bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2022–10–09
162 papers selected by
Yasmin Elkabani, Egyptian Foundation for Research and Community Development
  1. Therapeutic potential of genistein: preclinical studies, clinical evidence, and nanotechnology application.
  2. Clinical review of alkalization therapy in cancer treatment.
  3. Diverse antitumor effects of ascorbic acid on cancer cells and the tumor microenvironment.
  4. Anticancer potential of cryptotanshinone on breast cancer treatment; A narrative review.
  5. Medicinal plants' proposed nanocomposites for the management of endocrine disorders.
  6. Resveratrol in breast cancer treatment: from cellular effects to molecular mechanisms of action.
  7. Curcumin and berberine co-loaded liposomes for anti-hepatocellular carcinoma therapy by blocking the cross-talk between hepatic stellate cells and tumor cells.
  8. A smart nanoplatform for enhanced photo-ferrotherapy of hepatocellular carcinoma.
  9. Endoperoxides Compounds for Highly Efficient Cancer Treatment under Hypoxia.
  10. Polysaccharide-based porous biopolymers for enhanced bioaccessibility and bioavailability of bioactive food compounds: Challenges, advances, and opportunities.
  11. BRCA1 overexpression attenuates breast cancer cell growth and migration by regulating the pyruvate kinase M2-mediated Warburg effect via the PI3K/AKT signaling pathway.
  12. Bioconjugate-loaded solid lipid nanoparticles for enhanced anticancer drug delivery to brain cancer cells: An in vitro evaluation.
  13. Spotlight on Photoactivatable Liposomes beyond Drug Delivery: An Enabler of Multitargeting of Molecular Pathways.
  14. Characterization of resistant MCF-7 breast cancer cells developed by repeated cycles of photodynamic therapy.
  15. Targeted delivery of galbanic acid to colon cancer cells by PLGA nanoparticles incorporated into human mesenchymal stem cells.
  16. Synthesis and Characterization of a Novel Dual-Responsive Nanogel for Anticancer Drug Delivery.
  17. A revision of polymeric nanoparticles as a strategy to improve the biological activity of melatonin.
  18. Inhibition of alanine-serine-cysteine transporter 2-mediated auto-enhanced photodynamic cancer therapy of co-nanoassembly between V-9302 and photosensitizer.
  19. Targeted photodynamic therapy of glioblastoma mediated by platelets with photo-controlled release property.
  20. Nanotechnology for targeted drug delivery to treat osteoporosis.
  21. Potential Role of Phytochemical Extract from Saffron in Development of Functional Foods and Protection of Brain-Related Disorders.
  22. Differential glutamine metabolism in the tumor microenvironment - studies in diversity and heterogeneity: A mini-review.
  23. Mesoporous silica coated SPIONs containing curcumin and silymarin intended for breast cancer therapy.
  24. Superparamagnetic Tragacanth Coated Fe3O4@SiO2 Nanoparticles for the Loading and Delivery of Metformin.
  25. In situ Hydrogels for Effective Treatment of Cancer: Strategies and Polymers Used.
  26. Repurposing an Antiepileptic Drug for the Treatment of Glioblastoma.
  27. Ultrasonic-assisted extraction of swertisin from sour Jujube seed and comprehensive revelation of its antioxidant activity.
  28. Emerging photodynamic/sonodynamic therapies for urological cancers: progress and challenges.
  29. Natural Product-Inspired Targeted Protein Degraders: Advances and Perspectives.
  30. The Regulatory Effects of Traditional Chinese Medicine on Ferroptosis.
  31. Histone modification and histone modification-targeted anti-cancer drugs in breast cancer: Fundamentals and beyond.
  32. Progress on the efficacy and mechanism of action of panax ginseng monomer saponins treat toxicity.
  33. Targeting cancer stem cells with polymer nanoparticles for gastrointestinal cancer treatment.
  34. Advances in the development of cyclodextrin-based nanogels/microgels for biomedical applications: Drug delivery and beyond.
  35. Pharmacological effects and therapeutic potential of natural compounds in neuropsychiatric disorders: An update.
  36. Galangin inhibited ferroptosis through activation of the PI3K/AKT pathway in vitro and in vivo.
  37. Ascorbic acid-loaded gliadin nanoparticles as a novel nutraceutical formulation.
  38. Nonviral nanoparticle gene delivery into the CNS for neurological disorders and brain cancer applications.
  39. Covalent organic framework nanomedicines: Biocompatibility for advanced nanocarriers and cancer theranostics applications.
  40. Low Intensity Focused Ultrasound Ignited "Deep-Penetration Nanobomb" (DPNB) for Tetramodal Imaging Guided Hypoxia-Tolerant Sonodynamic Therapy Against Hypoxic Tumors.
  41. Spray-dried tenofovir alafenamide-chitosan nanoparticles loaded oleogels as a long-acting injectable depot system of anti-HIV drug.
  42. Ferroptosis: A novel therapeutic strategy and mechanism of action in glioma.
  43. Multifunctionality of Calebin A in inflammation, chronic diseases and cancer.
  44. Protective effect of microorganism biotransformation-produced resveratrol on the high fat diet-induced hyperlipidemia, hepatic steatosis and synaptic impairment in hamsters.
  45. Lipid nano-carriers loaded with Cannabis sativa extract for epilepsy treatment - in vitro characterization and in vivo efficacy studies.
  46. Physiology of PNS axons relies on glycolytic metabolism in myelinating Schwann cells.
  47. Physically stimulus-responsive nanoparticles for therapy and diagnosis.
  48. Pharmacology, Toxicology, and Rational Application of Cinnabar, Realgar, and Their Formulations.
  49. Aurora A-mediated pyruvate kinase M2 phosphorylation promotes biosynthesis with glycolytic metabolites and tumor cell cycle progression.
  50. Amygdalin as a chemoprotective agent in co-treatment with cisplatin.
  51. Gossypin: A flavonoid with diverse pharmacological effects.
  52. A new core-shell-type nanoparticle loaded with paclitaxel/norcantharidin and modified with APRPG enhances anti-tumor effects in hepatocellular carcinoma.
  53. Recent advances in medicinal and edible homologous polysaccharides: Extraction, purification, structure, modification, and biological activities.
  54. An Ethnopharmaceutical Study on the Hypolipidemic Formulae in Taiwan Issued by Traditional Chinese Medicine Pharmacies.
  55. Multifunctional light-activatable nanocomplex conducting temperate-heat photothermal therapy to avert excessive inflammation and trigger augmented immunotherapy.
  56. Upconverting nanoparticle-containing erythrocyte-sized hemoglobin microgels that generate heat, oxygen and reactive oxygen species for suppressing hypoxic tumors.
  57. A review: Pharmacokinetics and pharmacology of aminoalcohol-diterpenoid alkaloids from Aconitum species.
  58. The Role of Natural Products as Inhibitors of JAK/STAT Signaling Pathways in Glioblastoma Treatment.
  59. Strategies for the drug discovery and development of taxane anticancer therapeutics.
  60. Mitophagy: A novel perspective for insighting into cancer and cancer treatment.
  61. A straightforward access to trifluoromethylated natural products through late-stage functionalization.
  62. Potential Functional Food Products and Molecular Mechanisms of Portulaca Oleracea L. on Anticancer Activity: A Review.
  63. A novel approach of encapsulating curcumin and succinylated derivative in mannosylated-chitosan nanoparticles.
  64. Near-infrared light-responsive and antibacterial injectable hydrogels with antioxidant activity based on a Dopamine-functionalized Gellan Gum for wound healing.
  65. Pineapple processing waste (PPW): bioactive compounds, their extraction, and utilisation: a review.
  66. Anticancer peptides mechanisms, simple and complex.
  67. Biomimetic cell membrane-coated glucose/oxygen-exhausting nanoreactor for remodeling tumor microenvironment in targeted hypoxic tumor therapy.
  68. Sesquiterpenoid lactones as potential anti-cancer agents: an update on molecular mechanisms and recent studies.
  69. Bio-inspired engineered ferritin-albumin nanocomplexes for targeted ferroptosis therapy.
  70. Pharmacological and phytochemical potential of Rubus ellipticus: a wild edible with multiple health benefits.
  71. A network pharmacology approach to evaluate the synergistic effect of dihydromyricetin and myricitrin in vine tea on the proliferation of B16F10 cells.
  72. Oxidized Chitin Nanocrystals Greatly Strengthen the Stability of Resveratrol-Loaded Gliadin Nanoparticles.
  73. Polypseudorotaxane hydrogel based on Tween 80 and α-cyclodextrin for sustained delivery of low molecular weight heparin.
  74. Lagenaria siceraria fruit: A review of its phytochemistry, pharmacology, and promising traditional uses.
  75. Pharmacological effects of higenamine based on signalling pathways and mechanism of action.
  76. Three-layer core-shell structure of polypyrrole/polydopamine/poly(l-lactide) nanofibers for wound healing application.
  77. Preclinical development of carrier-free prodrug nanoparticles for enhanced antitumor therapeutic potential with less toxicity.
  78. Novel Nanostructured Lipid Carriers Co-Loaded with Mesalamine and Curcumin: Formulation, Optimization and In Vitro Evaluation.
  79. Recent progress and research trend of anti-cataract pharmacology therapy: A bibliometric analysis and literature review.
  80. Evolving spectrum of diabetic wound: Mechanistic insights and therapeutic targets.
  81. Focus on diet and exercise.
  82. Chitosan suspension as extractor and encapsulating agent of phenolics from acerola by-product.
  83. TRIM35 ubiquitination regulates the expression of PKM2 tetramer and dimer and affects the malignant behaviour of breast cancer by regulating the Warburg effect.
  84. Ameliorative Effect of Bouea macrophylla Griffth Seed Extract Against Bacteria-Induced Acne Inflammation: in vitro study.
  85. Effects of ferulic acid, a major component of rice bran, on proliferation, apoptosis, and autophagy of HepG2 cells.
  86. The Complex Composition of Trans-resveratrol, Quercetin, Vitamin E and Selenium Inhibits the Growth of Colorectal Carcinoma.
  87. Modernization of a traditional Siddha medicine Paccai eruvai into a novel nanogel formulation for the potent wound healing activity-A Phyto-Pharmaceutical approach.
  88. The botanical profile, phytochemistry, biological activities and protected-delivery systems for purple sweet potato (Ipomoea batatas (L.) Lam.): An up-to-date review.
  89. NSAID Hypersensitivity in the Pediatric Population: Classification and Diagnostic Strategies.
  90. Dietary compounds slow starch enzymatic digestion: A review.
  91. Properties of flavonoids in the treatment of bladder cancer (Review).
  92. Synthesis of glycyrrhetinic acid-modified liposomes to deliver Murrayafoline A for treatment of hepatocellular carcinoma.
  93. Neuroprotective potential of Moringa oleifera mediated by NF-kB/Nrf2/HO-1 signaling pathway: A review.
  94. Thioridazine combined with carboplatin results in synergistic inhibition of triple negative breast cancer by targeting cancer stem cells.
  95. Resveratrol activates the SIRT1/PGC-1 pathway in mice to improve synaptic-related cognitive impairment after TBI.
  96. Silk peptide-hyaluronic acid based nanogels for the enhancement of the topical administration of curcumin.
  97. Microenvironment immune response induced by tumor ferroptosis-the application of nanomedicine.
  98. Boosting immunotherapy of triple negative breast cancer through the synergy of mild PTT and Fe-loaded organosilica nanoparticles.
  99. The impact of cycleanine in cancer research: a computational study.
  100. Tumor microenvironment adrenergic nerves blockade liposomes for cancer therapy.
  101. Nanozymes for Regenerative Medicine.
  102. Soft nano and microstructures for the photomodulation of cellular signaling and behavior.
  103. A Polymer Prodrug Strategy to Switch from Intravenous to Subcutaneous Cancer Therapy for Irritant/Vesicant Drugs.
  104. Accelerating skin regeneration and wound healing by controlled ROS from photodynamic treatment.
  105. Effects of curcumin and/or coenzyme Q10 supplementation on metabolic control in subjects with metabolic syndrome: a randomized clinical trial.
  106. Chemical diversity, medicinal potentialities, biosynthesis, and pharmacokinetics of anthraquinones and their congeners derived from marine fungi: a comprehensive update.
  107. Ethanolic extract of root from Arctium lappa L ameliorates obesity and hepatic steatosis in rats by regulating the AMPK/ACC/CPT-1 pathway.
  108. The Role of Vitamins in DNA Methylation as Dietary Supplements or Neutraceuticals: A systematic review.
  109. Antinociceptive effect of plant-based natural products in chemotherapy-induced peripheral neuropathies: A systematic review.
  110. Injectable, Self-Healing and Multiple Responsive Histamine modified Hyaluronic Acid Hydrogels with Potentialities in Drug Delivery, Antibacterial and Tissue Engineering.
  111. "Disruption of the molecular clock severely affects lipid metabolism in a Hepatocellular Carcinoma Cell model".
  112. Development and Evaluation of Puerarin Loaded-Albumin Nanoparticles Thermoresponsive in situ Gel for Ophthalmic Delivery.
  113. Potential For Novel Therapeutic Uses Of Alpha Lipoic Acid.
  114. Promising influences of gingerols against metabolic syndrome: A mechanistic review.
  115. Diet and nutrition against inflammatory bowel disease: Trick or treat(ment)?
  116. Rapamycin inhibits oral cancer cell growth by promoting oxidative stress and suppressing ERK1/2, NF-κB and beta-catenin pathways.
  117. Upregulation of an estrogen receptor-regulated gene by first generation progestins requires both the progesterone receptor and estrogen receptor alpha.
  118. A Sonication-Activated Valence-Variable Sono-Sensitizer/Catalyst for Autography Inhibition/Ferroptosis-Induced Tumor Nanotherapy.
  119. Multiomic characterization and drug testing establish circulating tumor cells as an ex vivo tool for personalized medicine.
  120. The effects of L-carnitine-loaded solid lipid nanoparticles on performance, antioxidant parameters, and expression of genes associated with cholesterol metabolism in laying hens.
  121. Antitumor Potential of Sericite Treatment Mediated by Cell Cycle Arrest in Triple-Negative MDA-MB231 Breast Cancer Cells.
  122. An Overview on Plant Derived Phenolic Compounds and Their Role in Treatment and Management of Diabetes.
  123. Acyl Glucuronide and Coenzyme A Thioester Metabolites of Carboxylic Acid-Containing Drug Molecules: Layering Chemistry with Reactive Metabolism and Toxicology.
  124. Dendrimer-based delivery of macromolecules for the treatment of brain tumor.
  125. Hexokinase 2 Is a Pivot for Lovastatin-induced Glycolysis-to-Autophagy Reprogramming in Triple-Negative Breast Cancer Cells.
  126. Long non-coding RNAs affecting cell metabolism in cancer.
  127. Sepsis-induced AKI: From pathogenesis to therapeutic approaches.
  128. Comparative study on the phenolic composition and in vitro bioactivity of medicinal and aromatic plants from the Lamiaceae family.
  129. Engineering the right formulation for enhanced drug delivery.
  130. Systems Network Pharmacology-Based Prediction and Analysis of Potential Targets and Pharmacological Mechanism of Actinidia chinensis Planch. Root Extract for Application in Hepatocellular Carcinoma.
  131. Amelioration of hydrolyzed guar gum on high-fat diet-induced obesity: Integrated hepatic transcriptome and metabolome.
  132. Salvia miltiorrhiza in thorax and abdomainal organ fibrosis: A review of its pharmacology.
  133. Eupalinolide O Induces Apoptosis in Human Triple-Negative Breast Cancer Cells via Modulating ROS Generation and Akt/p38 MAPK Signaling Pathway.
  134. Fourier Transform Infrared Spectroscopy (FT-IR) of Pseudomonas aeruginosa post photodynamic therapy with Curcumin in vitro.
  135. Glycolysis in tumor microenvironment as a target to improve cancer immunotherapy.
  136. Ultrasound-modified protein-based colloidal particles: Interfacial activity, gelation properties, and encapsulation efficiency.
  137. Potential benefits of joint hypothetical interventions on diet, lead, and cadmium on mortality in US adults.
  138. Colon cancer and colorectal cancer: Prevention and treatment by potential natural products.
  139. Taming glutathione potentiates metallodrug action.
  140. [mTOR complex activity and metabolic changes as potential targets in solid tumors].
  141. A dual-responsive polydopamine-modified hydroxybutyl chitosan hydrogel for sequential regulation of bone regeneration.
  142. Modified Atkins diet versus ketogenic diet in children with drug-resistant epilepsy: A meta-analysis of comparative studies.
  143. Targeting K-Ras Mutations Show Promise Towards Ending Ras's "Undruggable" Era.
  144. Studying the Anticancer Effects of Thymoquinone on Breast Cancer Cells through Natural Killer Cell Activity.
  145. Photobiomodulation for the treatment of neuroinflammation: A systematic review of controlled laboratory animal studies.
  146. Catalytic Biomaterials and Nanomedicines with Exogenous and Endogenous Activations.
  147. A critical review on starch-based electrospun nanofibrous scaffolds for wound healing application.
  148. Counteracting Side-effects of Photodynamic Therapy for Actinic Keratoses.
  149. Effects of zinc supplementation on glycemic control and oxidative stress in experimental diabetes: A systematic review.
  150. Ferroptosis in Intracerebral Hemorrhage: A Panoramic Perspective of the Metabolism, Mechanism and Theranostics.
  151. Five centuries of Cirsium ehrenbergii Sch. Bip. (Asteraceae) in Mexico, from Huitzquilitl to Cardo Santo: History, ethnomedicine, pharmacology and chemistry.
  152. Anti-HMG-CoA Reductase, Anti-diabetic, Anti-urease, Anti-tyrosinase and Anti-leukemia Cancer Potentials of Panicolin as a Natural Compound:In vitro and in silico Study.
  153. Human serum albumin-poly(Lactide)-conjugated self-assembly NPs for targeted docetaxel delivery and improved therapeutic efficacy in oral cancer.
  154. Efficacy and acceptability of blue-wavelength light therapy for post-TBI behavioral symptoms: A systematic review and meta-analysis of randomized controlled trials.
  155. Critique of Public Health Guidance for Vitamin D and Sun Exposure in the Context of Cancer and COVID-19.
  156. A bright horizon of intelligent targeted-cancer therapy: nanoparticles against breast cancer stem cells.
  157. Enzymatic synthesis of ascorbyl oleate and evaluation of biological activities.
  158. A Systematic Review of Apoptosis in Correlation With Cancer: Should Apoptosis Be the Ultimate Target for Cancer Treatment?
  159. Role of insulin in pancreatic microcirculatory oxygen profile and bioenergetics.
  160. Relationship between Vitamin D level and metabolic parameters in obese children and response to Vitamin D treatment.
  161. Aerosolised micro and nanoparticle: formulation and delivery method for lung imaging.
  162. Preparation, properties and interaction of curcumin loaded zein/HP-β-CD nanoparticles based on electrostatic interactions by antisolvent co-precipitation.
  1. Curr Med Chem. 2022 Oct 04.
    Therapeutic potential of genistein: preclinical studies, clinical evidence, and nanotechnology application.
    Ana Joyce Coutinho, Marina Pinheiro, Ana Rute Neves, Madalena M M Pinto.
      Genistein (4',5,7-trihydroxyisoflavone) is a natural plant-derived phytoestrogen that can be found, for example, in soybean seeds. Genistein is present mainly in the human diet and is a common precursor in the antimicrobial phytoalexins biosynthesis and phytoanticipins in vegetables. The interest in genistein has increased due to its pharmacological effects, including anti-cancer activity, neuroprotective effects, cardiovascular protection, anti-inflammatory effects, antioxidant activity, and prevention of obesity. The most challenging issue for improving genistein is its low oral bioavailability, which has led to many animal and human pharmacokinetic studies and numerous clinical trials. Several drug delivery systems have been developed to protect and stabilize genistein to overcome the challenge of low bioavailability. This work concerns a revision of the literature reporting nano and microformulations for genistein encapsulation, including lipid nanoparticles, liposomes, tocotrienol-rich nanoemulsions, polymeric nanoparticles, dextran complexes, chitosan complexes, and Fe3O4 nanoparticles with carboxymethylated chitosan. Regarding the enormous potential of genistein, several clinical trials and marketed formulations can be found in the market.
    Keywords:  Genistein; clinical studies; drug delivery systems; nanotechnology; phytoestrogen; pleiotropic actions
    DOI:  https://doi.org/10.2174/0929867329666221004124800
  2. Front Oncol. 2022 ;12 1003588
    Clinical review of alkalization therapy in cancer treatment.
    Reo Hamaguchi, Masahide Isowa, Ryoko Narui, Hiromasa Morikawa, Hiromi Wada.
      One of the most unique characteristics of cancer metabolism is activated aerobic glycolysis, which is called the "Warburg effect", and is a hallmark of cancer. An acidic tumor microenvironment (TME) resulting from activated anaerobic glycolysis is associated with cancer progression, multi-drug resistance, and immune escape. Several in vitro and in vivo studies reported that neutralization of the acidic TME by alkalizing agents, such as bicarbonate, resulted in the suppression of cancer progression and a potential benefit for anti-cancer drug responses. In clinical settings, alkalizing effects were achieved not only by alkalizing agents, but also by a following a particular diet. An epidemiological study demonstrated that more fruits and vegetables and less meat and dairy products are associated with an increase in urine pH, which may reflect the alkalizing effect on the body. However, it remains unclear whether alkaline dietary intervention improves the effects of cancer treatment. Moreover, there are few clinical reports to date regarding cancer treatments being performed on patients together with alkalization therapy. In this review, we investigated whether alkalization therapy, which includes an alkaline diet and/or alkalizing agents, improves cancer treatment.
    Keywords:  alkalization therapy; cancer; cancer metabolism; chemotherapy; tumor microenvironment; urine pH
    DOI:  https://doi.org/10.3389/fonc.2022.1003588
  3. Front Oncol. 2022 ;12 981547
    Diverse antitumor effects of ascorbic acid on cancer cells and the tumor microenvironment.
    Takeru Maekawa, Toru Miyake, Masaji Tani, Shinji Uemoto.
      Ascorbic acid has attracted substantial attention for its potential antitumor effects by acting as an antioxidant in vivo and as a cofactor in diverse enzymatic reactions. However, solid proof of its clinical efficacy against cancer and the mechanism behind its effect have not been established. Moreover, cancer forms cancer-specific microenvironments and interacts with various cells, such as cancer-associated fibroblasts (CAFs), to maintain cancer growth and progression; however, the effect of ascorbic acid on the cancer microenvironment is unclear. This review discusses the effects and mechanisms of ascorbic acid on cancer, including the role of ascorbic acid concentration. In addition, we present future perspectives on the effects of ascorbic acid on cancer cells and the CAF microenvironment. Ascorbic acid has a variety of effects, which contributes to the complexity of these effects. Oral administration of ascorbic acid results in low blood concentrations (<0.2 mM) and acts as a cofactor for antioxidant effects, collagen secretion, and HIFα degradation. In contrast, intravenous treatment achieves large blood concentrations (>1 mM) and has oxidative-promoting actions that exert anticancer effects via reactive oxygen species. Therefore, intravenous administration at high concentrations is required to achieve the desired effects on cancer cells during treatment. Partial data on the effect of ascorbic acid on fibroblasts indicate that it may also modulate collagen secretion in CAFs and impart tumor-suppressive effects. Thus, future studies should verify the effect of ascorbic acid on CAFs. The findings of this review can be used to guide further research and clinical trials.
    Keywords:  antioxidant; antitumor effect; ascorbic acid; cancer; cancer-associated fibroblast; intravenous administration
    DOI:  https://doi.org/10.3389/fonc.2022.981547
  4. Front Pharmacol. 2022 ;13 979634
    Anticancer potential of cryptotanshinone on breast cancer treatment; A narrative review.
    Davood Dalil, Saeid Iranzadeh, Soroush Kohansal.
      Breast cancer has recently been known as the first lethal malignancy in women worldwide. Despite the existing treatments that have improved the patients' prognosis, some types of breast cancer are serious challenges to treat. Therefore, efforts are underway to provide more efficient therapy. Cryptotanshinone (CPT) is a liposoluble diterpenoid derivation of a traditional Chinese herbal medicine called Salvia miltiorrhiza Bunge. It has been considered in the past decades due to its vast therapeutic properties, including anti-tumor, anti-inflammatory, and anti-fibrosis. Recently, studies have found that CPT showed a significant anti-breast cancer effect in vivo and in vitro through different physiological and immunological mechanisms. This study summarized the latest research findings on the antitumor effect of CPT in breast cancer. Further, the main molecular mechanisms based on breast cancer types and combination with other drugs were reviewed to provide essential evidence for future longitudinal research and its clinical application in breast cancer treatment.
    Keywords:  breast cancer; cryptotanshinon; drug combination; estrogen receptor; molecular mechanism; salvia miltiorrhiza; tanshinone C
    DOI:  https://doi.org/10.3389/fphar.2022.979634
  5. Heliyon. 2022 Sep;8(9): e10665
    Medicinal plants' proposed nanocomposites for the management of endocrine disorders.
    Raghdaa Hamdan Al Zarzour, Ezatul Ezleen Kamarulzaman, Fadi G Saqallah, Fauziahanim Zakaria, Muhammad Asif, Khairul Niza Abdul Razak.
      Extensive attention has been focused on herbal medicine for the treatment of different endocrine disorders. In fact, compelling scientific evidence indicates that natural compounds might act as endocrine modulators by mimicking, stimulating, or inhibiting the actions of different hormones, such as thyroid, sex, steroidal, and glucose regulating hormones. These potentials might be effectively employed for therapeutic purposes related to the endocrine system as novel complementary choices. Nevertheless, despite the remarkable therapeutic effects, inadequate targeting efficiency and low aqueous solubility of the bioactive components are still essential challenges in their clinical accreditation. On the other hand, nanotechnology has pushed the wheels of combining inorganic nanoparticles with biological structures of medicinal bioactive compounds as one of the utmost exciting fields of research. Nanoparticle conjugations create an inclusive array of applications that provide greater compliance, higher bioavailability, and lower dosage. This can safeguard the global availability of these wealthy natural sources, regardless of their biological occurrence. This review inspects future challenges of medicinal plants in various endocrine disorders for safe and alternative treatments with examples of their nanoparticle formulations.
    Keywords:  Diabetes mellitus; Endocrine disorders; Medicinal plants; Nanoparticles; Steroidal effects; Thyroid
    DOI:  https://doi.org/10.1016/j.heliyon.2022.e10665
  6. Cell Mol Life Sci. 2022 Oct 04. 79(11): 539
    Resveratrol in breast cancer treatment: from cellular effects to molecular mechanisms of action.
    Mitra Behroozaghdam, Maryam Dehghani, Amirhossein Zabolian, Davood Kamali, Salar Javanshir, Farzaneh Hasani Sadi, Mehrdad Hashemi, Teimour Tabari, Mohsen Rashidi, Sepideh Mirzaei, Atefeh Zarepour, Ali Zarrabi, Danielle De Greef, Anupam Bishayee.
      Breast cancer (BC) is one of the most common cancers in females and is responsible for the highest cancer-related deaths following lung cancer. The complex tumor microenvironment and the aggressive behavior, heterogenous nature, high proliferation rate, and ability to resist treatment are the most well-known features of BC. Accordingly, it is critical to find an effective therapeutic agent to overcome these deleterious features of BC. Resveratrol (RES) is a polyphenol and can be found in common foods, such as pistachios, peanuts, bilberries, blueberries, and grapes. It has been used as a therapeutic agent for various diseases, such as diabetes, cardiovascular diseases, inflammation, and cancer. The anticancer mechanisms of RES in regard to breast cancer include the inhibition of cell proliferation, and reduction of cell viability, invasion, and metastasis. In addition, the synergistic effects of RES in combination with other chemotherapeutic agents, such as docetaxel, paclitaxel, cisplatin, and/or doxorubicin may contribute to enhancing the anticancer properties of RES on BC cells. Although, it demonstrates promising therapeutic features, the low water solubility of RES limits its use, suggesting the use of delivery systems to improve its bioavailability. Several types of nano drug delivery systems have therefore been introduced as good candidates for RES delivery. Due to RES's promising potential as a chemopreventive and chemotherapeutic agent for BC, this review aims to explore the anticancer mechanisms of RES using the most up to date research and addresses the effects of using nanomaterials as delivery systems to improve the anticancer properties of RES.
    Keywords:  Apoptosis; Breast cancer; Drug resistance; Nano-scale delivery; Radiotherapy; Resveratrol
    DOI:  https://doi.org/10.1007/s00018-022-04551-4
  7. Front Pharmacol. 2022 ;13 961788
    Curcumin and berberine co-loaded liposomes for anti-hepatocellular carcinoma therapy by blocking the cross-talk between hepatic stellate cells and tumor cells.
    Jingliang Wu, Cuiping Qi, Hao Wang, Qing Wang, Jingui Sun, Jinping Dong, Guohua Yu, Zhiqin Gao, Bo Zhang, Guixiang Tian.
      Cancer-associated fibroblasts (CAFs) are a major component of the tumor microenvironment (TME). In hepatocellular carcinoma (HCC), quiescent hepatic stellate cells (HSCs) could be activated to become CAFs, which play a critical role in tumor progression and drug resistance. Therefore, recent efforts have been focused on combining anti-HSC and pro-apoptotic activities to improve anti-tumor efficacy of drugs. In this study, glycyrrhetinic acid and hyaluronic acid-modified liposomes (GA-HA-Lip) were prepared for co-delivery of curcumin (CUR) and berberine (BBR) for the treatment of HCC. Furthermore, we established the LX-2+BEL-7402 co-cultured cell model and implanted the m-HSCs+H22 cells into a mouse to evaluate the anti-tumor effect of CUR&BBR/GA-HA-Lip both in vitro and in vivo. The results showed that CUR&BBR/GA-HA-Lip could accumulate in tumor tissues and be taken up by HSCs and BEL-7402 cells simultaneously. Compared with free CUR, the combination therapy based on GA-HA-Lip exhibits stronger pro-apoptotic and anti-proliferation effect both in vitro and in vivo. The anti-tumor mechanistic study revealed that CUR&BBR/GA-HA-Lip could inhibit the activation of HSCs and restrain drug resistance of tumor cells. In summary, CUR&BBR/GA-HA-Lip could be a promising nano-sized formulation for anti-tumor therapy.
    Keywords:  berberine; combination therapy; curcumin; delivery; liposomes
    DOI:  https://doi.org/10.3389/fphar.2022.961788
  8. Front Bioeng Biotechnol. 2022 ;10 1022330
    A smart nanoplatform for enhanced photo-ferrotherapy of hepatocellular carcinoma.
    Longguang Tang, Mingjian Ling, Madiha Zahra Syeda, Rui Sun, Minghui He, Qingchun Mu, Xiulong Zhu, Chunming Huang, Liao Cui.
      Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Emerging therapies, such as ferroptosis mediated cancer therapy and phototherapy, offer new opportunities for HCC treatment. The combination of multiple treatments is often more effective than monotherapy, but many of the current treatments are prone to serious side effects, resulting in a serious decline in patients' quality of life. Therefore, the combination therapy of tumor in situ controllable activation will improve the efficacy and reduce side effects for precise treatment of tumor. Herein, we synthesized a GSH-activatable nanomedicine to synergize photothermal therapy (PTT) and ferrotherapy. We utilized a near-infrared dye SQ890 as both an iron-chelating and a photothermal converter agent, which was encapsulated with a GSH-sensitive polymer (PLGA-SS-mPEG), to attain the biocompatible SQ890@Fe nanoparticles (NPs). In the tumor microenvironment (TME), SQ890@Fe NPs showed a GSH-activated photothermal effect that could increase the Fenton reaction rate. Meanwhile, the depletion of GSH could further increase ferroptosis effect. In turn, the increasing radical generated by ferrotherapy could impair the formation of heat shock proteins (HSPs) which could amplify PTT effects by limiting the self-protection mechanism. Overall, the intelligent nanomedicine SQ890@Fe NPs combines ferrotherapy and PTT to enhance the efficacy and safety of cancer treatment through the mutual promotion of the two treatment mechanisms, providing a new dimension for tumor combination therapy.
    Keywords:  GSH; PTT; ferrotherapy; hepatocellular carcinoma; nanoparticle
    DOI:  https://doi.org/10.3389/fbioe.2022.1022330
  9. Chemistry. 2022 Oct 02.
    Endoperoxides Compounds for Highly Efficient Cancer Treatment under Hypoxia.
    Li Wei, Zhishang Zhang, Ashish Kumar, Samya Banerjee, Huaiyi Huang.
      Photodynamic therapy (PDT) for cancer treatment has garnered great attention, with promising non-invasiveness, low side effects, and spatiotemporal selectivity. However, the hypoxic microenvironment in solid tumours remains a serious resistant factor to limit PDT effects. Endoperoxides are always utilized as chemical storage or supplier of singlet oxygen ( 1 O 2 ), the active substance for PDT in materials and other domains. Recent reports indicated that this type of compounds could remarkably enhance the therapeutic effects of PDT under hypoxia. This concept mainly introduces a few representative endoperoxides and outlook of their potent application for the treatment of hypoxic cancer cells.
    Keywords:  Photodynamic therapy * endoperoxides * singlet oxygen * anticancer * hypoxia
    DOI:  https://doi.org/10.1002/chem.202202233
  10. Compr Rev Food Sci Food Saf. 2022 Oct 05.
    Polysaccharide-based porous biopolymers for enhanced bioaccessibility and bioavailability of bioactive food compounds: Challenges, advances, and opportunities.
    Ali Ubeyitogullari, Safoura Ahmadzadeh, Gurshagan Kandhola, Jin-Woo Kim.
      Bioactive food compounds, such as lycopene, curcumin, phytosterols, and resveratrol, have received great attention due to their potential health benefits. However, these bioactive compounds (BCs) have poor chemical stability during processing and low bioavailability after consumption. Several delivery systems have been proposed for enhancing their stability and bioavailability. Among these methods, porous biopolymers have emerged as alternative encapsulation materials, as they have superior properties like high surface area, porosity, and tunable surface chemistry to entrap BCs. This reduces the crystallinity (especially for the lipophilic ones) and particle size, and in turn, increases solubilization and bioavailability. Also, loading BCs into the porous matrix can protect them against environmental stresses such as light, heat, oxygen, and pH. This review introduces polysaccharide-based porous biopolymers for improving the bioaccessibility/bioavailability of bioactive food compounds and discusses their recent applications in the food industry. First, bioaccessibility and bioavailability are described with a special emphasis on the factors affecting them. Then, porous biopolymer fabrication methods, including supercritical carbon dioxide (SC-CO2 ) drying, freeze-drying, and electrospinning and electrospraying, are thoroughly discussed. Finally, common polysaccharide-based biopolymers (i.e., starch, nanocellulose, alginate, and pectin) used for generating porous materials are reviewed, and their current and potential future food applications are critically discussed.
    Keywords:  bioaccessibility; bioactive compounds; bioavailability; biopolymers; porous
    DOI:  https://doi.org/10.1111/1541-4337.13049
  11. PeerJ. 2022 ;10 e14052
    BRCA1 overexpression attenuates breast cancer cell growth and migration by regulating the pyruvate kinase M2-mediated Warburg effect via the PI3K/AKT signaling pathway.
    Xiuli Liu, Hanxu Liu, Lei Zeng, Yuetao Lv.
      This work explored the mechanism of the effect of breast-cancer susceptibility gene 1 (BRCA1) on the metabolic characteristics of breast cancer cells, including the Warburg effect and its specific signaling. We transfected MCF-7 cells with a BRCA1-encoding LXSN plasmid or PKM2 siRNA and examined cancer cell metabolism using annexin V staining, inhibitory concentration determination, Western blotting, glucose uptake and lactic acid content measurements, and Transwell assays to assess glycolytic activity, cell apoptosis, and migration, and sensitivity to anti-cancer treatment. The BRCA1-expressing MCF-7 cells demonstrated low PKM2 expression and decreased glycolytic activity (downregulated hexokinase 2 (HK2) expression, upregulated isocitrate dehydrogenase 1 (IDH1) expression, and reduced O2 and glucose consumption and lactate production) via regulation of PI3K/AKT pathway compared with the empty LXSN group. BRCA1 transfection slightly increased apoptotic activity, decreased cell migration, and increased the IC50 index for doxorubicin, paclitaxel, and cisplatin. Inhibiting PKM2 using siRNA attenuated the IC50 index for doxorubicin, paclitaxel, and cisplatin compared with the control. Inhibiting PKM2 activated PI3K/AKT signaling, increased apoptosis, and decreased MCF-7 cell migration. Our data suggest that BRCA1 overexpression reverses the Warburg effect, inhibits cancer cell growth and migration, and enhances the sensitivity to anti-cancer treatment by decreasing PKM2 expression regulated by PI3K/AKT signaling. These novel metabolic findings represent a potential mechanism by which BRCA1 exerts its inhibitory effect on breast cancer.
    Keywords:  BRCA1; Breast cancer cell; Glycolysis; PI3K/Akt; PKM2
    DOI:  https://doi.org/10.7717/peerj.14052
  12. Indian J Med Res. 2022 Oct 03.
    Bioconjugate-loaded solid lipid nanoparticles for enhanced anticancer drug delivery to brain cancer cells: An in vitro evaluation.
    Priyanka Jain, Vikas Pandey, Vandana Soni.
       Background & objectives: The treatment of brain cancer is still challenging for an oncologist due to the presence of the blood-brain barrier (BBB) which inhibits the entry of more than 98 per cent of drugs used during the treatment of brain disease. The cytotoxic drugs used in chemotherapy for brain cancer treatment also affect the normal cells due to lack of targeting. Therefore, the objective of the study was to develop tween 80-coated solid lipid nanoparticles (SLNs) loaded with folic acid-doxorubicin (FAD) conjugate for site-specific drug delivery to brain cancer cells.
    Methods: The FAD conjugate was synthesized by the conjugation of folic acid with doxorubicin and characterized by Fourier transform infrared spectroscopy and proton nuclear magnetic resonance spectroscopy. SLNs loaded with FAD were prepared by the solvent injection method. The SLNs were characterized by the particle size, zeta potential, surface morphology, entrapment efficiency, etc.
    Results: The average particle size of FAD conjugate-loaded SLNs (SLN-C) was found to be 220.4±2.2 nm, with 36.2±0.6 per cent entrapment efficiency. The cytotoxicity and cellular uptake were determined on U87 MG cell lines. Half maximal inhibitory concentration value of the SLN-C was found to be 2.5 μg/ml, which confirmed the high antitumor activity against brain cancer cells.
    Interpretation & conclusions: The cell line studies confirmed the cytotoxicity and internalization of SLN-C in U87 MG brain cancer cells. The results confirmed that tween 80-coated SLNs have the potential to deliver the doxorubicin selectively in the brain cancer cells.
    Keywords:  Brain cancer - conjugate - doxorubicin - folic acid - solid lipid nanoparticles
    DOI:  https://doi.org/10.4103/ijmr.IJMR_514_19
  13. Bioconjug Chem. 2022 Oct 05.
    Spotlight on Photoactivatable Liposomes beyond Drug Delivery: An Enabler of Multitargeting of Molecular Pathways.
    Mohammad A Saad, Tayyaba Hasan.
      The potential of photoactivating certain molecules, photosensitizers (PS), resulting in photochemical processes, has long been realized in the form of photodynamic therapy (PDT) for the management of several cancerous and noncancerous pathologies. With an improved understanding of the photoactivation process and its broader implications, efforts are being made to exploit the various facets of photoactivation, PDT, and the associated phenomenon of photodynamic priming in enhancing treatment outcomes, specifically in cancer therapeutics. The parallel emergence of nanomedicine, specifically liposome-based nanoformulations, and the convergence of the two fields of liposome-based drug delivery and PDT have led to the development of unique hybrid systems, which combine the exciting features of liposomes with adequate complementation through the photoactivation process. While initially liposomes carrying photosensitizers (PSs) were developed for enhancing the pharmacokinetics and the general applicability of PSs, more recently, PS-loaded liposomes, apart from their utility in PDT, have found several applications including enhanced targeting of drugs, coloading multiple therapeutic agents to enhance synergistic effects, imaging, priming, triggering drug release, and facilitating the escape of therapeutic agents from the endolysosomal complex. This review discusses the design strategies, potential, and unique attributes of these hybrid systems, with not only photoactivation as an attribute but also the ability to encapsulate multiple agents for imaging, biomodulation, priming, and therapy referred to as photoactivatable multiagent/inhibitor liposomes (PMILS) and their targeted versions─targeted PMILS (TPMILS). While liposomes have formed their own niche in nanotechnology and nanomedicine with several clinically approved formulations, we try to highlight how using PS-loaded liposomes could address some of the limitations and concerns usually associated with liposomes to overcome them and enhance their preclinical and clinical utility in the future.
    DOI:  https://doi.org/10.1021/acs.bioconjchem.2c00376
  14. Front Pharmacol. 2022 ;13 964141
    Characterization of resistant MCF-7 breast cancer cells developed by repeated cycles of photodynamic therapy.
    Eric Chekwube Aniogo, Blassan P George, Heidi Abrahamse.
      Breast cancer mainly affects women and causes a severe global threat to health. It is often managed and treated with surgery, chemotherapy, immunotherapy, and radiation therapy. Generally, chemotherapy as a treatment option is often opposed by responsive tumor relapse and development of resistance, a significant setback of current treatment. Photodynamic therapy (PDT) offers a promising modality that can treat cancer by combining a photosensitizer and laser irradiation in the presence of oxygen. However, one problem of PDT in treating breast cancer is the apparition of the resistant cell population. Thus, we aimed for stepwise selection and characterization of MCF-7 cells resistant to PDT with a sulfonated zinc phthalocyanine (ZnPcS4) photosensitizer. The wild-type MCF-7 was exposed to successive cycles of ZnPcS4-PDT, and 10resistant populations were finally obtained. In wild-type and parental cells, we analyzed the cell morphology (light microscopy), cell cycle (BrdU staining), cell viability (MTT assay), antioxidant activity (superoxide dismutase measurement), and immunofluorescence expression of resistant p-glycoprotein (P-gp). The results indicate that resistant cells showed a mesenchymal cell phenotype, few differences in antioxidant activity, an increased DNA synthesis, and more expression of P-gp than the wild-type parental cells. These distinctive features of resistant cells can provide insight into the emergence of MCF-7 cell resistance to PDT, which was necessary to design the best therapeutic procedure for improved efficacy.
    Keywords:  MCF-7 cells; breast cancer; multidrug resistance; p-glycoprotein; photodynamic therapy
    DOI:  https://doi.org/10.3389/fphar.2022.964141
  15. Avicenna J Phytomed. 2022 May-Jun;12(3):12(3): 295-308
    Targeted delivery of galbanic acid to colon cancer cells by PLGA nanoparticles incorporated into human mesenchymal stem cells.
    Mahboubeh Ebrahimian, Sanaz Shahgordi, Rezvan Yazdian-Robati, Leila Etemad, Maryam Hashemi, Zahra Salmasi.
       Objective: The aim of this study was to investigate the efficacy of mesenchyme stem cells (MSCs) derived from human adipose tissue (hMSCs) as carriers for delivery of galbanic acid (GBA), a potential anticancer agent, loaded into poly (lactic-co-glycolic acid) (PLGA) nanoparticles (nano-engineered hMSCs) against tumor cells.
    Materials and Methods: GBA-loaded PLGA nanoparticles (PLGA/GBA) were prepared by single emulsion method and their physicochemical properties were evaluated. Then, PLGA/GBA nanoparticles were incorporated into hMSCs (hMSC/PLGA-GBA) and their migration ability and cytotoxicity against colon cancer cells were investigated.
    Results: The loading efficiency of PLGA/GBA nanoparticles with average size of 214±30.5 nm into hMSCs, was about 85 and 92% at GBA concentration of 20 and 40 μM, respectively. Nano-engineered hMSCs showed significant higher migration to cancer cells (C26) compared to normal cells (NIH/3T3). Furthermore, nano-engineered hMSCs could effectively induce cell death in C26 cells in comparison with non-engineered hMSCs.
    Conclusion: hMSCs could be implemented for efficient loading of PLGA/GBA nanoparticles to produce a targeted cellular carrier against cancer cells. Thus, according to minimal toxicity on normal cells, it deserves to be considered as a valuable platform for drug delivery in cancer therapy.
    Keywords:  Cancer; Cellular carrier; Galbanic acid; Nano-engineered mesenchymal stem cells; PLGA; Targeted delivery
    DOI:  https://doi.org/10.22038/AJP.2022.20022
  16. Oxid Med Cell Longev. 2022 ;2022 1548410
    Synthesis and Characterization of a Novel Dual-Responsive Nanogel for Anticancer Drug Delivery.
    Darya Aminoleslami, Sahar Porrang, Parviz Vahedi, Soodabeh Davaran.
      In this study, to reduce the side effects of anticancer drugs and also to increase the efficiency of current drug delivery systems, a pH and temperature-responsive polymeric nanogel was synthesized by copolymerization of N-vinylcaprolactam (VCL) and acrylic acid (AA) monomers (P(VCL-co-AA)) with a novel cross-linker, triethylene glycol dimethacrylate (TEGDMA), as a biocompatible and nontoxic component. The structural and physicochemical features of the P(VCL-co-AA) nanogel were characterized by FT-IR, DLS/Zeta potential, FE-SEM, and 1HNMR techniques. The results indicated that spherical polymeric nanogel was successfully synthesized with a 182 nm diameter. The results showed that the polymerization process continues with the opening of the carbon-carbon double bond of monomers, which was approved by C-C band removing located at 1600 cm-1. Doxorubicin (Dox) as a chemotherapeutic agent was loaded into the P(VCL-co-AA), whit a significant loading of Dox (83%), and the drug release profile was investigated in the physiological and cancerous site simulated conditions. P(VCL-co-AA) exhibited a pH and temperature-responsive behavior, with an enhanced release rate in the cancerous site condition. The biocompatibility and nontoxicity of P(VCL-co-AA) were approved by MTT assay on the normal human foreskin fibroblasts-2 (HFF-2) cell line. Also, Dox-loaded P(VCL-co-AA) had excellent toxic behavior on the Michigan Cancer Foundation-7 (MCF-7) cell line as model cancerous cells. Moreover, Dox-loaded P(VCL-co-AA) had higher toxicity in comparison with free Dox, which would be a vast advantage in reducing Dox side effects in the clinical cancer treatment applications.
    DOI:  https://doi.org/10.1155/2022/1548410
  17. Curr Med Chem. 2022 Oct 06.
    A revision of polymeric nanoparticles as a strategy to improve the biological activity of melatonin.
    Pablo Igor Ribeiro Franco, José Rodrigues do Carmo Neto, Viviane Lopes Rocha Correa, Juliana Reis Machado, Andre Correa Amaral, Marina Pacheco Miguel.
      Drug delivery systems based on nanotechnology exhibit a number of advantages over traditional pharmacological formulations. Polymeric nanoparticles are commonly used as delivery systems and consist of synthetic or natural polymers that protect drugs from degradation in physiological environments. In this context, indolamine melatonin has been associated with several biological functions, including antioxidant, antitumor, immunoregulatory, neuroprotective, and cardioprotective effects. However, its availability, half-life, and absorption depend upon the route of administration, and this can limit its therapeutic potential. An alternative is the use of polymeric nanoparticle formulations associated with melatonin to increase its bioavailability and therapeutic dose at sites of interest. Thus, the objective of this review is to provide a general and concise approach to the therapeutic association between melatonin and polymeric nanoparticles applied to different biological disorders and to also highlight its advantages and potential applications compared to those of the typical drug formulations that are available.
    Keywords:  anti-inflammatory agents; antioxidants; melatonin; polymeric nanoparticles; polymers
    DOI:  https://doi.org/10.2174/0929867329666221006113536
  18. J Colloid Interface Sci. 2022 May 27. pii: S0021-9797(22)00828-1. [Epub ahead of print]629(Pt B): 773-784
    Inhibition of alanine-serine-cysteine transporter 2-mediated auto-enhanced photodynamic cancer therapy of co-nanoassembly between V-9302 and photosensitizer.
    Qikun Jiang, Sirun Lu, Xiaolan Xu, Chenxia Bai, Qing Yan, Mengna Fang, Li Huang, Chunming Jin, Yunran Zhang, Jin Sun, Zhonggui He, Chunyang Zhao, Feng Qin, Yongjun Wang, Tianhong Zhang.
      The efficiency of reactive oxygen species (ROS)-based photodynamic therapy (PDT) is far from satisfactory, because cancer cells can adapt to PDT by upregulating glutathione (GSH) levels. The GSH levels in tumor cells are determined based on glutamine availability via alanine-serine-cysteine transporter 2 (ASCT2)-mediated entry into cells. Herein, we develop co-assembled nanoparticles (PPa/V-9302 NPs) of the photosensitizer pyropheophorbide a (PPa) and V-9302 (a known inhibitor of ASCT2) in a 1:1 M ratio using a one-step precipitation method to auto-enhance photodynamic therapy. The computational simulations revealed that PPa and V-9302 could self-assemble through different driving forces, such as π-π stacking, hydrophobic interactions, and ionic bonds. Such PPa/V-9302 NPs could disrupt the intracellular redox homeostasis due to enhanced ROS production via PPa-induced PDT and reduced GSH synthesis via inhibition of the ASCT2-mediated glutamine flux by V-9302. The in vivo assays reveal that PPa/V-9302 NPs could increase the drug accumulation in tumor sites and suppress tumor growth in BALB/c mice bearing mouse breast carcinoma (4 T1) tumor. Our findings provide a new paradigm for the rational design of the PDT-based combinational cancer therapy.
    Keywords:  Alanine-serine-cysteine transporter 2; Photodynamic therapy; enhanced ROS production; reduced GSH synthesis
    DOI:  https://doi.org/10.1016/j.jcis.2022.05.044
  19. Biomaterials. 2022 Sep 30. pii: S0142-9612(22)00473-2. [Epub ahead of print]290 121833
    Targeted photodynamic therapy of glioblastoma mediated by platelets with photo-controlled release property.
    Hua-Zhen Xu, Tong-Fei Li, Yan Ma, Ke Li, Quan Zhang, Yong-Hong Xu, Yu-Cai Zhang, Li Zhao, Xiao Chen.
      Photodynamic therapy (PDT) has recently emerged as a promising, targeted treatment modality for glioblastoma (GBM) which is the most vicious type of brain tumor. Successful GBM-PDT hinges upon light activation of a photosensitizer accumulated in the tumor. However, inadequate tumor accumulation of photosensitizer severely limits the success of PDT of GBM. To tackle this difficulty, we herein propose a drug delivery strategy of "platelets with photo-controlled release property". This strategy exploits platelets as carriers to deliver a photosensitizer which, in the current study, is a nano-composite (BNPD-Ce6) comprised of chlorine e6 (Ce6) loaded to boron nitride nanoparticles with a surface coating of polyglycerol and doxorubicin. To demonstrate the working mechanism and therapeutic advantage of this strategy, we loaded mouse platelets with BNPD-Ce6 to yield the nano-device BNPD-Ce6@Plt. In vitro experiments showed BNPD-Ce6@Plt to have a high loading capacity and efficiency. Laser irradiation (LI) at a wavelength of 808 nm induced ROS generation in BNPD-Ce6@Plt which displayed rapid activation, aggregation, and speedy discharge of BNPD-Ce6 into co-cultured GL261 mouse GBM cells which in turn, after LI, exhibited marked ROS generation, DNA damage, reduced viability, and cell death. In vivo animal experiments, mice that were intravenously injected with BNPD-Ce6@Plt exhibited rapid and extensive BNPD-Ce6 accumulation in both subcutaneous and intra-brain GL261 tumors shortly after LI of the tumors and the tumors displayed massive tissue necrosis after LI for a second time. Finally, a PDT regimen of two intravenous BNPD-Ce6@Plt injections each followed by multiple times of extracranial LI at the tumor site significantly inhibited the growth of intra-brain GL261 tumors and markedly increased the survival of the host animals. No apparent tissue damage was found in vital organs. Our findings make a compelling case for the notion that platelets are efficient carriers that can photo-controllably deliver nano-photosensitizers to achieve highly targeted and efficacious PDT of GBM. This work presents a novel approach to GBM-PDT with great translational potential.
    Keywords:  Glioblastoma; Photo-controlled release; Photodynamic therapy; Platelets; Targeted delivery
    DOI:  https://doi.org/10.1016/j.biomaterials.2022.121833
  20. Curr Drug Targets. 2022 Oct 04.
    Nanotechnology for targeted drug delivery to treat osteoporosis.
    Malkiet Kaur, Manju Nagpal, Geeta Aggarwal.
      Bone diseases such as rheumatoid arthritis, Paget's disease, and osteoporosis cause mortality and mobility limits. Nanomedicine and nano delivery systems have been utilised to deliver active drug moiety to the precisely targeted site in a controlled manner, and it serves as a means of diagnostic tools. The utilisation of nanomedicine is expanding vigorously for assured targeting and efficient drug delivery. Nanotechnology offers various advantages, such as site-specific targeting, precise drug release kinetics, and improved bone mineral density. Recent medications available for osteoporosis aren't viable due to the adverse effects associated with them and low patient compliance. There is an urgent need to develop biocompatible and appropriate drug delivery nanocarriers such as nanoparticles, liposomes, hydrogels, dendrimers, micelles, mesoporous particles, etc. These carriers enhance drug delivery and therapeutic effectiveness in bone tissues. The use of nanotechnology is also associated with toxicity. This article presents the review of various reports on nanocarrier systems and biologics for the treatment of osteoporosis. It aims to provide researchers with a clue for inventing a new drug delivery system with site-specific targeting for the treatment of osteoporosis.
    Keywords:  Biologics; Bone diseases; Nanomaterials; Nanostructured carriers; Nanotechnology; Nanotoxicity; Osteoporosis
    DOI:  https://doi.org/10.2174/1389450123666221004124040
  21. Oxid Med Cell Longev. 2022 ;2022 6480590
    Potential Role of Phytochemical Extract from Saffron in Development of Functional Foods and Protection of Brain-Related Disorders.
    Zahra Maqbool, Muhammad Sajid Arshad, Anwar Ali, Afifa Aziz, Waseem Khalid, Muhammad Faizan Afzal, Sneh Punia Bangar, Mohamed Addi, Christophe Hano, Jose Manuel Lorenzo.
      The present review is designed to measure the effects of saffron extract in functional foods and its pharmacological properties against various disorders. Saffron is a traditional medicinal plant used as a food additive. The stigma of saffron has bioactive compounds such as safranal, crocin, crocetin, picrocrocin, kaempferol, and flavonoid. These bioactive compounds can be extracted using conventional (maceration, solvent extraction, soxhlet extraction, and vapor or hydrodistillation) and novel techniques (emulsion liquid membrane extraction, ultrasound-assisted extraction, enzyme-associated extraction, pulsed electric field extraction, microwave-assisted extraction, and supercritical fluid extraction). Saffron is used as a functional ingredient, natural colorant, shelf-life enhancer, and fortifying agent in developing different food products. The demand for saffron has been increasing in the pharma industry due to its protection against cardiovascular and Alzheimer disease and its antioxidant, anti-inflammatory, antitumor, and antidepressant properties. Conclusively, the phytochemical compounds of saffron improve the nutrition value of products and protect humans against various disorders.
    DOI:  https://doi.org/10.1155/2022/6480590
  22. Front Oncol. 2022 ;12 1011191
    Differential glutamine metabolism in the tumor microenvironment - studies in diversity and heterogeneity: A mini-review.
    Michael D Claiborne, Robert Leone.
      Increased glutamine metabolism is a hallmark of many cancer types. In recent years, our understanding of the distinct and diverse metabolic pathways through which glutamine can be utilized has grown more refined. Additionally, the different metabolic requirements of the diverse array of cell types within the tumor microenvironment complicate the strategy of targeting any particular glutamine pathway as cancer therapy. In this Mini-Review, we discuss recent advances in further clarifying the cellular fate of glutamine through different metabolic pathways. We further discuss potential promising strategies which exploit the different requirements of cells in the tumor microenvironment as it pertains to glutamine metabolism in an attempt to suppress cancer growth and enhance anti-tumor immune responses.
    Keywords:  cancer; glutamine; immunooncology; metabolism; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2022.1011191
  23. Daru. 2022 Oct 05.
    Mesoporous silica coated SPIONs containing curcumin and silymarin intended for breast cancer therapy.
    Soosan Sadegha, Reyhaneh Varshochian, Pegah Dadras, Hosniyeh Hosseinzadeh, Ramin Sakhtianchi, Zahra Hadavand Mirzaie, Akram Shafiee, Fatemeh Atyabi, Rassoul Dinarvand.
       INTRODUCTION: Super-paramagnetic iron oxide nanoparticles (SPIONs) are known as promising theranostic nano-drug carriers with magnetic resonance imaging (MRI) properties. Applying the herbaceous components with cytotoxic effects as cargos can suggest a new approach in the field of cancer-therapy. In this study mesoporous silica coated SPIONs (mSiO2@SPIONs) containing curcumin (CUR) and silymarin (SIL) were prepared and evaluated on breast cancer cell line, MCF-7.
    METHODS: Nanoparticles (NPs) were formulated by reverse microemulsion method and characterized by DLS, SEM and VSM. The in vitro drug release, cellular cytotoxicity, and MRI properties of NPs were determined as well. The cellular uptake of NPs by MCF-7 cells was investigated through LysoTracker Red staining using confocal microscopy.
    RESULTS: The MTT results showed that the IC50 of CUR + SIL loaded mSiO2@SPIONs was reduced about 50% in comparison with that of the free drug mixture. The NPs indicated proper MRI features and cellular uptake through endocytosis.
    CONCLUSION: In conclusion the prepared formulation may offer a novel theranostic system for breast cancer researches.
    Keywords:  Curcumin; Mesoporous silica; Silymarin; Superparamagnetic iron oxide nanoparticles; Theranostic
    DOI:  https://doi.org/10.1007/s40199-022-00453-9
  24. Acta Chim Slov. 2022 Sep 26. 69(3): 714-721
    Superparamagnetic Tragacanth Coated Fe3O4@SiO2 Nanoparticles for the Loading and Delivery of Metformin.
    Fereshte Farajian, Payman Hashemi.
      A novel superparamagnetic nano-composite of Fe3O4@SiO2 coated by tragacanth gum (TG) as a natural product has been prepared. The obtained SiO2@Fe3O4@TG nanoparticles were characterized by Fourier transform infrared spectroscopy, energy dispersive X-ray analysis, scanning electron microscopy and dynamic light scattering analyzer. The magnetic nano-composite was applied for the loading and delivery of metformin, an oral diabetes medicine. The conditions for the loading of the drug were optimized by a central composite design optimization method. The maximum loading efficiency of the sorbent for metformin was obtained at pH 7 and its maximum in-vitro release was achieved at pH 1.6, using a phosphate-buffered saline medium. The loading capacity of the sorbent was dependent on the initial metformin concentration and exceeded to 19.6 mg/g in a 200 mg/L solution. A study of the adsorption isotherms for the drug indicated the best fitting into the Langmuir and Freundlich isotherms at the low and high metformin concentrations, respectively. The results indicated that the prepared Fe3O4@SiO2@TG adsorbent, as a non-toxic and low-cost sorbent, was quite appropriate for drug delivery applications.
    Keywords:  Hydrogel adsorbent; Magnetic nanoparticles; Metformin; Tragacanth
    DOI:  https://doi.org/10.17344/acsi.2021.7240
  25. Recent Adv Drug Deliv Formul. 2022 Oct 05.
    In situ Hydrogels for Effective Treatment of Cancer: Strategies and Polymers Used.
    Anshula Mehra, Abhay Tharmatt, Navdeep Saini, Gurdeep Singh, Kirandeep Kaur, Gurpreet Singh, Neena Bedi.
      Cancer is a worldwide health ailment with no known boundaries in terms of mortality and occurrence rates, thus is one of the biggest threats to humankind. Hence, there is an absolute need to develop novel therapeutics to bridge the infirmities associated with chemotherapy and conventional surgical methodologies including impairment of normal tissue, compromised drug efficiency and an escalation in side effects. In lieu of this, there's been a surge in curiosity towards development of injectable hydrogels for cancer therapy because local administration of the active pharmaceutical agent offers encouraging advantages such as providing higher effective dose at target site, prolonged retention time of drug, ease of administration, mitigation of dose in vivo ,improved patient compliance. Furthermore, due to its biocompatible nature such systems can significantly reduce the side effects that occur on long-term exposure to chemotherapy. The present review details the most recent advancements in in-situ gel forming polymers (natural and synthetic), polymeric cross-linking methodologies and in-situ gelling mechanisms, focusing on their clinical benefits in cancer therapy.
    Keywords:  Cancer; Cross-linking; Hydrogels; Injectable; Natural polymers; Synthetic polymers
    DOI:  https://doi.org/10.2174/2667387816666221005102931
  26. Pharm Res. 2022 Oct 04.
    Repurposing an Antiepileptic Drug for the Treatment of Glioblastoma.
    Anjali Yadav, Ali Alnakhli, Hari Priya Vemana, Shraddha Bhutkar, Aaron Muth, Vikas V Dukhande.
       PURPOSE: Glioblastoma multiforme (GBM) is a grade IV, highly proliferative, and malignant form of brain tumor with a 5-year survival rate at ~ 5%. Current treatment strategies for GBM include surgery, radiation, and chemotherapy. Major challenges in GBM management include difficulties in surgical resection due to brain's vital functions and GBM metastasis, development of resistance to temozolomide (TMZ), and protection of tumor by blood brain barrier (BBB). Therefore, we aimed to discover a novel therapeutic for GBM by targeting its metabolic reprogramming.
    METHOD: We screened metabolic inhibitors by their effects on GBM cell viability by MTT assay. We discovered an FDA-approved drug stiripentol (STP) in our screening of metabolic inhibitors in GBM cells. STP is used for Dravet syndrome (a rare epilepsy). We further tested efficacy of STP using proliferation assay, clonogenic assay, in vitro migration assay, cell cycle assay, apoptosis assay, and in U87 3D spheroids. We also tested the toxicity of STP, and combinations used in the study on normal human dermal fibroblasts.
    RESULTS: STP was effective in decreasing GBM cell viability, proliferation, clonogenic ability, and migration. Moreover, cell cycle changes were involved but robust apoptosis was absent in STP's anticancer effects. STP was effective in 3D spheroid models, and in TMZ-resistant cells. STP showed additive or synergistic effect with TMZ in different anticancer assays on GBM cells and was considerably less toxic in normal cells.
    CONCLUSION: Our results indicate that STP can be an effective GBM therapeutic that enhances the effects of TMZ on GBM cells. Importantly, STP reduced viability of TMZ-resistant cells. Our results warrant further studies in the mechanistic basis of STP's effects on GBM cells and the preclinical potential of STP in animal models.
    Keywords:  cancer metabolism; drug repurposing; glioblastoma; stiripentol; temozolomide
    DOI:  https://doi.org/10.1007/s11095-022-03399-4
  27. J Food Biochem. 2022 Oct 05. e14433
    Ultrasonic-assisted extraction of swertisin from sour Jujube seed and comprehensive revelation of its antioxidant activity.
    Jinrui Liu, Yanqing Zhang, Mei Zhang, Qing Wang, Junbo Xie.
      As a typical flavonoid glycoside, swertisin mainly exists in sour Jujube seed. In this study, swertisin was extracted by ultrasound-assisted extraction method optimized with Box-Behnken design and response surface methodology. The antioxidant effect of swertisin was determined in vitro and in Caenorhabditis elegans (C. elegans). Furthermore, the potential mechanisms of its antioxidant stress were comprehensively evaluated and explored with network pharmacology and molecular docking technology. The results showed obvious scavenging ability of swertisin on free radical and swertisin (50, 250, and 500 μmol/L) significantly enhanced antioxidative enzymes activity (GST-4, SOD-3, and GSH-PX ) and reduced the reactive oxygen species and malondialdehyde accumulation in C. elegans, thereby protecting them from oxidative stress (heat stress and hydrogen peroxide). A total of 139 antioxidant targets of swertisin were screened and 70 signal pathways were enriched, including cancer-related pathways, lipid metabolism, liver injury-related pathways, acute lung injury, nervous system diseases, etc. This study provides the basis for further investigation on the antioxidant stress mechanism and contributes to the development of relevant drugs from natural products. PRACTICAL APPLICATIONS: The imbalance between the antioxidant defense system and reactive oxygen species is one of the main causes of neurodegenerative diseases, cardiovascular diseases, cancer, and aging. Therefore, alleviating oxidative stress injury has become a common strategy, which is helpful for the multi-target treatment of related diseases. The flavonoid of sour Jujube seed possesses potential antioxidant activity with multiple food health effects. From this study results, we optimized ultrasound-assisted extraction method for extracting the swertisin from sour Jujube seed and supported the use of C. elegans as an in vivo experimental model. We can recommend that the swertisin as a natural ingredient has a positive effect on antioxidation, which provided a scientific basis for treating related diseases through relevant pharmacological mechanisms and making antiaging functional food formula.
    Keywords:   C. elegans ; antioxidant capacity; molecular docking; network pharmacology; oxidative stress; swertisin
    DOI:  https://doi.org/10.1111/jfbc.14433
  28. J Nanobiotechnology. 2022 Oct 04. 20(1): 437
    Emerging photodynamic/sonodynamic therapies for urological cancers: progress and challenges.
    Xiao Hu, Yu-Sen Zhang, Yi-Chao Liu, Na Wang, Xian-Tao Zeng, Ling-Ling Zhang.
      Photodynamic therapy (PDT), and sonodynamic therapy (SDT) that developed from PDT, have been studied for decades to treat solid tumors. Compared with other deep tumors, the accessibility of urological tumors (e.g., bladder tumor and prostate tumor) makes them more suitable for PDT/SDT that requires exogenous stimulation. Due to the introduction of nanobiotechnology, emerging photo/sonosensitizers modified with different functional components and improved physicochemical properties have many outstanding advantages in cancer treatment compared with traditional photo/sonosensitizers, such as alleviating hypoxia to improve quantum yield, passive/active tumor targeting to increase drug accumulation, and combination with other therapeutic modalities (e.g., chemotherapy, immunotherapy and targeted therapy) to achieve synergistic therapy. As WST11 (TOOKAD® soluble) is currently clinically approved for the treatment of prostate cancer, emerging photo/sonosensitizers have great potential for clinical translation, which requires multidisciplinary participation and extensive clinical trials. Herein, the latest research advances of newly developed photo/sonosensitizers for the treatment of urological cancers, and the efficacy, as well as potential biological effects, are highlighted. In addition, the clinical status of PDT/SDT for urological cancers is presented, and the optimization of the photo/sonosensitizer development procedure for clinical translation is discussed.
    Keywords:  Cancer therapy; Clinical translation; Nanobiotechnology; Photodynamic therapy; Sonodynamic therapy; Urological cancers
    DOI:  https://doi.org/10.1186/s12951-022-01637-w
  29. J Med Chem. 2022 Oct 07.
    Natural Product-Inspired Targeted Protein Degraders: Advances and Perspectives.
    Jiao Li, Zhenyu Cai, Xu-Wen Li, Chunlin Zhuang.
      Targeted protein degradation (TPD), a promising therapeutic strategy in drug discovery, has great potential to regulate the endogenous degradation of undruggable targets with small molecules. As vital resources that provide diverse structural templates for drug discovery, natural products (NPs) are a rising and robust arsenal for the development of therapeutic TPD. The first proof-of-concept study of proteolysis-targeting chimeras (PROTACs) was a natural polyketide ovalicin-derived degrader; since then, NPs have shown great potential to promote TPD technology. The use of NP-inspired targeted protein degraders has been confirmed to be a promising strategy to treat many human conditions, including cancer, inflammation, and nonalcoholic fatty liver disease. Nevertheless, the development of NP-inspired degraders is challenging, and the field is currently in its infancy. In this review, we summarize the bioactivities and mechanisms of NP-inspired degraders and discuss the associated challenges and future opportunities in this field.
    DOI:  https://doi.org/10.1021/acs.jmedchem.2c01223
  30. Oxid Med Cell Longev. 2022 ;2022 4578381
    The Regulatory Effects of Traditional Chinese Medicine on Ferroptosis.
    Qian Gao, Xue-Dong Yin, Fan Zhang, Yi-Zhun Zhu, Zhi-Ling Li.
      Traditional Chinese medicine (TCM) has significantly contributed to protecting human health and promoting the progress of world civilization. A total of 2,711 TCMs are included in the 2020 version of the Chinese Pharmacopoeia, which is an integral part of the world's medical resources. Tu Youyou and her team discovered and purified artemisinin. And their contributions made the values and advantageous effects of TCM more and more recognized by the international community. There has been a lot of studies on TCM to treat diseases through antioxidant mechanisms, the reports on the new mechanisms beyond antioxidants of TCM has also increased year by year. Recently, many TCMs appear to have significant effects in regulating ferroptosis. Ferroptosis is an iron-dependent, non-apoptotic, regulated cell death characterized by intracellular lipid peroxide accumulation and oxidative membrane damage. Recently, accumulating studies have demonstrated that numerous organ injuries and pathophysiological process of many diseases are companied with ferroptosis, such as cancer, neurodegenerative disease, acute renal injury, arteriosclerosis, diabetes, and ischemia-reperfusion injury. This work mainly introduces dozens of TCMs that can regulate ferroptosis and their possible mechanisms and targets.
    DOI:  https://doi.org/10.1155/2022/4578381
  31. Front Pharmacol. 2022 ;13 946811
    Histone modification and histone modification-targeted anti-cancer drugs in breast cancer: Fundamentals and beyond.
    Jianwei Feng, Xinyue Meng.
      Dysregulated epigenetic enzymes and resultant abnormal epigenetic modifications (EMs) have been suggested to be closely related to tumor occurrence and progression. Histone modifications (HMs) can assist in maintaining genome stability, DNA repair, transcription, and chromatin modulation within breast cancer (BC) cells. In addition, HMs are reversible, dynamic processes involving the associations of different enzymes with molecular compounds. Abnormal HMs (e.g. histone methylation and histone acetylation) have been identified to be tightly related to BC occurrence and development, even though their underlying mechanisms remain largely unclear. EMs are reversible, and as a result, epigenetic enzymes have aroused wide attention as anti-tumor therapeutic targets. At present, treatments to restore aberrant EMs within BC cells have entered preclinical or clinical trials. In addition, no existing studies have comprehensively analyzed aberrant HMs within BC cells; in addition, HM-targeting BC treatments remain to be further investigated. Histone and non-histone protein methylation is becoming an attractive anti-tumor epigenetic therapeutic target; such methylation-related enzyme inhibitors are under development at present. Consequently, the present work focuses on summarizing relevant studies on HMs related to BC and the possible mechanisms associated with abnormal HMs. Additionally, we also aim to analyze existing therapeutic agents together with those drugs approved and tested through pre-clinical and clinical trials, to assess their roles in HMs. Moreover, epi-drugs that target HMT inhibitors and HDAC inhibitors should be tested in preclinical and clinical studies for the treatment of BC. Epi-drugs that target histone methylation (HMT inhibitors) and histone acetylation (HDAC inhibitors) have now entered clinical trials or are approved by the US Food and Drug Administration (FDA). Therefore, the review covers the difficulties in applying HM-targeting treatments in clinics and proposes feasible approaches for overcoming such difficulties and promoting their use in treating BC cases.
    Keywords:  breast cancer; epi-drugs; epigenetics; histone modification; tumor suppressor gene
    DOI:  https://doi.org/10.3389/fphar.2022.946811
  32. Front Pharmacol. 2022 ;13 1022266
    Progress on the efficacy and mechanism of action of panax ginseng monomer saponins treat toxicity.
    Xinyi Wang, Rongcan Wang, Yongfei Qiao, Yali Li.
      As a traditional Chinese herbal medicine, Panax ginseng C. A. Meyer (PG) has preventive and therapeutic effects on various diseases. Ginsenosides are main active ingredients of PG and have good pharmacological effects. Due to the diversity of chemical structures and physicochemical properties of ginsenosides, Currently, related studies on PG monomer saponins are mainly focused on the cardiovascular system, nervous system, antidiabetic, and antitumor. There are few types of research on the toxin treatment, predominantly exogenous toxicity. PG and its monomer ginsenosides are undoubtedly a practical option for treating exogenous toxicity for drug-induced or metal-induced side effects such as nephrotoxicity, hepatotoxicity, cardiotoxicity, metal toxicity and other exogenous toxicity caused by drugs or metals. The mechanism focuses on antioxidant, anti-inflammatory, and anti-apoptotic, as well as modulation of signaling pathways. It summarized the therapeutic effects of ginseng monomer saponins on exogenous toxicity and demonstrated that ginsenosides could be used as potential drugs to treat exogenous toxicity and reduce drug toxicities.
    Keywords:  Panax ginseng monomer saponins; exogenous toxicity; ginsenosides; mini-review; treatment
    DOI:  https://doi.org/10.3389/fphar.2022.1022266
  33. Stem Cell Res Ther. 2022 Oct 01. 13(1): 489
    Targeting cancer stem cells with polymer nanoparticles for gastrointestinal cancer treatment.
    Yao Sun, Bo Li, Qian Cao, Tongjun Liu, Jiannan Li.
      Nanomaterials are developing rapidly in the medical field, bringing new hope for treating various refractory diseases. Among them, polymer nanomaterials, with their excellent properties, have been used to treat various diseases, such as malignant tumors, diabetes, and nervous system diseases. Gastrointestinal cancer is among the cancers with the highest morbidity and mortality worldwide. Cancer stem cells are believed to play an important role in the occurrence and development of tumors. This article summarizes the characteristics of gastrointestinal cancer stem cells and reviews the latest research progress in treating gastrointestinal malignant tumors using polymer nanoparticles to target cancer stem cells. In addition, the review article highlights the potential of polymer nanoparticles in targeting gastrointestinal cancer stem cells.
    Keywords:  Active targeting; Cancer stem cells; Gastrointestinal cancer; Nanoparticles; Passive targeting
    DOI:  https://doi.org/10.1186/s13287-022-03180-9
  34. Carbohydr Polym. 2022 Dec 01. pii: S0144-8617(22)00938-9. [Epub ahead of print]297 120033
    Advances in the development of cyclodextrin-based nanogels/microgels for biomedical applications: Drug delivery and beyond.
    Fuat Topuz, Tamer Uyar.
      Nanogels/microgels are swollen cross-linked polymer networks with tunable physicochemical properties and are commonly employed for the effective delivery of hydrophilic drugs. By structural engineering, they can be adapted for the delivery of hydrophobic drugs. Likewise, the use of cyclodextrins (CDs) as pharmaceutical excipients in nanogels drastically boosts the loading capacity of lipophilic drugs while enhancing their stability, bioavailability, and permeability owing to their capability of hosting drugs in their somewhat lipophilic cavity. Here, the synthesis and biomedical applications of CD-based nanogels/microgels were compiled with regard to the CD's role in nanogel synthesis. Even though most applications focused on using CD molecules as functional motifs to carry drugs and construct nanogels for biomedical applications, others used CDs in engineering nanogels to benefit from their supramolecular complexation ability. The applications of CD-based nanogels for drug-mediated cancer/tumor therapy were also discussed. Finally, the review points to the challenges/horizons to boost their biomedical applications.
    Keywords:  Biomedical applications; Chemotherapy; Cyclodextrin; Drug delivery; Nanogels; Self-healing
    DOI:  https://doi.org/10.1016/j.carbpol.2022.120033
  35. Front Pharmacol. 2022 ;13 926607
    Pharmacological effects and therapeutic potential of natural compounds in neuropsychiatric disorders: An update.
    Parina Asgharian, Cristina Quispe, Jesús Herrera-Bravo, Mahsa Sabernavaei, Kamran Hosseini, Haleh Forouhandeh, Tahereh Ebrahimi, Paria Sharafi-Badr, Vahideh Tarhriz, Saiedeh Razi Soofiyani, Paweł Helon, Jovana Rajkovic, Sevgi Durna Daştan, Anca Oana Docea, Javad Sharifi-Rad, Daniela Calina, Wojciech Koch, William C Cho.
      Neuropsychiatric diseases are a group of disorders that cause significant morbidity and disability. The symptoms of psychiatric disorders include anxiety, depression, eating disorders, autism spectrum disorders (ASD), attention-deficit/hyperactivity disorder, and conduct disorder. Various medicinal plants are frequently used as therapeutics in traditional medicine in different parts of the world. Nowadays, using medicinal plants as an alternative medication has been considered due to their biological safety. Despite the wide range of medications, many patients are unable to tolerate the side effects and eventually lose their response. By considering the therapeutic advantages of medicinal plants in the case of side effects, patients may prefer to use them instead of chemical drugs. Today, the use of medicinal plants in traditional medicine is diverse and increasing, and these plants are a precious heritage for humanity. Investigation about traditional medicine continues, and several studies have indicated the basic pharmacology and clinical efficacy of herbal medicine. In this article, we discuss five of the most important and common psychiatric illnesses investigated in various studies along with conventional therapies and their pharmacological therapies. For this comprehensive review, data were obtained from electronic databases such as MedLine/PubMed, Science Direct, Web of Science, EMBASE, DynaMed Plus, ScienceDirect, and TRIP database. Preclinical pharmacology studies have confirmed that some bioactive compounds may have beneficial therapeutic effects in some common psychiatric disorders. The mechanisms of action of the analyzed biocompounds are presented in detail. The bioactive compounds analyzed in this review are promising phytochemicals for adjuvant and complementary drug candidates in the pharmacotherapy of neuropsychiatric diseases. Although comparative studies have been carefully reviewed in the preclinical pharmacology field, no clinical studies have been found to confirm the efficacy of herbal medicines compared to FDA-approved medicines for the treatment of mental disorders. Therefore, future clinical studies are needed to accelerate the potential use of natural compounds in the management of these diseases.
    Keywords:  bioactive compounds; natural compounds; neuropsychiatric disorders; pharmacological mechanisms; preclinical pharmacology
    DOI:  https://doi.org/10.3389/fphar.2022.926607
  36. FASEB J. 2022 Nov;36(11): e22569
    Galangin inhibited ferroptosis through activation of the PI3K/AKT pathway in vitro and in vivo.
    Ke Chen, Ran Xue, Yaping Geng, Shenshen Zhang.
      Ferroptosis is an iron-dependent form of nonapoptotic cell death characterized by the accumulation of lipid peroxides in cells. In recent years, extensive attention has been dedicated to exploring safe and effective natural ferroptosis regulators which can provide novel treatment strategies for ferroptosis-related diseases. This study identified galangin, a natural flavonoid, as an effective inhibitor of ferroptosis, which could increase cell viability in RSL3-inhibited HT1080 cells, decrease levels of lipid ROS and MDA, improve PTGS2 mRNA expression, and enhance the expression of glutathione peroxidase 4 (GPX4). Ferroptosis is widely present in ischemia-reperfusion (IR) injury. This study found that galangin significantly ameliorated the pathological damage of liver tissue in mice with IR, reduced levels of serum ALT, AST, and MDA, and increased the expression of GPX4. The results of RNA-seq exhibited ferroptosis was significant and the PI3K/AKT pathway deserved to explore the inhibition effects of galangin on ferroptosis. Indeed, galangin treatment significantly rescued RSL3-inhibited phosphorylation levels of PI3K, AKT, and CREB proteins, and the ferroptosis inhibitory effects of galangin were counteracted by PI3K inhibitor LY294002. These findings indicated that galangin may exert its anti-ferroptosis effects via activating the PI3K/AKT/CREB signaling pathway and it will hopefully serve as a promising effective measure to attenuate IR injury by inhibiting ferroptosis.
    Keywords:  ferroptosis; galangin; glutathione peroxidase 4; signaling pathway
    DOI:  https://doi.org/10.1096/fj.202200935R
  37. Food Res Int. 2022 Nov;pii: S0963-9969(22)00927-9. [Epub ahead of print]161 111869
    Ascorbic acid-loaded gliadin nanoparticles as a novel nutraceutical formulation.
    Silvia Voci, Agnese Gagliardi, Massimo Fresta, Donato Cosco.
      Ascorbic acid (AA) is one of the foremost antioxidants. Unfortunately, its sensitivity to different external stimuli such as light, heat and oxygen are concrete limitations for its use. Various approaches have been investigated in order to circumvent this problem and enhance the stability of the active compound, besides promoting its use for different applications. In this investigation, AA was encapsulated in a vegetal protein-based matrix made up of gliadin, the prolamin obtained from wheat kernels, with the aim of proposing a novel nutraceutical formulation. The nanosystems were characterized by an average diameter of < 200 nm and a negative surface charge of ∼ -40 mV. The samples were not destabilized after incubation at different temperatures (up to 70 °C) or after the pasteurization procedure. Suitable stability was also observed in NaCl 100 mM, as well as after cryodesiccation when 10 % w/v of mannose was used. The gliadin nanoparticles showed the ability to retain high amounts of AA, promoting its prolonged release in PBS and under simulated gastrointestinal conditions. The nanosystems enhanced the antioxidant features of the compound as compared to its free form and preserved its chemical stability following UV exposition. The results demonstrate the potential application of the investigated nanoparticles as a novel nutraceutical formulation or as food fortificants.
    Keywords:  Antioxidant; Ascorbic acid; Food; Gliadin; Nanoparticles; Nutraceutical
    DOI:  https://doi.org/10.1016/j.foodres.2022.111869
  38. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2022 Oct 03. e1853
    Nonviral nanoparticle gene delivery into the CNS for neurological disorders and brain cancer applications.
    Joanna Yang, Kathryn M Luly, Jordan J Green.
      Nonviral nanoparticles have emerged as an attractive alternative to viral vectors for gene therapy applications, utilizing a range of lipid-based, polymeric, and inorganic materials. These materials can either encapsulate or be functionalized to bind nucleic acids and protect them from degradation. To effectively elicit changes to gene expression, the nanoparticle carrier needs to undergo a series of steps intracellularly, from interacting with the cellular membrane to facilitate cellular uptake to endosomal escape and nucleic acid release. Adjusting physiochemical properties of the nanoparticles, such as size, charge, and targeting ligands, can improve cellular uptake and ultimately gene delivery. Applications in the central nervous system (CNS; i.e., neurological diseases, brain cancers) face further extracellular barriers for a gene-carrying nanoparticle to surpass, with the most significant being the blood-brain barrier (BBB). Approaches to overcome these extracellular challenges to deliver nanoparticles into the CNS include systemic, intracerebroventricular, intrathecal, and intranasal administration. This review describes and compares different biomaterials for nonviral nanoparticle-mediated gene therapy to the CNS and explores challenges and recent preclinical and clinical developments in overcoming barriers to nanoparticle-mediated delivery to the brain. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies Nanotechnology Approaches to Biology > Nanoscale Systems in Biology.
    Keywords:  LNP; brain; gene delivery; nanoparticle; polymer
    DOI:  https://doi.org/10.1002/wnan.1853
  39. Bioact Mater. 2023 Mar;21 358-380
    Covalent organic framework nanomedicines: Biocompatibility for advanced nanocarriers and cancer theranostics applications.
    Nem Singh, Jungryun Kim, Jaewon Kim, Kyungwoo Lee, Zehra Zunbul, Injun Lee, Eunji Kim, Sung-Gil Chi, Jong Seung Kim.
      Nanomedicines for drug delivery and imaging-guided cancer therapy is a rapidly growing research area. The unique properties of nanomedicines have a massive potential in solving longstanding challenges of existing cancer drugs, such as poor localization at the tumor site, high drug doses and toxicity, recurrence, and poor immune response. However, inadequate biocompatibility restricts their potential in clinical translation. Therefore, advanced nanomaterials with high biocompatibility and enhanced therapeutic efficiency are highly desired to fast-track the clinical translation of nanomedicines. Intrinsic properties of nanoscale covalent organic frameworks (nCOFs), such as suitable size, modular pore geometry and porosity, and straightforward post-synthetic modification via simple organic transformations, make them incredibly attractive for future nanomedicines. The ability of COFs to disintegrate in a slightly acidic tumor microenvironment also gives them a competitive advantage in targeted delivery. This review summarizes recently published applications of COFs in drug delivery, photo-immuno therapy, sonodynamic therapy, photothermal therapy, chemotherapy, pyroptosis, and combination therapy. Herein we mainly focused on modifications of COFs to enhance their biocompatibility, efficacy and potential clinical translation. This review will provide the fundamental knowledge in designing biocompatible nCOFs-based nanomedicines and will help in the rapid development of cancer drug carriers and theranostics.
    DOI:  https://doi.org/10.1016/j.bioactmat.2022.08.016
  40. Int J Nanomedicine. 2022 ;17 4547-4565
    Low Intensity Focused Ultrasound Ignited "Deep-Penetration Nanobomb" (DPNB) for Tetramodal Imaging Guided Hypoxia-Tolerant Sonodynamic Therapy Against Hypoxic Tumors.
    Yuanli Luo, Bin Qiao, Chao Yang, Ping Zhang, Zhuoyan Xie, Jin Cao, Anyu Yang, Qinyanqiu Xiang, Haitao Ran, Zhigang Wang, Lan Hao, Yang Cao, Zhiyi Zhou, Jianli Ren.
       Background: Sonodynamic therapy (SDT) has been regarded as a novel therapeutic modality for killing tumors. However, the hypoxic tumor microenvironment, especially deep-seated tumors distant from blood vessels, severely restricts therapeutic efficacy due to the oxygen-dependent manner of SDT.
    Methods: Herein, we report a novel ultrasonic cavitation effect-based therapeutic modality that is able to facilitate the hypoxia-tolerant SDT for inducing hypoxic tumor death. A tLyP-1 functionalized liposomes is fabricated, composed of hematoporphyrin monomethyl ether gadolinium as the sonosentizer and perfluoropentane (PFP) as the acoustic environment regulator. Moreover, the tLyP-1 functioned liposomes could achieve active tumor homing and effective deep-penetrating into hypoxic tumors. Upon low intensity focused ultrasound (LIFU) irradiation, the acoustic droplet vaporization effect of PFP induced fast liquid-to-gas transition and quick bubbles explosion to generate hydroxyl radicals, efficiently promoting cell death in both normoxic and hypoxic microenvironment (acting as deep-penetration nanobomb, DPNB).
    Results: The loading of PFP is proved to significantly enhance the therapeutic efficacy of hypoxic tumors. In particular, these DPNB can also act as ultrasound, photoacoustic, magnetic resonance, and near-infrared fluorescence tetramodal imaging agents for guiding the therapeutic process.
    Conclusion: This study is the first report involving that liquid-to-gas transition based SDT has the potential to combat hypoxic tumors.
    Keywords:  deep-penetration; hypoxic tumors; low intensity focused ultrasound; sonodynamic therapy; tetramodal imaging
    DOI:  https://doi.org/10.2147/IJN.S361648
  41. Int J Biol Macromol. 2022 Sep 19. pii: S0141-8130(22)02095-5. [Epub ahead of print]222(Pt A): 473-486
    Spray-dried tenofovir alafenamide-chitosan nanoparticles loaded oleogels as a long-acting injectable depot system of anti-HIV drug.
    Vedha Hari B Narayanan, Artur Lewandowski, Ramyadevi Durai, Weronika Gonciarz, Paweł Wawrzyniak, Marek Brzezinski.
      The development of suitable drug delivery systems for prolonged action against HIV receives great attention in recent research. Herein, a long-acting injectable (LAI) of Tenofovir alafenamide-chitosan polymeric nanoparticles loaded oleogels developed with sesame oil and ethyl cellulose for prolonged release of the drug is reported for the first time. The research resulted with unique long-acting parenteral formulation for chronic anti-retroviral therapy, based on our experimental in-vitro and ex-vivo studies. The chitosan nanoparticles with 49 % drug content were produced through the spray-drying technique and characterized for their size (106-540 nm) and the other physico-chemical features through SEM, FT-IR, XRD, TGA, and DSC. The ethyl cellulose and sesame oil oleogels were developed through a heat-cool process by incorporating the drug-loaded chitosan nanoparticles. The oleogels exhibited extended release (56 %) of the drug for 16 days, which could be prolonged further to achieve the maximum drug release. Also, the ex-vivo permeation studies of the nanoparticles loaded oleogels demonstrated about 10-fold decrease in the flux and the permeation of the drug due to prolonged release of the drug across dual barriers of chitosan nanoparticles and ethyl cellulose gel matrix. The result provided proof-of-evidence that the developed Tenofovir alafenamide-chitosan polymeric nanoparticles loaded with ethyl cellulose oleogels could be potentially used as the long-acting injectable system for the treatment of patients infected with HIV/AIDS.
    Keywords:  Chitosan; Ethyl cellulose; Long-acting injectable; Nanoparticles; Oleogel; Sesame oil
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.09.164
  42. Front Oncol. 2022 ;12 947530
    Ferroptosis: A novel therapeutic strategy and mechanism of action in glioma.
    Gaosen Zhang, Yi Fang, Xiang Li, Zhen Zhang.
      Glioma is the most common malignant tumor of the central nervous system and resistance is easily developed to chemotherapy drugs during the treatment process, resulting in high mortality and short survival in glioma patients. Novel therapeutic approaches are urgently needed to improve the therapeutic efficacy of chemotherapeutic drugs and to improve the prognosis of patients with glioma. Ferroptosis is a novel regulatory cell death mechanism that plays a key role in cancer, neurodegenerative diseases, and other diseases. Studies have found that ferroptosis-related regulators are closely related to the survival of patients with glioma, and induction of ferroptosis can improve glioma resistance to chemotherapy drugs. Therefore, induction of tumor cell ferroptosis may be an effective therapeutic strategy for glioma. This review summarizes the relevant mechanisms of ferroptosis, systematically summarizes the key role of ferroptosis in the treatment of glioma and outlines the relationship between ferroptosis-related ncRNAs and the progression of glioma.
    Keywords:  GPx4; ferroptosis; glioma; ncRNA; system xc-
    DOI:  https://doi.org/10.3389/fonc.2022.947530
  43. Front Oncol. 2022 ;12 962066
    Multifunctionality of Calebin A in inflammation, chronic diseases and cancer.
    Aranka Brockmueller, Anna-Lena Mueller, Ajaikumar B Kunnumakkara, Bharat B Aggarwal, Mehdi Shakibaei.
      Chronic diseases including cancer have high case numbers as well as mortality rates. The efficient treatment of chronic diseases is a major ongoing medical challenge worldwide, because of their complexity and many inflammatory pathways such as JNK, p38/MAPK, MEK/ERK, JAK/STAT3, PI3K and NF-κB among others being implicated in their pathogenesis. Together with the versatility of chronic disease classical mono-target therapies are often insufficient. Therefore, the anti-inflammatory as well as anti-cancer capacities of polyphenols are currently investigated to complement and improve the effect of classical anti-inflammatory drugs, chemotherapeutic agents or to overcome drug resistance of cancer cells. Currently, research on Calebin A, a polyphenolic component of turmeric (Curcuma longa), is becoming of growing interest with regard to novel treatment strategies and has already been shown health-promoting as well as anti-tumor properties, including anti-oxidative and anti-inflammatory effects, in diverse cancer cells. Within this review, we describe already known anti-inflammatory activities of Calebin A via modulation of NF-κB and its associated signaling pathways, linked with TNF-α, TNF-β and COX-2 and further summarize Calebin A's tumor-inhibiting properties that are known up to date such as reduction of cancer cell viability, proliferation as well as metastasis. We also shed light on possible future prospects of Calebin A as an anti-cancer agent.
    Keywords:  Calebin A; NF-κB; cancer treatment; chronic inflammation; mitogen-activated protein kinase (MAPK); signaling pathways; tumor prevention; turmeric
    DOI:  https://doi.org/10.3389/fonc.2022.962066
  44. Int J Med Sci. 2022 ;19(10): 1586-1595
    Protective effect of microorganism biotransformation-produced resveratrol on the high fat diet-induced hyperlipidemia, hepatic steatosis and synaptic impairment in hamsters.
    Chun-Hung Su, Ho-Lin Wang, Min-Ling Tsai, Yi-Chun Lin, Jiuan-Miaw Liao, Cheng-Chieh Yen, Hung-Chih Ting, Ching-Han Yu.
      Background: Resveratrol, a natural antioxidant polyphenol, has the functions of anti-inflammation, anti-cancer, liver protection and cardioprotection. Microorganism biotransformation-produced resveratrol (MBR) product shows higher purity than the natural source of resveratrol and costs less than the chemically synthesized resveratrol. The aim of the present study was to investigate the protective effects of MBR in hamsters treated with a high-fat diet (HFD). Methods: MBR was obtained by the fermentative process of piceid. Hamsters were randomly divided into four groups: HFD plus oral administration of MBR 0 (C), 5 (L), 20 (M) or 50 mg/kg (H), respectively. After six-week of treatment, hamsters were sacrificed, and tissues were collected for further analysis. Results: MBR at these three dosages did not influence the appetite or growth of the hamsters. Liver enzymes, blood glucose, total cholesterol, triglyceride, and liver weight were significantly reduced in the MBR groups than in the control group. Additionally, high-density lipoprotein-cholesterol (HDL-C) was also elevated in all MBR groups. On the other hand, serum low-density lipoprotein-cholesterol (LDL-C) was decreased in the MBR groups. Triglyceride (TG) in liver tissue and fatty liver level were lower in group H. Memory-associated proteins, phosphorylation of calmodulin-dependent protein kinase II (p-CaMK II) and synaptophysin (SYP), were increased in the brains of MBR groups. Conclusion: The high yield- and short procedure-produced MBR has the potential to protect animals fed with HFD from hyperlipidemia, hepatic steatosis, hyperglycemia, and synaptic impairment, which might be beneficial for patients with these types of diseases.
    Keywords:  hepatic steatosis; hyperlipidemia; microorganism biotransformation-produced resveratrol; synaptic impairment.
    DOI:  https://doi.org/10.7150/ijms.59018
  45. J Pharm Sci. 2022 Sep 19. pii: S0022-3549(22)00417-8. [Epub ahead of print]
    Lipid nano-carriers loaded with Cannabis sativa extract for epilepsy treatment - in vitro characterization and in vivo efficacy studies.
    Ljubica Mihailova, Jana Tchekalarova, Dushko Shalabalija, Nikola Geskovski, Veronika Stoilkovska Gjorgievska, Gjoshe Stefkov, Paoleta Krasteva, Maja Simonoska Crcarevska, Marija Glavas Dodov.
      Taking into consideration the latest reported beneficial anticolvusant effects of cannabidiol (CBD) and cannabiodiolic acid (CBDA) for clinical applications and the advantages of lipid nano-systems as carriers for targeted brain delivery, the aim of this study was set in direction of in vitro physico-chemical and biopharmaceutical characterization and in vivo evaluation of nanoliposomes and nanostructured lipid carriers loaded with Cannabis sativa extract intended for safe and efficient transport via blood-brain barrier and treatment of epilepsy. These nanoliposomes and nanostructured lipid formulations were characterized with z-average diameter <200 nm, following unimodal particle size distribution, negative values for Z-potential, high drug encapsulation efficiency and prolonged release during 24h (38.84-60.91 %). Prepared formulations showed statistically significant higher antioxidant capacity compared to the extract. The results from in vivo studies of the anticonvulsant activity demonstrated that all formulations significantly elevated the latencies for myoclonic, clonic and tonic seizures and, therefore, could be used in preventing different types of seizures. A distinction in the potential of the nano-systems was noted, which was probably anticipated by the type and the characteristics of the prepared formulations.
    Keywords:  Anticonvulsant activity; Blood-brain barrier; Cannabidiolic acid; Cannabis sativa extract; Epilepsy; Nanoliposomes; Nanostructured lipid carriers
    DOI:  https://doi.org/10.1016/j.xphs.2022.09.012
  46. PLoS One. 2022 ;17(10): e0272097
    Physiology of PNS axons relies on glycolytic metabolism in myelinating Schwann cells.
    Marie Deck, Gerben Van Hameren, Graham Campbell, Nathalie Bernard-Marissal, Jérôme Devaux, Jade Berthelot, Alise Lattard, Jean-Jacques Médard, Benoît Gautier, Sophie Guelfi, Scarlette Abbou, Patrice Quintana, Juan Manuel Chao de la Barca, Pascal Reynier, Guy Lenaers, Roman Chrast, Nicolas Tricaud.
      While lactate shuttle theory states that glial cells metabolize glucose into lactate to shuttle it to neurons, how glial cells support axonal metabolism and function remains unclear. Lactate production is a common occurrence following anaerobic glycolysis in muscles. However, several other cell types, including some stem cells, activated macrophages and tumor cells, can produce lactate in presence of oxygen and cellular respiration, using Pyruvate Kinase 2 (PKM2) to divert pyruvate to lactate dehydrogenase. We show here that PKM2 is also upregulated in myelinating Schwann cells (mSC) of mature mouse sciatic nerve versus postnatal immature nerve. Deletion of this isoform in PLP-expressing cells in mice leads to a deficit of lactate in mSC and in peripheral nerves. While the structure of myelin sheath was preserved, mutant mice developed a peripheral neuropathy. Peripheral nerve axons of mutant mice failed to maintain lactate homeostasis upon activity, resulting in an impaired production of mitochondrial ATP. Action potential propagation was not altered but axonal mitochondria transport was slowed down, muscle axon terminals retracted and motor neurons displayed cellular stress. Additional reduction of lactate availability through dichloroacetate treatment, which diverts pyruvate to mitochondrial oxidative phosphorylation, further aggravated motor dysfunction in mutant mice. Thus, lactate production through PKM2 enzyme and aerobic glycolysis is essential in mSC for the long-term maintenance of peripheral nerve axon physiology and function.
    DOI:  https://doi.org/10.1371/journal.pone.0272097
  47. Front Chem. 2022 ;10 952675
    Physically stimulus-responsive nanoparticles for therapy and diagnosis.
    Fatemeh Farjadian, Soheila Ghasemi, Mohsen Akbarian, Mojtaba Hoseini-Ghahfarokhi, Mohsen Moghoofei, Mohammad Doroudian.
      Nanoparticles offer numerous advantages in various fields of science, particularly in medicine. Over recent years, the use of nanoparticles in disease diagnosis and treatments has increased dramatically by the development of stimuli-responsive nano-systems, which can respond to internal or external stimuli. In the last 10 years, many preclinical studies were performed on physically triggered nano-systems to develop and optimize stable, precise, and selective therapeutic or diagnostic agents. In this regard, the systems must meet the requirements of efficacy, toxicity, pharmacokinetics, and safety before clinical investigation. Several undesired aspects need to be addressed to successfully translate these physical stimuli-responsive nano-systems, as biomaterials, into clinical practice. These have to be commonly taken into account when developing physically triggered systems; thus, also applicable for nano-systems based on nanomaterials. This review focuses on physically triggered nano-systems (PTNSs), with diagnostic or therapeutic and theranostic applications. Several types of physically triggered nano-systems based on polymeric micelles and hydrogels, mesoporous silica, and magnets are reviewed and discussed in various aspects.
    Keywords:  diagnosis; drug delivery; hydrogel; liposomes; magnetic nanoparticles; mesoporous silica; micelles; theranostic
    DOI:  https://doi.org/10.3389/fchem.2022.952675
  48. Evid Based Complement Alternat Med. 2022 ;2022 6369150
    Pharmacology, Toxicology, and Rational Application of Cinnabar, Realgar, and Their Formulations.
    Huifang Guan, Yan Xu, Chunyu Ma, Dexi Zhao.
       Materials and Methods: A search was performed for the literature on cinnabar and realgar in PubMed, the Chinese Pharmacopeia, Google, and other sources. The search included studies using single herbs, traditional formulations, or novel dosage forms.
    Results: Cinnabar and cinnabar formulas exhibit good efficacy for sedation, sleep improvement, anxiety alleviation, and brain protection. However, previous studies on neurotransmitters have reached different conclusions, and detailed pharmacological mechanisms are lacking. Realgar and its formulas exert promising antitumor activity through regulation of cell cycle arrest, intrinsic and extrinsic apoptosis, induction of differentiation, autophagy, metabolic reprogramming, matrix metalloproteinase-9 (MMP-9) signaling, and reactive oxygen species (ROS) generation. In addition, realgar can be used to treat a variety of refractory diseases by regulating immunity and exerting antibacterial, antiviral, and other effects. However, the existing pharmacological research on the use of realgar for epidemic prevention is insufficient, and animal experiments and research at the cellular level are lacking. Inappropriate applications of cinnabar and realgar can cause toxicity, including neurotoxicity, liver toxicity, kidney toxicity, and genotoxicity. The toxicological mechanism is complex, and molecular-level research is limited. For clinical applications, theory and clinical experience must be combined to guide scientific and rational drug use and to achieve reduced toxicity and increased efficacy through the use of modern preparation methods or combined drugs. Notably, when cinnabar and realgar are used to treat targeted diseases, these agents have a bidirectional effect of "treatment" and "toxicity" on the central nervous system in pathological and normal states. The pharmacological and toxicological mechanisms need to be elucidated in greater detail in the future. Overall, systematic research is needed to provide a basis for better promotion of the rational use of cinnabar and realgar in the clinic.
    Conclusion: Mineral medicines are multicomponent, multiactivity, and multitargeted substances. The pharmacology and mechanisms of the toxicity and action of realgar and cinnabar are extremely complex. A number of Chinese medicinal preparations of realgar and cinnabar have demonstrated unique efficacy in the treatment of refractory diseases.
    DOI:  https://doi.org/10.1155/2022/6369150
  49. J Biol Chem. 2022 Oct 02. pii: S0021-9258(22)01005-5. [Epub ahead of print] 102561
    Aurora A-mediated pyruvate kinase M2 phosphorylation promotes biosynthesis with glycolytic metabolites and tumor cell cycle progression.
    Ya Jiang, Ting Wang, Dandan Sheng, Chaoqiang Han, Tian Xu, Peng Zhang, Weiyi You, Weiwei Fan, Zhiyong Zhang, Tengchuan Jin, Xiaotao Duan, Xiao Yuan, Xing Liu, Kaiguang Zhang, Ke Ruan, Jue Shi, Jing Guo, Aoxing Cheng, Zhenye Yang.
      Cancer cells have distinctive demands for intermediates from glucose metabolism for biosynthesis and energy in different cell cycle phases. However, how cell cycle regulators and glycolytic enzymes coordinate to orchestrate the essential metabolic processes are still poorly characterized. Here, we report a novel interaction between the mitotic kinase, Aurora A, and the glycolytic enzyme, pyruvate kinase M2 (PKM2), in the interphase of the cell cycle. We found Aurora A mediated phosphorylation of PKM2 at threonine 45. This phosphorylation significantly attenuated PKM2 enzymatic activity by reducing its tetramerization, and also promoted glycolytic flux and the branching anabolic pathways. Replacing the endogenous PKM2 with a non-phosphorylated PKM2 T45A mutant inhibited glycolysis, glycolytic branching pathways, and tumor growth in both in vitro and in vivo models. Together, our study revealed a new pro-tumor function of Aurora A through modulating a rate-limiting glycolytic enzyme, PKM2, mainly during the S phase of the cell cycle. Our findings also showed that although both Aurora A and Aurora B kinase phosphorylate PKM2 at the same residue, the spatial and temporal regulations of the specific kinase and PKM2 interaction are context-dependent, indicating intricate interconnectivity between cell cycle and glycolytic regulators.
    Keywords:  Aurora A; PKM2; biosynthesis; cell cycle progression; phosphorylation
    DOI:  https://doi.org/10.1016/j.jbc.2022.102561
  50. Front Pharmacol. 2022 ;13 1013692
    Amygdalin as a chemoprotective agent in co-treatment with cisplatin.
    Panayiota Christodoulou, Panagiotis Boutsikos, Christiana M Neophytou, Theodora-Christina Kyriakou, Maria-Ioanna Christodoulou, Panagiotis Papageorgis, Anastasis Stephanou, Ioannis Patrikios.
      Amygdalin is a naturally occurring glycoside used in traditional Chinese medicine and is known to have anti-cancer properties. Even though the anti-cancer properties of amygdalin are well known, its effect on normal cells has not been thoroughly investigated. The aim of the present study was to investigate a possible chemo-protective role of amygdalin against the cytotoxic effects of chemotherapy for normal human cells. Specifically, it was tested in combination with a strong chemotherapeutic drug cisplatin. Human non-tumorigenic MCF12F epithelial cell line, human fibroblasts cells, human breast cancer MCF7 and MDA-MB-231 cells were treated with cisplatin in a dose- and time-depended manner in the absence or presence of amygdalin. When MCF12F cells and fibroblasts underwent pre-treatment with amygdalin followed by cisplatin treatment (24 h amygdalin + 24 h cisplatin), the cell viability was increased (22%, p < 0.001) as indicated using MTT assay. As attested by flow cytometry, combination treatment was associated with decreased the percentage of late apoptotic cells compared with monotherapy (fold-change of decrease = 1.6 and 4.5 for 15 and 20 μΜ, respectively). Also, the proteins expression of PUMA, p53, phospho-p53 and Bax decreased, when a combination treatment was used vs. cisplatin alone, while the proapoptotic proteins Bcl-2 and Bcl-xL exhibited an increased tendency in the presence of amygdalin. Moreover, the levels of pro-apoptotic genes PUMA, p53, and BAX mRNA were significantly downregulated (∼83%, ∼66%, and ∼44%, respectively) vs. cisplatin alone, while the mRNA levels of anti-apoptotic genes BCl-2 and Bcl-XL were upregulated (∼44.5% and ∼51%, respectively), vs. cisplatin alone after 24 h of combination treatment. The study on the Combination index (CI) assay indicated that amygdalin could be possibly considered as an antagonist to cisplatin (2.2 and 2.3) for MCF12F and fibroblast cells, respectively. In contrast, for the breast cancer MCF7 and MDA-MB-231 cells, amygdalin and cisplatin indicated a synergistic effect (0.8 and 0.65), respectively. Our present findings suggest that amygdalin has chemo-modulatory effect when used in co-treatment with cisplatin and is able to protect normal breast cells as well as the fibroblasts during chemotherapy treatment, indicating a strong selective chemoprotective ability and may contribute to a better quality of life for cancer patients.
    Keywords:  amygdalin; breast cancer; chemoprotection; chemothearpy; natural products
    DOI:  https://doi.org/10.3389/fphar.2022.1013692
  51. Chem Biol Drug Des. 2022 Oct 05.
    Gossypin: A flavonoid with diverse pharmacological effects.
    Bocui Song, Xue Shen, Chunyu Tong, Shuang Zhang, Qian Chen, Yuqi Li, Shuang Li.
      Gossypin is a flavonoid compound prepared from chinese medicine Hibiscus, which not only has significant pharmacological activities in antioxidant, anti-inflammatory, neuroprotective, anti-cancer, anti-tumor and anti-diabetic aspects, but also has the advantages of small side effects and easy preparation because it is extracted from traditional chinese medicine, so it has received widespread attention from scholars and researchers. This paper reviews the pharmacological effects and mechanisms of gossypin in recent years, and hopes to provide a theoretical basis for its clinical application.
    Keywords:  Anti-cancer; Anti-inflammatory; Anti-tumor; Gossypin; Neuroprotective; Pharmacological activity
    DOI:  https://doi.org/10.1111/cbdd.14152
  52. Front Oncol. 2022 ;12 932156
    A new core-shell-type nanoparticle loaded with paclitaxel/norcantharidin and modified with APRPG enhances anti-tumor effects in hepatocellular carcinoma.
    Ming-Hua Xie, Zai-Lin Fu, Ai-Lian Hua, Ji-Fang Zhou, Qian Chen, Jian-Bo Li, Shen Yao, Xin-Jun Cai, Min Ge, Li Zhou, Jia Wu.
      Nanoparticle delivery systems have been shown to improve the therapeutic efficacy of anti-cancer drugs, including a variety of drugs for the treatment of hepatocellular carcinoma (HCC). However, the current systems show some limitations, and the delivery of more effective nanoparticle systems for anti-HCC drugs with better targeting ability are needed. Here, we created paclitaxel (PTX)/norcantharidin (NCTD)-loaded core-shell lipid nanoparticles modified with a tumor neovasculature-targeted peptide (Ala-Pro-Arg-Pro-Gly, APRPG) and investigated their anti-tumor effects in HCC. Core-shell-type lipid nanoparticles (PTX/NCTD-APRPG-NPs) were established by combining poly(lactic-co-glycolic acid) (PLGA)-wrapped PTX with phospholipid-wrapped NCTD, followed by modification with APRPG. For comparison, PTX-loaded PLGA nanoparticles (PTX-NPs) and PTX/NCTD-loaded core-shell-type nanoparticles without APRPG (PTX/NCTD-NPs) were prepared. The in vitro and in vivo anti-tumor effects were examined in HepG2 cells and tumor-bearing mice, respectively. Morphological and release characterization showed that PTX/NCTD-APRPG-NPs were prepared successfully and achieved up to 90% release of PTX in a sustained manner. Compared with PTX/NCTD-NPs, PTX/NCTD-APRPG-NPs significantly enhanced the uptake of PTX. Notably, the inhibition of proliferation and migration of hepatoma cells was significantly higher in the PTX/NCTD-APRPG-NP group than those in the PTX-NP and PTX/NCTD-NP groups, which reflected significantly greater anti-tumor properties as well. Furthermore, key molecules in cell proliferation and apoptosis signaling pathways were altered most in the PTX/NCTD-APRPG-NP group, compared with the PTX-NP and PTX/NCTD-NP groups. Collectively, PTX/NCTD-loaded core-shell lipid nanoparticles modified with APRPG enhance the effectiveness of anti-HCC drugs and may be an effective system for the delivery of anti-HCC drugs.
    Keywords:  APRPG; core–shell lipid nanoparticles; hepatocellular carcinoma; norcantharidin; paclitaxel
    DOI:  https://doi.org/10.3389/fonc.2022.932156
  53. Int J Biol Macromol. 2022 Sep 28. pii: S0141-8130(22)02166-3. [Epub ahead of print]222(Pt A): 1110-1126
    Recent advances in medicinal and edible homologous polysaccharides: Extraction, purification, structure, modification, and biological activities.
    Hongkun Xue, Wenli Wang, Jiayue Bian, Yuchao Gao, Zitong Hao, Jiaqi Tan.
      110 kinds of traditional Chinese medicines can be used for medicine and food from Chinese pharmacopoeia in 2021. With the deepening of research in recent years, medicinal and edible homologous (MEH) traditional Chinese medicines have great development and application prospects in many fields. Polysaccharides are one of the major and representative pharmacologically active macromolecules in traditional Chinese medicines with MEH. Moreover, traditional Chinese medicines with MEH have become the main source of natural polysaccharides with safety, high efficiency, and low side effects. Increasing researches have confirmed that MEH polysaccharides (MEHPs) have multiple biological activities both in vitro and in vivo methods, such as antioxidant, immunomodulatory, anti-tumor, anti-aging, anti-inflammatory, hypoglycemic, hypolipidemic activities, and regulating intestinal flora. Additionally, different raw materials, extraction, purification, and chemical modification methods result in differences in the structure and biological activities of MEHPs. The purpose of the present review is to provide comprehensively and systematically reorganized information in the extraction, purification, structure, modification, biological activities, and potential mechanism of MEHPs to support their therapeutic effects and health functions. New valuable insights and theoretical basis for the future researches and developments regarding MEHPs were proposed in the fields of medicine and food.
    Keywords:  Biological activities; Extraction and purification; Medicinal and edible homologous traditional Chinese medicines; Polysaccharides; Structure
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.09.227
  54. Front Pharmacol. 2022 ;13 900693
    An Ethnopharmaceutical Study on the Hypolipidemic Formulae in Taiwan Issued by Traditional Chinese Medicine Pharmacies.
    Min-Han Chi, Jung Chao, Chien-Yu Ko, Shyh-Shyun Huang.
      Globally, approximately one-third of ischemic heart diseases are due to hyperlipidemia, which has been shown to cause various metabolic disorders. This study was aimed to disassemble and analyze hypolipidemic formulae sold by traditional Chinese medicine (TCM) pharmacies. Using commonly used statistical parameters in ethnopharmacology, we identified the core drug combination of the hypolipidemic formulae, thereby exploring the strategy by which the Taiwanese people select hypolipidemic drugs. Most important of all, we preserved the inherited knowledge of TCM. We visited 116 TCM pharmacies in Taiwan and collected 91 TCM formulae. The formulae were mainly disassembled by macroscopical identification, and the medicinal materials with a relative frequency of citation (RFC) >0.2 were defined as commonly used medicinal materials. Subsequently, we sorted the information of medicinal materials recorded in the Pharmacopeia, searched for modern pharmacological research on commonly used medicinal materials using PubMed database, and visualized data based on the statistical results. Finally, the core hypolipidemic medicinal materials used in folk medicine were obtained. Of the 91 TCM formulae collected in this study, 80 traditional Chinese medicinal materials were used, belonging to 43 families, predominantly Lamiaceae. Roots were the most commonly used part as a medicinal material. There were 17 commonly used medicinal materials. Based on medicinal records in Pharmacopeia, most flavors and properties were warm and pungent, the majority traditional effects were "tonifying and replenishing" and "blood-regulating." Besides, the targeted diseases searching from modern pharmacological studies were diabetes mellitus and dyslipidemia. The core medicinal materials consisted of Astragalus mongholicus Bunge and Crataegus pinnatifida Bunge, and the core formulae were Bu-Yang-Huan-Wu-Tang and Xie-Fu-Zhu-Yu-Tang. In addition, 7 groups of folk misused medicinal materials were found. Although these TCMs have been used for a long period of time, their hypolipidemic mechanisms remain unclear, and further studies are needed to validate their safety and efficacy.
    Keywords:  drug combination; hyperlipidemia; hypolipidemic; pharmacies; traditional Chinese medicine
    DOI:  https://doi.org/10.3389/fphar.2022.900693
  55. Biomaterials. 2022 Sep 21. pii: S0142-9612(22)00455-0. [Epub ahead of print]290 121815
    Multifunctional light-activatable nanocomplex conducting temperate-heat photothermal therapy to avert excessive inflammation and trigger augmented immunotherapy.
    Lu Li, Xiuqi Liang, Tao He, Xinchao Li, Xianzhou Huang, Ning Wang, Meiling Shen, Yaqian Shu, Rui Wu, Miaomiao Zhang, Qinjie Wu, Changyang Gong.
      Photothermal therapy (PTT) has been known as an effective weapon against cancer. However, the necrosis induced by hyperthermia post PTT can trigger excessive inflammation response and arouse tumor self-protection resulting in tumor immunosuppression, metastasis and recurrence. To settle this issue, we here reported a multifunctional light-activatable nanocomplex (MILAN) to avoid hyperthermia and achieve temperate-heat PTT for extensive apoptosis, but not necrosis, and further antitumor immune response augmentation to inhibit metastasis and recurrence. Upon NIR irradiation, MILAN would controllably maintain around 43 °C, thus evoking the temperature-triggered phase transformation for the controllable drug release. Then, the released gambogic acid broke the thermoresistance of tumor cells, realizing enhanced apoptosis. Thereafter, the generated tumor-associated antigen accompanied with MILAN could facilitate dendritic cells (DCs) maturation for improved antigen presentation. Furthermore, MILAN promoted the tumor perfusion of DCs and T lymphocytes in triple-negative breast cancer (TNBC) models. Simultaneously, the immunosuppressive microenvironment was relieved and a strong systemic immune response was elicited against tumor progress through MILAN. Consequently, systemic immunity and persistent immune memory effect were fortified for pronounced cancer metastasis and recurrence inhibition. This work tactfully avoids the side effects of hyperthermia and brought a novel insight into cancer immunotherapy against TNBC.
    Keywords:  Cancer immunotherapy; Light-activatable nanocomplex; Temperate-heat PTT; Tumor metastasis; Tumor recurrence
    DOI:  https://doi.org/10.1016/j.biomaterials.2022.121815
  56. Bioact Mater. 2023 Apr;22 112-126
    Upconverting nanoparticle-containing erythrocyte-sized hemoglobin microgels that generate heat, oxygen and reactive oxygen species for suppressing hypoxic tumors.
    Hanju Kim, Johyun Yoon, Hwang Kyung Kim, Woo Tak Lee, Nguyen Thi Nguyen, Xuan Thien Le, Eun-Hee Lee, Eun Seong Lee, Kyung Taek Oh, Han-Gon Choi, Yu Seok Youn.
      Inspired by erythrocytes that contain oxygen-carrying hemoglobin (Hb) and that exhibit photo-driven activity, we introduce homogenous-sized erythrocyte-like Hb microgel (μGel) systems (5-6 μm) that can (i) emit heat, (ii) supply oxygen, and (iii) generate reactive oxygen species (ROS; 1O2) in response to near-infrared (NIR) laser irradiation. Hb μGels consist of Hb, bovine serum albumin (BSA), chlorin e6 (Ce6) and erbium@lutetium upconverting nanoparticles (UCNPs; ∼35 nm) that effectively convert 808 nm NIR light to 660 nm visible light. These Hb μGels are capable of releasing oxygen to help generate sufficient reactive oxygen species (1O2) from UCNPs/Ce6 under severely hypoxic condition upon NIR stimulation for efficient photodynamic activity. Moreover, the Hb μGels emit heat and increase surface temperature due to NIR light absorption by heme (iron protoporphyrin IX) and display photothermal activity. By changing the Hb/UCNP/Ce6 ratio and controlling the amount of NIR laser irradiation, it is possible to formulate bespoke Hb μGels with either photothermal or photodynamic activity or both in the context of combined therapeutic effect. These Hb μGels effectively suppress highly hypoxic 4T1 cell spheroid growth and xenograft mice tumors in vivo.
    Keywords:  Hemoglobin microgel; Hypoxic tumors; Oxygen-generation; Photodynamic therapy; Photothermal therapy; Upconversion
    DOI:  https://doi.org/10.1016/j.bioactmat.2022.09.020
  57. J Ethnopharmacol. 2022 Sep 29. pii: S0378-8741(22)00765-6. [Epub ahead of print]301 115726
    A review: Pharmacokinetics and pharmacology of aminoalcohol-diterpenoid alkaloids from Aconitum species.
    Honglin Tao, Xianfeng Liu, Ruimin Tian, Yue Liu, Yong Zeng, Xianli Meng, Yi Zhang.
       ETHNOPHARMACOLOGICAL RELEVANCE: Aconitum medicinal materials, such as Aconitum carmichaelii Debeaux (Chinese: Wutou/) and Aconitum kusnezoffii Reichb. (Chinese: Caowu/), are a kind of important Traditional Chinese Medicine (TCM) with great medicinal value. Statistics show that there are over 600 efficient TCM formulations comprising Aconitum medicinal materials. But high toxicity limits their clinical application. Clinically, the Aconitum medicinal materials must undergo a complex processing process that includes soaking, steaming, and boiling with pharmaceutical excipients, which makes highly toxic ester diterpenoid alkaloids are hydrolyzed to form less toxic aminoalcohol-diterpenoid alkaloids (ADAs).
    AIM OF THE STUDY: This review aims to summarize the pharmacokinetic and pharmacological activities of low-toxicity ADAs, providing a reference for future ADAs research and drug development.
    MATERIALS AND METHODS: Accessible literature on ADAs published between 1984 and 2022 were screened and obtained from available electronic databases such as PubMed, Web of Science, Springer, Science Direct and Google Scholar, followed by systematic analysis.
    RESULTS: ADAs are secondary products of plant metabolism, widely distributed in the Aconitum species and Delphinium species. The toxicity of ADAs as pharmacodynamic components of Aconitum medicinal materials is much lower than that of other diterpenoid alkaloids due to the absence of ester bonds. On the one hand, the pharmacokinetics of ADAs have received little attention compared to other toxic alkaloids. The research primarily focuses on aconine and mesaconine. According to existing studies, ADAs absorption in the gastrointestinal tract is primarily passive with a short Tmax. Simultaneously, efflux transporters have less impact on ADAs absorption than non-ADAs. After entering the body, ADAs are widely distributed in the heart, liver, lungs, and kidney, but less in the brain. Notably, aconine is not well metabolized by liver microsomes. Aconine and mesaconine are excreted in urine and feces, respectively. ADAs, on the other hand, have been shown to have a variety of pharmacological activities, including cardiac, analgesic, anti-inflammatory, anti-tumor, antioxidant, and regenerative effects via regulating multiple signaling pathways, including Nrf2/ARE, PERK/eIF2α/ATF4/Chop, ERK/CREB, NF-κB, Bcl-2/Bax, and GSK3β/β-catenin signaling pathways.
    CONCLUSIONS: ADAs have been shown to have beneficial effects on heart disease, neurological disease, and other systemic diseases. Moreover, ADAs have low toxicity and a wide range of safe doses. All of these suggest that ADAs have great potential for drug development.
    Keywords:  Alzheimer's disease; Aminoalcohol-diterpenoid alkaloids; Heart failure; Neuropathic pain; Pharmacokinetics; Pharmacology
    DOI:  https://doi.org/10.1016/j.jep.2022.115726
  58. Oxid Med Cell Longev. 2022 ;2022 7838583
    The Role of Natural Products as Inhibitors of JAK/STAT Signaling Pathways in Glioblastoma Treatment.
    Hanieh Fahmideh, Hooriyeh Shapourian, Rasol Moltafeti, Chanour Tavakol, Razieh Forghaniesfidvajani, Hamidreza Zalpoor, Mohsen Nabi-Afjadi.
      The permeability of glioblastoma, as well as its escaping the immune system, makes them one of the most deadly human malignancies. By avoiding programmed cell death (apoptosis), unlimited cell growth and metastatic ability could dramatically affect the immune system. Genetic mutations, epigenetic changes, and overexpression of oncogenes can cause this process. On the other hand, the blood-brain barrier (BBB) and intratumor heterogeneity are important factors causing resistance to therapy. Several signaling pathways have been identified in this field, including the Janus tyrosine kinase (JAK) converter and signal transducer and activator of transcription (STAT) activator pathways, which are closely related. In addition, the JAK/STAT signaling pathway contributes to a wide array of tumorigenesis functions, including replication, anti-apoptosis, angiogenesis, and immune suppression. Introducing this pathway as the main tumorigenesis and treatment resistance center can give a better understanding of how it operates. In light of this, it is an important goal in treating many disorders, particularly cancer. The inhibition of this signaling pathway is being considered an approach to the treatment of glioblastoma. The use of natural products alternatively to conventional therapies is another area of research interest among researchers. Some natural products that originate from plants or natural sources can interfere with JAK/STAT signaling in human malignant cells, also by stopping the progression and phosphorylation of JAK/STAT, inducing apoptosis, and stopping the cell cycle. Natural products are a viable alternative to conventional chemotherapy because of their cost-effectiveness, wide availability, and almost no side effects.
    DOI:  https://doi.org/10.1155/2022/7838583
  59. Expert Opin Drug Discov. 2022 Oct 06.
    Strategies for the drug discovery and development of taxane anticancer therapeutics.
    Changwei Wang, Angelo Aguilar, Iwao Ojima.
       INTRODUCTION: As epoch-making anticancer drugs, paclitaxel and docetaxel have been extensively used in the clinic over the past three decades. Although the patents of these first-generation taxanes have expired, their clinical applications, particularly new formulations and combination therapies are under active investigations. Inspired by the notable success of Abraxane and Lipusu, new formulations have been extensively developed. In parallel, to overcome multidrug resistance (MDR) and to eradicate cancer stem cells, immense efforts have been made on the discovery and development of new-generation taxanes with improved potency and superior pharmacological properties.
    AREAS COVERED: Starting from three taxanes used in clinic, this review covers (a) natural sources of advanced intermediates used for semi-synthesis of taxane API, (b) new formulations, (c) the major issues of FDA approved taxanes, (d) the design and development of next-generation taxanes, particularly those already in clinical trials or advanced preclinical development, (e) new mechanisms of action, and (f) a variety of taxane-based drug delivery systems. In particular, the next-generation taxanes are not only highly potent and capable of overcoming MDR, but also critically important as the payloads of efficacious tumor-targeted drug delivery systems.
    EXPERT OPINION: As the highly potent next-generation taxanes can eradicate cancer stem cells and overcome MDR, the priority is to develop these superior compounds as an integral part of cancer therapy, especially for the treatment of pancreatic, colon and prostate cancer patients who hardly respond to checkpoint inhibitors. In order to mitigate undesirable side effects, the exploration of effective nanoformulations and tumor-targeted drug delivery systems are essential. Therefore, it is expected that these research programs will be the major focus in taxane-based drug development for years to come.
    Keywords:  cancer; drug delivery system; nanoformulation; next-generation taxanes; paclitaxel
    DOI:  https://doi.org/10.1080/17460441.2022.2131766
  60. Cell Prolif. 2022 Oct 05. e13327
    Mitophagy: A novel perspective for insighting into cancer and cancer treatment.
    Congkuan Song, Shize Pan, Jinjin Zhang, Ning Li, Qing Geng.
       BACKGROUND: Mitophagy refers to the selective self-elimination of mitochondria under damaged or certain developmental conditions. As an important regulatory mechanism to remove damaged mitochondria and maintain the internal and external cellular balance, mitophagy plays pivotal roles in carcinogenesis and progression as well as treatment.
    MATERIALS AND METHODS: Here, we combined data from recent years to comprehensively describe the regulatory mechanisms of mitophagy and its multifaceted significance in cancer, and discusse the potential of targeted mitophagy as a cancer treatment strategy.
    RESULTS: The molecular mechanisms regulating mitophagy are complex, diverse, and cross-talk. Inducing or blocking mitophagy has the same or completely different effects in different cancer contexts. Mitophagy plays an indispensable role in regulating cancer metabolic reprogramming, cell stemness, and chemotherapy resistance for better adaptation to tumor microenvironment. In cancer cell biology, mitophagy is considered to be a double-edged sword. And to fully understand the role of mitophagy in cancer development can provide new targets for cancer treatment in clinical practice.
    CONCLUSIONS: This review synthesizes a large body of data to comprehensively describe the molecular mechanisms of mitophagy and its multidimensional significance in cancer and cancer treatment, which will undoubtedly deepen the understanding of mitophagy.
    DOI:  https://doi.org/10.1111/cpr.13327
  61. Nat Prod Rep. 2022 Oct 07.
    A straightforward access to trifluoromethylated natural products through late-stage functionalization.
    He-Ping Li, Xiang-Hong He, Cheng Peng, Jun-Long Li, Bo Han.
      Covering: 2011 to 2021Trifluoromethyl (CF3)-modified natural products have attracted increasing interest due to their magical effect in binding affinity and/or drug metabolism and pharmacokinetic properties. However, the chemo and regioselective construction of natural products (NPs) bearing a CF3 group still remains a long-standing challenge due to the complex chemical scaffolds and diverse reactive sites of NPs. In recent years, the development of late-stage functionalization strategies, including metal catalysis, organocatalysis, light-driven reactions, and electrochemical synthesis, has paved the way for direct trifluoromethylation process. In this review, we summarize the applications of these strategies in the late-stage trifluoromethylation of natural products in the past ten years with particular emphasis on the reaction model of each method. We also discuss the challenges, limitations, and future prospects of this approach.
    DOI:  https://doi.org/10.1039/d2np00056c
  62. Oxid Med Cell Longev. 2022 ;2022 7235412
    Potential Functional Food Products and Molecular Mechanisms of Portulaca Oleracea L. on Anticancer Activity: A Review.
    Pâmela Gomes de Souza, Amauri Rosenthal, Ellen Mayra Menezes Ayres, Anderson Junger Teodoro.
      Portulaca oleracea Linn. (P. oleracea L.) has recently gained attention as a functional food due to the chemical composition of this plant regarding bioactive compounds. The special attention to the use of P. oleracea as an ingredient in functional food products is also due to the promotion of sustainable food. It is an unconventional food plant, and its consumption may contribute to preserving biodiversity due to its cultivation in a polyculture system. Food sovereignty may be achieved, among other strategies, with the consumption of unconventional food plants that are more resistant in nature and easily cultivated in small places. P. oleracea grows spontaneously and may be found in streets and sidewalks, or it may be cultivated with seeds and cuttings propagation. The culinary versatility of P. oleracea opens up opportunities to explore the development of sustainable, functional food products. This mini-review shows that functional food products developed from P. oleracea are already available at the research level, but it is expected that more scientific literature focusing on the development of P. oleracea functional products with proven anticancer activities may be released in the near future. Polysaccharides, some phenolic compounds, alkaloids, and cerebrosides are associated with the inhibition and prevention of carcinogenesis through in vitro and in vivo investigations. The anticancer activities of P. oleracea, its bioactive compounds, and the involved molecular mechanisms have been reported in the literature. The importance of further elucidating the cancer inhibition mechanisms is in the interest of forthcoming applications in the development of food products with anticancer properties for implementation in the human diet.
    DOI:  https://doi.org/10.1155/2022/7235412
  63. Carbohydr Polym. 2022 Dec 01. pii: S0144-8617(22)00939-0. [Epub ahead of print]297 120034
    A novel approach of encapsulating curcumin and succinylated derivative in mannosylated-chitosan nanoparticles.
    Sourour Idoudi, Yousef Hijji, Takwa Bedhiafi, Hesham M Korashy, Shahab Uddin, Maysaloun Merhi, Said Dermime, Nashiru Billa.
      Curcumin (CUR) manifests anti-colon cancer activity but suffers from low solubility, bioavailability, and instability, rendering it not as effective as its chemotherapeutic cousins. Here, we conjugate CUR to succinic anhydride (SA), (CUR.SA conjugate), subsequently formulated in mannose-conjugated chitosan nanoparticles (CUR-NPs and CUR.SA-NPs). Instrumental analyses confirmed formation of CUR.SA and mannosylated chitosan (CM) conjugates, with CUR.SA being less crystalline thus, more soluble. Average particle size of CUR-NPs and CUR.SA-NPs were 268 ± 6 nm and 342 ± 4.6 nm, with drug entrapment of 93.34 ± 0.40 % and 98.46 ± 0.06 % respectively. In vitro releases of CUR and CUR.SA from nanoparticles in pH 1.2 and 6.8 media were slow and sustained over 2 h and 72 h, respectively. The physical characteristics of the nanoparticles were unchanged over 3 weeks of storage. Thus, a successful CUR.SA conjugate has been developed, couriered in CM nanoparticles, with favorable attributes that warrant further anti-colon cancer studies, which is ongoing.
    Keywords:  Chitosan nanoparticles; Curcumin; In vitro; Mannose; Physical; Succinic anhydride
    DOI:  https://doi.org/10.1016/j.carbpol.2022.120034
  64. Int J Pharm. 2022 Oct 01. pii: S0378-5173(22)00812-2. [Epub ahead of print] 122257
    Near-infrared light-responsive and antibacterial injectable hydrogels with antioxidant activity based on a Dopamine-functionalized Gellan Gum for wound healing.
    Giuseppina Biscari, Giovanna Pitarresi, Calogero Fiorica, Domenico Schillaci, Valentina Catania, Fabio Salvatore Palumbo, Gaetano Giammona.
      The development of wound dressings with combined antioxidant, antibacterial and tissue adhesion functions has been a difficult medical task for the treatment of wound infections. We synthetized a dopamine and PEG functionalized gellan gum (GG) to produce an injectable hydrogel with radical scavenging activity having both specific and aspecific antibiotic/antimicrobial properties. Using starting GG with different molecular weight, we obtained two derivatives that have been used to prepare the gel precursor dispersion, that undergoes gelation in the presence of colistin and dried microparticles (MPs) functionalized on the surface with polydopamine (PDA). Both were used to dope the hydrogel, increase the radical scavenger activity and impart near infrared light (NIR) responsiveness. Indeed, with an irradiation of 810 nm, the incorporated microparticles exhibit photothermal transformation properties and improve the release of antibiotics on demand. The combination of photothermal and antibiotic therapy with synergistic antibacterial action acts on Pseudomonas aeruginosa and leads to a bactericidal effect in a few hours, while on Staphylococcus aureus there is an effect of inhibition of growth over time due only to the hyperthermic effect. We believe this study provides a promising method for fabricating a multifunctional injectable hydrogel for the potential treatment of infected skin wounds.
    Keywords:  Antibiotic release; Antipseudomonal strategies; Gellan Gum; Photothermal therapy; Polydopamine; Radical scavenging
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.122257
  65. J Food Sci Technol. 2022 Nov;59(11): 4152-4164
    Pineapple processing waste (PPW): bioactive compounds, their extraction, and utilisation: a review.
    L Meena, Animesh Singh Sengar, Rooman Neog, C K Sunil.
      Fruits and vegetable processing industries contribute to the largest portion of food waste. With changing diet habits, the demand for the production and processing of fruits and vegetables has increased greatly to fulfil the rising demand amongst the masses. Waste generation begins from the harvesting of raw material until it gets processed. Pineapple processing industries produce processing waste (peel, core, pomace, and crown) which are rich in various bioactive compounds. In most cases, the by-products contain larger amounts of valuable compounds which have higher nutritional and therapeutic importance than its final produce. Researchers have studied the potential of pineapple wastes primarily for the extraction of enzymes (bromelain, pectinase, xylanase and cellulase) and secondarily as a low-cost substrate to produce dietary fibre, organic acids, and phenolic antioxidants. This review describes the bioactive compounds in pineapple wastes, their extraction techniques, and their potential applications as a polymer material, bio-sorbents, bioethanol and vanillin production, etc. It focuses primarily on bioactive compounds that have functional and medicinal value and can be used independently or incorporated with other ingredients to form the valorised product.
    Graphic abstract:
    Keywords:  Bioactive compounds; Extraction; Low-cost substrate; Pineapple wastes; Utilisation
    DOI:  https://doi.org/10.1007/s13197-021-05271-6
  66. Chem Biol Interact. 2022 Oct 01. pii: S0009-2797(22)00399-4. [Epub ahead of print] 110194
    Anticancer peptides mechanisms, simple and complex.
    Peiman Norouzi, Maryam Mirmohammadi, Mohammad Hassan Houshdar Tehrani.
      Peptide therapy has started since 1920s with the advent of insulin application, and now it has emerged as a new approach in treatment of diseases including cancer. Using anti-cancer peptides (ACPs) is a promising way of cancer therapy as ACPs are continuing to be approved and arrived at major pharmaceutical markets. Traditional cancer treatments face different problems like intensive adverse effects to patient's body, cell resistance to conventional chemical drugs and in some worse cases the occurrence of cell multidrug resistance (MDR) of cancerous tissues against chemotherapy. On the other hand, there are some benefits conceived for peptides usage in treatment of diseases specifically cancer, as these compounds present favorable characteristics such as smaller size, high activity, low immunogenicity, good biocompatibility in vivo, convenient and rapid way of synthesis, amenable to sequence modification and revision and there is no limitation for the type of cargo they carry. It is possible to achieve an optimum molecular and functional structure of peptides based on previous experience and bank of peptide motif data which may result in novel peptide design. Bioactive peptides are able to form pores in cell membrane and induce necrosis or apoptosis of abnormal cells. Moreover, recent researches have focused on the tumor recognizing peptide motifs with the ability to permeate to cancerous cells with the aim of cancer treatment at earlier stages. In this strategy the most important factors for addressing cancer are choosing peptides with easy accessibility to tumor cell without cytotoxicity effect towards normal cells. The peptides must also meet acceptable pharmacokinetic requirements. In this review, the characteristics of peptides and cancer cells are discussed. The various mechanisms of peptides' action proposed against cancer cells make the next part of discussion. It will be followed by giving information on peptides application, various methods of peptide designing along with introducing various databases. Future aspects of peptides for employing in area of cancer treatment come as conclusion at the end.
    Keywords:  Anticancer peptides; Cancer therapy; Cancerous cell; Cytotoxicity; Peptides; Protein
    DOI:  https://doi.org/10.1016/j.cbi.2022.110194
  67. Biomaterials. 2022 Sep 27. pii: S0142-9612(22)00461-6. [Epub ahead of print]290 121821
    Biomimetic cell membrane-coated glucose/oxygen-exhausting nanoreactor for remodeling tumor microenvironment in targeted hypoxic tumor therapy.
    Haoyu Guo, Weiyue Zhang, Lutong Wang, Zengwu Shao, Xin Huang.
      Hypoxia is a common feature within many types of solid tumors, which is closely associated with limited efficacy for tumor therapies. Moreover, the inability to reach hypoxic tumor cells that are distant from blood vessels results in tumor-targeting and penetrating drug delivery systems in urgent need. Here, glucose oxidase (GOX) and hypoxia-activated prodrug tirapazamine (TPZ) are loaded into photothermal conversion agent polydopamine (PDA) as the glucose/oxygen-exhausting nanoreactor named PGT. We further construct a tumor cell membrane-coated nanovesicle for the targeted delivery of PGT. This biomimetic nanovesicle exhibits significantly improved tumor-targeting and tumor-penetrating abilities. After internalization by the tumor cells, the loaded drug is quickly released in response to near-infrared (NIR) laser. The PGT nanoreactor can exhaust glucose and oxygen, and further enhance hypoxia within tumor, which efficiently inhibits hypoxic tumor by combining starvation therapy and hypoxia-activated chemotherapy. Mechanically, it is revealed that the nanoreactor significantly increases hypoxia level and downregulates the expression of hypoxia-inhibitory factor-1α (HIF-1α), thereby promoting T cell activation and macrophage polarization to remodel tumor immunosuppressive microenvironment. Therefore, this tumor microenvironment-regulable nanoreactor with sustainable and cascade targeted starvation-chemotherapy provides a novel insight into the treatment of hypoxic tumor.
    Keywords:  Cell membrane-coated nanovesicles; Hypoxia-activated chemotherapy; Hypoxic tumor; Starvation therapy
    DOI:  https://doi.org/10.1016/j.biomaterials.2022.121821
  68. Cancer Cell Int. 2022 Oct 07. 22(1): 305
    Sesquiterpenoid lactones as potential anti-cancer agents: an update on molecular mechanisms and recent studies.
    Praveen Dhyani, Priyanka Sati, Eshita Sharma, Dharam Chand Attri, Amit Bahukhandi, Bekzat Tynybekov, Agnieszka Szopa, Javad Sharifi-Rad, Daniela Calina, Hafiz A R Suleria, William C Cho.
      Plants-based natural compounds are well-identified and recognized chemoprotective agents that can be used for primary and secondary cancer prevention, as they have proven efficacy and fewer side effects. In today's scenario, when cancer cases rapidly increase in developed and developing countries, the anti-cancerous plant-based compounds become highly imperative. Among others, the Asteraceae (Compositae) family's plants are rich in sesquiterpenoid lactones, a subclass of terpenoids with wide structural diversity, and offer unique anti-cancerous effects. These plants are utilized in folk medicine against numerous diseases worldwide. However, these plants are now a part of the modern medical system, with their sesquiterpenoid lactones researched extensively to find more effective and efficient cancer drug regimens. Given the evolving importance of sesquiterpenoid lactones for cancer research, this review comprehensively covers different domains in a spectrum of sesquiterpenoid lactones viz (i) Guaianolides (ii) Pseudoguaianolide (iii) Eudesmanolide (iv) Melampodinin A and (v) Germacrene, from important plants such as Cynara scolymus (globe artichoke), Arnica montana (wolf weeds), Spilanthes acmella, Taraxacum officinale, Melampodium, Solidago spp. The review, therefore, envisages being a helpful resource for the growth of plant-based anti-cancerous drug development.
    Keywords:  Anti-tumor; Apoptosis; Cancer; Complementary medicine; Molecular mechanisms; Sesquiterpenoid lactones; Signaling pathway
    DOI:  https://doi.org/10.1186/s12935-022-02721-9
  69. J Control Release. 2022 Sep 30. pii: S0168-3659(22)00646-0. [Epub ahead of print]351 581-596
    Bio-inspired engineered ferritin-albumin nanocomplexes for targeted ferroptosis therapy.
    Chencheng Xue, Hui Zhang, Xuan Wang, Haoyu Du, Lu Lu, Yang Fei, Yanan Li, Yuchen Zhang, Menghuan Li, Zhong Luo.
      Nanotechnology-enabled ferroptosis therapy is an emerging paradigm for tumor treatment, but amplifying ferroptotic damage in tumor cells in a safe and selective manner is still challenging, which severely hinders its clinical translation. In this study, we constructed a bio-inspired protein nanocomplex based on natural-occurring bovine serum albumin (BSA) and ferritin for efficient tumor elimination via cooperatively enhanced ferroptosis therapy. The long-circulating BSA molecules provided multiple anchoring points for the efficient loading of the GPX4-inhibiting ferroptosis inducer (1S, 3R) RAS-selective lethal 3 (RSL3), which was further complexed with ferritin via acidity-responsive glutaraldehyde linkers. The ferritin moieties may not only bind to transferrin receptor 1 overexpressed on tumor cell membrane for targeted endocytic uptake but also be degraded in lysosomes to induce iron overload, which could substantially promote the lipid peroxidation in tumor cells and cooperate with the glutathione peroxidase 4 (GPX4)-inhibiting capability of RSL3 to induce pronounced ferroptosis. The in vitro and in vivo results collectively demonstrated that the albumin-ferritin-based nanocomplex could present superior antitumor effects with no obvious adverse effects, which may open new avenues for the clinical translation of ferroptosis-dependent therapeutic modalities.
    Keywords:  Bioinspired protein nanocomplexes; Cooperative tumor therapy; Ferroptosis; Targeted drug delivery
    DOI:  https://doi.org/10.1016/j.jconrel.2022.09.051
  70. J Pharm Pharmacol. 2022 Oct 07. pii: rgac053. [Epub ahead of print]
    Pharmacological and phytochemical potential of Rubus ellipticus: a wild edible with multiple health benefits.
    Pushpa Kewlani, Deepti Tiwari, Sandeep Rawat, Indra D Bhatt.
       OBJECTIVES: Rubus ellipticus (family Rosaceae) is used for its delicious edible fruits in the Himalayan region and other parts of the globe. However, the full potential of the species is yet to be harnessed. The current review focuses on the phytochemical, traditional uses, morphological, molecular and pharmacological potential of R. ellipticus.
    KEY FINDINGS: The review of the literature reveals that many health-promoting compounds of R. ellipticus have been reported from the species along with the different biological properties, such as nephroprotective, anti-inflammatory, analgesic, anti-pyretic, anti-proliferative, cytotoxicity, anti-cancer, wound healing, anti-fertility, anti-plasmodial, anti-microbial and antioxidant. Traditionally, it is used in many formulations, which are validated through primary pharmacological assays. However, several medicinal properties are still need to be validated through detailed pharmacological and clinical studies.
    SUMMARY: All the information is available in a scanty form, and the complete information is missing on a single platform. Such type of information will help researchers to better utilize the available data for initiating future research on the species as it has the potential to contribute to the food and pharmaceutical industry. The review highlights the need for further studies on the species to harness its potential in nutraceutical, functional food, energy supplement, and beneficial therapeutic drug development program.
    Keywords:   Rubus ; Himalaya Raspberry; berries; nutraceutical; wild edible
    DOI:  https://doi.org/10.1093/jpp/rgac053
  71. Front Nutr. 2022 ;9 993133
    A network pharmacology approach to evaluate the synergistic effect of dihydromyricetin and myricitrin in vine tea on the proliferation of B16F10 cells.
    Nanxing Zhao, Hongming Kong, Hesheng Liu, Qing Shi, Xiangyang Qi, Qiuping Chen.
       Aim of the study: Although vine tea has demonstrated broad-spectrum anti-cancer properties, its main active compounds, dihydromyricetin (DMY) and myricitrin (MYT), exert weaker effects than the tea extracts. This study aimed to investigate the synergistic inhibitory effects of DMY and MYT on B16F10 cell proliferation and their synergistic inhibitory effects.
    Methods: The effect of vine tea extracts (VTEs) and their active compounds on B16F10 cells was analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, fluorescence staining, and flow cytometry. The synergistic effects were calculated by the combination index (CI), and its mechanism was discussed by network pharmacology.
    Results: Different VTEs varied in their inhibition of B16F10 cell growth, with IC50 values ranging from 4.45 to 12.95 μg/mL, Among these, Guangzhou Qingyuan (Level 2), appeared to have the most potent inhibitory effect. The IC50 value of mix-use of DMY and MYT was 19.94∼64.4 μM, of which DMY: MYT = 8:1 had the minimum IC50 value of 19.94 μM. Combinations in the 1:1∼8:1 range had stronger effects than the isolated active compound. When they were mixed at the ratio of 1:4∼8:1, CI < 1, showing a synergistic effect. The combination of DMY and MYT also significantly inhibited the tyrosinase activity in B16F10 cells, consistent with its impact on cell proliferation. The eight potential targets were identified by network pharmacology regulating melanin metabolism, tyrosine metabolism, and melanogenesis signaling. According to the analysis of protein-protein interactions, TP53, TNF, and TYR might be critical targets for preventing and treating melanoma.
    Conclusion: We found that DMY and MYT induced apoptosis of B16F10 cells, and their combined application had a significant synergistic effect. The present findings indicated that vine tea had a multi-pathway and multi-target impact on the prevention and treatment of melanoma.
    Keywords:  cell cycle; dihydromyricetin; myricitrin; network pharmacology; proliferation inhibition; synergistic effect; vine tea
    DOI:  https://doi.org/10.3389/fnut.2022.993133
  72. J Agric Food Chem. 2022 Oct 05.
    Oxidized Chitin Nanocrystals Greatly Strengthen the Stability of Resveratrol-Loaded Gliadin Nanoparticles.
    Weiquan Zhong, Zijian Zhi, Jianbo Zhao, Danjie Li, Shan Yu, Mengxia Duan, Jingting Xu, Cailing Tong, Jie Pang, Chunhua Wu.
      Resveratrol (RES) is a natural polyphenol with a variety of health beneficial properties, but its application is greatly limited due to low aqueous solubility and poor bioavailability. This study aims to address these issues via gliadin nanoparticles stabilized with oxidized chitin nanocrystals (O-ChNCs) as a delivery system for RES. RES-loaded gliadin nanoparticles (GRNPs) were fabricated by an antisolvent method, and their formation mechanism was elucidated using zeta-potential, FTIR, XRD, and TEM. Furthermore, the effect of O-ChNCs on the colloidal stability and bioactiveness of GRNPs was discussed. The results demonstrate that O-ChNCs are adsorbed onto the surface of GRNPs through hydrogen bonding and electrostatic interactions, leading to the enhanced absolute potential and the improved hydrophobicity of the particles, which in turn facilitates the stability of the GRNPs. Furthermore, the changes in the release profile and antioxidant activity of RES in the simulated gastric and intestinal tracts indicate that the adsorption of O-ChNCs not only delays the release of RES but also has a protective effect on the antioxidant capacity of RES. This study provides significant implications for developing stable gliadin nanoparticles as delivery vehicles for bioactive substances.
    Keywords:  gliadin nanoparticles; oxidized chitin nanocrystals; resveratrol; stability
    DOI:  https://doi.org/10.1021/acs.jafc.2c04174
  73. Carbohydr Polym. 2022 Dec 01. pii: S0144-8617(22)00907-9. [Epub ahead of print]297 120002
    Polypseudorotaxane hydrogel based on Tween 80 and α-cyclodextrin for sustained delivery of low molecular weight heparin.
    Bo Tang, Xuewen Yang, Aiwen Zhang, Qiuxiang Wang, Lei Fan, Guihua Fang.
      Low molecular weight heparin (LMWH), an anionic polysaccharide, has been widely used as a clinical anticoagulant. However, repeated subcutaneous injection is sometimes required due to its short half-life. To reduce the dosing frequency, the injectable polypseudorotaxane hydrogel was fabricated by inclusion complexation formation between Tween 80 and α-Cyclodextrin (αCD) for sustained release of LMWH. The physicochemical properties of such hydrogel were characterized by SEM, XRD, DSC, and FTIR. This hydrogel showed shear-thinning and thixotropic behavior and was easily injected through standard syringe needles. The gelation time, mechanical strength, shear viscosity, in vitro drug release rate, in vitro hydrogel dissolution rate, and in vivo hydrogel retention could be tuned by αCD concentration in the hydrogel. In vivo safety evaluation indicated that the polypseudorotaxane hydrogel was biocompatible. Most importantly, this polypseudorotaxane hydrogel could sustain release of LMWH after subcutaneous injection.
    Keywords:  Low molecular weight heparin; Polypseudorotaxane hydrogel; Sustained release; Tween 80; α-Cyclodextrin
    DOI:  https://doi.org/10.1016/j.carbpol.2022.120002
  74. Front Nutr. 2022 ;9 927361
    Lagenaria siceraria fruit: A review of its phytochemistry, pharmacology, and promising traditional uses.
    Muhammad Saeed, Muhammad Sajjad Khan, Kinza Amir, Jannat Bi Bi, Muhammad Asif, Asadullah Madni, Asghar Ali Kamboh, Zahid Manzoor, Umair Younas, Sun Chao.
      Since ancient times, the Cucurbitaceae family is used as a therapeutic option in human medicine. This family has around 130 genera and 800 species. Researchers have studied the various plants of this family including Lagenaria siceraria due to their medicinal potential. Various properties are beneficial for human health, that have been attributed to L. siceraria like antioxidant, hypolipidemic, diuretic, laxative, hepatoprotective, analgesic, antihypertensive, cardioprotective, central nervous system stimulant, anthelmintic, free radical scavenging, immunosuppressive, and adaptogenic. The fruit of this plant is commonly used as a vegetable that has a low-calorie value. The species possess a diverse set of biological compounds like flavonoids, sterols, saponins, and terpenoids. Vitamins, choline, flavonoids, minerals, proteins, terpenoids, and other phytochemicals are also found in the edible parts of this plant. Besides 17 different amino acids, many minerals are reported to be present in the seeds of L. siceraria. According to the USDA nutritional database per 100 g of L. siceraria contains 14 Kcal energy, 3.39 g carbohydrates, 0.62 g protein, 0.2 g fat, and 0.5 g fiber. L. siceraria performs a wide range of pharmacological and physiological actions. The literature reviewed from various sources including PubMed, Science Direct, Google scholar, etc. shows the remarkable potential to treat various human and animal illnesses due to its' potent bioactive chemicals. The key objective of this thorough analysis is to present a summary of the data about the beneficial and harmful effects of L. siceraria intake on human health, as well as in veterinary fields.
    Keywords:  Lagenaria siceraria fruit; nutritional potential; pharmacological effect; pharmacology; phytochemistry
    DOI:  https://doi.org/10.3389/fnut.2022.927361
  75. Front Pharmacol. 2022 ;13 981048
    Pharmacological effects of higenamine based on signalling pathways and mechanism of action.
    De-Ta Chen, Wu Rao, Xue Shen, Lin Chen, Zi-Jian Wan, Xiao-Ping Sheng, Tian-You Fan.
      Higenamine (HG) is a chemical compound found in various plants, such as aconite. Recent pharmacological studies have demonstrated its effectiveness in the management of many diseases. Several mechanisms of action of HG have been proposed; however, they have not yet been classified. This review summarises the signalling pathways and pharmacological targets of HG, focusing on its potential as a naturally extracted drug. Articles related to the pharmacological effects, signalling pathways and pharmacological targets of HG were selected by searching the keyword "Higenamine" in the PubMed, Web of Science and Google Scholar databases without limiting the search by publication years. HG possesses anti-oxidant, anti-apoptotic, anti-inflammatory, electrophysiology regulatory, anti-fibrotic and lipid-lowering activities. It is a structural analogue of catecholamines and possesses characteristics similar to those of adrenergic receptor ligands. It can modulate multiple targets, including anti-inflammation- and anti-apoptosis-related targets and some transcription factors, which directly or indirectly influence the disease course. Other naturally occurring compounds, such as cucurbitacin B (Cu B) and 6-gingerol (6-GR), can be combined with HG to enhance its anti-apoptotic activity. Although significant research progress has been made, follow-up pharmacological studies are required to determine the exact mechanism of action, new signalling pathways and targets of HG and the effects of using it in combination with other drugs.
    Keywords:  TCM; higenamine; mechanism of action; pharmacological effect; signalling pathway
    DOI:  https://doi.org/10.3389/fphar.2022.981048
  76. Int J Biol Macromol. 2022 Oct 03. pii: S0141-8130(22)02223-1. [Epub ahead of print]
    Three-layer core-shell structure of polypyrrole/polydopamine/poly(l-lactide) nanofibers for wound healing application.
    Feng Xiong, Shuo Wei, Han Sheng, Shuyuan Wu, Zihao Liu, Wenzhuo Cui, Yunqian Sun, Yijia Wu, Biyun Li, Hongyun Xuan, Ye Xue, Huihua Yuan.
      Poor wound healing is a very common clinical problem, so far there is no completely satisfactory treatment. Electropsun nanofibrous wound dressings may provide an ideal structure to improve wound healing. Therefore, development of nanofibrous wound dressings with rapid hemostasis, antibacterial and tissue regenerative multi-functions has been a hotspot in the field of skin tissue engineering. In this work, polydopamine (PDA) and polypyrrole (PPy) were uniformly coated onto the surface of poly(l-lactide) (PLLA) nanofibers by in-situ polymerization, forming a novel PPy/PDA/PLLA three-layer core-shell structure. The homogeneously coated PPy and PDA two layers could significantly increase the hydrophilicity, conductivity, near-infrared photothermal antibacterial property, the speed of wound hemostasis, antioxidant capacity and reactive oxygen species (ROS) scavenging capacity, respectively. In addition, PPy/PDA/PLLA nanofibers showed good biocompatibility. Rat wound healing model confirmed that PPy/PDA/PLLA nanofibers could significantly accelerate wound repair in vivo. Thus, this novel nanofibrous wound dressing is a promising candidate for clinical wound healing.
    Keywords:  Antibacterial property; Hemostasis; Nanofibers; ROS; Wound healing
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.09.284
  77. J Nanobiotechnology. 2022 Oct 04. 20(1): 436
    Preclinical development of carrier-free prodrug nanoparticles for enhanced antitumor therapeutic potential with less toxicity.
    Man Kyu Shim, Suah Yang, Jooho Park, Jun Sik Yoon, Jinseong Kim, Yujeong Moon, Nayeon Shim, Mihee Jo, Yongwhan Choi, Kwangmeyung Kim.
       BACKGROUND: Nanomedicine has emerged as a promising strategy for cancer treatment. The most representative nanomedicine used in clinic is PEGylated liposomal doxorubicin DOXIL®, which is first FDA-approved nanomedicine. However, several shortcomings, such as low drug loading capacity, low tumor targeting, difficulty in mass production and potential toxicity of carrier materials, have hindered the successful clinical translation of nanomedicines. In this study, we report a preclinical development process of the carrier-free prodrug nanoparticles designed as an alternative formulation to overcome limitations of conventional nanomedicines in the terms of technical- and industrial-aspects.
    RESULTS: The carrier-free prodrug nanoparticles (F68-FDOX) are prepared by self-assembly of cathepsin B-specific cleavable peptide (FRRG) and doxorubicin (DOX) conjugates without any additional carrier materials, and further stabilized with Pluronic F68, resulting in high drug loading (> 50%). The precise and concise structure allow mass production with easily controllable quality control (QC), and its lyophilized powder form has a great long-term storage stability at different temperatures (- 4, 37 and 60 °C). With high cathepsin B-specificity, F68-FDOX induce a potent cytotoxicity preferentially in cancer cells, whereas their cytotoxicity is greatly minimized in normal cells with innately low cathepsin B expression. In tumor models, F68-FDOX efficiently accumulates within tumor tissues owing to enhanced permeability and retention (EPR) effect and subsequently release toxic DOX molecules by cathepsin B-specific cleavage mechanism, showing a broad therapeutic spectrum with significant antitumor activity in three types of colon, breast and pancreatic cancers. Finally, the safety of F68-FDOX treatment is investigated after single-/multi-dosage into mice, showing greatly minimized DOX-related toxicity, compared to free DOX in normal mice.
    CONCLUSIONS: Collectively, these results provide potential preclinical development process of an alternative approach, new formulation of carrier-free prodrug nanoparticles, for clinical translation of nanomedicines.
    Keywords:  Cathepsin B; Doxorubicin; Nanoparticles; Preclinical study; Prodrug; Targeted therapy
    DOI:  https://doi.org/10.1186/s12951-022-01644-x
  78. Pharm Res. 2022 Oct 04.
    Novel Nanostructured Lipid Carriers Co-Loaded with Mesalamine and Curcumin: Formulation, Optimization and In Vitro Evaluation.
    Ankit Awasthi, Bimlesh Kumar, Monica Gulati, Sukriti Vishwas, Leander Corrie, Jaskiran Kaur, Rubiya Khursheed, Rozhan Arif Muhammed, Duran Kala, Omji Porwal, Malakapogu Ravindra Babu, M V N L Chaitanya, Ankit Kumar, Narendra Kumar Pandey, Harish Dureja, Dinesh Kumar Chellappan, Niraj Kumar Jha, Gaurav Gupta, Parteek Prasher, Deepak Kumar, Kamal Dua, Sachin Kumar Singh.
       PURPOSE: The aim of current study is to formulate, optimize and characterize the developed formulation of Mesalamine-Curcumin Nanostructured Lipid Carriers (Mes-Cur NLCs).
    METHODS: It was formulated using high pressure homogenization followed by probe sonication and formulation variables were optimized using Central Composite Design. The particle size (PS), zeta potential (ZP), entrapment efficiency (EE), drug release, cytotoxicity on NIH 3T3 fibroblasts cells and HaCaT keratinocytes cells and efficacy on RAW264.7 cells for optimized formulation was determined.
    RESULTS: The PS, ZP and EE were found to be 85.26 nm, -23.7 ± 7.45 mV, 99.2 ± 2.62 % (Mes) and 84 ± 1.51 % (Cur), respectively. The good correlation between predicted and obtained value indicated suitability and reproducibility of experimental design. NLCs showed spherical shape as confirmed by TEM. In vitro drug release profile of prepared formulation showed that Mes exhibited 100 % release at 48 h, whereas Cur exhibited 82.23 ± 2.97% release at 120 h. Both the drugs exhibited sustained release upon incorporation into the NLCs. The absence of any significant cell death during MTT assay performed on NIH 3T3 fibroblasts cells and HaCaT keratinocytes cells indicated that NLCs' were safe for use. Furthermore, significant reduction in nitric oxide level during anti-inflammatory evaluation of formulation on RAW264.7 cells showed excellent potential for the formulation to treat inflammation. The formulation was found stable as no significant difference between the PS, ZP and EE of the fresh and aged NLCs was observed.
    CONCLUSION: The outcomes of study deciphered successful formulation of Mes-Cur NLCs.
    Keywords:  central composite design; curcumin; mesalamine; nanostructured lipid carriers; stability studies
    DOI:  https://doi.org/10.1007/s11095-022-03401-z
  79. Eur J Pharmacol. 2022 Sep 29. pii: S0014-2999(22)00560-X. [Epub ahead of print]934 175299
    Recent progress and research trend of anti-cataract pharmacology therapy: A bibliometric analysis and literature review.
    Ao Lu, Ping Duan, Jing Xie, Hui Gao, Mengmeng Chen, Yu Gong, Jiawen Li, Haiwei Xu.
      Cataract is the leading cause of blindness worldwide. Cataract phacoemulsification combined with intraocular lens implantation causes great burden to global healthcare, especially for low- and middle-income countries. Such burden would be significantly relieved if cataracts can effectively be treated or delayed by non-surgical means. Excitingly, novel drugs have been developed to treat cataracts in recent decades. For example, oxysterols are found to be able to innovatively reverse lens clouding, novel nanotechnology-loaded drugs improve anti-cataract pharmacological effect, and traditional Chinese medicine demonstrates promising therapeutic effects against cataracts. In the present review, we performed bibliometric analysis to provide an overview perspective regarding the research status, hot topics, and academic trends in the field of anti-cataract pharmacology therapy. We further reviewed the curative effects and molecular mechanisms of anti-cataract drugs such as lanosterol, metformin, resveratrol and curcumin, and prospected the possibility of their clinical application in future.
    Keywords:  Bibliometric analysis; Cataract; Chinese traditional medicine; Pharmacology
    DOI:  https://doi.org/10.1016/j.ejphar.2022.175299
  80. World J Diabetes. 2022 Sep 15. 13(9): 696-716
    Evolving spectrum of diabetic wound: Mechanistic insights and therapeutic targets.
    Raja Chakraborty, Pobitra Borah, Partha Pratim Dutta, Saikat Sen.
      Diabetes mellitus is a chronic metabolic disorder resulting in an increased blood glucose level and prolonged hyperglycemia, causes long term health conse-quences. Chronic wound is frequently occurring in diabetes patients due to compromised wound healing capability. Management of wounds in diabetic patients remains a clinical challenge despite many advancements in the field of science and technology. Increasing evidence indicates that alteration of the biochemical milieu resulting from alteration in inflammatory cytokines and matrix metalloproteinase, decrease in fibroblast and keratinocyte functioning, neuropathy, altered leukocyte functioning, infection, etc., plays a significant role in impaired wound healing in diabetic people. Apart from the current pharmacotherapy, different other approaches like the use of conventional drugs, antidiabetic medication, antibiotics, debridement, offloading, platelet-rich plasma, growth factor, oxygen therapy, negative pressure wound therapy, low-level laser, extracorporeal shock wave bioengineered substitute can be considered in the management of diabetic wounds. Drugs/therapeutic strategy that induce angiogenesis and collagen synthesis, inhibition of MMPs, reduction of oxidative stress, controlling hyperglycemia, increase growth factors, regulate inflammatory cytokines, cause NO induction, induce fibroblast and keratinocyte proliferation, control microbial infections are considered important in controlling diabetic wound. Further, medicinal plants and/or phytoconstituents also offer a viable alternative in the treatment of diabetic wound. The focus of the present review is to highlight the molecular and cellular mechanisms, and discuss the drug targets and treatment strategies involved in the diabetic wound.
    Keywords:  Diabetic Foot Ulcer; Diabetic Wound; Epigenetic mechanisms; Molecular Targets; Phytoconstituents; Therapeutic agents
    DOI:  https://doi.org/10.4239/wjd.v13.i9.696
  81. Cell Metab. 2022 Oct 04. pii: S1550-4131(22)00401-6. [Epub ahead of print]34(10): 1416-1419
    Focus on diet and exercise.
    John Speakman, Alexandra Johnstone, Trine Moholdt, Satchidananda Panda, Samuel Klein, Benjamin L Parker, Laurie Goodyear.
      Research-based lifestyle choices can help us live healthier lives, and in this issue of Cell Metabolism, we showcase articles focused on diet and exercise interventions. Here, we take a moment to learn about the motivation and challenges behind these studies and look forward to the next steps in applying these interventions to promote metabolic health.
    DOI:  https://doi.org/10.1016/j.cmet.2022.09.011
  82. Food Res Int. 2022 Nov;pii: S0963-9969(22)00913-9. [Epub ahead of print]161 111855
    Chitosan suspension as extractor and encapsulating agent of phenolics from acerola by-product.
    Natalia Cristina da Silva, Odílio Benedito Garrido Assis, Alan Giovanini de Oliveira Sartori, Severino Matias de Alencar, Milena Martelli-Tosi.
      The polymeric suspension of chitosan (Ch) has been an effective media for the extraction of total phenolic compounds (TPC) from the acerola by-product. It facilitates the subsequent production of nanoparticles loaded with the phenolics (Np-TPC) by ionic gelation. However, neither the effects of Ch concentration on encapsulation efficiency (EE%) of TPC nor which compounds are extracted in its media are known, being it the first objective of this study. The second objective was to analyze the stability of the Np-TPC under accelerated conditions and its release profile at pHs 3.0 and 7.0. The results showed that Ch does not affect the extraction of TPC. However, the EE increased from 35.0 to 48.1 % with the increase of Ch concentration (0.4 to 1.0 %). LC/ESI-QTOF MS analysis showed that phenolic acids and flavonoids are extracted in 0.8 % Ch medium. After encapsulation, microscopy images revealed particle sizes ranging between 110 and 150 nm. Additionally, the presence of phenolics did not change the stability of the particles under accelerated conditions and the actives were fully released into the released medium for 10 h. The Np-TPC suspension appears to be useful for the production of edible antioxidant coatings to preserve fruits/vegetables, with potential application as carrier of other food ingredients.
    Keywords:  Active compounds; Drug carrier; Food residue; Nanoencapsulation
    DOI:  https://doi.org/10.1016/j.foodres.2022.111855
  83. Int J Oncol. 2022 Dec;pii: 144. [Epub ahead of print]61(6):
    TRIM35 ubiquitination regulates the expression of PKM2 tetramer and dimer and affects the malignant behaviour of breast cancer by regulating the Warburg effect.
    Hao Wu, Xinyi Guo, Yile Jiao, Zhenru Wu, Qing Lv.
      Breast cancer has become the leading cause of death in females. After comprehensive treatment, the lives of patients are still threatened by tumor metastasis and recurrence. Therefore, there is an urgent requirement to find an effective treatment target for breast cancer. Tripartite motif‑containing 35 (TRIM35) is a ubiquitin ligase that has an important role in the recurrence and metastasis of malignant tumors. However, the role of TRIM35 in breast cancer has thus far remained elusive. The expression of TRIM35 was examined in a bioinformatics database and the effects of TRIM35 on the malignant biological behavior of breast cancer were analyzed by Cell Counting Kit‑8, cell migration and invasion assays, flow cytometry and nude mouse xenograft experiments. It was determined that TRIM35 was downregulated in breast cancer tumor tissues and cell lines. Patients with low TRIM35 expression had shorter overall survival. Functional assays revealed that overexpression of TRIM35 inhibited the proliferation, migration and invasion, and promoted apoptosis of breast cancer cells. Furthermore, overexpression of TRIM35 was able to inhibit the Warburg effect in breast cancer cells. Mechanistic analyses indicated that TRIM35 regulates the transition of tetramers and dimers of pyruvate kinase M2 (PKM2) through ubiquitination and thereby affects the Warburg effect. In conclusion, the present results indicated that TRIM35 regulates the tetramer and dimer transition of PKM2 through ubiquitination and affects the malignant biological behavior of breast cancer by modulating the Warburg effect.
    Keywords:  PKM2; TRIM35; Warburg effect; breast cancer; tumorigenicity; ubiquitination
    DOI:  https://doi.org/10.3892/ijo.2022.5434
  84. J Oleo Sci. 2022 ;71(10): 1521-1530
    Ameliorative Effect of Bouea macrophylla Griffth Seed Extract Against Bacteria-Induced Acne Inflammation: in vitro study.
    Worrapan Poomanee, Warat Leelapornpisid, Khajornsak Trakoolpua, Ivan Salamon, Pimporn Leelapornpisid.
      Currently, bioactive compounds derived from nature have been thought to be promising anti-acne substances owing to the variety of potential biological effects. This study aimed to evaluate the ameliorative effect of Bouea macrophylla Griffth seed extract against bacteria-induced acne inflammation for the first time in terms of antibacterial effects against acne-inducing bacteria, anti-inflammatory, and antioxidant properties. Initially, extracting procedures were optimized and five different extracts were obtained. Considering their antibacterial activities against Cutibacterium acnes, Staphylococcus aureus, and Staphylococcus epidermidis, ethanolic and ethyl acetate fractions exerted a notable effect which were highly superior above those of polyphenol standards. Additionally, these two extracts presented outstanding antioxidant capacities in terms of DPPH and ABTS radicals scavenging effects, reducing power, and inhibitory effect on lipid peroxidation which also play a role in the exacerbation of acne inflammation. Besides, inhibition on lipid peroxidation and reducing power of ethanolic fraction were significantly (p<0.05) better than those of ethyl acetate fraction which was corresponding to their phenolic and ellagic acid contents. However, flavonoids found in ethyl acetate fraction might play an important role in its potentials. After that, the anti-inflammatory effects of the extracts were elucidated by means of inhibition on nitric oxide production from LPS-induced RAW 264.7 cell lines at which the effects of both extracts were dosedependency. Taken together, our findings have apparently proven that B. macrophylla seed extracts exerted a variety of potential properties including antioxidation, anti-acne-inducing bacteria, and anti-inflammatory effects which could serve as a promising anti-acne agent for cosmeceutical applications.
    Keywords:  acne inflammation; anti-inflammation; antibacterial effect; antioxidation; maprang
    DOI:  https://doi.org/10.5650/jos.ess22168
  85. Food Res Int. 2022 Nov;pii: S0963-9969(22)00874-2. [Epub ahead of print]161 111816
    Effects of ferulic acid, a major component of rice bran, on proliferation, apoptosis, and autophagy of HepG2 cells.
    Jianqiang Wang, Xi Lai, Dan Yuan, Yichao Liu, Jian Wang, Ying Liang.
      Ferulic acid is an active substance that can inhibit the growth of cancer cells, and it also shows antioxidant activity. Previous studies examined the effect of ferulic acid as a nutritional supplement for inhibiting the proliferation and inducing the apoptosis of hepatocellular carcinoma cells. However, the effect of ferulic acid on the induction of autophagy in hepatocellular carcinoma cells is unknown. We examined the effect of ferulic acid on the proliferation, apoptosis, and autophagy of human hepatocellular carcinoma (HepG2) cells. The results showed that treatment of cells with 100 μg/mL ferulic acid for 48 h led to altered morphology, disruption of nucleoli, and decreased cell proliferation. Ferulic acid increased the percentage of cells in S phase (19.99 % to 34.31 %), increased the percentage of apoptotic cells (3.2 % to 34.7 %), and decreased mitochondrial membrane potential. Western blotting indicated that ferulic acid also increased the levels of biomarkers of apoptosis and autophagy (caspase-3, cleaved-caspase-3, beclin-1, LC3-I/LC3-II, PINK-1, and Parkin). Thus, ferulic acid inhibited the proliferation and increased the apoptosis and autophagy of HepG2 cells. These results provide a theoretical basis for subsequent research on the use of ferulic acid to inhibit the growth of hepatoma cells and the development of functional foods using rice bran, which contains abundant ferulic acid.
    Keywords:  Apoptosis; Autophagy; Ferulic acid; Hepatoma cell; Liver cancer; Proliferation inhibition
    DOI:  https://doi.org/10.1016/j.foodres.2022.111816
  86. Anticancer Res. 2022 Oct;42(10): 4763-4772
    The Complex Composition of Trans-resveratrol, Quercetin, Vitamin E and Selenium Inhibits the Growth of Colorectal Carcinoma.
    Justyna Czapla, Alina Drzyzga, Sybilla Matuszczak, Ewelina Pilny, Tomasz Cichoń, Krzysztof Stojecki, Ryszard Smolarczyk.
       BACKGROUND/AIM: Numerous studies have demonstrated an anti-cancer action of plant-derived polyphenols. Their action is mainly related to antioxidant, anti-inflammatory, immunomodulatory and inhibitory properties. It is expected that proper composition of nutrition factors with anti-cancer activity may prevent from cancer incidence or inhibit cancer progression. The aim of the study was to investigate the anti-cancer properties of a standardized composition of compounds: trans-resveratrol, quercetin, vitamin E and selenium (Neoplasmoxan, Vebiot) in a mouse model of CT26 colorectal carcinoma.
    MATERIALS AND METHODS: Colorectal carcinoma cells (CT26) were introduced subcutaneously (2×105/mouse) on the back of the mice. Neoplasmoxan suspension was administered intragastrically, daily, for 21 consecutive days. In collected tumors, the area occupied by tumor blood vessels and the number of immune cells; macrophages and CD8-positive cytotoxic T lymphocytes were evaluated.
    RESULTS: It was observed that administration of Neoplasmoxan inhibits the growth of colorectal carcinoma in mice. Tumor volume after Neoplasmoxan administration was 40% smaller than in control groups. No overall toxicity of Neoplasmoxan was observed. The area of blood vessels in tumors of mice that received Neoplasmoxan was reduced by approximately 20%. The area occupied by macrophages increased about 60% compared to the control group. However, no increased number of CD8-positive cytotoxic T lymphocytes was observed in the group that received Neoplasmoxan.
    CONCLUSION: A tendency of Neoplasmoxan to inhibit the growth of colorectal carcinoma was recorded. It also seems that additional combination of the tested preparation with standard chemotherapy or radiotherapy should bring a synergistic therapeutic effect.
    Keywords:  Colorectal carcinoma therapy; anti-angiogenic drug; dogs; plant derived polyphenols; quercetin; selenium; trans-resveratrol; vitamin E
    DOI:  https://doi.org/10.21873/anticanres.15981
  87. Pharm Nanotechnol. 2022 Oct 03.
    Modernization of a traditional Siddha medicine Paccai eruvai into a novel nanogel formulation for the potent wound healing activity-A Phyto-Pharmaceutical approach.
    Sakthiganapathi M, Prakash Yoganandam G, Gopal V.
       BACKGROUND: Paccai eruvai formulation has been widely used in traditional Siddha practice to treat ulcerous wounds due to the content of potentially active compounds.
    OBJECTIVE: The present study aimed to determine the enhancement potency of wound healing of nanogels containing Paccai eruvai in an incision and excision wound models.
    METHODS: Paccai eruvai nanogel was synthesized using the high-energy milling method, and characterization and enhancement of the wound healing potential of Paccai eruvai nanogel were assessed.
    RESULTS: Reportedly, Paccai eruvai nanogel has been produced successfully and its chemical properties confirmed, and physical properties characterized. Paccai eruvai nanogel showed homogeneity, green color, transparency, and an average size of 19.73 nm. We observed a significant reduction of wound area (p<0.001) in the Paccai eruvai nanogel-treated rats. The percentage of wound contraction on the 16th day was higher than the traditional formulation and nitrofurazone treatment. Notably, a lesser epithelialization period (14.33 days) and higher hydroxyproline content were observed in the 10% Paccai eruvai nanogel rats. We found that 10 % Paccai eruvai nanogel treatment increased tensile strength suggesting a better therapeutic indication.
    CONCLUSION: The present findings indicate that Paccai eruvai nanogel significantly contributes wound healing activities with the enhancement of collagen synthesis, wound contraction, and wound tensile strength.
    Keywords:  Paccai eruvai; Wound healing; hydroxyproline; nanogels; wound contraction; wound tensile strength
    DOI:  https://doi.org/10.2174/2211738510666221003113247
  88. Food Res Int. 2022 Nov;pii: S0963-9969(22)00869-9. [Epub ahead of print]161 111811
    The botanical profile, phytochemistry, biological activities and protected-delivery systems for purple sweet potato (Ipomoea batatas (L.) Lam.): An up-to-date review.
    Tian Jiang, Shuxin Ye, Wei Liao, Muci Wu, Jingren He, Nuno Mateus, Hélder Oliveira.
      Purple sweet potato (PSP) is an important economic crop in many countries, as a staple food and a source of bioactive compounds, which has attracted considerable attention. This review provides an up-to-date summary and discusses the available literature concerning PSP. Different issues, including its bioactive compounds, health effects and various efficient encapsulation strategies for PSP powders, extracts or individual substance are covered in detail, along with its utilization. In addition to the valuable nutritional composition, more than 135 bioactive compounds have been isolated and identified from these plants so far. Among the plenty of constituents, polysaccharides and flavonoids are the focus of attention and exhibit various biological activities.Additionally, protected-delivery systems are strongly proposed to shelter the bioactive compounds providing a better stability and improved pharmacological activities. Normally, PSP roots are the most attractive part to human because of their economic value. Even though PSP anthocyanins are the focus of researchers and industrial due to their attractive color and wide range of biological activities, PSP starch and protein also have wide applications in foods and nonfoods industries. However, the exploitation of PSP considering comprehensive utilization of various compounds, such as starch, non-starch polysaccharides, protein, and bioactive compounds should be considered.
    Keywords:  Biological activities; Chemical composition; Comprehensive utilization; Encapsulation systems; Purple sweet potato
    DOI:  https://doi.org/10.1016/j.foodres.2022.111811
  89. J Asthma Allergy. 2022 ;15 1383-1399
    NSAID Hypersensitivity in the Pediatric Population: Classification and Diagnostic Strategies.
    Ozlem Cavkaytar, Mustafa Arga.
      Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most frequently administered drugs, mainly for their anti-pyretic, but also for pain-relieving and anti-inflammatory effects in children. NSAIDs are composed of structurally divergent subgroups of drugs with similar pharmacological and adverse effects. Aspirin originates from salicin and was the first synthesized analgesic. As a prototype of NSAIDs; aspirin-induced hypersensitivity reactions were first reported, but subsequently, other phenotypes of hypersensitivity reactions were also described with aspirin and other NSAIDs. There are certain challenging aspects of NSAID-hypersensitivity in the pediatric population that need to be further investigated. These include the effect of age on drug metabolism and the natural history of the various phenotypes of NSAID-hypersensitivity, the effect of certain co-factors (infections, exercise) on NSAID-hypersensitivity, and diagnostic clinical and laboratory biomarkers clarifying the endotypes. In recent years, a non-negligible number of case series, studies and expert panel reports have been published in this field with some novel features and diagnostic modalities in the pediatric population. With the current review; the clinical phenotypes and diagnostic and management modalities of suspected NSAID-induced hypersensitivity reactions in childhood and adolescence were explained and updated by examining past and current publications.
    Keywords:  allergy; aspirin; child; drug; ibuprofen; paracetamol
    DOI:  https://doi.org/10.2147/JAA.S267005
  90. Front Nutr. 2022 ;9 1004966
    Dietary compounds slow starch enzymatic digestion: A review.
    Chengdeng Chi, Miaomiao Shi, Yingting Zhao, Bilian Chen, Yongjin He, Meiying Wang.
      Dietary compounds significantly affected starch enzymatic digestion. However, effects of dietary compounds on starch digestion and their underlying mechanisms have been not systematically discussed yet. This review summarized the effects of dietary compounds including cell walls, proteins, lipids, non-starchy polysaccharides, and polyphenols on starch enzymatic digestion. Cell walls, proteins, and non-starchy polysaccharides restricted starch disruption during hydrothermal treatment and the retained ordered structures limited enzymatic binding. Moreover, they encapsulated starch granules and formed physical barriers for enzyme accessibility. Proteins, non-starchy polysaccharides along with lipids and polyphenols interacted with starch and formed ordered assemblies. Furthermore, non-starchy polysaccharides and polyphenols showed robust abilities to reduce activities of α-amylase and α-glucosidase. Accordingly, it can be concluded that dietary compounds lowered starch digestion mainly by three modes: (i) prevented ordered structures from disruption and formed ordered assemblies chaperoned with these dietary compounds; (ii) formed physical barriers and prevented enzymes from accessing/binding to starch; (iii) reduced enzymes activities. Dietary compounds showed great potentials in lowering starch enzymatic digestion, thereby modulating postprandial glucose response to food and preventing or treating type II diabetes disease.
    Keywords:  dietary compounds; enzyme activity; nutrition; starch digestion; starch structure
    DOI:  https://doi.org/10.3389/fnut.2022.1004966
  91. Exp Ther Med. 2022 Nov;24(5): 676
    Properties of flavonoids in the treatment of bladder cancer (Review).
    Yue Lv, Zhonghao Liu, Haixing Jia, Youcheng Xiu, Zan Liu, Leihong Deng.
      Given its high recurrence and rapid progress, bladder cancer (BLCA) treatment has become a major problem for clinicians. BLCA is difficult to control even with surgical resection and extensive use of chemotherapeutic drugs. The non-toxicity and ease of accessibility of natural compounds have attracted much attention in recent years. Flavonoids serve an essential role given their antioxidant, antibacterial, anticancer and cardiovascular properties. They are mainly divided into several subclasses; flavones, flavanones, flavonols, flavanols, anthocyanins isoflavones and chalcones. Over the years, the role of flavonoids in BLCA has been extensively studied. The present review provided a comprehensive overview of the classification of flavonoids and substantiate the role of epithelial-mesenchymal transition, cancer stem cells, angiogenesis, epigenetic regulation and programmed cell death in BLCA. The present review emphasized that flavonoids for BLCA treatment are worthy of further study and anti-BLCA drugs have huge prospects for clinical use.
    Keywords:  apoptosis; bladder cancer; cell cycle; flavonoids
    DOI:  https://doi.org/10.3892/etm.2022.11612
  92. J Mater Sci Mater Med. 2022 Oct 04. 33(10): 72
    Synthesis of glycyrrhetinic acid-modified liposomes to deliver Murrayafoline A for treatment of hepatocellular carcinoma.
    Cuc Thi Dinh, Ha Thi Vu, Quynh Thi Huong Phan, Linh Phuong Nguyen, Toan Quoc Tran, Dung Van Tran, Nguyen Ngoc Quy, Dung Thuy Nguyen Pham, Duong Thanh Nguyen.
      Hepatocellular carcinoma is a common type of cancer associated with a high mortality rate. Among several bioactive compounds, Murrayafoline A (MuA) has been proved as a bio substance that exhibits great potentials in treating liver cancer. In order to overcome the high cytotoxicity and low solubility of MuA, a delivery system based on nanocarriers is necessary to deliver MuA towards the desired target. In the present study, 18β-glycyrrhetinic acid (GA), which is known as a ligand for liver targeting, was used to construct the cholesterol-poly (ethylene glycol)-glycyrrhetinic acid (GA-PEG-Chol) conjugate and liposome for MuA administration. The compound was then examined for therapeutic efficacy and safety in HUVEC and HepG2 cells in 2D and 3D cell cultures. Results have shown that MuA-loaded liposomes had IC50 value of 2 µM in HepG2 and had the cytosolic absorption of 8.83 ± 0.97 ng/105 cells, while The IC50 value of MuA-loaded liposomes in HUVEC cell lines was 15 µM and the the cytosolic absorption was recorded as 3.62 ± 0.61 cells. The drug test on the 3D cancer sphere platform of the HepG2 cancer sphere showed that MuA-loaded GA liposomes had the highest efficacy at a concentration of 100 µg/mL. In short, these results suggest that MuA-loaded GA liposomes have the potential for maintenance drug delivery and liver targeting.
    DOI:  https://doi.org/10.1007/s10856-022-06692-1
  93. J Food Biochem. 2022 Oct 07. e14451
    Neuroprotective potential of Moringa oleifera mediated by NF-kB/Nrf2/HO-1 signaling pathway: A review.
    Maroti Mundkar, Anjali Bijalwan, Divya Soni, Puneet Kumar.
      Moringa oleifera is a traditional Indian herb belonging to the Moringaceae family, it is commonly known as the horse-radish tree, drumstick, or sahajna. In developing countries, Moringa is used as feed for both humans and animals due to its well-known antioxidant, anti-inflammatory, and anti-apoptotic properties owing to its several phytoconstituents including β-carotene, quercetin, kaempferol, ascorbic acid, flavonoids, phenolic acid, rhamnose, glycosylates, glucomoringin, and isothiocyanates. These constituents help to maintain the brain antioxidant enzyme levels, mitochondrial functions, and neurogenesis, showing neuroprotective effects in several neurodegenerative disorders including Parkinson's Disease, Alzheimer's Disease, Huntington's Disease, and Amyotrophic lateral sclerosis. This review discusses various phytoconstituent of moringa and their therapeutic potential in various neurological disorders. Additionally, we also concise the safety and toxicity profile, of different molecular pathways involved in the neuroprotective effect of M. oleifera including M. oleifera nanoparticles for better therapeutic value. PRACTICAL APPLICATIONS: Several clinical and preclinical studies on Moringa oleifera have been conducted, and the outcomes indicate moringa could be used in the treatment of brain disorders. As a result, we conclude that moringa and its nanoformulations could be employed to treat neurological problems. In the future, M. oleifera phytoconstituents could be evaluated against specific signaling pathways, which could aid researchers in discovering their mechanism of action. Furthermore, the use of moringa as a nutraceutical owing to its myriad pharmacological potential will go a long way in boosting the economy of countries that grow moringa on a large scale.
    Keywords:   Moringa oleifera ; anti-inflammatory; antioxidants; mitochondrial dysfunction; neurodegenerative disorders; neuroprotection
    DOI:  https://doi.org/10.1111/jfbc.14451
  94. Transl Oncol. 2022 Sep 30. pii: S1936-5233(22)00208-X. [Epub ahead of print]26 101549
    Thioridazine combined with carboplatin results in synergistic inhibition of triple negative breast cancer by targeting cancer stem cells.
    Yi Wang, Leiming Xia, Jing Lin, Li Gong, Yang Xia, Yang Xu, Liu Liu, Jian Bao, Congshu Zhang, Yuqing Chai, Hongxia Li.
      Cancer stem cells (CSCs) in triple-negative breast cancer (TNBC) are closely related to tumorigenesis and metastasis. Thioridazine (THZ) is a usual phenothiazine antipsychotic drug that can destroy CSCs. We aimed to explore whether THZ could sensitize metastatic TNBC cells, especially the CSCs, to carboplatin (CBP) treatment. Metastatic TNBC cells, 4T1 cells, and tumor-bearing mice were treated with THZ and CBP as monotherapy or combination therapy. MTT, flow cytometry, electron microscopy, immunohistochemistry and western blotting were applied to assess the cell viability, apoptosis, mitochondrial morphology and the relevant protein levels, respectively. Tumor size and lung metastasis under different treatments as well as tumorigenesis of residual tumor cells from each group were monitored. THZ combined with CBP inhibited 4T1 tumor cell proliferation and induced apoptosis by inhibiting the PI3K-AKT-mTOR pathway and activating estrogen receptor stress. THZ also showed strong activity against breast CSCs, THZ combined with CBP significantly destroyed cancer cells, inhibited lung metastasis and relieved the tumor burden; Our data demonstrated that THZ can sensitize TNBC cells to CBP treatment and this combination therapy may provide a bright strategy for TNBC treatment by targeting both cancer cells and CSCs.
    Keywords:  Cancer stem cells; Carboplatin; Lung metastasis; Synergistic inhibition; Thioridazine
    DOI:  https://doi.org/10.1016/j.tranon.2022.101549
  95. Brain Res. 2022 Sep 29. pii: S0006-8993(22)00333-X. [Epub ahead of print]1796 148109
    Resveratrol activates the SIRT1/PGC-1 pathway in mice to improve synaptic-related cognitive impairment after TBI.
    Dong Yu, Xing-Yuan Zhao, Qing-Peng Meng, Da Teng, Ke Deng, Ning Lin.
      Traumatic brain injury (TBI) is the most common form of craniocerebral injury. Post-TBI neurological impairment is often accompanied by cognitive dysfunction. The potential molecular mechanisms of post-TBI cognitive impairment are not well characterized. Resveratrol, a natural polyphenolic agent, has been shown to improve cognitive function in neurological disorders and aging models through its anti-inflammatory activity. However, whether it can affect synapses to improve cognitive function and the potential mechanisms are not clear. Synapse plays an important role in cognitive function, and synaptophysin(SYN) is one of the important factors involved in synapse formation. Sirtuin 1 (SIRT1) has a neuroprotective effect via its effect on various biological processes, such as inflammation, metabolism, apoptosis, and autophagy. The results of this research suggest that resveratrol increases synaptophysin by activating the SIRT1/PGC-1 pathway and improves post-TBI cognitive function. Use of SIRT1 inhibitor (EX-527) and agonist (SRT1720) in the mice experiments verified the effect and mechanism of action of resveratrol in improving cognitive function. Our study identifies potential therapeutic targets for post-TBI cognitive dysfunction.
    Keywords:  Resveratrol; SIRT1; Synaptophysin; TBI
    DOI:  https://doi.org/10.1016/j.brainres.2022.148109
  96. Front Chem. 2022 ;10 1028372
    Silk peptide-hyaluronic acid based nanogels for the enhancement of the topical administration of curcumin.
    Jiangxiu Niu, Ming Yuan, Yao Liu, Liye Wang, Zigui Tang, Yihan Wang, Yueheng Qi, Yansong Zhang, Huiyuan Ya, Yanli Fan.
      The present study focused on the development of Cur-loaded SOHA nanogels (Cur-SHNGs) to enhance the topical administration of Cur. The physiochemical properties of Cur-SHNGs were characterized. Results showed that the morphology of the Cur-SHNGs was spherical, the average size was 171.37 nm with a zeta potential of -13.23 mV. Skin permeation experiments were carried out using the diffusion cell systems. It was found that the skin retention of Cur-SHNGs was significantly improved since it showed the best retention value (0.66 ± 0.17 μg/cm2). In addition, the hematoxylin and eosin staining showed that the Cur-SHNGs improved transdermal drug delivery by altering the skin microstructure. Fluorescence imaging indicated that Cur-SHNGs could effectively deliver the drug to the deeper layers of the skin. Additionally, Cur-SHNGs showed significant analgesic and anti-inflammatory activity with no skin irritation. Taken together, Cur-SHNGs could be effectively used for the topical delivery of therapeutic drugs.
    Keywords:  curcumin; hyaluronic acid; nanogels; silk peptide; topical administration
    DOI:  https://doi.org/10.3389/fchem.2022.1028372
  97. Front Oncol. 2022 ;12 1019654
    Microenvironment immune response induced by tumor ferroptosis-the application of nanomedicine.
    Tian Yun, Zhenzhu Liu, Jianbo Wang, Rui Wang, Liang Zhu, Zheng Zhu, Xuejian Wang.
      Ferroptosis is a non-apoptotic regulatory form of cell death that has sparked significant interest and research in cancer treatment and certain small chemical inducers have been used in the clinic. These inducers's weak water solubility, poor targeting, rapid metabolism; and other undesirable characteristics; however, for therapeutic approaches that combine immunotherapy and ferroptosis, challenges such as medication delivery, the complexity of the tumor microenvironment, and immunosuppression remain. The targeted, low toxicity, and efficient distribution benefits of nanotechnology have considerably enhanced the therapeutic efficacy of combining immunotherapy with ferroptosis. This paper describes the distinct mechanism of ferroptosis in tumor therapy and immunotherapy, as well as the application and benefits of nanotechnology in the combination of tumor immunotherapy and ferroptosis.
    Systematic review registration: http://clinicaltrials.gov/, NCT00941070.
    Keywords:  cancer therapy; ferroptosis; immunity therapy; nanotechnology; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2022.1019654
  98. J Mater Chem B. 2022 Oct 06.
    Boosting immunotherapy of triple negative breast cancer through the synergy of mild PTT and Fe-loaded organosilica nanoparticles.
    Ben Yang, Hui Fu, Ronghua Kong, Gang Zheng, Xihong Wang, Yang Dong, Zhenlin Yang.
      Triple negative breast cancer (TNBC) is associated with drug resistance, metastasis, and poor immune response. The development of novel strategies to evoke a robust immune response against TNBC is necessary. In this study, we propose a TNBC tumor immunotherapy modality by synergizing nanocatalytic medicine with mild photothermal therapy. Briefly, mesoporous organosilica nanoparticles (MONs) and an Fe3+-loaded MON (MOF) were prepared. Then, the MOF was modified by hyaluronic acid (HA) and loaded with indocyanine green (ICG) to obtain MOFH (IMOFH). The IMOFH was spherical with a uniform particle size and showed pH-dependent Fe3+ release behavior. In vitro experiments showed that IMOFH was effectively internalized by 4T1 cells, which resulted in Fe3+-mediated oxidative cell death in synergy with mild PTT. Furthermore, this synergistic therapy activated dendritic cells (DCs) through damage-associated molecular pattern (DAMP) exposure resulting from enhanced oxidative damage in tumor cells. In vivo experiments showed that the application of mild PTT promoted IMOFH-mediated maturation of DCs and infiltration of CD8+ T cells. The synergistic effects of IMOFH and mild PTT resulted in boosted activation of adaptive immunity. The pH responsive nanocatalytic medicine IMOFH promoted significant adaptive immunity through the exposure of tumor associated antigens via the Fe3+ mediated Fenton reaction in concert with mild PTT. These effects resulted in the elimination of TNBC tumors without obvious side effects. Therefore, such a synergistic modality of IMOFH + mild PTT is promising for TNBC therapy.
    DOI:  https://doi.org/10.1039/d2tb01424f
  99. J Mol Model. 2022 Oct 04. 28(11): 340
    The impact of cycleanine in cancer research: a computational study.
    Ogochukwu Ngozi Nwaefulu, Nizar A Al-Shar'i, Josephine Omonkhelin Owolabi, Sreenivasa Rao Sagineedu, Lim Chee Woei, Lam Kok Wai, Mohammad Kaisarul Islam, Sivaraman Jayanthi, Johnson Stanslas.
      Cancer is imposing a global health burden because of the steady increase in new cases. Moreover, current anticancer therapeutics are associated with many drawbacks, mainly the emergence of resistance and the severe adverse effects. Therefore, there is a continuous need for developing new anticancer agents with novel mechanisms of action and lower side effects. Natural products have been a rich source of anticancer medication. Cycleanine, a natural product, was reported to exert an antiproliferative effect on ovarian cancer cells by causing apoptosis through activation of caspases 3/7 and cleavage of poly (ADP-ribose) polymerase to form poly (ADP-ribose) polymerase-1 (PARP1). It is well-established that PARP1 is associated with carcinogenesis, and different PARP1 inhibitors are approved as anticancer drugs. In this study, the cytotoxic activity of cycleanine was computationally investigated to determine whether it is a PARP1 inhibitor or a caspase activator. Molecular docking and molecular dynamics (MD) simulations were utilized for this purpose. The results showed that cycleanine has a good binding affinity to PARP1; moreover, MD simulation showed that it forms a stable complex with the enzyme. Consequently, the results showed that cycleanine is a potential inhibitor of the PARP1 enzyme.
    Keywords:  Antiproliferative activity; Caspase-3; Cycleanine; Cytotoxicity; Molecular dynamics simulation; PARP1 inhibitor
    DOI:  https://doi.org/10.1007/s00894-022-05326-1
  100. J Control Release. 2022 Sep 29. pii: S0168-3659(22)00644-7. [Epub ahead of print]
    Tumor microenvironment adrenergic nerves blockade liposomes for cancer therapy.
    Shuang Zhou, Jinbo Li, Jiang Yu, Yuequan Wang, Zhaomeng Wang, Zhonggui He, Defang Ouyang, Hongzhuo Liu, Yongjun Wang.
      Adrenergic nerves, which are innervated in the tumor, regulate tumor initiation, angiogenesis, and the establishment of the tumor immunosuppressive microenvironment. The study aimed to evaluate the effectiveness of propranolol liposomes (Lipo pro) in inhibiting adrenergic nerve signaling in cancer therapy. Lipo pro significantly regulated the distribution of tumor microenvironment adrenergic nerves, tumor blood vessels, and immunosuppressive microenvironment. Furthermore, it displayed considerable therapeutic effects on prostatic cancer, pancreatic ductal adenocarcinoma, and melanoma. The combination therapeutic regimen, in which Lipo pro was the primary treatment and was supplemented by chemotherapy, showed significant advantages over any single treatment, effectively restraining tumor growth in situ and metastasis, thereby prolonging the survival of mice. This study established a proof-of-concept by targeting tumor adrenergic nerve signaling for cancer therapy.
    Keywords:  Adrenergic nerves; Combination regimen; Liposome; Propranolol; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.jconrel.2022.09.049
  101. Small Methods. 2022 Oct 06. e2200997
    Nanozymes for Regenerative Medicine.
    Xiaozhou Mou, Qingyuan Wu, Zheao Zhang, Yunhang Liu, Jungang Zhang, Chengwu Zhang, Xiaoyi Chen, Kelong Fan, Huiyu Liu.
      Nanozymes refer to nanomaterials that catalyze enzyme substrates into products under relevant physiological conditions following enzyme kinetics. Compared to natural enzymes, nanozymes possess the characteristics of higher stability, easier preparation, and lower cost. Importantly, nanozymes possess the magnetic, fluorescent, and electrical properties of nanomaterials, making them promising replacements for natural enzymes in industrial, biological, and medical fields. On account of the rapid development of nanozymes recently, their application potentials in regeneration medicine are gradually being explored. To highlight the achievements in the regeneration medicine field, this review summarizes the catalytic mechanism of four types of representative nanozymes. Then, the strategies to improve the biocompatibility of nanozymes are discussed. Importantly, this review covers the recent advances in nanozymes in tissue regeneration medicine including wound healing, nerve defect repair, bone regeneration, and cardiovascular disease treatment. In addition, challenges and prospects of nanozyme researches in regeneration medicine are summarized.
    Keywords:  bone regeneration; cardiovascular diseases; nanozymes; nerve defect repair; regeneration medicine
    DOI:  https://doi.org/10.1002/smtd.202200997
  102. Adv Drug Deliv Rev. 2022 Sep 28. pii: S0169-409X(22)00444-6. [Epub ahead of print]190 114554
    Soft nano and microstructures for the photomodulation of cellular signaling and behavior.
    Nicolas Muzzio, Manuel Eduardo Martinez-Cartagena, Gabriela Romero.
      Photoresponsive soft materials are everywhere in the nature, from human's retina tissues to plants, and have been the inspiration for engineers in the development of modern biomedical materials. Light as an external stimulus is particularly attractive because it is relatively cheap, noninvasive to superficial biological tissues, can be delivered contactless and offers high spatiotemporal control. In the biomedical field, soft materials that respond to long wavelength or that incorporate a photon upconversion mechanism are desired to overcome the limited UV-visible light penetration into biological tissues. Upon light exposure, photosensitive soft materials respond through mechanisms of isomerization, crosslinking or cleavage, hyperthermia, photoreactions, electrical current generation, among others. In this review, we discuss the most recent applications of photosensitive soft materials in the modulation of cellular behavior, for tissue engineering and regenerative medicine, in drug delivery and for phototherapies.
    Keywords:  Cell Behavior; Drug Delivery; Photocleavage; Photodynamic; Photoisomerization; Phototherapies; Photothermal; Photovoltaic/Optoelectronic; Regenerative Medicine; Smart Soft Materials
    DOI:  https://doi.org/10.1016/j.addr.2022.114554
  103. J Am Chem Soc. 2022 Oct 03.
    A Polymer Prodrug Strategy to Switch from Intravenous to Subcutaneous Cancer Therapy for Irritant/Vesicant Drugs.
    Alexandre Bordat, Tanguy Boissenot, Nada Ibrahim, Marianne Ferrere, Manon Levêque, Léa Potiron, Stéphanie Denis, Sébastien Garcia-Argote, Olivia Carvalho, Jérôme Abadie, Catherine Cailleau, Grégory Pieters, Nicolas Tsapis, Julien Nicolas.
      Chemotherapy is almost exclusively administered via the intravenous (IV) route, which has serious limitations (e.g., patient discomfort, long hospital stays, need for trained staff, high cost, catheter failures, infections). Therefore, the development of effective and less costly chemotherapy that is more comfortable for the patient would revolutionize cancer therapy. While subcutaneous (SC) administration has the potential to meet these criteria, it is extremely restrictive as it cannot be applied to most anticancer drugs, such as irritant or vesicant ones, for local toxicity reasons. Herein, we report a facile, general, and scalable approach for the SC administration of anticancer drugs through the design of well-defined hydrophilic polymer prodrugs. This was applied to the anticancer drug paclitaxel (Ptx) as a worst-case scenario due to its high hydrophobicity and vesicant properties (two factors promoting necrosis at the injection site). After a preliminary screening of well-established polymers used in nanomedicine, polyacrylamide (PAAm) was chosen as a hydrophilic polymer owing to its greater physicochemical, pharmacokinetic, and tumor accumulation properties. A small library of Ptx-based polymer prodrugs was designed by adjusting the nature of the linker (ester, diglycolate, and carbonate) and then evaluated in terms of rheological/viscosity properties in aqueous solutions, drug release kinetics in PBS and in murine plasma, cytotoxicity on two different cancer cell lines, acute local and systemic toxicity, pharmacokinetics and biodistribution, and finally their anticancer efficacy. We demonstrated that Ptx-PAAm polymer prodrugs could be safely injected subcutaneously without inducing local toxicity while outperforming Taxol, the commercial formulation of Ptx, thus opening the door to the safe transposition from IV to SC chemotherapy.
    DOI:  https://doi.org/10.1021/jacs.2c04944
  104. Inflamm Regen. 2022 Oct 04. 42(1): 40
    Accelerating skin regeneration and wound healing by controlled ROS from photodynamic treatment.
    Khatereh Khorsandi, Reza Hosseinzadeh, HomaSadat Esfahani, Kavosh Zandsalimi, Fedora Khatibi Shahidi, Heidi Abrahamse.
      Cellular metabolisms produce reactive oxygen species (ROS) which are essential for cellular signaling pathways and physiological functions. Nevertheless, ROS act as "double-edged swords" that have an unstable redox balance between ROS production and removal. A little raise of ROS results in cell proliferation enhancement, survival, and soft immune responses, while a high level of ROS could lead to cellular damage consequently protein, nucleic acid, and lipid damages and finally cell death. ROS play an important role in various pathological circumstances. On the contrary, ROS can show selective toxicity which is used against cancer cells and pathogens. Photodynamic therapy (PDT) is based on three important components including a photosensitizer (PS), oxygen, and light. Upon excitation of the PS at a specific wavelength, the PDT process begins which leads to ROS generation. ROS produced during PDT could induce two different pathways. If PDT produces control and low ROS, it can lead to cell proliferation and differentiation. However, excess production of ROS by PDT causes cellular photo damage which is the main mechanism used in cancer treatment. This review summarizes the functions of ROS in living systems and describes role of PDT in production of controllable ROS and finally a special focus on current ROS-generating therapeutic protocols for regeneration and wound healing.
    Keywords:  Oxidative stress; Photodynamic therapy; ROS; Skin regeneration; Wound healing
    DOI:  https://doi.org/10.1186/s41232-022-00226-6
  105. Nutr J. 2022 Oct 03. 21(1): 62
    Effects of curcumin and/or coenzyme Q10 supplementation on metabolic control in subjects with metabolic syndrome: a randomized clinical trial.
    Abbas Ali Sangouni, Maryam Taghdir, Javad Mirahmadi, Mojtaba Sepandi, Karim Parastouei.
       BACKGROUND: Metabolic syndrome (MetS) as a cluster of conditions including hyperlipidemia, hypertension, hyperglycemia, insulin resistance, and abdominal obesity is linked to cardiovascular diseases and type 2 diabetes. Evidence suggested that intake of curcumin and coenzyme Q10 may have therapeutic effects in the management of MetS.
    AIMS: We investigated the effects of curcumin and/or coenzyme Q10 supplementation on metabolic syndrome components including systolic blood pressure (SBP), diastolic blood pressure (DBP), waist circumference (WC), triglyceride (TG), high density lipoprotein-cholesterol (HDL-c) and fasting plasma glucose (FPG) as primary outcomes, and total cholesterol (TC), low density lipoprotein-cholesterol (LDL-c) and body mass index (BMI) as secondary outcomes in subjects with MetS.
    METHODS: In this 2 × 2 factorial, randomized, double-blinded, placebo-controlled study, 88 subjects with MetS were randomly assigned into four groups including curcumin plus placebo (CP), or coenzyme Q10 plus placebo (QP), or curcumin plus coenzyme Q10 (CQ), or double placebo (DP) for 12 weeks.
    RESULTS: The CP group compared with the three other groups showed a significant reduction in HDL-c (P = 0.001), TG (P <  0.001), TC (P <  0.001), and LDL-c (P <  0.001). No significant differences were seen between the four groups in terms of SBP, DBP, FPG, WC, BMI and weight.
    CONCLUSION: Curcumin improved dyslipidemia, but had no effect on body composition, hypertension and glycemic control. Furthermore, coenzyme Q10 as well as the combination of curcumin and coenzyme Q10 showed no therapeutic effects in subjects with MetS. The trial was registered on 09/21/2018 at the Iranian clinical trials website (IRCT20180201038585N2), URL: https://www.irct.ir/trial/32518 .
    Keywords:  Blood pressure; Body composition; Coenzyme Q10; Curcumin; Lipid profile; Metabolic syndrome
    DOI:  https://doi.org/10.1186/s12937-022-00816-7
  106. RSC Adv. 2022 Aug 30. 12(38): 24887-24921
    Chemical diversity, medicinal potentialities, biosynthesis, and pharmacokinetics of anthraquinones and their congeners derived from marine fungi: a comprehensive update.
    Mohamed Sebak, Fatma Molham, Claudio Greco, Mohamed A Tammam, Mansour Sobeh, Amr El-Demerdash.
      Marine fungi receive excessive attention as prolific producers of structurally unique secondary metabolites, offering promising potential as substitutes or conjugates for current therapeutics, whereas existing research has only scratched the surface in terms of secondary metabolite diversity and potential industrial applications as only a small share of bioactive natural products have been identified from marine-derived fungi thus far. Anthraquinones derived from filamentous fungi are a distinct large group of polyketides containing compounds which feature a common 9,10-dioxoanthracene core, while their derivatives are generated through enzymatic reactions such as methylation, oxidation, or dimerization to produce a large variety of anthraquinone derivatives. A considerable number of reported anthraquinones and their derivatives have shown significant biological activities as well as highly economical, commercial, and biomedical potentialities such as anticancer, antimicrobial, antioxidant, and anti-inflammatory activities. Accordingly, and in this context, this review comprehensively covers the state-of-art over 20 years of about 208 structurally diverse anthraquinones and their derivatives isolated from different species of marine-derived fungal genera along with their reported bioactivity wherever applicable. Also, in this manuscript, we will present in brief recent insights centred on their experimentally proved biosynthetic routes. Moreover, all reported compounds were extensively investigated for their in-silico drug-likeness and pharmacokinetics properties which intriguingly highlighted a list of 20 anthraquinone-containing compounds that could be considered as potential drug lead scaffolds.
    DOI:  https://doi.org/10.1039/d2ra03610j
  107. J Food Biochem. 2022 Oct 01. e14455
    Ethanolic extract of root from Arctium lappa L ameliorates obesity and hepatic steatosis in rats by regulating the AMPK/ACC/CPT-1 pathway.
    Kaiyang Ma, Weixi Sheng, Rong Gao, Jin Feng, Wuyang Huang, Li Cui, Jun Liu, Ying Li.
      Burdock (Arctium lappa L) root is eaten as a vegetable in many countries and used as an ethnomedicine because of its various pharmacological effects. The objective of this study was to investigate the underlying mechanisms of ethanolic extract of root from Arctium lappa L root (ALE) to lose weight and regulate lipid metabolism. The results showed that ALE can regulate lipid metabolism level and inhibit the weight gain of rats induced by the high-sugar and high-fat diet. The contents of triglyceride and cholesterol in the liver of obese rats significantly reduced, and hepatic steatosis was ameliorated. In addition, this study identified that ALE enhanced hepatic fatty acid β-oxidation and ameliorated hepatic steatosis by activating AMPK/ACC/CPT-1 pathway. These results indicated that ALE has a potential preventive and therapeutic effect on metabolic-associated fatty liver disease and obesity. PRACTICAL APPLICATIONS: Obesity is already a global health problem. Obesity causes accumulation of triglycerides, which leads to hepatic steatosis. Long-term steatosis causes liver damage and metabolic fatty liver disease. Plant-derived functional foods or herbal medicines have better effects on weight loss and liver protection, which are more conducive to long-term use with less toxic side effects. As a medicinal and edible plant material, Arctium lappa L root has the effect in losing weight. Our study showed that ethanolic extract of Arctium lappa L root effectively regulates lipid metabolism and inhibits hepatic steatosis. Arctium lappa L root may be used as a therapeutic drug and functional food raw material for obesity and fatty liver disease.
    Keywords:  AMPK; Arctium lappa L; fatty acid β-oxidation; metabolic-associated fatty liver disease; obesity; steatosis
    DOI:  https://doi.org/10.1111/jfbc.14455
  108. Curr Mol Med. 2022 Oct 04.
    The Role of Vitamins in DNA Methylation as Dietary Supplements or Neutraceuticals: A systematic review.
    Muhammad Mazhar Fareed, Sana Ullah, Maryam Qasmi, Sergey Shityakov.
      The epigenetic modifications play a vital role in gene regulation associated with different pathologies. Various nutrients in our diet, such as vitamins, can modulate these epigenetic mechanism.They also can regulatenderlying pathophysiological factors and processes that directly or indirectly. Most importantly, A, B, C, and D vitamins have recently been shown to be involved in this type of regulation together with vitamins E and K. Despite their effect on the DNA methylation process, an in-depth understanding of vitamin-mediated epigenetic alterations have yet to be investigated. Moreover, the role of vitamins in DNA methylation as nutraceuticals might be important to use for targeted therapy of various human diseases. Overall, this review provides a brief survey of the role of vitamins as epigenetic modulators or nutraceuticals, emphasizing their potential in epigenetic therapy.
    Keywords:  DNA methylation; Epigenetic; epigenome; modifications; nutraceuticals; vitamins
    DOI:  https://doi.org/10.2174/1566524023666221004140858
  109. Front Pharmacol. 2022 ;13 1001276
    Antinociceptive effect of plant-based natural products in chemotherapy-induced peripheral neuropathies: A systematic review.
    Wagner Barbosa Da Rocha Santos, Juliana Oliveira Guimarães, Lícia Tairiny Santos Pina, Mairim Russo Serafini, Adriana Gibara Guimarães.
      Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most prevalent and difficult-to-treat symptoms in cancer patients. For this reason, the explore for unused helpful choices able of filling these impediments is essential. Natural products from plants stand out as a valuable source of therapeutic agents, being options for the treatment of this growing public health problem. Therefore, the objective of this study was to report the effects of natural products from plants and the mechanisms of action involved in the reduction of neuropathy caused by chemotherapy. The search was performed in PubMed, Scopus and Web of Science in March/2021. Two reviewers independently selected the articles and extracted data on characteristics, methods, study results and methodological quality (SYRCLE). Twenty-two studies were selected, describing the potential effect of 22 different phytochemicals in the treatment of CIPN, with emphasis on terpenes, flavonoids and alkaloids. The effect of these compounds was demonstrated in different experimental protocols, with several action targets being proposed, such as modulation of inflammatory mediators and reduction of oxidative stress. The studies demonstrated a predominance of the risk of uncertain bias for randomization, baseline characteristics and concealment of the experimental groups. Our findings suggest a potential antinociceptive effect of natural products from plants on CIPN, probably acting in several places of action, being strategic for the development of new therapeutic options for this multifactorial condition.
    Keywords:  antinociceptive; chemotherapy; natural product; pain; peripheral neuropathies; plants
    DOI:  https://doi.org/10.3389/fphar.2022.1001276
  110. Macromol Rapid Commun. 2022 Oct 07. e2200674
    Injectable, Self-Healing and Multiple Responsive Histamine modified Hyaluronic Acid Hydrogels with Potentialities in Drug Delivery, Antibacterial and Tissue Engineering.
    Sijie Zhou, Dejun Yang, Dong Yang, Yan Guo, Ronggui Hu, Yuan Li, Xingjie Zan, Xingxing Zhang.
      Hydrogels are three-dimensional network structures composed of physically- or chemically-crosslinked, hydrophilic molecules. Compared with conventional hydrogels with static and permanent network structures, injectable and responsive hydrogels generated from dynamic networks, have attracted increasing attention from various disciplines due to their wide-ranging applications in tissue engineering, drug delivery, soft robotics, etc. Herein, we developed an injectable self-healing and multiple-responsive hyaluronic acid (HA)- histamine (His)/metal hydrogel by modifying His onto HA and the subsequent, dynamic coordination between imidazole and metal ions. The pH-responsive and mechanical behaviors exhibited by the HA-His/metal hydrogels were tunable with the kinds and concentrations of metal ions. The HA-His/Zr4+ hydrogels demonstrated a moldable capability at a neutral pH and a multistimulus-responsive capability when exposed to a weak alkaline environment and hyaluronidase, which inhibited bacterial growth and biofilm formation. Biocompatibilities and accelerated wound healing were demonstrated in vitro and in vivo and were thoroughly investigated and well characterized. We believe that the HA-His/Zr4+ hydrogel has great potential in various biomedical applications, such as pH- and hyaluronidase-responsive sustained release, antibacterial, and implantable materials for tissue engineering. This article is protected by copyright. All rights reserved.
    Keywords:  hydrogel; imidazole-metal ion coordination; injectable; pH-responsive; self-healing
    DOI:  https://doi.org/10.1002/marc.202200674
  111. J Biol Chem. 2022 Sep 29. pii: S0021-9258(22)00995-4. [Epub ahead of print] 102551
    "Disruption of the molecular clock severely affects lipid metabolism in a Hepatocellular Carcinoma Cell model".
    Natalia M Monjes, Paula M Wagner, Mario E Guido.
      Involved in triglyceride (TG) and glycerophospholipid (GPL) metabolism, the liver plays a crucial physiological role in the human body both as a major metabolic integrator and a central hub for lipid and energy homeostasis. Metabolic disorders can be caused by various factors that promote abnormal lipid accumulation in storage organelles called lipid droplets (LDs), as in hepatic steatosis, a metabolic syndrome manifestation that can progress to a hepatocellular carcinoma (HCC), the most common primary liver malignancy worldwide. Modern life involves conditions that disrupt the biological clock, causing metabolic disorders and higher cancer risk. A circadian clock is present in the liver and in immortalized cell lines, and temporally regulates physiological processes by driving transcriptional and metabolic rhythms. Here we investigated metabolic rhythms in HepG2 cells, a human HCC-derived cell line, and the link between these rhythms and the circadian clock in control (B-WT) and Bmal1-disrupted (B-D) cells having their molecular clock impaired. Rhythms in the expression of lipid-synthesizing enzymes ChoKα, Pcyt2, and Lipin1, in the metabolism of particular GPLs such as phosphatidylcholine (PC) and phosphatidylethanolamine (PE), and in the PC/PE ratio and TG and LD content were observed in B-WT cells. By contrast, in the B-D model, the whole hepatic metabolism was severely altered with a significant reduction in the TG and LD content as well as in ChoKα and other related lipid enzymes. Together, our results suggest a very strong cross-talk between the molecular clock and lipid metabolism, which exhibits an exacerbated pathological condition in B-D cells.
    Keywords:  HepG2; circadian rhythms; clock genes; glycerophospholipid metabolism; lipid droplets; liver; metabolic oscillations; phosphatidylcholine
    DOI:  https://doi.org/10.1016/j.jbc.2022.102551
  112. Drug Des Devel Ther. 2022 ;16 3315-3326
    Development and Evaluation of Puerarin Loaded-Albumin Nanoparticles Thermoresponsive in situ Gel for Ophthalmic Delivery.
    Lixiu Hu, Yong Xu, Hui Meng.
       Purpose: Puerarin (PUR) is a major bioactive ingredient extracted from the root of Pueraria lobata (Willd.) Ohwi, which is known as Gegen in traditional Chinese medicine. Conventional PUR ophthalmic dosage forms such as solutions and suspensions have many drawbacks, including-rapid precorneal elimination of the drug mainly due to lacrimal duct drainage. The purpose of this study is to develop a thermal responsive in situ gel system containing PUR-loaded human albumin nanoparticles (PUR-HSA-NPs ISG).
    Methods: The system has the required sol-gel phase transition temperature, and therefore can be used for local ocular administration to treat glaucoma. The formulation was evaluated for its sol-gel transition temperature, viscosity and in vitro release. In vivo eye irritation was evaluated in rabbits. In this study, the animal model of glaucoma was used to evaluate the pharmacodynamics of PUR-HSA-NPs ISG in vivo.
    Results: Morphologically, the PUR-HSA-NPs ISG exhibited a normal spherical shape with no aggregation or degradation. It had a mean size of 64.8 nm, and the drug-loading and encapsulation efficiency were 7.1%±0.3% and 80.7%±7.4%, respectively. The gelation temperature of the prepared PUR-HSA-NPs ISG thermogelling solutions was 37°C. Meanwhile, the PUR-HSA-NPs ISG showed thixotropic behavior with the downward curve exhibiting lower shear stress values as compared to corresponding points on the upward curve. The pharmacological results showed a continuous reduction of the IOP value for a long time and that the value remained in a lower-level range compared to that in the PUR eye drop group. According to the pharmacodynamic results, the Bcl-2/Bax ratio of the PUR-HSA-NPs ISG group was closest to 1 (0.8798, 24 h), with obvious reduction of tissue cell apoptosis.
    Conclusion: Through this study, it was found that PUR-HSA-NPs ISG is an ideal ocular drug delivery system. It is hoped that this product could be further promoted for clinical applications in the future.
    Keywords:  albumin nanoparticles; ophthalmic delivery; puerarin; thermoresponsive in situ gel
    DOI:  https://doi.org/10.2147/DDDT.S374061
  113. Curr Med Chem. 2022 Oct 06.
    Potential For Novel Therapeutic Uses Of Alpha Lipoic Acid.
    Babatunde Fasipe, Andre Faria, Ismail Laher.
      Alpha-lipoic acid (ALA) is a potent antioxidant used in the management of diabetic neuropathy due to its ability to prevent neuronal lipid peroxidation. ALA also chelates transition metals, which can be beneficial in some diseases related to metal overload. Because of its unique antioxidant properties, ALA has potential novel applications in other diseases related to oxidative stress and inflammation. This review summarizes aspects of recent clinical trials in addition to the well described uses to manage neuropathies. The unique pharmacological actions of ALA, coupled with a relatively low toxicity, has other led to several trials on the potential therapeutic uses of ALA in the management of other diseases associated with increases in oxidative stress, inflammation and metal overload.
    Keywords:  Alpha Lipoic Acid ; Inflammation; Oxidative Stress
    DOI:  https://doi.org/10.2174/0929867329666221006115329
  114. Biofactors. 2022 Oct 03.
    Promising influences of gingerols against metabolic syndrome: A mechanistic review.
    Alieh Alipour, Vafa Baradaran Rahimi, Vahid Reza Askari.
      Metabolic syndrome is an inflammatory disorder characterized by diabetes, obesity, atherosclerosis, and hypertension. Globally, this disease is increasing, especially in developed countries. Supposedly, herbal treatments for this disease likely have fewer adverse effects than chemical medications. Thus, they can be suitable options among the available chemical treatments. Ginger has been used as a spice and medicinal plant in traditional medicine and cooking. This herbal compound and its derivatives, such as 6-gingerol, have shown promising effects on various molecular aspects of metabolic syndrome. In this study, we reviewed and discussed the significant impacts of gingerol, a derivative of ginger, on metabolic syndrome through various mechanisms. The benefits of 6-gingerol include its effects on AMP-activated protein kinase (AMPK), which prevent diabetes, lipid regulating effect (peroxisome proliferator-activated receptors, PPARs), as well as its effects on enzymes and proteins preventing hyperlipidemia caused by a high-fat diet. In addition, 6-gingerol has anti-atherosclerosis and anti-hypertension effects through several molecular mechanisms. The current review will discuss various effects of 6-gingerol on molecular pathways involved in diabetes, obesity, atherosclerosis, and hypertension as characterizing features of metabolic syndrome and suggests that 6-gingerol can be a potential treatment agent for metabolic syndrome and shed light on a higher requirement for more pre-clinical and clinical investigations.
    Keywords:  atherosclerosis; diabetes; gingerol; hypertension; inflammation; metabolic syndrome; obesity
    DOI:  https://doi.org/10.1002/biof.1892
  115. World J Exp Med. 2022 Sep 20. 12(5): 104-107
    Diet and nutrition against inflammatory bowel disease: Trick or treat(ment)?
    Salvatore Greco, Beatrice Bonsi, Nicolò Fabbri.
      Even if the relationships between nutrition and inflammatory bowel disease (IBD) remain underexplored, the current literature is providing, day by day, much more evidence on the effects of various diets in both prevention and treatment of such illnesses. Wrong dietary habits, together with other environmental factors such as pollution, breastfeeding, smoke, and/or antibiotics, are among the theoretical pathogenetic causes of IBD, whose multifactorial aetiology has been already confirmed. While some of these risk factors are potentially reversible, some others cannot be avoided, and efficient treatments become necessary to prevent IBD spread or recurrence. Furthermore, the drugs currently available for treatment of such disease provide low-to-no effect against the symptoms, making the illnesses still strongly disabling. Whether nutrition and specific diets will prove to effectively interrupt the course of IBD has still to be clarified and, in this sense, further research concerning the applications of such dietary interventions is still needed.
    Keywords:  Crohn’s disease; Diet; Inflammatory bowel disease; Nutrition; Treatment; Ulcerative colitis
    DOI:  https://doi.org/10.5493/wjem.v12.i5.104
  116. Front Oncol. 2022 ;12 873447
    Rapamycin inhibits oral cancer cell growth by promoting oxidative stress and suppressing ERK1/2, NF-κB and beta-catenin pathways.
    Abdelhabib Semlali, Sofia Papadakos, Camille Contant, Ikram Zouaoui, Mahmoud Rouabhia.
      Treatment of oral cancer is based exclusively on surgery combined with or without chemotherapy. However, it has several side effects. Targeting a new, more effective therapy has become an urgent matter. The purpose of this study was to evaluate the anti-tumor activity of rapamycin in oral cancer and its mechanism of action. Human gingival carcinoma cells were stimulated with different concentrations of rapamycin to assess proliferation, colony formation, cell migration, as well as apoptosis, and autophagy. The expression of proteins involved in the cell cycle (cyclin D1, p15, p21, p27) and autophagy, as well as that of oncogenes and tumor suppressor genes, were determined by quantitative PCR. The signaling pathways were evaluated by Western blotting. Our results show that rapamycin has a selective effect at a low dose on cancer cell growth/survival. This was confirmed by low colony formation and the inhibition of cell migration, while increasing cell apoptosis by activating caspase-9 and -3. Rapamycin promoted cell autophagy and increased mitochondrial oxidative stress by being involved in DNA damage in the exposed cells. Finally, rapamycin exhibits potent anti-oral cancer properties through inhibition of several cancer-promoting pathways (MAPK, NF-κB, and Wnt/beta-catenin). These results indicate that rapamycin could be a potential agent for the treatment of oral cancer and for a prevention strategy.
    Keywords:  MAPK; Wnt pathway; apoptosis; autophagy; oral cancer; oxidative stress; rapamycin
    DOI:  https://doi.org/10.3389/fonc.2022.873447
  117. Front Endocrinol (Lausanne). 2022 ;13 959396
    Upregulation of an estrogen receptor-regulated gene by first generation progestins requires both the progesterone receptor and estrogen receptor alpha.
    Meghan S Perkins, Renate Louw-du Toit, Hayley Jackson, Mishkah Simons, Donita Africander.
      Progestins, synthetic compounds designed to mimic the activity of natural progesterone (P4), are used globally in menopausal hormone therapy. Although the older progestins medroxyprogesterone acetate (MPA) and norethisterone (NET) have been implicated in increased breast cancer risk, little is known regarding newer progestins, and no significant risk has been associated with P4. Considering that breast cancer is the leading cause of mortality in women, establishing which progestins increase breast cancer incidence and elucidating the underlying mechanisms is a global priority. We showed for the first time that the newer-generation progestin drospirenone (DRSP) is the least potent progestin in terms of proliferation of the estrogen-responsive MCF-7 BUS breast cancer cell line, while NET and P4 have similar potencies to estradiol (E2), the known driver of breast cancer cell proliferation. Notably, MPA, the progestin most frequently associated with increased breast cancer risk, was significantly more potent than E2. While all the progestogens enhanced the anchorage-independent growth of the MCF-7 BUS cell line, MPA promoted a greater number of colonies than P4, NET or DRSP. None of the progestogens inhibited E2-induced proliferation and anchorage-independent growth. We also showed that under non-estrogenic conditions, MPA and NET, unlike P4 and DRSP, increased the expression of the estrogen receptor (ER) target gene, cathepsin D, via a mechanism requiring the co-recruitment of ERα and the progesterone receptor (PR) to the promoter region. In contrast, all progestogens promoted the association of the PR and ERα on the promoter of the PR target gene, MYC, thereby increasing its expression under non-estrogenic and estrogenic conditions. These results suggest that progestins differentially regulate the way the PR and ER converge to modulate the expression of PR and ER-regulated genes. Our novel findings indicating similarities and differences between P4 and the progestins, emphasize the importance of comparatively investigating effects of individual progestins rather than grouping them as a class. Further studies are required to underpin the clinical relevance of PR/ERα crosstalk in response to different progestins in both normal and malignant breast tissue, to either confirm or refute their suitability in combination therapy for ER-positive breast cancer.
    Keywords:  breast cancer; estrogen receptor; menopausal hormone therapy; progesterone receptor; progestins; steroid receptor crosstalk
    DOI:  https://doi.org/10.3389/fendo.2022.959396
  118. Angew Chem Int Ed Engl. 2022 Oct 05.
    A Sonication-Activated Valence-Variable Sono-Sensitizer/Catalyst for Autography Inhibition/Ferroptosis-Induced Tumor Nanotherapy.
    Wei Feng, Zhonglong Liu, Lili Xia, Meng Chen, Xinyue Dai, Hui Huang, Caihong Dong, Yue He, Yu Chen.
      The effective deployment of reactive oxygen species (ROS)-mediated oncotherapy in practice remains challenging, mired by uncontrollable catalytic processes, stern reaction conditions and safety concerns. Herein, we develop a copper nanodot integrating sonodynamic and catalytic effects within one active center, which responds to exogenous ultrasound (US) and endogenous H2O2 stimuli. US irradiation induces the valence conversion from Cu(II) to Cu(I) catalyzing H2O2 into •OH for chemodynamic therapy. Meanwhile, valence transformation results in electron-hole pairs separation, promoting ROS generation for sonodynamic therapy. Notably, copper nanodots not only block lysosome fusion and degradation leading to autophagy flux blockage, but also interfere with the glutathione peroxidase 4 and cystine-glutamate antiporter SLC7A11 function achieving ferroptosis. Furthermore, reversible valence changes, inherent hydrophilicity and renal clearance ultrasmall size guarantee biosafety.
    Keywords:  Ferroptosis; Nanodynamic therapy; reactive oxygen species regulation; spatiotemporal control
    DOI:  https://doi.org/10.1002/anie.202212021
  119. iScience. 2022 Oct 21. 25(10): 105081
    Multiomic characterization and drug testing establish circulating tumor cells as an ex vivo tool for personalized medicine.
    Jia-Yang Chen, Hsu-Huan Chou, Syer Choon Lim, Yen-Jang Huang, Kuan-Chen Lai, Chin-Lin Guo, Chien-Yi Tung, Chung-Tsai Su, Jocelyn Wang, Edward Liu, Hsiao-Fen Han, Po-Ying Yeh, Chun-Mei Hu, Alexander R Dunn, Curtis W Frank, Yi-Chun Wu, Muh-Hwa Yang, Ying-Chih Chang.
      Matching the treatment to an individual patient's tumor state can increase therapeutic efficacy and reduce tumor recurrence. Circulating tumor cells (CTCs) derived from solid tumors are promising subjects for theragnostic analysis. To analyze how CTCs represent tumor states, we established cell lines from CTCs, primary and metastatic tumors from a mouse model and provided phenotypic and multiomic analyses of these cells. CTCs and metastatic cells, but not primary tumor cells, shared stochastic mutations and similar hypomethylation levels at transcription start sites. CTCs and metastatic tumor cells shared a hybrid epithelial/mesenchymal transcriptome state with reduced adhesive and enhanced mobilization characteristics. We tested anti-cancer drugs on tumor cells from a metastatic breast cancer patient. CTC responses mirrored the impact of drugs on metastatic rather than primary tumors. Our multiomic and clinical anti-cancer drug response results reveal that CTCs resemble metastatic tumors and establish CTCs as an ex vivo tool for personalized medicine.
    Keywords:  Cancer; Omics; Precision medicine; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2022.105081
  120. Poult Sci. 2022 Aug 30. pii: S0032-5791(22)00451-5. [Epub ahead of print]101(12): 102162
    The effects of L-carnitine-loaded solid lipid nanoparticles on performance, antioxidant parameters, and expression of genes associated with cholesterol metabolism in laying hens.
    Masoud Eskandani, Bahman Navidshad, Morteza Eskandani, Somayeh Vandghanooni, Farzad Mirzaei Aghjehgheshlagh, Ali Nobakht, Amir Ali Shahbazfar.
      The purpose of this study was to investigate the production performance, antioxidant parameters, egg yolk cholesterol content, and expression of genes related to cholesterol metabolism in laying hens fed L-carnitine (LC) and L-carnitine-loaded solid lipid nanoparticles (LC-SLNs). A total of 350 Hy-Line (w-36) laying hens at 50 wk of age (1520.0 ± 0.7 g) were randomly assigned to 35 units (5 replicates and 50 hens in each treatment) with seven dietary treatments as a completely randomized design. The dietary treatments were corn-soybean meal-based diets, including 1) Control (basal diet); 2) Basal diet +50 mg/kg LC (50LC); 3) Basal diet +100 mg/kg LC (100LC); 4) Basal diet +150 mg/kg LC (150LC); 5) Basal diet +50 mg/kg LC-SLNs (50LC-SLNs); 6) Basal diet +100 mg/kg LC-SLNs (100LC-SLNs) and 7) Basal diet +150 mg/kg LC-SLNs (150LC-SLNs). Results showed that the 50LC-SLNs had the least feed conversion ratio (FCR) in all groups (P < 0.05). The dietary supplementation of 100LC-SLNs decreased (P < 0.01) the egg yolk cholesterol concentration from 14.71 to 11.76 mg/g yolk (25%). The 50LC-SLNs group produced the most total antioxidant capacity with a difference of 58.44% compared to the control group (P < 0.01). The greatest amount of total superoxide dismutase was found for 50LC-SLNs (P < 0.05), while the glutathione peroxidase was not affected by the experimental treatments (P > 0.05). Serum malondialdehyde levels were reduced by 50.52% in laying hens fed 50LC-SLNs compared to the control group (P < 0.05). The transcript level of 3-hydroxy-3-methylglutaryl coenzyme A reductase was significantly decreased (P < 0.01) in the LC and LC-SLNs groups. The expression of cholesterol 7α-hydroxylase was significantly increased (P < 0.01) in the plain LC (∼83%) and LC-SLNs (∼91%) groups. The inclusion of LC-SLNs in the diet increased (P < 0.05) the villus height and decreased villus width in all three parts of the small intestine. Dietary inclusion of LC was found to reduce egg yolk and serum cholesterol content by improving the production performance and antioxidant status. The LC-SLNs groups were more affected than the plain LC groups, which may be attributed to the increased bioavailability of LC.
    Keywords:  L-carnitine; cholesterol; egg; laying hens; solid lipid nanoparticles
    DOI:  https://doi.org/10.1016/j.psj.2022.102162
  121. Evid Based Complement Alternat Med. 2022 ;2022 2885293
    Antitumor Potential of Sericite Treatment Mediated by Cell Cycle Arrest in Triple-Negative MDA-MB231 Breast Cancer Cells.
    Seonhee Kim, Harsha Nagar, Ikjun Lee, Su-Jeong Choi, Shuyu Piao, Byeong Hwa Jeon, Shin Kwang Kang, Hee-Jung Song, Cuk-Seong Kim.
      Breast cancer is the most common cancer and the leading cause of cancer-related mortality among females worldwide. Triple-negative breast cancer (TNBC) accounts for about 10-15% of all breast cancers and is usually more aggressive and has a poorer prognosis. Sericite has been known to have antitumor and immune-stimulatory effects. Although the chemopreventive potential of sericite has been demonstrated in other cancers, its molecular pathways in TNBC still require investigation. Thus, in the present study, the antitumor mechanism of sericite against MDA-MB231 breast cancer cells was examined in vitro and in an in vivo xenograft mouse model. Sericite treatment reduced cell proliferation and cell proliferation marker proliferating cell nuclear antigen (PCNA) in MDA-MB231 cells. It also decreased the total cell number and arrested cells in the G0/G1 phase of the cell cycle with an increase in the phosphorylation of P53 and upregulation of cell cycle regulatory proteins P21 and P16. In addition, sericite treatment also induced apoptosis signaling, which was evident by the upregulation of apoptotic protein markers cleaved caspases 3 and 9. A reduction in reactive oxygen species (ROS), NADPH oxidase 4 (NOX4), p22phox, and heat shock proteins (HSPs) was also observed. Similar results were obtained in vivo with significantly reduced tumor volume in sericite-administered mice. Collectively, these findings suggest that sericite has antitumor potential based on its property to induce cell cycle arrest and apoptotic cell death and therefore could serve as a potential therapeutic agent and crucial candidate in anticancer drug development for TNBC.
    DOI:  https://doi.org/10.1155/2022/2885293
  122. J Pharmacopuncture. 2022 Sep 30. 25(3): 199-208
    An Overview on Plant Derived Phenolic Compounds and Their Role in Treatment and Management of Diabetes.
    Himangshu Deka, Ananta Choudhury, Biplab Kumar Dey.
       Objectives: In recent decades, the trend for treating diabetes mellitus (DM) has shifted toward alternative medicines that are obtained from plant sources. Existing literature suggests that phenolic compounds derived from plants possess promising health-promoting properties. This study aimed to discuss the role of plant-derived phenolic compounds in the effective treatment and management of diabetes.
    Methods: Information about plant secondary metabolites, phenolic compounds, and their role in the treatment and management of diabetes was collected from different databases, such as Pubmed, ScienceDirect, Scopus, and Google Scholar. Keywords like secondary metabolites, phenolic compounds, simple phenol, flavonoids, lignans, stilbenes, and diabetes were searched. Research and review articles with relevant information were included in the study.
    Results: Anti-diabetic studies of the four major classes of phenolic compounds were included in this review. The plant-derived phenolic compounds were reported to have potent anti-diabetic activities. However, each class of phenolic compounds was found to behave differently according to various mechanisms.
    Conclusion: The obtained results suggest that phenolic compounds derived from natural sources display promising anti-diabetic activities. Based on the available information, it can be concluded that phenolic compounds obtained from various natural sources play key roles in the treatment and management of diabetes.
    Keywords:  diabetes mellitus; flavonoids; phenolic acids; secondary metabolites; stilbenes
    DOI:  https://doi.org/10.3831/KPI.2022.25.3.199
  123. Chem Res Toxicol. 2022 Oct 06.
    Acyl Glucuronide and Coenzyme A Thioester Metabolites of Carboxylic Acid-Containing Drug Molecules: Layering Chemistry with Reactive Metabolism and Toxicology.
    Kaushik Mitra.
      Glucuronidation and CoA (coenzyme A) conjugation are common pathways for the elimination of carboxylic acid-containing drug molecules. In some instances, these biotransformations have been associated with toxicity (such as idiosyncratic hepatic injury, renal impairment, hemolytic anemia, gastrointestinal inflammation, and bladder cancer) attributed to, in part, the propensity of acyl glucuronides and acyl CoA thioesters to covalently modify biological macromolecules such as proteins and DNA. It is to be noted that, while acyl glucuronidation and CoA conjugation are indeed implicated in adverse effects, there are many safe drugs in the market that are cleared by these reactive pathways. It is therefore important that new molecular entities with carboxylic acid groups are evaluated for toxicity in a manner that is not unreasonably risk-averse. In the absence of truly predictable methods, therefore, the general approach is to apply a set of end points to generate a weight-of-evidence evaluation. In practice, the focus is to identify structural liabilities and provide structure-activity recommendations early in the program, at a stage where an attempt to improve reactive metabolism does not deoptimize other critical drug-quality criteria. This review will present a high-level overview of the chemistry of glucuronidation and CoA conjugation and provide a discussion of the possible mechanisms of adverse effects that have been associated with these pathways, as well as how such potential hazards are addressed while delivering a new chemical entity for clinical evaluation.
    DOI:  https://doi.org/10.1021/acs.chemrestox.2c00188
  124. Biomater Adv. 2022 Oct;pii: S2772-9508(22)00395-8. [Epub ahead of print]141 213118
    Dendrimer-based delivery of macromolecules for the treatment of brain tumor.
    Hira Choudhury, Manisha Pandey, Raxshanaa Mohgan, Jim Sii Jack Jong, Roshini Nicole David, Wan Yi Ngan, Tze Liang Chin, Shereen Ting, Prashant Kesharwani, Bapi Gorain.
      Brain tumor represents the most lethal form of cancer with the highest mortality and morbidity rates irrespective of age and sex. Advancements in macromolecule-based therapy (such as nucleic acids and peptides) have shown promising roles in the treatment of brain tumor where the phenomenon of severe toxicities due to the conventional chemotherapeutic agents can be circumvented. Despite its preclinical progress, successful targeting of these macromolecules across the blood-brain barrier without altering their physical and chemical characteristics is of great challenge. With the advent of nanotechnology, nowadays targeted delivery of therapeutics is being explored extensively and these macromolecules, including peptides and nucleic acids, have shown initial success in the treatment, where dendrimer has shown its potential for optimal delivery. Dendrimers are being favored as a mode of drug delivery due to their nano-spherical size and structure, high solubilization potential, multivalent surface, and high loading capacity, where biomolecule resembling characteristics of dendritic 3D structures has shown effective delivery of various therapeutic agents to the brain. Armed with targeting ligands to these dendrimers further expedite the transportation of these multifunctional shuttles specifically to the glioblastoma cells. Thus, a focus has been made in this review on therapeutic applications of dendrimer platforms in brain tumor treatment. The future development of dendrimers as a potential platform for nucleic acid and peptide delivery and its promising clinical application could provide effective and target-specific treatment against brain tumors.
    Keywords:  Blood-brain barrier; Dendrimer-peptide conjugates; Glioblastoma; Nanocarriers; Nucleic acid; Peptide delivery
    DOI:  https://doi.org/10.1016/j.bioadv.2022.213118
  125. J Cancer. 2022 ;13(12): 3368-3377
    Hexokinase 2 Is a Pivot for Lovastatin-induced Glycolysis-to-Autophagy Reprogramming in Triple-Negative Breast Cancer Cells.
    Lian Xue, Mi Wu, Ying Li, Sisi Chen, Muyao Wu, Jianyu Zhu, Siyu Ding, Qiuting Zhang, Chanjuan Zheng, Guangchun He, Shujun Fu, Guifei Li, Xiyun Deng.
      Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with limited therapeutic options available. We have recently demonstrated that lovastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, suppresses TNBC cell proliferation and stemness properties in vitro and in vivo. However, the mechanisms through which lovastatin inhibits TNBC cells are not fully understood. Here, we used 1H NMR-based metabolomic profiling to investigate lovastatin-induced metabolic changes in TNBC cell line MDA-MB-231. Among the 46 metabolites identified, lactate demonstrated the highest variable importance in projection (VIP) score. Glycolysis stress test revealed that lovastatin significantly decreased the extracellular acidification rate (ECAR) in MDA-MB-231 cells. Furthermore, lovastatin treatment down-regulated the levels of glycolysis-related proteins including GLUT1, PFK1, and PKM2 in MDA-MB-231 but not non-TNBC MDA-MB-453 cells. In addition, lovastatin induced autophagy as evidenced by increased LC3 puncta formation and LC3-II/I ratio, increased AMPK phosphorylation, and decreased Akt phosphorylation. We also revealed the interaction between the glycolytic enzyme hexokinase 2 (HK2) and the mitochondrial membrane protein voltage-dependent anion channel 1 (VDAC1), an important regulator of autophagy. Further bioinformatics analysis revealed that VDAC1 was expressed at a higher level in breast cancer than normal tissues and higher level of VDAC1 predicted poorer survival outcomes in breast cancer patients. The present study suggests that lovastatin might exert anti-tumor activity by reprogramming glycolysis toward autophagy in TNBC cells through HK2-VDAC1 interaction.
    Keywords:  Autophagy; Glycolysis; Lovastatin; Metabolomics; Triple-negative breast cancer
    DOI:  https://doi.org/10.7150/jca.71592
  126. Biol Direct. 2022 Oct 01. 17(1): 26
    Long non-coding RNAs affecting cell metabolism in cancer.
    Massimiliano Agostini, Mara Mancini, Eleonora Candi.
      Metabolic reprogramming is commonly recognized as one important hallmark of cancers. Cancer cells present significant alteration of glucose metabolism, oxidative phosphorylation, and lipid metabolism. Recent findings demonstrated that long non-coding RNAs control cancer development and progression by modulating cell metabolism. Here, we give an overview of breast cancer metabolic reprogramming and the role of long non-coding RNAs in driving cancer-specific metabolic alteration.
    Keywords:  Breast cancer; Cell metabolism; Long non-coding RNAs
    DOI:  https://doi.org/10.1186/s13062-022-00341-x
  127. Front Pharmacol. 2022 ;13 981578
    Sepsis-induced AKI: From pathogenesis to therapeutic approaches.
    Fang-Fang He, Yu-Mei Wang, Yi-Yuan Chen, Wei Huang, Zi-Qi Li, Chun Zhang.
      Sepsis is a heterogenous and highly complex clinical syndrome, which is caused by infectious or noninfectious factors. Acute kidney injury (AKI) is one of the most common and severe complication of sepsis, and it is associated with high mortality and poor outcomes. Recent evidence has identified that autophagy participates in the pathophysiology of sepsis-associated AKI. Despite the use of antibiotics, the mortality rate is still at an extremely high level in patients with sepsis. Besides traditional treatments, many natural products, including phytochemicals and their derivatives, are proved to exert protective effects through multiple mechanisms, such as regulation of autophagy, inhibition of inflammation, fibrosis, and apoptosis, etc. Accumulating evidence has also shown that many pharmacological inhibitors might have potential therapeutic effects in sepsis-induced AKI. Hence, understanding the pathophysiology of sepsis-induced AKI may help to develop novel therapeutics to attenuate the complications of sepsis and lower the mortality rate. This review updates the recent progress of underlying pathophysiological mechanisms of sepsis-associated AKI, focuses specifically on autophagy, and summarizes the potential therapeutic effects of phytochemicals and pharmacological inhibitors.
    Keywords:  acute kidney injury; autophagy; inflammation; phytochemicals; sepsis
    DOI:  https://doi.org/10.3389/fphar.2022.981578
  128. Food Res Int. 2022 Nov;pii: S0963-9969(22)00933-4. [Epub ahead of print]161 111875
    Comparative study on the phenolic composition and in vitro bioactivity of medicinal and aromatic plants from the Lamiaceae family.
    Rafael Mascoloti Spréa, Cristina Caleja, José Pinela, Tiane C Finimundy, Ricardo C Calhelha, Marina Kostić, Marina Sokovic, Miguel A Prieto, Eliana Pereira, Joana S Amaral, Lillian Barros.
      Medicinal and aromatic plants (MAP) have been described as a source of phenolic compounds with potential as antioxidant, antiproliferative and antimicrobial agents. MAP from the Lamiaceae family (Origanum vulgare L., Thymus vulgaris L., Ocimum basilicum L., Salvia officinalis L., Melissa officinalis L., and MatricariachamomillaL.) were selected to perform a phytochemical and biological screening for their further exploitation as natural bioactive ingredients. The total content of phenolic compounds varied from 184.02 mg/g extract in M. officinalis to 17.97 mg/g extract in M. chamomilla. Caffeic and rosmarinic acids were the main phenolic acids found in the respective hydroalcoholic extracts. The extracts showed a promising antioxidant activity in vitro, being related the phenolic compositions of the extracts, furthermore, all extracts being able to combat lipid peroxidation in TBARS assays with an IC50 under 26 μg/mL, moreover all the plant extract has prevented the oxidative haemolysis in OxHLIA assays at concentrations below 67 μg/mL in a Δt 60 min and under 118 μg/mL for a Δt 120 min. Regarding to the bactericidal and fungicidal action the plant extracts were able to inhibit growth against bacteria associated with food hazards, such as Salmonella typhimurium (MIC < 1) and Listeria monocytogenes (MIC < 1), regarding to fungicidal activity it can be highlighted the MIC values under to 0.25 for Aspergillus versicolor and Trichoderma viride. Overall, the selected Lamiaceae plants stood out as a source of active phytochemicals that can be used by different industries, such as food and cosmetics.
    Keywords:  Biological bioactivity; Lamiaceae family; Medicinal and aromatic plants; Phenolic compounds; Phytochemical composition
    DOI:  https://doi.org/10.1016/j.foodres.2022.111875
  129. Adv Drug Deliv Rev. 2022 Sep 30. pii: S0169-409X(22)00451-3. [Epub ahead of print] 114561
    Engineering the right formulation for enhanced drug delivery.
    Wei-Ren Ke, Rachel Yoon Kyung Chang, Hak-Kim Chan.
      Dry powder inhalers (DPIs) can be used with a wide range of drugs such as small molecules and biologics and offer several advantages for inhaled therapy. Early DPI products were intended to treat asthma and lung chronic inflammatory disease by administering low-dose, high-potency drugs blended with lactose carrier particles. The use of lactose blends is still the most common approach to aid powder flowability and dose metering in DPI products. However, this conventional approach may not meet the high demand for formulation physical stability, aerosolisation performance, and bioavailability. To overcome these issues, innovative techniques coupled with modification of the traditional methods have been explored to engineer particles for enhanced drug delivery. Different particle engineering techniques have been utilised depending on the types of the active pharmaceutical ingredient (e.g., small molecules, peptides, proteins, cells) and the inhaled dose. This review discusses the challenges of formulating DPI formulations of low-dose and high-dose small molecule drugs, and biologics, followed by recent and emerging particle engineering strategies utilised in developing the right inhalable powder formulations for enhanced drug delivery.
    Keywords:  Inhaled drug therapy; aerosolisation; dry powder; formulation; particle engineering; particulate properties
    DOI:  https://doi.org/10.1016/j.addr.2022.114561
  130. Evid Based Complement Alternat Med. 2022 ;2022 2116006
    Systems Network Pharmacology-Based Prediction and Analysis of Potential Targets and Pharmacological Mechanism of Actinidia chinensis Planch. Root Extract for Application in Hepatocellular Carcinoma.
    Yue Hu, Liang Yang, Yunfei Lu, Yong Wang, Jianshuai Jiang, Yahui Liu, Qing Cao.
       Purpose: Traditional Chinese medicine (TCM) sometimes plays a crucial role in advanced cancer treatment. Despite the significant therapeutic efficacy in hepatocellular carcinoma (HCC) that Actinidia chinensis Planch root extract (acRoots) has proven, its complex composition and underlying mechanism have not been fully elucidated. Therefore, this study analyzed the multiple chemical compounds in acRoots and their targets via network pharmacology and bioinformatics analysis, with the overarching goal of revealing the potential mechanisms of the anti-HCC effect.
    Methods: The main ingredients contained in acRoots were initially screened from the traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), and the candidate bioactive ingredient targets were identified using DrugBank and the UniProt public databases. Second, the biological processes of the targets of active molecules filtered from the ingredients of acRoots were evaluated using gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Third, weighted gene coexpression network analysis (WGCNA) was performed to identify gene coexpression modules associated with HCC. The hub genes of acRoots in HCC were defined via contrasting the above module eigengenes with candidate target genes of acRoots. Furthermore, the target-pathway network was analyzed to explore the mechanism for anti-HCC effect of hub genes. Kaplan-Meier plotter database analysis was performed to validate the hub genes of acRoots correlation with prognostic values in HCC. In order to verify the results of the network pharmacological analysis, we performed a molecular docking approach on the active ingredients and key targets using the Discovery Studio software. The viability of SMMC-7721 and HL-7702 cells was determined by Cell counting kit-8 (CCK-8) after being treated with different concentrations of (+)-catechin (0, 50, 100, 150, 200, and 250 g/ml) for 24, 48, and 72 hours, respectively. Finally, qRT-PCR and Western blot involving human hepatocarcinoma cells were utilized to verify the impact of (+)-catechin on the hub genes associated with prognosis.
    Results: 6 out of 26 active ingredients extracted from TCMSP were deemed as the core ingredients of acRoots. 175 bioactive-ingredient targets of acRoots were obtained and a bioactive-ingredient targets network was established correspondingly. The biological processes (BP) of target genes mainly involved processes, such as toxic substance and wounding. The results of KEGG pathways indicated that the target genes were mainly enriched in pathways in cancer, AGE-RAGE signaling pathway in diabetic complications, IL-17 signaling pathway, and other pathways. Also, the two hub genes (i.e., ESR1 and CAT) were closely associated with the prognosis of HCC patients. As a consequence, we predicated a series of signaling pathways, including estrogen signaling pathway and longevity regulation pathway, through which acRoots could facilitate the treatment for HCC. The molecular docking experiment ascertained that ESR1 and CAT had an effective binding force with (+)-catechin, one of the core ingredients of acRoots. Furthermore, (+)-catechin inhibited SMMC-7721 cell growth in a dose-dependent manner and a time-dependent manner. Finally, we suggest that the expression level of ESR1 and CAT is positively related to the (+)-catechin concentrations in in-vitro experiments.
    Conclusion: The bioactive ingredients of acRoots, including quercetin, (+)-catechin, beta-sitosterol, and aloe-emodin, have synergistic interactions in reinforcing the anticancer effect in HCC. Evidently, acRoots took effect by regulating multitargets and multipathways through its active ingredients. Further, (+)-catechin, the possible paramount anti-HCC active ingredient in acRoots, helped improve the prognosis of HCC patients by increasing the expression of ESR1 and CAT. Additionally, the findings yielded provide a conceptual guidance for the clinical treatment of HCC and the methods adopted are potentially applicable in the future comprehensive analysis of the underlying mechanisms of TCMs.
    DOI:  https://doi.org/10.1155/2022/2116006
  131. Carbohydr Polym. 2022 Dec 01. pii: S0144-8617(22)00956-0. [Epub ahead of print]297 120051
    Amelioration of hydrolyzed guar gum on high-fat diet-induced obesity: Integrated hepatic transcriptome and metabolome.
    Xiaodan Fu, Zhemin Liu, Rong Li, Junyi Yin, Han Sun, Changliang Zhu, Qing Kong, Haijin Mou, Shaoping Nie.
      Hydrolyzed guar gum has gained attention as an anti-obesity agent; however, few studies have focused on its role in amelioration of hepatic-associated metabolic processes. Here, the anti-obesity effect of low molecular weight hydrolyzed guar gum (GMLP, 1-10 kDa) on high-fat diet (HFD)-fed C57BL/6 J mice was investigated via transcriptome and metabolome in liver. GMLP reduced body weight gain and hepatic lipid accumulation dose-dependently, regulated blood lipid levels, and improved liver damage in HFD-fed mice. Integrated transcriptome and metabolome indicated that GMLP mainly altered lipid metabolism pathways (glycerophospholipid metabolism, glycerolipid metabolism, and fatty acid degradation), reduced disease biomarkers of ethyl glucuronide and neopterin, and increased levels of choline, flavin adenine dinucleotide, and pantetheine metabolites. Real-time quantitative PCR showed that GMLP downregulated key genes involved in de novo lipogenesis and triacylglycerol synthesis, while promoting fatty acid oxidation and choline synthesis. This study provides a theoretical basis for GMLP treatment in future clinical applications.
    Keywords:  Fatty acid metabolism; Hepatic metabolome; Hepatic transcriptome; Hyperlipidemia; Low molecular weight hydrolyzed guar gum; Obesity
    DOI:  https://doi.org/10.1016/j.carbpol.2022.120051
  132. Front Pharmacol. 2022 ;13 999604
    Salvia miltiorrhiza in thorax and abdomainal organ fibrosis: A review of its pharmacology.
    Zhao Yang, Jingshu Qi, Dabing Ping, Xin Sun, Yanyan Tao, Chenghai Liu, Yuan Peng.
      Organ fibrosis is a common pathological change that finally results in organ failure, which involves the destruction of parenchyma cells, the activation of mesenchymal cells and the imbalance of immunological cells. In recent years, although some breakthroughs have been made in understanding the pathogenesis and therapeutics of organ fibrosis, no registered drugs could directly target the fibrotic process, which constitutes a major biomedical challenge. Salvia miltiorrhiza (SM) is a well-known medicinal plant in China, which has been widely applied because of its pharmacological effects on anti-oxidative, anti-myocardial infarction, anti-fibrotic, anti-inflammatory, and anti-neoplastic properties. Accumulated evidence suggested that SM played critical roles against organ fibrosis in vivo and in vitro experiments by its multiple biological compounds. In this review, we discussed the recent advances on the phytochemistry and pharmacological mechanisms of SM and its active ingredients in liver, lung, kidney, and heart fibrosis, which might help to promote the treatment of fibrotic diseases in thorax and abdomainal viscera in clinic.
    Keywords:  Salvia miltiorrhiza; ingredients; organ fibrosis; pharmacological mechanism; review
    DOI:  https://doi.org/10.3389/fphar.2022.999604
  133. J Oncol. 2022 ;2022 8802453
    Eupalinolide O Induces Apoptosis in Human Triple-Negative Breast Cancer Cells via Modulating ROS Generation and Akt/p38 MAPK Signaling Pathway.
    Yaping Zhao, Liping Fu, Jinbai Chen, Junhao Zhou, Chongmei Tian, Daotang Zhou, Rui Zhu.
       Background: Triple-negative breast cancer (TNBC) is a subtype of breast cancer with limited therapeutic options. Eupalinolide O (EO) was reported to inhibit tumor growth. This study is aimed at exploring the role of EO on TNBC both in vivo and in vitro. Methods. In in vitro experiments, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and clonogenic assay were conducted to measure the impact of EO on TNBC cell growth at different concentrations and time points. Flow cytometry was conducted to evaluate cell apoptosis. Mitochondrial membrane potential (MMP) loss, caspase-3 activity, and reactive oxygen species (ROS) generation were assessed. The expressions of apoptosis-related mRNAs and Akt/p38 MAPK signaling pathway-related proteins were measured. In in vivo experiments, by injecting TNBC cells into the nude mice to induce xenograft tumor, mice were treated with EO for 20 days. Then, in vivo bioluminescence imaging system was utilized to monitor the growth and distribution of TNBC cells. Tumor volume and weight were also recorded. Hematoxylin-eosin (HE) staining and ELISA assay were applied to observe tumor tissue morphology and ROS levels. Furthermore, western blotting was conducted to observe the expression of apoptosis-related proteins and Akt/p38 MAPK signaling pathway-associated proteins.
    Results: EO inhibited the cell viability and proliferation of TNBC cells but not normal epithelial cells. Furthermore, EO induced apoptosis, decreased MMP, and elevated caspase-3 activity and ROS content in TNBC cells. Meanwhile, the expression of apoptosis-related mRNAs and Akt/p38 MAPK pathway-related proteins was regulated by EO treatment. Besides, in vivo experiments demonstrated EO not only suppressed tumor growth, Ki67 expression, ROS generation, and Akt phosphorylation but also upregulated caspase-3 expression and p-38 phosphorylation.
    Conclusion: EO may induce cell apoptosis in TNBC via regulating ROS generation and Akt/p38 MAPK pathway, indicating EO may be a candidate drug for TNBC.
    DOI:  https://doi.org/10.1155/2022/8802453
  134. Spectrochim Acta A Mol Biomol Spectrosc. 2022 Sep 24. pii: S1386-1425(22)01064-2. [Epub ahead of print]285 121916
    Fourier Transform Infrared Spectroscopy (FT-IR) of Pseudomonas aeruginosa post photodynamic therapy with Curcumin in vitro.
    Camila Monteiro Santos Marques, Juliana Teixeira Pedroso, Tanmoy Bhattacharjee, Breno Pupin, Juliana Guerra Pinto, Juliana Ferreira-Strixino, Kumiko Koibuchi Sakane.
      Alternative therapies against pathogens are under intense investigation because of their increasing resistance to antibiotics. Photodynamic therapy (PDT) is one such alternative that has shown promising results. However, for the widespread use of PDT, it is essential to decipher underlying mechanisms, so as to improve PDT's therapeutic applications. Because of this, we have studied biochemical changes in pathogen Pseudomonas aeruginosa, a medically important bacteria that has developed antibiotic resistance, after PDT with curcumin photosensitizer. Results show a drastic decrease in α-helix protein and increased disordered and β-sheet secondary structure proteins in P. Aeruginosa post-PDT compared to control. Interestingly, these biochemical changes differ from PDT of pathogens Leishmania braziliensis and Leishmania major with photosensitizer methylene blue. This observation underlines the need for extensive studies on PDT of different pathogens to understand mechanisms of action and develop better PDT strategies.
    Keywords:  Curcumin; FT-IR spectroscopy; Photodynamic therapy; Pseudomonas aeruginosa
    DOI:  https://doi.org/10.1016/j.saa.2022.121916
  135. Front Cell Dev Biol. 2022 ;10 1013885
    Glycolysis in tumor microenvironment as a target to improve cancer immunotherapy.
    Chu Xiao, He Tian, Yujia Zheng, Zhenlin Yang, Shuofeng Li, Tao Fan, Jiachen Xu, Guangyu Bai, Jingjing Liu, Ziqin Deng, Chunxiang Li, Jie He.
      Cancer cells and immune cells all undergo remarkably metabolic reprogramming during the oncogenesis and tumor immunogenic killing processes. The increased dependency on glycolysis is the most typical trait, profoundly involved in the tumor immune microenvironment and cancer immunity regulation. However, how to best utilize glycolytic targets to boost anti-tumor immunity and improve immunotherapies are not fully illustrated. In this review, we describe the glycolytic remodeling of various immune cells within the tumor microenvironment (TME) and the deleterious effects of limited nutrients and acidification derived from enhanced tumor glycolysis on immunological anti-tumor capacity. Moreover, we elucidate the underlying regulatory mechanisms of glycolytic reprogramming, including the crosstalk between metabolic pathways and immune checkpoint signaling. Importantly, we summarize the potential glycolysis-related targets that are expected to improve immunotherapy benefits. Our understanding of metabolic effects on anti-tumor immunity will be instrumental for future therapeutic regimen development.
    Keywords:  TME; cancer metabolism; glycolysis; immunity regulation; immunotherapy
    DOI:  https://doi.org/10.3389/fcell.2022.1013885
  136. Adv Colloid Interface Sci. 2022 Aug 29. pii: S0001-8686(22)00170-1. [Epub ahead of print]309 102768
    Ultrasound-modified protein-based colloidal particles: Interfacial activity, gelation properties, and encapsulation efficiency.
    Rassoul Mozafarpour, Arash Koocheki, Mahmood Alizadeh Sani, David Julian McClements, Hamed Mahdavian Mehr.
      Proteins are natural amphiphilic polymers that often have good emulsifying, gelling, and structure forming properties. Consequently, they can be used to assemble protein-based colloidal delivery systems for bioactive agents, such as nanoemulsions, protein nanoparticles, or microgels. However, the functional performance of some proteins is limited because of their poor water-solubility, a tendency to aggregate, and or low surface activity, which limits their application for this purpose. Therefore, physicochemical modification is often necessary to improve their technofunctional characteristics. High-intensity ultrasound (HIU) is a non-thermal processing method that has considerable potential for the modification of the structural, physicochemical, and functional properties of proteins. In this article, we review the impact of sonication on the properties of proteins, including their size, charge, surface hydrophobicity, flexibility, solubility, free sulfhydryl groups, and disulfide bond formation. In addition, the influence of sonication on the emulsifying, foaming, gelling, and encapsulation properties of proteins is reviewed. Previous studies show that high-intensity ultrasound treatments have a strong influence on the molecular characteristics of proteins (increasing their solubility, flexibility, and functionality), which improves their ability to form colloidal delivery systems.
    Keywords:  Colloidal systems; Dispersibility; Gelling properties; Interfacial properties; Ultrasound
    DOI:  https://doi.org/10.1016/j.cis.2022.102768
  137. Environ Health. 2022 Oct 05. 21(1): 93
    Potential benefits of joint hypothetical interventions on diet, lead, and cadmium on mortality in US adults.
    Nasser Laouali, Tarik Benmarhnia, Youssef Oulhote.
       BACKGROUND: Previous studies reported associations between high blood lead levels (BLLs) and urinary cadmium (UCd) concentrations and all-cause and cause-specific mortality. It is hypothesized that these associations are mediated by inflammation; therefore, adherence to an anti-inflammatory diet may mitigate these effects. We sought to estimate the potential effects of joint hypothetical interventions on metals levels and adherence to an anti-inflammatory diet or fruits and vegetables (FV) intake on the expected mortality distributions.
    METHODS: We used data on 14,311 adults aged ≥ 20 years enrolled in the NHANES-III between 1988 and 1994 and followed up through Dec 31, 2015. We estimated daily FV servings and adherence to the dietary inflammatory index at baseline using 24-hour dietary recalls. Mortality was determined from the National Death Index records. We used the parametric g-formula with pooled logistic regression models to estimate the absolute risk of all-cause, cardiovascular, and cancer mortality under different hypothetical interventions compared to the natural course (no intervention).
    RESULTS: Overall, we observed a decreased mortality risk when intervening to lower metals levels or increasing adherence to an anti-inflammatory diet or the daily FV servings. The joint intervention to lower BLLs and UCd and increase the adherence to the anti-inflammatory diet had the strongest impact on cancer mortality risk (risk difference [RD] = -1.50% (-2.52% to -0.62%)) compared to the joint intervention only on metals levels RD= -0.97% (-1.89 to 0.70). The same pattern of associations was observed for the joint intervention to lower both metals and increased daily FV servings and cardiovascular diseases mortality risk.
    CONCLUSION: Higher diet quality may constitute a complementary approach to the interventions to reduce exposures to cadmium and lead to further minimize their effects on mortality. A paradigm shift is required from a pollutant-focused only to a combination with a human-focused approach for primary prevention against these metals.
    Keywords:  Cancer; Cardiovascular; Diet; Inflammation; Metals; Mortality; NHANES
    DOI:  https://doi.org/10.1186/s12940-022-00905-4
  138. Chem Biol Interact. 2022 Oct 03. pii: S0009-2797(22)00375-1. [Epub ahead of print] 110170
    Colon cancer and colorectal cancer: Prevention and treatment by potential natural products.
    Md Rezaul Islam, Shopnil Akash, Md Mominur Rahman, Feana Tasmim Nowrin, Tamanna Akter, Sheikh Shohag, Abdur Rauf, Abdullah S M Aljohani, Jesus Simal-Gandara.
      Colon cancer affects both men and women and is the world's second most significant cause of cancer-related mortality. Colon cancer death rates have risen worldwide due to the current food habit and lifestyle, which include a lot of meat, alcohol, and not enough physical exercise. As a result, novel, less harmful pharmacological treatments for colon cancer are needed now more than ever before. Colorectal cancer (CRC) affects a significant portion of the world's population. Chemotherapy's limits, as demonstrated by side effects and resistance in CRC patients, are now being sought after despite recent breakthroughs that have improved patient care and survival. Numerous chemical compounds present in medicinal herbs have shown anti-tumor and anti-apoptotic properties against various cancers, including CRC, in animal experiments. These chemicals, which come from several phytochemical families, activate several signaling pathways. This article discusses research on the anti-CRC benefits of many plants conducted in vitro, as well as the phytochemical components of plants that may play a role in the study. Researchers are also looking into the impact of these compounds on various pathways involved in cancer signaling. According to this review, anti-CRC compounds may be generated from medicinal plants. That's why we're looking at how natural items can help treat cancer while lowering the risk of developing it.
    Keywords:  Cancer; Colon cancer; Colorectal cancer; Malignancy; Metastasis; Natural products
    DOI:  https://doi.org/10.1016/j.cbi.2022.110170
  139. Curr Opin Chem Biol. 2022 Oct 04. pii: S1367-5931(22)00098-9. [Epub ahead of print]71 102213
    Taming glutathione potentiates metallodrug action.
    Hieu D Nguyen, Loi H Do.
      Metallodrugs that are redox sensitive or have labile coordination sites are particularly susceptible to inhibition by glutathione (GSH) and other endogenous thiols. Because GSH is an essential antioxidant, strategies to prevent thiol deactivation must consider their potential effects on normal cellular functions. In this short review, we describe general approaches for taming glutathione in metallodrug therapy and discuss their strengths and limitations. We also offer our perspectives on developing practical solutions that are effective and clinically relevant.
    Keywords:  Drug resistance; Glutathione; Metallodrugs; Metals in medicine; Toxicity
    DOI:  https://doi.org/10.1016/j.cbpa.2022.102213
  140. Magy Onkol. 2022 Oct 05. 66(3): 239-241
    [mTOR complex activity and metabolic changes as potential targets in solid tumors].
    Gábor Petővári.
      We investigated the activity and inhibition of mTOR and other metabolic pathways with their clinical significance in human breast tumors (using ten cell lines and nearly a hundred biopsy samples).Based on our results, the metabolic and mTOR inhibitor treatments showed a moderate tumor growth inhibitory effect in the cell lines subtype independently, which indicates tumor cell and tissue adaptation. Providing human tissue samples, we found a subtype independent correlation between high mTOR activity and protein expression characterizing alternative metabolic pathways with increased expression and the poor prognosis of breast tumors. Breast tumors are characterized by metabolic heterogeneity and significant metabolic plasticity, which can be targeted by combining anti-metabolic treatments and new therapies. Concerning these, an immunohistochemical evaluation (IHC panel) can be recommended, which is suitable for both metabolic plasticity evaluation and recognition of cases that may require stricter follow-up or metabolic targeted therapy due to the expected poor prognosis.
  141. Carbohydr Polym. 2022 Dec 01. pii: S0144-8617(22)00932-8. [Epub ahead of print]297 120027
    A dual-responsive polydopamine-modified hydroxybutyl chitosan hydrogel for sequential regulation of bone regeneration.
    Zhuqing Wan, Qinyuan Dong, Xiaodong Guo, Xiaoqiang Bai, Xiao Zhang, Ping Zhang, Yunsong Liu, Longwei Lv, Yongsheng Zhou.
      Delayed inflammatory reaction and poor osteogenesis are the two main causes of failure for bone-defect healing. Accordingly, in the present study, a dual-responsive hydrogel composite was successfully fabricated in which near-infrared (NIR)-light-responsive polydopamine-coated magnesium-calcium carbonate microspheres are incorporated into a thermo-responsive hydroxybutyl chitosan hydrogel to provide sequential delivery of the anti-inflammatory drug aspirin and osteogenic bone morphogenetic protein 2 (BMP-2). By initially releasing aspirin rapidly, the hydrogel composite efficiently ameliorates early-stage inflammatory reaction and promotes transition to the regenerative phase. Then, the hydrogel composite allows NIR-light-responsive release of BMP-2, which maximizes its osteoinductive effects. Using an SD rat calvaria-defect model, the sequential and controllable release achieved by the hydrogel is demonstrated to promote new-bone formation. Thus, the current study provides an efficient alternative strategy for developing multifunctional therapeutic biomaterials for bone tissue engineering.
    Keywords:  Anti-inflammation; Bone regeneration; Hydroxybutyl chitosan; Near-infrared light; Polydopamine; Sequential delivery
    DOI:  https://doi.org/10.1016/j.carbpol.2022.120027
  142. Clin Nutr ESPEN. 2022 Oct;pii: S2405-4577(22)00467-3. [Epub ahead of print]51 112-119
    Modified Atkins diet versus ketogenic diet in children with drug-resistant epilepsy: A meta-analysis of comparative studies.
    Asmaa Mhanna, Mohammed Mhanna, Azizullah Beran, Mustafa Al-Chalabi, Nameer Aladamat, Naeem Mahfooz.
       INTRODUCTION: The modified Atkins diet (MAD), a less restrictive form of the ketogenic diet (KD), has gained popularity and is proposed to be an alternative to the traditional KD in the management of drug-resistant epilepsy (DRE). However, the evidence to support this hypothesis remains limited. In this meta-analysis, we aimed to evaluate the efficacy and tolerability of MAD compared to traditional KD in children with DRE.
    METHOD: We systematically searched multiple databases through March 2022 for all the studies that evaluated the clinical utility of MAD versus KD for DRE in a pediatric population. The primary outcome was the proportion of children who had seizure frequency reduction (SFR) > 50%. The secondary outcomes were SFR >90%, seizure freedom, and diet-related side effects. All measurements were taken 6 months after starting the regimens. Pooled risk ratio (RR) and corresponding 95% confidence intervals (CIs) were calculated and combined using random-effects model meta-analysis.
    RESULTS: Six studies, with 397 patients with DRE (201 followed MAD vs. 196 with KD), were included. There was a significant difference in the proportion of patients who attained SFR >50% favoring the traditional KD (RR: 0.63; 95% CI: 0.47-0.83; P = 0.001). However, there was no significant differences in SFR >90% (RR: 0.73; 95% CI: 0.49-1.10; P = 0.13) or the proportion of patients who had seizure freedom (RR: 0.83; 95% CI: 0.49-1.41; P = 0.49). Furthermore, both regimens had comparable safety profiles (RR: 1.00; 95% CI: 0.95-1.05; P = 0.96).
    CONCLUSIONS: Our meta-analysis demonstrated the superiority of traditional KD over MAD in achieving SFR > 50% at 6 months in pediatric patients with DRE. However, SFR > 90% and seizure freedom were comparable between KD and MAD at 6 months. The tolerability profile between the two regimens was similar as well. Large-scale RCTs are necessary to validate our findings.
    Keywords:  Drug resistant epilepsy; Efficacy; Ketogenic diet; Modified atkins diet; Refractory epilepsy
    DOI:  https://doi.org/10.1016/j.clnesp.2022.09.004
  143. Protein Pept Lett. 2022 Oct 03.
    Targeting K-Ras Mutations Show Promise Towards Ending Ras's "Undruggable" Era.
    Paul D Adams, D Jamali Muhoza.
      It has almost been 40 years since the Ras proteins were discovered as the first human oncogenes. They remain among the most important genes for regulating mammalian cell growth and are involved in more than a quarter of human cancers. Out of 167 members of the Ras superfamily, K-Ras mutations are the most abundant in human cancers. Particularly, the K-Ras G12C mutations are known to be involved in pancreatic, colon and lung cancers as well as leukemias. Though progress has been made, approaches that target Ras proteins for therapeutic purposes still remain challenging. In fact, no drugs treating Ras-related cancers are currently on the market. However, there is now renewed interest in the Ras area and newer approaches have highlighted the targeting of several types of tumors and treating cancer patients. In this review, we will summarize recent K-Ras drug candidates and approaches in the pre-clinical, clinical and post clinical pipelines that show promise for targeting and reducing Ras-related tumors. Macromolecules such as mRNA vaccines, siRNA, and T-cell receptors that target Ras will also be discussed. The newer molecules and the recent approaches to be discussed suggest that the "undruggable" era of Ras proteins could be coming to an end.
    Keywords:  Drug targets; Ras; Small molecule inhibitor; effectors
    DOI:  https://doi.org/10.2174/0929866529666221003124202
  144. Biomed Res Int. 2022 ;2022 9218640
    Studying the Anticancer Effects of Thymoquinone on Breast Cancer Cells through Natural Killer Cell Activity.
    Huda F Alshaibi, Nouf A Aldarmahi, Nuha A Alkhattabi, Hadeil M Alsufiani, Nesrin I Tarbiah.
      Cancer immunotherapy is quickly growing and can now be viewed as the "fifth column" of cancer treatment. In addition, cancer immunotherapy has shown promising results with different kinds of cancers and may be used as a complementary therapy with various types of treatments. Thus, "immuno-oncology" is showing astounding advantages. However, one of the main challenges that face this type of therapy is that cancer cells can evade immune system elimination through different mechanisms. Many studies were done to overcome this issue including adding immune stimulants to generate synergistic effects or by genetically modifying NK cells themselves to be stronger and more resistant. Nigella sativa, also known as black cumin, is a well-known example of a widely applicable herbal medicine. It can effectively treat a variety of diseases, such as hypertension, diabetes, bronchitis, gastrointestinal upset, and cancer. The anticancer qualities of Nigella sativa appear to be mediated by an immune-modulatory effect that stimulates human natural killer (NK) cells. These are a type of lymphocyte and first line of defense against pathogens. Objectives. In this study, we investigated the therapeutic effect of thymoquinone, a major component of Nigella sativa, on the cytotoxic pathways of NK cells. Methods. NK cells were cultured with breast cancer cell line Michigan Cancer Foundation-7 (MCF-7); and were treated with Thymoquinone. The cytotoxicity of NK cells on cancer cells was measured. The cultured media were then collected and measured via enzyme-linked immunosorbent assay (ELISA) for concentrations of perforin, granzyme B and interferon-α (IFN-α). Results. The cytotoxic effect of NK cells on tumor cells was increased in the presence of thymoquinone, with an increased release of perforin, granzyme B, and IFN-α. Conclusion. Thymoquinone promotes the cytotoxic activity of NK cells against breast cancer MCF-7 cells.
    DOI:  https://doi.org/10.1155/2022/9218640
  145. Front Neurosci. 2022 ;16 1006031
    Photobiomodulation for the treatment of neuroinflammation: A systematic review of controlled laboratory animal studies.
    Fabrízio Dos Santos Cardoso, Farzad Salehpour, Norberto Cysne Coimbra, Francisco Gonzalez-Lima, Sérgio Gomes da Silva.
       Background: Neuroinflammation is a response that involves different cell lineages of the central nervous system, such as neurons and glial cells. Among the non-pharmacological interventions for neuroinflammation, photobiomodulation (PBM) is gaining prominence because of its beneficial effects found in experimental brain research. We systematically reviewed the effects of PBM on laboratory animal models, specially to investigate potential benefits of PBM as an efficient anti-inflammatory therapy.
    Methods: We conducted a systematic search on the bibliographic databases (PubMed and ScienceDirect) with the keywords based on MeSH terms: photobiomodulation, low-level laser therapy, brain, neuroinflammation, inflammation, cytokine, and microglia. Data search was limited from 2009 to June 2022. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. The initial systematic search identified 140 articles. Among them, 54 articles were removed for duplication and 59 articles by screening. Therefore, 27 studies met the inclusion criteria.
    Results: The studies showed that PBM has anti-inflammatory properties in several conditions, such as traumatic brain injury, edema formation and hyperalgesia, ischemia, neurodegenerative conditions, aging, epilepsy, depression, and spinal cord injury.
    Conclusion: Taken together, these results indicate that transcranial PBM therapy is a promising strategy to treat brain pathological conditions induced by neuroinflammation.
    Keywords:  brain; cytokine; inflammation; low-level laser (light) therapy; microglia; neuroinflammation; photobiomodulation
    DOI:  https://doi.org/10.3389/fnins.2022.1006031
  146. Adv Healthc Mater. 2022 Oct 03. e2201607
    Catalytic Biomaterials and Nanomedicines with Exogenous and Endogenous Activations.
    Hui Huang, Zeyu Wang, Liang Chen, Hong Yu, Yu Chen.
      Catalytic therapy can concurrently enhance therapeutic efficacy and decrease side effects by converting less toxic or nontoxic endogenous substances into various highly toxic reactive species (e.g., toxic radicals) to induce cell apoptosis/necrosis, which has been exploited to combat different types of diseases. As material science and nanotechnology evolve for application in disease therapies, a variety of catalytic biomaterials and nanomedicines have been elaborately designed and synthesized to mediate catalytic reactions and/or enhance the corresponding catalytic treatment efficacy. In this review, we systematically summarize, outline, and discuss the state-of-the-art advances in the development and use of catalytic biomaterials and nanomedicines in diverse biomedical applications, particularly concentrating on their endogenous activators, exogenous stimuli (e.g., light, heat, ultrasound, and magnetic field), and the integration of endogenous/exogenous triggers to improve the efficacy of biomaterials/nanomedicine-enabled catalytic treatments. We also discuss the biosafety and biocompatibility of various catalytic biomaterials and nanomedicines for biomedical applications. Finally, we highlight the current challenges and future opportunities for advancement of catalytic biomaterials and nanomedicines, aiming to boost their early fulfillment of practical clinical applications. This article is protected by copyright. All rights reserved.
    Keywords:  antibacteria; biomaterial; catalytic therapy; nanomedicine; tumor therapy
    DOI:  https://doi.org/10.1002/adhm.202201607
  147. Int J Biol Macromol. 2022 Oct 01. pii: S0141-8130(22)02214-0. [Epub ahead of print]
    A critical review on starch-based electrospun nanofibrous scaffolds for wound healing application.
    Chella Perumal Palanisamy, Bo Cui, Hongxia Zhang, Vinoth Prasanna Gunasekaran, Adeniran Lateef Ariyo, Selvaraj Jayaraman, Ponnulakshmi Rajagopal, Qianfa Long.
      Starch-based nanofibrous scaffolds exhibit a potential wound healing processes as they are cost-effective, flexible, and biocompatible. Recently, natural polymers have received greater importance in regenerative medicine, mainly in the process of healing wounds and burns due to their unique properties which also include safety, biocompatibility, and biodegradability. In this respect, starch is considered to be one of the reliable natural polymers to promote the process of wound healing at a significantly faster rate. Starch and starch-based electrospun nanofibrous scaffolds have been used for the wound healing process which includes the process of adhesion, proliferation, differentiation, and regeneration of cells. It also possesses significant activity to encapsulate and deliver biomaterials at a specific site which persuades the wound healing process at an increased rate. As the aforementioned scaffolds mimic the native extracellular matrix more closely, may help in the acceleration of wound closure, which in turn may lead to the promotion of tissue reorganization and remodeling. In-depth knowledge in understanding the properties of nanofibrous scaffolds paves a way to unfold novel methods and therapies, also to overcome challenges associated with wound healing. This review is intended to provide comprehensive information and recent advances in starch-based electrospun nanofibrous scaffolds for wound healing.
    Keywords:  Electrospinning method; Nanofibrous scaffolds; Starch-based materials; Wound healing application
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.09.274
  148. Anticancer Res. 2022 Oct;42(10): 5017-5020
    Counteracting Side-effects of Photodynamic Therapy for Actinic Keratoses.
    Hans Christian Wulf, Ida M Heerfordt.
       BACKGROUND/AIM: Actinic keratoses (AKs) are precursors of squamous cell carcinomas and early intervention is important. Photodynamic therapy (PDT) is often first-choice treatment for widespread AKs. Classic PDT consists of: Superficial curettage, application of 5-aminolevulinic acid or methyl aminolevulinate, incubation and protoporphyrin IX (PpIX) accumulation under occlusion for 3 hours, followed by illumination with red light-emitting diode light (37 J/cm2). Classic PDT is effective in treating AKs, but side-effects include unpleasant pretreatment, severe pain during illumination, inflammation after treatment, and long waiting time in the clinic.
    MATERIALS AND METHODS: This targeted mini review describes efforts to counteract side-effects and simplify the procedure considering the clinic capacity. Changes are only acceptable if treatment effect is maintained.
    RESULTS: We introduce the following procedure changes: (i) reducing pre-treatment pain, bleeding, and oozing by omitting curettage; (ii) long-term illumination for 2 hours during PpIX formation (already in use as daylight PDT) and shortening of incubation time from 3 hours to 30 minutes to minimize pain and inflammation risk. In addition, options of timing, incubation, and illumination indoors and outdoors are discussed, focusing on advantages and disadvantages for patients and clinics.
    CONCLUSION: We report several options to counteract side-effects of classic PDT.
    Keywords:  Actinic keratosis; adverse events; photodynamic therapy; protoporphyrin IX; review; skin
    DOI:  https://doi.org/10.21873/anticanres.16009
  149. Clin Nutr ESPEN. 2022 Oct;pii: S2405-4577(22)00432-6. [Epub ahead of print]51 28-36
    Effects of zinc supplementation on glycemic control and oxidative stress in experimental diabetes: A systematic review.
    Maria do Perpétuo Socorro Carvalho Martins, Amanda Suellenn da Silva Santos Oliveira, Maria do Carmo de Carvalho E Martins, Vanessa Brito Lira de Carvalho, Lays Arnoud Rosal Lopes Rodrigues, Daniel Dias Rufino Arcanjo, Marcos Antonio Pereira Dos Santos, Juliany Sales Ramos Machado, Maurisrael de Moura Rocha.
       INTRODUCTION: Diabetes mellitus (DM), an important public health problem worldwide, can cause imbalances in the homeostasis of trace elements such as zinc (Zn). It is possible that an adequate nutritional status related to nutrients is essential for the normal functioning of antioxidant defense systems, and any change in the concentration of these substances could increase the chances of DM complications.
    OBJECTIVE: To present a review on the effect of zinc supplementation on glycemic control and oxidative stress in experimental diabetes.
    METHODS: This is a systematic review of articles that investigated the effects of zinc supplementation on glycemic control and oxidative stress in diabetic rats. The PICOS strategy was used for the development of the research question, and the Syrcle tool for the quality assessment of the studies included in the review. Articles available in the PubMed, Scopus, and Web of Science databases were included without restriction on year of publication. The Syrcle tool was used to assess the risk of bias of the included studies.
    RESULTS: Fifteen studies were included in the review, seven of which evaluated glycemic control and oxidative stress after zinc supplementation, five only oxidative stress and three only glycemic control after zinc treatment. In all the studies included, diabetes was induced by the administration of streptozotocin (STZ) at doses ranging from 40 to 100 mg/kg. Zinc supplementation was made in the diet or drinking water or by gavage or intraperitoneal injection. The most used doses were 100 mg/kg of body weight by gavage and 0.32 and 0.64 g/kg in diet. The supplementation period ranged from 14 days to 8 weeks. Six studies revealed that zinc supplementation decreased fasting blood glucose as well as insulin resistance; nine studies included in this review reported decreased MDA concentration; in five studies, there was an increase in the activity of antioxidant enzymes (GPx, SOD, GSH and catalase); and one of the studies reported a reduction in glycated hemoglobin.
    CONCLUSION: Zinc supplementation improved hyperglycemia and revealed a protective potential against oxidative stress associated with experimental diabetes.
    Keywords:  Diabetes mellitus; Dietary supplementation; Oxidative stress; Zinc
    DOI:  https://doi.org/10.1016/j.clnesp.2022.08.003
  150. Aging Dis. 2022 Oct 01. 13(5): 1348-1364
    Ferroptosis in Intracerebral Hemorrhage: A Panoramic Perspective of the Metabolism, Mechanism and Theranostics.
    Chenxiao Lu, Changwu Tan, Hongfei Ouyang, Zhuohui Chen, Zhouyi Yan, Mengqi Zhang.
      Iron is one of the most crucial elements in the human body. In recent years, a kind of programmed, non-apoptotic cell death closely related to iron metabolism-called ferroptosis- has aroused much interest among many scientists. Ferroptosis also interacts with other pathways involved in cell death including iron abnormality, the cystine/glutamate antiporter and lipid peroxidation. Together these pathological pathways exert great impacts on intracerebral hemorrhage (ICH), a lethal cerebrovascular disease with a high incidence rate and mortality rate. Furthermore, the ferroptosis also affects different brain cells (neurons and neuroglial cells) and different organelles (mitochondria and endoplasmic reticulum). Clinical treatments for ferroptosis in ICH have been closely investigated recently. This perspective provides a comprehensive summary of ferroptosis mechanisms after ICH and its interaction with other cell death patterns. Understanding the role of ferroptosis in ICH will open new windows for the future treatments and preventions for ICH and other intracerebral diseases.
    Keywords:  antioxidant; ferroptosis; intracerebral hemorrhage; iron metabolism; lipid peroxidation
    DOI:  https://doi.org/10.14336/AD.2022.01302
  151. J Ethnopharmacol. 2022 Oct 03. pii: S0378-8741(22)00817-0. [Epub ahead of print] 115778
    Five centuries of Cirsium ehrenbergii Sch. Bip. (Asteraceae) in Mexico, from Huitzquilitl to Cardo Santo: History, ethnomedicine, pharmacology and chemistry.
    Silvia Laura Guzmán-Gutiérrez, Ricardo Reyes-Chilpa, Laura Rigel González-Diego, Mayra Silva-Miranda, Alfredo López-Caamal, Karla Paola García-Cruz, María Sofía Jiménez-Mendoza, Amira Arciniegas, Clara Espitia.
       ETHNOPHARMACOLOGICAL RELEVANCE: Several medicinal plants, including the endemic herb Cirsum ehrenbergii (Asteraceae), have been documented in manuscripts, medical and botanical books written in Mexico since the XVI century until the present. This unique circumstance is a real window in the time that allows to investigate historical and contemporary ethnopharmacological knowledge.
    AIM OF THE STUDY: To examine the persistence, disappearance, and transformation of ethnomedicinal knowledge of C. ehrenbergii along time. To investigate the chemistry and pharmacology of this species in relation to its historical and present day main ethnomedical applications related to Central Nervous System and inflammation.
    MATERIALS AND METHODS: A thorough review was performed of written sources of medicinal plants from XVI and onwards. For the pharmacological studies, the organic extracts were tested in mice models to assess its anti-depressant and anti-inflammatory properties. The active extracts were studied chemically. The isolated compounds were identified by 1H, 13C NMR, or characterized by GC-MS.
    RESULTS: Cirsum ehrenbergii was illustrated for the first time (1552) in the Libellus de Medicinalibus Indorum Herbis (Booklet of Medicinal Plants of the Indians) and named in the Nahuatl native language as Huitzquilitl (edible thistle). It was there recommended as nigris sanguinis remedium (remedy for black blood), and for the treatment of illnesses with an inflammatory component. Nigris sanguinis was well known in the European medicine of that time and currently it has been interpreted as "depression". At the present time, peasants and native population in Mexico mainly name C. ehrenbergii in Spanish as Cardo Santo (holy thistle). Its original Nahuatl name has been almost forgotten. However, these communities use this species, among other maladies, to heal "nervios" (anxiety and/or depression) and for anti-inflammatory purposes. These ailments and treatments resemble those recorded in the Libellus and along centuries in several medicinal plant books. The ethanol extract of Cirsium ehrenbergii roots showed antidepressant-like activity in mice administered at 300 mg/kg, as indicated by the forced swim test (FST). The glycosylated flavonoid Linarin was identified as antidepressant principle and was active at the doses of 30 and 60 mg/kg in the FST. Regarding to anti-inflammatory activity, the most active was the methylene chloride extract of the aerial parts, which contains taraxasterol, β-sitosterol and stigmasterol.
    CONCLUSIONS: Cirsium ehrenbergii extracts possess antidepressant (roots, EtOH) and anti-inflammatory (aerial parts, CH2Cl2) properties, containing active compounds. Our results sustain historical and present day ethnomedical applications of this species documented along five centuries.
    Keywords:  Anti-depressant like activity; Anti-inflammatory activity; Cirsium ehrenbergii; Historical ethnopharmacology; Linarin
    DOI:  https://doi.org/10.1016/j.jep.2022.115778
  152. J Oleo Sci. 2022 ;71(10): 1469-1480
    Anti-HMG-CoA Reductase, Anti-diabetic, Anti-urease, Anti-tyrosinase and Anti-leukemia Cancer Potentials of Panicolin as a Natural Compound:In vitro and in silico Study.
    Ling Li, Xiyue Song, Meng Ouyang, Attalla F El-Kott, Mutasem Z Bani-Fwaz, Zebing Yu.
      Flavonoid compounds are a group of polyphenolic molecules that are in vegetables, fruit, and grain. Laboratory studies and epidemiological investigations have indicated diverse beneficial biochemical properties of flavonoids, including anticancer, anti-inflammation, anti-oxidation, and anti-osteoporosis. We have recorded results for the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) Reductase and urease enzymes at the µM level. In this search, inhibition results of Panicolin on HMG-CoA reductase and tyrosinase enzymes recorded lower values of 113.98±14.38 and 2.57±0.20 µg /mL, respectively. Additionally, inhibition results of Panicolin on urease and α-amylase showed good values of 64.20±7.43 and 15.92±2.81 µg/mL, respectively. The chemical activities of panicolin against α-amylase, urease, tyrosinase, and HMG-CoA reductase, were determined by performing the molecular modeling study. The anti-cancer activities of panicolin were investigated against HL-60, THP-1, K562, and Molt-4 cell lines and IC50 values of Panicolin on these cell lines were obtained 12.94±1.04, 63.17±5.81, 15.05±1.02, and 10.84±0.65 µg/mL, respectively. The chemical activities of this compound against some of the expressed surface receptor proteins (Platelet-activating factor receptor, CD13, transferrin receptor, and CD44) in the cell lines were evaluated using molecular modeling calculations. The results revealed the possible interactions and their features at an atomic level. The docking scores suggested that panicolin has a significant binding affinity to the enzymes and proteins. Moreover, this compound constructed strong contacts with the enzymes and receptors. Therefore, panicolin could be a potential inhibitor for enzymes and cancer cells.
    Keywords:   in silico study; HMG-CoA reductase; anti-leukemia; panicolin; surface receptor proteins
    DOI:  https://doi.org/10.5650/jos.ess22156
  153. Int J Biol Macromol. 2022 Sep 30. pii: S0141-8130(22)02189-4. [Epub ahead of print]
    Human serum albumin-poly(Lactide)-conjugated self-assembly NPs for targeted docetaxel delivery and improved therapeutic efficacy in oral cancer.
    Soniya Kumbham, Adrija Ghosh, Balaram Ghosh, Swati Biswas.
      Oral cancer is one of the most prevalent malignancies worldwide. Here, to prepare a biocompatible tumor-targeted nanoformulation capable of efficient loading of the hydrophobic drug, DTX, human serum albumin was conjugated to poly(lactide) at different HSA: PLA ratios (1:1, 2, 3). The HSA-(PLA)1-3 conjugates were physicochemically characterized by UV, IR, NMR, GPC, pyrene incorporation, and surface tension analysis. Next, the DTX-loaded DTX@HSA-(PLA)1-3 NPs were prepared by the desolvation-self-assembly technique, which was further optimized by DOE. The NPs were characterized by DLS, SEM, DSC, XRD, CD spectroscopy, SDS-PAGE, drug entrapment and loading efficiencies, kinetic stability, drug release, and hemolysis assays. Murine and human oral cancer cell lines, MOC2 and FaDu, were used in monolayers/multicellular spheroids to assess cellular uptake, the extent of cell viability, and apoptosis induction following NPs treatment. The DTX@HSA-(PLA)1-3 NPs were ~ 149-212 nm size range, drug entrapment, ~75-96 %, and loading efficiency, ~21-27 %. The selected DTX@HSA-(PLA)2 NPs showed time-dependent improved targetability towards cancer cells than HSA NPs, indicating the benefit of HSA polymerization in NPs internalization. A time-dependent decrease in cell viability was observed for both the cell lines with IC50 values, 7.12 ± 1.84 and 6.38 ± 1.63 μg/mL, for FaDu and MOC2 cell lines, respectively (48 h post-treatment). The DTX@ HSA-(PLA)2 NPs treatment induced higher apoptotic marker expressions, cell-cycle arrest in the G2/M-phase, DNA damage, and mitochondrial depolarization than free DTX and DTX@HSA NPs. Further, DTX@HSA-(PLA)2 NPs (iv) showed significantly reduced plasma clearance (p < 0.05) and volume of distribution (Vd) than DTX and DTX@HSA NPs. Therefore, the developed polyprotein NPs offer superior therapeutic effect due to their stable drug incorporation, improved cell internalization, and long circulation, revealing their potential as an effective nanomedicine for oral cancer treatment.
    Keywords:  Docetaxel; Human serum albumin; Nanoparticles; Oral cancer; Poly(lactide)
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.09.250
  154. PLoS One. 2022 ;17(10): e0274025
    Efficacy and acceptability of blue-wavelength light therapy for post-TBI behavioral symptoms: A systematic review and meta-analysis of randomized controlled trials.
    Karan Srisurapanont, Yanisa Samakarn, Boonyasit Kamklong, Phichayakan Siratrairat, Arina Bumiputra, Montita Jaikwang, Manit Srisurapanont.
       OBJECTIVE: Behavioral symptoms are common after traumatic brain injury (TBI), but their treatments remain unsatisfactory. This systematic review and meta-analysis compared the efficacy and acceptability between blue-wavelength light therapy (BWLT) and long-wavelength/no light therapy (LW/NLT) for post-TBI sleepiness, sleep disturbance, depressive symptoms, and fatigue.
    METHODS: This study included randomized controlled trials comparing the effects of BWLT and LW/NLT on post-TBI sleepiness, sleep disturbance, depression, or fatigue. We searched Pubmed, Embase, CINAHL, and Cochrane Central Register of Controlled of Trials on April 13, 2022. The revised tool for assessing the risk of bias in randomized trials was applied. We performed a frequentist pairwise meta-analysis using a random-effects model.
    RESULTS: Of 233 retrieved records, six trials (N = 278) were included in this meta-analysis. TBIs ranged from mild to severe, and the interventions were administered for a median of 35 days. Most trials delivered light therapy via lightboxes. Three trials had a high risk of bias. BWLT was significantly superior to LW/NLT in reducing sleep disturbance (5 trials; SMD = -0.63; 95% CI = -1.21 to -0.05; p = 0.03; I2 = 61%) and depressive symptoms (4 trials; SMD = -1.00; 95% CI = -1.62 to -0.38; p < 0.01; I2 = 56%). There were trends that BWLT was superior to LW/NLT in reducing sleepiness (6 trials; SMD = -0.92; 95% CI = -1.84 to 0.00; p = 0.05; I2 = 88%) and fatigue (4 trials; SMD = -1.44; 95% CI = -2.95 to 0.08; p = 0.06; I2 = 91%). All-cause dropout rates were not significantly different between groups.
    CONCLUSION: Limited and heterogenous evidence suggests that short-term BWLT is well accepted, has a large treatment effect on post-TBI depressive symptoms, and may have a moderate treatment effect on post-TBI sleep disturbance.
    DOI:  https://doi.org/10.1371/journal.pone.0274025
  155. Anticancer Res. 2022 Oct;42(10): 5027-5034
    Critique of Public Health Guidance for Vitamin D and Sun Exposure in the Context of Cancer and COVID-19.
    Reinhold Vieth.
      Official public health pronouncements about sun exposure and vitamin D can be summarized as follows: First, there is no such thing as a safe tan. Therefore, avoid exposing the skin to sunshine. Second, in the absence of sunshine, a daily intake of 800 IU/day (20 mcg/d) vitamin D or less is sufficient for the health needs of almost all members of the population. However, exposure of the skin to sunlight induces multiple mechanisms that lower blood pressure, while also initiating production of vitamin D, which is needed to produce a hormone that regulates multiple systems including the cellular biology that affects cancer mortality. Disease-prevention relationships point to a beneficial threshold for serum 25-hydroxyvitamin D [25(OH)D; the index of vitamin D nutrition] that is at least 75 nmol/l (30 ng/ml). To ensure the threshold for all adults, an average per-day minimum total input of vitamin D3 from sunshine/UVB exposure, and/or from food (natural food like fish or fortified food like milk), and/or vitamin supplementation of at least 4,000 IU/d (100 mcg/d) is required. Strong, although not Level-1, evidence indicates that the maintenance of that threshold will lower mortality overall, lower mortality from cancer, and lower the risk of certain other diseases such as respiratory infection and COVID-19.
    Keywords:  COVID-19; RDA; Recommended daily intake; clinical trial study design; evidence-based medicine; evolution; primary disease prevention; primate biology; public health; review; vitamin D toxicity
    DOI:  https://doi.org/10.21873/anticanres.16011
  156. Curr Stem Cell Res Ther. 2022 Oct 04.
    A bright horizon of intelligent targeted-cancer therapy: nanoparticles against breast cancer stem cells.
    Ahmad Vaez, Milad Abbasi, Leili Shabani, Esmat Azizipour, Mostafa Shafiee, Mohammad Ali Zare, Omid Rahbar, Arezo Azari, Ali Mohammad Amani, Ali Golchin.
      Breast cancer stem cells (BCSCs) are heterogeneous tumor-initiating cell subgroups of breast cancers that possess some stem cell markers and are sustained after chemotherapy. Due to BCSCs being sufficient for tumor relapse, and given that the biological behaviors of BCSCs are so complex, it is critical to figure out exactly how they work, learn more about their cell biology, and discover biomarkers and strategies for explicitly targeting and destructing cancer stem cells. In order to accomplish innovative treatment for breast cancer, it is also essential to target BCSCs. Despite the vast quantities of BCSC target chemicals, their therapeutic implementation is limited due to off-target behavior and bioavailability issues. Targeted drug delivery systems based on nanoparticles have advantages for transporting anti-BCSC materials, especially to targeted locations. Hence, breast cancer therapy using a nanoparticle-based BCSCs targeting system is a promising strategy. Such targeted drug delivery systems can resolve the biodistribution obstacles of nanosystems. Throughout this paper, we highlight various strategies for targeting BCSCs utilizing nano-based systems. In conclusion, issues about the inadequate stability of nanoparticles and the possibility for loaded drug leakage during delivery systems have yet to be answered. More fundamental and applied research is required, and proper methods such as coating or surface modification.
    Keywords:  Breast cancer stem cells; Cancer treatment; Nanoparticles; Targeted Therapy
    DOI:  https://doi.org/10.2174/1574888X17666221004105330
  157. Food Res Int. 2022 Nov;pii: S0963-9969(22)00909-7. [Epub ahead of print]161 111851
    Enzymatic synthesis of ascorbyl oleate and evaluation of biological activities.
    Karine Angélica Dalla Costa, Amanda Santa Catarina, Ivana Correa Ramos Leal, Plínio Cunha Sathler, Débora de Oliveira, Alana Agnes Silva Camargo de Oliveira, Rogério Luis Cansian, Rogério Marcos Dallago, Jamile Zeni, Natalia Paroul.
      Compounds that reduce or neutralize free radicals have been evaluated for use as nutraceutical or antioxidant additives in processed foods. This study aimed to enzymatically produce ascorbyl oleate and assess its biological properties. The synthesis was performed under previously maximized conditions (L-ascorbic acid/oleic acid 1:9 molar ratio, 70 °C, 1 h reaction). Immobilized commercial lipase from Candida antarctica (NS 88011) was used as biocatalyst. The reaction product was isolated, and its structure was confirmed by High-Performance Liquid Chromatography and Nuclear Magnetic Resonance. Ascorbyl oleate showed antioxidant and antimicrobial activity, besides no toxicity, did not influencing blood coagulation and also not presenting hemolytic profile. Better storage stability was achieved under refrigerated conditions, and the oxidative stability demonstrated free radicals fighting efficiency, increasing olive oil's shelf life. In vitro gastrointestinal simulation showed that ascorbyl oleate maintained antioxidant potential up to the duodenum stage during the digestive process. Therefore, the synthesized natural compound presented a high potential to be applied in the food and pharmaceutical industries.
    Keywords:  Antioxidant; Biocatalysis; Gastrointestinal digestion; Lipid oxidation
    DOI:  https://doi.org/10.1016/j.foodres.2022.111851
  158. Cureus. 2022 Aug;14(8): e28496
    A Systematic Review of Apoptosis in Correlation With Cancer: Should Apoptosis Be the Ultimate Target for Cancer Treatment?
    Abdelrahman Abaza, Advait M Vasavada, Akhil Sadhu, Carla Valencia, Hameeda Fatima, Ijeoma Nwankwo, Mahvish Anam, Shrinkhala Maharjan, Zainab Amjad, Safeera Khan.
      Targeting apoptosis in cancer therapy has become increasingly popular, and there has been an increasing debate on whether apoptosis should be one of the main targets of therapy in cancer management. This study demonstrates the definition of apoptosis, the signaling pathways, and the pathogenesis behind it. We also show the correlation between apoptosis and cancer and how cancer can evade apoptosis to develop resistance to therapy. In addition, we illustrate the efficacy of adding pro-apoptotic therapy to conventional radio-chemotherapy cancer treatment. A systematic review was conducted using PubMed, PubMed Central (PMC), and ResearchGate, including papers written in English, focusing on adult and geriatric populations, in literature reviews, systematic reviews, and randomized controlled trials published in the last 25 years with relevance to the question. Based on the findings of this review, we conclude that apoptosis is a very sophisticated programmed cellular death with many signaling pathways. Its evasion should be considered one of the hallmarks of cancer and is responsible for multiple drug resistance (MDR) to cancer therapy. Targeting apoptosis seems promising, especially if combined with radio-chemotherapy.
    Keywords:  anti-apoptotic therapy; apoptosis; cancer; multiple drug resistance; regulated cell death
    DOI:  https://doi.org/10.7759/cureus.28496
  159. World J Diabetes. 2022 Sep 15. 13(9): 765-775
    Role of insulin in pancreatic microcirculatory oxygen profile and bioenergetics.
    Bing-Wei Li, Yuan Li, Xu Zhang, Sun-Jing Fu, Bing Wang, Xiao-Yan Zhang, Xue-Ting Liu, Qin Wang, Ai-Ling Li, Ming-Ming Liu.
       BACKGROUND: The pancreatic islet microcirculation adapts its metabolism to cope with limited oxygen availability and nutrient delivery. In diabetes, the balance between oxygen delivery and consumption is impaired. Insulin has been proven to exert complex actions promoting the maintenance of homeostasis of the pancreas under glucotoxicity.
    AIM: To test the hypothesis that insulin administration can improve the integrated pancreatic microcirculatory oxygen profile and bioenergetics.
    METHODS: The pancreatic microcirculatory partial oxygen pressure (PO2), relative hemoglobin (rHb) and hemoglobin oxygen saturation (SO2) were evaluated in nondiabetic, type 1 diabetes mellitus (T1DM), and insulin-treated mice. A three-dimensional framework was generated to visualize the microcirculatory oxygen profile. Ultrastructural changes in the microvasculature were examined using transmission electron microscopy. An Extracellular Flux Analyzer was used to detect the real-time changes in bioenergetics by measuring the oxygen consumption rate and extracellular acidification rate in islet microvascular endothelial cells (IMECs).
    RESULTS: Significantly lower PO2, rHb, and SO2 values were observed in T1DM mice than in nondiabetic controls. Insulin administration ameliorated the streptozotocin-induced decreases in these microcirculatory oxygen parameters and improved the mitochondrial ultrastructural abnormalities in IMECs. Bioenergetic profiling revealed that the IMECs did not have spare respiratory capacity. Insulin-treated IMECs exhibited significantly greater basal respiration than glucotoxicity-exposed IMECs (P < 0.05). An energy map revealed increased energetic metabolism in insulin-treated IMECs, with significantly increased ATP production, non-mitochondrial respiration, and oxidative metabolism (all P < 0.05). Significant negative correlations were revealed between microcirculatory SO2 and bioenergetic parameters.
    CONCLUSION: Glucotoxicity deteriorates the integrated pancreatic microcirculatory oxygen profile and bioenergetics, but this deterioration can be reversed by insulin administration.
    Keywords:  Bioenergetics; Diabetes mellitus; Endothelial cells; Glucotoxicity; Microcirculation; Mitochondria
    DOI:  https://doi.org/10.4239/wjd.v13.i9.765
  160. North Clin Istanb. 2022 ;9(3): 235-240
    Relationship between Vitamin D level and metabolic parameters in obese children and response to Vitamin D treatment.
    Dilek Damla Saymazlar, Ozlem Kara, Betul Biner Orhaner.
       OBJECTIVE: Vitamin D deficiency is common in children. The effects of Vitamin D on bone health are well-known. However, its effect on glucose and lipid metabolism in obese children remains controversial. This study projected to evaluate the association between Vitamin D level and glucose, lipid, and bone metabolism parameters in obese children. In addition, the objective of the study was to determine the change in insulin resistance after Vitamin D replacement therapy in obese children with Vitamin D deficiency.
    METHODS: Hundred fifty children with obesity were included in our retrospective cross-sectional study. The patients were separated into two groups as the study group (serum 25(OH)D level <20 ng/ml) and the control group (serum 25(OH)D level ≥20 ng/ml). Physical examination, body fat mass, and laboratory findings of the two groups were compared. Moreover, patients in the study group were supplemented with Vitamin D 2000 IU/d for 24 weeks. Glucose, insulin levels were analyzed before and after treatment.
    RESULTS: Body fat mass and percentage were evaluated as more raised in the study group than those in the control group. The study group had a higher level of insulin resistance. There was a significant loss in body weight of patients after treatment in the study group and insulin resistance of the study group decreased after Vitamin D3 treatment.
    CONCLUSION: Considering the low side effects and affordability of Vitamin D, it would be a reasonable approach to identify serum Vitamin D levels in obese children and to administer a treatment to those with Vitamin D deficiency.
    Keywords:  Insulin resistance; Vitamin D deficiency; obesity
    DOI:  https://doi.org/10.14744/nci.2021.15870
  161. Clin Transl Imaging. 2022 Sep 29. 1-18
    Aerosolised micro and nanoparticle: formulation and delivery method for lung imaging.
    Miftakul Munir, Herlan Setiawan, Rohadi Awaludin, Vicky L Kett.
       Purpose: The application of contrast and tracing agents is essential for lung imaging, as indicated by the wide use in recent decades and the discovery of various new contrast and tracing agents. Different aerosol production and pulmonary administration methods have been developed to improve lung imaging quality. This review details and discusses the ideal characteristics of aerosol administered via pulmonary delivery for lung imaging and the methods for the production and pulmonary administration of dry or liquid aerosol.
    Methods: We explored several databases, including PubMed, Scopus, and Google Scholar, while preparing this review to discover and obtain the abstracts, reports, review articles, and research papers related to aerosol delivery for lung imaging and the formulation and pulmonary delivery method of dry and liquid aerosol. The search terms used were "dry aerosol delivery", "liquid aerosol delivery", "MRI for lung imaging", "CT scan for lung imaging", "SPECT for lung imaging", "PET for lung imaging", "magnetic particle imaging", "dry powder inhalation", "nebuliser", and "pressurised metered-dose inhaler".
    Results: Through the literature review, we found that the critical considerations in aerosol delivery for lung imaging are appropriate lung deposition of inhaled aerosol and avoiding toxicity. The important tracing agent was also found to be Technetium-99m (99mTc), Gallium-68 (68Ga) and superparamagnetic iron oxide nanoparticle (SPION), while the essential contrast agents are gold, iodine, silver gadolinium, iron and manganese-based particles. The pulmonary delivery of such tracing and contrast agents can be performed using dry formulation (graphite ablation, spark ignition and spray dried powder) and liquid aerosol (nebulisation, pressurised metered-dose inhalation and air spray).
    Conclusion: A dual-imaging modality with the combination of different tracing or contrast agents is a future development of aerosolised micro and nanoparticles for lung imaging to improve diagnosis success.
    Graphical abstract:
    Keywords:  Aerosol; Lung imaging; Micro- or nanoparticle; Pulmonary delivery
    DOI:  https://doi.org/10.1007/s40336-022-00527-3
  162. Food Chem. 2022 Sep 21. pii: S0308-8146(22)02306-8. [Epub ahead of print]403 134344
    Preparation, properties and interaction of curcumin loaded zein/HP-β-CD nanoparticles based on electrostatic interactions by antisolvent co-precipitation.
    Zhiheng Zhang, Xiaojing Li, Shangyuan Sang, David Julian McClements, Long Chen, Jie Long, Aiquan Jiao, Zhengyu Jin, Chao Qiu.
      In this study, zein/hydroxypropyl-beta-cyclodextrin nanoparticles (ZHNPs) were synthesized using a combination of antisolvent co-precipitation and electrostatic attraction. The structural and physicochemical properties of the NPs were characterized using a variety of analytical methods. NPs with small mean diameters (143.6 nm) and strong cationic surface potentials (+62.1 mV) could be obtained at a mass ratio of zein-to-HP-β-CD of 1:1. These NPs were then used to encapsulate a model hydrophobic nutraceutical, curcumin. The results of zeta-potential, Fourier-transform infrared spectroscopy, X-ray diffractometry, and fluorescence spectroscopy measurements suggested that electrostatic, hydrogen bonding, and hydrophobic interactions were the main driving forces for NPs formation and curcumin encapsulation. The NPs had a relatively high encapsulation efficiency (89.41 %) for curcumin and improved its antioxidant activity (3.6-fold that of free curcumin) and photostability. Consequently, they could be used as effective food-grade delivery systems for low water-soluble bioactive substances.
    Keywords:  Bioactive molecules; Bioavailability; Delivery system; Hydroxypropyl-beta-cyclodextrin; Interaction; Plant proteins
    DOI:  https://doi.org/10.1016/j.foodchem.2022.134344
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