Oct 26.
    Natural Products for the Treatment of Drug Addiction: a Narrative review.
    Mona Raslan.
      Drug addiction is considered a chronic disorder affecting the individual's life, his/her family and society. Up till now the treatment of drug addiction is considered a problematic issue. Synthetic drugs available for the treatment of drug addiction are few, of limited efficacy and associated with serious side effects. Therefore, there is a continuous search for better therapeutic agents for drug addiction. Natural products represent a promising source for drug addiction treatment. This review summaries drug addiction definition, its mechanism of action, its types, its diagnosis, factors affecting its development and different available approaches for its treatment especially the use of natural products. Six plants were discussed thoroughly in this review, including, Tabernanthe iboga Baill., Mitragyna speciosa Korth., Pueraria montana var. lobata (Willd.) Sanjappa & Pradeep, Hypericum perforatum L., Panax ginseng C.A. Mey., and Withania somnifera (L.) Dunal.
    Keywords:  Drug addiction; Mechanism of action; Natural products; diagnosis; treatments
    DOI:  https://doi.org/10.1002/cbdv.202200702
  120. Int J Mol Sci. 2022 Oct 17. pii: 12403. [Epub ahead of print]23(20):
    The α-Ketoglutarate Dehydrogenase Complex as a Hub of Plasticity in Neurodegeneration and Regeneration.
    Grace E Hansen, Gary E Gibson.
      Abnormal glucose metabolism is central to neurodegeneration, and considerable evidence suggests that abnormalities in key enzymes of the tricarboxylic acid (TCA) cycle underlie the metabolic deficits. Significant recent advances in the role of metabolism in cancer provide new insight that facilitates our understanding of the role of metabolism in neurodegeneration. Research indicates that the rate-limiting step of the TCA cycle, the α-ketoglutarate dehydrogenase complex (KGDHC) and its substrate alpha ketoglutarate (KG), serve as a signaling hub that regulates multiple cellular processes: (1) is the rate-limiting step of the TCA cycle, (2) is sensitive to reactive oxygen species (ROS) and produces ROS, (3) determines whether KG is used for energy or synthesis of compounds to support growth, (4) regulates the cellular responses to hypoxia, (5) controls the post-translational modification of hundreds of cell proteins in the mitochondria, cytosol, and nucleus through succinylation, (6) controls critical aspects of transcription, (7) modulates protein signaling within cells, and (8) modulates cellular calcium. The primary focus of this review is to understand how reductions in KGDHC are translated to pathologically important changes that underlie both neurodegeneration and cancer. An understanding of each role is necessary to develop new therapeutic strategies to treat neurodegenerative disease.
    Keywords:  Alzheimer’s disease; cell signaling; metabolic plasticity; mitochondria; oxidative stress; transcription; tricarboxylic acid cycle; α-ketoglutarate; α-ketoglutarate dehydrogenase complex
    DOI:  https://doi.org/10.3390/ijms232012403
  121. Curr Drug Deliv. 2022 Oct 19.
    A Review on Proniosomes: A Propitious Outlook to the Provesicular Drug Delivery System.
    Anamika Saxena, Pragya Apurvi, Ramsha Aslam.
      Currently, various kinds of research are going in the evolution of the Novel Drug Delivery System. NDDS mainly emphasizes the development of a system with improved sustained, controlled, and targeted drug delivery with minimum toxicity. Proniosomes are dry free-flowing formulation that minimizes the drawbacks associated with liposomes and niosomes. Proniosomes are carrier particles that are water-soluble and covered with a surfactant which upon hydration in a hot aqueous medium with agitation gives niosomal dispersion. Proniosomes derived niosomes are superior substitutes as compared to other vesicular delivery due to preferable physicochemical properties and improved chemical stability. The proniosomes deliver additional convenience of transportation, storage, distribution, and dosing which makes dry niosomes a versatile commercial product. This illustrated review emphasizes the components, method of preparation, factors affecting the formation of proniosomes, characterization, and various routes of administration of proniosomes. This review will help you to explore the efficacy and functionality of proniosomes in different fields for their upcoming supremacy in the field of drug delivery.
    Keywords:  Colloidal particulate carrier delivery.; Niosomes; Non-ionic surfactant; Proniosomes; Provesicular Delivery
    DOI:  https://doi.org/10.2174/1567201820666221019093921
  122. Minerva Endocrinol (Torino). 2022 Oct 26.
    Short- and long- term efficacy of Very Low and Low Calorie Ketogenic Diets on metabolic and cardiometabolic risk factors: a narrative review.
    Gianluigi Gaspa, Anda M Naciu, Claudia DI Rosa, Greta Lattanzi, Ivan Beato, Vanessa Micheli, Clara Turriziani, Yeganeh M Khazrai, Roberto Cesareo.
      Worldwide obesity and cardiovascular diseases have encouraged the adoption of new and efficient dietary strategies. Among various proposed diets, ketogenic diets, both the Very-Low-Calorie Ketogenic Diet (VLCKD) and the Low-Calorie Ketogenic Diet (LCKD), have been suggested in recent years as an effective nutritional approach for obesity management. The VLCKD and the LCKD are characterized by a low carbohydrate content (< 50 g/day), 1-1.5 g of protein/kg of ideal body weight, less than 20-30 g of lipids, and a daily intake of about 800 calories for VLCKD and about 1200-1400 calories for LCKD. The purpose of our narrative review is to offer an overview of the most impactful studies in the scientific literature regarding VLCKD and LCKD to discuss their short- and long-term effects (less than 12 months and more than 12 months respectively) on weight loss, metabolic and cardiovascular aspects. Articles we focused on were cohort studies, case-control studies, cross-sectional studies, randomized controlled trials, and meta-analyses. Results indicate that VLCKD and LCKD could be helpful to ameliorate metabolic and cardiovascular risk factors such as weight loss, glucose, and cholesterol levels, both in the short and long- term. Further research in this area may include more randomized controlled trials to gather more data.
    DOI:  https://doi.org/10.23736/S2724-6507.22.03922-7
  123. Curr Issues Mol Biol. 2022 Oct 16. 44(10): 4930-4949
    Novel Strategies for Cancer Combat: Drug Combination Using Repurposed Drugs Induces Synergistic Growth Inhibition of MCF-7 Breast and HT-29 Colon Cancer Cells.
    Diana Duarte, Inês Guerreiro, Nuno Vale.
      Our group developed a new model of drug combination consisting of the use of antineoplastic drugs and different repurposed drugs, having demonstrated that antimalarial and central nervous system (CNS) drugs have a promising anticancer profile as standalone agents, as well as in combined regimens. Here, we evaluated the anticancer profiles of two different CNS drugs (edaravone and quetiapine), both alone and in combination with antineoplastic agents for breast and colon cancer, to explore whether these repurposed drugs could synergistically enhance the anticancer potential of chemotherapeutic drugs. We also developed a new model of combination using two repurposed drugs, to explore whether this model of combination could also be suitable for application in breast and colon cancer therapy. MCF-7 and HT-29 cancer cells were incubated for 48 h with each individual drug (0.01-100 µM) to determine their IC50. Cells were then treated with the IC50 value for doxorubicin or paclitaxel (MCF-7) or 5-fluorouracil (HT-29) and combined with increasing concentrations of edaravone or quetiapine for 48 h. Both cell lines were also treated with a combination of two antimalarial drugs (mefloquine and pyronaridine) or two CNS drugs (fluphenazine and sertraline) for 48 h. We found that the use of quetiapine in combined therapies seems to synergistically enhance the anticancer activity of doxorubicin for the management of breast cancer. Both CNS drugs significantly improved the cytotoxic potential of 5-fluorouracil in HT-29 cells, with quetiapine synergistically interacting with the antineoplastic drug in this drug combination. Regarding the combination of repurposed drugs, only found one synergic combination regimen (sertraline IC50 plus variable concentrations of fluphenazine) with anticancer potential against HT-29 colon cancer cells was found. Taken together, these results suggest that quetiapine and edaravone can be used as adjuvant agents in chemotherapy for colon cancer. It was also found that the combination of repurposed drugs, specifically the CNS drugs sertraline and fluphenazine, may have an interesting profile for application in colon cancer novel therapies.
    Keywords:  CNS drugs; antimalarial drugs; cancer therapy; drug combination; drug repurposing; synergism evaluation
    DOI:  https://doi.org/10.3390/cimb44100335
  124. Cancers (Basel). 2022 Oct 19. pii: 5125. [Epub ahead of print]14(20):
    TRAIL in the Treatment of Cancer: From Soluble Cytokine to Nanosystems.
    Hojjat Alizadeh Zeinabad, Eva Szegezdi.
      The death ligand tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF cytokine superfamily, has long been recognized for its potential as a cancer therapeutic due to its low toxicity against normal cells. However, its translation into a therapeutic molecule has not been successful to date, due to its short in vivo half-life associated with insufficient tumor accumulation and resistance of tumor cells to TRAIL-induced killing. Nanotechnology has the capacity to offer solutions to these limitations. This review provides a perspective and a critical assessment of the most promising approaches to realize TRAIL's potential as an anticancer therapeutic, including the development of fusion constructs, encapsulation, nanoparticle functionalization and tumor-targeting, and discusses the current challenges and future perspectives.
    Keywords:  TRAIL resistance; cancer; death receptor; nanoparticles; tumor necrosis factor-related apoptosis-inducing ligand (TRAIL); tumor-targeting
    DOI:  https://doi.org/10.3390/cancers14205125
  125. Subcell Biochem. 2022 ;100 67-80
    Iron in Cancer Progression: Does BACH1 Promote Metastasis by Altering Iron Homeostasis?
    Kazuhiko Igarashi, Hironari Nishizawa, Mitsuyo Matsumoto.
      The transcription factor BACH1, which is regulated by direct binding of prosthetic group heme, promotes epithelial-mesenchymal transition (EMT) and drives metastasis of diverse types of cancer cells. De-regulated target genes of BACH1 in cancer cells include those for glycolysis, oxidative phosphorylation, epithelial cell adhesion, and mesodermal cell motility. In addition, the canonical target genes of BACH1 include genes for the regulation of iron homeostasis. Importantly, cancer cells are addicted to iron. We summarize known functions of BACH1 in cancer and discuss how BACH1 may affect iron homeostasis in cancer cells to support their progression by increasing mobile iron within cells. The dependency on BACH1 for cancer progression may also confer upon cancer cells susceptibility to iron-dependent cell death ferroptosis. Finally, we discuss that the human transcription factors provide research opportunities for better understanding of cancer cell properties.
    Keywords:  BACH1; Cancer; Epigenetics; Epithelial-Mesenchymal transition; Iron; Metastasis; Transcription factor
    DOI:  https://doi.org/10.1007/978-3-031-07634-3_2
  126. Biomedicines. 2022 Oct 03. pii: 2473. [Epub ahead of print]10(10):
    Vitamin E and Non-Communicable Diseases: A Review.
    Giulia Ciarcià, Simone Bianchi, Barbara Tomasello, Rosaria Acquaviva, Giuseppe Antonio Malfa, Irina Naletova, Alfonsina La Mantia, Claudia Di Giacomo.
      Vitamin E, a nutrient found in several foods, comprises eight lipophilic vitamers, the α-, β-, γ- and δ-tocopherols and the α-, β-, γ- and δ-tocotrienols. This vitamin is capable of exerting antioxidant and anti-inflammatory activities, and acting as immunomodulators. Despite these well-known biological activities, the findings regarding the ability of vitamin E and its serum metabolites to prevent and/or control chronic disease are often conflicting and inconsistent. In this review, we have described the metabolism of vitamin E and its interaction with the gut microbiota, considering that these factors may be partially responsible for the divergent results obtained. In addition, we focused on the correlations between vitamin E serum levels, dietary intake and/or supplementation, and the main non-communicable diseases, including diabetes mellitus, asthma, cardiovascular diseases, and the four most common cancers (breast cancer, lung cancer, colorectal cancer, and prostate cancer) with the intention of providing an overview of its health effects in the non-communicable-diseases prevention.
    Keywords:  Vitamin E; anti-inflammatory; antioxidant; asthma; cancer; cardiovascular diseases; diabetes; tocopherols; tocotrienols
    DOI:  https://doi.org/10.3390/biomedicines10102473
  127. Biomed Pharmacother. 2022 Oct 23. pii: S0753-3322(22)01301-4. [Epub ahead of print]156 113912
    Role of ginsenoside Rh2 in tumor therapy and tumor microenvironment immunomodulation.
    Sun Xiaodan, Cheng Ying.
      Ginsenoside Rh2 (Rh2), the major bio-active ginsenoside that originated from the root of Panax ginseng, has become a "hot topic" for playing multifunctional roles in both tumor treatment and tumor microenvironment (TME) immunomodulation. Up to now, emerging experimental research about Rh2 in tumor therapy and immuno-regulation has been published, however, the specific reviews focused on its role in the TME were limited. Hence, in this article, we briefly summarized existing evidence supporting the anticancer effects and potential mechanisms of Rh2 according to the tumor type, including anti-proliferation, anti-invasion, and metastasis, induction of cell cycle arrest, anti-angiogenesis, promotion of reactive oxygen species and differentiation. Meanwhile, we shed light on the role of Rh2 in TME, with an emphasis on regulating tumor immunogenicity, immune cells, cytokines, and physicochemical properties of TME. Finally, the current research limitation and prospects of Rh2 were discussed.
    Keywords:  Ginsenoside; Tumor microenvironment; Tumor therapy
    DOI:  https://doi.org/10.1016/j.biopha.2022.113912
  128. Drug Deliv. 2022 Dec;29(1): 3233-3244
    Polycaprolactone based pharmaceutical nanoemulsion loaded with acriflavine: optimization and in vivo burn wound healing activity.
    Touseef Nawaz, Muhammad Iqbal, Barkat Ali Khan, Naveed Ahmed, Asif Nawaz, Akhtar Rasul, Waleed Y Rizg, Abdulmajeed M Jali, Rayan A Ahmed, Awaji Y Safhi.
      Cutaneous burn wounds are a common and troublesome critical issue of public health. Over the last decade, many researchers have investigated the development of novel therapeutic modalities which are capable of fully regeneration and reinstatement of structure and function of the skin with no or limited scar formation. Novel pharmaceutical carriers are offering a potential platform to deliver the drug effectively and to overcome the limitation associated with conventional wound dressings. The aim of this study was to investigate a pharmaceutical acriflavine-loaded polycaprolactone nanoemulsion (ACR-PCL-NE) for burn wound healing. Nanoemulsion was prepared by using the double emulsion solvent evaporation technique and it was subjected to thermodynamic stability testing, droplet size, polydispersity, zeta potential, pH, and surface morphology analysis. The in vivo study was performed to evaluate the efficacy of nanoemulsion using Sprague-Dawley rats as an animal model. The results of this study revealed that the optimized nanoemulsion was stable and had desirable physicochemical properties. The pH was about 4.02 at 25 °C and the particle size was found to be in the range of 302 ± 4.62 nm while the zeta potential was -7.8 ± 1.22 mV and the polydispersity index of 0.221 ± 0.017. The wound regeneration process was evaluated in vivo by different techniques, the formulation group (FG) showed high wound healing potential as compared to the standard group (SD) and control group (CG). These findings reveal that this nanoemulsion formulation can be used effectively for wound healing.
    Keywords:  Nanoemulsion; acriflavine; burn wound; drug delivery; topical
    DOI:  https://doi.org/10.1080/10717544.2022.2136783
  129. Front Oncol. 2022 ;12 983874
    Platelet-promoting drug delivery efficiency for inhibition of tumor growth, metastasis, and recurrence.
    Xiaoliang Li, Lanyue Hu, Chengning Tan, Xiaojie Wang, Qian Ran, Li Chen, Zhongjun Li.
      Nanomedicines are considered one of the promising strategies for anticancer therapy; however, the low targeting efficiency of nanomedicines in vivo is a great obstacle to their clinical applications. Camouflaging nanomedicines with either platelet membrane (PM) or platelet would significantly prolong the retention time of nanomedicines in the bloodstream, enhance the targeting ability of nanomedicines to tumor cells, and reduce the off-target effect of nanomedicines in major organs during the anticancer treatment. In the current review, the advantages of using PM or platelet as smart carriers for delivering nanomedicines to inhibit tumor growth, metastasis, and recurrence were summarized. The opportunities and challenges of this camouflaging strategy for anticancer treatment were also discussed.
    Keywords:  anticancer therapy; delivery system; nanomedicine; platelet; platelet membrane
    DOI:  https://doi.org/10.3389/fonc.2022.983874
  130. Int J Environ Res Public Health. 2022 Oct 11. pii: 13076. [Epub ahead of print]19(20):
    Gut Microbiome: The Interplay of an "Invisible Organ" with Herbal Medicine and Its Derived Compounds in Chronic Metabolic Disorders.
    Dong-Woo Lim, Jing-Hua Wang.
      Resembling a concealed "organ" in a holobiont, trillions of gut microbes play complex roles in the maintenance of homeostasis, including participating in drug metabolism. The conventional opinion is that most of any drug is metabolized by the host and that individual differences are principally due to host genetic factors. However, current evidence indicates that only about 60% of the individual differences in drug metabolism are attributable to host genetics. Although most common chemical drugs regulate the gut microbiota, the gut microbiota is also known to be involved in drug metabolism, like the host. Interestingly, many traditional herbal medicines and derived compounds are biotransformed by gut microbiota, manipulating the compounds' effects. Accordingly, the gut microbiota and its specified metabolic pathways can be deemed a promising target for promoting drug efficacy and safety. However, the evidence regarding causality and the corresponding mechanisms concerning gut microbiota and drug metabolism remains insufficient, especially regarding drugs used to treat metabolic disorders. Therefore, the present review aims to comprehensively summarize the bidirectional roles of gut microbiota in the effects of herbal medicine in metabolic diseases to provide vital clues for guiding the clinical application of precision medicine and personalized drug development.
    Keywords:  drug metabolism; drug–gut microbe interaction; gut microbiota; herbal medicine; metabolic disorder
    DOI:  https://doi.org/10.3390/ijerph192013076
  131. Pharmaceutics. 2022 Oct 19. pii: 2237. [Epub ahead of print]14(10):
    Blood-Brain Barrier Transport of Transferrin Receptor-Targeted Nanoparticles.
    Maj Schneider Thomsen, Kasper Bendix Johnsen, Krzysztof Kucharz, Martin Lauritzen, Torben Moos.
      The blood-brain barrier (BBB), built by brain endothelial cells (BECs), is impermeable to biologics. Liposomes and other nanoparticles are good candidates for the delivery of biologics across the BECs, as they can encapsulate numerous molecules of interest in an omnipotent manner. The liposomes need attachment of a targeting molecule, as BECs unfortunately are virtually incapable of uptake of non-targeted liposomes from the circulation. Experiments of independent research groups have qualified antibodies targeting the transferrin receptor as superior for targeted delivery of nanoparticles to BECs. Functionalization of nanoparticles via conjugation with anti-transferrin receptor antibodies leads to nanoparticle uptake by endothelial cells of both brain capillaries and post-capillary venules. Reducing the density of transferrin receptor-targeted antibodies conjugated to liposomes limits uptake in BECs. Opposing the transport of nanoparticles conjugated to high-affine anti-transferrin receptor antibodies, lowering the affinity of the targeting antibodies or implementing monovalent antibodies increase uptake by BECs and allows for further transport across the BBB. The novel demonstration of transport of targeted liposomes in post-capillary venules from blood to the brain is interesting and clearly warrants further mechanistic pursuit. The recent evidence for passing targeted nanoparticles through the BBB shows great promise for future drug delivery of biologics to the brain.
    Keywords:  antibody; blood–brain barrier; endosomal; liposome; nanoparticle; targeting; transferrin
    DOI:  https://doi.org/10.3390/pharmaceutics14102237
  132. Food Funct. 2022 Oct 24.
    Co-encapsulation of quercetin and resveratrol in zein/carboxymethyl cellulose nanoparticles: characterization, stability and in vitro digestion.
    Zhongyu Yang, David Julian McClements, Xinwen Peng, Chao Qiu, Jie Long, Jianwei Zhao, Zhenlin Xu, Man Meng, Long Chen, Zhengyu Jin.
      Oral administration of combinations of specific nutrients and nutraceuticals can provide synergistic health benefits to humans. In this work, zein/carboxymethyl cellulose composite nanoparticles were successfully prepared using antisolvent precipitation methods. Zein/carboxymethyl cellulose nanoparticles with the smallest size (204.6 nm) were formed when the mass ratio of zein to CMC was 2 : 1. Hydrogen bonding and hydrophobic interactions were dominant binding forces to stabilize the composite nanoparticles. Quercetin and resveratrol were then encapsulated within these nanocarriers, which improved their resistance to both light and thermal degradation. Encapsulation of the nutraceuticals was shown to delay their release under simulated gastrointestinal conditions, which may be beneficial for some applications. Moreover, encapsulation increased the in vitro bioaccessibility of the quercetin and resveratrol. Our results indicate that zein/carboxymethyl cellulose nanoparticles can be used to co-deliver combinations of bioactive compounds, which may be useful for the development of functional foods, supplements, and pharmaceuticals.
    DOI:  https://doi.org/10.1039/d2fo02718f
  133. Gels. 2022 Oct 07. pii: 635. [Epub ahead of print]8(10):
    Novel Metoprolol-Loaded Chitosan-Coated Deformable Liposomes in Thermosensitive In Situ Gels for the Management of Glaucoma: A Repurposing Approach.
    Mohamed M Badran, Abdullah H Alomrani, Aliyah Almomen, Yousef A Bin Jardan, Amal El Sayeh Abou El Ela.
      Glaucoma is a long-term eye disease associated with high intraocular pressure (IOP), which seriously damages the eyes, causing blindness. For successful therapy, potent drugs and delivery systems are required. Metoprolol (MT) is believed to help reduce elevated IOP. The paradigm of ocular therapeutics may be changed by the integration of chitosan-coated liposomes (CLPs) with thermosensitive in situ gel (ISG). Therefore, MT-CLPs were developed and characterized and compared to uncoated ones (MT-LPs). Furthermore, MT-LP- and MT-CLP-loaded ISGs were prepared and characterized in in vitro, ex vivo, and in vivo studies. MT-LPs and MT-CLPs displayed spherical shapes with nanosize range, reasonable EE%, and significant bioadhesion. The zeta potential changed from negative to positive after CS coating. The extended in vitro drug release of MT-CLPs showed significant mucin mucoadhesion. The formed ISGs were homogeneous with a pH range of 7.34 to 7.08 and a rapid sol-gel transition at physiological temperature. MT-ISG1 (MT-LP) and MT-ISG2 (MT-CLPs-0.5) could increase ocular permeability by 2-fold and 4.4-fold compared to MT-ISG (pure MT). MT-ISG2 demonstrated significantly reduced IOP in rabbits without causing any irritation. In conclusion, MT-ISG2 markedly enhanced corneal permeability and reduced IOP. They would be promising carriers for MT for glaucoma management.
    Keywords:  IOP; chitosan-coated deformable liposomes; in situ gels; metoprolol; ocular delivery
    DOI:  https://doi.org/10.3390/gels8100635
  134. Mar Drugs. 2022 Sep 30. pii: 625. [Epub ahead of print]20(10):
    Marine Compounds, Mitochondria, and Malignancy: A Therapeutic Nexus.
    Sajad Fakhri, Sadaf Abdian, Seyed Zachariah Moradi, Blake E Delgadillo, Carmela Fimognari, Anupam Bishayee.
      The marine environment is important yet generally underexplored. It contains new sources of functional constituents that can affect various pathways in food processing, storage, and fortification. Bioactive secondary metabolites produced by marine microorganisms may have significant potential applications for humans. Various components isolated from disparate marine microorganisms, including fungi, microalgae, bacteria, and myxomycetes, showed considerable biological effects, such as anticancer, antioxidant, antiviral, antibacterial, and neuroprotective activities. Growing studies are revealing that potential anticancer effects of marine agents could be achieved through the modulation of several organelles. Mitochondria are known organelles that influence growth, differentiation, and death of cells via influencing the biosynthetic, bioenergetic, and various signaling pathways related to oxidative stress and cellular metabolism. Consequently, mitochondria play an essential role in tumorigenesis and cancer treatments by adapting to alterations in environmental and cellular conditions. The growing interest in marine-derived anticancer agents, combined with the development and progression of novel technology in the extraction and cultures of marine life, led to revelations of new compounds with meaningful pharmacological applications. This is the first critical review on marine-derived anticancer agents that have the potential for targeting mitochondrial function during tumorigenesis. This study aims to provide promising strategies in cancer prevention and treatment.
    Keywords:  anticancer activities; marine compounds; marine microorganisms; mitochondria
    DOI:  https://doi.org/10.3390/md20100625
  135. Front Pharmacol. 2022 ;13 975181
    The role of melatonin in the development of postmenopausal osteoporosis.
    Keda Yang, Xueshan Qiu, Lili Cao, Shui Qiu.
      Melatonin is an important endogenous hormone that modulates homeostasis in the microenvironment. Recent studies have indicated that serum melatonin levels are closely associated with the occurrence and development of osteoporosis in postmenopausal women. Exogenous melatonin could also improve bone mass and increase skeletal strength. To determine the underlying mechanisms of melatonin in the prevention and treatment of postmenopausal osteoporosis, we performed this review to analyze the role of melatonin in bone metabolism according to its physiological functions. Serum melatonin is related to bone mass, the measurement of which is a potential method for the diagnosis of osteoporosis. Melatonin has a direct effect on bone remodeling by promoting osteogenesis and suppressing osteoclastogenesis. Melatonin also regulates the biological rhythm of bone tissue, which benefits its osteogenic effect. Additionally, melatonin participates in the modulation of the bone microenvironment. Melatonin attenuates the damage induced by oxidative stress and inflammation on osteoblasts and prevents osteolysis from reactive oxygen species and inflammatory factors. As an alternative drug for osteoporosis, melatonin can improve the gut ecology, remodel microbiota composition, regulate substance absorption and maintain metabolic balance, all of which are beneficial to the health of bone structure. In conclusion, our review systematically demonstrates the effects of melatonin on bone metabolism. Based on the evidence in this review, melatonin will play a more important role in the diagnosis, prevention and treatment of postmenopausal osteoporosis.
    Keywords:  anti-inflammation; antioxidant; biological rhythms; gut microbiota; immuomodulation; melatonin; postmenopausal osteoporosis
    DOI:  https://doi.org/10.3389/fphar.2022.975181
  136. J Mater Chem B. 2022 Oct 24.
    New insights into ruthenium(II) metallodendrimers as anticancer drug nanocarriers: from synthesis to preclinic behaviour.
    Dina Maciel, Nádia Nunes, Francisco Santos, Yu Fan, Gaoming Li, Mingwu Shen, Helena Tomás, Xiangyang Shi, João Rodrigues.
      Dendrimers have been studied as promising materials for the delivery of anticancer drugs. In this work, low-generation (0-2) nitrile poly(alkylidenamine)-based dendrimers were explored as nanocarriers for the organometallic complex [Ru(η5-C5H5)(PPh3)2]+ (RuCp+) and investigated for their anticancer action and involved mechanisms, which were evaluated both in vitro and in vivo. It was observed that their biological behaviour is generation dependent, where the highest generation metallodendrimer (G2Ru) was overall more effective than the other metallodendrimers. G2Ru was active against a set of six cancer cell lines, revealing its important selectivity for these cells (the IC50 values were about 4-fold lower than that for non-cancer cells). Importantly, the in vivo studies with G2Ru in an MCF-7 xenograft mouse model showed that it exhibited low systemic toxicity, low accumulation in the main organs of the mice, preferential accumulation in the tumour, and remarkable capacity to limit tumour growth. The in vitro and in vivo studies revealed that G2Ru caused high levels of cell necrosis and apoptosis. The in vitro cell death mechanism studies showed the capacity of G2Ru to induce mitochondrial depolarization and ROS production. Altogether, pre-clinical results indicated G2Ru as a promising anticancer drug and the potential of low-generation poly(alkylidenamine)-based dendrimers as drug nanocarriers.
    DOI:  https://doi.org/10.1039/d2tb01280d
  137. Antioxidants (Basel). 2022 Sep 28. pii: 1929. [Epub ahead of print]11(10):
    Alpinumisoflavone Impairs Mitochondrial Respiration via Oxidative Stress and MAPK/PI3K Regulation in Hepatocellular Carcinoma Cells.
    Hyewon Jang, Jiyeon Ham, Jisoo Song, Gwonhwa Song, Whasun Lim.
      Alpinumisoflavone is a natural prenylated isoflavonoid extracted from the raw fruit of Cudrania tricuspidata. Several studies have reported the beneficial characteristics of alpinumisoflavone, such as its antioxidant, anti-inflammation, anti-bacterial, osteoprotective, and neuroprotective effects. Alpinumisoflavone also has anti-cancer effects on thyroid, renal, and ovarian cancers, but its therapeutic effects on hepatocellular carcinoma (HCC) have not yet been demonstrated. We investigated the anti-cancer effects of alpinumisoflavone on HCC using human liver cancer cell lines, Hep3B and Huh7. Our results confirmed that alpinumisoflavone inhibited viability and regulated the MAPK/PI3K pathway in Hep3B and Huh7 cells. We also verified that alpinumisoflavone can depolarize the mitochondrial membrane potential and suppress the mitochondrial respiration in HCC cells. Moreover, we confirmed the dysregulation of the mitochondrial complexes I, III, and V involving mitochondrial oxidative phosphorylation at the mRNA level and the accumulation of calcium ions in the mitochondrial matrix. Lastly, we demonstrated that alpinumisoflavone induced mitochondria-mediated apoptosis via regulation of the Bcl-xL and BAK proteins. This study elucidates the anti-cancer effects of alpinumisoflavone on HCC.
    Keywords:  OXPHOS; alpinumisoflavone; calcium homeostasis; liver cancer; oxidative stress
    DOI:  https://doi.org/10.3390/antiox11101929
  138. Nanoscale Res Lett. 2022 Oct 29. 17(1): 103
    H2O2/pH Dual-Responsive Biomimetic Nanoenzyme Drugs Delivery System for Enhanced Tumor Photodynamic Therapy.
    Xinyuan Li, Qing Ji, Chao Yan, Ziyu Zhu, Zhihui Yan, Ping Chen, Yisen Wang, Li Song.
      Phototherapy has been recognized as a photochemical process to treat tumor via induce cancer cells necrosis and death, with minimal invasiveness, higher selectivity, and few side effects. However, the therapy effects of phototherapy are often compromised by the hypoxia, high levels of hydrogen peroxide, and glutathione of tumor microenvironment (TME). Therefore, we constructed a catalase-like activity bionic metal-organic framework drugs delivery system (FA-EM@MnO2/ZIF-8/ICG) with tumor microenvironment controllable releasing. In this system, photosensitizer indocyanine green (ICG) was introduced into zeolite imidazole salt skeleton 8 (ZIF-8) by one-step methods, forming ZIF-8/ICG nano-platform, which can effectively avoid ICG-induced phototoxicity and aggregation-induced quenching during transport. MnO2 with catalase-like activity was coated on the surface of ZIF-8/ICG nano-platform, which made it have the ability of self-supplying O2 under the condition of H2O2 in TME. Exposure under near-infrared light can alleviate the anoxic TME, thus improving the phototherapy efficiency. In addition, folate-functionalized erythrocyte membrane is coated on the surface of MnO2/ZIF-8/ICG, which can endow FA-EM@MnO2/ZIF-8/ICG with the ability of targeted drug administration and immune elimination avoidance. Therefore, FA-EM@MnO2/ZIF-8/ICG nano-platform has the catalase-like activity, which can alleviate the oxidative stress state of TME and provide a beneficial environment for photodynamic therapy of tumor.
    Keywords:  Catalase-like activity; Nano-platform; Phototherapy; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s11671-022-03738-9
  139. Gels. 2022 Oct 09. pii: 639. [Epub ahead of print]8(10):
    Ultraviolet Radiation Protective and Anti-Inflammatory Effects of Kaempferia galanga L. Rhizome Oil and Microemulsion: Formulation, Characterization, and Hydrogel Preparation.
    Chuda Chittasupho, Sakdanai Ditsri, Sudarshan Singh, Mayuree Kanlayavattanakul, Natthachai Duangnin, Warintorn Ruksiriwanich, Sirivan Athikomkulchai.
      Long-term UV radiation exposure can induce skin disorders such as cancer and photoallergic reactions. Natural products have been considered as non-irritate and potential sunscreen resources due to their UV absorption and anti-inflammatory activities. This study aimed to evaluate the in vitro ultraviolet radiation protective effect and anti-inflammatory activity of K. galanga rhizome oil and microemulsions. The chemical components of K. galanga rhizome oil was analyzed via gas chromatography coupled with mass spectrometry. Microemulsions containing K. galanga rhizome oil were formulated using a phase-titration method. The microemulsion was characterized for droplet size, polydispersity index, and zeta potential, using a dynamic light-scattering technique. The physical and chemical stability of the microemulsion were evaluated via a dynamic light scattering technique and UV-Vis spectrophotometry, respectively. The UV protection of K. galanga rhizome oil and its microemulsion were investigated using an ultraviolet transmittance analyzer. The protective effect of K. galanga rhizome oil against LPS-induced inflammation was investigated via MTT and nitric oxide inhibitory assays. In addition, a hydrogel containing K. galanga rhizome oil microemulsion was developed, stored for 90 days at 4, 30, and 45 °C, and characterized for viscosity, rheology, and pH. The chemical degradation of the main active compound in the microemulsion was analyzed via UV-Vis spectrophotometry. The formulated O/W microemulsion contained a high loading efficiency (101.24 ± 2.08%) of K. galanga rhizome oil, suggesting a successful delivery system of the oil. The size, polydispersity index, and zeta potential values of the microemulsion were optimized and found to be stable when stored at 4, 30, and 45 °C. K. galanga rhizome oil and microemulsion demonstrated moderate sun protective activity and reduced the nitric oxide production induced by LPS in macrophage cells, indicating that microemulsion containing K. galanga rhizome oil may help protect human skin from UV damage and inflammation. A hydrogel containing K. galanga rhizome oil microemulsion was developed as a topical preparation. The hydrogel showed good physical stability after heating and cooling cycles and long-term storage (3 months) at 4 °C. The use of K. galanga rhizome oil as a natural sun-protective substance may provide a protective effect against inflammation on the skin. K. galanga rhizome oil microemulsion was successfully incorporated into the hydrogel and has the potential to be used as a topical sunscreen preparation.
    Keywords:  Zingiberaceae; essential oil; ethyl cinnamate; nitric oxide; sunscreen
    DOI:  https://doi.org/10.3390/gels8100639
  140. Plants (Basel). 2022 Oct 16. pii: 2737. [Epub ahead of print]11(20):
    Chemical Modification of Curcumin into Its Semi-Synthetic Analogs Bearing Pyrimidinone Moiety as Anticancer Agents.
    Obaid Afzal, Mohammad Yusuf, Mohamed Jawed Ahsan, Abdulmalik S A Altamimi, Md Afroz Bakht, Amena Ali, Salahuddin.
      Natural products (NPs) continue to provide a structural template for the design of novel therapeutic agents and expedite the drug discovery process. The majority of FDA-approved pharmaceuticals used in medical practice can be traced back to natural sources, and NPs play a significant role in drug development. Curcumin, one of the most well-studied chemicals among the NPs, is currently the subject of intense investigation for its biological effects, including the prevention and treatment of cancer. Cancer has overtaken all other causes of death in the world today, with 19.3 million new cases and nearly 10 million deaths predicted in 2020. In the present investigation, we reported the synthesis of three semi-synthetic analogues of curcumin-bearing pyrimidinone moiety by the chemical modification of the diketone function of curcumin followed by their characterization by analytical techniques including infrared (IR), nuclear magnetic resonance (NMR), and mass spectral data. According to the National Cancer Institute (NCI US) methodology, the curcumin analogues (C1-C3) were tested for their anticancer efficacy against 59 cancer cell lines in a single dose assay. 1-(2,6-Dichlorophenyl)-4,6-bis((E)-4-hydroxy-3-methoxystyryl)pyrimidin-2(1H)-one (C2) demonstrated the most promising anticancer activity with mean percent growth inhibition (%GIs) of 68.22 in single dose assay at 10 µM. The compound exhibited &gt;68 %GIs against 31 out of 59 cancer cell lines and was found to be highly active against all leukemia and breast cancer cell lines. The compound C2 showed a lethal effect on HT29 (colon cancer) with %GI of 130.44, while 99.44 %GI was observed against RPMI-8226 (Leukemia). The compound C2 displayed better anticancer activity against the panels of CNS, melanoma, ovarian, prostate, and breast cancer cell lines than curcumin and other anti-EGFR agents gefitinib and imatinib in single dose assay. The compound C2 also demonstrated potent anticancer activity in a 5-dose assay (0.001 to 100 µM) with GI50 values ranging from 1.31 to 4.68 µM; however, it was found to be non-selective with SR values ranging from 0.73 to 1.35. The GI50 values of compound C2 were found to be better than that of the curcumin against all nine panels of cancer cell lines. All of the curcumin analogues were subsequently investigated for molecular docking simulation against EGFR, one of the most attractive targets for antiproliferative action. In molecular docking studies, all the ligands were found to accommodate the active site of EGFR and the binding affinity of ligand C2 was found to be -5.086 kcal/mol. The ligand C2 exhibited three different types of interactions: H-bond (Thr790 and Thr854), π-cationic (Arg841), and aromatic H-bond (Asn842). The curcumin analogues reported in the current investigation may provide valuable therapeutic intervention for the prevention and treatment of cancer and accelerate anticancer drug discovery programs in the future.
    Keywords:  anti-EGFR; antiproliferative activity; curcumin analogues; molecular docking; pyrimidinone; synthesis
    DOI:  https://doi.org/10.3390/plants11202737
  141. Biomaterials. 2022 Oct 14. pii: S0142-9612(22)00493-8. [Epub ahead of print]290 121853
    Enhanced manipulation of tumor microenvironments by nanomotor for synergistic therapy of malignant tumor.
    Xiaowei Chang, Man Zhu, Xiaoyu Tang, Xiaoqian Yu, Feng Liu, Li Chen, Tian Yin, Zeren Zhu, Yanmin Zhang, Xin Chen.
      Tumor microenvironments (TME) play critical roles in the growth and metastasis of tumor tissue, which provide a promising way to treat malignant tumor via manipulation of TME. However, developing proper strategy to effectively control TME is still a challenge. Herein, a Ce6@AT-PEG-MSN-Pt (CAPMP) nanomotor is fabricated to spontaneously move in tumor tissue and concurrently perform the enhanced manipulation of various tumor microenvironments including copper levels, hypoxia, local temperature and reactive oxygen species (ROS) for effective tumor therapy. The CAPMP nanomotor consists of a janus platinum-mesoporous silica core with acyl thioureas groups (copper chelator) conjugated polyethylene glycol on the surface and chlorin e6 (photosensitizer) in the pores. During therapy, the acyl thioureas groups on CAPMP would capture the over-expressed copper in tumor tissue and tumor cells to cause dramatic copper-deficiency of tumor. The chlorin e6 is in charge of the ROS (1O2) generation in tumor via photodynamic process, which would be triggered by 660 nm irradiation. The platinum layer of CAPMP served as both photothermal agent and O2 producer. It rapidly raised the local temperature under 808 nm irradiation, meanwhile converted the over-expressed H2O2 in tumor tissue to O2via catalytic reaction. The O2 production not only drove the CAPMP for sustained movement to promote its efficiency of copper capture, but reversed the hypoxic environment of tumor tissue in large and deep area, which further promoted the 1O2 generation property of CAPMP. Both in vitro and in vivo experiments demonstrate that the raise of local temperature and enhanced 1O2 concentration performed significant damage of tumor tissue for primary tumor elimination, while the copper deficiency and hypoxia reversion further hindered the migration of tumor cells for metastasis inhibition, resulting in an effective strategy to treat malignant tumor.
    Keywords:  Metastasis inhibition; Primary tumor elimination; Self-driven nanomotor; Synergistic therapy; Tumor microenvironments manipulation
    DOI:  https://doi.org/10.1016/j.biomaterials.2022.121853
  142. Biomed Microdevices. 2022 Oct 24. 24(4): 35
    A comparative analysis of low intensity ultrasound effects on living cells: from simulation to experiments.
    Giulia Tamboia, Michele Campanini, Veronica Vighetto, Luisa Racca, Luca Spigarelli, Giancarlo Canavese, Valentina Cauda.
      Ultrasounds are already broadly exploited in clinical diagnostics and are now becoming a powerful and not harmful tool in antitumoral therapies, as they are able to produce damages towards cancer cells, thank to inertial cavitation and temperature increase. The use of US alone or combined to molecular compounds, microbubbles or solid-state nanoparticles is the focus of current research and clinical trials, like thermoablation, drug sonoporation or sonodynamic therapies. In the present work, we discuss on the non-thermal effects of ultrasound and the conditions which enable oxygen radical production and which role they can have in provoking the death of different cancer cell lines. In this perspective, we set a mathematical model to predict the pressure spatial distribution in a defined water sample volume and thus obtain a map of acoustic pressures and acoustic intensities of the applied ultrasound at different input powers. We then validate and verify these numerical results with direct acoustic measurements and by detecting the production of reactive oxygen species (ROS) by means of sonochemiluminescence (SCL) and electron paramagnetic resonance (EPR) spectroscopy, applied to the same water sample volume and using the same US input parameters adopted in the simulation. Finally, the various US conditions are applied to two different set of cancer cell lines, a cervical adenocarcinoma and a hematological cancer, Burkitt's lymphoma. We hypothesize how the ROS generation can influence the recorded cell death. In a second set of experiments, the role of semiconductor metal oxide nanocrystals, i.e. zinc oxide, is also evaluated by adding them to the water and biological systems. In particular, the role of ZnO in enhancing the ROS production is verified. Furthermore, the interplay among US and ZnO nanocrystals is evaluated in provoking cancer cell death at specific conditions. This study demonstrates a useful correlation between numerical simulation and experimental acoustic validation as well as with ROS measurement at both qualitative and quantitative levels during US irradiation of simple water solution. It further tries to translate the obtained results to justify one of the possible mechanisms responsible of cancer cell death. It thus aims to pave the way for the use of US in cancer therapy and a better understanding on the non-thermal effect that a specific set of US parameters can have on cancer cells cultured in vitro.
    Keywords:  Acoustic cavitation; Acoustic field simulation; Electron paramagnetic spectroscopy; Nanoparticles; Reactive oxygen species; Sonochemiluminescence
    DOI:  https://doi.org/10.1007/s10544-022-00635-x
  143. Gels. 2022 Oct 17. pii: 664. [Epub ahead of print]8(10):
    Hydrogel on a Smart Nanomaterial Interface to Carry Therapeutics for Digitalized Glioma Treatment.
    Xinyi Zhao, Bilal Javed, Furong Tian, Kangze Liu.
      Glioma is considered the primary brain tumor to cause brain illnesses, and it is difficult to treat and shows resistance to various routine therapeutics. The most common treatments to cure glioma are the surgical removal of tumors followed by adjuvant chemotherapy and radiation therapy. The latest biocompatible interfaces have been incorporated into therapeutic modalities such as the targeted delivery of drugs using hydrogels to treat and manage brain glioma. This review illustrates the applications of the multimodal hydrogel as the carrier of therapeutics, gene therapy, therapeutic tactics, and glioma devices. The scientific articles were retrieved from 2019 to 2022 on Google Scholar and the Scopus database and screened to determine whether they were suitable for review. The 20 articles that fit the study are summarized in this review. These studies indicated that the sizes of the hydrogel range from 28 nm to 500 nm. There are 16 out of 20 articles that also explain the post-surgical application of hydrogels, and 13 out of 20 articles are employed in 3D culture and other structural manifestations of hydrogels. The pros of the hydrogel include the quick formulation for a sufficient filling of irregular damage sites, solubilizing hydrophobic drugs, continuously slowing drug release, provision of a 3D cell growth environment, improving efficacy, targetability of soluble biomolecules, increasing patient compliance, and decreased side effects. The cons of the hydrogel include difficult real-time monitoring, genetic manipulations, the cumbersome synchronized release of components, and lack of safety data. The prospects of the hydrogel may include the development of electronic hydrogel sensors that can be used to enhance guidance for the precise targeting patterns using patient-specific pathological idiosyncrasies. This technology has the potential to revolutionize the precision medicine approaches that would aid in the early detection and management of solid brain tumors.
    Keywords:  biosensor; digitalized; gene therapy; glioma; hydrogel; precision medicine
    DOI:  https://doi.org/10.3390/gels8100664
  144. iScience. 2022 Oct 21. 25(10): 105190
    Link between glucose metabolism and epithelial-to-mesenchymal transition drives triple-negative breast cancer migratory heterogeneity.
    Samantha C Schwager, Jenna A Mosier, Reethi S Padmanabhan, Addison White, Qinzhe Xing, Lauren A Hapach, Paul V Taufalele, Ismael Ortiz, Cynthia A Reinhart-King.
      Intracellular and environmental cues result in heterogeneous cancer cell populations with different metabolic and migratory behaviors. Although glucose metabolism and epithelial-to-mesenchymal transition have previously been linked, we aim to understand how this relationship fuels cancer cell migration. We show that while glycolysis drives single-cell migration in confining microtracks, fast and slow cells display different migratory sensitivities to glycolysis and oxidative phosphorylation inhibition. Phenotypic sorting of highly and weakly migratory subpopulations (MDA+, MDA-) reveals that more mesenchymal, highly migratory MDA+ preferentially use glycolysis while more epithelial, weakly migratory MDA- utilize mitochondrial respiration. These phenotypes are plastic and MDA+ can be made less glycolytic, mesenchymal, and migratory and MDA- can be made more glycolytic, mesenchymal, and migratory via modulation of glucose metabolism or EMT. These findings reveal an intrinsic link between EMT and glucose metabolism that controls migration. Identifying mechanisms fueling phenotypic heterogeneity is essential to develop targeted metastatic therapeutics.
    Keywords:  Biological sciences; cancer; human metabolism; physiology
    DOI:  https://doi.org/10.1016/j.isci.2022.105190
  145. Recent Adv Inflamm Allergy Drug Discov. 2022 Oct 27.
    Anti-inflammatory therapeutics: Conventional concepts and future with nanotechnology.
    Manju Bernela, Priya Kaushal, Naveen Verma, Rajesh Thakur, Munish Ahuja, Pawan Kaur.
      With the advent of globalization, there has been a continuous increase in the risk of inflammatory diseases which in turn leads to the maximum usage of anti-inflammatory drugs. Currently, drugs used for anti-inflammatory therapies are costly with low efficacy, high health risk, and socio-economic impact due to the concern issue of their toxicity. Recently, nano-drug delivery system has been experiencing foremost interest as a new approach for targeting therapeutic agents to the target sites in a controlled, sustained manner and has various advantages as compared to the conventional drug delivery system like increased solubility, bioavailability, improves pharmacokinetic profile of drugs, surface area and rate of dissolution and additionally, overcomes the problems related to hydrophobicity, toxicity.
    Keywords:  Anti-inflammatory; Conventional ; Nanoformulations; Nanotechnology; Nanotherapuetics; Phytopharmacueticles
    DOI:  https://doi.org/10.2174/2772270817666221027154402
  146. Endocrinology. 2022 Oct 25. pii: bqac177. [Epub ahead of print]
    Gut and breast microbiota as endocrine regulators of hormone receptor-positive breast cancer risk and therapy response.
    Alana A Arnone, Katherine L Cook.
      Despite advances in treatment strategies, breast cancer remains one of the most prevalent cancers worldwide. Recent studies implicate the gut microbiome as a potential risk factor for breast cancer development. Alterations in gut microbial diversity resulting in dysbiosis have been linked to breast carcinogenesis by modulating host immune responses and inflammatory pathways, favoring tumorigenesis and progression. Moreover, gut microbiota populations are different between women with breast cancer versus those that are cancer-free, further implicating the role of the gut microbiome in cancer development. This alteration in gut microbiota is also associated with changes in estrogen metabolism, which strongly correlates with breast cancer development. Gut microbiota that expresses the enzyme β-glucuronidase (GUS) may increase estrogen bioavailability by deconjugating estrogen-glucuronide moieties enabling reabsorption into circulation. Increased circulating estrogens may, in turn, drive estrogen receptor-positive breast cancer. GUS-expressing microbiota also impact cancer therapy efficacy and toxicity by modifying glucuronide-conjugated drug metabolites. Therefore, GUS inhibitors have emerged as a potential anti-tumor treatment. However, the effectiveness of GUS inhibitors is still exploratory. Further studies are needed to determine how oral endocrine targeting therapies may influence or be influenced by the microbiota and how that may impact carcinogenesis initiation and tumor recurrence.
    Keywords:  Gut microbiome; breast cancer; estrogen; menopause; β-glucuronidase
    DOI:  https://doi.org/10.1210/endocr/bqac177
  147. Pharmaceutics. 2022 Oct 02. pii: 2110. [Epub ahead of print]14(10):
    Preparation of pH-Responsive Hydrogels Based on Chondroitin Sulfate/Alginate for Oral Drug Delivery.
    Muhammad Suhail, Hamid Ullah, Quoc Lam Vu, Arshad Khan, Ming-Jun Tsai, Pao-Chu Wu.
      This study investigates pH-sensitive hydrogels based on biocompatible, biodegradable polysaccharides and natural polymers such as chondroitin sulfate and alginate in combination with synthetic monomer such as acrylic acid, as controlled drug carriers. Investigations were conducted for chondroitin sulfate/alginate-graft-poly(acrylic acid) hydrogel in various mixing ratios of chondroitin sulfate, alginate and acrylic acid in the presence of ammonium persulfate and N',N'-Methylene bisacrylamide. Crosslinking and loading of drug were confirmed by Fourier transform infrared spectroscopy. Thermal stability of both polymers was enhanced after crosslinking as indicated by thermogravimetric analysis and differential scanning calorimeter thermogram of developed hydrogel. Similarly, surface morphology was evaluated by scanning electron microscopy, whereas crystallinity of the polymers and developed hydrogel was investigated by powder X-ray diffraction. Furthermore, swelling and drug-release studies were investigated in acidic and basic medium of pH 1.2 and 7.4 at 37 °C, respectively. Maximum swelling and drug release were detected at pH 7.4 as compared to pH 1.2. Increased incorporation of hydrogel contents led to an increase in porosity, drug loading, and gel fraction while a reduction in sol fraction was seen. The polymer volume fraction was found to be low at pH 7.4 compared to pH 1.2, indicating a prominent and greater swelling of the prepared hydrogels at pH 7.4. Likewise, a biodegradation study revealed a slow degradation rate of the developed hydrogel. Hence, we can conclude from the results that a fabricated system of hydrogel could be used as a suitable carrier for the controlled delivery of ketorolac tromethamine.
    Keywords:  biodegradation study; drug release; hydrogels; porosity; swelling
    DOI:  https://doi.org/10.3390/pharmaceutics14102110
  148. Subcell Biochem. 2022 ;100 361-390
    Epigenetic Regulation During Hypoxia and Its Implications in Cancer.
    Deepak Pant, Srinivas Abhishek Mutnuru, Sanjeev Shukla.
      Hypoxia is defined as a cellular stress condition caused by a decrease in oxygen below physiologically normal levels. Cells in the core of a rapidly growing solid tumor are faced with the challenge of inadequate supply of oxygen through the blood, owing to improper vasculature inside the tumor. This hypoxic microenvironment inside the tumor initiates a gene expression program that alters numerous signaling pathways, allowing the cancer cell to eventually evade adverse conditions and attain a more aggressive phenotype. A multitude of studies covering diverse aspects of gene regulation has tried to uncover the mechanisms involved in hypoxia-induced tumorigenesis. The role of epigenetics in executing widespread and dynamic changes in gene expression under hypoxia has been gaining an increasing amount of support in recent years. This chapter discusses, in detail, various epigenetic mechanisms driving the cellular response to hypoxia in cancer.
    Keywords:  Cancer; Chromatin modifications; DNA methylation; Epigenetics; Histone modifications; Hypoxia; Noncoding RNA; RNA methylation
    DOI:  https://doi.org/10.1007/978-3-031-07634-3_11
  149. Biology (Basel). 2022 Sep 27. pii: 1410. [Epub ahead of print]11(10):
    Lysosomes and Their Role in Regulating the Metabolism of Hematopoietic Stem Cells.
    Tasleem Arif.
      Hematopoietic stem cells (HSCs) have the capacity to renew blood cells at all stages of life and are largely quiescent at a steady state. It is essential to understand the processes that govern quiescence in HSCs to enhance bone marrow transplantation. It is hypothesized that in their quiescent state, HSCs primarily use glycolysis for energy production rather than mitochondrial oxidative phosphorylation (OXPHOS). In addition, the HSC switch from quiescence to activation occurs along a continuous developmental path that is driven by metabolism. Specifying the metabolic regulation pathway of HSC quiescence will provide insights into HSC homeostasis for therapeutic application. Therefore, understanding the metabolic demands of HSCs at a steady state is key to developing innovative hematological therapeutics. Lysosomes are the major degradative organelle in eukaryotic cells. Catabolic, anabolic, and lysosomal function abnormalities are connected to an expanding list of diseases. In recent years, lysosomes have emerged as control centers of cellular metabolism, particularly in HSC quiescence, and essential regulators of cell signaling have been found on the lysosomal membrane. In addition to autophagic processes, lysosomal activities have been shown to be crucial in sustaining quiescence by restricting HSCs access to a nutritional reserve essential for their activation into the cell cycle. Lysosomal activity may preserve HSC quiescence by altering glycolysis-mitochondrial biogenesis. The understanding of HSC metabolism has significantly expanded over the decade, revealing previously unknown requirements of HSCs in both their dividing (active) and quiescent states. Therefore, understanding the role of lysosomes in HSCs will allow for the development of innovative treatment methods based on HSCs to fight clonal hematopoiesis and HSC aging.
    Keywords:  HSCs; glycolysis; lysosomes; metabolism; mitochondria; quiescence
    DOI:  https://doi.org/10.3390/biology11101410
  150. Nat Commun. 2022 Oct 24. 13(1): 6323
    Computational pharmacogenomic screen identifies drugs that potentiate the anti-breast cancer activity of statins.
    Jenna E van Leeuwen, Wail Ba-Alawi, Emily Branchard, Jennifer Cruickshank, Wiebke Schormann, Joseph Longo, Jennifer Silvester, Peter L Gross, David W Andrews, David W Cescon, Benjamin Haibe-Kains, Linda Z Penn, Deena M A Gendoo.
      Statins, a family of FDA-approved cholesterol-lowering drugs that inhibit the rate-limiting enzyme of the mevalonate metabolic pathway, have demonstrated anticancer activity. Evidence shows that dipyridamole potentiates statin-induced cancer cell death by blocking a restorative feedback loop triggered by statin treatment. Leveraging this knowledge, we develop an integrative pharmacogenomics pipeline to identify compounds similar to dipyridamole at the level of drug structure, cell sensitivity and molecular perturbation. To overcome the complex polypharmacology of dipyridamole, we focus our pharmacogenomics pipeline on mevalonate pathway genes, which we name mevalonate drug-network fusion (MVA-DNF). We validate top-ranked compounds, nelfinavir and honokiol, and identify that low expression of the canonical epithelial cell marker, E-cadherin, is associated with statin-compound synergy. Analysis of remaining prioritized hits led to the validation of additional compounds, clotrimazole and vemurafenib. Thus, our computational pharmacogenomic approach identifies actionable compounds with pathway-specific activities.
    DOI:  https://doi.org/10.1038/s41467-022-33144-9
  151. J Funct Biomater. 2022 Oct 20. pii: 196. [Epub ahead of print]13(4):
    Overview of Physicochemical Properties of Nanoparticles as Drug Carriers for Targeted Cancer Therapy.
    Vugar Yagublu, Aynura Karimova, Javahir Hajibabazadeh, Christoph Reissfelder, Mustafa Muradov, Stefano Bellucci, Adil Allahverdiyev.
      The advent of nanotechnology has brought about revolutionary innovations in biological research techniques and medical practice. In recent years, various "smart" nanocarriers have been introduced to deliver therapeutic agents specifically to the tumor tissue in a controlled manner, thereby minimizing their side effects and reducing both dosage and dosage frequency. A large number of nanoparticles have demonstrated initial success in preclinical evaluation but modest therapeutic benefits in the clinical setting, partly due to insufficient delivery to the tumor site and penetration in tumor tissue. Therefore, a precise understanding of the relationships betweenthe physicochemical properties of nanoparticles and their interaction with the surrounding microenvironment in the body is extremely important for achieving higher concentrations and better functionality in tumor tissues. This knowledge would help to effectively combine multiple advantageous functions in one nanoparticle. The main focus of the discussion in this review, therefore, will relate to the main physicochemical properties of nanoparticles while interacting within the body and their tuning potential for increased performance.
    Keywords:  drug carriers; nanoparticles; protein corona; surface modification; tumor microenvironment
    DOI:  https://doi.org/10.3390/jfb13040196
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