bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2022–01–23
155 papers selected by
Yasmin Elkabani, Egyptian Foundation for Research and Community Development
  1. Prospects of Curcumin Nanoformulations in Cancer Management.
  2. Construction and evaluation of curcumin upconversion nanocarriers decorated with MnO2 for tumor photodynamic therapy.
  3. Binary dimeric prodrug nanoparticles for self-boosted drug release and synergistic chemo-photodynamic therapy.
  4. Multifunctional MnO2/Ag3SbS3 Nanotheranostic Agent for Single-Laser-Triggered Tumor Synergistic Therapy in the NIR-II Biowindow.
  5. Nanodiamond-based multifunctional platform for oral chemo-photothermal combinational therapy of orthotopic colon cancer.
  6. Design and Characterisation of pH-Responsive Photosensitiser-Loaded Nano-Transfersomes for Enhanced Photodynamic Therapy.
  7. Near-Infrared Light-Triggered Generation of Reactive Oxygen Species and Induction of Local Hyperthermia from Indocyanine Green Encapsulated Mesoporous Silica-Coated Graphene Oxide for Colorectal Cancer Therapy.
  8. Calorie Restriction for Cancer Prevention and Therapy: Mechanisms, Expectations, and Efficacy.
  9. Resveratrol as a modulatory of apoptosis and autophagy in cancer therapy.
  10. Melittin-Based Nano-Delivery Systems for Cancer Therapy.
  11. Silica-Based Stimuli-Responsive Systems for Antitumor Drug Delivery and Controlled Release.
  12. Methylglyoxal induces ambience for cancer promotion in HepG2 cells via Warburg effect and promotes glycation.
  13. NIR and Reduction Dual-Sensitive Polymeric Prodrug Nanoparticles for Bioimaging and Combined Chemo-Phototherapy.
  14. Glycol chitosan/iron oxide/polypyrrole nanoclusters for precise chemodynamic/photothermal synergistic therapy.
  15. NIR-II Fluorescent Activatable Drug Delivery Nanoplatform for Cancer-Targeted Combined Photodynamic and Chemotherapy.
  16. Mitochondria-targeting multifunctional nanoplatform for cascade phototherapy and hypoxia-activated chemotherapy.
  17. Metformin inhibits the tumor-promoting effect of low-dose resveratrol, and enhances the anti-tumor activity of high-dose resveratrol by increasing its reducibility in triple negative breast cancer.
  18. The Role of Rosmarinic Acid on the Bioproduction of Gold Nanoparticles as Part of a Photothermal Approach for Breast Cancer Treatment.
  19. Revisiting the Oxidation of Flavonoids: Loss, Conservation or Enhancement of Their Antioxidant Properties.
  20. Polyoxometalate Modified by Zeolite Imidazole Framework for the pH-Responsive Electrodynamic/Chemodynamic Therapy.
  21. Ultrasound controlled mechanophore activation in hydrogels for cancer therapy.
  22. Engineering Nanoplatform for Combined Cancer Therapeutics via Complementary Autophagy Inhibition.
  23. Curcumin and Weight Loss: Does It Work?
  24. Advances in metformin‑based metabolic therapy for non‑small cell lung cancer (Review).
  25. Repurposing Artemisinin and its Derivatives as Anticancer Drugs: A Chance or Challenge?
  26. Influence of Olive Oil and Its Components on Breast Cancer: Molecular Mechanisms.
  27. From Microenvironment Remediation to Novel Anti-Cancer Strategy: The Emergence of Zero Valent Iron Nanoparticles.
  28. Combinatorial Therapeutic Approaches with Nanomaterial-Based Photodynamic Cancer Therapy.
  29. Progress on the Application of Bortezomib and Bortezomib-Based Nanoformulations.
  30. Glucose Limitation Sensitizes Cancer Cells to Selenite-Induced Cytotoxicity via SLC7A11-Mediated Redox Collapse.
  31. An active-passive strategy for enhanced synergistic photothermal-ferroptosis therapy in the NIR-I/II biowindows.
  32. Combined and targeted drugs delivery system for colorectal cancer treatment: Conatumumab decorated, reactive oxygen species sensitive irinotecan prodrug and quercetin co-loaded nanostructured lipid carriers.
  33. Organic Nanoparticles Based on D-A-D Small Molecule: Self-Assembly, Photophysical Properties, and Synergistic Photodynamic/Photothermal Effects.
  34. Transforming Tea Catechins into Potent Anticancer Compound: Analysis of Three Boronated-PEG Delivery System.
  35. Anticancer properties of medicinal plants and their bioactive compounds against breast cancer: a review on recent investigations.
  36. Metabolic Adaptions/Reprogramming in Islet Beta-Cells in Response to Physiological Stimulators-What Are the Consequences.
  37. Novel ROS-responsive marine biomaterial fucoidan nanocarriers with AIE effect and chemodynamic therapy.
  38. Can Polyphenols Inhibit Ferroptosis?
  39. Therapeutic potential of flavonoids in cancer: ROS-mediated mechanisms.
  40. Combining Nanocarrier-Assisted Delivery of Molecules and Radiotherapy.
  41. Drug Delivery Based on Stimuli-Responsive Injectable Hydrogels for Breast Cancer Therapy: A Review.
  42. Chitosan Nanoparticle-Based System: A New Insight into the Promising Controlled Release System for Lung Cancer Treatment.
  43. Nanocarrier System for Increasing the Therapeutic Efficacy of Oxaliplatin.
  44. Curcumin suppresses tumorigenesis by ferroptosis in breast cancer.
  45. Gold-Polymer Nanocomposites for Future Therapeutic and Tissue Engineering Applications.
  46. Recent advances in multifunctional nanomaterials for photothermal-enhanced Fenton-based chemodynamic tumor therapy.
  47. Enzyme-Activated Multifunctional Prodrug Combining Site-Specific Chemotherapy with Light-Triggered Photodynamic Therapy.
  48. The path to the clinic: a comprehensive review on direct KRASG12C inhibitors.
  49. A tumor microenvironment-responsive poly(amidoamine) dendrimer nanoplatform for hypoxia-responsive chemo/chemodynamic therapy.
  50. Combined Antitumor Therapy Using In Situ Injectable Hydrogels Formulated with Albumin Nanoparticles Containing Indocyanine Green, Chlorin e6, and Perfluorocarbon in Hypoxic Tumors.
  51. Enzyme-Responsive Amphiphilic Peptide Nanoparticles for Biocompatible and Efficient Drug Delivery.
  52. Current Advances in Coptidis Rhizoma for Gastrointestinal and Other Cancers.
  53. Engineering Cellular Membrane for Dual Mode Therapy Using NIR Responsive Photosensitizer and Reversible Topoisomerase Inhibition Activity.
  54. An Up-to-Date Review of Natural Nanoparticles for Cancer Management.
  55. Calcium Phosphate-Based Bioceramics in the Treatment of Osteosarcoma: Drug Delivery Composites and Magnetic Hyperthermia Agents.
  56. Nanofiber Systems as Herbal Bioactive Compounds Carriers: Current Applications in Healthcare.
  57. Copper-induced tumor cell death mechanisms and antitumor theragnostic applications of copper complexes.
  58. Synthesis of sialic acid conjugates of the clinical near-infrared dye as next-generation theranostics for cancer phototherapy.
  59. Peptide-based semiconducting polymer nanoparticles for osteosarcoma-targeted NIR-II fluorescence/NIR-I photoacoustic dual-model imaging and photothermal/photodynamic therapies.
  60. A self-amplified ROS-responsive chemodrug-inhibitor conjugate for multi-drug resistance tumor therapy.
  61. A "Valve-Closing" Starvation Strategy for Amplification of Tumor-Specific Chemotherapy.
  62. Dynamic Adjust of Non-Radiative and Radiative Attenuation of AIE Molecules Reinforces NIR-II Imaging Mediated Photothermal Therapy and Immunotherapy.
  63. The Potential Applications of Stem Cells for Cancer Treatment.
  64. Interactions of Analgesics with Cisplatin: Modulation of Anticancer Efficacy and Potential Organ Toxicity.
  65. Amplifying Free Radical Generation of AIE Photosensitizer with Small Singlet-Triplet Splitting for Hypoxia-Overcoming Photodynamic Therapy.
  66. Design of Magnetic Nanoplatforms for Cancer Theranostics.
  67. Diet-derived small molecules (nutraceuticals) inhibit cellular proliferation by interfering with key oncogenic pathways: an overview of experimental evidence in cancer chemoprevention.
  68. Alpha-solanine anti-tumor effects in non-small cell lung cancer through regulating the energy metabolism pathway.
  69. The Pivotal Role of Oleuropein in the Anti-Diabetic Action of the Mediterranean Diet: A Concise Review.
  70. Withanolides, the hidden gem in Physalis minima: A mini review on their anti-inflammatory, anti-neuroinflammatory and anti-cancer effects.
  71. Modified chitosan-hyaluronic acid based hydrogel for the pH-responsive Co-delivery of cisplatin and doxorubicin.
  72. Hepatorenal protective effect of nano-curcumin against nano‑copper oxide-mediated toxicity in rats: Behavioral performance, antioxidant, anti-inflammatory, apoptosis, and histopathology.
  73. Recent Advances in Strategies for Addressing Hypoxia in Tumor Photodynamic Therapy.
  74. Nfe2l2 Regulates Metabolic Rewiring and Epigenetic Reprogramming in Mediating Cancer Protective Effect by Fucoxanthin.
  75. Applications of Chitosan-Alginate-Based Nanoparticles-An Up-to-Date Review.
  76. Curcuminoid Co-Loading Platinum Heparin-Poloxamer P403 Nanogel Increasing Effectiveness in Antitumor Activity.
  77. Bacteria-Assisted Transport of Nanomaterials to Improve Drug Delivery in Cancer Therapy.
  78. Molybdenum Diphosphide Nanorods with Laser-Potentiated Peroxidase Catalytic/Mild-Photothermal Therapy of Oral Cancer.
  79. A Breakthrough Brought about by Targeting KRASG12C: Nonconformity Is Punished.
  80. Ratiometric co-delivery of doxorubicin and paclitaxel prodrug by remote-loading liposomes for the treatment of triple-negative breast cancer.
  81. Polymeric Nanoshell-Stabilized Liquid Metal for Bactericidal Photonanomedicine.
  82. Antidiabetic potential of seaweed and their bioactive compounds: a review of developments in last decade.
  83. An Urchin-Shaped Copper-Based Metalloporphyrin Nanosystem as a Sonosensitizer for Sonodynamic Therapy.
  84. Study on the stability and oral bioavailability of curcumin loaded (-)-epigallocatechin-3-gallate/poly(N-vinylpyrrolidone) nanoparticles based on hydrogen bonding-driven self-assembly.
  85. Celecoxib-Loaded Solid Lipid Nanoparticles for Colon Delivery: Formulation Optimization and In Vitro Assessment of Anti-Cancer Activity.
  86. Multifunctional Iron Oxide Magnetic Nanoparticles for Biomedical Applications: A Review.
  87. Anti-VEGFR2-labeled Enzyme-Immobilized Metal-Organic Frameworks for Tumor Vasculature Targeted Catalytic Therapy.
  88. Induction of Paraptotic Cell Death in Breast Cancer Cells by a Novel Pyrazolo[3,4-h]quinoline Derivative through ROS Production and Endoplasmic Reticulum Stress.
  89. In situ polydopamine functionalized poly-L-lactic acid nanofibers with near-infrared-triggered antibacterial and reactive oxygen species scavenging capability.
  90. Engineering nanomedicines to inhibit hypoxia-inducible Factor-1 for cancer therapy.
  91. Biomineralized synthesis of palladium nanoflowers for photothermal treatment of cancer and wound healing.
  92. Sex differences in vitamin D metabolism, serum levels and action.
  93. Hollow Mesoporous Manganese Oxides: Application in Cancer Diagnosis and Therapy.
  94. Nano-Nutraceuticals Dietary Supplements for Athletes: An Eminent Approach for Managing Traumatic Brain Injuries.
  95. Preparation of Curcumin Hydrogel Beads for the Development of Functional Kulfi: A Tailoring Delivery System.
  96. Human lactate dehydrogenase A undergoes allosteric transitions under pH conditions inducing the dissociation of the tetrameric enzyme.
  97. Enhanced photothermal heating and combination therapy of NIR dye via conversion to self-assembled ionic nanomaterials.
  98. Rewired Cellular Metabolic Profiles in Response to Metformin under Different Oxygen and Nutrient Conditions.
  99. Co-Delivery of Letrozole and Cyclophosphamide via Folic Acid-Decorated Nanoniosomes for Breast Cancer Therapy: Synergic Effect, Augmentation of Cytotoxicity, and Apoptosis Gene Expression.
  100. Epigallocatechin 3-gallate: From green tea to cancer therapeutics.
  101. Cancer Therapy by Silver Nanoparticles: Fiction or Reality?
  102. Novel Selectively Targeted Multifunctional Nanostructured Lipid Carriers for Prostate Cancer Treatment.
  103. Metabolic Reprogramming of Glioblastoma Cells during HCMV Infection Induces Secretome-Mediated Paracrine Effects in the Microenvironment.
  104. The Role of Diet in Prognosis among Cancer Survivors: A Systematic Review and Meta-Analysis of Dietary Patterns and Diet Interventions.
  105. Development of Pharmaceutical Nanomedicines: From the Bench to the Market.
  106. Aerobic Glycolysis: A DeOxymoron of (Neuro)Biology.
  107. Treatment Strategies Against Triple-Negative Breast Cancer: An Updated Review.
  108. Ketogenic diet for human diseases: the underlying mechanisms and potential for clinical implementations.
  109. Role of Sulphur and Heavier Chalcogens on the Antioxidant Power and Bioactivity of Natural Phenolic Compounds.
  110. pH-Responsive Liposomes of Dioleoyl Phosphatidylethanolamine and Cholesteryl Hemisuccinate for the Enhanced Anticancer Efficacy of Cisplatin.
  111. Enhanced Anticancer Efficacy of Chemotherapy by Amphiphilic Y-Shaped Polypeptide Micelles.
  112. Targeting Cancer Metabolism Plasticity with JX06 Nanoparticles via Inhibiting PDK1 Combined with Metformin for Endometrial Cancer Patients with Diabetes.
  113. Hypoxia-Inducible Factors in Cancer.
  114. Reflections on drug resistance to KRASG12C inhibitors and gene silencing/editing tools for targeting mutant KRAS in cancer treatment.
  115. Tumor Microenvironment pH-Responsive Pentagonal Gold Prism-Based Nanoplatform for Multimodal Imaging and Combined Therapy of Castration-Resistant Prostate Cancer.
  116. Potential anti-inflammatory effects of legumes - A review.
  117. An Overview of Alkylresorcinols Biological Properties and Effects.
  118. Computational Modeling of Combination of Magnetic Hyperthermia and Temperature-Sensitive Liposome for Controlled Drug Release in Solid Tumor.
  119. Betulinic acid self-assembled nanoparticles for effective treatment of glioblastoma.
  120. Synergistic Effect of Squalene and Hydroxytyrosol on Highly Invasive MDA-MB-231 Breast Cancer Cells.
  121. Tumor-targeted biomimetic nanoplatform precisely integrates photodynamic therapy and autophagy inhibition for collaborative treatment of oral cancer.
  122. A review on the applications of Traditional Chinese medicine polysaccharides in drug delivery systems.
  123. Molecular Engineering of Peptide-Drug Conjugates for Therapeutics.
  124. Macrophage-Mimic Hollow Mesoporous Fe-Based Nanocatalysts for Self-Amplified Chemodynamic Therapy and Metastasis Inhibition via Tumor Microenvironment Remodeling.
  125. An overview of the therapeutic effects of curcumin in reproductive disorders with a focus on the antiinflammatory and immunomodulatory activities.
  126. Folic Acid-Decorated β-Cyclodextrin-Based Poly(ε-caprolactone)-dextran Star Polymer with Disulfide Bond-Linker as Theranostic Nanoparticle for Tumor-Targeted MRI and Chemotherapy.
  127. Lemongrass Essential Oil Components with Antimicrobial and Anticancer Activities.
  128. Overcoming MDR by Associating Doxorubicin and pH-Sensitive PLGA Nanoparticles Containing a Novel Organoselenium Compound-An In Vitro Study.
  129. The Epithelial-Mesenchymal Transition at the Crossroads between Metabolism and Tumor Progression.
  130. Genetic Profile of Adenomatoid Odontogenic Tumor and Ameloblastoma. A Systematic Review.
  131. REDOX IMBALANCE INDUCES REMODELING OF GLUCOSE METABOLISM IN RHIPICEPHALUS MICROPLUS EMBRYONIC CELL LINE.
  132. Protective Efficacy of Spilanthes acmella Murr. Extracts and Bioactive Constituents in Neuronal Cell Death.
  133. Study on the Effect of Polymer Excipients on the Dispersibility, Interaction, Solubility, and Scavenging Reactive Oxygen Species of Myricetin Solid Dispersion: Experiment and Molecular Simulation.
  134. Applications of Extracellular Vesicles in Triple-Negative Breast Cancer.
  135. Abundance and Metabolism Disruptions of Intratumoral Microbiota by Chemical and Physical Actions Unfreeze Tumor Treatment Resistance.
  136. Corrigendum to "A dual fluorescent reverse targeting drug delivery system based on curcumin-loaded ovalbumin nanoparticles for allergy treatment" [Nanomedicine: Nanotechnology, Biology, and Medicine 16 (2019) 56-68/NANO 1908].
  137. Resveratrol inhibits the expression of RYR2 and is a potential treatment for pancreatic cancer.
  138. Nrf2-Related Therapeutic Effects of Curcumin in Different Disorders.
  139. PKM2 Modulation in Head and Neck Squamous Cell Carcinoma.
  140. Roles and drug development of METTL3 (methyltransferase-like 3) in anti-tumor therapy.
  141. Mitochondria-mediated oxidative stress during viral infection.
  142. Cytotoxic effects of Garcinia mangostana pericarp extract in cancer cell lines.
  143. The Interconnected Mechanisms of Oxidative Stress and Neuroinflammation in Epilepsy.
  144. GMT8 aptamer conjugated PEGylated Ag@Au core-shell nanoparticles as a novel radiosensitizer for targeted radiotherapy of glioma.
  145. Phenolic-Rich Plant Extracts With Antimicrobial Activity: An Alternative to Food Preservatives and Biocides?
  146. A Review on Plants and Microorganisms Mediated Synthesis of Silver Nanoparticles, Role of Plants Metabolites and Applications.
  147. Comprehensive review on potential applications of microfluidization in food processing.
  148. Capsaicin ameliorate the nephrotoxicity induced by methotrexate.
  149. Nutrient timing and metabolic regulation symposium review from "Novel dietary approaches to appetite regulation, health and performance (2021)".
  150. Encapsulation of Curcumin in a Ternary Nanocomplex Prepared with Carboxymethyl Short Linear Glucan-Sodium-Caseinate-Pectin Via Electrostatic Interactions.
  151. Contribution of antimicrobial photo-sonodynamic therapy in wound healing: an in vivo effect of curcumin-nisin-based poly (L-lactic acid) nanoparticle on Acinetobacter baumannii biofilms.
  152. Metabolomics Coupled with Pathway Analysis Provides Insights into Sarco-Osteoporosis Metabolic Alterations and Estrogen Therapeutic Effects in Mice.
  153. The Intracellular and Extracellular Microenvironment of Tumor Site: The Trigger of Stimuli-Responsive Drug Delivery Systems.
  154. Targeted Delivery of Exosomes Armed with Anti-Cancer Therapeutics.
  155. Nanomedicine in Clinical Photodynamic Therapy for the Treatment of Brain Tumors.
  1. Molecules. 2022 Jan 07. pii: 361. [Epub ahead of print]27(2):
    Prospects of Curcumin Nanoformulations in Cancer Management.
    Hilda Amekyeh, Enas Alkhader, Rayan Sabra, Nashiru Billa.
      There is increasing interest in the use of natural compounds with beneficial pharmacological effects for managing diseases. Curcumin (CUR) is a phytochemical that is reportedly effective against some cancers through its ability to regulate signaling pathways and protein expression in cancer development and progression. Unfortunately, its use is limited due to its hydrophobicity, low bioavailability, chemical instability, photodegradation, and fast metabolism. Nanoparticles (NPs) are drug delivery systems that can increase the bioavailability of hydrophobic drugs and improve drug targeting to cancer cells via different mechanisms and formulation techniques. In this review, we have discussed various CUR-NPs that have been evaluated for their potential use in treating cancers. Formulations reviewed include lipid, gold, zinc oxide, magnetic, polymeric, and silica NPs, as well as micelles, dendrimers, nanogels, cyclodextrin complexes, and liposomes, with an emphasis on their formulation and characteristics. CUR incorporation into the NPs enhanced its pharmaceutical and therapeutic significance with respect to solubility, absorption, bioavailability, stability, plasma half-life, targeted delivery, and anticancer effect. Our review shows that several CUR-NPs have promising anticancer activity; however, clinical reports on them are limited. We believe that clinical trials must be conducted on CUR-NPs to ensure their effective translation into clinical applications.
    Keywords:  bioavailability; cancer; chemotherapy; curcumin; drug delivery; nanoparticles
    DOI:  https://doi.org/10.3390/molecules27020361
  2. Drug Deliv Transl Res. 2022 Jan 21.
    Construction and evaluation of curcumin upconversion nanocarriers decorated with MnO2 for tumor photodynamic therapy.
    Xinru Chen, Quandong Li, Zipeng Huang, Wen Lin, Yan Ma.
      The limited tissue penetration depth and tumor hypoxic microenvironment have become the two pivotal obstacles that alleviate the antineoplastic efficacy in tumor photodynamic therapy (PDT). In the research, MnO2-decorated upconversion nanoparticles (UCSMn) have been designed to generate certain oxygen within the solid tumor, and also increase the light penetrating depth due to the optical conversion ability derived from upconversion nanoparticles. Furthermore, upconversion nanoparticles as the inner core are coated by mesoporous silica for the loading of curcumin as photosensitizer and chemotherapeutics, and then a MnO2 shell is proceeding to grow via redox method. When reaching the tumor tissue, the MnO2 nanoshells of UCSMn could be rapidly degraded into manganese ions (Mn2+) owing to the reaction with H2O2 in acidic tumor microenvironment, meanwhile producing oxygen and facilitating curcumin release. Once the tumor is illuminated by 980 nm light, the upconversion nanoparticles can transform the infrared light to visible light of 450 nm and 475.5 nm, which can be efficiently absorbed by curcumin, and then produce singlet oxygen to induce tumor cell apoptosis. Curcumin played a dual role which can not only be acted as a photosensitizer, but also a chemotherapeutic agent to further reinforce the antitumor activity. In short, the intelligent nanostructure has the potential to overcome the above-mentioned shortcomings existed in PDT and eventually do work well in the hypoxia tumors. MnO2-decorated upconversion nanoparticle to solve the tissue penetration and tumor hypoxic microenvironment for tumor photodynamic therapy.
    Keywords:  Hypoxia; Manganese dioxide; Photodynamic therapy; Upconversion nanoparticles
    DOI:  https://doi.org/10.1007/s13346-022-01118-5
  3. J Mater Chem B. 2022 Jan 19.
    Binary dimeric prodrug nanoparticles for self-boosted drug release and synergistic chemo-photodynamic therapy.
    Youwei Zhang, Qing Pei, Ying Yue, Zhigang Xie.
      Chemotherapy is the major strategy for cancer therapy, but its limited therapeutic efficiency and serious toxicity to normal tissues greatly restrict its clinical performance. Herein, we develop carrier-free self-activated prodrug nanoparticles combining chemotherapy and photodynamic therapy to enhance the antitumor efficiency. Reactive oxygen species (ROS)-responsive paclitaxel and porphyrin prodrugs are synthesized and co-assembled into nanoparticles without the addition of any adjuvants, which improves the drug content and reduces carrier-associated toxicity. After entering cancer cells, the obtained co-assembled nanoparticles can generate sufficient ROS upon light irradiation not only for photodynamic therapy, but also triggering on-demand drug release for chemotherapy, thus realizing self-enhanced prodrug activation and synergistic chemo-photodynamic therapy. This simple and effective carrier-free prodrug nanoplatform unifies the distinct traits of on-demand drug release and combination therapy, thus possessing great potential in advancing cancer treatment.
    DOI:  https://doi.org/10.1039/d1tb02638k
  4. ACS Appl Mater Interfaces. 2022 Jan 20.
    Multifunctional MnO2/Ag3SbS3 Nanotheranostic Agent for Single-Laser-Triggered Tumor Synergistic Therapy in the NIR-II Biowindow.
    Qian Wang, Botao Qu, Juan Li, Yuqin Liu, Jie Dong, Xiaoyang Peng, Ruiping Zhang.
      Regulating the level of reactive oxygen species (ROS) in a tumor is an efficient and innovative anticancer strategy. However, the therapeutic efficacy of ROS-based therapies, such as chemodynamic therapy (CDT) and photodynamic therapy (PDT), offers finite outcomes due to the oxygen dependence and limited concentration of hydrogen peroxide (H2O2) and overexpression of glutathione (GSH) within the tumor microenvironment (TME), so a single therapeutic strategy is insufficient to completely eliminate tumors. Therefore, we demonstrated an omnipotent nanoplatform MnO2/Ag3SbS3 (abbreviated as MA) with strong optical absorbance in the NIR-II biowindow and oxygen self-sufficient ROS-mediated ability, which not only relieves tumor hypoxia significantly but also enhances the photothermal therapy (PTT)/PDT/CDT efficacy. By 1064 nm laser irradiation, MnO2/Ag3SbS3 nanoparticles (NPs) reveal a favorable photothermal conversion efficiency of 23.15% and achieve a single-laser-triggered NIR-II PTT/PDT effect, resulting in effective tumor elimination. Once internalized into the tumor, MnO2/Ag3SbS3 NPs will be degraded to Mn2+ and Ag3SbS3. The released Ag3SbS3 NPs as a NIR-II phototherapy agent could be utilized for photoacoustic imaging-guided NIR-II PDT/PTT. Mn2+ could be used as a Fenton-like catalyst to continuously catalyze endogenous H2O2 for generating highly virulent hydroxyl radicals (•OH) for CDT and O2 for PDT, enhancing the efficiency of PDT and CDT, respectively. Meanwhile, Mn2+ realizes magnetic resonance imaging-guided accurate tumor therapy. Moreover, the MnO2/Ag3SbS3 NPs could deplete intracellular GSH in TME to promote oxidative stress of the tumor, further strengthening ROS-mediated antitumor treatment efficacy. Overall, this work presents a distinctive paradigm of TME-responsive PDT/CDT/PTT in the second near-infrared biowindow by depleting GSH and decomposing H2O2 for efficient and precise cancer treatment.
    Keywords:  MnO2/Ag3SbS3 nanoparticles; NIR-II biowindow; TME-responsive; photoacoustic imaging; photodynamic therapy
    DOI:  https://doi.org/10.1021/acsami.1c21752
  5. Pharmacol Res. 2022 Jan 12. pii: S1043-6618(22)00025-1. [Epub ahead of print]176 106080
    Nanodiamond-based multifunctional platform for oral chemo-photothermal combinational therapy of orthotopic colon cancer.
    Yunjian Li, Yupei Su, Hao Pan, Wenbin Deng, Jiahui Wang, Dandan Liu, Weisan Pan.
      Combination therapy system has become a promising strategy for achieving favorable antitumor efficacy. Herein, a novel oral drug delivery system with colon localization and tumor targeting functions was designed for orthotopic colon cancer chemotherapy and photothermal combinational therapy. The polydopamine coated nanodiamond (PND) was used as the photothermal carrier, through the coupling of sulfhydryl-polyethylene glycol-folate (SH-PEG-FA) on the surface of PND to achieve systematic colon tumor targeting, curcumin (CUR) was loaded as the model drug, and then coated with chitosan (CS) to achieve the long gastrointestinal tract retention and colon localization functions to obtain PND-PEG-FA/CUR@CS nanoparticles. It has high photothermal conversion efficiency and good photothermal stability and exhibited near-infrared (NIR) laser-responsive drug release behavior. Folate (FA) modification effectively promotes the intracellular uptake of nanoparticles by CT26 cells, and the combination of chemotherapy and photothermal therapy (CT/PTT) can enhance cytotoxicity. Compared with free CUR group, nanoparticles prolonged the gastrointestinal tract retention time, accumulated more in colon tumor tissues, and exhibited good photothermal effect in vivo. More importantly, the CT/PTT group exhibited satisfactory tumor growth inhibition effects with good biocompatibility in vivo. In summary, this oral drug delivery system is an efficient platform for chemotherapy and photothermal combinational therapy of orthotopic colon cancer.
    Keywords:  Chemo-photothermal combinational therapy; Nanodiamond; Orthotopic colon cancer; Polydopamine
    DOI:  https://doi.org/10.1016/j.phrs.2022.106080
  6. Pharmaceutics. 2022 Jan 16. pii: 210. [Epub ahead of print]14(1):
    Design and Characterisation of pH-Responsive Photosensitiser-Loaded Nano-Transfersomes for Enhanced Photodynamic Therapy.
    Sooho Yeo, Il Yoon, Woo Kyoung Lee.
      Photodynamic therapy (PDT) is a non-invasive and tumour-specific therapy. Photosensitizers (PSs) (essential ingredients in PDT) aggregate easily owing to their lipophilic properties. The aim of this study was to synthesise a PS (methyl pheophorbide a, MPa) and design a biocompatible lipid-based nanocarrier to improve its bioavailability and pharmacological effects. MPa-loaded nano-transfersomes were fabricated by sonication. The characteristics of synthesised PS and nano-transfersomes were assessed. The effects of PDT were evaluated by 1,3-diphenylisobenzofuran assay and by measuring photo-cytotoxicity against HeLa and A549 cell lines. The mean particle size and zeta potential for nano-transfersomes ranged from 95.84 to 267.53 nm and -19.53 to -45.08 mV, respectively. Nano-transfersomes exhibited sustained drug release for 48 h in a physiological environment (as against burst release in an acidic environment), which enables its use as a pH-responsive drug release system in PDT with enhanced photodynamic activity and reduced side effects. The formulations showed light cytotoxicity, but no dark toxicity, which meant that light irradiation resulted in anti-cancer effects. Additionally, formulations with the smallest size exhibited photodynamic activity to a larger extent than those with the highest loading capacity or free MPa. These results suggest that our MPa-loaded nano-transfersome system is a promising anti-cancer strategy for PDT.
    Keywords:  anti-cancer therapy; nano-transfersomes; pH-responsive drug delivery system; photodynamic therapy; photosensitisers
    DOI:  https://doi.org/10.3390/pharmaceutics14010210
  7. Antioxidants (Basel). 2022 Jan 17. pii: 174. [Epub ahead of print]11(1):
    Near-Infrared Light-Triggered Generation of Reactive Oxygen Species and Induction of Local Hyperthermia from Indocyanine Green Encapsulated Mesoporous Silica-Coated Graphene Oxide for Colorectal Cancer Therapy.
    Hyung Woo Choi, Jae Hyun Lim, Chan Woo Kim, Eunmi Lee, Jin-Moo Kim, Kiyuk Chang, Bong Geun Chung.
      Near-infrared (NIR) light-mediated photothermal therapy (PTT) and photodynamic therapy (PDT) have widely been used for cancer treatment applications. However, a number of limitations (e.g., low NIR absorption capacity of photothermal agents, insufficient loading efficiency of photosensitive molecules) have hindered the widespread use of NIR-mediated cancer therapy. Therefore, we developed a mesoporous silica-coated reduced graphene oxide (rGO) nanocomposite that could provide a high encapsulation rate of indocyanine green (ICG) and enhance PTT/PDT efficiency in vitro and in vivo. The ICG-encapsulated nanocomposite not only enhances the photothermal effect but also generates a large number of tumor toxic reactive oxygen species (ROS). By conjugation of polyethylene glycol (PEG) with folic acid (FA) as a tumor targeting moiety, we confirmed that ICG-encapsulated mesoporous silica (MS)-coated rGO nanocomposite (ICG@MS-rGO-FA) exhibited high colloidal stability and intracellular uptake in folate receptor-expressing CT-26 colorectal cancer cells. Upon NIR laser irradiation, this ICG@MS-rGO-FA nanocomposite induced the apoptosis of only CT-26 cells via enhanced PTT and PDT effects without any damage to normal cells. Furthermore, the ICG@MS-rGO-FA nanocomposite revealed satisfactory tumor targeting and biocompatibility in CT-26 tumor-bearing mice, thereby enhancing the therapeutic effects of PTT and PDT in vivo. Therefore, this tumor-targeted ICG@MS-rGO-FA nanocomposite shows a great potential for phototherapy applications.
    Keywords:  indocyanine green; mesoporous silica; photothermal and photodynamic therapy; reduced graphene oxide; tumor targeting
    DOI:  https://doi.org/10.3390/antiox11010174
  8. J Cancer Prev. 2021 Dec 30. 26(4): 224-236
    Calorie Restriction for Cancer Prevention and Therapy: Mechanisms, Expectations, and Efficacy.
    Chiara Vidoni, Alessandra Ferraresi, Andrea Esposito, Chinmay Maheshwari, Danny N Dhanasekaran, Vincenzo Mollace, Ciro Isidoro.
      Cancer is one of the most frequently diagnosed diseases, and despite the continuous efforts in searching for new and more effective treatments, its morbidity and mortality remain a significant health problem worldwide. Calorie restriction, a dietary manipulation that consists in a reduction of the calorie intake, is gaining attention as a potential adjuvant intervention for preventing and/or fighting cancer. Several forms of energy reduction intake, which includes caloric restriction tout-court, dietary restrictions, and intermittent fasting, are being explored for their ability to prevent or slow down cancer progression. Additionally, another anti-cancer approach being under investigation relies on the use of nutraceuticals known as "Caloric Restriction Mimetics" that can provide caloric restriction-mediated benefits without subjecting the patients to a strict diet. Preclinical in vitro and in vivo studies consistently show that diet modifiers reducing the calorie have impact on tumor microenvironment and cancer metabolism, resulting in reduced growth and progression of cancer. Preliminary clinical studies show that patients subjected to a reduced nutrient/energy intake experience improved outcomes from chemo- and radiotherapy while better tolerating the side effects. Here, we review the state of the art on the therapeutic potential of calorie restriction and of caloric restriction mimetics in preventing or retarding tumor development by modulating a subset of cellular processes. The most recent clinical progresses with caloric restriction mimetics in the clinical practice are also discussed.
    Keywords:  Caloric restriction mimetics; Drug therapy; Ketogenic diet; Tumor microenvironment; Warburg effect
    DOI:  https://doi.org/10.15430/JCP.2021.26.4.224
  9. Clin Transl Oncol. 2022 Jan 17.
    Resveratrol as a modulatory of apoptosis and autophagy in cancer therapy.
    R Yang, H Dong, S Jia, Z Yang.
      Cancer is one of the leading causes of death, with a heavy socio-economical burden for countries. Despite the great advances that have been made in the treatment of cancer, chemotherapy is still the most common method of treatment. However, many side effects, including hepatotoxicity, renal toxicity, and cardiotoxicity, limit the efficacy of conventional chemotherapy. Over recent years, natural products have attracted attention as therapeutic agents against various diseases, such as cancer. Resveratrol (RES), a natural polyphenol occurring in grapes, nuts, wine, and berries, exhibited potential for preventing and treating various cancer types. RES also ameliorates chemotherapy-induced detrimental effects. Furthermore, RES could modulate apoptosis and autophagy as the main forms of cancer cell deaths by targeting various signaling pathways and up/downregulation of apoptotic and autophagic genes. This review will summarize the anti-cancer effects of RES and focus on the fundamental mechanisms and targets for modulating apoptosis and autophagy by RES.
    Keywords:  Apoptosis; Autophagy; Cancer; Cancer cell death; Resveratrol
    DOI:  https://doi.org/10.1007/s12094-021-02770-y
  10. Biomolecules. 2022 Jan 12. pii: 118. [Epub ahead of print]12(1):
    Melittin-Based Nano-Delivery Systems for Cancer Therapy.
    Anqi Wang, Yuan Zheng, Wanxin Zhu, Liuxin Yang, Yang Yang, Jinliang Peng.
      Melittin (MEL) is a 26-amino acid polypeptide with a variety of pharmacological and toxicological effects, which include strong surface activity on cell lipid membranes, hemolytic activity, and potential anti-tumor properties. However, the clinical application of melittin is restricted due to its severe hemolytic activity. Different nanocarrier systems have been developed to achieve stable loading, side effects shielding, and tumor-targeted delivery, such as liposomes, cationic polymers, lipodisks, etc. In addition, MEL can be modified on nano drugs as a non-selective cytolytic peptide to enhance cellular uptake and endosomal/lysosomal escape. In this review, we discuss recent advances in MEL's nano-delivery systems and MEL-modified nano drug carriers for cancer therapy.
    Keywords:  hemolysis; melittin; nano-delivery system; stable loading; tumor therapy
    DOI:  https://doi.org/10.3390/biom12010118
  11. Pharmaceutics. 2022 Jan 04. pii: 110. [Epub ahead of print]14(1):
    Silica-Based Stimuli-Responsive Systems for Antitumor Drug Delivery and Controlled Release.
    Avelino Corma, Pablo Botella, Eva Rivero-Buceta.
      The administration of cytotoxic drugs in classical chemotherapy is frequently limited by water solubility, low plasmatic stability, and a myriad of secondary effects associated with their diffusion to healthy tissue. In this sense, novel pharmaceutical forms able to deliver selectively these drugs to the malign cells, and imposing a space-time precise control of their discharge, are needed. In the last two decades, silica nanoparticles have been proposed as safe vehicles for antitumor molecules due to their stability in physiological medium, high surface area and easy functionalization, and good biocompatibility. In this review, we focus on silica-based nanomedicines provided with specific mechanisms for intracellular drug release. According to silica nature (amorphous, mesostructured, and hybrids) nanocarriers responding to a variety of stimuli endogenously (e.g., pH, redox potential, and enzyme activity) or exogenously (e.g., magnetic field, light, temperature, and ultrasound) are proposed. Furthermore, the incorporation of targeting molecules (e.g., monoclonal antibodies) that interact with specific cell membrane receptors allows a selective delivery to cancer cells to be carried out. Eventually, we present some remarks on the most important formulations in the pipeline for clinical approval, and we discuss the most difficult tasks to tackle in the near future, in order to extend the use of these nanomedicines to real patients.
    Keywords:  camptothecin; cancer therapy; controlled release; docetaxel; doxorubicin; drug delivery; silica nanoparticles; stimuli-responsive
    DOI:  https://doi.org/10.3390/pharmaceutics14010110
  12. J Cell Biochem. 2022 Jan 18.
    Methylglyoxal induces ambience for cancer promotion in HepG2 cells via Warburg effect and promotes glycation.
    C R Sruthi, K G Raghu.
      Methylglyoxal (MGO) is a toxic, highly reactive metabolite derived mainly from glucose and amino acids degradation. MGO is also one of the prime precursors for advanced glycation end products formation. The present research was performed to check whether MGO has any role in the promotion of cancer in HepG2 cells. For this, cells were incubated with MGO (50 µM) for 24 h and subjected to various analyses. Aminoguanidine (200 µM) was positive control. The various biochemical and protein expression studies, relevant to the MGO detoxification system, oxidative stress, and glycolysis were performed. MGO caused the reduction of expression of GLO 1 (27%) and GLO 2 (11%) causing weakening of the innate detoxification system. This is followed by an increase of RAGE (95%), AGEs or methylglyoxal adducts. We also observed hypoxia via estimation of oxygen consumption rate and surplus reactive oxygen species (ROS) (24%). To investigate the off-target effect of MGO we checked its effect on glucose transport, and its associated proteins. Glucose uptake was found to increase (15%) significantly with overexpression of GLUT 1 (35%). We also found a significant increase of glycolytic enzymes such as hexokinase II, phosphofructokinase 1, and lactate dehydrogenase along with lactate production. Observation of surplus ROS and enhanced glycolysis led us to check the expression of HIF 1α which is their downstream signaling pathway. Interestingly HIF 1α was found to increase significantly (35%). It is known that enhanced glycolysis and oxidative stress are catalysts for the overexpression of HIF 1α which in turn creates an ambience for the promotion of cancer. Aminoguanidine was able to prevent the adverse effect of MGO partially. This is the first study to show the potential of MGO for the promotion of cancer in the non-tumorigenic HepG2 cells via the Warburg effect and glycation.
    Keywords:  GLUT1; HIF 1α; HepG2; aerobic glycolysis; methylglyoxal
    DOI:  https://doi.org/10.1002/jcb.30215
  13. Polymers (Basel). 2022 Jan 11. pii: 287. [Epub ahead of print]14(2):
    NIR and Reduction Dual-Sensitive Polymeric Prodrug Nanoparticles for Bioimaging and Combined Chemo-Phototherapy.
    Shuying Li, Yanjuan Wu, Xiukun Xue, Siyuan Liu.
      The combination of chemotherapy, photothermal therapy (PTT) and photodynamic therapy (PDT) based on a single nanosystem is highly desirable for cancer treatment. In this study, we developed a versatile Pt(IV) prodrug-based nanodrug, PVPt@Cy NPs, to realize synchronous chemotherapy, PDT and PTT and integrate cancer treatment with bioimaging. To construct PVPt@Cy NPs, the amphiphilic Pt(IV)-based polymeric prodrug PVPt was synthesized by a facile one-pot coupling reaction, and then it was used to encapsulate an optotheranostic agent (HOCyOH, Cy) via hydrophobic interaction-induced self-assembly. These NPs would disaggregate under acidic, reductive conditions and NIR irradiation, which are accompanied by photothermal conversion and reactive oxygen species (ROS) generation. Moreover, the PVPt@Cy NPs exhibited an enhanced in vitro anticancer efficiency with 808-nm light irradiation. Furthermore, the PVPt@Cy NPs showed strong NIR fluorescence and photothermal imaging in H22 tumor-bearing mice, allowing the detection of the tumor site and monitoring of the drug biodistribution. Therefore, PVPt@Cy NPs displayed an enormous potential in combined chemo-phototherapy.
    Keywords:  Pt(IV) prodrug; bioimaging; combined chemo-phototherapy; nanoparticle
    DOI:  https://doi.org/10.3390/polym14020287
  14. Int J Biol Macromol. 2022 Jan 17. pii: S0141-8130(22)00101-5. [Epub ahead of print]
    Glycol chitosan/iron oxide/polypyrrole nanoclusters for precise chemodynamic/photothermal synergistic therapy.
    Edgar Danie Quiñones, Ting-Yu Lu, Kuan-Ting Liu, Yu-Jui Fan, Er-Yuan Chuang, Jiashing Yu.
      Noninvasive photothermal therapy (PTT) represents a promising direction for more modern and precise medical applications. However, PTT efficacy is still not satisfactory due to the existence of heat shock proteins (HSPs) and poorly targeted delivery. Herein, the design of a nanosystem with improved delivery efficacy for anticancer treatment employing the synergetic effects of reactive oxygen species (ROS)-driven chemodynamic therapy (CDT) to inactivated HSPs with photothermal-hyperthermia was therefore achieved through the development of pH-targeting glycol chitosan/iron oxide enclosed core polypyrrole nanoclusters (GCPI NCs). The designed NCs effectively accumulated toward cancer cells due to their acidic microenvironment, initiating ROS generation via Fenton reaction at the outset and performing site-specific near infrared (NIR)-photothermal effect. A comprehensive analysis of both surface and bulk material properties of the CDT/PTT NCs as well as biointerface properties were ascertained via numerous surface specific analytical techniques by bringing together heightened accumulation of CDT/PTT NCs, which can significantly eradicate cancer cells thus minimizing the side effects of conventional chemotherapies. All of these attributes act in synergy over the cancer cells succeeding in fashioning NC's able to act as competent agents in the MRI-monitored enhanced CDT/PTT synergistic therapy. Findings in this study evoke attention in future oncological therapeutic strategies.
    Keywords:  Magnetic resonance imaging; Photothermal and chemodynamic treatment; pH-targeting
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.01.085
  15. ACS Appl Bio Mater. 2022 Jan 19.
    NIR-II Fluorescent Activatable Drug Delivery Nanoplatform for Cancer-Targeted Combined Photodynamic and Chemotherapy.
    Qian Xie, Junzhi Liu, Bin Chen, Xiaoguang Ge, Xuan Zhang, Shi Gao, Qingjie Ma, Jibin Song.
      Nanotheranostics with integrated imaging functions can help monitor nanoparticle accumulation in tumors, thus achieving synergism and higher therapeutic accuracy in cancer therapy. However, it remains challenging to monitor the release of therapeutic drugs in real time from a nanoparticulate drug delivery system (nano-DDS) in the body. Herein, we developed a nano-DDS for fluorescence imaging in the second near-infrared window (NIR-II) region, which can be used for monitoring the responsive release of drugs and cancer-targeted combined photodynamic and chemotherapy. There is a linear correlation between the cumulative release of the drug and the NIR-II fluorescence intensity. Moreover, hyaluronidase/glutathione dual-response RGD-SS-DOX/Ce6@HA-IR-1061 (RSSDCHI) exhibited a higher tumor-to-normal-tissue ratio in NIR-II fluorescence imaging and enhanced antitumor efficacy in vivo. This makes it possible to visualize drug release at the cellular level by the nanocomposites and to predict the treatment effect according to the NIR-II fluorescence intensity in the tumor site, serving as a promising nanoplatform for precision nanomedicine.
    Keywords:  NIR-II; combined therapy; fluorescence imaging; theranostics; tumor microenvironment
    DOI:  https://doi.org/10.1021/acsabm.1c01139
  16. J Nanobiotechnology. 2022 Jan 21. 20(1): 42
    Mitochondria-targeting multifunctional nanoplatform for cascade phototherapy and hypoxia-activated chemotherapy.
    Jie Lv, Shuangling Wang, Duo Qiao, Yulong Lin, Shuyang Hu, Meng Li.
      Despite considerable progress has been achieved in hypoxia-associated anti-tumor therapy, the efficacy of utilizing hypoxia-activated prodrugs alone is not satisfied owing to the inadequate hypoxia within the tumor regions. In this work, a mitochondrial targeted nanoplatform integrating photodynamic therapy, photothermal therapy and hypoxia-activated chemotherapy has been developed to synergistically treat cancer and maximize the therapeutic window. Polydopamine coated hollow copper sulfide nanoparticles were used as the photothermal nanoagents and thermosensitive drug carriers for loading the hypoxia-activated prodrug, TH302, in our study. Chlorin e6 (Ce6) and triphenyl phosphonium (TPP) were conjugated onto the surface of the nanoplatform. Under the action of TPP, the obtained nanoplatform preferentially accumulated in mitochondria to restore the drug activity and avoid drug resistance. Using 660 nm laser to excite Ce6 can generate ROS and simultaneously exacerbate the cellular hypoxia. While under the irradiation of 808 nm laser, the nanoplatform produced local heat which can increase the release of TH302 in tumor cells, ablate cancer cells as well as intensify the tumor hypoxia levels. The aggravated tumor hypoxia then significantly boosted the anti-tumor efficiency of TH302. Both in vitro and in vivo studies demonstrated the greatly improved anti-cancer activity compared to conventional hypoxia-associated chemotherapy. This work highlights the potential of using a combination of hypoxia-activated prodrugs plus phototherapy for synergistic cancer treatment.
    Keywords:  Combination therapy; Drug delivery; Hypoxia-activated prodrug; Mitochondria-targeting; Phototherapy
    DOI:  https://doi.org/10.1186/s12951-022-01244-9
  17. Free Radic Biol Med. 2022 Jan 14. pii: S0891-5849(22)00021-1. [Epub ahead of print]180 108-120
    Metformin inhibits the tumor-promoting effect of low-dose resveratrol, and enhances the anti-tumor activity of high-dose resveratrol by increasing its reducibility in triple negative breast cancer.
    Tingting Cheng, Cheng Wang, Qianqian Lu, Yuru Cao, Weiwei Yu, Wenzhen Li, Ben Liu, Xue Gao, Junhong Lü, Xiaohong Pan.
      Resveratrol, a natural antioxidant that maintains better bioactivity under hypoxia, has anti-tumor effects, but its underlying mechanism is controversial and the effect on Triple-negative breast cancer (TNBC) remains unclear. Herein, we investigated the anti-TNBC mechanism of resveratrol under a mimic hypoxic tumor microenvironment and explored a method of combining metformin to improve the therapeutic effect. The results showed an inverted "U" shaped relationship between the cell viability and resveratrol concentrations. Low concentrations of resveratrol (LRes) promoted proliferation and migration in MDA-MB-231 cells by activating JAK3/STAT3 signaling pathway, while high concentrations of resveratrol (HRes) inhibited cell growth and induced both autophagy and apoptosis through MAPK signaling pathway. Meanwhile, HRes treatment resulted in the up-regulation of antioxidant-related genes SOD3 and FAM213B, the increase of catalase activity and NAD(P)H level, which leading to a reducing microenvironment in cells. Notably, metformin could inhibit the proliferation and migration induced by LRes, whereas promote apoptosis induced by HRes. Moreover, metformin enhanced the reducing environment via further increasing the catalase activity and NAD(P)H level. These findings conclude the anti-TNBC mechanism of HRes should be attributed to its antioxidant activity and metformin enhances its reducibility. Metformin combined with resveratrol exerts a synergistic therapeutic effect on TNBC and effectively prevents tumor progression.
    Keywords:  Antioxidant; JAK3; MAPK; Metformin; Resveratrol; Triple-negative breast cancer (TNBC)
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.01.010
  18. Biomolecules. 2022 Jan 04. pii: 71. [Epub ahead of print]12(1):
    The Role of Rosmarinic Acid on the Bioproduction of Gold Nanoparticles as Part of a Photothermal Approach for Breast Cancer Treatment.
    Tânia Ferreira-Gonçalves, Maria Manuela Gaspar, João M P Coelho, Vanda Marques, Ana S Viana, Lia Ascensão, Lina Carvalho, Cecília M P Rodrigues, Hugo Alexandre Ferreira, David Ferreira, Catarina Pinto Reis.
      Breast cancer is a high-burden malignancy for society, whose impact boosts a continuous search for novel diagnostic and therapeutic tools. Among the recent therapeutic approaches, photothermal therapy (PTT), which causes tumor cell death by hyperthermia after being irradiated with a light source, represents a high-potential strategy. Furthermore, the effectiveness of PTT can be improved by combining near infrared (NIR) irradiation with gold nanoparticles (AuNPs) as photothermal enhancers. Herein, an alternative synthetic method using rosmarinic acid (RA) for synthesizing AuNPs is reported. The RA concentration was varied and its impact on the AuNPs physicochemical and optical features was assessed. Results showed that RA concentration plays an active role on AuNPs features, allowing the optimization of mean size and maximum absorbance peak. Moreover, the synthetic method explored here allowed us to obtain negatively charged AuNPs with sizes favoring the local particle accumulation at tumor site and maximum absorbance peaks within the NIR region. In addition, AuNPs were safe both in vitro and in vivo. In conclusion, the synthesized AuNPs present favorable properties to be applied as part of a PTT system combining AuNPs with a NIR laser for the treatment of breast cancer.
    Keywords:  breast cancer treatment; gold nanoparticles; photothermal therapy; rosmarinic acid
    DOI:  https://doi.org/10.3390/biom12010071
  19. Antioxidants (Basel). 2022 Jan 07. pii: 133. [Epub ahead of print]11(1):
    Revisiting the Oxidation of Flavonoids: Loss, Conservation or Enhancement of Their Antioxidant Properties.
    Hernan Speisky, Fereidoon Shahidi, Adriano Costa de Camargo, Jocelyn Fuentes.
      Flavonoids display a broad range of health-promoting bioactivities. Among these, their capacity to act as antioxidants has remained most prominent. The canonical reactive oxygen species (ROS)-scavenging mode of the antioxidant action of flavonoids relies on the high susceptibility of their phenolic moieties to undergo oxidation. As a consequence, upon reaction with ROS, the antioxidant capacity of flavonoids is severely compromised. Other phenol-compromising reactions, such as those involved in the biotransformation of flavonoids, can also markedly affect their antioxidant properties. In recent years, however, increasing evidence has indicated that, at least for some flavonoids, the oxidation of such residues can in fact markedly enhance their original antioxidant properties. In such apparent paradoxical cases, the antioxidant activity arises from the pro-oxidant and/or electrophilic character of some of their oxidation-derived metabolites and is exerted by activating the Nrf2-Keap1 pathway, which upregulates the cell's endogenous antioxidant capacity, and/or, by preventing the activation of the pro-oxidant and pro-inflammatory NF-κB pathway. This review focuses on the effects that the oxidative and/or non-oxidative modification of the phenolic groups of flavonoids may have on the ability of the resulting metabolites to promote direct and/or indirect antioxidant actions. Considering the case of a metabolite resulting from the oxidation of quercetin, we offer a comprehensive description of the evidence that increasingly supports the concept that, in the case of certain flavonoids, the oxidation of phenolics emerges as a mechanism that markedly amplifies their original antioxidant properties. An overlooked topic of great phytomedicine potential is thus unraveled.
    Keywords:  antioxidants; benzofuranones; flavonoid oxidation; flavonoids
    DOI:  https://doi.org/10.3390/antiox11010133
  20. ACS Appl Mater Interfaces. 2022 Jan 20.
    Polyoxometalate Modified by Zeolite Imidazole Framework for the pH-Responsive Electrodynamic/Chemodynamic Therapy.
    Yan Song, Yuan Sun, Minglu Tang, Zhengya Yue, Jiatong Ni, Junge Zhao, Wenxin Wang, Tiedong Sun, Lianxu Shi, Lei Wang.
      Electrodynamic therapy (EDT) and chemodynamic therapy (CDT) have the potential for future tumor treatment; however, their underlying applications are greatly hindered owing to their inherent drawbacks. The combination of EDT and CDT has been considered to be an effective way to maximize the superiorities of these two ROS-based methodologies. However, the development of novel nanomaterials with "one-for-all" functions still remains a big challenge. In this work, the polyoxometalate nanoparticles (NPs) were decorated using the zeolite imidazole framework (POM@ZIF-8) in order to integrate the EDT with CDT. The resulting POM@ZIF-8 NPs can effectively induce the generation of reactive oxygen species (ROS) via a catalytic reaction on the surface of POM NPs induced by an electric field (E). At the same time, POM@ZIF-8 NPs can catalyze the intracellular H2O2 into ROS via a Fenton-like reaction, thereby achieving the combination of EDT and CDT. Besides, since ZIF-8 is acid-responsive, it can protect normal tissues and avoid side effects. Of great note is that the cytotoxicity and the apoptosis rate of the POM@ZIF-8+E group (80%) were found to be significantly higher than that of the E group (55%). As a result, a high tumor inhibition phenomenon can be observed both in vitro and in vivo. The present study thus provides an alternative concept for combinational therapeutic modality with exceptional efficacy.
    Keywords:  chemodynamic therapy; combinational therapy; electrodynamic therapy; polyoxometalate; zeolitic imidazolate framework
    DOI:  https://doi.org/10.1021/acsami.1c19985
  21. Proc Natl Acad Sci U S A. 2022 Jan 25. pii: e2109791119. [Epub ahead of print]119(4):
    Ultrasound controlled mechanophore activation in hydrogels for cancer therapy.
    Gun Kim, Qiong Wu, James L Chu, Emily J Smith, Michael L Oelze, Jeffrey S Moore, King C Li.
      Mechanophores are molecular motifs that respond to mechanical perturbance with targeted chemical reactions toward desirable changes in material properties. A large variety of mechanophores have been investigated, with applications focusing on functional materials, such as strain/stress sensors, nanolithography, and self-healing polymers, among others. The responses of engineered mechanophores, such as light emittance, change in fluorescence, and generation of free radicals (FRs), have potential for bioimaging and therapy. However, the biomedical applications of mechanophores are not well explored. Herein, we report an in vitro demonstration of an FR-generating mechanophore embedded in biocompatible hydrogels for noninvasive cancer therapy. Controlled by high-intensity focused ultrasound (HIFU), a clinically proven therapeutic technique, mechanophores were activated with spatiotemporal precision to generate FRs that converted to reactive oxygen species (ROS) to effectively kill tumor cells. The mechanophore hydrogels exhibited no cytotoxicity under physiological conditions. Upon activation with HIFU sonication, the therapeutic efficacies in killing in vitro murine melanoma and breast cancer tumor cells were comparable with lethal doses of H2O2 This process demonstrated the potential for mechanophore-integrated HIFU combination as a noninvasive cancer treatment platform, named "mechanochemical dynamic therapy" (MDT). MDT has two distinct advantages over other noninvasive cancer treatments, such as photodynamic therapy (PDT) and sonodynamic therapy (SDT). 1) MDT is ultrasound based, with larger penetration depth than PDT. 2) MDT does not rely on sonosensitizers or the acoustic cavitation effect, both of which are necessary for SDT. Taking advantage of the strengths of mechanophores and HIFU, MDT can provide noninvasive treatments for diverse cancer types.
    Keywords:  cancer therapy; hydrogel; mechanochemistry; reactive oxygen species; ultrasound
    DOI:  https://doi.org/10.1073/pnas.2109791119
  22. Int J Mol Sci. 2022 Jan 07. pii: 657. [Epub ahead of print]23(2):
    Engineering Nanoplatform for Combined Cancer Therapeutics via Complementary Autophagy Inhibition.
    Xuan Wang, Yunhao Li, Jianqing Lu, Xiongwei Deng, Yan Wu.
      Despite advances in the development of tumor treatments, mortality from cancer continues to increase. Nanotechnology is expected to provide an innovative anti-cancer therapy, to combat challenges such as multidrug resistance and tumor recurrence. Nevertheless, tumors can greatly rely on autophagy as an alternative source for metabolites, and which desensitizes cancer cells to therapeutic stress, hindering the success of any current treatment paradigm. Autophagy is a conserved process by which cells turn over their own constituents to maintain cellular homeostasis. The multistep autophagic pathway provides potentially druggable targets to inhibit pro-survival autophagy under various therapeutic stimuli. In this review, we focus on autophagy inhibition based on functional nanoplatforms, which may be a potential strategy to increase therapeutic sensitivity in combinational cancer therapies, including chemotherapy, radiotherapy, phototherapy, sonodynamic therapy, and immunotherapy.
    Keywords:  autophagy inhibition; nanoparticles; tumor treatment
    DOI:  https://doi.org/10.3390/ijms23020657
  23. Int J Mol Sci. 2022 Jan 07. pii: 639. [Epub ahead of print]23(2):
    Curcumin and Weight Loss: Does It Work?
    Kamila Kasprzak-Drozd, Tomasz Oniszczuk, Marek Gancarz, Adrianna Kondracka, Robert Rusinek, Anna Oniszczuk.
      Obesity is a global health problem needing urgent research. Synthetic anti-obesity drugs show side effects and variable effectiveness. Thus, there is a tendency to use natural compounds for the management of obesity. There is a considerable body of knowledge, supported by rigorous experimental data, that natural polyphenols, including curcumin, can be an effective and safer alternative for managing obesity. Curcumin is a is an important compound present in Curcuma longa L. rhizome. It is a lipophilic molecule that rapidly permeates cell membrane. Curcumin has been used as a pharmacological traditional medicinal agent in Ayurvedic medicine for ∼6000 years. This plant metabolite doubtless effectiveness has been reported through increasingly detailed in vitro, in vivo and clinical trials. Regarding its biological effects, multiple health-promoting, disease-preventing and even treatment attributes have been remarkably highlighted. This review documents the status of research on anti-obesity mechanisms and evaluates the effectiveness of curcumin for management of obesity. It summarizes different mechanisms of anti-obesity action, associated with the enzymes, energy expenditure, adipocyte differentiation, lipid metabolism, gut microbiota and anti-inflammatory potential of curcumin. However, there is still a need for systematic and targeted clinical studies before curcumin can be used as the mainstream therapy for managing obesity.
    Keywords:  adipogenesis; curcumin; lipid metabolism; natural compounds; obesity
    DOI:  https://doi.org/10.3390/ijms23020639
  24. Oncol Rep. 2022 Mar;pii: 55. [Epub ahead of print]47(3):
    Advances in metformin‑based metabolic therapy for non‑small cell lung cancer (Review).
    Na Chen, Yi-Shu Zhou, Li-Cui Wang, Jin-Bai Huang.
      Therapeutic approaches that target the metabolism of tumor cells have been a popular research topic in recent years. Previous studies have demonstrated that glycolysis inhibitors reduce the proliferation of non‑small cell lung cancer (NSCLC) cells by interfering with the aerobic glycolytic pathway. However, the mitochondrial oxidative phosphorylation (OXPHOS) pathway in tumor cells has also been implicated in lung cancer metabolism. Metformin, a known inhibitor of mitochondrial OXPHOS, has been indicated to reduce NSCLC morbidity and mortality in clinical studies. The present article reviewed the therapeutic effects of metformin against NSCLC, both as a single agent and combined with other anticancer treatments, in order to provide a theoretical basis for its clinical use in adjuvant therapy for NSCLC.
    Keywords:  anticancer; combination therapy; metabolism; metformin; non‑small cell lung cancer
    DOI:  https://doi.org/10.3892/or.2022.8266
  25. Front Pharmacol. 2021 ;12 828856
    Repurposing Artemisinin and its Derivatives as Anticancer Drugs: A Chance or Challenge?
    Zhaowu Ma, Clariis Yi-Ning Woon, Chen-Guang Liu, Jun-Ting Cheng, Mingliang You, Gautam Sethi, Andrea Li-Ann Wong, Paul Chi-Lui Ho, Daping Zhang, Peishi Ong, Lingzhi Wang, Boon-Cher Goh.
      Cancer has become a global health problem, accounting for one out of six deaths. Despite the recent advances in cancer therapy, there is still an ever-growing need for readily accessible new therapies. The process of drug discovery and development is arduous and takes many years, and while it is ongoing, the time for the current lead compounds to reach clinical trial phase is very long. Drug repurposing has recently gained significant attention as it expedites the process of discovering new entities for anticancer therapy. One such potential candidate is the antimalarial drug, artemisinin that has shown anticancer activities in vitro and in vivo. In this review, major molecular and cellular mechanisms underlying the anticancer effect of artemisinin and its derivatives are summarised. Furthermore, major mechanisms of action and some key signaling pathways of this group of compounds have been reviewed to explore potential targets that contribute to the proliferation and metastasis of tumor cells. Despite its established profile in malaria treatment, pharmacokinetic properties, anticancer potency, and current formulations that hinder the clinical translation of artemisinin as an anticancer agent, have been discussed. Finally, potential solutions or new strategies are identified to overcome the bottlenecks in repurposing artemisinin-type compounds as anticancer drugs.
    Keywords:  anticancer therapy; artemisinin; artemisinin derivatives; drug repurposing; pharmacokinetics; signalling pathways
    DOI:  https://doi.org/10.3389/fphar.2021.828856
  26. Molecules. 2022 Jan 12. pii: 477. [Epub ahead of print]27(2):
    Influence of Olive Oil and Its Components on Breast Cancer: Molecular Mechanisms.
    Raquel Moral, Eduard Escrich.
      Breast cancer is the most frequent malignant neoplasia and a leading cause of mortality in women worldwide. The Mediterranean diet has been proposed as a healthy dietary pattern with protective effects in several chronic diseases, including breast cancer. This diet is characterized by the consumption of abundant plant foods and olive oil as the principal source of fat, which is considered one of the main components with potential antioxidant, anti-inflammatory and anticancer effects. Extra-virgin olive oil (EVOO) has several bioactive compounds, mainly including monounsaturated fatty acids, triterpenes and polyphenols, such as phenolic alcohols (e.g., hydroxytyrosol), secoiridoids (e.g., oleuropein and oleocanthal), lignans (e.g., pinoresinol) or flavonoids (e.g., luteolin). While epidemiological evidence is still limited, experimental in vivo and in vitro data have shown a protective effect of this oil and its compounds on mammary carcinogenesis. Such effects account through complex and multiple mechanisms, including changes in epigenetics, transcriptome and protein expression that modulate several signaling pathways. Molecular targets of EVOO compounds have a role in the acquisition of cancer hallmarks. Although further research is needed to elucidate their beneficial effects on human prevention and progression of the disease, evidence points to EVOO in the context of the Mediterranean diet as a heathy choice, while EVOO components may be promising adjuvants in anticancer strategies.
    Keywords:  EVOO; apoptosis; breast cancer; migration; minor compounds; olive oil; proliferation
    DOI:  https://doi.org/10.3390/molecules27020477
  27. Pharmaceutics. 2022 Jan 02. pii: 99. [Epub ahead of print]14(1):
    From Microenvironment Remediation to Novel Anti-Cancer Strategy: The Emergence of Zero Valent Iron Nanoparticles.
    Ya-Na Wu, Li-Xing Yang, Pei-Wen Wang, Filip Braet, Dar-Bin Shieh.
      Accumulated studies indicate that zero-valent iron (ZVI) nanoparticles demonstrate endogenous cancer-selective cytotoxicity, without any external electric field, lights, or energy, while sparing healthy non-cancerous cells in vitro and in vivo. The anti-cancer activity of ZVI-based nanoparticles was anti-proportional to the oxidative status of the materials, which indicates that the elemental iron is crucial for the observed cancer selectivity. In this thematic article, distinctive endogenous anti-cancer mechanisms of ZVI-related nanomaterials at the cellular and molecular levels are reviewed, including the related gene modulating profile in vitro and in vivo. From a material science perspective, the underlying mechanisms are also analyzed. In summary, ZVI-based nanomaterials demonstrated prominent potential in precision medicine to modulate both programmed cell death of cancer cells, as well as the tumor microenvironment. We believe that this will inspire advanced anti-cancer therapy in the future.
    Keywords:  ROS; angiogenesis; cancer; ferroptosis; macrophages; nanomedicine; nanoparticles; tumor; tumor microenvironment; zero-valent iron
    DOI:  https://doi.org/10.3390/pharmaceutics14010099
  28. Pharmaceutics. 2022 Jan 04. pii: 120. [Epub ahead of print]14(1):
    Combinatorial Therapeutic Approaches with Nanomaterial-Based Photodynamic Cancer Therapy.
    Yang Hao, Chih Kit Chung, Zhenfeng Yu, Ruben V Huis In 't Veld, Ferry A Ossendorp, Peter Ten Dijke, Luis J Cruz.
      Photodynamic therapy (PDT), in which a light source is used in combination with a photosensitizer to induce local cell death, has shown great promise in therapeutically targeting primary tumors with negligible toxicity and minimal invasiveness. However, numerous studies have shown that noninvasive PDT alone is not sufficient to completely ablate tumors in deep tissues, due to its inherent shortcomings. Therefore, depending on the characteristics and type of tumor, PDT can be combined with surgery, radiotherapy, immunomodulators, chemotherapy, and/or targeted therapy, preferably in a patient-tailored manner. Nanoparticles are attractive delivery vehicles that can overcome the shortcomings of traditional photosensitizers, as well as enable the codelivery of multiple therapeutic drugs in a spatiotemporally controlled manner. Nanotechnology-based combination strategies have provided inspiration to improve the anticancer effects of PDT. Here, we briefly introduce the mechanism of PDT and summarize the photosensitizers that have been tested preclinically for various cancer types and clinically approved for cancer treatment. Moreover, we discuss the current challenges facing the combination of PDT and multiple cancer treatment options, and we highlight the opportunities of nanoparticle-based PDT in cancer therapies.
    Keywords:  cancer photodynamic therapy; cancer vaccines; checkpoint inhibitor therapy; chemotherapy; combined therapy; drug delivery; radiotherapy
    DOI:  https://doi.org/10.3390/pharmaceutics14010120
  29. Biomolecules. 2021 Dec 30. pii: 51. [Epub ahead of print]12(1):
    Progress on the Application of Bortezomib and Bortezomib-Based Nanoformulations.
    Jianhao Liu, Ruogang Zhao, Xiaowen Jiang, Zhaohuan Li, Bo Zhang.
      Bortezomib (BTZ) is the first proteasome inhibitor approved by the Food and Drug Administration. It can bind to the amino acid residues of the 26S proteasome, thereby causing the death of tumor cells. BTZ plays an irreplaceable role in the treatment of mantle cell lymphoma and multiple myeloma. Moreover, its use in the treatment of other hematological cancers and solid tumors has been investigated in numerous clinical trials and preclinical studies. Nevertheless, the applications of BTZ are limited due to its insufficient specificity, poor permeability, and low bioavailability. Therefore, in recent years, different BTZ-based drug delivery systems have been evaluated. In this review, we firstly discussed the functions of proteasome inhibitors and their mechanisms of action. Secondly, the properties of BTZ, as well as recent advances in both clinical and preclinical research, were reviewed. Finally, progress in research regarding BTZ-based nanoformulations was summarized.
    Keywords:  bortezomib; cancer therapy; nanoformulations; proteasome inhibitor
    DOI:  https://doi.org/10.3390/biom12010051
  30. Cancers (Basel). 2022 Jan 11. pii: 345. [Epub ahead of print]14(2):
    Glucose Limitation Sensitizes Cancer Cells to Selenite-Induced Cytotoxicity via SLC7A11-Mediated Redox Collapse.
    Hui Chen, Han Zhang, Lixing Cao, Jinling Cui, Xuan Ma, Chong Zhao, Shutao Yin, Hongbo Hu.
      Combination of intermittent fasting and chemotherapy has been drawn an increasing attention because of the encouraging efficacy. In this study, we evaluated the anti-cancer effect of combination of glucose limitation and selenite (Se), a representative inorganic form of selenium, that is preferentially accumulated in tumors. Results showed that cytotoxic effect of selenite on cancer cells, but not on normal cells, was significantly enhanced in response to the combination of selenite and glucose limitation. Furthermore, in vivo therapeutic efficacy of combining selenite with fasting was dramatically improved in xenograft models of lung and colon cancer. Mechanistically, we found that SLC7A11 expression in cancer cells was up-regulated by selenite both in vitro and in vivo. The elevated SLC7A11 led to cystine accumulation, NADPH depletion and the conversion of cystine to cysteine inhibition, which in turn boosted selenite-mediated reactive oxygen species (ROS), followed by enhancement of selenite-mediated cytotoxic effect. The findings of the present study provide an effective and practical approach for increasing the therapeutic window of selenite and imply that combination of selenite and fasting holds promising potential to be developed a clinically useful regimen for treating certain types of cancer.
    Keywords:  NADPH; ROS; SLC7A11; glucose limitation; selenite
    DOI:  https://doi.org/10.3390/cancers14020345
  31. Biomater Sci. 2022 Jan 19.
    An active-passive strategy for enhanced synergistic photothermal-ferroptosis therapy in the NIR-I/II biowindows.
    Fengxia Wu, Haoran Chen, Ruiqi Liu, Yongkuan Suo, Qiqing Li, Youlin Zhang, Hongguang Liu, Zhen Cheng, Yulei Chang.
      Ferroptosis therapy (FT) is an attractive strategy to selectively damage cancer cells through lipid peroxide (LPO) over-accumulation. However, this therapy suffers from poor therapeutic efficacy due to the limited Fenton reaction efficiency and the evolved intrinsic resistance mechanism in the tumor microenvironment (TME). The exploitation of novel ferroptosis inducers is of significance for improving the efficacy of FT. Here, we develop a plate-like Bi2Se3-Fe3O4/Au (BFA) theranostic nanoplatform, which can increase the Fenton reaction rate to enhance FT in an active-passive way. In detail, benefiting from the internal synergistic effect of Fe3O4 NPs and Au NPs and external NIR-mediated hyperthermia, the BFA NPs can boost hydroxyl radical (˙OH) generation to enhance intracellular oxidative stress and further induce ferroptosis by inactivating glutathione peroxidase 4 (GPX4). Furthermore, the BFA NPs show high photothermal conversion efficiency in both the NIR-I and NIR-II windows (66.2% at 808 nm and 58.2% at 1064 nm, respectively); therefore, as a photothermal agent (PTA), they can also ablate cancer cells directly by NIR-triggered photothermal therapy (PTT). Meanwhile, BFA NPs could be used as an efficient diagnostic agent for photoacoustic (PA)/magnetic resonance (MR)/X-ray imaging to guide the synergistic therapy of photothermal-ferroptosis. Therefore, BFA NP-mediated enhanced photothermal-ferroptosis therapy represents a promising strategy for the application of nanomaterials in tumor therapy.
    DOI:  https://doi.org/10.1039/d1bm01908b
  32. Drug Deliv. 2022 Dec;29(1): 342-350
    Combined and targeted drugs delivery system for colorectal cancer treatment: Conatumumab decorated, reactive oxygen species sensitive irinotecan prodrug and quercetin co-loaded nanostructured lipid carriers.
    Youqiang Liu, Hongxin Zhang, Haijing Cui, Futong Zhang, Liyan Zhao, Yibing Liu, Qingju Meng.
       PURPOSE: Colorectal cancer (CRC) is the third most frequently diagnosed cancer and this study aimed to develop a conatumumab decorated, irinotecan prodrug and quercetin co-loaded delivery system for combined and targeted colorectal cancer treatment.
    METHODS: A conatumumab (C) decorated, irinotecan prodrug (I-p) and quercetin (Q) co-encapsulated NLC (C I-p/Q NLC) was developed. In vitro and in vivo antitumor efficiency of NLC was evaluated on CRC cells and mice xenograft.
    RESULTS: The results showed that the HT-29 cells uptake of C I-p/Q NLC was over 70%. Reactive oxygen species (ROS) sensitive irinotecan prodrug formulation showed improved drug release ability in hypoxic conditions. C I-p/Q NLC showed significantly higher cytotoxicity than non-decorated NLC, single drug-loaded NLC and free drugs. In vivo studies in a CRC-bearing model corroborated the capability of nanoparticles for the inhibition of cancer, leading to a reduction of tumor growth without systemic toxicity.
    CONCLUSION: The conatumumab decorated, ROS sensitive prodrug contained combination nano-system is a promising platform for CRC therapy.
    Keywords:  Colorectal cancer; irinotecan prodrug; lipid nanoparticles; reactive oxygen species sensitive
    DOI:  https://doi.org/10.1080/10717544.2022.2027573
  33. Materials (Basel). 2022 Jan 10. pii: 502. [Epub ahead of print]15(2):
    Organic Nanoparticles Based on D-A-D Small Molecule: Self-Assembly, Photophysical Properties, and Synergistic Photodynamic/Photothermal Effects.
    Liangliang Yue, Haolan Li, Qi Sun, Xiaogang Luo, Fengshou Wu, Xunjin Zhu.
      Cancer is one of the major diseases threatening human health. Traditional cancer treatments have notable side-effects as they can damage the immune system. Recently, phototherapy, as a potential strategy for clinical cancer therapy, has received wide attention due to its minimal invasiveness and high efficiency. Herein, a small organic molecule (PTA) with a D-A-D structure was prepared via a Sonogashira coupling reaction between the electron-withdrawing dibromo-perylenediimide and electron-donating 4-ethynyl-N,N-diphenylaniline. The amphiphilic organic molecule was then transformed into nanoparticles (PTA-NPs) through the self-assembling method. Upon laser irradiation at 635 nm, PTA-NPs displayed a high photothermal conversion efficiency (PCE = 43%) together with efficient reactive oxygen species (ROS) generation. The fluorescence images also indicated the production of ROS in cancer cells with PTA-NPs. In addition, the biocompatibility and photocytotoxicity of PTA-NPs were evaluated by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and live/dead cell co-staining test. Therefore, the as-prepared organic nanomaterials were demonstrated as promising nanomaterials for cancer phototherapy in the clinic.
    Keywords:  organic nanomaterials; perylene diimide; photothermal therapy; reactive oxygen species; self-assembly
    DOI:  https://doi.org/10.3390/ma15020502
  34. Micromachines (Basel). 2021 Dec 28. pii: 45. [Epub ahead of print]13(1):
    Transforming Tea Catechins into Potent Anticancer Compound: Analysis of Three Boronated-PEG Delivery System.
    Mingyan Guo, Lukas Marek, Yixia Liang, Phei Er Saw.
      Chemotherapy has led to many undesirable side effects, as these are toxic drugs that are unable to differentiate between cancer and normal cells. Polyphenols (tea catechins) are an ideal option as alternative chemotherapeutics owing to their inherent anticancer properties, antioxidant properties and being naturally occurring compounds, are deemed safe for consumption. However, without proper administration, the bioavailability of these compounds is low and inefficient. Therefore, proper delivery of these phenolic compounds is vital for cancer therapy. Herein, we analyzed three potential solutions to creating nanoparticle drugs using naturally occurring phenolic compounds (piceatannol (PIC), epigallocatechin gallate hydrophilic (EGCG) and l-epicatechin (EPI)). By using a simple pi-pi stacking mechanism, we utilized boronated PEG (PEG-Br) as an anchor to efficiently load EPI, PIC and EGCG, respectively, to produce three effective phenolic compound-based nanoparticles, which could be delivered safely in systemic circulation, yet detach from its cargo intracellularly to exert its anticancer effect for effective cancer therapy.
    Keywords:  boronated-PEG; epigallocatechin gallate hydrophilic; l-epicatechin; piceatannol; tea catechin
    DOI:  https://doi.org/10.3390/mi13010045
  35. Environ Sci Pollut Res Int. 2022 Jan 22.
    Anticancer properties of medicinal plants and their bioactive compounds against breast cancer: a review on recent investigations.
    Muhammad Idrees Khan, Abdelhakim Bouyahya, Naoufal E L Hachlafi, Naoual El Menyiy, Muhammad Akram, Sabira Sultana, Gokhan Zengin, Lilya Ponomareva, Mohammad Ali Shariati, Oluwafemi Adeleke Ojo, Stefano Dall'Acqua, Tobiloba Christiana Elebiyo.
      Breast cancer (BC) is one of the most common and recurring diseases and the second leading cause of death in women. Despite prevention, diagnostics, and therapeutic options such as radiation therapy and chemotherapy, the number of occurrences increases every year. Therefore, novel therapeutic drugs targeting specifically different checkpoints should be developed against breast cancer. Among drugs that can be developed to treat breast cancer, natural products, such as plant-derived compounds, showed significant anti-breast cancer properties. These substances belong to different chemical classes such as flavonoids, terpenoids, phenolic acids, and alkaloids. They exert their in vitro and in vivo cytotoxic activities against breast cancer cell lines via different mechanisms, including the inhibition of extrinsic and intrinsic apoptotic pathways, the arrest of the cell cycle, and the activation of autophagy. Moreover, they also exhibit anti-angiogenesis and antimetastatic action. Moreover, chemoprevention effects of these bioactive compounds were signaled only for certain drugs. Therefore, the aim of this review is to highlight the pharmacological actions of medicinal plants and their bioactive compounds on breast cancer. Moreover, the role of these substances in breast cancer chemoprevention was also discussed.
    Keywords:  Bioactive compounds; Breast cancer; Herbal medicine; Medicinal plant
    DOI:  https://doi.org/10.1007/s11356-021-17795-7
  36. Antioxidants (Basel). 2022 Jan 04. pii: 108. [Epub ahead of print]11(1):
    Metabolic Adaptions/Reprogramming in Islet Beta-Cells in Response to Physiological Stimulators-What Are the Consequences.
    Philip Newsholme, Jordan Rowlands, Roselyn Rose'Meyer, Vinicius Cruzat.
      Irreversible pancreatic β-cell damage may be a result of chronic exposure to supraphysiological glucose or lipid concentrations or chronic exposure to therapeutic anti-diabetic drugs. The β-cells are able to respond to blood glucose in a narrow concentration range and release insulin in response, following activation of metabolic pathways such as glycolysis and the TCA cycle. The β-cell cannot protect itself from glucose toxicity by blocking glucose uptake, but indeed relies on alternative metabolic protection mechanisms to avoid dysfunction and death. Alteration of normal metabolic pathway function occurs as a counter regulatory response to high nutrient, inflammatory factor, hormone or therapeutic drug concentrations. Metabolic reprogramming is a term widely used to describe a change in regulation of various metabolic enzymes and transporters, usually associated with cell growth and proliferation and may involve reshaping epigenetic responses, in particular the acetylation and methylation of histone proteins and DNA. Other metabolic modifications such as Malonylation, Succinylation, Hydroxybutyrylation, ADP-ribosylation, and Lactylation, may impact regulatory processes, many of which need to be investigated in detail to contribute to current advances in metabolism. By describing multiple mechanisms of metabolic adaption that are available to the β-cell across its lifespan, we hope to identify sites for metabolic reprogramming mechanisms, most of which are incompletely described or understood. Many of these mechanisms are related to prominent antioxidant responses. Here, we have attempted to describe the key β-cell metabolic adaptions and changes which are required for survival and function in various physiological, pathological and pharmacological conditions.
    Keywords:  antidiabetic therapeutics; glucose metabolism; insulin; islet inflammation; lipid metabolism; metabolic reprogramming
    DOI:  https://doi.org/10.3390/antiox11010108
  37. Int J Biol Macromol. 2022 Jan 15. pii: S0141-8130(22)00076-9. [Epub ahead of print]202 112-121
    Novel ROS-responsive marine biomaterial fucoidan nanocarriers with AIE effect and chemodynamic therapy.
    Chunjing Guo, Yanguo Su, Ziting Cheng, Qiang Chen, Huimin Guo, Ming Kong, Daquan Chen.
      Chemodynamic therapy (CDT) has been widely used in the treatment of many kinds of tumors, which can effectively induce tumor cell apoptosis by using produced reactive oxygen species (ROS). In this paper, ROS-sensitive multifunctional marine biomaterial natural polysaccharide nanoparticles were designed. Aggregation-induced emission (AIE) molecules tetraphenylethylene (TPE) labeled and caffeic acid (CA) modified fucoidan (FUC) amphiphilic carrier material (CA-FUC-TK-TPE, CFTT) was fabricated, in which the thioketal bond(TK) was used as the linkage arm between TPE and fucoidan chain, giving the CFTT material ROS sensitivity. In addition, amphiphilic carrier material (FUC-TK-VE, FTVE) composed of thioketal-linked vitamin E and fucoidan was synthesized. The mixed carrier material CFTT and FTVE self-assembled in water to form nanoparticles (CFTT - FTVE@PTX-Fe3+) loaded with PTX and Fe3+. The CDT effect was combined with the chemotherapeutic drug PTX to achieve tumor inhibition. In vitro cell studies have proved that CT/PTX nanoparticles have excellent cell permeability and tumor cytotoxicity. In vivo antitumor experiments confirmed effective antitumor activity and reduced side effects.
    Keywords:  Aggregation-induced emission; Chemodynamic therapy; Fucoidan; Paclitaxel; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.01.060
  38. Antioxidants (Basel). 2022 Jan 12. pii: 150. [Epub ahead of print]11(1):
    Can Polyphenols Inhibit Ferroptosis?
    Marija Lesjak, Nataša Simin, Surjit K S Srai.
      Polyphenols, a diverse group of naturally occurring molecules commonly found in higher plants, have been heavily investigated over the last two decades due to their potent biological activities-among which the most important are their antioxidant, antimicrobial, anticancer, anti-inflammatory and neuroprotective activities. A common route of polyphenol intake in humans is through the diet. Since they are subjected to excessive metabolism in vivo it has been questioned whether their much-proven in vitro bioactivity could be translated to in vivo systems. Ferroptosis is a newly introduced, iron-dependent, regulated mode of oxidative cell death, characterized by increased lipid peroxidation and the accumulation of toxic lipid peroxides, which are considered to be toxic reactive oxygen species. There is a growing body of evidence that ferroptosis is involved in the development of almost all chronic diseases. Thus, ferroptosis is considered a new therapeutic target for offsetting many diseases, and researchers are putting great expectations on this field of research and medicine. The aim of this review is to critically analyse the potential of polyphenols to modulate ferroptosis and whether they can be considered promising compounds for the alleviation of chronic conditions.
    Keywords:  ferroptosis inhibition; metabolites; polyphenols
    DOI:  https://doi.org/10.3390/antiox11010150
  39. Biomed Pharmacother. 2022 Feb;pii: S0753-3322(21)01228-2. [Epub ahead of print]146 112442
    Therapeutic potential of flavonoids in cancer: ROS-mediated mechanisms.
    Hasan Slika, Hadi Mansour, Nadine Wehbe, Suzanne A Nasser, Rabah Iratni, Gheyath Nasrallah, Abdullah Shaito, Tarek Ghaddar, Firas Kobeissy, Ali H Eid.
      Cancer is a leading cause of morbidity and mortality around the globe. Reactive oxygen species (ROS) play contradicting roles in cancer incidence and progression. Antioxidants have attracted attention as emerging therapeutic agents. Among these are flavonoids, which are natural polyphenols with established anticancer and antioxidant capacities. Increasing evidence shows that flavonoids can inhibit carcinogenesis via suppressing ROS levels. Surprisingly, flavonoids can also trigger excessive oxidative stress, but this can also induce death of malignant cells. In this review, we explore the inherent characteristics that contribute to the antioxidant capacity of flavonoids, and we dissect the scenarios in which they play the contrasting role as pro-oxidants. Furthermore, we elaborate on the pathways that link flavonoid-mediated modulation of ROS to the prevention and treatment of cancer. Special attention is given to the ROS-mediated anticancer functions that (-)-epigallocatechin gallate (EGCG), hesperetin, naringenin, quercetin, luteolin, and apigenin evoke in various cancers. We also delve into the structure-function relations that make flavonoids potent antioxidants. This review provides a detailed perspective that can be utilized in future experiments or trials that aim at utilizing flavonoids or verifying their efficacy for developing new pharmacologic agents. We support the argument that flavonoids are attractive candidates for cancer therapy.
    Keywords:  Antioxidants; Cancer therapy; Flavonoids; Natural polyphenols; Oxidative stress; Phytomedicine
    DOI:  https://doi.org/10.1016/j.biopha.2021.112442
  40. Pharmaceutics. 2022 Jan 03. pii: 105. [Epub ahead of print]14(1):
    Combining Nanocarrier-Assisted Delivery of Molecules and Radiotherapy.
    Eliza Rocha Gomes, Marina Santiago Franco.
      Cancer is responsible for a significant proportion of death all over the world. Therefore, strategies to improve its treatment are highly desired. The use of nanocarriers to deliver anticancer treatments has been extensively investigated and improved since the approval of the first liposomal formulation for cancer treatment in 1995. Radiotherapy (RT) is present in the disease management strategy of around 50% of cancer patients. In the present review, we bring the state-of-the-art information on the combination of nanocarrier-assisted delivery of molecules and RT. We start with formulations designed to encapsulate single or multiple molecules that, once delivered to the tumor site, act directly on the cells to improve the effects of RT. Then, we describe formulations designed to modulate the tumor microenvironment by delivering oxygen or to boost the abscopal effect. Finally, we present how RT can be employed to trigger molecule delivery from nanocarriers or to modulate the EPR effect.
    Keywords:  abscopal effect; cancer; chemotherapy; hypoxia; nanocarriers; nanosystems; radiosensitizer; radiotherapy; synergism
    DOI:  https://doi.org/10.3390/pharmaceutics14010105
  41. Gels. 2022 Jan 07. pii: 45. [Epub ahead of print]8(1):
    Drug Delivery Based on Stimuli-Responsive Injectable Hydrogels for Breast Cancer Therapy: A Review.
    Hai Xin, Sina Naficy.
      Breast cancer is the most common and biggest health threat for women. There is an urgent need to develop novel breast cancer therapies to overcome the shortcomings of conventional surgery and chemotherapy, which include poor drug efficiency, damage to normal tissues, and increased side effects. Drug delivery systems based on injectable hydrogels have recently gained remarkable attention, as they offer encouraging solutions for localized, targeted, and controlled drug release to the tumor site. Such systems have great potential for improving drug efficiency and reducing the side effects caused by long-term exposure to chemotherapy. The present review aims to provide a critical analysis of the latest developments in the application of drug delivery systems using stimuli-responsive injectable hydrogels for breast cancer treatment. The focus is on discussing how such hydrogel systems enhance treatment efficacy and incorporate multiple breast cancer therapies into one system, in response to multiple stimuli, including temperature, pH, photo-, magnetic field, and glutathione. The present work also features a brief outline of the recent progress in the use of tough hydrogels. As the breast undergoes significant physical stress and movement during sporting and daily activities, it is important for drug delivery hydrogels to have sufficient mechanical toughness to maintain structural integrity for a desired period of time.
    Keywords:  breast cancer; injectable hydrogel; stimuli responsiveness; tough hydrogel
    DOI:  https://doi.org/10.3390/gels8010045
  42. Molecules. 2022 Jan 12. pii: 473. [Epub ahead of print]27(2):
    Chitosan Nanoparticle-Based System: A New Insight into the Promising Controlled Release System for Lung Cancer Treatment.
    Cha Yee Kuen, Mas Jaffri Masarudin.
      Lung cancer has been recognized as one of the most often diagnosed and perhaps most lethal cancer diseases worldwide. Conventional chemotherapy for lung cancer-related diseases has bumped into various limitations and challenges, including non-targeted drug delivery, short drug retention period, low therapeutic efficacy, and multidrug resistance (MDR). Chitosan (CS), a natural polymer derived from deacetylation of chitin, and comprised of arbitrarily distributed β-(1-4)-linked d-glucosamine (deacetylated unit) and N-acetyl-d-glucosamine (acetylated unit) that exhibits magnificent characteristics, including being mucoadhesive, biodegradable, and biocompatible, has emerged as an essential element for the development of a nano-particulate delivery vehicle. Additionally, the flexibility of CS structure due to the free protonable amino groups in the CS backbone has made it easy for the modification and functionalization of CS to be developed into a nanoparticle system with high adaptability in lung cancer treatment. In this review, the current state of chitosan nanoparticle (CNP) systems, including the advantages, challenges, and opportunities, will be discussed, followed by drug release mechanisms and mathematical kinetic models. Subsequently, various modification routes of CNP for improved and enhanced therapeutic efficacy, as well as other restrictions of conventional drug administration for lung cancer treatment, are covered.
    Keywords:  chitosan nanoparticle; controlled release; drug delivery systems; lung cancer; nanomedicine
    DOI:  https://doi.org/10.3390/molecules27020473
  43. Curr Cancer Drug Targets. 2022 Jan 20.
    Nanocarrier System for Increasing the Therapeutic Efficacy of Oxaliplatin.
    Negin Alavi, Majid Rezaei, Parvaneh Maghami, Azar Fanipakdel, Amir Avan.
      The application of Oxaliplatin (OxPt) in different malignancies is reported to be accompanied by several side effects including neuropathy, nausea, vomiting, diarrhea, mouth sores, low blood counts, loss of appetite, etc. The passive or active targeting of different tumors can improve OxPt delivery. Considering the demand for novel systems meant to improve the OxPt efficacy and define the shortcomings, we provided an overview of different approaches regarding the delivery of OxPt. There is an extending body of data that exhibits the value of Liposomes and polymer-based drug delivery systems as the most successful systems among the OxPt drug delivery procedures. Several clinical trials have been carried out to investigate the side effects and dose-limiting toxicity of liposomal oxaliplatin such as the assessment on Safety Study of MBP-426 (Liposomal Oxaliplatin Suspension for Injection) to Treat Advanced or Metastatic Solid Tumors. In addition, several studies indicated the biocompatibility and biodegradability of this product, as well as its option for being fictionalized to derive specialized smart nanosystems for the treatment of cancer. The better delivery of OxPt with weaker side effects could be generated by the exertion of Oxaliplatin, which involves the aggregation of new particles and multifaceted nanocarriers to compose a nanocomposite with both inorganic and organic nanoparticles.
    Keywords:  Drug delivery; cancer; nanocarrier; nanotechnology; oxaliplatin; toxicity
    DOI:  https://doi.org/10.2174/1568009622666220120115140
  44. PLoS One. 2022 ;17(1): e0261370
    Curcumin suppresses tumorigenesis by ferroptosis in breast cancer.
    Xuelei Cao, Yao Li, Yongbin Wang, Tao Yu, Chao Zhu, Xuezhi Zhang, Jialiang Guan.
      Breast cancer (BC) is one of the most common malignant tumors found in females. Previous studies have demonstrated that curcumin, which is a type of polyphenol compound extracted from Curcuma longa underground rhizome, is able to inhibit the survival of cancer cells. However, the functional role and mechanism of curcumin in BC are still unclear. The Cell Counting Kit-8 assay was performed to examine the effects of curcumin on cell viability in the BC cell lines MDA-MB-453 and MCF-7. The levels of lipid reactive oxygen species (ROS), malondialdehyde (MDA) production, and intracellular Fe2+ were determined to assess the effects of curcumin on cell ferroptosis. Western blot analysis was also carried out to detect the protein levels. Finally, the antitumorigenic effect of curcumin on BC was identified in a xenograft tumor model. In the present study, the results indicated that curcumin could dose-dependently suppress the viability of both MDA-MB-453 and MCF-7 cells. Further studies revealed that curcumin facilitated solute carrier family 1 member 5 (SLC1A5)-mediated ferroptosis in both MDA-MB-453 and MCF-7 cells by enhancing lipid ROS levels, lipid peroxidation end-product MDA accumulation, and intracellular Fe2+ levels. In vivo experiments demonstrated that curcumin could significantly hamper tumor growth. Collectively, the results demonstrated that curcumin exhibited antitumorigenic activity in BC by promoting SLC1A5-mediated ferroptosis, which suggests its use as a potential therapeutic agent for the treatment of BC.
    DOI:  https://doi.org/10.1371/journal.pone.0261370
  45. Pharmaceutics. 2021 Dec 28. pii: 70. [Epub ahead of print]14(1):
    Gold-Polymer Nanocomposites for Future Therapeutic and Tissue Engineering Applications.
    Panangattukara Prabhakaran Praveen Kumar, Dong-Kwon Lim.
      Gold nanoparticles (AuNPs) have been extensively investigated for their use in various biomedical applications. Owing to their biocompatibility, simple surface modifications, and electrical and unique optical properties, AuNPs are considered promising nanomaterials for use in in vitro disease diagnosis, in vivo imaging, drug delivery, and tissue engineering applications. The functionality of AuNPs may be further expanded by producing hybrid nanocomposites with polymers that provide additional functions, responsiveness, and improved biocompatibility. Polymers may deliver large quantities of drugs or genes in therapeutic applications. A polymer alters the surface charges of AuNPs to improve or modulate cellular uptake efficiency and their biodistribution in the body. Furthermore, designing the functionality of nanocomposites to respond to an endo- or exogenous stimulus, such as pH, enzymes, or light, may facilitate the development of novel therapeutic applications. In this review, we focus on the recent progress in the use of AuNPs and Au-polymer nanocomposites in therapeutic applications such as drug or gene delivery, photothermal therapy, and tissue engineering.
    Keywords:  drug delivery; gold nanoparticles; photodynamic therapy; photothermal therapy; polymers; tissue engineering
    DOI:  https://doi.org/10.3390/pharmaceutics14010070
  46. Mater Today Bio. 2022 Jan;13 100197
    Recent advances in multifunctional nanomaterials for photothermal-enhanced Fenton-based chemodynamic tumor therapy.
    Panchanathan Manivasagan, Ara Joe, Hyo-Won Han, Thavasyappan Thambi, Manickam Selvaraj, Kumarappan Chidambaram, Jungbae Kim, Eue-Soon Jang.
      Photothermal (PT)-enhanced Fenton-based chemodynamic therapy (CDT) has attracted a significant amount of research attention over the last five years as a highly effective, safe, and tumor-specific nanomedicine-based therapy. CDT is a new emerging nanocatalyst-based therapeutic strategy for the in situ treatment of tumors via the Fenton reaction or Fenton-like reaction, which has got fast progress in recent years because of its high specificity and activation by endogenous substances. A variety of multifunctional nanomaterials such as metal-, metal oxide-, and metal-sulfide-based nanocatalysts have been designed and constructed to trigger the in situ Fenton or Fenton-like reaction within the tumor microenvironment (TME) to generate highly cytotoxic hydroxyl radicals (•OH), which is highly efficient for the killing of tumor cells. However, research is still required to enhance the curative outcomes and minimize its side effects. Specifically, the therapeutic efficiency of certain CDTs is still hindered by the TME, including low levels of endogenous hydrogen peroxide (H2O2), overexpression of reduced glutathione (GSH), and low catalytic efficacy of Fenton or Fenton-like reactions (pH 5.6-6.8), which makes it difficult to completely cure cancer using monotherapy. For this reason, photothermal therapy (PTT) has been utilized in combination with CDT to enhance therapeutic efficacy. More interestingly, tumor heating during PTT not only causes damage to the tumor cells but can also accelerate the generation of •OH via the Fenton and Fenton-like reactions, thus enhancing the CDT efficacy, providing more effective cancer treatment when compared with monotherapy. Currently, synergistic PT-enhanced CDT using multifunctional nanomaterials with both PT and chemodynamic properties has made enormous progress in cancer theranostics. However, there has been no comprehensive review on this subject published to date. In this review, we first summarize the recent progress in PT-enhanced Fenton-based CDT for cancer treatment. We then discuss the potential and challenges in the future development of PT-enhanced Fenton-based nanocatalytic tumor therapy for clinical application.
    Keywords:  Chemodynamic therapy; Combination therapy; Fenton reaction; Nanomaterials; Photothermal therapy
    DOI:  https://doi.org/10.1016/j.mtbio.2021.100197
  47. Mol Pharm. 2022 Jan 15.
    Enzyme-Activated Multifunctional Prodrug Combining Site-Specific Chemotherapy with Light-Triggered Photodynamic Therapy.
    Hong-Xia Zhang, Hao-Hua Lin, Dan Su, De-Chao Yang, Jian-Yong Liu.
      Combination treatments are more effective than conventional monotherapy in combating cancer. Herein, a multifunctional prodrug BDP-L-CPT was rationally engineered and prepared by the conjugation of a boron dipyrromethene (BDP)-based photosensitizer (PS) to the active site of the chemotherapeutic drug camptothecin (CPT) via a phenyl benzoate group. After modification, the cytotoxicity of CPT was locked. Moreover, the fluorescence emission at 430 nm from the CPT component in the prodrug was substantially inhibited through the intramolecular fluorescence resonance energy transfer process. The phenyl benzoate linker in BDP-L-CPT could be selectively cleaved by exogenous carboxylesterase in phosphate-buffered saline solution and endogenous carboxylesterase overexpressed in cancer cells, which was followed by self-immolation to release free CPT. The drug release process could be monitored by the turn-on of CPT fluorescence in solution and cells. Owing to the combination of site-specific chemotherapy with light-driven photodynamic therapy, the IC50 values of the prodrug BDP-L-CPT against HepG2 human hepatocellular carcinoma and HeLa human cervical carcinoma cells were lower than those of the controls, BDP-COOH and CPT. The combined antitumor effects of the prodrug BDP-L-CPT were also observed in the mice bearing H22 tumors. Furthermore, BDP-L-CPT had a more prolonged blood circulation time in mice than CPT, which is beneficial to persistent therapy. This study may provide a promising strategy for a selective combination cancer treatment by conjugating a prodrug to a PS.
    Keywords:  boron dipyrromethene; carboxylesterase; combination therapy; multifunctional prodrug; photodynamic therapy; site-specific chemotherapy
    DOI:  https://doi.org/10.1021/acs.molpharmaceut.1c00761
  48. J Exp Clin Cancer Res. 2022 Jan 19. 41(1): 27
    The path to the clinic: a comprehensive review on direct KRASG12C inhibitors.
    Albert K Kwan, Gary A Piazza, Adam B Keeton, Caio A Leite.
      The RAS oncogene is both the most frequently mutated oncogene in human cancer and the first confirmed human oncogene to be discovered in 1982. After decades of research, in 2013, the Shokat lab achieved a seminal breakthrough by showing that the activated KRAS isozyme caused by the G12C mutation in the KRAS gene can be directly inhibited via a newly unearthed switch II pocket. Building upon this groundbreaking discovery, sotorasib (AMG510) obtained approval by the United States Food and Drug Administration in 2021 to become the first therapy to directly target the KRAS oncoprotein in any KRAS-mutant cancers, particularly those harboring the KRASG12C mutation. Adagrasib (MRTX849) and other direct KRASG12C inhibitors are currently being investigated in multiple clinical trials. In this review, we delve into the path leading to the development of this novel KRAS inhibitor, starting with the discovery, structure, and function of the RAS family of oncoproteins. We then examine the clinical relevance of KRAS, especially the KRASG12C mutation in human cancer, by providing an in-depth analysis of its cancer epidemiology. Finally, we review the preclinical evidence that supported the initial development of the direct KRASG12C inhibitors and summarize the ongoing clinical trials of all direct KRASG12C inhibitors.
    Keywords:  Adagrasib; Cancer; Clinical trial; Direct RAS inhibitor; Drug development; Epidemiology; Immunotherapy; KRASG12C; Sotorasib
    DOI:  https://doi.org/10.1186/s13046-021-02225-w
  49. J Nanobiotechnology. 2022 Jan 21. 20(1): 43
    A tumor microenvironment-responsive poly(amidoamine) dendrimer nanoplatform for hypoxia-responsive chemo/chemodynamic therapy.
    Yingchao Hao, Yue Gao, Yu Fan, Changchang Zhang, Mengsi Zhan, Xueyan Cao, Xiangyang Shi, Rui Guo.
       BACKGROUND: Chemodynamic therapy is a promising cancer treatment with specific therapeutic effect at tumor sites, as toxic hydroxyl radical (·OH) could only be generated by Fenton or Fenton-like reaction in the tumor microenvironment (TME) with low pH and high level of endogenous hydrogen peroxide. However, the low concentration of catalytic metal ions, excessive glutathione (GSH) and aggressive hypoxia at tumor site seriously restrict the curative outcomes of conventional chemodynamic therapy.
    RESULTS: In this study, polyethylene glycol-phenylboronic acid (PEG-PBA)-modified generation 5 (G5) poly(amidoamine) (PAMAM) dendrimers were synthesized as a targeted nanocarrier to chelate Cu(II) and then encapsulate hypoxia-sensitive drug tirapazamine (TPZ) by the formation of hydrophobic Cu(II)/TPZ complex for hypoxia-enhanced chemo/chemodynamic therapy. The formed G5.NHAc-PEG-PBA@Cu(II)/TPZ (GPPCT) nanoplatform has good stability and hemocompatibility, and could release Cu(II) ions and TPZ quickly in weakly acidic tumor sites via pH-sensitive dissociation of Cu(II)/TPZ. In vitro experiments showed that the GPPCT nanoplatforms can efficiently target murine breast cancer cells (4T1) cells overexpressing sialic acid residues, and show a significantly enhanced inhibitory effect on hypoxic cells by the activation of TPZ. The excessive GSH in tumors could be depleted by the reduction of Cu(II) to Cu(I), and abundant of toxic ·OH would be generated in tumor cells by Fenton reaction for chemodynamic therapy. In vivo experiments demonstrated that the GPPCT nanoplatform could specifically accumulate at tumors, effectively inhibit the growth and metastasis of tumors by the combination of CDT and chemotherapy, and be metabolized with no systemic toxicity.
    CONCLUSIONS: The targeted GPPCT nanoplatform may represent an effective model for the synergistic inhibition of different tumor types by hypoxia-enhanced chemo/chemodynamic therapy.
    Keywords:  Chemodynamic therapy (CDT); PAMAM dendrimer; Synergistic therapy; Tirapazamine (TPZ); Tumor microenvironment-responsive
    DOI:  https://doi.org/10.1186/s12951-022-01247-6
  50. Pharmaceutics. 2022 Jan 08. pii: 148. [Epub ahead of print]14(1):
    Combined Antitumor Therapy Using In Situ Injectable Hydrogels Formulated with Albumin Nanoparticles Containing Indocyanine Green, Chlorin e6, and Perfluorocarbon in Hypoxic Tumors.
    Woo Tak Lee, Johyun Yoon, Sung Soo Kim, Hanju Kim, Nguyen Thi Nguyen, Xuan Thien Le, Eun Seong Lee, Kyung Taek Oh, Han-Gon Choi, Yu Seok Youn.
      Combined therapy using photothermal and photodynamic treatments together with chemotherapeutic agents is considered one of the most synergistic treatment protocols to ablate hypoxic tumors. Herein, we sought to fabricate an in situ-injectable PEG hydrogel system having such multifunctional effects. This PEG hydrogel was prepared with (i) nabTM-technique-based paclitaxel (PTX)-bound albumin nanoparticles with chlorin-e6 (Ce6)-conjugated bovine serum albumin (BSA-Ce6) and indocyanine green (ICG), named ICG/PTX/BSA-Ce6-NPs (~175 nm), and (ii) an albumin-stabilized perfluorocarbon (PFC) nano-emulsion (BSA-PFC-NEs; ~320 nm). This multifunctional PEG hydrogel induced moderate and severe hyperthermia (41-42 °C and >48 °C, respectively) at the target site under two different 808 nm laser irradiation protocols, and also induced efficient singlet oxygen (1O2) generation under 660 nm laser irradiation supplemented by oxygen produced by ultrasound-triggered PFC. Due to such multifunctionality, our PEG hydrogel formula displayed significantly enhanced killing of three-dimensional 4T1 cell spheroids and also suppressed the growth of xenografted 4T1 cell tumors in mice (tumor volume: 47.7 ± 11.6 and 63.4 ± 13.0 mm3 for photothermal and photodynamic treatment, respectively, vs. PBS group (805.9 ± 138.5 mm3), presumably based on sufficient generation of moderate heat as well as 1O2/O2 even under hypoxic conditions. Our PEG hydrogel formula also showed excellent hyperthermal efficacy (>50 °C), ablating the 4T1 tumors when the irradiation duration was extended and output intensity was increased. We expect that our multifunctional PEG hydrogel formula will become a prototype for ablation of otherwise poorly responsive hypoxic tumors.
    Keywords:  combined antitumor effect; hydrogel; hypoxic tumor; oxygenation; photodynamic therapy; photothermal therapy
    DOI:  https://doi.org/10.3390/pharmaceutics14010148
  51. Pharmaceutics. 2022 Jan 07. pii: 143. [Epub ahead of print]14(1):
    Enzyme-Responsive Amphiphilic Peptide Nanoparticles for Biocompatible and Efficient Drug Delivery.
    Su Jeong Song, Joon Sig Choi.
      Self-assembled peptide nanostructures recently have gained much attention as drug delivery systems. As biomolecules, peptides have enhanced biocompatibility and biodegradability compared to polymer-based carriers. We introduce a peptide nanoparticle system containing arginine, histidine, and an enzyme-responsive core of repeating GLFG oligopeptides. GLFG oligopeptides exhibit specific sensitivity towards the enzyme cathepsin B that helps effective controlled release of cargo molecules in the cytoplasm. Arginine can induce cell penetration, and histidine facilitates lysosomal escape by its buffering capacity. Herein, we propose an enzyme-responsive amphiphilic peptide delivery system (Arg-His-(Gly-Phe-Lue-Gly)3, RH-(GFLG)3). The self-assembled RH-(GFLG)3 globular nanoparticle structure exhibited a positive charge and formulation stability for 35 days. Nile Red-tagged RH-(GFLG)3 nanoparticles showed good cellular uptake compared to the non-enzyme-responsive control groups with d-form peptides (LD (LRH-D(GFLG)3), DL (DRH-L(GFLG)3), and DD (DRH-D(GFLG)3). The RH-(GFLG)3 nanoparticles showed negligible cytotoxicity in HeLa cells and human RBCs. To determine the drug delivery efficacy, we introduced the anticancer drug doxorubicin (Dox) in the RH-(GFLG)3 nanoparticle system. LL-Dox exhibited formulation stability, maintaining the physical properties of the nanostructure, as well as a robust anticancer effect in HeLa cells compared to DD-Dox. These results indicate that the enzyme-sensitive RH-(GFLG)3 peptide nanoparticles are promising candidates as drug delivery carriers for biomedical applications.
    Keywords:  cytotoxicity; doxorubicin; drug delivery systems; peptide nanoparticle
    DOI:  https://doi.org/10.3390/pharmaceutics14010143
  52. Front Pharmacol. 2021 ;12 775084
    Current Advances in Coptidis Rhizoma for Gastrointestinal and Other Cancers.
    Luying He, Man Chen, Qilian Liang, Yitao Wang, Wen Tan.
      Cancer is a serious disease with an increasing number of reported cases and high mortality worldwide. Gastrointestinal cancer defines a group of cancers in the digestive system, e.g., liver cancer, colorectal cancer, and gastric cancer. Coptidis Rhizoma (C. Rhizoma; Huanglian, in Chinese) is a classical Chinese medicinal botanical drug for the treatment of gastrointestinal disorders and has been shown to have a wide variety of pharmacological activity, including antifungal, antivirus, anticancer, antidiabetic, hypoglycemic, and cardioprotective effects. Recent studies on C. Rhizoma present significant progress on its anticancer effects and the corresponding mechanisms as well as its clinical applications. Herein, keywords related to C. Rhizoma, cancer, gastrointestinal cancer, and omics were searched in PubMed and the Web of Science databases, and more than three hundred recent publications were reviewed and discussed. C. Rhizoma extract along with its main components, berberine, palmatine, coptisine, magnoflorine, jatrorrhizine, epiberberine, oxyepiberberine, oxyberberine, dihydroberberine, columbamine, limonin, and derivatives, are reviewed. We describe novel and classic anticancer mechanisms from various perspectives of pharmacology, pharmaceutical chemistry, and pharmaceutics. Researchers have transformed the chemical structures and drug delivery systems of these components to obtain better efficacy and bioavailability of C. Rhizoma. Furthermore, C. Rhizoma in combination with other drugs and their clinical application are also summarized. Taken together, C. Rhizoma has broad prospects as a potential adjuvant candidate against cancers, making it reasonable to conduct additional preclinical studies and clinical trials in gastrointestinal cancer in the future.
    Keywords:  clinical research; coptidis rhizoma; gastrointestinal cancer; medicinal plant; omics
    DOI:  https://doi.org/10.3389/fphar.2021.775084
  53. ACS Appl Bio Mater. 2022 Jan 18.
    Engineering Cellular Membrane for Dual Mode Therapy Using NIR Responsive Photosensitizer and Reversible Topoisomerase Inhibition Activity.
    Sahil Malhotra, Shweta Dumoga, Supriya Mehta, E Pranshu Rao, Sujata Mohanty, Neetu Singh.
      Extensive research over past few decades has highlighted the challenges of chemotherapy and prompted the need for multimodality therapy because chemotherapy alone cannot fully eradicate the tumor due to physiological barriers in its effective delivery and systemic side effects. It can be mitigated by adopting nanoparticles as more effective delivery method, but none of them completely prevents drug toxicities. Utilizing multiple therapeutic modes such as phototherapy that can act synergistically with chemotherapy in controlling tumor growth, while reducing the overall dosage, could become a preferred route for cancer management. Careful selection of nanoparticle system, which can simultaneously deliver both drug and photosensitizer, can significantly enhance the therapeutic outcome. Therefore, in this paper, we report development and potential of immune-compatible and long circulating nanoerythrosomes for enhancing the therapeutic potential of camptothecin and indocyanine green against murine cancer model. The RBCs membrane simultaneously loaded the nonpolar drug and amphiphilic photosensitizer in its lipid bilayer, which self-assembled to form stable nanoparticles. These nano constructs absorbed light in the near-infrared region and hence are suitable for targeting deep seated tissues. The dual chemo-phototherapy had great effect on cell viability and had therapeutic value.
    Keywords:  camptothecin; chemo-photothermal/photodynamic therapy; dual therapy; indocyanine green; nanovesicles; reactive oxygen species (ROS)
    DOI:  https://doi.org/10.1021/acsabm.1c01070
  54. Pharmaceutics. 2021 Dec 22. pii: 18. [Epub ahead of print]14(1):
    An Up-to-Date Review of Natural Nanoparticles for Cancer Management.
    Daniel Ion, Adelina-Gabriela Niculescu, Dan Nicolae Păduraru, Octavian Andronic, Florentina Mușat, Alexandru Mihai Grumezescu, Alexandra Bolocan.
      Cancer represents one of the leading causes of morbidity and mortality worldwide, imposing an urgent need to develop more efficient treatment alternatives. In this respect, much attention has been drawn from conventional cancer treatments to more modern approaches, such as the use of nanotechnology. Extensive research has been done for designing innovative nanoparticles able to specifically target tumor cells and ensure the controlled release of anticancer agents. To avoid the potential toxicity of synthetic materials, natural nanoparticles started to attract increasing scientific interest. In this context, this paper aims to review the most important natural nanoparticles used as active ingredients (e.g., polyphenols, polysaccharides, proteins, and sterol-like compounds) or as carriers (e.g., proteins, polysaccharides, viral nanoparticles, and exosomes) of various anticancer moieties, focusing on their recent applications in treating diverse malignancies.
    Keywords:  chemotherapeutic agents targeted delivery; natural anticancer compounds; natural cancer therapies; natural nanocarriers; natural nanoparticles; novel cancer treatment alternatives
    DOI:  https://doi.org/10.3390/pharmaceutics14010018
  55. Front Med Technol. 2021 ;3 700266
    Calcium Phosphate-Based Bioceramics in the Treatment of Osteosarcoma: Drug Delivery Composites and Magnetic Hyperthermia Agents.
    Tiê Menezes Oliveira, Fernanda Costa Brandão Berti, Sidney Carlos Gasoto, Bertoldo Schneider, Marco Augusto Stimamiglio, Lucas Freitas Berti.
      The use of biomaterials in medicine is not recent, and in the last few decades, the research and development of biocompatible materials had emerged. Hydroxyapatite (HAp), a calcium phosphate that constitutes a large part of the inorganic composition of human bones and teeth, has been used as an interesting bioceramic material. Among its applications, HAp has been used to carry antitumor drugs, such as doxorubicin, cisplatin, and gemcitabine. Such HAp-based composites have an essential role in anticancer drug delivery systems, including the treatment of osteosarcoma. In addition, the association of this bioceramic with magnetic nanoparticles (MNPs) has also been used as an effective agent of local magnetic hyperthermia. Further, the combined approach of the aforementioned techniques (HAp scaffolds combined with anti-tumor drugs and MNPs) is also an attractive therapeutical alternative. Considering the promising role of the use of bioceramics in modern medicine, we proposed this review, presenting an updated perspective on the use of HAp in the treatment of cancer, especially osteosarcoma. Finally, after giving the current progress in this field, we highlight the urgent need for efforts to provide a better understanding of their potential applications.
    Keywords:  bioceramic material; calcium phosphate; drug-delivery systems; hydroxyapatite; magnetic hyperthermia; osteosarcoma
    DOI:  https://doi.org/10.3389/fmedt.2021.700266
  56. Pharmaceutics. 2022 Jan 14. pii: 191. [Epub ahead of print]14(1):
    Nanofiber Systems as Herbal Bioactive Compounds Carriers: Current Applications in Healthcare.
    Kathya Huesca-Urióstegui, Elsy J García-Valderrama, Janet A Gutierrez-Uribe, Marilena Antunes-Ricardo, Daniel Guajardo-Flores.
      Nanofibers have emerged as a potential novel platform due to their physicochemical properties for healthcare applications. Nanofibers' advantages rely on their high specific surface-area-to-volume and highly porous mesh. Their peculiar assembly allows cell accommodation, nutrient infiltration, gas exchange, waste excretion, high drug release rate, and stable structure. This review provided comprehensive information on the design and development of natural-based polymer nanofibers with the incorporation of herbal medicines for the treatment of common diseases and their in vivo studies. Natural and synthetic polymers have been widely used for the fabrication of nanofibers capable of mimicking extracellular matrix structure. Among them, natural polymers are preferred because of their biocompatibility, biodegradability, and similarity with extracellular matrix proteins. Herbal bioactive compounds from natural extracts have raised special interest due to their prominent beneficial properties in healthcare. Nanofiber properties allow these systems to serve as bioactive compound carriers to generate functional matrices with antimicrobial, anti-inflammatory, antioxidant, antiseptic, anti-viral, and other properties which have been studied in vitro and in vivo, mostly to prove their wound healing capacity and anti-inflammation properties.
    Keywords:  bioactive compounds; healthcare; herbal extracts; in vivo studies; nanofibers
    DOI:  https://doi.org/10.3390/pharmaceutics14010191
  57. Nanomedicine (Lond). 2022 Jan 21.
    Copper-induced tumor cell death mechanisms and antitumor theragnostic applications of copper complexes.
    Yicheng Jiang, Zhiyi Huo, Xiaole Qi, Tongmei Zuo, Zhenghong Wu.
      Recent studies found that unbalanced copper homeostasis affect tumor growth, causing irreversible damage. Copper can induce multiple forms of cell death, including apoptosis and autophagy, through various mechanisms, including reactive oxygen species accumulation, proteasome inhibition, and antiangiogenesis. Hence, copper in vivo has attracted tremendous attention and is in the research spotlight in the field of tumor treatment. This review first highlights three typical forms of copper's antitumor mechanisms. Then, the development of diverse biomaterials and nanotechnology allowing copper to be fabricated into diverse structures to realize its theragnostic action is discussed. Novel copper complexes and their clinical applications are subsequently described.
    Keywords:  Fenton reaction; antitumor; bioimaging; chemodynamic therapy; copper; phototherapy; reactive oxygen species
    DOI:  https://doi.org/10.2217/nnm-2021-0374
  58. J Mater Chem B. 2022 Jan 21.
    Synthesis of sialic acid conjugates of the clinical near-infrared dye as next-generation theranostics for cancer phototherapy.
    Huiling Dong, Yanan Gao, Xuefei Huang, Xuanjun Wu.
      Cancer is a multifaceted global health problem that requires continuous action to develop next-generation cancer theranostics. Inspired by the emerging use of indocyanine green (ICG), the only clinically approved near-infrared (NIR) dye for cancer phototherapy, here we synthesized two ICG conjugate theranostics by coupling ICG to sialic acid (Sia) through the C2 and C9 positions of Sia, respectively, referred to as Sia-C2-ICG and Sia-C9-ICG. Encouragingly, Sia-C2/C9-ICGs show superior in vitro properties, including enhanced stability, reduced non-specific binding to serum proteins, and improved blood compatibility, highlighting the benefits of Sia coupling. Notably, in vivo NIR imaging shows that Sia-C9-ICG significantly promotes tumor targeting and effectively prolongs the circulation time in the body, while Sia-C2-ICG is superior to ICG but inferior to Sia-C9-ICG in targeting tumors. Furthermore, Sia-C9-ICG combined with NIR laser irradiation can lead to excellent photothermal and photodynamic therapies for cancer cells, resulting in superior solid tumor ablation. To our knowledge, this is the first report of Sia-NIR conjugates achieving significant tumor reduction in vivo. Together, these advances render Sia-C9-ICG an attractive lead as next-generation cancer theranostics that can be translated clinically to treat human patients.
    DOI:  https://doi.org/10.1039/d1tb02693c
  59. J Nanobiotechnology. 2022 Jan 21. 20(1): 44
    Peptide-based semiconducting polymer nanoparticles for osteosarcoma-targeted NIR-II fluorescence/NIR-I photoacoustic dual-model imaging and photothermal/photodynamic therapies.
    Ying Yuan, Shanchao Diao, Xiaoyue Ni, Dong Zhang, Wanrong Yi, Chao Jian, Xiang Hu, Daifeng Li, Aixi Yu, Wen Zhou, Quli Fan.
       BACKGROUND: The overall survival rate of osteosarcoma (OS) patients has not been improved for 30 years, and the diagnosis and treatment of OS is still a critical issue. To improve OS treatment and prognosis, novel kinds of theranostic modalities are required. Molecular optical imaging and phototherapy, including photothermal therapy (PTT) and photodynamic therapy (PDT), are promising strategies for cancer theranostics that exhibit high imaging sensitivity as well as favorable therapeutic efficacy with minimal side effect. In this study, semiconducting polymer nanoparticles (SPN-PT) for OS-targeted PTT/PDT are designed and prepared, using a semiconducting polymer (PCPDTBT), providing fluorescent emission in the second near-infrared window (NIR-II, 1000 - 1700 nm) and photoacoustic (PA) signal in the first near-infrared window (NIR-I, 650 - 900 nm), served as the photosensitizer, and a polyethylene glycolylated (PEGylated) peptide PT, providing targeting ability to OS.
    RESULTS: The results showed that SPN-PT nanoparticles significantly accelerated OS-specific cellular uptake and enhanced therapeutic efficiency of PTT and PDT effects in OS cell lines and xenograft mouse models. SPN-PT carried out significant anti-tumor activities against OS both in vitro and in vivo.
    CONCLUSIONS: Peptide-based semiconducting polymer nanoparticles permit efficient NIR-II fluorescence/NIR-I PA dual-modal imaging and targeted PTT/PDT for OS.
    Keywords:  Dual-modal imaging; Osteosarcoma-targeted; Photodynamic therapy; Photothermal therapy
    DOI:  https://doi.org/10.1186/s12951-022-01249-4
  60. Biomater Sci. 2022 Jan 19.
    A self-amplified ROS-responsive chemodrug-inhibitor conjugate for multi-drug resistance tumor therapy.
    Tingting Sun, Jie Xu, Tianbao Chen, Chunlai Tu, Lijuan Zhu, Deyue Yan.
      P-glycoprotein (P-gp) induced multidrug resistance (MDR) is the main reason for the failure of cancer chemotherapy. The combined delivery of chemodrug and P-gp inhibitor is a promising pathway to reverse MDR. However, the intrinsic stimuli in the tumor microenvironment could not realize a complete drug release, which would induce poor cancer therapeutic efficacy. Herein, we conjugated tamoxifen (TAM) with D-α-tocopherol polyethylene glycol1000 succinate (TPGS) based on a reactive oxygen species (ROS)-responsive aryl boronic ester bond to construct a self-amplified ROS-responsive chemodrug-inhibitor (TPGS-TAM) co-delivery system. Due to its amphiphilic property, the TPGS-TAM conjugates could self-assemble into uniform spherical nanoparticles (NPs). After effective endocytosis by cancer cells, the intracellular ROS cleaved the aryl boronic ester bond and initiated the release of TAM and α-tocopherol succinate (α-TOS) from the NPs. Subsequently, the released α-TOS further generated ROS to facilitate the release of TAM. Moreover, α-TOS also consumed adenosine triphosphate (ATP) to impair ATP-dependent P-gp mediated drug efflux to reverse the tumor's drug resistance. As a result, the TPGS-TAM NPs enhanced the antitumor effect with a tumor inhibition rate (TIR) high up to 74.6 ± 6.1% in an MCF-7/ADR tumor model. Based on systematic in vitro and in vivo assessments, this self-amplified ROS-responsive carrier-free conjugate of chemodrug/P-gp inhibitor may shed light on the potential application for the MDR cancer therapy.
    DOI:  https://doi.org/10.1039/d1bm01605a
  61. Adv Sci (Weinh). 2022 Jan 17. e2104671
    A "Valve-Closing" Starvation Strategy for Amplification of Tumor-Specific Chemotherapy.
    Xianglong Li, Cong Jiang, Qinghua Wang, Shaobo Yang, Yuanyuan Cao, Ji-Na Hao, Dechao Niu, Yan Chen, Bo Han, Xin Jia, Peng Zhang, Yongsheng Li.
      Starvation-dependent differential stress sensitization effect between normal and tumor cells provides a potentially promising strategy to amplify chemotherapy effects and reduce side effects. However, the conventional starvation approaches such as glucose oxidase (Gox)-induced glucose depletion and nanomedicine-enabled vascular embolism usually suffer from aggravated tumor hypoxia, systemic toxicity, and unpredictable metabolic syndrome. Herein, a novel "valve-closing" starvation strategy is developed to amplify the chemotherapy effects via closing the "valve" of glucose transported into tumor cells, which is accomplished by a glucose transporters 1 (GLUT1, valve of glucose uptake) inhibitor (Genistein, Gen) and chemotherapeutic agent (Curcumin, Cur) coloaded hybrid organosilica-micelles nanomedicine (designated as (Gen + Cur)@FOS) with controllable stability. In vitro and in vivo results demonstrate that (Gen + Cur)@FOS can effectively reduce glucose/adenosine triphosphate levels in tumor cells by inhibiting GLUT1 expression (i.e., "valve-closing") to induce the starvation of tumor cells, thus weakening the resistance of tumor cells to apoptosis caused by chemotherapy, and consequently contributing to the remarkably improved antitumor efficiency and minimized side effects based on the stress sensitization effect mediated by GLUT1 inhibition-induced starvation. This "valve-closing" starvation strategy provides a promising paradigm for the development of novel nanotherapeutics with amplified chemotherapy effect.
    Keywords:  GLUT1 inhibition; differential stress sensitization; glucose metabolism; stability-controllable nanomedicines; starvation-sensitized chemotherapy
    DOI:  https://doi.org/10.1002/advs.202104671
  62. Adv Sci (Weinh). 2022 Jan 22. e2104793
    Dynamic Adjust of Non-Radiative and Radiative Attenuation of AIE Molecules Reinforces NIR-II Imaging Mediated Photothermal Therapy and Immunotherapy.
    Zhenjie Wang, Ling Yu, Yuehua Wang, Chenlu Wang, Qingchun Mu, Xiaojing Liu, Meng Yu, Kang-Nan Wang, Guangyu Yao, Zhiqiang Yu.
      Due to the aggregation-caused quenching effect and near-infrared I poor penetration capabilities of common fluorescent molecules, their applications in visualized imaging and photoactivated treatment are limited. Therefore, new near-infrared II (NIR-II) molecule (named TST), which had the abilities of aggregation-induced emission (AIE) and photothermal therapy are synthesized. Moreover, in order to further improve its fluorescent yield and therapeutic effect, camptothecin prodrug (CPT-S-PEG) and novel immune checkpoint inhibitor AZD4635 are used to co-assemble with TST into nanoparticles for drug delivery. On account of the strong interaction of camptothecin and TST, the intramolecular rotation of TST is limited, thereby inhibiting non-radiation attenuation and promoting fluorescence generation when the nanoparticles are intact. As nanoparticles uptake by cancer cells, redox sensitive CPT-S-PEG is degraded and the nanoparticles disintegrate. The released TST enhances non-radiative attenuation and expedites photothermal conversion because of the removal of the constraint of camptothecin. Furthermore, photothermal therapy induces immunogenic cell death of cancer cells and releases abundant ATP into the tumor microenvironment to recruit immune cells. However, superfluous ATP is converted into immunosuppressive adenosine through the CD39-CD73-A2AR pathway. The AZD4635 released by photothermal disintegration of the nanoparticles just blocks this pathway timely, achieving favorable synergistic effect of photothermal therapy, chemotherapy, and immunotherapy.
    Keywords:  AIE; CD39-CD73-A2AR; NIR-II; immunogenic cell death; photothermal therapy
    DOI:  https://doi.org/10.1002/advs.202104793
  63. Curr Stem Cell Res Ther. 2022 ;17(1): 26-42
    The Potential Applications of Stem Cells for Cancer Treatment.
    Malikeh Rad Niknam, Farnoosh Attari.
      Scientists encounter many obstacles in traditional cancer therapies, including the side effects on the healthy cells, drug resistance, tumor relapse, the short half-life of employed drugs in the blood circulation, and the improper delivery of drugs toward the tumor site. The unique traits of stem cells (SCs) such as self-renewal, differentiation, tumor tropism, the release of bioactive molecules, and immunosuppression have opened a new window for utilizing SCs as a novel tool in cancer treatment. In this regard, engineered SCs can secrete anti-cancer proteins or express enzymes used in suicide gene therapy which locally induce apoptosis in neoplastic cells via the bystander effect. These cells also stand as proper candidates to serve as careers for drug-loaded nanoparticles or to play suitable hosts for oncolytic viruses. Moreover, they harbor great potential to be employed in immunotherapy and combination therapy. However, tactful strategies should be devised to allow easier transplantation and protection of SCs from in vivo immune responses. In spite of the great hope concerning SCs application in cancer therapy, there are shortcomings and challenges to be addressed. This review tends to elaborate on recent advances on the various applications of SCs in cancer therapy and existing challenges in this regard.
    Keywords:  Stem cells; cancer treatment; encapsulation; immunosuppression; nanoparticle carrier; suicide gene therapy
    DOI:  https://doi.org/10.2174/1574888X16666210810100858
  64. Medicina (Kaunas). 2021 Dec 28. pii: 46. [Epub ahead of print]58(1):
    Interactions of Analgesics with Cisplatin: Modulation of Anticancer Efficacy and Potential Organ Toxicity.
    Azza El-Sheikh, Zenat Khired.
      Cisplatin (CDDP), one of the most eminent cancer chemotherapeutic agents, has been successfully used to treat more than half of all known cancers worldwide. Despite its effectiveness, CDDP might cause severe toxic adverse effects on multiple body organs during cancer chemotherapy, including the kidneys, heart, liver, gastrointestinal tract, and auditory system, as well as peripheral nerves causing severely painful neuropathy. The latter, among other pains patients feel during chemotherapy, is an indication for the use of analgesics during treatment with CDDP. Different types of analgesics, such as acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS), and narcotic analgesics, could be used according to the severity of pain. Administered analgesics might modulate CDDP's efficacy as an anticancer drug. NSAIDS, on one hand, might have cytotoxic effects on their own and few of them can potentiate CDDP's anticancer effects via inhibiting the CDDP-induced cyclooxygenase (COX) enzyme, or through COX-independent mechanisms. On the other hand, some narcotic analgesics might ameliorate CDDP's anti-neoplastic effects, causing chemotherapy to fail. Concerning safety, some analgesics share the same adverse effects on normal tissues as CDDP, augmenting its potentially hazardous effects on organ impairment. This article offers an overview of the reported literature on the interactions between analgesics and CDDP, paying special attention to possible mechanisms that modulate CDDP's cytotoxic efficacy and potential adverse reactions.
    Keywords:  acetaminophen; analgesics; cisplatin; cytotoxicity; morphine; non-steroidal anti-inflammatory drugs
    DOI:  https://doi.org/10.3390/medicina58010046
  65. ACS Appl Mater Interfaces. 2022 Jan 20.
    Amplifying Free Radical Generation of AIE Photosensitizer with Small Singlet-Triplet Splitting for Hypoxia-Overcoming Photodynamic Therapy.
    Ya-Fang Xiao, Wen-Cheng Chen, Jia-Xiong Chen, Guihong Lu, Shuang Tian, Xiao Cui, Zhen Zhang, Huan Chen, Yingpeng Wan, Shengliang Li, Chun-Sing Lee.
      Type-I photodynamic therapy (PDT) with less oxygen consumption shows great potential for overcoming the vicious hypoxia typically observed in solid tumors. However, the development of type-I PDT is hindered by insufficient radical generation and the ambiguous design strategy of type-I photosensitizers (PSs). Therefore, developing highly efficient type-I PSs and unveiling their structure-function relationship are still urgent and challenging. Herein, we develop two phenanthro[9,10-d]imidazole derivatives (AQPO and AQPI) with aggregation-induced emission (AIE) characteristics and boost their reactive oxygen species (ROS) generation efficiency by reducing singlet-triplet splitting (ΔEST). Both AQPO and AQPI show ultrasmall ΔEST values of 0.09 and 0.12 eV, respectively. By incorporating electron-rich anisole, the categories of generated ROS by AIE PSs are changed from type-II (singlet oxygen, 1O2) to type-I (superoxide anion radical, O2•- and hydroxyl radical, •OH). We demonstrate that the assembled AQPO nanoparticles (NPs) achieve a 3.2- and 2.9-fold increase in the O2•- and •OH generation efficiencies, respectively, compared to those of AQPI NPs (without anisole) in water, whereas the 1O2 generation efficiency of AQPO NPs is lower (0.4-fold) than that of AQPI NPs. The small ΔEST and anisole group endow AQPO with an excellent capacity for type-I ROS generation. In vitro and in vivo experiments show that AQPO NPs achieve an excellent hypoxia-overcoming PDT effect by efficiently eliminating tumor cells upon white light irradiation with good biosafety.
    Keywords:  aggregate-induced emission; electron-rich group; hypoxia; singlet−triplet splitting; type-I photodynamic therapy
    DOI:  https://doi.org/10.1021/acsami.1c23797
  66. Biosensors (Basel). 2022 Jan 12. pii: 38. [Epub ahead of print]12(1):
    Design of Magnetic Nanoplatforms for Cancer Theranostics.
    Wangbo Jiao, Tingbin Zhang, Mingli Peng, Jiabao Yi, Yuan He, Haiming Fan.
      Cancer is the top cause of death globally. Developing smart nanomedicines that are capable of diagnosis and therapy (theranostics) in one-nanoparticle systems are highly desirable for improving cancer treatment outcomes. The magnetic nanoplatforms are the ideal system for cancer theranostics, because of their diverse physiochemical properties and biological effects. In particular, a biocompatible iron oxide nanoparticle based magnetic nanoplatform can exhibit multiple magnetic-responsive behaviors under an external magnetic field and realize the integration of diagnosis (magnetic resonance imaging, ultrasonic imaging, photoacoustic imaging, etc.) and therapy (magnetic hyperthermia, photothermal therapy, controlled drug delivery and release, etc.) in vivo. Furthermore, due to considerable variation among tumors and individual patients, it is a requirement to design iron oxide nanoplatforms by the coordination of diverse functionalities for efficient and individualized theranostics. In this article, we will present an up-to-date overview on iron oxide nanoplatforms, including both iron oxide nanomaterials and those that can respond to an externally applied magnetic field, with an emphasis on their applications in cancer theranostics.
    Keywords:  cancer; iron oxide nanoparticles; magnetotheranostics
    DOI:  https://doi.org/10.3390/bios12010038
  67. Biol Futur. 2022 Jan 17.
    Diet-derived small molecules (nutraceuticals) inhibit cellular proliferation by interfering with key oncogenic pathways: an overview of experimental evidence in cancer chemoprevention.
    Mohammad Fahad Ullah, Aamir Ahmad, Showket H Bhat, Faisel M Abuduhier, Syed Khalid Mustafa, Shazia Usmani.
      Discouraging statistics of cancer disease has projected an increase in the global cancer burden from 19.3 to 28.4 million incidences annually within the next two decades. Currently, there has been a revival of interest in nutraceuticals with evidence of pharmacological properties against human diseases including cancer. Diet is an integral part of lifestyle, and it has been proposed that an estimated one-third of human cancers can be prevented through appropriate lifestyle modification including dietary habits; hence, it is considered significant to explore the pharmacological benefits of these agents, which are easily accessible and have higher safety index. Accordingly, an impressive embodiment of evidence supports the concept that the dietary factors are critical modulators to prevent, retard, block, or reverse carcinogenesis. Such an action reflects the ability of these molecules to interfere with multitude of pathways to subdue and neutralize several oncogenic factors and thereby keep a restraint on neoplastic transformations. This review provides a series of experimental evidence based on the current literature to highlight the translational potential of nutraceuticals for the prevention of the disease through consumption of enriched diets and its efficacious management by means of novel interventions. Specifically, this review provides the current understanding of the chemopreventive pharmacology of nutraceuticals such as cucurbitacins, morin, fisetin, curcumin, luteolin and garcinol toward their potential as anticancer agents.
    Keywords:  Apoptosis; Cancer; Chemoprevention; Nutraceuticals; Signaling pathways
    DOI:  https://doi.org/10.1007/s42977-022-00110-x
  68. Recent Pat Anticancer Drug Discov. 2022 Jan 13.
    Alpha-solanine anti-tumor effects in non-small cell lung cancer through regulating the energy metabolism pathway.
    Tao Zou, Li Gu, Liqiong Yang, Junsong Wei, Yueshui Zhao, Jing Shen, Mingxing Li, Xu Wu, Fukuan Du, Yu Chen, Yun Ye, Zhangang Xiao, Zhigui Wu.
       BACKGROUND: Lung cancer is a malignant tumor with a high incidence in China, especially non-small cell lung cancer (NSCLC), which is the main threat to human life, with terrible morbidity and mortality. The research on the treatment and mechanism of NSCLC has been the forefront and hotspot of research. Recent patents shows that alpha-solanine (α-solanine) exhibits the best anti-cancer activity, although its target and related mechanism remain to be elucidated.
    OBJECTIVE: This study aims to explore the possible targets and mechanisms of α-solanine in the treatment of NSCLC through network pharmacology and experimental verification.
    METHODS: Network pharmacology was applied to screen the possible targets of α-solanine on NSCLC, construct core networks, and perform GO enrichment and KEGG pathway analysis, to predict the mechanism of α-solanine against NSCLC. Experiments were implemented to verify the results of network pharmacology in vitro. The A549 and PC-9 cells were exposed to α-solanine to assess the antitumor effect. Cell apoptosis was determined by the Annexin-V/PI assay. Targeted energy metabolomics was used to further validate the results in network pharmacology and energy metabolism pathway-related proteins were detected by immunofluorescence and western blot.
    RESULTS: Network pharmacology showed that there were 130 potential targets of α-solanine and NSCLC. GO and KEGG analysis showed that the energy metabolism pathway is the main pathway for α-solanine to exert anti-tumor effects on NSCLC. Experimental results showed that α-solanine inhibited cell proliferation, migration, invasion, and promoted cell apoptosis. At the same time, after α-solanine treatment, the expression of the energy metabolism pathway-related proteins including GPI, ALDOA, TPI1, PKLR, LDHA and ALDH3 was reduced. In addition, α-solanine also affects the amino acid metabolism of A549 and PC-9 cells.
    CONCLUSION: Based on a combination of network pharmacological prediction and experimental verification, α-solanine may exert anti-NSCLC effects by regulating the energy metabolism pathway.
    Keywords:  Alpha-solanine; Energy Metabolism pathway; Metabolomics; NSCLC; Network Pharmacology
    DOI:  https://doi.org/10.2174/1574892817666220113144635
  69. Pharmaceutics. 2021 Dec 25. pii: 40. [Epub ahead of print]14(1):
    The Pivotal Role of Oleuropein in the Anti-Diabetic Action of the Mediterranean Diet: A Concise Review.
    Andrea Da Porto, Gabriele Brosolo, Viviana Casarsa, Luca Bulfone, Laura Scandolin, Cristiana Catena, Leonardo A Sechi.
      Type 2 diabetes currently accounts for more than 90% of all diabetic patients. Lifestyle interventions and notably dietary modifications are one of the mainstays for the prevention and treatment of type 2 diabetes. In this context, the Mediterranean diet with its elevated content of phytonutrients has been demonstrated to effectively improve glucose homeostasis. Oleuropein is the most abundant polyphenolic compound contained in extra-virgin olive oil and might account for some of the anti-diabetic actions of the Mediterranean diet. With the aim to provide an overview of the possible contributions of oleuropein to glucose metabolism, we conducted a PubMed/Medline search in order to provide an update to the available evidence regarding this interesting compound. This narrative review summarizes the data that was obtained in in vitro and animal studies and the results of clinical investigations. Preclinical studies indicate that oleuropein improves glucose transport, increases insulin sensitivity, and facilitates insulin secretion by pancreatic β-cells, thereby supporting the hypothesis of the possible benefits of the control of hyperglycemia. However, on the clinical side, the available evidence is still preliminary and requires more extensive investigations. Thus, many questions remain unanswered in regards to the potential benefits of oleuropein in diabetes prevention and treatment. These questions should be addressed in appropriately designed studies in the future.
    Keywords:  Mediterranean diet; diabetes; metabolic syndrome; oleuropein
    DOI:  https://doi.org/10.3390/pharmaceutics14010040
  70. Food Chem. 2022 Jan 03. pii: S0308-8146(21)03008-9. [Epub ahead of print]377 132002
    Withanolides, the hidden gem in Physalis minima: A mini review on their anti-inflammatory, anti-neuroinflammatory and anti-cancer effects.
    Fui Fui Lem, Yoong Soon Yong, Saintella Goh, Su Na Chin, Fong Tyng Chee.
      The Southeast Asian rainforests, notably in East Malaysia, are home to a diverse range of medicinal plant species with limitless therapeutic potential. Physalis minima (family Solanaceae) is a native East Malaysia plant which is closely linked to P. angulata, are recognized for their various pharmacology properties are abundance in Withanolides, a C28-steroidal lactones based on an ergostane skeleton. This review focuses on the bioactive compounds of this herb, as it is frequently used to treat inflammation, neurodegenerative disease and cancer among East Malaysian ethnic groups. In this review, a total of 103 Withanolides were reported, with 59 of them being newly characterized. Previous scientific data revealed that Withanolides were intriguing principal compounds for inflammatory, neuroinflammatory and cancer treatment due to unique steroidal structure and strong bioactivities. Despite their excellent pharmacological characteristics, only a few Withanolides have been extensively studied, and the majority of them, particularly the newly discovered Withanolides, remained unknown for their therapeutic properties. This indicates that P. minima compounds are worth to be investigate for its pharmacological effects.
    Keywords:  Anticancer; Antiinflammation; Antineuroinflammation; Neurodegenerative diseases; Physalis minima; Withanolides
    DOI:  https://doi.org/10.1016/j.foodchem.2021.132002
  71. Int J Biol Macromol. 2022 Jan 14. pii: S0141-8130(22)00029-0. [Epub ahead of print]201 378-388
    Modified chitosan-hyaluronic acid based hydrogel for the pH-responsive Co-delivery of cisplatin and doxorubicin.
    T S Anirudhan, Maneesh Mohan, M R Rajeev.
      Combination chemotherapy has attracted more attention in the field of anticancer treatment due to the synergetic effects achieved in the targeted delivery of anticancer drugs. In the present work a hydrogel-based drug delivery system (CS-NSA/A-HA) was successfully developed from chitosan modified by nitrosalicylaldehyde and aldehyde hyaluronic acid. Anticancer drugs, Cisplatin (CDDP) and Doxorubicin (DOX) were incorporated into this hydrogel separately and a dual drug loaded system was synthesized and the potential of the single and dual drug loaded materials for lung cancer therapy was compared. The obtained hydrogel was characterized by various spectroscopic techniques. Morphological studies conducted by FE-SEM analysis. The loading and encapsulation efficiencies and percentage of drug release were determined by UV-Vis spectroscopy at different pHs. Cytotoxicity studies performed in A549 lung cancer cells confirmed the enhanced activity of the material as a dual drug carrier compared with the single loaded system. All the findings strongly suggest the applicability of the material for lung cancer therapy.
    Keywords:  Aldehyde hyaluronic acid; Nitrosalicylaldehyde; Synergistic effect of CDDP and DOX; pH responsive hydrogel
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.01.022
  72. Life Sci. 2022 Jan 16. pii: S0024-3205(21)01283-2. [Epub ahead of print] 120296
    Hepatorenal protective effect of nano-curcumin against nano‑copper oxide-mediated toxicity in rats: Behavioral performance, antioxidant, anti-inflammatory, apoptosis, and histopathology.
    Hossam G Tohamy, Osama S El Okle, Amira A Goma, Mohamed M Abdel-Daim, Mustafa Shukry.
       BACKGROUND: Metal oxide nanoparticles (NPs) induce oxidative stress that can cause cellular toxicity. A natural antioxidant that can be used to protect tissues from oxidative stress is curcumin.
    PURPOSE: In the present study, we evaluated the protective effect of curcumin nanoparticles (curcumin-NPs) against copper oxide nanoparticle (CuO-NP)-mediated hepatorenal effects on behavioral performance, biochemical markers, antioxidants, inflammation, apoptosis, and histopathology in rats.
    STUDY DESIGN: Twenty Wistar adult male rats were randomly divided into four groups (n = 5); Group Ι served as a control, group ΙΙ was orally gavaged with curcumin-NPs (100 mg/Kg), group ΙΙI orally received CuO-NPs (100 mg/kg), and group ΙV received both CuO-NPs and curcumin-NPs orally for 14 days.
    METHODS: Behavioral performance, biochemical markers, antioxidants, inflammatory mediators, and apoptotic gene expression were evaluated in addition to histopathological and immunohistochemical examination.
    RESULTS: The results revealed that rats exposed to CuO-NPs suffered from behavioral alterations and hepatic and renal damages, which indicates a marked elevation of serum biochemical parameters, including alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, lactate dehydrogenase, urea, uric acid, and creatinine and a decline of total protein. Moreover, there was a significant downregulation in the expression of antioxidants genes, whereas inflammatory mediator expression was upregulated. The histopathological and immunohistochemical examination also corroborated these findings. In contrast, rats co-treated with curcumin-NPs exhibited better behavioral performance, biochemical profile, gene expression, histological architecture, and immunohistochemical staining results.
    CONCLUSION: These findings strongly indicated that curcumin-NPs exert significant protection against the behavioral and hepatorenal disorders induced by CuO-NP toxicity by modulating oxidative stress regulators and gene expression.
    Keywords:  Behavioral performance; CuO-NPs; Curcumin-NPs; Gene expression; Oxidative stress
    DOI:  https://doi.org/10.1016/j.lfs.2021.120296
  73. Biomolecules. 2022 Jan 05. pii: 81. [Epub ahead of print]12(1):
    Recent Advances in Strategies for Addressing Hypoxia in Tumor Photodynamic Therapy.
    Liang Hong, Jiangmin Li, Yali Luo, Tao Guo, Chenshuang Zhang, Sha Ou, Yaohang Long, Zuquan Hu.
      Photodynamic therapy (PDT) is a treatment modality that uses light to target tumors and minimize damage to normal tissues. It offers advantages including high spatiotemporal selectivity, low side effects, and maximal preservation of tissue functions. However, the PDT efficiency is severely impeded by the hypoxic feature of tumors. Moreover, hypoxia may promote tumor metastasis and tumor resistance to multiple therapies. Therefore, addressing tumor hypoxia to improve PDT efficacy has been the focus of antitumor treatment, and research on this theme is continuously emerging. In this review, we summarize state-of-the-art advances in strategies for overcoming hypoxia in tumor PDTs, categorizing them into oxygen-independent phototherapy, oxygen-economizing PDT, and oxygen-supplementing PDT. Moreover, we highlight strategies possessing intriguing advantages such as exceedingly high PDT efficiency and high novelty, analyze the strengths and shortcomings of different methods, and envision the opportunities and challenges for future research.
    Keywords:  hypoxia; nanomaterials; oxygen; photodynamic therapy; tumor
    DOI:  https://doi.org/10.3390/biom12010081
  74. AAPS J. 2022 Jan 18. 24(1): 30
    Nfe2l2 Regulates Metabolic Rewiring and Epigenetic Reprogramming in Mediating Cancer Protective Effect by Fucoxanthin.
    Lujing Wang, Renyi Wu, Davit Sargsyan, Shan Su, Hsiao-Chen Kuo, Shanyi Li, Pochung Chou, Md Shahid Sarwar, Ameya Phadnis, Yujue Wang, Xiaoyang Su, Ah-Ng Kong.
      Fucoxanthin (FX) is a carotenoid with many pharmaceutical properties due to its antioxidant/anti-inflammatory and epigenetic effects. NFE2L2 is involved in the defense against oxidative stress/inflammation-mediated diseases, like anticancer effects elicited by phytochemicals including FX. However, the role of FX and NFE2L2 in metabolic rewiring, epigenomic reprogramming, and transcriptomic network in blocking pro-tumorigenic signaling and eliciting cancer-protective effects remains unknown. Herein, we utilized multi-omics approaches to evaluate the role of NFE2L2 and the impact of FX on tumor promoter TPA-induced skin cell transformation. FX blocked TPA-induced ROS and oxidized GSSG/reduced GSH in Nfe2l2wild-type(WT) but not Nfe2l2-knockdown (KD) cells. Both Nfe2l2 KD and TPA altered cellular metabolisms and metabolites which are tightly coupled to epigenetic machinery. The suppressive effects of FX on TPA-enhancedSAM/SAH was abrogated by Nfe2l2 KD indicating Nfe2l2 plays a critical role in FX-mediated metabolic rewiring and its potential consequences on epigenetic reprogramming. Epigenomic CpG methyl-seq revealed that FX attenuated TPA-induced differentially methylated regions (DMRs) of Uhrf1 and Dnmt1 genes. Transcriptomic RNA-seq showed that FX abrogated TPA-induced differentially expressed genes (DEGs) of Nfe2l2-related genes Nqo1, Ho1, and Keap1. Associative analysis of DEGs and DMRs identified that the mRNA expressions of Uhrf1 and Dnmt1 were correlated with the promoter CpG methylation status. Chromatin immunoprecipitation assay showed that FX restored Uhrf1 expression by regulating H3K27Me3 enrichment in the promoter region. In this context, FX/Nfe2l2's redox signaling drives metabolic rewiring causing epigenetic and transcriptomic reprogramming potentially contributing to the protection of TPA-induced JB6 cellular transformation skin cancer model. Graphical abstract.
    Keywords:  Epigenetic; Fucoxanthin; Metabolic rewiring; Nuclear factor erythroid-2 like 2 (Nef2l2); Reactive oxygen species (ROS)
    DOI:  https://doi.org/10.1208/s12248-022-00679-0
  75. Nanomaterials (Basel). 2022 Jan 06. pii: 186. [Epub ahead of print]12(2):
    Applications of Chitosan-Alginate-Based Nanoparticles-An Up-to-Date Review.
    Adelina-Gabriela Niculescu, Alexandru Mihai Grumezescu.
      Chitosan and alginate are two of the most studied natural polymers that have attracted interest for multiple uses in their nano form. The biomedical field is one of the domains benefiting the most from the development of nanotechnology, as increasing research interest has been oriented to developing chitosan-alginate biocompatible delivery vehicles, antimicrobial agents, and vaccine adjuvants. Moreover, these nanomaterials of natural origin have also become appealing for environmental protection (e.g., water treatment, environmental-friendly fertilizers, herbicides, and pesticides) and the food industry. In this respect, the present paper aims to discuss some of the newest applications of chitosan-alginate-based nanomaterials and serve as an inception point for further research in the field.
    Keywords:  alginate; biomedical applications; chitosan; chitosan-alginate nanoparticles; drug delivery systems; polysaccharide nanoparticles
    DOI:  https://doi.org/10.3390/nano12020186
  76. Gels. 2022 Jan 14. pii: 59. [Epub ahead of print]8(1):
    Curcuminoid Co-Loading Platinum Heparin-Poloxamer P403 Nanogel Increasing Effectiveness in Antitumor Activity.
    Ngoc The Nguyen, Quynh Anh Bui, Hoang Huong Nhu Nguyen, Tien Thanh Nguyen, Khanh Linh Ly, Ha Le Bao Tran, Vu Nguyen Doan, Tran Thi Yen Nhi, Ngoc Hoa Nguyen, Ngoc Hao Nguyen, Ngoc Quyen Tran, Dinh Trung Nguyen.
      Nanosized multi-drug delivery systems provide synergistic effects between drugs and bioactive compounds, resulting in increased overall efficiency and restricted side effects compared to conventional single-drug chemotherapy. In this study, we develop an amphiphilic heparin-poloxamer P403 (HP403) nanogel that could effectively co-load curcuminoid (Cur) and cisplatin hydrate (CisOH) (HP403@CisOH@Cur) via two loading mechanisms. The HP403 nanogels and HP403@CisOH@Cur nanogels were closely analyzed with 1H-NMR spectroscopy, FT-IR spectroscopy, TEM, and DLS, exhibiting high stability in spherical forms. In drug release profiles, accelerated behavior of Cur and CisOH at pH 5.5 compared with neutral pH was observed, suggesting effective delivery of the compounds in tumor sites. In vitro studies showed high antitumor activity of HP403@CisOH@Cur nanogels, while in vivo assays showed that the dual-drug platform prolonged the survival time of mice and prevented tail necrosis. In summary, HP403@CisOH@Cur offers an intriguing strategy to achieve the cisplatin and curcumin synergistic effect in a well-designed delivery platform that increases antitumor effectiveness and overcomes undesired consequences caused by cisplatin in breast cancer treatment.
    Keywords:  MCF-7; heparin; multi-drug delivery; nanogel; poloxamer P403
    DOI:  https://doi.org/10.3390/gels8010059
  77. Nanomaterials (Basel). 2022 Jan 17. pii: 288. [Epub ahead of print]12(2):
    Bacteria-Assisted Transport of Nanomaterials to Improve Drug Delivery in Cancer Therapy.
    Carla Jiménez-Jiménez, Víctor M Moreno, María Vallet-Regí.
      Currently, the design of nanomaterials for the treatment of different pathologies is presenting a major impact on biomedical research. Thanks to this, nanoparticles represent a successful strategy for the delivery of high amounts of drugs for the treatment of cancer. Different nanosystems have been designed to combat this pathology. However, the poor penetration of these nanomaterials into the tumor tissue prevents the drug from entering the inner regions of the tumor. Some bacterial strains have self-propulsion and guiding capacity thanks to their flagella. They also have a preference to accumulate in certain tumor regions due to the presence of different chemo-attractants factors. Bioconjugation reactions allow the binding of nanoparticles in living systems, such as cells or bacteria, in a simple way. Therefore, bacteria are being used as a transport vehicle for nanoparticles, facilitating their penetration and the subsequent release of the drug inside the tumor. This review would summarize the literature on the anchoring methods of diverse nanosystems in bacteria and, interestingly, their advantages and possible applications in cancer therapy.
    Keywords:  bacteria; cancer; drug delivery; nanocarrier; nanoparticles
    DOI:  https://doi.org/10.3390/nano12020288
  78. Adv Sci (Weinh). 2022 Jan;9(1): 2101527
    Molybdenum Diphosphide Nanorods with Laser-Potentiated Peroxidase Catalytic/Mild-Photothermal Therapy of Oral Cancer.
    Min Qian, Ziqiang Cheng, Guanghong Luo, Massimiliano Galluzzi, Yuehong Shen, Zhibin Li, Hongyu Yang, Xue-Feng Yu.
      Chemodynamic therapy (CDT) is an emerging treatment that usually employs chemical agents to decompose hydrogen peroxide (H2O2) into hydroxyl radical (•OH) via Fenton or Fenton-like reactions, inducing cell apoptosis or necrosis by damaging biomacromolecules such as, lipids, proteins, and DNA. Generally, CDT shows high tumor-specificity and minimal-invasiveness in patients, thus it has attracted extensive research interests. However, the catalytic reaction efficiency of CDT is largely limited by the relatively high pH at the tumor sites. Herein, a 808 nm laser-potentiated peroxidase catalytic/mild-photothermal therapy of molybdenum diphosphide nanorods (MoP2 NRs) is developed to improve CDT performance, and simultaneously achieve effective tumor eradication and anti-infection. In this system, MoP2 NRs exhibit a favorable cytocompatibility due to their inherent excellent elemental biocompatibility. Upon irradiation with an 808 nm laser, MoP2 NRs act as photosensitizers to efficiently capture the photo-excited band electrons and valance band holes, exhibiting enhanced peroxidase-like catalytic activity to sustainedly decompose tumor endogenous H2O2 to •OH, which subsequently destroy the cellular biomacromolecules both in tumor cells and bacteria. As demonstrated both in vitro and in vivo, this system exhibits a superior therapeutic efficiency with inappreciable toxicity. Hence, the work may provide a promising therapeutic technique for further clinical applications.
    Keywords:  chemodynamic therapy; mild‐photothermal therapy; molybdenum diphosphide nanorods; oral cancer; peroxidase‐like catalytic
    DOI:  https://doi.org/10.1002/advs.202101527
  79. Cancers (Basel). 2022 Jan 13. pii: 390. [Epub ahead of print]14(2):
    A Breakthrough Brought about by Targeting KRASG12C: Nonconformity Is Punished.
    Wenjuan Ning, Zhang Yang, Gregor J Kocher, Patrick Dorn, Ren-Wang Peng.
      KRAS is the most frequently mutated oncogene in lung carcinomas, accounting for 25% of total incidence, with half of them being KRASG12C mutations. In past decades, KRAS enjoyed the notorious reputation of being untargetable-that is, until the advent of G12C inhibitors, which put an end to this legend by covalently targeting the G12C (glycine to cysteine) substitution in the switch-II pocket of the protein, inhibiting the affinity of the mutant KRAS with GTP and subsequently the downstream signaling pathways, such as Raf/MEK/ERK. KRASG12C-selective inhibitors, e.g., the FDA-approved AMG510 and MRTX849, have demonstrated potent clinical efficacy and selectivity in patients with KRASG12C-driven cancers only, which spares other driver KRAS mutations (e.g., G12D/V/S, G13D, and Q61H) and has ushered in an unprecedented breakthrough in the field in recent decades. However, accumulating evidence from preclinical and clinical studies has shown that G12C-targeted therapeutics as single agents are inevitably thwarted by drug resistance, a persistent problem associated with targeted therapies. A promising strategy to optimize G12C inhibitor therapy is combination treatments with other therapeutic agents, the identification of which is empowered by the insightful appreciation of compensatory signaling pathways or evasive mechanisms, such as those that attenuate immune responses. Here, we review recent advances in targeting KRASG12C and discuss the challenges of KRASG12C inhibitor therapy, as well as future directions.
    Keywords:  KRAS-mutant cancer; KRASG12C; KRASG12C inhibitors; acquired resistance; combination therapy
    DOI:  https://doi.org/10.3390/cancers14020390
  80. Drug Deliv Transl Res. 2022 Jan 19.
    Ratiometric co-delivery of doxorubicin and paclitaxel prodrug by remote-loading liposomes for the treatment of triple-negative breast cancer.
    Yingli Wang, Lixue Chen, Zonglin Zhang, Wenqi Liu, Lei Li.
      Liposomal delivery system that concurrent delivery of multiple drugs can improve efficacy of cancer treatments, yet remain challenging because of differential properties, fairly low loading thresholds of many drugs, and drug burst release. Here, we report a ratiometrically designed liposomal nanoplatform with synergistic efficacy, utilizing remote loading to co-encapsulate ROS-sensitive paclitaxel prodrug (PSN) and doxorubicin (DOX). This novel dual-delivery liposomes possess high two-drug encapsulation efficacy and colloidal stability, resulting in synergistic cytotoxicity, extended blood circulation, favorable biodistribution, always maintain the ratiometrically synergistic drug ratio in vivo, and potent synergistic anticancer activity. Such a combination of PSN and DOX with synergistic effects encapsulated in a safe and effective dual-delivery liposomal nanomedicine may hold promise for the further clinical translation and provides a new strategy for high-efficient combination chemotherapy.
    Keywords:  co-encapsulate; doxorubicin; liposome; paclitaxel prodrug
    DOI:  https://doi.org/10.1007/s13346-021-01105-2
  81. ACS Appl Bio Mater. 2022 Jan 21.
    Polymeric Nanoshell-Stabilized Liquid Metal for Bactericidal Photonanomedicine.
    Yong Liu, Juanjuan Li, Li Yi, Hao Wang.
      Liquid metals (LMs), typically gallium and its alloys, are emerging functional materials for nanotechnology, yet the applications of LM nanoparticles (LMNPs) in biomedical areas are still in their infancy. This predicament occurs primarily because LMNPs are generally synthesized with inadequately protected surfaces rendering rapid uncontrollable oxidation in physiological conditions. Herein, we show that depositing a polymeric supra-nanoparticle shell on LMNPs through sonochemical assembly can alleviate their oxidation kinetics and maintain their designed functionalities, even during hyperthermia processing. The LMNPs with polymer encapsulation promise to be excellent candidate materials for stable, biocompatible, and reusable photothermal converters under near-infrared (NIR) laser irradiation, showing doubled photothermal conversion efficiency compared with unprotected ones. Besides, they are employed, alone or synergistically with a hydrogel matrix, as potent photothermal bactericidal agents, both in vitro and in vivo. Specifically, the LMNPs-embedded agarose hydrogel allows the disinfection and concurrently accelerated healing of full-thickness skin wounds. The nanoshell-enabled heat resistance of LMNPs is expected to broaden the horizons of LM-based nano/biomedicine, potentially against superbugs and cancer.
    Keywords:  liquid metal; photothermal therapy; polymer encapsulation; sonochemical synthesis; wound healing
    DOI:  https://doi.org/10.1021/acsabm.1c01169
  82. Crit Rev Food Sci Nutr. 2022 Jan 20. 1-32
    Antidiabetic potential of seaweed and their bioactive compounds: a review of developments in last decade.
    Surbhi Agarwal, Vikas Singh, Komal Chauhan.
      Diabetes Mellitus is a public health problem worldwide due to high morbidity and mortality rate associated with it. Diabetes can be managed by synthetic hypoglycemic drugs, although their persistent uses have several side effects. Hence, there is a paradigm shift toward the use of natural products having antidiabetic potential. Seaweeds, large marine benthic algae, are an affluent source of various bioactive compounds, including phytochemicals and antioxidants thus exhibiting various health promoting properties. Seaweed extracts and its bioactive compounds have antidiabetic potential as they inhibit carbohydrate hydrolyzing enzymes in vitro and exhibit blood glucose lowering effect in random and post prandial blood glucose tests in vivo. In addition, they have been associated with reduced weight gain in animals probably by decreasing mRNA expression of pro-inflammatory cytokines with concomitant increase in mRNA expression levels of anti-inflammatory cytokines. Their beneficial effect has been seen in serum and hepatic lipid profile and antioxidant enzymes indicating the protective role of seaweeds against free radicals mediated oxidative stress induced hyperglycemia and associated hyperlipidemia. However, the detailed and in-depth studies of seaweeds as whole, their bioactive isolates and their extracts need to be explored further for their health benefits and wide application in food, nutraceutical and pharmaceutical industries.
    Keywords:  Fucoidan; fucoxanthin; hyperglycemia; phlorotannins; polyphenols; polysaccharides
    DOI:  https://doi.org/10.1080/10408398.2021.2024130
  83. Nanomaterials (Basel). 2022 Jan 10. pii: 209. [Epub ahead of print]12(2):
    An Urchin-Shaped Copper-Based Metalloporphyrin Nanosystem as a Sonosensitizer for Sonodynamic Therapy.
    Aiqing Ma, Hui Ran, Jiaxing Wang, Rui Ding, Chengyu Lu, Lanlan Liu, Yingmei Luo, Huaqing Chen, Ting Yin.
      Sonodynamic therapy (SDT), as a novel cancer therapy strategy, might be a promising approach due to the depth-penetration property in tissue. Sonosensitizers are the key element for efficient SDT. However, the development of sonosensitizers with strong sonosensitization efficacy is still a significant challenge. Herein, an urchin-shaped copper-based metalloporphyrin liposome nanosystem (FA-L-CuPP) is constructed and identified as an excellent sonosensitizer. Under ultrasound (US) irradiation, FA-L-CuPP can be highly excited to generate several reactive oxygen species (ROS), such as singlet oxygen (1O2) and free radicals (⋅OH). The molecular orbital distribution calculations reveal that a strong intramolecular charge transfer might occur in the CuPP complex under US irradiation, which could afford enough energy to the surrounding O2 and H2O to concert 1O2, O2- and ⋅OH. Working as "ammunitions", the largely produced ROS can kill 4T1 tumor cells, effectively inhibiting tumor growth. This work provides an urchin-shaped nanosonosensitizer based on a copper complex, which might provide an idea to design a novel sonosensitizer for noninvasive and precise SDT antitumor applications.
    Keywords:  copper-based metalloporphyrin; noninvasive therapy; sonodynamic therapy; sonosensitizer; urchin-shaped
    DOI:  https://doi.org/10.3390/nano12020209
  84. Food Chem. 2022 Jan 08. pii: S0308-8146(22)00052-8. [Epub ahead of print]378 132091
    Study on the stability and oral bioavailability of curcumin loaded (-)-epigallocatechin-3-gallate/poly(N-vinylpyrrolidone) nanoparticles based on hydrogen bonding-driven self-assembly.
    Yuanyuan Chen, Jingting Wang, Zhenan Rao, Junfeng Hu, Qiming Wang, Yueru Sun, Xiaojuan Lei, Jichun Zhao, Kaifang Zeng, Zhigang Xu, Jian Ming.
      The biological activity and absorption of curcumin (Cur) is limited in application due to its low water solubility, poorstabilityand rapid metabolism. In this work, Cur loaded (-)-epigallocatechin-3-gallate (EGCG)/poly(N-vinylpyrrolidone) (PVP) nanoparticles (CEP-NPs) was successfully fabricated via self-assembly driven by hydrogen bonding, providing with desirable Cur-loading efficiency, high stability, strong antioxidant capacity, and pH-triggered intestinal targeted release properties. Molecular dynamics simulations further indicated the Cur was coated with EGCG and PVP in CEP-NPs and high acid prolonged release property was attribute to low ionization degree of EGCG. Besides, the enhanced intestinal absorption of Cur was related to inhibition of Cur metabolism by EGCG, enhancement of cellular uptake and higher Caco-2 monolayer permeation. Pharmacokinetic study showed that the oral bioavailability presented nearly 12-fold increment. Therefore, this study provides a new horizon for improving the Cur utilization in food and pharmaceutical fields.
    Keywords:  (-)-Epigallocatechin-3-gallate; Curcumin; Hydrogen bonding; Oral bioavailability; Poly(N-vinylpyrrolidone)
    DOI:  https://doi.org/10.1016/j.foodchem.2022.132091
  85. Pharmaceutics. 2022 Jan 05. pii: 131. [Epub ahead of print]14(1):
    Celecoxib-Loaded Solid Lipid Nanoparticles for Colon Delivery: Formulation Optimization and In Vitro Assessment of Anti-Cancer Activity.
    Hamdan N Alajami, Ehab A Fouad, Abdelkader E Ashour, Ashok Kumar, Alaa Eldeen B Yassin.
      This work aimed to optimize a celecoxib (CXB)-loaded solid lipid nanoparticles (SLN) colon delivery system for the enhancement of anticancer activity. An ultrasonic melt-emulsification method was employed in this work for the preparation of SLN. The physical attributes were characterized for their particle sizes, charges, morphology, and entrapment efficiency (%EE), in addition to DSC and FTIR. The in vitro drug release profiles were evaluated, and the anticancer activity was examined utilizing an MTT assay in three cancer cell lines: the colon cancer HT29, medulloblastoma Daoy, and hepatocellular carcinoma HepG2 cells. All of the prepared SLN formulations had nanoscale particle sizes ranging from 238 nm to 757 nm. High zeta-potential values (mv) within -30 s mv were reported. The %EE was in the range 86.76-96.6%. The amorphous nature of the SLN-entrapped CXB was confirmed from SLN DSC thermograms. The in vitro release profile revealed a slow constant rate of release with no burst release, which is unusual for SLN. Both the F9 and F14 demonstrated almost complete CXB release within 24 h, with only 25% completed within the first 5 h. F9 caused a significant percentage of cell death in the three cancer cell lines tested after 24 h of incubation and maintained this effect for 72 h. The prepared CXB-loaded SLN exhibited unique properties such as slow release with no burst and a high %EE. The anticancer activity of one formulation was extremely significant in all tested cancer cell lines at all incubation times, which is very promising.
    Keywords:  HT29; MTT; celecoxib; solid lipid nanoparticles; ultrasonic melt-emulsification; zeta-potential
    DOI:  https://doi.org/10.3390/pharmaceutics14010131
  86. Materials (Basel). 2022 Jan 10. pii: 503. [Epub ahead of print]15(2):
    Multifunctional Iron Oxide Magnetic Nanoparticles for Biomedical Applications: A Review.
    Hung-Vu Tran, Nhat M Ngo, Riddhiman Medhi, Pannaree Srinoi, Tingting Liu, Supparesk Rittikulsittichai, T Randall Lee.
      Due to their good magnetic properties, excellent biocompatibility, and low price, magnetic iron oxide nanoparticles (IONPs) are the most commonly used magnetic nanomaterials and have been extensively explored in biomedical applications. Although magnetic IONPs can be used for a variety of applications in biomedicine, most practical applications require IONP-based platforms that can perform several tasks in parallel. Thus, appropriate engineering and integration of magnetic IONPs with different classes of organic and inorganic materials can produce multifunctional nanoplatforms that can perform several functions simultaneously, allowing their application in a broad spectrum of biomedical fields. This review article summarizes the fabrication of current composite nanoplatforms based on integration of magnetic IONPs with organic dyes, biomolecules (e.g., lipids, DNAs, aptamers, and antibodies), quantum dots, noble metal NPs, and stimuli-responsive polymers. We also highlight the recent technological advances achieved from such integrated multifunctional platforms and their potential use in biomedical applications, including dual-mode imaging for biomolecule detection, targeted drug delivery, photodynamic therapy, chemotherapy, and magnetic hyperthermia therapy.
    Keywords:  Fe3O4; antibacterial; bacterial detection; biomedical applications; biomolecules; cancer treatment; diagnosis; drug delivery; fluorescence imaging; magnetic nanoparticles; magnetic resonance imaging; metal nanoparticles; organic dyes; photodynamic therapy; photothermal ablation; quantum dots; stimuli-responsive polymers; surface functionalization; tumor targeting
    DOI:  https://doi.org/10.3390/ma15020503
  87. Acta Biomater. 2022 Jan 18. pii: S1742-7061(22)00046-0. [Epub ahead of print]
    Anti-VEGFR2-labeled Enzyme-Immobilized Metal-Organic Frameworks for Tumor Vasculature Targeted Catalytic Therapy.
    Jingrong Zhou, Kai Wang, Shuaishuai Ding, Lijuan Zeng, Jingya Miao, Yuhua Cao, Xiao Zhang, Gan Tian, Xiu-Wu Bian.
      Tumor vasculature-targeting therapy either using angiogenesis inhibitors or vascular disrupting agents offers an important new avenue for cancer therapy. In this work, a tumor-specific catalytic nanomedicine for enhanced tumor ablation accompanied with tumor vasculature disruption and angiogenesis inhibition was developed through a cascade reaction with enzyme glucose oxidase (GOD) modified on Fe-based metal organic framework (Fe-MOF) coupled with anti-VEGFR2.The GOD enzyme could catalyze the intratumoral glucose decomposition to trigger tumor starvation and yet provide abundant hydrogen peroxide as the substrate for Fenton-like reaction catalyzed by Fe-MOF to produce sufficient highly toxic hydroxyl radicals for enhanced chemodynamic therapy and instantly attacked tumor vascular endothelial cells to destroy the existing vasculature, while the anti-VEGFR2 antibody guided the nanohybrids to target blood vessels and block the VEGF-VEGFR2 connection to prevent angiogenesis. Both in vitro and in vivo results demonstrated the smart nanohybrids could cause the tumor cell apoptosis and vasculature disruption, and exhibited enhanced tumor regression in A549 xenograft tumor-bearing mice model. This study suggested that synergistic targeting tumor growth and its vasculature network would be more promising for curing solid tumors. STATEMENT OF SIGNIFICANCE: : Cooperative destruction of tumor cells and tumor vasculature offers a potential avenue for cancer therapy. Under this premise, a tumor-specific catalytic nanomedicine for enhanced tumor ablation accompanied with tumor vasculature disruption and new angiogenesis inhibition was developed through a cascade reaction with glucose oxidase modified on the surface of iron-based metal organic framework coupled with VEGFR2 antibody. The resulting data demonstrated that a therapeutic regimen targeting tumor growth as well as its vasculature with both existing vasculature disruption and neovasculature inhibition would be more potential for complete eradication of tumors.
    Keywords:  Metal-organic framework; anti-VEGFR2; anti-angiogenesis; synergistic efficacy; tumor catalytic therapy
    DOI:  https://doi.org/10.1016/j.actbio.2022.01.037
  88. Antioxidants (Basel). 2022 Jan 05. pii: 117. [Epub ahead of print]11(1):
    Induction of Paraptotic Cell Death in Breast Cancer Cells by a Novel Pyrazolo[3,4-h]quinoline Derivative through ROS Production and Endoplasmic Reticulum Stress.
    Phuong Linh Nguyen, Chang Hoon Lee, Heesoon Lee, Jungsook Cho.
      Chemotherapy has been a standard intervention for a variety of cancers to impede tumor growth, mainly by inducing apoptosis. However, development of resistance to this regimen has led to a growing interest and demand for drugs targeting alternative cell death modes, such as paraptosis. Here, we designed and synthesized a novel derivative of a pyrazolo[3,4-h]quinoline scaffold (YRL1091), evaluated its cytotoxic effect, and elucidated the underlying molecular mechanisms of cell death in MDA-MB-231 and MCF-7 breast cancer (BC) cells. We found that YRL1091 induced cytotoxicity in these cells with numerous cytoplasmic vacuoles, one of the distinct characteristics of paraptosis. YRL1091-treated BC cells displayed several other distinguishing features of paraptosis, excluding autophagy or apoptosis. Briefly, YRL1091-induced cell death was associated with upregulation of microtubule-associated protein 1 light chain 3B, downregulation of multifunctional adapter protein Alix, and activation of extracellular signal-regulated kinase 1/2 and c-Jun N-terminal kinase. Furthermore, the production of reactive oxygen species (ROS) and newly synthesized proteins were also observed, subsequently causing ubiquitinated protein accumulation and endoplasmic reticulum (ER) stress. Collectively, these results indicate that YRL1091 induces paraptosis in BC cells through ROS generation and ER stress. Therefore, YRL1091 can serve as a potential candidate for the development of a novel anticancer drug triggering paraptosis, which may provide benefit for the treatment of cancers resistant to conventional chemotherapy.
    Keywords:  breast cancer cells; cytoplasmic vacuolization; drug resistance; endoplasmic reticulum stress; paraptosis; pyrazolo[3,4-h]quinoline scaffold; reactive oxygen species
    DOI:  https://doi.org/10.3390/antiox11010117
  89. Int J Biol Macromol. 2022 Jan 13. pii: S0141-8130(22)00031-9. [Epub ahead of print]201 338-350
    In situ polydopamine functionalized poly-L-lactic acid nanofibers with near-infrared-triggered antibacterial and reactive oxygen species scavenging capability.
    Feng Xiong, Shuo Wei, Han Sheng, Xiang Han, Wei Jiang, Zhuojun Zhang, Biyun Li, Hongyun Xuan, Ye Xue, Huihua Yuan.
      The development of a new multi-functional poly(L)-lactide (PLLA) nanofibrous scaffold with excellent antibacterial and reactive oxygen species (ROS) scavenging capability is quite important in tissue engineering. In this study, polydopamine (PDA)/PLLA nanofibers were prepared by combining electrospinning and post in-situ polymerization. The post in-situ polymerization of PDA on the PLLA nanofiber enable PDA uniformly distribute on PLLA nanofiber surface. PDA/PLLA nanofibrous composites also achieved stronger mechanical strength, hydrophilicity, good oxidation resistance and enhanced near-infrared photothermal effect. The near-infrared photothermal effect from PDA made the PDA/PLLA a good antibacterial material. The in vitro ROS scavenging ability of the PDA made PDA/PLLA be beneficial to damaged tissue repair. These results indicate that PDA/PLLA nanofibrous scaffold can be used as a tissue engineering scaffold material with versatile biomedical applications.
    Keywords:  Antibacterial; In-situ polymerization; PDA/PLLA nanofiber; ROS scavenging ability
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.01.024
  90. Cancer Lett. 2022 Jan 15. pii: S0304-3835(22)00020-9. [Epub ahead of print]
    Engineering nanomedicines to inhibit hypoxia-inducible Factor-1 for cancer therapy.
    Xiaojuan Zhang, Chuanchuan He, Guangya Xiang.
      Hypoxia-inducible factor-1 (HIF-1), an essential promoter of tumor progression, has attracted increasing attention as a therapeutic target. In addition to hypoxic cellular conditions, HIF-1 activation can be triggered by cancer treatment, which causes drug tolerance and therapeutic failure. To date, a series of effective strategies have been explored to suppress HIF-1 function, including silencing the HIF-1α gene, inhibiting HIF-1α protein translation, degrading HIF-1α protein, and inhibiting HIF-1 transcription. Furthermore, nanoparticle-based drug delivery systems have been widely developed to improve the stability and pharmacokinetics of HIF-1 inhibitors or achieve HIF-1-targeted combination therapies as a nanoplatform. In this review, we summarize the current literature on nanomedicines targeting HIF-1 to combat cancer and discuss their potential for future development.
    Keywords:  Combination therapy; Drug delivery systems; HIF-1; Inhibitors; Nanoplatforms
    DOI:  https://doi.org/10.1016/j.canlet.2022.01.012
  91. Int J Pharm. 2022 Jan 18. pii: S0378-5173(22)00042-4. [Epub ahead of print] 121489
    Biomineralized synthesis of palladium nanoflowers for photothermal treatment of cancer and wound healing.
    Jinfeng He, Jing Wang, Shoubei Gao, Yanshuai Cui, Xianbing Ji, Xiaoyu Zhang, Longgang Wang.
      Photothermal therapy uses photothermal agents (PTAs) to convert light energy to heat energy under near-infrared light to kill local tumors in cancer patients or speed up wound healing in diabetic patients.However, it is difficult to achieve high photothermal conversion efficiency for most of PTAs. Herein, daptomycin (Dap) micelles-stabilized palladium nanoflowers (Dap-PdNFs) were prepared for the first time. The palladium nanoflowers (PdNFs) inside of the Dap-PdNFs were 106 nm. The temperature of the Dap-PdNFs solution quickly rose from 26.8°C to 52.0°C within 10 min under irradiation with high photothermal conversion efficiency up to 38%. In addition, the cell viability of HeLa cells and HT-29 cells of Dap-PdNFs exceeded 95% in the absence of near-infrared light, indicating that Dap-PdNFs had good biocompatibility. Meanwhile, the inhibition rate of Dap-PdNFs on HeLa cells was as high as 71.2% under irradiation of 808 nm near-infrared light. More importantly, Dap-PdNFs had a good healing effect on wounds of diabetic mice under irradiation of 808 nm near-infrared light. In short, this research provides a facile method for the application of Dap-PdNFs in safe and efficient tumor treatment and wound healing.
    Keywords:  biocompatibility; daptomycin; palladium nanoflowers; photothermal; wound healing; zwitterionic
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.121489
  92. Br J Nutr. 2022 Jan 19. 1-46
    Sex differences in vitamin D metabolism, serum levels and action.
    Alicja Wierzbicka, Maria Oczkowicz.
      The ubiquity of vitamin D metabolizing enzymes and vitamin D receptors in mammalian organisms suggests that vitamin D has pleiotropic effects. There are quite a few studies indicating the anticancer, cardioprotective and anti-diabetic effects of vitamin D, however, the best-documented actions of vitamin D are the regulation of calcium-phosphate balance and its effect on immune function.Vitamin D levels in organisms are modulated by many environmental and nonenvironmental factors. One potential factor that may influence vitamin D levels and effects is the sex of the individuals studied. This review focuses on the scientific evidence indicating different synthesis and metabolism of vitamin D in females and males, mainly from PubMed database sources. The article verifies the sex differences in vitamin D levels reported around the world. Moreover, the different effects of vitamin D on the musculoskeletal, cardiovascular, nervous, and immune systems, as well as cancer in males and females, were discussed.Most studies addressing sex differences in vitamin D levels and effects are observational studies with conflicting results. Therefore, carefully designed clinical trials and experiments on animal models should be carried out to determine the role of nonenvironmental factors that may differentiate vitamin D levels in females and males.
    Keywords:  deficiency; nutrigenomics; sex; sex differences; vitamin D
    DOI:  https://doi.org/10.1017/S0007114522000149
  93. Small. 2022 Jan 18. e2106511
    Hollow Mesoporous Manganese Oxides: Application in Cancer Diagnosis and Therapy.
    Wenjing Xu, Xin Qing, Shengli Liu, Dongliang Yang, Xiaochen Dong, Yewei Zhang.
      The precision, minimal invasiveness, and integration of diagnosis and treatment are critical factors for tumor treatment at the present. Although nanomedicine has shown the potential in tumor precision treatment, nanocarriers with high efficiency, excellent targeting, controlled release, and good biocompatibility still need to be further explored. Hollow mesoporous manganese oxides nanomaterials (HM-MONs), as an efficient drug delivery carrier, have attracted substantial attention in applications of tumor diagnosis and therapy due to their unique properties, such as tumor microenvironment stimuli-responsiveness, prominent catalytic activity, excellent biodegradation, and outstanding magnetic resonance imaging ability. The HM-MONs can not only enhance the therapeutic efficiency but also realize multimodal diagnosis of tumors. Consequently, it is necessary to introduce applications based on HM-MONs in cancer diagnosis and therapy. In this review, the representative progress of HM-MONs in synthesis is discussed. Then, several promising applications in drug delivery, bio-imaging, and bio-detection are highlighted. Finally, the challenges and perspectives of the anticancer applications are summarized, which is expected to provide meaningful guidance on further research.
    Keywords:  cancer treatment; combination therapy; drug delivery; hollow mesoporous manganese oxides; multimodal diagnosis
    DOI:  https://doi.org/10.1002/smll.202106511
  94. Curr Mol Pharmacol. 2022 ;15(1): 1-2
    Nano-Nutraceuticals Dietary Supplements for Athletes: An Eminent Approach for Managing Traumatic Brain Injuries.
    Noushad Javed, Faheem Hyder Pottoo, George E Barreto.
      
    DOI:  https://doi.org/10.2174/1874467215666220104212247
  95. Foods. 2022 Jan 11. pii: 182. [Epub ahead of print]11(2):
    Preparation of Curcumin Hydrogel Beads for the Development of Functional Kulfi: A Tailoring Delivery System.
    Minaxi Sharma, Baskaran Stephen Inbaraj, Praveen Kumar Dikkala, Kandi Sridhar, Arjun Naik Mude, Kairam Narsaiah.
      Curcumin has been demonstrated to have biological activities and its fortification in food products is an important strategy to deliver bioactive ingredients at target sites. However, studies have documented a curcumin low bioavailability and low intake. Hence, combining functional ingredients with food should be needed to prevent widespread nutrient intake shortfalls and associated deficiencies. Thus, curcumin was encapsulated in calcium-alginate and their characteristics as well as in vitro release behavior of curcumin hydrogel beads (CHBs) was studied. Moreover, CHBs were fortified in development of functional Kulfi and their quality characteristics were studied. The encapsulation efficiency was up to 95.04%, indicating that most of the curcumin was entrapped. FTIR shifts in the bands were due to the replacement of sodium ions to the calcium ions. In vitro release (%) for CHBs was found to be 67.15% after 2 h, which increased slightly up to 67.88% after 4 h. The average swelling index of CHBs was found to be 10.21 to 37.92 from 2 to 12 h in PBS (pH 7.40). Control and Kulfi fortified with CHBs showed no significant difference (p > 0.05) in colour (L = 73.03 and 75.88) and the melting rate (0.88 mL/min and 0.63 mL/min), respectively. Standard plate count was reduced in the Kulfi fortified with CHBs (13.77 × 104 CFU/mL) with high sensory score for overall acceptability (8.56) compared to the control (154.70 × 104 CFU/mL). These findings suggested the feasibility of developing CHBs to mask the bitterness, enhance the solubility, and increase the bioavailability in gastrointestinal conditions. Additionally, Kulfi could be a suitable dairy delivery system for curcumin bioactive compounds.
    Keywords:  curcumin; encapsulation efficiency; fortification; functional Kulfi; hydrogel beads; in vitro release; sensory evaluation
    DOI:  https://doi.org/10.3390/foods11020182
  96. Biosci Rep. 2022 Jan 20. pii: BSR20212654. [Epub ahead of print]
    Human lactate dehydrogenase A undergoes allosteric transitions under pH conditions inducing the dissociation of the tetrameric enzyme.
    Alberto Pietro Pasti, Valentina Rossi, Giuseppina Di Stefano, Maurizio Brigotti, Alejandro Hochkoeppler.
      The aerobic energetic metabolism of eukaryotic cells relies on the glycolytic generation of pyruvate, which is subsequently channelled to the oxidative phosphorylation taking place in mitochondria. However, under conditions limiting oxidative phosphorylation pyruvate is coupled to alternative energetic pathways, e.g. its reduction to lactate catalysed by lactate dehydrogenases (LDHs). This biochemical process is known to induce a significant decrease of cytosolic pH, and is accordingly denoted lactic acidosis. Nevertheless, the mutual dependence of LDHs action and lactic acidosis is far from being fully understood. Using human LDH-A, here we show that when exposed to acidic pH this enzyme is subjected to homotropic allosteric transitions triggered by pyruvate. Conversely, human LDH-A features Michaelis-Menten kinetics at pH values equal to 7.0 or higher. Further, citrate, isocitrate, and malate were observed to activate human LDH-A, both at pH 5.0 and 6.5, with citrate and isocitrate being responsible for major effects. Dynamic light scattering experiments revealed that the occurrence of allosteric kinetics in human LDH-A is mirrored by a consistent dissociation of the enzyme tetramer, suggesting that pyruvate promotes tetramer association under acidic conditions. Finally, using the human liver cancer cell line HepG2 we isolated cells featuring cytosolic pH equal to 7.3 or 6.5, and we observed a concomitant decrease of cytosolic pH and lactate secretion. Overall, our observations indicate the occurrence of a negative feedback between lactic acidosis and human LDH-A activity, and a complex regulation of this feedback by pyruvate and by some intermediates of the Krebs cycle.
    Keywords:  allosteric regulation; enzyme kinetics; lactate dehydrogenase; lactic acid; liver
    DOI:  https://doi.org/10.1042/BSR20212654
  97. J Mater Chem B. 2022 Jan 19.
    Enhanced photothermal heating and combination therapy of NIR dye via conversion to self-assembled ionic nanomaterials.
    Samantha Macchi, Amanda Jalihal, Nasrin Hooshmand, Mohd Zubair, Samir Jenkins, Nabeel Alwan, Mostafa El-Sayed, Nawab Ali, Robert J Griffin, Noureen Siraj.
      Combination nanodrugs are promising therapeutic agents for cancer treatment. However, they often require the use of complex nanovehicles for transportation into the tumor site. Herein, a new class of carrier-free ionic nanomaterials (INMs) is presented, which are self-assembled by the drug molecules themselves. In this regard, a photothermal therapy (PTT) mechanism is combined with a chemotherapy (chemo) mechanism using ionic liquid chemistry to develop a combination drug to deliver multiple cytotoxic mechanisms simultaneously. Nanodrugs were developed from an ionic material-based chemo-PTT combination drug by using a simple reprecipitation method. Detailed examination of the photophysical properties (absorption, fluorescence emission, quantum yield, radiative and non-radiative rate) of the INMs revealed significant spectral changes which are directly related to their therapeutic effect. The reactive oxygen species quantum yield and the light to heat conversion efficiency of the photothermal agents were shown to be enhanced in combination nanomedicines as compared to their respective parent compounds. The ionic nanodrugs exhibited an improved dark and light cytotoxicity in vitro as compared to either the chemotherapeutic or photothermal parent compounds individually, due to a synergistic effect of the combined therapies, improved photophysical properties and their nanoparticles' morphology that enhanced the cellular uptake of the drugs. This study presents a general framework for the development of carrier-free dual-mechanism nanotherapeutics.
    DOI:  https://doi.org/10.1039/d1tb02280f
  98. Int J Mol Sci. 2022 Jan 17. pii: 989. [Epub ahead of print]23(2):
    Rewired Cellular Metabolic Profiles in Response to Metformin under Different Oxygen and Nutrient Conditions.
    Shan Liu, Jumpei Washio, Satoko Sato, Yuki Abiko, Yuta Shinohara, Yuri Kobayashi, Haruki Otani, Shiori Sasaki, Xiaoyi Wang, Nobuhiro Takahashi.
      Metformin is a metabolic disruptor, and its efficacy and effects on metabolic profiles under different oxygen and nutrient conditions remain unclear. Therefore, the present study examined the effects of metformin on cell growth, the metabolic activities and consumption of glucose, glutamine, and pyruvate, and the intracellular ratio of nicotinamide adenine dinucleotide (NAD+) and reduced nicotinamide adenine dinucleotide (NADH) under normoxic (21% O2) and hypoxic (1% O2) conditions. The efficacy of metformin with nutrient removal from culture media was also investigated. The results obtained show that the efficacy of metformin was closely associated with cell types and environmental factors. Acute exposure to metformin had no effect on lactate production from glucose, glutamine, or pyruvate, whereas long-term exposure to metformin increased the consumption of glucose and pyruvate and the production of lactate in the culture media of HeLa and HaCaT cells as well as the metabolic activity of glucose. The NAD+/NADH ratio decreased during growth with metformin regardless of its efficacy. Furthermore, the inhibitory effects of metformin were enhanced in all cell lines following the removal of glucose or pyruvate from culture media. Collectively, the present results reveal that metformin efficacy may be regulated by oxygen conditions and nutrient availability, and indicate the potential of the metabolic switch induced by metformin as combinational therapy.
    Keywords:  dentistry; hypoxia; metformin; nutrient availability; oral cancer; rewired metabolic activity
    DOI:  https://doi.org/10.3390/ijms23020989
  99. Pharmaceuticals (Basel). 2021 Dec 21. pii: 6. [Epub ahead of print]15(1):
    Co-Delivery of Letrozole and Cyclophosphamide via Folic Acid-Decorated Nanoniosomes for Breast Cancer Therapy: Synergic Effect, Augmentation of Cytotoxicity, and Apoptosis Gene Expression.
    Hamidreza Sahrayi, Elham Hosseini, Sara Karimifard, Nazanin Khayam, Seyed Mohammadmahdi Meybodi, Sahar Amiri, Mahsa Bourbour, Bahareh Farasati Far, Iman Akbarzadeh, Mohammed Bhia, Clare Hoskins, Chaiyavat Chaiyasut.
      Breast cancer is one of the most prevalent causes of cancer mortality in women. In order to increase patient prognosis and survival rates, new technologies are urgently required to deliver therapeutics in a more effective and efficient manner. Niosome nanoparticles have been recently employed as therapeutic platforms capable of loading and carrying drugs within their core for both mono and combination therapy. Here, niosome-based nanoscale carriers were investigated as a targeted delivery system for breast cancer therapy. The platform developed consists of niosomes loaded with letrozole and cyclophosphamide (NLC) and surface-functionalized with a folic-acid-targeting moiety (NLCPFA). Drug release from the formulated particles exhibited pH-sensitive properties in which the niosome showed low and high release in physiological and cancerous conditions, respectively. The results revealed a synergic effect in cytotoxicity by co-loading letrozole and cyclophosphamide with an efficacy increment in NLCPFA use in comparison with NLC. The NLCPFA resulted in the greatest drug internalization compared to the non-targeted formulation and the free drug. Additionally, downregulation of cyclin-D, cyclin-E, MMP-2, and MMP-9 and upregulating the expression of caspase-3 and caspase-9 genes were observed more prominently in the nanoformulation (particularly for NLCPFA) compared to the free drug. This exciting data indicated that niosome-based nanocarriers containing letrozole and cyclophosphamide with controlled release could be a promising platform for drug delivery with potential in breast cancer therapy.
    Keywords:  breast cancer; cyclophosphamide; drug delivery; folic acid; letrozole; nanomedicine; nanoparticles; neoplasms; niosomes
    DOI:  https://doi.org/10.3390/ph15010006
  100. Food Chem. 2022 Jan 11. pii: S0308-8146(22)00096-6. [Epub ahead of print]379 132135
    Epigallocatechin 3-gallate: From green tea to cancer therapeutics.
    Manzar Alam, Sabeeha Ali, Ghulam Md Ashraf, Anwar L Bilgrami, Dharmendra Kumar Yadav, Md Imtaiyaz Hassan.
      Epigallocatechin 3-gallate (EGCG) possesses various biological functions, including anti-cancer and anti-inflammatory properties. EGCG is an abundant polyphenolic component originating from green tea extract that has exhibited versatile bioactivities in combating several cancers. This review highlights the pharmacological features of EGCG and its therapeutic implications in cancer and other metabolic diseases. It modulates numerous signaling pathways, regulating cells' undesired survival and proliferation, thus imparting strong tumor chemopreventive and therapeutic effects. EGCG initiates cell death through the intrinsic pathway and causes inhibition of EGFR, STAT3, and ERK pathways in several cancers. EGCG alters and inhibits ERK1/2, NF-κB, and Akt-mediated signaling, altering the Bcl-2 family proteins ratio and activating caspases in tumor cells. This review focuses on anti-cancer, anti-oxidant, anti-inflammatory, anti-angiogenesis, and apoptotic effects of EGCG. We further highlighted the potential of EGCG in different types of cancer, emphasizing clinical trials formulations that further improve our understanding of the therapeutic management of cancer and inflammatory diseases.
    Keywords:  Cancer therapy; Chemotherapy; Drug discovery; Epigallocatechin gallate; Green tea extracts; Natural products; Signaling pathways
    DOI:  https://doi.org/10.1016/j.foodchem.2022.132135
  101. Int J Mol Sci. 2022 Jan 13. pii: 839. [Epub ahead of print]23(2):
    Cancer Therapy by Silver Nanoparticles: Fiction or Reality?
    Dávid Kovács, Nóra Igaz, Mohana K Gopisetty, Mónika Kiricsi.
      As an emerging new class, metal nanoparticles and especially silver nanoparticles hold great potential in the field of cancer biology. Due to cancer-specific targeting, the consequently attenuated side-effects and the massive anti-cancer features render nanoparticle therapeutics desirable platforms for clinically relevant drug development. In this review, we highlight those characteristics of silver nanoparticle-based therapeutic concepts that are unique, exploitable, and achievable, as well as those that represent the critical hurdle in their advancement to clinical utilization. The collection of findings presented here will describe the features that distinguish silver nanoparticles from other anti-cancer agents and display the realistic opportunities and implications in oncotherapeutic innovations to find out whether cancer therapy by silver nanoparticles is fiction or reality.
    Keywords:  cancer therapy; metal nanoparticles; silver nanoparticles
    DOI:  https://doi.org/10.3390/ijms23020839
  102. Pharmaceutics. 2021 Dec 30. pii: 88. [Epub ahead of print]14(1):
    Novel Selectively Targeted Multifunctional Nanostructured Lipid Carriers for Prostate Cancer Treatment.
    Lital Cohen, Yehuda G Assaraf, Yoav D Livney.
      Prostate cancer (PC) is the most common cancer in men over 50 and the 4th most prevalent human malignancy. PC treatment may include surgery, androgen deprivation therapy, chemotherapy, and radiation therapy. However, the therapeutic efficacy of systemic chemotherapy is limited due to low drug solubility and insufficient tumor specificity, inflicting toxic side effects and frequently provoking the emergence of drug resistance. Towards the efficacious treatment of PC, we herein developed novel selectively PC-targeted nanoparticles (NPs) harboring a cytotoxic drug cargo. This delivery system is based upon PEGylated nanostructured lipid carriers (NLCs), decorated with a selective ligand, targeted to prostate-specific membrane antigen (PSMA). NPs loaded with cabazitaxel (CTX) displayed a remarkable loading capacity of 168 ± 3 mg drug/g SA-PEG, encapsulation efficiency of 67 ± 1%, and an average diameter of 159 ± 3 nm. The time-course of in vitro drug release from NPs revealed a substantial drug retention profile compared to the unencapsulated drug. These NPs were selectively internalized into target PC cells overexpressing PSMA, and displayed a dose-dependent growth inhibition compared to cells devoid of the PSMA receptor. Remarkably, these targeted NPs exhibited growth-inhibitory activity at pM CTX concentrations, being markedly more potent than the free drug. This selectively targeted nano-delivery platform bears the promise of enhanced efficacy and minimal untoward toxicity.
    Keywords:  cabazitaxel; encapsulation; nanoparticles; nanostructured lipid carriers; prostate cancer; prostate-specific membrane antigen; targeted delivery
    DOI:  https://doi.org/10.3390/pharmaceutics14010088
  103. Viruses. 2022 Jan 07. pii: 103. [Epub ahead of print]14(1):
    Metabolic Reprogramming of Glioblastoma Cells during HCMV Infection Induces Secretome-Mediated Paracrine Effects in the Microenvironment.
    Mark A A Harrison, Emily M Hochreiner, Brooke P Benjamin, Sean E Lawler, Kevin J Zwezdaryk.
      Glioblastoma (GBM) is an aggressive primary central nervous system neoplasia with limited therapeutic options and poor prognosis. Following reports of cytomegalovirus (HCMV) in GBM tumors, the anti-viral drug Valganciclovir was administered and found to significantly increase the longevity of GBM patients. While these findings suggest a role for HCMV in GBM, the relationship between them is not clear and remains controversial. Treatment with anti-viral drugs may prove clinically useful; however, their results do not explain the underlying mechanism between HCMV infection and GBM progression. We hypothesized that HCMV infection would metabolically reprogram GBM cells and that these changes would allow for increased tumor progression. We infected LN-18 GBM cells and employed a Seahorse Bioanalyzer to characterize cellular metabolism. Increased mitochondrial respiration and glycolytic rates were observed following infection. These changes were accompanied by elevated production of reactive oxygen species and lactate. Due to lactate's numerous tumor-promoting effects, we examined the impact of paracrine signaling of HCMV-infected GBM cells on uninfected stromal cells. Our results indicated that, independent of viral transmission, the secretome of HCMV-infected GBM cells was able to alter the expression of key metabolic proteins and epigenetic markers. This suggests a mechanism of action where reprogramming of GBM cells alters the surrounding tumor microenvironment to be permissive to tumor progression in a manner akin to the Reverse-Warburg Effect. Overall, this suggests a potential oncomodulatory role for HCMV in the context of GBM.
    Keywords:  aerobic glycolysis; glioblastoma (GBM); human cytomegalovirus (HCMV); lactate; metabolism; oxidative phosphorylation (OXPHOS); reactive oxygen species; tumor microenvironment
    DOI:  https://doi.org/10.3390/v14010103
  104. Nutrients. 2022 Jan 14. pii: 348. [Epub ahead of print]14(2):
    The Role of Diet in Prognosis among Cancer Survivors: A Systematic Review and Meta-Analysis of Dietary Patterns and Diet Interventions.
    Carlota Castro-Espin, Antonio Agudo.
      Cancer survival continues to improve in high-income countries, partly explained by advances in screening and treatment. Previous studies have mainly examined the relationship between individual dietary components and cancer prognosis in tumours with good therapeutic response (breast, colon and prostate cancers). The aim of this review is to assess qualitatively (and quantitatively where appropriate) the associations of dietary patterns and cancer prognosis from published prospective cohort studies, as well as the effect of diet interventions by means of randomised controlled trials (RCT). A systematic search was conducted in PubMed, and a total of 35 prospective cohort studies and 14 RCT published between 2011 and 2021 were selected. Better overall diet quality was associated with improved survival among breast and colorectal cancer survivors; adherence to the Mediterranean diet was associated to lower risk of mortality in colorectal and prostate cancer survivors. A meta-analysis using a random-effects model showed that higher versus lower diet quality was associated with a 23% reduction in overall mortality in breast cancer survivors. There was evidence that dietary interventions, generally combined with physical activity, improved overall quality of life, though most studies were in breast cancer survivors. Further cohort and intervention studies in other cancers are needed to make more specific recommendations.
    Keywords:  cancer prognosis; cancer survival; dietary intervention; dietary pattern; meta-analysis; prospective cohort; randomised controlled trial; systematic review
    DOI:  https://doi.org/10.3390/nu14020348
  105. Pharmaceutics. 2022 Jan 03. pii: 106. [Epub ahead of print]14(1):
    Development of Pharmaceutical Nanomedicines: From the Bench to the Market.
    Abdulrahman A Halwani.
      Nanotechnology plays a significant role in the field of medicine and in drug delivery, mainly due to the major limitations affecting the conventional pharmaceutical agents, and older formulations and delivery systems. The effect of nanotechnology on healthcare is already being felt, as various nanotechnology applications have been developed, and several nanotechnology-based medicines are now on the market. Across many parts of the world, nanotechnology draws increasing investment from public authorities and the private sector. Most conventional drug-delivery systems (CDDSs) have an immediate, high drug release after administration, leading to increased administration frequency. Thus, many studies have been carried out worldwide focusing on the development of pharmaceutical nanomedicines for translation into products manufactured by local pharmaceutical companies. Pharmaceutical nanomedicine products are projected to play a major role in the global pharmaceutical market and healthcare system. Our objectives were to examine the nanomedicines approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in the global market, to briefly cover the challenges faced during their development, and to look at future perspectives. Additionally, the importance of nanotechnology in developing pharmaceutical products, the ideal properties of nanocarriers, the reasons behind the failure of some nanomedicines, and the important considerations in the development of nanomedicines will be discussed in brief.
    Keywords:  drug delivery; nanoparticles; nanotechnology; pharmaceutical nanomedicines
    DOI:  https://doi.org/10.3390/pharmaceutics14010106
  106. Metabolites. 2022 Jan 13. pii: 72. [Epub ahead of print]12(1):
    Aerobic Glycolysis: A DeOxymoron of (Neuro)Biology.
    Avital Schurr, Salvatore Passarella.
      The term 'aerobic glycolysis' has been in use ever since Warburg conducted his research on cancer cells' proliferation and discovered that cells use glycolysis to produce adenosine triphosphate (ATP) rather than the more efficient oxidative phosphorylation (oxphos) pathway, despite an abundance of oxygen. When measurements of glucose and oxygen utilization by activated neural tissue indicated that glucose was consumed without an accompanied oxygen consumption, the investigators who performed those measurements also termed their discovery 'aerobic glycolysis'. Red blood cells do not contain mitochondria and, therefore, produce their energy needs via glycolysis alone. Other processes within the central nervous system (CNS) and additional organs and tissues (heart, muscle, and so on), such as ion pumps, are also known to utilize glycolysis only for the production of ATP necessary to support their function. Unfortunately, the phenomenon of 'aerobic glycolysis' is an enigma wherever it is encountered, thus several hypotheses have been produced in attempts to explain it; that is, whether it occurs in cancer cells, in activated neural tissue, or during postprandial or exercise metabolism. Here, it is argued that, where the phenomenon in neural tissue is concerned, the prefix 'aerobic' in the term 'aerobic glycolysis' should be removed. Data collected over the past three decades indicate that L-lactate, the end product of the glycolytic pathway, plays an essential role in brain energy metabolism, justifying the elimination of the prefix 'aerobic'. Similar justification is probably appropriate for other tissues as well.
    Keywords:  BOLD fMRI (blood oxygen level-dependent functional magnetic resonance imaging); CMR (cerebral metabolic rate); L-lactate; aerobic glycolysis; astroglial-neuronal L-lactate shuttle; glucose; mitochondrial oxidative phosphorylation; oxygen
    DOI:  https://doi.org/10.3390/metabo12010072
  107. Breast Cancer (Dove Med Press). 2022 ;14 15-24
    Treatment Strategies Against Triple-Negative Breast Cancer: An Updated Review.
    Mudasir Maqbool, Firomsa Bekele, Ginenus Fekadu.
      Triple-negative breast cancer (TNBC) is associated with an increased risk of early recurrence and distant metastasis, as well as the development of therapeutic resistance and poor prognosis. TNBC is characterized by a wide range of genetic, immunophenotypic, morphological, and clinical features. TNBC is coined to describe cancers that lack estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). As a result, hormonal or trastuzumab-based treatments are ineffective in TNBC patients. TNBCs are biologically aggressive, and despite some evidence that they respond to treatment better than other forms of breast cancer, the prognosis remains poor. This is attributed to a shorter disease-free interval in adjuvant and neoadjuvant settings, as well as a more aggressive metastatic course. TNBC has a lot of clinical ramifications. In terms of new treatment methods, TNBC has lagged behind other types of breast cancer. There are not many options for treating this form of breast cancer because it is progressive. Many effective treatments for most breast cancers block the growth-stimulating effects of ER, PR, and/or HER2, leaving TNBC with few choices. Finding new and effective treatment options for TNBC remains a critical clinical need. To develop more effective drugs, new experimental approaches must be tested in patients with TNBC.
    Keywords:  breast cancer; genetic; human epidermal growth factor receptor 2; progesterone receptor
    DOI:  https://doi.org/10.2147/BCTT.S348060
  108. Signal Transduct Target Ther. 2022 Jan 17. 7(1): 11
    Ketogenic diet for human diseases: the underlying mechanisms and potential for clinical implementations.
    Huiyuan Zhu, Dexi Bi, Youhua Zhang, Cheng Kong, Jiahao Du, Xiawei Wu, Qing Wei, Huanlong Qin.
      The ketogenic diet (KD) is a high-fat, adequate-protein, and very-low-carbohydrate diet regimen that mimics the metabolism of the fasting state to induce the production of ketone bodies. The KD has long been established as a remarkably successful dietary approach for the treatment of intractable epilepsy and has increasingly garnered research attention rapidly in the past decade, subject to emerging evidence of the promising therapeutic potential of the KD for various diseases, besides epilepsy, from obesity to malignancies. In this review, we summarize the experimental and/or clinical evidence of the efficacy and safety of the KD in different diseases, and discuss the possible mechanisms of action based on recent advances in understanding the influence of the KD at the cellular and molecular levels. We emphasize that the KD may function through multiple mechanisms, which remain to be further elucidated. The challenges and future directions for the clinical implementation of the KD in the treatment of a spectrum of diseases have been discussed. We suggest that, with encouraging evidence of therapeutic effects and increasing insights into the mechanisms of action, randomized controlled trials should be conducted to elucidate a foundation for the clinical use of the KD.
    DOI:  https://doi.org/10.1038/s41392-021-00831-w
  109. Biomolecules. 2022 Jan 06. pii: 90. [Epub ahead of print]12(1):
    Role of Sulphur and Heavier Chalcogens on the Antioxidant Power and Bioactivity of Natural Phenolic Compounds.
    Maria Laura Alfieri, Lucia Panzella, Riccardo Amorati, Alice Cariola, Luca Valgimigli, Alessandra Napolitano.
      The activity of natural phenols is primarily associated to their antioxidant potential, but is ultimately expressed in a variety of biological effects. Molecular scaffold manipulation of this large variety of compounds is a currently pursued approach to boost or modulate their properties. Insertion of S/Se/Te containing substituents on phenols may increase/decrease their H-donor/acceptor ability by electronic and stereo-electronic effects related to the site of substitution and geometrical constrains. Oxygen to sulphur/selenium isosteric replacement in resveratrol or ferulic acid leads to an increase in the radical scavenging activity with respect to the parent phenol. Several chalcogen-substituted phenols inspired by Vitamin E and flavonoids have been prepared, which in some cases prove to be chain-breaking antioxidants, far better than the natural counterparts. Conjugation of catechols with biological thiols (cysteine, glutathione, dihydrolipoic acid) is easily achieved by addition to the corresponding ortho-quinones. Noticeable examples of compounds with potentiated antioxidant activities are the human metabolite 5-S-cysteinyldopa, with high iron-induced lipid peroxidation inhibitory activity, due to strong iron (III) binding, 5-S-glutathionylpiceatannol a most effective inhibitor of nitrosation processes, and 5-S-lipoylhydroxytyrosol, and its polysulfides that proved valuable oxidative-stress protective agents in various cellular models. Different methodologies have been used for evaluation of the antioxidant power of these compounds against the parent compounds. These include kinetics of inhibition of lipid peroxidation alkylperoxyl radicals, common chemical assays of radical scavenging, inhibition of the OH• mediated hydroxylation/oxidation of model systems, ferric- or copper-reducing power, scavenging of nitrosating species. In addition, computational methods allowed researchers to determine the Bond Dissociation Enthalpy values of the OH groups of chalcogen modified phenolics and predict the best performing derivative. Finally, the activity of Se and Te containing compounds as mimic of glutathione peroxidase has been evaluated, together with other biological activities including anticancer action and (neuro)protective effects in various cellular models. These and other achievements are discussed and rationalized to guide future development in the field.
    Keywords:  Bond Dissociation Energy; DFT calculations; S/Se/Te-substituted phenols; alkylperoxyl radicals; antioxidant chemical assays; dihydrolipoic acid; glutathione peroxidase-like activity; glutathionyl/cysteinylcatechols; kinetic constant; lipid peroxidation; thia/selenotocopherols
    DOI:  https://doi.org/10.3390/biom12010090
  110. Pharmaceutics. 2022 Jan 05. pii: 129. [Epub ahead of print]14(1):
    pH-Responsive Liposomes of Dioleoyl Phosphatidylethanolamine and Cholesteryl Hemisuccinate for the Enhanced Anticancer Efficacy of Cisplatin.
    Hassan Shah, Asadullah Madni, Muhammad Muzamil Khan, Fiaz-Ud-Din Ahmad, Nasrullah Jan, Safiullah Khan, Muhammad Abdur Rahim, Shahzeb Khan, Meser M Ali, Mohsin Kazi.
      The current study aimed to develop pH-responsive cisplatin-loaded liposomes (CDDP@PLs) via the thin film hydration method. Formulations with varied ratios of dioleoyl phosphatidylethanolamine (DOPE) to cholesteryl hemisuccinate (CHEMS) were investigated to obtain the optimal particle size, zeta potential, entrapment efficiency, in vitro release profile, and stability. The particle size of the CDDP@PLs was in the range of 153.2 ± 3.08-206.4 ± 2.26 nm, zeta potential was -17.8 ± 1.26 to -24.6 ± 1.72, and PDI displayed an acceptable size distribution. Transmission electron microscopy revealed a spherical shape with ~200 nm size. Fourier transform infrared spectroscopic analysis showed the physicochemical stability of CDDP@PLs, and differential scanning calorimetry analysis showed the loss of the crystalline nature of cisplatin in liposomes. In vitro release study of CDDP@PLs at pH 7.4 depicted the lower release rate of cisplatin (less than 40%), and at a pH of 6.5, an almost 65% release rate was achieved compared to the release rate at pH 5.5 (more than 80%) showing the tumor-specific drug release. The cytotoxicity study showed the improved cytotoxicity of CDDP@PLs compared to cisplatin solution in MDA-MB-231 and SK-OV-3 cell lines, and fluorescence microscopy also showed enhanced cellular internalization. The acute toxicity study showed the safety and biocompatibility of the developed carrier system for the potential delivery of chemotherapeutic agents. These studies suggest that CDDP@PLs could be utilized as an efficient delivery system for the enhancement of therapeutic efficacy and to minimize the side effects of chemotherapy by releasing cisplatin at the tumor site.
    Keywords:  MDA-MB-231 cell lines; SK-OV-3 cell lines; cisplatin; confocal scanning laser microscopy; pH-responsive liposomes
    DOI:  https://doi.org/10.3390/pharmaceutics14010129
  111. Front Bioeng Biotechnol. 2021 ;9 817143
    Enhanced Anticancer Efficacy of Chemotherapy by Amphiphilic Y-Shaped Polypeptide Micelles.
    Cong Hua, Yi Zhang, Yuanhao Liu.
      Although the treatment modalities of cancers are developing rapidly, chemotherapy is still the primary treatment strategy for most solid cancers. The progress in nanotechnology provides an opportunity to upregulate the tumor suppression efficacy and decreases the systemic toxicities. As a promising nanoplatform, the polymer micelles are fascinating nanocarriers for the encapsulation and delivery of chemotherapeutic agents. The chemical and physical properties of amphiphilic co-polymers could significantly regulate the performances of the micellar self-assembly and affect the behaviors of controlled release of drugs. Herein, two amphiphilic Y-shaped polypeptides are prepared by the ring-opening polymerization of cyclic monomer l-leucine N-carboxyanhydride (l-Leu NCA) initiated by a dual-amino-ended macroinitiator poly(ethylene glycol) [mPEG-(NH2)2]. The block co-polypeptides with PLeu8 and PLeu16 segments could form spontaneously into micelles in an aqueous solution with hydrodynamic radii of 80.0 ± 6.0 and 69.1 ± 4.8 nm, respectively. The developed doxorubicin (DOX)-loaded micelles could release the payload in a sustained pattern and inhibit the growth of xenografted human HepG2 hepatocellular carcinoma with decreased systemic toxicity. The results demonstrated the great potential of polypeptide micellar formulations in cancer therapy clinically.
    Keywords:  cancer therapy; controlled drug delivery; micelle; polymer topology; polypeptide
    DOI:  https://doi.org/10.3389/fbioe.2021.817143
  112. Adv Sci (Weinh). 2022 Jan 22. e2104472
    Targeting Cancer Metabolism Plasticity with JX06 Nanoparticles via Inhibiting PDK1 Combined with Metformin for Endometrial Cancer Patients with Diabetes.
    Xiao Yang, Yuan Cheng, Jingyi Zhou, Lingpu Zhang, Xingchen Li, Zhiqi Wang, Shenyi Yin, LiRong Zhai, Ting Huang, Xiaotong Wu, Boqiang Shen, Yangyang Dong, Lijun Zhao, Yujing Chi, Yuanyuan Jia, Jiaqi Wang, Yijiao He, Xiying Dong, Haihua Xiao, Jianliu Wang.
      Diabetes is closely related to the occurrence of endometrial cancer (EC) and its poor prognosis. However, there is no effective clinical treatment for EC patients with diabetes (patientEC+/dia+ ). To explore new therapeutic targets, Ishikawa is cultured with high glucose (IshikawaHG ) mimicking hyperglycemia in patientEC+/dia+ . Subsequently, it is discovered that IshikawaHG exhibits glucose metabolic reprogramming characterized by increased glycolysis and decreased oxidative phosphorylation. Further, pyruvate dehydrogenase kinase 1 (PDK1) is identified to promote glycolysis of IshikawaHG by proteomics. Most importantly, JX06, a novel PDK1 inhibitor combined metformin (Met) significantly inhibits IshikawaHG proliferation though IshikawaHG is resistant to Met. Furthermore, a reduction-sensitive biodegradable polymer is adopted to encapsulate JX06 to form nanoparticles (JX06-NPs) for drug delivery. It is found that in vitro JX06-NPs have better inhibitory effect on the growth of IshikawaHG as well as patient-derived EC cells (PDC) than JX06. Additionally, it is found that JX06-NPs can accumulate to the tumor of EC-bearing mouse with diabetes (miceEC+/dia+ ) after intravenous injection, and JX06-NPs combined Met can significantly inhibit tumor growth of miceEC+/dia+ . Taken together, the study demonstrates that the combination of JX06-NPs and Met can target the cancer metabolism plasticity, which significantly inhibits the growth of EC, thereby provides a new adjuvant therapy for patientsEC+/dia+ .
    Keywords:  PDK1; cell metabolic reprogramming; diabetes; endometrial cancer; high glucose; metformin
    DOI:  https://doi.org/10.1002/advs.202104472
  113. Cancer Res. 2022 Jan 15. 82(2): 195-196
    Hypoxia-Inducible Factors in Cancer.
    Laura C Kim, M Celeste Simon.
      Low oxygen concentrations (hypoxia) are detrimental to most species on Earth; thus, cells have evolved with adaptations allowing them to withstand transient hypoxia. As with other survival pathways, cancer cells have co-opted these mechanisms to keep up with the metabolic demands of rapid growth and proliferation in harsh tumor microenvironments. The most well-studied oxygen response pathway involves hypoxia-inducible factors (HIF) and their regulation by the von Hippel-Lindau protein (pVHL) and the prolyl hydroxylases (PHD1-3). This study from Zhong and colleagues, published in Cancer Research in 1999, was the first to show increased HIF1α expression in several cancer types and in metastases, suggesting a role for HIFs in disease progression. Since publication, significant progress has been made in the understanding of tumor hypoxia responses and efforts to target this pathway as a therapeutic strategy for patients with cancer are underway.See related article by Zhong and colleagues, Cancer Res 1999;59:5830-5.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-3780
  114. Biochim Biophys Acta Rev Cancer. 2022 Jan 13. pii: S0304-419X(22)00002-6. [Epub ahead of print] 188677
    Reflections on drug resistance to KRASG12C inhibitors and gene silencing/editing tools for targeting mutant KRAS in cancer treatment.
    ZhaoYong Han, Ding Zhou, JiaMan Wang, Bruce Jiang, XiYu Liu.
      KRAS is the most commonly mutated oncogene in human tumors, especially in lung, pancreatic, and colorectal cancers. Small-molecule inhibitors targeting mutant KRASG12C demonstrated promising anti-tumor effect in patients with non-small cell lung cancer harboring KRASG12C mutation, while the intrinsic and acquired drug resistance occurred frequently and might be inevitable. Unlike the protein-level inhibition approach, gene silencing/editing tools for DNA-level knockout and RNA-level knockdown of mutant KRAS may be advantageous since these approaches directly eliminate the production of mutant KRAS-encoded protein. An in-depth understanding of KRAS biology, drug resistance to KRASG12C inhibitors and gene silencing/editing methods applied for anti-KRAS therapy may give new insight into the therapeutic strategy for cancer treatment.
    Keywords:  Anti-KRAS; Gene silencing/editing; Inhibitors; KRAS
    DOI:  https://doi.org/10.1016/j.bbcan.2022.188677
  115. Acta Biomater. 2022 Jan 12. pii: S1742-7061(22)00011-3. [Epub ahead of print]
    Tumor Microenvironment pH-Responsive Pentagonal Gold Prism-Based Nanoplatform for Multimodal Imaging and Combined Therapy of Castration-Resistant Prostate Cancer.
    Haisong Tan, Yanlei Liu, Nan Hou, Shengsheng Cui, Bin Liu, Shanshan Fan, Guopeng Yu, Chao Han, Dachao Zheng, Wenzhi Li, Yushan Liu, Bin Xu, Zhong Wang, Daxiang Cui.
      Given that there is lack of effective therapies for castration-resistant prostate cancer (CRPC), the combination of photothermal (PTT), photodynamic (PDT), and chemical therapy (CT) has emerged as a prominent strategy. Tumor-targeted delivery and controlled release of antitumor drug are key-elements of any combined therapy. Considering these important elements, we designed and constructed tumor microenvironment (TME)-activated nanoprobes (PGP/CaCO3@IR820/DTX-HA). The CaCO3 shell could efficiently entrap the photosensitizer IR820 and the chemotherapeutic docetaxel (DTX) on the surface of pentagonal gold prisms (PGPs) to prevent elimination from the circulation, and it could act as a TME-trigger to achieve TME-responsive drug release. After modification with hyaluronic acid, PGP/CaCO3@IR820/DTX-HA was capable of synergistic TME-triggered PTT/PDT/CT and tumor-targeted delivery. Our in vitro and in vivo studies demonstrate that PGP/CaCO3@IR820/DTX-HA could achieve synergistic antitumor effects following near-infrared (NIR)-light irradiation. In addition, using the NIR fluorescence signal from IR820 and the photoacoustic (PA) signal from PGPs, i.e., through multimodal fluorescence/photoacoustic imaging, we could monitor the in vivo distribution and excretion of PGP/CaCO3@IR820/DTX-HA. Therefore, it can be concluded that PGP/CaCO3@IR820/DTX-HA shows promising clinical translational potential as a treatment for CRPC. STATEMENT OF SIGNIFICANCE: Utilizing pentagonal gold prisms (PGPs), we constructed a multifunctional nanoplatform (PGP/CaCO3@IR820/DTX-HA) for effectively delivering agents into the tumor microenvironment (TME) for the diagnosis and therapy of castration-resistant prostate cancer (CRPC). The synthetic nanoplatform can satisfy TME-activated synergistic photothermal therapy (PTT)/photodynamic therapy (PDT)/chemical therapy (CT) and NIR fluorescence imaging/photoacoustic (PA) imaging. Hyaluronic acid (HA) on the surface of nanoplatform allowed the specific tumor-targeting capacity and biocompatibility. In conclusion, PGP/CaCO3@IR820/DTX-HA could be a promising integrated nanoplatform for CRPC diagnosis and treatment.
    Keywords:  castration-resistant prostate cancer; combined therapy; multimodal imaging; pentagonal gold prisms
    DOI:  https://doi.org/10.1016/j.actbio.2022.01.012
  116. Br J Nutr. 2022 Jan 19. 1-36
    Potential anti-inflammatory effects of legumes - A review.
    Milagros Faridy Juárez-Chairez, Ofelia Gabriela Meza-Márquez, Yazmín Karina Márquez-Flores, Cristian Jiménez-Martínez.
      Legumes are a staple of diets all around the world. In some least developed countries, they are the primary source of protein; however, their beneficial properties go beyond their nutritional value. Recent research has shown that legumes have bioactive compounds like peptides, polyphenols, and saponins; which exhibit antioxidant, antihypertensive, anti-inflammatory, and other biological activities. Thus, these compounds could be an alternative treatment for inflammatory diseases, in particular, chronic inflammation such as arthritis, obesity, and cancer. Nowadays, there is a growing interest in alternative therapies derived from natural products; accordingly, the present review has compiled the bioactive compounds found in legumes that have demonstrated an anti- inflammatory effect in non-clinical studies.
    Keywords:  Inflammatory process; bean; carbohydrates; peptides; phenolic compounds; soybean
    DOI:  https://doi.org/10.1017/S0007114522000137
  117. J Nutr Metab. 2022 ;2022 4667607
    An Overview of Alkylresorcinols Biological Properties and Effects.
    Anastasia A Zabolotneva, Olga P Shatova, Anastasia A Sadova, Aleksandr V Shestopalov, Sergei A Roumiantsev.
      The investigation of alkylresorcinols has drawn an increasing interest recently. Alkylresorcinols (ARs) are natural chemical compounds synthesized by bacteria, fungi, sponges, and higher plants, possessing a lipophilic polyphenol structures and a myriad of biological properties. Human takes ARs as a component of a whole grain diet (from whole grain rye, wheat, and barley products), and thus, alkylresorcinols are frequently used as whole grain intake markers. Besides, ARs are considered as promising bioregulators of metabolic and immune processes, as well as adjuvant therapeutic agents for antimicrobial and anticancer treatment. In this review, we attempted to systematize the accumulated information concerning ARs origin, metabolism, biological properties, and their effect on human health.
    DOI:  https://doi.org/10.1155/2022/4667607
  118. Pharmaceutics. 2021 Dec 24. pii: 35. [Epub ahead of print]14(1):
    Computational Modeling of Combination of Magnetic Hyperthermia and Temperature-Sensitive Liposome for Controlled Drug Release in Solid Tumor.
    Masoud H H Tehrani, M Soltani, Farshad Moradi Kashkooli, Mohammadreza Mahmoudi, Kaamran Raahemifar.
      Combination therapy, a treatment modality that combines two or more therapeutic methods, provides a novel pathway for cancer treatment, as it targets the region of interest (ROI) in a characteristically synergistic or additive manner. To date, liposomes are the only nano-drug delivery platforms that have been used in clinical trials. Here, we speculated that it could be promising to improve treatment efficacy and reduce side effects by intravenous administration of thermo-sensitive liposomes loaded with doxorubicin (TSL-Dox) during magnetic hyperthermia (MHT). A multi-scale computational model using the finite element method was developed to simulate both MHT and temperature-sensitive liposome (TSL) delivery to a solid tumor to obtain spatial drug concentration maps and temperature profiles. The results showed that the killing rate of MHT alone was about 15%, which increased to 50% using the suggested combination therapy. The results also revealed that this combination treatment increased the fraction of killed cells (FKCs) inside the tumor compared to conventional chemotherapy by 15% in addition to reducing side effects. Furthermore, the impacts of vessel wall pore size, the time interval between TSL delivery and MHT, and the initial dose of TSLs were also investigated. A considerable reduction in drug accumulation was observed in the tumor by decreasing the vessel wall pore size of the tumor. The results also revealed that the treatment procedure plays an essential role in the therapeutic potential of anti-cancer drugs. The results suggest that the administration of MHT can be beneficial in the TSL delivery system and that it can be employed as a guideline for upcoming preclinical studies.
    Keywords:  magnetic hyperthermia; magnetic nanoparticles; multi-scale cancer modeling; solid tumor; targeted drug delivery; temperature-sensitive liposomes
    DOI:  https://doi.org/10.3390/pharmaceutics14010035
  119. J Nanobiotechnology. 2022 Jan 21. 20(1): 39
    Betulinic acid self-assembled nanoparticles for effective treatment of glioblastoma.
    Yong Li, Yixuan Wang, Lun Gao, Yinqiu Tan, Jiayang Cai, Zhang Ye, Ann T Chen, Yang Xu, Linyao Zhao, Shiao Tong, Qian Sun, Baohui Liu, Shenqi Zhang, Daofeng Tian, Gang Deng, Jiangbing Zhou, Qianxue Chen.
       BACKGROUND: Glioblastoma (GBM) is the most common and fatal primary tumor in the central nervous system (CNS). Due to the existence of blood-brain barrier (BBB), most therapeutics cannot efficiently reach tumors in the brain, and as a result, they are unable to be used for effective GBM treatment. Accumulating evidence shows that delivery of therapeutics in form of nanoparticles (NPs) may allow crossing the BBB for effective GBM treatment.
    METHODS: Betulinic acid NPs (BA NPs) were synthesized by the standard emulsion approach and characterized by electron microscopy and dynamic light scattering analysis. The resulting NPs were characterized for their anti-tumor effects by cell viability assay, EdU-DNA synthesis assay, cell cycle assay, mitochondrial membrane potential, and PI-FITC apoptosis assay. Further mechanistic studies were carried out through Western Blot and immunostaining analyses. Finally, we evaluated BA NPs in vivo for their pharmacokinetics and antitumor effects in intracranial xenograft GBM mouse models.
    RESULTS: BA NPs were successfully prepared and formed into rod shape. BA NPs could significantly suppress glioma cell proliferation, induce apoptosis, and arrest the cell cycle in the G0/G1 phase in vitro. Furthermore, BA NPs downregulated the Akt/NFκB-p65 signaling pathway in a concentration dependent manner. We found that the observed anti-tumor effect of BA NPs was dependent on the function of CB1/CB2 receptors. Moreover, in the intracranial GBM xenograft mouse models, BA NPs could effectively cross the BBB and greatly prolong the survival time of the mice.
    CONCLUSIONS: We successfully synthesized BA NPs, which could cross the BBB and demonstrated a strong anti-tumor effect. Therefore, BA NPs may potentially be used for effective treatment of GBM.
    Keywords:  Apoptosis; Betulinic acid; CB1/CB2; Nanoparticles; Proliferation
    DOI:  https://doi.org/10.1186/s12951-022-01238-7
  120. Nutrients. 2022 Jan 07. pii: 255. [Epub ahead of print]14(2):
    Synergistic Effect of Squalene and Hydroxytyrosol on Highly Invasive MDA-MB-231 Breast Cancer Cells.
    Cristina Sánchez-Quesada, Francisco Gutiérrez-Santiago, Carmen Rodríguez-García, José J Gaforio.
      Several studies relate Mediterranean diet and virgin olive oil (VOO) intake with lower risk of several chronic diseases, including breast cancer. Many of them described antitumor properties of isolated minor compounds present in VOO, but beneficial properties of VOO arise from the effects of all its compounds acting together. The aim of the present study was to test the antitumor effects of two minor compounds from VOO (hydroxytyrosol (HT) and squalene (SQ)) on highly metastatic human breast tumor cells (MDA-MB-231) when acting in combination. Both isolated compounds were previously analyzed without showing any antitumoral effect on highly invasive MDA-MB-231 breast cancer cells, but the present results show that HT at 100 µM, combined with different concentrations of SQ, could exert antitumor effects. When they are combined, HT and SQ are able to inhibit cell proliferation, promoting apoptosis and DNA damage in metastatic breast cancer cells. Therefore, our results suggest that the health-promoting properties of VOO may be due, at least in part, to the combined action of these two minor compounds.
    Keywords:  DNA damage; antitumor; apoptosis; breast cancer; comet assay; proliferation; virgin olive oils
    DOI:  https://doi.org/10.3390/nu14020255
  121. Biomater Sci. 2022 Jan 20.
    Tumor-targeted biomimetic nanoplatform precisely integrates photodynamic therapy and autophagy inhibition for collaborative treatment of oral cancer.
    Hao Dai, Han Yan, Fan Dong, Ludan Zhang, Ning Du, Lisha Sun, Ningyu Li, Guohui Yu, Zeyuan Yang, Yuguang Wang, Mingwei Huang.
      Oral cancer is a common malignant tumor in the maxillofacial region. Surgical resection is the preferred treatment, but the severe functional impairment after surgery forces us to look for noninvasive treatments. As a promising noninvasive treatment method, photodynamic therapy (PDT) has received widespread attention in the field of cancer therapy, but the inefficient uptake capacity of tumor cells and the damage repair mechanisms limit the actual therapeutic effect. The establishment of a targeted therapy function and autophagy inhibition strategy is considered to be an important way to further enhance the effect of PDT. Based on this, we developed the biomimetic nanomaterial PCN-CQ@CCM. The metal-organic framework material PCN-224 was used as a carrier to load the autophagy inhibitor chloroquine (CQ) and it was coated onto the surface with isolated oral squamous cell carcinoma (OSCC) cell membranes. Owing to the immune evasion and homologous targeting ability of the biomimetic functionalized surface, PCN-CQ@CCM can escape macrophage phagocytosis and homologously adhere to tumor cells, enhancing the retention and uptake of nanomaterials in the tumor microenvironment. After being activated with a 660 nm laser, the generated reactive oxygen species (ROS) triggered the apoptosis pathway, as assessed by mitochondrial damage, and the released CQ further aggravated the ROS lethal pathway by effectively inhibiting the protective autophagic flux. Therefore, PCN-CQ@CCM achieves the precise synergy of PDT and autophagy inhibition through the biomimetic homologous targeting method, and the highly effective tumor suppression effect expands the field of vision for the noninvasive diagnosis and treatment of oral cancer.
    DOI:  https://doi.org/10.1039/d1bm01780b
  122. Chin Med. 2022 Jan 15. 17(1): 12
    A review on the applications of Traditional Chinese medicine polysaccharides in drug delivery systems.
    Bei Wang, Xianfeng Wang, Zhiwei Xiong, Guanzheng Lu, Weikun Ma, Qinglin Lv, Long Wang, Xiaobin Jia, Liang Feng.
      Traditional Chinese medicine polysaccharides (TCMPs) are plentiful and renewable resources with properties such as biocompatibility, hydrophilicity, biodegradability, and low cytotoxicity. Because the polysaccharide molecular chain contains a variety of active groups, different polysaccharide derivatives can be easily produced through chemical modification. They have been increasingly used in drug delivery systems (DDS). However, the potential of polysaccharides is usually ignored due to their structural complexity, poor stability or ambiguity of mechanisms of actions. This review summarized the applications of TCMPs in DDS around four main aspects. The general characteristics of TCMPs as drug delivery carriers, as well as the relationships between structure and function of them were summarized. Meanwhile, the direction of preparing multifunctional drug delivery materials with synergistic effect by using TCMPs was discussed. This review aims to become a reference for further research of TCMPs and their derivatives, especially applications of them as carriers in pharmaceutical preparation industry.
    Keywords:  Drug delivery systems; Polysaccharide; Synergistic effect; Traditional Chinese medicine
    DOI:  https://doi.org/10.1186/s13020-021-00567-3
  123. Pharmaceutics. 2022 Jan 17. pii: 212. [Epub ahead of print]14(1):
    Molecular Engineering of Peptide-Drug Conjugates for Therapeutics.
    Yu Fang, Huaimin Wang.
      In recent years, hundreds of novel small molecular drugs used for different treatments have been studied in the three phases of clinical trials around the world. However, less than 10% of them are eventually used due to diverse problems. Even some traditional drugs that have been approved by the Food and Drug Administration (FDA) have faced similar dilemmas. For instance, many drugs have poor water solubility, are easily hydrolyzed, or possess undesirable toxicity, while a variety of cancer cells develop drug resistance (DR) or multiple drug resistance (MDR) towards chemotherapeutic agents after long-term therapy. In order to improve the efficacy and efficiency of drugs, research has been directed forward towards the creation of assemblies of peptide-drug conjugates (PDCs) which have proven to possess wide potential for overcoming such complications based on their excellent biocompatibility, controllable biodegradability, site-selective targeting, and comparably low cytotoxicity. In this review, we focus on the recent developments and advances made in the creation of self-assembled nanostructures of PDCs for cancer therapy, on the chemical and physical properties of such drugs and peptides, and how they are arranged together to form diverse supramolecular nanostructures. Additionally, we cover certain mechanisms regarding how peptides or their derivatives enhance the efficiency and efficacy of those selected drugs and provide a brief discussion regarding the perspectives and remaining challenges in this intriguing field.
    Keywords:  hydrogel; nanotechnology; peptide–drug conjugate (PDC); prodrug; self-assembly
    DOI:  https://doi.org/10.3390/pharmaceutics14010212
  124. ACS Appl Mater Interfaces. 2022 Jan 18.
    Macrophage-Mimic Hollow Mesoporous Fe-Based Nanocatalysts for Self-Amplified Chemodynamic Therapy and Metastasis Inhibition via Tumor Microenvironment Remodeling.
    Wenbao Zuo, Weibin Chen, Jinxue Liu, Shuying Huang, Luping Chen, Qingna Liu, Nian Liu, Quanyi Jin, Yang Li, Peiyuan Wang, Xuan Zhu.
      Fe-based nanomaterials with Fenton reaction activity are promising for tumor-specific chemodynamic therapy (CDT). However, most of the nanomaterials suffer from low catalytic efficiency due to its insufficient active site exposure and the relatively high tumor intracellular pH, which greatly impede its clinical application. Herein, macrophage membrane-camouflaged carbonic anhydrase IX inhibitor (CAI)-loaded hollow mesoporous ferric oxide (HMFe) nanocatalysts are designed to remodel the tumor microenvironment with decreased intracellular pH for self-amplified CDT. The HMFe not only serves as a Fenton agent with high active-atom exposure to enhance CDT but also provides hollow cavity for CAI loading. Meanwhile, the macrophage membrane-camouflaging endows the nanocatalysts with immune evading capability and improves tumoritropic accumulation by recognizing tumor endothelium and cancer cells through α4/VCAM-1 interaction. Once internalized by tumor cells, the CAI could be specifically released, which can not only inhibit CA IX to induce intracellular H+ accumulation for accelerating the Fenton reaction but also could prevent tumor metastasis because of the insufficient H+ formation outside cells for tumor extracellular matrix degradation. In addition, the HMFe can be employed to highly efficient magnetic resonance imaging to real-time monitor the agents' bio-distribution and treatment progress. Both in vitro and in vivo results well demonstrated that the nanocatalysts could realize self-amplified CDT and breast cancer metastasis inhibition via tumor microenvironment remodeling, which also provides a promising paradigm for improving CDT and antimetastatic treatment.
    Keywords:  carbonic anhydrase IX; chemodynamic therapy; macrophage membrane; metastatic breast cancer; tumor microenvironment remodeling
    DOI:  https://doi.org/10.1021/acsami.1c22432
  125. Phytother Res. 2022 Jan 18.
    An overview of the therapeutic effects of curcumin in reproductive disorders with a focus on the antiinflammatory and immunomodulatory activities.
    Bita Saifi, Saeed Mohammadian Haftcheshmeh, Marco Feligioni, Esmael Izadpanah, Kaveh Rahimi, Kambiz Hassanzadeh, Asadollah Mohammadi, Amirhossein Sahebkar.
      Curcumin, the polyphenolic compound obtained from turmeric, has several pharmacological properties. These properties include antioxidant, antimicrobial, anti-angiogenic, anticarcinogenic, antiinflammatory, and immunomodulatory activities. Therefore, the clinical efficacy of this substance has been largely investigated for curing numerous disorders. Based on a growing body of literature, this review aimed to investigate curcumin's molecular and clinical effects on reproduction and related disorders. Curcumin in the female reproductive system attenuates folliculogenesis, promotes apoptosis of oocytes and blastocyst, and decreases embryo implantation and survival. Curcumin at <100 mg concentration shows protective effects against testicular injury. The concentration of >250 mg of curcumin exhibits immobilizing action on sperms, and at 500 mg concentration completely blocks pregnancy. Curcumin inhibits vaginal infections, attenuates the severity of the premenstrual syndrome, ameliorates inflammatory conditions in polycystic ovary syndrome, improves preeclampsia, and prevents ectopic endometrial lesions. Taken together, curcumin, because of the numerous biological activities, low level of toxicity, and lower adverse effects compared to the synthetic drugs, could be considered as a protective agent for preserving the semen quality parameters, a contraceptive, and chemotherapeutic or chemopreventive agent, as well as an appropriate agent for the treatment of female reproductive disorders.
    Keywords:  curcumin; immunomodulation; inflammation; reproductive disorder; reproductive system
    DOI:  https://doi.org/10.1002/ptr.7360
  126. Pharmaceutics. 2021 Dec 27. pii: 52. [Epub ahead of print]14(1):
    Folic Acid-Decorated β-Cyclodextrin-Based Poly(ε-caprolactone)-dextran Star Polymer with Disulfide Bond-Linker as Theranostic Nanoparticle for Tumor-Targeted MRI and Chemotherapy.
    Huikang Yang, Nianhua Wang, Ruimeng Yang, Liming Zhang, Xinqing Jiang.
      β-cyclodextrin(βCD)-based star polymers have attracted much interest because of their unique structures and potential biomedical and biological applications. Herein, a well-defined folic acid (FA)-conjugated and disulfide bond-linked star polymer ((FA-Dex-SS)-βCD-(PCL)14) was synthesized via a couple reaction between βCD-based 14 arms poly(ε-caprolactone) (βCD-(PCL)14) and disulfide-containing α-alkyne dextran (alkyne-SS-Dex), and acted as theranostic nanoparticles for tumor-targeted MRI and chemotherapy. Theranostic nanoparticles were obtained by loading doxorubicin (DOX), and superparamagnetic iron oxide (SPIO) particles were loaded into the star polymer nanoparticles to obtain ((FA-Dex-SS)-βCD-(PCL)14@DOX-SPIO) theranostic nanoparticles. In vitro drug release studies showed that approximately 100% of the DOX was released from disulfide bond-linked theranostic nanoparticles within 24 h under a reducing environment in the presence of 10.0 mM GSH. DOX and SPIO could be delivered into HepG2 cells efficiently, owing to the folate receptor-mediated endocytosis process of the nanoparticles and glutathione (GSH), which triggered disulfide-bonds cleaving. Moreover, (FA-Dex-SS)-βCD-(PCL)14@DOX-SPIO showed strong MRI contrast enhancement properties. In conclusion, folic acid-decorated reduction-sensitive star polymeric nanoparticles are a potential theranostic nanoparticle candidate for tumor-targeted MRI and chemotherapy.
    Keywords:  disulfide bond; star polymer; theranostic nanoparticles; tumor-targeted; β-cyclodextrin
    DOI:  https://doi.org/10.3390/pharmaceutics14010052
  127. Antioxidants (Basel). 2021 Dec 22. pii: 20. [Epub ahead of print]11(1):
    Lemongrass Essential Oil Components with Antimicrobial and Anticancer Activities.
    Mohammad Mukarram, Sadaf Choudhary, Mo Ahamad Khan, Palmiro Poltronieri, M Masroor A Khan, Jamin Ali, Daniel Kurjak, Mohd Shahid.
      The prominent cultivation of lemongrass (Cymbopogon spp.) relies on the pharmacological incentives of its essential oil. Lemongrass essential oil (LEO) carries a significant amount of numerous bioactive compounds, such as citral (mixture of geranial and neral), isoneral, isogeranial, geraniol, geranyl acetate, citronellal, citronellol, germacrene-D, and elemol, in addition to other bioactive compounds. These components confer various pharmacological actions to LEO, including antifungal, antibacterial, antiviral, anticancer, and antioxidant properties. These LEO attributes are commercially exploited in the pharmaceutical, cosmetics, and food preservations industries. Furthermore, the application of LEO in the treatment of cancer opens a new vista in the field of therapeutics. Although different LEO components have shown promising anticancer activities in vitro, their effects have not yet been assessed in the human system. Hence, further studies on the anticancer mechanisms conferred by LEO components are required. The present review intends to provide a timely discussion on the relevance of LEO in combating cancer and sustaining human healthcare, as well as in food industry applications.
    Keywords:  Cymbopogon; anticancer; antimicrobial; antioxidants; cancer signalling; citral; essential oil
    DOI:  https://doi.org/10.3390/antiox11010020
  128. Pharmaceutics. 2021 Dec 29. pii: 80. [Epub ahead of print]14(1):
    Overcoming MDR by Associating Doxorubicin and pH-Sensitive PLGA Nanoparticles Containing a Novel Organoselenium Compound-An In Vitro Study.
    Letícia Bueno Macedo, Daniele Rubert Nogueira-Librelotto, Daniela Mathes, Josiele Melo de Vargas, Raquel Mello da Rosa, Oscar Endrigo Dorneles Rodrigues, Maria Pilar Vinardell, Montserrat Mitjans, Clarice Madalena Bueno Rolim.
      In this study, we developed PLGA nanoparticles (NPs) as an effective carrier for 5'-Se-(phenyl)-3-(amino)-thymidine (ACAT-Se), an organoselenium compound, nucleoside analogue that showed promising antitumor activity in vitro. The PLGA NPs were prepared by the nanoprecipitation method and modified with a pH-responsive lysine-based surfactant (77KL). The ACAT-Se-PLGA-77KL-NPs presented nanometric size (around 120 nm), polydispersity index values < 0.20 and negative zeta potential values. The nanoencapsulation of ACAT-Se increased its antioxidant (DPPH and ABTS assays) and antitumor activity in MCF-7 tumor cells. Hemolysis study indicated that ACAT-Se-PLGA-77KL-NPs are hemocompatible and that 77KL provided a pH-sensitive membranolytic behavior to the NPs. The NPs did not induce cytotoxic effects on the nontumor cell line 3T3, suggesting its selectivity for the tumor cells. Moreover, the in vitro antiproliferative activity of NPs was evaluated in association with the antitumor drug doxorubicin. This combination result in synergistic effect in sensitive (MCF-7) and resistant (NCI/ADR-RES) tumor cells, being especially able to successfully sensitize the MDR cells. The obtained results suggested that the proposed ACAT-Se-loaded NPs are a promising delivery system for cancer therapy, especially associated with doxorubicin.
    Keywords:  combination therapy; multidrug resistance (MDR); pH-responsive nanoparticles; selenium compounds; tumor cell lines
    DOI:  https://doi.org/10.3390/pharmaceutics14010080
  129. Int J Mol Sci. 2022 Jan 12. pii: 800. [Epub ahead of print]23(2):
    The Epithelial-Mesenchymal Transition at the Crossroads between Metabolism and Tumor Progression.
    Monica Fedele, Riccardo Sgarra, Sabrina Battista, Laura Cerchia, Guidalberto Manfioletti.
      The transition between epithelial and mesenchymal phenotype is emerging as a key determinant of tumor cell invasion and metastasis. It is a plastic process in which epithelial cells first acquire the ability to invade the extracellular matrix and migrate into the bloodstream via transdifferentiation into mesenchymal cells, a phenomenon known as epithelial-mesenchymal transition (EMT), and then reacquire the epithelial phenotype, the reverse process called mesenchymal-epithelial transition (MET), to colonize a new organ. During all metastatic stages, metabolic changes, which give cancer cells the ability to adapt to increased energy demand and to withstand a hostile new environment, are also important determinants of successful cancer progression. In this review, we describe the complex interaction between EMT and metabolism during tumor progression. First, we outline the main connections between the two processes, with particular emphasis on the role of cancer stem cells and LncRNAs. Then, we focus on some specific cancers, such as breast, lung, and thyroid cancer.
    Keywords:  Warburg effect; breast cancer; cancer; epithelial–mesenchymal transition (EMT); lung cancer; metabolic rewiring; metabolism; thyroid cancer; tumor progression
    DOI:  https://doi.org/10.3390/ijms23020800
  130. Front Oral Health. 2021 ;2 767474
    Genetic Profile of Adenomatoid Odontogenic Tumor and Ameloblastoma. A Systematic Review.
    Constanza Marín, Sven E Niklander, René Martínez-Flores.
      Purpose: To perform a comprehensive and systematic critical appraisal of the genetic alterations reported to be present in adenomatoid odontogenic tumor (AOT) compared to ameloblastoma (AM), to aid in the understanding in their development and different behavior. Methods: An electronic search was conducted in PubMed, Scopus, and Web of Science during March 2021. Eligibility criteria included publications on humans which included genetic analysis of AOT or AM. Results: A total of 43 articles reporting 59 AOTs and 680 AMs were included. Different genomic techniques were used, including whole-exome sequencing, direct sequencing, targeted next-generation sequencing panels and TaqMan allele-specific qPCR. Somatic mutations affecting KRAS were identified in 75.9% of all AOTs, mainly G12V; whereas a 71% of the AMs harbored BRAF mutations, mainly V600E. Conclusions: The available genetic data reports that AOTs and AM harbor somatic mutations in well-known oncogenes, being KRAS G12V/R and BRAFV600E mutations the most common, respectively. The relatively high frequency of ameloblastoma compared to other odontogenic tumors, such as AOT, has facilitated the performance of different sequencing techniques, allowing the discovery of different mutational signatures. On the contrary, the low frequency of AOTs is an important limitation for this. The number of studies that have a assessed the genetic landscape of AOT is still very limited, not providing enough evidence to draw a conclusion regarding the relationship between the genomic alterations and its clinical behavior. Thus, the presence of other mutational signatures with clinical impact, co-occurring with background KRAS mutations or in wild-type KRAS cases, cannot be ruled out. Since BRAF and RAS are in the same MAPK pathway, it is interesting that ameloblastomas, frequently associated with BRAFV600E mutation have aggressive clinical behavior, but in contrast, AOTs, frequently associated with RAS mutations have indolent behavior. Functional studies might be required to solve this question.
    Keywords:  BRAF; KRAS; adenomatoid odontogenic tumor; amelobalstoma; genetic mutation; odontogenic tumors
    DOI:  https://doi.org/10.3389/froh.2021.767474
  131. J Biol Chem. 2022 Jan 18. pii: S0021-9258(22)00039-4. [Epub ahead of print] 101599
    REDOX IMBALANCE INDUCES REMODELING OF GLUCOSE METABOLISM IN RHIPICEPHALUS MICROPLUS EMBRYONIC CELL LINE.
    Bárbara Della Noce, Renato Martins da Silva, Marcelle Vianna de Carvalho Uhl, Satoru Konnai, Kazuhiko Ohashi, Christiano Calixto, Angélica Arcanjo, Leonardo Araujo de Abreu, Stephanie Serafim de Carvalho, Itabajara da Silva Vaz, Carlos Logullo.
      Carbohydrate metabolism functions in supplying cellular energy, but also has an important role in maintaining physiological homeostasis and in preventing oxidative damage caused by reactive oxygen species (ROS). Previously, we addressed by studies showing that arthropod embryonic cell lines have high tolerance to H2O2 exposure. Here, we describe that Rhipicephalus microplus tick embryonic cell line (BME26) employs an adaptive glucose metabolism mechanism that confers tolerance to hydrogen peroxide at concentrations too high for other organisms. This adaptive mechanism sustained by glucose metabolism remodeling promotes cell survival and redox balance in BME26 cell line after millimolar H2O2 exposure. The present work shows that this tick cell line could tolerate high H2O2 concentrations by initiating a carbohydrate-related adaptive response. We demonstrate that gluconeogenesis was induced as a compensation strategy that involved, among other molecules, the metabolic enzymes NADP-ICDH, G6PDH, and PEPCK. We also found that this phenomenon was coupled to glycogen accumulation and glucose uptake, supporting the pentose phosphate pathway to sustain NADPH production, and leading to cell survival and proliferation. Importantly, our findings suggest that the described response is not atypical, being also observed in cancer cells, which highlights the importance of this model to all proliferative cells. We propose that these results will be useful in generating basic biological information to support the development of new strategies for disease treatment and parasite control.
    Keywords:  Arthropod; Embryogenesis; Glucose; Metabolism; ROS
    DOI:  https://doi.org/10.1016/j.jbc.2022.101599
  132. Rejuvenation Res. 2022 Jan 19.
    Protective Efficacy of Spilanthes acmella Murr. Extracts and Bioactive Constituents in Neuronal Cell Death.
    Wilasinee Suwanjang, Chayanit Sirisuwat, Sujittra Srisung, Chartchalerm Isarankura-Na-Ayudhya, Supitcha Pannengpetch, Supaluk Prachayasittikul.
      Spilanthes acmella Murr., a well-known Thai traditional medicine, has been used for treatment of toothache, rheumatism and fever. Diverse pharmacological activities of S. acmella Murr. have been reported. In the present study antioxidative and neuroprotective effects of S. acmella Murr. extracts as well as bioactive scopoletin, vanillic acid and trans-ferulic acid found in the aerial parts of this plant species have been described. Protective effect of S. acmella Murr. extracts and bioactive compounds on dexamethasone induced neuronal cells death was investigated. Different plant crude ethyl acetate (EtOAc) and methanol (MeOH) extracts including pure compounds of S. acmella Murr. were evaluated in human neuroblastoma SH-SY5Y cells. Cytotoxic effects were performed by MTT assay. Mechanisms involved in the antioxidant effects of S. acmella Murr. regarding the activation of antioxidant marker proteins such as SOD2 and SIRT3 were determined using DCFH-DA assay, western blot analysis and immunocytochemistry. Dexamethasone significantly caused the decrease of SH-SY5Y cell viability. Conversely, the increases in reactive oxygen species (ROS), autophagy and apoptosis were observed in dexamethasone-treated cells. S. acmella Murr. MeOH and EtOAc extracts, as well as the bioactive compounds reversed the toxic effect of dexamethasone by increasing the cell viability, SIRT3 protein expression but reducing the ROS, autophagy and apoptosis. This study demonstrated that S. acmella Murr. may exert its protective effects against ROS through SOD2 and SIRT3 signaling pathways in dexamethasone-induced neurotoxicity. S. acmella Murr. may be a candidate therapy for neuroprotection.
    DOI:  https://doi.org/10.1089/rej.2021.0002
  133. ACS Omega. 2022 Jan 11. 7(1): 1514-1526
    Study on the Effect of Polymer Excipients on the Dispersibility, Interaction, Solubility, and Scavenging Reactive Oxygen Species of Myricetin Solid Dispersion: Experiment and Molecular Simulation.
    Sidian Zhang, Xue Zhang, Jie Meng, Ling Lu, Shanda Du, Haiyan Xu, Sizhu Wu.
      Although the preparation of amorphous solid dispersions can improve the solubility of crystalline drugs, there is still a lack of guidance on the micromechanism in the screening and evaluation of polymer excipients. In this study, a particular method of experimental characterization combined with molecular simulation was attempted on solubilization of myricetin (MYR) by solid dispersion. According to the analysis of the dispersibility and hydrogen-bond interaction, the effectiveness of the solid dispersion and the predicted sequence of poly(vinyl pyrrolidone) (PVP) > hypromellose (HPMC) > poly(ethylene glycol) (PEG) as the polymer excipient were verified. Through the dissolution, cell viability, and reactive oxygen species (ROS)-level detection, the reliability of simulation and micromechanism analysis was further confirmed. This work not only provided the theoretical guidance and screening basis for the miscibility of solid dispersions from the microscopic level but also served as a reference for the modification of new drugs.
    DOI:  https://doi.org/10.1021/acsomega.1c06329
  134. Cancers (Basel). 2022 Jan 17. pii: 451. [Epub ahead of print]14(2):
    Applications of Extracellular Vesicles in Triple-Negative Breast Cancer.
    Frederic St-Denis-Bissonnette, Rachil Khoury, Karan Mediratta, Sara El-Sahli, Lisheng Wang, Jessie R Lavoie.
      Triple-negative breast cancer (TNBC) is the most aggressive and refractory subtype of breast cancer, often occurring in younger patients with poor clinical prognosis. Given the current lack of specific targets for effective intervention, the development of better treatment strategies remains an unmet medical need. Over the last decade, the field of extracellular vesicles (EVs) has grown tremendously, offering immense potential for clinical diagnosis/prognosis and therapeutic applications. While TNBC-EVs have been shown to play an important role in tumorigenesis, chemoresistance and metastasis, they could be repurposed as potential biomarkers for TNBC diagnosis and prognosis. Furthermore, EVs from various cell types can be utilized as nanoscale drug delivery systems (NDDS) for TNBC treatment. Remarkably, EVs generated from specific immune cell subsets have been shown to delay solid tumour growth and reduce tumour burden, suggesting a new immunotherapy approach for TNBC. Intrinsically, EVs can cross the blood-brain barrier (BBB), which holds great potential to treat the brain metastases diagnosed in one third of TNBC patients that remains a substantial clinical challenge. In this review, we present the most recent applications of EVs in TNBC as diagnostic/prognostic biomarkers, nanoscale drug delivery systems and immunotherapeutic agents, as well as discuss the associated challenges and future directions of EVs in cancer immunotherapy.
    Keywords:  biomarkers; blood–brain barrier (BBB); cancer; chemotherapy; diagnosis; exosome; extracellular vesicles (EVs); immunotherapy; nanomedicine; nanoparticles (NPs); nanoscale drug delivery system (NDDS); prognosis; solid tumour; triple-negative breast cancer (TNBC)
    DOI:  https://doi.org/10.3390/cancers14020451
  135. Adv Sci (Weinh). 2022 Jan 17. e2105523
    Abundance and Metabolism Disruptions of Intratumoral Microbiota by Chemical and Physical Actions Unfreeze Tumor Treatment Resistance.
    Fanlei Kong, Chao Fang, Yan Zhang, Lixia Duan, Dou Du, Guang Xu, Xiaolong Li, Hongyan Li, Yifei Yin, Huixiong Xu, Kun Zhang.
      Intratumoral or intestinal microbiota correlates with tumorigenesis and progression, and microbiota regulation for reinforcing various anti-tumor approaches is of significant importance, which, however, suffers from no precise regulation method and unclear underlying mechanism. Herein, a microbiome metabolism-engineered phototherapy strategy is established, wherein Nb2 C/Au nanocomposite and the corresponding phototherapy are harnessed to realize "chemical" and "physical" bacterial regulations. Flora analysis and mass spectrometry (MS) and metabonomics combined tests demonstrate that the synergistic microbiota regulations can alter the abundance, diversity of intratumoral microbiome, and disrupt metabolic pathways of microbiome and tumor microenvironment, wherein the differential singling pathways and biosynthetic necessities or metabolites that can affect tumor progression are identified. As well, anti-TNFα is introduced to unite with bacterial regulation to synergistically mitigate bacterial-induced inflammation, which, along with the metabolism disruptions of intratumoral microbiota and tumor microenvironment, unfreezes tumor resistance and harvests significantly-intensified phototherapy-based anti-tumor outcomes against 4T1 and CT26 tumors. The clear underlying principles of microbiome-regulated tumorigenesis and the established microbiome metabolism regulation method provide distinctive insights into tumor therapy, and can be also extended to other gut microbiome-associated lesions interference.
    Keywords:  flora analysis; inflammation regulation; metabolomics analysis; microbiome metabolism disruption; phototherapy; tumor microenvironment re-shaping
    DOI:  https://doi.org/10.1002/advs.202105523
  136. Nanomedicine. 2022 Jan 17. pii: S1549-9634(22)00011-9. [Epub ahead of print] 102525
    Corrigendum to "A dual fluorescent reverse targeting drug delivery system based on curcumin-loaded ovalbumin nanoparticles for allergy treatment" [Nanomedicine: Nanotechnology, Biology, and Medicine 16 (2019) 56-68/NANO 1908].
    Jie Liang, Xia Dong, Afeng Yang, Dunwan Zhu, Deling Kong, Feng Lv.
      
    DOI:  https://doi.org/10.1016/j.nano.2022.102525
  137. Naunyn Schmiedebergs Arch Pharmacol. 2022 Jan 19.
    Resveratrol inhibits the expression of RYR2 and is a potential treatment for pancreatic cancer.
    He Jiang, Guotai Wang, Jingtao Gu, Ying Xiao, Pengli Wang, Xin Huang, Huanchen Sha, Zheng Wang, Qingyong Ma.
      Resveratrol is a polyphonous natural compound that has cardioprotective, anticancer, and anti-inflammatory properties. Studies have proved that resveratrol (RES) inhibits cancer cell proliferation, migration, and invasion and promotes apoptosis. Elevated expression of ryanodine receptor type 2 (RYR2) may participate in the pathway responsible for calcium metabolism as well as anti-apoptosis and anti-autophagy events in malignant tumor cells. However, the underlying molecular mechanisms of RES anticancer effects with RYR2 are not completely understood in pancreatic cancer. The aim of the present study was tantamount to study the effect of RES in human pancreatic cancer and investigate the underlying mechanisms of RES. We found that RES inhibits proliferation, migration, and invasion and suppresses RYR2 expression in pancreatic cancer cells. In addition, RYR2 knockdown impedes the proliferation, migration, and invasiveness of pancreatic cancer cells. RYR2 knockdown can also increase PTEN expression, while increased RYR2 expression can inhibit PTEN expression. Moreover, RES can upregulate PTEN expression. Taken together, these results indicate that RES could play an antitumor role by decreasing RYR2 expression.
    Keywords:  Invasion; Migration; Pancreatic cancer; RYR2; Resveratrol
    DOI:  https://doi.org/10.1007/s00210-022-02203-9
  138. Biomolecules. 2022 Jan 05. pii: 82. [Epub ahead of print]12(1):
    Nrf2-Related Therapeutic Effects of Curcumin in Different Disorders.
    Soudeh Ghafouri-Fard, Hamed Shoorei, Zahra Bahroudi, Bashdar Mahmud Hussen, Seyedeh Fahimeh Talebi, Mohammad Taheri, Seyed Abdulmajid Ayatollahi.
      Curcumin is a natural polyphenol with antioxidant, antibacterial, anti-cancer, and anti-inflammation effects. This substance has been shown to affect the activity of Nrf2 signaling, a pathway that is activated in response to stress and decreases levels of reactive oxygen species and electrophilic substances. Nrf2-related effects of curcumin have been investigated in different contexts, including gastrointestinal disorders, ischemia-reperfusion injury, diabetes mellitus, nervous system diseases, renal diseases, pulmonary diseases, cardiovascular diseases as well as cancers. In the current review, we discuss the Nrf2-mediated therapeutic effects of curcumin in these conditions. The data reviewed in the current manuscript indicates curcumin as a potential activator of Nrf2 and a therapeutic substance for the protection of cells in several pathological conditions.
    Keywords:  Nrf2; cancer; curcumin; disorders
    DOI:  https://doi.org/10.3390/biom12010082
  139. Int J Mol Sci. 2022 Jan 11. pii: 775. [Epub ahead of print]23(2):
    PKM2 Modulation in Head and Neck Squamous Cell Carcinoma.
    Verena Boschert, Jonas Teusch, Urs D A Müller-Richter, Roman C Brands, Stefan Hartmann.
      The enzyme pyruvate kinase M2 (PKM2) plays a major role in the switch of tumor cells from oxidative phosphorylation to aerobic glycolysis, one of the hallmarks of cancer. Different allosteric inhibitors or activators and several posttranslational modifications regulate its activity. Head and neck squamous cell carcinoma (HNSCC) is a common disease with a high rate of recurrence. To find out more about PKM2 and its modulation in HNSCC, we examined a panel of HNSCC cells using real-time cell metabolic analysis and Western blotting with an emphasis on phosphorylation variant Tyr105 and two reagents known to impair PKM2 activity. Our results show that in HNSCC, PKM2 is commonly phosphorylated at Tyrosine 105. Its levels depended on tyrosine kinase activity, emphasizing the importance of growth factors such as EGF (epidermal growth factor) on HNSCC metabolism. Furthermore, its correlation with the expression of CD44 indicates a role in cancer stemness. Cells generally reacted with higher glycolysis to PKM2 activator DASA-58 and lower glycolysis to PKM2 inhibitor Compound 3k, but some were more susceptible to activation and others to inhibition. Our findings emphasize the need to further investigate the role of PKM2 in HNSCC, as it could aid understanding and treatment of the disease.
    Keywords:  AMPK; CD44; Compound 3k; DASA-58; HNSCC; PKM2; TXNIP; Warburg effect; cancer metabolism; glycolysis; head and neck cancer
    DOI:  https://doi.org/10.3390/ijms23020775
  140. Eur J Med Chem. 2022 Jan 12. pii: S0223-5234(22)00020-4. [Epub ahead of print]230 114118
    Roles and drug development of METTL3 (methyltransferase-like 3) in anti-tumor therapy.
    Pengfei Xu, Raoling Ge.
      Methyltransferase complex, such as METTL3/METTL14/WTP, catalyze N6-methyladenosine (m6A), which is the most abundant mRNA modification in mammals. Besides acting as a m6A methyltransferase, METTL3 also regulates mRNA translation and other biological processes. Studies have identified numerous roles and molecular mechanisms associated with METTL3 in multiple biological processes especially in tumors in recent years. Furthermore, targeting METTL3 as an efficient therapeutic way for the treatment of different kinds of tumors has gained a lot of attention. However, these findings and researches have not been summarized. In this review, the most recent important roles of METTL3 in various tumors including acute myeloid leukemia, lung cancer, breast cancer, liver cancer, gastric cancer, pancreatic cancer, colorectal cancer, bladder cancer, prostate cancer and glioblastoma were systematically summarized. In addition, disclosed METTL3 inhibitors recently were also summarized and discussed for medicinal chemists investigating METTL3 inhibitors with different skeleton structures for the application of human cancer therapy.
    Keywords:  Cancer therapy; Drug discovery; METTL3; Medicinal chemistry; m(6)A modification
    DOI:  https://doi.org/10.1016/j.ejmech.2022.114118
  141. Trends Microbiol. 2022 Jan 18. pii: S0966-842X(21)00318-8. [Epub ahead of print]
    Mitochondria-mediated oxidative stress during viral infection.
    Jonathan Foo, Gregory Bellot, Shazib Pervaiz, Sylvie Alonso.
      Through oxidative phosphorylation, mitochondria play a central role in energy production and are an important production source of reactive oxygen species (ROS). Not surprisingly, viruses have evolved to exploit this organelle in order to support their infection cycle. Beyond its role in the cellular antiviral response, induction of oxidative stress has emerged as a common strategy employed by many viruses to promote their replication. Here, we review the key molecular mechanisms employed by viruses to interact with mitochondria and induce oxidative stress. Furthermore, we discuss how viruses benefit from increased ROS levels, how they control ROS production to maintain a favorable redox environment, and how they cope with ROS-mediated cell death.
    Keywords:  antioxidant therapy; electron transport chain (ETC); endoplasmic reticulum (ER) stress; intrinsic apoptosis; oxidative phosphorylation (OXPHOS); reactive oxygen species (ROS)
    DOI:  https://doi.org/10.1016/j.tim.2021.12.011
  142. Curr Drug Discov Technol. 2022 Jan 13.
    Cytotoxic effects of Garcinia mangostana pericarp extract in cancer cell lines.
    Roghayeh Rashidi, Fatemeh Forouzanfar, Mohammad Soukhtanloo, Shirin Ghasemian, Seyed Hadi Mousavi.
       BACKGROUND: Garcinia mangostana, commonly also called mangosteen, is an evergreen tropical tree, and its pericarps have been used in traditional herbal medicine for different diseases. The anticancer efficacy of the ethanolic extract from pericarps of Garcinia mangostana was investigated in human prostate cancer cells (PC3), melanoma cells (B16F10), breast cancer cells (MCF7) and glioblastoma (U87) cell lines.
    METHODS: 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay was used to measure cell viability. propidium iodide (PI) staining and analysis on a flow cytometer was used to identify apoptosis. Action on cell migration was evaluated by scratch assay and gelatin zymography. Furthermore, the level of intracellular reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) activity was measured. Moreover, we investigated the synergistic efficacy with several combinations of Garcinia mangostana extract (GME) with doxorubicin.
    RESULTS: GME reduced cell viability in malignant cell dose and time-dependently. GME-induced sub-G1 peak in flow cytometry histogram of treated cells control representing apoptotic cell death is involved in GME toxicity. Furthermore, GME exhibited inhibitory effects on the migration ability of U87 cells, which was accompanied by inhibition in the activity and expression of MMP2 (matrix metalloproteinase-2). Besides, GSH level and SOD activity was significantly reduced while there was an increase in ROS and MDA concentration following 24 hr GME treatment. Moreover, combination of GME (1.5-25μg/mL) with Dox (6 µg/mL) displayed synergistic efficacy and cell growth inhibition.
    CONCLUSION: In conclusion, GME could cause cell death in PC3, MCF7, U87, and B16F10 cell lines, in which apoptosis plays an imperative role. Plant extract decreased the migration ability of the cells by inhibiting the activity and expression of Matrix metalloproteinases (MMPs). G. mangostana could be a promising therapeutic strategy to treat cancer in the future.
    Keywords:  Garcinia mangostana; HPLC analysis; apoptosis; cancer; carcinoma cells; cytotoxic
    DOI:  https://doi.org/10.2174/1570163819666220113100039
  143. Antioxidants (Basel). 2022 Jan 14. pii: 157. [Epub ahead of print]11(1):
    The Interconnected Mechanisms of Oxidative Stress and Neuroinflammation in Epilepsy.
    Anna L M Parsons, Eboni M V Bucknor, Enrico Castroflorio, Tânia R Soares, Peter L Oliver, Daniel Rial.
      One of the most important characteristics of the brain compared to other organs is its elevated metabolic demand. Consequently, neurons consume high quantities of oxygen, generating significant amounts of reactive oxygen species (ROS) as a by-product. These potentially toxic molecules cause oxidative stress (OS) and are associated with many disorders of the nervous system, where pathological processes such as aberrant protein oxidation can ultimately lead to cellular dysfunction and death. Epilepsy, characterized by a long-term predisposition to epileptic seizures, is one of the most common of the neurological disorders associated with OS. Evidence shows that increased neuronal excitability-the hallmark of epilepsy-is accompanied by neuroinflammation and an excessive production of ROS; together, these factors are likely key features of seizure initiation and propagation. This review discusses the role of OS in epilepsy, its connection to neuroinflammation and the impact on synaptic function. Considering that the pharmacological treatment options for epilepsy are limited by the heterogeneity of these disorders, we also introduce the latest advances in anti-epileptic drugs (AEDs) and how they interact with OS. We conclude that OS is intertwined with numerous physiological and molecular mechanisms in epilepsy, although a causal relationship is yet to be established.
    Keywords:  astrocyte; epilepsy; neuroinflammation; neuron; neurotransmission; oxidative stress; seizure; synapse
    DOI:  https://doi.org/10.3390/antiox11010157
  144. Colloids Surf B Biointerfaces. 2022 Jan 10. pii: S0927-7765(22)00013-3. [Epub ahead of print]211 112330
    GMT8 aptamer conjugated PEGylated Ag@Au core-shell nanoparticles as a novel radiosensitizer for targeted radiotherapy of glioma.
    Dongdong Li, Jing Zhao, Jun Ma, Huiquan Yang, Xiaodong Zhang, Yuyu Cao, Peidang Liu.
      Radiotherapy is one of the main treatment modalities for glioma, but the therapeutic efficacy is often limited by the radioresistance of tumor cells. The radiosensitization effects of silver nanoparticles (AgNPs) and gold nanoparticles (AuNPs) on tumors have been confirmed by previous studies. To enhance the specific killing effect of irradiation on tumor cells, targeted modification of radiosensitizers is urgently needed. Herein, we developed polyethylene glycol (PEG)-coated Ag@Au core-shell nanoparticles (PSGNPs) modified with GMT8 aptamer (GSGNPs) and evaluated their radiosensitization effects on glioma cells through in vivo and in vitro experiments. Transmission electron microscope image showed that the prepared PSGNPs had a spherical core-shell structure with an average size of 11 nm. The ultraviolet-visible absorption spectra and Fourier transform infrared spectra displayed that GMT8 was successfully conjugated to PSGNPs. The results of dark-field imaging revealed that the targeting ability of GSGNPs to U87 glioma cells was much better than that to normal human microvascular endothelial cells. Additionally, it was also found that the endocytic pathways of GSGNPs mainly involved clathrin-mediated endocytosis and macropinocytosis. The sensitization enhancement ratio of GSGNPs was calculated to be 1.62, which was higher than that of PSGNPs. In vivo imaging results showed that GSGNPs exhibited good tumor targeting and retention capabilities, and the fluorescence intensity ratio of Cy5-GSGNPs to Cy5-PSGNPs reached a peak at 4 h after injection. More importantly, the median survival time of mice bearing U87 glioma was significantly prolonged after intravenous administration of GSGNPs combined with radiotherapy. This work demonstrated that GSGNPs could be used as an effective nano-radiosensitizer for targeted radiotherapy of glioma.
    Keywords:  Ag@Au core-shell nanoparticles; GMT8 aptamer; Glioma; Radiosensitization
    DOI:  https://doi.org/10.1016/j.colsurfb.2022.112330
  145. Front Microbiol. 2021 ;12 753518
    Phenolic-Rich Plant Extracts With Antimicrobial Activity: An Alternative to Food Preservatives and Biocides?
    Nadia Oulahal, Pascal Degraeve.
      In recent years, the search for natural plant-based antimicrobial compounds as alternatives to some synthetic food preservatives or biocides has been stimulated by sanitary, environmental, regulatory, and marketing concerns. In this context, besides their established antioxidant activity, the antimicrobial activity of many plant phenolics deserved increased attention. Indeed, industries processing agricultural plants generate considerable quantities of phenolic-rich products and by-products, which could be valuable natural sources of natural antimicrobial molecules. Plant extracts containing volatile (e.g., essential oils) and non-volatile antimicrobial molecules can be distinguished. Plant essential oils are outside the scope of this review. This review will thus provide an overview of current knowledge regarding the promises and the limits of phenolic-rich plant extracts for food preservation and biofilm control on food-contacting surfaces. After a presentation of the major groups of antimicrobial plant phenolics, of their antimicrobial activity spectrum, and of the diversity of their mechanisms of action, their most promising sources will be reviewed. Since antimicrobial activity reduction often observed when comparing in vitro and in situ activities of plant phenolics has often been reported as a limit for their application, the effects of the composition and the microstructure of the matrices in which unwanted microorganisms are present (e.g., food and/or microbial biofilms) on their activity will be discussed. Then, the different strategies of delivery of antimicrobial phenolics to promote their activity in such matrices, such as their encapsulation or their association with edible coatings or food packaging materials are presented. The possibilities offered by encapsulation or association with polymers of packaging materials or coatings to increase the stability and ease of use of plant phenolics before their application, as well as to get systems for their controlled release are presented and discussed. Finally, the necessity to consider phenolic-rich antimicrobial plant extracts in combination with other factors consistently with hurdle technology principles will be discussed. For instance, several authors recently suggested that natural phenolic-rich extracts could not only extend the shelf-life of foods by controlling bacterial contamination, but could also coexist with probiotic lactic acid bacteria in food systems to provide enhanced health benefits to human.
    Keywords:  antimicrobial activity; biocides; biofilms; delivery systems; food preservation; phenolic-rich plant extracts
    DOI:  https://doi.org/10.3389/fmicb.2021.753518
  146. Int J Environ Res Public Health. 2022 Jan 07. pii: 674. [Epub ahead of print]19(2):
    A Review on Plants and Microorganisms Mediated Synthesis of Silver Nanoparticles, Role of Plants Metabolites and Applications.
    Tijjani Mustapha, Norashiqin Misni, Nur Raihana Ithnin, Abdullahi Muhammad Daskum, Ngah Zasmy Unyah.
      Silver nanoparticles are one of the most extensively studied nanomaterials due to their high stability and low chemical reactivity in comparison to other metals. They are commonly synthesized using toxic chemical reducing agents which reduce metal ions into uncharged nanoparticles. However, in the last few decades, several efforts were made to develop green synthesis methods to avoid the use of hazardous materials. The natural biomolecules found in plants such as proteins/enzymes, amino acids, polysaccharides, alkaloids, alcoholic compounds, and vitamins are responsible for the formation of silver nanoparticles. The green synthesis of silver nanoparticles is an eco-friendly approach, which should be further explored for the potential of different plants to synthesize nanoparticles. In the present review we describe the green synthesis of nanoparticles using plants, bacteria, and fungi and the role of plant metabolites in the synthesis process. Moreover, the present review also describes some applications of silver nanoparticles in different aspects such as antimicrobial, biomedicine, mosquito control, environment and wastewater treatment, agricultural, food safety, and food packaging.
    Keywords:  green synthesis; plant metabolites; silver nanoparticles
    DOI:  https://doi.org/10.3390/ijerph19020674
  147. Food Sci Biotechnol. 2022 Jan;31(1): 17-36
    Comprehensive review on potential applications of microfluidization in food processing.
    Anit Kumar, Atul Dhiman, Rajat Suhag, Rachna Sehrawat, Ashutosh Upadhyay, David Julian McClements.
      Microfluidizer is one of the emerging processing technologies which has brought tremendous and desirable changes in food matrix. By generating high cavitation, shear, velocity impact and turbulent forces, microfluidizer brought structural modifications in food which led to significant improvements in physicochemical, functional, nutritional, rheological and sensory properties of food products without affecting their natural flavour. Reduction in particle size and thereby increase in surface area has brought these unique modifications. Microfluidization also improved bioavailability and bioaccessibility of bioactives by making them more exposed. Applications of microfluidizer includes stable emulsion/suspension formation, encapsulation, and nanoparticle production. It has also shown its preservation potential by inactivating enzymes and microbes thus improving food stability. The present review comprehensively discusses the working principle and effect of microfluidizer on dairy products, fruit juices, cereals, starches, egg yolk, emulsions, suspensions, and other novel products formulations. Microfluidization has opened a new channel for developing novel food ingredients non-thermally.
    Keywords:  Cereal products; Dairy products; Fruits and Vegetables; Microfluidization; Nano-emulsions
    DOI:  https://doi.org/10.1007/s10068-021-01010-x
  148. Pak J Pharm Sci. 2021 Nov;34(6): 2191-2195
    Capsaicin ameliorate the nephrotoxicity induced by methotrexate.
    Sara A Aldossary, Muhammad Shahzad Chohan, Mohammed Al Mohaini, Sahibzada Tasleem Rasool.
      Although methotrexate (MTX) is an effective immunosuppressive and anti-cancer agent, it is associated with side effects, including nephrotoxicity. Capsaicin, a component of hot chilli peppers, induces rapid desensitization of TRPV1 pain receptors and therefore has uses in pain treatment. Capsaicin also has anti-cancer activity, including anti-inflammatory properties. Thus, capsaicin may have potential in preventing MTX-induced nephrotoxicity. The purpose of this research work was to observe protective effects of capsaicin towards renal toxicity caused by methotrexate and mechanisms responsible for these effects. As expected, capsaicin had nephroprotective effects in MTX-intoxicated rats. Serum creatinine urea, nitric oxide (NO) and renal malondialdehyde (MDA) levels decreased significantly, with a concurrent increase in superoxide dismutase (SOD) and renal glutathione peroxidase (GPx) activities as compared to rats that had been untreated with nephrotoxic. Biochemical analyses confirmed the protective effects of capsaicin. We conclude that capsaicin provides protection against MTX-nephrotoxicity in rats via anti-inflammatory and antioxidant activities.
  149. J Physiol. 2022 Jan 17.
    Nutrient timing and metabolic regulation symposium review from "Novel dietary approaches to appetite regulation, health and performance (2021)".
    Harry A Smith, James A Betts.
      Daily (circadian) rhythms coordinate our physiology and behaviour with regular environmental changes. Molecular clocks in peripheral tissues (e.g. liver, skeletal muscle, and adipose) give rise to rhythms in macronutrient metabolism, appetite regulation and the components of energy balance - such that our bodies can align the periodic delivery of nutrients with ongoing metabolic requirements. The timing of meals both in absolute terms (i.e. relative to clock time) and in relative terms (i.e. relative to other daily events) is therefore relevant to metabolism and health. Experimental manipulation of feeding-fasting cycles can advance understanding of the absolute and relative timing of meals on metabolism and health. Such studies have extended the overnight fast by regular breakfast omission and revealed that morning fasting can alter the metabolic response to subsequent meals later in the day, whilst also eliciting compensatory behavioural responses (i.e. reduced physical activity). Similarly, restricting energy intake via alternate-day fasting also has the potential to elicit a compensatory reduction in physical activity, so can undermine weight-loss efforts (i.e. to preserve body fat stores). Interrupting the usual overnight fast (and therefore also the usual sleep cycle) by nocturnal feeding has also been examined and further research is needed to understand the importance of this period for either nutritional intervention or nutritional withdrawal. In summary, it is important for dietary guidelines for human health to consider nutrient timing (i.e. when we eat) alongside the conventional focus on nutrient quantity and nutrient quality (i.e. how much we eat and what we eat). This article is protected by copyright. All rights reserved.
    DOI:  https://doi.org/10.1113/JP280756
  150. J Food Sci. 2022 Jan 17.
    Encapsulation of Curcumin in a Ternary Nanocomplex Prepared with Carboxymethyl Short Linear Glucan-Sodium-Caseinate-Pectin Via Electrostatic Interactions.
    Wenhui Li, Ying Yu, Ziyang Dai, Jielong Peng, Jinhong Wu, Zhengwu Wang.
      This work chemically modified short linear glucan (SLG) by introducing a surface carboxymethyl group to obtain carboxymethylated SLG (CMSLG), then prepared CMSLG-based ternary nanocomplex particles based on electrostatic interactions with sodium-caseinate (NaCas) and pectin. These nanocomplex particles are homogeneous, generally exhibiting sizes of <200 nm with spherical shape and negative surface charge. In addition, the results showed the increase in both the mass ratio of CMSLG and NaCas and the synthesis temperature can improve the colloidal stability of nanocomplex particles when they are exposed to simulated gastrointestinal fluids containing digestive enzymes. Moreover, nanocomplex particles have an exceptional capability to encapsulate curcumin, and this encapsulation efficiency increased as the mass ratios of CMSLG and NaCas were increased. The study also investigated the antioxidant activity and in vitro release properties of curcumin encapsulated by nanocomplex particles and found that CMSLG/NaCas/pectin had improved higher ABTS radical scavenging capacity and allowed for the controlled, sustained release of curcumin in simulated gastrointestinal fluid within 6 hours. Thus, this study provides new insights into the design of a CMSLG-based ternary nanocomplex and its use as a potential oral delivery system for lipophilic bioactive compounds. PRACTICAL APPLICATION: Curcumin, as a sort of natural polyphenolic compound, has many physiologic functions such as anti-oxidation, anticancer, and prevention of Alzheimer's disease. However, the application of the curcumin has been limited by its poor water solubility and unstable physicochemical property. To solve this problem, the nanotechnology has been used to prepare the nano-delivery carriers for curcumin. This work prepared a ternary nanoparticle based on the carboxymethyl short linear glucan, sodium-caseinate, and pectin. The ternary nanoparticle can achieve a higher encapsulation efficiency for curcumin. In addition, the ternary nanoparticle can enhance the ABTS radical scavenging capacity and provided control and sustained release of curcumin in the simulated gastrointestinal fluid.
    Keywords:  casein-sodium; curcumin; pectin; short linear glucan; ternary nanocomplex
    DOI:  https://doi.org/10.1111/1750-3841.16026
  151. BMC Microbiol. 2022 Jan 17. 22(1): 28
    Contribution of antimicrobial photo-sonodynamic therapy in wound healing: an in vivo effect of curcumin-nisin-based poly (L-lactic acid) nanoparticle on Acinetobacter baumannii biofilms.
    Maryam Pourhajibagher, Babak Pourakbari, Abbas Bahador.
       BACKGROUND: The biofilm-forming ability of Acinetobacter baumannii in the burn wound is clinically problematic due to the development of antibiotic-resistant characteristics, leading to new approaches for treatment being needed. In this study, antimicrobial photo-sonodynamic therapy (aPSDT) was used to assess the anti-biofilm efficacy and wound healing activity in mice with established A. baumannii infections.
    METHODS: Following synthesis and confirmation of Curcumin-Nisin-based poly (L-lactic acid) nanoparticle (CurNisNp), its cytotoxic and release times were evaluated. After determination of the sub-significant reduction (SSR) doses of CurNisNp, irradiation time of light, and ultrasound intensity against A. baumannii, anti-biofilm activity and the intracellular reactive oxygen species (ROS) generation were evaluated. The antibacterial and anti-virulence effects, as well as, histopathological examination of the burn wound sites of treated mice by CurNisNp-mediated aPSDTSSR were assessed and compared with silver sulfadiazine (SSD) as the standard treatment group.
    RESULTS: The results showed that non-cytotoxic CurNisNp has a homogeneous surface and a sphere-shaped vesicle with continuous release until the 14th day. The dose-dependent reduction in cell viability of A. baumannii was achieved by increasing the concentrations of CurNisNp, irradiation time of light, and ultrasound intensity. There was a time-dependent reduction in biofilm growth, changes in gene expression, and promotion in wound healing by the acceleration of skin re-epithelialization in mice. Not only there was no significant difference between aPSDTSSR and SSD groups in antibacterial and anti-virulence activities, but also wound healing and re-epithelialization occurred more efficiently in aPSDTSSR than in the SSD group.
    CONCLUSIONS: In conclusion, CurNisNp-mediated aPSDT might be a promising complementary approach to treat burn wound infections.
    Keywords:  Antimicrobial photodynamic therapy; Antimicrobial sonodynamic therapy; Biofilms; Burn wound infection; Curcumin; Nisin; Silver sulfadiazine
    DOI:  https://doi.org/10.1186/s12866-022-02438-9
  152. Biomolecules. 2021 Dec 28. pii: 41. [Epub ahead of print]12(1):
    Metabolomics Coupled with Pathway Analysis Provides Insights into Sarco-Osteoporosis Metabolic Alterations and Estrogen Therapeutic Effects in Mice.
    Ziheng Wei, Fei Ge, Yanting Che, Si Wu, Xin Dong, Dianwen Song.
      Postmenopausal osteoporosis (PMOP) and sarcopenia are common diseases that predominantly affect postmenopausal women. In the occurrence and development of these two diseases, they are potentially pathologically connected with each other at various molecular levels. However, the application of metabolomics in sarco-osteoporosis and the metabolic rewiring happening throughout the estrogen loss-replenish process have not been reported. To investigate the metabolic alteration of sarco-osteoporosis and the possible therapeutical effects of estradiol, 24 mice were randomly divided into sham surgery, ovariectomy (OVX), and estradiol-treated groups. Three-dimensional reconstructions and histopathology examination showed significant bone loss after ovariectomy. Estrogen can well protect against OVX-induced bone loss deterioration. UHPLC-Q-TOF/MS was preformed to profile semi- polar metabolites of skeletal muscle samples from all groups. Metabolomics analysis revealed metabolic rewiring occurred in OVX group, most of which can be reversed by estrogen supplementation. In total, 65 differential metabolites were identified, and pathway analysis revealed that sarco-osteoporosis was related to the alterations in purine metabolism, glycerophospholipid metabolism, arginine biosynthesis, tryptophan metabolism, histidine metabolism, oxidative phosphorylation, and thermogenesis, which provided possible explanations for the metabolic mechanism of sarco-osteoporosis. This study indicates that an UHPLC-Q-TOF/MS-based metabolomics approach can elucidate the metabolic reprogramming mechanisms of sarco-osteoporosis and provide biological evidence of the therapeutical effects of estrogen on sarco-osteoporosis.
    Keywords:  estrogen; metabolomics; postmenopausal osteoporosis; sarcopenia; skeletal muscles
    DOI:  https://doi.org/10.3390/biom12010041
  153. Small Methods. 2022 Jan 20. e2101437
    The Intracellular and Extracellular Microenvironment of Tumor Site: The Trigger of Stimuli-Responsive Drug Delivery Systems.
    Xiaodong Jing, Hao Hu, Yanzhen Sun, Bing Yu, Hailin Cong, Youqing Shen.
      The tumor microenvironment (TME), including intracellular and extracellular microenvironment, contains many biochemical indicators (such as acidity/alkalinity, oxygen content, and enzymatic activity) that are different from the normal physiological environment. These abnormal biochemical indicators can accelerate the heterogeneity of tumors, but on the other hand, they also provide opportunities for the design of intelligent drug delivery systems (DDSs). The TME-responsive DDSs have shown great potential in reducing the side effects of chemotherapy and improving the curative effect of tumors. In this review, the abnormal biochemical indicators of TME are introduced in detail from both the extracellular and intracellular aspects. In view of the various physiological barriers encountered during drug delivery, the strategy of constructing TME-responsive DDSs is discussed. By summarizing the typical research progress, the authors prospect the development of TME-responsive DDS in the future.
    Keywords:  drug delivery systems; nano carriers; stimuli-responsiveness; tumor microenvironment; tumor treatments
    DOI:  https://doi.org/10.1002/smtd.202101437
  154. Membranes (Basel). 2022 Jan 13. pii: 85. [Epub ahead of print]12(1):
    Targeted Delivery of Exosomes Armed with Anti-Cancer Therapeutics.
    Hojun Choi, Hwayoung Yim, Cheolhyoung Park, So-Hee Ahn, Yura Ahn, Areum Lee, Heekyoung Yang, Chulhee Choi.
      Among extracellular vesicles, exosomes have gained great attention for their role as therapeutic vehicles for delivering various active pharmaceutical ingredients (APIs). Exosomes "armed" with anti-cancer therapeutics possess great potential for an efficient intracellular delivery of anti-cancer APIs and enhanced targetability to tumor cells. Various technologies are being developed to efficiently incorporate anti-cancer APIs such as genetic materials (miRNA, siRNA, mRNA), chemotherapeutics, and proteins into exosomes and to induce targeted delivery to tumor burden by exosomal surface modification. Exosomes can incorporate the desired therapeutic molecules via direct exogenous methods (e.g., electroporation and sonication) or indirect methods by modifying cells to produce "armed" exosomes. The targeted delivery of "armed" exosomes to tumor burden could be accomplished either by "passive" targeting using the natural tropism of exosomes or by "active" targeting via the surface engineering of exosomal membranes. Although anti-cancer exosome therapeutics demonstrated promising results in preclinical studies, success in clinical trials requires thorough validation in terms of chemistry, manufacturing, and control techniques. While exosomes possess multiple advantages over synthetic nanoparticles, challenges remain in increasing the loading efficiency of anti-cancer agents into exosomes, as well as establishing quantitative and qualitative analytical methods for monitoring the delivery of in vivo administered exosomes and exosome-incorporated anti-cancer agents to the tumor parenchyma.
    Keywords:  cancer therapeutics; cargo loading; exosome; scalable manufacturing; targeted delivery
    DOI:  https://doi.org/10.3390/membranes12010085
  155. Biomedicines. 2022 Jan 03. pii: 96. [Epub ahead of print]10(1):
    Nanomedicine in Clinical Photodynamic Therapy for the Treatment of Brain Tumors.
    Hyung Shik Kim, Dong Yun Lee.
      The current treatment for malignant brain tumors includes surgical resection, radiotherapy, and chemotherapy. Nevertheless, the survival rate for patients with glioblastoma multiforme (GBM) with a high grade of malignancy is less than one year. From a clinical point of view, effective treatment of GBM is limited by several challenges. First, the anatomical complexity of the brain influences the extent of resection because a fine balance must be struck between maximal removal of malignant tissue and minimal surgical risk. Second, the central nervous system has a distinct microenvironment that is protected by the blood-brain barrier, restricting systemically delivered drugs from accessing the brain. Additionally, GBM is characterized by high intra-tumor and inter-tumor heterogeneity at cellular and histological levels. This peculiarity of GBM-constituent tissues induces different responses to therapeutic agents, leading to failure of targeted therapies. Unlike surgical resection and radiotherapy, photodynamic therapy (PDT) can treat micro-invasive areas while protecting sensitive brain regions. PDT involves photoactivation of photosensitizers (PSs) that are selectively incorporated into tumor cells. Photo-irradiation activates the PS by transfer of energy, resulting in production of reactive oxygen species to induce cell death. Clinical outcomes of PDT-treated GBM can be advanced in terms of nanomedicine. This review discusses clinical PDT applications of nanomedicine for the treatment of GBM.
    Keywords:  blood–brain barrier (BBB); chemotherapy; glioblastoma multiform (GBM); photodynamic therapy (PDT); photosensitizer (PS); radiotherapy; reactive oxygen species (ROS); surgical resection; targeted therapy; tumor microenvironment
    DOI:  https://doi.org/10.3390/biomedicines10010096
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