bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2022–06–05
116 papers selected by
Yasmin Elkabani, Egyptian Foundation for Research and Community Development
  1. Acid-Responsive Micelles Releasing Cinnamaldehyde Enhance RSL3-Induced Ferroptosis in Tumor Cells.
  2. Coordination-driven Metal-polyphenolic Nanoparticles toward Effective Anticancer Therapy.
  3. Combined photothermal-photodynamic therapy by indocyanine green loaded polydopamine nanoparticles enhances anti-mammary gland tumor efficacy.
  4. Curcumin-based nanotechnology approaches and therapeutics in restoration of autoimmune diseases.
  5. Nanocarriers for anticancer drugs: Challenges and perspectives.
  6. Applications of lipid-engineered nanoplatforms in the delivery of various cancer therapeutics to surmount breast cancer.
  7. Effects of hypericin encapsulated on Pluronic F127 photodynamic therapy against triple negative breast cancer.
  8. The versatile emodin: A natural easily acquired anthraquinone possesses promising anticancer properties against a variety of cancers.
  9. Recent Advances in Nanotechnology-Based Targeted Therapeutics for Breast Cancer Management.
  10. Mulberry plant as a source of functional food with therapeutic and nutritional applications: A review.
  11. Nanoparticles-in-nanofibers composites: Emphasis on some recent biomedical applications.
  12. Metabolic Reprogramming by Dual-targeting Biomimetic Nanoparticles for Enhanced Tumor Chemo-Immunotherapy.
  13. Evolving Roles of Natural Terpenoids From Traditional Chinese Medicine in the Treatment of Osteoporosis.
  14. Solid lipid nanoparticles and nanostructured lipid carriers: A review of the methods of manufacture and routes of administration.
  15. Antitumor Efficacy of Doxorubicin-Loaded Electrospun Attapulgite-Poly(lactic-co-glycolic acid) Composite Nanofibers.
  16. Trends in advanced oral drug delivery system for curcumin: A systematic review.
  17. Preparation and in vitro evaluation of injectable formulations of levothyroxine sodium using in situ forming hydrogel temperature-responsive systems based on PLA-PEG-PLA and PLGA-PEG-PLGA triblock copolymers.
  18. Research Advances on Anti-Cancer Natural Products.
  19. Nucleus-Targeting Phototherapy Nanodrugs for High-Effective Anti-Cancer Treatment.
  20. Nanomedicines: A Focus on Nanomaterials as Drug Delivery System with Current Trends and Future Advancement.
  21. Nutritional and Metabolic Control of Ferroptosis.
  22. A self-delivery chimeric peptide for high efficient cell membrane-targeting low-temperature photothermal/photodynamic combinational therapy and metastasis suppression of tumor.
  23. Recent trends in the application of nanoparticles in cancer therapy: The involvement of oxidative stress.
  24. An Injectable Nanocomposite Hydrogel Improves Tumor Penetration and Cancer Treatment Efficacy.
  25. Recent Progress of Metal-Organic Framework-Based Photodynamic Therapy for Cancer Treatment.
  26. 100th Anniversary of Macromolecular Science Viewpoint: Biological Stimuli-Sensitive Polymer Prodrugs and Nanoparticles for Tumor-Specific Drug Delivery.
  27. An oxygen-economical nano-photosensitizer with a high photodynamic therapeutic outcome via simultaneous reduction of the cellular respiration and oxygen depletion of PDT.
  28. A review of nanostructured delivery systems for the encapsulation, protection, and delivery of silymarin: An emerging nutraceutical.
  29. Natural bioactives in perspective: The future of active packaging based on essential oils and plant extracts themselves and those complexed by cyclodextrins.
  30. The long-circulating effect of pegylated nanoparticles revisited via simultaneous monitoring of both the drug payloads and nanocarriers.
  31. Role of Curcumin in the Management of Schizophrenia: A Narrative Review.
  32. Chemotherapeutics activities of dietary phytoestrogens against prostate cancer: From observational to clinical studies.
  33. Size Optimization of Organic Nanoparticles with Aggregation-Induced Emission Characteristics for Improved ROS Generation and Photodynamic Cancer Cell Ablation.
  34. The Targeting of Noncoding RNAs by Quercetin in Cancer Prevention and Therapy.
  35. Sustainable drug release using nanoparticle encapsulated microneedles.
  36. Fermented foods: An update on evidence-based health benefits and future perspectives.
  37. Intermittent Fasting in Cancer: a Role in Survivorship?
  38. Polydatin, A Glycoside of Resveratrol, Is Better Than Resveratrol in Alleviating Non-alcoholic Fatty Liver Disease in Mice Fed a High-Fructose Diet.
  39. Eutectic Gallium-Indium Nanoparticles for Photodynamic Therapy of Pancreatic Cancer.
  40. Size Changeable Nanomedicines Assembled by Noncovalent Interactions of Responsive Small Molecules for Enhancing Tumor Therapy.
  41. Colorectal cancer management: Strategies in drug delivery.
  42. Senescence-mediated anticancer effects of quercetin.
  43. Correction to "Light-Induced Reactive Oxygen Species (ROS) Generator for Tumor Therapy through an ROS Burst in Mitochondria and AKT-Inactivation-Induced Apoptosis".
  44. PAMAM Dendritic Nanoparticle-Incorporated Hydrogel to Enhance the Immunogenic Cell Death and Immune Response of Immunochemotherapy.
  45. Therapeutic Effects of Natural Products on Cervical Cancer: Based on Inflammatory Pathways.
  46. Botanical Drugs in Traditional Chinese Medicine With Wound Healing Properties.
  47. Targeting Glioma Cells with Nutraceuticals: Therapeutic Effects Based on Molecular Mechanisms, New Evidence, and Perspectives.
  48. Boosting the anti-inflammatory effect of self-assembled hybrid lecithin-chitosan nanoparticles via hybridization with gold nanoparticles for the treatment of psoriasis: elemental mapping and in vivo modeling.
  49. The enhanced antitumor activity of the polymeric conjugate covalently coupled with docetaxel and docosahexaenoic acid.
  50. Identification of human LDHC4 as a potential target for anticancer drug discovery.
  51. Melatonin inhibits glycolysis in hepatocellular carcinoma cells by downregulating mitochondrial respiration and mTORC1 activity.
  52. Emerging concepts in designing next-generation multifunctional nanomedicine for cancer treatment.
  53. Alpha-tomatine and the two sides of the same coin: An anti-nutritional glycoalkaloid with potential in human health.
  54. Intranasal delivery in glioblastoma treatment: prospective molecular treatment modalities.
  55. Recent advances in natural phthalides: Distribution, chemistry, and biological activities.
  56. Moringa oleifera: Antioxidant, Anticancer, Anti-inflammatory, and Related Properties of Extracts in Cell Lines: A Review of Medicinal Effects, Phytochemistry, and Applications.
  57. Melatonin Increases the Sensitivity of Osteosarcoma Cells to Chemotherapy Drug Cisplatin.
  58. A minimalist and robust chemo-photothermal nanoplatform capable of augmenting autophagy-modulated immune response against breast cancer.
  59. Metabolic Strategies in Healthcare: A New Era.
  60. Active Targeting Redox-Responsive Mannosylated Prodrug Nanocolloids Promote Tumor Recognition and Cell Internalization for Enhanced Colon Cancer Chemotherapy.
  61. Precision therapy through breaking the intracellular redox balance with an MOF-based hydrogel intelligent nanobot for enhancing ferroptosis and activating immunotherapy.
  62. Nano-enabled plant-based colloidal delivery systems for bioactive agents in foods: Design, formulation, and application.
  63. Isoprenylated Coumarin Exhibits Anti-proliferative Effects in Pancreatic Cancer Cells Under Nutrient Starvation by Inhibiting Autophagy.
  64. Preparation, characterization, and biodistribution of glutathione PEGylated nanoliposomal doxorubicin for brain drug delivery with a post-insertion approach.
  65. Protective effects of curcumin against thyroid hormone imbalance after gas explosion-induced traumatic brain injury via activation of the hypothalamic-pituitary-thyroid axis in male rats.
  66. Caralluma edulis (Apocynaceae): A comprehensive review on its Traditional uses, Phytochemical profile and pharmacological effects.
  67. Hypoxia-inducible factors: cancer progression and clinical translation.
  68. Inflammatory auto-immune diseases of the intestine and their management by natural bioactive compounds.
  69. [Probiotics' Ameliorating Effect on Side Effects of Cancer Treatment: Reflections and Prospects].
  70. Multifunctional Nanosystems Powered Photodynamic Immunotherapy.
  71. A Narrative Review of the Antitumor Activity of Monoterpenes from Essential Oils: An Update.
  72. A nanomedicine enables synergistic chemo/photodynamic therapy for pancreatic cancer treatment.
  73. Long chain triglyceride-lipid formulation promotes the oral absorption of the lipidic prodrugs through coincident intestinal behaviors.
  74. Utility of Indian fruits in cancer prevention and treatment: Time to undertake translational and bedside studies.
  75. Antimicrobial, Pesticidal and Food preservative Applications of Lemongrass Oil Nanoemulsion: a Mini-Review.
  76. Tumor-Derived Lactate Creates a Favorable Niche for Tumor via Supplying Energy Source for Tumor and Modulating the Tumor Microenvironment.
  77. A Review: Cereals on Modulating the Microbiota/Metabolome for Metabolic Health.
  78. Targeting metabolism: A potential strategy for hematological cancer therapy.
  79. A review on ethnobotany, phytochemistry, and pharmacology of the genus Didymocarpus wall. (Gesneriaceae).
  80. Interplay of Vitamin D and CYP3A4 Polymorphisms in Endocrine Disorders and Cancer.
  81. 5-Aminolevulinic Acid-mediated Photodynamic Therapy on Primary Bone Tumor and Bone Metastases Cell Lines.
  82. Novel Insights on Lipid Metabolism Alterations in Drug Resistance in Cancer.
  83. Laser Treatment for Choroidal Melanoma: Current Concepts.
  84. The Effect of the Kirsten Rat Sarcoma Viral Oncogene Homolog (Kras) Proto-Oncogene, GTPase Genetic Polymorphism on the Safety and Efficacy of Bevacizumab Combination Treatment Regimens for Patients with Nonsquamous, Non-Small Cell Lung Cancer with Brain Metastases.
  85. Regulation of Ca2+ for Cancer Cell Apoptosis through Photothermal Conjugated Nanoparticles.
  86. Relationship between metabolic syndrome and its components with bladder cancer: a systematic review and meta-analysis in cohort studies.
  87. Fatty acid oxidation protects cancer cells from apoptosis by increasing mitochondrial membrane lipids.
  88. The Mitochondrial Pyruvate Carrier at the Crossroads of Intermediary Metabolism.
  89. The effect of dietary-based lifestyle modification approaches on anthropometric indices and dietary intake parameters in women with breast cancer: a systematic review and meta-analysis of randomized controlled trials.
  90. Curcumin-induced antitumor effects on triple-negative breast cancer patient-derived xenograft tumor mice through inhibiting salt-induced kinase-3 protein.
  91. Mannose: A Sweet Option in the Treatment of Cancer and Inflammation.
  92. Almond and date fruits enhance antioxidant status and have erectogenic effect: Evidence from in vitro and in vivo studies.
  93. Ozone combined with doxorubicin exerts cytotoxic and anticancer effects on Luminal-A subtype human breast cancer cell line.
  94. The Microbiome and Gut Endocannabinoid System in the Regulation of Stress Responses and Metabolism.
  95. Pantoprazole promotes the sensitivity of cervical cancer cells to cisplatin by inhibiting cisplatin-induced autophagy.
  96. Celebrating A Century Of Insulin Discovery: A Critical Appraisal Of The Emerging Alternative Insulin Delivery Systems.
  97. Molecular basis of melatonin protective effects in metastasis: A novel target of melatonin.
  98. The effect of vitamin D levels on lipid, glucose profiles and depression in perimenopausal women.
  99. The effect of aerobic exercise on tumour blood delivery: a systematic review and meta-analysis.
  100. The Therapeutic Benefits of Nanoencapsulation in Drug Delivery to the Anterior Segment of the Eye: A Systematic Review.
  101. Mesoporous peroxidase nanozyme for synergistic chemodynamic therapy and chemotherapy.
  102. Evaluation of curcumin as add-on therapy in patients with Parkinson's disease: A pilot randomized, triple-blind, placebo-controlled trial.
  103. A Comprehensive Review on Therapeutic Potential of Chrysin in Brain Related Disorders.
  104. Evidence and suggestions for establishing vitamin D intake standards in Koreans for the prevention of chronic diseases.
  105. Relationship Between Dietary Fiber and Vitamin C Intake and Oral Cancer.
  106. Comparison of different decision support software programs in perspective of potential drug-drug interactions in the oncology clinic.
  107. Hyaluronic acid-based Glucose-responsive Antioxidant Hydrogel Platform for Enhanced Diabetic Wound Repair.
  108. Influence of ethanolic extract of Allium sativum on TP53 gene and its anticancer potential in N-Nitrosodiethylamine (NDEA)-induced hepatocellular carcinoma in male albino rats.
  109. Ginsenoside Rg1 Alleviates Acute Ulcerative Colitis by Modulating Gut Microbiota and Microbial Tryptophan Metabolism.
  110. The potential roles of retinoids in combating drug resistance in cancer: implications of ATP-binding cassette (ABC) transporters.
  111. Smart active-targeting of lipid-polymer hybrid nanoparticles for therapeutic applications: Recent advances and challenges.
  112. Rationale and Recent Advances in Targeted Drug Delivery for Cancer Pain: Is It Time to Change the Paradigm?
  113. Novel taxanes in development: hopes or hypes?
  114. The role of drug-metabolizing enzymes in synthetic lethality of cancer.
  115. The therapeutic potential of urolithin A for cancer treatment and prevention.
  116. NADPH Oxidase 4: A Potential Therapeutic Target of Malignancy.
  1. ACS Biomater Sci Eng. 2022 Jun 01.
    Acid-Responsive Micelles Releasing Cinnamaldehyde Enhance RSL3-Induced Ferroptosis in Tumor Cells.
    Ziliang Yan, Shaojie Wu, Yue Zhou, Feng Li.
      Ferroptosis is a novel type of regulated cell death characterized by the accumulation of lipid peroxides to lethal levels. Most tumor cells are extremely vulnerable to ferroptosis due to the high levels of reactive oxygen species (ROS) produced by their active metabolism. Therefore, tumor cells rely on glutathione (GSH) to reduce lipid peroxides catalyzed by glutathione peroxidase 4 (GPX4), and this pathway is also an important target for a variety of drugs that promote tumor cell ferroptosis. Herein, RSL3@PCA was designed to simultaneously deplete intracellular GSH and inhibit the activity of GPX4, thereby significantly promoting tumor cell ferroptosis. RSL3@PCA was successfully prepared by encapsulating a selective inhibitor of GPX4 into acid-responsive nanoparticle PCA. After being taken up by tumor cells, the acid-responsive nanoparticle gradually degraded to release cinnamaldehyde (CA) and the encapsulated RSL3. CA and RSL3 block the reduction of lipid peroxides in cells, thereby inducing ferroptosis. By a cytotoxicity assay and 4T1 cell xenotransplantation model, we confirmed that RSL3@PCA has excellent inhibition of tumor growth without significant toxicity to normal cells and tissues and still has a good therapeutic effect on tumor cells that are resistant to conventional chemotherapy drugs. This work provides new drug combinations for promoting ferroptosis in tumor cells without severe side effects in normal organs.
    Keywords:  RSL3; cinnamaldehyde; ferroptosis; glutathione; glutathione peroxidase 4
    DOI:  https://doi.org/10.1021/acsbiomaterials.2c00236
  2. Adv Healthc Mater. 2022 Jun 01. e2200559
    Coordination-driven Metal-polyphenolic Nanoparticles toward Effective Anticancer Therapy.
    Di Wu, Bin Zhou, Jing Li, Xinyi Wang, Bin Li, Hongshan Liang.
      Stabilization of bioactive components, especially for hydrophobic functional factors, is a promising approach for improving their biological activity. Here, a metal-phenolic coordination chemistry that synthesizes biocompatible and biodegradable thin-film based on tannic acid (TA) and trivalent metal ion (Fe3+ or Al3+ ) is addressed, and the results also demonstrate its use for encapsulating a hydrophobic drug (Nobiletin, NOB) and triggering drug release for cancer treatment both in vitro and in vivo. This assembled system provides drug-loaded nanoparticles (NPs) with small, but uniform, size (∼200 nm). It displays beneficial potential in enhancing colloidal stability and preventing premature drug leakage. Moreover, the metal-phenolic coating is found to possess high cell biocompatibility as a delivery vector for controlled drug delivery, while the final fabricated drug NPs have effective anti-tumor activity by both inducing higher tumor apoptosis and inhibiting tumor metastasis, which is superior to naked drug formulations. Overall, our findings propose an effective and straightforward way for coating hydrophobic drugs employing interfacial adhesion and assembly, which could be a highly promising vehicle for controlled-release biomedical applications for cancer therapy. This article is protected by copyright. All rights reserved.
    Keywords:  anti-tumor; drug delivery; metal-phenolic; nanoparticles
    DOI:  https://doi.org/10.1002/adhm.202200559
  3. J Mater Chem B. 2022 Jun 01.
    Combined photothermal-photodynamic therapy by indocyanine green loaded polydopamine nanoparticles enhances anti-mammary gland tumor efficacy.
    Xu Liu, Na Xu, Ximing Pu, Juan Wang, Xiaoming Liao, Zhongbing Huang, Guangfu Yin.
      Various nano-targeted drug delivery systems have been developed for combined photothermal-photodynamic (PTT-PDT) treatment of tumors due to better outcomes compared with monomodality therapy. Here, we constructed a facile two-step method without core templates to obtain indocyanine green (ICG) loaded-hyaluronic acid (HA) surface-coated polydopamine nanoparticles (IIPH). The prepared nanoparticles demonstrated an excellent photothermal conversion capacity and efficient singlet oxygen production. Both in vitro and in vivo studies proved that IIPH could significantly inhibit the growth of tumor by PTT-PDT combinational treatment. All the results indicated that IIPH NPs hold great potential to be utilized as a new photothermal-photodynamic composite for cancer treatment.
    DOI:  https://doi.org/10.1039/d2tb00565d
  4. J Control Release. 2022 May 29. pii: S0168-3659(22)00318-2. [Epub ahead of print]
    Curcumin-based nanotechnology approaches and therapeutics in restoration of autoimmune diseases.
    Niloufar Rahiman, Nikita G Nikiforov, Prashant Kesharwani, Thomas P Johnston, Amirhossein Sahebkar.
      Autoimmune diseases usually arise as a result of an aberrant immune system attack on normal tissues of the body, which leads to a cascade of inflammatory reactions. The immune system employs different types of protective and anti-inflammatory cells for the regulation of this process. Curcumin is a known natural anti-inflammatory agent that inhibits pathological autoimmune processes by regulating inflammatory cytokines and their associated signaling pathways in immune cells. Due to the unstable nature of curcumin and its susceptibility to either degradation, or metabolism into other chemical entities (i.e., metabolites), encapsulation of this agent into various nanocarriers would appear to be an appropriate strategy for attaining greater beneficial effects from curcumin as it pertains to immunomodulation. Many studies have focused on the design and development of curcumin nanodelivery systems (micelles, dendrimers, and diverse nanocarriers) and are summarized in this review in order to obtain greater insight into novel drug delivery systems for curcumin and their suitability for the management of autoimmune diseases.
    Keywords:  Autoimmunity; Curcumin; Inflammatory bowel disease (IBD); Multiple sclerosis (MS); Nanocarriers; Psoriasis; Rheumatoid arthritis (RA); Type I diabetes (T1D)
    DOI:  https://doi.org/10.1016/j.jconrel.2022.05.046
  5. Saudi J Biol Sci. 2022 Jun;29(6): 103298
    Nanocarriers for anticancer drugs: Challenges and perspectives.
    Amany I Alqosaibi.
      Cancer is the second most common cause of death globally, surpassed only by cardiovascular disease. One of the hallmarks of cancer is uncontrolled cell division and resistance to cell death. Multiple approaches have been developed to tackle this disease, including surgery, radiotherapy and chemotherapy. Although chemotherapy is used primarily to control cell division and induce cell death, some cancer cells are able to resist apoptosis and develop tolerance to these drugs. The side effects of chemotherapy are often overwhelming, and patients can experience more adverse effects than benefits. Furthermore, the bioavailability and stability of drugs used for chemotherapy are crucial issues that must be addressed, and there is therefore a high demand for a reliable delivery system that ensures fast and accurate targeting of treatment. In this review, we discuss the different types of nanocarriers, their properties and recent advances in formulations, with respect to relevant advantages and disadvantages of each.
    Keywords:  Nano formula cancer therapy; Nanocarrier; Nanosystem
    DOI:  https://doi.org/10.1016/j.sjbs.2022.103298
  6. J Control Release. 2022 May 28. pii: S0168-3659(22)00305-4. [Epub ahead of print]
    Applications of lipid-engineered nanoplatforms in the delivery of various cancer therapeutics to surmount breast cancer.
    Ujala Gupta, Brojendra Nath Saren, Kedar Khaparkhuntikar, Jitender Madan, Pankaj Kumar Singh.
      Breast cancer (BC) is the most extensively accounted malignancy among the women across the globe and is treatable in 70-80% of patients with early-stage, non-metastatic cancer. The current available therapies have been found to be less effective to treat distant organ metastases and advanced breast cancers. The clinical efficacy hugely suffers from chemoresistance, non-specific toxicity, relapse and other associated adverse effects. Furthermore, lack of controlled delivery and effective temporospatial presence of chemotherapeutics has resulted in suboptimal therapeutic response. Nanotechnology based approaches have been widely used over the period as they are nanometric, offer controlled and site-specific drug release along with reduced toxicity, improved half-life, and stability. Lipid-based nanoplatforms have grabbed a tremendous attention for delivering cancer therapeutics as they are cost-effective, scalable and provide better entrapment efficiency. In this review, all the promising applications of lipid-engineered nanotechnological tools for breast cancer will be summarized and discussed. Subsequently, BC therapy achieved with the aid of chemotherapeutics, phytomedicine, genes, peptides, photosensitizers, diagnostic and immunogenic agents etc. will be reviewed and discussed. This review gives tabular information on all the results obtained pertaining to the physicochemical properties of the lipidic nanocarrier, in vitro studies conferring to mechanistic drug release profile, cell viability, cellular apoptosis and in vivo studies referring to cellular internalisation, reduction of tumor volume, PK-PD profile, bioavailability achieved and anti-tumor activity in detail. It also gives complete information on the most relevant clinical trials done on lipidic nanoplatforms over two decades in tabular form. The review highlights the current status and future prospects of lipidic nanoplatforms with streamlined focus on cancer nanotherapeutics.
    Keywords:  Breast cancer; Cancer therapeutics; Drug delivery; Lipid-engineered nanocarriers; Nanotechnology
    DOI:  https://doi.org/10.1016/j.jconrel.2022.05.034
  7. Asian Pac J Cancer Prev. 2022 May 01. pii: 90126. [Epub ahead of print]23(5): 1741-1751
    Effects of hypericin encapsulated on Pluronic F127 photodynamic therapy against triple negative breast cancer.
    Maria V F De Souza, Cristiane S Shinobu-Mesquita, Lyvia E F Meirelles, Natália L Mari, Gabriel B César, Renato S Gonçalves, Wilker Caetano, Edilson Damke, Vânia Rs Silva, Gabrielle Mzf Damke, Marcia E L Consolaro.
       OBJECTIVE: Breast cancer (BC) currently has no effective treatment especially for the highly aggressive and metastatic triple negative breast cancer (TNBC). Here, we investigated the antitumoral and antimigratory effects of hypericin (HYP) encapsulated on Pluronic F127 (F127/HYP) photodynamic therapy (PDT) against TNBC cell line MDA-MB-231 compared to a nontumorigenic human breast ductal cell line (MCF-10A).
    METHODS: The phototoxicity/cytotoxicity was assessed by MTT assay, long-term cytotoxicity by clonogenic assay, cell uptake, subcellular distribution, and cellular oxidative stress by fluorescence microscopy, cell death with annexin V-FITC/propidium iodide, PDT mechanism using sodium azide and D-mannitol, and cell migration by wound-healing assay.
    RESULTS: The treatment promoted phototoxic effect on tumor cell line in a dose-dependent and selective manner. Internalization of F127/HYP was efficient and accumulation occurred in the endoplasmic reticulum and mitochondria, resulting in cellular oxidative stress mainly by the type II mechanism, induced by necrosis. Furthermore, F127/HYP decreased colony formation and reduced the cell migration ability in MDA-MB-231 cells.
    CONCLUSION: Our results suggest a potentially useful role of F127/HYP micelles as a platform for HYP delivery to more specifically and effectively treat TNBC.
    Keywords:  Hypericin; Micelles; Photodynamic therapy, Pluronic F127; triple negative breast cancer
    DOI:  https://doi.org/10.31557/APJCP.2022.23.5.1741
  8. Int J Biol Sci. 2022 ;18(8): 3498-3527
    The versatile emodin: A natural easily acquired anthraquinone possesses promising anticancer properties against a variety of cancers.
    Qing Zhang, Wen Wen Chen, Xue Sun, Die Qian, Dan Dan Tang, Li Lin Zhang, Mei Yan Li, Lin Yu Wang, Chun-Jie Wu, Wei Peng.
      Cancers are generally recognized as the leading cause of death and a predominant barrier to prolonging life expectancy in both developed and developing countries. Emodin is a typical anthraquinone derivative from various plants that exhibits a wide spectrum of biological activities, such as anticancer, antibacterial, hepatoprotective and anti-inflammatory activities. Much previous preclinical evidence has demonstrated that emodin exhibits reliable effects on several cancer types, including lung cancer, liver cancer, colon cancer, breast cancer, pancreatic cancer, leukemia, cervical cancer, and ovarian cancer, etc. The related molecular mechanisms corresponding to the anticancer activities of emodin are involved in the induction of apoptosis, inhibition of cell proliferation, enhanced reactive oxygen species (ROS) accumulation, and induction of autophagy, etc. In the present review, we summarized the sources, anticancer properties in vitro and in vivo, molecular mechanisms, metabolic transformation and toxicities of emodin. In addition, we also discussed the limitations of the present investigations of emodin against cancers and gave some perspectives for them, which would be beneficial for the further exploration and development of this natural compound as a clinical cancer drug.
    Keywords:  Apoptosis; Autophagy; Cycle arrest; Drug resistant; Emodin; Metastasis and invasion
    DOI:  https://doi.org/10.7150/ijbs.70447
  9. Curr Drug Metab. 2022 May 14.
    Recent Advances in Nanotechnology-Based Targeted Therapeutics for Breast Cancer Management.
    Abdulsalam Alhalmi, Sarwar Beg, Waleed H Almalki, Saad Alghamdi, Kanchan Kohli.
      Despite the great efforts that have been achieved in breast cancer treatment, it remains a significant cause of death in women and a serious health problem. Treatment with chemotherapy drugs faces various challenges, such as toxicity and chemoresistance to chemotherapeutic drugs, which hinder their therapeutic success and clinical experiments. This review focuses on targeting nanocarrier approaches to target chemotherapy drugs to receptor targets that are overexpressed on the surface of breast cancer cells. In particular, we are reviewing the most commonly targeted nanocarriers for the chemotherapeutic agents examined by the different researcher groups, such as liposomes, dendrimers, polymeric micelles, lipid particulates, polymeric nanoparticles, and carbon nanotubes. Moreover, we summarized the molecular receptors or targets that are the most commonly overexpressed in breast cancer cells and the natural and synthetic ligands that have been studied for use as targeting moieties to functionalize chemotherapeutically loaded nanocarriers for potential specific breast cancer targeting.
    Keywords:  Breast cancer; active targeted; chemotherapy.; ligands; nanocarriers; receptors
    DOI:  https://doi.org/10.2174/1389200223666220514151110
  10. J Food Biochem. 2022 May 31. e14263
    Mulberry plant as a source of functional food with therapeutic and nutritional applications: A review.
    Maria Maqsood, Raakia Anam Saeed, Amna Sahar, Muhammad Issa Khan.
      Medicinal plants from the family Moraceae have diverse applications in agriculture, cosmetics, food, and the pharmaceutical industry. Their extensive spectrum of pharmacological activity for treating numerous inflammatory illnesses, cancer, cardiovascular diseases, and gastrointestinal problems reflects their biological and therapeutic value. This article summarizes the molecular mechanisms related to the biological implications of mulberry extracts, fractions, and isolated bioactive compounds from different parts in various health-related ailments. Additionally, the food industry and animal nutrition applications are summarized. Phytochemicals such as steroids, saponins, alkaloids, glycosides, polysaccharides, and phenolic compounds including terpenoids, flavonoids, anthocyanins, and tannins are found in this medicinal plant. The aqueous, ethanolic, and methanolic extracts, as well as bioactive compounds, have anti-oxidative, hypoglycemic, nephroprotective, antimicrobial, neuroprotective, anti-mutagenic, hepatoprotective, anthelmintic, immune-modulatory, cardioprotective, and skin protecting activities. Mulberry supplementation in food products improves the stability of phenolics, sensory properties, antioxidant activity, and antimicrobial properties. Mulberry leaves in animal feed increase the nutrient digestibility, growth parameters, antimicrobial, and antioxidant properties. PRACTICAL APPLICATIONS: This review summarized the in vivo and in vitro biological activities of the mulberry and isolated constituents in various health conditions. In addition, the food uses such as antioxidant potential, antimicrobial, and physicochemical properties were discussed. Furthermore, in vivo studies revealed mulberry as a significant protein source and its flavonoids as potential animal foliage.
    Keywords:  anthelmintic; cardioprotective; hepatoprotective; nephroprotective; pharmacological activities; phytochemicals
    DOI:  https://doi.org/10.1111/jfbc.14263
  11. J Control Release. 2022 May 27. pii: S0168-3659(22)00308-X. [Epub ahead of print]
    Nanoparticles-in-nanofibers composites: Emphasis on some recent biomedical applications.
    Asmaa M Elsherbini, Sally A Sabra.
      Nanoparticles-in-nanofibers composites comprise an attractive approach for controlling release and delivery of many active molecules for versatile biomedical applications. Incorporation of drug-loaded nanoparticles within these composites can afford the encapsulation of one or more drug with sequential drug release, which can be tuned according to the assigned function. Moreover, existence of nanoparticles within the nanofibrous matrix was found to favor the morphological and mechanical properties of the developed composites. In this review, the latest biomedical advances for nanoparticles-in-nanofibers composites will be highlighted including; tissue regeneration, antimicrobial applications, wound healing, cancer management, cardiovascular disorders, ophthalmic applications, vaginal drug delivery, biosensors and biomedical filters. These composites incorporating multiple types of nanoparticles could be very promising drug delivery platforms.
    Keywords:  Antimicrobial effect; Biomedical filters; Biosensors; Cardiovascular disorders; Nanoparticles-in-nanofibers scaffold; Ophthalmic disorders; Tissue regeneration, wound healing; Vaginal delivery
    DOI:  https://doi.org/10.1016/j.jconrel.2022.05.037
  12. Acta Biomater. 2022 May 29. pii: S1742-7061(22)00321-X. [Epub ahead of print]
    Metabolic Reprogramming by Dual-targeting Biomimetic Nanoparticles for Enhanced Tumor Chemo-Immunotherapy.
    Shuya Zang, Kexin Huang, Jiaxin Li, Kebai Ren, Ting Li, Xuan He, Yuan Tao, Jiao He, Ziyan Dong, Man Li, Qin He.
      Cancer-associated fibroblasts (CAFs)-mediated metabolic support plays a vital role in tumorigenesis. The metabolic network between cancer cells and CAFs may serve as promising targets for cancer therapy. Here, aiming at targeted blockade of the metabolic support of CAFs to cancer cells, a biomimetic nanocarrier is designed by coating solid lipid nanoparticles containing chemotherapeutic paclitaxel (PTX) and glycolysis inhibitor PFK15 with hybrid membranes of cancer cells and activated fibroblasts. The nanoparticles possess outstanding dual-targeting ability which can simultaneously target cancer cells and CAFs. The encapsulated glycolysis inhibitor PFK15 can prevent the glycolysis of cancer cells and CAFs at the same time, thus increasing the chemosensitivity of cancer cells and blocking the metabolic support of CAFs to cancer cells. The results showed that the combination of PTX and PFK15 exhibited synergistic effects and inhibited tumor growth effectively. Moreover, the biomimetic nanoparticles obviously reduced the lactate production in the tumor microenvironment, leading to activated immune responses and enhanced tumor suppression. This work presents a facile strategy to destroy the metabolic network between cancer cells and CAFs, and proves the potential to elevate chemo-immunotherapy by glycolysis inhibition. STATEMENT OF SIGNIFICANCE: : In many solid tumors, most cancer cells produce energy and carry out biosynthesis through glycolysis, even in aerobic conditions. As the main tumor stromal cells, cancer-associated fibroblasts (CAFs) usually turn oxidative phosphorylation into aerobic glycolysis with metabolic reprogramming and provide high-energy glycolytic metabolites for cancer cells. The metabolic network between cancer cells and CAFs is regarded as the vulnerability among cancer cells. Moreover, lactate produced by cancer cells and CAFs through glycolysis often leads to the immunosuppressive tumor microenvironment. The present study provides an effective approach to destroy the metabolic network between cancer cells and CAFs and greatly improves the antitumor immune response by reducing lactate production, which serves as a promising strategy for combined chemo-immunotherapy mediated by glycolysis.
    Keywords:  biomimetic nanoparticles; chemo-immunotherapy; dual-target; glycolysis; metabolic support
    DOI:  https://doi.org/10.1016/j.actbio.2022.05.045
  13. Front Endocrinol (Lausanne). 2022 ;13 901545
    Evolving Roles of Natural Terpenoids From Traditional Chinese Medicine in the Treatment of Osteoporosis.
    Yue Zhuo, Meng Li, Qiyao Jiang, Hanzhong Ke, Qingchun Liang, Ling-Feng Zeng, Jiansong Fang.
      Osteoporosis (OP) is a systemic metabolic skeletal disease which can lead to reduction in bone mass and increased risk of bone fracture due to the microstructural degradation. Traditional Chinese medicine (TCM) has been applied in the prevention and treatment of osteoporosis for a long time. Terpenoids, a class of natural products that are rich in TCM, have been widely studied for their therapeutic efficacy on bone resorption, osteogenesis, and concomitant inflammation. Terpenoids can be classified in four categories by structures, monoterpenoids, sesquiterpenoids, diterpenoids, and triterpenoids. In this review, we comprehensively summarize all the currently known TCM-derived terpenoids in the treatment of OP. In addition, we discuss the possible mechanistic-of-actions of all four category terpenoids in anti-OP and assess their therapeutic potential for OP treatment.
    Keywords:  osteoblast; osteoclast; osteoporosis; terpenoids; traditional Chinese medicine
    DOI:  https://doi.org/10.3389/fendo.2022.901545
  14. Pharm Dev Technol. 2022 May 30. 1-53
    Solid lipid nanoparticles and nanostructured lipid carriers: A review of the methods of manufacture and routes of administration.
    Jafar Akbari, Majid Saeedi, Fatemeh Ahmadi, Seyyed Mohammad Hassan Hashemi, Amirhossein Babaei, Sadra Yaddollahi, Seyyed Sohrab Rostamkalaei, Kofi Asare-Addo, Ali Nokhodchi.
      The bioavailability of drugs is dependent on several factors such as solubility and the administration route. A drug with poor aqueous solubility, therefore, poses challenges with regards to its pharmaceutical advance and ultimately its biological usage. Lipid nanoparticles have been used in pharmaceutical science due to their importance in green chemistry. Their biochemical properties as "green" materials and biochemical processes as "green" processes mean they can be environmentally sustainable. Generally, lipid nanoparticles can be employed as carriers for both lipophilic and hydrophilic drugs. The proposed administration route for nanoparticles can present advantages and disadvantages which should be considered by a formulator. Solid lipid nanoparticles and nanostructured lipid carriers are attractive delivery systems because of their ease of manufacture, biocompatibility, biodegradability and scale-up capacity of formulation constituents. The easy and simple scalability of novel solid lipid nanoparticles and nano lipid carriers, along with their various processing procedures, recent developments, limitation and toxicity, formulation optimization and approaches for the manufacture of lipid nanoparticles, lyophilization and drug release are comprehensively discussed in this review. This review also summarizes the research data related to the various preparation methods and excipients used for solid lipid nanoparticles and nanostructured lipid carriers in recent years.
    Keywords:  Administration route; Hydrophilic drugs; Lipophilic drugs; Manufacturing method; Nanostructured lipid carriers; Solid lipid nanoparticles
    DOI:  https://doi.org/10.1080/10837450.2022.2084554
  15. J Funct Biomater. 2022 May 10. pii: 55. [Epub ahead of print]13(2):
    Antitumor Efficacy of Doxorubicin-Loaded Electrospun Attapulgite-Poly(lactic-co-glycolic acid) Composite Nanofibers.
    Zhe Wang, Yili Zhao, Mingwu Shen, Helena Tomás, Benqing Zhou, Xiangyang Shi.
      Currently, cancer chemotherapeutic drugs still have the defects of high toxicity and low bioavailability, so it is critical to design novel drug release systems for cancer chemotherapy. Here, we report a method to fabricate electrospun drug-loaded organic/inorganic hybrid nanofibrous system for antitumor therapy applications. In this work, rod-like attapulgite (ATT) was utilized to load a model anticancer drug doxorubicin (DOX), and mixed with poly(lactic-co-glycolic acid) (PLGA) to form electrospun hybrid nanofibers. The ATT/DOX/PLGA composite nanofibers were characterized through various techniques. It is feasible to load DOX onto ATT surfaces, and the ATT/DOX/PLGA nanofibers show a smooth and uniform morphology with improved mechanical durability. Under neutral and acidic pH conditions, the loaded DOX was released from ATT/DOX/PLGA nanofibers in a sustained manner. In addition, the released DOX from the nanofibers could significantly inhibit the growth of tumor cells. Owing to the significantly reduced burst release profile and increased mechanical durability of the ATT/DOX/PLGA nanofibers, the designed organic-inorganic hybrid nanofibers may hold great promise as a nanoplatform to encapsulate different drugs for enhanced local tumor therapy applications.
    Keywords:  antitumor therapy; attapulgite; drug release; nanofibers; poly(lactic-co-glycolic acid)
    DOI:  https://doi.org/10.3390/jfb13020055
  16. J Control Release. 2022 May 30. pii: S0168-3659(22)00317-0. [Epub ahead of print]
    Trends in advanced oral drug delivery system for curcumin: A systematic review.
    Suchiwa Pan-On, Piyameth Dilokthornsakul, Waree Tiyaboonchai.
      Although curcumin is globally recognized for its health benefits, its clinical application has been restricted by its poor aqueous solubility and stability. To overcome these limitations, nanocarrier-based drug delivery systems (NDS) are one of the most effective approaches being extensively explored over the last few decades to improve curcumin's physicochemical and pharmacological effects. Various NDS could provide productive platforms for addressing the formulation challenge of curcumin, but evidence of such systems has not been summarized. This study aimed to systematically review current evidence of lipid and polymer-based NDS for an oral delivery of curcumin focusing on in vivo models and clinical studies. Among the 48 included studies, 3 studies were randomized controlled clinical trials, while 45 studies were animal models. To date, only five curcumin NDS have been studied in healthy volunteers: γ-cyclodextrin, phytosome, liposome, microemulsion and solid dispersion, while most curcumin NDS have been studied in animal models. Most included studies found that NDS could increase oral bioavailability of curcumin as compared to free curcumin. In conclusion, this systematic review showed evidence of the positive effect of NDS for enhancement of oral bioavailability of curcumin. EXECUTIVE SUMMARY: Curcumin is globally recognized for its health benefits, but its clinical application has been limited by its poor aqueous solubility and stability, which causes poor absorption in the gastrointestinal tract (GI tract) via oral administration. Nanocarrier-based drug delivery systems (NDS) are considered as a productive platform to solve the formulation challenge of curcumin, but evidence of such systems has not been summarized. This study aimed to systematically review current evidence of lipid and polymer-based NDS for an oral delivery of curcumin focusing on in vivo models and clinical studies. Overall, most studies found that all studied NDS could increase the absorption of curcumin as compared to free curcumin. Curcumin was rapidly absorbed and exhibited a long residence time after oral administration of curcumin NDS. In summary, this systematic review showed positive impacts of NDS for enhancement of oral absorption of curcumin.
    Keywords:  Bioavailability; Curcumin; Nanocarriers; Oral; Solubility; Stability
    DOI:  https://doi.org/10.1016/j.jconrel.2022.05.048
  17. Iran J Basic Med Sci. 2022 Mar;25(3): 341-351
    Preparation and in vitro evaluation of injectable formulations of levothyroxine sodium using in situ forming hydrogel temperature-responsive systems based on PLA-PEG-PLA and PLGA-PEG-PLGA triblock copolymers.
    Jebraeil Movaffagh, Farzin Hadizadeh, Elham Khodaverdi, Bahnaz Khalili, Seyedeh Nesa Rezaeian Shiadeh, Hossein Kamali, Fatemeh Oroojalian.
       Objectives: Recently, great attention has been paid to developing new drug delivery systems to manage the rate, time, and site of drug release. We aimed to design a novel drug delivery system to support targeted and gradual delivery of levothyroxine sodium.
    Materials and Methods: The triblock copolymers of PLA-PEG-PLA and PLGA-PEG-PLGA were constructed using the ring-opening copolymerization method and then purified and characterized by 1H-NMR, DSC, and GPC techniques. The phase transition temperature of the polymers was determined, and levothyroxine sodium stability was investigated in a phosphate-based buffer (pH 7.4). In vitro drug release into the PBS was measured at different concentrations of the triblocks for one month.
    Results: The results of NMR and GPC showed successful fabrication of the copolymers with low molecular weight dispersion and Tg points of -8.19 °C and -5.19 °C for PLA-PEG-PLA and PLGA-PEG-PLGA, respectively. Stability tests showed that during one month, most of the triblocks' masses degraded at 37 °C while levothyroxine sodium remained stable. Initial burst release of the drug in both copolymers is inversely correlated with the concentration of the polymer. Evaluation of drug release for 35 days showed that PLA-PEG-PLA had a slower drug release rate than PLGA-PEG-PLGA.
    Conclusion: Considering the low initial burst release, as well as continuous and long-term release kinetics of PLA-PEG-PLA and PLGA-PEG-PLGA copolymers, they can be used to gradually deliver levothyroxine sodium, obviating the need for frequent administrations and concerns over drug-food interactions.
    Keywords:  In situ forming hydrogel- gelling; Levothyroxine sodium; Smart hydrogels; Temperature-responsive- systems; Triblock copolymer
    DOI:  https://doi.org/10.22038/IJBMS.2022.62576.13842
  18. Front Oncol. 2022 ;12 866154
    Research Advances on Anti-Cancer Natural Products.
    Meng Guo, Jie Jin, Dong Zhao, Zheng Rong, Lu-Qi Cao, Ai-Hong Li, Xiao-Ying Sun, Li-Yi Jia, Yin-Di Wang, Ling Huang, Yi-Heng Li, Zhong-Jing He, Long Li, Rui-Kang Ma, Yi-Fan Lv, Ke-Ke Shao, Hui-Ling Cao.
      Malignant tumors seriously threaten people's health and life worldwide. Natural products, with definite pharmacological effects and known chemical structures, present dual advantages of Chinese herbs and chemotherapeutic drug. Some of them exhibit favorable anti-cancer activity. Natural products were categorized into eight classes according to their chemical structures, including alkaloids, terpenoids and volatile oils, inorganic salts, phenylpropanoids, flavonoids and isoflavones, quinone, saponins and polysaccharides. The review focused on the latest advances in anti-cancer activity of representative natural products for every class. Additionally, anti-cancer molecular mechanism and derivatization of natural products were summarized in detail, which would provide new core structures and new insights for anti-cancer new drug development.
    Keywords:  anti-cancer; core structure; derivatization; molecular mechanism; natural product
    DOI:  https://doi.org/10.3389/fonc.2022.866154
  19. Front Pharmacol. 2022 ;13 905375
    Nucleus-Targeting Phototherapy Nanodrugs for High-Effective Anti-Cancer Treatment.
    Xingyu Long, Xiaojie Zhang, Qiaohui Chen, Min Liu, Yuting Xiang, Yuqi Yang, Zuoxiu Xiao, Jia Huang, Xiaoyuan Wang, Chong Liu, Yayun Nan, Qiong Huang.
      DNA is always one of the most important targets for cancer therapy due to its leading role in the proliferation of cancer cells. Phototherapy kills cancer cells by generating reactive oxygen species (ROS) and local hyperthermia under light. It has attracted extensive interest in the clinical treatment of tumors because of many advantages such as non-invasiveness, high patient compliance, and low toxicity and side effects. However, the short ROS diffusion distance and limited thermal diffusion rate make it difficult for phototherapy to damage DNA deep in the nucleus. Therefore, nucleus-targeting phototherapy that can destroy DNAs via in-situ generation of ROS and high temperature can be a very effective strategy to address this bottleneck. Recently, some emerging nucleus-targeting phototherapy nanodrugs have demonstrated extremely effective anticancer effects. However, reviews in the field are still rarely reported. Here, we comprehensively summarized recent advances in nucleus-targeting phototherapy in recent years. We classified nucleus-targeting phototherapy into three categories based on the characteristics of these nucleus-targeting strategies. The first category is the passive targeting strategy, which mainly targets the nucleus by adjusting the physicochemical characteristics of phototherapy nanomedicines. The second category is to mediate the phototherapy nanodrugs into the nucleus by modifying functional groups that actively target the nucleus. The third category is to assist nanodrugs enter into the nucleus in a light-controlled way. Finally, we provided our insights and prospects for nucleus-targeting phototherapy nanodrugs. This minireview provides unique insights and valuable clues in the design of phototherapy nanodrugs and other nucleus-targeting drugs.
    Keywords:  nanomaterials; nucleus-targeting; photodynamic therapy; photothermal therapy; subcellular organelle
    DOI:  https://doi.org/10.3389/fphar.2022.905375
  20. Drug Res (Stuttg). 2022 May 30.
    Nanomedicines: A Focus on Nanomaterials as Drug Delivery System with Current Trends and Future Advancement.
    Jaya Pandey, Ragini Dubey, Aditya Kate, Bhairav Prasad, Arzoo Sinha, Mohit S Mishra.
      The rapid advancement of nanomedicine presents novel alternatives that have the potential to transform health care. Targeted drug delivery as well as the synthesis of nanocarriers is a growing discipline that has been intensively researched to reduce the complexity of present medicines in a variety of diseases and to develop new treatment and diagnostic techniques. There are several designed nanomaterials used as a delivery system such as liposomes, micelles, dendrimers, polymers, carbon-based materials, and many other substances, which deliver the drug moiety directly into its targeted body area reducing toxic effect of conventional drug delivery, thus reducing the amount of drug required for therapeutic efficacy and offering many more advantages. Currently, these are used in many applications, including cancer treatment, imaging contrast agents, and biomarker detection and so on. This review provides a comprehensive update in the field of targeted nano-based drug delivery systems, by conducting a thorough examination of the drug synthesis, types, targets, and application of nanomedicines in improving the therapeutic efficiency.
    DOI:  https://doi.org/10.1055/a-1824-4619
  21. Annu Rev Nutr. 2022 Jun 01.
    Nutritional and Metabolic Control of Ferroptosis.
    Eikan Mishima, Marcus Conrad.
      Ferroptosis is a type of regulated cell death characterized by an excessive lipid peroxidation of cellular membranes caused by the disruption of the antioxidant defense system and/or an imbalanced cellular metabolism. Ferroptosis differentiates from other forms of regulated cell death in that several metabolic pathways and nutritional aspects, including endogenous antioxidants (such as coenzyme Q10, vitamin E, and di/tetrahydrobiopterin), iron handling, energy sensing, selenium utilization, amino acids, and fatty acids, directly regulate the cells' sensitivity to lipid peroxidation and ferroptosis. As hallmarks of ferroptosis have been documented in a variety of diseases, including neurodegeneration, acute organ injury, and therapy-resistant tumors, the modulation of ferroptosis using pharmacological tools or by metabolic reprogramming holds great potential for the treatment of ferroptosis-associated diseases and cancer therapy. Hence, this review focuses on the regulation of ferroptosis by metabolic and nutritional cues and discusses the potential of nutritional interventions for therapy by targeting ferroptosis. Expected final online publication date for the Annual Review of Nutrition, Volume 42 is August 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-nutr-062320-114541
  22. Biomaterials. 2022 May 23. pii: S0142-9612(22)00233-2. [Epub ahead of print]286 121593
    A self-delivery chimeric peptide for high efficient cell membrane-targeting low-temperature photothermal/photodynamic combinational therapy and metastasis suppression of tumor.
    Pei-Ling Chen, Pei-Ying Huang, Jiao-Yu Chen, Qun-Ying Shi, Yin-Yin Zhu, Yi Chen, Li-Han Liu, Xian-Zheng Zhang.
      Cellular barriers such as the cell membranes, lysosomes or nuclear pores of tumor cells hinder the drugs delivery and weaken the efficiency of traditional tumor therapies. Targeted destructing tumor cell membranes can quickly destroy cell homeostasis and kill cells without facing intracellular delivery barriers. Herein, we designed a self-delivery phototherapeutic chimeric peptide (CCP) for high efficient cell membrane-targeting combinational low-temperature photothermal therapy (LTPTT) and photodynamic therapy (PDT). The self-assembled CCP nanoparticles display remarkable tumor accumulation after systemic administration without additional carriers, avoiding the carriers related side toxicities. The CCPs are able to generate reactive oxygen species (ROS) and mild heat (<45 °C) locally at cell membrane and quickly induce immunogenic cell death to achieve efficient combinational LTPTT/PDT. The damage-associated molecular patterns released after cell membrane rupture effectively elicit antitumor immunity to eradicate residual tumor cells. With a single dosage and short-term near-infrared (NIR) light irradiation, CCPs significantly inhibit growth and metastasis of tumor, and prolong survival time of tumor-bearing mice. This work presents a unique cell membrane-targeting phototherapy strategy to kill tumor and suppress metastasis in an effective, safe and minimally invasive manner.
    Keywords:  Cell membrane-targeting; Immunogenic cell death; Low temperature photothermal therapy; Peptide self-delivery; Photodynamic therapy
    DOI:  https://doi.org/10.1016/j.biomaterials.2022.121593
  23. J Control Release. 2022 May 26. pii: S0168-3659(22)00306-6. [Epub ahead of print]
    Recent trends in the application of nanoparticles in cancer therapy: The involvement of oxidative stress.
    Mehdi Sanati, Amir R Afshari, Prashant Kesharwani, Vasily N Sukhorukov, Amirhossein Sahebkar.
      In the biomedical area, the interdisciplinary field of nanotechnology has the potential to bring numerous unique applications, including better tactics for cancer detection, diagnosis, and therapy. Nanoparticles (NPs) have been the topic of many research and material applications throughout the last decade. Unlike small-molecule medications, NPs are defined by distinct physicochemical characteristics, such as a large surface-to-volume ratio, which allows them to permeate live cells with relative ease. The versatility of NPs as both therapeutics and diagnostics makes them ideal for a broad spectrum of illnesses, from infectious diseases to cancer. A significant amount of data has been participated in the current scientific publications, emphasizing the concept that NPs often produce reactive oxygen species (ROS) to a larger degree than micro-sized particles. It is important to note that oxidative stress governs a wide range of cell signaling cascades, many of which are responsible for cancer cell cytotoxicity. Here, we aimed to provide insight into the signaling pathways triggered by oxidative stress in cancer cells in response to several types of nanomaterials, such as metallic and polymeric NPs and quantum dots. We discuss recent advances in developing integrated anticancer medicines based on NPs targeted to destroy malignant cells by increasing their ROS setpoint.
    Keywords:  Cancer; Nanoparticle; Nanotechnology; Oxidative stress; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.jconrel.2022.05.035
  24. Acta Biomater. 2022 May 26. pii: S1742-7061(22)00318-X. [Epub ahead of print]
    An Injectable Nanocomposite Hydrogel Improves Tumor Penetration and Cancer Treatment Efficacy.
    Feng Qin Luo, Wei Xu, Jing-Yang Zhang, Rong Liu, Yong-Cong Huang, Chunsheng Xiao, Jin-Zhi Du.
      Hydrogel as a local drug depot can increase drug concentration at the tumor site. However, conventional drug-loaded hydrogel is typically formed by direct dissolution of drug molecules inside the hydrogel, which usually suffers from limited drug retention and poor tumor penetration. In this study, a nanocomposite hydrogel consisting of oxaliplatin (OXA)-conjugated G5 polyamidoamine (G5-OXA) and oxidized dextran (Dex-CHO) is constructed to improve local drug delivery. The OXA-containing nanocomposite hydrogel (denoted as PDO gel) is injectable and could maintain in vivo up to more than three weeks, which increases drug retention in tumor tissues. More interestingly, G5-OXA released from the PDO gel show potent tumor penetration mainly through an active transcytosis process. In vivo antitumor studies in an orthotopic 4T1 tumor model show that PDO gel significantly inhibits primary tumor growth as well as the metastasis. In addition, the PDO gel can also activate the immunosuppressive tumor microenvironment through immunogenic cell death effect, and further improves therapeutic efficacy with the combination of PD-1 antibody. These results demonstrate that the nanocomposite hydrogel can simultaneously enhance the retention and penetration of chemotherapeutic drugs via the combination of both advantages of hydrogel and nanoparticles, which provides new insights for the design of local drug delivery systems. STATEMENT OF SIGNIFICANCE: : Hydrogel represents an important class of local drug delivery depot. However, conventional drug-loaded hydrogel is usually achieved by direct dissolution of small drug molecules inside the hydrogel, which typically suffers from limited drug retention and poor tumor penetration. Herein, we developed a nanocomposite hydrogel, which could gradually degrade and release drug-conjugated small nanoparticles (∼ 6 nm) for improved tumor penetration through the combination of an active transcytosis process and a passive diffusion process. This nanocomposite hydrogel system improved tumor penetration and retention of drug in primary tumors as well as the drug deposition in lymph nodes, which significantly suppressed tumor growth and metastasis.
    Keywords:  nanocomposite hydrogel; nanoparticles; transcytosis; tumor penetration
    DOI:  https://doi.org/10.1016/j.actbio.2022.05.042
  25. Int J Nanomedicine. 2022 ;17 2367-2395
    Recent Progress of Metal-Organic Framework-Based Photodynamic Therapy for Cancer Treatment.
    Yuyun Ye, Yifan Zhao, Yong Sun, Jie Cao.
      Photodynamic therapy (PDT), combining photosensitizers (PSs) and excitation light at a specific wavelength to produce toxic reactive oxygen species, has been a novel and promising approach to cancer treatment with non-invasiveness, spatial specificity, and minimal systemic toxicity, compared with conventional cancer treatment. Recently, numerous basic research and clinical research have demonstrated the potential of PDT in the treatment of a variety of malignant tumors, such as esophageal cancer, bladder cancer, and so on. Metal-organic framework (MOF) has been developed as a new type of nanomaterial with the advantages of high porosity, large specific surface area, adjustable pore size, and easy functionalization, which could serve as carriers to load PSs or increase the accumulation of PSs in target cells during PDT. Moreover, active MOFs have the potential to construct multifunctional systems, which are conducive to refining the tumor microenvironment (TME) and implementing combination therapy to improve PDT efficacy. Hence, a comprehensive and in-depth depiction of the whole scene of the recent development of MOFs-based PDT in cancer treatment is desirable. This review summarized the recent research strategies of MOFs-based PDT in antitumor therapy from the perspective of MOFs functions, including active MOFs, inactive MOFs, and their further combination therapies in clinical antitumor treatment. In addition, the bottlenecks and obstacles in the application of MOFs in PDT are also described.
    Keywords:  active MOFs; inactive MOFs; metal-organic framework; photodynamic therapy; tumor microenvironment
    DOI:  https://doi.org/10.2147/IJN.S362759
  26. ACS Macro Lett. 2020 Sep 15. 9(9): 1292-1302
    100th Anniversary of Macromolecular Science Viewpoint: Biological Stimuli-Sensitive Polymer Prodrugs and Nanoparticles for Tumor-Specific Drug Delivery.
    Huanli Sun, Zhiyuan Zhong.
      The development of smart polymer vehicles to carry and release cytotoxic drugs to tumor tissues and cells while reducing the exposure of drugs in the blood and healthy organs is a highly challenging task with continuously growing interest from multiple fields, including polymer science, pharmaceutical science, nanotechnology, and clinical oncology. Inspired by the unique tumor microenvironment, such as mild acidity and overexpressed enzymes, functional polymer prodrugs and nanoparticles with reversible charge, detachable PEG shell, activatable ligand, and switchable size have been designed to enhance tumor deposition, tumor penetration, tumor cell uptake, and tumoral drug release. Utilizing biological signals inside tumor cells, such as acidic endo/lysosomal pH, elevated glutathione levels, and reactive oxygen species, responsive polymer prodrugs and nanoparticles with good extracellular stability but fast intracellular disintegration have been engineered for specific intracellular drug release. These biological stimuli-sensitive polymer prodrugs and nanoparticles have shown superior specificity and therapeutic efficacy to nonsensitive counterparts and, in certain cases, even clinically approved systems in varying tumor models. In this Viewpoint, design strategies and recent advances of biological stimuli-responsive polymer prodrugs and nanoparticles for tumor-specific drug delivery will be highlighted, and their challenges and future perspectives will be discussed.
    DOI:  https://doi.org/10.1021/acsmacrolett.0c00488
  27. J Mater Chem B. 2022 Jun 01.
    An oxygen-economical nano-photosensitizer with a high photodynamic therapeutic outcome via simultaneous reduction of the cellular respiration and oxygen depletion of PDT.
    Hao Zhang, Xiaosa Yan, Yongkang Zhang, Chenlu Bao, Changhua Li.
      The development of photodynamic nanomedicines that can alleviate intratumoral oxygen deficiency during photodynamic therapy (PDT) is of great significance for improving the therapeutic outcome of solid tumors characterized by severe hypoxia. Massive oxygen consumption due to vigorous cellular respiration, i.e., mitochondrial-associated oxidative phosphorylation (OXPHOS), is another major cause of severe tumor hypoxia in addition to insufficient oxygen supply. Moreover, oxygen depletion during PDT further exacerbates the shortage of intratumoral oxygen. In this work, we engineered a novel oxygen-economical nano-photosensitizer via co-encapsulation of an OXPHOS inhibitor (ATO) and a newly developed type-I photosensitizer (IPS) into a polymeric micelle of PEG-b-PCL. By controlling the length of hydrophobic PCL segments, we successfully optimized the micelle size to around 30 nm for enhanced tumor penetration. The orchestration of the two functional components, ATO and IPS, can simultaneously hinder the two major tumor oxygen-consuming pathways, where ATO targets mitochondrial complex III to inhibit cellular respiration, while IPS generates ROS through a low oxygen-consuming type-I photochemical pathway, enabling remarkable PDT efficacies in both hypoxic cells and a 4T1 tumor-bearing BALB/c mouse model. This work sheds new light on the construction of nano-photosensitizers to rejuvenate PDT against hypoxic solid tumors.
    DOI:  https://doi.org/10.1039/d2tb00309k
  28. Food Res Int. 2022 Jun;pii: S0963-9969(22)00371-4. [Epub ahead of print]156 111314
    A review of nanostructured delivery systems for the encapsulation, protection, and delivery of silymarin: An emerging nutraceutical.
    Zhiheng Zhang, Xiaojing Li, Shangyuan Sang, David Julian McClements, Long Chen, Jie Long, Aiquan Jiao, Jinpeng Wang, Zhengyu Jin, Chao Qiu.
      Silymarin exhibits biological activities that may promote human health and wellbeing, including antioxidant, antimicrobial, anti-inflammatory, and anti-cancer activities. Consequently, it has potential for application as a nutraceutical ingredient in functional foods and supplements. But its application for this purpose is currently limited by its poor water solubility, chemical stability, and bioavailability. The potential of nano-delivery systems to improve the functional performance of silymarin was reviewed in this manuscript. The formation, attributes, and applications of biopolymer-based, lipid-based, surfactant-based, and miscellaneous nanocarriers are discussed. In particular, the impact of the different delivery systems such as biopolymer-based, lipid-based delivery systems on the gastrointestinal fate of silymarin is summarized. The encapsulation in edible nanocarriers can improve the bioavailability of silymarin by enhancing its water-dispersibility, inhibiting its degradation, and increasing its absorption.These nanocarriers may therefore be utilized to incorporate this nutraceutical into functional foods and supplements in a bioavailable form.
    Keywords:  Bioavailability; Delivery systems; Nanocapsules; Nanotechnology; Nutraceutical; Silymarin
    DOI:  https://doi.org/10.1016/j.foodres.2022.111314
  29. Food Res Int. 2022 Jun;pii: S0963-9969(22)00217-4. [Epub ahead of print]156 111160
    Natural bioactives in perspective: The future of active packaging based on essential oils and plant extracts themselves and those complexed by cyclodextrins.
    Tarsila Rodrigues Arruda, Patrícia Campos Bernardes, Allan Robledo Fialho E Moraes, Nilda de Fátima Ferreira Soares.
      Aiming to attend to consumers' increasing demand for synthetic additives-free food products (stimulated by personal preferences or health concerns), the food industry has been trying to introduce natural bioactive compounds as food preservatives. In this respect, the development of active food packaging incorporated with natural compounds could be of great interest. However, this scenario still has some particularities that can hinder its application in the food industry, such as relatively reduced stability and, in some cases, undesirable sensorial properties. Cyclodextrins showed up as an option to circumvent these drawbacks by forming inclusion complexes that can protect the active compounds and perform their controlled release for contact with packaged food. For industrial manufacturing of active packages based on naturally occurring bioactive compounds, inclusion complexation can be considered one of the most promising alternatives. Therefore, this review summarizes the potential of nanotechnology in active food packaging by applying cyclodextrins as a carrier for natural active compounds, which can be provided by conventional sources and alternatively (and cost-effectively) agro-food by-products. The present study will benefit prospects for exploring cyclodextrins in active food packaging, which industrial application, without a doubt, will increase in the coming years.
    Keywords:  Active films; Bioactivity; Cyclodextrins; Food packaging; Natural compounds
    DOI:  https://doi.org/10.1016/j.foodres.2022.111160
  30. Acta Pharm Sin B. 2022 May;12(5): 2479-2493
    The long-circulating effect of pegylated nanoparticles revisited via simultaneous monitoring of both the drug payloads and nanocarriers.
    Wufa Fan, Haixia Peng, Zhou Yu, Luting Wang, Haisheng He, Yuhua Ma, Jianping Qi, Yi Lu, Wei Wu.
      The long-circulating effect is revisited by simultaneous monitoring of the drug payloads and nanocarriers following intravenous administration of doxorubicin (DOX)-loaded methoxy polyethylene glycol-polycaprolactone (mPEG-PCL) nanoparticles. Comparison of the kinetic profiles of both DOX and nanocarriers verifies the long-circulating effect, though of limited degree, as a result of pegylation. The nanocarrier profiles display fast clearance from the blood despite dense PEG decoration; DOX is cleared faster than the nanocarriers. The nanocarriers circulate longer than DOX in the blood, suggesting possible leakage of DOX from the nanocarriers. Hepatic accumulation is the highest among all organs and tissues investigated, which however is reversely proportionate to blood circulation time. Pegylation and reduction in particle size prove to extend circulation of drug nanocarriers in the blood with simultaneous decrease in uptake by various organs of the mononuclear phagocytic system. It is concluded that the long-circulating effect of mPEG-PCL nanoparticles is reconfirmed by monitoring of either DOX or the nanocarriers, but the faster clearance of DOX suggests possible leakage of a fraction of the payloads. The findings of this study are of potential translational significance in design of nanocarriers towards optimization of both therapeutic and toxic effects.
    Keywords:  Aggregation-caused quenching; Doxorubicin; Drug delivery; In vivo fate; Long-circulating; Nanoparticles; Pharmacokinetics; mPEG-PCL
    DOI:  https://doi.org/10.1016/j.apsb.2021.11.016
  31. Indian J Psychol Med. 2022 Mar;44(2): 107-113
    Role of Curcumin in the Management of Schizophrenia: A Narrative Review.
    Damodharan Dinakaran, Vanteemar S Sreeraj, Ganesan Venkatasubramanian.
      Nutraceutical agents and food supplements are commonly used as treatment adjuncts in neuropsychiatric disorders. Curcumin, a bioactive agent obtained from the rhizome of Curcuma longa, with its antioxidant and anti-inflammatory properties, has gained much research attention in the last few decades. In this narrative review, we intend to summarize the evidence available for curcumin as an add-on agent in the management of schizophrenia. We searched PubMed/EBSCO for both human and animal trials utilizing curcumin in the management of schizophrenia. We obtained ten articles (five preclinical and five clinical) from the focused literature search. Clinical research utilizing curcumin in schizophrenia is limited to negative and cognitive symptoms. Available preclinical studies suggest curcumin's utility in ameliorating extrapyramidal and metabolic side effects when given as an adjunct with antipsychotics. Curcumin, as an add-on agent, appears promising to improve the negative and cognitive symptoms of schizophrenia. Notably, curcumin was tolerable and safe in all the randomized human clinical trials. The poor oral bioavailability is, however, a limiting factor in its widespread use.
    Keywords:  adverse effects; antipsychotics; cognition; curcumin; psychosis; schizophrenia
    DOI:  https://doi.org/10.1177/02537176211033331
  32. Curr Pharm Des. 2022 Jun 01.
    Chemotherapeutics activities of dietary phytoestrogens against prostate cancer: From observational to clinical studies.
    Md Sohel, Habiba Sultana, Tayeba Sultana, Abdullah Al Mamun, Mohammad Nurul Amin, Md Arju Hossain, Md Chayan Ali, Suraiya Aktar, Armin Sultana, Zahed Bin Rahim, Sarmistha Mitra, Raju Dash.
      Prostate cancer remains one of the most frequent and deadliest malignancies in males, where the rate of disease progression is closely associated with the type of dietary intake, specifically Western-style diet. Indeed intake of the Asian diet, which contains abundant phytoestrogens, is inversely correlated with a higher risk of prostate cancer, suggesting a chemoprotective effect of phytoestrogen against cancer progression. Although the role of phytoestrogens in cancer treatment was well documented, their impact on prostate cancer is not well understood. Therefore, the present review discusses the possible chemopreventive effect of phytoestrogens, emphasizing their efficacy at the different stages of carcinogenesis. Furthermore, phytoestrogens provide a cytoprotective effect in conventional chemotherapy and enhance chemosensitivity to tumor cells, which have also been discussed. This compilation provides a solid basis for future research on phytoestrogens as a promising avenue for anticancer drug development and also recommends these beneficiary compounds in the daily diet to manage and prevent prostate cancer.
    Keywords:  Phytoestrogens; and synergism; anticancer effect; drug resistance; nano-formulation; prostate cancer
    DOI:  https://doi.org/10.2174/1381612828666220601153426
  33. Small. 2022 Jun 02. e2202242
    Size Optimization of Organic Nanoparticles with Aggregation-Induced Emission Characteristics for Improved ROS Generation and Photodynamic Cancer Cell Ablation.
    Shengming Gan, Wenbo Wu, Guangxue Feng, Zhiming Wang, Bin Liu, Ben Zhong Tang.
      Aggregation-induced emission (AIE) fluorogens provide new opportunities to promote efficient reactive oxygen species (ROS) production in aggregates, which represent the promising candidates to construct theranostic nanoparticles for photodynamic therapy (PDT), but the size effect has been rarely explored. Herein, a universal method to fabricate organic nanoparticles with controllable sizes is reported and it demonstrates that ≈45 nm is the optimal size of AIE nanoparticles for PDT. Different from conventional Ce6 nanoparticles which show largely reduced fluorescence and ROS generation with increasing nanoparticle size, AIE nanoparticles show gradually enhanced brightness and ROS generation upon increasing the sizes from 6 to ≈45 nm. Further increasing sizes could continue to intensify the nanoparticle's brightness at the expense of ROS production, with the optimal size for ROS generation being achieved at ≈45 nm. Both 2D monolayer cell and 3D multicellular spheroid experiments confirm that 45 nm AIE nanoparticles have the highest cellular uptake, the deepest penetration depth, and the best photodynamic killing effect. Such a study not only manifests the advantages of AIE photosensitizers, but also delivers the optimal size ranging for efficient PDT, which shall provide an attractive paradigm to guide the development of phototheranostic nanoparticles besides molecular design to further promote PDT applications.
    Keywords:  aggregation-induced emission; cancer therapy; nanoparticle sizes; organic nanoparticles; photodynamic therapy
    DOI:  https://doi.org/10.1002/smll.202202242
  34. Oxid Med Cell Longev. 2022 ;2022 4330681
    The Targeting of Noncoding RNAs by Quercetin in Cancer Prevention and Therapy.
    Man Wang, Xinzhe Chen, Fei Yu, Lei Zhang, Yuan Zhang, Wenguang Chang.
      The dietary flavonoid quercetin is ubiquitously distributed in fruits, vegetables, and medicinal herbs. Quercetin has been a focal point in recent years due to its versatile health-promoting benefits and high pharmacological values. It has well documented that quercetin exerts anticancer actions by inhibiting cell proliferation, inducing apoptosis, and retarding the invasion and metastasis of cancer cells. However, the exact mechanism of quercetin-mediated cancer chemoprevention is still not fully understood. With the advances in high-throughput sequencing technologies, the intricate oncogenic signaling networks have been gradually characterized. Increasing evidence on the close association between noncoding RNA (ncRNAs) and cancer etiopathogenesis emphasizes the potential of ncRNAs as promising molecular targets for cancer treatment. Available experimental studies indicate that quercetin can dominate multiple cancer-associated ncRNAs, hence repressing carcinogenesis and cancer development. Thus, modulation of ncRNAs serves as a key mechanism responsible for the anticancer effects of quercetin. In this review, we focus on the chemopreventive effects of quercetin on cancer pathogenesis by targeting cancer-relevant ncRNAs, supporting the viewpoint that quercetin holds promise as a drug candidate for cancer chemoprevention and chemotherapy. An in-depth comprehension of the interplay between quercetin and ncRNAs in the inhibition of cancer development and progression will raise the possibility of developing this bioactive compound as an anticancer agent that could be highly efficacious and safe in clinical practice.
    DOI:  https://doi.org/10.1155/2022/4330681
  35. Chem Asian J. 2022 May 29.
    Sustainable drug release using nanoparticle encapsulated microneedles.
    Sin-Jin Oh, Jae Hwan Jung.
      Microneedle (MN) is a minimally invasive drug delivery method that is directly inserted into the skin without pain to improve the efficiency of transdermal administration and is a drug delivery system used to treat various diseases. Furthermore, nanoparticle (NP)-based drug delivery methods suggest therapeutic strategies to improve drug solubility and increase drug delivery efficiency. Therefore, the drug delivery system in which NPs and MNs are integrated is a promising alternative to the existing delivery methods of poorly soluble and hydrophobic drugs and nucleic acid therapeutics. This system can increase the solubility of drugs and biocompatibility in the body and improve the therapeutic efficacy with sustained drug release. In this review, we investigated recent studies of NPs designed for drug delivery, sustained-release drug delivery MNs based on these NPs, and the applications for clinical treatments.
    Keywords:  sustainable release, nanoparticles, microneedles, transdermal drug delivery, drug delivery, disease therapy
    DOI:  https://doi.org/10.1002/asia.202200333
  36. Food Res Int. 2022 Jun;pii: S0963-9969(22)00190-9. [Epub ahead of print]156 111133
    Fermented foods: An update on evidence-based health benefits and future perspectives.
    Iñaki Diez-Ozaeta, Oihana Juaristi Astiazaran.
      In recent years, an unstoppable trend toward minimally processed foods has increased the popularity of fermented foods as a beneficial nutritional and functional strategy. Within food fermentations, complex microbial communities trigger different biochemical reactions that result in the release of multiple bioactive compounds with beneficial effects on human health. In the present review the latest studies on fermented foods are summarized. Special attention has been paid on the health benefits of main fermented foods available nowadays, the principal bioactive compounds responsible for such properties as well as the future trends of research studies regarding their potentialities. This review emphasizes the need of clinical evidence to ensure that fermented foods may entail a significant improvement on well-being. Fermented foods may represent a non-invasive strategy to face multiple disorders, as hypertension, diabetes, hyperlipidemia, oxidative stress and multiple cognitive disordes, among others. Release of bioactive compounds, microbial enzymatic conversions or probiotic activities are the main responsible for such interesting properties. However, the need of well-designed clinical trials is a must in order to obtain conclusive results. Bioavailability and biodisponibility of bioactive compounds as well as the design of precision probiotics are also another focus of interest in which it must be deepen.
    Keywords:  Bioactive compounds; Clinical study; Fermented food; Gut-brain axis; Lactic acid bacteria; Probiotics
    DOI:  https://doi.org/10.1016/j.foodres.2022.111133
  37. Curr Nutr Rep. 2022 May 31.
    Intermittent Fasting in Cancer: a Role in Survivorship?
    Eleah Stringer, Julian J Lum, Nicol Macpherson.
       PURPOSE OF REVIEW: To discuss the historical development of intermittent fasting, its potential underlying mechanisms, and the state of clinical trials, and to reflect on considerations for practice and future recommendations.
    RECENT FINDINGS: Preclinical studies consistently show the robust disease-modifying efficacy of intermittent fasting in various metabolic diseases which may hold implications for cancer prevention and survivorship. Twenty-one clinical trials have or are being conducted on fasting in cancer, utilizing various fasting regimens across different tumor types as a stand-alone intervention or in adjunct to anticancer treatment, with heterogenous outcome variables. Though there are no known, reproducible diets, to cure or prevent cancer recurrence, preliminary research on the underlying mechanisms, tolerance, and safety of intermittent fasting in cancer warrants further investigation. The inherent flexibility of intermittent fasting to accommodate all types of diets is of necessity in oncology.
    Keywords:  Cancer survivorship; Intermittent fasting; Oncology; Time-restricted feeding
    DOI:  https://doi.org/10.1007/s13668-022-00425-0
  38. Front Nutr. 2022 ;9 857879
    Polydatin, A Glycoside of Resveratrol, Is Better Than Resveratrol in Alleviating Non-alcoholic Fatty Liver Disease in Mice Fed a High-Fructose Diet.
    Guangshan Zhao, Lian Yang, Wenshen Zhong, Yuze Hu, Yu Tan, Zhe Ren, Qiuyan Ban, Chung S Yang, Yifei Wang, Zhiping Wang.
      Resveratrol (RES) is considered to be an activator of AMP-activated protein kinase (AMPK) with many reported health benefits. Polydatin (POD) is a natural precursor and glycosylated form of RES. The glycoside structure of POD alters the bioactivity. Overnutrition-stimulated reactive oxygen species (ROS) promote the AMPK suppression and metabolic dysregulation. The present work compared the effects of POD and RES in ameliorating energy homeostasis imbalance in mice fed a high-fructose diet and elucidated the underlying mechanisms of action. Our results showed that POD elevated the fecal levels of valeric acid and caproic acid via modification of gut microbiota, while RES did not significantly influence the levels of fecal short-chain fatty acids (SCFAs). Both POD and RES markedly decreased the oxidative stress and activated the AMPK signaling pathways in the liver. POD and RES exerted a similar effect in alleviating glucose dysmetabolism, but POD was more effective in ameliorating lipid dysmetabolism than RES. Furthermore, valeric acid and caproic acid alone can activate the AMPK and ameliorate hypercholesterolemia, and enhance the effects of POD on improving lipid metabolism in mice. Overall, for the first time, we demonstrated that POD administration elevated the fecal levels of valeric acid and caproic acid by modifying gut microbiota, thus promoting AMPK activation may be the underlying mechanism that POD is superior to RES in alleviating the lipid dysmetabolism. Our results suggest that POD may be an alternative for RES as an AMPK activator.
    Keywords:  5′-aMP-activated protein kinase; gut microbiota; non-alcoholic fatty liver disease; polydatin; resveratrol; short-chain fatty acids
    DOI:  https://doi.org/10.3389/fnut.2022.857879
  39. ACS Appl Nano Mater. 2022 May 27. 5(5): 6125-6139
    Eutectic Gallium-Indium Nanoparticles for Photodynamic Therapy of Pancreatic Cancer.
    Sabrina S Hafiz, Marvin Xavierselvan, Sumeyra Gokalp, Daniela Labadini, Sebastian Barros, Jeanne Duong, Michelle Foster, Srivalleesha Mallidi.
      Developing a cancer theranostic nanoplatform with diagnosis and treatment capabilities to effectively treat tumors and reduce side effects is of great significance. Herein, we present a drug delivery strategy for photosensitizers based on a new liquid metal nanoplatform that leverages the tumor microenvironment to achieve photodynamic therapeutic effects in pancreatic cancer. Eutectic gallium indium (EGaIn) nanoparticles were successfully conjugated with a water-soluble cancer targeting ligand, hyaluronic acid, and a photosensitizer, benzoporphyrin derivative, creating EGaIn nanoparticles (EGaPs) via a simple green sonication method. The prepared sphere-shaped EGaPs, with a core-shell structure, presented high biocompatibility and stability. EGaPs had greater cellular uptake, manifested targeting competence, and generated significantly higher intracellular ROS. Further, near-infrared light activation of EGaPs demonstrated their potential to effectively eliminate cancer cells due to their single oxygen generation capability. Finally, from in vivo studies, EGaPs caused tumor regression and resulted in 2.3-fold higher necrosis than the control, therefore making a good vehicle for photodynamic therapy. The overall results highlight that EGaPs provide a new way to assemble liquid metal nanomaterials with different ligands for enhanced cancer therapy.
    DOI:  https://doi.org/10.1021/acsanm.1c04353
  40. ACS Appl Mater Interfaces. 2022 Jun 01.
    Size Changeable Nanomedicines Assembled by Noncovalent Interactions of Responsive Small Molecules for Enhancing Tumor Therapy.
    Xiaomin Ma, Xiangyu Chen, Zeng Yi, Zhiwen Deng, Wen Su, Guangcan Chen, Lei Ma, Yaqin Ran, Qiulan Tong, Xudong Li.
      The size of nanocarriers strongly affects their performance in biological systems, especially the capacity to overcome various barriers before delivering the payloads to destinations. However, the optimum size varies at different delivery stages in cancer therapy due to the complicated tumor microenvironment. Relatively large particles are favored for long-term circulation in vivo, while smaller particles contribute to deep penetration into tumor tissues. This dilemma in the size of particles stimulates the development of stimuli-responsive size-shrinking nanocarriers. Herein, we report a facile strategy to construct a tumor-triggered tannic acid (TA) nanoassembly with improved drug delivery efficiency. Cystamine (CA), a small molecule with a disulfide bond, is thus used to mediate TA assembling via cooperative noncovalent interactions, which endows the nanoassembly with intrinsic pH/GSH dual-responsiveness. The obtained TA nanoassemblies were systematically investigated. DOX encapsulated nanoassembly labeled TCFD NP shows high drug loading efficiency, pH/GSH-responsiveness and significant size shrinkage from 122 to 10 nm with simultaneous drug release. The in vitro and in vivo experimental results demonstrate the excellent biocompatibility, sufficient intracellular delivery, enhanced tumor retention/penetration, and superior anticancer efficacy of the small-molecule-mediated nanoassembly. This noncovalent strategy provides a simple method to fabricate a tumor-triggered size-changeable delivery platform to overcome biological barriers.
    Keywords:  biological barriers; cooperative noncovalent interactions; intratumoral/intracellular delivery; size-shrinkage; tumor retention/penetration
    DOI:  https://doi.org/10.1021/acsami.2c04698
  41. Expert Opin Drug Deliv. 2022 Jun 03.
    Colorectal cancer management: Strategies in drug delivery.
    Prabha Singh, Pramita Waghambare, Tabassum Khan, Abdelwahab Omri.
       INTRODUCTION: Colorectal cancer (CRC) is the third most common cancer leading to death worldwide following breast and lung cancer with the incidence rate of 10%. The treatment comprises of surgery, radiation, and ablation therapy depending upon the stage of cancer.
    AREAS COVERED: The review focuses on various drug delivery strategies explored to circumvent the major constraints associated with the conventional drug delivery systems- poor bioavailability, intra- and inter individual variability, exposure of normal cells to antineoplastic agents, and presence of efflux pump. All these attributes impact the effective delivery of chemotherapeutic agents at the tumor site. The various target specific drug delivery systems developed for colorectal cancer include pH dependent, microbiologically triggered, time dependent, magnetically driven, pressure dependent, prodrug/polysaccharide based, osmotic and ligand mediated systems. This review enumerates novel target specific approaches developed and investigated for potential utility in CRC therapeutics.
    EXPERT OPINION: The limitations of conventional delivery systems can be overcome by development of colon-specific targeted drug delivery systems that overcome the obstacles of nonspecific biodistribution, drug resistance and unwanted adverse effects of conventional drug delivery systems. In addition, nanotechnology approaches help to increase drug solubility, bioavailability, reduce side effects and provide superior drug response in CRC.
    Keywords:  Chemotherapeutics and Nanotechnology; Colon cancer; Drug targeting; Site specific delivery; Tumour targeting
    DOI:  https://doi.org/10.1080/17425247.2022.2084531
  42. Nutr Res. 2022 May 10. pii: S0271-5317(22)00043-4. [Epub ahead of print]104 82-90
    Senescence-mediated anticancer effects of quercetin.
    Serpil Özsoy Gökbilen, Eda Becer, Hafize Seda Vatansever.
      Cellular senescence plays a key role in aging and age-related disease initiation. It is a highly dynamic and multistep process that can be stimulated by various stimuli, including cellular stress, DNA damage, telomere shortening, and oncogene activation. Also, senescence is a potent antitumor mechanism, by preventing the proliferation of cancerous cells. However, some of the senescent cells have apoptosis resistance and can cause recurrence in cancer. A new class of drugs termed senolytics selectively kill and eliminate senescent cells. In recent years, natural compounds such as quercetin have been discovered to be effective as senolytic agents. Quercetin is a phytochemical that has strong antioxidant properties and pro-apoptotic effects and has been investigated for many years. Additionally, it has great potential to be used as a senolytic agent. According to preclinical and early-phase clinical data of senolytic agent research, quercetin administration appears to be effective in preventing or alleviating cancer formation. In this paper, we review the importance of cellular senescence in carcinogenesis and the effects of quercetin on senescence, as well as quercetin's potential effects as a pro-apoptotic agent and suppressor of cancer cell proliferation.
    Keywords:  Cancer prevention; Cellular senescence; Polyphenols; Proliferation; Quercetin
    DOI:  https://doi.org/10.1016/j.nutres.2022.04.007
  43. ACS Appl Bio Mater. 2022 Jun 02.
    Correction to "Light-Induced Reactive Oxygen Species (ROS) Generator for Tumor Therapy through an ROS Burst in Mitochondria and AKT-Inactivation-Induced Apoptosis".
    Yinuo Tu, Yuping Zhou, Di Zhang, Jinghong Yang, Xiang Li, Kaiyuan Ji, Xu Wu, Ruiyuan Liu, Qianbing Zhang.
      
    DOI:  https://doi.org/10.1021/acsabm.2c00430
  44. ACS Biomater Sci Eng. 2022 Jun 01.
    PAMAM Dendritic Nanoparticle-Incorporated Hydrogel to Enhance the Immunogenic Cell Death and Immune Response of Immunochemotherapy.
    Endris Yibru Hanurry, Yihenew Simegniew Birhan, Haile Fentahun Darge, Tefera Worku Mekonnen, Vinothini Arunagiri, Hsiao-Ying Chou, Chih-Chia Cheng, Juin-Yih Lai, Hsieh-Chih Tsai.
      The efficiency of chemotherapy is frequently affected by its multidrug resistance, immune suppression, and severe side effects. Its combination with immunotherapy to reverse immune suppression and enhance immunogenic cell death (ICD) has emerged as a new strategy to overcome the aforementioned issues. Herein, we construct a pH-responsive PAMAM dendritic nanocarrier-incorporated hydrogel for the co-delivery of immunochemotherapeutic drugs. The stepwise conjugation of moieties and drug load was confirmed by various techniques. In vitro experimental results demonstrated that PAMAM dendritic nanoparticles loaded with a combination of drugs exhibited spherical nanosized particles, facilitated the sustained release of drugs, enhanced cellular uptake, mitigated cell viability, and induced apoptosis. The incorporation of PAB-DOX/IND nanoparticles into thermosensitive hydrogels also revealed the formation of a gel state at a physiological temperature and further a robust sustained release of drugs at the tumor microenvironment. Local injection of this formulation into HeLa cell-grafted mice significantly suppressed tumor growth, induced immunogenic cell death-associated cytokines, reduced cancer cell proliferation, and triggered a CD8+ T-cell-mediated immune response without obvious systemic toxicity, which indicates a synergistic ICD effect and reverse of immunosuppression. Hence, the localized delivery of immunochemotherapeutic drugs by a PAMAM dendritic nanoparticle-incorporated hydrogel could provide a promising strategy to enhance antitumor activity in cancer therapy.
    Keywords:  IDO1; PAMAM dendrimer; cytokine; immunochemotherapy; immunogenic cell death
    DOI:  https://doi.org/10.1021/acsbiomaterials.2c00171
  45. Front Pharmacol. 2022 ;13 899208
    Therapeutic Effects of Natural Products on Cervical Cancer: Based on Inflammatory Pathways.
    Zi-Wei Zhou, Hui-Zhi Long, Shuo-Guo Xu, Feng-Jiao Li, Yan Cheng, Hong-Yu Luo, Li-Chen Gao.
      Inflammation is a protective response of the body to an irritant. When an inflammatory response occurs, immune cells are recruited to the injury, eliminating the irritation. The excessive inflammatory response can cause harm to the organism. Inflammation has been found to contribute to cervical cancer if there is a problem with the regulation of inflammatory response. Cervical cancer is one of the most common malignant tumors globally, and the incidence tends to be younger. The harm of cervical cancer cannot be ignored. The standard treatments for cervical cancer include surgery, radiotherapy and chemotherapy. However, the prognosis for this treatment is poor, so it is urgent to find a safer and more effective treatment. Natural products are considered excellent candidates for the treatment of cervical cancer. In this review, we first describe the mechanisms by which inflammation induces cervical cancer. Subsequently, we highlight natural products that can treat cervical cancer through inflammatory pathways. We also introduce natural products for the treatment of cervical cancer in clinical trials. Finally, methods to improve the anticancer properties of natural products were added, and the development status of natural products was discussed.
    Keywords:  HPV; cervical cancer; inflammatory; natural products; therapeutic
    DOI:  https://doi.org/10.3389/fphar.2022.899208
  46. Front Pharmacol. 2022 ;13 885484
    Botanical Drugs in Traditional Chinese Medicine With Wound Healing Properties.
    Shuyi Ning, Jie Zang, Bingyang Zhang, Xinchi Feng, Feng Qiu.
      Chronic and unhealed wound is a serious public problem, which brings severe economic burdens and psychological pressure to patients. Various botanical drugs in traditional Chinese medicine have been used for the treatment of wounds since ancient time. Nowadays, multiple wound healing therapeutics derived from botanical drugs are commercially available worldwide. An increasing number of investigations have been conducted to elucidate the wound healing activities and the potential mechanisms of botanical drugs in recent years. The aim of this review is to summarize the botanical drugs in traditional Chinese medicine with wound healing properties and the underlying mechanisms of them, which can contribute to the research of wound healing and drug development. Taken together, five botanical drugs that have been developed into commercially available products, and 24 botanical drugs with excellent wound healing activities and several multiherbal preparations are reviewed in this article.
    Keywords:  anti-inflammatory; antibacterial; botanical drugs; multiherbal preparations; proangiogenic; wound healing
    DOI:  https://doi.org/10.3389/fphar.2022.885484
  47. Mini Rev Med Chem. 2022 May 31.
    Targeting Glioma Cells with Nutraceuticals: Therapeutic Effects Based on Molecular Mechanisms, New Evidence, and Perspectives.
    Marziyeh Salami, Raziyeh Salami, Mohammad-Hossein Aarabi, Alireza Mafi, Seyedeh Sara Ghorbanhosseini, Rana Shafabakhsh, Zatollah Asemi.
      Gliomas are the most common malignant cancers of the brain that have unregulated proliferation known as a highly invasive tumor. Hence, their relapse rate is high and the prognosis is low. Despite remarkable advances in neuroimaging, neurosurgery, and radiation therapy, they, especially glioblastoma, are highly resistant to treatments including radiotherapy, surgery, and temozolomide chemotherapy. The average survival rate for patients with malignant glioma is still less than two years, accordingly, the search for new treatment options has recently become an urgent need. Today, a number of nutraceuticals have been considered because of their special role in inhibiting the angiogenic process, metastasis, and apoptosis, and ultimately inhibiting tumor growth, including glioma. Nutraceuticals can disrupt cancer cells by affecting different pathways. In fact, these compounds can reduce the growth of cancer cells, inhibit their proliferation and angiogenesis, as well as induce apoptosis in these cells and play an important role in various stages of treatment. One of the key target of nutraceuticals may be to regulate cellular signaling pathways such as PI3K/Akt/mTORC1, JAK/STAT, and GSK-3 or to exert their effects through other mechanisms such as cytokine receptors and inflammatory pathways, reactive oxygen species, and miRNAs. This review refers to the results of recent studies and target molecules as well as signaling pathways affected by some nutraceuticals in glioma cells. These studies indicated that clinical trials are imminent and new approaches can be beneficial for patients.
    Keywords:  Glioma; anti-cancer; apoptosis; inflammation; nutraceutical; signaling pathway.
    DOI:  https://doi.org/10.2174/1389557522666220531151137
  48. Drug Deliv. 2022 Dec;29(1): 1726-1742
    Boosting the anti-inflammatory effect of self-assembled hybrid lecithin-chitosan nanoparticles via hybridization with gold nanoparticles for the treatment of psoriasis: elemental mapping and in vivo modeling.
    Salma Fereig, Ghada M El-Zaafarany, Mona Arafa, Mona M A Abdel-Mottaleb.
      Gold nanoparticles are a promising drug delivery system for treatment of inflammatory skin conditions, including psoriasis, due to their small size and anti-inflammatory properties. The aim of this study was to conjugate gold nanoparticles with anti-psoriatic formulations that previously showed successful results in the treatment of psoriasis (tacrolimus-loaded chitosan nanoparticles and lecithin-chitosan nanoparticles) by virtue of their surface charges, then examine whether the hybridization with gold nanoparticles would enhance the anti-psoriatic efficacy in vivo. Successful formation of gold nanoparticles was examined by elemental mapping and selected area electron diffraction (SAED). Hybrid conjugates were examined in terms of particle size and zeta potential by dynamic light scattering (DLS). Morphological features were captured by transmission electron microscope (TEM) and X-ray diffraction (XRD) analysis was conducted, as well. All characterization was conducted for the conjugated nanoparticles and compared with their bare counterparts. The in vivo results on imiquimod (IMQ)-induced mouse model showed promising anti-psoriatic effects upon application of gold conjugated tacrolimus-loaded lecithin-chitosan hybrid nanoparticles with a significant difference from the bare hybrid nanoparticles in some of the inflammatory markers. The anti-inflammatory effect of the gold conjugate was also evident by a lower spleen to body weight ratio and a better histopathological skin condition compared to other tested formulations.
    Keywords:  Gold nanoparticle conjugates; dermal delivery; elemental mapping; psoriasis; tacrolimus
    DOI:  https://doi.org/10.1080/10717544.2022.2081383
  49. Biomater Sci. 2022 Jun 01.
    The enhanced antitumor activity of the polymeric conjugate covalently coupled with docetaxel and docosahexaenoic acid.
    Peng Dong, Jiaojiao Liu, Hongshuai Lv, Jiaan Wu, Naining Zhang, Si Wang, Xiaohai Li, Jinghua Hu, Anny Wang, Daisy J Li, Dandan Wang, Shengnan Cao, Liangyu Xie, Yikang Shi.
      Docetaxel (DTX) has been widely used for the treatment of many types of cancer. However, DTX is poorly water-soluble and commercial DTX is formulated in non-ionic surfactant polysorbate 80 and ethanol, thereby leading to hypersensitivity and serious side effects. Herein, a polymer dual drug conjugate was synthesized by coupling DTX and docosahexaenoic acid (DHA) with bifunctionalized dextran. The polysaccharide conjugate dextran-DHA-DTX possessed high water solubility and was self-assembled into nanoparticles with a diameter of 98.0 ± 6.4 nm. Pharmacokinetic and biodistribution studies showed that the dextran-DHA-DTX dual drug conjugate not only had significantly prolonged blood circulation but was also selectively accumulated in the tumor with reduced drug distribution in normal tissues. The conjugate exhibited a superior therapeutic effect in both xenograft nude mice models without causing any systemic side effects. Notably, the conjugate nearly eliminated all xenograft tumors in nude mice bearing breast cancer cells MCF-7. This study revealed that the dextran-based dual drug delivery system may provide an effective strategy to selectively deliver DTX to tumor sites.
    DOI:  https://doi.org/10.1039/d2bm00337f
  50. Acta Pharm Sin B. 2022 May;12(5): 2348-2357
    Identification of human LDHC4 as a potential target for anticancer drug discovery.
    Hong Tan, Huali Wang, Jinhu Ma, Hui Deng, Qinghua He, Qiang Chen, Qinglian Zhang.
      One of the distinct hallmarks of cancer cells is aerobic glycolysis (Warburg effect). Lactate dehydrogenase A (LDHA) is thought to play a key role in aerobic glycolysis and has been extensively studied, while lactate dehydrogenase C (LDHC), an isoform of LDHA, has received much less attention. Here we showed that human LDHC was significantly expressed in lung cancer tissues, overexpression of Ldhc in mice could promote tumor growth, and knock-down of LDHC could inhibit the proliferation of lung cancer A549 cells. We solved the first crystal structure of human LDHC4 and found that the active-site loop of LDHC4 adopted a distinct conformation compared to LDHA4 and lactate dehydrogenase B4 (LDHB4). Moreover, we found that (ethylamino) (oxo)acetic acid shows about 10 times selective inhibition against LDHC4 over LDHA4 and LDHB4. Our studies suggest that LDHC4 is a potential target for anticancer drug discovery and (ethylamino) (oxo)acetic acid provides a good start to develop lead compounds for selective drugs targeting LDHC4.
    Keywords:  (Ethylamino) (oxo)acetic acid; Anticancer target; LDH isoforms; LDHC; LDHC4 structure; Lung cancer; Tissue microarray; Warburg effect
    DOI:  https://doi.org/10.1016/j.apsb.2021.12.002
  51. BMB Rep. 2022 Jun 02. pii: 5522. [Epub ahead of print]
    Melatonin inhibits glycolysis in hepatocellular carcinoma cells by downregulating mitochondrial respiration and mTORC1 activity.
    Seunghyeong Lee, Jun-Kyu Byun, Na-Young Kim, Jonghwa Jin, Hyein Woo, Yeon-Kyung Choi, Keun-Gyu Park.
      Various mechanisms have been suggested to explain the chemopreventive and tumor-inhibitory effects of melatonin. Despite the growing evidence supporting melatonin-induced mitochondrial dysfunction, it remains largely unknown how this phenomenon modulates metabolic reprogramming in cancer cells. The aim of our study was to identify the mechanism underlying the anti-proliferative and apoptotic effects of melatonin, which is known to inhibit glycolysis. We analyzed the time-dependent effects of melatonin on mitochondrial respiration and glycolysis in liver cancer cells. The results showed that from a cell bioenergetic point of view, melatonin caused an acute reduction in mitochondrial respiration, however, increased reactive oxygen species production, thereby inhibiting mTORC1 activity from an early stage post-treatment without affecting glycolysis. Nevertheless, administration of melatonin for a longer time reduced expression of c-Myc protein, thereby suppressing glycolysis via downregulation of HK2 and LDHA. The data presented herein suggest that melatonin suppresses mitochondrial respiration and glycolysis simultaneously in HCC cells, leading to anti-cancer effects. Thus, melatonin can be used as an adjuvant agent for therapy of liver cancer.
  52. Biosci Rep. 2022 May 31. pii: BSR20212051. [Epub ahead of print]
    Emerging concepts in designing next-generation multifunctional nanomedicine for cancer treatment.
    Kasturee Chakraborty, Archana Tripathi, Sukumar Mishra, Argha Mario Mallick, Rituparna Sinha Roy.
      Nanotherapy has emerged as an improved anticancer therapeutic strategy to circumvent the harmful side effects of chemotherapy. It has been proven to be beneficial to offer multiple advantages, including their capacity to carry different therapeutic agents, longer circulation time and increased therapeutic index with reduced toxicity. Over time, nanotherapy evolved in terms of their designing strategies like geometry, size, composition or chemistry to circumvent the biological barriers. Multifunctional nanoscale materials are widely used as molecular transporter for delivering therapeutics and imaging agents. Nanomedicine involving multi-component chemotherapeutic drug-based combination therapy has been found to be an improved promising approach to increase the efficacy of cancer treatment. Next-generation nanomedicine has also utilized and combined immunotherapy to increase its therapeutic efficacy. It helps in targeting tumor immune response sparing the healthy systemic immune function. In this review, we have summarized the progress of nanotechnology in terms of nanoparticle designing and targeting cancer. We have also discussed its further applications in combination therapy and cancer immunotherapy. Integrating patient-specific proteomics and biomarker based information and harnessing clinically safe nanotechnology, the development of precision nanomedicine could revolutionize the effective cancer therapy.
    Keywords:  Cancer; Combination therapy; Immuno therapy; Nanomedicine; peptide
    DOI:  https://doi.org/10.1042/BSR20212051
  53. Food Chem. 2022 May 20. pii: S0308-8146(22)01223-7. [Epub ahead of print]391 133261
    Alpha-tomatine and the two sides of the same coin: An anti-nutritional glycoalkaloid with potential in human health.
    Catarina Faria-Silva, Miriam de Sousa, Manuela Colla Carvalheiro, Pedro Simões, Sandra Simões.
      Discovery of new selective anticancer, anti-inflammatory, and anti-microbial agents is a crucial and necessary step to ensure a pipeline for innovative products to improve disease management. Several new bioactive agents derived from plants have been investigated and an example is the steroidal glycoalkaloid (SGA) class of natural products found in plants, investigated for their health-beneficial biological activities. Among them, α-tomatine is a SGA derived from the plant parts of unripe green tomatoes. In this review we aimed at searching for two different perspectives to study α-tomatine from green tomatoes, namely from its dual action point of view: as an anti-nutrient and as a health promoter. The aspects associated to its synthesis and degradation were considered. Finally, the current strategies for its extraction from natural sources and the methodologies commonly used for its identification and quantification were discussed.
    Keywords:  Alpha-tomatine; Anticancer activity; Green tomatoes; Steroidal glycoalkaloids
    DOI:  https://doi.org/10.1016/j.foodchem.2022.133261
  54. Heliyon. 2022 May;8(5): e09517
    Intranasal delivery in glioblastoma treatment: prospective molecular treatment modalities.
    Daniel E Morales, Shaker Mousa.
      Glioblastoma multiforme (GBM) is rare and fatal glioma with limited treatment options. Treatments provide minimal improvement in prognosis and only 6.8% of GBM patients have a life expectancy greater than five years. Surgical resection of this malignant glioma is difficult due to its highly invasive nature and follow-up radiotherapy with concomitant temozolomide, the currently approved standard of care, and will only extend the life of patients by a few months. It has been nearly two decades since the approval of temozolomide and there have been no clinically relevant major breakthroughs since, painting a dismal picture for patients with GBM. Although the future of GBM management seems bleak, there are many new treatment options on the horizon that propose methods of delivery to circumvent current limitations in the standard of care, i.e., the blood brain barrier and treatment resistance mechanisms. The nose is a highly accessible non-invasive route of delivery that has been incorporated into many investigational studies within the past five years and potentially paves the path to a brighter future for the management of GBM. Intranasal administration has its limitations however, as drugs can be degraded and/or fail to reach the site of action. This has prompted many studies for implementation of nanoparticle systems to overcome these limitations and to accurately deliver drugs to the site of action. This review highlights the advances in intranasal therapy delivery and impact of nanotechnology in the management of GBM and discusses potential treatment modalities that show promise for further investigation.
    Keywords:  Blood brain barrier; Glioblastoma; Intranasal; Nanoparticles; Nanotechnology; Non-invasive
    DOI:  https://doi.org/10.1016/j.heliyon.2022.e09517
  55. Fitoterapia. 2022 May 30. pii: S0367-326X(22)00101-0. [Epub ahead of print] 105223
    Recent advances in natural phthalides: Distribution, chemistry, and biological activities.
    Xiaodong Wei, Yanping Zeng, Chao Sun, Fancheng Meng, Yibo Wang.
      Phthalides, an important class of bioactive natural products, are widely distributed in plants, fungi, lichens, and liverworts. Amon them, n-butylphthalide, a phthalide monomer, has been approved to cure ischemic stroke. Owing to their good bioactivities in anti-microbial, anti-inflammatory, anti-tumor, anti-diabetic, and other aspects, a large number of researches have been conducted on phthalides from nature materials. In recent years, hundreds of novel natural phthalides were obtained. This review provides profiles of the advances in the distribution, chemistry, and biological activities of natural phthalides in 2016-2022.
    Keywords:  Biological activities; Chemistry; Distribution; Natural phthalides
    DOI:  https://doi.org/10.1016/j.fitote.2022.105223
  56. J Contemp Dent Pract. 2021 Dec 01. 22(12): 1483-1492
    Moringa oleifera: Antioxidant, Anticancer, Anti-inflammatory, and Related Properties of Extracts in Cell Lines: A Review of Medicinal Effects, Phytochemistry, and Applications.
    Shanmugapriya Ramamurthy, Sheeja Varghese, Sabitha Sudarsan, Jayanandan Muruganandhan, Shazia Mushtaq, Prema B Patil, A Thirumal Raj, Alessio Zanza, Luca Testarelli, Shankargouda Patil.
      Moringa oleifera (MO), or the common drumstick possesses antioxidant properties, and its pods, seeds, leaves, and bark have been used for the treatment of inflammatory and cancerous conditions. This systematic review attempts to synthesize original studies of MO extracts in cell lines to determine their specific antiproliferative, antioxidant, anti-inflammatory, and related effects. The literature was obtained from PubMed central, the Cochrane registry, and other sources including Google Scholar, and Embase. Studies fulfilling the inclusion criteria were selected. Custom data collection forms were employed and two independent evaluators compiled the relevant information. Eighteen studies were selected after applying inclusion and exclusion criteria. In most studies, MO leaves had more potent properties compared to other parts of the plant. Ethyl acetate and ethanolic extractions improved the potency of the extract. Effects were selective (different for normal cells and cancer cells) and dose-dependent. Anticancer and antioxidant activities were consistently reported, with effects exerted at the genetic and molecular levels. MO extracts potentially could be employed for therapeutic applications. The optimal sources, preparation protocols, and dosages have been researched, though further scrutiny is needed for a comprehensive formulation. Keywords: Anticancer, Anti-inflammatory, Antioxidant, Moringa oleifera.
  57. Drug Res (Stuttg). 2022 May 30.
    Melatonin Increases the Sensitivity of Osteosarcoma Cells to Chemotherapy Drug Cisplatin.
    Foroogh Hosseini, Dariush Shanehbandi, Jafar Soleimanpour, Bahman Yousefi, Forough Alemi.
      Chemotherapy, which is one of the common treatments for osteosarcoma (OS), has many side effects and in some cases has low effectiveness due to chemoresistance, hence it is vital to study new therapies for OS. In this regard, we combined melatonin with cisplatin and evaluate their effect on MG63 OS cells. Since melatonin has anti-cancer properties, we hypothesized that its combination with cisplatin could increase the effectiveness of cisplatin. Firstly, MTT assay was used to evaluate the cell viability and cytotoxicity of cisplatin on MG63 cells and the results showed that melatonin in combination with cisplatin increases the sensitivity of MG63 cells to cisplatin. In addition, qRT-PCR results showed that the expressions of miR-181 and P53, CYLD, CBX7 and BCL2 genes change in MG63 cells after treatment with the combination of cisplatin and melatonin, so that the expression of P53, CYLD and CBX7 increased and the expression of BCL2 and miR-181b decreases significantly. Furthermore, analysis of Annexin V/FITC assay data revealed that the rate of apoptosis in MG63 OS cell line remarkably promoted after treated with cisplatin and melatonin combination. As a result, our findings show that melatonin in combination with cisplatin increases the effectiveness of cisplatin in osteosarcoma cells and this study provides a new therapeutic approach for OS.
    DOI:  https://doi.org/10.1055/a-1830-8716
  58. Mater Today Bio. 2022 Jun;15 100289
    A minimalist and robust chemo-photothermal nanoplatform capable of augmenting autophagy-modulated immune response against breast cancer.
    Hui Ming, Bowen Li, Hailong Tian, Li Zhou, Jingwen Jiang, Tingting Zhang, Ling Qiao, Peijie Wu, Edouard C Nice, Wei Zhang, Weifeng He, Canhua Huang, Haiyuan Zhang.
      Previously used in anti-fungal therapy, itraconazole has now been shown to be successful in treating advanced breast cancer (NCT00798135). However, its poor solubility still restricts its application in clinical treatment. There is therefore an urgent need for combined methods to enhance the therapeutic effect of itraconazole (IC) in breast cancer treatment. With this goal, co-assembled IC/IR820 NPs with synergistic photonic hyperthermia and itraconazole payloads have been constructed to overcome these shortcomings. The IC/IR820 NPs show an enhanced therapeutic effect on breast cancer by inducing reactive oxygen species (ROS)-mediated apoptosis and autophagic death. Further evaluation in a mouse model has shown impressive effects of the IC/IR820 NPs on both inhibiting tumor metastasis and activating immunity to prevent tumor recurrence. Mechanistically, itraconazole may promote both tumor cell antigen presentation through autophagy and the activation of dendritic cells to induce an immune response, which displays a synergistic effect with the immune response generated by photothermal therapy to inhibit tumor recurrence. This strategy of combining itraconazole and IR820 into one minimalist and robust nanoplatform through co-assembly results in excellent therapeutic efficacy, suggesting its potential application as an alternative method for the clinical treatment of breast cancer.
    Keywords:  Autophagy; Breast cancer; IR820; Immunotherapy; Itraconazole; Photothermal therapy
    DOI:  https://doi.org/10.1016/j.mtbio.2022.100289
  59. Aging Dis. 2022 Jun;13(3): 655-672
    Metabolic Strategies in Healthcare: A New Era.
    Matthew Cl Phillips.
      Modern healthcare systems are founded on a disease-centric paradigm, which has conferred many notable successes against infectious disorders in the past. However, today's leading causes of death are dominated by non-infectious "lifestyle" disorders, broadly represented by the metabolic syndrome, atherosclerosis, cancer, and neurodegeneration. Our disease-centric paradigm regards these disorders as distinct disease processes, caused and driven by disease targets that must be suppressed or eliminated to clear the disease. By contrast, a health-centric paradigm recognizes the lifestyle disorders as a series of hormonal and metabolic responses to a singular, lifestyle-induced disease of mitochondria dysfunction, a disease target that must be restored to improve health, which may be defined as optimized mitochondria function. Seen from a health-centric perspective, most drugs target a response rather than the disease, whereas metabolic strategies, such as fasting and carbohydrate-restricted diets, aim to restore mitochondria function, mitigating the impetus that underlies and drives the lifestyle disorders. Substantial human evidence indicates either strategy can effectively mitigate the metabolic syndrome. Preliminary evidence also indicates potential benefits in atherosclerosis, cancer, and neurodegeneration. Given the existing evidence, integrating metabolic strategies into modern healthcare systems should be identified as a global health priority.
    Keywords:  atherosclerosis; cancer; carbohydrate-restricted diets; fasting; health; metabolic syndrome; metabolism; mitochondria dysfunction; neurodegeneration
    DOI:  https://doi.org/10.14336/AD.2021.1018
  60. Acta Biomater. 2022 May 28. pii: S1742-7061(22)00322-1. [Epub ahead of print]
    Active Targeting Redox-Responsive Mannosylated Prodrug Nanocolloids Promote Tumor Recognition and Cell Internalization for Enhanced Colon Cancer Chemotherapy.
    Yuan Gao, Wei Qiu, Mengyun Liang, Xianbin Ma, Mengjie Ye, Peng Xue, Yuejun Kang, Jun Deng, Zhigang Xu.
      Despite the diversified therapeutic approaches for malignant tumors, chemotherapy remains the backbone of current cancer treatment. However, conventional chemotherapeutics was found to be associated with deficient recognition of tumor, low uptake efficiency, insolubility, short circulation, poor biocompatibility and low therapeutic outcomes. Herein, the active targeting redox-responsive mannosylated prodrug nanocolloids (HM NCs) were constructed for enhanced chemotherapy of colon cancer. HM NCs were prepared by the covalent cross-linking of 10-hydroxycamptothecin (HCPT) and mannose (MAN) via redox-responsive cross-linker containing disulfide bonds, and modified with moderate amount of polyethylene glycol (PEG). The large amount of mannose contained in HM NCs could actively target overexpressed mannose receptors on the surface of cancer cells and enhance cancer cell internalization through mannose receptor-mediated endocytosis. Owing to the combination of active targeting and the enhanced permeability and retention (EPR) passive targeting, HM NCs could effectively accumulate in tumors and high glutathione (GSH) in tumor microenvironment triggered cleavage of redox-responsive bonds and precise drug release. HM NCs exhibited superior antitumor activity both in vitro and in vivo and appreciably extended the mouse survival rate with good biocompatibility. The innovative HM NCs are expected to be conducive to overcome the limitations of conventional chemotherapy of colon cancer and provide more choices for future clinical translation. STATEMENT OF SIGNIFICANCE: Despite the enhanced permeability and retention effect, the passive targeting can be interfered with by the complex biologic barriers in the body. In this study, an active targeting system (HM NCs) was constructed by covalent cross-linking of mannose and anticancer drug 10-hydroxycamptothecin via redox-responsive disulfide bonds for enhanced colon cancer chemotherapy. Mannosylation could promote hydrophilia and stability for prolonged blood circulation. Mannose could promote tumor recognition and cell internalization via mannose receptor-mediated endocytosis. High glutathione level could trigger the redox-responsive release of anticancer drugs and further induce cell apoptosis via DNA damage. The HM NCs exhibited superior antitumor activity both in vitro and in vivo and appreciably extended the mouse survival rate with good biocompatibility.
    Keywords:  Drug delivery system; Enhanced chemotherapy; Mannose; Prodrug nanocolloids; Redox-responsive; Tumor-targeting
    DOI:  https://doi.org/10.1016/j.actbio.2022.05.046
  61. Nanoscale. 2022 Jun 01.
    Precision therapy through breaking the intracellular redox balance with an MOF-based hydrogel intelligent nanobot for enhancing ferroptosis and activating immunotherapy.
    Dongsheng Zhang, Yanfei Meng, Yingzi Song, Ping Cui, Zunfu Hu, Xiuwen Zheng.
      With the advancement and development of nanomedicine, tumor precision therapy provides technical support for effective accumulation and targeted drug delivery, and reduces toxic side effects. In cancer cells, breaking the redox balance could induce cancer cell death. Herein, a novel iron-containing intelligent hydrogel nanobot (FeSe2-Ce6/MOF@HA/PEI/CpG@HHPA NPs, abbreviated as FSMH) is proposed to break the intracellular redox balance and trigger the immune response. The as-fabricated multifunctional FSMH could not only exert Fenton reactions in the acidic tumor microenvironment, converting hydrogen peroxide (H2O2) into highly toxic hydroxyl radicals (˙OH), but also effectively consume GSH to attenuate the intracellular oxidative stress. The negative charge of the FSMH nanohydrogel system guarantees its superexcellent stabilization in blood circulation and optimal tumor collection. Subsequently, the surface charge of the endocytosed FSMH was transformed to a positive charge after exposure to the acidic tumor environment, further improving its tumor collection and locally releasing Fe ions and immune adjuvants. Furthermore, Ce6 was released in a pH-responsive manner in the acidic microenvironment. In the presence of near-infrared light, singlet oxygen was produced by the FSMH nanohydrogel system, to ablate tumors and promote the maturation of dendritic cells, achieving the precision-combined strategies effect of CDT, PDT, and immunotherapy.
    DOI:  https://doi.org/10.1039/d2nr00950a
  62. Adv Colloid Interface Sci. 2022 May 26. pii: S0001-8686(22)00111-7. [Epub ahead of print]305 102709
    Nano-enabled plant-based colloidal delivery systems for bioactive agents in foods: Design, formulation, and application.
    Mahmood Alizadeh Sani, Milad Tavassoli, Maryam Azizi-Lalabadi, Keyhan Mohammadi, David Julian McClements.
      Consumers are becoming increasingly aware of the impact of their dietary choices on the environment, animal welfare, and health, which is causing many of them to adopt more plant-based diets. For this reason, many sectors of the food industry are reformulating their products to contain more plant-based ingredients. This article describes recent research on the formation and application of nano-enabled colloidal delivery systems formulated from plant-based ingredients, such as polysaccharides, proteins, lipids, and phospholipids. These delivery systems include nanoemulsions, solid lipid nanoparticles, nanoliposomes, nanophytosomes, and biopolymer nanoparticles. The composition, size, structure, and charge of the particles in these delivery systems can be manipulated to create novel or improved functionalities, such as improved robustness, higher optical clarity, controlled release, and increased bioavailability. There have been major advances in the design, assembly, and application of plant-based edible nanoparticles within the food industry over the past decade or so. As a result, there are now a wide range of different options available for creating delivery systems for specific applications. In the future, it will be important to establish whether these formulations can be produced using economically viable methods and provide the desired functionality in real-life applications.
    Keywords:  Bioactive agent-delivery systems; Bioavailability; Colloidal systems; Functional nanomaterial; Phytochemicals
    DOI:  https://doi.org/10.1016/j.cis.2022.102709
  63. Anticancer Res. 2022 Jun;42(6): 2835-2845
    Isoprenylated Coumarin Exhibits Anti-proliferative Effects in Pancreatic Cancer Cells Under Nutrient Starvation by Inhibiting Autophagy.
    Ronghao Zhou, Erika Kusaka, Yin Wang, Jing Zhang, Andrew Webb, Dora Carrico-Moniz.
       BACKGROUND/AIM: Due to the lack of early detection methods and effective treatments, pancreatic cancer has one of the lowest five-year survival rates among all cancers. We have previously identified novel isoprenylated coumarin compounds that exhibit preferential cytotoxicity against pancreatic adenocarcinoma cell line PANC-1 exclusively under glucose deprivation conditions.
    MATERIALS AND METHODS: Using cell cytotoxicity assays, we investigated the anti-proliferative mechanism of our most potent isoprenylated coumarin compound of the series, DCM-MJ-I-21, with respect to time, against two other pancreatic cancer cell lines, BxPC-3 and Capan-2. We used western blotting to quantify the autophagic flux influenced by our compound, autophagy inducers (starvation and Rapamycin), and autophagy inhibitors (chloroquine and wortmannin).
    RESULTS: We observed a clear dependence on glucose in DCM-MJ-I-21 in BxPC-3 and Capan-2 pancreatic cancer cell lines, suggesting that our compound targets a pathway shared by these cancer cell lines when glycolysis is not an option for survival. Our lead compound increased the conversion of LC3-I to LC3-II in PANC-1, similar to the effect of chloroquine, an autophagy inhibitor. In addition, Spautin-1, another autophagy inhibitor, showed almost the same anti-proliferative activities at the same concentration under nutrient-deprived conditions as our lead compound in both 2D and 3D cell cultures.
    CONCLUSION: Our lead isoprenylated coumarin compound induces selective pancreatic cancer cell death under nutrient-deprived conditions through inhibition of autophagy, potentially providing insights into new therapeutic options.
    Keywords:  Novel anti-pancreatic cancer agent; autophagy; coumarin derivative; selective cytotoxicity
    DOI:  https://doi.org/10.21873/anticanres.15765
  64. Iran J Basic Med Sci. 2022 Mar;25(3): 302-312
    Preparation, characterization, and biodistribution of glutathione PEGylated nanoliposomal doxorubicin for brain drug delivery with a post-insertion approach.
    Amin Mehrabian, Roghayyeh Vakili-Ghartavol, Mohammad Mashreghi, Sara Shokooh Saremi, Ali Badiee, Leila Arabi, Seyedeh Hoda Alavizadeh, Seyedeh Alia Moosavian, Mahmoud Reza Jaafari.
       Objectives: Brain cancer treatments have mainly failed due to their inability to cross the blood-brain barrier. Several studies have confirmed the presence of glutathione (GSH) receptors on BBB's surface, as a result, products like 2B3-101, which contain over 5% pre-inserted GSH PEGylated liposomal doxorubicin, are being tested in clinical trials. Here we conducted the PEGylated nanoliposomal doxorubicin particles that are covalently attached to the glutathione using the post-insertion technique. Compared with the pre-insertion approach, the post-insertion method is notably simpler, faster, and more cost-effective, making it ideal for large-scale pharmaceutical manufacturing.
    Materials and Methods: The ligands of the DSPE PEG(2000) Maleimide-GSH were introduced in the amounts of 25, 50, 100, 200, and 400 on the available Caelyx. Following physicochemical evaluations, animal experiments such as biodistribution, fluorescence microscopy, and pharmacokinetics were done.
    Results: In comparison with Caelyx, the 200L and 400L treatment arms were the most promising formulations. We showed that nanocarriers containing 40 times fewer GSH micelles than 2B3-101 significantly increased blood-brain barrier penetrance. Due to the expressed GSH receptors on tissues as an endogenous antioxidant, doxorubicin will likely concentrate in the liver, spleen, heart, and lung in comparison with Caelyx, according to other tissue analyses.
    Conclusion: The post-insertion technique was found a successful approach with more pharmaceutical aspects for large-scale production. Moreover, further investigations are highly recommended to determine the efficacy of 5% post-inserted GSH targeted nanoliposomes versus 2B3-101 as a similar formulation with a different preparation method.
    Keywords:  Biodistribution; Blood-brain barrier; Brain drug delivery; Glutathione; Liposome; Post-insertion
    DOI:  https://doi.org/10.22038/IJBMS.2022.60306.13369
  65. Environ Sci Pollut Res Int. 2022 May 31.
    Protective effects of curcumin against thyroid hormone imbalance after gas explosion-induced traumatic brain injury via activation of the hypothalamic-pituitary-thyroid axis in male rats.
    Xinwen Dong, Lvfei Deng, Sanqiao Yao, Weidong Wu, Jia Cao, Lei Sun, Yichun Bai, Haibin Li, Xiaogang Weng, Houcheng Ren, Wenjie Ren.
      Gas explosion (GE)-induced traumatic brain injury (TBI) can affect thyroid hormone (TH) homeostasis in miners. This study evaluated the effects of hepatic transthyretin and hypothalamic-pituitary-thyroid (HPT) axis on thyroids and explored the protective effect and mechanism of curcumin on GE-induced TBI. Thirty rats were randomly divided into three groups (10 per group): first group (control group)-rats received GE treatment once; second group (GE group)-rats received GE treatment (200 m from the source of the explosion once); third group (GE + Cur group)-rats received curcumin (Cur) by lavage at a dose of 100 mg/kg/day once every other day for 7 days after receiving GE. After GE, the pathological changes were analyzed by hemotoxylin and eosin staining, and the levels of serum reactive oxygen species (ROS), urine iodine (UI), THs, nuclear factor-kappa B (NF-κB), superoxide dismutase (SOD), glutathione peroxidase (Gpx), and malondialdehyde (MDA) were analyzed using ELISA. Expression of proteins in the HPT axis of rats was examined by immunohistochemistry and Western blotting. We found that GE could induce pathologic changes in rat thyroid and liver. Serum levels of THs, NF-κB and serum redox state became unbalanced in rats after GE. GE could inhibit the biosynthesis and biotransformation of THs by affecting key HPT axis proteins. Additionally, GE reduced the level of hepatic transthyretin. Serum THs levels and thyroid sections were almost recovered to normal after curcumin treatment. The aforementioned key HPT axis proteins in the curcumin group showed opposite expression trends. In summary, GE affected THs balance while curcumin can protect against these injury effects by affecting TH biosynthesis, biotransformation, and transport, and inducing oxidative stress and inflammatory responses.
    Keywords:  Curcumin; Gas explosion; HPT axis; Hepatic transthyretin; Thyroid hormone imbalance; Traumatic brain injury
    DOI:  https://doi.org/10.1007/s11356-022-20943-2
  66. Curr Top Med Chem. 2022 May 27.
    Caralluma edulis (Apocynaceae): A comprehensive review on its Traditional uses, Phytochemical profile and pharmacological effects.
    Bushra Ansari, Tapan Behl, Abdul Saboor Pirzada, Haroon Khan.
      Caralluma edulis is a well-known species of the genus Caralluma from Apocynaceae, commonly known as chunga. Caralluma species are mostly succulent perennial herbs, several of which are edible species. The plant has an outstanding therapeutic background in the traditional system of treatment. It has been recommended for the treatment of a number medical disorder such as hypertension, Alzheimer disease, rheumatism, gastric problems and leprosy. Traditionally the stem was boiled in water and this extract was then used to cure diabetes. The pharmacological effects of C.edulis have also been explored in various in vitro and in vivo experiments. In this regard, the extract of the plant exhibited strong antioxidant activity, analgesic, against inflammation as well as xylene mediated ear edema for topical effects. The significant anti-hyperlipidemic effect of the plant extract is also reported. However, the extract was found insignificant in the reversal of alloxan-induced diabetes in rabbit model at test doses. These pharmacological effects are strongly supported by the presence of different bioactive phytochemicals in the plant. These groups of compounds include sterols, terpenoids, flavonoids, and pregnane glycosides. C.edulis is a very potential member of the genus Caralluma with strong traditional history, phytochemistry and phytopharmacology, needed further exploration for clinically used lead compounds. In this review, we have focused to combined different reported data on the traditional uses of the plant, phytochemical profile and pharmacological effects in different experimental assay and subsequent future prospects.
    Keywords:  Caralluma edulis; Choung; chunga; edulis plant; plant description
    DOI:  https://doi.org/10.2174/1568026622666220527092825
  67. J Clin Invest. 2022 Jun 01. pii: e159839. [Epub ahead of print]132(11):
    Hypoxia-inducible factors: cancer progression and clinical translation.
    Elizabeth E Wicks, Gregg L Semenza.
      Hypoxia-inducible factors (HIFs) are master regulators of oxygen homeostasis that match O2 supply and demand for each of the 50 trillion cells in the adult human body. Cancer cells co-opt this homeostatic system to drive cancer progression. HIFs activate the transcription of thousands of genes that mediate angiogenesis, cancer stem cell specification, cell motility, epithelial-mesenchymal transition, extracellular matrix remodeling, glucose and lipid metabolism, immune evasion, invasion, and metastasis. In this Review, the mechanisms and consequences of HIF activation in cancer cells are presented. The current status and future prospects of small-molecule HIF inhibitors for use as cancer therapeutics are discussed.
    DOI:  https://doi.org/10.1172/JCI159839
  68. Biomed Pharmacother. 2022 May 26. pii: S0753-3322(22)00547-9. [Epub ahead of print]151 113158
    Inflammatory auto-immune diseases of the intestine and their management by natural bioactive compounds.
    Naoual El Menyiy, Aicha El Allam, Sara Aboulaghras, Imane Jaouadi, Saad Bakrim, Nasreddine El Omari, Mohammad Ali Shariati, Alevtin Miftakhutdinov, Polrat Wilairatana, Mohammad S Mubarak, Abdelhakim Bouyahya.
      Autoimmune diseases are caused by the overactivity of the immune system towards self-constituents. Risk factors of autoimmune diseases are multiple and include genetic, epigenetic, environmental, and psychological. Autoimmune chronic inflammatory bowel diseases, including celiac and inflammatory diseases (Crohn's disease and ulcerative colitis), constitute a significant health problem worldwide. Besides the complexity of the symptoms of these diseases, their treatments have only been palliative. Numerous investigations showed that natural phytochemicals could be promising strategies to fight against these autoimmune diseases. In this respect, plant-derived natural compounds such as flavonoids, phenolic acids, and terpenoids exhibited significant effects against three autoimmune diseases affecting the intestine, particularly bowel diseases. This review focuses on the role of natural compounds obtained from medicinal plants in modulating inflammatory auto-immune diseases of the intestine. It covers the most recent literature related to the effect of these natural compounds in the treatment and prevention of auto-immune diseases of the intestine.
    Keywords:  Autoimmune diseases; Bioactive compounds; Bowel diseases; Celiac diseases; Pharmacodynamic action
    DOI:  https://doi.org/10.1016/j.biopha.2022.113158
  69. Sichuan Da Xue Xue Bao Yi Xue Ban. 2022 May;53(3): 532-537
    [Probiotics' Ameliorating Effect on Side Effects of Cancer Treatment: Reflections and Prospects].
    Wen-Jie Chen, Jing Wei, Ting-Tao Chen.
      Surgical resection, radiotherapy, chemotherapy, and immunotherapy are the main therapies for cancers. These cancer therapies all prolong patient survival, but also bring multiple side effects. Gut microbiota participates in almost all the physiological and biochemical processes of the host, playing a key role in human health and diseases. As an exogenous intervention, probiotics can prevent diseases and enhance immunity. Their anti-cancer ability and ameliorative effect have received increasing recognition. Herein, we reported the latest findings on gut microbiota and cancer pathogenesis, focusing on the application of probiotics in reducing the side effects caused by cancer therapies and hoping to provide supportive references for the clinical use of probiotics in cancer treatment.
    Keywords:  Cancer treatment; Gut microbiota; Probiotics; Side effects
    DOI:  https://doi.org/10.12182/20220560508
  70. Front Pharmacol. 2022 ;13 905078
    Multifunctional Nanosystems Powered Photodynamic Immunotherapy.
    Yunong Ma, Fengfeng Xiao, Cuixia Lu, Liewei Wen.
      Photodynamic Therapy (PDT) with the intrinsic advantages including non-invasiveness, spatiotemporal selectivity, low side-effects, and immune activation ability has been clinically approved for the treatment of head and neck cancer, esophageal cancer, pancreatic cancer, prostate cancer, and esophageal squamous cell carcinoma. Nevertheless, the PDT is only a strategy for local control of primary tumor, that it is hard to remove the residual tumor cells and inhibit the tumor metastasis. Recently, various smart nanomedicine-based strategies are developed to overcome the barriers of traditional PDT including the drawbacks of traditional photosensitizers, limited tissue penetrability of light, inefficient induction of tumor cell death and tumor resistance to the therapy. More notably, a growing number of studies have focused on improving the therapeutic efficiency by eliciting host immune system with versatile nanoplatforms, which heralds a broader clinical application prospect of PDT in the future. Herein, the pathways of PDT induced-tumor destruction, especially the host immune response is summarized, and focusing on the recent progress of nanosystems-enhanced PDT through eliciting innate immunity and adaptive immunity. We expect it will provide some insights for conquering the drawbacks current PDT and expand the range of clinical application through this review.
    Keywords:  adaptive immunity; innate immunity; nanosystems; photodynamic therapy; photosensitizers
    DOI:  https://doi.org/10.3389/fphar.2022.905078
  71. Biomed Res Int. 2022 ;2022 6317201
    A Narrative Review of the Antitumor Activity of Monoterpenes from Essential Oils: An Update.
    Thaíssa Q Machado, Anna C C da Fonseca, Allana B S Duarte, Bruno K Robbs, Damião P de Sousa.
      Monoterpenes are a group of natural products that have been widely studied due to their therapeutic potential against various pathologies. These compounds are abundant in the chemical composition of essential oils. Cancer is a term that covers more than 100 different types of malignant diseases and is among the leading causes of death in the world. Therefore, the search for new pharmacotherapeutic options applicable to cancer is urgent. In this review, studies on the antitumor activity of monoterpenes found in essential oils were selected, and botanical, chemical, and pharmacological aspects were discussed. The most investigated monoterpenes were carvacrol and linalool with highly significant in vitro and in vivo tumor inhibition in several types of cancers. The action mechanisms of these natural products are also presented and are wildly varied being apoptosis the most prevalent followed by cell cycle impairment, ROS production, autophagy, necroptosis, and others. The studies reported here confirm the antitumor properties of monoterpenes and their anticancer potential against various types of tumors, as demonstrated in in vitro and in vivo studies using various types of cancer cells and tumors in animal models. The data described serve as a reference for the advancement in the mechanistic studies of these compounds and in the preparation of synthetic derivatives or analogues with a better antitumor profile.
    DOI:  https://doi.org/10.1155/2022/6317201
  72. Biomater Sci. 2022 Jun 01.
    A nanomedicine enables synergistic chemo/photodynamic therapy for pancreatic cancer treatment.
    Liwei Zhu, Shanmeng Lin, Wenqiang Cui, Youwei Xu, Liang Wang, Zhaohan Wang, Shuguang Yuan, Yichuan Zhang, Yingfang Fan, Jin Geng.
      Pancreatic cancer is one of the leading causes of cancer-related deaths worldwide. Gemcitabine (Gem) has been a key chemotherapy agent for pancreatic cancer treatment by suppressing cell proliferation and inducing apoptosis. However, the overexpression of inhibitors of apoptosis (IAP) family of proteins during the carcinogenesis of pancreatic cancer can develop resistance to chemotherapy treatment and result in poor efficacy. To achieve the synergistic combinations of multiple strategies for this dismal disease, we developed a robust nanomedicine system, consisting of a photodynamic therapeutic agent (chlorine e6, Ce6) and a pro-apoptotic peptide-Gem conjugate. To have spatiotemporally controlled drug release, the pro-apoptotic peptide-Gem conjugate was designed to have a vinyldithioether linker that was sensitive to reactive oxygen species (ROS). The nanomedicine was fabricated by the direct self-assembly of the pro-apoptotic peptide-Gem conjugate with Ce6. After being delivered into tumors, the nanomedicine disassembled and rapidly released Gem, Ce6, and the pro-apoptotic peptide upon light illumination (660 nm). Both in vitro and in vivo studies in pancreatic cancer models confirmed the tumor inhibition efficacy with low systemic toxicity to animals.
    DOI:  https://doi.org/10.1039/d2bm00437b
  73. Eur J Pharm Biopharm. 2022 May 25. pii: S0939-6411(22)00111-4. [Epub ahead of print]
    Long chain triglyceride-lipid formulation promotes the oral absorption of the lipidic prodrugs through coincident intestinal behaviors.
    Chu-Tong Tian, Jing-Jing Guo, Yi-Fan Miao, He-Lin Wang, Qing Ye, Chun-Lin Guo, Ming-Yang Zhang, Zhong-Gui He, Jin Sun.
      Oral administration of chemotherapy agents, such as docetaxel (DTX), is expected to reduce side effects significantly and increase dosing frequency. However, they often suffer from poor oral bioavailability, impeding their oral application. Dietary lipids such as triglycerides favor lymphatic transport nor vein system, bypassing the first-pass metabolism. Inspired by this concept, we developed a triglyceride-like prodrug of DTX (named as OATG) and explored the effect of lipid types on the OATG oral delivery. The plasma profile in rats revealed that long chain triglyceride (LCT)-based lipid formulations (LBLF) were more promising for OATG delivery than medium chain triglyceride (MCT) ones. The OATG LBLF elicited a markedly enhanced absorption compared with oral Taxotere or DTX LBLF, resulting in relative bioavailability 6.11 or 2.47-fold higher, respectively. The coincident intestinal behaviors of lipid excipients and TG-like prodrug facilitate the oral absorption of the prodrug. The effectiveness of the prodrug formulation was also examined in beagles with absolute bioavailability up to 41.08%, in sharp contrast to that of control DTX group (8%). Besides, the OATG oral formulation could be schedule-intensively administrated with no hypersensitivity, gastrointestinal and hematological toxicity. The current strategy provides an effective lipid formulation and a promising chance for chemotherapy at home.
    Keywords:  Docetaxel; Oral chemotherapy; Reduction-sensitive; Self-micro emulsifying drug delivery system; Triglyceride-like prodrug
    DOI:  https://doi.org/10.1016/j.ejpb.2022.05.015
  74. Curr Pharm Des. 2022 Jun 01.
    Utility of Indian fruits in cancer prevention and treatment: Time to undertake translational and bedside studies.
    Pankaj Prabhakar, Giriyapura Srikantachar Pavankumar, Shamprasad Varija Raghu, Suresh Rao, Krishna Prasad, Thomas George, Manjeshwar Shrinath Baliga.
      The World Health Organization predicts a 70% increase in cancer incidents in developing nations over the next decade, and it will be the second leading cause of death worldwide. Traditional plant-based medicine systems play an important role against various diseases and provide health care to a large section of the population in developing countries. Indigenous fruits and their bioactive compounds with beneficial effects like antioxidant, antiproliferative, and immunomodulatory are shown to be useful in preventing the incidence of cancer. India is one of the biodiversity regions and is native to numerous flora and fauna in the world. Of the many fruiting trees indigenous to India, Mango (Mangifera indica), Black plum (Eugenia jambolana or Syzygium jambolana), Indian gooseberry (Emblica officinalis or Phyllanthus emblica), kokum (Garcinia indica or Brindonia indica), stone apple or bael (Aegle marmelos), Jackfruit (Artocarpus heterophyllus), Karaunda (Carissa carandas) and Phalsa (Grewia asiatica), Monkey Jackfruit (Artocarpus lakoocha) and Elephant apple (Dillenia indica) have been shown to be beneficial in preventing cancer and in the treatment of cancer in validated preclinical models of study. In this review, efforts are also made to collate the fruits' anticancer effects and the important phytochemicals. Efforts are also made at emphasizing the underlying mechanism/s responsible for the beneficial effects in cancer prevention and treatment. These fruits have been a part of the diet, are non-toxic, and easily acceptable for human application. The plants and some of their phytochemicals possess diverse medicinal properties. The authors propose that future studies should be directed at detailed studies with various preclinical models of study with both composite fruit extract/juice and the individual phytochemicals. Additionally, translational studies should be planned with the highly beneficial, well-investigated and pharmacologically multifactorial amla to understand its usefulness as a cancer preventive in the high-risk population and as a supportive agent in cancer survivors. The outcome of both preclinical and clinical studies will be useful for patients, the healthcare fraternity, pharmaceutical, and agro-based sectors.
    Keywords:  Aegle marmelos; Artocarpus lakoocha; Chemoprevention; Dillenia indica; Emblica officinalis; Eugenia jambolana; Garcinia indica; Grewia asiatica; Mangifera indica; Phyllanthus emblica
    DOI:  https://doi.org/10.2174/1381612828666220601151931
  75. Recent Pat Food Nutr Agric. 2022 May 27.
    Antimicrobial, Pesticidal and Food preservative Applications of Lemongrass Oil Nanoemulsion: a Mini-Review.
    Deepika B, Agnishwar Girigoswami, Koyeli Girigoswami.
       BACKGROUND: Essential oils that are extracted from plants have shown beneficial effects on humans and animals, evidenced by traditional medicine. They possess many essential phytocomponents that act as antimicrobial agents, and most of them are safe for external usage.
    INTRODUCTION: Lemongrass essential oil is extracted from the grass, such as Cymbopogon flexuosus, and is used for the antimicrobial activity for a long time. The efficacy of this oil is limited due to the poor solubility and microbial penetration, easy vaporization, and lower stability. Nanoformulations and nanoencapsulations are a field of nanotechnology that aims to improve the bioavailability of many natural compounds and enhances the stability of compounds. Lemongrass oil has also been nanoformulated as nanoemulsion, and various antimicrobial activities against various pathogens have been demonstrated, which are superior to free lemongrass oil.
    METHODOLOGY: We have used the search engines PubMed and Google Scholar for the mentioned keywords and selected the recent references related to this topic.
    CONCLUSION: In this review we have discussed various antimicrobial properties of lemongrass essential oil nanoemulsion and its application, such as antibacterial, antifungal, pesticidal, food preservative, and antibiofilm activity.
    Keywords:  antimicrobial; food preservative; lemongrass; nanoemulsion; pesticidal activit
    DOI:  https://doi.org/10.2174/2212798412666220527154707
  76. Front Cell Dev Biol. 2022 ;10 808859
    Tumor-Derived Lactate Creates a Favorable Niche for Tumor via Supplying Energy Source for Tumor and Modulating the Tumor Microenvironment.
    Mengyao Jin, Wei Cao, Bo Chen, Maoming Xiong, Guodong Cao.
      Tumor evolution is influenced by events involving tumor cells and the environment in which they live, known as the tumor microenvironment (TME). TME is a functional and structural niche composed of tumor cells, endothelial cells (ECs), cancer-associated fibroblasts (CAFs), mesenchymal stromal cells (MSCs), and a subset of immune cells (macrophages, dendritic cells, natural killer cells, T cells, B cells). Otto Warburg revealed the Warburg effect in 1923, a characteristic metabolic mechanism of tumor cells that performs high glucose uptake and excessive lactate formation even in abundant oxygen. Tumor tissues excrete a large amount of lactate into the extracellular microenvironment in response to TME's hypoxic or semi-hypoxic state. High lactate concentrations in tumor biopsies have been linked to metastasis and poor clinical outcome. This indicates that the metabolite may play a role in carcinogenesis and lead to immune escape in TME. Lactate is now recognized as an essential carbon source for cellular metabolism and as a signaling molecule in TME, forming an active niche that influences tumor progression. This review summarized the advanced literature demonstrating the functional role of lactate in TME remodeling, elucidating how lactate shapes the behavior and the phenotype of both tumor cells and tumor-associated cells. We also concluded the intriguing interactions of multiple immune cells in TME. Additionally, we demonstrated how lactate functioned as a novel function factor by being used in a new histone modification, histone lysine lactylation, and to regulate gene expression in TME. Ultimately, because lactate created a favorable niche for tumor progression, we summarized potential anti-tumor strategies targeting lactate metabolism and signaling to investigate better cancer treatment.
    Keywords:  energy source; immune response; lactate; lactylation; tumor micoenvironment
    DOI:  https://doi.org/10.3389/fcell.2022.808859
  77. Curr Nutr Rep. 2022 Jun 03.
    A Review: Cereals on Modulating the Microbiota/Metabolome for Metabolic Health.
    Jayani Kulathunga, Senay Simsek.
       PURPOSE OF REVIEW: Diet can modulate both the composition and functionality of the human gut microbiota. Cereals are rich in specific macro and functional elements that are considered important dietary components for maintaining human health; therefore, it is important to examine precise nutritional mechanism involved in exerting the health benefits via modulating gut microbiota. The purpose of this review is to summarize recent research on how different cereals in the diet can regulate the microbiota for health and disease.
    RECENT FINDINGS: There is an increased interest in targeting the gut microbiome for the treatment of chronic diseases. Cereals can alter the gut microbiome and may improve energy and glucose homeostasis, interfere with host energy homeostasis, appetite, blood glucose regulation, insulin sensitivity, and regulation of host metabolism. However, more human research is necessary to confirm the beneficial health outcomes of cereals via modulating gut microbiota. Cereals play an essential role in shaping the intestinal microbiota that contributes to exerting health effects on various diseases.
    Keywords:  Cereals; Colon health; Diabetes; Hyperlipidemia; Hypertension; Inflammation; Metabolites; Obesity; Short-chain fatty acids
    DOI:  https://doi.org/10.1007/s13668-022-00424-1
  78. World J Clin Cases. 2022 Apr 06. 10(10): 2990-3004
    Targeting metabolism: A potential strategy for hematological cancer therapy.
    Xue Tang, Fen Chen, Li-Chun Xie, Si-Xi Liu, Hui-Rong Mai.
      Most hematological cancer-related relapses and deaths are caused by metastasis; thus, the importance of this process as a target of therapy should be considered. Hematological cancer is a type of cancer in which metabolism plays an essential role in progression. Therefore, we are required to block fundamental metastatic processes and develop specific preclinical and clinical strategies against those biomarkers involved in the metabolic regulation of hematological cancer cells, which do not rely on primary tumor responses. To understand progress in this field, we provide a summary of recent developments in the understanding of metabolism in hematological cancer and a general understanding of biomarkers currently used and under investigation for clinical and preclinical applications involving drug development. The signaling pathways involved in cancer cell metabolism are highlighted and shed light on how we could identify novel biomarkers involved in cancer development and treatment. This review provides new insights into biomolecular carriers that could be targeted as anticancer biomarkers.
    Keywords:  Anticancer; Biomarker; Cancer; Hematological cancer; Metabolism; Metastasis
    DOI:  https://doi.org/10.12998/wjcc.v10.i10.2990
  79. J Ethnopharmacol. 2022 May 26. pii: S0378-8741(22)00443-3. [Epub ahead of print]295 115404
    A review on ethnobotany, phytochemistry, and pharmacology of the genus Didymocarpus wall. (Gesneriaceae).
    Consolata Nanjala, Wyclif Ochieng Odago, Peninah Cheptoo Rono, Emmanuel Nyongesa Waswa, Elizabeth Syowai Mutinda, Millicent Akinyi Oulo, Felix Wambua Muema, Vincent Okelo Wanga, Elijah Mbandi Mkala, Josiah Kuja, Moses Mucugi Njire, Guang-Wan Hu.
       ETHNOPHARMACOLOGICAL RELEVANCE: Medicinal plants have been extensively used to treat various illnesses since the dawn of civilization. The genus Didymorcapus Wall. comprises 100 species widely distributed in the tropical regions of Asia, with a few found scattered in Africa and Australia. Species in this genus have long been used in folk medicine to treat various illnesses, including wounds, kidney stones, inflammations, asthma, flu, eczema, dysentery, fractures, colic etc. Some species have applications as weight loss agents, laxatives, and protective medication after childbirth.
    AIM: To provide comprehensive information on the current knowledge of the ethnobotanical uses, phytochemical compounds, pharmacological applications, and toxicology of genus Didymocarpus to reveal its therapeutic potential, offering insights into future research opportunities.
    MATERIALS AND METHODS: Data were systematically obtained from books and online databases such as PubMed, Web of Science, Scopus, Sci Finder, Google Scholar, Science direct, ACS Publications, Elsevier, Wiley Online Library.
    RESULTS: Seventeen Didymocarpus species have applications in traditional medicine in different Asian countries. A total of 166 compounds have been isolated from the genus Didymocarpus including terpenoids, flavonoids, phenolic compounds, fatty acids, chalcones, steroids, and others. Among these constituents, terpenoids, flavonoids, chalcones, and phenolics are the significant contributors to pharmacological activities of the genus Didymocarpus, possessing wide-reaching biological activities both in vivo and in vitro. The crude extracts and isolated phytochemical compounds from this genus have been shown to exhibit various pharmacological activities, including antiurolithiatic, nephro-protective, antimicrobial, anticancer, antidiabetic, cytotoxic, wound healing, and antioxidant activities.
    CONCLUSIONS: Traditional uses and scientific evaluation of Didymocarpus indicate that Didymocarpus pedicellata is one of the most widely used species in some parts of the world. Although substantial progress on the chemical and pharmacological properties of Didymocarpus species has been made, further studies on the pharmacology and toxicology of these species are needed to ensure safety, efficacy, and quality. Also, further research on the structure-activity relationship of some of the isolated phytocompounds may improve their biological potency and scientific exploitation of traditional uses of the Didymocarpus taxa.
    Keywords:  Didymocarpus; Ethnobotany; Pharmacology; Phytochemistry; Toxicology
    DOI:  https://doi.org/10.1016/j.jep.2022.115404
  80. Endocrinol Metab (Seoul). 2022 Jun 03.
    Interplay of Vitamin D and CYP3A4 Polymorphisms in Endocrine Disorders and Cancer.
    Siva Swapna Kasarla, Vannuruswamy Garikapati, Yashwant Kumar, Sujatha Dodoala.
      Vitamin D has received considerable optimistic attention as a potentially important factor in many pathological states over the past few decades. However, the proportion of the active form of vitamin D metabolites responsible for biological activity is highly questionable in disease states due to flexible alterations in the enzymes responsible for their metabolism. For instance, CYP3A4 plays a crucial role in the biotransformation of vitamin D and other drug substances. Food-drug and/or drug-drug interactions, the disease state, genetic polymorphism, age, sex, diet, and environmental factors all influence CYP3A4 activity. Genetic polymorphisms in CYP450-encoding genes have received considerable attention in the past few decades due to their extensive impact on the pharmacokinetic and dynamic properties of drugs and endogenous substances. In this review, we focused on CYP3A4 polymorphisms and their interplay with vitamin D metabolism and summarized the role of vitamin D in calcium homeostasis, bone diseases, diabetes, cancer, other diseases, and drug substances. We also reviewed clinical observations pertaining to CYP3A4 polymorphisms among the aforementioned disease conditions. In addition, we highlighted the future perspectives of studying the pharmacogenetics of CYP3A4, which may have potential clinical significance for developing novel diagnostic genetic markers that will ascertain disease risk and progression.
    Keywords:  Bone diseases; COVID-19; Cytochrome P-450 CYP3A; Diabetes mellitus; Immune system; Neoplasms; Vitamin D
    DOI:  https://doi.org/10.3803/EnM.2021.1349
  81. J Vis Exp. 2022 May 10.
    5-Aminolevulinic Acid-mediated Photodynamic Therapy on Primary Bone Tumor and Bone Metastases Cell Lines.
    Saskia Magdalen Sachsenmaier, Christian Walter, Chen Liang, Rosa Riester, Nikolaus Wülker, Marina Danalache.
      Bone metastases are associated with poor prognosis and low quality of life for the affected patients. Photodynamic therapy (PDT) emerges as a noninvasive therapy that can target local metastatic bone lesions. This paper presents an in vitro method to study the PDT effect in adherent cell lines. To this end, we demonstrate a step-by-step approach to subject both primary (giant cell bone tumor) and human bone metastatic cancer cell lines (derived from a primary invasive ductal breast carcinoma and renal carcinoma) to 5-aminolevulinic acid (5-ALA)-mediated PDT. After 24 h post 5-ALA-PDT irradiation (blue light-wavelength 436 nm), the therapeutic effect was assessed in terms of cell migration potential, viability, apoptotic features, and cellular growth arrest (senescence). Post 5-ALA-PDT irradiation, musculoskeletal-derived cell lines respond differently to the same doses and exposure of PDT. Depending on the extent of cellular damage triggered by PDT exposure, two different cell fates-apoptosis and senescence were noted. Variable sensitivity to PDT therapy among different bone cancer cell lines provides useful information for selecting more appropriate PDT settings in clinical settings. This protocol is designed to exemplify the use of PDT in the context of musculoskeletal neoplastic cell lines. It may be adjusted to investigate the therapeutic effect of PDT on various cancer cell lines and various photosensitizers and light sources.
    DOI:  https://doi.org/10.3791/63644
  82. Front Cell Dev Biol. 2022 ;10 875318
    Novel Insights on Lipid Metabolism Alterations in Drug Resistance in Cancer.
    Ruixue Yang, Mei Yi, Bo Xiang.
      Chemotherapy is one of the primary treatments for most human cancers. Despite great progress in cancer therapeutics, chemotherapy continues to be important for improving the survival of cancer patients, especially for those who has unresectable metastatic tumors or fail to respond to immunotherapy. However, intrinsic or acquired chemoresistance results in tumor recurrence, which remains a major obstacle in anti-cancer treatment. The high prevalence of chemoresistant cancer makes it urgent to deepen our understanding on chemoresistance mechanisms and to develop novel therapeutic strategies. Multiple mechanisms, including drug efflux, enhanced DNA damage reparability, increased detoxifying enzymes levels, presence of cancer stem cells (CSCs), epithelial mesenchymal transition (EMT), autophagy, ferroptosis and resistance to apoptosis, underlie the development of chemoresistance. Recently, accumulating evidence suggests that lipid metabolism alteration is closely related to drug resistance in tumor. Targeting lipid metabolism in combination with traditional chemotherapeutic drugs is a promising strategy to overcome drug resistance. Therefore, this review compiles the current knowledge about aberrant lipid metabolism in chemoresistant cancer, mainly focusing on aberrant fatty acid metabolism, and presents novel therapeutic strategies targeting altered lipid metabolism to overcome chemoresistance in cancer.
    Keywords:  Cancer chemoresistance; drug resistance; fatty acid metabolism; lipid metabolism; multi-drug resistance
    DOI:  https://doi.org/10.3389/fcell.2022.875318
  83. Surv Ophthalmol. 2022 May 26. pii: S0039-6257(22)00080-7. [Epub ahead of print]
    Laser Treatment for Choroidal Melanoma: Current Concepts.
    Abhilasha Maheshwari, Paul T Finger.
      Laser treatment has offered a relatively nonsurgical alternative for eye, life, and vision-sparing treatment of malignant melanoma of the choroid. Historically, the most commonly used forms of lasers were xenon-arc, argon laser, krypton laser, and the more recent transpupillary thermotherapy (TTT) and photodynamic therapy (PDT). Melanomas selected for laser treatment tend to be smaller and visibly accessible, which means these tumors are usually located in the posterior choroid. Laser treatments have been associated with both local tumor destruction and side effects. Unlike radiation therapy, laser treatment has been commonly associated with retinal traction, hemorrhage, chorioretinal neovascularization, and extra scleral tumor extension, as well as higher rates of local treatment failure. In addition, however, laser-treatment has been successfully used to treat tumor-related retinal detachments, radiation retinopathy, and neovascular glaucoma. We review the world's experience of ophthalmic laser treatment for choroidal melanoma, offer safety and efficacy guidelines, as well as a comparison of laser treatment to radiation therapy outcomes.
    Keywords:  Choroidal melanoma; Complications; Eye; Laser; Photocoagulation; Photodynamic therapy; Primary treatment; Transpupillary thermotherapy; Tumor
    DOI:  https://doi.org/10.1016/j.survophthal.2022.05.002
  84. Genet Test Mol Biomarkers. 2022 May;26(5): 290-297
    The Effect of the Kirsten Rat Sarcoma Viral Oncogene Homolog (Kras) Proto-Oncogene, GTPase Genetic Polymorphism on the Safety and Efficacy of Bevacizumab Combination Treatment Regimens for Patients with Nonsquamous, Non-Small Cell Lung Cancer with Brain Metastases.
    Zizheng Song, Guanying Ren, Xiaolei Wang, Ling Hu.
      Background: Non-small cell lung cancer with brain metastasis (NSCLCBM) is normally observed in advanced-stage patients. Bevacizumab has shown to improve survival in the first-line treatment of metastatic brain NSCLC when added as a bolus plus irinotecan. However, a better understanding of the molecular mechanism is required to further drive progress in this field. Methods: A total of 155 patients were selected, including 42.10% with Kirsten rat sarcoma viral oncogene homolog (Kras)-mutant tumors. Of the 155 patients, 62.04% had developed brain metastasis (BM). Seven functional single-nucleotide polymorphisms (SNPs) in the Kras gene were extracted from the HapMap SNP database and were used for genotyping. The haplologit command in Statistical Software for Data Science (STATA) was used to model the association between haplotypes and case status. A Cox analysis was used to evaluate the prognostic value of the SNPs. Results: Among the patients treated with combination regimens, recurrence after local treatment was more frequent in those with two types of Kras mutations (odds ratio [OR] = 2.033 [0.5015-4.2552], p = 0.009). Among the patients with untreated BM, overall survival was shorter than that of patients with Kras mutations according to univariate analysis (OR = 5.130 [1.240-41.012], p = 0.033). Conclusions: Kras mutations have a predictive role for BM recurrence and outcome in patients with NSCLC treated with bevacizumab combination regimens.
    Keywords:  KRAS; NSCLC; SNP; bevacizumab; brain metastases
    DOI:  https://doi.org/10.1089/gtmb.2021.0219
  85. ACS Appl Bio Mater. 2022 Jun 01.
    Regulation of Ca2+ for Cancer Cell Apoptosis through Photothermal Conjugated Nanoparticles.
    Mei Zhou, Boying Li, Ning Li, Mengying Li, Chengfen Xing.
      Ca2+ overload is caused by the abnormal accumulation of Ca2+, which is a potential therapeutic strategy for inhibiting tumor growth. However, due to the limited intracellular Ca2+ concentration, its anticancer effect is non-significant. Herein, near-infrared (NIR)-responsive nanoparticles NPs-PCa (DPPC-DSPE-PEG2000-NH2@PDPP@CaO2@DOX) were designed and prepared to achieve photothermal trigger of Ca2+ release, thereby increasing intracellular Ca2+ content. Furthermore, the nanoparticles convert light to heat to activate the transient receptor potential cation channel subfamily V member 1 (TRPV1) ion channels, allowing external Ca2+ to flow into the cells, further increasing the Ca2+ concentration. NPs-PCa nanoparticles overcome the limitation of insufficient concentration by increasing Ca2+ in both internal and external approaches. Meanwhile, an imbalance of intracellular Ca2+ induces mitochondrial dysfunction and ultimately results in cancer cell death. This study provides an effective strategy for inhibiting breast cancer tumor growth by regulating Ca2+ concentration.
    Keywords:  Ca2+; TRPV1 ion channel; antitumor; near-infrared light; photothermal conjugated polymer nanoparticles; regulation
    DOI:  https://doi.org/10.1021/acsabm.2c00236
  86. Epidemiol Health. 2022 May 30. e2022050
    Relationship between metabolic syndrome and its components with bladder cancer: a systematic review and meta-analysis in cohort studies.
    Mozhgan Ahmadinezhad, Maedeh Arshadi, Elahe Hesari, Maedeh Sharafoddin, Hosein Azizi, Farzad Khodamoradi.
       Objectives: Previous meta-analysis study entitled "the association between metabolic syndrome and bladder cancer susceptibility and prognosis: an updated comprehensive evidence synthesis of 95 observational studies involving 97,795,299 subjects", focused on all observational studies, but in this meta-analysis study, we focused on cohort studies to obtain more accurate and stronger evidence to evaluate the association between metabolic syndrome and its component with bladder cancer in cohort studies.
    Methods: PubMed, EMBASE, Scopus, and Web of Science were searched to identify studies on the association between metabolic syndrome and its component with bladder cancer from January 1, 2000, through May 23, 2021. The pooled relative risk (RR) and the 95% confidence intervals (CI) were used to measure this relationship by assuming a random effects meta-analytic model. Quality appraisal was undertaken using the Newcastle - Ottawa Critical Appraisal Tool.
    Results: A total of 56 studies were included. Our study revealed that there was a statistically significant relationship between metabolic syndrome and bladder cancer 1.09 [95% CI: 1.02, 1.17] and there was evidence of moderate heterogeneity among these studies. Also, our findings indicated a statistically significant relationship between diabetes1.23 [95% CI: 1.16, 1.31] and hypertension1.07 [95% CI: 1.01, 1.13] with bladder cancer, but no association was found between obesity and overweight and bladder cancer. We found no evidence of publication bias.
    Conclusion: Our analysis demonstrated a statistically significant relationship between metabolic syndrome and the risk of bladder cancer. Diabetes and hypertension had a relationship with the risk of bladder cancer.
    Keywords:  bladder cancer; cohort; meta-analysis; metabolic syndrome; metabolic syndrome components
    DOI:  https://doi.org/10.4178/epih.e2022050
  87. Cell Rep. 2022 May 31. pii: S2211-1247(22)00645-3. [Epub ahead of print]39(9): 110870
    Fatty acid oxidation protects cancer cells from apoptosis by increasing mitochondrial membrane lipids.
    Yi-Jia Li, Johannes Francois Fahrmann, Maryam Aftabizadeh, Qianqian Zhao, Satyendra C Tripathi, Chunyan Zhang, Yuan Yuan, David Ann, Samir Hanash, Hua Yu.
      Overcoming resistance to chemotherapies remains a major unmet need for cancers, such as triple-negative breast cancer (TNBC). Therefore, mechanistic studies to provide insight for drug development are urgently needed to overcome TNBC therapy resistance. Recently, an important role of fatty acid β-oxidation (FAO) in chemoresistance has been shown. But how FAO might mitigate tumor cell apoptosis by chemotherapy is unclear. Here, we show that elevated FAO activates STAT3 by acetylation via elevated acetyl-coenzyme A (CoA). Acetylated STAT3 upregulates expression of long-chain acyl-CoA synthetase 4 (ACSL4), resulting in increased phospholipid synthesis. Elevating phospholipids in mitochondrial membranes leads to heightened mitochondrial integrity, which in turn overcomes chemotherapy-induced tumor cell apoptosis. Conversely, in both cultured tumor cells and xenograft tumors, enhanced cancer cell apoptosis by inhibiting ASCL4 or specifically targeting acetylated-STAT3 is associated with a reduction in phospholipids within mitochondrial membranes. This study demonstrates a critical mechanism underlying tumor cell chemoresistance.
    Keywords:  ACSL; CP: Cancer; CP: Metabolism; STAT3 acetylation; anti-apoptosis; chemoresistance; fatty acid oxidation; mitochondrial membrane potential; phospholipids
    DOI:  https://doi.org/10.1016/j.celrep.2022.110870
  88. Am J Physiol Endocrinol Metab. 2022 May 30.
    The Mitochondrial Pyruvate Carrier at the Crossroads of Intermediary Metabolism.
    Nicole K H Yiew, Brian N Finck.
      Pyruvate metabolism, a central nexus of carbon homeostasis, is an evolutionarily-conserved process and aberrant pyruvate metabolism is associated with and contributes to numerous human metabolic disorders including diabetes, cancer, and heart disease. As a product of glycolysis, pyruvate is primarily generated in the cytosol before being transported into the mitochondrion for further metabolism. Pyruvate entry into the mitochondrial matrix is a critical step for efficient generation of reducing equivalents and ATP and for the biosynthesis of glucose, fatty acids, and amino acids from pyruvate. However, for many years the identity of the carrier protein(s) that transported pyruvate into the mitochondrial matrix remained a mystery. In 2012, the molecular-genetic identification of the mitochondrial pyruvate carrier (MPC), a heterodimeric complex composed of protein subunits MPC1 and MPC2, enabled studies that shed light on the many metabolic and physiologic processes regulated by pyruvate metabolism. A better understanding of the mechanisms regulating pyruvate transport and the processes affected by pyruvate metabolism may enable novel therapeutics to modulate mitochondrial pyruvate flux to treat a variety disorders. Herein, we review our current knowledge of the MPC, discuss recent advances in the understanding of mitochondrial pyruvate metabolism in various tissue and cell types, and address some of the outstanding questions relevant to this field.
    Keywords:  adipose tissue; heart; liver; mitochondrion; pyruvate
    DOI:  https://doi.org/10.1152/ajpendo.00074.2022
  89. Adv Nutr. 2022 May 31. pii: nmac062. [Epub ahead of print]
    The effect of dietary-based lifestyle modification approaches on anthropometric indices and dietary intake parameters in women with breast cancer: a systematic review and meta-analysis of randomized controlled trials.
    Mahsa Raji Lahiji, Saeideh Vafa, Russell J de Souza, Mitra Zarrati, Akram Sajadian, Elham Razmpoosh, Shapour Jaberzadeh.
      This systematic review and meta-analysis aimed to investigate the effect of dietary-based lifestyle modification interventions ("diet", or "diet +exercise", or "diet +exercise+ behavioral" intervention) on the measures of anthropometric and dietary intake parameters in women with BC. Databases were searched until June 2021. Inclusion criteria were randomized controlled trials that enrolled only women with breast cancer(BC). Studies that used exercise or behavioral interventions alone were not included. Mean±SD changes were extracted for each outcome, and pooled them using a random-effects model; 7315 studies were identified. 51 studies(n=7743) were included. The median(SD) duration of treatment was 24(16.65) weeks. Dietary-based interventions significantly reduced body weight [45 studies(n=7239), WMD(95%CI): -2.6(-3.2, -2.1)kg], body mass index(BMI) [31 studies(n=5384), WMD(95%CI): -1.0(-1.3, -0.7)kg/m2], lean body mass(LBM) [15 studies(n=1194); WMD(95%CI: -0.6(-0.7, -0.4)kg], fat mass (11 studies(n=913; WMD(95%CI): -2.6(-3.3, -1.8)kg], fat percentage [17 studies(n=897); WMD(95%CI): -1.5(-1.9, -1.3)%], hip circumference(HC) [9 studies(n=489; WMD(95%CI): -2.43(-3.34, -1.54)cm], and waist circumference(WC) [7 studies(n=309); WMD(95%CI): 0.02(-0.03, -0.005cm)]. Significant reductions in energy intakes [20 studies(n=4608), WMD(95%CI): -162(-220, 104)kcal/d] and fat intakes ([7 studies(n=4316), WMD(95%CI): -7.5(-7.8, -7.2)%energy/d], and an increase in fiber intakes [11 studies(n=4241), WMD(95%CI): 2.4(0.7, 4.1)g/d] were observed. No significant changes were seen in protein, carbohydrate, and fruit and vegetable intakes. Subgroup analyses showed that changes in anthropometric and dietary intake indices were significant in studies that enrolled patients with both obesity, and normal weight, studies that used diet therapy in combination with exercise and behavioral therapy, and studies that started the intervention during the treatment period. Overall, a multi-modal dietary-based lifestyle intervention had significant effects on anthropometric and dietary intake parameters in women with BC, specifically when started as early as the diagnosis.
    Keywords:  Body Weight; Breast Neoplasms, Cancer Survivors; Epidemiologic Research Design; Nutrition Therapy; Nutritional Intake
    DOI:  https://doi.org/10.1093/advances/nmac062
  90. J Food Drug Anal. 2021 Dec 15. 29(4): 622-637
    Curcumin-induced antitumor effects on triple-negative breast cancer patient-derived xenograft tumor mice through inhibiting salt-induced kinase-3 protein.
    Tzu-Chun Cheng, John Oliver Sayseng, Shih-Hsin Tu, Ting-Ching Juan, Chia-Lang Fang, You-Cheng Liao, Cheng-Ying Chu, Hui-Wen Chang, Yun Yen, Li-Ching Chen, Yuan-Soon Ho.
      This study demonstrated for the first time that curcumin effectively inhibits the growth of triple-negative breast cancer (TNBC) tumors by inhibiting the expression of salt-induced kinase-3 (SIK3) protein in patient-derived xenografted tumor mice (TNBC-PDX). For TNBC patients, chemotherapy is the only option for postoperative adjuvant treatment. In this study, we detected the SIK3 mRNA expression in paired-breast cancer tissues by qPCR analysis. The results revealed that SIK3 mRNA expression was significantly higher in tumor tissues when compared to the normal adjacent tissues (73.25 times, n = 183). Thus, it is proposed for the first time that the antitumor effect induced by curcumin by targeting SIK3 can be used as a novel strategy for the therapy of TNBC tumors. In vitro mechanism studies have shown that curcumin (>25 μM) inhibits the SIK3-mediated cyclin D upregulation, thereby inhibiting the G1/S cell cycle and arresting TNBC (MDA-MB-231) cancer cell growth. The SIK3 overexpression was associated with increased mesenchymal markers (i.e., Vimentin, α-SMA, MMP3, and Twist) during epithelial-mesenchymal transition (EMT). Our results demonstrated that curcumin inhibits the SIK3-mediated EMT, effectively attenuating the tumor migration. For clinical indications, dietary nutrients (such as curcumin) as an adjuvant to chemotherapy should be helpful to TNBC patients because the current trend is to shrink the tumor with preoperative chemotherapy and then perform surgery. In addition, from the perspective of chemoprevention, curcumin has excellent clinical application value.
    DOI:  https://doi.org/10.38212/2224-6614.3387
  91. Front Pharmacol. 2022 ;13 877543
    Mannose: A Sweet Option in the Treatment of Cancer and Inflammation.
    Fang Nan, Yutong Sun, Hantian Liang, Jingyang Zhou, Xiao Ma, Dunfang Zhang.
      As a natural sugar, mannose is a type of hexose that is abundant in many different types of fruits. Since mannose is rarely used for glycolysis in mammals, studies on the role of mannose have not attracted much attention. Glycosylation of specific proteins was thought to be the major function of mannose. Surprisingly, during the past few years, mannose was found to be effective in promoting immune tolerance and suppressing inflammatory diseases related to autoimmunity and allergy. Moreover importantly, mannose was also found to be efficient in suppressing tumors by suppressing glycolysis and enhancing chemotherapeutic agents. In this review, we summarize the recent studies of mannose on antitumor properties and anti-inflammatory characteristics. We emphasize that mannose could play a beneficial role in the treatment of a variety of diseases, including cancers and inflammatory diseases, and could be a novel therapeutic strategy that deserves continued evaluation.
    Keywords:  autoimmune disorders; glycolysis; mannose; mannose phosphate isomerase; treg cells; tumor therapy
    DOI:  https://doi.org/10.3389/fphar.2022.877543
  92. J Food Biochem. 2022 May 29. e14255
    Almond and date fruits enhance antioxidant status and have erectogenic effect: Evidence from in vitro and in vivo studies.
    Adeniyi A Adebayo, Ganiyu Oboh, Ayokunle O Ademosun.
      This study was designed to investigate the efficacies of almond and date fruits on redox imbalance and enzymes relevant to the pathogenesis of erectile dysfunction. The total polyphenol contents, ferric reducing antioxidant power, and vitamin C content were determined spectrophotometrically. Phenolic and amino acid compositions were quantified using HPLC; meanwhile, the antioxidant activities were determined using DPPH, ABTS, FRAP, and metal chelation. Also, the effect of almond and date extract on advanced glycated end-products (AGEs) formation, arginase, and phosphodiesterase-5 activities was evaluated in vitro. Thereafter, the influence of almond and date supplemented diets on copulatory behaviors in normal rats was assessed, followed by arginase and phosphodiesterase-5 activities determination in vivo. The results revealed that date and almond extracts exerted antioxidant properties, prevented AGEs formation in vitro, and inhibited arginase and phosphodiesterase-5 activities in vitro and in vivo. Besides, almond and date supplemented diets significantly enhance sexual behaviors in normal rats when compared with the control. Among the active compounds identified were gallic acid, ellagic acid, quercetin, and rutin. All the 20 basic amino acids were identified. Given the aforementioned, date and almond could represent a reliable source of functional foods highly rich in compounds with antioxidant activity, and arginase and PDE-5 inhibitory properties. PRACTICAL APPLICATIONS: Fruits are essential part of the human diet that furnish the body with important nutrients. Despite the crucial roles of fruits in human diets, some fruits like almond and date are underutilized among Nigerians. However, we characterized the important compounds present in these fruits and how their presence contributes to the biological activities of the fruits. Finally, we relate the chemical composition and the observed biological activities to the overall health and wellness of the consumers.
    Keywords:  advanced glycated end-products; almond; arginase; date; phosphodiesterase-5
    DOI:  https://doi.org/10.1111/jfbc.14255
  93. Rev Assoc Med Bras (1992). 2022 Apr;pii: S0104-42302022000400507. [Epub ahead of print]68(4): 507-513
    Ozone combined with doxorubicin exerts cytotoxic and anticancer effects on Luminal-A subtype human breast cancer cell line.
    Onur Olgac Karagulle, Asiye Gok Yurttas.
       OBJECTIVE: We aimed to examine the potential anticancer effects of ozone applied after chemotherapeutic treatment with different concentrations of doxorubicin in Luminal-A subtype of human breast cancer cell line (MCF-7) and compare the results with effects on L929 fibroblast cell line.
    METHODS: Both cell lines were incubated with increasing doses of doxorubicin (1-50 μM) for 24 h at 37°C. Then, half of groups were incubated with 30 μg/mL ozone for 25 min as combination groups. Cell viability was analyzed by MTT assay, apoptosis by flow cytometry, and levels of tumor necrosis factor alpha, transforming growth factor beta, and matrix metalloproteinase-2 and MMP-9 by immunocytochemistry.
    RESULTS: Doxorubicin + ozone treatment enhanced viability of L929 (p<0.01) but reduced viability of MCF-7 compared to only doxorubicin-applied cells without ozone treatment (p<0.001). This combined treatment also enhanced apoptotic effect of doxorubicin on MCF-cells (p<0.001), but not on L929. It significantly increased all protein levels of L929 compared with those of other groups (p<0.05 for tumor necrosis factor alpha and MMP-2; p<0.01 for transforming growth factor beta and MMP-9). This treatment reversed the effect of doxorubicin on tumor necrosis factor alpha levels and considerably reduced MMP-2 and MMP-9 levels of MCF-7 compared with those of control group (p<0.01 and p<0.001, respectively).
    CONCLUSION: Ozone treatment potentiated the apoptotic and anticancer activities of doxorubicin in MCF-7 cells and showed repairing and healing effect on healthy fibroblast cells, which were damaged from cytotoxic effects of chemotherapeutic agent. MCF-7 cells may acquire sensitivity against the doxorubicin combined with ozone treatment through activating tumor necrosis factor alpha, MMP-2, and MMP-9 expressions.
    DOI:  https://doi.org/10.1590/1806-9282.20211193
  94. Front Cell Neurosci. 2022 ;16 867267
    The Microbiome and Gut Endocannabinoid System in the Regulation of Stress Responses and Metabolism.
    Raj Kamal Srivastava, Beat Lutz, Inigo Ruiz de Azua.
      The endocannabinoid system, with its receptors and ligands, is present in the gut epithelium and enteroendocrine cells, and is able to modulate brain functions, both indirectly through circulating gut-derived factors and directly through the vagus nerve, finally acting on the brain's mechanisms regarding metabolism and behavior. The gut endocannabinoid system also regulates gut motility, permeability, and inflammatory responses. Furthermore, microbiota composition has been shown to influence the activity of the endocannabinoid system. This review examines the interaction between microbiota, intestinal endocannabinoid system, metabolism, and stress responses. We hypothesize that the crosstalk between microbiota and intestinal endocannabinoid system has a prominent role in stress-induced changes in the gut-brain axis affecting metabolic and mental health. Inter-individual differences are commonly observed in stress responses, but mechanisms underlying resilience and vulnerability to stress are far from understood. Both gut microbiota and the endocannabinoid system have been implicated in stress resilience. We also discuss interventions targeting the microbiota and the endocannabinoid system to mitigate metabolic and stress-related disorders.
    Keywords:  endocannabinoid system; gut microbiota; gut-brain axis; metabolism and obesity; stress; stress resilience
    DOI:  https://doi.org/10.3389/fncel.2022.867267
  95. J Cancer Res Ther. 2022 Apr;18(2): 362-369
    Pantoprazole promotes the sensitivity of cervical cancer cells to cisplatin by inhibiting cisplatin-induced autophagy.
    Guangzhu Su, Xiaolu Chen, Hongyan Yang.
       Aim: This study aimed to explore the role of pantoprazole (PPZ) in affecting the sensitivity of cervical cancer (CC) cells to cisplatin.
    Methods: HeLa and CaSki cells were exposed to cisplatin and/or PPZ treatment. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, colony formation, flow cytometry, wound healing, and transwell assays were performed to detect cell viability, proliferation, apoptosis, migration, and invasion of CC cells, respectively. Then, expressions of Beclin-1, LC3, and p62 were measured by western blot. Rapamycin (Rapa), acting as an autophagy activator, was applied to confirm the effect of autophagy on the sensitivity of CC cells to cisplatin.
    Results: Cisplatin treatment suppressed cell viability and proliferation and accelerated apoptosis of CC cells. Combination of cisplatin and PPZ or PPZ alone significantly inhibited cell viability, proliferation, migration, and invasion, and increased cell apoptosis of CC cells. Cisplatin enhanced expression levels of Beclin1 and LC3II/I, and reduced p62 expression. Combination of cisplatin and PPZ significantly decreased the expression levels of Beclin1 and LC3II/I, but increased p62 expression. The autophagy activator, Rapa, eliminated the inhibitory effects of the combination of cisplatin and PPZ on autophagy, and enhanced cell viability, but inhibited apoptosis of CC cells.
    Conclusion: PPZ promotes the sensitivity of CC cells to cisplatin by inhibiting cisplatin-induced cell autophagy.
    Keywords:  Autophagy; cervical cancer; cisplatin sensitivity; pantoprazole
    DOI:  https://doi.org/10.4103/jcrt.jcrt_968_21
  96. Curr Drug Deliv. 2022 May 31.
    Celebrating A Century Of Insulin Discovery: A Critical Appraisal Of The Emerging Alternative Insulin Delivery Systems.
    Ntethelelo Sibiya, Bonisiwe Mbatha, Phikelelani Ngubane, Andile Khathi.
      Since the discovery of insulin, continuous developments of this peptide have led to better management of diabetes mellitus, thus leading to a decrease in diabetes-related mortality. Despite these developments, we have seen an increase in diabetes cases, which has further necessitated for more innovative methods of diabetes management. The subcutaneous administration of insulin remains the mainstay therapy for type 1 diabetes mellitus. However, despite the availability of insulin analogues with improved pharmacokinetics, challenges with the conventional administration exists. The challenges associated with insulin injections include hypoglycaemic episodes, needle phobia, and injection-site inflammation which all have been reported to reduce patient compliance. Ongoing research on diabetes management strives to develop therapies that provide improved glycaemic control with minimal side effects. It is, in part, for these reasons that we have seen an increase in the search and development of alternative insulin delivery systems that are envisaged to circumvent the shortfalls associated with the conventional administration route. In the last century, several alternative drug delivery systems such as oral, pulmonary, buccal, nasal and transdermal have been explored. These efforts have not been without victory, as we have seen the emergence of pulmonary (Exubera and Afrezza) and buccal insulin delivery systems licenced for therapeutic use. Despite the success seen in these two systems, their marketability and popularity have been severely compromised due to reported safety concerns. Although oral insulin delivery has always shown promise in the past decades, however it was only limited to preclinical trials. The main challenge associated this with delivery route is poor bioavaialabiltiy which necessitates high insulin concentration to be administered. Recent developments have however seen oral insulin reaching phase 3 clinical trials. It is believed that patients would welcome oral insulin as their preference is often observed for oral antidiabetics over injected ones. In the last decade, transdermal insulin has also gained interest, where delivery of insulin with concomitant reducation in blood glucose concentration have been demonstrated in vivo. However, at present, there are no clinical studies that have reported the efficacy of transdermal insulin administration With technological advancement, there is a potential to develop yet another insulin delivery system which would likely enter the markets. Although these novel delivery systems are welcome, however, emerging competing products should be welcome and appreciated.
    Keywords:  bioavailability; blood glucose absorption; diabetes mellitus; insulin delivery systems; pharmacokinetics
    DOI:  https://doi.org/10.2174/1567201819666220531101203
  97. Biochimie. 2022 May 27. pii: S0300-9084(22)00132-8. [Epub ahead of print]
    Molecular basis of melatonin protective effects in metastasis: A novel target of melatonin.
    Fatemeh Sadoughi, Parisa Maleki Dana, Mina Homayoonfal, Mehran Sharifi, Zatollah Asemi.
      Currently, cancer is ranked among the top ten causes of death worldwide. Despite the advances made in the field of cancer treatment, 5-year survival rates of various types of cancer are still low due to the recurrence of the disease and/or metastasis. Dissemination of cancer cells, infiltration into the blood vessels, migration to the targeted organs, extravasation, and colonization are the main steps of metastasis. Various factors and signaling pathways are involved in each of these steps. Melatonin (MLT) is a hormone derived from tryptophan and secreted by the pineal gland. This hormone has shown a variety of anti-tumor effects, including anti-oxidative activities, inhibiting the proliferation of tumor cells, inducing apoptosis, and suppressing metastasis. Due to these extensive effects, several studies have been conducted on the applications of MLT in treating different types of cancer. Herein, we review the mechanisms of MLT's effects on the metastasis inhibition of the most lethal types of cancer including the cancer of lung, breast, stomach, kidney, colon, liver, bladder, and pancreas. We discuss how MLT targets different molecules and signaling pathways in each step of the metastasis, such as angiogenesis, remodeling of the extracellular matrix, migration, and epithelial-to-mesenchymal transition.
    Keywords:  Angiogenesis; Breast cancer; Colorectal cancer; EMT; Gastric cancer; Invasion; Lung cancer; MLT; Metastasis; Migration
    DOI:  https://doi.org/10.1016/j.biochi.2022.05.012
  98. Eur Rev Med Pharmacol Sci. 2022 May;pii: 28844. [Epub ahead of print]26(10): 3493-3505
    The effect of vitamin D levels on lipid, glucose profiles and depression in perimenopausal women.
    D Kostecka, D Schneider-Matyka, K Barczak, M Starczewska, M Szkup, P Ustianowski, J Brodowski, E Grochans.
       OBJECTIVE: Vitamin D deficiency is a significant problem that affects the population living in most countries. This issue is independent by place of residence, sex, age or skin color. It is mainly influenced by the environment we live in and by an unhealthy lifestyle, including bad eating habits. The aim of this study was to evaluate lipid profile, glucose levels, and vitamin D levels, considering sociodemographic variables, smoking and alcohol consumption in perimenopausal women. Depressive mood was also assessed considering sociodemographic variables and vitamin D levels.
    PATIENTS AND METHODS: The study was conducted on a group of 191 women and performed in two stages. The first of them was carried out using a diagnostic survey with the use of a technique questionnaire. The applied research instruments were the author's questionnaire (concerning sociodemographic and selected medical data), and the Beck Depression Inventory. The second stage of the study involved the collection of peripheral blood from each respondent, in order to determine lipid profile, glycemia and serum vitamin D levels.
    RESULTS: The age of the female respondents ranged from 45 to 65 years, mean age was 53.1 ± 5.37 years, median 53 years. Vitamin D levels were below normal in 78%; 77% had elevated total cholesterol levels; 91.6% of the respondents had high density lipoprotein (HDL) cholesterol levels within the normal range; 64.4% was characterized by too high (low-density lipoprotein) LDL cholesterol, and 84.8% of the women showed normal triglyceride levels. Among the respondents, 91.1% had normal glycemic levels. Analysis of the collected data showed a weak negative correlation between serum vitamin D levels and the levels of total cholesterol (rho=-0.14; p=0.05), LDL cholesterol (rho=-0.16; p=0.026), and triglycerides (rho=-0.22; p=0.002). Only in the case of HDL cholesterol (p=0.067), there was no statistically significant correlation. There were also no statistically significant correlations between serum vitamin D levels and glycemia or severity of depression.
    CONCLUSIONS: 1. The majority of the women did not manifest depressive disorders. Of all factors analyzed, only education was associated with the severity of depressiveness. 2. Smoking adversely affected serum vitamin D levels in the studied women. 3. The cessation of menstruation affected carbohydrate metabolism and vitamin D levels. Blood glucose levels increased with the age of the studied women. 4. Relationships were found between the levels of vitamin D and the levels of total cholesterol, LDL cholesterol, and triglycerides. Therefore, it is important to maintain normal vitamin D levels.
    DOI:  https://doi.org/10.26355/eurrev_202205_28844
  99. Support Care Cancer. 2022 Jun 02.
    The effect of aerobic exercise on tumour blood delivery: a systematic review and meta-analysis.
    Catherine Seet-Lee, Jasmine Yee, Heidi Morahan, Lois S Ross, Kate M Edwards.
       PURPOSE: Tumour blood vessels are structurally and functionally abnormal, resulting in areas of hypoxia and heterogeneous blood supply. Aerobic exercise may modulate tumour blood flow and normalise the tumour microenvironment to improve chemotherapy delivery. This systematic review and meta-analysis aimed to evaluate the effect of the aerobic exercise mode on tumour hypoxia, vascularisation and blood flow.
    METHODS: Four online databases were searched. Preclinical and clinical randomised controlled trials examining the effects of aerobic exercise training on hypoxia, vascularisation or blood flow in solid tumours were included. The risk of bias was assessed and a meta-analysis performed.
    RESULTS: Seventeen preclinical studies and one clinical study met criteria. Eleven studies assessed hypoxia, 15 studies assessed vascularisation and seven evaluated blood flow. There was large variability in measurement methods, tumour types and exercise program designs. The overall risk of bias was unclear in clinical and preclinical studies, owing to poor reporting. There was no significant effect of aerobic exercise on hypoxia (SMD = -0.17; 95% CI = -0.62, 0.28; I2 = 60%), vascularisation (SMD = 0.07; 95% CI = -0.40, 0.55; I2 = 71%) or blood flow (SMD = 0.01; 95% CI = -0.59, 0.61; I2 = 63%).
    CONCLUSION: There is heterogeneity in methodology, resulting in evidence that is inconsistent and inconclusive for the effects of aerobic exercise on hypoxia, vascularisation and blood flow. Most evidence of aerobic exercise effects on tumour blood flow is in animal models, with very limited evidence in humans.
    Keywords:  Blood flow; Exercise; Hypoxia; Tumour; Vascularisation
    DOI:  https://doi.org/10.1007/s00520-022-07132-0
  100. Front Pharmacol. 2022 ;13 903519
    The Therapeutic Benefits of Nanoencapsulation in Drug Delivery to the Anterior Segment of the Eye: A Systematic Review.
    Madhavi Bhandari, Sanko Nguyen, Mazyar Yazdani, Tor Paaske Utheim, Ellen Hagesaether.
      Background: Although numerous nanoparticle formulations have been developed for ocular administration, concerns are being raised about a possible mismatch between potential promises made by the field of nanoparticle research and demonstration of actual therapeutic benefit. Therefore, the primary focus of this present review was to critically assess to what extent nanoencapsulation of ocular drugs improved the therapeutic outcome when treating conditions in the anterior segment of the eye. Methods: A systematic search was conducted using Medline, PubMed, and Embase databases as well as Google Scholar for published peer-reviewed articles in English focusing on conventional nanoparticles used as drug delivery systems to the anterior segment of the eye in in vivo studies. The major therapeutic outcomes were intraocular pressure, tear secretion, number of polymorphonuclear leucocytes and pupil size. The outcome after encapsulation was compared to the non-encapsulated drug. Results: From the search, 250 results were retrieved. Thirty-eight studies met the inclusion criteria. Rabbits were used as study subjects in all but one study, and the number of animals ranged from 3 to 10. Coated and uncoated liposomes, lipid-based and polymeric nanoparticles, as well as micelles, were studied, varying in both particle size and surface charge, and encapsulating a total of 24 different drugs, including 6 salts. The majority of the in vivo studies demonstrated some improvement after nanoencapsulation, but the duration of the benefit varied from less than 1 h to more than 20 h. The most common in vitro methods performed in the studies were drug release, transcorneal permeation, and mucin interaction. Discussion: Nanoparticles that are small and mucoadhesive, often due to positive surface charge, appeared beneficial. Although in vitro assays can unravel more of the hidden and sophisticated interplay between the encapsulated drug and the nanoparticle structure, they suffered from a lack of in vitro-in vivo correlation. Therefore, more research should be focused towards developing predictive in vitro models, allowing rational design and systematic optimization of ocular nanoparticles with minimal animal experimentation.
    Keywords:  animal studies; drug delivery; encapsulation; in vivo efficacy; nanoparticle; ocular drug delivery; topical administration
    DOI:  https://doi.org/10.3389/fphar.2022.903519
  101. Colloids Surf B Biointerfaces. 2022 May 27. pii: S0927-7765(22)00286-7. [Epub ahead of print]216 112603
    Mesoporous peroxidase nanozyme for synergistic chemodynamic therapy and chemotherapy.
    Xingyu Fan, Xiyu Gong, Fangfang Zhou, Botao Chen, Songwen Tan, Hui Xu, Anqiang Pan, Shuquan Liang, Yongju He.
      Peroxidase nanozyme, enabling decomposition of hydrogen peroxide (H2O2) into highly toxic hydroxyl radical (•OH), is an emerging technology for tumor treatment. However, limited by the low H2O2 level in the tumor microenvironment, the standalone peroxidase nanozyme-mediated therapy usually fails to achieve desirable therapeutic outcomes. Herein, we presented a mesoporous nanozyme that not only had peroxidase-like activity but also could deliver anticancer drug for synergistic tumor therapy. The nanozyme, that was, iron-doped mesoporous silica nanoparticle (FeMSN), was prepared by a sol-gel method and then a calcination treatment. The introduction of iron endowed FeMSN with peroxidase-like activity that could decompose H2O2 into •OH under acidic condition for chemodynamic therapy of tumors. Meanwhile, the mesoporous structure enabled FeMSN to deliver anticancer drug doxorubicin (DOX) for chemotherapy and enhanced chemodynamic therapy through H2O2 production, ultimately achieving synergistic effect to improve the efficacy of tumor treatment. The in-vitro and in-vivo results demonstrated that DOX-loaded FeMSN exhibited significant cancer cell-killing effect and potently inhibited tumor growth. Collectively, this study represented a paradigm for achieving efficient tumor therapy through design of peroxidase-like nanozyme with drug delivery capability, which might advance the development of nanozyme in tumor chemodynamic therapy.
    Keywords:  Chemodynamic therapy; Iron; Mesoporous silica; Nanozyme; Peroxidase
    DOI:  https://doi.org/10.1016/j.colsurfb.2022.112603
  102. Clin Neurol Neurosurg. 2022 May 18. pii: S0303-8467(22)00181-0. [Epub ahead of print]218 107300
    Evaluation of curcumin as add-on therapy in patients with Parkinson's disease: A pilot randomized, triple-blind, placebo-controlled trial.
    Hamidreza Ghodsi, Hamid Reza Rahimi, Seyedeh Mehrnaz Aghili, Amin Saberi, Ali Shoeibi.
       BACKGROUND AND OBJECTIVE: Preclinical studies suggest that curcumin might be a potential neuroprotective agent in Parkinson's disease (PD). This clinical trial aimed to evaluate the efficacy of adding nanomicelle curcumin on improving the motor and non-motor symptoms of PD patients and their quality of life.
    MATERIAL AND METHODS: Idiopathic PD patients aged ≥30≥ 30 whose symptoms were under control were included in this pilot, randomized, triple-blind, placebo-controlled, add-on trial. Eligible patients were randomly assigned to either the curcumin (n = 30, 80 mg/day) or placebo (n = 30) groups and were followed for nine months. Primary outcomes were the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and Parkinson's Disease Questionnaire (PDQ-39). These variables, along with demographic data, drug history, and possible side effects of curcumin, were gathered at the beginning of the study and every three months. A mixed effects model was used to compare the group-by-time interaction, followed by post hoc analysis.
    RESULTS: Although the mean MDS-UPDRS and PDQ-39 scores were not significantly different between the curcumin and placebo groups at any time points, MDS-UPDRS part III (P = 0.04) showed a significant difference in its overall trend between the study groups. However, post hoc analysis failed to spot this difference at study time points. The most common side effects of curcumin were nausea and vomiting (P = 0.25) and gastroesophageal reflux (P = 0.42).
    CONCLUSION: While curcumin is a well-tolerated natural compound, this trial was unsuccessful in showing its efficacy in quality of life and clinical symptoms of PD patients.
    Keywords:  Curcumin; MDS-UPDRS; Nanomicelle; PDQ-39; Parkinson's disease
    DOI:  https://doi.org/10.1016/j.clineuro.2022.107300
  103. CNS Neurol Disord Drug Targets. 2022 Jun 02.
    A Comprehensive Review on Therapeutic Potential of Chrysin in Brain Related Disorders.
    Ahsas Goyal, Geetanjali Singh, Aanchal Verma.
      Brain disorders are currently one of the world's most serious and difficult health issues. These brain disorders are accountable for a massive number of morbidities and mortalities around the world. The current treatments of these disorders are frequently accompanied by severe side effects and cause a detrimental effect on health. Recently, plant flavonoids have sparked a surge in public and scientific attention in recent years because of their alleged health promoting impact and almost no adverse repercussions. Also, scientific research has shown that phytochemicals possess numerous neuroprotective properties under in vivo and in vitro conditions. Chrysin is a therapeutic phytochemical that falls under the class of flavonoids based on its structure. The biological activities and pharmacological effects of chrysin include anticancer, antioxidant, and anti-inflammatory activities as well as amyloidogenic and neurotrophic effects. These therapeutic abilities of chrysin are attributed to its structural diverseness arising in ring-A and lack of oxygenation in B and C ring. Several studies have highlighted the rising significance of chrysin in a variety of brain illnesses, like Alzheimer's disease, Parkinson's disease, depression, anxiety, brain tumours, epilepsy, multiple sclerosis, traumatic brain injury, spinal cord injury, and ischemic stroke. This study depicts the relationship of chrysin with different brain related disorders and discusses the mechanisms responsible for the potential role of chrysin as a pharmacological agent for the treatment and management of different brain disorders, based on the results of several preclinical studies and taking into account the therapeutic effects of the compound.
    Keywords:  Alzheimer’s disease; Chrysin; Depression; Epilepsy.; Flavonoid; Parkinson’s disease
    DOI:  https://doi.org/10.2174/1871527321666220602111935
  104. Nutr Res Pract. 2022 May;16(Suppl 1): S57-S69
    Evidence and suggestions for establishing vitamin D intake standards in Koreans for the prevention of chronic diseases.
    Jung Hyun Kim, Hyoung Su Park, Munkyong Pae, Kyung Hee Park, Oran Kwon.
       BACKGROUND/OBJECTIVES: Vitamin D is produced in the skin during sun exposure and is also ingested from foods. The role of vitamin D needs to be considered in the prevention and management of various diseases. Moreover, since the majority of Koreans spend their days indoors, becoming susceptible to the risk of vitamin D deficiency. The current study aims to prepare a basis for determining dietary reference intake of vitamin D in Korea, by reviewing the evidence against various diseases and risks.
    MATERIALS/METHODS: Literature published in Korea and other countries between 2014 and 2018 was prioritized based on their study design and other criteria, and evaluated using the RoB 2.0 assessment form and United States Department of Agriculture Nutrition Evidence Library Conclusion Statement Evaluation Criteria.
    RESULTS: Of the 1,709 studies, 128 studies were included in the final systematic analysis after screening. To set the dietary reference intakes of vitamin D based on the selected articles, blood 25(OH)D levels and indicators of bone health were used collectively. Blood vitamin D levels and ultraviolet (UV) exposure time derived from the Korean National Health and Nutrition Examination Survey were analyzed to establish the dietary reference intakes of vitamin D for each stage of the life cycle. The adequate intake levels of vitamin D, according to age and gender, were determined to be in the range of 5-15 μg/day, and the tolerable upper intake level was established at 25-100 μg/day.
    CONCLUSIONS: The most important variable for vitamin D nutrition is lifestyle. A balanced diet comprising foods with high contents of vitamin D is important, as is vitamin D synthesis after UV exposure. The adequate intake level of vitamin D mentioned in the 2015 Dietary Reference Intakes for Korean (KDRI) remained unchanged in the 2020 KDRI for the management of vitamin D nutrition in Koreans.
    Keywords:  Dietary Reference Intake; Vitamin D; chronic disease; life cycle stages; systematic review
    DOI:  https://doi.org/10.4162/nrp.2022.16.S1.S57
  105. Front Public Health. 2022 ;10 880506
    Relationship Between Dietary Fiber and Vitamin C Intake and Oral Cancer.
    Jing Wang, Yi Fan, Jiawen Qian, Sijie Wang, Yanni Li, Mingming Xu, Fa Chen, Jing Wang, Yu Qiu, Lisong Lin, Baochang He, Fengqiong Liu.
       Background: Dietary fiber and vitamin C has been reported to play a possible role in tumorigenesis. However, few studies have estimated their association with oral cancer risk. In this project, we investigated the relationship between dietary fiber and vitamin C and oral cancer risk in adults in Southern China.
    Methods: 382 patients newly diagnosed with oral cancer were matched to 382 hospital derived controls by frequency matching in age and sex. Pre-diagnostic consumption of dietary fiber and vitamin C intake were measured through food frequency questionnaire. Association between nutrients intake and oral cancer risk were evaluated by logistic regression. OR value and 95% confidence interval was calculated.
    Results: Intake of dietary fiber and vitamin C was significantly lower in oral cancer patients (8.15 g/day) than in control participants (8.88 g/day). Increased dietary fiber or vitamin C intake was linked to a decreased incidence of OC after adjustment of age, marital status, residence, BMI, occupation, education, tobacco smoking, alcohol consumption and family history of cancer P trend < 0.001). Compared with the lowest tertile, the adjusted OR of the top tertile of dietary fiber was 0.47 (95 % CI 0.32, 0.68). While the adjusted OR of the highest tertile was 0.60 (95 % CI 0.42, 0.87) compared with the lowest tertile of vitamin C.
    Conclusions: Dietary intake of fiber and vitamin C were lower in oral cancer patients than in control participants. Dietary fiber and vitamin C were inversely related to risk of oral cancer risk.
    Keywords:  case-control; dietary fiber; food frequency questionnaires; oral cancer; vitamin C
    DOI:  https://doi.org/10.3389/fpubh.2022.880506
  106. J Oncol Pharm Pract. 2022 May 31. 10781552221104814
    Comparison of different decision support software programs in perspective of potential drug-drug interactions in the oncology clinic.
    Muhammed Yunus Bektay, Zehra Seker, Hatice Kubra Eke, Haci Mehmet Turk, Fikret Vehbi Izzettin.
       INTRODUCTION: One of the most intriguing situations for healthcare providers is cancer therapy. Drug-drug interactions (DDIs) account for 20-30% of all adverse effects. Cancer patients are more likely to have potential-DDIs since they are taking other drugs with anticancer treatments to prevent the side effects of chemotherapeutic agents. The purpose of this research is to compare various decision support software (CDSS) programs in terms of potential DDIs.
    METHODS: A cross-sectional study was carried out. A clinical pharmacist assessed the treatment regimens of 231 cancer patients. pDDIs were evaluated using three sources: Lexicomp®, Medscape®, and Micromedex®. The ethical approval was given in November 2017 with decision number 21/286.
    RESULTS: A total of 231 participants who were receiving therapy and had a median age of 61.5 ± 9.18 years were assessed. Almost half of the patients (49%) were female, and 155 had at least one comorbidity in addition to cancer. Medscape had a substantial pDDI ratio of 7.09%, Micromedex had a ratio of 11.15%, and Lexicomp had a ratio of 19.50%. The total number of pDDIs for major/X/contraindicated were 363-2716 (1.56-11.7 pDDI/patient) for Medscape®, 60-1723 (0.26-7.4 pDDI/patient) for Micromedex, and 145-984 (0.62-2.24 pDDI/patient) for Lexicomp®. One of the most common pDDI found was diclofenac and dexamethasone. Interactions between escitalopram and granisetron were also common, and different CDSSs made different recommendations.
    CONCLUSIONS: In this study, significant disparities in the quantity and severity of CDSS across distinct CDSS were discovered. One of the major finding of our study was suboptimal prescribing. To address this issue, regulatory organizations should establish and verify validation and reporting mechanisms.
    Keywords:  Drug–drug interaction; clinical decision support software; clinical pharmacist; oncology
    DOI:  https://doi.org/10.1177/10781552221104814
  107. Acta Biomater. 2022 May 29. pii: S1742-7061(22)00323-3. [Epub ahead of print]
    Hyaluronic acid-based Glucose-responsive Antioxidant Hydrogel Platform for Enhanced Diabetic Wound Repair.
    Zejun Xu, Guiting Liu, Ping Liu, Yueying Hu, Yongxin Chen, Yifen Fang, Guoming Sun, Hai Huang, Jun Wu.
      Hyaluronic acid (HA)-based antioxidant hydrogels have achieved remarkable results in diabetic wound repair. However, the realization of their glucose-responsive antioxidant functions remains a significant challenge. In this study, we modified hyaluronic acid methacrylate (HAMA) with phenylboronic acid (PBA) and developed a glucose-responsive HA derivative (HAMA-PBA). A glucose-responsive HAMA-PBA/catechin (HMPC) hydrogel platform was then fabricated by forming a borate ester bond between HAMA-PBA and catechin. The results showed that the HMPC hybrid hydrogel not only had a three-dimensional network structure and Young's modulus similar to those of skin tissue but also possessed biocompatibility. The HMPC hydrogel also showed unique glucose-responsive catechin release behavior and remarkable antioxidant capability, which could effectively eliminate intracellular reactive oxygen species and protect cells from oxidative stress damage (increased superoxide dismutase activity, stabilized reduced glutathione/oxidized glutathione ratio, and reduced malondialdehyde content). Additionally, in vitro and in vivo experimental results showed that the HMPC hydrogel effectively promoted angiogenesis (enhanced VEGF and CD31 expression) and reduced inflammatory responses (decreased IL-6 level and increased IL-10 level), thus rapidly repairing diabetic wounds (within three weeks). This was a significant improvement as compared to that observed for the untreated control group and the HMP hydrogel group. These results indicated the potential for the application of the HMPC hydrogel for treating diabetic wounds. STATEMENT OF SIGNIFICANCE: At present, the delayed closure rate of diabetic chronic wounds caused by excessive reactive oxygen species (ROS) remains a worldwide challenge. Hyaluronic acid (HA)-based antioxidant hydrogels have made remarkable achievements in diabetic wound repair; however, the realization of their glucose-responsive antioxidant functions is a tough challenge. In this work, we developed a novel HA-based hydrogel platform with glucose-responsive antioxidant activity for rapid repair of diabetic wounds. In vitro and in vivo experimental results showed that the HMPC hydrogel could effectively promote angiogenesis (enhanced VEGF and CD31 expression) and reduce inflammatory response (decreased IL-6 level and increased IL-10 level), thus rapidly repairing diabetic wounds (within 3 weeks). These results indicated the potential of the HMPC hydrogel for application in diabetic wound treatment.
    Keywords:  Antioxidation; Diabetic wound; Glucose-responsive; Hyaluronic acid; Hydrogel
    DOI:  https://doi.org/10.1016/j.actbio.2022.05.047
  108. Iran J Basic Med Sci. 2022 Apr;25(4): 497-505
    Influence of ethanolic extract of Allium sativum on TP53 gene and its anticancer potential in N-Nitrosodiethylamine (NDEA)-induced hepatocellular carcinoma in male albino rats.
    Godwin Offumobi Ogar, Joseph Bamidele Minari, Adebayo Joseph Bello, Janet Chiwetalu, Oluwafunto Eunice Omogunwa, Oluwadamilola Suzan Oshikoya, Micheal Tobiloba Otaru, Chioma Anastacia Anyanele.
       Objectives: Cancer is a group of genetic disorders in which the behavior of the cell is disturbed by mutation and other abnormalities thereby posing as the leading cause of morbidity and mortality globally. Hepatocellular Carcinoma (HCC) is the most common form of liver cancer, highly aggressive with high mortality and incidence rate; and has limited therapeutic options. Most of the conventional cancer chemotherapeutics are associated with undesirable side effects, toxicity, chemoresistance, and high treatment cost, driving the need for a safer and more effective treatment alternative. Medicinal plants and herbs have shown very promising anti-cancer properties which are important for cancer treatment due to their multiple chemical compounds.
    Materials and Methods: Qualitative screening of the ethanolic extractof Allium sativum was conducted showing the different phytochemicalspresent. The levels of liver function and hematological parameters wasdetermined via spectrophotometric analysis. Polymerase Chain Reaction techniquewas used to assess the gene patterns of Tumorsuppressor p53 (TP53).
    Results: Phytochemical analysis revealed that Allium sativum has properties that antagonize the proliferating process of carcinogenesis in the liver. The NDEA-group showed significant distortion in the liver architecture characterized by vascular congestion of blood sinusoids, cirrhosis, and congestive hepatopathy while the treated groups showed a reduction in the abnormalities and malignant formation. The treated group showed a significant (P<0.05) increase and restored activities of Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Alkaline phosphatase (ALP), Bilirubin and hematological parameters (RBCs, WBCs, and Platelets). TP53 gene amplification was significantly (P<0.05) visible after treatment.
    Conclusion: Ethanolic plant extract of A. sativum demonstrates its anticancer properties by improving the liver architecture, increasing the antioxidant defense systems, and activation of the tumor suppressor (TP53) gene. Garlic extract has anti-proliferating properties and can be used as an alternative mode of treatment and prevention for hepatocellular carcinoma.
    Keywords:  Antineoplastic agents; Carcinogens; Carcinoma; Diethylnitrosamine; Garlic; Hepatocellular; Medicinal; p53
    DOI:  https://doi.org/10.22038/IJBMS.2022.62295.13787
  109. Front Immunol. 2022 ;13 817600
    Ginsenoside Rg1 Alleviates Acute Ulcerative Colitis by Modulating Gut Microbiota and Microbial Tryptophan Metabolism.
    Hao Cheng, Juan Liu, Dandan Zhang, Jing Wang, Yuzhu Tan, Wuwen Feng, Cheng Peng.
      Ulcerative colitis (UC) is a chronic and recurrent inflammatory disorder in the gastrointestinal tract. Here, we examined the pharmacological effects of ginsenoside Rg1, a natural compound with low bioavailability, on the acute experimental colitis mice induced by dextran sulfate sodium (DSS) and explored underlying mechanisms. Acute UC was induced in C57BL/6 mice by 2.5% DSS for 7 days, meanwhile, 2 mg/10 g b.w. ginsenoside Rg1 was administrated to treat the mice. Body weight, colon length, colon tissue pathology, and colon tissue inflammatory cytokines were assessed. The composition structure of gut microbiota was profiled using 16s rRNA sequencing. Global metabolomic profiling of the feces was performed, and tryptophan and its metabolites in the serum were detected. The results showed that Rg1 significantly ameliorated DSS-induced colonic injury and colonic inflammation. In addition, Rg1 also partly reversed the imbalance of gut microbiota composition caused by DSS. Rg1 intervention can regulate various metabolic pathways of gut microbiota such as valine, leucine, and isoleucine biosynthesis and vitamin B6 metabolism and the most prominent metabolic alteration was tryptophan metabolism. DSS decreased the levels of tryptophan metabolites in the serum, including indole-3-carboxaldehyde, indole-3-lactic acid, 3-indolepropionic acid, and niacinamide and Rg1 can increase the levels of these metabolites. In conclusion, the study discovered that Rg1 can protect the intestinal barrier and alleviate colon inflammation in UC mice, and the underlying mechanism is closely related to the regulation of gut microbiota composition and microbial tryptophan metabolism.
    Keywords:  ginsenoside Rg1; gut microbiota; metabolomics; tryptophan; ulcerative colitis
    DOI:  https://doi.org/10.3389/fimmu.2022.817600
  110. Open Biol. 2022 Jun;12(6): 220001
    The potential roles of retinoids in combating drug resistance in cancer: implications of ATP-binding cassette (ABC) transporters.
    Mohamed R Abdelaal, Hesham Haffez.
      Multidrug resistance (MDR) means that tumour cells become unresponsive during or after the course of treatment to one or more of chemotherapeutic drugs. Chemotherapeutic resistance critically limits the treatment outcomes and remains a key challenge for clinicians. The alternation in intracellular drug concentration through the modulation of its transport across the plasma membrane is the major cause for MDR and is adopted by various mediators, including ATP-requiring enzymes (ATPases). Among these ATPases, ABC transporters have been extensively studied, and found to be highly implicated in tumorigenesis and MDR. The present review sheds light on the documented effects of retinoids on ABC enzymes to understand their mechanism in combating cancer cell resistance. This would open the gate to test the mechanism and applicability of different new synthetic retinoids in literature and market as modulators of ATP-dependent efflux pumping activity, and promote their applicability in diminishing anti-cancer drug resistance.
    Keywords:  ABC transporter; BCRP; MDR; MRP-1; P-glycoprotein; retinoids
    DOI:  https://doi.org/10.1098/rsob.220001
  111. Int J Biol Macromol. 2022 May 26. pii: S0141-8130(22)01140-0. [Epub ahead of print]
    Smart active-targeting of lipid-polymer hybrid nanoparticles for therapeutic applications: Recent advances and challenges.
    Leila Khalili, Gholamreza Dehghan, Nader Sheibani, Alireza Khataee.
      The advances in producing multifunctional lipid-polymer hybrid nanoparticles (LPHNs) by combining the biomimetic behavior of liposomes and architectural advantages of polymers have provided great opportunities for selective and efficient therapeutics delivery. The constructed LPHNs exhibit different therapeutic efficacies for special uses based on characteristics of different excipients. However, the high mechanical/structural stability of hybrid nano-systems could be viewed as both a negative property and a positive feature, where the concomitant release of drug molecules in a controllable manner is required. In addition, difficulties in scaling up the LPHNs production, due to involvement of several criteria, limit their application for biomedical fields, especially in monitoring, bioimaging, and drug delivery. To address these challenges bio-modifications have exhibited enormous potential to prepare reproducible LPHNs for site-specific therapeutics delivery, diagnostic and preventative applications. The ever-growing surface bio-functionality has provided continuous vitality to this biotechnology and has also posed desirable biosafety to nanoparticles (NPs). As a proof-of-concept, this manuscript provides a crucial review of coated lipid and polymer NPs displaying excellent surface functionality and architectural advantages. We also provide a description of structural classifications and production methodologies, as well as the biomedical possibilities and translational obstacles in the development of surface modified nanocarrier technology.
    Keywords:  Active targeting; Liposome; Nab-technology; Nano-materials; Phase separation
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.05.156
  112. Pain Physician. 2022 May;25(3): E414-E425
    Rationale and Recent Advances in Targeted Drug Delivery for Cancer Pain: Is It Time to Change the Paradigm?
    Denis Dupoiron, Rui Duarte, Gabriel Carvajal, Frederic Aubrun, Sam Eldabe.
       BACKGROUND: Cancer pain prevalence remains high with more than 60% of patients with advanced cancer experiencing cancer-related pain. The undertreatment of pain due to concerns of opioid dependence or diversion, as well as the potential effect of opioids on tumor neogenesis, add to the suffering among cancer populations.
    OBJECTIVES: The aim of this narrative review was to assess evidence on the effectiveness, safety, cost-effectiveness, and advances of Intrathecal (IT) Drug Delivery Systems (IDDS) for the management of cancer pain.
    STUDY DESIGN: The present review was performed by searching for articles indexed in PubMed, MEDLINE, SciELO, Google Scholar, and Scopus.
    METHODS: Studies were included if they investigated patients with chronic cancer-related pain treated with IDDS and assessed experienced pain. We performed a narrative synthesis.
    RESULTS: IDDS have demonstrated efficacy in relieving cancer pain even in the challenging treatment of head and neck cancer pain. IDDS is also associated with a large reduction in serum opioid concentrations limiting adverse effects. When combined with other analgesics commonly used in the spinal space, but not systemically, pain relief may be dramatically improved. Advances in IT drug diffusion, including mixtures created with pharmaceutical compounding, improve the safety and accuracy of this therapy. IDDS is cost-effective and safe yet remains underutilized in this patient population.
    LIMITATIONS: Despite numerous clinical studies, only a small number of randomized trials have been conducted to evaluate the effectiveness of IDDS for cancer pain.
    CONCLUSIONS: This article presents an overview of the current state of evidence on the effectiveness, safety, cost-effectiveness, and advances of IDDS for the management of cancer pain. Despite current evidence, IDDS remains underutilized for people with cancer pain. Potential areas to facilitate its use are discussed. A shift in the paradigm of cancer pain treatment should be considered given the undertreatment rate, lack of benefits, and considerable risks associated with oral opioid medication in many patients who suffer from chronic cancer pain.
    Keywords:   intrathecal drug delivery systems; narrative review; opioids; undertreatment ; Cancer pain
  113. Crit Rev Oncol Hematol. 2022 May 26. pii: S1040-8428(22)00151-2. [Epub ahead of print] 103727
    Novel taxanes in development: hopes or hypes?
    Lei Lei, Xiao-Jia Wang, Shou-Ching Tang.
      Taxanes are the backbone cytotoxic agents that have been prescribed in most solid malignant treatments for decades. Taxane-induced peripheral neuropathy (PN) and drug resistance are inevitable. Novel taxanes include semisynthetic taxanes, taxane analogs, taxanes with a different drug-delivery method, taxanes without lipid carries, oral taxanes, taxanes with resistance to permeability glycoprotein (P-gp), and taxanes with easy penetration of the blood-brain barrier (BBB). Some taxanes have already shown promising activity in the clinic and have shown abilities to overcome the drug resistance commonly occurring with traditional taxane treatment. Predictive b for response to taxanes are being explored in order to offer precision medicine in cancer therapy. This review will focus on the history, current, and future directions of taxane development in breast cancer, especially that of novel taxanes such as oral taxanes. Clinical trials on novel taxanes, including the mature phase III trials of oral taxane and the recent setback, as well as the future direction of taxane research, will be discussed.
    Keywords:  Biomarkers; Breast cancer; Clinical trials; Novel taxanes; Oral formulation; Review
    DOI:  https://doi.org/10.1016/j.critrevonc.2022.103727
  114. Pharmacol Ther. 2022 May 27. pii: S0163-7258(22)00113-9. [Epub ahead of print] 108219
    The role of drug-metabolizing enzymes in synthetic lethality of cancer.
    Zekun Zeng, Wenfang Zheng, Peng Hou.
      Drug-metabolizing enzymes (DMEs) have shown increasing importance in anticancer therapy. It is not only due to their effect on activation or deactivation of anticancer drugs, but also because of their extensive connections with pathological and biochemistry changes during tumorigenesis. Meanwhile, it has become more accessible to discovery anticancer drugs that selectively targeted cancer cells with the development of synthetic lethal screen technology. Synthetic lethal strategy makes use of unique genetic markers that different cancer cells from normal tissues to discovery anticancer agents. Dysregulation of DMEs has been found in various cancers, making them promising candidates for synthetic lethal strategy. In this review, we will systematically discuss about the role of DMEs in tumor progression, the application of synthetic lethality strategy in drug discovery, and a link between DMEs and synthetic lethal of cancer.
    Keywords:  Drug discovery; Drug metabolizing enzymes (DMEs); Synthetic lethality; Tumor progression; cancer therapy
    DOI:  https://doi.org/10.1016/j.pharmthera.2022.108219
  115. Curr Cancer Drug Targets. 2022 Jun 02.
    The therapeutic potential of urolithin A for cancer treatment and prevention.
    Vladimir Rogovskii.
       BACKGROUND: Urolithin A is the metabolite of natural polyphenol ellagic acid and ellagitannins, generated by gut microbiota. Urolithin A is better absorbed in the gastrointestinal tract than its parent substances. Thus, the variable effects of ellagitannin-reach food (like pomegranate fruit, walnuts, tea, and others) on people's health might be linked with the differences in individual microbiota content. Urolithin A possesses various anti-inflammatory and anticancer effects, shown by in vivo and in vitro studies.
    OBJECTIVE: In the current review, we consider anti-inflammatory and direct anticancer urolithin A effects as well as their molecular mechanisms, which might be the basement of clinical trials, estimating urolithin A anticancer effects.
    CONCLUSION: Urolithin A attenuated the pro-inflammatory factors production (IL-6, IL-1β, NOS2 and others) in vitro studies. Oral urolithin A treatment caused prominent anticancer and anti-inflammatory action in various in vivo studies, including colitis rat model, carrageenan-induced paw edema mice model, models of pancreatic cancer, and models of obesity. The main molecular mechanisms of these effects might be the modulation of aryl hydrocarbon receptors, which antagonism may lead to decreasing of chronic inflammation. Other primary targets of urolithin A might be the processes of protein phosphorylation (for instance, it decreases the phosphorylation of protein kinase B) and p53 stabilization. Anti-inflammatory effects of urolithin A can be reached in physiologically relevant concentrations. This might be of vital importance for preventing immune suppression, associated with chronic inflammation in cancer. Considering the favorable urolithin A safety profile, it is the promising compound for cancer treatment and prevention.
    Keywords:  AhR antagonist; cancer; ellagitannins.; inflammation; polyphenols; urolithin A
    DOI:  https://doi.org/10.2174/1568009622666220602125343
  116. Front Cell Dev Biol. 2022 ;10 884412
    NADPH Oxidase 4: A Potential Therapeutic Target of Malignancy.
    Shulei Gong, Shiyang Wang, Mingrui Shao.
      Reactive oxygen species (ROS) play a crucial role in the regulation of tumor occurrence and development. As a main source of ROS, NADPH oxidases are key enzymes that mediate electron transport within intracellular membranes. Of the NOX members that have been reported to be dysregulated in a wide variety of tumors, NOX4 is the member to be most frequently expressed. Numerous studies have elucidated that NOX4 gets involved in the regulation of tumor proliferation, metastasis, therapy resistance, tumor-stromal interaction and dysregulated tumor metabolism. In this review, we primarily discussed the biological function of NOX4 in tumorigenesis and progression of multiple cancer models, including its role in activating oncogenic signaling pathways, rewiring the metabolic phenotype and mediating immune response. Besides, the development of NOX4 inhibitors has also been unraveled. Herein, we discussed the interplay between NOX4 and tumorigenesis, proposing NOX4 as a promising therapeutic target waiting for further exploration.
    Keywords:  NOX4; cancer; metabolism; reactive oxygen species; tumor microenevironment
    DOI:  https://doi.org/10.3389/fcell.2022.884412
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