bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2022–09–04
169 papers selected by
Yasmin Elkabani, Egyptian Foundation for Research and Community Development
  1. Folate receptor-mediated delivery of mitoxantrone-loaded solid lipid nanoparticles to breast cancer cells.
  2. Evidence of Potential Plant-derived Compounds With Anticancer Effects on Lung Cancer: Clinical and Molecular Pharmacology Approaches.
  3. Recent advances in the development of biocompatible nanocarriers and their cancer cell targeting efficiency in photodynamic therapy.
  4. Investigation of ROS generating capacity of curcumin-loaded liposomes and its in vitro cytotoxicity on MCF-7 cell lines using photodynamic therapy.
  5. Cassia fistula nutrition rich flower tea derived biotic nanoparticles synthesis, characterization and their antioxidant and anti-hyperglycaemic properties.
  6. Molecular mechanisms of Sanguinarine in cancer prevention and treatment.
  7. Fabrication of Ginsenoside-Based Nanodrugs for Enhanced Antitumor Efficacy on Triple-Negative Breast Cancer.
  8. Activated aggregation strategies to construct size-increasing nanoparticles for cancer therapy.
  9. RNA Aptamer-Functionalized Polymeric Nanoparticles in Targeted Delivery and Cancer Therapy: An up-to-date Review.
  10. Folate-modified erythrocyte membrane nanoparticles loaded with Fe3O4 and artemisinin enhance ferroptosis of tumors by low-intensity focused ultrasound.
  11. Cellular reprogramming, chemoresistance, and dietary interventions in breast cancer.
  12. Targeting KRAS: Crossroads of Signaling and Immune Inhibition.
  13. Carrier free nanomedicine to reverse anti-apoptosis and elevate endoplasmic reticulum stress for enhanced photodynamic therapy.
  14. Multifunctional PEGylated Niosomal Nanoparticle-Loaded Herbal Drugs as a Novel Nano-Radiosensitizer and Stimuli-Sensitive Nanocarrier for Synergistic Cancer Therapy.
  15. The Role of RNA m6A Modification in Cancer Glycolytic Reprogrammingc.
  16. Crosstalk between xanthine oxidase (XO) inhibiting and cancer chemotherapeutic properties of comestible flavonoids- a comprehensive update.
  17. Natural products as chemo-radiation therapy sensitizers in cancers.
  18. Secure transplantation by tissue purging using photodynamic therapy to eradicate malignant cells.
  19. Nanotechnology-integrated ferroptosis inducers: a sharp sword against tumor drug resistance.
  20. The Roles and Regulation of Ferroptosis in Cancer progression.
  21. Potential roles and molecular mechanisms of phytochemicals against cancer.
  22. Injectable thermosensitive hydrogel to enhance the photothermal ablation and systemic immunotherapy of breast tumors.
  23. Amalgamation of Nanoparticles within Drug Carriers: A Synergistic Approach or a Futile Attempt?
  24. Advances in nanobiotechnology-propelled multidrug resistance circumvention of cancer.
  25. Fine-tuning the encapsulation of a photosensitizer in nanoparticles reveals the relationship between internal structure and phototherapeutic effects.
  26. The crosstalk effect between ferrous and other ions metabolism in ferroptosis for therapy of cancer.
  27. [Impact of vitamin D on health. Difficulties and strategies to reach the recommended intakes].
  28. Natural Radioprotectors on Current and Future Perspectives: A Mini-Review.
  29. The crosstalk between sonodynamic therapy and autophagy in cancer.
  30. Immunomodulatory-Photodynamic Nano-Stimulators for Invoking Pyroptosis to Augment Tumor Immunotherapy.
  31. Poly lactic-co-glycolic acid-based nanoparticles as delivery systems for enhanced cancer immunotherapy.
  32. Tumor Microenvironment Stimuli-Responsive Single-NIR-Laser Activated Synergistic Phototherapy for Hypoxic Cancer by Perylene Functionalized Dual-Targeted Upconversion Nanoparticles.
  33. Near-infrared light and redox dual-activatable nanosystems for synergistically cascaded cancer phototherapy with reduced skin photosensitization.
  34. Epithelial to Mesenchymal Transition in Lung Cancer: Potential EMT-Targeting Natural Product-derived Compounds.
  35. Xanthones: A class of heterocyclic compounds with anticancer potential.
  36. Metformin and histone deacetylase inhibitor based anti-inflammatory nanoplatform for epithelial-mesenchymal transition suppression and metastatic tumor treatment.
  37. Features and Facts of a Gastroretentive Drug Delivery System-A Review.
  38. Cancer and apoptosis: The apoptotic activity of plant and marine natural products and their potential as targeted cancer therapeutics.
  39. The role of ferroptosis in prostate cancer: a novel therapeutic strategy.
  40. Dual contribution of the mTOR pathway and of the metabolism of amino acids in prostate cancer.
  41. Perspectives and mechanisms for targeting ferroptosis in the treatment of hepatocellular carcinoma.
  42. In Situ Transformable Supramolecular Nanomedicine Targeted Activating Hippo Pathway for Triple-Negative Breast Cancer Growth and Metastasis Inhibition.
  43. Hybrid Histone Deacetylase Inhibitor: an Effective Strategy for Cancer Therapy.
  44. Cyclodextrin-based supramolecular nanoparticles break the redox balance in chemodynamic therapy-enhanced chemotherapy.
  45. Nanotechnological Systems and Lung: A Perfect Combination for Lung Pharmaceutical Applications.
  46. Vitamin A- and C-rich Pouteria camito fruit derived superparamagnetic nanoparticles synthesis, characterization, and their cytotoxicity.
  47. An ROS-responsive artesunate prodrug nanosystem co-delivers dexamethasone for rheumatoid arthritis treatment through the HIF-1α/NF-κB cascade regulation of ROS scavenging and macrophage repolarization.
  48. A Review of Ketogenic Diet and Lifestyle.
  49. Transpapillary iontophoretic delivery of resveratrol loaded transfersomes for localized delivery to breast cancer.
  50. Agrimonia pilosa Ledeb.: A review of its traditional uses, botany, phytochemistry, pharmacology, and toxicology.
  51. Inhibiting Cytoprotective Autophagy in Cancer Therapy: An Update on Pharmacological Small-Molecule Compounds.
  52. [Research progress on antitumor effect and molecular mechanism of capsaicin].
  53. Hydrogen peroxide self-sufficient and glutathione-depleted nanoplatform for boosting chemodynamic therapy synergetic phototherapy.
  54. Intracellular glutathione levels affect the outcomes of verteporfin-mediated photodynamic therapy in esophageal cancer cells.
  55. Oncopreventive and Oncotherapeutic Potential of Licorice Chalcone Compounds: Molecular Insights.
  56. Anti-proliferation effects of Apatinib in combination with Curcumin in breast cancer cells.
  57. Co-delivery of curcumin and Bcl-2 siRNA to enhance therapeutic effect against breast cancer cells using PEI-functionalized PLGA nanoparticles.
  58. Recent advances in aptamer-based targeted drug delivery systems for cancer therapy.
  59. Ketogenic diet: an effective treatment approach for neurodegenerative diseases.
  60. Recent advances in chemical composition and transdermal delivery systems for topical bio-actives in skin cancer.
  61. Pharmacological effects and mechanisms of tannic acid.
  62. A Selective Reduction of Osteosarcoma by Mitochondrial Apoptosis Using Hydroxyapatite Nanoparticles.
  63. Antipsychotic-induced weight gain and metabolic effects show diurnal dependence and are reversible with time restricted feeding.
  64. Compound Library Screening for Synergistic Drug Combinations: mTOR Inhibitor and Proteasome Inhibitor Effective Against Osteosarcoma Cells.
  65. Gut microbiota: An emerging therapeutic approach of herbal medicine for prevention of colorectal cancer.
  66. Recent advancements on hyperthermia driven controlled drug delivery from nanotherapeutics.
  67. Strategies for drug targeting in pancreatic cancer.
  68. Rapid oral transmucosal delivery of zaleplon-lavender oil utilizing self-nanoemulsifying lyophilized tablets technology: development, optimization and pharmacokinetic evaluation.
  69. Understanding doxorubicin associated calcium remodeling during triple-negative breast cancer treatment: an in silico study.
  70. Kigelia africana inhibits proliferation and induces cell death in stage 4 Neuroblastoma cell lines.
  71. [Studies on the Isolation and Molecular Mechanisms of Bioactive Phytochemicals].
  72. A mitochondria targeted cascade reaction nanosystem for improved therapeutic effect by overcoming cellular resistance.
  73. Flavonoids regulate tumor-associated macrophages - From structure-activity relationship to clinical potential (Review).
  74. Lactate metabolism in human health and disease.
  75. Emerging Strategies in Stimuli-Responsive Prodrug Nanosystems for Cancer Therapy.
  76. Preparation of starch-based functional food nano-microcapsule delivery system and its controlled release characteristics.
  77. Macrophage membrane-camouflaged lipoprotein nanoparticles for effective obesity treatment based on a sustainable self-reinforcement strategy.
  78. Dual Targeting Anti-Osteoporotic Therapy through Potential Nanotherapeutic Approaches.
  79. Anticancer action of plant products: changing stereotyped attitudes.
  80. Pharmaceutical and drug delivery applications of chitosan biopolymer and its modified nanocomposite: A review.
  81. Optimal treatment occasion for ultrasound stimulated microbubbles in promoting gemcitabine delivery to VX2 tumors.
  82. Selective extraction and stabilization of bioactive compounds from rosemary leaves using a biphasic NADES.
  83. pH-activated nanoplatform for visualized photodynamic and ferroptosis synergistic therapy of tumors.
  84. "Two-birds-one-stone" colon-targeted nanomedicine treats ulcerative colitis via remodeling immune microenvironment and anti-fibrosis.
  85. Smart pH-responsive polyhydralazine/bortezomib nanoparticles for remodeling tumor microenvironment and enhancing chemotherapy.
  86. Investigation on wound healing effect of Mediterranean medicinal plants and some related phenolic compounds: A review.
  87. Metabolic reprogramming and crosstalk of cancer-related fibroblasts and immune cells in the tumor microenvironment.
  88. Recent advances in biological properties of brown algae-derived compounds for nutraceutical applications.
  89. A dual gate-controlled intelligent nanoreactor enables collaborative precise treatment for cancer nanotherapy.
  90. Protective effects of curcumin against traumatic brain injury.
  91. Nanotechnology Advances in the Detection and Treatment of Cancer: An Overview.
  92. Nutrients and amyloid β status in the brain: a narrative review.
  93. Stealth Liposomal Chemotherapeutic Agent for Triple Negative Breast Cancer with Improved Pharmacokinetics.
  94. Vitamin D and musculoskeletal health: outstanding aspects to be considered for the current evidence.
  95. A simple, robust and scalable route to prepare sub-50 nm soft PDMS nanoparticles for intracellular delivery of anticancer drugs.
  96. Finasteride-loaded nano-lipidic carriers for follicular drug delivery: preformulation screening and Box-Behnken experimental design for optimization of variables.
  97. Mechanism Study on Chinese Medicine in Treatment of Nodular Goiter.
  98. Lubricant-entrenched Slippery Surface-based Nanocarriers to Avoid Macrophage Uptake and Improve Drug Utilization.
  99. Potential of Anti-inflammatory Molecules in the Chemoprevention of Breast Cancer.
  100. Manganese-Based Nanozymes: Preparation, Catalytic Mechanisms, and Biomedical Applications.
  101. PEGylated Cisplatin Nanoparticles for Treating Colorectal Cancer in a pH-Responsive Manner.
  102. In Situ Forming Chitosan-Alginate Interpolymer Complex Bioplatform for Wound Healing and Regeneration.
  103. Functionalized PEG-PLA nanoparticles for brain targeted delivery of ketoconazole contribute to pregnane X receptor overexpressing in drug-resistant epilepsy.
  104. The mechanistic immunosuppressive role of the tumour vasculature and potential nanoparticle-mediated therapeutic strategies.
  105. MYC Promotes LDHA Expression through MicroRNA-122-5p to Potentiate Glycolysis in Hepatocellular Carcinoma.
  106. Phytonutrients: Sources, bioavailability, interaction with gut microbiota, and their impacts on human health.
  107. The elevated D-2-hydroxyglutarate level found as a characteristic metabolic change of colon cancer in both in vitro and in vivo models.
  108. Cationic Okra gum coated nanoliposomes as a pH-sensitive carrier for co-delivery of hesperetin and oxaliplatin in colorectal cancers.
  109. Modeling and simulation of smart magnetic self-assembled nanomicelle trajectories in an internal thoracic artery flow for breast cancer therapy.
  110. Oncocyte Membrane-Camouflaged Multi-Stimuli-Responsive Nanohybrids for Synergistic Amplification of Tumor Oxidative Stresses and Photothermal Enhanced Cancer Therapy.
  111. A toxicological profile of silica nanoparticles.
  112. Proniosome: A Promising Approach for Vesicular Drug Delivery.
  113. Fermented natural product targeting gut microbiota regulate immunity and anti-inflammatory activity: A possible way to prevent COVID-19 in daily diet.
  114. Editorial: Biomedical advances in ultrasound-mediated drug/molecule delivery.
  115. The promising potential of piperlongumine as an emerging therapeutics for cancer.
  116. Addition of Gallic Acid Overcomes Resistance to Cisplatin in Ovarian Cancer Cell Lines.
  117. Potential of histone deacetylase inhibitors in the control and regulation of prostate, breast and ovarian cancer.
  118. Recent insights into oxidative metabolism of quercetin: catabolic profiles, degradation pathways, catalyzing metalloenzymes and molecular mechanisms.
  119. Ultrasound-assisted encapsulation of curcumin and fisetin into Saccharomyces cerevisiae cells: a multistage batch process protocol.
  120. The γ-Glutamylcyclotransferase Inhibitor Pro-GA Induces an Antiproliferative Effect Through the Generation of Mitochondrial Reactive Oxygen Species.
  121. Metformin anticancer: Reverses tumor hypoxia induced by bevacizumab and reduces the expression of cancer stem cell markers CD44/CD117 in human ovarian cancer SKOV3 cells.
  122. Metabolism-Based Molecular Subtyping Endows Effective Ketogenic Therapy in p53-Mutant Colon Cancer.
  123. Oxidative stress and inflammatory response to high dietary fat and carbonated soda intake in male and female Wistar rats.
  124. Gui Shao Tea Extracts Inhibit Gastric Cancer Growth in Vitro and in Vivo and Prolong Survival in Nude Mice.
  125. Anoikis in cancer: The role of lipid signaling.
  126. Lactate Dehydrogenase-Inhibitors Isolated from Ethyl Acetate Extract of Selaginella doederleinii by Using a Rapid Screening Method with Enzyme-Immobilized Magnetic Nanoparticles.
  127. Low-intensity ultrasound: A novel technique for adjuvant treatment of gliomas.
  128. Synergistic enhancement of cell death by triple combination therapy of docetaxel, ultrasound and microbubbles, and radiotherapy on PC3 a prostate cancer cell line.
  129. Functional Excipients and Novel Drug Delivery Scenario in Self-nanoemulsifying Drug Delivery System: A Critical Note.
  130. Therapeutic potential of NR4A1 in cancer: Focus on metabolism.
  131. Enhanced Intracellular Transcytosis of Nanoparticles by Degrading Extracellular Matrix for Deep Tissue Radiotherapy of Pancreatic Adenocarcinoma.
  132. Inhibitory Effects of Vitamin A and Its Derivatives on Cancer Cell Growth Not Mediated by Retinoic Acid Receptors.
  133. Curcumin and vitamin E improve hot flashes, lipid profile, and fasting blood glucose without any detrimental effect on the liver and renal function in postmenopausal women: A triple-blind placebo-controlled clinical trial.
  134. Rational design, synthesis, and pharmacological characterisation of dicarbonyl curcuminoid analogues with improved stability against lung cancer via ROS and ER stress mediated cell apoptosis and pyroptosis.
  135. Editorial: Natural compounds as scaffolds for the discovery of new anti-cancer drugs: Focus on terpenoids and flavonoids.
  136. Formation of biocompatible MgO/cellulose grafted hydrogel for efficient bactericidal and controlled release of doxorubicin.
  137. A concise review of inflammatory biomarkers targeted cancer therapy.
  138. Steviol glycosides affect functional properties and macromolecular expression of breast cancer cells.
  139. A mucoadhesive patch loaded with freeze-dried liposomes for the local treatment of oral tumors.
  140. Current Cannabidiol Safety: A Review.
  141. Surface stabilization determines macrophage uptake, cytotoxicity, and bioactivity of curcumin nanocrystals.
  142. Novel Formulation Approaches Used for the Management of Osteoarthritis: A Recent Review.
  143. The adverse effect of heat stress and potential nutritional interventions.
  144. Ethanolic Leaf Extract of C. angustifolia Instigates ROS Mediated Apoptosis within Glioblastoma C6 Cells.
  145. Dietary acid load and esophageal cancer risk: A case-control study.
  146. Repurposed itraconazole for use in the treatment of malignancies as a promising therapeutic strategy.
  147. Fe3+ opposes the 1,25(OH)2D3-induced calcium transport across intestinal epithelium-like Caco-2 monolayer in the presence or absence of ascorbic acid.
  148. The Potential Role of Naringin and Naringenin as Nutraceuticals against Metabolic Syndrome.
  149. Catechol-chitosan/polyacrylamide hydrogel wound dressing for regulating local inflammation.
  150. Potential anticancer effect of sodium caprate on human gastric cancer cells.
  151. The effect of Green green tea consumption on body mass index, lipoprotein, liver enzymes, and liver cancer: An updated systemic review incorporating a meta-analysis.
  152. Strategies for persistent retention of macromolecules and nanoparticles in the blood circulation.
  153. Versatile use of Carmofur: A comprehensive review of its chemistry and pharmacology.
  154. Development of a novel tocopheryl ester for suppression of lipid accumulation without cytotoxicity by optimization of dicarboxylic ester moiety.
  155. Engineering nano-drug biointerface to overcome biological barriers toward precision drug delivery.
  156. The anti-inflammatory effects of a Mediterranean diet: a review.
  157. An insight into the potential of berberine in animal nutrition: Current knowledge and future perspectives.
  158. The marine natural product, dicitrinone B, induces apoptosis through autophagy blockade in breast cancer.
  159. Does the gut microbiome environment influence response to systemic breast cancer treatment?
  160. An overview of the potential anticancer properties of cardamonin.
  161. Role of solid lipid nanoparticle for the delivery of Lipophilic Drugs and Herbal Medicines in the treatment of pulmonary hypertension.
  162. Role of curcumin in selected head and neck lesions. Limitations on the use of the Hep-2 cell line: A critical review.
  163. Phytochemicals: A potential next generation agent for radioprotection.
  164. Basics of Compounding: Compounding with Microneedle Arrays, Part 1: Introduction and Overview.
  165. Engaging plasticity: Differentiation therapy in solid tumors.
  166. Jasmonates in plant growth and development and elicitation of secondary metabolites: An updated overview.
  167. AMPK: An odyssey of a metabolic regulator, a tumor suppressor, and now a contextual oncogene.
  168. Interface between obesity with dysfunctional metabolism and inflammation, and the triple-negative breast cancer in African American women.
  169. Role of Reactive Oxygen Species in Aging and Age-Related Diseases: A Review.
  1. Biomed Pharmacother. 2022 Aug 29. pii: S0753-3322(22)00914-3. [Epub ahead of print]154 113525
    Folate receptor-mediated delivery of mitoxantrone-loaded solid lipid nanoparticles to breast cancer cells.
    Andreia Granja, Cláudia Nunes, Célia T Sousa, Salette Reis.
      The standard breast cancer therapy still faces major challenges due to non-specific tumor distribution and occurrence of dose-limiting adverse side-effects. Nanomedicine constitutes an appealing approach to improve the therapeutic index of different anti-cancer drugs. Given their biocompatibility, low-cost manufacture and easy surface modification, lipid nanoparticles, such as solid lipid nanoparticles (SLN), have a great potential for drug delivery in cancer therapy. In this work, SLN entrapping the antineoplastic drug Mitoxantrone (Mito) were developed and functionalized with Disteroylphosphatidylethanolamine-poly(ethylene glycol)-folic acid (DSPE-PEG-FA) ligand to improve blood circulation and tumor selectivity and limit the drug systemic side-effects. Nanoparticles presented adequate size and size distribution for intravenous injection and were stable for at least 6 months. Additionally, their hemocompatibility was demonstrated. Moreover, functionalized nanoparticles were able to improve the anti-cancer effect of the free drug, as assessed by the values of IC50 and the apoptotic effects in MCF-7 cells. Moreover, an enhanced cellular internalization of the functionalized SLN was demonstrated by confocal microscopy and flow cytometry studies. Finally, the cellular uptake of the SLN was found to occur via macropinocytosis and clathrin-mediated endocytosis, suggesting the involvement of (folate receptor) (FR)-mediated endocytosis. Overall these findings highlight that the developed SLN are efficient nanocarriers for the selective delivery of Mito to breast cancer cells.
    Keywords:  Active targeting; Cellular uptake pathways; Folate receptor; Folic acid; MCF-7 cells
    DOI:  https://doi.org/10.1016/j.biopha.2022.113525
  2. Anticancer Res. 2022 Sep;42(9): 4247-4258
    Evidence of Potential Plant-derived Compounds With Anticancer Effects on Lung Cancer: Clinical and Molecular Pharmacology Approaches.
    Monruedee Sukprasansap, Pithi Chanvorachote.
      The effects of plant-derived active compounds on cancer cells have been intensively investigated, leading to the possibility of dietary-based cancer prevention regimens and recommendations for patients with cancer. Many studies have revealed that several compounds can attenuate oxidative stress, suppress survival and proliferative signals, and diminish or suppress cancer stem cells (CSCs). These may provide novel lead compounds for drug development and benefit cancer therapy. The important pharmacological shift in anticancer therapy is the transition of drug discovery for cytotoxic drugs toward targeted therapy and more specific therapy like CSC-targeted therapy. Cancer-driven signaling, as well as survival pathways, have become vital targets for targeted therapeutic drug action. Furthermore, in aggressive cancers, such as lung cancer, it was shown that CSCs drive cancer initiation, progression, metastasis, and therapeutic failure. Moreover, plant-derived compounds are found as a component in diet and are considered safe. Here, we review cancer-protective elements found in plants, including phenolic compounds such as curcumin, carotenoids (β-carotene and lycopene), epigallocatechin-3-gallate, ginsenoside Rg3, resveratrol, and sulforaphane, for their possible anticancer, anti-metastasis, and cancer-preventive actions against lung cancer, especially in clinical and molecular pharmacological approaches. This review comprehensively summarizes the anticancer properties, target proteins, and CSC suppression capabilities of these plant-derived compounds that may potentially benefit the development of novel anticancer drugs or dietary recommendations for patients with lung cancer.
    Keywords:  Lung cancer; anticancer; cancer stem cell; plant-derived compounds; review
    DOI:  https://doi.org/10.21873/anticanres.15924
  3. Front Chem. 2022 ;10 969809
    Recent advances in the development of biocompatible nanocarriers and their cancer cell targeting efficiency in photodynamic therapy.
    Sathish Sundar Dhilip Kumar, Heidi Abrahamse.
      In recent years, the role of biocompatible nanocarriers (BNs) and their cancer cell targeting efficiency in photodynamic therapy (PDT) holds potential benefits for cancer treatment. Biocompatible and biodegradable nanoparticles are successfully used as carrier molecules to deliver cancer drugs and photosensitizers due to their material safety in the drug delivery system. Biocompatible nanocarriers are non-toxic and ensure high-level biocompatibility with blood, cells, and physiological conditions. The physicochemical properties of BNs often enable them to modify their surface chemistry, which makes conjugating specific ligands or antibodies to achieve cancer cell targeting drug delivery in PDT. This review article focuses on the various types of BNs used in targeted drug delivery, physicochemical properties, and surface chemistry of BNs in targeted drug delivery, advantages of BNs in drug delivery systems, and the targeting efficiency of BNs on some specific targeting receptors for cancer therapy. Furthermore, the review briefly recaps the nanocarrier-based targeted approaches in cancer PDT.
    Keywords:  cancer; nanocarriers; photodynamic therapy; photosensitizers; surface modification; targeted drug delivery
    DOI:  https://doi.org/10.3389/fchem.2022.969809
  4. Photodiagnosis Photodyn Ther. 2022 Aug 25. pii: S1572-1000(22)00377-5. [Epub ahead of print] 103091
    Investigation of ROS generating capacity of curcumin-loaded liposomes and its in vitro cytotoxicity on MCF-7 cell lines using photodynamic therapy.
    E Venkata Prathyusha, A Prabakaran, Hafiz Ahmed, Mithun Rajendra Dethe, Mukta Agrawal, Vijayakumar Gangipangi, S Sudhagar, Kowthavarapu Venkata Krishna, Sunil Kumar Dubey, Deepak Bharadwaj, Amit Alexander.
      Photodynamic therapy (PDT) is highly efficient in eradicating a specific cell by using potential photosensitizers (PS) triggered by external energy and therefore is a point of attraction to the research fraternity working in cancer research. At the same time, nanotechnology helps increase the solubility and effective delivery of PS towards improving its efficacy. Curcumin (Cur) was used as a natural PS for PDT in the present work. Briefly, curcumin was encapsulated in liposomes (LPs) using the thin film hydration method and optimized using the QbD approach through the Box-Behnken Design (BBD) to optimize the responses like entrapment efficiency and drug loading with a smaller vesicle size. The in vitro release studies performed using a dialysis bag (MWCO 12KDa) suggested a sustained release of the Cur over 72 h in pH 7.4 PBS following the Weibull drug release kinetics. In addition, the ROS generating capabilities upon application of blue light (460 nm) and resulting cytotoxicity were evaluated in MCF-7 cell lines. The Cur-loaded liposome exhibited significant ROS generation and cytotoxicity to the cancer cells than free curcumin. Thus, the Cur-loaded liposomes could be used to treat breast cancer with photodynamic therapy.
    Keywords:  Curcumin; breast cancer; liposomes; photodynamic therapy; photosensitizer
    DOI:  https://doi.org/10.1016/j.pdpdt.2022.103091
  5. Afr Health Sci. 2022 Mar;22(1): 384-394
    Cassia fistula nutrition rich flower tea derived biotic nanoparticles synthesis, characterization and their antioxidant and anti-hyperglycaemic properties.
    Chinnadurai Veeramani, Ahmed S El Newehy, Mohammed A Alsaif, Khalid S Al-Numair.
       Background: Cassia fistula (CF) is a nutrient-rich flowering plant and it has been used to cure numerous human health problems including cardiac diseases, bacterial infection, and inflammation.
    Objective: The purpose of this study was to investigate the production and characterisation of biomimetic iron oxide nanoparticles (ICF) derived from CF flower tea as well as evaluate their antioxidant and anti-hyperglycemic properties.
    Methodology: CF tea derived ICF synthesis and characterized by established physical-chemical methods. Moreover, this synthesized ICF were checked for their antioxidant and anti-hyperglycemic properties such as alpha-amylase, glucose intake, total antioxidant (TAA), ferrous reducing (FA), and radical scavenging (DPPH) properties.
    Results: The synthesized ICF characterization and size were confirmed primarily by described physical and chemical methods. Our findings revealed that ICF have a powerful antihyperglycemic mechanism by involving alpha-amylase inhibition and enhanced glucose absorption. Meanwhile, this ICF exhibited distinguished antioxidant competence by improving TAA and free radical scavenging (TAA, DPPH) properties. Finally, this ICF has proven anti-hyperglycemic and antioxidant mechanisms due to their presence of nano-sized biomolecules.
    Conclusion: In this study, it might be concluded that the CF is the best source for iron oxide nanoparticles production with clarity, small size and high solidity. Moreover, this nanoparticle has proven in vitro anti-hyperglycemic and antioxidant mechanisms.
    Keywords:  Cassia fistula; Nanoparticles; drug delivery; glucose mechanism; iron III chloride
    DOI:  https://doi.org/10.4314/ahs.v22i1.47
  6. Anticancer Agents Med Chem. 2022 Aug 31.
    Molecular mechanisms of Sanguinarine in cancer prevention and treatment.
    Asmat Ullah, Najeeb Ullah, Touseef Nawaz, Tariq Aziz.
      Historically, natural plant-derived drugs received a great impact of consideration in the treatment of several human-associated disorders. Cancer is a devastating disease and the second most cause of mortality. Sanguinarine (SANG), a naturally isolated plant alkaloidal agent, possesses chemo-preventive effects. Several studies have revealed that SANG impedes tumor metastasis and development by disrupting a wide range of cell signaling pathways and its molecular targets such as BCL-2, MAPKs, Akt, NF-κB, ROS, and microRNAs (miRNAs). Although its low chemical stability and poor oral bioavailability continue to be a key issue in its use as a medicinal molecule. A novel method (e.g., liposomes, nanoparticles, and micelles) and alternative analogs provide an exciting approach to alleviate these problems and broaden its pharmacokinetic profile. Cancer-specific miRNAs expression is synchronized by SANG, which has also been uncertain. In this critical study, we review the utilization of SANG mimics and nano-technologies to improve its support in cancer. We focus on recently disclosed studies on SANG anti-cancer properties.
    Keywords:  Cancer; Molecular target; Nanoparticle; Natural agent; Sanguinarine
    DOI:  https://doi.org/10.2174/1871520622666220831124321
  7. Front Bioeng Biotechnol. 2022 ;10 945472
    Fabrication of Ginsenoside-Based Nanodrugs for Enhanced Antitumor Efficacy on Triple-Negative Breast Cancer.
    Shuting Zuo, Jing Wang, Xianquan An, Zhenyu Wang, Xiao Zheng, Yan Zhang.
      There is an urgent need to identify chemotherapeutic agents with improved efficacy and safety against triple-negative breast cancer (TNBC). Ginsenosides can reportedly induce tumor cell death, invasion, and metastasis; however, poor water solubility, low oral absorption rate, and rapid blood clearance limit their clinical application. Utilizing the amphiphilic property of ginsenosides as building blocks of biomaterials, we fabricated a carrier-free nanodrug composed of ginsenosides Rg3 and Rb1 using a nano-reprecipitation method without any additional carriers. After characterizing and demonstrating their uniform morphology and pH-sensitive drug release properties, we observed that Rg3-Rb1 nanoparticles (NPs) exhibited stronger antitumor and anti-invasive effects on TNBCs in vitro than those mediated by free ginsenosides. Consequently, Rg3-Rb1 NPs afforded superior inhibition of tumor growth and reduction of pulmonary metastasis than the Rg3 and Rb1 mixture, with no obvious systematic toxicity in vivo. Collectively, our results provide a proof-of-concept that self-assembled engineered ginsenoside nanodrugs may be efficient and safe for TNBC therapy.
    Keywords:  biomaterial; ginsenoside; nanodrug; self-assembly; triple-negative breast cancer
    DOI:  https://doi.org/10.3389/fbioe.2022.945472
  8. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2022 Aug 30. e1848
    Activated aggregation strategies to construct size-increasing nanoparticles for cancer therapy.
    Zhenni Lu, Dongya Liu, Peng Wei, Tao Yi.
      The development of novel therapeutic strategies and modalities for tumors is still one of the important areas of current scientific research. Low permeability and short residence time of drugs in solid tumor areas are important reasons for the low efficiency of existing therapeutic strategies. Typically, nanoparticles with large size displayed enhanced residence time but low permeability. Therefore, to prolong the retention time of materials in solid tumors, size-increasing strategies have been developed to directly generate large-scale nanoparticles using small molecular compounds or increase the size of small nanoparticles in solid tumor areas. In this review, we summarize recently reported activatable aggregation systems that could be activated by cancer-related substances for cancer therapy and classify them by the mechanisms that lead to aggregation. In the end, we propose some potential challenges briefly from the view of our opinion. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.
    Keywords:  activation strategy; aggregation strategies; cancer therapy; size-increasing nanoparticles
    DOI:  https://doi.org/10.1002/wnan.1848
  9. Curr Pharm Des. 2022 Sep 03.
    RNA Aptamer-Functionalized Polymeric Nanoparticles in Targeted Delivery and Cancer Therapy: An up-to-date Review.
    Karina Marangoni, Regina Menezes.
      Cancer nanotechnology takes advantage of nanoparticles to diagnose and treat cancer. The use of natural and synthetic polymers for drug delivery has become increasingly popular. Polymeric nanoparticles (PNPs) can be loaded with chemotherapeutics, small chemicals, and/or biological therapeutics. Major problems in delivering such therapeutics to the desired targets are associated with the lack of specificity and the low capacity of PNPs to cross cell membranes, which seems to be even more difficult to overcome in multidrug-resistant cancer cells with rigid lipid bilayers. Despite the progress of these nanocarrier delivery systems (NDSs), active targeting approaches to complement the enhanced permeability and retention (EPR) effect are necessary to improve their therapeutic efficiency and to reduce systemic toxicity. For this, a targeting moiety is required to deliver the nanocarrier systems to a specific location. A strategy to overcome these limitations and raise the uptake of PNPs is the conjugation with RNA aptamers (RNApt) with specificity for cancer cells. The site-directed delivery of drugs is made by the functionalization of these specific ligands on the NDSs surface, thereby creating specificity for features of cancer cell membranes or for an overexpressed target/receptor exposed to those cells. Despite the advances in the field, NDSs development and functionalization are still in their early stages and numerous challenges are expected to impact the technology. Thus, RNApt supply a promising reply to the common problem related to drug delivery by NDSs. This review summarizes the current knowledge on the use of RNApt to generate functionalized PNPs for cancer therapy, discussing the most relevant studies in the area.
    Keywords:  Polymeric nanoparticles; RNA aptamers; SELEX.; cancer therapy; drug delivery; nanosystem
    DOI:  https://doi.org/10.2174/1381612828666220903120755
  10. Front Oncol. 2022 ;12 864444
    Folate-modified erythrocyte membrane nanoparticles loaded with Fe3O4 and artemisinin enhance ferroptosis of tumors by low-intensity focused ultrasound.
    Xingyue Wang, Peng Li, Xiangxiang Jing, Yun Zhou, Yongfu Shao, Min Zheng, Junrui Wang, Haitao Ran, Hailin Tang.
      To overcome the challenges of the low efficiency of artemisinin (ART) in anticancer therapy due to its poor water solubility and poor bioavailability, we constructed folate (FA)-modified erythrocyte membrane (EM)-camouflaged poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) (PFH/ART@PLGA/Fe3O4-eFA). Specifically, the inner core of these NPs is mainly composed of phase-changeable perfluorohexane (PFH), magnetic Fe3O4 and ART. In vitro experiments showed that the prepared PFH/ART@PLGA/Fe3O4-eFA was readily taken up by 4T1 cancer cells. PFH/ART@PLGA/Fe3O4-eFA was exposed to low-intensity focused ultrasound (LIFU) irradiation to induce PFH phase transition and NPs collapse, which promoted the release of ART and Fe3O4. After LIFU irradiation, the proportion of dead 4T1 cells, the level of reactive oxygen species (ROS) and the concentration of intracellular Fe2+ ions in the PFH/ART@PLGA/Fe3O4-eFA group were much higher than those in the other group, indicating that the synergistic effect between the intracellular Fe2+ ions and the released ART played a critical role in tumor cell ferroptosis by enhancing ROS generation in vitro. We demonstrated that FA-modified EM NPs could enhance the targeting and accumulation of the NPs at the tumor site in vivo. After LIFU irradiation at 3 W/m2 for 7 min, tumor growth was completely suppressed through FA-modified EM NPs collapse and the release of ART and Fe3O4, which exerted synergistic effects in inducing tumor ferroptosis. Because of these characteristics, these NPs are considered as a promising approach for the delivery of drugs with poor water solubility for efficient cancer therapy.
    Keywords:  artemisinin; cell membrane biomimetic; controlled drug release; ferroptosis; low-intensity focused ultrasound
    DOI:  https://doi.org/10.3389/fonc.2022.864444
  11. Crit Rev Oncol Hematol. 2022 Aug 29. pii: S1040-8428(22)00220-7. [Epub ahead of print] 103796
    Cellular reprogramming, chemoresistance, and dietary interventions in breast cancer.
    Irislene Costa Pereira, Isabele Frazão Mascarenhas, Vinícius Cooper Capetini, Paulo Michel Pinheiro Ferreira, Marcelo Macedo Rogero, Francisco Leonardo Torres-Leal.
      Breast cancer (BC) diagnosis has been associated with significant risk factors, including family history, late menopause, obesity, poor eating habits, and alcoholism. Despite the advances in the last decades regarding cancer treatment, some obstacles still hinder the effectiveness of therapy. For example, chemotherapy resistance is common in locally advanced or metastatic cancer, reducing treatment options and contributing to mortality. In this review, we provide an overview of BC metabolic changes, including the impact of restrictive diets associated with chemoresistance, the therapeutic potential of the diet on tumor progression, pathways related to metabolic health in oncology, and perspectives on the future in the area of oncological nutrition.
    Keywords:  Breast neoplasm; caloric restriction; chemotherapy; drug resistance; fasting
    DOI:  https://doi.org/10.1016/j.critrevonc.2022.103796
  12. J Immunother Precis Oncol. 2022 Aug;5(3): 68-78
    Targeting KRAS: Crossroads of Signaling and Immune Inhibition.
    Shumei Kato, Yu Fujiwara, David S Hong.
      Mutations of RAS are commonly seen in human cancers, especially in lung, colorectal, and pancreatic adenocarcinoma. Despite huge effort for decades, targeting RAS mutations has been "undruggable" because of the molecular instability of RAS protein inhibition. However, the recent discovery of the KRAS G12C inhibitor paved the way to expand therapeutic options for patients with cancer harboring the KRAS G12C mutation. At the same time, the successful development of immune checkpoint inhibitors (ICIs) drastically changed the paradigm of cancer treatment and resulted in a better understanding of the tumor immune microenvironment in patients with KRAS-mutant cancer. This review describes the following: the clinical characteristics of cancer with KRAS mutation; successful development of the KRAS G12C inhibitor and its impact on the tumor immune microenvironment; and potential new avenues such as the combination strategy using KRAS inhibitor and ICI, with preclinical and clinical rationales for overcoming resistance to inhibition of KRAS to improve therapeutic efficacy for patients with cancer harboring KRAS mutations.
    Keywords:  KRAS G12C inhibitor; KRAS mutation; immune checkpoint inhibitor; tumor immune microenvironment
    DOI:  https://doi.org/10.36401/JIPO-22-5
  13. Acta Biomater. 2022 Aug 25. pii: S1742-7061(22)00521-9. [Epub ahead of print]
    Carrier free nanomedicine to reverse anti-apoptosis and elevate endoplasmic reticulum stress for enhanced photodynamic therapy.
    Xiang Zhou, Yanmei Li, Xinyu Li, Jiaqi Huang, Renjiang Kong, Lingshan Liu, Hong Cheng.
      As a first studied and generally accepted programmed cell death regulator, Bcl-2 has been identified to overexpress in many types of cancer promoting tumor proliferation and progression. Herein, inspired by drug self-delivery systems, a self-assembled nanomedicine (designated as GosCe) was designed based on the hydrophobic interaction between chlorin e6 (Ce6) and gossypol (Gos). Without extra carriers, GosCe exhibited high drug loading rates, favorable size distribution, and a long-term stability at aqueous phase. More importantly, GosCe could be internalized by tumor cells more effectively than free Ce6, which brought about its multiple toxicity. Upon intravenous injection, GosCe preferred to accumulate in tumor site through enhanced permeability and retention (EPR) effect. After cellular internalization, Gos contributed to increasing the lethality of Ce6-guided photodynamic therapy (PDT) by down-regulating Bcl-2 protein expression and inducing endoplasmic reticulum (ER) stress. Both in vitro and in vivo investigations indicated that the Gos-assisted PDT greatly inhibit cell proliferation and tumor growth. This study might shed light on developing carrier free nanomedicine for PDT-based synergistic tumor therapy. STATEMENT OF SIGNIFICANCE: Metabolic abnormalities of tumor cells create defensive microenvironments which induce a therapeutic resistance against photodynamic therapy (PDT). Among which, the upregulated B-cell lymphoma (Bcl-2) in tumors could inhibit the PDT-induced cell apoptosis. In this work, a self-delivery nanomedicine (GosCe) was developed based on a Bcl-2 inhibitor and photosensitizer through intermolecular interactions, which had favorable size distribution, high drug contents and improved drug delivery efficiency. Importantly, GosCe increased the PDT efficacy by Bcl-2 inhibition and endoplasmic reticulum stress elevation. Thus, GosCe greatly inhibited the tumor growth while caused a reduced side effect in vivo. This carrier free nanomedicine with tumor microenvironment regulation would advance the development of photodynamic nanoplatform in tumor treatment.
    Keywords:  Anti-apoptosis; Carrier free; Endoplasmic reticulum stress; Nanomedicine; Photodynamic therapy
    DOI:  https://doi.org/10.1016/j.actbio.2022.08.045
  14. Front Bioeng Biotechnol. 2022 ;10 917368
    Multifunctional PEGylated Niosomal Nanoparticle-Loaded Herbal Drugs as a Novel Nano-Radiosensitizer and Stimuli-Sensitive Nanocarrier for Synergistic Cancer Therapy.
    Saeid Afereydoon, Fateme Haghiralsadat, Nima Hamzian, Ali Shams, Mahdie Hemati, Seyed Morteza Naghib, Masoud Shabani, Behrouz Zandieh-Doulabi, Davood Tofighi.
      Nowadays, radiotherapy is one of the most effective treatments for breast cancer. In order to overcome the radioresistance of cancer cells, radio-sensitizing agents can be used combined with irradiation to increase the therapeutic efficiency. Curcumin can enhance the radiosensitivity of cancer cells and decrease their viability by the accumulation of these cells in the G2 phase. The encapsulation of curcumin in a nanoniosomal delivery system increases aqueous solubility and bioavailability, resulting in increased radio sensitivity. The present study aimed to enhance the radio-sensitizing effect of the curcumin-containing nanoniosome (Cur-Nio) when combined with irradiation. Thus, curcumin (0.5 mg ml-1) was loaded on a PEGylated nanoniosome containing Tween 60, cholesterol, DOTAP, and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene glycol) (DSPE-PEG) (at ratios of 70:30:10:5, respectively) by the thin-film hydration method. The particle size, zeta potential, entrapment efficiency, and drug-release rate of formulated nanoniosomes were determined. In order to assess cytotoxicity and apoptosis, different doses of irradiation along with various concentrations of free curcumin and Cur-Nio (single or in combination with irradiation) were treated with breast cancer cells. The particle size and zeta potential of Cur-Nio were reported to be 117.5 nm and -15.1 mV, respectively. The entrapment efficiency (EE%) and loading capacities were 72.3% and 6.68%, respectively. The drug-release rate during 6 h was 65.9%. Cell survival in the presence of curcumin at doses of 1 and 3 Gy showed a significant reduction compared with cells irradiated at 48 h and 72 h (p < 0.000). Also, the rate of cytotoxicity and apoptosis was significantly higher in cells treated with the combination of curcumin-containing nanoniosomes and irradiation in comparison with those treated with free curcumin. These findings indicate that the efficacy of pre-treatment with Cur-Nio as a radiosensitizer during radiotherapy enhances irradiation-induced breast cancer cell apoptosis and is a useful strategy to increase the effectiveness of breast cancer therapy.
    Keywords:  breast cancer; curcumin; irradiation; niosome nanoparticles; radiosensitizing
    DOI:  https://doi.org/10.3389/fbioe.2022.917368
  15. Curr Gene Ther. 2022 Aug 30.
    The Role of RNA m6A Modification in Cancer Glycolytic Reprogrammingc.
    Yuanqi Li, Hao Huang, Shaoxian Wu, You Zhou, Tao Huang, Jingting Jiang.
      As one of the main characteristics of neoplasia, metabolic reprogramming provides nutrition and energy to enhance cell proliferation and maintain environment homeostasis. Glycolysis is one of the most important components of cancer metabolism and Warburg effect contributes to the competitive advantages of cancer cells in the threatened microenvironment. Studies show strong links between N6-methyladenosine (m6A) modification and metabolic recombination of cancer cells. As the most abundant modification in eukaryotic RNA, m6A methylation plays important roles in regulating RNA processing including splicing, stability, transportation, translation and degradation. The aberration of m6A modification can be observed in a variety of diseases such as diabetes, neurological diseases and cancers. This review describes the mechanisms of m6A on cancer glycolysis and their applications in cancer therapy and prognosis evaluation, aiming to emphasize the importance of targeting m6A on modulating cancer metabolism.
    Keywords:  Cancer; Glycolysis; N6-methyladenosine; RNA modification
    DOI:  https://doi.org/10.2174/1566523222666220830150446
  16. J Nutr Biochem. 2022 Aug 29. pii: S0955-2863(22)00215-7. [Epub ahead of print] 109147
    Crosstalk between xanthine oxidase (XO) inhibiting and cancer chemotherapeutic properties of comestible flavonoids- a comprehensive update.
    Md Sohanur Rahaman, Md Afjalus Siraj, Md Arman Islam, Prayas Chakma Shanto, Ordha Islam, Md Amirul Islam, Jesus Simal-Gandara.
      Gout is an inflammatory disease caused by metabolic disorder or genetic inheritance. People throughout the world are strongly dependent on ethnomedicine for the treatment of gout and some receive satisfactory curative treatment. The natural remedies as well as established drugs derived from natural sources or synthetically made exert their action by mechanisms that are closely associated with anticancer treatment mechanisms regarding inhibition of xanthine oxidase (XO), feedback inhibition of de novo purine synthesis, depolymerization and disappearance of microtubule, inhibition of NF-ĸB activation, induction of TRAIL, promotion of apoptosis, and caspase activation and proteasome inhibition. Some anti-gout and anticancer novel compounds interact with same receptors for their action e.g., colchicine and colchicine analogues. Dietary flavonoids i.e. chrysin, kaempferol, quercetin, fisetin, pelargonidin, apigenin, luteolin, myricetin, isorhamnetin, phloretinetc etc. have comparable IC50 values with established anti-gout drug and effective against both cancer and gout. Moreover, a noticeable number of newer anticancer compounds have already been isolated from plants that have been using by local traditional healers and herbal practitioners to treat gout. Therefore, the anti-gout plants might have greater potentiality to become selective candidate for screening of newer anticancer leads.
    Keywords:  Xanthine oxidase; and chemotherapeutic; anti-gout; anticancer; flavonoids
    DOI:  https://doi.org/10.1016/j.jnutbio.2022.109147
  17. Biomed Pharmacother. 2022 Aug 26. pii: S0753-3322(22)00999-4. [Epub ahead of print]154 113610
    Natural products as chemo-radiation therapy sensitizers in cancers.
    Sabah Nisar, Tariq Masoodi, Kirti S Prabhu, Shilpa Kuttikrishnan, Lubna Zarif, Summaiya Khatoon, Shahid Ali, Shahab Uddin, Ammira Al-Shabeeb Akil, Mayank Singh, Muzafar A Macha, Ajaz A Bhat.
      Cancer is a devastating disease and is the second leading cause of death worldwide. Surgery, chemotherapy (CT), and/or radiation therapy (RT) are the treatment of choice for most advanced tumors. Unfortunately, treatment failure due to intrinsic and acquired resistance to the current CT and RT is a significant challenge associated with poor patient prognosis. There is an urgent need to develop and identify agents that can sensitize tumor cells to chemo-radiation therapy (CRT) with minimal cytotoxicity to the healthy tissues. While many recent studies have identified the underlying molecular mechanisms and therapeutic targets for CRT failure, using small molecule inhibitors to chemo/radio sensitize tumors is associated with high toxicity and increased morbidity. Natural products have long been used as chemopreventive agents in many cancers. Combining many of these compounds with the standard chemotherapeutic agents or with RT has shown synergistic effects on cancer cell death and overall improvement in patient survival. Based on the available data, there is strong evidence that natural products have a robust therapeutic potential along with CRT and their well-known chemopreventive effects in many solid tumors. This review article reports updated literature on different natural products used as CT or RT sensitizers in many solid tumors. This is the first review discussing CT and RT sensitizers together in cancer.
    Keywords:  Anti-Inflammatory; Apoptosis; Cancer; Chemotherapy; Cytotoxicity; Immunosuppression; Natural product; Radiotherapy
    DOI:  https://doi.org/10.1016/j.biopha.2022.113610
  18. J Photochem Photobiol B. 2022 Aug 20. pii: S1011-1344(22)00160-9. [Epub ahead of print]234 112546
    Secure transplantation by tissue purging using photodynamic therapy to eradicate malignant cells.
    Saeid Moghassemi, Arezoo Dadashzadeh, Ricardo Bentes de Azevedo, Christiani A Amorim.
      The field of photodynamic therapy (PDT) for treating various malignant neoplasms has been given researchers' attention due to its ability to be a selective and minimally invasive cancer therapy strategy. The possibility of tumor cell infection and hence high recurrence rates in cancer patients tends to restrict autologous transplantation. So, the photodynamic tissue purging process, which consists of selective photoinactivation of the malignant cells in the graft, is defined as a compromising strategy to purify contaminated tissues before transplantation. In this strategy, the direct malignant cells' death results from the reactive oxygen species (ROS) generation through the activation of a photosensitizer (PS) by light exposure in the presence of oxygen. Since new PS generations can effectively penetrate the tissue, PDT could be an ideal ex vivo tissue purging protocol that eradicates cancer cells derived from various malignancies. The challenge is that the applied pharmacologic ex vivo tissue purging should efficiently induce tumor cells with minor influence on normal tissue cells. This review aims to provide an overview of the current status of the most effective PDT strategies and PS development concerning their potential application in ex vivo purging before hematopoietic stem cell or ovarian tissue transplantation.
    Keywords:  Cancer therapy; Nanomedicine; Photodynamic therapy; Photosensitizer; Tissue purging
    DOI:  https://doi.org/10.1016/j.jphotobiol.2022.112546
  19. J Mater Chem B. 2022 Aug 31.
    Nanotechnology-integrated ferroptosis inducers: a sharp sword against tumor drug resistance.
    Chaoqun Li, Xiaodong Wu, Caihong Zheng, Shanshan Xu, Yunxi Liu, Jiale Qin, Xiaoyu Fan, Yiqing Ye, Weidong Fei.
      Presently, the biggest hurdle to cancer therapy is the inevitable emergence of drug resistance. Since conventional therapeutic schedules fall short of the expectations in curbing drug resistance, the development of novel drug resistance management strategies is critical. Extensive research over the last decade has revealed that the process of ferroptosis is correlated with cancer resistance; moreover, it has been demonstrated that ferroptosis inducers reverse drug resistance. To elucidate the development and promote the clinical transformation of ferroptosis strategies in cancer therapy, we first analyzed the roles of key ferroptosis-regulating molecules in the progression of drug resistance in-depth and then reviewed the design of ferroptosis-inducing strategies based on nanotechnology for overcoming drug resistance, including glutathione depletion, reactive oxygen species generation, iron donation, lipid peroxidation aggregation, and multiple-drug resistance-associated tumor cell destruction. Finally, the prospects and challenges of regulating ferroptosis as a therapeutic strategy for reversing cancer therapy resistance were evaluated. This review aimed to provide a comprehensive understanding for researchers to develop ferroptosis-inducing nanoplatforms that can overcome drug resistance.
    DOI:  https://doi.org/10.1039/d2tb01350a
  20. Comb Chem High Throughput Screen. 2022 Aug 31.
    The Roles and Regulation of Ferroptosis in Cancer progression.
    Yu Yang, Te Ma, Ting Hu, Chengcheng Ma, Huiqing Tu, Shunqin Zhu.
      Ferroptosis is an iron-dependent, nonapoptotic form of regulatory death, and has received extensive attention. Fenton reactions related to iron metabolism release high levels of Reactive oxygen species (ROS), and the intracellular ROS content is closely related to a variety of diseases; the iron ion concentration in many diseased cells is also disordered. In this paper, the advances in ferroptosis research are summarized, and the regulatory mechanisms of ferroptosis, including inducers and regulatory protein of ferroptosis in cancer progression. We expect that this study will be beneficial to the further development of basic research and clinical application of ferroptosis for cancer treatment.
    Keywords:  GPX4; ROS; cancer progression ; ferroptosis; system Xc-
    DOI:  https://doi.org/10.2174/1386207325666220831151036
  21. Food Funct. 2022 Sep 01.
    Potential roles and molecular mechanisms of phytochemicals against cancer.
    Zhaodi Zheng, Leilei Zhang, Xitan Hou.
      Increasing evidence has been reported regarding phytochemicals, plant secondary metabolites, having therapeutic functions against numerous human diseases. Recently, phytochemicals (flavonoids, polyphenols, terpenoids, alkaloids, saponins, coumarins and so on) have shown promising anti-cancer efficacy with their distinct advantages of high efficiency and low toxicity. They regulate programmed cell death (apoptosis, pyroptosis, and autophagy), migration and senescence-related signaling pathways of cancer via the modulation of reactive oxygen species (ROS), mitogen activated protein kinase (MAPK) pathway, deleted in liver cancer 1 (DLC1), nuclear factor κ light-chain-enhancer of activated B cell (NF-κB) pathways and glycolytic enzymes. Here, we review the molecular mechanisms by which phytochemicals prevent the development of cancer. Furthermore, phytochemicals combined with chemotherapeutic agents could target the crosstalk among multiple signal cascades to block chemoresistance and attenuate carcinogenic properties, and can be considered as a novel and potential therapeutic strategy. Our review highlights that the mechanisms and promising applications are required to be understood to decisively establish the anti-cancer efficacy of natural phytochemicals.
    DOI:  https://doi.org/10.1039/d2fo01663j
  22. Biomater Sci. 2022 Sep 02.
    Injectable thermosensitive hydrogel to enhance the photothermal ablation and systemic immunotherapy of breast tumors.
    Tao Qin, Ruipeng Li, Huiqin Jin, Yunxia Wang, Liheng Feng.
      As the high-frequency tumor in women around the world, breast cancer has high mortality due to metastasis tumors making it difficult to cure. Herein, we report a near-infrared (NIR) activated bio-multifunctional thermosensitive hydrogel (denoted as AMDR) with powerful cell killing and immunogenicity amplifying ability. Based on the molecular engineering strategy, a photothermal agent (M-4) with 52.4% conversion efficiency was synthesized. Accordingly, the designed injectable thermosensitive hydrogel AMDR is simply fabricated by the employment of the M-4 photothermal agent, doxorubicin hydrochloride (DOX) as the antitumor drug, and imiquimod (R837) as the immunologic adjuvant by self-assembly. Under NIR irradiation, the AMDR hydrogel can generate local mild heat to release DOX for synergistic killing of tumor cells with little damage to normal cells. The immunogenic cell death induced by potent in situ killing combined with heat-released R837 can trigger robust immune response to inhibit and kill metastasis tumors. The developed AMDR hydrogel is successfully applied in the treatment of primary tumors and inhibition of distal tumors of tumor-bearing mice. The study provides a novel strategy and platform for complete treatment of breast cancer and also offers ideas for designing high-efficiency photothermal agents.
    DOI:  https://doi.org/10.1039/d2bm01037b
  23. Pharm Nanotechnol. 2022 Sep 02.
    Amalgamation of Nanoparticles within Drug Carriers: A Synergistic Approach or a Futile Attempt?
    Nikhil Mehta, Rohan Pai.
      In recent years, nanotechnology has gained much attention from scientists and significant advances in therapeutic potential. Nano-delivery systems have emerged as an effective way in order to improve the therapeutic properties of drugs including solubility, stability, prolongation of half-life as well as promoting the accumulation of drug at the target site. The nanoparticles have also been incorporated into various conventional drug delivery systems. This review study aims to introduce the amalgamation of nanoparticles into drug carriers. To overcome the limitations of single nanoparticles such as toxicity, high instability, rapid drug release as well as limited drug loading capacity, a multi-component system is developed. Liposomes, microparticles, nanofibers, dendrimers etc., are promising drug carriers, having some limitations that can be minimized, and the compilation of nanoparticles synergizes the properties. The amalgamated nanocarriers are used for the diagnostic purpose as well as treatment of various chronic diseases. It also increases the solubility of hydrophobic drugs. However, each system has its advantages and disadvantages based on its physicochemical properties, efficacy, and other parameters. This review details the past and present state of development for the fusion of nanoparticles within drug carriers and from which we identify future research works needed for the same.
    Keywords:  amalgamated; drug carriers; fusion; multi-component; nanoparticles; nanotechnology.
    DOI:  https://doi.org/10.2174/2211738510666220902150449
  24. Nanoscale. 2022 Sep 03.
    Advances in nanobiotechnology-propelled multidrug resistance circumvention of cancer.
    Jie Chen, Xin Yu, Xinyu Liu, Jinliang Ni, Guangcan Yang, Kun Zhang.
      Multidrug resistance (MDR) is one of the main reasons for the failure of tumor chemotherapy and has a negative influence on the therapeutic effect. MDR is primarily attributable to two mechanisms: the activation of efflux pumps for drugs, which can transport intracellular drug molecules from cells, and other mechanisms not related to efflux pumps, e.g., apoptosis prevention, strengthened DNA repair, and strong oxidation resistance. Nanodrug-delivery systems have recently attracted much attention, showing some unparalleled advantages such as drug targeting and reduced drug efflux, drug toxicity and side effects in reversing MDR. Notably, in drug-delivery platforms based on nanotechnology, multiple therapeutic strategies are integrated into one system, which can compensate for the limitations of individual strategies. In this review, the mechanisms of tumor MDR as well as common vectors and nanocarrier-combined therapy strategies to reverse MDR were summarized to promote the understanding of the latest progress in improving the efficiency of chemotherapy and synergistic strategies. In particular, the adoption of nanotechnology has been highlighted and the principles underlying this phenomenon have been elucidated, which may provide guidance for the development of more effective anticancer strategies.
    DOI:  https://doi.org/10.1039/d2nr04418h
  25. J Biophotonics. 2022 Sep 01. e202200119
    Fine-tuning the encapsulation of a photosensitizer in nanoparticles reveals the relationship between internal structure and phototherapeutic effects.
    Fumika Kubota, Satrialdi, Yuta Takano, Masatoshi Maeki, Manabu Tokeshi, Hideyoshi Harashima, Yuma Yamada.
      Photodynamic therapy (PDT) is a cancer therapy that uses a photosensitizer (PS) in the presence of oxygen molecules. Since singlet oxygen is highly reactive, it is important to deliver it to the target site. Thus, an efficient drug delivery system (DDS) is essential for enhancing the efficacy of such a treatment and protecting against the side effects of PDT. Here, we report on attempts to increase the therapeutic effect of PDT by using a DDS, a lipid nanoparticle (LNP). We prepared a porphyrin analog, rTPA (PS) that was encapsulated in LNPs using a microfluidic device. The findings indicated that the internal structure of the prepared particles changed depending on the amount of rTPA in LNPs. The photoactivity and cell-killing effect of PS in LNPs also changed when the amount of the cargo increased. These results suggest that the internal structure of LNPs is important factors that affect drug efficacy. This article is protected by copyright. All rights reserved.
    Keywords:  microfluidic device; mitochondria; nanocarrier; photodynamic therapy
    DOI:  https://doi.org/10.1002/jbio.202200119
  26. Front Oncol. 2022 ;12 916082
    The crosstalk effect between ferrous and other ions metabolism in ferroptosis for therapy of cancer.
    Kun Ke, Li Li, Chao Lu, Qicong Zhu, Yuanyu Wang, Yiping Mou, Huiju Wang, Weiwei Jin.
      Ferroptosis is an iron-dependent cell death process characterized by excessive accumulation of reactive oxygen species and lipid peroxidation. The elucidation of ferroptosis pathways may lead to novel cancer therapies. Current evidence suggests that the mechanism of ferroptosis can be summarized as oxidative stress and antioxidant defense mechanisms. During this process, ferrous ions play a crucial role in cellular oxidation, plasma membrane damage, reactive oxygen species removal imbalance and lipid peroxidation. Although, disregulation of intracellular cations (Fe2+, Ca2+, Zn2+, etc.) and anions (Cl-, etc.) have been widely reported to be involved in ferroptosis, their specific regulatory mechanisms have not been established. To further understand the crosstalk effect between ferrous and other ions in ferroptosis, we reviewed the ferroptosis process from the perspective of ions metabolism. In addition, the role of ferrous and other ions in tumor therapy is briefly summarized.
    Keywords:  cancer therapy; ferroptosis; glutathione metabolism; ion metabolism; lipid peroxidation
    DOI:  https://doi.org/10.3389/fonc.2022.916082
  27. Nutr Hosp. 2022 Sep 01. 39(Spec No3): 30-34
    [Impact of vitamin D on health. Difficulties and strategies to reach the recommended intakes].
    Ana M López-Sobaler, Mar Larrosa, María Dolores Salas-González, Ana María Lorenzo-Mora, Viviana Loria-Kohen, Aránzazu Aparicio.
       Introduction: Vitamin D is a key nutrient for health. Recent research has shown that it is not only necessary for the maintenance of bone health, but also for the prevention of cardiovascular diseases, insulin resistance, respiratory diseases, infections, and cancer, among others. Solar synthesis of vitamin D is usually insufficient, so it is necessary to provide enough vitamin D through the diet in order to maintain an adequate nutritional status. Studies carried out in Spain and other countries have shown that serum levels of the vitamin were usually insufficient and that average dietary intakes were well below those marked as recommended, while the main food sources of vitamin D were fatty fish, breakfast cereals, eggs, and dairy. Food sources of vitamin D are scarce, and it is naturally located in the fatty part of foods of animal origin, and in the liver and viscera. Fortifying foods that are not natural food sources of vitamin D but are regularly consumed by a significant percentage of the population, is a strategy that could help to increase vitamin D intake. In this regard, dairy products and breakfast cereals are two of the most widely used food matrices for vitamin D fortification, and their incorporation into the usual diet has proven to be an effective strategy to improve the nutritional situation of the population in vitamin D.
    Keywords:  Vitamina D. Lácteos. Fortificación.
    DOI:  https://doi.org/10.20960/nh.04307
  28. J Pharm Bioallied Sci. 2022 Apr-Jun;14(2):14(2): 57-71
    Natural Radioprotectors on Current and Future Perspectives: A Mini-Review.
    Pooja Shivappa, Grisilda Vidya Bernhardt.
      Radiation therapy is used as the primary treatment for cancer. Eighty percent of cancer patients require radiation therapy during treatment or for medical purposes. During treatment, radiation causes various biological defects in the cells. The prevalence of cytotoxicity limits the dose used for effective treatment. This method is designed to strike a balance between removing cancer cells and protecting normal tissues. Unfortunately, effective radiation is unavailable once acute toxicity occurs during clinical radiation therapy. Therefore, a lot of research interest is needed in the discovery of radioprotective drugs to accelerate treatment to reduce this toxicity (i.e., normal tissue toxicity to cancer cell death). Radiation protectors may be chemicals or drugs that minimize the damage caused due to radiation therapy in living organisms. The determination of effective and nontoxic radiation protection is an essential goal for radiation oncologists and basic radiobiologists. However, despite the advantages, many radioprotectors were found to have disadvantages which include cost, less duration, toxicity, and effect on the central nervous system. Therefore in recent years, the focus has been diverted to finding out optimal natural products to act as radioprotectors. Natural radiation protectors are plant compounds that protect normal (noncancerous) cells from damage from radiation therapy. Natural herbal products are nontoxic with proven therapeutic benefits and have long been used to treat various diseases. In conclusion, we find that there are various radiation protectors with different purposes and mechanisms of action.
    Keywords:  DNA damage; radiation; radioprotectors
    DOI:  https://doi.org/10.4103/jpbs.jpbs_502_21
  29. Front Pharmacol. 2022 ;13 961725
    The crosstalk between sonodynamic therapy and autophagy in cancer.
    Yujie Zhang, Yuanru Zhao, Yuanyuan Zhang, Qingguang Liu, Mingzhen Zhang, Kangsheng Tu.
      As a noninvasive treatment approach for cancer and other diseases, sonodynamic therapy (SDT) has attracted extensive attention due to the deep penetration of ultrasound, good focusing, and selective irradiation sites. However, intrinsic limitations of traditional sonosensitizers hinder the widespread application of SDT. With the development of nanotechnology, nanoparticles as sonosensitizers or as a vehicle to deliver sonosensitizers have been designed and used to target tissues or tumor cells with high specificity and accuracy. Autophagy is a common metabolic alteration in both normal cells and tumor cells. When autophagy happens, a double-membrane autophagosome with sequestrated intracellular components is delivered and fused with lysosomes for degradation. Recycling these cell materials can promote survival under a variety of stress conditions. Numerous studies have revealed that both apoptosis and autophagy occur after SDT. This review summarizes recent progress in autophagy activation by SDT through multiple mechanisms in tumor therapies, drug resistance, and lipid catabolism. A promising tumor therapy, which combines SDT with autophagy inhibition using a nanoparticle delivering system, is presented and investigated.
    Keywords:  autophagy; cancer; nanoparticles; sonodynamic therapy (SDT); sonosensitizers
    DOI:  https://doi.org/10.3389/fphar.2022.961725
  30. Adv Healthc Mater. 2022 Sep 01. e2201233
    Immunomodulatory-Photodynamic Nano-Stimulators for Invoking Pyroptosis to Augment Tumor Immunotherapy.
    Wei Qiu, Wen Su, Jiming Xu, Mengyun Liang, Xianbin Ma, Peng Xue, Yuejun Kang, Zhi-Jun Sun, Zhigang Xu.
      Cancer immunotherapy is restricted to immune resistance caused by immunosuppressive tumor microenvironment. Pyroptosis involved in antitumor immunotherapy as a novel therapeutic schedule is prospective to reverse immunosuppression. Herein, acidic tumor micro-environment (TME) evoked MRC nanoparticles (MRC NPs) co-delivering immune agonist RGX-104 and photosensitizer chlorine e6 (Ce6) is reported for pyroptosis-mediated precise immunotherapy. RGX-104 remodels TME by transcriptional activation of ApoE to regress myeloid-derived suppressor cells (MDSCs) activity, which fitly creates foreshadowing for intensifying pyroptosis. Considering Ce6-triggered photodynamic therapy (PDT) can strengthen oxidative stress and organelles destruction to increase immunogenicity, immunomodulatory-photodynamic MRC nanodrugs will implement aforesaid two-pronged strategy to synergistically enhance gasdermin E (GSDME)-dependent pyroptosis. RNA-seq analysis of MRC at the cellular level is introduced to first elucidate the intimate relationship between RGX-104 acting on LXR/ApoE axis and pyroptosis, where RGX-104 provides the prerequisite for pyroptosis participating in antitumor therapy. Briefly, MRC with favorable biocompatibility tackles the obstacle of hydrophobic drugs delivery, and becomes a powerful pyroptosis inducer to reinforce immune efficacy. MRC-elicited pyroptosis in combination with anti-PD-1 blockade therapy boosts immune response in solid tumors, successfully arresting invasive metastasis and extending survival based on its remarkable antitumor immunity. MRC may initiate a new window for immuno-photo pyroptosis stimulators augmenting pyroptosis-based immunotherapy. This article is protected by copyright. All rights reserved.
    Keywords:  Nano immunotherapy; RGX-104; photodynamic therapy; pyroptosis; transcriptome analysis
    DOI:  https://doi.org/10.1002/adhm.202201233
  31. Front Chem. 2022 ;10 973666
    Poly lactic-co-glycolic acid-based nanoparticles as delivery systems for enhanced cancer immunotherapy.
    Lei Gao, Jing Li, Tianhang Song.
      Cancer has emerged as one of the most severe diseases in modern times, various therapies have advanced remarkably in recent decades. Unlike the direct therapeutic targeting tumor cells, immunotherapy is a promising strategy that stimulate the immune system. In cancer immunotherapy, polymeric-based nanoparticles can serve as deliver systems for antigens and immunostimulatory molecules, and they have attracted increasing attention and revolutionized cancer therapy. Poly (lactic-co-glycolic acid) (PLGA) is the most frequently used clinically approved biodegradable polymer and has a broad scope of modification of its inherent properties. Recent advances in PLGA based drug delivery systems in cancer immunotherapy have been described in this mini review, with special emphasis on cancer vaccines and tumor microenvironment modulation.
    Keywords:  PLGA; adjuvants; antigens; cancer; drug delivery; immunotherapy; nanoparticles
    DOI:  https://doi.org/10.3389/fchem.2022.973666
  32. Adv Sci (Weinh). 2022 Aug 28. e2203292
    Tumor Microenvironment Stimuli-Responsive Single-NIR-Laser Activated Synergistic Phototherapy for Hypoxic Cancer by Perylene Functionalized Dual-Targeted Upconversion Nanoparticles.
    Xiuna Jia, Deming Liu, Cong Yu, Niu Niu, Dan Li, Jin Wang, Erkang Wang.
      Although synergistic therapy has shown great promise for effective treatment of cancer, the unsatisfactory therapeutic efficacy of photothermal therapy/photodynamic therapy is resulted from the absorption wavelength mismatch, tumor hypoxia, photosensitizer leakage, and inability in intelligent on-demand activation. Herein, based on the characteristics of tumor microenvironment (TME), such as the slight acidity, hypoxia, and overexpression of H2 O2 , a TME stimuli-responsive and dual-targeted composite nanoplatform (UCTTD-PC4) is strategically explored by coating a tannic acid (TA)/Fe3+ nanofilm with good biocompatibility onto the upconversion nanoparticles in an ultrafast, green and simple way. The pH-responsive feature of UCTTD-PC4 remains stable during the blood circulation, while rapidly releases Fe3+ in the slightly acidic tumor cells, which results in catalyzing H2 O2 to produce O2 and overcoming the tumor hypoxia. Notably, the emission spectrum of the UCTTD perfectly matches the absorption spectrum of the photosensitizer (perylene probe (PC4)) to achieve the enhanced therapeutic effect triggered by a single laser. This study provides a new strategy for the rational design and development of the safe and efficient single near-infrared laser-triggered synergistic treatment platform for hypoxic cancer under the guidance of multimodal imaging.
    Keywords:  TME-responsive; antihypoxic cancer; dual-targeted nanosystem; photothermal-photodynamic synergistic therapy; single-NIR-laser trigger
    DOI:  https://doi.org/10.1002/advs.202203292
  33. Biomaterials. 2022 Aug 17. pii: S0142-9612(22)00340-4. [Epub ahead of print] 121700
    Near-infrared light and redox dual-activatable nanosystems for synergistically cascaded cancer phototherapy with reduced skin photosensitization.
    YiCong Li, DanRong Hu, Meng Pan, Ying Qu, BingYang Chu, JinFeng Liao, XiaoHan Zhou, QingYa Liu, Shuang Cheng, Yu Chen, Quan Wei, ZhiYong Qian.
      Currently, activatable photodynamic therapy (PDT) that is precisely regulated by endogenous or exogenous stimuli to selectively produce cytotoxic reactive oxygen species at the tumor site is urgently in demand. Herein, we fabricated a dual-activatable PDT nanosystem regulated by the redox tumor microenvironment and near-infrared (NIR) light-induced photothermal therapy (PTT). In this study, photosensitizer chlorin e6 (Ce6) was conjugated to hyaluronic acid (HA) via a diselenide bond to form an amphiphilic polymer (HSeC) for loading PTT agent IR780 to produce HSeC/IR nanoparticles (NPs). The photoactivity of Ce6 for PDT was "double-locked" by the aggregation-caused quenching (ACQ) effect and the fluorescence resonance energy transfer (FRET) from Ce6 to IR780 during blood circulation. After selective accumulation into tumors, HSeC/IR NPs were subsequently dissociated due to the "double-key", which included diselenide bond dissociation under high redox conditions and IR780 degradation upon NIR laser irradiation, resulting in recovering Ce6. In vitro studies indicated that Ce6 photoactivity in HSeC/IR NPs was significantly suppressed when compared with free Ce6 or in HSeC NPs. Moreover, BALB/c mice treated with HSeC/IR NPs displayed distinctly alleviated skin damage during PDT. Synergetic cascaded PTT-PDT with superior tumor suppression was observed in SCC7 tumor-bearing mice. Therefore, the study findings could provide a promising treatment strategy for PTT-facilitated PDT with high antitumor efficacies and reduced skin phototoxicity levels.
    Keywords:  Activatable photodynamic therapy; Fluorescence resonance energy transfer; Head and neck squamous cell carcinoma; Photothermal therapy; Skin photosensitization
    DOI:  https://doi.org/10.1016/j.biomaterials.2022.121700
  34. Anticancer Res. 2022 Sep;42(9): 4237-4246
    Epithelial to Mesenchymal Transition in Lung Cancer: Potential EMT-Targeting Natural Product-derived Compounds.
    Pithi Chanvorachote, Korrakod Petsri, Sunisa Thongsom.
      Epithelial to mesenchymal transition (EMT) is the cellular transition process of epithelium-associated phenotypes and behaviors into mesenchymal phenotypes. EMT is linked with cancer, and it is believed to be an important factor facilitating the motility and invasive activity of solid tumor cells. EMT facilitates the capability of cancer cells to metastasize because it promotes cell survival in detached conditions and facilitates the establishment of new tumors. In lung cancer, EMT has garnered considerable attention because of its importance in metastasis and has been recognized as an important target for anticancer drug therapy. Several studies have pointed out the promising activities of natural product-derived compounds and other agents that have EMT-suppressive activities and may facilitate the development of novel strategies for lung cancer management. In this review, we discuss the recent discoveries regarding the fundamental signaling regulating EMT and identify molecular targets for anti-EMT activities of the natural product-derived compounds. We also highlight the anti-EMT effect of natural compounds with their molecular targets and mechanisms of action that may benefit the understanding of and support the development of EMT targeting therapy.
    Keywords:  Epithelial to mesenchymal transition; lung cancer; potential compounds targeting EMT; review
    DOI:  https://doi.org/10.21873/anticanres.15923
  35. Curr Top Med Chem. 2022 Sep 01.
    Xanthones: A class of heterocyclic compounds with anticancer potential.
    Somia Gul, Khadija Aslam, Quratulain Pirzada, Abdur Rauf, Anees Ahmed Khalil, Prabhakar Semwal, Sami Bawazeer, Yahya S Al-Awthan, Omar Bahattab, Mohammed A Al-Duais, Muthu Thiruvengadam.
      Xanthones (9H xanthen-9-one) are an important class of heterocyclic compounds containing oxygen and moiety of gamma-pirone, dense with a two-benzene ring structured, distributed widely in nature. Naturally occurring xanthones are found in micro-organisms and higher plants as secondary metabolites in fungi and lichens. Compounds of the family Calophyllaceae, Guttiferae and Gentianaceae are the most common natural source of xanthones. The structure of xanthones nucleus, coupled with its biogenetic source, imposes that the carbons are numbered according to the biosynthetic pact. The characteristics oxygenation pattern of xanthones earlier is mixed shikimate-acetate biogenesis. The major class of xanthones includes simple oxygenated, non-oxygenated, xanthonolignoids, bisxanthones, prenylated and related xanthones, as well as miscellaneous xanthones. Their great pharmacological importance and interesting scaffolds were highly encouraged by scientists to investigate either the synthesis design or natural products for cancer treatment. Because currently used antitumor drugs possess high toxicity and low selectivity, efficacious treatment may be compromised. This review is limited to the antitumor activity of xanthones and the chemistry of xanthone core, which may help provide fundamental knowledge to the medicinal chemist for new and advanced research in drug development.
    Keywords:  Xanthone derivatives; antitumor activity; bioactive compounds; biomedical uses.; cancer; pharmacophore
    DOI:  https://doi.org/10.2174/1568026622666220901145002
  36. J Nanobiotechnology. 2022 Aug 31. 20(1): 394
    Metformin and histone deacetylase inhibitor based anti-inflammatory nanoplatform for epithelial-mesenchymal transition suppression and metastatic tumor treatment.
    Tianze Jiang, Laozhi Xie, Songlei Zhou, Yipu Liu, Yukun Huang, Ni Mei, Fenfen Ma, Jingru Gong, Xiaoling Gao, Jun Chen.
      Epithelial-mesenchymal transition (EMT), a differentiation process with aberrant changes of tumor cells, is identified as an initial and vital procedure for metastatic processes. Inflammation is a significant inducer of EMT and provides an indispensable target for blocking EMT, however, an anti-inflammatory therapeutic with highlighted safety and efficacy is deficient. Metformin is a promising anti-inflammatory agent with low side effects, but tumor monotherapy with an anti-inflammation drug could generate therapy resistance, cell adaptation or even promote tumor development. Combination therapies with various anti-inflammatory mechanisms can be favorable options improving therapeutic effects of metformin, here we develop a tumor targeting hybrid micelle based on metformin and a histone deacetylase inhibitor propofol-docosahexaenoic acid for efficient therapeutic efficacies of anti-inflammatory drugs. Triptolide is further encapsulated in hybrid micelles for orthotopic tumor therapies. The final multifunctional nanoplatforms (HAOPTs) with hyaluronic acid (HA) modification can target tumor efficiently, inhibit tumor cell EMT processes, repress metastasis establishment and suppress metastatic tumor development in a synergistic manner. Collectively, the results afford proof of concept that the tumor targeting anti-inflammatory nanoplatform can provide a potent, safe and clinical translational approach for EMT inhibition and metastatic tumor therapy.
    Keywords:  Anti-inflammation; Epithelial-mesenchymal transition; Histone deacetylase inhibitor; Metformin; Nanoplatform; Tumor metastasis
    DOI:  https://doi.org/10.1186/s12951-022-01592-6
  37. Turk J Pharm Sci. 2022 Aug 31. 19(4): 476-487
    Features and Facts of a Gastroretentive Drug Delivery System-A Review.
    Kuldeep Vinchurkar, Jitendra Sainy, Masheer Ahmed Khan, Sheetal Mane, Dinesh K Mishra, Pankaj Dixit.
      English oral delivery of drug was the commonly used modality because of patient compliance and ease of administration. After oral administration of any drug, its bioavailability is affected by its residence time in stomach. Recently, gastroretentive drug delivery systems (GRDDS) have gained wide acceptance for drugs with a narrow absorption window, decreased stability at high alkaline pH, and increased solubility at low pH. This approach develops a drug delivery system, which gets retained within gastric fluid, thereby releasing its active principles in the stomach. Some methods used to achieve gastric retention of drugs include the use of effervescence agents, mucoadhesive polymers, magnetic material, bouncy enhancing excipient, and techniques that form plug-like devices that resist gastric emptying. This review provides a concise account of various attributes of recently developed approaches for GRDDS.
    Keywords:  Bioavailability; bio/mucoadhesive system; gastric emptying; therapeutic window
    DOI:  https://doi.org/10.4274/tjps.galenos.2021.44959
  38. Front Pharmacol. 2022 ;13 842376
    Cancer and apoptosis: The apoptotic activity of plant and marine natural products and their potential as targeted cancer therapeutics.
    Gul-E-Saba Chaudhry, Abdah Md Akim, Yeong Yik Sung, Tengku Muhammad Tengku Sifzizul.
      Cancer is a multifactorial, multi-stage disease, including complex cascades of signaling pathways-the cell growth governed by dysregulated and abrupt cell division. Due to the complexity and multi-regulatory cancer progression, cancer is still a challenging disease to treat and survive. The screening of extracts and fractions from plants and marine species might lead to the discovery of more effective compounds for cancer therapeutics. The isolated compounds and reformed analogs were known as future prospective contenders for anti-cancer chemotherapy. For example, Taxol, a potent mitotic inhibitor discovered from Taxus brevifolia, suppresses cell growth and arrest, induces apoptosis, and inhibits proliferation. Similarly, marine sponges show remarkable tumor chemo preventive and chemotherapeutic potential. However, there is limited research to date. Several plants and marine-derived anti-cancer compounds having the property to induce apoptosis have been approved for clinical trials. The anti-cancer activity kills the cell and slows the growth of cancer cells. Among cell death mechanisms, apoptosis induction is a more profound mechanism of cell death triggered by naturally isolated anti-cancer agents. Evading apoptosis is the major hurdle in killing cancer cells, a mechanism mainly regulated as intrinsic and extrinsic. However, it is possible to modify the apoptosis-resistant phenotype of the cell by altering many of these mechanisms. Various extracts and fractions successfully induce apoptosis, cell-cycle modulation, apoptosis, and anti-proliferative activity. Therefore, there is a pressing need to develop new anti-cancer drugs of natural origins to reduce the effects on normal cells. Here, we've emphasized the most critical elements: i) A better understanding of cancer progression and development and its origins, ii) Molecular strategies to inhibit the cell proliferation/Carcino-genesis, iii) Critical regulators of cancer cell proliferation and development, iv) Signaling Pathways in Apoptosis: Potential Targets for targeted therapeutics, v) Why Apoptosis induction is mandatory for effective chemotherapy, vi) Plants extracts/fractions as potential apoptotic inducers, vii) Marine extracts as Apoptotic inducers, viii) Marine isolated Targeted compounds as Apoptotic inducers (FDA Approved/treatment Phase). This study provides a potential therapeutic option for cancer, although more clinical studies are needed to verify its efficacy in cancer chemotherapy.
    Keywords:  apoptosis; apoptotic inducers; cancer; marine drug; natural product; targeted therapeutic
    DOI:  https://doi.org/10.3389/fphar.2022.842376
  39. Prostate Cancer Prostatic Dis. 2022 Sep 02.
    The role of ferroptosis in prostate cancer: a novel therapeutic strategy.
    Yue Wang, Yifan Ma, Kui Jiang.
      The incidence of prostate cancer is the second most among male cancers after lung cancer. Prostate cancer develops rapidly and is inclined to metastasize, and castration-resistant prostate cancer (CRPC) can be formed in the later stage, which brings great challenges to the prognosis and treatment. At present, the main treatment of prostate cancer is generally divided into four methods: surgery, chemotherapy, radiotherapy and endocrine therapy. However, the efficacy of these methods fails to satisfy the demands of patient prognosis. Ferroptosis is a newly discovered iron-dependent process, characterized by lipid peroxidation. Ferroptosis is associated with many diseases, especially tumor growth. In recent years, inhibiting tumor growth and overcoming tumor drug resistance by inducing ferroptosis has become a hot research topic. Previous studies have shown that induction of ferroptosis may be a new treatment for prostate cancer. We review the research progress of ferroptosis in prostate cancer in order to provide highly effective therapies for patients with prostate cancer.
    DOI:  https://doi.org/10.1038/s41391-022-00583-w
  40. Cell Oncol (Dordr). 2022 Aug 29.
    Dual contribution of the mTOR pathway and of the metabolism of amino acids in prostate cancer.
    Alejandro Schcolnik-Cabrera, Daniel Juárez-López.
       BACKGROUND: Prostate cancer is the leading cause of cancer in men, and its incidence increases with age. Among other risk factors, pre-existing metabolic diseases have been recently linked with prostate cancer, and our current knowledge recognizes prostate cancer as a condition with important metabolic anomalies as well. In malignancies, metabolic disorders are commonly associated with aberrations in mTOR, which is the master regulator of protein synthesis and energetic homeostasis. Although there are reports demonstrating the high dependency of prostate cancer cells for lipid derivatives and even for carbohydrates, the understanding regarding amino acids, and the relationship with the mTOR pathway ultimately resulting in metabolic aberrations, is still scarce.
    CONCLUSIONS AND PERSPECTIVES: In this review, we briefly provide evidence supporting prostate cancer as a metabolic disease, and discuss what is known about mTOR signaling and prostate cancer. Next, we emphasized on the amino acids glutamine, leucine, serine, glycine, sarcosine, proline and arginine, commonly related to prostate cancer, to explore the alterations in their regulatory pathways and to link them with the associated metabolic reprogramming events seen in prostate cancer. Finally, we display potential therapeutic strategies for targeting mTOR and the referred amino acids, as experimental approaches to selectively attack prostate cancer cells.
    Keywords:  Amino acids; Cancer metabolism; Prostate cancer; mTOR
    DOI:  https://doi.org/10.1007/s13402-022-00706-4
  41. Front Mol Biosci. 2022 ;9 947208
    Perspectives and mechanisms for targeting ferroptosis in the treatment of hepatocellular carcinoma.
    Lanqing Li, Xiaoqiang Wang, Haiying Xu, Xianqiong Liu, Kang Xu.
      Ferroptosis is a novel process of regulated cell death discovered in recent years, mainly caused by intracellular lipid peroxidation. It is morphologically manifested as shrinking of mitochondria, swelling of cytoplasm and organelles, rupture of plasma membrane, and formation of double-membrane vesicles. Work done in the past 5 years indicates that induction of ferroptosis is a promising strategy in the treatment of hepatocellular carcinoma (HCC). System xc - /GSH/GPX4, iron metabolism, p53 and lipid peroxidation pathways are the main focus areas in ferroptosis research. In this paper, we analyze the ferroptosis-inducing drugs and experimental agents that have been used in the last 5 years in the treatment of HCC. We summarize four different key molecular mechanisms that induce ferroptosis, i.e., system xc - /GSH/GPX4, iron metabolism, p53 and lipid peroxidation. Finally, we outline the prognostic analysis associated with ferroptosis in HCC. The findings summarized suggest that ferroptosis induction can serve as a promising new therapeutic approach for HCC and can provide a basis for clinical diagnosis and prevention of this disease.
    Keywords:  cell death; ferroptosis; hepatocellular carcinoma; molecular signaling; targeted therapy
    DOI:  https://doi.org/10.3389/fmolb.2022.947208
  42. ACS Nano. 2022 Sep 01.
    In Situ Transformable Supramolecular Nanomedicine Targeted Activating Hippo Pathway for Triple-Negative Breast Cancer Growth and Metastasis Inhibition.
    Zhilong Wang, Cuihong Yang, Hao Zhang, Yang Gao, Meng Xiao, Zhongyan Wang, Lijun Yang, Jiamin Zhang, Chunhua Ren, Jianfeng Liu.
      As it is closely associated with tumor proliferation, metastasis, and the immunosuppressive microenvironment, the dysfunctional Hippo pathway has become an extremely attractive target for treating multiple cancers. However, to date, the corresponding chemotherapeutic nanomedicines have not been developed. Herein, a supramolecular self-delivery nanomedicine with in situ transforming capacity was tailor-constructed for Hippo-pathway restoration, and its inhibitory effect against tumor growth and metastasis was investigated in a highly aggressive triple-negative breast cancer (TNBC) model. Stimulated by overexpressed glutathione (GSH) and esterase in cancer cells, the self-assembled nanomedicine transformed from inactive nanospheres to active nanofibers conjugating tyrosvaline and spatiotemporally synchronously released the covalently linked flufenamic acid in situ, together activating the maladjusted Hippo pathway by simultaneously acting on different targets upstream and downstream. The transcriptional expression of Yes-associated protein (YAP) and related growth-promoted genes were significantly reduced, finally significantly repressing the proliferation and metastasis of cancer cells. Additionally, the Hippo-pathway restoration showed an excellent radiosensitization effect, making the targeted therapy combined with radiotherapy display a prominent synergistic in vivo anticancer effect against TNBC. This work reports a specifically designed smart nanomedicine to restore the function of the Hippo pathway and sensitize radiotherapy, providing an attractive paradigm for targeted drug delivery and cancer combination therapy.
    Keywords:  Hippo pathway; radiosensitization; self-assembly; stimuli responsive; targeted therapy; triple-negative breast cancer
    DOI:  https://doi.org/10.1021/acsnano.2c05263
  43. Curr Med Chem. 2022 Aug 26.
    Hybrid Histone Deacetylase Inhibitor: an Effective Strategy for Cancer Therapy.
    Jiyong Wu, Jing Nie, Yepeng Luan, Yanjiao Ding.
      Inhibition of histone deacetylases (HDACs) has proven to be an effective strategy for cancer therapy. To date, five histone deacetylase inhibitors (HDACis) have been approved for cancer treatment, and numerous others are undergoing clinical trials. It is proposed an agent that can simultaneously and effectively inhibit two or more targets may offer greater therapeutic benefits over single-acting agents in both preventing resistance to treatment and potentiating synergistic effects. A prime example of a bifunctional agent is the hybrid HDACi. Representative classes of reported hybrid HDACis are reviewed here with the purpose of shedding light on the design of novel hybrid HDACis for cancer therapy.
    Keywords:  antitumor; bifunctional agent.; cancer therapy; histone deacetylase; hybrid; multitarget inhibitors
    DOI:  https://doi.org/10.2174/0929867329666220826163626
  44. J Colloid Interface Sci. 2022 Aug 19. pii: S0021-9797(22)01482-5. [Epub ahead of print]628(Pt B): 864-876
    Cyclodextrin-based supramolecular nanoparticles break the redox balance in chemodynamic therapy-enhanced chemotherapy.
    Chengyuan Xing, Huikun Chen, Yupeng Guan, Shiqiang Zhang, Tongyu Tong, Ni Ding, Tingting Luo, Yang Kang, Jun Pang.
      Drug delivery based on abnormal features of the tumor microenvironment (TME) has attracted considerable interest worldwide. In this study, we proposed an applicable strategy to increase the reactive oxygen species (ROS) and inhibit glutathione (GSH), in an effort to amplify oxidative damage in prostate cancer cells. Specifically, we developed dual-responsive supramolecular self-assembled nanoparticles (NPs) based on polymerized methacrylic acid (MA) and polymerized poly(ethylene glycol) dimethyl acrylate-modified β-cyclodextrin (CD) with ferrocene (Fc)-connected (S) (+)-camptothecin (CPT) (designated as MA-CD/Fc-CPT NPs). The as-prepared negatively charged supramolecular NPs can be taken up by tumor cells successfully owing to their reversible negative-to-positive charge transition capacity at acidic pH. The supramolecular NPs increased ROS generation and decreased GSH to amplify oxidative stress and improve the therapeutic effect of chemotherapy. As expected, MA-CD/Fc-CPT NPs displayed good drug delivery capabilities to tumor cells or tissues. MA-CD/Fc-CPT NPs also inhibited cancer cell proliferation in both the cells and tissues. This result was partially due to increased ROS generation and decreased GSH, which contributed to more pronounced oxidative stress. The as-prepared supramolecular NPs displayed great biosafety to normal tissues. According to our results, negatively charged supramolecular MA-CD/Fc-CPT NPs are well-suited for drug delivery and improved cancer treatment in TMEs.
    Keywords:  Drug delivery; Fenton reaction; Redox balance; Supramolecular self-assembly
    DOI:  https://doi.org/10.1016/j.jcis.2022.08.110
  45. Curr Med Chem. 2022 Aug 29.
    Nanotechnological Systems and Lung: A Perfect Combination for Lung Pharmaceutical Applications.
    Debora Santonocito, Carmelo Puglia.
      Nowadays, lungs are the most common organs affected by diseases due to climate change, tobacco smoking, pollution and genetic factors. Conventional pharmacotherapy (oral medication or injection) is poorly selective; this causes toxicity problems and numerous systemic side effects. Furthermore, although pulmonary administration is an interesting route of drug administration for the treatment of lung diseases, inhalation therapy is complex mainly due to the defense mechanisms of the lungs that lead to rapid drug elimination. To overcome these issues, pulmonary drug delivery using nanocarriers appears to be the best therapeutic strategy. In fact, these nanosystems are able to reduce both drug therapeutic dose and side effects improving patient compliance, avoid alveolar macrophage clearance, protect the drug from degradation processes, and provide a controlled and targeted drug release. Therefore, this review aims to analyze the scientific literature regarding the use of nanocarriers to treat the main lung diseases (cancer, asthma, infections). In particular, attention was devoted to liposomes, polymer- and lipid-based nanoparticles, being the topic of most published articles in the last decade.
    Keywords:  Lipid Nanoparticles; Liposomes; Lung; Lung Diseases; Polymeric Nanoparticles; Pulmonary Drug Delivery
    DOI:  https://doi.org/10.2174/0929867329666220829092323
  46. Afr Health Sci. 2022 Mar;22(1): 673-680
    Vitamin A- and C-rich Pouteria camito fruit derived superparamagnetic nanoparticles synthesis, characterization, and their cytotoxicity.
    Chinnadurai Veeramani, Ahmed S El Newehy, Mohammed A Alsaif, Khalid S Al-Numair.
       Background: Recently, green nanoparticles are gaining importance in drug development because of their lower toxicity, sustainability, cost effectiveness, simplicity, and ecofriendly nature compared with toxic chemicals.
    Objective: In this study, we developed a nontoxic method for synthesizing iron oxide nanoparticles by using the fruit of Pouteria caimito that is rich in vitamin A and C and evaluated their cytotoxicity.
    Methods: Pouteria caimito fruit¬-derived superparamagnetic nanoparticles (PCSNs) were characterized using physical and chemical methods, and their cytotoxicity was examined using the 3-(4, 5-dimethylthiazol-2-yl)-2-5-diphenyltetrazolium bromide (MTT) assay.
    Results: Ultraviolet-visible spectroscopy (UV-Vis spectro) analysis of PSNs showed a peak at 277 nm. Transmission electron microscopy (TEM) findings showed that PSNs exhibited a nanorod shape with their sizes ranging from 9.41 nm to 16.96 nm (average size: 13.08 nm). The findings of dynamic light scattering (DLS) indicated that the particle size was 186. 6-847.3 d.nm with an average of 367.5 d.nm. The Zeta potential analysis indicated that PSNs exhibited uniform surface charge distribution, and their surface charge was equal to -13.7 mV. Fourier-transform infrared spectroscopy (FTIR) analysis showed that PSNs exhibited bands at 3412, 1629, 1384, 1075, 818, 697, and 471 cm-1. Energy-dispersive X-ray spectroscopy (EDX) results showed that iron was the major element present in PCSNs, followed by other biomolecules such as C, O, and Cl, indicating the production of iron oxide nanoparticles.
    Conclusion: The Pouteria caimito fruit that possesses strong oxidizing and nontoxic properties can be a potentially attractive source for the production of iron oxide nanoparticles. Moreover, the cytotoxicity assay results revealed that iron oxide nanoparticles synthesized using the Pouteria caimito fruit extract derived can be used for targeting cancer cells and treating other diseases because of their nontoxic nature. These nanoparticles can be used for the treatment of cancer and other diseases in the future.
    Keywords:  Fruit; Pouteria caimito; cytotoxicity; ferric chloride; superparamagnetic nanoparticles
    DOI:  https://doi.org/10.4314/ahs.v22i1.78
  47. Acta Biomater. 2022 Aug 30. pii: S1742-7061(22)00530-X. [Epub ahead of print]
    An ROS-responsive artesunate prodrug nanosystem co-delivers dexamethasone for rheumatoid arthritis treatment through the HIF-1α/NF-κB cascade regulation of ROS scavenging and macrophage repolarization.
    Yifan Li, Qiangwei Liang, Liyue Zhou, Yongjing Cao, Jiayu Yang, Juan Li, Jinxia Liu, Jiawei Bi, Yanhua Liu.
      The signaling cascade between nuclear factor-kappa B (NF-κB) and hypoxia-inducible factor-1α (HIF-1α) can be activated by proinflammatory M1 macrophages in rheumatoid arthritis (RA), which produces reactive oxygen species (ROS) and enhances M1 macrophage polarization, thus aggravating the development of RA. Therefore, an ROS-responsive artesunate prodrug micellar nanosystem for co-delivery of dexamethasone (DEX/HA-TK-ART micelles, abbreviated as DEX/HTA) was developed for synergistic inhibition of the HIF-1α/NF-κB cascade to regulate ROS scavenging and macrophage repolarization in RA combination therapy. DEX/HTA micelles displayed prolonged circulation in blood and efficiently co-delivered ART&DEX in the inflamed joints of adjuvant-induced arthritis (AIA) rats; moreover, they were specifically recognized and internalized into M1 macrophages through CD44 receptor-mediated endocytosis. ROS-responsive co-released ART&DEX then exerted a synergistic action to efficiently perform ROS scavenging and repolarization of M1 to M2 macrophages by inhibition of the HIF-1α/NF-κB cascade. The intravenous administration of DEX/HTA micelles into AIA rat models significantly alleviated inflammatory cell infiltration and repaired cartilage injury in the joint. Collectively, our study highlights the therapeutic potential of DEX/HTA micelles for treating RA through synergistic inhibition of the HIF-1α/NF-κB signaling cascade to regulate ROS scavenging and macrophage repolarization. STATEMENT OF SIGNIFICANCE: An ROS-responsive artesunate (ART) prodrug micellar nanosystem for co-delivering dexamethasone (DEX), abbreviated as DEX/HA-TK-ART micelle, was developed for synergistic cascade regulation of the HIF-1α/NF-κB pathway on ROS scavenging and macrophage repolarization in combination therapy for rheumatoid arthritis. The well-designed nanosystem showed prolonged circulation in blood and superior ART&DEX accumulation in the inflamed joints of AIA rats; moreover, the micelles were specifically internalized into M1 macrophages and co-released ART&DEX, subsequently leading to inhibition of the HIF-1α/NF-κB pathway for ROS scavenging and macrophage repolarization, thus generating synergistic anti-inflammatory effects in RAW 264.7 cells and AIA rats. The HIF-1α/NF-κB cascade regulation on ROS scavenging and macrophage repolarization based on ART&DEX combination with smart nanotechnology could serve as a promising approach for rheumatoid arthritis therapy.
    Keywords:  DEX/HTA prodrug micelles; HIF-1α/NF-κB cascade regulation; RA therapy; ROS scavenging; macrophage repolarization
    DOI:  https://doi.org/10.1016/j.actbio.2022.08.054
  48. Mo Med. 2022 Jan-Feb;119(1):119(1): 84-88
    A Review of Ketogenic Diet and Lifestyle.
    Erin McGaugh, Brandon Barthel.
      The ketogenic diet has become increasing popular in recent years. With 25.4 million unique searches, the keto diet was the most Googled diet in the United States in 2020.1 With increased consumer interest, the "keto" food industry has grown rapidly, and as a result, the global ketogenic diet market was valued at $9.57 billion in 2019.2 The ketogenic diet has been discussed in popular culture by celebrities, health magazines, and documentaries. The popularity of this diet, and diets in general may be explained by the obesity epidemic in the United States and Missouri.
  49. Biomater Adv. 2022 Aug 24. pii: S2772-9508(22)00362-4. [Epub ahead of print]140 213085
    Transpapillary iontophoretic delivery of resveratrol loaded transfersomes for localized delivery to breast cancer.
    Shivaprasad Gadag, Reema Narayan, Jayalakshmi N Sabhahit, Gangadhar Hari, Yogendra Nayak, Karkala Sreedhara Ranganath Pai, Sanjay Garg, Usha Y Nayak.
      Localized drug delivery to the breast tissues is an area of interest as a potential route to ensure site-specific drug delivery. Transpapillary delivery via the mammary papilla has advantages as most breast tumors arise from the milk ducts. The present study explored the plausibility of transpapillary delivery of a phytochemical, resveratrol (RVT), for breast cancer treatment. RVT was encapsulated within the transfersomes (RVT-TRF) to enable a sustained release of the drug using the biomaterial soya phosphatidylcholine (SPC). Iontophoresis was applied to further accelerate the penetration of the RVT-TRF across the mammary papilla to the breast tissue. The RVT-TRF development was optimized by the Design of Experiments (DoE) approach. The in vitro transpapillary iontophoresis study on porcine mammary papilla showed an enhanced penetration of RVT-TRF when compared to passive diffusion. The transpapillary delivery was further confirmed from the in vitro fluorescent microscopy study using FITC conjugated RVT-TRF. The optimized RVT-TRF delivered via transpapillary route showed a higher Cmax and AUC when compared to pure RVT given orally. A significant reduction in the tumor volume and the serum biomarker CA 15-3, when evaluated in a chemically induced breast cancer rat model, provided evidence of the effectiveness of the developed formulation when delivered locally via transpapillary route compared to the oral route. Thus the developed RVT-TRF administered via transpapillary iontophoresis technique is a promising strategy enabling a localized delivery for effective breast cancer therapy.
    Keywords:  Breast cancer; Iontophoresis; Localized; Resveratrol; Soya phosphatidylcholine; Transfersomes; Transpapillary
    DOI:  https://doi.org/10.1016/j.bioadv.2022.213085
  50. Heliyon. 2022 Aug;8(8): e09972
    Agrimonia pilosa Ledeb.: A review of its traditional uses, botany, phytochemistry, pharmacology, and toxicology.
    Sihua Wen, Xiaofei Zhang, Yanan Wu, Shangshang Yu, Wei Zhang, Ding Liu, Kai Yang, Jing Sun.
       Ethnopharmacological relevance: Agrimonia pilosa Ledeb. is the dried above-ground part of dragon's tooth grass, a plant of the Rosaceae family, which is widely distributed in China, Korea, and Japan. Agrimonia pilosa Ledeb. is a herbal medicine with great scope for development and use. It is astringent and hemostatic, and it is used for treating malaria, preventing dysentery, detoxification, and as a tonic for deficiency.
    Aim of the review: We summarize the traditional uses, botanical and chemical composition, extraction methods, and pharmacological and toxicological progress of Agrimonia pilosa Ledeb. and discuss the future research trends and development prospects of this plant.
    Materials and methods: Information on Agrimonia pilosa Ledeb. was gathered via the Internet (China National Knowledge Infrastructure, Google Scholar, PubMed, Web of Science, SpringerLink, Wiley, Wanfang Data, and Baidu Academic). Additional information was obtained from books (Ben Cao Tu Jing, A Textual Research on the Name and Reality of Plants, Modern Practical Chinese Medicine, Zhen Nan Ben Cao) and PhD and MS dissertations.
    Results: Phytochemical studies have identified more than 252 compounds from Agrimonia pilosa Ledeb., including flavonoids, volatile oils, tannins, phenols, m-benzotrienols, pentacyclic triterpenoids, isocoumarins, lignans, organic acids, and other chemical constituents. The compounds and extracts isolated from Agrimonia pilosa Ledeb. show various pharmacological activities, including anti-inflammatory, anticancer, antitumor effects, antioxidant, analgesic effects, and other pharmacological effects.
    Conclusion: This review highlights the botany, phytochemistry, pharmacology, toxicology, and traditional uses of Agrimonia pilosa Ledeb., providing a basis for future research and clinical applications. Agrimonia pilosa Ledeb. has shown remarkable effectiveness in the treatment of various diseases, especially enteritis, gastric ulcers, and gastrointestinal bleeding. Most prescriptions for Agrimonia pilosa Ledeb. are empirical and lack rigorous clinical observation. For these reasons, the toxicology, standardized clinical studies, nature of active ingredients, pharmacokinetics, mechanism, and metabolism of Agrimonia pilosa Ledeb. should be deepened, especially through clinical trials, to ensure the clinical safety of its use for further research.
    Keywords:  Agrimonia pilosa Ledeb; Botany; Chemical composition; Pharmacological effects; Traditional uses
    DOI:  https://doi.org/10.1016/j.heliyon.2022.e09972
  51. Front Pharmacol. 2022 ;13 966012
    Inhibiting Cytoprotective Autophagy in Cancer Therapy: An Update on Pharmacological Small-Molecule Compounds.
    Lijuan Zhang, Yuxuan Zhu, Jiahui Zhang, Lan Zhang, Lu Chen.
      Autophagy is a self-degradation process in which damaged proteins and organelles are engulfed into autophagosomes for digestion and eventually recycled for cellular metabolism to maintain intracellular homeostasis. Accumulating studies have reported that autophagy has the Janus role in cancer as a tumor suppressor or an oncogenic role to promote the growth of established tumors and developing drug resistance. Importantly, cytoprotective autophagy plays a prominent role in many types of human cancers, thus inhibiting autophagy, and has been regarded as a promising therapeutic strategy for cancer therapy. Here, we focus on summarizing small-molecule compounds inhibiting the autophagy process, as well as further discuss other dual-target small-molecule compounds, combination strategies, and other strategies to improve potential cancer therapy. Therefore, these findings will shed new light on exploiting more small-molecule compounds inhibiting cytoprotective autophagy as candidate drugs for fighting human cancers in the future.
    Keywords:  autophagy; cancer therapy; cytoprotective autophagy; inhibitor; small-molecule compound
    DOI:  https://doi.org/10.3389/fphar.2022.966012
  52. Zhongguo Zhong Yao Za Zhi. 2022 Aug;47(16): 4277-4283
    [Research progress on antitumor effect and molecular mechanism of capsaicin].
    Xin-Yue Zhou, Xia-Yang Liu, Zhuang Li, Xiao-Hong Guo.
      Capsaicin is a lipid-soluble vanillin alkaloid extracted from Capsicum plants in the Solanaceae family, which is the main active ingredient in capsicum, with multiple functions such as anti-inflammation, analgesia, cardiovascular expansion, and gastric mucosa protection. Recently, capsaicin has been confirmed as a potential antitumor compound. It can induce cell cycle arrest, inhibit cancer cell proliferation, metastasis, invasion, and angiogenesis, and promote apoptosis or autophagy in malignancy cell models and animal models of lung cancer, breast cancer, gastric cancer, and liver cancer. Meanwhile, capsaicin shows a synergistic antitumor effect when combined with other antitumor drugs such as sorafenib. Based on the recent literature on the antitumor effect of capsaicin, the present study analyzed the molecular mechanism of capsaicin in resisting tumors by inducing apoptosis and reviewed the effects of capsaicin in inducing tumor cell cycle arrest, inhibiting tumor cell proliferation, metastasis, and angiogenesis, and combating tumors with other drugs, thereby providing a theoretical basis for further research of capsaicin and its rational development and utilization.
    Keywords:  angiogenesis; antitumor; apoptosis; capsaicin; molecular mechanism
    DOI:  https://doi.org/10.19540/j.cnki.cjcmm.20220421.601
  53. J Colloid Interface Sci. 2022 Aug 28. pii: S0021-9797(22)01534-X. [Epub ahead of print]629(Pt A): 103-113
    Hydrogen peroxide self-sufficient and glutathione-depleted nanoplatform for boosting chemodynamic therapy synergetic phototherapy.
    Huijun Zhang, Renlu Han, Pengxin Song, Xiangjun Wei, Yafei Hou, Jiancheng Yu, Keqi Tang.
      Chemodynamic therapy (CDT), which suppresses tumors via the conversion of endogenous hydrogen peroxide (H2O2) to highly toxic hydroxyl radicals (•OH), is deemed as a cutting-edge antitumor strategy. However, the insufficient endogenous H2O2 and up-regulated antioxidant glutathione (GSH) in the tumor microenvironment (TME) greatly impede the therapeutic effect of CDT. Herein, a versatile nanoplatform MgO2@SnFe2O4@PEG (MSnFeP) is elaborately fabricated for boosting CDT synergetic phototherapy. In the TME, the activation of MSnFeP contributes to in situ supply of H2O2, generation of •OH and consumption of GSH for boosted CDT. Furthermore, photothermal therapy (PTT) and photodynamic therapy (PDT) are simultaneously stimulated by near-infrared (NIR) light exposure on MSnFeP to increase the toxic free radical yield. This strategy not only amplifies the CDT efficacy hindered by H2O2 deficiency and GSH overexpression, but also further enhances the therapeutic effect with the combination of phototherapy.
    Keywords:  Amplified tumor therapy; Chemodynamic therapy; Glutathione-depleted; Hydrogen peroxide self-sufficient; Magnesium peroxide
    DOI:  https://doi.org/10.1016/j.jcis.2022.08.156
  54. Photodiagnosis Photodyn Ther. 2022 Aug 25. pii: S1572-1000(22)00376-3. [Epub ahead of print] 103090
    Intracellular glutathione levels affect the outcomes of verteporfin-mediated photodynamic therapy in esophageal cancer cells.
    Mirai Edano, Tsutomu Kanda, Ryohei Tarumoto, Wataru Hamamoto, Takashi Hasegawa, Yukari Mae, Takumi Onoyama, Tomoaki Takata, Takaaki Sugihara, Hajime Isomoto.
      Photodynamic therapy (PDT) induces cancer cell death by generating reactive oxygen species (ROS). In this process, photosensitizers accumulate in cancer cells irradiated by laser light of a specific wavelength, leading to ROS generation. Verteporfin (VP), a second-generation photosensitizer, is used in PDT for age-related macular degeneration. However, the antitumor effects of VP-PDT remain unknown. This study investigated the antitumor effects of VP-PDT on esophageal cancer (EC) cell lines in vitro. Two types of EC cell lines, the KYSE30 cell line, derived from highly differentiated esophageal carcinoma, and the KYSE170 cell line, derived from moderately differentiated carcinoma, were used in this study. VP-PDT exerted effective anticancer effects in both cell lines. Our results revealed that the low-density lipoprotein receptor, albumin receptor, and heme carrier protein-1 in VP uptake were not involved in VP uptake. However, cells rich in intracellular glutathione were resistant to VP-PDT. Our study outcomes suggest that lowering intracellular glutathione via a glutathione synthesis inhibitor or sulfasalazine can increase the effectiveness of VP-PDT-mediated anticancer effects.
    Keywords:  Esophageal cancer; glutathione; photodynamic therapy; sulfasalazine; verteporfin
    DOI:  https://doi.org/10.1016/j.pdpdt.2022.103090
  55. Mini Rev Med Chem. 2022 Aug 27.
    Oncopreventive and Oncotherapeutic Potential of Licorice Chalcone Compounds: Molecular Insights.
    Yushu Wang, Wenxin Xia, Mengxin Tao, Xueyan Fu.
       BACKGROUND: Licorice is an important traditional Chinese medicine commonly used in clinical practice and contains more than 300 flavonoids. Chalcone is one of the main types of flavonoids with a wide range of biological functions and pharmacological activities. In the anticancer research, chalcone compounds have excellent performance.
    OBJECTIVE: This review aims to summarize the biosynthetic pathway and pharmacokinetics of chalcone from licorice and provide evidence for the anticancer effects of chalcone and the underlying mechanisms involved.
    METHOD: For this review, the following databases were consulted: the PubMed Database (https://pubmed.ncbi.nlm.nih.gov), Chinese National Knowledge Infrastructure (http://www.cnki.net), National Science and Technology Library (http://www.nstl.gov.cn/), Wanfang Data (http://www.wanfangdata.com.cn/), and the Web of Science Database (http://apps.webofknowledge.com/).
    RESULTS: To date, about 56 chalcones have been isolated and identified from licorice, 14 of which have antitumor effects. These chalcones have a wide range of biological activities and can inhibit the viability, proliferation, and migration of cancer cells by blocking the cancer cell cycle, thus inducing apoptosis and autophagy. However, the molecular mechanism of the anticancer effects of chalcone is not fully understood.
    CONCLUSION: In this paper, the molecular mechanism of chalcone regulating different types of cancer is reviewed in detail from the biosynthetic pathway. This comprehensive review article summarizes the biosynthetic pathway and pharmacokinetics of chalcone from the traditional Chinese medicine licorice and provides evidence for the potential anticancer effects of chalcone and the respective mechanisms of action. This paper also provides a basis for structural modification, biosynthesis, and new drug development of chalcone compounds in Glycyrrhiza uralensis.
    Keywords:  antitumor; biosynthesis; chalcones; licorice; pharmacology; phytochemistry
    DOI:  https://doi.org/10.2174/1389557522666220827161943
  56. Horm Mol Biol Clin Investig. 2022 Sep 05.
    Anti-proliferation effects of Apatinib in combination with Curcumin in breast cancer cells.
    Mahdi Farhoudi Sefidan Jadid, Gholamreza Jahangirzadehd, Javad Behroozi.
       OBJECTIVES: Despite remarkable development of new therapeutic strategies to improve survival rates and treatment of patients with cancer, there are still many limitations in management of patients with distant metastasis breast cancer. Therefore, the aim of this study was to investigate a novel method to enhance therapeutic efficacy of Apatinib (as a chemotherapeutic agent) by co-administration of Curcumin (as a bioactive herbal compound) in breast cancer treatment.
    METHODS: Effects of Apatinib, Curcumin, and their combinations (Apa-Cur) was evaluated on viability and proliferation of breast cell line (MCF7) by MTT assay. Moreover, effects of Apatinib, Curcumin, and Apa-Cur was investigated on apoptosis rate in the cancer cells. Expression levels of apoptosis-related genes (BAX, SMAC, BCL2, and SURVIVIN) in treated cancer cells and untreated controls were evaluated using the Real-Time PCR method.
    RESULTS: The obtained results showed that all treatments of Apatinib, Curcumin, and Apa-Cur significantly decreased viability and proliferation of the breast cancer cells in a concentration- and time-dependent manner. However, anti-proliferation activity of Apa-Cur combination was significantly higher than Apatinib and Curcumin treatment alone. In addition, Apatinib, Curcumin, and Apa-Cur increased apoptosis percentage in the treated cancer cells through regulation of apoptosis-related genes expression.
    CONCLUSIONS: In general, Apa-Cur combination therapy exerts more profound anti-proliferation effects on breast cancer cell than Apatinib or Curcumin monotherapy. However, further studies are required to identify other possible signaling pathways and mechanisms involved in the anticancer effects of Apatinib, Curcumin, and Apa-Cur.
    Keywords:  Apatinib; Curcumin; apoptosis; breast cancer; gene expression
    DOI:  https://doi.org/10.1515/hmbci-2022-0036
  57. Pharm Dev Technol. 2022 Aug 31. 1-13
    Co-delivery of curcumin and Bcl-2 siRNA to enhance therapeutic effect against breast cancer cells using PEI-functionalized PLGA nanoparticles.
    Leila Mohammad Gholinia Sarpoli, Shohreh Zare-Karizi, Erfan Heidari, Akbar Hasanzadeh, Mehrdad Bayandori, Fereshteh Azedi, Michael R Hamblin, Mahdi Karimi.
       PURPOSE: Breast cancer is the second major cause of death worldwide among women. Co-delivery of anticancer drugs and nucleic acids targeting the apoptosis pathway could be a promising new approach.
    METHODS: In the present study, we synthesized a novel nanostructure for co-delivery of curcumin and siRNA to breast cancer cells. Curcumin-loaded polylactic-co-glycolic acid (PLGA) was synthesized using an O/W emulsion-solvent diffusion method. It was coated with polyethylenimine (PEI) and subsequently complexed with Bcl-2 siRNA. Also nanoparticles were characterized such as zeta potential, size distribution and drug encapsulation. Finally the cytotoxicity of NP and Bcl2 experession was evaluated.
    RESULTS: The curcumin loaded PLGA nanoparticles were 70nm in size, and increased to 84 nm after incorporation of PEI plus Bcl-2 siRNA. The encapsulation ratio of drug in our nanoparticle was 78%. Cellular internalization PLGA-CUR-PEI/Bcl-2 siRNA NPs was confirmed by fluorescence microscopy with broadcasting of the fluorescence in the cytoplasm and into the nucleus. The results of the cell viability assay revealed that curcumin-loaded PLGA coated with PEI and Bcl-2 siRNA exhibited the highest cytotoxicity against the T47D cell line, while the siRNA decreased the Bcl-2 expression by 90.7%.
    CONCLUSION: The co-delivery of curcumin plus Bcl-2 siRNA with the PLGA-PEI nanosystem could be a synergistic drug carrier against breast cancer cells.
    Keywords:  Bcl-2 siRNA; Curcumin; breast cancer; nanodelivery; polylactic-co-glycolic acid
    DOI:  https://doi.org/10.1080/10837450.2022.2120003
  58. Front Bioeng Biotechnol. 2022 ;10 972933
    Recent advances in aptamer-based targeted drug delivery systems for cancer therapy.
    Fei Gao, Jianhui Yin, Yan Chen, Changyong Guo, Honggang Hu, Jiacan Su.
      The past decade has become an important strategy in precision medicine for the targeted therapy of many diseases, expecially various types of cancer. As a promising targeted element, nucleic acid aptamers are single-stranded functional oligonucleotides which have specific abilities to bind with various target molecules ranging from small molecules to entire organisms. They are often named 'chemical antibody' and have aroused extensive interest in diverse clinical studies on account of their advantages, such as considerable biostability, versatile chemical modification, low immunogenicity and quick tissue penetration. Thus, aptamer-embedded drug delivery systems offer an unprecedented opportunity in bioanalysis and biomedicine. In this short review, we endeavor to discuss the recent advances in aptamer-based targeted drug delivery platforms for cancer therapy. Some perspectives on the advantages, challenges and opportunities are also presented.
    Keywords:  aptamer-based nanomaterial system; aptamer-drug conjugates (ApDCs); aptamers; cancer therapy; targeted drug delivery
    DOI:  https://doi.org/10.3389/fbioe.2022.972933
  59. Curr Neuropharmacol. 2022 Aug 30.
    Ketogenic diet: an effective treatment approach for neurodegenerative diseases.
    Ye Tao, Sean X Leng, Haiyan Zhang.
      This review discusses the effects and mechanisms of ketogenic diet on neurodegenerative diseases on the basis of available evidence. A ketogenic diet refers to a high-fat, medium-protein, and low-carbohydrate diet that leads to a metabolic shift to ketosis. This review systematically summarizes the scientific literature supporting this effective treatment approach for neurodegenerative diseases, including effects on mitochondrial function, oxidative stress, neuronal apoptosis, neuroinflammation, and the microbiota-gut-brain axis. It also highlights the clinical evidence for the effects of ketogenic diet in the treatment of Alzheimer's disease, Parkinson's disease, and motor neuron disease. Finally, it discusses the common adverse effects of ketogenic therapy. Although the complete mechanism of ketogenic diet in the treatment of neurodegenerative diseases remains to be elucidated, its clinical efficacy has attracted many new followers. The ketogenic diet is a good candidate for adjuvant therapy, but its specific applicability depends on the type and the degree of the disease.
    Keywords:  Alzheimer's disease ; Amyotrophic lateral sclerosis ; Ketogenic diet ; Parkinson's disease ; microbiota–gut–brain axis; neurodegenerative diseases
    DOI:  https://doi.org/10.2174/1570159X20666220830102628
  60. Curr Top Med Chem. 2022 Sep 02.
    Recent advances in chemical composition and transdermal delivery systems for topical bio-actives in skin cancer.
    Jitu Halder, Ajit Mishra, Biswakanth Kar, Goutam Ghosh, Goutam Rath.
      Skin cancer, including basal cell carcinoma, melanoma, and squamous cell carcinoma, is conventionally treated by surgery, phototherapy, immunotherapy, and chemotherapy. For decades, surgical removal of malignant cancers has favored patients' therapeutic options. However, multiple aspects, such as the patient's comorbidities, the anatomical location of the lesion, and possible resistance to recurrent excisions, can influence the decision to conduct surgery. Therefore, topical and transdermal therapy may be a more appropriate option, allowing for higher therapeutic levels at the site of action and reducing toxicity than systemic therapy. The most commonly used topical agents for treating skin carcinoma are- 5-fluorouracil, imiquimod, sonidegib, dacarbazine, etc. However, drug physicochemical characteristics and skin physiological barriers limit the anticancer potency of topical as well as transdermal drug delivery. In recent years, unquestionable signs of progress have been demonstrated to circumvent these challenges. In particular, significant studies have been made, including modification of bio-actives, permeability enhancers, incorporation of advanced nano and microcarriers, and physical enhancement devices. This critical review summarizes the advancement in the chemical composition of bioactives used in skin cancer, such as sinecatechins, BIL-010t, patidegib, gingerol, curcumin, remetinostat, epigallocatechin-3-gallate, etc. Furthermore, this review, specifically addresses the progress in transdermal delivery systems for melanoma and non-melanoma cancer therapy, emphasizing advances in physical and chemical penetration enhancement and nanocarrier-assisted transdermal systems.
    Keywords:  Topical anticancer bioactive; chemical composition; melanoma; non-melanoma cancer; transdermal therapy.
    DOI:  https://doi.org/10.2174/1568026622666220902104906
  61. Biomed Pharmacother. 2022 Aug 24. pii: S0753-3322(22)00950-7. [Epub ahead of print]154 113561
    Pharmacological effects and mechanisms of tannic acid.
    Wang Jing, Chen Xiaolan, Chen Yu, Qin Feng, Yang Haifeng.
      In recent years, increasing attention has been paid to the pharmacological efficacy of tannins. Tannic acid (TA), the simplest hydrolysable tannin that has been approved by the FDA as a safe food additive, is one of the most important components of these traditional medicines. Studies have shown that TA displays a wide range of pharmacological activities, such as anti-inflammatory, neuroprotective, antitumor, cardioprotective, and anti-pathogenic effects. Here, we summarize the known pharmacological effects and associated mechanisms of TA. We focus on the effect and mechanism of TA in various animal models of inflammatory disease and organ, brain, and cardiovascular injury. Moreover, we discuss the possible molecular targets and signaling pathways of TA, in addition to the pharmacological effects of TA-based nanoparticles and TA in combination with chemotherapeutic drugs.
    Keywords:  Anti-inflammatory; Antitumor; Cardioprotective; Neuroprotective; Pharmacological efficacy; Tannic acid
    DOI:  https://doi.org/10.1016/j.biopha.2022.113561
  62. Int J Nanomedicine. 2022 ;17 3691-3710
    A Selective Reduction of Osteosarcoma by Mitochondrial Apoptosis Using Hydroxyapatite Nanoparticles.
    Hongfeng Wu, Shuo Liu, Siyu Chen, Yuchen Hua, Xiangfeng Li, Qin Zeng, Yong Zhou, Xiao Yang, Xiangdong Zhu, Chongqi Tu, Xingdong Zhang.
       Background: In recent years, using hydroxyapatite nanoparticles (HANPs) for tumor therapy attracted increasing attention because HANPs were found to selectively suppress the growth of tumor cells but exhibit ignorable toxicity to normal cells.
    Purpose: This study aimed to investigate the capacities of HANPs with different morphologies and particle sizes against two kinds of osteosarcoma (OS) cells, human OS 143B cells and rat OS UMR106 cells.
    Methods: Six kinds of HANPs with different morphologies and particle sizes were prepared by wet chemical method. Then, the antitumor effect of these nanoparticles was characterized by means of in vitro cell experiments and in vivo tumor-bearing mice model. The underlying antitumor mechanism involving mitochondrial apoptosis was also investigated by analysis of intracellular calcium, expression of apoptosis-related genes, reactive oxygen species (ROS), and the endocytosis efficiency of the particles in tumor cells.
    Results: Both in vitro cell experiments and in vivo mice model evaluation revealed the anti-OS performance of HANPs depended on the concentration, morphology, and particle size of the nanoparticles, as well as the OS cell lines. Among the six HANPs, rod-like HANPs (R-HANPs) showed the best inhibitory activity on 143B cells, while needle-like HANPs (N-HANPs) inhibited the growth of UMR106 cells most efficiently. We further demonstrated that HANPs induced mitochondrial apoptosis by selectively raising intracellular Ca2+ and the gene expression levels of mitochondrial apoptosis-related molecules, and depolarizing mitochondrial membrane potential in tumor cells but not in MC3T3-E1, a mouse pre-osteoblast line. Additionally, the anti-OS activity of HANPs also linked with the endocytosis efficiency of the particles in the tumor cells, and their ability to drive oxidative damage and immunogenic cell death (ICD).
    Conclusion: The current study provides an effective strategy for OS therapy where the effectiveness was associated with the particle morphology and cell line.
    Keywords:  cell line; hydroxyapatite nanoparticles; material features; mitochondrial apoptosis; osteosarcoma
    DOI:  https://doi.org/10.2147/IJN.S375950
  63. Schizophrenia (Heidelb). 2022 Aug 30. 8(1): 70
    Antipsychotic-induced weight gain and metabolic effects show diurnal dependence and are reversible with time restricted feeding.
    Rizaldy C Zapata, Allison Silver, Dongmin Yoon, Besma Chaudry, Avraham Libster, Michael J McCarthy, Olivia Osborn.
      Antipsychotic drugs (AP) are highly efficacious treatments for psychiatric disorders but are associated with significant metabolic side-effects. The circadian clock maintains metabolic homeostasis by sustaining daily rhythms in feeding, fasting and hormone regulation but how circadian rhythms interact with AP and its associated metabolic side-effects is not well-known. We hypothesized that time of AP dosing impacts the development of metabolic side-effects. Weight gain and metabolic side-effects were compared in C57Bl/6 mice and humans dosed with APs in either the morning or evening. In mice, AP dosing at the start of the light cycle/rest period (AM) resulted in significant increase in food intake and weight gain compared with equivalent dose before the onset of darkness/active period (PM). Time of AP dosing also impacted circadian gene expression, metabolic hormones and inflammatory pathways and their diurnal expression patterns. We also conducted a retrospective examination of weight and metabolic outcomes in patients who received risperidone (RIS) for the treatment of serious mental illness and observed a significant association between time of dosing and severity of RIS-induced metabolic side-effects. Time restricted feeding (TRF) has been shown in both mouse and some human studies to be an effective therapeutic intervention against obesity and metabolic disease. We demonstrate, for the first time, that TRF is an effective intervention to reduce AP-induced metabolic side effects in mice. These studies identify highly effective and translatable interventions with potential to mitigate AP-induced metabolic side effects.
    DOI:  https://doi.org/10.1038/s41537-022-00276-2
  64. Anticancer Res. 2022 Sep;42(9): 4319-4328
    Compound Library Screening for Synergistic Drug Combinations: mTOR Inhibitor and Proteasome Inhibitor Effective Against Osteosarcoma Cells.
    Kunihiro Asanuma, Tomoki Nakamura, Koichi Nakamura, Tomohito Hagi, Takayuki Okamoto, Kouji Kita, Yumi Matsuyama, Keisuke Yoshida, Yumiko Asanuma, Akihiro Sudo.
       BACKGROUND/AIM: The development of new drugs is urgently needed for new treatment strategies that can improve the prognosis of osteosarcoma (OS). In this study, we attempted to identify combinations of new molecular-targeted agents for OS.
    MATERIALS AND METHODS: A library containing 324 compounds was used. For the first screening, MG-63 OS cells were treated with each of the compounds and cell viability was measured. After the best candidate compound was decided, the compound was included in a second screening. The combination of most effective compounds was decided. The antiproliferative effect of the combination was examined and the cell signaling mechanism was evaluated by western blot analysis. 143B OS-bearing mice were used for in vivo antitumor testing.
    RESULTS: In the first screening, bortezomib was chosen as the effective drug. In the second screening with bortezomib, everolimus was chosen. This combination showed a synergistic inhibitory effect on cell proliferation when compared to monotherapy with each of these drugs alone. Compared to monotherapy, the combination therapy enhanced the levels of cleaved poly (ADP-ribose) polymerase, caspase-3, caspase-8 and caspase-9, phospho-c-Jun N-terminal kinase, and P38. In contrast, the levels of c-MYC proto-oncogene bHLH transcription factor, survivin, and phospho-cyclin D1 were reduced. The combination effectively induced apoptosis and interfered with cell cycle progression. In the in vivo analysis, the combination therapy significantly inhibited tumor growth.
    CONCLUSION: The combination of everolimus and bortezomib demonstrated a synergistic effect against OS both in vitro and in vivo. These results indicate that this combination may be useful as a novel therapeutic strategy for OS.
    Keywords:  Osteosarcoma; bortezomib; compound library; everolimus; synergistic effect
    DOI:  https://doi.org/10.21873/anticanres.15932
  65. Front Cell Infect Microbiol. 2022 ;12 969526
    Gut microbiota: An emerging therapeutic approach of herbal medicine for prevention of colorectal cancer.
    Hua-Zhong Ying, Wei Xie, Meng-Chuan Wang, Jia-Qi He, Huan-Huan Zhang, Chen-Huan Yu.
      The gut dysbiosis has emerged as a prominent player in the pathogenesis and development of colorectal cancer (CRC), which in turn intensifies dysregulated gut microbiota composition and inflammation. Since most drugs are given orally, this dysbiosis directly and indirectly impinges the absorption and metabolism of drugs in the gastrointestinal tract, and subsequently affects the clinical outcome of patients with CRC. Herbal medicine, including the natural bioactive products, have been used traditionally for centuries and can be considered as novel medicinal sources for anticancer drug discovery. Due to their various structures and pharmacological effects, natural products have been found to improve microbiota composition, repair intestinal barrier and reduce inflammation in human and animal models of CRC. This review summarizes the chemo-preventive effects of extracts and/or compounds derived from natural herbs as the promising antineoplastic agents against CRC, and will provide innovative strategies to counteract dysregulated microbiota and improve the lives of CRC patients.
    Keywords:  chronic inflammation; immunoenhancement; intestinal homeostasis; natural products; probiotic; tumor microenvironment
    DOI:  https://doi.org/10.3389/fcimb.2022.969526
  66. Recent Adv Drug Deliv Formul. 2022 Sep 02.
    Recent advancements on hyperthermia driven controlled drug delivery from nanotherapeutics.
    Mirza Shahed Baig, M Akiful Haque, Teja Kumar Reddy Konatham, Badrud Duza Mohammad, Barrawaz Aateka Yahya, Shaikh Sana Saffiruddin, Falak A Siddiqui, Sharuk L Khan.
      Previous reviews of the works on magnetic nanoparticles for hyperthermia induced treatment concentrated mostly on magnetic fluid hyperthermia (MFH) employing monometallic/metal oxide nanocomposites. In the literature, the word "hyperthermia" was also limited to the use of heat for medicinal purposes. A number of publications have recently been published demonstrating that magnetic nanoparticle-based hyperthermia may produce restricted high temperatures, resulting in the release of medicines that are either connected to the magnetic nanoparticles or encased in polymer matrices. In this debate, we propose broadening the concept of "hyperthermia" to encompass temperature-based treatment as well as magnetically controlled medication delivery. The review also addresses core-shell magnetic nanomaterials, particularly nanoshells made by stacked assembly, for the use of hyperthermia-based treatment and precise administration of drugs. The primary objective of this review article is to demonstrate how the combination of hyperthermia-induced therapy and 'on demand' drug release models may lead to effective applications in personalized medicine.
    Keywords:  Magnetic nanomaterials; controlled drug delivery; hyperthermia; polymeric matrix; thermotherapy
    DOI:  https://doi.org/10.2174/2667387816666220902091043
  67. Pancreatology. 2022 Aug 05. pii: S1424-3903(22)00472-0. [Epub ahead of print]
    Strategies for drug targeting in pancreatic cancer.
    Navni Sharma, Vimal Arora.
       BACKGROUND: Pancreatic cancer is expected to replace lung cancer as the second greatest cause of cancer mortality by 2025. It has been a particularly the most lethal kind of cancer.
    OBJECTIVE: Despite the new innovations, research, and improvements in drug design; there are many hurdles limiting their therapeutic applications such as intrinsic resistance to chemotherapeutics, inability to deliver a sufficient concentration of drug to the target site, lack of effectiveness of drug delivery systems. These are the major contributing factors to limit the treatment. So, the main objective is to overcome these types of problems by nanotechnology and ligand conjugation approach to achieve targeted drug delivery.
    METHOD: Nanotechnology has emerged as a major approach to develop cancer treatment. Regardless of the severity, there are several issues that restrict the therapeutic impact, including inadequate transport across biological barriers, limited cellular absorption, degradation, and faster clearance.
    RESULT: Targeted drug delivery may overcome these obstacles by binding a natural ligand to the surface of nanocarriers, which enhances the drug's capacity to release at the desired site and minimizes adverse effects.
    CONCLUSION: This study will investigate the possible outcomes of targeted therapeutic agent delivery in the treatment of pancreatic cancer, as well as the limitations and future prospects.
    Keywords:  Bioconjugation; Biomarkers; Nanotechnology; Pancreatic cancer; Stability issues; Targeted drug delivery
    DOI:  https://doi.org/10.1016/j.pan.2022.08.001
  68. Drug Deliv. 2022 Dec;29(1): 2773-2783
    Rapid oral transmucosal delivery of zaleplon-lavender oil utilizing self-nanoemulsifying lyophilized tablets technology: development, optimization and pharmacokinetic evaluation.
    Sarah A Ali, Nabil A Alhakamy, Khaled M Hosny, Eman Alfayez, Deena M Bukhary, Awaji Y Safhi, Moutaz Y Badr, Rayan Y Mushtaq, Majed Alharbi, Bader Huwaimel, Mohammed Alissa, Sameer Alshehri, Ali H Alamri, Taha Alqahtani.
      Based on the administration convenience, transmucosal buccal drug delivery allows special strength points over peroral routes for systemic delivery. It could achieve local or systemic effect and boost drugs' bioavailability for agents with first pass metabolism. The current study aimed to manufacture and optimize a lavender oil-based nanoemulsion loaded with zaleplon and incorporate it into fast-disintegrating tablets to promote its dissolution and oral bioavailability via oral mucosa. Zaleplon-loaded nanoemulsions were devised with various levels of lavender oil (10% to 25%), the surfactant Sorbeth-20 (35% to 65%), and the co-surfactant HCO-60 (20% to 40%); the extreme vertices mixture statistical design was adopted. The droplet size and drug-loading efficiency were the evaluated. The optimal formulation was transformed into self-nanoemulsified lyophilized tablets (ZP-LV-SNELTs), which were tested for their uniformity of content, friability, and disintegration time with in-vitro release. Finally, the pharmacokinetic parameters of the ZP-LV-SNELTs were determined and compared with those of marketed formulations. The optimal nanoemulsion had a droplet size of 87 nm and drug-loading capacity of 185 mg/mL. ZP-LV-SNELTs exhibited acceptable friability and weight uniformity and a short disintegration time. The in-vitro release of ZP-LV-SNELTs was 17 times faster than that of the marketed tablet. Moreover, the optimal ZP-LV-SNELTs increased the bioavailability of zaleplon in rabbits by 1.6-fold compared with the commercial tablets. Hence, this investigation revealed that ZP-LV-SNELTs delivered zaleplon with enhanced solubility, a fast release, and boosted bioavailability thru oral mucosa which provided a favorable route for drug administration which is suggested to be clinically investigated in future studies.
    Keywords:  Zaleplon; fast-disintegrating tablet; lavender oil; mixture design; pharmacokinetics
    DOI:  https://doi.org/10.1080/10717544.2022.2115165
  69. Explor Target Antitumor Ther. 2021 ;2(2): 208-226
    Understanding doxorubicin associated calcium remodeling during triple-negative breast cancer treatment: an in silico study.
    Garhima Arora, Sumana Ghosh, Samrat Chatterjee.
       Aim: Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer with high heterogeneity, rapid progression, and paucity of treatment options. The most effective chemotherapeutic drug used to treat TNBC is doxorubicin (Doxo) which is an anthracycline antibiotic. However, Doxo treatment alters cytosolic calcium dynamics leading to drug-resistance condition. The aim of this study is to capture the alterations in the activity of various calcium channels and pumps during Doxo treatment and their consequences on cytosolic calcium dynamics that ultimately result in drug resistance.
    Methods: In the present study, a mathematical model is proposed to capture the complex dynamical landscape of intracellular calcium during Doxo treatment. This study provides an insight into Doxo remodeling of calcium dynamics and associated drug-resistance effect. The model was first analyzed analytically and then explored through numerical simulation using techniques like global sensitivity analysis, parameter recalibration, etc.
    Results: The model is used to predict the potential combination therapy for Doxo that can overcome Doxo associated drug resistance. The results show targeting the dysregulated Ca2+ channels and pumps might provide efficient chemotherapy in TNBC. It was also observed that the indispensability of calcium influx rate is paramount in the Doxo drug resistance. Finally, three drugs were identified from existing literature that could be used as a combination therapy along with Doxo.
    Conclusions: The investigation highlights the importance of integrating the calcium signaling of various calcium regulating compounds for their effective anti-tumor effects deliverance along with chemotherapeutic agents. The results from this study might provide a new direction to the experimental biologists to explore different combination therapies with Doxo to enhance its anti-tumor effect.
    Keywords:  Triple-negative breast cancer; calcium signaling; doxorubicin; drug resistance; mathematical model
    DOI:  https://doi.org/10.37349/etat.2021.00042
  70. Biomed Pharmacother. 2022 Aug 24. pii: S0753-3322(22)00973-8. [Epub ahead of print]154 113584
    Kigelia africana inhibits proliferation and induces cell death in stage 4 Neuroblastoma cell lines.
    Sofia Ahrens, Birgit Appl, Magdalena Trochimiuk, Charlotte Dücker, Gemma Feixas Serra, Albert Oliver Grau, Konrad Reinshagen, Laia Pagerols Raluy.
      Neuroblastoma (NB) is one of the most common solid pediatric tumors and especially high-risk NBs still account for about 12-15% of cancer related deaths in children. Kigelia africana (KA) is a plant used in traditional African medicine which has already shown its anti-cancer potential in several in vitro and in vivo studies. The aim of this study is to evaluate the effect of KA fruit extract on stage 4 high-risk NB cells. Therefore, NB cell lines with and without MYCN amplification and non-neoplastic cells were treated with KA fruit extract at different concentrations. The effect of KA on cell viability and apoptosis rate were assessed by bioluminescence-/fluorescence-based assays. Several proteins involved in survival, tumor growth, inflammation and metastasis were detected via western blot and immunofluorescence. Secreted cytokines were detected via ELISA. Phytochemical composition of the extract was analyzed by liquid chromatography with tandem mass spectrometry (LC/MS/MS). Our group demonstrates a dose- and time-dependent selective cytotoxic effect of KA fruit extract on NB, especially in MYCN non-amplified tumor cells, by inhibiting cell proliferation and inducing cell death. Western blot and immunofluorescence results demonstrate a regulation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), disialoganglioside GD2 and epidermal growth factor receptor (EGFR) in KA-treated tumor cells. Our results evidence striking anti-cancer properties of KA fruit and pave the way for further surveys on the therapeutic properties and mechanisms of action in NB.
    Keywords:  Cancer; EGFR; Kigelia africana; NF-κB; Neuroblastoma; Phytotherapeutics
    DOI:  https://doi.org/10.1016/j.biopha.2022.113584
  71. Yakugaku Zasshi. 2022 ;142(9): 977-991
    [Studies on the Isolation and Molecular Mechanisms of Bioactive Phytochemicals].
    Norio Kaneda.
      Studies on the isolation and molecular mechanisms of phytochemicals with anti-tumor or anti-inflammatory properties are important to developing new drugs for cancer and neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. In the course of a study to screen bioactive isoflavones from Erythrina poeppigiana (Leguminosae), we isolated an isoflavone with potent apoptosis-inducing activity against human leukemia HL-60 cells. It was designated erypoegin K. The studies demonstrated an enantiomer, (S)-erypoegin K, displayed selective cytotoxic activity, was a novel inhibitor of topoisomerase II, and possessed anti-tumor activity both in vitro and in vivo. We identified other apoptosis-inducing isoflavones with the ability to inhibit glyoxalase I. Dimeric acridone alkaloids, carbazole alkaloids, and coumarin and quinoline derivatives-all obtained mainly from plants in the family Rutaceae-induced apoptosis of HL-60 cells via the production of reactive oxygen species and mitochondrial dysfunction. We also identified terpenoid coumarins, carbazole quinones, rotenoid derivatives, and quinolone alkaloids with anti-inflammatory activities. These compounds reduced nitric oxide (NO) production from RAW264.7 macrophage cells stimulated with lipopolysaccharides and interferon-γ. Some of the compounds displayed neuroprotective activity by reducing NO production. This review primarily describes our recent studies on erypoegin K, and other compounds with apoptosis-inducing and anti-inflammatory activities.
    Keywords:  anti-inflammation; apoptosis; isoflavone; phytochemical; topoisomerase II
    DOI:  https://doi.org/10.1248/yakushi.22-00043
  72. Biomater Sci. 2022 Aug 31.
    A mitochondria targeted cascade reaction nanosystem for improved therapeutic effect by overcoming cellular resistance.
    Zhen Sun, Weihua Chen, Dianshuai Huang, Chunhuan Jiang, Lehui Lu.
      Mitigating cellular resistance, which could enhance the sensitivity of tumor cells to treatment, is a promising approach for obtaining better therapeutic outcomes. However, the present designs of materials generally disregard this point, or only focus on a single specific resistance. Herein, a strategy based on a series of cascade reactions aiming to suppress multiple cellular resistances is designed by integrating photothermal and chemotherapy into a mitochondria targeted nanosystem (AuBPs@TD). The intelligent nanosystem is fabricated by modifying gold nanobipyramids (AuBPs) with triphenylphosphonium (TPP) functionalized dichloroacetic acid (DCA). TPP serves as a "navigation system" and facilitates the location of AuBPs@TD in the mitochondria. Moreover, the released DCA promoted by the photothermal effect of AuBPs, as the mitochondrial kinase inhibitor, could inhibit glycolysis, and lead to a repressed expression of heat shock protein 90, which is the main resistance protein in cancer cells against photothermal therapy (PTT). Thus, the photothermal antitumor effect can be significantly improved. For the other cascade passage, the hyperthermal atmosphere depresses the expression of P-glycoprotein, a protein associated with drug resistance, and consequently prevents DCA molecules from being expelled in return. Furthermore, the retained DCA molecules elevate the concentration of intracellular hydrogen peroxide, and due to the peroxidase-like activity of AuBPs, increased intracellular reactive oxygen species could be obtained to accelerate apoptosis. As a result, these cascade reactions lead to significant inhibition of cellular resistance and greatly improve the therapeutic performance. This work paves a new way for suppressing cellular resistance to achieve the desired therapeutic effect.
    DOI:  https://doi.org/10.1039/d2bm00956k
  73. Pharmacol Res. 2022 Aug 27. pii: S1043-6618(22)00364-4. [Epub ahead of print]184 106419
    Flavonoids regulate tumor-associated macrophages - From structure-activity relationship to clinical potential (Review).
    Qi Sun, Qi Liu, Xintong Zhou, Xiaomin Wang, Huayao Li, Wenfeng Zhang, Hailian Yuan, Changgang Sun.
      In recent years, the strategy for tumor therapy has changed from focusing on the direct killing effect of different types of therapeutic agents on cancer cells to the new mainstream of multi-mode and -pathway combined interventions in the microenvironment of the developing tumor. Flavonoids, with unique tricyclic structures, have diverse and extensive immunomodulatory and anti-cancer activities in the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) are the most abundant immunosuppressive cells in the TME. The regulation of macrophages to fight cancer is a promising immunotherapeutic strategy. This study covers the most comprehensive cognition of flavonoids in regulating TAMs so far. Far more than a simple list of studies, we try to dig out evidence of crosstalk at the molecular level between flavonoids and TAMs from literature, in order to discuss the most relevant chemical structure and its possible relationship with the multimodal pharmacological activity, as well as systematically build a structure-activity relationship between flavonoids and TAMs. Additionally, we point out the advantages of the macro-control of flavonoids in the TME and discuss the potential clinical implications as well as areas for future research of flavonoids in regulating TAMs. These results will provide hopeful directions for the research of antitumor drugs, while providing new ideas for the pharmaceutical industry to develop more effective forms of flavonoids.
    Keywords:  Apigenin (PubChem CID: 5280443); Baicalin (PubChem CID: 64982); Epicatechin (PubChem CID: 72276); Flavonoid; Genistein (PubChem CID: 5280961); Hesperidin (PubChem CID: 10621); Luteolin (PubChem CID: 5280445); Myricetin (PubChem CID: 5281672); Naringenin (PubChem CID: 932); Pharmacological mechanism; Polyphenols (PubChem CID: 5280443); Quercetin (PubChem CID: 5280343); Structure–activity relationship; Tumor microenvironment; Tumor-associated macrophage; Xanthohumol (PubChem CID: 639665)
    DOI:  https://doi.org/10.1016/j.phrs.2022.106419
  74. Signal Transduct Target Ther. 2022 Sep 01. 7(1): 305
    Lactate metabolism in human health and disease.
    Xiaolu Li, Yanyan Yang, Bei Zhang, Xiaotong Lin, Xiuxiu Fu, Yi An, Yulin Zou, Jian-Xun Wang, Zhibin Wang, Tao Yu.
      The current understanding of lactate extends from its origins as a byproduct of glycolysis to its role in tumor metabolism, as identified by studies on the Warburg effect. The lactate shuttle hypothesis suggests that lactate plays an important role as a bridging signaling molecule that coordinates signaling among different cells, organs and tissues. Lactylation is a posttranslational modification initially reported by Professor Yingming Zhao's research group in 2019. Subsequent studies confirmed that lactylation is a vital component of lactate function and is involved in tumor proliferation, neural excitation, inflammation and other biological processes. An indispensable substance for various physiological cellular functions, lactate plays a regulatory role in different aspects of energy metabolism and signal transduction. Therefore, a comprehensive review and summary of lactate is presented to clarify the role of lactate in disease and to provide a reference and direction for future research. This review offers a systematic overview of lactate homeostasis and its roles in physiological and pathological processes, as well as a comprehensive overview of the effects of lactylation in various diseases, particularly inflammation and cancer.
    DOI:  https://doi.org/10.1038/s41392-022-01151-3
  75. ACS Nano. 2022 Sep 01.
    Emerging Strategies in Stimuli-Responsive Prodrug Nanosystems for Cancer Therapy.
    Chendi Ding, Chunbo Chen, Xiaowei Zeng, Hongzhong Chen, Yanli Zhao.
      Prodrugs are chemically modified drug molecules that are inactive before administration. After administration, they are converted in situ to parent drugs and induce the mechanism of action. The development of prodrugs has upgraded conventional drug treatments in terms of bioavailability, targeting, and reduced side effects. Especially in cancer therapy, the application of prodrugs has achieved substantial therapeutic effects. From serendipitous discovery in the early stage to functional design with pertinence nowadays, the importance of prodrugs in drug design is self-evident. At present, studying stimuli-responsive activation mechanisms, regulating the stimuli intensity in vivo, and designing nanoscale prodrug formulations are the major strategies to promote the development of prodrugs. In this review, we provide an outlook of recent cutting-edge studies on stimuli-responsive prodrug nanosystems from these three aspects. We also discuss prospects and challenges in the future development of such prodrugs.
    Keywords:  biomedical nanotechnology; cancer therapy; controlled release; drug delivery; nanomedicine; nanoscale prodrugs; on-demand activation; stimuli responsiveness
    DOI:  https://doi.org/10.1021/acsnano.2c05379
  76. Front Nutr. 2022 ;9 982370
    Preparation of starch-based functional food nano-microcapsule delivery system and its controlled release characteristics.
    Shuangqi Tian, Xing'ao Xue, Xinwei Wang, Zhicheng Chen.
      Most of the functional substances in food are absorbed in the small intestine, but before entering the small intestine, the strong acid and enzymes in the stomach limit the amount that can reach the small intestine. Therefore, in this paper, to develop a delivery system for functional food ingredients, maintain the biological activity of the ingredients, and deliver them to the target digestive organs, preparation of starch-based functional food nano-microcapsule delivery system and its controlled release characteristics were reviewed. Embedding unstable food active ingredients in starch-based nano-microcapsules can give the core material excellent stability and certain functional effects. Starch-based wall materials refer to a type of natural polymer material that uses starch or its derivatives to coat fat-soluble components with its hydrophobic cavities. The preparation methods of starch-based wall materials mainly include spray drying, extrusion, freeze drying, ultra-high pressure, coagulation, fluidized bed coating, molecular inclusion, chemical, and enzymic methods. The controlled release of functional food can be achieved by preparing starch-based nano-microcapsules to encapsulate the active agents. It has been reported that that compared with traditional embedding agents such as gelatin, acacia gum, and xanthan gum, starch-based functional food nano-microcapsule delivery system had many good properties, including improving antioxidant capacity, bioavailability, probiotics, and concealing bad flavors. From this review, we can learn which method should be chosen to prepare starch-based functional food nano-microcapsule delivery system and understand the mechanism of controlled release.
    Keywords:  delivery system; functional food; nano-microcapsule; release characteristic; starch
    DOI:  https://doi.org/10.3389/fnut.2022.982370
  77. Acta Biomater. 2022 Aug 30. pii: S1742-7061(22)00531-1. [Epub ahead of print]
    Macrophage membrane-camouflaged lipoprotein nanoparticles for effective obesity treatment based on a sustainable self-reinforcement strategy.
    Yujie Su, Wei Wang, Qiaqia Xiao, Lu Tang, Tingting Wang, Mengying Xie, Yangnan Su.
      Modern lifestyle has led to an increase in the incidence of obesity as a public health concern; however, current anti-obesity medications often show limited efficacy with severe side effects. Therapeutic drugs that are selectively delivered to adipose tissue and accelerate energy consumption are promising strategies to overcome the limitations of existing anti-obesity treatment approaches. Herein, a drug delivery platform based on a macrophage cell membrane (Ma)-camouflaged recombinant high-density lipoprotein (rHDL) that was further decorated with a P3 peptide was fabricated to realize targeted drug delivery to adipose tissue. By co-delivering rosiglitazone (Rosi), a peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonist, and sildenafil (Sild), a phosphodiesterase type 5 (PDE5) inhibitor, a synergistic therapeutic outcome was achieved in the regulation of diet-induced obesity in a mice model. Body weight reduction and the metabolic status of obese mice were significantly improved after 28 days of treatment. More importantly, a sustainable self-reinforcement effect in multidose therapy was found after using this delivery system. The continuous treatment increased prohibitin (PHB) expression and capillary density in adipose tissue, which in turn improved the accumulation of the drugs in subsequent administration. Taken together, this constructed drug delivery system showed high effectiveness with good safety by combining two anti-obesity therapeutic agents, which exhibits promising research potential for adipose-targeted delivery. STATEMENT OF SIGNIFICANCE: Therapeutic strategies that directly target adipose tissue to increase energy consumption and regulate metabolism are promising but challenging. Herein, an adipose tissue-targeted delivery system was developed using a reconstituted high-density lipoprotein (rHDL) coated by a P3 peptide-decorated macrophage membrane. For the first time, we combined rosiglitazone (Rosi) and sildenafil (Sild) in the system and achieved synergy of adipose browning and angiogenesis for anti-obesity treatment. The therapy induced prohibitin expression and angiogenesis, which improved drug accumulation in adipose tissue in subsequent administrations. This resulted in a sustainable self-reinforcement effect with improved capacity for diet-induced obesity regulation. This study highlights the combination of adipose browning and angiogenesis in anti-obesity treatment and provides an innovative concept of enhancing adipose-targeted delivery.
    Keywords:  adipose browning; angiogenesis; diet-induced obesity regulation; drug combination; sustainable self-reinforcement effect
    DOI:  https://doi.org/10.1016/j.actbio.2022.08.055
  78. Pharm Nanotechnol. 2022 Sep 02.
    Dual Targeting Anti-Osteoporotic Therapy through Potential Nanotherapeutic Approaches.
    Sagar Salave, Dhwani Rana, Derajram Benival.
      Osteoporosis is characterised by a major public health burden, particularly taking into account the ageing global population. Therapeutic modalities for osteoporosis are categorised on the basis of their effect on bone remodeling: antiresorptive agents and anabolic agents. Anabolic drugs are favoured as they promote the formation of new bone, whereas antiresorptive drugs terminate the further deterioration of bone. Non-specific delivery of anabolic agents results in prolonged kidney exposure causing malignant hypercalcemia, whereas antiresorptive agents and bisphosphonates may produce osteonecrosis of the jaw. Several clinical trials have been reported for combinational therapy of anabolic agents and antiresorptive agents for osteoporosis. However, none of them have proven their cumulative effectiveness in the treatment of disease. The present work emphasizes on dual-targeting drug delivery approach comprising of bone anabolic and antiresorptive agents that would deliver the therapeutic agents to both the zones of bone simultaneously. The anticipated pioneering delivery approach will intensify the explicit interaction between the therapeutic agent and bone surfaces separately without developing severe adverse effects and improve the osteoporotic therapy effectively compared to non-targeted drug delivery.
    Keywords:  Anabolic agent; antiresorptive; dual drug delivery; nanotechnology; osteoporosis; targeted drug delivery.
    DOI:  https://doi.org/10.2174/2211738510666220902124653
  79. Explor Target Antitumor Ther. 2022 ;3(4): 423-427
    Anticancer action of plant products: changing stereotyped attitudes.
    Katrin Sak.
      Compared to humans, plants can synthesize an extremely diverse array of chemical compounds, including phenolic acids, flavonoids, stilbenes, lignans, terpenoids, alkaloids, and many other types of secondary metabolites that have been demonstrated to exert important bioactivities and impacts on the human health. As a result of extensive and sustained efforts, some phytochemicals like vincristine, vinblastine, and paclitaxel have already been approved as anticancer drugs today, while several others are under clinical trials. However, despite this remarkable success, studies on anticancer action of plant-derived products have been and paradoxically are still in some places, mixed up with alternative approaches and thereby considered non-credible, especially in regions where the role of traditional medicine has not been historically so prevalent as in several Asian countries. As a result, only about 10% of higher plants have been explored regarding the potential therapeutic effects of their constituents. Moreover, as one function of secondary metabolites includes the protection of plants against diverse environmental stresses, the content and composition of these phytochemicals might importantly vary between different regional habitats. Therefore, the stereotyped attitudes to plant products as something related to alternative medicine must be changed to identify new lead molecules for novel anticancer drugs. It is possible that plants still harbor an important spectrum of pharmaceutically interesting, but still unidentified, chemical compounds.
    Keywords:  Natural anticancer products; chemotherapeutic drugs; phytochemicals
    DOI:  https://doi.org/10.37349/etat.2022.00092
  80. Heliyon. 2022 Aug;8(8): e10196
    Pharmaceutical and drug delivery applications of chitosan biopolymer and its modified nanocomposite: A review.
    Welela Meka Kedir, Gamachu Fikadu Abdi, Meta Mamo Goro, Leta Deressa Tolesa.
      Due to their improved structural and functional properties as well as biocompatibility, biodegradability, and nontoxicity, chitosan and its nanoparticles are currently grasping the interest of researchers. Although numerous attempts have been made to apply chitosan and its derivatives to biological applications, few have reported in achieving its pharmacological and drug delivery. The goal of the current work is to provide a summary of the chitosan biopolymer's physical, chemical, and biological properties as well as its synthesis of nanoparticles and characterization of its modified nanocomposites. The drug delivery method and pharmaceutical applications of chitosan biopolymer and its modified nanocomposites are examined in further detail in this research. We will introduce also about the most current publications in this field of study as well as its recent expansion.
    Keywords:  Biopolymer; Chitosan; Drug delivery; Nanocomposite; Pharmaceutical
    DOI:  https://doi.org/10.1016/j.heliyon.2022.e10196
  81. Drug Deliv. 2022 Dec;29(1): 2796-2804
    Optimal treatment occasion for ultrasound stimulated microbubbles in promoting gemcitabine delivery to VX2 tumors.
    Tingting Luo, Luhua Bai, Yi Zhang, Leidan Huang, Hui Li, Shunji Gao, Xiaoxiao Dong, Ningshan Li, Zheng Liu.
      Ultrasound stimulated microbubbles (USMB) is a widely used technology that can promote chemotherapeutic delivery to tumors yet the best treatment occasion for USMB is unknown or ignored. We aimed to determine the optimal treatment occasion for USMB treatment to enhance tumor chemotherapy to achieve the highest drug concentration in tumors. Experiments were conducted on VX2 tumors implanted in 60 rabbits. Gemcitabine (GEM) was intravenously infused as a chemotherapeutic agent and USMB was administered before, during or after chemotherapy. USMB was conducted with a modified diagnostic ultrasound at 3 MHz employing short bursts (5 cycles and 0.125% duty cycle) at 0.26 MPa in combination with a lipid microbubble. Subsequently, tumor blood perfusion quantitation, drug concentration detection, and fluorescence microscopy were performed. The results showed that the group that received USMB treatment immediately after GEM infusion had the highest drug concentration in tumors, which was 2.83 times that of the control group. Fifteen tumors were then treated repeatedly with the optimal USMB-plus-GEM combination, and along with the GEM and the control groups, were studied for tumor growth, tumor cell proliferation, apoptosis, and related cytokine contents. The combined treatment significantly inhibited tumor growth and promoted apoptosis. The levels of related cytokines, including HIF-1α, decreased after six combination therapies. These results suggest that the optimal treatment occasion for USMB occurs immediately after chemotherapy and tumor hypoxia improves after multiple combination therapies.
    Keywords:  chemotherapy; diagnostic ultrasound; drug concentration; microbubbles; treatment occasion
    DOI:  https://doi.org/10.1080/10717544.2022.2115163
  82. Front Chem. 2022 ;10 954835
    Selective extraction and stabilization of bioactive compounds from rosemary leaves using a biphasic NADES.
    Carolina Vieira, Sílvia Rebocho, Rita Craveiro, Alexandre Paiva, Ana Rita C Duarte.
      Rosemary (Rosmarinus officinalis) is a natural source of bioactive compounds that have high antioxidant activity. It has been in use as a medicinal herb since ancient times, and it currently is in widespread use due to its inherent pharmacological and therapeutic potential, in the pharmaceutical, food, and cosmetic industries. Natural deep eutectic systems (NADESs) have recently been considered as suitable extraction solvents for bioactive compounds, with high solvent power, low toxicity, biodegradability, and low environmental impact. The present work concerns the extraction of compounds such as rosmarinic acid, carnosol, carnosic acid, and caffeic acid, from rosemary using NADESs. This extraction was carried out using heat and stirring (HS) and ultrasound-assisted extraction (UAE). A NADES composed of menthol and lauric acid at a molar ratio of 2:1 (Me:Lau) extracted carnosic acid and carnosol preferentially, showing that this NADES exhibits selectivity for nonpolar compounds. On the other hand, a system of lactic acid and glucose (LA:Glu (5:1)) extracted preferentially rosmaniric acid, which is a more polar compound. Taking advantage of the different polarities of these NADESs, a simultaneous extraction was carried out, where the two NADESs form a biphasic system. The system LA:Glu (5:1)/Men:Lau (2:1) presented the most promising results, reaching 1.00 ± 0.12 mg of rosmarinic acid/g rosemary and 0.26 ± 0.04 mg caffeic acid/g rosemary in the more polar phase and 2.30 ± 0.18 mg of carnosol/g of rosemary and 17.54 ± 1.88 mg carnosic acid/g rosemary in the nonpolar phase. This work reveals that is possible to use two different systems at the same time and extract different compounds in a single-step process under the same conditions. NADESs are also reported to stabilize bioactive compounds, due to their interactions established with NADES components. To determine the stability of the extracts over time, the compounds of interest were quantified by HPLC at different time points. This allows the conclusion that bioactive compounds from rosemary were stable in NADESs for long periods of time; in particular, carnosic acid presented a decrease of only 25% in its antioxidant activity after 3 months, whereas the carnosic acid extracted and kept in the methanol was no longer detected after 15 days. The stabilizing ability of NADESs to extract phenolic/bioactive compounds shows a great promise for future industrial applications.
    Keywords:  Rosmarinus officinalis; antioxidants; natural deep eutectic systems; rosmarinic acid; ultrasound-assisted extraction
    DOI:  https://doi.org/10.3389/fchem.2022.954835
  83. J Control Release. 2022 Aug 30. pii: S0168-3659(22)00557-0. [Epub ahead of print]
    pH-activated nanoplatform for visualized photodynamic and ferroptosis synergistic therapy of tumors.
    Rui Sun, Wen Ma, Mingjian Ling, Chenhong Tang, Min Zhong, Jingyue Dai, Meiyan Zhu, Xuzi Cai, Guang Li, Qing Xu, Longguang Tang, Zhiqiang Yu, Zhenwei Peng.
      To overcome drug resistance and improve precision theranostics for hepatocellular carcinoma (HCC), a nanoplatform with an "off/on" function for multimodality imaging (near-infrared-II (NIR-II) fluorescence imaging, MRI, and photoacoustic imaging) and synergistic therapy (photodynamic therapy and ferroptosis) activated by an acidic pH in the tumor microenvironment is proposed. Although many photosensitizers with photodynamic effects have been reported, very few of them have outstanding photodynamic effect and high stability with response to endogenous stimuli capable of NIR-II imaging. Herein, a new amphiphilic photosensitizer SR780 derived from croconaine dye, was developed with satisfactory photodynamic effects and pH-responsive NIR-II imaging. Interestingly, it was deactivated by coordination with Fe3+ (SR780@Fe) and activated during their release under mild acidic condition. Ferroptosis can generate hydroxyl free radical and lipid peroxide, which aggravate the oxidative stress of tumor cells and mediate their death while depleting glutathione (GSH) to enhance photodynamic effect. In situ pH-activatable theranostic nanoplatform, SR780@Fe-PAE-GP, was thus developed by loading SR780@Fe with pH-responsive polymers, modified by a glypican-3 (GPC-3) receptor-targeting peptide. The synergistic antitumor effects were confirmed both in vitro and in vivo, and the tumor inhibition rate of the SR780@Fe-PAE-GP + L treatment group reached 98%.
    Keywords:  Ferroptosis; Multimodality imaging; NIR-II imaging; Photodynamic therapy; pH-activatable
    DOI:  https://doi.org/10.1016/j.jconrel.2022.08.050
  84. J Nanobiotechnology. 2022 Aug 30. 20(1): 389
    "Two-birds-one-stone" colon-targeted nanomedicine treats ulcerative colitis via remodeling immune microenvironment and anti-fibrosis.
    Jiaxin Zhang, Ante Ou, Xueping Tang, Rong Wang, Yujuan Fan, Yuefei Fang, Yuge Zhao, Pengfei Zhao, Dongying Chen, Bing Wang, Yongzhuo Huang.
      Dysregulated mucosal immune responses and colonic fibrosis impose two formidable challenges for ulcerative colitis treatment. It indicates that monotherapy could not sufficiently deal with this complicated disease and combination therapy may provide a potential solution. A chitosan-modified poly(lactic-co-glycolic acid) nanoparticle (CS-PLGA NP) system was developed for co-delivering patchouli alcohol and simvastatin to the inflamed colonic epithelium to alleviate the symptoms of ulcerative colitis via remodeling immune microenvironment and anti-fibrosis, a so-called "two-birds-one-stone" nanotherapeutic strategy. The bioadhesive nanomedicine enhanced the intestinal epithelial cell uptake efficiency and improved the drug stability in the gastrointestinal tract. The nanomedicine effectively regulated the Akt/MAPK/NF-κB pathway and reshaped the immune microenvironment through repolarizing M2Φ, promoting regulatory T cells and G-MDSC, suppressing neutrophil and inflammatory monocyte infiltration, as well as inhibiting dendritic cell maturation. Additionally, the nanomedicine alleviated colonic fibrosis. Our work elucidates that the colon-targeted codelivery for combination therapy is promising for ulcerative colitis treatment and to address the unmet medical need.
    Keywords:  Anti-fibrosis; Colonic drug delivery; Inflammatory microenvironment; Patchouli alcohol; Simvastatin; Ulcerative colitis
    DOI:  https://doi.org/10.1186/s12951-022-01598-0
  85. Biomaterials. 2022 Aug 20. pii: S0142-9612(22)00377-5. [Epub ahead of print] 121737
    Smart pH-responsive polyhydralazine/bortezomib nanoparticles for remodeling tumor microenvironment and enhancing chemotherapy.
    Rui Wang, Xiaodan Xu, Dongdong Li, Wei Zhang, Xueying Shi, Hongxia Xu, Jianqiao Hong, Shasha Yao, Jiwei Liu, Zhenli Wei, Ying Piao, Zhuxian Zhou, Youqing Shen, Jianbin Tang.
      The clinical translation of nanomedicines has been impeded by the unfavorable tumor microenvironment (TME), particularly the tortuous vasculature networks, which significantly influence the transport and distribution of nanomedicines into tumors. In this work, a smart pH-responsive bortezomib (BTZ)-loaded polyhydralazine nanoparticle (PHDZ/BTZ) is presented, which has a great capacity to augment the accumulation of BTZ in tumors by dilating tumor blood vessels via specific release of vasodilator hydralazine (HDZ). The Lewis acid-base coordination effect between the boronic bond of BTZ and amino of HDZ empowered PHDZ/BTZ nanoparticles with great stability and high drug loading contents. Once triggered by the acidic tumor environment, HDZ could be released quickly to remodel TME through tumor vessel dilation, hypoxia attenuation, and lead to an increased intratumoral BTZ accumulation. Additionally, our investigation revealed that this pH-responsive nanoparticle dramatically suppressed tumor growth, inhibited the occurrence of lung metastasis with fewer side effects and induced immunogenic cell death (ICD), thereby eliciting immune activation including massive cytotoxic T lymphocytes (CTLs) infiltration in tumors and efficient serum proinflammatory cytokine secretion compared with free BTZ treatment. Thus, with efficient drug loading capacity and potent immune activation, PHDZ nanoparticles exhibit great potential in the delivery of boronic acid-containing drugs aimed at a wide range of diseases.
    Keywords:  Chemo-immunotherapy; Tumor microenvironment modulation; Tumor vessel dilation; pH-responsive nanoparticles
    DOI:  https://doi.org/10.1016/j.biomaterials.2022.121737
  86. J Ethnopharmacol. 2022 Aug 28. pii: S0378-8741(22)00702-4. [Epub ahead of print]298 115663
    Investigation on wound healing effect of Mediterranean medicinal plants and some related phenolic compounds: A review.
    Ibrahim Mssillou, Meryem Bakour, Meryem Slighoua, Hassan Laaroussi, Hamza Saghrouchni, Fatima Ez-Zahra Amrati, Badiaa Lyoussi, Elhoussine Derwich.
       ETHNOPHARMACOLOGICAL RELEVANCE: The human skin constitutes a biological barrier against external stress and wounds can reduce the role of its physiological structure. In medical sciences, wounds are considered a major problem that requires urgent intervention. For centuries, medicinal plants have been used in the Mediterranean countries for many purposes and against wounds.
    AIM OF THIS REVIEW: Provides an outlook on the Mediterranean medicinal plants used in wound healing. Furthermore, the wound healing effect of polyphenolic compounds and their chemical structures are also summarized. Moreover, we discussed the wound healing process, the structure of the skin, and the current therapies in wound healing.
    MATERIALS AND METHODS: The search was performed in several databases such as ScienceDirect, PubMed, Google Scholar, Scopus, and Web of Science. The following Keywords were used individually and/or in combination: the Mediterranean, wound healing, medicinal plants, phenolic compounds, composition, flavonoid, tannin.
    RESULTS: The wound healing process is distinguished by four phases, which are respectively, hemostasis, inflammation, proliferation, and remodeling. The Mediterranean medicinal plants are widely used in the treatment of wounds. The finding showed that eighty-nine species belonging to forty families were evaluated for their wound-healing effect in this area. The Asteraceae family was the most reported family with 12 species followed by Lamiaceae (11 species). Tunisia, Egypt, Morocco, and Algeria were the countries where these plants are frequently used in wound healing. In addition to medicinal plants, results showed that nineteen phenolic compounds from different classes are used in wound treatment. Tyrosol, hydroxytyrosol, curcumin, luteolin, chrysin, rutin, kaempferol, quercetin, icariin, morin, epigallocatechin gallate, taxifolin, silymarin, hesperidin, naringin, isoliquiritin, puerarin, genistein, and daidzein were the main compounds that showed wound-healing effect.
    CONCLUSION: In conclusion, medicinal plants and polyphenolic compounds provide therapeutic evidence in wound healing and for the development of new drugs in this field.
    Keywords:  Mediterranean medicinal plants; Polyphenolic compounds; Skin anatomy; Therapies; Wound healing
    DOI:  https://doi.org/10.1016/j.jep.2022.115663
  87. Front Endocrinol (Lausanne). 2022 ;13 988295
    Metabolic reprogramming and crosstalk of cancer-related fibroblasts and immune cells in the tumor microenvironment.
    Yifei Zhu, Xinyan Li, Lei Wang, Xiwei Hong, Jie Yang.
      It is notorious that cancer cells alter their metabolism to adjust to harsh environments of hypoxia and nutritional starvation. Metabolic reprogramming most often occurs in the tumor microenvironment (TME). TME is defined as the cellular environment in which the tumor resides. This includes surrounding blood vessels, fibroblasts, immune cells, signaling molecules and the extracellular matrix (ECM). It is increasingly recognized that cancer cells, fibroblasts and immune cells within TME can regulate tumor progression through metabolic reprogramming. As the most significant proportion of cells among all the stromal cells that constitute TME, cancer-associated fibroblasts (CAFs) are closely associated with tumorigenesis and progression. Multitudinous studies have shown that CAFs participate in and promote tumor metabolic reprogramming and exert regulatory effects via the dysregulation of metabolic pathways. Previous studies have demonstrated that curbing the substance exchange between CAFs and tumor cells can dramatically restrain tumor growth. Emerging studies suggest that CAFs within the TME have emerged as important determinants of metabolic reprogramming. Metabolic reprogramming also occurs in the metabolic pattern of immune cells. In the meanwhile, immune cell phenotype and functions are metabolically regulated. Notably, immune cell functions influenced by metabolic programs may ultimately lead to alterations in tumor immunity. Despite the fact that multiple previous researches have been devoted to studying the interplays between different cells in the tumor microenvironment, the complicated relationship between CAFs and immune cells and implications of metabolic reprogramming remains unknown and requires further investigation. In this review, we discuss our current comprehension of metabolic reprogramming of CAFs and immune cells (mainly glucose, amino acid, and lipid metabolism) and crosstalk between them that induces immune responses, and we also highlight their contributions to tumorigenesis and progression. Furthermore, we underscore potential therapeutic opportunities arising from metabolism dysregulation and metabolic crosstalk, focusing on strategies targeting CAFs and immune cell metabolic crosstalk in cancer immunotherapy.
    Keywords:  Tumor microenvironment; cancer-associated fibroblasts; immune cells; immunotherapy; metabolic reprogramming
    DOI:  https://doi.org/10.3389/fendo.2022.988295
  88. Crit Rev Food Sci Nutr. 2022 Aug 29. 1-29
    Recent advances in biological properties of brown algae-derived compounds for nutraceutical applications.
    Aurora Silva, Lucia Cassani, Clara Grosso, Paula Garcia-Oliveira, Stephanie L Morais, Javier Echave, Maria Carpena, Jianbo Xiao, M Fatima Barroso, Jesus Simal-Gandara, Miguel A Prieto.
      The increasing demand for nutraceuticals in the circular economy era has driven the research toward studying bioactive compounds from renewable underexploited resources. In this regard, the exploration of brown algae has shown significant growth and maintains a great promise for the future. One possible explanation could be that brown algae are rich sources of nutritional compounds (polyunsaturated fatty acids, fiber, proteins, minerals, and vitamins) and unique metabolic compounds (phlorotannins, fucoxanthin, fucoidan) with promising biological activities that make them good candidates for nutraceutical applications with increased value-added. In this review, a deep description of bioactive compounds from brown algae is presented. In addition, recent advances in biological activities ascribed to these compounds through in vitro and in vivo assays are pointed out. Delivery strategies to overcome some drawbacks related to the direct application of algae-derived compounds (low solubility, thermal instability, bioavailability, unpleasant organoleptic properties) are also reviewed. Finally, current commercial and legal statuses of ingredients from brown algae are presented, considering future therapeutical and market perspectives as nutraceuticals.
    Keywords:  Macroalgae; bioactivities; current market; encapsulation; health-promoting compounds
    DOI:  https://doi.org/10.1080/10408398.2022.2115004
  89. Nanoscale. 2022 Sep 02.
    A dual gate-controlled intelligent nanoreactor enables collaborative precise treatment for cancer nanotherapy.
    Huimin Zhang, Weina Tang, Qi Gong, Xinyi Yang, Yunqiang Sun, Zhichao Dai, Zunfu Hu, Xiuwen Zheng.
      Recently, disulfiram (DSF), approved by the FDA as an anti-alcoholic drug, has been proved as an effective antitumor drug after chelating with Cu2+. To overcome the shortage of intracellular Cu2+, we have constructed a dual gate-controlled intelligent nanoreactor (HA-DSF@HCuS@FePtMn, HDHF) via the ingenious combination of hollow copper sulfide (HCuS) nanoparticles, DSF and FePtMn nanocrystals. HDHF has a NIR-actuated gate and enzyme-actuated gate that could be opened in the hyaluronidase-abundant tumor microenvironment with NIR laser irradiation to trigger drug (DSF/FePtMn) release and synergistic therapy. Moreover, the FePtMn nanocrystals could continuously release Fe2+, which could catalyze H2O2 into highly cytotoxic hydroxyl radicals (˙OH), triggering chemodynamic therapy (CDT). When exposed to NIR laser, HCuS could collapse and release Cu2+, which could immediately chelate with DSF, forming the effective anticancer drug (Cu(DTC)2) and enabling DSF-based chemotherapy. More importantly, the efficient photothermal therapy (PTT) effect of HCuS could accelerate the FePtMn-based CDT and the release of Cu2+/DSF, improving tumor treatment efficiency. Thus, this study represents a distinctive paradigm of a dual gate-controlled intelligent nanoreactor enabled PTT-augmented DSF-based chemotherapy and FePtMn-based CDT for cancer nanotherapy.
    DOI:  https://doi.org/10.1039/d2nr03676b
  90. Biomed Pharmacother. 2022 Aug 30. pii: S0753-3322(22)01010-1. [Epub ahead of print]154 113621
    Protective effects of curcumin against traumatic brain injury.
    Danial Khayatan, Seyed Mehrad Razavi, Zahra Najafi Arab, Amir Hossein Niknejad, Kiana Nouri, Saeideh Momtaz, Eric Gumpricht, Tannaz Jamialahmadi, Amir Hossein Abdolghaffari, George E Barreto, Amirhossein Sahebkar.
      Neuroinflammation is a key pathophysiological mechanism implicated in the neurodegenerative condition. One such condition implicating neuroinflammation is traumatic brain injury (TBI). Over the past decades, various alternative natural compounds, such as curcumin, have been investigated as novel therapeutic options to mitigate the pathophysiological pathways and clinical sequelae involved in TBI. As the main component of turmeric (Curcuma longa), curcumin has a broad range of clinical properties due to its considerable antioxidative and anti-inflammatory actions. This review discusses the pleiotropic mechanisms, the side effects, curcumin's delivery to the central nervous system (CNS), and its immunomodulatory and protective effects on TBI. Clinical trials, in vivo, and in vitro studies were extracted from different scientific databases, including PubMed, Scopus, and Google Scholar, to assess the effects of curcumin or its derivatives in TBI. Findings reveal that curcumin exhibited some protective effects on TBI via modulation of cell signaling pathways including toll-like receptor-4 (TLR-4), nuclear factor kappa B (NF-κB), and Nod-like receptor family proteins (NLRPs). Moreover, curcumin upregulates the brain-derived Neurotrophic Factor/Tropomyosin receptor kinase B (BDNF/TrkB) signaling pathway, phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT), nuclear factor erythroid 2-related factor 2 (Nrf2), which have crucial functions in modulation of TBI pathophysiological-mediated pathways. Curcumin displays beneficial immunomodulatory functions and protective capacities in different TBI models, although more clinical experiments are required to clarify curcumin's precise mechanisms and function in TBI.
    Keywords:  Curcumin; Neurodegenerative diseases; Neuroinflammation; Traumatic brain injury (TBI)
    DOI:  https://doi.org/10.1016/j.biopha.2022.113621
  91. Nanotheranostics. 2022 ;6(4): 400-423
    Nanotechnology Advances in the Detection and Treatment of Cancer: An Overview.
    Sareh Mosleh-Shirazi, Milad Abbasi, Mohammad Reza Moaddeli, Ahmad Vaez, Mostafa Shafiee, Seyed Reza Kasaee, Ali Mohammad Amani, Saeid Hatam.
      Over the last few years, progress has been made across the nanomedicine landscape, in particular, the invention of contemporary nanostructures for cancer diagnosis and overcoming complexities in the clinical treatment of cancerous tissues. Thanks to their small diameter and large surface-to-volume proportions, nanomaterials have special physicochemical properties that empower them to bind, absorb and transport high-efficiency substances, such as small molecular drugs, DNA, proteins, RNAs, and probes. They also have excellent durability, high carrier potential, the ability to integrate both hydrophobic and hydrophilic compounds, and compatibility with various transport routes, making them especially appealing over a wide range of oncology fields. This is also due to their configurable scale, structure, and surface properties. This review paper discusses how nanostructures can function as therapeutic vectors to enhance the therapeutic value of molecules; how nanomaterials can be used as medicinal products in gene therapy, photodynamics, and thermal treatment; and finally, the application of nanomaterials in the form of molecular imaging agents to diagnose and map tumor growth.
    Keywords:  Cancer detection; Cancer imaging; Cancer therapy; Nanostructures; Nanotechnology
    DOI:  https://doi.org/10.7150/ntno.74613
  92. Ageing Res Rev. 2022 Aug 29. pii: S1568-1637(22)00170-2. [Epub ahead of print] 101728
    Nutrients and amyloid β status in the brain: a narrative review.
    Gustavo Díaz, Laetitia Lengele, Sandrine Sourdet, Gaëlle Soriano, Philipe de Souto Barreto.
      Amyloid beta (Aβ) is a peptide and a hallmark of Alzheimer's disease (AD). Emerging evidence suggests that Aβ levels could be influenced by diet. However, the evidence is sparse and for some nutrients, controversial. The aim of this narrative review is to gather the findings of observational and clinical trials involving human participants on the relationships between nutrients and brain Aβ status. Some dietary patterns are associated to reduced levels of Aβ in the brain, such as the Mediterranean diet, ketogenic diet as well as low intake of saturated fat, high-glycemic-index food, sodium, and junk/fast food. Low Aβ status in the brain was also associated with higher density lipoproteins (HDL) cholesterol and polyunsaturated fatty acids consumption. Data on alcohol intake is not conclusive. On the contrary, high Aβ levels in the brain were related to a higher intake of total cholesterol, triglycerides, low-density lipoproteins (LDL) cholesterol, saturated fat, sucrose, and fructose. Folic acid, cobalamin, vitamin E, and vitamin D were not associated to Aβ status, while high blood concentrations of Calcium, Aluminum, Zinc, Copper, and Manganese were associated with decreased Aβ blood levels but were not associated with Aβ cerebral spinal fluid (CSF) concentrations. In conclusion, certain dietary patterns and nutrients are associated to brain Aβ status. Further research on the association between nutrients and brain Aβ status is needed in order to pave the way to use nutritional interventions as efficacious strategies to prevent Aβ disturbance and potentially AD.
    Keywords:  Alzheimer’s disease; amyloid beta; diet; dietary patterns; nutrients; nutrition
    DOI:  https://doi.org/10.1016/j.arr.2022.101728
  93. Nanotheranostics. 2022 ;6(4): 424-435
    Stealth Liposomal Chemotherapeutic Agent for Triple Negative Breast Cancer with Improved Pharmacokinetics.
    Nagavendra Kommineni, David Paul, Raju Saka, Wahid Khan, Satheeshkumar Nanjappan.
      Triple-negative breast cancer is one of the most lethal cancers. Chemotherapeutics for targeting CDK4 and CDK6 like Palbociclib (PAB) in triple-negative breast cancer was widely explored. However, poor bioavailability and severe side effects profile limiting its clinical usage in the field of cancer chemotherapy. Herein, we set out to develop the stealth liposomes (LPS) of PAB by rotary thin film evaporation with a vesicle size of less than 100 nm. In vitro, drug release studies were performed and fitted into different release kinetic models. LPS were characterized by electron microscopic techniques for morphology. The engineered nanotherapeutics agents were further evaluated in 4T1 triple-negative breast cancer cell lines for its anti-cancer potential and cellular uptake. The hemolytic potential and pharmacokinetic (PK) behavior of developed LPS-PAB and PAB were analyzed by using robust UHPLC-QTOF-MS method. LPS-PAB demonstrates biphasic release profile with first-order release kinetics. Further, LPS-PAB has shown less IC50 value (1.99 µM) compared to PAB alone (3.24 µM). The designed nanoliposomes were tagged with fluorescent FITC dye to check rapid cellular uptake. Importantly, stealth LPS-PAB has shown a 1.75-fold reduction in hemolytic potential as compared to PAB plain drug at 100 µg/mL concentration. The PK results obtained was displayed 2.5-fold increase in Cmax, 1.45-fold increase in AUCtot, 1.8-fold increase in half-life and 1.3-fold increase in MRT with LPS-PAB when compared to orally administered PAB suspension. These findings suggest that novel LPS-PAB can be employed as an alternate therapeutic strategy to eradicate triple-negative breast cancer.
    Keywords:  Liposomes; PEGylation; Palbociclib; Pharmacokinetics; Triple Negative Breast Cancer
    DOI:  https://doi.org/10.7150/ntno.76370
  94. Endocr Connect. 2022 Sep 01. pii: EC-21-0596. [Epub ahead of print]
    Vitamin D and musculoskeletal health: outstanding aspects to be considered for the current evidence.
    Marcela Moraes Mendes, Patricia Borges Botelho, Helena Ribeiro.
      Vitamin D enhances calcium absorption, bone mineralisation and promotes maintenance of muscle function and is crucial for musculoskeletal health. Low vitamin D status triggers secondary hyperparathyroidism, increases bone loss, and leads to muscle weakness. The primary physiologic function of vitamin D and its metabolites is maintaining calcium homeostasis for metabolic functioning, signal transduction and neuromuscular activity. A considerable amount of human evidence supports the well-recognised contribution of adequate serum 25(OH)D concentrations for bone homeostasis maintenance and prevention and treatment strategies for osteoporosis when combined with adequate calcium intake. This paper aimed to review the literature published, mainly in the last 20 years, on the effect of vitamin D and its supplementation for musculoskeletal health in order to identify the aspects that remain unclear or controversial and therefore require further investigation and debate. There is a clear need for consistent data to establish realistic and meaningful recommendations of vitamin D status that considers different population groups and locations. Moreover, there is still a lack of consensus on thresholds for vitamin D deficiency and optimal status as well as toxicity; optimal intake of vitamin D; vitamin D supplement alone as a strategy to prevent fractures and falls; recommended sun exposure at different latitudes and for different skin pigmentations; and the extra skeletal effects of vitamin D.
    DOI:  https://doi.org/10.1530/EC-21-0596
  95. Nanotechnology. 2022 Aug 30.
    A simple, robust and scalable route to prepare sub-50 nm soft PDMS nanoparticles for intracellular delivery of anticancer drugs.
    Auhin Kumar Maparu, Prerana Singh, Beena Rai, Ashutosh Sharma, Sri Sivakumar.
      Soft nanoparticles (NPs) have recently emerged as a promising material for intracellular drug delivery. In this regard, NPs derived from polydimethylsiloxane (PDMS), an FDA approved polymer can be a suitable alternative to conventional soft NPs due to their intrinsic organelle targeting ability. However, the available synthesis methods of PDMS NPs are complicated or require inorganic fillers, forming composite NPs and compromising their native softness. Herein, for the first time, we present a simple, robust and scalable strategy for preparation of virgin sub-50 nm PDMS NPs at room temperature. The NPs are soft in nature, hydrophobic and about 30 nm in size. They are stable in physiological medium for two months and biocompatible. The NPs have been successful in delivering anticancer drug doxorubicin to mitochondria and nucleus of cervical and breast cancer cells with more than four-fold decrease in IC50 value of doxorubicin as compared to its free form. Furthermore, evaluation of cytotoxicity in reactive oxygen species detection, DNA fragmentation, apoptosis-associated gene expression and tumor spheroid growth inhibition demonstrate the PDMS NPs to be an excellent candidate for delivery of anticancer drugs in mitochondria and nucleus of cancer cells.
    Keywords:  doxorubicin; intracellular drug delivery; polydimethylsiloxane; soft nanoparticles
    DOI:  https://doi.org/10.1088/1361-6528/ac8d99
  96. Heliyon. 2022 Aug;8(8): e10175
    Finasteride-loaded nano-lipidic carriers for follicular drug delivery: preformulation screening and Box-Behnken experimental design for optimization of variables.
    Shweta Ramkar, Preeti K Suresh.
      Finasteride (FIN), a 5-α reductase enzyme inhibitor is mainly used orally for the treatment of androgenic alopecia and benign prostate hyperplasia. The present study was undertaken for systematic optimization and assessment of the designed nanostructured lipid carriers (NLC) to enhance follicular delivery of FIN by topical administration. The NLCs were prepared by microemulsion method, by employing a 33 Box-Behnken design and subsequently confirmed by ANOVA analysis. Compritol ATO-888 and Fenugreek oil were selected as the solid lipid and liquid lipid respectively for the fabrication of NLCs. The formulations were characterized for particle size, zeta potential, entrapment efficiency, storage stability and in vitro drug release profile. Morphological profile of the NLCs nanocarriers was studied by transmission electron microscopy (TEM). The Fourier Transform Infrared Spectroscopy (FT-IR) spectrum and differential scanning calorimetry (DSC) thermogram demonstrated that FIN entrapment within NLCs was devoid of chemical interaction with the components. The prepared NLCs had satisfactory particle dimensions, zeta potential and entrapment efficiency. The numerical optimization process indicated the optimal NLC composition with 3 mg of SPC, 6 mg lipid and 5 mg of drug. NLCs loaded with FIN had acceptable particle size at 379.8 nm, zeta potential of -37.1 mV and an entrapment efficiency of 84%. Transmission electron microscopy indicated the spherical morphology. In vitro release profile indicated a fast initial release and subsequently a prolonged release of FIN from the carrier for 24 h. The release kinetics data displayed a Higuchi diffusion release model with the best match R2 value (0.848). Short-term stability tests conducted over 4 weeks at 6° and 25 °C demonstrated that the formulation could retain their initial properties during the test period.
    Keywords:  Follicular; Lipidic carriers; Nanomedicine; Optimization; Quality-by-design; Response surface methodology; Transfollicular
    DOI:  https://doi.org/10.1016/j.heliyon.2022.e10175
  97. Chin J Integr Med. 2022 Aug 31.
    Mechanism Study on Chinese Medicine in Treatment of Nodular Goiter.
    Chang-Lin Wang, Ming-Zhou Gao, Xiang-Ju Gao, Xiang-Yu Mu, Jie-Qiong Wang, Dong-Mei Gao, Ming-Qi Qiao.
      Nodular goiter has become increasingly prevalent in recent years. Clinically, there has been a burgeoning interest in nodular goiter due to the risk of progression to thyroid cancer. This review aims to provide a comprehensive summary of the mechanisms underlying the therapeutic effect of Chinese medicine (CM) in nodular goiter. Articles were systematically retrieved from databases, including PubMed, Web of Science and China National Knowledge Infrastructure. New evidence showed that CM exhibited multi-pathway and multi-target characteristics in the treatment of nodular goiter, involving hypothalamus-pituitary-thyroid axis, oxidative stress, blood rheology, cell proliferation, apoptosis, and autophagy, especially inhibition of cell proliferation and promotion of cell apoptosis, involving multiple signal pathways and a variety of cytokines. This review provides a scientific basis for the therapeutic use of CM against nodular goiter. Nonetheless, future studies are warranted to identify more regulatory genes and pathways to provide new approaches for the treatment of nodular goiter.
    Keywords:  Chinese medicine; mechanism; nodular goiter; pharmacology; review
    DOI:  https://doi.org/10.1007/s11655-022-3724-3
  98. J Adv Res. 2022 Aug 27. pii: S2090-1232(22)00196-5. [Epub ahead of print]
    Lubricant-entrenched Slippery Surface-based Nanocarriers to Avoid Macrophage Uptake and Improve Drug Utilization.
    Chengduan Yang, Jianming Feng, Ziqi Liu, Juan Jiang, Xiafeng Wang, Cheng Yang, Hui-Jiuan Chen, Xi Xie, Liru Shang, Ji Wang, Zhenwei Peng.
       INTRODUCTION: Reducing the protein adsorption of nanoparticles (NPs) as drug carriers to slow their rapid clearance by macrophages uptake is a critical challenge for NPs clinical translational applications. Despite extensive research efforts to inhibit cellular uptake, including covering biological agents or surface chemical coatings to impart "stealth" properties to NPs, their stability remains insufficient.
    OBJECTIVES: Developed a novel surface modification technology based on a physical infusion engineering approach to achieve persistent inhibition of protein adhesion and cellular uptake by nanocarriers.
    METHODS: The nanoparticles were prepared based on conventional drug carrier mesoporous silica NPs through a two-step process. A functional nanoscale slippery surface was formed by grafting "liquid-like" brushes on the particles surface, and then a lubricant-entrenched slippery surfaces (LESS) was formed by infusing silicone oil lubricant into the entire surface. Co-incubation with macrophages (in vitro and in vivo) was used to examine the anti-uptake properties of modified NPs. The anti-adhesion properties of LESS coating surfaces to various liquids, proteins and cells were used to analyze the anti-uptake mechanism. Loaded with drugs, combined with tumor models, to evaluate the drug utilization of modified NPs.
    RESULTS: Relying on the stable and slippery LESS coating, the modified surface could prevent the adhesion of various liquids and effectively shield against the adhesion of proteins and cells, as well as remarkably reduce macrophage cellular uptake in vitro and in vivo. In addition, the LESS coating does not affect cell activity and allows NPs to be loaded with drugs, significantly improving the utilization of drugs in vitro and in vivo. This allows the NPs to reach to the target tumor site for drug delivery without active clearance by macrophages.
    CONCLUSION: Our research introduces a new nanocarrier technology to improve anti-biofouling performance and stealth efficiency that will facilitate the development of nanomedicines for clinical transformation applications.
    Keywords:  Nanocarriers; anti-adhesion of proteins; anti-uptake of macrophage; improving drug utilization; lubricant-entrenched slippery surfaces
    DOI:  https://doi.org/10.1016/j.jare.2022.08.015
  99. Recent Adv Inflamm Allergy Drug Discov. 2022 Aug 29.
    Potential of Anti-inflammatory Molecules in the Chemoprevention of Breast Cancer.
    Vaishnavi Gadi, Saritha Shetty.
      Breast cancer is a global issue, affecting greater than 1 million women per annum. Over the past two decades, there have been numerous clinical trials involving the use of various pharmacological substances as chemopreventive agents for breast cancer. Various pre-clinical as well as clinical studies have established numerous anti-inflammatory molecules, including non-steroidal anti-inflammatory drugs (NSAIDs) and dietary phytochemicals as promising agents for chemoprevention of several cancers, including breast cancer. The overexpression of COX-2 has been detected in approximately 40% of human breast cancer cases and in pre-invasive ductal carcinoma in-situ lesions, associated with aggressive elements of breast cancer such as large size of the tumour, ER/PR negative and HER-2 overexpression, among others. Anti-inflammatory molecules inhibit COX, thereby inhibiting the formation of prostaglandins and inhibit nuclear factor-κB-mediated signals (NF-kB). Another probable explanation entails inflammation-induced degranulation, with production of angiogenesis-regulating factors, such as vascular endothelial growth factor, which can be possibly regulated by anti-inflammatory molecules. Apart from NSAIDS, many dietary phytochemicals have the ability to decrease, delay, or stop the progression and/or incidence of breast cancer by their antioxidant action, by regulating inflammatory and proliferative cell signalling pathways as well as by inducing apoptosis. The rapid progress in chemoprevention research has also established innovative strategies that can be implemented to prevent breast cancer. This article gives a comprehensive overview of the recent advancements in using anti-inflammatory molecules in chemoprevention of breast cancer along with their mechanism of action, supported by latest preclinical and clinical data. The merits of anti-inflammatory chemopreventive agents in prevention of cardiotoxicity have been described. We have also highlighted the ongoing research and advancements in improving the efficacy of using anti-inflammatory molecules as chemopreventive agents.
    Keywords:  COX-2 inhibitor; NSAIDs; angiogenesis; anti-oxidant; apoptosis; chemopreventive; dietary phytochemical; prostaglandin
    DOI:  https://doi.org/10.2174/2772270816666220829090716
  100. Adv Healthc Mater. 2022 Sep 01. e2201733
    Manganese-Based Nanozymes: Preparation, Catalytic Mechanisms, and Biomedical Applications.
    Minglu Tang, Zhaocong Zhang, Tiedong Sun, Bin Li, Zhiguang Wu.
      Manganese (Mn) has attracted widespread attention due to its low-cost, nontoxicity, and valence-rich transition. Various Mn-based nanomaterials have sprung up and are employed in diverse fields, particularly Mn-based nanozymes, which combine the physicochemical properties of Mn-based nanomaterials with the catalytic activity of natural enzymes, and are attracting a surge of research, especially in the field of biomedical research. In this review, the typical preparation strategies, catalytic mechanisms, advances and perspectives of Mn-based nanozymes for biomedical applications are systematically summarized. The application of Mn-based nanozymes in tumor therapy and sensing detection, together with an overview of their mechanism of action is highlighted. Finally, the prospective directions of Mn-based nanozymes from five perspectives: innovation, activity enhancement, selectivity, biocompatibility, and application broadening are discussed.
    Keywords:  biomedical research; catalytic activity; manganese-based nanomaterials; nanozymes; therapy
    DOI:  https://doi.org/10.1002/adhm.202201733
  101. J Immunol Res. 2022 ;2022 8023915
    PEGylated Cisplatin Nanoparticles for Treating Colorectal Cancer in a pH-Responsive Manner.
    Wei Li, Yongjun Sun, Jian Chen, Zhibin Jiang, Jinbao Yang.
      Colorectal cancer (CRC) is a common malignant tumor, and its incidence ranks third and mortality rate ranks second in the world. Cisplatin cannot target CRC cells and has notable toxicity, which significantly limits its clinical application. The emerging PEGylated nanodrug delivery system can improve circulation time and enhance tumor targeting. In this study, the HA-mPEG-Cis NPs were synthesized by self-assembly, which can target CD44-positive CRC cells and dissolve the PEG hydration layer responsive to the weakly acidic tumor environment. The average hydrodynamic diameter of HA-mPEG-Cis NPs was 48 nm with the polydispersity index of 0.13. The in vitro cisplatin release was in a pH-responsive manner. The HA-mPEG-Cis NPs group showed the highest apoptosis rate (25.1%). The HA-mPEG-Cis NPs exhibited antitumor efficacy via the PI3K/AKT/mTOR signaling pathway. The HA-mPEG-Cis NPs showed the lowest tumor volume and weight among all the groups in CT26 cell-bearing mouse model. The HA-mPEG-Cis nanodrug delivery system not only increases the stability and circulation time but also reduces the side effects of loaded cisplatin. Overall, the in vitro and in vivo experiments confirmed the satisfied antitumor efficacy of HA-mPEG-Cis NPs. Therefore, this study provides a rational design for application of pH-responsive HA-mPEG-Cis nanodrug delivery system in the future.
    DOI:  https://doi.org/10.1155/2022/8023915
  102. AAPS PharmSciTech. 2022 Sep 01. 23(7): 247
    In Situ Forming Chitosan-Alginate Interpolymer Complex Bioplatform for Wound Healing and Regeneration.
    Hillary Mndlovu, Pradeep Kumar, Lisa C du Toit, Yahya E Choonara.
      Cytocompatibility, biocompatibility, and biodegradability are amongst the most desirable qualities of wound dressings and can be tuned during the bioplatform fabrication steps to enhance wound healing capabilities. A three-stepped approach (partial-crosslinking, freeze-drying, and pulverisation) was employed in fabricating a particulate, partially crosslinked (PC), and transferulic acid (TFA)-loaded chitosan-alginate (CS-Alg) interpolymer complex (IPC) with enhanced wound healing capabilities. The PC TFA-CS-Alg IPC bioplatform displayed fluid uptake of 3102% in 24 h and a stepwise degradation up to 53.5% in 14 days. The PC TFA-CS-Alg bioplatform was used as a bioactive delivery system with an encapsulation efficiency of 65.6%, bioactive loading of 9.4%, burst release of 58.27%, and a steady release of 1.91% per day. PC TFA-CS-Alg displayed a shift in cytocompatibility from slightly cytotoxic (60-90% cell viability) to nontoxic (> 90% cell viability) over a 72-h period in NIH-3T3 cells. The wound closure and histological evaluations of the lesions indicated better wound healing performance in lesions treated with PC TFA-CS-Alg and PC CS-Alg compared to those treated with the commercial product and the control. Application of the particulate bioplatform on the wound via sprinkles, the in situ hydrogel formation under fluid exposure, and the accelerated wound healing performances of the bioplatforms make it a good candidate for bioactive delivery system and skin tissue regeneration.
    Keywords:  alginate; chitosan; in situ hydrogel; partial crosslinking; wound healing
    DOI:  https://doi.org/10.1208/s12249-022-02397-4
  103. Epilepsy Res. 2022 Aug 23. pii: S0920-1211(22)00151-6. [Epub ahead of print]186 107000
    Functionalized PEG-PLA nanoparticles for brain targeted delivery of ketoconazole contribute to pregnane X receptor overexpressing in drug-resistant epilepsy.
    Jianhong Wang, Junyan Fu, Wanbing Sun, Xuyang Yin, Kun Lv, Jun Zhang.
       OBJECTIVE: To develop a functionalized PEG-PLA nanoparticle system containing ketoconazole (KCZ) to overcome the overactivity of pregnane X receptor (PXR) for the treatment of drug-resistant epilepsy (DRE).
    SIGNIFICANCE: KCZ was developed as a therapy strategy for DRE limited by its lethal hepatotoxicity and minute brain concentration. KCZ-incorporated nanoparticles modified with angiopep-2 (NPs/KCZ) could reduce adverse effects of KCZ and achieve epileptic foci-targeted drug delivery.
    METHODS: NPs/KCZ was prepared by thin-film hydration method and characterized in vitro and in vivo. The efficacy evaluation of NPs/KCZ was evaluated in a kainic acid (KA)-induced mice model of epilepsy with carbamazepine (CBZ) treatment.
    RESULTS: The mean particle size and Zeta potential of NPs/KCZ were 17.84 ± 0.33 nm and - 2.28 ± 0.12 mV, respectively. The drug-loading (DL%) of KCZ in nanoparticles was 8.96 ± 0.12 % and the entrapment efficiency (EE%) was 98.56 ± 0.02 %. The critical value of critical micelle concentration was 10-3.3 mg/ml. No obvious cytotoxicity was found in vitro. The behavioral and electrographic seizure activities were obviously attenuated in NPs/KCZ+CBZ group. The CBZ concentration of brain tissues in mice treated with NPs/KCZ+CBZ was significantly increased than those treated with CBZ alone (P = 0.0028). A significantly decreased expression level of PXR and its downstream proteins was observed in NPs/KCZ+CBZ group compared with that in the control and CBZ group (All P < 0.05).
    CONCLUSION: Our results showed that NPs/KCZ achieved the epileptic foci-targeted delivery of KCZ and ameliorated the efficacy of CBZ on DRE by attenuating the overactivity of PXR.
    Keywords:  Carbamazepine; Drug-resistant epilepsy; Ketoconazole; Nanoparticle; Pregnane X receptor
    DOI:  https://doi.org/10.1016/j.eplepsyres.2022.107000
  104. Front Immunol. 2022 ;13 976677
    The mechanistic immunosuppressive role of the tumour vasculature and potential nanoparticle-mediated therapeutic strategies.
    Zakaria Elias Ileiwat, Tanveer A Tabish, Dmitry A Zinovkin, Jale Yuzugulen, Nahid Arghiani, Md Zahidul I Pranjol.
      The tumour vasculature is well-established to display irregular structure and hierarchy that is conducive to promoting tumour growth and metastasis while maintaining immunosuppression. As tumours grow, their metabolic rate increases while their distance from blood vessels furthers, generating a hypoxic and acidic tumour microenvironment. Consequently, cancer cells upregulate the expression of pro-angiogenic factors which propagate aberrant blood vessel formation. This generates atypical vascular features that reduce chemotherapy, radiotherapy, and immunotherapy efficacy. Therefore, the development of therapies aiming to restore the vasculature to a functional state remains a necessary research target. Many anti-angiogenic therapies aim to target this such as bevacizumab or sunitinib but have shown variable efficacy in solid tumours due to intrinsic or acquired resistance. Therefore, novel therapeutic strategies such as combination therapies and nanotechnology-mediated therapies may provide alternatives to overcoming the barriers generated by the tumour vasculature. This review summarises the mechanisms that induce abnormal tumour angiogenesis and how the vasculature's features elicit immunosuppression. Furthermore, the review explores examples of treatment regiments that target the tumour vasculature.
    Keywords:  angiogenesis; endothelium; immunosuppression; nanotherapy; vascular normalisation
    DOI:  https://doi.org/10.3389/fimmu.2022.976677
  105. Anal Cell Pathol (Amst). 2022 ;2022 1435173
    MYC Promotes LDHA Expression through MicroRNA-122-5p to Potentiate Glycolysis in Hepatocellular Carcinoma.
    Xiaofei Wang, Penghua Zhang, Ke Deng.
      MYC is a notorious oncogene in a vast network of malignancies, whereas liver-specific microRNA- (miR-) 122-5p is downregulated in hepatocellular cancer (HCC). Here, we studied the possible correlation between these two and their involvement in glycolysis in HCC. MYC was overexpressed in HCC tissues and cells compared to normal liver tissues and normal hepatocytes NHC, which predicted a poor survival of HCC sufferers. Functional assays demonstrated that silencing of MYC inhibited the glycolysis in HCC cells, as evidenced by significantly weaker glucose consumption, lactate production, adenosine triphosphate (ATP) levels, and downregulated HK1 and HK2 protein expression. Moreover, MYC bound to the miR-122-5p promoter and repressed the miR-122-5p expression. Rescue experiments showed that miR-122-5p inhibitor rescued the diminished glycolysis after MYC silencing. In addition, lactate dehydrogenase (LDHA) was identified as a downstream target of miR-122-5p. The overexpression of LDHA mitigated the effects of si-MYC and miR-122-5p mimic on glycolysis of HCC cells, respectively. In conclusion, the MYC/miR-122-5p/LDHA axis modulates glycolysis in HCC cells and possibly affects HCC progression.
    DOI:  https://doi.org/10.1155/2022/1435173
  106. Front Nutr. 2022 ;9 960309
    Phytonutrients: Sources, bioavailability, interaction with gut microbiota, and their impacts on human health.
    Juntao Kan, Feng Wu, Feijie Wang, Jianheng Zheng, Junrui Cheng, Yuan Li, Yuexin Yang, Jun Du.
      Phytonutrients are natural bioactive components present in the daily diet that can exert a positive impact on human health. Studies have shown that phytonutrients may act as antioxidants and improve metabolism after being ingested, which help to regulate physiological processes and prevent metabolic disorders and diseases. However, their efficacy is limited by their low bioavailability. The gut microbiota is symbiotic with humans and its abundance and profile are related to most diseases. Interestingly, studies have shown that the gut microbiota is associated with the metabolism of phytonutrients by converting them into small molecules that can be absorbed by the body, thereby enhancing their bioavailability. Furthermore, phytonutrients can modulate the composition of the gut microbiota, and therefore improve the host's health. Here, we focus on uncovering the mechanisms by which phytonutrients and gut microbiota play roles in health, and the interrelationships between phytonutrients and gut microbiota were summarized. We also reviewed the studies that reported the efficacy of phytonutrients in human health and the future directions.
    Keywords:  bioavailability; gut microbiota; health outcomes; metabolism; phytonutrients
    DOI:  https://doi.org/10.3389/fnut.2022.960309
  107. Biochem Biophys Res Commun. 2022 Aug 18. pii: S0006-291X(22)01132-9. [Epub ahead of print]627 191-199
    The elevated D-2-hydroxyglutarate level found as a characteristic metabolic change of colon cancer in both in vitro and in vivo models.
    Esra Bulut Atalay, Hulya Ayar Kayali.
      The D-2-hydroxyglutarate (D-2-HG), whose normal cellular concentration is low, can be accumulated 10-100 times natural levels in some cancer types and participates in the carcinogenesis process. D-2-HG is produced by different pathways specific to cancer type. In this study, the level of significant metabolites produced in some metabolic pathways related to D-2-HG in the energy metabolism was determined in colon adenocarcinoma cell lines at different stages. Then, the differences in TCA and Cori cycle, glutaminolysis, and Glycolysis were investigated in the brain, colon, liver, and tumor tissues extracted from xenograft models. The levels of glucose, pyruvate, lactate, all TCA cycle intermediates, and D-2-HG were determined by the HPLC analysis, DNS method, and pyruvate assay. The intracellular D-2-HG level was found at 22.6 μmol/mg in primary (Caco-2) and 152.6 μmol/mg in metastatic (SW620) colon adenocarcinoma cells, whereas it could not be detected in colon epithelial cell line (CCD-18Co). In the xenograft models, D-2-HG could not be detected in CCD-18Co colon and brain tissues, whereas it was produced in Caco-2 and SW620 tissues. Most importantly, the level of D-2-HG was 7.4 and 19.9-fold increased in Caco-2 and SW620 tumor tissues compared to healthy tissue, respectively. In addition, the D-2-HG production pathways were investigated. The results revealed that the carbon source of D-2-HG is glucose, and the imbalance of wt-IDH1/2 enzymes plays a role in its production. Overall, the in vitro and in vivo results show that the enhanced production of endogenous D-2-HG is a characteristic change in the metabolism of colon cancer.
    Keywords:  2-Hydroxyglutarate; Colon cancer; Cori cycle; Metabolism; TCA cycle; wt-IDH1/2
    DOI:  https://doi.org/10.1016/j.bbrc.2022.08.019
  108. Pharm Dev Technol. 2022 Aug 30. 1-16
    Cationic Okra gum coated nanoliposomes as a pH-sensitive carrier for co-delivery of hesperetin and oxaliplatin in colorectal cancers.
    Mahboobeh Hodaei, Jaleh Varshosaz.
      Oxaliplatin (OXP) is the typical treatment of colorectal cancer. Combining chemotherapeutic drugs can reduce drug resistance and side effects. In the present study, the co-delivery of OXP with Hesperetin (HSP), a natural anti-cancer flavonoid, by nanoliposomes was studied against HT-29 colon cancer cells. Cationic Okra gum (COG) was synthesized to coat nanoliposomes. The successful synthesis of COG was confirmed by NMR spectroscopy. Liposomes were prepared by thin film hydration technique. Formulations containing 0.5, 1 and 2 mg.ml-1 COG, had particle sizes ranging from 145 to 175 nm and zeta potentials for uncoated and coated formulations changed between -29 to -0.403 mV. Coated liposomes released 98% and 66% of HSP and OXP, respectively during 24 h pH-dependently. Cationic Okra gum enhanced physical stability of the liposomes for about 30 days. The composite liposomes containing OXP and HSP at final concentrations of 1.125 µM and 125 µM, respectively could generate significant cytotoxicity at 48 hours in comparison of each drug alone. Extracted drug-target interactions from STITCH database, showed that Catalase (CAT) is the common target between OXP and HSP drugs. Measurement of the CAT activity may be used as an indicator to investigate the mechanism of action of these drugs in subsequent experiments.
    Keywords:  Cationic Okra gum; Hesperetin; Nanoliposomes; Oxaliplatin
    DOI:  https://doi.org/10.1080/10837450.2022.2119249
  109. Drug Deliv Transl Res. 2022 Sep 02.
    Modeling and simulation of smart magnetic self-assembled nanomicelle trajectories in an internal thoracic artery flow for breast cancer therapy.
    Saad Sulttan, Sohrab Rohani.
      Magnetic drug targeting (MDT) is one of the most modern techniques in cancer therapy for its ability to reduce the side effects of chemotherapy experienced by systemic drug administration. In this study, a comprehensive mathematical model has been developed to predict the drug particle trajectories of anticancer dasatinib magnetic nanomicelles (DAS-MNM) released in an internal thoracic artery (ITA) blood flow for breast cancer therapy using an external magnetic field. Several factors are investigated in regard to the efficiency of MDT through the ITA, including magnetic field strength (MFS), relative magnetic permeability, magnet size, drug particle size, and initial position of drug particle. The drug particle trajectory results confirmed the successful MDT using an external magnetic field with a capture efficiency of more than 90%. This was achieved by employing a wide range of particle sizes of DAS-MNM close to the external magnetic field source at the arterial wall than in other positions. Moreover, the results showed that the number of trapped particles increased with increasing both MFS and drug particle diameter within the target tissue, while the drug particle permeability did not have a considerable effect on the particle retention. In addition, for achieving a successful drug/cargo delivery through the arteries, the magnetic field, the particle size, and the initial release locations should be adjusted simultaneously. The present work offers insights into the critical factors in MDT with a significant impact on breast cancer therapy, tissue engineering, and regenerative medicine. Magnetic drug targeting model of anticancer dasatinib magnetic nanomicelles (DAS-MNM) released in an internal thoracic artery blood flow for breast cancer therapy.
    Keywords:  Breast cancer; Dasatinib; Drug targeting; Internal thoracic artery; Micelles; Nanomagnetic
    DOI:  https://doi.org/10.1007/s13346-022-01234-2
  110. ACS Appl Mater Interfaces. 2022 Sep 02.
    Oncocyte Membrane-Camouflaged Multi-Stimuli-Responsive Nanohybrids for Synergistic Amplification of Tumor Oxidative Stresses and Photothermal Enhanced Cancer Therapy.
    Feifei Zhang, Chenglong Xin, Zhichao Dai, Heli Hu, Qi An, Fei Wang, Zunfu Hu, Yunqiang Sun, Lu Tian, Xiuwen Zheng.
      The combination of various therapeutic modalities has received considerable attention for improving antitumor performance. Herein, an innovative nanohybrid, namely CaO2@FePt-DOX@PDA@CM (CFDPM), was developed for synergistic chemotherapy/chemodynamic therapy/Ca2+ overloading-mediated amplification of tumor oxidative stress and photothermal enhanced cancer therapy. Camouflage of the 4T1 cell membrane enabled CFDPM to escape the immune surveillance and accumulate in the tumor tissue. Ca2+, released from CaO2, could lead to mitochondrial dysfunction and facilitate the production of reactive oxygen species to amplify intracellular oxidative stress. Meanwhile, the increase of H2O2 concentration could enhance the efficiency of the chemodynamic therapy (CDT). Moreover, the hypoxic condition could be alleviated remarkably, which is attributed to the sufficient O2 supply by CaO2, resulting in the suppression of drug resistance and promotion of the chemotherapeutic effect. The nanohybrids involving Ca2+ overloading/CDT/chemotherapy could synergistically amplify the tumor oxidative stresses and remarkably aggravate the death of cancer cells. Significantly, the excellent photothermal conversion performance of CFDPM could further promote the tumoricidal effect. The in vitro and in vivo studies revealed that CFDPM could effectively advance the therapeutic efficiency via the cooperation of various therapeutic modalities to optimize their individual virtue, which would open a valuable avenue for effective cancer treatment.
    Keywords:  H2O2 self-supply; calcium peroxide; chemodynamic therapy; oxidative stress; synergetic therapy
    DOI:  https://doi.org/10.1021/acsami.2c11200
  111. Toxicol Res (Camb). 2022 Aug;11(4): 565-582
    A toxicological profile of silica nanoparticles.
    James Y Liu, Christie M Sayes.
      Humans are regularly exposed to silica nanoparticles in environmental and occupational contexts, and these exposures have been implicated in the onset of adverse health effects. Existing reviews on silica nanoparticle toxicity are few and not comprehensive. There are natural and synthetic sources by which crystalline and amorphous silica nanoparticles are produced. These processes influence physiochemical properties, which are factors that can dictate toxicological effects. Toxicological assessment includes exposure scenario (e.g. environmental, occupational), route of exposure, toxicokinetics, and toxicodynamics. Broader considerations include pathology, risk assessment, regulation, and treatment after injury. This review aims to consolidate the most relevant and up-to-date research in these areas to provide an exhaustive toxicological profile of silica nanoparticles.
    Keywords:  anthropogenic emissions; environmental exposure; human health effects; occupational exposure; silica nanoparticles; toxicity
    DOI:  https://doi.org/10.1093/toxres/tfac038
  112. Turk J Pharm Sci. 2022 Aug 31. 19(4): 462-475
    Proniosome: A Promising Approach for Vesicular Drug Delivery.
    Marzina Ajrin, Fahmida Anjum.
      Different types of drug delivery systems are intended to deliver therapeutic agents to the appropriate site of interest to get desired pharmacological effect. In the field of drug delivery, the advancement of nanotechnology helps develop novel dosage forms such as liposome, noisome, and proniosome. Proniosomes are promising drug carriers, that are dry formulations, and after hydration, are converted to noisome dispersion. Dry proniosomal powder can deliver a unit dose of the drug with improved drug stability and solubility. By using this formulation, both the hydrophilic and lipophilic drugs can be delivered through different routes like oral, topical, transdermal, vaginal, etc. This review revolves on different features of proniosomes such as their structure, formulation materials of proniosomes, preparation methods, evaluation, and application.
    Keywords:  Proniosomes; application of proniosome; evaluation of proniosome; vesicular drug delivery
    DOI:  https://doi.org/10.4274/tjps.galenos.2021.53533
  113. J Funct Foods. 2022 Oct;97 105229
    Fermented natural product targeting gut microbiota regulate immunity and anti-inflammatory activity: A possible way to prevent COVID-19 in daily diet.
    Quancen Li, Na Li, Wenwen Cai, Meifang Xiao, Bin Liu, Feng Zeng.
      Low immune function makes the body vulnerable to being invaded by external bacteria or viruses, causing influenza and inflammation of various organs, and this trend is shifting to the young and middle-aged group. It has been pointed out that natural products fermented by probiotic have benign changes about their active ingredients in some studies, and it have shown strong nutritional value in anti-oxidation, anti-aging, regulating lipid metabolism, anti-inflammatory and improving immunity. In recent years, the gut microbiota plays a key role and has been extensively studied in improving immunity and anti-inflammation activity. By linking the relationship between natural products fermented by probiotic, gut microbiota, immunity, and inflammation, this review presents the modulating effects of probiotics and their fermented natural products on the body, including immunity-enhancing and anti-inflammatory activities by modulating gut microbiota, and it is discussed that the current understanding of its molecular mechanisms. It may become a possible way to prevent COVID-19 through consuming natural products fermented by probiotic in our daily diet.
    Keywords:  Active substances; Anti-inflammatory activity; Gut microbiota; Immunity; Natural products; Probiotics
    DOI:  https://doi.org/10.1016/j.jff.2022.105229
  114. Front Pharmacol. 2022 ;13 974921
    Editorial: Biomedical advances in ultrasound-mediated drug/molecule delivery.
    Agata A Exner, Jean-Michel Escoffre.
      
    Keywords:  biological barriers; drug delivery; pharmacodynamics; pharmacokinetics; therapeutic ultrasound
    DOI:  https://doi.org/10.3389/fphar.2022.974921
  115. Explor Target Antitumor Ther. 2021 ;2(4): 323-354
    The promising potential of piperlongumine as an emerging therapeutics for cancer.
    Dey Parama, Varsha Rana, Sosmitha Girisa, Elika Verma, Uzini Devi Daimary, Krishan Kumar Thakur, Aviral Kumar, Ajaikumar B Kunnumakkara.
      In spite of the immense advancement in the diagnostic and treatment modalities, cancer continues to be one of the leading causes of mortality across the globe, responsible for the death of around 10 million patients every year. The foremost challenges faced in the treatment of this disease are chemoresistance, adverse effects of the drugs, and the high cost of treatment. Though scientific studies over the past few decades have foreseen and are focusing on the cancer-preventive and therapeutic potential of natural products and their underlying mechanism of action, many more of these agents are not still explored. Piperlongumine (PL), or piplartine, is one such alkaloid isolated from Piper longum Linn., which is shown to be safe and has significant potential in the prevention and therapy of cancer. Numerous shreds of evidence have established the ability of this alkaloid and its analogs and nanoformulations in modulating various complex molecular pathways such as phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin, nuclear factor-kappa B, Janus kinases/signal transducer and activator of transcription 3, etc. and inhibit different hallmarks of cancer such as cell survival, proliferation, invasion, angiogenesis, epithelial-mesenchymal-transition, metastases, etc. In addition, PL was also shown to inhibit radioresistance and chemoresistance and sensitize the cancer cells to the standard chemotherapeutic agents. Therefore, this compound has high potential as a drug candidate for the prevention and treatment of different cancers. The current review briefly reiterates the anti-cancer properties of PL against different types of cancer, which permits further investigation by conducting clinical studies.
    Keywords:  Piper longum Linn.; Piperlongumine; cancer; chemotherapy; piplartine; radiotherapy; signaling pathways; toxicity
    DOI:  https://doi.org/10.37349/etat.2021.00049
  116. Asian Pac J Cancer Prev. 2022 Aug 01. pii: 90248. [Epub ahead of print]23(8): 2661-2669
    Addition of Gallic Acid Overcomes Resistance to Cisplatin in Ovarian Cancer Cell Lines.
    Najwa Al Balushi, Syed Imran Hassan, Nada Abdullah, Buthaina Al Dhahli, Shadia Al Bahlani, Ikhlas Ahmed, Benjamin K Tsang, Sergey Dobretsov, Yahya Tamimi, Ikram A Burney.
       OBJECTIVE: Ovarian cancer is one of the leading causes of cancer-related mortality in women, and is often associated with drug resistance. Therefore, finding effective drugs, including naturally derived compounds, is urgently needed. Herein, we aimed to test the anti-cancer potential of gallic acid monohydrate (GA) and its congeners on cisplatin-sensitive (A2780S), and resistant (A2780CP) ovarian cancer and normal ovarian (HOSE6-3) cell lines.
    METHODS: Cytotoxicity was assessed by AlamarBlue and CCK08 assays by exposing cells to different concentrations of cisplatin (0-21µg/mL), GA and its congeners (0-100µg/mL), and a combination of GA and cisplatin. Apoptosis was estimated by Hoechst stain and monitoring the relative RNA expression of the apoptotic effector caspase-3 using qRT-PCR.
    RESULTS: GA decreased cell viability in a concentration-dependent manner in all cell lines, with an IC50 of 19.39µg/mL (A2780S), 35.59 µg/mL (A2780CP), and 49.32µg/mL (HOSE6-3). GA displayed higher cytotoxicity than its congeners. An apoptotic rate estimation of approximately 20% and 30% was obtained in A2780S and A2780CP. While the cytotoxicity observed with cisplatin and GA was comparable, combining the two enhanced the cytotoxicity significantly, especially in the A2780CP cell line (p<0.05).
    CONCLUSION: These data suggest that GA may help overcome the resistance. Hence, the cytotoxic effects of GA, especially on chemo-resistant ovarian cancer cells merit further investigation.<br />.
    Keywords:  Chemo-resistance; Cisplatin; Cytotoxicity; Gallic acid; Ovarian Cancer
    DOI:  https://doi.org/10.31557/APJCP.2022.23.8.2661
  117. Front Chem. 2022 ;10 948217
    Potential of histone deacetylase inhibitors in the control and regulation of prostate, breast and ovarian cancer.
    Siddhartha Das Pramanik, Amit Kumar Halder, Ushmita Mukherjee, Dharmendra Kumar, Yadu Nandan Dey, Mogana R.
      Histone deacetylases (HDACs) are enzymes that play a role in chromatin remodeling and epigenetics. They belong to a specific category of enzymes that eliminate the acetyl part of the histones' -N-acetyl lysine, causing the histones to be wrapped compactly around DNA. Numerous biological processes rely on HDACs, including cell proliferation and differentiation, angiogenesis, metastasis, gene regulation, and transcription. Epigenetic changes, specifically increased expression and activity of HDACs, are commonly detected in cancer. As a result, HDACi could be used to develop anticancer drugs. Although preclinical outcomes with HDACs as monotherapy have been promising clinical trials have had mixed results and limited success. In both preclinical and clinical trials, however, combination therapy with different anticancer medicines has proved to have synergistic effects. Furthermore, these combinations improved efficacy, decreased tumor resistance to therapy, and decreased toxicity. In the present review, the detailed modes of action, classification of HDACs, and their correlation with different cancers like prostate, breast, and ovarian cancer were discussed. Further, the different cell signaling pathways and the structure-activity relationship and pharmaco-toxicological properties of the HDACi, and their synergistic effects with other anticancer drugs observed in recent preclinical and clinical studies used in combination therapy were discussed for prostate, breast, and ovarian cancer treatment.
    Keywords:  HDAC inhibitors (HDACi); Histone deacetylase (HDAC); breast cancer; ovarian cancer; prostate cancer
    DOI:  https://doi.org/10.3389/fchem.2022.948217
  118. Crit Rev Food Sci Nutr. 2022 Aug 29. 1-28
    Recent insights into oxidative metabolism of quercetin: catabolic profiles, degradation pathways, catalyzing metalloenzymes and molecular mechanisms.
    Bin Guo, Fang Chou, Libin Huang, Feifan Yin, Jing Fang, Jian-Bo Wang, Zongchao Jia.
      Quercetin is the most abundant polyphenolic flavonoid (flavonol subclass) in vegetal foods and medicinal plants. This dietary chemopreventive agent has drawn significant interest for its multiple beneficial health effects ("polypharmacology") largely associated with the well-documented antioxidant properties. However, controversies exist in the literature due to its dual anti-/pro-oxidant character, poor stability/bioavailability but multifaceted bioactivities, leaving much confusion as to its exact roles in vivo. Increasing evidence indicates that a prior oxidation of quercetin to generate an array of chemical diverse products with redox-active/electrophilic moieties is emerging as a new linkage to its versatile actions. The present review aims to provide a comprehensive overview of the oxidative conversion of quercetin by systematically analyzing the current quercetin-related knowledge, with a particular focus on the complete spectrum of metabolite products, the enzymes involved in the catabolism and the underlying molecular mechanisms. Herein we review and compare the oxidation pathways, protein structures and catalytic patterns of the related metalloenzymes (phenol oxidases, heme enzymes and specially quercetinases), aiming for a deeper mechanistic understanding of the unusual biotransformation behaviors of quercetin and its seemingly controversial biological functions.
    Keywords:  Quercetin; catalytic mechanism; degradation products; metabolic pathways; metalloenzymes; quercetinase
    DOI:  https://doi.org/10.1080/10408398.2022.2115456
  119. Lett Appl Microbiol. 2022 Aug 29.
    Ultrasound-assisted encapsulation of curcumin and fisetin into Saccharomyces cerevisiae cells: a multistage batch process protocol.
    Eduardo Wagner Vasconcelos de Andrade, Roberta Targino Hoskin, Márcia Regina da Silva Pedrini.
      Some of the challenges of yeast encapsulation protocols are low phytochemical internalization rates and limited intracellular compartment of yeasts. This study uses an ultrasound-assisted batch encapsulation (UABE) protocol to optimize the encapsulation of curcumin and fisetin by recovering non-encapsulated biomaterial and further incorporating it into non-loaded yeasts in three encapsulation stages (1ES, 2ES, and 3ES). The effect of selected acoustic energies (166.7 and 333.3 W L-1 ) on the encapsulation efficiency (EE), yield (EY), and antioxidant activity retention were evaluated, and then, compared with a control process (without ultrasound treatment). Compared to the control, enhanced EEs were achieved for both curcumin (10.9% control to 58.5% UABE) and fisetin (18.6% control to 76.6% UABE) after 3ES and the use of 333.3 W L-1 . Similarly, the yeast maximum loading capacity was improved from 6.6 to 13.4 mg g-1 for curcumin; and from 11.1 to 26.4 mg g-1 for fisetin after UABE protocol. The antioxidant activity of produced biocapsules was positively correlated with the bioactive loaded content of yeasts when ultrasound treatment was applied. Overall, results from this study provide valuable information regarding UABE processes, and moreover, bring new and creative perspectives for the ultrasound technology in the food industry.
    Keywords:  antioxidant activity; bioprocess; food biotechnology; lipophilic compounds; yeast-based carriers
    DOI:  https://doi.org/10.1111/lam.13820
  120. Anticancer Res. 2022 Sep;42(9): 4311-4317
    The γ-Glutamylcyclotransferase Inhibitor Pro-GA Induces an Antiproliferative Effect Through the Generation of Mitochondrial Reactive Oxygen Species.
    Hiromi Ii, Keiko Taniguchi, Taku Yoshiya, Yukie Nohara, Susumu Kageyama, Akihiro Kawauchi, Susumu Nakata.
       BACKGROUND/AIM: γ-Glutamylcyclotransferase (GGCT) is up-regulated in a broad range of cancers, including breast cancer, and GGCT inhibition has been shown to be a promising strategy for therapy. Herein, we evaluated the efficacy and mechanism of action of pro-GA, a GGCT enzymatic inhibitor, in MCF7 breast cancer cells.
    MATERIALS AND METHODS: Proliferation was evaluated by WST-8 and trypan blue dye exclusion assays. Western blot analysis was conducted to examine the expression of cyclin-dependent kinase inhibitors (CDKI), including p21, p27, and p16. Induction of senescence was assessed by senescence-associated β-galactosidase staining. Generation of mitochondrial superoxide reactive oxygen species (ROS) was assessed using flow cytometry. The effect of N-acetylcysteine (NAC) on pro-GA dependent inhibition of proliferation, ROS generation, and senescence was also studied. The efficacy of systemic administration of pro-GA was evaluated in a MCF7 xenograft mouse model.
    RESULTS: Treatment with pro-GA inhibited proliferation of MCF7 cells, increased CDKI expression and mitochondrial ROS, and induced cellular senescence. We found that cotreatment with NAC restored proliferation in pro-GA treated cells. NAC similarly suppressed CDKI expression, mitochondrial ROS generation, and senescence induced by pro-GA. Furthermore, the systemic administration of pro-GA in an MCF7 xenograft model had significant antitumor effects without toxicity.
    CONCLUSION: Pro-GA may be a promising therapeutic agent for the treatment of breast cancer.
    Keywords:  N-acetylcysteine; breast cancer; cyclin-dependent kinase inhibitors; pro-GA; reactive oxygen species; γ-glutamylcyclotransferase
    DOI:  https://doi.org/10.21873/anticanres.15931
  121. Front Pharmacol. 2022 ;13 955984
    Metformin anticancer: Reverses tumor hypoxia induced by bevacizumab and reduces the expression of cancer stem cell markers CD44/CD117 in human ovarian cancer SKOV3 cells.
    Yuanchun Fan, Huimin Cheng, Yueping Liu, Shihao Liu, Scott Lowe, Yaru Li, Rachel Bentley, Bethany King, John Pocholo W Tuason, Qin Zhou, Chenyu Sun, Hui Zhang.
      Background: The occurrence and development of solid tumors depend on the blood supply in the tumor microenvironment (TME). Blocking angiogenesis is a new therapeutic strategy to inhibit tumor growth. The anti-angiogenic drug bevacizumab has been approved for gynecological malignancies, especially for advanced recurring cervical cancers and recurring ovarian cancers (OC). Studies in OC have shown a limited effect of bevacizumab in the general population, with a slight improvement in progression-free survival (PFS) and no effect on overall survival (OS). This might be related to the bevacizumab's role in aggravating the hypoxia in the TME, which helps maintain the stemness of ovarian cancer stem cells (CSCs) and promotes the invasion and metastasis of cancer cells. Drugs that target CSCs, such as metformin, may enhance the efficacy of anti-vascular therapies. Therefore, this study aimed to evaluate the effect of metformin combined with bevacizumab on the proliferation of OC cells both in vitro and in vivo, as well as on tumor hypoxia and tumor stem cell markers of human ovarian cancer SKOV3 cells. Methods: The OC cell model SKOV3 was treated with metformin, bevacizumab, and cisplatin alone or in combinations. Cell Counting Kit-8 (CCK-8) was used to measure the rate of cell proliferation. Metformin and bevacizumab were studied in vivo in nude mice. SKOV3 cells were transplanted subcutaneously in nude mice, and different drug interventions were performed after tumor formation, including blank control, bevacizumab alone, metformin alone, cisplatin alone, bevacizumab + metformin, bevacizumab + cisplatin, metformin + cisplatin, and bevacizumab + metformin + cisplatin treatments. The growth of transplanted tumors was routinely monitored and visualized by the tumor growth curve. We used flow cytometry to examine the proportion of CD44+/CD117+ CSCs in each group. The immunohistochemistry (IHC) method was applied to detect expressions of vascular endothelial growth factor (VEGF), hypoxia-inducible factor 1α (HIF-1α), and microvascular density-associated factor CD34 in tumor cells. The limit dilution method was used to re-inject tumor cells in nude mice to examine the tumor recurrence rate. Results: Combination therapy of metformin and bevacizumab significantly reduced the proliferation rate of SKOV3 cells and the growth rate of transplanted tumors in nude mice compared with the monotherapy effects. In vivo results showed that metformin significantly reduced the proportion of CD44+/CD117+ CSCs (p < 0.01). Although bevacizumab increased the proportion of CD44+/CD117+ CSCs, the addition of metformin did offset this fluctuating trend. The combination of bevacizumab, metformin, and cisplatin efficiently decreased the proportion of CSCs in the OC animal model. IHC results exhibited that expressions of VEGF, CD34, and HIF-1α in transplanted tumors were decreased by metformin alone compared with the control (p < 0.05). In the bevacizumab treatment, VEGF, and CD34 expressions were decreased, while that of HIF-1α was increased, suggesting that the degree of hypoxia was differentially aggravated after the bevacizumab treatment. The VEGF, CD34, and HIF-1α expressions in the bevacizumab + metformin + cisplatin group were the lowest among all other treatment groups (p < 0.05). Subcutaneous statistics of nude mice reseeded by the limit dilution method showed that the tumor recurrence rate in the bevacizumab + metformin + cisplatin group was relatively lower. Conclusion: Metformin, bevacizumab combined with platinum-based chemotherapy can significantly inhibit the growth of ovarian cancer cells and transplanted tumors, which is due to the reduction of the proportion of CD44+/CD117+ CSCs and the alleviation of hypoxia in the tumor microenvironment. Therefore, this may be a reasonable and promising treatment regimen.
    Keywords:  CSCs; HIF-1α; VEGF; bevacizumab; metformin
    DOI:  https://doi.org/10.3389/fphar.2022.955984
  122. Adv Sci (Weinh). 2022 Aug 28. e2201992
    Metabolism-Based Molecular Subtyping Endows Effective Ketogenic Therapy in p53-Mutant Colon Cancer.
    Meng Tang, Hui Xu, Hongyan Huang, Hao Kuang, Chenxi Wang, Qinqin Li, Xin Zhang, Yizhong Ge, Mengmeng Song, Xi Zhang, Ziwen Wang, Chaobing Ma, Jinlin Kang, Wanfang Zhang, You Wang, Bo Zhang, Xiaowei Zhang, Yongbing Chen, Minghua Cong, Gerry Melino, Xiaobin Wang, Fuxiang Zhou, Qiang Sun, Hanping Shi.
      Although targeting cancer metabolism is a promising therapeutic strategy, clinical success depends on accurate molecular and metabolic subtyping. Here, this study reports two metabolism-based molecular subtypes associated with the ketogenic treatment of colon cancer: glycolytic (glycolysis+ /ketolysis- ) and ketolytic (glycolysis+ /ketolysis+ ), which are manifested by distinct profiles of metabolic enzymes and mitochondrial dysfunction, and by different responses to ketone-containing interventions in vitro and in vivo. Notably, the glycolytic subtype is able to be transformed into the ketolytic subtype in p53-mutated tumors upon glucose limitation, rendering resistance to ketogenic therapy associated with upregulation of ketolytic enzymes, such as OXCT1 by mutant p53. The allosteric activator of mutant p53 effectively blocks the rewired molecular expression and the reprogrammed metabolism, leading to the suppression of tumor growth. The findings highlight the utility of metabolic subtyping to guide ketogenic therapy in colon cancer and identify mutant p53 as a synthetic lethality target for ketogenic treatment.
    Keywords:  OXCT1; colon cancer; ketogenic therapy; metabolic subtype; p53
    DOI:  https://doi.org/10.1002/advs.202201992
  123. Nutrition. 2022 Jul 22. pii: S0899-9007(22)00213-1. [Epub ahead of print]103-104 111800
    Oxidative stress and inflammatory response to high dietary fat and carbonated soda intake in male and female Wistar rats.
    Temitope G Adedeji, Sikirullai O Jeje, Tosan P Omayone, Worship O Agbonifo.
       OBJECTIVE: An increasing population in many countries consume diets high in fat and refined sugars (often in carbonated soda). Although high-fat diets have been extensively studied, less attention has been paid to carbonated soda. The aim of this study was to investigate the combined effects of a high-fat diet and soda consumption on oxidative stress and inflammation in Wistar rats.
    METHODS: Thirty-two male and female Wistar rats were equally divided into four dietary groups as follows: control, soda only, high fat (HFD), and high fat and carbonated soda (HFD/soda) and were placed on the dietary treatment for 14 wk, after acclimatization. At the end of the dietary treatment period, anthropometrics, lipid profile, lipid peroxidation, antioxidant activity, and inflammatory markers were assessed.
    RESULTS: Anthropometric variables and lipid peroxidation were increased in animals fed the high fat and soda diet. There was a decrease in antioxidant levels.
    CONCLUSION: The results from this study demonstrated that a HFD in combination with soda increased the effects of oxidative stress and inflammation in Wistar rats.
    Keywords:  Carbonated soda; Dietary fat; Inflammation; Obesity; Oxidative stress
    DOI:  https://doi.org/10.1016/j.nut.2022.111800
  124. Front Biosci (Landmark Ed). 2022 Aug 18. 27(8): 250
    Gui Shao Tea Extracts Inhibit Gastric Cancer Growth in Vitro and in Vivo and Prolong Survival in Nude Mice.
    Yue Liu, Zhouyue Jiang, Hongwei Yang, Jingyi Yuan, Jiali Zeng, Jiayan Wu, Zhijian Xu.
       BACKGROUND: Gui Shao Tea (GST), a long-aged tea with a Chinese herbal aroma, can treat many stubborn and malignant diseases, according to traditional Chinese medicine. This research aimed to discover and define GST, study the anti-gastric cancer effects of GST extracts and preliminarily elucidate the mechanism of action in the PI3K/Akt signaling pathway and the gut microbiota.
    METHODS: GST was analyzed by GC/MS and HPLC. Cell proliferation, the cell cycle and apoptosis were evaluated by a CCK8 assay and flow cytometry. The effects of GST extracts on tumor inhibition and survival time were explored by a gastric cancer xenograft model in nude mice. The PI3K/Akt signaling pathway was assessed by western blotting and immunohistochemistry. Gut microbiota detection and fecal microbiota transplantation were performed to examine whether the tumor inhibition observed in mice was related to gut microbiota changes.
    RESULTS: The ingredients in GST, mostly terpenes and their derivatives, were novel and more concentrated than those in tea made from the branches and leaves of the same plant species, Camellia sinensis, picked and produced the same year, while the levels of polyphenols and alkaloids were significantly reduced. In BGC-823, MGC-803, and SGC-7901 gastric cancer cells, GST extracts significantly inhibited proliferation (p = 0.037), induced G0/G1 arrest (p < 0.001) and promoted early apoptosis (p = 0.041). In mice, gastric tumor growth was significantly inhibited in both the high-dose (HTF) and middle-dose (MTF) GST-fed groups. The inhibition rate in the HTF group was 33.77% on Day 14 (p = 0.042), and that in the MTF group was 55.21% on Day 14 (p = 0.002) and 61.6% on Day 28 (p = 0.008). The survival time of MTF group mice was significantly prolonged by 22.2% (p = 0.013). GST extracts inhibited the PI3K/AKT signaling pathway in gastric cancer cells (p = 0.016) and tissues (p = 0.029), downregulated the protein p-Rb and further downregulated E2F1, thereby affecting the cell cycle and proliferation. GST extracts altered the gut microbiota in mice, but these alterations alone were insufficient to inhibit gastric cancer growth.
    CONCLUSIONS: We confirmed the anti-gastric cancer effects of GST extracts, which might provide new approaches and methods for research and development of gastric cancer drugs.
    Keywords:  Gui Shao Tea; antitumor; gastric cancer; terpenoids
    DOI:  https://doi.org/10.31083/j.fbl2708250
  125. Cell Biol Int. 2022 Aug 28.
    Anoikis in cancer: The role of lipid signaling.
    Mortaza Raeisi, Mojtaba Zehtabi, Kobra Velaei, Parisa Fayyazpour, Negar Aghaei, Amir Mehdizadeh.
      Malignantly transformed cells must alter their metabolic status to stay viable in a harsh microenvironment and maintain their ability to invade and spread. Anoikis, a specific detachment-related form of apoptotic cell death, is a potential barrier to cancer cell metastasis. Several molecular/pathway alterations have been implicated in preventing anoikis in metastatic cancers. Specific alterations in the lipid metabolism machinery (such as an increase in fatty acid uptake and synthesis) and modifications in the carbohydrate and amino acid metabolism are partially identified mechanisms associated with the anoikis resistance in various types of cancers, among other survival benefits. Following a summary of the molecular basis of the anoikis pathway, its resistance mechanisms, and the fundamentals of lipid metabolism in cancer, this article aims to elucidate the impact of lipid metabolism deviations recruited by cancer cells to escape anoikis.
    Keywords:  anoikis; fatty acids; lipogenesis; malignancy; metastasis
    DOI:  https://doi.org/10.1002/cbin.11896
  126. Front Biosci (Landmark Ed). 2022 Jul 26. 27(8): 229
    Lactate Dehydrogenase-Inhibitors Isolated from Ethyl Acetate Extract of Selaginella doederleinii by Using a Rapid Screening Method with Enzyme-Immobilized Magnetic Nanoparticles.
    Feng Zhang, Huiyun Li, Chao Liu, Kun Fang, Yongmei Jiang, Mingjiang Wu, Shiji Xiao, Lei Zhu, Jiaqi Yu, Shenge Li, Gang Wang.
       BACKGROUND: Lactate dehydrogenase (LDH) is one of the important enzyme systems for glycolysis and gluconeogenesis. It can catalyze the reduction and oxidation reaction between propionic acid and L-lactic acid, which is usually overexpressed in cancer cells. Therefore, inhibiting the activity of LDH is a promising way for the treatment of cancer. In this study, an effective method based on ligand fishing and ultra performance liquid chromatography-mass spectrum (UPLC-MS) was established to screen and identify active ingredients from Selaginella doederleinii with potential inhibitory activity for LDH.
    METHODS: Firstly, LDH was immobilized on the magnetic nanoparticles (MNPs), three immobilization parameters including LDH concentration, immobilization time and pH were optimized by single factor and response surface methodology for maximum (max) immobilization yield. Then, a mixed model of galloflavin and chlorogenic acid (inhibitors and non-inhibitors of LDH) was used to verify the specificity of immobilized LDH ligand fishing, and the conditions of ligand fishing were further optimized. Finally, combined with UPLC-MS, immobilized LDH was used to simultaneously screen and identify potential LDH inhibitors from the ethyl acetate extract of Selaginella doederleinii.
    RESULTS: The prepared fishing material was comprehensively characterized by scanning electron microscopy (SEM), transmission electron microscope (TEM), X-ray diffraction (XRD) and fourier transform infrared spectrometer (FT-IR). The optimal immobilization conditions were obtained as LDH concentration of 0.7 mg/mL, pH value of 4.5, and immobilization time of 3.5 h. Under these conditions, the max immobilization yield was (3.79 ± 0.08) × 103 U/g. The specificity analysis showed that immobilized LDH could recognize and capture ligands, and the optimal ligand fishing conditions included that the incubation time was 30 min, the elution time was 20 min, and the concentration of methanol as eluent was 80%. Finally, two LDH inhibitors, amentoflavone and robustaflavone, were screened by immobilized LDH from the ethyl acetate extract of Selaginella doederleinii.
    CONCLUSIONS: The study provided a meaningful evidence for discovering the bioactive constituents in ethyl acetate extract of Selaginella doederleinii related to cancer treatment, and this ligand fishing method was feasible for screening enzyme inhibitors from similar complex mixtures.
    Keywords:  Selaginella doederleini; biflavonoids; functionalized magnetic nanoparticles; lactate dehydrogenase (LDH) inhibitor; ligand fishing
    DOI:  https://doi.org/10.31083/j.fbl2708229
  127. Biomed Pharmacother. 2022 Jul 13. pii: S0753-3322(22)00783-1. [Epub ahead of print]153 113394
    Low-intensity ultrasound: A novel technique for adjuvant treatment of gliomas.
    Yi Fang, Gaosen Zhang, Zhiqun Bai, Yudie Yan, Xiaole Song, Xiaodi Zhao, Puxu Yang, Zhen Zhang.
      Glioma is the most common primary malignant tumor of the central nervous system. Although surgical treatment combined with radiotherapy, chemotherapy, and immunotherapy are commonly used for glioma treatment, the prognosis of glioma is still unsatisfactory. The poor effect of glioma treatment could be due to the blocking effect of blood-brain barrier (BBB) on most drugs and the multidrug resistance in tumor cells. In recent years, preclinical trials have shown that low-intensity ultrasound (LIUS) can reversibly open the BBB, inhibit the proliferation of tumor cells, and improve the delivery of drugs to brain tissue. This technology has also recently been used in clinical trials, and achieved encouraging preliminary results. In this review, the existing research results, the effect of LIUS on the adjuvant therapy of glioma under safe conditions, and the physical and biological mechanisms have been discussed. This review aims to show the potential and prospect of LIUS technique in the clinical treatment of glioma.
    Keywords:  Biological effect of ultrasound; Blood-brain barrier; Glioma; Low-intensity ultrasound
    DOI:  https://doi.org/10.1016/j.biopha.2022.113394
  128. Heliyon. 2022 Aug;8(8): e10213
    Synergistic enhancement of cell death by triple combination therapy of docetaxel, ultrasound and microbubbles, and radiotherapy on PC3 a prostate cancer cell line.
    Firas Almasri, Raffi Karshafian.
      The application of ultrasound and microbubbles (USMB) has been shown to enhance both chemotherapy and radiotherapy. This study investigated the potential of triple combination therapy comprised of USMB, docetaxel (Taxotere: TXT) chemotherapy and XRT to enhance treatment efficacy. Prostate cancer (PC3) cells in suspension were treated with various combinations of USMB, chemotherapy and radiotherapy. Cells were treated with ultrasound and microbubbles (500 kHz pulse center frequency, 580 kPa peak negative pressure, 10 μs pulse duration, 60 s insonation time and 2% Definity microbubbles (v/v)), XRT (2 Gy), and Taxotere (TXT) at concentrations ranging from 0.001 to 0.1 nM for 5- and 120-minutes duration. Following treatment, cell viability was assessed using a clonogenic assay. Therapeutic efficiency of the combined treatments depended on chemotherapy and microbubble exposure conditions. Under the exposure conditions of the study, the triple combination therapy synergistically enhanced clonogenic cell death compared to single and double combination therapy. Cell viability of ∼2% was achieved with the triple combination therapy corresponding to ∼29, ∼37, and ∼38 folds decrease compared to XRT (57%), USMB (74%) and TXT (76%) alone conditions, respectively. In addition, the triple combination therapy decreased cell viability by ∼29, ∼19- and ∼11 folds compared to TXT2hr + USMB (58%), TXT2hr + XRT (37%), and USMB + XRT (22%), respectively. The in vivo PC3 tumours showed that USMB significantly enhanced cell death through detection of apoptosis (TUNEL) with both TXT and TXT + XRT. The study demonstrated that the triple combination therapy can significantly enhance cell death in prostate cancer cells both in vitro and in vivo under relatively low chemotherapy and ionizing radiation doses.
    Keywords:  Chemotherapy; Radio-enhancement; Radiotherapy; Sonoporation; Ultrasound and microbubble; Ultrasound therapy
    DOI:  https://doi.org/10.1016/j.heliyon.2022.e10213
  129. Pharm Nanotechnol. 2022 Aug 29.
    Functional Excipients and Novel Drug Delivery Scenario in Self-nanoemulsifying Drug Delivery System: A Critical Note.
    Russel Tonjan, Dilpreet Singh.
      Lipid-based formulations have emerged as prospective dosage forms for extracting the therapeutic effects of existing lipophilic compounds and novel chemical entities more efficiently. Compared to other excipients, lipids have the added benefit of enhancing the bioavailability of lipophilic and highly metabolizable drugs due to their unique physicochemical features and similarities to in vivo components. Furthermore, lipids can minimize the needed dose and even the toxicity of drugs with poor aqueous solubility when employed as the primary excipient. Hence, the aim of the present review is to highlight the functional behavior of lipid excipients used in SNEDD formulation along with the stability aspects of the formulation in vivo. Moreover, this review also covered the importance of SNEDDS in drug delivery, the therapeutic and manufacturing benefits of lipids as excipients, and the technological advances made so far to convert liquid to solid SNEDDS like melt granulation, adsorption on solid support, spray cooling, melt extrusion/ spheronization has also highlighted. The mechanistic understanding of SNEDD absorption in vivo is highly complex, which was discussed very critically in this review. An emphasis on their application and success on an industrial scale was presented, as supported by case studies and patent surveys.
    Keywords:  Absorption; Excipient; Lipid; Poor Solubility; SNEDDS
    DOI:  https://doi.org/10.2174/2211738510666220829085745
  130. Front Oncol. 2022 ;12 972984
    Therapeutic potential of NR4A1 in cancer: Focus on metabolism.
    Shan Deng, Bo Chen, Jiege Huo, Xin Liu.
      Metabolic reprogramming is a vital hallmark of cancer, and it provides the necessary energy and biological materials to support the continuous proliferation and survival of tumor cells. NR4A1 is belonging to nuclear subfamily 4 (NR4A) receptors. NR4A1 plays diverse roles in many tumors, including melanoma, colorectal cancer, breast cancer, and hepatocellular cancer, to regulate cell growth, apoptosis, metastasis. Recent reports shown that NR4A1 exhibits unique metabolic regulating effects in cancers. This receptor was first found to mediate glycolysis via key enzymes glucose transporters (GLUTs), hexokinase 2 (HK2), fructose phosphate kinase (PFK), and pyruvate kinase (PK). Then its functions extended to fatty acid synthesis by modulating CD36, fatty acid-binding proteins (FABPs), sterol regulatory element-binding protein 1 (SREBP1), glutamine by Myc, mammalian target of rapamycin (mTOR), and hypoxia-inducible factors alpha (HIF-1α), respectively. In addition, NR4A1 is involving in amino acid metabolism and tumor immunity by metabolic processes. More and more NR4A1 ligands are found to participate in tumor metabolic reprogramming, suggesting that regulating NR4A1 by novel ligands is a promising approach to alter metabolism signaling pathways in cancer therapy. Basic on this, this review highlighted the diverse metabolic roles of NR4A1 in cancers, which provides vital references for the clinical application.
    Keywords:  NR4A1; cancers; metabolic reprogramming; signaling pathways; tumor cells
    DOI:  https://doi.org/10.3389/fonc.2022.972984
  131. Nano Lett. 2022 Aug 29.
    Enhanced Intracellular Transcytosis of Nanoparticles by Degrading Extracellular Matrix for Deep Tissue Radiotherapy of Pancreatic Adenocarcinoma.
    Li Wang, Jiaxiang Dou, Wei Jiang, Qin Wang, Yi Liu, Hang Liu, Yucai Wang.
      Intracellular transcytosis can enhance the penetration of nanomedicines to deep avascular tumor tissues, but strategies that can improve transcytosis are limited. In this study, we discovered that pyknomorphic extracellular matrix (ECM) is a shield that impairs endocytosis of nanoparticles and their movement between adjacent cells and thus limits their active transcytosis in tumors. We further showed that degradation of pivotal constituent of ECM (i.e., collagen) effectively enhances intracellular transcytosis of nanoparticles. Specifically, a collagenase conjugating transcytosis nanoparticle (Col-TNP) can dissociate into collagenase and cationized gold nanoparticles in response to tumor acidity, which enables their ECM tampering ability and active transcytosis in tumors. The breakage of ECM further enhances the active transcytosis of cationized nanoparticles into deep tumor tissues as well as radiosensitization efficacy of pancreatic adenocarcinoma. Our study opens up new paths to enhance the active transcytosis of nanomedicines for the treatment of cancers and other diseases.
    Keywords:  Cancer Radiotherapy; Extracellular Matrix; Pancreatic Adenocarcinoma; Programmed Self-assembly; Transcytosis
    DOI:  https://doi.org/10.1021/acs.nanolett.2c01005
  132. Biol Pharm Bull. 2022 ;45(9): 1213-1224
    Inhibitory Effects of Vitamin A and Its Derivatives on Cancer Cell Growth Not Mediated by Retinoic Acid Receptors.
    Noriko Takahashi.
      Vitamin A is an important trace essential nutrient. Vitamin A is present as a retinyl ester in animal foods and as β-carotene (provitamin A), which is a precursor of vitamin A, in plant foods such as green and yellow vegetables. After ingestion and absorption in the body, these are converted into retinol and stored as retinyl esters in stellate cells in the liver. The stored retinyl esters are decomposed into retinol as needed, and converted into the aldehyde retinal, which plays an important role in vision. Retinoic acid (RA) has a variety of effects. In particular, RA is used as a therapeutic agent for acute promyelocytic leukemia. This review will cover (1) elucidation of anti-refractory cancer effects of retinol (vitamin A) not mediated by RA receptors, (2) elucidation of anti-cancer effects of RA not mediated by RA receptors and (3) the development of candidate new anti-cancer agents that combine the actions of RA and retinol. Lessons learned from these findings are that vitamin A has anti-cancer activity not mediated by RA receptors; that nutritional management of vitamin A leads to prevention and treatment of cancer, and that new compounds developed from RA derivatives represent good anti-cancer drug candidates that are in various stages of clinical trials.
    Keywords:  cancer; cell growth inhibition; retinoic acid; retinol; retinoylation; vitamin A
    DOI:  https://doi.org/10.1248/bpb.b22-00315
  133. Health Care Women Int. 2022 Sep 02. 1-23
    Curcumin and vitamin E improve hot flashes, lipid profile, and fasting blood glucose without any detrimental effect on the liver and renal function in postmenopausal women: A triple-blind placebo-controlled clinical trial.
    Hamidreza Yousefi-Nodeh, Azizeh Farshbaf-Khalili, Behnaz Sadeghzadeh Oskouei, Nayyer Jafarilar-Aghdam, Negin Kazemi-Zanjani, Samira Pourzeinali.
      We conducted this study to evaluate the efficacy of Curcumin and vitamin E on hot flashes, lipid profile, blood glucose, and hepatic & renal biomarkers. Eighty-four postmenopausal women were randomly assigned into three groups to receive one Curcumin 500 milligram, vitamin E 200 IU, or placebo capsules twice/daily/eight weeks. In comparison with placebo, vitamin E significantly decreased the number of hot flashes (P = 0.002), serum triglyceride (P < 0.001), and aspartate aminotransferase (P = 0.007), while it increased high-density lipoprotein cholesterol (P = 0.005). Curcumin decreased significantly fasting blood glucose (P = 0.007), total cholesterol (P = 0.015), and triglyceride (P = 0.007) compared to placebo. We conclude that vitamin E reduced the incidence of hot flashes by nearly one-third of the base amount. It improved serum lipid profile and aspartate aminotransferase. Curcumin ameliorated fasting blood glucose and serum lipid profile.
    DOI:  https://doi.org/10.1080/07399332.2022.2117815
  134. J Enzyme Inhib Med Chem. 2022 Dec;37(1): 2357-2369
    Rational design, synthesis, and pharmacological characterisation of dicarbonyl curcuminoid analogues with improved stability against lung cancer via ROS and ER stress mediated cell apoptosis and pyroptosis.
    Tao Wei, Zhiwei Zheng, Xiaoyan Wei, Yugang Liu, Wentao Li, Bingqing Fang, Di Yun, Zhaojun Dong, Baozhu Yi, Wulan Li, Xiaoping Wu, Dezhi Chen, Liping Chen, Jianzhang Wu.
      Curcumin is a natural medicine with a wide range of anti-tumour activities. However, due to β-diketone moiety, curcumin exhibits poor stability and pharmacokinetics which significantly limits its clinical applications. In this article, two types of dicarbonyl curcumin analogues with improved stability were designed through the calculation of molecular stability by density functional theory. Twenty compounds were synthesised, and their anti-tumour activity was screened. A plurality of analogues had significantly stronger activity than curcumin. In particular, compound B2 ((2E,2'E)-3,3'-(1,4-phenylene)bis(1-(2-chlorophenyl)prop-2-en-1-one)) exhibited excellent anti-lung cancer activity in vivo and in vitro. In addition, B2 could upregulate the level of reactive oxygen species in lung cancer cells, which in turn activated the endoplasmic reticulum stress and led to cell apoptosis and pyroptosis. Taken together, curcumin analogue B2 is expected to be a novel candidate for lung cancer treatment with improved chemical and biological characteristics.
    Keywords:  Dicarbonyl curcumin analogues; anti-lung cancer activity; density functional theory; pyroptosis; stability
    DOI:  https://doi.org/10.1080/14756366.2022.2116015
  135. Front Pharmacol. 2022 ;13 984849
    Editorial: Natural compounds as scaffolds for the discovery of new anti-cancer drugs: Focus on terpenoids and flavonoids.
    Valeria P Sülsen, Constantinos M Athanassopoulos, José M Padrón, Rodrigo E Tamura.
      
    Keywords:  anti-cancer; diterpenoids; flavonoids; natural compounds; neoplasm; sesquiterpene lactones; tumor
    DOI:  https://doi.org/10.3389/fphar.2022.984849
  136. Int J Biol Macromol. 2022 Aug 25. pii: S0141-8130(22)01845-1. [Epub ahead of print]
    Formation of biocompatible MgO/cellulose grafted hydrogel for efficient bactericidal and controlled release of doxorubicin.
    Iram Shahzadi, Muhammad Islam, Hamid Saeed, Ali Haider, Anum Shahzadi, Junaid Haider, Nadeem Ahmed, Anwar Ul-Hamid, Walid Nabgan, Muhammad Ikram, Hassaan Anwer Rathore.
      In this study, MgO-doped CNC-g-PAA hydrogel was synthesized by grafting poly (acrylic acid) (PAA) onto cellulose nanocrystals (CNC) and then doped Magnesium oxide (MgO) using pH 7.0 and 12.0 to obtain an efficient nanocomposite hydrogel for antibacterial and anti-cancer activities. The synthesized nanocomposite hydrogels were evaluated by detailed characterization and confirmed the formation of a well-interconnected porous structure. MgO/CNC-g-PAA (pH = 12.0) exhibited improved bactericidal tendencies towards gram-negative and gram-positive bacteria, which was further investigated by in-silico molecular docking analyses and also examined the reactive oxygen species production by photocatalysis and free radical-scavenging assay. After this, Doxorubicin (DOX), a model anticancer drug, was successfully loaded into nanocomposites (~79 %) by electrostatic interaction and confirmed pH-triggered based release, which was over 53.7 % in 24 h. Finally, in vitro cytotoxicity-based analysis confirmed the improved antitumor efficacy of nanocomposite hydrogels. These findings revealed that MgO/CNC-g-PAA hydrogels might be prospective carriers for controlled drug delivery.
    Keywords:  Cellulose nanocrystals (CNC); Hydrogel; Poly (acrylic acid) (PAA)
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.08.142
  137. Folia Med (Plovdiv). 2022 Aug 31. 64(4): 572-580
    A concise review of inflammatory biomarkers targeted cancer therapy.
    Ashish Shah, Chhagan Patel.
      Inflammation is considered a general protective reaction of localized tissue against injury, irritation, or swelling. Inflammation may be acute, which is part of the defensive response; or chronic, which may lead to the development of various diseases including cancer. Several pro-inflammatory genes play important role in the various cellular processes like cell proliferation, angiogenesis, metastasis, and suppression of apoptosis. These pro-inflammatory genes include TNF-α, interleukins, chemokines, MMPs, cyclooxygenase, lipoxygenase, iNOS, Jak/STAT pathway, etc. All these genes are mainly regulated by the transcription factor NF-κB, which is found active in many types of neoplastic cells. Therefore, developing molecules that target pro-inflammatory genes or transcription factor is believed to be one of the good strategies for development of anti-cancer agents. Literature data suggest that many anti-inflammatory agents, including non-steroidal anti-inflammatory drugs, corticosteroids, statins, metformin, embelin, and some natural products, can interfere with the tumor microenvironment by inhibiting pro-inflammatory genes or transcription factors and increasing cell apoptosis. This review describes the link between inflammation and cancer, the role of pro-inflammatory genes and transcription factors in the development of tumor cells, and the use of anti-inflammatory agents in cancer.
    Keywords:  anti-inflammatory agents; cancer; cancer prevention; inflammation; inflammatory biomarkers
    DOI:  https://doi.org/10.3897/folmed.64.e68365
  138. IUBMB Life. 2022 Sep 02.
    Steviol glycosides affect functional properties and macromolecular expression of breast cancer cells.
    Christos Velesiotis, Marinos Kanellakis, Demitrios H Vynios.
      Steviol glycosides, the active sweet components of stevia plant, have been recently found to possess a number of therapeutic properties, including some recorded anticancer ones against various cancer cell types (breast, ovarian, cervical, pancreatic, and colon cancer). Our aim was to investigate this anticancer potential on the two most commonly used breast cancer cell lines which differ in the phenotype and estrogen receptor (ER) status: the low metastatic, ERα+ MCF-7 and the highly metastatic, ERα-/ERβ+ MDA-MB-231. Specifically, glycosides' effect was studied on cancer cells': (a) viability, (b) functionality (proliferation, migration, and adhesion), and (c) gene expression (mRNA level) of crucial molecules implicated in cancer's pathophysiology. Results showed that steviol glycosides induced cell death in both cell lines, in the first 24 hr, which was in line with the antiapoptotic BCL2 decrease. However, cells that managed to survive showcased diametrically opposite behavior. The low metastatic ERα+ MCF-7 cells acquired an aggressive phenotype, depicted by the upregulation of all receptors and co-receptors (ESR, PGR, AR, GPER1, EGFR, IGF1R, CD44, SDC2, and SDC4), as well as VIM and MMP14. On the contrary, the highly metastatic ERα-/ERβ+ MDA-MB-231 cells became less aggressive as pointed out by the respective downregulation of EGFR, IGF1R, CD44, and SDC2. Changes observed in gene expression were compatible with altered cell functions. Glycosides increased MCF-7 cells migration and adhesion, but reduced MDA-MB-231 cells migratory and metastatic potential. In conclusion, the above data clearly demonstrate that steviol glycosides have different effects on breast cancer cells according to their ER status, suggesting that steviol glycosides might be examined for their potential anticancer activity against breast cancer, especially triple negative breast cancer (TNBC).
    Keywords:  Stevia rebaudiana; Steviol glycosides; TNBC; breast cancer; cytotoxicity; epithelial-to-mesenchymal transition; estrogen receptors; extracellular matrix; phytoestrogens
    DOI:  https://doi.org/10.1002/iub.2669
  139. Drug Deliv Transl Res. 2022 Sep 01.
    A mucoadhesive patch loaded with freeze-dried liposomes for the local treatment of oral tumors.
    Layan Habib, Mohammed Alyan, Yasmine Ghantous, Jeny Shklover, Janna Shainsky, Imad Abu El-Naaj, Havazelet Bianco-Peled, Avi Schroeder.
      Oral cancers affect millions of people globally, with increasing incidences among adults aged 35 and above. Poor drug uptake by lesions in the oral cavity following systemic administration, as well as limited localized treatment modalities for oral tumors, result in poor patient quality of life and high mortality. Here, we describe a solid, dissolvable, bioadhesive alginate patch containing freeze-dried doxorubicin-loaded liposomes as a local treatment for oral tumors located on the tongue. By varying the alginate-to-liposome ratio in the mucoadhesive patch, we could control the degree of bioadhesion to the tongue and the release profile of the drug-loaded liposomes from the matrix. In vitro, exposing squamous cell carcinoma (SCC) to the alginate mucoadhesive patch or tablet resulted in dose-dependent cancer-cell death. In vivo, the efficacy of the local treatment was demonstrated in mice bearing orthotopic SCC tumors in the tongue. The bioadhesive patch, applied directly above the lesion, significantly reduced the tumor size and treatment-associated side effects compared to implanted patches or systemic drug administration. This study demonstrates that local bioadhesive therapies are effective in treating cancers of the oral cavity.
    Keywords:  Alginate; Freeze-dried; Liposome; Mucoadhesive; Nanoparticle; Oral cancer
    DOI:  https://doi.org/10.1007/s13346-022-01224-4
  140. Curr Drug Saf. 2022 Sep 02.
    Current Cannabidiol Safety: A Review.
    Chander Singh, Komal Rao, Nikita Yadav, Yogesh Vashist, Palak Chugh, Nidhi Bansal, Neha Minocha.
      Background- Marijuana, also known as cannabis, is the second most widely used illegal psychoactive substance smoked worldwide after tobacco, mainly due to the psychoactive effects induced by D-9-tetrahydrocannabinol (9-THC). Cannabidiol (CBD) is extracted from cannabis and may be used as an anti-inflammatory agent. Some patents on cannabidiol are discussed in this review. The cannabinoid is a non-psychoactive isomer of the more infamous tetrahydrocannabinol (THC); and is available in several administration modes, most known as CBD oil. Objectives- This study aims to provide an enhanced review of cannabidiol properties used in treating inflammation. This review also emphasises the current safety profile of cannabidiol. Method- Cannabis is also called Marijuana. It is the second most commonly used illegal psychoactive substance in the universe after tobacco. D-9-tetrahydrocannabinol (9-THC) present in cannabis produces psychoactive effects. Cannabidiol (CBD) extracted from cannabis is used for anti-inflammatory purposes. Cannabis smoking causes various types of cancer, such as lung, tongue, and jaw. The current review took literature from Google Scholar, PubMed, and Google Patents. Many clinical investigations are included in this review. Result- After analysing the literature on cannabis, it has been suggested that although cannabis is banned in some countries, it may be included in the treatment and mitigation of some diseases and symptoms like pain management, epilepsy, cancer, and anxiety disorder. Mild side effects were frequently observed in cannabis medications, which included infertility in females, liver damage, etc. Conclusion- Cannabis contains chemical compounds such as the cannabinoids delta-9-tetrahydrocannabinol (THC), a psychoactive substance, and non-psychoactive cannabidiol (CBD). Cannabidiol has been confirmed as an efficient treatment of epilepsy in several clinical trials, with one pure CBD product named Epidiolex. It is also used in treating anxiety and acne, as a pain reliever, and has anti-inflammatory properties.
    Keywords:  CBD; Cannabidiol; Cannabis; D-9-tetrahydrocannabinol (9-THC); Marijuana; Safety
    DOI:  https://doi.org/10.2174/1574886317666220902100511
  141. Int J Pharm. 2022 Aug 30. pii: S0378-5173(22)00686-X. [Epub ahead of print] 122133
    Surface stabilization determines macrophage uptake, cytotoxicity, and bioactivity of curcumin nanocrystals.
    Denisa Lizoňová, Filip Hládek, Stanislav Chvíla, Adam Baláž, Štěpánka Staňková, František Štěpánek.
      Pharmaceutical nanocrystals represent a promising new formulation that combines the benefits of bulk crystalline materials and colloidal nanoparticles. To be applied in vivo, nanocrystals must meet several criteria, namely colloidal stability in physiological media, non-toxicity to healthy cells, avoidance of macrophage clearance, and bioactivity in the target tissue. In the present work curcumin, a naturally occurring poorly water-soluble molecule with a broad spectrum of bioactivity has been considered as a candidate substance for preparing pharmaceutical nanocrystals. Curcumin nanocrystals in the size range of 40-90 nm were prepared by wet milling using the following combination of steric and ionic stabilizers: Tween 80, sodium dodecyl sulfate, Poloxamer 188, hydroxypropyl methylcellulose, phospholipids (with and without polyethylene glycol), and their combination. Nanocrystals stabilized by a combination of phospholipids enriched with polyethylene glycol proved to be the most successful in all evaluated criteria; they were colloidally stable in all media, exhibited low macrophage clearance, and proved non-toxic to healthy cells. This curcumin nanoformulation also exhibited outstanding anticancer potential comparable to commercially used cytostatics (IC50=73 µM; 24 h, HT-29 colorectal carcinoma cell line) which represents an improvement of several orders of magnitude when compared to previously studied curcumin formulations. This work shows that the preparation of phospholipid-stabilized nanocrystals allows for the conversion of poorly soluble compounds into a highly effective "solution-like" drug delivery system at pharmaceutically relevant drug concentrations.
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.122133
  142. Curr Drug Deliv. 2022 Sep 01.
    Novel Formulation Approaches Used for the Management of Osteoarthritis: A Recent Review.
    Mohit Kumar, Raghav Dogra, Uttam Kumar Mandal.
      Background The osteoarthritis (OA) causes economic, social, and health difficulties to the patients. Approximately 10% to 15% of all persons above the age of 60 have some degree of OA. OA is more common in women than in males. Diagnosed OA prevalence varies widely among EU member states, from 2.8% in Romania to 18.3% in Hungary. Introduction Osteoarthritis (OA) is a slow-progressing, non-inflammatory disorder. This disorder ultimately destroys articular cartilage and other joint components. The main symptoms are stiffness, pain, loss of flexibility, swelling, and bone spurs. Many risk factors, both modifiable and non-modifiable, have been associated with osteoarthritis (OA), including obesity and lack of exercise, genetic susceptibility, bone density, work-related damage, and trauma. Method Hydrogels, micro and nano-sized particles, and novel topical gels are among the most common examples. Hydrogels are cross-linked polymers with 3-D architecture that can hold water and expand like living tissue. The Micro-carriers, and nano-based drug delivery systems provide several advantages and may demonstrate prolonged release, controlled release, and higher joint half-life. Result OA-induced male Lewis rats were injected with celecoxib-loaded PEA microspheres to assess in vivo biocompatibility and degradation. According to the findings of this research, PEA microspheres loaded with celecoxib may be employed as safe delivery of drug with self-regulating behavior for the pain treatment related to knee osteoarthritis. Conclusion The concept of novel drug delivery systems has shown tangible benefits as a new avenue for precise, safe, and high-quality drug delivery for OA treatment. Currently, herbal drugs are also used in osteoarthritis treatment due to their potency and fewer side effects in contrast to synthetic drugs. The herbo-synthetic approach is a new concept for the delivery of both herbal and synthetic drugs together to exploit their individual beneficial effects while reducing undesirable side effects.
    Keywords:  Osteoarthritis; hydrogel; medicinal plants; microsphere; nanoparticle; synthetic drugs.
    DOI:  https://doi.org/10.2174/1567201819666220901092832
  143. Food Funct. 2022 Aug 30.
    The adverse effect of heat stress and potential nutritional interventions.
    Xinwei Chen, Wanlu Liu, He Li, Jian Zhang, Changli Hu, Xinqi Liu.
      Heat stress can cause tissue damage and metabolic disturbances, including intestinal and liver dysfunction, acid-base imbalance, oxidative damage, inflammatory response, and immune suppression. Serious cases can lead to heatstroke, which can be life-threatening. The body often finds it challenging to counteract these adverse effects, and traditional cooling methods are limited by the inconvenience of tool portability and the difficulty of determining the cooling endpoint. Consequently, more research was conducted to prevent and mitigate the negative effect of heat stress via nutritional intervention. This article reviewed the pathological changes and altered metabolic mechanisms caused by heat stress and discussed the protein (amino acid), vitamin, trace element, and electrolyte action pathways and mechanisms to mitigate heat stress and prevent heat-related disease. The main food sources for these nutrients and the recommended micronutrient supplementation forms were summarized to provide scientific dietary protocols for special populations.
    DOI:  https://doi.org/10.1039/d2fo01813f
  144. J Oleo Sci. 2022 ;71(9): 1375-1385
    Ethanolic Leaf Extract of C. angustifolia Instigates ROS Mediated Apoptosis within Glioblastoma C6 Cells.
    Xiaojun Pang, Haojun Huang, Yuyu Wei, Jiyong Leng.
      Glioblastoma multiforme or GBM is a destructive malignancy of the central nervous system and is accountable for leading cause of cancer related mortality. Inadequate success rate of surgical interventions and development of resistance towards the current therapeutical regime provides impetus for exploring novel therapeutical interventions against the disease. Recently, several epidemiological studies have explored the plausible utility of natural, dietary compounds in influencing the development, progression, and cancer metastasis. Recently, different phytoconstituents of Cassia angustifolia were found to be associated with anti-microbial, anti-cancer and anti-inflammatory effects. Therefore, the aim of the present study was to evaluate the anti-proliferative efficacy of ethanolic leaf extract of C. angustifolia (LCaEt-OH) against rat derived glioblastoma C6 cells. Briefly, the anti-proliferative potential of LCaEt-OH was assessed using MTT assay, quantitative estimation of ROS, and evaluation of mitochondrial membrane potential (ΔΨm). Moreover, the activity of caspases involved in intrinsic apoptotic pathways was also investigated using colorimetric kit followed by quantitative RT-PCR evaluation of modulation in gene expressions triggered due to LCaEt-OH treatment. Treatment of LCaEt-OH on C6 cells elucidated substantial dose-dependent decline in cellular viability. Furthermore, LCaEt-OH showed its efficacy in substantially enhancing intracellular ROS. LCaEt-OH also incited apoptosis in C6 cells by instigating nuclear condensation and dissipation of ΔΨm. In addition, LCaEt-OH mediated instigation of apoptosis was directly influenced by increased activity of caspases indispensable for intrinsic apoptotic pathway. These conclusive evidences indicate towards anticancer efficacy of LCaEt-OH against C6 cells.
    Keywords:  C6 cells; apoptosis; glioblastoma multiforme; oxidative stress; phytocompounds
    DOI:  https://doi.org/10.5650/jos.ess22143
  145. Thorac Cancer. 2022 Aug 21.
    Dietary acid load and esophageal cancer risk: A case-control study.
    Alvaro Luis Ronco, Wilner Martínez-López, Juan M Calderón, Maximilian Andreas Storz.
       BACKGROUND: A high dietary acid load (DAL) can produce metabolic acidosis, which is linked to cancer development through mechanisms of inflammation and cell transformation. There is limited epidemiological evidence linking DAL and cancer risk; however, none of the published studies focused on DAL and esophageal cancer (EC) risk in particular. Therefore, we sought to explore this association in the present study.
    METHODS: A case-control study was performed in 1295 male patients (185 squamous cell EC cases and 1110 age-frequency and urban/rural residence matched controls) through a multitopic inquiry, including a food frequency questionnaire. Food-derived nutrients were calculated from available databases. The DAL was calculated based on two validated measures: Potential renal acid load (PRAL) score and net endogenous acid production (NEAP) score. Odds ratios (OR) and their 95% confidence intervals (95% CI) were estimated by unconditional logistic regression, adjusting for confounders.
    RESULTS: We found direct, significant associations between dietary acid load and EC risk: (OR = 2.28, 95% CI: 1.44-3.61, ptrend <0.0001) and (OR = 2.17, 95% CI: 1.38-3.41, ptrend <0.0001) for highest PRAL and NEAP tertiles, respectively. Our data raise the possibility that a high DAL may contribute to EC development. Both acid load scores were directly associated with animal-based foods (mainly meat) and inversely associated with the intake of plant-based foods.
    CONCLUSION: To the best of our knowledge, this is the first epidemiological case-control study analyzing associations of DAL and squamous cell EC risk. Further research is warranted to confirm our findings.
    Keywords:  NEAP; PRAL; cancer; dietary acid load; epidemiology; esophagus
    DOI:  https://doi.org/10.1111/1759-7714.14612
  146. Biomed Pharmacother. 2022 Aug 30. pii: S0753-3322(22)01005-8. [Epub ahead of print]154 113616
    Repurposed itraconazole for use in the treatment of malignancies as a promising therapeutic strategy.
    Chun-Lan Li, Ze-Xuan Fang, Zheng Wu, Yan-Yu Hou, Hua-Tao Wu, Jing Liu.
      Understanding cancer biology and the development of novel agents for cancer treatment has always been the goal of cancer researchers. However, the research and development of new drugs is hindered by its long development time, exorbitant cost, high regulatory hurdles, and staggering failure rates. Given the challenges involved drug development for cancer therapies, alternative strategies, in particular the repurposing of 'old' drugs that have been approved for other indications, are attractive. Itraconazole is an FDA-approved anti-fungal drug of the triazole class, and has been used clinically for more than 30 years. Recent drug repurposing screens revealed itraconazole exerts anti-cancer activity via inhibiting angiogenesis and multiple oncogenic signaling pathways. To explore the potential utilization of itraconazole in different types of malignancies, we retrieved the published literature relating to itraconazole in cancer and reviewed the mechanisms of itraconazole in preclinical and clinical cancer studies. Current research predicts the hedgehog signaling pathway as the main target by which itraconazole inhibits a variety of solid and hematological cancers. As clinical trial results become available, itraconazole could emerge as a new antitumor drug that can be used in combination with first-line antitumor drugs.
    Keywords:  Hedgehog signaling; Itraconazole; Malignancy; Repurposed therapy
    DOI:  https://doi.org/10.1016/j.biopha.2022.113616
  147. PLoS One. 2022 ;17(8): e0273267
    Fe3+ opposes the 1,25(OH)2D3-induced calcium transport across intestinal epithelium-like Caco-2 monolayer in the presence or absence of ascorbic acid.
    Sukpapohn Phummisutthigoon, Kornkamon Lertsuwan, Nattapon Panupinthu, Ratchaneevan Aeimlapa, Jarinthorn Teerapornpuntakit, Wasutorn Chankamngoen, Jirawan Thongbunchoo, Narattaphol Charoenphandhu, Kannikar Wongdee.
      Although iron is an essential element for hemoglobin and cytochrome synthesis, excessive intestinal iron absorption-as seen in dietary iron supplementation and hereditary disease called thalassemia-could interfere with transepithelial transport of calcium across the intestinal mucosa. The underlying cellular mechanism of iron-induced decrease in intestinal calcium absorption remains elusive, but it has been hypothesized that excess iron probably negates the actions of 1,25-dihydroxyvitamin D [1,25(OH)2D3]. Herein, we exposed the 1,25(OH)2D3-treated epithelium-like Caco-2 monolayer to FeCl3 to demonstrate the inhibitory effect of ferric ion on 1,25(OH)2D3-induced transepithelial calcium transport. We found that a 24-h exposure to FeCl3 on the apical side significantly decreased calcium transport, while increasing the transepithelial resistance (TER) in 1,25(OH)2D3-treated monolayer. The inhibitory action of FeCl3 was considered rapid since 60-min exposure was sufficient to block the 1,25(OH)2D3-induced decrease in TER and increase in calcium flux. Interestingly, FeCl3 did not affect the baseline calcium transport in the absence of 1,25(OH)2D3 treatment. Furthermore, although ascorbic acid is often administered to maximize calcium solubility and to enhance intestinal calcium absorption, it apparently had no effect on calcium transport across the FeCl3- and 1,25(OH)2D3-treated Caco-2 monolayer. In conclusion, apical exposure to ferric ion appeared to negate the 1,25(OH)2D3-stimulated calcium transport across the intestinal epithelium. The present finding has, therefore, provided important information for development of calcium and iron supplement products and treatment protocol for specific groups of individuals, such as thalassemia patients and pregnant women.
    DOI:  https://doi.org/10.1371/journal.pone.0273267
  148. Endocr Metab Immune Disord Drug Targets. 2022 Aug 27.
    The Potential Role of Naringin and Naringenin as Nutraceuticals against Metabolic Syndrome.
    Luca Massaro, Anna Raguzzini, Paola Aiello, Débora Villaño Valencia.
      Metabolic syndrome, an increasing problem in western society, is a cluster of conditions which affects cardiovascular health, lipid and glucose management, increasing the risk of heart diseases, stroke and diabetes. Bioactive flavonoids are a great resource of compounds with proved anti-inflammatory activities. Naringin, a natural flavanone found in citrus fruits, and its aglycone have demonstrated to ameliorate obesity, dyslipidemia, and insulin resistance in animal models. The principal mechanisms by which these flavonoids exert their action involved AMPK and PPARα up-regulation, and the down-regulation of genes involved in lipid metabolism. Although different studies have been carried out to define the pharmacological effects of these flavonoids, their therapeutic use is still limited.
    Keywords:  anti-inflammatory; citrus fruits; flavonoids; metabolic syndrome.; naringenin; naringin
    DOI:  https://doi.org/10.2174/1871530322666220827141203
  149. Mater Today Bio. 2022 Dec;16 100392
    Catechol-chitosan/polyacrylamide hydrogel wound dressing for regulating local inflammation.
    Bingyang Lu, Xiao Han, Dan Zou, Xiao Luo, Li Liu, Jingyue Wang, Manfred F Maitz, Ping Yang, Nan Huang, Ansha Zhao.
      Chronic wounds and the accompanying inflammation are ongoing challenges in clinical treatment. They are usually accompanied by low pH and high oxidative stress environments, limiting cell growth and proliferation. Ordinary medical gauze has limited therapeutic effects on chronic wounds, and there is active research to develop new wound dressings. The chitosan hydrogel could be widely used in biomedical science with great biocompatibility, but the low mechanical properties limit its development. This work uses polyacrylamide to prepare double-network (DN) hydrogels based on bioadhesive catechol-chitosan hydrogels. Cystamine and N, N'-Bis(acryloyl)cystamine, which can be cross-linking agents with disulfide bonds to prepare redox-responsive DN hydrogels and pH-responsive nanoparticles (NPs) prepared by acetalized cyclodextrin (ACD) are used to intelligently release drugs against chronic inflammation microenvironments. The addition of catechol groups and ACD-NPs loaded with the Resolvin E1 (RvE1), promotes cell adhesion and regulates the inflammatory response at the wound site. The preparation of the DN hydrogel in this study can be used to treat and regulate the inflammatory microenvironment of chronic wounds accurately. It provides new ideas for using inflammation resolving factor loaded in DN hydrogel of good biocompatibility with enhanced mechanical properties to intelligent regulate the wound inflammation and promote the wound repaired.
    Keywords:  Chronic wounds and inflammation; Double network hydrogel; Drug delivery; Resolvin; pH and redox responsive
    DOI:  https://doi.org/10.1016/j.mtbio.2022.100392
  150. Hum Exp Toxicol. 2022 Jan-Dec;41:41 9603271221119182
    Potential anticancer effect of sodium caprate on human gastric cancer cells.
    Nam-Hee Kim, Jung Ho Park, Dong-Hoe Koo, Taeheon Lee, Jeong-Yoon Yang, Hee-Young Lee.
      The role of sodium caprate (C10) in enhancing drug absorption is well established; however, little information is available on its role as an anticancer drug. This study aimed to evaluate the anticancer effect of C10 in gastric cancer cells. The mechanism of cytotoxicity of C10 was evaluated by western blotting following treatment of the gastric cancer cells with various concentrations of C10. C10 cytotoxicity was measured via MTS (3-(4, 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H tetrazolium), lactate dehydrogenase (LDH), cAMP, and ATP assays. Gastric cancer cells were observed by electron microscopy following treatment with C10. Then, xenograft mice that were inoculated with gastric cancer cells were treated with C10 for 4 weeks, after which the changes in tumor size were measured. C10 triggered apoptosis in the gastric cancer cells through the mitochondrial pathway at concentrations of more than 0.2 mM. However, 15 mM of C10 induced necrosis in gastric cancer cells by causing cellular swelling and the formation of holes in the cell membrane. Levels of cAMP and ATP decreased significantly following exposure to 15 mM C10 for 1 h. Additionally, the size of the xenograft tumors was significantly reduced by 24% after 4 weeks of C10 treatment (p < 0.05). This study indicates that C10 induces apoptosis and necrosis in a concentration-dependent manner and has clear anticancer effects on gastric cancer cells.
    Keywords:  Sodium caprate; apoptosis; gastric cancer; necrosis; xenograft
    DOI:  https://doi.org/10.1177/09603271221119182
  151. Crit Rev Food Sci Nutr. 2022 Aug 29. 1-9
    The effect of Green green tea consumption on body mass index, lipoprotein, liver enzymes, and liver cancer: An updated systemic review incorporating a meta-analysis.
    Mingzhen Li, Yunjie Duan, Ying Wang, Lei Chen, Mohamed E A Abdelrahim, Jun Yan.
       INTRODUCTION: Green tea is related to the reduction of liver enzymes, lipoprotein, and body mass index. However, some reports related green tea to the risk of developing liver cancer, but their outcomes were conflicting. Hence, the present study aimed to determine the relationship between green tea intake and lipoprotein, liver enzymes, body mass index, and liver cancer.
    METHODS: A systematic literature search up to January 2022 was performed and 22 studies with a total of 169599 subjects participated in the studies with 97316 subjects of them used green tea intake. Odds ratio (OR) or standardized mean difference (MD) with 95% confidence intervals (CIs) was calculated to evaluate the relationship between green tea intake and lipoprotein, liver enzymes, body mass index, and liver cancer using the dichotomous or the contentious method with a random effect model.
    RESULTS: Green tea intake significantly lowered the risk of developing liver cancer (OR, 0.85; 95% CI, 0.74 to 0.97, p = 0.02), and body mass index (MD, -0.69; 95% CI, -0.95to -0.42, p < 0.001) compared to no green tea intake. Also, there was a significant lowering effect of green tea intake on liver enzymes including alanine aminotransferase (MD, -0.65; 95% CI, -0.92 to -0.38, p < 0.001), and aspartate aminotransferase (MD, -0.77; 95% CI, -1.40 to -0.14, p = 0.02) compared to no green tea intake. There was also a significant lowering effect of green tea intake on lipoprotein including triglycerides (MD, -0.70; 95% CI, -1.35 to -0.04, p = 0.04), total cholesterol (MD, -0.39; 95% CI, -0.74 to -0.04, p = 0.03) and law-density lipoprotein (MD, -0.44; 95% CI, -0.69- -0.19, p < 0.001) compared to no green tea intake. However, no significant different was found between green tea intake and no green tea intake on high-density lipoprotein (MD, 0.16; 95% CI, -0.11 to 0.44, p = 0.24).
    CONCLUSIONS: Based on this meta-analysis, green tea intake had a significant lowering effect on the risk of developing liver cancer and had a significantly improving effect on body mass index, liver enzymes, and lipoprotein compared to no green tea intake. These results suggest that green tea may be added to the daily dietary program to improve cardiovascular status with no possible risk of liver cancer. It even may have a protecting effect against liver cancer in the usual daily number of cups.
    Keywords:  Green tea; body mass index; lipoprotein; liver cancer; liver enzymes
    DOI:  https://doi.org/10.1080/10408398.2022.2113360
  152. J Control Release. 2022 Aug 24. pii: S0168-3659(22)00543-0. [Epub ahead of print]
    Strategies for persistent retention of macromolecules and nanoparticles in the blood circulation.
    Yoshinobu Takakura, Yuki Takahashi.
      The enhanced permeability and retention (EPR) effect has been the gold standard in developing drug delivery systems for passive tumor targeting. Although the importance of this concept remains unchanged, some controversies have arisen. In this review, various strategies for tumor targeting using macromolecules and nanoparticles based on the EPR effect are discussed from the viewpoint of pharmacokinetics. Overall, such strategies seek to retain therapeutic material in the blood circulation, which is a key factor for successful targeting. Strategies using macromolecules, including antibody-drug conjugates, serum albumin-based delivery systems, PEGylated recombinant proteins, and stealth liposomes as well as nanoparticle-based strategies such as those based on lipid nanoparticles, and polymeric micelles, have been discussed. The feasibility of small extracellular vesicles, a new class of nanosized delivery carriers, is also discussed.
    Keywords:  EPR effect; Macromolecules; Nanoparticles; Small extracellular vesicles; Tumor targeting
    DOI:  https://doi.org/10.1016/j.jconrel.2022.05.063
  153. Drug Dev Res. 2022 Aug 28.
    Versatile use of Carmofur: A comprehensive review of its chemistry and pharmacology.
    Mohammad Mohiminul Islam, Shama P Mirza.
      Carmofur, 1-hexylcarbamoyl-5-fluorouracil (HCFU) is an antineoplastic drug, which has been in clinics in Japan since 1981 for the treatment of colorectal cancer. Subsequently, it was also introduced in China, Korea, and Finland. Besides colorectal cancer, it has also shown antitumor activity in other cancers such as breast, head and neck, pancreatic, gastrointestinal, and solid brain tumors. A prodrug of 5-fluorouracil (5-FU), carmofur has shown better gastrointestinal stability and superior antiproliferative activity compared to its active counterpart 5-FU. Recently, carmofur has gained attention as an acid ceramidase inhibitor and as a potential lead compound against several noncancerous diseases such as coronavirus disease 2019, Krabbe disease, acute lung injury, Parkinson's disease, dementia, childhood ependymoma etc. Carmofur has also been reported to have antifungal, and antimicrobial properties. Nevertheless, no comprehensive review is available on this drug. Herein, we summarized the chemistry, pharmacokinetics, and pharmacology of carmofur based on the literature published between January 1976 and March 2022 as identified from PubMed and Google Scholar search engines.
    Keywords:  5-fluorouracil; HCFU; acid ceramidase inhibitor; cancer; carmofur; glioblastoma
    DOI:  https://doi.org/10.1002/ddr.21984
  154. Biochem Biophys Rep. 2022 Sep;31 101329
    Development of a novel tocopheryl ester for suppression of lipid accumulation without cytotoxicity by optimization of dicarboxylic ester moiety.
    Misaki Yamasaki, Yuika Seto, Mizune Ozono, Michiyasu Nakao, Akira Shigenaga, Akira Otaka, Shigeki Sano, Kentaro Kogure.
      Tocopheryl succinate (Tsuc) is a succinic acid ester of the well-known antioxidant α-tocopherol (T). Tsuc exhibits various biological activities, including tumor growth suppression via activation of cell signaling and prevention of lipid accumulation in mouse adipocyte 3T3-L1 cells. The latter findings suggest that Tsuc may be a drug candidate for the treatment of obesity. However, Tsuc was found to induce apoptosis of normal cells (in addition to cancer cells), demonstrating the need to reduce the cytotoxicity of Tsuc without losing the suppression effect on lipid accumulation. Based on our previous findings, we focused on the ester structure of Tsuc for controlling cytotoxicity. Herein, we examined the cytotoxicity and lipid accumulation suppression effect of various T ester derivatives. We found that the terminal carboxylic group is necessary for suppression of lipid accumulation. We synthesized tocopheryl glutarate (Tglu) and tocopheryl adipate (Tadi) by elongation of carbon atoms 1 and 2 of the dicarboxylic moiety, respectively. Tglu and Tadi did not show any cytotoxicity, and both esters suppressed lipid accumulation, although their suppression activities were weaker than that of Tsuc. Tadi showed a more potent lipid accumulation inhibitory effect than Tglu. Although Tadi inhibited lipogenesis and promoted lipolysis, lipolysis was induced at lower concentrations than inhibition of lipogenesis, suggesting that Tadi mainly affects lipolysis. Taken together, we succeeded in the reduction of cytotoxicity, without loss of the suppression effect on lipid accumulation, by elongation of the dicarboxylic moiety of Tsuc. Tadi may be a promising candidate as an anti-obesity drug.
    Keywords:  Anti-obesity; Cytotoxicity; Lipid accumulation suppression; Tocopheryl ester
    DOI:  https://doi.org/10.1016/j.bbrep.2022.101329
  155. J Nanobiotechnology. 2022 Aug 31. 20(1): 395
    Engineering nano-drug biointerface to overcome biological barriers toward precision drug delivery.
    Saquib Waheed, Zhibin Li, Fangyingnan Zhang, Anna Chiarini, Ubaldo Armato, Jun Wu.
      The rapid advancement of nanomedicine and nanoparticle (NP) materials presents novel solutions potentially capable of revolutionizing health care by improving efficacy, bioavailability, drug targeting, and safety. NPs are intriguing when considering medical applications because of their essential and unique qualities, including a significantly higher surface to mass ratio, quantum properties, and the potential to adsorb and transport drugs and other compounds. However, NPs must overcome or navigate several biological barriers of the human body to successfully deliver drugs at precise locations. Engineering the drug carrier biointerface can help overcome the main biological barriers and optimize the drug delivery in a more personalized manner. This review discusses the significant heterogeneous biological delivery barriers and how biointerface engineering can promote drug carriers to prevail over hurdles and navigate in a more personalized manner, thus ushering in the era of Precision Medicine. We also summarize the nanomedicines' current advantages and disadvantages in drug administration, from natural/synthetic sources to clinical applications. Additionally, we explore the innovative NP designs used in both non-personalized and customized applications as well as how they can attain a precise therapeutic strategy.
    Keywords:  Biological barriers; Drug delivery; Nanomedicine; Nanoparticle
    DOI:  https://doi.org/10.1186/s12951-022-01605-4
  156. Curr Opin Clin Nutr Metab Care. 2022 Aug 31.
    The anti-inflammatory effects of a Mediterranean diet: a review.
    Catherine Itsiopoulos, Hannah L Mayr, Colleen J Thomas.
       PURPOSE OF REVIEW: Chronic noncommunicable diseases remain the leading cause of morbidity and mortality worldwide and the majority are preventable with a healthy diet and lifestyle, but controversy remains as to the best approach. Greater adherence to a traditional Mediterranean diet has consistently been associated with lower morbidity and mortality from cardiovascular disease, diabetes and many cancers, and lower all-cause mortality. Despite the well known benefits on chronic disease risk there remains some scepticism as to the effects of this dietary pattern across populations outside the Mediterranean and the mechanisms of action of this traditional plant-based dietary pattern.This narrative review aims to summarize the latest evidence on the health protective effects of a traditional Mediterranean diet on chronic noncommunicable diseases, specifically focussing on the anti-inflammatory effects of this highly published dietary pattern.
    RECENT FINDINGS: Recent high-quality evidence now supports a Mediterranean diet in secondary prevention of cardiovascular disease with impacts on atherosclerosis progression, likely through reduction of systemic inflammation and irrespective of changes in cholesterol or weight. The Mediterranean diet has a low Dietary Inflammatory Index illustrating its anti-inflammatory potential. This dietary pattern beneficially modulates the gut microbiota and immune system, including emerging evidence for efficacy against severe acute respiratory syndrome coronavirus 2 (coronavirus disease 2019). Emerging evidence shows clinicians are not routinely recommending a Mediterranean diet despite well known evidence due to barriers such as lack of training, patient materials and concerns about potential patient adherence.
    SUMMARY: The physiological mechanisms of action of this healthy diet pattern are becoming better understood to be multisystem and involving the gut. Larger controlled trials investigating mechanistic effects in broader non-Mediterranean populations are warranted. Although reflected in therapeutic guidelines for chronic disease management worldwide there are individual, clinical practice and health system barriers to its implementation that need a multisectoral approach to address.
    DOI:  https://doi.org/10.1097/MCO.0000000000000872
  157. J Anim Physiol Anim Nutr (Berl). 2022 Aug 29.
    An insight into the potential of berberine in animal nutrition: Current knowledge and future perspectives.
    Navid Ghavipanje, Mohammad Hasan Fathi Nasri, Einar Vargas-Bello-Pérez.
      In animal nutrition, the interest for novel feed additives has expanded with elevating industry standards and consumer awareness besides the demand for healthy animal-derived food products. Consumer and animal health are leading concerns dictating the importance of novel animal feed additives. Berberine (BBR) is a natural pentacyclic isoquinoline alkaloid that has exhibited diverse pharmacological properties, including metabolism-regulating, hepatoprotective, and inflammatory alleviative in addition to its antioxidant activity. Despite detailed information on cellular mechanisms associated with BBR therapeutics, and strong clinical evidence, only a few studies have focused on BBR applied to animal nutrition. However, great pieces of evidence have shown that dietary BBR supplementation could result in improved growth performance, enhanced oxido-inflammatory markers, and mitigated metabolic dysfunctions in both monogastric and ruminant animals. The data discussed in the present review may set the basis for further research on BBR in animal diets for developing novel strategies aiming to improve animal health as well as products with beneficial properties for humans.
    Keywords:  anti-inflammatory; antioxidants; berberine; metabolism; performance; poultry; ruminants
    DOI:  https://doi.org/10.1111/jpn.13769
  158. Int J Mol Med. 2022 Oct;pii: 130. [Epub ahead of print]50(4):
    The marine natural product, dicitrinone B, induces apoptosis through autophagy blockade in breast cancer.
    Qinying Liu, Yi Yang, Miaomiao Cheng, Fangting Cheng, Shanshan Chen, Qiuhong Zheng, Yang Sun, Li Chen.
      Being a highly conserved catabolic process, autophagy is induced by various forms of cellular stress, and its modulation has considerable potential as a cancer therapeutic approach. In the present study, it was demonstrated that dicitrinone B (DB), a rare carbon‑bridged citrinin dimer, may exert anticancer effects by blocking autophagy at a late stage, without disrupting lysosomal function in MCF7 breast cancer and MDA‑MB‑231 triple‑negative breast cancer cells. Furthermore, it was discovered that DB significantly enhanced intracellular reactive oxygen species (ROS) production and that the removal of ROS was followed by the attenuation of autophagy inhibition. In addition, DB exerted notable inhibitory effects on the proliferation and promoting effects on the apoptosis of MCF7 and MDA‑MB‑231 cells. In combination with conventional chemotherapeutic drugs, DB exhibited a further enhanced synergistic effect than when used as a single agent. Overall, the data of the present study demonstrate that DB may prove to be a promising autophagy inhibitor with anticancer activity against breast cancer.
    Keywords:  adriamycin; autophagy inhibitor; breast cancer; dicitrinone B; reactive oxygen species
    DOI:  https://doi.org/10.3892/ijmm.2022.5186
  159. Explor Target Antitumor Ther. 2021 ;2(4): 374-384
    Does the gut microbiome environment influence response to systemic breast cancer treatment?
    Eilidh Bruce, Stanislau Makaranka, Gordon Urquhart, Beatrix Elsberger.
      The gut microbiome is a novel player in the pathogenesis and treatment of breast cancer. The term "microbiome" is used to describe the diverse community of micro-organisms existing within the gastrointestinal tract. The gut microbiome plays an important role in oestrogen metabolism through its ability to deconjugate oestrogens within the gut resulting in their reabsorption. Therefore, it is not unsurprising that "dysbiosis", the disruption of normal gut microbiota composition, is now thought to play a role in the development of the disease, as women with breast cancer have been shown to have altered gut microbiota and this has been correlated with tumour characteristics. There is emerging evidence to suggest that the gut microbiota may also impact on breast cancer treatment, by mediating both drug efficacy and toxicity. The present review will discuss the influence of the gut microbiota on systemic treatments for breast cancer, including chemotherapy, anti-human epidermal growth factor receptor 2 (HER2) therapy, endocrine therapy and immunotherapy as well as other targeted treatments.
    Keywords:  Breast cancer; dysbiosis; estrobolome; gut microbiome; gut microbiota
    DOI:  https://doi.org/10.37349/etat.2021.00051
  160. Explor Target Antitumor Ther. 2020 ;1(6): 413-426
    An overview of the potential anticancer properties of cardamonin.
    Shanaya Ramchandani, Irum Naz, Namrata Dhudha, Manoj Garg.
      Cancer is one of the leading causes of mortality, contributing to 9.6 million deaths globally in 2018 alone. Although several cancer treatments exist, they are often associated with severe side effects and high toxicities, leaving room for significant advancements to be made in the field. In recent years, several phytochemicals from plants and natural bioresources have been extracted and tested against various human malignancies using both in vitro and in vivo preclinical model systems. Cardamonin, a chalcone extracted from the Alpinia species, is an example of a natural therapeutic agent that has anti-cancer and anti-inflammatory effects against human cancer cell lines, including breast, lung, colon, and gastric, in both in vitro culture systems as well as xenograft mouse models. Earlier, cardamonin was used as a natural medicine against stomach related issues, diarrhea, insulin resistance, nephroprotection against cisplatin treatment, vasorelaxant and antinociceptive. The compound is well-known to inhibit proliferation, migration, invasion, and induce apoptosis, through the involvement of Wnt/β-catenin, NF-κB, and PI3K/Akt pathways. The good biosafety and pharmacokinetic profiling of cardamonin satisfy it as an attractive molecule for the development of an anticancer agent. The present review has summarized the chemo-preventive ability of cardamonin as an anticancer agent against numerous human malignancies.
    Keywords:  Cancer; NF-κB, PI3K/Akt; Wnt/β-catenin; apoptosis; cardamonin; chalcone; proliferation
    DOI:  https://doi.org/10.37349/etat.2020.00026
  161. Pharm Nanotechnol. 2022 Aug 31.
    Role of solid lipid nanoparticle for the delivery of Lipophilic Drugs and Herbal Medicines in the treatment of pulmonary hypertension.
    Tanuja Bhatia, G D Gupta, Balak Das Kurmi, Dilpreet Singh.
      Pulmonary arterial hypertension (PAH) is an uncommon condition marked by elevated pulmonary artery pressure that leads to right ventricular failure. The majority of drugs are now been approved by FDA for PAH, however, several biopharmaceutical hindrances lead to failure of the therapy. Various novel drug delivery systems are available in the literature from which lipid-based nanoparticles i.e. solid lipid nanoparticle is widely investigated for improving the solubility and bioavailability of drugs. In this paper, the prototype phytoconstituents used in pulmonary arterial hypertension have limited solubility and bioavailability. We highlighted the novel concepts of SLN for lipophilic phytoconstituents with their potential applications. This paper also reviews the present state of the art regarding production techniques for SLN like High-Pressure Homogenization, Micro-emulsion Technique, and Phase Inversion Temperature Method, etc. Furthermore, toxicity aspects and in vivo fate of SLN are also highlighted in this review. In a nutshell, safer delivery of phytoconstituents by SLN added a novel feather to the cap of successful drug delivery technologies.
    Keywords:  Bioavailability; Drugs; Pulmonary arterial hypertension; Solid lipid nanoparticle; Solubility
    DOI:  https://doi.org/10.2174/2211738510666220831113857
  162. Biomed Pharmacother. 2022 Aug 26. pii: S0753-3322(22)00949-0. [Epub ahead of print]154 113560
    Role of curcumin in selected head and neck lesions. Limitations on the use of the Hep-2 cell line: A critical review.
    Ludwika Piwowarczyk, Maciej Stawny, Krzysztof Piwowarczyk, Dariusz T Mlynarczyk, Izabela Muszalska-Kolos, Malgorzata Wierzbicka, Tomasz Goslinski, Anna Jelinska.
      Neoplastic diseases of the upper respiratory airways, as well as head and neck cancers, are a frequent cause of death and significantly affect the quality of life of both patients and survivors. As the frequency increases, new and improved treatment techniques are sought. Promising properties in this respect are expressed by a natural compound - curcumin. Along with its derivatives, it was found useful in the treatment of a series of cancers. Curcumin was found to be effective in clinical trials and in vitro, in vivo anticancer experiments. Nanoformulations (e.g., poly(lactide-co-glycolic acid)-based nanoparticles, nanoemulsions), and modifications of curcumin, as well as its combinations with other substances (e.g., catechins, cisplatin) or treatments (e.g., radiotherapy or local use in inhalation), were found to enhance the antitumor effect. This review aims to summarize the recent findings for the treatment of head and neck diseases, especially squamous cell carcinomas (HNSCCs), including drawing attention to the constant use of the misidentified Hep-2 cell line and proposing databases purposed at eliminating this problem. Moreover, this manuscript focuses on pointing out the molecular mechanisms of therapy that have been reached and emphasizing the shortcomings that still need to be addressed.
    Keywords:  Curcumin; Head and neck cancer; Larynx; Misidentified Hep-2 cell line; Nanoformulations
    DOI:  https://doi.org/10.1016/j.biopha.2022.113560
  163. Phytomedicine. 2022 May 21. pii: S0944-7113(22)00266-5. [Epub ahead of print]106 154188
    Phytochemicals: A potential next generation agent for radioprotection.
    Bimal Prasad Jit, Subhaswaraj Pattnaik, Rakesh Arya, Rutumbara Dash, Saubhagya Subhadarsini Sahoo, Biswajita Pradhan, Prajna Paramita Bhuyan, Pradyota Kumar Behera, Mrutyunjay Jena, Ashok Sharma, Paban Kumar Agrawala, Rajendra Kumar Behera.
       BACKGROUND: Radiation hazards are accountable for extensive damage in the biological system and acts as a public health burden. Owing to the rapid increasing in radiation technology, both Ionizing radiation (IR) from natural and man made source poses detrimental outcome to public health. IR releases free radicals which induces oxidative stress and deleterious biological damage by modulating radiation induced signalling intermediates. The efficacy of existing therapeutic approach and treatment strategy are limited owing to their toxicity and associated side effects. Indian system of traditional medicine is enriched with prospective phytochemicals with potential radioprotection ability.
    PURPOSE: The present review elucidated and summarized the potential role of plant derived novel chemical compound with prospective radioprotective potential.
    METHOD: So far as the traditional system of Indian medicine is concerned, plant kingdom is enriched with potential bioactive molecules with diverse pharmacological activities. We reviewed several compounds mostly secondary metabolites from plant origin using various search engines.
    RESULTS: Both compounds from land plants and marine source exhibited antioxidant antiinflammatory, free radical scavenging ability. These compounds have tremendous potential in fine-tuning of several signalling intermediates, which are actively participated in the progression and development of a pathological condition associated with radiation stress.
    CONCLUSION: Development and explore of an operational radioprotective agent from originated from plant source that can be used as a novel molecular tool to eliminate the widespread damage caused by space exploration, ionizing radiation, nuclear war and radiotherapy has been significantly appreciated. Through extensive literature search we highlighted several compounds from both land plant and marine origin can be implemented for a better therapeutic potential against radiation induced injury. Furthermore, extensive clinical trials must be carried out in near future for better therapeutic modality and clinical efficacy.
    Keywords:  Ionising radiation; Phytochemicals; Radioprotection; Secondary metabolites
    DOI:  https://doi.org/10.1016/j.phymed.2022.154188
  164. Int J Pharm Compd. 2022 Sep-Oct;26(5):26(5): 400-408
    Basics of Compounding: Compounding with Microneedle Arrays, Part 1: Introduction and Overview.
    Loyd V Allen.
      Over the years, numerous approaches have been used to increase drug penetration of the skin. Transdermal drug delivery has potential advantages over other conventional routes of drug delivery, as it can provide a non- invasive and painless alternative to parenteral routes. Also, the pharmacokinetic profiles of drugs can be more uniform with less variability, resulting in improved patient compliance. Classical topical formulations are different from those intended for transdermal drug delivery, as they are generally applied to broken, diseased, or damaged skin, whereas, transdermal drugs are applied to healthy skin. On the negative side, the use of transdermal drug delivery is limited by the restrictions inherent in the lipophilic stratum corneum barrier, which allows a limited number of drug molecules with certain physicochemical properties to be delivered. This article, which represents part 1 of a series of articles on compounding with microneedles, provides an introduction and overview of this topic.
  165. Front Pharmacol. 2022 ;13 944773
    Engaging plasticity: Differentiation therapy in solid tumors.
    Neta Bar-Hai, Dana Ishay-Ronen.
      Cancer is a systemic heterogeneous disease that can undergo several rounds of latency and activation. Tumor progression evolves by increasing diversity, adaptation to signals from the microenvironment and escape mechanisms from therapy. These dynamic processes indicate necessity for cell plasticity. Epithelial-mesenchymal transition (EMT) plays a major role in facilitating cell plasticity in solid tumors by inducing dedifferentiation and cell type transitions. These two practices, plasticity and dedifferentiation enhance tumor heterogeneity creating a key challenge in cancer treatment. In this review we will explore cancer cell plasticity and elaborate treatment modalities that aspire to overcome such dynamic processes in solid tumors. We will further discuss the therapeutic potential of utilizing enhanced cell plasticity for differentiation therapy.
    Keywords:  EMT; TGFb signaling; cancer cell plasticity; differentiation therapy; solid tumors; trans-differentiation
    DOI:  https://doi.org/10.3389/fphar.2022.944773
  166. Front Plant Sci. 2022 ;13 942789
    Jasmonates in plant growth and development and elicitation of secondary metabolites: An updated overview.
    Soo-In Sohn, Subramani Pandian, Kasinathan Rakkammal, Muthiah Joe Virgin Largia, Senthil Kumar Thamilarasan, Sekaran Balaji, Yedomon Ange Bovys Zoclanclounon, Jayabalan Shilpha, Manikandan Ramesh.
      Secondary metabolites are incontestably key specialized molecules with proven health-promoting effects on human beings. Naturally synthesized secondary metabolites are considered an important source of pharmaceuticals, food additives, cosmetics, flavors, etc., Therefore, enhancing the biosynthesis of these relevant metabolites by maintaining natural authenticity is getting more attention. The application of exogenous jasmonates (JAs) is well recognized for its ability to trigger plant growth and development. JAs have a large spectrum of action that covers seed germination, hypocotyl growth regulation, root elongation, petal expansion, and apical hook growth. This hormone is considered as one of the key regulators of the plant's growth and development when the plant is under biotic or abiotic stress. The JAs regulate signal transduction through cross-talking with other genes in plants and thereby deploy an appropriate metabolism in the normal or stressed conditions. It has also been found to be an effective chemical elicitor for the synthesis of naturally occurring secondary metabolites. This review discusses the significance of JAs in the growth and development of plants and the successful outcomes of jasmonate-driven elicitation of secondary metabolites including flavonoids, anthraquinones, anthocyanin, xanthonoid, and more from various plant species. However, as the enhancement of these metabolites is essentially measured via in vitro cell culture or foliar spray, the large-scale production is significantly limited. Recent advancements in the plant cell culture technology lay the possibilities for the large-scale manufacturing of plant-derived secondary metabolites. With the insights about the genetic background of the metabolite biosynthetic pathway, synthetic biology also appears to be a potential avenue for accelerating their production. This review, therefore, also discussed the potential manoeuvres that can be deployed to synthesis plant secondary metabolites at the large-scale using plant cell, tissue, and organ cultures.
    Keywords:  elicitation; jasmonic acid; medicinal plants; methyl jasmonate; plant growth; secondary metabolites
    DOI:  https://doi.org/10.3389/fpls.2022.942789
  167. Biochim Biophys Acta Rev Cancer. 2022 Aug 27. pii: S0304-419X(22)00110-X. [Epub ahead of print]1877(5): 188785
    AMPK: An odyssey of a metabolic regulator, a tumor suppressor, and now a contextual oncogene.
    Vasudevarao Penugurti, Yasaswi Gayatri Mishra, Bramanandam Manavathi.
      Metabolic reprogramming is a unique but complex biochemical adaptation that allows solid tumors to tolerate various stresses that challenge cancer cells for survival. Under conditions of metabolic stress, mammalian cells employ adenosine monophosphate (AMP)-activated protein kinase (AMPK) to regulate energy homeostasis by controlling cellular metabolism. AMPK has been described as a cellular energy sensor that communicates with various metabolic pathways and networks to maintain energy balance. Earlier studies characterized AMPK as a tumor suppressor in the context of cancer. Later, a paradigm shift occurred in support of the oncogenic nature of AMPK, considering it a contextual oncogene. In support of this, various cellular and mouse models of tumorigenesis and clinicopathological studies demonstrated increased AMPK activity in various cancers. This review will describe AMPK's pro-tumorigenic activity in various malignancies and explain the rationale and context for using AMPK inhibitors in combination with anti-metabolite drugs to treat AMPK-driven cancers.
    DOI:  https://doi.org/10.1016/j.bbcan.2022.188785
  168. Explor Target Antitumor Ther. 2021 ;2(6): 602-616
    Interface between obesity with dysfunctional metabolism and inflammation, and the triple-negative breast cancer in African American women.
    Katarzyna Rygiel.
      Obesity has dramatically increased over the past fifty years. In the last decade, it has been noted that augmented body mass, metabolic abnormalities, and the relevant "obese" tumor microenvironment (TME) are connected with signaling molecular networks, which in turn, may contribute to aggressive tumor biology in some patients with breast malignancies. This article presents the associations between obesity, metabolic derangements, inflammatory processes in the adipose tissue or TME, and aggressive behavior of triple-negative breast cancer (TNBC) in African American (AA) women. It also describes some abnormal molecular signaling patterns in the "obese" TME with relevance to TNBC biology. Ethnic disparities in TNBC can be due to a variety of biological features (e.g., genetic mutations and tumor heterogeneity), comorbidities (e.g., cardio-metabolic diseases, including diabetes mellitus), and reproductive factors (e.g., multiparty or short breastfeeding period). Such a constellation of biological variables potentially leads to the association between obesity, metabolic derangements, inflammatory processes in the adipose tissue or TME, and aggressive behavior of TNBC in AA women. Since the TNBC and its TME can display very aggressive behavior, it is crucial that the afflicted AA women make efforts to maintain healthy body weight, "flexible" metabolism, and a well-functioning immune system. Further studies are merited to explore the multi-disciplinary factors that can affect TNBC prevention, management, and outcomes to optimize treatment strategies and survival among AA women.
    Keywords:  African American; Triple-negative breast cancer; body mass index; central obesity; cytokines; inflammation; tumor microenvironment; waist-to-hip ratio
    DOI:  https://doi.org/10.37349/etat.2021.00066
  169. ACS Appl Bio Mater. 2022 Aug 31.
    Role of Reactive Oxygen Species in Aging and Age-Related Diseases: A Review.
    Muzahidul I Anik, Niaz Mahmud, Abdullah Al Masud, Md Ishak Khan, Md Nurul Islam, Shihab Uddin, M Khalid Hossain.
      Research on the role of reactive oxygen species (ROS) in the aging process has advanced significantly over the last two decades. In light of recent findings, ROS takes part in the aging process of cells along with contributing to various physiological signaling pathways. Antioxidants being cells' natural defense mechanism against ROS-mediated alteration, play an imperative role to maintain intracellular ROS homeostasis. Although the complete understanding of the ROS regulated aging process is yet to be fully comprehended, current insights into various sources of cellular ROS and their correlation with the aging process and age-related diseases are portrayed in this review. In addition, results on the effect of antioxidants on ROS homeostasis and the aging process as well as their advances in clinical trials are also discussed in detail. The future perspective in ROS-antioxidant dynamics on antiaging research is also marshaled to provide future directions for ROS-mediated antiaging research fields.
    Keywords:  Alzheimer’s diseases; age-related diseases; aging; antioxidants; reactive oxygen species
    DOI:  https://doi.org/10.1021/acsabm.2c00411
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