bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2022‒02‒06
116 papers selected by
Yasmin Elkabani
Egyptian Foundation for Research and Community Development
  1. Oxygen self-supplied enzyme nanogels for tumor targeting with amplified synergistic starvation and photodynamic therapy.
  2. Folic Acid-Functionalized Metal-Organic Framework Nanoparticles as Drug Carriers Improved Bufalin Antitumor Activity Against Breast Cancer.
  3. Bioenzyme-based nanomedicines for enhanced cancer therapy.
  4. The Most Recent Discoveries in Heterocyclic Nanoformulations for Targeted Anticancer Therapy.
  5. Targeting KRAS in Lung Cancer Beyond KRAS G12C Inhibitors: The Immune Regulatory Role of KRAS and Novel Therapeutic Strategies.
  6. Nanodrug delivery systems for ferroptosis-based cancer therapy.
  7. pH-Responsive Nanoparticles for Enhanced Antitumor Activity by High-Intensity Focused Ultrasound Therapy Combined with Sonodynamic Therapy.
  8. γ-Fe2 O3 Loading Mitoxantrone and Glucose Oxidase for pH-Responsive Chemo/Chemodynamic/Photothermal Synergistic Cancer Therapy.
  9. Quercetin- and rutin-based nano-formulations for cancer treatment: A systematic review of improved efficacy and molecular mechanisms.
  10. Unraveling and targeting RAS-driven metabolic signaling for therapeutic gain.
  11. Near-Infrared Light-Excited Reactive Oxygen Species Generation by Thulium Oxide Nanoparticles.
  12. Rationally Driven Drug Nonradiative Decay via a Label-free Polyprodrug Strategy to Renew Tumor Cascade Photothermal-Chemotherapy.
  13. A dual-responsive nanoplatform with feedback amplification improves antitumor efficacy of photodynamic therapy.
  14. Functions of polyphenols and its anticancer properties in biomedical research: a narrative review.
  15. The interplay between reactive oxygen species and antioxidants in cancer progression and therapy: a narrative review.
  16. Research advances in NQO1-responsive prodrugs and nanocarriers for cancer treatment.
  17. Nanozyme-Based Enhanced Cancer Immunotherapy.
  18. Methionine Restriction: Ready for Prime Time in the Cancer Clinic?
  19. The interactions of paclitaxel with tumour microenvironment.
  20. Jatrorrhizine: A Review of Sources, Pharmacology, Pharmacokinetics and Toxicity.
  21. Pan-RAS inhibitors: Hitting multiple RAS isozymes with one stone.
  22. Polymeric nanoparticles for the treatment of prostate cancer - technological prospecting and critical analysis.
  23. Cancer metabolism challenges genomic instability and clonal evolution as therapeutic targets.
  24. Photothermally triggered melting and perfusion: responsive colloidosomes for cytosolic delivery of membrane-impermeable drugs in tumor therapy.
  25. Emerging Roles of the Tumor Suppressor p53 in Metabolism.
  26. Cancer Chemoprevention: A Strategic Approach Using Phytochemicals.
  27. Synthetic adiponectin-receptor agonist, AdipoRon, induces glycolytic dependence in pancreatic cancer cells.
  28. Fully armed photodynamic therapy with spear and shear for topical deep hypertrophic scar treatment.
  29. Statin as a therapeutic agent in gastroenterological cancer.
  30. Inhibitory Effect of Oxaliplatin-loaded Engineered Milk Extracellular Vesicles on Tumor Progression.
  31. Huaier increases the antitumor effect of gemcitabine on pancreatic cancer in vitro and in vivo.
  32. Targeting the ERK mitogen-activated protein kinase cascade for the treatment of KRAS-mutant pancreatic cancer.
  33. Wogonin and its analogs for the prevention and treatment of cancer: A systematic review.
  34. Phenylboronic-acid-based Functional Chemical Materials for Fluorescence Imaging and Tumor Therapy.
  35. Tumor-targeted delivery of honokiol via polysialic acid modified zein nanoparticles prevents breast cancer progression and metastasis.
  36. Polymethine dyes for PDT: recent advances and perspectives to drive future applications.
  37. Construction of calcium carbonate-liposome dual-film coated mesoporous silica as a delayed drug release system for antitumor therapy.
  38. A functionalized graphene oxide with improved cytocompatibility for stimuli-responsive co-delivery of curcumin and doxorubicin in cancer treatment.
  39. Evaluation of debridement effects of bromelain-loaded sodium alginate nanoparticles incorporated into chitosan hydrogel in animal models.
  40. Polyoxometalate-covalent organic framework hybrid materials for pH-responsive photothermal tumor therapy.
  41. A review of the genus Chrysosplenium as a traditional Tibetan medicine and its preparations.
  42. Nanoparticle-based drug delivery systems in cancer: A focus on inflammatory pathways.
  43. Nanotechnology-based advances in the efficient delivery of melatonin.
  44. Inhibition of Walker-256 Tumor Growth by Combining Microbubble-Enhanced Ultrasound and Endostar.
  45. Metabolic Reprogramming in Gastric Cancer: Trojan Horse Effect.
  46. Ponicidin suppresses pancreatic cancer growth by inducing ferroptosis: Insight gained by mass spectrometry-based metabolomics.
  47. Transferrin Protein Corona-Modified CuGd Core-Shell Nanoplatform for Tumor-Targeting Photothermal and Chemodynamic Synergistic Therapies.
  48. Aberrant lipid metabolism reprogramming and immune microenvironment for gastric cancer: a literature review.
  49. Unravelling potential biomedical applications of the edible flower Tulbaghia violacea.
  50. Clinical application of nano-targeting for enhancing chemotherapeutic efficacy and safety in cancer management.
  51. Effects of some cosmetic dyes and pigments on the proliferation of human foreskin fibroblasts and cellular oxidative stress; potential cytotoxicity of chlorophyllin and indigo carmine on fibroblasts.
  52. Biodegradable Bismuth-Based Nano-Heterojunction for Enhanced Sonodynamic Oncotherapy Through Charge Separation Engineering.
  53. Recent advances of chitosan-based nanoparticles for biomedical and biotechnological applications.
  54. Disrupted Liver Oxidative Metabolism in Glycine N-Methyltransferase-Deficient Mice is Mitigated by Dietary Methionine Restriction.
  55. Molecular regulatory mechanism of ferroptosis and its role in gastrointestinal oncology: Progress and updates.
  56. Statins and Gliomas: A Systematic Review of the Preclinical Studies and Meta-Analysis of the Clinical Literature.
  57. Effect of selenium biofortification on bioactive compounds and antioxidant activity in germinated black soybean.
  58. Mesoporous SBA-15 Silica-Loaded Nano-formulation of Quercetin: A Probable Radio-Sensitizer for Lung Carcinoma.
  59. Dextran sulfate-based MMP-2 enzyme-sensitive SR-A receptor targeting nanomicelles for the treatment of rheumatoid arthritis.
  60. Horseradish Peroxidase-Functionalized Gold Nanoconjugates for Breast Cancer Treatment Based on Enzyme Prodrug Therapy.
  61. Culinary Spices in Food and Medicine: An Overview of Syzygium aromaticum (L.) Merr. and L. M. Perry [Myrtaceae].
  62. Fabrication of a magnetic nanocarrier for doxorubicin delivery based on hyperbranched polyglycerol and carboxymethyl cellulose: An investigation on the effect of borax cross-linker on pH-sensitivity.
  63. Effective Anticancer Therapy by Combination of Nanoparticles Encapsulating Chemotherapeutic Agents and Weak Electric Current.
  64. Platismatia glauca-Lichen species with suppressive properties on migration and invasiveness of two different colorectal carcinoma cell lines.
  65. High-dose vitamin D metabolite delivery inhibits breast cancer metastasis.
  66. Triple-negative breast cancer brain metastasis: an update on druggable targets, current clinical trials, and future treatment options.
  67. Engineering 2D Cu-composed metal-organic framework nanosheets for augmented nanocatalytic tumor therapy.
  68. Acid-Degradable Hydrogen-Generating Metal-Organic Framework for Overcoming Cancer Resistance/Metastasis and Off-Target Side Effects.
  69. Biodegradable Ru-Containing Polycarbonate Micelles for Photoinduced Anticancer Multitherapeutic Agent Delivery and Phototherapy Enhancement.
  70. Recent advances on transdermal delivery systems for the treatment of arthritic injuries: From classical treatment to nanomedicines.
  71. Emerging Mechanisms and Disease Implications of Ferroptosis: Potential Applications of Natural Products.
  72. Recent progress in polymeric non-invasive insulin delivery.
  73. Assessing the cost-effectiveness of DNA origami nanostructures for targeted delivery of anti-cancer drugs to tumours.
  74. Application Potential of Plant-Derived Medicines in Prevention and Treatment of Platinum-Induced Peripheral Neurotoxicity.
  75. Loss of TET reprograms Wnt signaling through impaired demethylation to promote lung cancer development.
  76. Nanotheranostics: A powerful next-generation solution to tackle hepatocellular carcinoma.
  77. Dietary Intake and Cancer in Sub-Saharan Africa: A Critical Review of Epidemiological Studies.
  78. Polymethine dyes-loaded solid lipid nanoparticles (SLN) as promising photosensitizers for biomedical applications.
  79. A nanomicelle with miR-34a and doxorubicin reverses the drug resistance of cisplatin in esophageal carcinoma cells by inhibiting SIRT1 signal pathway.
  80. Inhibitory activities of grape bioactive compounds against enzymes linked with human diseases.
  81. Investigation of Antioxidant and Cytotoxicity Effects of Silver Nanoparticles Produced by Biosynthesis Using Lactobacillus gasseri.
  82. Distribution, biotransformation, pharmacological effects, metabolic mechanism and safety evaluation of Platycodin D：A comprehensive review.
  83. Hippocalcin-like 1 is a key regulator of LDHA activation that promotes the growth of non-small cell lung carcinoma.
  84. A novel targeted nanoparticle for traumatic brain injury treatment: combined effect of ROS depletion and calcium overload inhibition.
  85. Piperlongumine loaded PLGA nanoparticles inhibit cancer stem-like cells through modulation of STAT3 in mammosphere model of triple negative breast cancer.
  86. Current perspectives on naturally occurring saponins as anticancer agents.
  87. Polymeric biocompatible iron oxide nanoparticles labeled with peptides for imaging in ovarian cancer.
  88. Mechanisms of Compound Kushen Injection for the treatment of bladder cancer based on bioinformatics and network pharmacology with experimental validation.
  89. An in situ spontaneously forming micelle-hydrogel system with programmable release for the sequential therapy of anaplastic thyroid cancer.
  90. Case Report: Effectiveness of Targeted Treatment in a Patient With Pancreatic Cancer Harboring PALB2 Germline Mutation and KRAS Somatic Mutation.
  91. Nigericin exerts anticancer effects through inhibition of the SRC/STAT3/BCL-2 in osteosarcoma.
  92. Molecular Mechanisms of Exercise on Cancer: A Bibliometrics Study and Visualization Analysis via CiteSpace.
  93. Cinnamophilin enhances temozolomide-induced cytotoxicity against malignant glioma: the roles of ROS and cell cycle arrest.
  94. Gamma-tocotrienol Synergistically Promotes the Anti-proliferative and Pro-apoptotic Effects of Etoposide on Breast Cancer Cell Lines.
  95. Mutant Kras co-opts a proto-oncogenic enhancer network in inflammation-induced metaplastic progenitor cells to initiate pancreatic cancer.
  96. Chrysin Modulates Aberrant Epigenetic Variations and Hampers Migratory Behavior of Human Cervical (HeLa) Cells.
  97. A GSH/CB Dual-Controlled Self-Assembled Nanomedicine for High-Efficacy Doxorubicin-Resistant Breast Cancer Therapy.
  98. Nutraceutical Profiling, Bioactive Composition, and Biological Applications of Lepidium sativum L.
  99. Association between cancer treatment and progression of all-cause dementia.
  100. Evaluating the Therapeutic Efficacy of Radiolabeled BSA@CuS Nanoparticle-induced Radio-photothermal Therapy against Anaplastic Thyroid Cancer.
  101. mPEG-Cholic acid/TPGS mixed micelles for combined delivery of paclitaxel and bufalin to treat hepatocellular carcinoma.
  102. Combinatorial effect of thymoquinone with chemo agents for tumor therapy.
  103. SiRNA-circFARSA-loaded porous silicon nanomaterials for pancreatic cancer treatment via inhibition of CircFARSA expression.
  104. Antioxidant Effect of Curcumin on the Prevention of Oxidative Damage to the Cochlea in an Ototoxic Rat Model Based on Malondialdehyde Expression.
  105. Her-2 directed systemic delivery of fatty acid synthase (FASN) siRNA with novel liposomal carrier systems in the breast cancer mouse model.
  106. Recent total syntheses of anthraquinone-based natural products.
  107. Exploring the molecular targets and mechanisms of [10]-Gingerol for treating triple-negative breast cancer using bioinformatics approaches, molecular docking, and in vivo experiments.
  108. CAQK modification enhances the targeted accumulation of metformin-loaded nanoparticles in rats with spinal cord injury.
  109. MnO2 coated nanotheranostic LDH for synergistic cascade chemo/chemodynamic cancer therapy under the guidance of MRI-targeted diagnosis.
  110. The anti-tumoral effects of the oxygen carrier YQ23 in a triple-negative breast cancer syngeneic model.
  111. The role of ROS in tumour development and progression.
  112. A brief history of RAS and the RAS Initiative.
  113. Targeting RAS oncogenesis with SOS1 inhibitors.
  114. PEGylated dendritic polyurethane as unimolecular micelles for tumor chemotherapy: Effect of molecular architecture.
  115. Photodynamic inactivation (PDI) as a promising alternative to current pharmaceuticals for the treatment of resistant microorganisms.
  116. Anticancer Effects of Taraxacum via Cell Cycle Arrest, Necrosis, Apoptosis, and Endoplasmic Reticulum Stress.
  1. Acta Biomater. 2022 Jan 31. pii: S1742-7061(22)00066-6. [Epub ahead of print]
    Oxygen self-supplied enzyme nanogels for tumor targeting with amplified synergistic starvation and photodynamic therapy.
    Xiaotong Fan, Zheng Luo, Ying Chen, Jayven Chee Chuan Yeo, Zibiao Li, Yun-Long Wu, Chaobin He.
      Tumor tissues need vast supply of nutrients and energy to sustain the rapid proliferation of cancer cells. Cutting off the glucose supply represents a promising cancer therapy approach. Herein, a tumor tissue-targeted enzyme nanogel (rGCP nanogel) with self-supply oxygen capability was developed. The enzyme nanogel synergistically enhanced starvation therapy and photodynamic therapy (PDT) to mitigate the rapid proliferation of cancer cells. The rGCP nanogel was fabricated by copolymerizing two monomers, porphyrin and cancer cells-targeted, Arg-Gly-Asp (RGD), onto the glucose oxidase (GOX) and catalase (CAT) surfaces. The cascade reaction within the rGCP nanogel could efficiently consume intracellular glucose catalyzed by GOX. Concurrently, CAT safely decomposed the produced H2O2 with systemic toxicity to promote oxygen generation and achieved low toxicity starvation therapy. The produced oxygen subsequently facilitated the glucose oxidation reaction and significantly enhanced the generation of cytotoxic singlet oxygen (1O2) in the presence of 660 nm light irradiation. Combining starvation therapy and PDT, the designed enzyme nanogel system presented an amplified synergic cancer therapy effect. This approach potentially paved a new way to fabricate a combinatorial therapy approach by employing cascaded catalytic nanomedicines with good tumor selectivity and efficient anti-cancer effect. STATEMENT OF SIGNIFICANCE: The performance of starvation and photodynamic therapy (PDT) is usually suppressed by intrinsic tumorous hypoxia. Herein, an oxygen self-supplied and tumor tissue-targeted enzyme nanogel was created by copolymerization of two monomers, porphyrin and cancer cell-targeted Arg-Gly-Asp (RGD), onto the surface of glucose oxidase (GOX) and catalase (CAT), which synergistically enhanced starvation therapy and PDT. Moreover, the enzyme nanogels possessed high stability and could be synthesized straightforwardly. This anti-cancer system provides an approach for constructing a combinatorial therapy approach by employing cascaded catalytic nanomedicine with good tumor selectivity and therapeutic efficacy.
    Keywords:  Anti-cancer; Enzyme nanogels; Oxygen self-production; Photodynamic therapy; Polymerization; Starvation therapy
    DOI:  https://doi.org/10.1016/j.actbio.2022.01.056
  2. Front Pharmacol. 2021 ;12 747992
    Folic Acid-Functionalized Metal-Organic Framework Nanoparticles as Drug Carriers Improved Bufalin Antitumor Activity Against Breast Cancer.
    Hairong Zeng, Chao Xia, Bei Zhao, Mengmeng Zhu, HaoYue Zhang, Die Zhang, Xin Rui, Huili Li, Yi Yuan.
      Bufalin (Buf), an active ingredient of the traditional Chinese medicine Chansu, is known to have anticancer effects for breast cancer. However, its poor solubility, high toxicity, and extensive side effects limit its use. Metal-organic frameworks (MOFs) are a class of promising drug delivery systems known for their high porosity. Here, we designed and constructed pH-sensitive and redox-responsive folic acid-modified MOFs as drug carriers of Buf (FA-MOF/Buf). Moreover, the anticancer activity of nanomedicines was also explored in vitro and in vivo. Compared to free Buf, the FA-MOF/Buf nanoparticles demonstrated improved water solubility and stability, higher intracellular uptake, and enhanced cytotoxicity in breast cancer cells in vitro. Furthermore, it displayed improved accumulation in the tumor site, enhanced anticancer activity, and reduced side effects in vivo. Our results demonstrated that FA-MOF could be developed as a potential delivery system for Buf to improve its antitumor activity for breast cancer treatment.
    Keywords:  MOF; antitumor; breast cancer; bufalin; drug delivery; tumor targeting
    DOI:  https://doi.org/10.3389/fphar.2021.747992
  3. Nano Converg. 2022 Feb 04. 9(1): 7
    Bioenzyme-based nanomedicines for enhanced cancer therapy.
    Mengbin Ding, Yijing Zhang, Jingchao Li, Kanyi Pu.
      Bioenzymes that catalyze reactions within living systems show a great promise for cancer therapy, particularly when they are integrated with nanoparticles to improve their accumulation into tumor sites. Nanomedicines can deliver toxic bioenzymes into cancer cells to directly cause their death for cancer treatment. By modulating the tumor microenvironment, such as pH, glucose concentration, hypoxia, redox levels and heat shock protein expression, bioenzyme-based nanomedicines play crucial roles in improving the therapeutic efficacy of treatments. Moreover, bioenzyme-mediated degradation of the major components in tumor extracellular matrix greatly increases the penetration and retention of nanoparticles in deep tumors and infiltration of immune cells into tumor tissues, thus enhancing the efficacies of chemotherapy, phototherapy and immunotherapy. In this review, we summarize the recent progresses of bioenzyme-based nanomedicines for enhanced cancer therapy. The design and working mechanisms of the bioenzyme-based nanomedicines to achieve enhanced chemotherapy, photothermal therapy, photodynamic therapy, chemodynamic therapy, radiotherapy and immunotherapy are introduced in detail. At the end of this review, a conclusion and current challenges and perspectives in this field are given.
    Keywords:  Cancer therapy; Drug delivery system; Enzyme; Nanomedicine; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s40580-022-00297-8
  4. Mini Rev Med Chem. 2022 Feb 02.
    The Most Recent Discoveries in Heterocyclic Nanoformulations for Targeted Anticancer Therapy.
    Sankha Bhattacharya, Rajat Patel, Aalind Joshi.
      Every day, new cases of cancer patients whose recovery is delayed by multidrug resistance and chemotherapy side effects are identified, which severely limit treatment options. One of the most recent advances in nanotechnology is the effective usage of nanotechnology as drug carriers for cancer therapy. As a consequence, heterocyclic nanocarriers were put into practice to see whether they could have a better cure with positive results. The potential of a therapeutic agent to meet its desired goal is vital to its success in treating any disease. Heterocyclic moieties are molecules that have a wide variety of chemically therapeutic functions as well as a significant biological activity profile. Heterocyclic nano formulations play an important role in cell physiology and as possible arbitrators for typical biological reactions, making them valuable in cancer research. As a result, experts are working with heterocyclic nanoformulations to discover alternative approaches to treat cancer. Due to their unique physicochemical properties, heterocyclic compounds are real cornerstones in medicinal chemistry and promising compounds for the future drug delivery system. This review briefly explores the therapeutic relevance of heterocyclic compounds in cancer treatment, the various nanoformulations, and actively describes heterocyclic magnetic nano catalysts and heterocyclic moiety, as well as their mode of action, which have favorable anti - cancer effects.
    Keywords:  Heterocyclic compounds; anticancer therapy; chitosan derivatives; cisplatin; farnesol nanoparticles; in-vivo interactions; lactoferrin nanoparticles; molecularcompounds; nanoformulation
    DOI:  https://doi.org/10.2174/138955752203220202164839
  5. Front Oncol. 2021 ;11 793121
    Targeting KRAS in Lung Cancer Beyond KRAS G12C Inhibitors: The Immune Regulatory Role of KRAS and Novel Therapeutic Strategies.
    Marc Cucurull, Lucia Notario, Montse Sanchez-Cespedes, Cinta Hierro, Anna Estival, Enric Carcereny, Maria Saigí.
      Approximately 20% of lung adenocarcinomas harbor KRAS mutations, an oncogene that drives tumorigenesis and has the ability to alter the immune system and the tumor immune microenvironment. While KRAS was considered "undruggable" for decades, specific KRAS G12C covalent inhibitors have recently emerged, although their promising results are limited to a subset of patients. Several other drugs targeting KRAS activation and downstream signaling pathways are currently under investigation in early-phase clinical trials. In addition, KRAS mutations can co-exist with other mutations in significant genes in cancer (e.g., STK11 and KEAP1) which induces tumor heterogeneity and promotes different responses to therapies. This review describes the molecular characterization of KRAS mutant lung cancers from a biologic perspective to its clinical implications. We aim to summarize the tumor heterogeneity of KRAS mutant lung cancers and its immune-regulatory role, to report the efficacy achieved with current immunotherapies, and to overview the therapeutic approaches targeting KRAS mutations besides KRAS G12C inhibitors.
    Keywords:  ICI; KRAS; NSCLC; PD-L1; STK11
    DOI:  https://doi.org/10.3389/fonc.2021.793121
  6. J Control Release. 2022 Jan 28. pii: S0168-3659(22)00047-5. [Epub ahead of print]
    Nanodrug delivery systems for ferroptosis-based cancer therapy.
    Yu Wang, Tao Sun, Chen Jiang.
      Ferroptosis is an iron-dependent form of cell death accompanied by iron and lipid peroxidase accumulation and has drawn substantial attentions since its first discovery in 2012. Various studies have shown that tumor cells with high tumorigenicity, invasiveness, and metastatic potential are sensitive to ferroptosis. Consequently, many strategies to induce ferroptosis have been used in the design of antitumor nanodrug delivery systems (NDDSs). Prior reviews have thoroughly summarized the mechanism underlying ferroptosis, related pathways, and NDDSs materials. Recent studies have demonstrated that ferroptosis is interacted with several metabolic pathways, and these pathways have provided a basis for designing strategies for NDDSs-induced ferroptosis. Therefore, this review summarizes NDDSs designs for ferroptosis driven by different metabolic pathways, emphasizes the feasibility of inducing ferroptosis in cancer treatment, and finally discusses limitations of NDDSs and future developments in the field.
    Keywords:  Ferroptosis; Metabolism; Nanodrug delivery system
    DOI:  https://doi.org/10.1016/j.jconrel.2022.01.034
  7. Int J Nanomedicine. 2022 ;17 333-350
    pH-Responsive Nanoparticles for Enhanced Antitumor Activity by High-Intensity Focused Ultrasound Therapy Combined with Sonodynamic Therapy.
    Hui Gao, Zhaoxia Wang, Mixiao Tan, Weiwei Liu, Liang Zhang, Ju Huang, Yang Cao, Pan Li, Zhigang Wang, Jiexin Wen, Tingting Shang, Haitao Ran.
      Background: Therapeutic ultrasound (US) has been extensively explored for its inherent high tissue-penetrating capability and on-demand irradiation without radioactive damage. Although high-intensity focused ultrasound (HIFU) is evolved as such an outstanding US-based approach, its insufficient therapeutic effect and the high-intensity induced potential damage to surrounding normal tissues hindered its development towards practical application. As opposed to high intensity ultrasound, sonodynamic therapy (SDT) is a low intensity US-based method which exhibits certain therapeutic effects against cancer via sonosensitizers-generated reactive oxygen species (ROS) overproduction.Methods: Hematoporphyrin monomethyl ether (HMME) loaded CaCO3 nanoparticles (designated as Ca@H) were synthesized by a gas diffusion method. The pH-responsive performance, in vitro SDT, ex vivo HIFU therapy (HIFUT), photoacoustic (PA) imaging and in vivo HIFUT combined with SDT were investigated thoroughly.
    Results: Ca@H NPs gradually decomposed in acid tumor microenvironment, produced CO2 and released HMME. Both CO2 and HMME enhanced photoacoustic (PA) imaging. The generated CO2 bubbles also enhanced HIFUT by inducing an enlarged ablation area. The tumor ablation efficiency (61.04%) was significantly improved with a combination of HIFU therapy and SDT.
    Conclusion: pH-responsive Ca@H NPs have been successfully constructed for PA imaging-guided/monitored HIFUT combined with SDT. With the assistance of pH-responsive Ca@H NPs, the combination of these two US-based therapies is expected to play a role in the treatment of non-invasive tumor in the future.
    Keywords:  CaCO3 nanoparticles; high-intensity focused ultrasound therapy; nanomedicine; sonodynamic therapy; ultrasound
    DOI:  https://doi.org/10.2147/IJN.S336632
  8. Adv Healthc Mater. 2022 Feb 02. e2102632
    γ-Fe2 O3 Loading Mitoxantrone and Glucose Oxidase for pH-Responsive Chemo/Chemodynamic/Photothermal Synergistic Cancer Therapy.
    Zhihao Zhong, Chao Liu, Yatao Xu, Weili Si, Wenjun Wang, Liping Zhong, Yongxiang Zhao, Xiaochen Dong.
      Traditional cancer therapy is limited by poor prognosis and risk of recurrence. Emerging therapies offer alternatives to these problems. In addition, synergistic therapy can combine the advantages of multiple therapies to eliminate cancer cells while attenuating damage to normal tissues. Herein, a theranostic nanoplatform based on chemotherapeutic drug mitoxantrone (MTO) and glucose oxidase (GOx) co-loaded γ-Fe2 O3 nanoparticles (MTO-GOx@γ-Fe2 O3 NPs) was designed and prepared to realize photoacoustic imaging-guided chemo/chemodynamic/photothermal (CT/CDT/PTT) synergistic cancer therapy. With a particle size of about 86.2 nm, the synthesized MTO-GOx@γ-Fe2 O3 NPs could selectively accumulate at tumor sites by enhanced permeability and retention (EPR) effect. After entering cancer cells by endocytosis, MTO-GOx@γ-Fe2 O3 NPs decompose into Fe3+ ions and release cargo because of their pH-responsive characteristic. As Food and Drug Administration (FDA)-approved chemotherapy drug, MTO showed strong DNA disruption ability and satisfying photothermal conversion ability under laser irradiation for photothermal therapy. Simultaneously, GOx catalyzed the decomposition of glucose and generated H2 O2 to enhance the chemodynamic therapy efficiency. In vitro and in vivo experiments both revealed that MTO-GOx@γ-Fe2 O3 NPs possessed a significant synergistic therapeutic effect in cancer treatment. This article is protected by copyright. All rights reserved.
    Keywords:  Glucose oxidase; Mitoxantrone; Synergistic therapy; γ-Fe2O3
    DOI:  https://doi.org/10.1002/adhm.202102632
  9. Phytomedicine. 2021 Dec 28. pii: S0944-7113(21)00449-9. [Epub ahead of print]97 153909
    Quercetin- and rutin-based nano-formulations for cancer treatment: A systematic review of improved efficacy and molecular mechanisms.
    Maryam Ghanbari-Movahed, Arijit Mondal, Mohammad Hosein Farzaei, Anupam Bishayee.
      BACKGROUND: Natural products, with incredible chemical diversity, have been widely studied for their antitumor potential. Quercetin (QU) and quercetin glycoside (rutin), both polyphenolic flavonoids, stick out amongst the natural products, through various studies. Rutin (RU) and its aglycone (QU) have various biological properties that include antioxidant, anti-inflammatory, and anticarcinogenic activities. However, several side effects have restricted the efficacy of these polyphenolic flavonoids, which makes it necessary to use new strategies involving low and pharmacological doses of QU and RU, either alone or in combination with other anticancer drugs.PURPOSE: The aim of this study is to present a comprehensive and critical evaluation of the anticancer ability of different nano-formulations of RU and QU for improved treatment of various malignancies.
    METHODS: Studies were recognized via systematic searches of ScienceDirect, PubMed, and Scopus databases. Eligibility checks were conducted based upon predefined selection criteria. Ninety articles were included in this study.
    RESULTS: There was conclusive evidence for the association between anticancer activity and treatment with RU or QU. Furthermore, studies indicated that nano-formulations of RU and QU have greater anticancer activities in comparison to either agent alone, which leads to increased efficiency for treating cancer.
    CONCLUSION: The results of this systematic review demonstrate the anticancer activities of nano-formulations of RU and QU and their molecular mechanisms through preclinical studies. This paper also attempts to contribute to further research by addressing the current limitations/challenges and proposing additional studies to realize the full potential of RU- and QU-based formulations for cancer treatment.
    Keywords:  Cancer; Nano-formulation; Natural products; Quercetin; Rutin; Targeted therapy
    DOI:  https://doi.org/10.1016/j.phymed.2021.153909
  10. Adv Cancer Res. 2022 ;pii: S0065-230X(21)00081-6. [Epub ahead of print]153 267-304
    Unraveling and targeting RAS-driven metabolic signaling for therapeutic gain.
    Jonathan M DeLiberty, Ryan Robb, Claire E Gates, Kirsten L Bryant.
      RAS mutations are among the most frequent oncogenic drivers observed in human cancers. With a lack of available treatment options, RAS-mutant cancers account for many of the deadliest cancers in the United States. Recent studies established that altered metabolic requirements are a hallmark of cancer, and many of these alterations are driven by aberrant RAS signaling. Specifically, RAS-driven cancers are characterized by upregulated glycolysis, the differential channeling of glycolytic intermediates, upregulated nutrient scavenging pathways such as autophagy and macropinocytosis, and altered glutamine utilization and mitochondrial function. This unique metabolic landscape promotes tumorigenesis, proliferation, survival in nutrient deficient environments and confers resistance to conventional cytotoxic and targeted therapies. Emerging work demonstrates how these dependencies can be therapeutically exploited in vitro and in vivo with many metabolic inhibitors currently in clinical trials. This review aims to outline the unique metabolic requirements induced by aberrant RAS signaling and how these altered dependencies present opportunities for therapeutic intervention.
    Keywords:  Autophagy; Glycolysis; Macropinocytosis; Metabolism; Mitochondria; RAS; Scavenging
    DOI:  https://doi.org/10.1016/bs.acr.2021.07.010
  11. J Am Chem Soc. 2022 Feb 04.
    Near-Infrared Light-Excited Reactive Oxygen Species Generation by Thulium Oxide Nanoparticles.
    Dida Duosiken, Ruihao Yang, Yingfan Dai, Zeinab Marfavi, Quanjie Lv, Hanyin Li, Kang Sun, Ke Tao.
      Exploring materials that can absorb near-infrared (NIR) light to produce reactive oxygen species (ROS) is necessary for many fields. Herein we show that thulium oxide nanoparticles are viable for NIR-stimulated ROS generation. This property may be related to the unique energy levels, large absorption cross section, low fluorescence emission, and ∼10-3 s lifetime of the 3H4 state of Tm ions. We further demonstrate the impact of these nanoparticles on photodynamic therapy (PDT), in which impressive tumor inhibition was recorded after exposure to either a broadband halogen lamp or an 808 nm laser. Our results may provide insight into the areas of photocatalysis, pollution treatment, and fine chemical synthesis.
    DOI:  https://doi.org/10.1021/jacs.1c11704
  12. Macromol Rapid Commun. 2022 Feb 01. e2100918
    Rationally Driven Drug Nonradiative Decay via a Label-free Polyprodrug Strategy to Renew Tumor Cascade Photothermal-Chemotherapy.
    Wenjia Zhang, Xiaoming Lyu, Li Zhang, Wenhui Wang, Qi Shen, Siyu Lu, Ligong Lu, Meixiao Zhan, Xianglong Hu.
      Drugs are frequently used for only chemotherapy that ignores their photophysical properties that potentially endow them with other therapeutic potency. Additionally, current photothermal-chemotherapy replies on the co-delivery of drugs and photothermal agents, but their spatiotemporal delivery and precise release is unsatisfactory. Herein, we report label-free doxorubicin (DOX) polyprodrug nanoparticles (DPNs) formulated from disulfide bonds-tethered DOX polyprodrug amphiphiles (PDMA-b-PDOXM). Benefiting from boosted nonradiative decay of high-density DOX, significant fluorescence quenching and photothermal effect are observed for DPNs without common photothermal agents. Upon cellular uptake and laser irradiation, the heat can promote lysosomal escape of DPNs into reductive cytosol, whereupon free DOX is released to activate chemotherapy and fluorescence, achieving rational cascade photothermal-chemotherapy. Current label-free polyprodrug strategy can make full use of drug, it provides an alternative insight to extend the therapeutic domain of drugs. This article is protected by copyright. All rights reserved.
    Keywords:  chemotherapy; doxorubicin; nonradiative decay; photothermal therapy; polyprodrug
    DOI:  https://doi.org/10.1002/marc.202100918
  13. Nanoscale. 2022 Feb 03.
    A dual-responsive nanoplatform with feedback amplification improves antitumor efficacy of photodynamic therapy.
    Yuan Xue, Shuting Bai, Leilei Wang, Shi Luo, Zhirong Zhang, Tao Gong, Ling Zhang.
      A good photosensitizer (PS) delivery system could enhance the efficiency and reduce the side effects of anti-tumor photodynamic therapy (PDT) by improving accumulation in the tumor, uptake by tumor cells, and intracellular release of the PS. Thus, we rationally developed a multi-stimulus-responsive PS nanocarrier with a double-layered core-shell structure: mPEG-azo-hyaluronic acid-sulfide-Ce6 (PaHAsC). In PaHAsC, the mPEG coat provides protection before entering the hypoxic tumor microenvironment, where mPEG leaves to expose the HA layer. HA then targets overexpressed CD44 on tumor cells for enhanced internalization. Finally, GSH-mediated intracellular release of Ce6 augments ROS generation and O2 consumption under light stimulation. This also aggravates hypoxia in tumor sites to accelerate mPEG removal, forming a positive feedback loop. Data show that PaHAsC dramatically improved the PDT efficacy of Ce6, eliminating most tumors and 80% of tumor-bearing mice survived. With a safe profile, PaHAsC has potential for further development and is a useful example of a PS delivery system.
    DOI:  https://doi.org/10.1039/d1nr06875j
  14. Transl Cancer Res. 2020 Dec;9(12): 7619-7631
    Functions of polyphenols and its anticancer properties in biomedical research: a narrative review.
    Pritam Bhagwan Bhosale, Sang Eun Ha, Preethi Vetrivel, Hun Hwan Kim, Seong Min Kim, Gon Sup Kim.
      Cancer is a major health concern as the incidence is growing worldwide and still lacks successful therapies. Plant-derived functional foods are getting considerable attention, primarily due to their safety and therapeutic potential. Polyphenols are a group of mostly natural, water-soluble organic compounds. Here, we review the functions of selected polyphenols and their anticancer properties on numerous cancer cell lines and their mechanisms. The literature search was performed using the electronic database PubMed, Google scholar up to June 2020, with the following keywords-polyphenol, polyphenol anticancer, quercetin anticancer, resveratrol anticancer, curcumin anticancer, and kaempferol anticancer. Chemical structures of the selected polyphenols were obtained using the ChemDraw program. The initial search identified 40,554 polyphenols papers and among that, 2,559 were limited to polyphenol and cancer, 987 quercetin and cancer, 2,174 curcumin and cancer, 1,079 resveratrol and cancer, and 226 were limited to kaempferol and cancer. A total of 84 papers are included in this review paper. Most studies report the multiple anticarcinogenic properties of plant-derived polyphenols, including its inhibitory effects on the proliferation of cancer cells, tumor expansion, angiogenesis, inflammation, and metastasis. Besides, some studies shows potential synergistic effects when polyphenol treatment combined with chemotherapeutic agents. Anticancer effects of polyphenolic compounds like quercetin, curcumin, resveratrol, and kaempferol are investigated on numerous cancer cell lines and have shown prominent results. The present review provides a direction to determine the anticarcinogenic ability of the selected polyphenols in vitro and in vivo. Consequently, the use of polyphenols in cancer treatment should be investigated in-depth in the future.
    Keywords:  Anticancer effect; curcumin; kaempferol; polyphenols; quercetin; resveratrol
    DOI:  https://doi.org/10.21037/tcr-20-2359
  15. Transl Cancer Res. 2021 Sep;10(9): 4196-4206
    The interplay between reactive oxygen species and antioxidants in cancer progression and therapy: a narrative review.
    Osama Hussein Bekhet, Mohamed Elsayed Eid.
      Objective: To unveil the role of reactive oxygen species (ROS) and antioxidants in signaling and involvement in cancer progression and therapy.Background: Cancer is considered one of the main causes of mortality in developed countries and expected to be more in developing countries as well. Although some cancers may develop at young age, yet almost all types of cancers are an accumulation of genetic and epigenetic cell damages. Cancer is considered a diverse collection of diseases on a cellular level rather than a single disease; and each disease has a different cause as well. ROS have been seen as harmful toxic molecules; however, they are recognized for cellular signaling capabilities. Elevated levels of ROS have protumorigenic activities; they induce cancer cell proliferation, and adaptation to hypoxia in addition to other effects like DNA damage and genetic instability. They are produced excessively by cancer cells to hyperactivate cellular transformation meanwhile increasing antioxidant capacity to avoid cell death.
    Methods: We discussed peer reviewed published research work from 1987 to 2021. In this paper, we review the role of antioxidants as defensive barrier against excessive ROS levels for maintaining oxidation-reduction (redox) balance; however, antioxidant can also strive in tumor cells with their scavenging capacities and maintain protumorigenic signaling and resist the cancer cell oxidative stress and apoptosis. High doses of antioxidant compounds could be toxic to cells as they are capable of reacting with the physiological concentrations of ROS present for normal cellular processes and signaling.
    Conclusions: Maintaining cellular redox homeostasis is vital for healthy biological system. Therefore, therapeutic modalities for cancer including antioxidants and ROS management should be used at certain doses to target specific redox pathways involved in cancer progression without disrupting the overall redox balance in normal cells.
    Keywords:  Cancer; antioxidants; oxidative stress; reactive oxygen species (ROS); signaling
    DOI:  https://doi.org/10.21037/tcr-21-629
  16. Future Med Chem. 2022 Feb 01.
    Research advances in NQO1-responsive prodrugs and nanocarriers for cancer treatment.
    Xiaojuan Yang, Jiaxue Duan, Liqiang Wu.
      NAD(P)H: quinine oxidoreductase (NQO1) is a class of flavoprotein enzymes commonly expressed in eukaryotic cells. It actively participates in the metabolism of various quinones and their in vivo bioactivation through electron reduction reactions. The expression level of NQO1 is highly upregulated in many solid tumor cells compared with that in normal cells. NQO1 has been considered a candidate molecular target because of its overexpression and bioactivity in different tumors. NQO1-responsive prodrugs and nanocarriers have recently been identified as effective objectives for achieving controlled drug release, reducing adverse reactions and improving clinical efficacy. This review systematically introduces the research advances in applying NQO1-responsive prodrugs and nanocarriers to cancer treatment. It also discusses the existing problems and the developmental prospects of these two antitumor drug delivery systems.
    Keywords:  NQO1; NQO1-responsive nanocarriers; NQO1-responsive prodrugs; antitumor; stimuli-responsive nanocarriers
    DOI:  https://doi.org/10.4155/fmc-2021-0289
  17. Tissue Eng Regen Med. 2022 Jan 31.
    Nanozyme-Based Enhanced Cancer Immunotherapy.
    Ngoc Man Phan, Thanh Loc Nguyen, Jaeyun Kim.
      Catalytic nanoparticles with natural enzyme-mimicking properties, known as nanozymes, have emerged as excellent candidate materials for cancer immunotherapy. Owing to their enzymatic activities, artificial nanozymes not only serve as responsive carriers to load drugs and therapeutic molecules for cancer treatment, but also act as enzymes for modulating the immunosuppression of the tumor microenvironment (TME) via the catalytic activities of catalase, peroxidase, superoxide dismutase, and oxidase. The immunosuppressive pro-tumor TME can be reversed to the immunoactive anti-tumor TME by utilizing both reactive oxygen species (ROS)-generating and ROS-scavenging nanozymes, which enhance the efficacy of cancer immunotherapy. In this review, we introduce representative ROS-generating and ROS-scavenging nanozymes and discuss how artificial nanozymes respond to the conditions of the TME. Based on the mutual interaction between nanozymes and TME, recent therapeutic pathways to provoke anti-cancer immune responses using nanozymes are discussed.
    Keywords:  Cancer immunotherapy; Immunogenic cell death; Nanozymes; Reactive oxygen species; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s13770-022-00430-y
  18. Anticancer Res. 2022 Feb;42(2): 641-644
    Methionine Restriction: Ready for Prime Time in the Cancer Clinic?
    Jun Yamamoto, Qinghong Han, Mark Simon, Daniel Thomas, Robert M Hoffman.
      Attempts to selectively starve cancers in the clinic have been made at least since the time of Warburg beginning 100 years ago. Calorie-restriction or low-carbohydrate diets have had limited success with cancer patients. Methionine restriction is another strategy to selectively starve cancer cells, since cancers are addicted to methionine, unlike normal cells. Methionine addiction of cancer is termed the Hoffman effect. Numerous preclinical studies over the past half century have shown methionine restriction to be highly effective against all major cancer types and synergistic with chemotherapy. Low-methionine medical diets can be effective in lowering methionine and have shown some clinical promise, but they are not palatable and thereby not sustainable. However, selectively choosing among plant-based foods allows a variety of low-methionine diets that are sustainable. Our laboratory has developed a methioninase that can be administered orally as a supplement and has resulted in anecdotal positive results in patients with advanced cancer, including hormone-independent prostate cancer, and other recalcitrant cancers. The question is whether methionine restriction through a low-methionine diet, or even greater methionine restriction with methioninase in combination with a low-methionine diet, is ready for prime time in the clinic, especially in combination with other synergistic therapy. The question will hopefully be answered in the near future, especially for advanced cancer patients who have failed all standard therapy.
    Keywords:  Cancer; Hoffman effect; clinical treatment; methioninase; methionine addiction; methionine restriction; review
    DOI:  https://doi.org/10.21873/anticanres.15521
  19. Int Immunopharmacol. 2022 Feb 01. pii: S1567-5769(22)00039-X. [Epub ahead of print]105 108555
    The interactions of paclitaxel with tumour microenvironment.
    Ding-Li Yu, Zhi-Ping Lou, Feng-Yun Ma, Masoud Najafi.
      Today, it is well-known that the interactions and secretion within the tumour are crucial to consider for cancer therapy. Some novel cancer therapy modalities such as immunotherapy or tumour vaccination therapy work based on the control of interactions within the tumour microenvironment (TME). It has been revealed that anti-cancer drugs or radiotherapy can modulate some interactions in favour of cancer therapy. However, they may induce some mechanisms to increase the resistance of cancer cells to therapy. Paclitaxel is known as the first approved herbal derived chemotherapy drug. Although the main known anti-cancer effect of paclitaxel is the inhibition of the cell cycle, today, it has been well known that paclitaxel may suppress the tumour via modulating several interactions in TME. Furthermore, paclitaxel may increase the expression of some tumour resistance drivers. This review aims to discuss the interactions within TME following treatment with paclitaxel. The effects of paclitaxel on the anti-tumour immunity, immunosuppressive cells, hypoxia, and also angiogenesis will be discussed. The targeting of these interactions may be interesting to increase therapy efficiency using the combination modalities.
    Keywords:  CD8+ T lymphocytes; Cancer resistance; Natural killer (NK) cells; Paclitaxel; Regulatory T cells (Tregs); Tumour microenvironment (TME)
    DOI:  https://doi.org/10.1016/j.intimp.2022.108555
  20. Front Pharmacol. 2021 ;12 783127
    Jatrorrhizine: A Review of Sources, Pharmacology, Pharmacokinetics and Toxicity.
    Furong Zhong, Yang Chen, Jia Chen, Hailang Liao, Yirou Li, Yuntong Ma.
      Jatrorrhizine, an isoquinoline alkaloid, is a bioactive metabolite in common medicinal plants, such as Berberis vernae Schneid., Tinospora sagittata (Oliv.) Gagnep. and Coptis chinensis Franch. These plants have been used for centuries in traditional medicine for their wide-ranging pharmacological properties. This review emphasizes the latest and comprehensive information on the sources, pharmacology, pharmacokinetics and toxicity of jatrorrhizine. Studies on this alkaloid were collected from scientific internet databases, including the Web of Science, PubMed, ScienceDirect, Google Scholar, Elsevier, Springer, Wiley Online Library and Europe PMC and CNKI, using a combination of keywords involving "jatrorrhizine", "sources", "pharmacology," "pharmacokinetics," and "toxicology". Jatrorrhizine exhibits anti-diabetic, antimicrobial, antiprotozoal, anticancer, anti-obesity and hypolipidemic properties, along with central nervous system activities and other beneficial activity. Studies of jatrorrhizine have laid the foundation for its application to the treatment of various diseases, but some issues still exist. Further investigations might emphasize 1) specific curative mechanisms of jatrorrhizine and clinical utility, 2) application prospect in the treatment of metabolic disorders, 3) comprehensive investigations of the toxicity mechanisms and 4) interactions of jatrorrhizine with other pharmaceuticals and development of derivatives.
    Keywords:  jatrorrhizine; natural products; pharmacokinetics; pharmacological properties; toxicology
    DOI:  https://doi.org/10.3389/fphar.2021.783127
  21. Adv Cancer Res. 2022 ;pii: S0065-230X(21)00080-4. [Epub ahead of print]153 131-168
    Pan-RAS inhibitors: Hitting multiple RAS isozymes with one stone.
    Alexander B Coley, Antonio Ward, Adam B Keeton, Xi Chen, Yulia Maxuitenko, Aishwarya Prakash, Feng Li, Jeremy B Foote, Donald J Buchsbaum, Gary A Piazza.
      Mutations in the three RAS oncogenes are present in approximately 30% of all human cancers that drive tumor growth and metastasis by aberrant activation of RAS-mediated signaling. Despite the well-established role of RAS in tumorigenesis, past efforts to develop small molecule inhibitors have failed for various reasons leading many to consider RAS as "undruggable." Advances over the past decade with KRAS(G12C) mutation-specific inhibitors have culminated in the first FDA-approved RAS drug, sotorasib. However, the patient population that stands to benefit from KRAS(G12C) inhibitors is inherently limited to those patients harboring KRAS(G12C) mutations. Additionally, both intrinsic and acquired mechanisms of resistance have been reported that indicate allele-specificity may afford disadvantages. For example, the compensatory activation of uninhibited wild-type (WT) NRAS and HRAS isozymes can rescue cancer cells harboring KRAS(G12C) mutations from allele-specific inhibition or the occurrence of other mutations in KRAS. It is therefore prudent to consider alternative drug discovery strategies that may overcome these potential limitations. One such approach is pan-RAS inhibition, whereby all RAS isozymes co-expressed in the tumor cell population are targeted by a single inhibitor to block constitutively activated RAS regardless of the underlying mutation. This chapter provides a review of past and ongoing strategies to develop pan-RAS inhibitors in detail and seeks to outline the trajectory of this promising strategy of RAS inhibition.
    Keywords:  Cancer; Drug discovery; HRAS; KRAS; NRAS; RAS inhibitors; pan-RAS
    DOI:  https://doi.org/10.1016/bs.acr.2021.07.009
  22. Recent Pat Nanotechnol. 2022 Jan 31.
    Polymeric nanoparticles for the treatment of prostate cancer - technological prospecting and critical analysis.
    Clauberto Rodrigues de Oliveira, Daniela Droppa-Almeida, Francine Ferreira Padilha, Roberto Rodrigues de Souza, Ricardo Luiz Cavalcanti de Albuquerque-Júnior.
      BACKGROUND: Polymeric nanoparticles have a wide diversity, and due to their toxicity and biodegradability they have been widely used in the health area. Its use allows stability of some compounds, targeted delivery, and increased half-life, in this context, making some treatment proposals more effective. Prostate cancer, in turn, is among the types of cancer with the highest mortality, and the lack of effective treatment causes several strategies to meet this need.OBJECTIVE: The objective of this work was to verify patents that use polymeric nanoparticles for the treatment of prostate cancer.
    METHODS: For that, specific keywords to direct the search were applied in Patent Scope. After obtaining the patents, one was selected for the development of critical analysis in relation to its chemistry and biology.
    RESULTS: A total of five patents were found and, of these, an invention that used PCL-PLGA-PEG-COOH polymeric nanoparticles with two natural compounds, resveratrol and celastrol, providing an alternative method to traditional monotherapies.
    CONCLUSION: The prospective analysis serves to direct us in relation to the technologies currently used in certain fields. Based on several cases of cancer and specifically the countless cases of prostate cancer, five recent patents were found using polymeric nanoparticles. However, only one brought a different aspect of all the treatments used lately. It brought an invention containing two natural compounds being carried with polymeric nanoparticles with promising results.
    Keywords:  bioactive compounds; chemoprevention; chemotherapy; nanosystems
    DOI:  https://doi.org/10.2174/1872210516666220131092642
  23. Cancer Sci. 2022 Feb 03.
    Cancer metabolism challenges genomic instability and clonal evolution as therapeutic targets.
    Yu Takeda, Ryota Chijimatsu, Ken Ofusa, Shogo Kobayashi, Yuichiro Doki, Hidetoshi Eguchi, Hideshi Ishii.
      Although cancer precision medicine has improved diagnosis and therapy, refractory cancers such as pancreatic cancer remain to be challenging targets. Clinical sequencing has identified the significant alterations in driver genes and traced their clonal evolutions. Recent studies indicated that the tumor microenvironment elicits alterations in cancer metabolism, although its involvement in the cause and development of genomic alterations have not been established. Genomic abnormalities can contribute to the survival of selected subpopulations, recently recognized as clonal evolution, and dysfunction can lead to DNA mutations. Here, we present the most recent studies on the mechanisms of cancer metabolism involved in the maintenance of genomic stability to update current understanding of such processes. Sirtuins, which are NAD+-dependent protein deacetylases, appear to be involved in the control of genomic stability. Alterations of deleterious subpopulations would be exposed to selective pressure for cell survival. Recent studies indicated that a new type of cell death, ferroptosis, determines the survival of clones and exert cancer-restricting or -promoting effects to surrounding cells in the tumor microenvironment. Suppressing genomic instability and eliminating deleterious clones by cell death will contribute to the improvement of cancer medicine. Furthermore, the elucidation of the mechanisms involved is seen as a bridgehead to the pharmacologic suppression of such refractory cancers as pancreatic cancer.
    Keywords:  ferroptosis; metabolism; oxidative stress; pancreatic cancer; sirtuins
    DOI:  https://doi.org/10.1111/cas.15279
  24. J Mater Chem B. 2022 Feb 01.
    Photothermally triggered melting and perfusion: responsive colloidosomes for cytosolic delivery of membrane-impermeable drugs in tumor therapy.
    Tao Ding, Jing Zhu, Haidi Guan, Daqing Xia, Yuxin Xing, Jixi Huang, Zhenqiang Wang, Kaiyong Cai, Jixi Zhang.
      A cell membrane barrier which dominates the therapeutic efficacy and systemic side effects is a major bottleneck in the field of drug delivery. Herein, a therapeutic system capable of photothermally triggered on-demand and cytosolic delivery was achieved by polydopamine (PDA) nanoparticle-stabilized colloidosomes. An organic phase change material (PCM, saturated fatty acids) was employed as the lipid core for Pickering emulsification and drug encapsulation, and arginine was utilized as a linker to induce the directional interactions between nanoemulsion droplets and heterogeneously nucleated PDA nanoparticles. Moreover, the PDA particle stabilizers concomitantly mediated the grafting of hydrophilic polymer PEG to further improve dispersibility. The resultant colloidosomes after cooling possess lowered melting points and superior dispersion stability over 7 days. When irradiated with near-infrared light (808 nm), sequential processes of fatty acid melting and direct drug perfusion into the cytosol took place within 10 min. The employment of vorinostat (SAHA, histone deacetylase inhibitor) as a model membrane-impermeable drug resulted in remarkable enhancement of anti-cancer effects both in vitro (5.2 fold reduction in IC50) and in vivo (7.3 fold increase in tumor inhibition rate) with respect to the free drug. The remotely triggered transformable nanoplatform paves a new avenue of responsive and efficient cytosolic perfusion to overcome biological membrane barriers on the basis of colloidosomes.
    DOI:  https://doi.org/10.1039/d1tb02503a
  25. Front Cell Dev Biol. 2021 ;9 762742
    Emerging Roles of the Tumor Suppressor p53 in Metabolism.
    Lili Yu, Meng Wu, Gaoyang Zhu, Yang Xu.
      Metabolism plays critical roles in maintaining the homeostasis of cells. Metabolic abnormalities are often considered as one of the main driving forces for cancer progression, providing energy and substrates of biosynthesis to support neoplastic proliferation effectively. The tumor suppressor p53 is well known for its roles in inducing cell cycle arrest, apoptosis, senescence and ferroptosis. Recently, emerging evidence has shown that p53 is also actively involved in the reprogramming of cellular metabolism. In this review, we focus on recent advances in our understanding of the interplay between p53 and metabolism of glucose, fatty acid as well as amino acid, and discuss how the deregulation of p53 in these processes could lead to cancer.
    Keywords:  amino acid metabolism; ferroptosis; glucose metabolism; iron metabolism; lipid metabolism; p53
    DOI:  https://doi.org/10.3389/fcell.2021.762742
  26. Front Pharmacol. 2021 ;12 809308
    Cancer Chemoprevention: A Strategic Approach Using Phytochemicals.
    Mohan Shankar G, Mundanattu Swetha, C K Keerthana, Tennyson P Rayginia, Ruby John Anto.
      Cancer chemoprevention approaches are aimed at preventing, delaying, or suppressing tumor incidence using synthetic or natural bioactive agents. Mechanistically, chemopreventive agents also aid in mitigating cancer development, either by impeding DNA damage or by blocking the division of premalignant cells with DNA damage. Several pre-clinical studies have substantiated the benefits of using various dietary components as chemopreventives in cancer therapy. The incessant rise in the number of cancer cases globally is an issue of major concern. The excessive toxicity and chemoresistance associated with conventional chemotherapies decrease the success rates of the existent chemotherapeutic regimen, which warrants the need for an efficient and safer alternative therapeutic approach. In this scenario, chemopreventive agents have been proven to be successful in protecting the high-risk populations from cancer, which further validates chemoprevention strategy as rational and promising. Clinical studies have shown the effectiveness of this approach in managing cancers of different origins. Phytochemicals, which constitute an appreciable proportion of currently used chemotherapeutic drugs, have been tested for their chemopreventive efficacy. This review primarily aims to highlight the efficacy of phytochemicals, currently being investigated globally as chemopreventives. The clinical relevance of chemoprevention, with special emphasis on the phytochemicals, curcumin, resveratrol, tryptanthrin, kaempferol, gingerol, emodin, quercetin genistein and epigallocatechingallate, which are potential candidates due to their ability to regulate multiple survival pathways without inducing toxicity, forms the crux of this review. The majority of these phytochemicals are polyphenols and flavanoids. We have analyzed how the key molecular targets of these chemopreventives potentially counteract the key drivers of chemoresistance, causing minimum toxicity to the body. An overview of the underlying mechanism of action of these phytochemicals in regulating the key players of cancer progression and tumor suppression is discussed in this review. A summary of the clinical trials on the important phytochemicals that emerge as chemopreventives is also incorporated. We elaborate on the pre-clinical and clinical observations, pharmacokinetics, mechanism of action, and molecular targets of some of these natural products. To summarize, the scope of this review comprises of the current status, limitations, and future directions of cancer chemoprevention, emphasizing the potency of phytochemicals as effective chemopreventives.
    Keywords:  chemoprevention; chemopreventives; chemotherapeutics; phenolic compounds; phytochemicals; tumor suppression
    DOI:  https://doi.org/10.3389/fphar.2021.809308
  27. Cell Death Dis. 2022 Feb 04. 13(2): 114
    Synthetic adiponectin-receptor agonist, AdipoRon, induces glycolytic dependence in pancreatic cancer cells.
    Sharon J Manley, Appolinaire A Olou, Jarrid L Jack, Mariana T Ruckert, R McKinnon Walsh, Austin E Eades, Bailey A Bye, Joe Ambrose, Fanuel Messaggio, Shrikant Anant, Michael N VanSaun.
      Obesity creates a localized inflammatory reaction in the adipose, altering secretion of adipocyte-derived factors that contribute to pathologies including cancer. We have previously shown that adiponectin inhibits pancreatic cancer by antagonizing leptin-induced STAT3 activation. Yet, the effects of adiponectin on pancreatic cancer cell metabolism have not been addressed. In these studies, we have uncovered a novel metabolic function for the synthetic adiponectin-receptor agonist, AdipoRon. Treatment of PDAC cells with AdipoRon led to mitochondrial uncoupling and loss of ATP production. Concomitantly, AdipoRon-treated cells increased glucose uptake and utilization. This metabolic switch further correlated with AMPK mediated inhibition of the prolipogenic factor acetyl coenzyme A carboxylase 1 (ACC1), which is known to initiate fatty acid catabolism. Yet, measurements of fatty acid oxidation failed to detect any alteration in response to AdipoRon treatment, suggesting a deficiency for compensation. Additional disruption of glycolytic dependence, using either a glycolysis inhibitor or low-glucose conditions, demonstrated an impairment of growth and survival of all pancreatic cancer cell lines tested. Collectively, these studies provide evidence that pancreatic cancer cells utilize metabolic plasticity to upregulate glycolysis in order to adapt to suppression of oxidative phosphorylation in the presence of AdipoRon.
    DOI:  https://doi.org/10.1038/s41419-022-04572-8
  28. J Control Release. 2022 Jan 29. pii: S0168-3659(22)00057-8. [Epub ahead of print]
    Fully armed photodynamic therapy with spear and shear for topical deep hypertrophic scar treatment.
    Yao Huang, Tingting Peng, Wanshan Hu, XinYi Gao, Yangyan Chen, Qian Zhang, Chuanbin Wu, Xin Pan.
      5-aminolevulinic acid (ALA)-mediated photodynamic therapy (PDT) has emerged as a promising therapy for hypertrophic scar (HS). However, the poor permeability of ALA across biological barriers and pro-survival autophagy of fibroblasts largely restricted the efficacy of PDT. Herein, PDT was well equipped with spear and shear to overcome the therapeutic resistance. Specifically, hyaluronidase (HAase) based dissolving microneedles (MN)with improved stiffness and permeability were developed as a spear to deliver ALA into deep lesions by combating the dual barriers of stratum corneum and dense extracellular matrix (ECM). Besides, metformin (Met) MN was applied as a shear to intervene the respiration and autophagic process for amplified PDT. HAase significantly enhanced the in vitro and in vivo transdermal delivery efficiency of ALA, while the combination of HAase and Met successfully amplified the anti-scarring efficacy of PDT by elevating cytotoxicity, promoting permeation, activating signal pathways, and interdicting the autophagy process simultaneously. The pharmacodynamics study revealed that the combination therapy achieved the lowest scar elevation index (SEI), downregulated expression of collagen I and TGF-β1, and decreased LC3 II/I ratio, showing excellent therapeutic efficacy. Therefore, such a fully armed PDT integrating double-prolonged attack on the physiological and pathological barriers offers a promising topical treatment for deep HS.
    Keywords:  Autophagy; Hyaluronidase; Hypertrophic scar; Microneedle; Photodynamic therapy
    DOI:  https://doi.org/10.1016/j.jconrel.2022.01.043
  29. World J Gastrointest Oncol. 2022 Jan 15. 14(1): 110-123
    Statin as a therapeutic agent in gastroenterological cancer.
    Norio Uemura, Hiromitsu Hayashi, Hideo Baba.
      Statins inhibit 3-hydroxy-3-methylglutaryl-CoA reductase, the rate-limiting enzyme of the mevalonate pathway, and are widely used as an effective and safe approach handle hypercholesterolemia. The mevalonate pathway is a vital metabolic pathway that uses acetyl-CoA to generate isoprenoids and sterols that are crucial to tumor growth and progression. Multiple studies have indicated that statins improve patient prognosis in various carcinomas. Basic research on the mechanisms underlying the antitumor effects of statins is underway. The development of new anti-cancer drugs is progressing, but increasing medical costs from drug development have become a major obstacle. Readily available, inexpensive and well-tolerated drugs like statins have not yet been successfully repurposed for cancer treatment. Identifying the cancer patients that may benefit from statins is key to improved patient treatment. This review summarizes recent advances in statin research in cancer and suggests important considerations for the clinical use of statins to improve outcomes for cancer patients.
    Keywords:  Cancer; HMG CoA reductase inhibitor; Mevalonate pathway; Statin
    DOI:  https://doi.org/10.4251/wjgo.v14.i1.110
  30. Anticancer Res. 2022 Feb;42(2): 857-866
    Inhibitory Effect of Oxaliplatin-loaded Engineered Milk Extracellular Vesicles on Tumor Progression.
    Gyeongyun Go, Hee Jung Park, Jun Hee Lee, Chul Won Yun, Sang Hun Lee.
      BACKGROUND/AIM: Anti-cancer chemotherapy is an effective therapeutic approach. Milk extracellular vesicles (EVs) loaded with chemotherapeutics have a potential anticancer effect by acting as a drug delivery system. Thus, our study aimed to explore the effect of engineered milk extracellular vesicles.MATERIALS AND METHODS: To treat epidermal growth factor receptor (EGFR) expressing solid tumors, we established oxaliplatin-loaded milk EV conjugated with GE11 peptide (GE11Milk EVoxal), which has a high affinity to EGFR and assessed their anti-cancer effect in vitro and in vivo.
    RESULTS: Drug-loaded GE11Milk EVoxal showed significantly higher incorporation into EGFR expressing cancer cells compared with milk EV without GE11 conjugation (Milk EVoxal), leading to apoptosis of cancer cells. GE11Milk EVoxal also inhibited cell viability compared to milk EVoxal or oxaliplatin alone. In colorectal cancer xenograft murine model, GE11Milk EVoxal showed the maximum therapeutic effect on tumor progression. These findings indicate that GE11Milk EVoxal suppresses EGFR expressing cancer through GE11 peptide-mediated EGFR targeting and subsequently anti-cancer drug delivery.
    CONCLUSION: Anti-cancer drug-loaded engineered milk EVs might be a novel therapeutic approach for treating patients with EGFR expressing solid tumors.
    Keywords:  EGFR expressing tumor; GE11 peptide; Milk extracellular vesicles; bio-engineered drug carrier; drug delivery system
    DOI:  https://doi.org/10.21873/anticanres.15543
  31. Transl Cancer Res. 2021 Mar;10(3): 1368-1377
    Huaier increases the antitumor effect of gemcitabine on pancreatic cancer in vitro and in vivo.
    Tao Chen, Dongbao Li, Chao Feng, Zixiang Zhang, Dongming Zhu, Dechun Li, Xin Zhao.
      Background: Pancreatic cancer has a high degree of malignancy and poor prognosis. As the first-line chemotherapy drug for pancreatic cancer, gemcitabine is widely used but is limited in its efficacy due to the development of chemoresistance. Huaier is a traditional Chinese medicine with anticancer effects. This present study explored the antitumor effect of gemcitabine combined with Huaier on pancreatic cancer in vitro and in vivo.Methods: After treatment with gemcitabine combined with Huaier in PaTu8988 pancreatic cancer cells, including 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, wound healing, and Transwell invasion in vitro assays were performed to investigate the proliferation, migration and invasion of cells, respectively. The apoptotic rate of cells was detected by propidium iodide-annexin V staining and flow cytometry. In vivo PaTu8988 pancreatic cancer xenograft and tail vein injection into lung metastasis nude mice models were used to determine the tumor growth and lung metastasis efficiency.
    Results: Huaier could not only inhibit the proliferation, migration, and invasion of cancer cells, but could also induce the apoptosis of pancreatic cancer in vitro and suppress tumor growth and lung metastasis in vivo. It further significantly increased the tumor suppressing effects of gemcitabine, and combined use of the two drugs exhibited a synergistic effect.
    Conclusions: Our present study concluded that Huaier was capable of enhancing the antitumor effect of gemcitabine in pancreatic cancer in vitro and in vivo. Therefore, Huaier may be a potential drug to increase the therapy sensitivity of gemcitabine and improve the prognosis of pancreatic cancer patients.
    Keywords:  Huaier; antitumor; gemcitabine; pancreatic cancer; traditional Chinese medicine (TCM)
    DOI:  https://doi.org/10.21037/tcr-20-2627
  32. Adv Cancer Res. 2022 ;pii: S0065-230X(21)00079-8. [Epub ahead of print]153 101-130
    Targeting the ERK mitogen-activated protein kinase cascade for the treatment of KRAS-mutant pancreatic cancer.
    J Nathaniel Diehl, Priya S Hibshman, Irem Ozkan-Dagliyan, Craig M Goodwin, Sarah V Howard, Adrienne D Cox, Channing J Der.
      Mutational activation of the KRAS oncogene is found in ~95% of pancreatic ductal adenocarcinoma (PDAC), the major form of pancreatic cancer. With substantial experimental evidence that continued aberrant KRAS function is essential for the maintenance of PDAC tumorigenic growth, the National Cancer Institute has identified the development of effective anti-KRAS therapies as one of four major initiatives for pancreatic cancer research. The recent clinical success in the development of an anti-KRAS therapy targeting one specific KRAS mutant (G12C) supports the significant potential impact of anti-KRAS therapies. However, KRASG12C mutations comprise only 2% of KRAS mutations in PDAC. Thus, there remains a dire need for additional therapeutic approaches for targeting the majority of KRAS-mutant PDAC. Among the different directions currently being pursued for anti-KRAS drug development, one of the most promising involves inhibitors of the key KRAS effector pathway, the three-tiered RAF-MEK-ERK mitogen-activated protein kinase (MAPK) cascade. We address the promises and challenges of targeting ERK MAPK signaling as an anti-KRAS therapy for PDAC. In particular, we also summarize the key role of the MYC transcription factor and oncoprotein in supporting ERK-dependent growth of KRAS-mutant PDAC.
    Keywords:  ERK; KRAS; MYC; Mitogen-activated protein kinase; Pancreatic cancer
    DOI:  https://doi.org/10.1016/bs.acr.2021.07.008
  33. Phytother Res. 2022 Jan 31.
    Wogonin and its analogs for the prevention and treatment of cancer: A systematic review.
    Kishore Banik, Elina Khatoon, Choudhary Harsha, Varsha Rana, Dey Parama, Krishan Kumar Thakur, Anupam Bishayee, Ajaikumar B Kunnumakkara.
      The medicinal plant Scutellaria baicalensis, commonly known as Chinese skullcap or Huang-Qin, has been used as a traditional medicine for several thousand years. The roots of this plant contain bioactive compounds, such as wogonin (WOG), wogonoside, baicalein, and baicalin. The aim of this article is to evaluate the therapeutic potential and mechanisms of action of WOG against different cancers. Numerous in vitro and in vivo studies have revealed that WOG exerts immense therapeutic potential against bladder cancer, breast cancer, cholangiocarcinoma, cervical cancer, colorectal cancer, gallbladder cancer, gastric cancer, glioblastoma, head and neck cancer, hepatic cancer, leukemia, lung cancer, lymphoma, melanoma, multiple myeloma, neuroblastoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, and renal cancer by regulating various cell signaling pathways. WOG, in combination with established chemotherapeutic drugs, improves the efficacy of treatment and lowers toxicity. Nevertheless, human trials are warranted to validate these findings. Numerous preclinical studies, combined with an extensive margin of safety and no severe side effects, underscore WOG's therapeutic potential as an anticancer drug. These studies propound the use of WOG as a potential anticancer candidate; however, further high-quality studies are required to firmly establish the clinical efficacy of WOG for the prevention and treatment of human malignancies.
    Keywords:  Wogonin; cancer; chemoprevention; in vitro; in vivo; molecular targets; therapy
    DOI:  https://doi.org/10.1002/ptr.7386
  34. ACS Omega. 2022 Jan 25. 7(3): 2520-2532
    Phenylboronic-acid-based Functional Chemical Materials for Fluorescence Imaging and Tumor Therapy.
    Shuo Li, XinHui Hou, Yufan Ma, Zhuo Wang.
      Various functional chemical materials have been widely used in imaging and tumor therapy. Targeted ligands such as antibodies, peptides, and small molecules have been combined with functional materials to enhance cellular uptake and are used for active targeting of cancer cells and tumors. Among them, phenylboronic acid (PBA), as a small molecular ligand, has the characteristics of low cytotoxicity and easy modification. PBA improves the cancer cell imaging and tumor treatment effect by binding to glycans on the surface of cancer cells. In this Mini-Review, we introduced the modification strategy and targeting strategy of PBA. We focused on the applications of PBA-based functional materials in fluorescence imaging and tumor therapy. For fluorescence imaging, the potential of PBA-based functional chemical materials in cancer diagnosis and tumor targeting was proved by cell imaging and in vivo imaging. For tumor therapy, we mainly discussed the applications of PBA-based functional chemical materials in chemotherapy, gene therapy, phototherapy, and immunotherapy. PBA-based functional chemical materials provide a useful method for cancer diagnosis and treatment.
    DOI:  https://doi.org/10.1021/acsomega.1c06558
  35. Int J Biol Macromol. 2022 Jan 28. pii: S0141-8130(22)00163-5. [Epub ahead of print]203 280-291
    Tumor-targeted delivery of honokiol via polysialic acid modified zein nanoparticles prevents breast cancer progression and metastasis.
    Qi Zhang, Dong Li, Shuang Guan, Dan Liu, Jing Wang, Guihua Xing, Liling Yue, Defu Cai.
      In this work, we developed polysialic acid (PSA) modified zein nanoparticles for targeted delivery of honokiol (HNK) to enhance drug delivery efficiency and specific biodistribution at tumor sites. The antisolvent precipitation and electrostatic interaction methods were employed to fabricate the PSA-Zein-HNK nanoparticles, which exhibited mean size of 107.2 ± 10.1 nm and HNK encapsulation efficiency of 79.2 ± 2.3%. The PSA-Zein-HNK maintained a uniform dispersion in serum for 48 h, implying the improved colloid stability of zein nanoparticles via PSA coating. The cellular uptake of PSA-Zein-Cou6 nanoparticles in 4 T1 cells was 2.58-fold higher than non-targeting Zein-Cou6. In addition, the IC50 value at 48 h for PSA-Zein-HNK (4.37 μg/mL) was significantly higher than the Zein-HNK (7.74 μg/mL). Enhanced tumor accumulation of the PSA-Zein-HNK was confirmed in 4 T1 breast cancer-bearing mice by near-infrared fluorescence imaging, resulting in desirable antitumor efficacy and favorable biosafety. Besides, compared with non-targeting zein nanoparticles, the PSA-Zein-HNK achieved a higher tumor growth inhibition rate of 52.3%. In particular, the metastasis of breast cancer to the lung or liver was remarkably suppressed by PSA-Zein-HNK. Together, our results demonstrated that the PSA-Zein-HNK could be a potential tumor-targeted drug delivery strategy for efficient treatment of breast cancer.
    Keywords:  Breast cancer metastasis; Polysialic acid; Zein nanoparticles
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.01.148
  36. Photochem Photobiol Sci. 2022 Feb 01.
    Polymethine dyes for PDT: recent advances and perspectives to drive future applications.
    Degnet Melese Dereje, Carlotta Pontremoli, Maria Jesus Moran Plata, Sonja Visentin, Nadia Barbero.
      It has been proved that the effectiveness of photodynamic therapy (PDT) is closely related to the intrinsic features of the photosensitizer (PS). Over the recent years, several efforts have been devoted to the discovery of novel and more efficient photosensitizers showing higher efficacy and lower side effects. In this context, squaraine and cyanine dyes have been reported to potentially overcome the drawbacks related to the traditional PSs. In fact, squaraines and cyanines are characterized by sharp and intense absorption bands and narrow emission bands with high extinction coefficients typically in the red and near-infrared region, good photo and thermal stability and a strong fluorescent emission in organic solvents. In addition, biocompatibility and low toxicity make them suitable for biological applications. Despite these interesting intrinsic features, their chemical instability and self-aggregation properties in biological media still limit their use in PDT. To overcome these drawbacks, the self-assembly and incorporation into smart nanoparticle systems are forwarded promising approaches that can control their physicochemical properties, providing rational solutions for the limitation of free dye administration in the PDT application. The present review summarizes the latest advances in squaraine and cyanine dyes for PDT application, analyzing the different strategies, i.e.the self-assembly and the incorporation into nanoparticles, to further enhance their photochemical properties and therapeutic potential. The in vivo assessments are still limited, thus further delaying their effective application in PDT.
    Keywords:  Cyanines; Photodynamic therapy; Polymethine dyes; Self-assembly; Smart nanocarrier; Squaraines
    DOI:  https://doi.org/10.1007/s43630-022-00175-6
  37. Colloids Surf B Biointerfaces. 2022 Jan 22. pii: S0927-7765(22)00040-6. [Epub ahead of print]212 112357
    Construction of calcium carbonate-liposome dual-film coated mesoporous silica as a delayed drug release system for antitumor therapy.
    Yuwen Wang, Kun Zhao, Luyao Xie, Kexin Li, Wei Zhang, Ziyue Xi, Xiyu Wang, Mingyu Xia, Lu Xu.
      As is well known to all, delivering drug precisely to the tumor site is beneficial to improve antitumor effect. In this study, we reported mesoporous silica nanoparticles (MSNs) coated with dual-film of calcium carbonate (CaCO3) and lipid bilayer (denoted as MSNs@CaCO3@liposomes) innovatively which achieve sustained drug release anchored at tumor microenvironment and enhanced biocompatibility. The pH-sensitive CaCO3 film acted as a guide to cap the pore channels of MSNs allowed pH-triggered drug release when transporting into cancer cells. Furthermore, MSNs@CaCO3 was capsuled by lipid bilayer to improve cellular uptake efficiency and biocompatibility in blood circulation. Morphology of nanoparticles was characterized by transmission electron microscopy (TEM) and field emission scanning electron microscopy (FESEM) to confirm that double films were coated successfully. Doxorubicin hydrochloride (DOX) was efficaciously loaded into mesoporous pores as a model drug with a high drug loading content of 28%, forming DOX-loaded MSNs@CaCO3@liposomes (DOX/MSNs@CaCO3@liposomes). Non-specific protein adsorption and hemolysis test revealed enhanced biocompatibility. Drug release study in vitro showed DOX/MSNs@CaCO3@liposomes could delay to release DOX at pH 5.0 and avoid releasing at pH 7.4. In vitro and in vivo antitumor efficiency evaluation showed that DOX/MSNs@CaCO3@liposomes have a desirable inhibitory activity on tumor growth. Therefore, dual-film coated MSNs could be a good candidate for an antitumor drug delivery system.
    Keywords:  Antitumor therapy; Delayed drug release; Dual-film coating; Mesoporous silica nanoparticles; pH-sensitive
    DOI:  https://doi.org/10.1016/j.colsurfb.2022.112357
  38. Sci Rep. 2022 Feb 04. 12(1): 1959
    A functionalized graphene oxide with improved cytocompatibility for stimuli-responsive co-delivery of curcumin and doxorubicin in cancer treatment.
    Fatemeh Yaghoubi, Najmeh Sadat Hosseini Motlagh, Seyed Morteza Naghib, Fateme Haghiralsadat, Hossein Zarei Jaliani, Ali Moradi.
      Nowadays, the usage of nanoparticles in various fields such as drug delivery, attracts the attention of many researchers in the treatment of cancers. Graphene oxide (GO) is one of the novel drug delivery systems which is used broadly owing to its unique features. In this survey, doxorubicin (DOX) was accompanied by natural medicine, curcumin (CUR), to diminish its side effects and enhance its efficiency. Cytotoxicity assay in human gastric cancer (AGS), prostate cancer (PC3), and ovarian cancer (A2780), was evaluated. Also, the uptake of DOX and CUR into cells, was assessed using a fluorescence microscope. Moreover, real-time PCR was applied for the evaluation of the expression of RB1 and CDK2 genes, which were involved in the cell cycle. In both separate and simultaneous forms, DOX and CUR were loaded with high efficiency and the release behavior of both drugs was pH-sensitive. The higher release rate was attained at pH 5.5 and 42 °C for DOX (80.23%) and CUR (13.06), respectively. The intensity of fluorescence in the free form of the drugs, was higher than the loaded form. In the same concentration, the free form of CUR and DOX were more toxic than the loaded form in all cell lines. Also, free drugs showed more impact on the expression of RB1 and CDK2 genes. Co-delivery of CUR and DOX into the mentioned cell lines, was more effective than the free form of CUR and DOX due to its lower toxicity to normal cells.
    DOI:  https://doi.org/10.1038/s41598-022-05793-9
  39. Iran J Basic Med Sci. 2021 Oct;24(10): 1404-1412
    Evaluation of debridement effects of bromelain-loaded sodium alginate nanoparticles incorporated into chitosan hydrogel in animal models.
    Samaneh Bayat, Akram Rabbani Zabihi, Sara Amel Farzad, Jebrail Movaffagh, Ezzat Hashemi, Sepideh Arabzadeh, Maryam Hahsemi.
      Objectives: Bromelain, a mixture of proteolytic enzymes from pineapple (Ananas comosus) is known as a potential debriding agent in burn treatment. In this research, the debridement efficiency of chitosan hydrogel loaded by sodium alginate-chitosan nanoparticles (NPs) containing bromelain (Br 10%-AG-CS NPs) was evaluated in animal models.Materials and Methods: The NPs were prepared using the ionic gelation technique and their properties were identified. Then, the debridement effect of bromelain NPs incorporated into chitosan hydrogel was evaluated 4 hr after wound treatment in animal models.
    Results: The particle size of positively charged Br-AG-Cs NPs was about 390±25 nm. The encapsulation efficiency of bromelain into AG-CS NPs was about 92%. The in vitro release profile showed that the maximum release of bromelain from NPs occurred during the first 4 hr (70%). The hydrogel structure did not significantly affect the profile release of bromelain in the formulation. After 6 months of storage at 4 and 25 °C, the synthesized NPs indicated no significant changes in bromelain activity. It was found that Br 10%-Ag-Cs NPs-CS hydrogel had the most beneficial effects on reducing necrotic tissues and resulted in re-epithelialization compared with other treated groups (negative and positive control, CS hydrogel, and Br 10%-CS hydrogel).
    Conclusion: Therefore, using this novel formulation can be considered a potential debridement agent.
    Keywords:  Bromelain; Chitosan; Debridement; Nanoparticles; Sodium alginate
    DOI:  https://doi.org/10.22038/IJBMS.2021.58798.13060
  40. J Mater Chem B. 2022 Feb 02.
    Polyoxometalate-covalent organic framework hybrid materials for pH-responsive photothermal tumor therapy.
    Wenxin Wang, Yuting Song, Jiayi Chen, Yanyan Yang, Jiawei Wang, Yan Song, Jiatong Ni, Minglu Tang, Junge Zhao, Yuan Sun, Tiedong Sun, Jinsong Peng.
      Photothermal therapy (PTT) has become one of the most effective methods for tumor treatment. With the development of medicine, studies focusing primarily on therapeutic and diagnostic agents with desirable biocompatibility, targeting and stability are still of great significance. Heteropoly blue (HPB) is an ideal photothermal therapy agent (PTA) with decent photothermal conversion efficiency. Covalent organic frameworks (COFs) are considered to be good carriers with excellent biocompatibility. Due to their superior characteristics, such as being adjustable, and having high thermal stability and porous structures, COFs have been broadly applied in various fields. In this study, HPB was successfully in situ loaded into a COF via a one-pot method. The resultant HPB@COF platform exhibited desirable biocompatibility, pH-responsive release properties and high tumor inhibition efficiency, which can be used for PTT to effectively inhibit tumor growth. Our work provides a valuable paradigm for the fabrication of safer and effective HPB@COF NPs for future pH-responsive photothermal therapy.
    DOI:  https://doi.org/10.1039/d1tb02255e
  41. J Ethnopharmacol. 2022 Jan 27. pii: S0378-8741(22)00076-9. [Epub ahead of print] 115042
    A review of the genus Chrysosplenium as a traditional Tibetan medicine and its preparations.
    Jiajia Zhao, Xiang Qiu, Yunyan Zhao, Rui Wu, Panhong Wei, Chengtian Tao, Li Wan.
      ETHNOPHARMACOLOGICAL RELEVANCE: Plants of genus Chrysosplenium have a long history of application and are distributed in many countries, especially in Tibetan regions of China. The genus has been used locally in the treatment of various hepatobiliary diseases such as "Chiba disease" (related to cholecystitis, cholelithiasis, acute icteric hepatitis, and acute liver necrosis in modern medicine).AIM OF THE REVIEW: This review summarizes and critically analyzes the aspects of the botanical morphology and distribution, traditional uses, phytochemistry, pharmacological activities, quality control, and development status of preparations of the genus Chrysosplenium. Moreover, the future research direction and focus of the genus are also discussed. We hope to provide a valuable reference for researchers who are interested in the genus Chrysosplenium.
    MATERIALS AND METHODS: The relevant information of the genus Chrysosplenium was gathered through electronic databases from 1968 to 2021, including PubMed, Web of Science, ScienceDirect, Google Scholar, Springer, CNKI, and Wan Fang, as well as PhD, MSc thesis, Chinese Pharmacopoeia (2020 edition), Tibetan medicine monographs. In addition, plant names were verified by "The Plant List" (The Plant List Database, http://www.theplantlist.org).
    RESULTS: Based on existing studies of chemical compositions, more than 90 compounds have been identified from Chrysosplenium species, including flavonoids, triterpenoids, volatile oils, steroids, alkaloids, and other compounds. The highly hydroxylated and methoxylated flavonoids and triterpenoids are the main active components. In addition, many studies have shown that the extracts and some components isolated from the genus Chrysosplenium have a variety of pharmacological activities, such as anti-tumor, antibacterial, anti-viral, hepatoprotective, and insecticidal properties. Furthermore, there are only 9 preparations with Chrysosplenium species as one of the medicinal materials. Among these preparations, C. nudicaule is used more and other Chrysosplenium species are rarely involved.
    CONCLUSIONS: Most medicinal species of Chrysosplenium have not only good therapeutic effects in traditional uses, but also a great potential for development in modern pharmaceutical studies. However, the material basis and mechanism of action of this genus have not been well explained. Therefore, further systematic and comprehensive research on the genus Chrysosplenium is still required to provide a scientific basis for its clinical applications.
    Keywords:  Chrysosplenium; Flavonoids; Pharmacological activities; Phytochemistry; Preparations; Traditional uses
    DOI:  https://doi.org/10.1016/j.jep.2022.115042
  42. Semin Cancer Biol. 2022 Jan 31. pii: S1044-579X(22)00018-9. [Epub ahead of print]
    Nanoparticle-based drug delivery systems in cancer: A focus on inflammatory pathways.
    Amir R Afshari, Mehdi Sanati, Hamid Mollazadeh, Prashant Kesharwani, Thomas P Johnston, Amirhossein Sahebkar.
      It has become necessary to accept the clinical reality of therapeutic agents targeting the cancer-associated immune system. In recent decades, several investigations have highlighted the role of inflammation in cancer development. It has now been recognized that inflammatory cells secrete mediators, including enzymes, chemokines, and cytokines. These secreted substances produce an inflammatory microenvironment that is critically involved in cancer growth. Inflammation may enhance genomic instability leading to DNA damage, activation of oncogenes, or compromised tumor suppressor activity, all of which may promote various phases of carcinogenesis. Conventional cancer treatment includes surgery, radiation, and chemotherapy. However, treatment failure occurs because current strategies are unable to achieve complete local control due to metastasis. Nanoparticles (NPs) are a broad spectrum of drug carriers typically below the size of 100 nm, targeting tumor sites while reducing off-target consequences. More importantly, NPs can stimulate innate and adaptive immune systems in the tumor microenvironment (TME); hence, they induce a cancer-fighting immune response. Strikingly, targeting cancer cells with NPs helps eliminate drug resistance and tumor recurrence, as well as prevents inflammation. Throughout this review, we provide recent data on the role of inflammation in cancer and explore nano-therapeutic initiatives to target significant mediators, for example, nuclear factor-kappa B (NF-κB), tumor necrosis factor-α (TNF-α), and interleukins (ILs) associated with cancer-related inflammation, to escort the immunomodulators to cancer cells and associated systemic compartments. We also highlight the necessity of better identifying inflammatory pathways in cancer pathophysiology to develop effective treatment plans.
    Keywords:  Immune response; Inflammation; Malignancy; Nanoparticle
    DOI:  https://doi.org/10.1016/j.semcancer.2022.01.008
  43. Cancer Cell Int. 2022 Jan 29. 22(1): 43
    Nanotechnology-based advances in the efficient delivery of melatonin.
    Mohammad Mirza-Aghazadeh-Attari, Ainaz Mihanfar, Bahman Yousefi, Maryam Majidinia.
      N-[2-(5-methoxy-1H-indol-3-yl) ethyl] or simply melatonin is a biogenic amine produced by pineal gland and recently recognized various other organs. Because of a broad range of biological function melatonin is considered as a therapeutic agent with high efficacy in the treatment of multiple disorders, such as cancer, degenerative disorders and immune disease. However, since melatonin can affect receptors on the cellular membrane, in the nucleus and can act as an anti-oxidant molecule, some unwanted effects may be observed after administration. Therefore, the entrapment of melatonin in biocompatible, biodegradable and safe nano-delivery systems can prevent its degradation in circulation; decrease its toxicity with increased half-life, enhanced pharmacokinetic profile leading to improved patient compliance. Because of this, nanoparticles have been used to deliver melatonin in multiple studies, and the present article aims to cumulatively illustrate their findings.
    Keywords:  Chitosan; Liposomes; Melatonin; Nano-delivery; PLGA; Solid lipid nanoparticles
    DOI:  https://doi.org/10.1186/s12935-022-02472-7
  44. J Ultrasound Med. 2022 Feb 02.
    Inhibition of Walker-256 Tumor Growth by Combining Microbubble-Enhanced Ultrasound and Endostar.
    Yanlan Yu, Wei Qiao, Shuang Feng, Cuo Yi, Zheng Liu.
      OBJECTIVES: This research is to investigate the anti-tumor effects by combining anti-vascular effect of microbubble enhanced ultrasound (MEUS) mechanical destruction and anti-angiogenic effect of Endostar.METHODS: Rats bearing Walker-256 tumor were randomly divided into 4 groups treated by Endostar + MEUS combination, Endostar, MEUS or Sham ultrasound (US), respectively. MEUS was induced by Sonazoid microbubble and a focused therapeutic US device. Contrast-enhanced ultrasound (CEUS) was used to assess tumor perfusion before and after treatment. Microvessel density (MVD) was evaluated with immunohistochemical staining of CD31, CD34, and VEGFA. TUNEL assay was used to determine the apoptosis rate of tumor cells.
    RESULTS: Endostar + MEUS combined group induced the most reduced blood perfusion and most retarded tumor growth compared with other 3 groups. Decreased MVD was shown in Endostar + MEUS, Endostar and MEUS group, but the lowest MVD value was presented in the combined treatment group. Significant increase was observed in the combined therapy group and MEUS group.
    CONCLUSIONS: This study showed an improved anti-vascular and anti-angiogenic effect achieved by combining Endostar and MEUS, and may provide a new method potential for anti-tumor therapy.
    Keywords:  Walker-256 tumor; angiogenesis; cavitation; microbubble-enhanced ultrasound; therapeutic ultrasound
    DOI:  https://doi.org/10.1002/jum.15949
  45. Front Oncol. 2021 ;11 745209
    Metabolic Reprogramming in Gastric Cancer: Trojan Horse Effect.
    Yu-Ling Bin, Hong-Sai Hu, Feng Tian, Zhen-Hua Wen, Mei-Feng Yang, Ben-Hua Wu, Li-Sheng Wang, Jun Yao, De-Feng Li.
      Worldwide, gastric cancer (GC) represents the fifth most common cancer for incidence and the third leading cause of death in developed countries. Despite the development of combination chemotherapies, the survival rates of GC patients remain unsatisfactory. The reprogramming of energy metabolism is a hallmark of cancer, especially increased dependence on aerobic glycolysis. In the present review, we summarized current evidence on how metabolic reprogramming in GC targets the tumor microenvironment, modulates metabolic networks and overcomes drug resistance. Preclinical and clinical studies on the combination of metabolic reprogramming targeted agents and conventional chemotherapeutics or molecularly targeted treatments [including vascular endothelial growth factor receptor (VEGFR) and HER2] and the value of biomarkers are examined. This deeper understanding of the molecular mechanisms underlying successful pharmacological combinations is crucial in finding the best-personalized treatment regimens for cancer patients.
    Keywords:  drug resistance; gastric cancer; glycolysis; metabolic reprogramming; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2021.745209
  46. Phytomedicine. 2022 Jan 14. pii: S0944-7113(22)00021-6. [Epub ahead of print]98 153943
    Ponicidin suppresses pancreatic cancer growth by inducing ferroptosis: Insight gained by mass spectrometry-based metabolomics.
    Weiqi Cui, Junwei Zhang, Deqiao Wu, Jingxian Zhang, Hui Zhou, Ying Rong, Fanglin Liu, Bo Wei, Xia Xu.
      BACKGROUND: Pancreatic cancer is one of the most common malignant tumors of the digestive tract. Ponicidin, a tetracyclic diterpenoid active ingredient extracted from the traditional phytomedicine Rubescens, has high safety and great inhibitory effect on the proliferation of a variety of cancer cells, especially malignant tumor cells of the digestive tract. However, the inhibitory effect and mechanism of ponicidin on pancreatic cancer cells is still unclear. Our study aimed to use metabonomics technology to analyze and explore the suppressive effect of ponidicin against pancreatic cancer cells.METHODS: MTT and flow cytometry were conducted to study the potential effect of ponicidin on SW1990 cells. Secondly, UPLC-MS/MS was used to analyze the small molecule metabolites and relevant differential metabolic pathways induced by ponicidin treatment. Furthermore, through the determination of glutathione peroxidase 4 (GPX4) activity and molecular docking simulation experiments, the effects of intracellular GPX4 activity and GSH/GSSG ratio after ponicidin were evaluated. Finally, the determination of the content of iron ions and malondialdehyde in cells, and the experiment of the effect of ferroptosis inhibitors on cell viability, the effect of ponicidin on the induction of ferroptosis in SW1990 cells was also detected.
    RESULTS: The IC50 of ponicidin on SW1990 cells was 20 μM, which could significantly induce cell apoptosis and arrest the cells in G2/M phase. Metabolomics results showed that the contents of endogenous small molecules such as gamma-glutamylcysteine, 5-oxoproline, glutamic acid, reduced glutathione (GSH), oxidized glutathione (GSSG) and arachidonic acid have changed significantly. Main differential compounds were involved in the gamma-glutamyl cycle and polyunsaturated fatty acid metabolism of pancreatic cancer cell lines. Additionally, ponicidin could covalently bind to GSH in SW1990 cells to form a conjugate Pon-GSH, which further reduced the content of free GSH and GPX4 activity in cells. Notably, ponicidin dose-dependently increased levels of iron ions, malondialdehyde and reactive oxygen species in SW1990 cells, and the ferroptosis inhibitors could significantly block the effects of ponicidin on the proliferation of SW1990 cells.
    CONCLUSION: Ponicidin could suppress the pancreatic cancer cell proliferation via inducing ferroptosis by inhibiting the gamma-glutamyl cycle and regulating the polyunsaturated fatty acid metabolism in SW1990 cells.
    Keywords:  Ferroptosis; Glutathione; Gpx4; Ponicidin
    DOI:  https://doi.org/10.1016/j.phymed.2022.153943
  47. ACS Appl Mater Interfaces. 2022 Feb 04.
    Transferrin Protein Corona-Modified CuGd Core-Shell Nanoplatform for Tumor-Targeting Photothermal and Chemodynamic Synergistic Therapies.
    Xiangyu Qi, Gang Wang, Peng Wang, Yao Pei, Caiyun Zhang, Miao Yan, Pengfei Wei, Geng Tian, Guilong Zhang.
      Herein, we developed a novel transferrin protein corona (Tpc)-modified CuGd nanoplatform (Tpc-CuGd) for tumor-targeting photothermal (PT) and chemodynamic synergistic therapy. In addition, Tpc-CuGd had an ultrahigh PT conversion efficiency (∼55.6%) and excellent PT stability. By the calculation, the Fenton-catalytic activity of Tpc-CuGd was approximately 13.6 times that of classical ultrasmall iron oxide, endowing strong chemodynamic therapy ability in the tumor. Upon internalization of Tpc-CuGd nanoparticles (NPs), an abundance of Cu(II) was released from Tpc-CuGd and then was quickly reduced to high Fenton-catalytic activity of Cu(I) by elemental copper and cellular GSH. Next, the generated Cu(I) quickly catalyzed H2O2 into highly toxic •OH, causing mitochondria damage and inducing cancer cell death. In addition, the systemic delivery of Tpc-CuGd significantly inhibited tumor growth and showed a very low toxicity. Notably, the PT effect of Tpc-CuGd NPs not only promoted their tumor inhibitory capability but also significantly restricted the continued growth of the tumor after the discontinuation of the treatment. In addition, Tpc-CuGd significantly strengthened the T1-weighted signal of tumors and realized accurate cancer diagnosis. Therefore, this nanoplatform could be a great promising candidate for PT and chemodynamic synergistic theranostics.
    Keywords:  CuGd nanocomposite; Fenton catalysis; MRI; chemotherapy; photothermal therapy
    DOI:  https://doi.org/10.1021/acsami.1c22998
  48. Transl Cancer Res. 2021 Aug;10(8): 3829-3842
    Aberrant lipid metabolism reprogramming and immune microenvironment for gastric cancer: a literature review.
    Meng-Ying Cui, Xing Yi, Dan-Xia Zhu, Jun Wu.
      Objective: We summarize the aberrant lipid metabolism disorders associated with enzyme activity and expression changes and related immune microenvironment for gastric cancer.Background: Gastric cancer is a malignant tumor of the primary digestive system with high incidence, poor prognosis characterized by extensive metastasis and poor effect with radiotherapy and chemotherapy. One of the most important metabolic characteristics of cancer cells is lipid metabolism reprogramming to adapt to the tumor micro-environment.
    Methods: The focus of research in recent years has also been on lipid metabolism disorders, particularly aberrant metabolism of fatty acids (FAs) in gastric cancer cells, as well as an upregulation of the expression and activity of key enzymes in lipid metabolism. These changes remind us of the occurrence and development of gastric cancer. These metabolic changes are not unique to cancer cells. Changes in metabolic procedures also determine the function and viability of immune cells. In the immune microenvironment of gastric cancer, the metabolic competition and interaction between cancer cells and immune cells are not very clear, while a deeper understanding of the topic is critical to targeting the differential metabolic requirements of them that comprise an immune response to cancer offers an opportunity to selectively regulate immune cell function.
    Conclusions: Recent research suggests that targeting metabolism is an emerging and potentially promising treatment strategy for gastric cancer patients. We need to explore it further.
    Keywords:  Lipid metabolism related enzymes; gastric cancer; targeted metabolism treatment; tumor immunosuppression microenvironment
    DOI:  https://doi.org/10.21037/tcr-21-655
  49. Food Chem. 2022 Jan 08. pii: S0308-8146(22)00057-7. [Epub ahead of print] 132096
    Unravelling potential biomedical applications of the edible flower Tulbaghia violacea.
    Lorenzo Rivas-García, Jose M Romero-Márquez, M D Navarro-Hortal, Adelaida Esteban-Muñoz, Francesca Giampieri, Sandra Sumalla-Cano, Maurizio Battino, José L Quiles, Juan Llopis, Cristina Sánchez-González.
      Traditionally, edible flowers have been used as foods and for therapeutic purposes, today they have gained importance due to their bioactive compounds such as flavonols, anthocyanins or other phenolic compounds, which give them potential for biomedical applications. This work evaluated a methanolic extract of Tulbaghia violacea. Eleven individual phenolic compounds were found and quantified by mass spectrometry in the extract. Antioxidant activity tests (TEAC, FRAP and DPPH) and other characterization parameters were assayed (total phenolic content and total flavonoid content). In vitro studies showed antitumoral activity against ovarian tumoral cells mediated by the induction of non-dependent caspase cell death and by the activation of reactive oxygen species. The effect of the extract against features of Alzheimer disease was in vivo assayed in Caenorhabditis elegans. Tulbaghia extract led to a reduction in the 1-42 beta amyloid peptide formation and prevented oxidative stress. These results suggested that Tulbaghia violacea could be a new source of phenolic compounds for nutraceuticals and functional food development.
    Keywords:  Alzheimer disease; Antioxidants; Autophagy; Flower; Quercetin; ROS
    DOI:  https://doi.org/10.1016/j.foodchem.2022.132096
  50. Nanomedicine (Lond). 2022 Feb 04.
    Clinical application of nano-targeting for enhancing chemotherapeutic efficacy and safety in cancer management.
    Matthew C Phillips, Shaker A Mousa.
      Despite improvements in treatment, cancer remains a leading cause of death worldwide. While chemotherapy is effective, it also damages healthy tissue, leading to severe, dose-limiting side effects that can impair efficacy and even contribute to chemoresistance. Nano-based drug-delivery systems can potentially target the delivery of chemotherapy to improve efficacy and reduce adverse effects. A number of nanocarriers have been investigated for the delivery of chemotherapy, and many of the most promising agents have advanced to clinical trials. This review examines the safety and efficacy of nanoformulated chemotherapeutic agents in clinical trials, with particular emphasis on anthracyclines, taxanes and platinum compounds. It also briefly discusses the role nano-targeting might play in the prevention and treatment of chemoresistance.
    Keywords:  active targeting; chemotherapy; clinical nanotechnology; clinical trials; efficacy; nanomedicine; nanoparticles; passive targeting; safety; targeted therapy
    DOI:  https://doi.org/10.2217/nnm-2021-0361
  51. J Cosmet Dermatol. 2022 Jan 30.
    Effects of some cosmetic dyes and pigments on the proliferation of human foreskin fibroblasts and cellular oxidative stress; potential cytotoxicity of chlorophyllin and indigo carmine on fibroblasts.
    Ardalan Pasdaran, Negar Azarpira, Reza Heidari, Simin Nourinejad, Maryam Zare, Azadeh Hamedi.
      INTRODUCTION: Fibroblasts and fibroblast-like cells (FLCs) are highly distributed in the dermis layer of the skin and gastrointestinal tract. A few studies have investigated the effects of color additives of cosmetic products on human fibroblasts. Therefore, this in vitro study was conducted to investigate the effects of 9 synthetic and natural dyes (indigo carmine, carmine, sunset yellow, tropaeolin, acid green 25, chlorophyllin, tartrazine, lissamine, and amaranth) on human foreskin fibroblast cells.METHODS: MTT assay was applied to investigate the effects of dyes on human normal fibroblast cells. For investigating the possible mechanism of cytotoxicity, the effect of dyes was evaluated on parameters of cellular oxidative stress including lipid peroxidation and reactive oxygen species (ROS) as well as lactate dehydrogenase.
    RESULTS: In the MTT assay, a significant reduction (p ≤ 0.05) was observed in the viability of fibroblast cells by chlorophyllin and indigo carmine at concentrations higher than 10 and 100 (μg/ml), respectively. Acid green 25 caused a significant reduction at very high concentrations (1000 and 2000 μg/ml), which was not toxic. The effect of other investigated dyes was not significant on the fibroblasts. A trend in increased cell proliferation by amaranth and carmine was observed, but this enhancement was not statistically significant. No significant changes were observed in lipid peroxidation or lactate dehydrogenase. Chlorophyllin caused a significant increase in the production of cellular ROS.
    CONCLUSIONS: Indigo carmine and chlorophyllin had cytotoxicity on human fibroblasts, and thus, further studies are required on their safety of use in cosmetics and pharmaceuticals.
    Keywords:  cosmetic; dye; fibroblast; skin; toxicity
    DOI:  https://doi.org/10.1111/jocd.14695
  52. Adv Healthc Mater. 2022 Feb 03. e2102503
    Biodegradable Bismuth-Based Nano-Heterojunction for Enhanced Sonodynamic Oncotherapy Through Charge Separation Engineering.
    Kang Song, Jun Du, Xiang Wang, Lulu Zheng, Ruizhuo Ouyang, Yuhao Li, Yuqing Miao, Dawei Zhang.
      Sonodynamic therapy is a noninvasive treatment method that generates reactive oxygen species (ROS) triggered by ultrasound, to achieve oxidative damage to tumors. However, methods are required to improve the efficiency of ROS generation and achieve continuous oxidative damage. We prepared a ternary heterojunction sonosensitizer composed of Bi@BiO2-x @Bi2 S3 -PEG (BOS) to achieve thermal injury-assisted continuous sonodynamic therapy for tumors. The oxygen vacancy in BOS can capture hot electrons and promote the separation of hot carriers on the bismuth surface. The local electric field induced by localized surface plasmon resonance also contributes to the rapid transfer of electrons. Therefore, BOS not only possesses the functions of each component but also exhibits higher catalytic activity to generate ROS. Meanwhile, BOS continuously consumes glutathione, which is conducive to its biodegradation and achieves continuous oxidative stress injury. In addition, the photothermal conversion of BOS under near-infrared irradiation helps to achieve thermal tumor damage and further relieves tumor hypoxia, thus amplifying the sonodynamic therapeutic efficacy. This process not only provides a strategy for thermal damage to amplify the efficacy of sonodynamic therapy, but also expands the application of bismuth-based heterojunction nanomaterials as sonosensitizers in sonodynamic therapy. This article is protected by copyright. All rights reserved.
    Keywords:  biodegradation; bismuth; charge separation; glutathione depletion; heterojunction; sonodynamic therapy; synergistic therapy
    DOI:  https://doi.org/10.1002/adhm.202102503
  53. Int J Biol Macromol. 2022 Jan 29. pii: S0141-8130(22)00183-0. [Epub ahead of print]
    Recent advances of chitosan-based nanoparticles for biomedical and biotechnological applications.
    Yanyun Gao, Wu Yuling.
      Chitosan is a natural alkaline polysaccharide, which widely exists in marine crustaceans such as shrimp and crab, has been shown to have various biological activities. It has attracted considerable attention in biomedicine and nanomaterials fields because of its excellent properties, such as biocompatibility, biodegradability, non-toxicity and easy access. In addition, because of active hydroxyl and amino groups in chitosan molecules, different functional groups can be introduced into chitosan molecules by molecular modification or chemical modification, which extends their applications. Nanoparticles with small size and large surface area can be used as diagnostic and therapeutic tools in the biomedical field, which make it easier to understand, detect and treat human diseases. The nanomaterials based on chitosan have important applications in biomedicine, industry, pharmacy, agriculture, and other fields. This review highlights the recent advances on chitosan-based nanoparticles for antibacterial property, drug and gene delivery, cancer and hyperthermia therapy, cell imaging, restorative dentistry, wound healing, tissue engineering and other biomedical fields. The nanotechnology fields involving biosensors, water treatment, food industry and agriculture are also briefly reviewed.
    Keywords:  Application; Biomedical; Biotechnological; Chitosan; Nanoparticles
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.01.162
  54. Mol Metab. 2022 Feb 01. pii: S2212-8778(22)00021-7. [Epub ahead of print] 101452
    Disrupted Liver Oxidative Metabolism in Glycine N-Methyltransferase-Deficient Mice is Mitigated by Dietary Methionine Restriction.
    Ferrol I Rome, Curtis C Hughey.
      OBJECTIVE: One-carbon metabolism is routinely dysregulated in nonalcoholic fatty liver disease. This includes decreased glycine N-methyltransferase (GNMT), a critical regulator of s-adenosylmethionine (SAM). Deletion of GNMT in mice increases SAM and promotes liver steatosis. Lower liver oxidative metabolism as indicated by a decline in gluconeogenesis, citric acid cycle flux, and oxidative phosphorylation contributes to liver steatosis in GNMT-null mice, however, the extent to which this phenotype is mediated by higher SAM remains unclear. Here, we determined the SAM-dependent impairment in liver oxidative metabolism by loss of GNMT.METHODS: GNMT knockout (KO) mice were fed a methionine-restricted diet to prevent increased SAM. 2H/13C metabolic flux analysis was performed in conscious, unrestrained mice to quantify liver nutrient fluxes. Metabolomics and high-resolution respirometry was used to quantify liver nutrient pool sizes and mitochondrial oxidative phosphorylation, respectively. Folic acid-supplemented and serine/glycine-deficient diets were used independently to further define the metabolic implications of perturbed one-carbon donor availability.
    RESULTS: Dietary methionine restriction prevented a 75-fold increase in SAM and 53% rise in triacylglycerides in livers of KO mice. Dietary methionine restriction increased gluconeogenesis independent of genotype and restored cytochrome c oxidase respiratory function in KO mice. Citric acid cycle fluxes remained lower in KO mice irrespective of diet. Restricting dietary methionine abrogated markers of increased lipogenesis and folate cycle dysfunction in KO mice.
    CONCLUSION: The impaired liver oxidative metabolism following loss of GNMT is both dependent and independent of greater SAM availability. Lower in vivo citric acid cycle flux is independent of increased SAM. In contrast, gluconeogenesis and oxidative phosphorylation are negatively regulated by excess SAM. Lipid accumulation in livers of mice lacking GNMT is also linked to the higher SAM.
    Keywords:  citric acid cycle; gluconeogenesis; lipogenesis; nonalcoholic fatty liver disease; one-carbon metabolism; oxidative phosphorylation
    DOI:  https://doi.org/10.1016/j.molmet.2022.101452
  55. World J Gastrointest Oncol. 2022 Jan 15. 14(1): 1-18
    Molecular regulatory mechanism of ferroptosis and its role in gastrointestinal oncology: Progress and updates.
    Fan Yang, Si-Yu Sun, Sheng Wang, Jin-Tao Guo, Xiang Liu, Nan Ge, Guo-Xin Wang.
      Gastrointestinal (GI) tumors, including liver, pancreatic, gastric, and colorectal cancers, have a high incidence rate and low survival rate due to the lack of effective therapeutic methods and frequent relapses. Surgery and postoperative chemoradiotherapy have largely reduced the fatality rates for most GI tumors, but these therapeutic approaches result in poor prognoses due to severe adverse reactions and the development of drug resistance. Recent studies have shown that ferroptosis plays an important role in the onset and progression of GI tumors. Ferroptosis is a new non-apoptotic form of cell death, which is iron-dependent, non-apoptotic cell death characterized by the accumulation of lipid reactive oxygen species (ROS). The activation of ferroptosis can lead to tumor cell death. Thus, regulating ferroptosis in tumor cells may become a new therapeutic approach for tumors, making it become a research hotspot. Current studies suggest that ferroptosis is mainly triggered by the accumulation of lipid ROS. Furthermore, several studies have indicated that ferroptosis may be a new approach for the treatment of GI tumors. Here, we review current research progress on the mechanism of ferroptosis, current inducers and inhibitors of ferroptosis, and the role of ferroptosis in GI tumors to propose new methods for the treatment of such tumors.
    Keywords:  Colorectal cancer; Ferroptosis; Gastric cancer; Gastrointestinal oncology; Hepatocellular carcinoma; Pancreatic cancer
    DOI:  https://doi.org/10.4251/wjgo.v14.i1.1
  56. Drugs. 2022 Feb 05.
    Statins and Gliomas: A Systematic Review of the Preclinical Studies and Meta-Analysis of the Clinical Literature.
    Luis F Rendon, Ishaan A Tewarie, David J Cote, Aaron Gabriel, Timothy R Smith, Marike L D Broekman, Rania A Mekary.
      BACKGROUND: Gliomas represent most common primary brain tumors. Glioblastoma (GBM) is the most common subtype and carries a poor prognosis. There is growing interest in the anti-glioma properties of statins. The aim of this study was to conduct a systematic review of the preclinical literature and to meta-analyze existing clinical studies to determine what benefit, if any, statins may confer in the context of glioma.METHODS: The PubMed, Embase, Cochrane, and Web of Science libraries were queried in May 2021. Preclinical studies were included if they investigated the anti-cancer effects of statins in glioma in vitro and in vivo. Clinical studies were included if they reported incidence rates of glioma by statin use, or mortality outcomes among GBM patients by statin use. Pooled point estimates were calculated using a random-effects model.
    RESULTS: In total, 64 publications, 51 preclinical and 13 clinical, were included. Preclinical studies indicated that statins inhibited glioma cell proliferation, migration, and invasion. These effects were time- and concentration-dependent. Synergistic anti-glioma effects were observed when statins were combined with other anti-cancer therapies. Clinical observational studies showed an inverse, albeit non-statistically significant, association between statin use and incidence rate of glioma (HR = 0.84, 95% CI 0.62-1.13, I2 = 72%, p-heterogeneity = 0.003, 6 studies). Statin use was not associated with better overall survival following GBM surgery (HR = 1.05, 95% CI 0.85-1.30, I2 = 30%, p-heterogeneity = 0.23, 4 studies).
    CONCLUSION: Statins were potent anti-cancer drugs that suppressed glioma growth through various mechanisms in vitro; these effects have translated into the clinical realm, clinically but not statistically, in terms of glioma incidence but not GBM survival.
    DOI:  https://doi.org/10.1007/s40265-021-01668-x
  57. J Food Sci. 2022 Feb 04.
    Effect of selenium biofortification on bioactive compounds and antioxidant activity in germinated black soybean.
    Junyi Huang, Jiana Qian, Shanshan Wang, Yingqiu Li, Xiaolin Zhai, Tosin Michael Olajide, Garry X Shen, Xianyan Liao.
      Biofortification using inorganic selenium has become an effective strategy to enhance selenium content in crops. In the present study, the effects of selenium biofortification on the chemical composition and antioxidant capacity of black soybean (BS) during germination were studied. The contents of selenium, total sugar, vitamin C, γ-aminobutyric acid, total polyphenols, and total flavonoids in selenium biofortified germinated black soybeans (GBS-Se) significantly increased compared to germinated black soybeans (GBS). However, the contents of soluble protein, fat, and reducing sugar were decreased, while fatty acid composition was not significantly different between GBS and BS. HPLC analysis showed that 12 phenolic acids of all samples, which mainly existed in free forms. Their contents increased at low concentration of selenium and decreased along with the rise of selenium concentrations. The antioxidant activity of GBS-Se as analyzed by Pearson correlation analysis positively correlated with the accumulation of phenolic substances. Principal component analysis (PCA) showed that GBS and GBS-Se were significantly different from BS. Moreover, the physicochemical indexes of GBS showed regularly changes with increasing selenium content, and those of GBS-Se50 and GBS-Se75 were significantly different from GBS. The results provide a systematic evaluation on the effect of selenium fortification on the germination of seeds and useful information for the development of Se-enriched functional foods. PRACTICAL APPLICATION: The organic selenium black soybean (BS) produced by the germination method can be directly processed and eaten to improve human health. In addition, complexes of organic selenium, vitamin C, and γ-aminobutyric acid of germinated BS can be developed into functional substances and applied to food or health products as functional ingredient and/or natural antioxidant supplements.
    Keywords:  antioxidant activity; black soybean; germination; phenolic acid; selenium biofortification
    DOI:  https://doi.org/10.1111/1750-3841.16014
  58. Dose Response. 2022 Jan-Mar;20(1):20(1): 15593258211050532
    Mesoporous SBA-15 Silica-Loaded Nano-formulation of Quercetin: A Probable Radio-Sensitizer for Lung Carcinoma.
    Saad Alkahtani, Saud Alarifi, Nada H Aljarba, Hamzah A Alghamdi, Abdullah A Alkahtane.
      Lung cancer is considered as one of the most serious disease worldwide. The progress of drug carriers based on nonmaterial, which selectively hold chemotherapeutic agents to cancer cells, has become a major focus in biomedical research. This study aimed to evaluate the growth inhibition and apoptosis induction of the human lung cancer cells (A-549) by Q-loaded SBA-15 conjugate system. Mesoporous silica nanoparticles (SBA-15) as host materials for transporting therapeutics medicaments were fabricated for targeted drug delivery toward lung cancer. With the objective of increasing bioavailability and aqueous solubility of flavonoids, SBA-15 was successfully loaded with the quercetin (Q)-a major flavonoid and characterized with the help of Fourier-transform infrared spectroscopy (FTIR) and transmission electron microscopy (TEM). The biological investigation on A549 cell line confirmed that the efficacy of Q-SBA-15 is much higher than only Q. Moreover, the apoptotic pathway of synthesized Q-SBA-15 NPs examined that the Q-SBA-15-mediated apoptosis via PI3K/AKT/mTOR signaling pathway. Thus, the newly conjugated Q-SBA-15 system improved the apoptotic fate through caspase-mediated apoptosis via PI3K/AKT/mTOR signaling pathway and hence, it can be potentially employed as an anticancer agent for lung cancer.
    Keywords:  apoptosis; lung cancer; mesoporous; nanoparticles; quercetin
    DOI:  https://doi.org/10.1177/15593258211050532
  59. Drug Deliv. 2022 Dec;29(1): 454-465
    Dextran sulfate-based MMP-2 enzyme-sensitive SR-A receptor targeting nanomicelles for the treatment of rheumatoid arthritis.
    Caiwei Yu, Hui Liu, Chunjing Guo, Qiang Chen, Yanguo Su, Huimin Guo, Xiaoya Hou, Feng Zhao, Huaying Fan, Hui Xu, Yan Zhao, Xiaofeng Mu, Guohua Wang, Haiyu Xu, Daquan Chen.
      Rheumatoid arthritis (RA) is an ordinarily occurring autoimmune disease with systemic inflammatory. Targeted drug delivery systems have many successful applications in the treatment of rheumatoid arthritis. In order to develop nanoparticles for targeted delivery of Celastrol (Cel) to rheumatoid arthritis and specific drug release, the dextran sulfate (DS) was modified as the targeting molecular by binding to the scavenger receptor of macrophage. The dextran-sulfate-PVGLIG-celastrol (DS-PVGLIG-Cel), named DPC, amphiphilic polymeric prodrug was synthesized and characterized. The resulting DPC@Cel micelles had the average size of 189.9 nm. Moreover, the micelles had ultrahigh entrapment efficiency (about 44.04%) and zeta potential of -11.91 mV. In the in vitro release study, due to the excessive production of matrix metalloproteinase-2 (MMP-2) at the inflammatory joint, the MMP-2 reactive peptide was used to crack in the inflammatory microenvironment to accelerate the release of Cel. The results have shown that the nanoparticles can effectively deliver Cel to activated macrophages and significantly improve the bioavailability. In vivo experiments showed that DPC@Cel have better anti-rheumatoid arthritis effects and lower systemic toxicity than free Cel. This study provided a new therapeutic strategy for the treatment of RA.
    Keywords:  MMP-2 response; Rheumatoid arthritis; celastrol; dextran sulfate; targeting drug delivery system
    DOI:  https://doi.org/10.1080/10717544.2022.2032482
  60. Int J Nanomedicine. 2022 ;17 409-422
    Horseradish Peroxidase-Functionalized Gold Nanoconjugates for Breast Cancer Treatment Based on Enzyme Prodrug Therapy.
    Gema Vivo-Llorca, Ángela Morellá-Aucejo, Alba García-Fernández, Paula Díez, Antoni Llopis-Lorente, Mar Orzáez, Ramón Martínez-Máñez.
      Introduction: Breast cancer has the highest mortality rate among cancers in women. Patients suffering from certain breast cancers, such as triple-negative breast cancer (TNBC), lack effective treatments. This represents a clinical concern due to the associated poor prognosis and high mortality. As an approach to succeed over conventional therapy limitations, we present herein the design and evaluation of a novel nanodevice based on enzyme-functionalized gold nanoparticles to efficiently perform enzyme prodrug therapy (EPT) in breast cancer cells.Results: In particular, the enzyme horseradish peroxidase (HRP) - which oxidizes the prodrug indole-3-acetic acid (IAA) to release toxic oxidative species - is incorporated on gold nanoconjugates (HRP-AuNCs), obtaining an efficient nanoplatform for EPT. The nanodevice is biocompatible and effectively internalized by breast cancer cell lines. Remarkably, co-treatment with HRP-AuNCs and IAA (HRP-AuNCs/IAA) reduces the viability of breast cancer cells below 5%. Interestingly, 3D tumor models (multicellular tumor spheroid-like cultures) co-treated with HRP-AuNCs/IAA exhibit a 74% reduction of cell viability, whereas the free formulated components (HRP, IAA) have no effect.
    Conclusion: Altogether, our results demonstrate that the designed HRP-AuNCs nanoformulation shows a remarkable therapeutic performance. These findings might help to bypass the clinical limitations of current tumor enzyme therapies and advance towards the use of nanoformulations for EPT in breast cancer.
    Keywords:  breast cancer; enzyme prodrug therapy; gold nanoconjugates; horseradish peroxidase; indole-3-acetic acid
    DOI:  https://doi.org/10.2147/IJN.S323802
  61. Front Pharmacol. 2021 ;12 793200
    Culinary Spices in Food and Medicine: An Overview of Syzygium aromaticum (L.) Merr. and L. M. Perry [Myrtaceae].
    Gloria Aderonke Otunola.
      Spices-dried aromatic parts of plants (leaves, seeds, bark, roots, rhizomes, buds, etc) used to enhance flavour, taste and colour (sensory quality) of foods, are increasingly finding other useful roles in healthcare beyond their primary use as culinary organoleptic enhancers. Several spices are currently being investigated for their potential health benefits, because of the failing efficacy, toxicity and high cost associated with conventional drugs. One such spice: Syzygium aromaticum (L.) Merr. and L.M.Perry [Myrtaceae] (Clove), has a multi-dimensional role in diet, medicine, functional foods and nutraceuticals, agriculture, among other industries. Peer-reviewed articles, mostly from PubMed and Google Scholar, were consulted for the purpose of this review. The nutritional and phytochemical contents, selected biological activities as well as some functional foods and beverages of clove and their uses for human health are presented. Although these observations are largely empirical, the efficacious attributes have led to their pharmacological applications in the indigenous system of medicine all over the world and bridge between food, diet and medicine. Considering the GRAS status of clove, more studies on bioavailability, accumulation, toxicity, dosage and efficacy of clove as a spice drug or functional foods in biological systems especially in humans are required. Meanwhile, clove and its products can be used as co-adjuvants in the prevention, treatment and management of chronic diseases. Further, many applications of clove in food, health, cosmetics, pharmaceutics, nanoparticles and agricultural industries are still open for investigations.
    Keywords:  clove; culinary spices (food additives for taste); functional foods and nutraceuticals; nutritional content; pharmacological
    DOI:  https://doi.org/10.3389/fphar.2021.793200
  62. Int J Biol Macromol. 2022 Jan 29. pii: S0141-8130(22)00165-9. [Epub ahead of print]203 80-92
    Fabrication of a magnetic nanocarrier for doxorubicin delivery based on hyperbranched polyglycerol and carboxymethyl cellulose: An investigation on the effect of borax cross-linker on pH-sensitivity.
    Nasrin Zohreh, Nafiseh Karimi, Seyed Hassan Hosseini, Cosmin Istrate, Cristina Busuioc.
      A new core-shell pH-responsive nanocarrier was prepared based on magnetic nanoparticle (MNP) core. Magnetic nanoparticles were first modified with hyperbranched polyglycerol as the first shell. Then the magnetic core was decorated with doxorubicin anticancer drug (DOX) and covered with PEGylated carboxymethylcellulose as the second shell. Borax was used to partially cross-link organic shells in order to evaluate drug loading content and pH-sensitivity. The structure of nanocarrier, organic shell loadings, magnetic responsibility, morphology, size, dispersibility, and drug loading content were investigated by IR, NMR, TG, VSM, XRD, DLS, HR-TEM and UV-Vis analyses. In vitro release investigations demonstrated that the use of borax as cross-linker between organic shells make the nanocarrier highly sensitive to pH so that more that 70% of DOX is released in acidic pH. A reverse pH-sensitivity was observed for the nanocarrier without borax cross-linker. The MTT assay determined that the nanocarrier exhibited excellent biocompatibility toward normal cells (HEK-293) and high toxicity against cancerous cells (HeLa). The nanocarrier also showed high hemocompatibility. Cellular uptake revealed high ability of nanocarrier toward HeLa cells comparable with free DOX. The results also suggested that low concentration of nanocarrier has a great potential for use as contrast agent in magnetic resonance imaging (MRI).
    Keywords:  Borax; Carboxymethylcellulose; Core- shell smart nanocarrier; Doxorubicin; Magnetic nanoparticles; Polyglycerol; pH-sensitive
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.01.150
  63. Biol Pharm Bull. 2022 ;45(2): 194-199
    Effective Anticancer Therapy by Combination of Nanoparticles Encapsulating Chemotherapeutic Agents and Weak Electric Current.
    Anowara Khatun, Mahadi Hasan, Mahran Mohamed Abd El-Emam, Tatsuya Fukuta, Miyuki Mimura, Riho Tashima, Shintaro Yoneda, Shintaro Yoshimi, Kentaro Kogure.
      Delivery of medicines using nanoparticles via the enhanced permeability and retention (EPR) effect is a common strategy for anticancer chemotherapy. However, the extensive heterogeneity of tumors affects the applicability of the EPR effect, which needs to overcome for effective anticancer therapy. Previously, we succeeded in the noninvasive transdermal delivery of nanoparticles by weak electric current (WEC) and confirmed that WEC regulates the intercellular junctions in the skin by activating cell signaling pathways (J. Biol. Chem., 289, 2014, Hama et al.). In this study, we applied WEC to tumors and investigated the EPR effect with polyethylene glycol (PEG)-modified doxorubicin (DOX) encapsulated nanoparticles (DOX-NP) administered via intravenous injection into melanoma-bearing mice. The application of WEC resulted in a 2.3-fold higher intratumor accumulation of nanoparticles. WEC decreased the amount of connexin 43 in tumors while increasing its phosphorylation; therefore, the enhancing of intratumor delivery of DOX-NP is likely due to the opening of gap junctions. Furthermore, WEC combined with DOX-NP induced a significant suppression of tumor growth, which was stronger than with DOX-NP alone. In addition, WEC alone showed tumor growth inhibition, although it was not significant compared with non-treated group. These results are the first to demonstrate that effective anticancer therapy by combination of nanoparticles encapsulating chemotherapeutic agents and WEC.
    Keywords:  anticancer therapy; enhanced permeability and retention effect; nanoparticle; weak electric current
    DOI:  https://doi.org/10.1248/bpb.b21-00714
  64. J Food Biochem. 2022 Feb 01. e14096
    Platismatia glauca-Lichen species with suppressive properties on migration and invasiveness of two different colorectal carcinoma cell lines.
    Dragana S Šeklić, Milena M Jovanović.
      Platismatia glauca is a popular lichen traditionally used as a spice and possesses significant anti-cancer potential, whose anti-migratory/anti-invasive properties were mostly disregarded. Migration/invasion of cancer cells is processed in cancer metastasis and targeting their markers is an important strategy in anti-cancer treatment. We examined the anti-migratory/anti-invasive properties of P. glauca extract on two colorectal carcinoma cell lines (HCT-116 and SW-480) and elucidated possible mechanisms underlying these properties. Cell migration was evaluated by wound healing and RTCA methods. Immunofluorescent assay was used for the analysis of protein, while qRT-PCR for gene expression of migratory/invasive markers. ELISA assay was applied for the determination of MMP-9 concentration. P. glauca extract inhibited the motility of tested cells, by reducing pro-migratory/pro-invasive markers and potentially retaining intercellular connections. Treatment showed cell-selective effects, and HCT-116 cells were more responsive. Our study presents important scientific novelty, thus these lichen properties should be furtherly examined regarding the amelioration of anti-cancer treatment. PRACTICAL APPLICATIONS: Based on the evidence we provided in the present study, we have demonstrated that lichen species Platismatia glauca possess important biological activity, which has not been sufficiently investigated so far. It is of great importance to explore its anti-cancer potential, not only from a cytotoxic point of view but especially anti-migratory and anti-invasive. Herein, we showed that this species expresses significant suppressive effects on migration and invasiveness of colorectal carcinoma cells. This tested lichen has the potential to be used as a natural complementary anti-cancer treatment, with special reference on the dose applied and type of carcinoma. Our study represents a significant novelty in the field of scientific investigation of lichens and natural products, and further detailed studies are needed on in vitro and in vivo model systems.
    Keywords:  E-cadherin; Vimentin; collective cell migration; lichen; matrix-metalloproteinases
    DOI:  https://doi.org/10.1111/jfbc.14096
  65. Bioeng Transl Med. 2022 Jan;7(1): e10263
    High-dose vitamin D metabolite delivery inhibits breast cancer metastasis.
    Jiaye Liu, Junyi Shen, Chunyang Mu, Yang Liu, Dongsheng He, Han Luo, Wenshuang Wu, Xun Zheng, Yi Liu, Sunrui Chen, Qiuwei Pan, Yiguo Hu, Yinyun Ni, Yang Wang, Yong Liu, Zhihui Li.
      Besides its well-known benefits on human health, calcitriol, the hormonally active form of vitamin D3, has been being evaluated in clinical trials as an anticancer agent. However, currently available results are contradictory and not fundamentally deciphered. To the best of our knowledge, hypercalcemia caused by high-dose calcitriol administration and its low bioavailability limit its anticancer investigations and translations. Here, we show that the one-step self-assembly of calcitriol and amphiphilic cholesterol-based conjugates leads to the formation of a stable minimalist micellar nanosystem. When administered to mice, this nanosystem demonstrates high calcitriol doses in breast tumor cells, significant tumor growth inhibition and antimetastasis capability, as well as good biocompatibility. We further reveal that the underlying molecular antimetastatic mechanisms involve downregulation of proteins facilitating metastasis and upregulation of paxillin, the key protein of focal adhesion, in primary tumors.
    Keywords:  breast cancer; calcitriol; drug delivery; metastasis; vitamin D
    DOI:  https://doi.org/10.1002/btm2.10263
  66. Drug Discov Today. 2022 Jan 28. pii: S1359-6446(22)00032-0. [Epub ahead of print]
    Triple-negative breast cancer brain metastasis: an update on druggable targets, current clinical trials, and future treatment options.
    Maryam Nakhjavani, Rasika M Samarasinghe, Sarah Shigdar.
      The key challenges with the treatment of triple-negative breast cancer brain metastasis (TNBC-BM) are the lack of any targeted therapy and difficulties associated with drug delivery to the brain. These add to the high toxicity profile of existing treatments and the poor outcomes for patient. In this review, we introduce current drugs based on their molecular targets and look to improve brain drug delivery using more efficient and promising drug delivery systems. We describe ongoing clinical trials on druggable targets in TNBC-BM for a more targeted treatment and introduce the obstacles hindering drug delivery to the brain, bringing strategies and advancing knowledge for future steps in the treatment of patients with TNBC-BM.
    Keywords:  aptamer; brain metastasis; drug development; nanoparticle; novel drug delivery systems; triple-negative breast cancer
    DOI:  https://doi.org/10.1016/j.drudis.2022.01.010
  67. J Nanobiotechnology. 2022 Feb 04. 20(1): 66
    Engineering 2D Cu-composed metal-organic framework nanosheets for augmented nanocatalytic tumor therapy.
    Shangwen Zhuang, Huijing Xiang, Yixin Chen, Lulu Wang, Yu Chen, Jun Zhang.
      The engineered nanoformulation that can be activated by intracellular tumor microenvironment, including acidic pH, overexpressed H2O2, and high concentration of glutathione (GSH), features high efficacy to eradicate tumor cells with the intrinsic specificity and therapeutic biosafety. However, the relatively slow reaction rate of traditional Fe2+-mediated Fenton reaction induces the low production amount of reactive oxygen species (ROS) and subsequently the limited therapeutic outcome against tumors. Here, we established Cu (II)-based two-dimensional (2D) metal-organic framework (MOF) nanosheets as a distinct chemoreactive nanocatalyst for GSH-triggered and H2O2-augmented chemodynamic therapy (CDT), depending on the "AND" logic gate, for significant tumor suppression. After internalization by tumor cells, the MOF catalytic nanosheets reacted with local GSH for inducing GSH consumption and reducing the Cu2+ into Cu+. Subsequently, abundant hydroxyl radicals (·OH) generation was achieved via Cu+-mediated Fenton-like catalytic reaction. The dual effects of ·OH production and GSH depletion thus enhanced ROS production and accumulation in tumor cells, leading to significant cellular apoptosis and tumor inhibition, which was systematically demonstrated in both 4T1 and MDA-MB-231 tumor models. Therefore, GSH and H2O2, serve as an "AND" logic gate to trigger the Cu+-mediated Fenton-like reaction and reduce GSH level for augmented CDT with high therapeutic specificity and efficacy, thus inducing cellular apoptosis primarily through ferroptosis at the RNA sequence level.
    Keywords:  Fenton reaction; Metal–organic framework; Nanocatalytic therapy; Nanomedicine; Tumor therapy
    DOI:  https://doi.org/10.1186/s12951-022-01250-x
  68. Adv Sci (Weinh). 2022 Jan 31. e2101965
    Acid-Degradable Hydrogen-Generating Metal-Organic Framework for Overcoming Cancer Resistance/Metastasis and Off-Target Side Effects.
    Xianxian Yao, Danyang Chen, Bin Zhao, Binru Yang, Zhaokui Jin, Mingjian Fan, Geru Tao, Shucun Qin, Wuli Yang, Qianjun He.
      The development of stimuli-responsively degradable porous carriers for both controlled drug release and high biosafety is vitally important to their clinical translation, but still challenging at present. A new type of porphyrin-iron metal organic framework (Fe-MOF) nanocrystals is engineered here as acid-degradable drug carrier and hydrogen donor by the coordination between porphyrin and zero-valence Fe atom. Fe-MOF nanocrystals exhibit excellent acid-responsive degradation for H2 generation and simultaneous release of the loaded drug for combined hydrogen-chemotherapy of cancer multidrug resistance (MDR) and metastasis and for local hydrogen eradication of the off-target induced toxic side effects of the drug to normal cells/tissues. Mechanistically, released H2 assists chemotherapeutic drug to efficiently inhibit cancer metastasis by immunoactivating intratumoral M1-phenotype macrophages and consequently downregulating the expression of metastasis-related matrix metalloproteinase-2 (MMP-2) and can also downregulate the expressions of both P-glycoprotein (P-gp) protein and adenosine triphosphate (ATP) in MDR cancer cells to sensitize chemotherapeutic drug for enhanced damage to mitochondria and DNA. High anti-MDR/antimetastasis efficacies and high biocompatibility endow Fe-MOF nanocrystals and the Fe-MOF-based nanomedicine with high potential for clinical translation.
    Keywords:  controlled release; drug delivery; hydrogen therapy; metal-organic framework; metastasis; multidrug resistance; nanomedicine
    DOI:  https://doi.org/10.1002/advs.202101965
  69. Biomacromolecules. 2022 Feb 02.
    Biodegradable Ru-Containing Polycarbonate Micelles for Photoinduced Anticancer Multitherapeutic Agent Delivery and Phototherapy Enhancement.
    Maomao He, Ran Wang, Peiyuan Wan, Hexiang Wang, Yi Cheng, Pengcheng Miao, Zhiyong Wei, Xuefei Leng, Yang Li, Jianjun Du, Jiangli Fan, Wen Sun, Xiaojun Peng.
      The lack of selectivity between tumor and healthy cells, along with inefficient reactive oxygen species production in solid tumors, are two major impediments to the development of anticancer Ru complexes. The development of photoinduced combination therapy based on biodegradable polymers that can be light activated in the "therapeutic window" would be beneficial for enhancing the therapeutic efficacy of Ru complexes. Herein, a biodegradable Ru-containing polymer (poly(DCARu)) is developed, in which two different therapeutics (the drug and the Ru complex) are rationally integrated and then conjugated to a diblock copolymer (MPEG-b-PMCC) containing hydrophilic poly(ethylene glycol) and cyano-functionalized polycarbonate with good degradability and biocompatibility. The polymer self-assembles into micelles with high drug loading capacity, which can be efficiently internalized into tumor cells. Red light induces the generation of singlet oxygen and the release of anticancer drug-Ru complex conjugates from poly(DCARu) micelles, hence inhibiting tumor cell growth. Furthermore, the phototherapy of polymer micelles demonstrates remarkable inhibition of tumor growth in vivo. Meanwhile, polymer micelles exhibit good biocompatibility with blood and healthy tissues, which opens up opportunities for multitherapeutic agent delivery and enhanced phototherapy.
    DOI:  https://doi.org/10.1021/acs.biomac.1c01651
  70. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2022 Feb 02. e1778
    Recent advances on transdermal delivery systems for the treatment of arthritic injuries: From classical treatment to nanomedicines.
    Hongtao Shang, Ayesha Younas, Nan Zhang.
      Arthritic injuries happen frequently during a lifetime due to accidents, sports, aging, diseases, etc. Such injuries can be cartilage/bone injuries, tendon injuries, ligament injuries, inflammation, pain, and/or synovitis. Oral and injective administration of therapeutics are typically used but cause many side effects. Transdermal administration is an alternative route for safe and efficient delivery. Transdermal formulations of non-steroidal anti-inflammatory drugs have been available on market for years and show promising efficacy in pain relieving, inflammation alleviation, infection control, and so on. Innovative transdermal patches, gels/films, and microneedles have also been widely explored as formulations to deliver therapeutics to combat arthritic injuries. However, transdermal formulations that halt disease progression and promote damage repair are translated slowly from lab bench to clinical applications. One major reason is that the skin barrier and synovial capsule barrier limit the efficacy of transdermal delivery. Recently, many nanocarriers, such as nanoparticles, nanolipids, nanoemulsions, nanocrystals, exosomes, etc., have been incorporated into transdermal formulations to advance drug delivery. The combined transdermal formulations show promising safety and efficacy. Therefore, this review will focus on stating the current development of nanomedicine-based transdermal formulations for the treatment of arthritic injuries. The advances, limitations, and future perspectives in this field will also be provided to inspire future studies and accelerate clinical translational studies. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Implantable Materials and Surgical Technologies > Nanotechnology in Tissue Repair and Replacement Biology-Inspired Nanomaterials > Lipid-Based Structures.
    Keywords:  Arthritic injuries; Nanomedicines; Transdermal delivery; microneedles
    DOI:  https://doi.org/10.1002/wnan.1778
  71. Front Cell Dev Biol. 2021 ;9 774957
    Emerging Mechanisms and Disease Implications of Ferroptosis: Potential Applications of Natural Products.
    Chun Ge, Sujie Zhang, Huiwen Mu, Shaojun Zheng, Zhaoyi Tan, Xintong Huang, Chen Xu, Jianjun Zou, Yubing Zhu, Dong Feng, Jiye Aa.
      Ferroptosis, a newly discovered form of regulatory cell death (RCD), has been demonstrated to be distinct from other types of RCD, such as apoptosis, necroptosis, and autophagy. Ferroptosis is characterized by iron-dependent lipid peroxidation and oxidative perturbation, and is inhibited by iron chelators and lipophilic antioxidants. This process is regulated by specific pathways and is implicated in diverse biological contexts, mainly including iron homeostasis, lipid metabolism, and glutathione metabolism. A large body of evidence suggests that ferroptosis is interrelated with various physiological and pathological processes, including tumor progression (neuro)degenerative diseases, and hepatic and renal failure. There is an urgent need for the discovery of novel effective ferroptosis-modulating compounds, even though some experimental reagents and approved clinical drugs have been well documented to have anti- or pro-ferroptotic properties. This review outlines recent advances in molecular mechanisms of the ferroptotic death process and discusses its multiple roles in diverse pathophysiological contexts. Furthermore, we summarize chemical compounds and natural products, that act as inducers or inhibitors of ferroptosis in the prevention and treatment of various diseases. Herein, it is particularly highlighted that natural products show promising prospects in ferroptosis-associated (adjuvant) therapy with unique advantages of having multiple components, multiple biotargets and slight side effects.
    Keywords:  cancer; iron homeostasis; lipid peroxidation; natural products; neurodegenerative diseases; redox signaling
    DOI:  https://doi.org/10.3389/fcell.2021.774957
  72. Int J Biol Macromol. 2022 Jan 29. pii: S0141-8130(22)00149-0. [Epub ahead of print]203 222-243
    Recent progress in polymeric non-invasive insulin delivery.
    Farzaneh Sabbagh, Ida Idayu Muhamad, Razieh Niazmand, Pritam Kumar Dikshit, Beom Soo Kim.
      The design of carriers for insulin delivery has recently attracted major research attentions in the biomedical field. In general, the release of drug from polymers is driven via a variety of polymers. Several mechanisms such as matrix release, leaching of drug, swelling, and diffusion are usually adopted for the release of drug through polymers. Insulin is one of the most predominant therapeutic drugs for the treatment of both diabetes mellitus; type-I (insulin-dependent) and type II (insulin-independent). Currently, insulin is administered subcutaneously, which makes the patient feel discomfort, pain, hyperinsulinemia, allergic responses, lipodystrophy surrounding the injection area, and occurrence of miscarried glycemic control. Therefore, significant research interest has been focused on designing and developing new insulin delivery technologies to control blood glucose levels and time, which can enhance the patient compliance simultaneously through alternative routes as non-invasive insulin delivery. The aim of this review is to emphasize various non-invasive insulin delivery mechanisms including oral, transdermal, rectal, vaginal, ocular, and nasal. In addition, this review highlights different smart stimuli-responsive insulin delivery systems including glucose, pH, enzymes, near-infrared, ultrasound, magnetic and electric fields, and the application of various polymers as insulin carriers. Finally, the advantages, limitations, and the effect of each non-invasive route on insulin delivery are discussed in detail.
    Keywords:  Insulin delivery; Nasal; Ocular; Oral; Polymers; Transdermal; Vaginal
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.01.134
  73. Biomed Phys Eng Express. 2020 Nov 24. 6(6):
    Assessing the cost-effectiveness of DNA origami nanostructures for targeted delivery of anti-cancer drugs to tumours.
    Edward L Coleridge, Katherine E Dunn.
      Chemotherapy drugs are generally cytotoxic and can cause major side effects, including vomiting/nausea, fatigue, hair loss and pain. The use of targeted nanostructures to deliver drugs directly to tumours has the potential to reduce the side effects by decreasing the exposure of healthy cells and reducing the amount of drug needed. DNA can be used as a structural material to build drug-delivering nanorobots, but questions remain over the practicality of this approach. Here we show that it is potentially feasible for DNA nanostructure drug delivery to be more cost-effective than the drug-only approach. Our result suggests that the barriers to the development of DNA nanostructure-based drug delivery are likely to be primarily technical, regulatory and ethical rather than financial, as the potential exists for this to be a profitable therapeutic approach.
    Keywords:  DNA nanotechnology; chemotherapy; cost-effectiveness; health economics; targeted drug delivery
    DOI:  https://doi.org/10.1088/2057-1976/abbe73
  74. Front Pharmacol. 2021 ;12 792331
    Application Potential of Plant-Derived Medicines in Prevention and Treatment of Platinum-Induced Peripheral Neurotoxicity.
    Xiaowei Xu, Liqun Jia, Xiaoran Ma, Huayao Li, Changgang Sun.
      As observed with other chemotherapeutic agents, the clinical application of platinum agents is a double-edged sword. Platinum-induced peripheral neuropathy (PIPN) is a common adverse event that negatively affects clinical outcomes and patients' quality of life. Considering the unavailability of effective established agents for preventing or treating PIPN and the increasing population of cancer survivors, the identification and development of novel, effective interventions are the need of the hour. Plant-derived medicines, recognized as ideal agents, can not only help improve PIPN without affecting chemotherapy efficacy, but may also produce synergy. In this review, we present a brief summary of the mechanisms of platinum agents and PIPN and then focus on exploring the preventive or curative effects and underlying mechanisms of plant-derived medicines, which have been evaluated under platinum-induced neurotoxicity conditions. We identified 11 plant extracts as well as 17 plant secondary metabolites, and four polyherbal preparations. Their effects against PIPN are focused on oxidative stress and mitochondrial dysfunction, glial activation and inflammation response, and ion channel dysfunction. Also, ten clinical trials have assessed the effect of herbal products in patients with PIPN. The understanding of the molecular mechanism is still limited, the quality of clinical trials need to be further improved, and in terms of their efficacy, safety, and cost effectiveness studies have not provided sufficient evidence to establish a standard practice. But plant-derived medicines have been found to be invaluable sources for the development of natural agents with beneficial effects in the prevention and treatment of PIPN.
    Keywords:  mechanism; medicinal plant; peripheral neurotoxicity; phytotherapy; platinum agents
    DOI:  https://doi.org/10.3389/fphar.2021.792331
  75. Proc Natl Acad Sci U S A. 2022 Feb 08. pii: e2107599119. [Epub ahead of print]119(6):
    Loss of TET reprograms Wnt signaling through impaired demethylation to promote lung cancer development.
    Qin Xu, Chao Wang, Jia-Xin Zhou, Zhi-Mei Xu, Juan Gao, Pengfei Sui, Colum P Walsh, Hongbin Ji, Guo-Liang Xu.
      Oncogenic imbalance of DNA methylation is well recognized in cancer development. The ten-eleven translocation (TET) family of dioxygenases, which facilitates DNA demethylation, is frequently dysregulated in cancers. How such dysregulation contributes to tumorigenesis remains poorly understood, especially in solid tumors which present infrequent mutational incidence of TET genes. Here, we identify loss-of-function mutations of TET in 7.4% of human lung adenocarcinoma (LUAD), which frequently co-occur with oncogenic KRAS mutations, and this co-occurrence is predictive of poor survival in LUAD patients. Using an autochthonous mouse model of KrasG12D -driven LUAD, we show that individual or combinational loss of Tet genes markedly promotes tumor development. In this Kras-mutant and Tet-deficient model, the premalignant lung epithelium undergoes neoplastic reprogramming of DNA methylation and transcription, with a particular impact on Wnt signaling. Among the Wnt-associated components that undergo reprogramming, multiple canonical Wnt antagonizing genes present impaired expression arising from elevated DNA methylation, triggering aberrant activation of Wnt signaling. These impairments can be largely reversed upon the restoration of TET activity. Correspondingly, genetic depletion of β-catenin, the transcriptional effector of Wnt signaling, substantially reverts the malignant progression of Tet-deficient LUAD. These findings reveal TET enzymes as critical epigenetic barriers against lung tumorigenesis and highlight the therapeutic vulnerability of TET-mutant lung cancer through targeting Wnt signaling.
    Keywords:  DNA dioxygenases; Wnt antagonizing genes; epigenetic barriers; lung adenocarcinoma; mouse models
    DOI:  https://doi.org/10.1073/pnas.2107599119
  76. World J Gastroenterol. 2022 Jan 14. 28(2): 176-187
    Nanotheranostics: A powerful next-generation solution to tackle hepatocellular carcinoma.
    Rusdina Bte Ladju, Zulvikar Syambani Ulhaq, Gita Vita Soraya.
      Hepatocellular carcinoma (HCC) is an epidemic burden and remains highly prevalent worldwide. The significant mortality rates of HCC are largely due to the tendency of late diagnosis and the multifaceted, complex nature of treatment. Meanwhile, current therapeutic modalities such as liver resection and transplantation are only effective for resolving early-stage HCC. Hence, alternative approaches are required to improve detection and enhance the efficacy of current treatment options. Nanotheranostic platforms, which utilize biocompatible nanoparticles to perform both diagnostics and targeted delivery, has been considered a potential approach for cancer management in the past few decades. Advancement of nanomaterials and biomedical engineering techniques has led to rapid expansion of the nanotheranostics field, allowing for more sensitive and specific diagnosis, real-time monitoring of drug delivery, and enhanced treatment efficacies across various malignancies. The focus of this review is on the applications of nanotheranostics for HCC. The review first explores the current epidemiology and the commonly encountered obstacles in HCC diagnosis and treatment. It then presents the current technological and functional advancements in nanotheranostic technology for cancer in general, and then specifically explores the use of nanotheranostic modalities as a promising option to address the key challenges present in HCC management.
    Keywords:  Future therapy; Hepatic cancer; Hepatocellular carcinoma; Nanoplatform; Nanotheranostic; Personalized medicine
    DOI:  https://doi.org/10.3748/wjg.v28.i2.176
  77. Nutr Cancer. 2022 Feb 01. 1-12
    Dietary Intake and Cancer in Sub-Saharan Africa: A Critical Review of Epidemiological Studies.
    Galya Bigman, Linda Otieno, Sally N Adebamowo, Clement Adebamowo.
      Cancer incidence is rising rapidly in Sub-Saharan Africa (SSA). Dietary intake is an established risk factor for certain cancers but only a few epidemiological studies have been conducted in SSA. This study systematically reviewed and summarized the published literature on this issue and identified gaps that can be addressed in future research. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and literature searched was conducted until 11/2/2021. Out of the 5,457 potential references, we reviewed 19 eligible studies: 17 case-controls, two cross-sectionals and no cohort study. South Africa and Kenya conducted the majorities of the studies. The commonest studied cancers were esophageal (9/19), colorectal (4/19) and breast (4/19). Only four studies utilized a validated Food Frequency Questionnaire (FFQ). Although most studies (16/19) reported associations between dietary intake and cancer risks, they were lacking important confounders including total energy intake, multivitamin intake, body fat measures, physical-activity, smoking, and alcohol. Despite rapidly expanding cases of cancer associated with diet, the existent evidence on diet-cancer relationship is too scarce to deduce solid conclusions. There is a need for large cohorts with comprehensive datasets, validated dietary instruments while using advanced statistical analyses that can provide further insights into the imperative links between African diet and cancer risk.Supplemental data for this article is available online at https://doi.org/10.1080/01635581.2022.2032217 .
    DOI:  https://doi.org/10.1080/01635581.2022.2032217
  78. Spectrochim Acta A Mol Biomol Spectrosc. 2022 Jan 19. pii: S1386-1425(22)00057-9. [Epub ahead of print]271 120909
    Polymethine dyes-loaded solid lipid nanoparticles (SLN) as promising photosensitizers for biomedical applications.
    Giorgia Chinigò, Ana Gonzalez-Paredes, Alessandra Gilardino, Nadia Barbero, Claudia Barolo, Paolo Gasco, Alessandra Fiorio Pla, Sonja Visentin.
      Polymethine dyes (PMD) have proved to be excellent candidates in the biomedical field for potential applications in both diagnostic and therapeutic. However, PMD application in biomedicine is hindered by their poor solubility and stability in physiological conditions. Therefore, the incorporation of these dyes in nanosystems could be important to prevent the formation of dye aggregates in aqueous environment and to protect their photophysical characteristics. In the present work, two PMD based on the benzoindolenine ring (bromine benzo-cyanine-C4 and bromine benzo-squaraine-C4) were incorporated into Solid Lipid Nanoparticles (SLN) to solubilize and stabilize them in aqueous solutions. Obtained SLN showed a high incorporation efficiency for both PMD (≈90%) and not only preserved their spectroscopic properties in the NIR region even under physiological conditions but also improved them. Viability assays showed good biocompatibility of both empty and loaded nanocarriers while the cellular uptake and intracellular localization showed the effective internalization in MCF-7 cells, with a partial mitochondrial localization for CY-SLN. Moreover, in vitro phototoxicity assay showed that cyanine loaded-SLN (CY-SLN) is more photoactive than the free dye.
    Keywords:  Nanocarrier; Optical imaging; Photodynamic activity; Polymethine dyes; SLN; Solubility
    DOI:  https://doi.org/10.1016/j.saa.2022.120909
  79. Transl Cancer Res. 2020 Jul;9(7): 4131-4140
    A nanomicelle with miR-34a and doxorubicin reverses the drug resistance of cisplatin in esophageal carcinoma cells by inhibiting SIRT1 signal pathway.
    Jun Fang, Yuezhen Wang, Zhun Wang, Tieming Xie, Fengqin Yan, Lei Wang, Jianfeng Hua, Fangzheng Wang, Zhenfu Fu, Zhimin Ye.
      Background: Esophageal carcinoma (EC) is one of the most deadly malignant tumors in the world. Surgery, combined with chemotherapy or radiotherapy, is the traditional strategy for the treatment of EC. Cisplatin (CDDP) is a common chemotherapy drug widely used to treat EC due to its powerful anti-tumor effect. However, CDDP is subject to intrinsic or acquired resistance in EC cells, which badly hinders the efficacy of chemotherapy. The resistance phenomenon is mostly caused by the p53 mutant in the EC and the low efficiency of the drug delivery system.Methods: In this study, a specially designed nanomicelle was used to promote the anti-tumor effect of chemotherapy drugs against the CDDP-resistant EC cells. The nanomicelle consisted of miR-34a, doxorubicin (DOX), polyethylene glycol (PEG), and other excipients in an appropriate ratio.
    Results: The results showed that the nanomicelle could exert significant cell proliferation inhibition and apoptosis-inducing effects in the CDDP-resistant EC cells. The endogenous expression of miR-34a in the CDDP-resistant EC cells was promoted by the incubation with the nanomicelle. After incubation with the nanomicelle, the expression of protein SIRT1 was inhibited, and the expression of caspase3 was promoted significantly in the CDDP-resistant EC cells.
    Conclusions: Our results indicate that the specially designed nanomicelle can exert promising anti-tumor effects by introducing miR-34a to inhibit SIRT1 signaling pathway and enhance the efficiency of the drug delivery system.
    Keywords:  Nanomicelle; SIRT1; drug resistance; esophageal carcinoma (EC); miR-34a; p53
    DOI:  https://doi.org/10.21037/tcr-19-975
  80. Appl Microbiol Biotechnol. 2022 Feb 02.
    Inhibitory activities of grape bioactive compounds against enzymes linked with human diseases.
    Vagish Dwibedi, Sahil Jain, Divya Singhal, Anuradha Mittal, Santosh Kumar Rath, Sanjai Saxena.
      A quest for identification of novel, safe and efficient natural compounds, as additives in the modern food and cosmetic industries, has been prompted by concerns about toxicity and side effects of synthetic products. Plant phenolic compounds are one of the most documented natural products due to their multifarious biological applications. Grape (Vitis vinifera) is an important source of phenolic compounds such as phenolic acids, tannins, quinones, coumarins and, most importantly, flavonoids/flavones. This review crisply encapsulates enzyme inhibitory activities of various grape polyphenols towards different key human-ailment-associated enzymes: xanthine oxidase (gout), tyrosinase (hyperpigmentation), α-amylase and α-glucosidase (diabetes mellitus), pancreatic lipase (obesity), cholinesterase (Alzheimer's disease), angiotensin i-converting enzymes (hypertension), α-synuclein (Parkinson's disease) and histone deacetylase (various diseases). The review also depicts the enzyme inhibitory mechanism of various grape polyphenols and briefly discusses their stature as potential therapeutic and drug development candidates. KEY POINTS: • Nineteen major bioactive polyphenols from the grape/grape products and their disease targets are presented • Sixty-two important polyphenols as enzyme inhibitors from grape/grape products are presented • A thorough description and graphical presentation of biological significance of polyphenols against various diseases.
    Keywords:  Enzyme inhibitors; Grape coumarins; Grape flavonoids; Grape polyphenols; Natural anti-oxidants; Phenolic compounds
    DOI:  https://doi.org/10.1007/s00253-022-11801-9
  81. Arch Razi Inst. 2021 Oct;76(4): 781-793
    Investigation of Antioxidant and Cytotoxicity Effects of Silver Nanoparticles Produced by Biosynthesis Using Lactobacillus gasseri.
    R Abduladheem Jabbar, N Neima Hussien.
      The biosynthesis of silver nanoparticles (AgNPs) is a new approach in nanotechnology which was optimistically implemented in medicine, food control, and pharmacology. The present study aimed to investigate the antioxidant and cytotoxicity effects of AgNPs produced by Lactobacillus gasseri filtrate. Also, changing color from yellow to brown confirmed the production of AgNPs. AgNPs were characterized using ultraviolet-visible spectroscopy, FE-SEM, and Fourier Transform Infrared Spectroscopy (FTIR). The antioxidant activity of AgNPs was tested using the DPPH assay. The scavenging test for DPPH showed 19.3%, 32.6%, 47.6%, 72%, 85.3% at concentrations (6.25, 12.5, 25, 52, 100) µg/ml, respectively, which proved that the scavenging percentage increased with increasing concentration. The effect of AgNPs on the chromosomal pattern was also studied. The results of the experiment of AgNPs against SK-GT-4 cancer cells showed the toxic activity of the used particles against the strains of these human esophageal cancer cells and failed to affect normal cells.
    Keywords:   Cancer Cells; Chromosomal Aberrations; Nanoparticles
    DOI:  https://doi.org/10.22092/ari.2021.355949.1747
  82. Curr Drug Metab. 2022 Feb 02.
    Distribution, biotransformation, pharmacological effects, metabolic mechanism and safety evaluation of Platycodin D：A comprehensive review.
    Qianqian Li, Tan Yang, Shuang Zhao, Qifeng Zheng, Yaxin Li, Zhiyuan Zhang, Xiuyan Sun, Yan Liu, Yanqing Zhang, Junbo Xie.
      Platycodonis Radix (Jiegeng), the dried root of Platycodon grandiflorum, is a traditional herb used as both medicine and food. Its clinical application for the treatment of cough, phlegm, sore throat, pulmonary and respiratory diseases has been thousands of years in China. Platycodin D is the main active ingredient in Platycodonis Radix, which belongs to the family of pentacyclic triterpenoid saponins because it contains an oleanolane type aglycone linked with double sugar chains. Modern pharmacology has demonstrated that Platycodin D displays various biological activities, such as analgesics, expectoration and cough suppression, promoting weight loss, anti-tumor and immune regulation, suggesting that Platycodin D has the potential to be a drug candidate and an interesting target as a natural product for clinical research. In this review, the distribution and biotransformation, pharmacological effects, metabolic mechanism and safety evaluation of Platycodin D are summarized to lay the foundation for further studies.
    Keywords:  Platycodin D; biotransformation; distribution; metabolic mechanism; pharmacological effects; safety evaluation
    DOI:  https://doi.org/10.2174/1389200223666220202090137
  83. Cell Oncol (Dordr). 2022 Jan 31.
    Hippocalcin-like 1 is a key regulator of LDHA activation that promotes the growth of non-small cell lung carcinoma.
    Xiangyu Wang, Xiaomeng Xie, Yuanyuan Zhang, Fayang Ma, Mengjun Pang, Kyle Vaughn Laster, Xiang Li, Kangdong Liu, Zigang Dong, Dong Joon Kim.
      BACKGROUND: Hippocalcin-like 1 (HPCAL1), a neuronal calcium sensor protein family member, has been reported to regulate cancer growth. As yet, however, the biological functions of HPCAL1 and its molecular mechanisms have not been investigated in non-small cell lung carcinoma (NSCLC).METHODS: HPCAL1 expression in NSCLC samples was detected using immunohistochemistry, Western blotting and RT-PCR. The anticancer effects of HPCAL1 knockdown were determined by MTT, soft agar, cell cycle, oxygen consumption and reactive oxygen species assays. The effect of HPCAL1 knockdown on in vivo tumor growth was assessed using NSCLC cancer patient-derived xenograft models. Potentially interacting protein partners of HPCAL1 were identified using IP-MS/MS, immunoprecipitation and Western blotting assays. Metabolic alterations resulting from HPCAL1 knockdown were investigated using non-targeted metabolomics and RNA sequencing analyses.
    RESULTS: We found that HPCAL1 is highly expressed in NSCLC tissues and is positively correlated with low survival rates and AJCC clinical staging in lung cancer patients. Knockdown of HPCAL1 strongly increased oxygen consumption rates and the production of reactive oxygen species. HPCAL1 knockdown also inhibited NSCLC cell growth and patient-derived NSCLC tumor growth in vivo. Mechanistically, we found that HPCAL1 can directly bind to LDHA and enhance SRC-mediated phosphorylation of LDHA at tyrosine 10. The metabolomics and RNA sequencing analyses indicated that HPCAL1 knockdown reduces amino acid levels and induces fatty acid synthesis through regulating the expression of metabolism-related genes. Additionally, rescued cells expressing wild-type or mutant LDHA in HPCAL1 knockdown cells suggest that LDHA may serve as the main substrate of HPCAL1.
    CONCLUSIONS: Our data indicate that the effect of HPCAL1 knockdown on reducing SRC-mediated LDHA activity attenuates NSCLC growth. Our findings reveal novel biological functions and a mechanism underlying the role of HPCAL1 in NSCLC growth in vitro and in vivo.
    Keywords:  Cancer growth; HPCAL1; LDHA; Non-small cell lung carcinoma; SRC
    DOI:  https://doi.org/10.1007/s13402-022-00661-0
  84. Adv Healthc Mater. 2022 Feb 03. e2102256
    A novel targeted nanoparticle for traumatic brain injury treatment: combined effect of ROS depletion and calcium overload inhibition.
    Zhengzhong Han, Yuhan Han, Xuyang Huang, Hongwei Ma, Xuefeng Zhang, Jingyuan Song, Jun Dong, Shanshan Li, Rutong Yu, Hongmei Liu.
      Survival after severe traumatic brain injury (TBI) depends on minimizing or avoiding secondary insults to the brain. Overproduction of reactive oxygen species (ROS) and Ca2+ influx at the damaged site are the key factors that cause secondary injury upon TBI. Herein, we developed a TBI-targeted lipid covered radical scavenger nanoparticle to deliver nimodipine (Np) (CL-PPS/Np), in order to inhibit Ca2+ influx in neurons by Np and to scavenge ROS in the brain trauma microenvironment (BTE) by poly(propylene sulfide)60 (PPS60 ) and thus prevent TBI-associated secondary injury. In post-TBI models, CL-PPS/Np effectively accumulated into the wound cavity and prolonged the time of systemic circulation of Np. CL-PPS/Np could markedly protect the integrity of blood-brain barrier (BBB), prevent brain edema, reduce cell death and inflammatory responses, and promote functional recovery after TBI. These findings might provide a new therapy for TBI to prevent the spread of the secondary injury. This article is protected by copyright. All rights reserved.
    Keywords:  Ca2+ influx; lipid-radical scavenger nanoparticle; nimodipine; reactive oxygen species; targeted drug delivery; traumatic brain injury
    DOI:  https://doi.org/10.1002/adhm.202102256
  85. Int J Pharm. 2022 Jan 29. pii: S0378-5173(22)00080-1. [Epub ahead of print] 121526
    Piperlongumine loaded PLGA nanoparticles inhibit cancer stem-like cells through modulation of STAT3 in mammosphere model of triple negative breast cancer.
    Priya Singh, Sanjeeb Kumar Sahoo.
      TNBC exhibits higher rate of chemoresistance, metastasis, and relapse among all subtypes of breast cancer. This malignant statein TNBC is due to self-renewing sub-population of cells called cancer stem cells (CSCs). They are major caveats in TNBC treatment and need to be obliterated. In this regard, we explored piperlongumine (PL) that has remarkable anti-cancerous property but poor pharmacokinetics limits its application. So, to enhance its biological activity we developed PLGA based nanoformulation for PL (PL-NPs) and examined anti-CSCs effects of PL and PL-NPs in mammospheres. Results indicated that PL-NPs have higher cellular uptake than PL in mammospheres. Further, we demonstrated that PL-NPs remarkably inhibit various characteristics of CSCs like expression of ALDH, self-renewability, chemoresistance, and EMT in mammopsheres. We next investigated the possible mechanism underlying these multi-modal effects, and found that inhibition of STAT3 might be the driving force. In order to confirm this, we used colivelin a potent synthetic peptide activator of STAT3 in combination with treatments and found that anti-CSCs effects of PL and PL-NPs were reversed. Taken together, our data indicates that PL-NPs show enhanced inhibition of CSCs through downregulation of STAT3 and provides insight into development of PL based nanomedicine for targeting CSCs in TNBC.
    Keywords:  Cancer stem cells; STAT3; Triple negative breast cancer; nanomedicine; piperlongumine
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.121526
  86. Arch Pharm (Weinheim). 2022 Feb 04. e2100469
    Current perspectives on naturally occurring saponins as anticancer agents.
    Ruo Wang.
      Saponins, a heterogeneous group of sterol and triterpene glycosides, are distributed widely in nature. Naturally occurring saponins could act on diverse targets in cancer cells and consequently exert potential antiproliferative effects in various cancers, including drug-resistant forms. Therefore, naturally occurring saponins are useful templates for the discovery of novel anticancer candidates. Covering articles published between January 2020 and October 2021, this review aims to outline the recent development of naturally occurring steroidal and triterpenoidal saponins with anticancer potential to provide novel anticancer lead hits/candidates.
    Keywords:  anticancer activity; natural products; saponins; steroidal; triterpenoidal
    DOI:  https://doi.org/10.1002/ardp.202100469
  87. Biosci Rep. 2022 Feb 01. pii: BSR20212622. [Epub ahead of print]
    Polymeric biocompatible iron oxide nanoparticles labeled with peptides for imaging in ovarian cancer.
    Deepshikha Shahdeo, Akanksha Roberts, Veerbhan Kesarwani, Milena Horvat, Raghuraj Singh Chouhan, Sonu Gandhi.
      Compared to other nanomaterial, surface-modified iron oxide nanoparticles (IONPs) have gained attraction for cancer therapy applications due to its low toxicity, and long retention time. An innocuous targeting strategy was developed by generation of Fluorescein isothiocyanate (FITC) labeled peptide (Growth factor domain (GFD) and somatomedin B domain (SMB)) functionalized, chitosan coated IONPs (IONPs/C).  It can be used to target urokinase plasminogen activator receptor (uPAR), which is a surface biomarker, in ovarian cancer.  Binding affinity between uPAR and peptides (GFD and SMB) were revealed by in-silico docking studies. The biophysical characterizations of IONPs, IONPs/C, and IONPs/C /GFD-FITC or SMB-FITC nanoprobes were assessed via Vibrating Sample Magnetometer (VSM), Transmission Electron Microscope (TEM), Dynamic light scattering (DLS), and Fourier Transform Infrared Spectroscopy (FT-IR). Prussian blue staining, fluorescence spectroscopy, and fluorescence imaging were performed to confirm the targeting of nanoprobes with the surface receptor uPAR. The combination of IONPs/C/GFD+SMB showed efficient targeting of uPAR in the tumor microenvironment, and thus can be implemented as a molecular magnetic nanoprobe for cancer cell imaging and targeting.
    Keywords:  Iron oxide nanoparticles; chitosan; metastasis
    DOI:  https://doi.org/10.1042/BSR20212622
  88. Chin J Nat Med. 2022 Jan;pii: S1875-5364(22)60144-4. [Epub ahead of print]20(1): 43-53
    Mechanisms of Compound Kushen Injection for the treatment of bladder cancer based on bioinformatics and network pharmacology with experimental validation.
    Li-Hui Zhang, Wan-Ying Zhang, Jia-Ming Xiong, Xiu-Mei Duan, Li-Na Hai, Yu-Liang Zhang, Miao-Miao Zhang, Gui-Fang Qin, Guo-Wei Zhang.
      Bladder cancer is the most common malignancy of the urinary system. Compound Kushen Injection (CKI) is a Chinese medicinal preparation that has been widely used in the treatment of various types of cancers in the past two decades. However, the pharmacological effect of CKI on bladder cancer is not still completely understood. In the current study, network pharmacology combined with bioinformatics was used to elucidate the therapeutic mechanism and potential targets of CKI in bladder cancer. The mechanism by which CKI was effective against bladder cancer was further verified in vitro using human bladder cancer cell line T24. Network pharmacology analysis identified 35 active compounds and 268 target genes of CKI. Bioinformatics data indicated 5500 differentially expressed genes associated with bladder cancer. Common genes of CKI and bladder cancer suggested that CKI exerted anti-bladder cancer effects by regulating genes such as MMP-9, JUN, EGFR, and ERK1. Functional enrichment analysis indicated that CKI exerted therapeutic effects on bladder cancer by regulating certain biological processes, including cell proliferation, cell migration, and cell apoptosis. In addition, Kyoto Encyclopedia of Genes and Genomes enrichment analysis implicated pathways related to cancer, bladder cancer, and the PI3K-Akt signaling pathway. Consistently, cell experiments indicated that CKI inhibited the proliferation and migration of T24 cells, and induced their apoptosis. Moreover, RT-qPCR and Western blot results demonstrated that CKI was likely to treat bladder cancer by down-regulating the gene and protein expression of MMP-9, JUN, EGFR, and ERK1. CKI inhibited the proliferation and migration, and induced the apoptosis of T24 bladder cancer cells through multiple biological pathways and targets. CKI also exhibited significant effects on the regulation of key genes and proteins associated with bladder cancer. Overall, our findings provide solid evidence and deepen current understanding of the therapeutic effects of CKI for bladder cancer, and further support its clinical use.
    Keywords:  Bladder cancer; Compound Kushen Injection; GEO; Molecular mechanism; Network pharmacology
    DOI:  https://doi.org/10.1016/S1875-5364(22)60144-4
  89. J Mater Chem B. 2022 Feb 04.
    An in situ spontaneously forming micelle-hydrogel system with programmable release for the sequential therapy of anaplastic thyroid cancer.
    Xi Yang, Lingyun Zhang, Lingnan Zheng, Yan Wang, Ling Gao, Rui Luo, Xinchao Li, Changyang Gong, Han Luo, Qinjie Wu.
      Anaplastic thyroid carcinoma (ATC) is a lethal malignancy with a 1 year survival rate of less than 20%. Combination chemotherapy with cisplatin and paclitaxel is recommended as a critical therapeutic approach toward ATC. However, harsh side-effects on patients and unsatisfactory intratumoral concentrations hamper the effectiveness of systemic chemotherapy. In this work, an in situ spontaneously forming micelle-hydrogel system (iMHS) with programmable-release characteristics was developed for sequential chemotherapy. Taking advantage of the diffusion rate of the hydrophobic drug in the micellar network and the degradation of the hydrogel matrix, iMHS supported sequential chemotherapy via programmatic release. Moreover, in vitro and in vivo studies demonstrated the superiority of sequential release from iMHS over other approaches, regardless of the genetic profile (e.g., different BRAF, TP53, and TERT promoter mutations, etc.). Additionally, iMHS presented the significant ability to prevent local tumor recurrence in a post-surgical model. Overall, iMHS may serve as a promising strategy for the enhanced localized treatment of ATC via the programmable release of chemotherapy drugs with implied translational value.
    DOI:  https://doi.org/10.1039/d1tb01904j
  90. Front Med (Lausanne). 2021 ;8 746637
    Case Report: Effectiveness of Targeted Treatment in a Patient With Pancreatic Cancer Harboring PALB2 Germline Mutation and KRAS Somatic Mutation.
    Wei Wu, Yu Liu, Yuzhi Jin, Lulu Liu, Yixuan Guo, Mian Xu, Qing Hao, Dazhi Li, Weijia Fang, Aibin Zhang, Peng Zhao.
      Pancreatic cancer is one of the most leading causes of cancer death worldwide. The rapid development of next-generation sequencing (NGS) and precision medicine promote us to seek potential targets for the treatment of pancreatic cancer. Here, we report a female pancreatic cancer patient who underwent radical surgical excision after neoadjuvant chemotherapy. After the surgery, the patient underwent gemcitabine + S-1 therapy, capecitabine + albumin paclitaxel therapy and irinotecan therapy successively, however, MRI review revealed tumor progression. The surgical tissue sample was subjected to next-generation sequencing (NGS), and PALB2 germline mutation and KRAS somatic mutation were identified. The patient then received olaparib (a PARP inhibitor) + irinotecan and the disease stabilized for one year. Due to the increased CA19-9, treatment of the patient with a combination of trametinib (a MEK inhibitor) and hydroxychloroquine resulted in stable disease (SD) with a significant decrease of CA19-9. This case demonstrated that the NGS may be a reliable method for finding potential therapeutic targets for pancreatic cancer.
    Keywords:  KRAS somatic mutation; PALB2 germline mutation; case report; pancreatic cancer; targeted therapy
    DOI:  https://doi.org/10.3389/fmed.2021.746637
  91. Biochem Pharmacol. 2022 Jan 31. pii: S0006-2952(22)00032-6. [Epub ahead of print] 114938
    Nigericin exerts anticancer effects through inhibition of the SRC/STAT3/BCL-2 in osteosarcoma.
    Zhiqiang Yang, Jiangtao Xie, Jiayu Fang, Minchao Lv, Min Yang, Zhouming Deng, Yuanlong Xie, Lin Cai.
      The treatment of osteosarcoma has reached a bottleneck period in recent 30 years, there is an urgent need to find new drugs and treatment methods. Nigericin, an antibiotic derived from Streptomyces hygroscopicus, has exerted promising antitumoral effect in various tumors. The anticancer effect of Nigericin in human osteosarcoma has never been reported. In the present study, we explored the anticancer effects of Nigericin in osteosarcoma in vitro and in vivo. Our results showed that nigericin treatment significantly reduced tumor cell proliferation in dose-dependent and time-dependent in human osteosarcoma cells. Nigericin can inhibit cell growth of osteosarcoma cells, in addition to S-phase cycle arrest, the nigericin induces apoptosis. Furthermore, bioinformatics predicted that Nigericin exerts anticancer effects through inhibiting SRC/STAT3 signaling pathway in osteosarcoma. The direct binding between SRC and activator of transcription 3 (STAT3) was confirmed by Western blot. Nigericin can down regulate STAT3 and Bcl-2. In order to further elucidate the inhibitory effect of nigericin on SRC / STAT3 / Bcl-2 signal transduction mechanism, we established human osteosarcoma cancer cells stably expressing STAT3. Western blot confirmed that nigericin exerts anticancer effects on human osteosarcoma cancer cells by directly targeting STAT3. In addition, Nigericin can significantly inhibit tumor migration and invasion. Finally, Nigericin inhibits tumor growth in a mouse osteosarcoma model. The nigericin targeting the SRC/STAT3/BCL-2 signaling pathway may provide new insights into the molecular mechanism of nigericin on cancer cells and suggest its possible clinical application in osteosarcoma.
    Keywords:  Nigericin; SRC/STAT3/BCL-2 signaling pathway; anticancer-effects; osteosarcoma
    DOI:  https://doi.org/10.1016/j.bcp.2022.114938
  92. Front Mol Biosci. 2021 ;8 797902
    Molecular Mechanisms of Exercise on Cancer: A Bibliometrics Study and Visualization Analysis via CiteSpace.
    Dongling Zhong, Yuxi Li, Yijie Huang, Xiaojuan Hong, Juan Li, Rongjiang Jin.
      Objective: To analyze the research hot spots and frontiers of molecular mechanisms of exercise on cancer via CiteSpace. Method: Related publications in the Web of Science Core Collection Science Citation Index Expanded were retrieved from inception to November 27th, 2021. Then we used CiteSpace to generate network maps and identify top authors, institutions, countries, keywords, co-cited authors, journals, references and research trends. Results: A total of 1,130 related publications were retrieved. The most productive author and journal were Lee W Jones and PLOS ONE. Hanahan D and Warburg O were the most cited authors. Fudan University and Shanghai Jiao Tong University were the leading institutions, while China was the leading country. Top-cited authors and references generally focused on the epidemiology and hallmarks of cancer. Top five keywords with both high frequency and high betweenness centrality were breast cancer, aerobic glycolysis, oxidative stress, gene expression, skeletal muscle. Keyword "warburg effect" ranked first with the highest citation burst, while "inflammation", "hepatocellular carcinoma", "epithelial mesenchymal transition", and "adipose tissue" were emerging research foci. Conclusion: This study analyzed the research hot spots and frontiers of molecular mechanisms of exercise on cancer via CiteSpace. Based on the results, altered metabolism (aerobic glycolysis, insulin resistance, myokines), oxidative stress, gene expression and apoptosis were hot-research mechanisms of exercise on cancer. Emerging research foci of mechanisms were generally around inflammation, epithelial mesenchymal transition and adipokines. In addition, future studies could carry in-depth research of interactions between different mechanisms and try to elucidate the recommended doses and intensities of exercise for cancer, especially in breast, colorectal, prostate cancer and hepatocellular carcinoma.
    Keywords:  bibliometrics; cancer; citespace; exercise; molecular mechanisms; visualization analysis
    DOI:  https://doi.org/10.3389/fmolb.2021.797902
  93. Transl Cancer Res. 2021 Sep;10(9): 3906-3920
    Cinnamophilin enhances temozolomide-induced cytotoxicity against malignant glioma: the roles of ROS and cell cycle arrest.
    Shih-Hang Tai, Yu-Wen Lin, Tung-Yi Huang, Che-Chao Chang, Liang-Chun Chao, Tian-Shung Wu, E-Jian Lee.
      Background: Temozolomide (TMZ) has been widely used to treat glioblastoma multiforme (GBM). However, many mechanisms are known to quickly adapt GBM cells to chemotherapy with TMZ, leading to drug resistance and expansion of tumor cell populations.Methods: We subjected human glioblastoma cell lines and an animal model of glioblastoma xenografts with TMZ-based adjuvant treatments to evaluate the synergistic effect of cinnamophilin (CINN), a free radical scavenger.
    Results: Our results showed that the combined treatment of CINN and TMZ potentiated the anticancer effect and apoptotic cell death in glioma cell lines and enhanced antitumor action in glioma xenografts. TMZ induced reactive oxygen species (ROS) burst and elevated G2 arrest in glioma cells. The CINN-suppressed ROS burst in TMZ-treated glioma cells might be associated with increased apoptosis, as indicated by the upregulation of TUNEL-positive glioma cells. CINN-pretreated glioma cells exhibited increased cyclin B expression and reduced phosphorylation of Cdk1, suggesting reduced G2 arrest in the combined treatment group. Moreover, CINN lowered the protein level of LC3, a hallmark of autophagy, in TMZ-treated cells.
    Conclusions: These findings suggest that CINN may restore TMZ toxicity in glioma cancer by suppressing the ROS/G2 arrest pathway.
    Keywords:  Glioblastoma multiforme (GBM); autophagy; cinnamophilin; reactive oxygen species; temozolomide
    DOI:  https://doi.org/10.21037/tcr-20-3426
  94. Curr Mol Pharmacol. 2022 Jan 31.
    Gamma-tocotrienol Synergistically Promotes the Anti-proliferative and Pro-apoptotic Effects of Etoposide on Breast Cancer Cell Lines.
    Maya Idriss, Maria Younes, Sonia Abou Najem, Mohammad Hassan Hodroj, Rajaa Fakhoury, Sandra Rizk.
      BACKGROUND: Breast Cancer is one of the most commonly diagnosed cancers worldwide and a major cause of death among women. Although chemotherapeutic agents remain the keystones in cancer therapy, significant side effects have failed to provide a safe and tolerable treatment for cancer patients. Dietary antioxidant vitamins were extensively investigated over the past years and their relevance in cancer chemotherapy remains to be elucidated.OBJECTIVE: In the current study, we aimed to investigate the anti-proliferative and apoptotic effects of combining γ-tocotrienol, a member of the vitamin E family, with the chemotherapeutic drug etoposide in MCF-7 and MDA-MB-231 breast cancer cell lines.
    METHODS: The antiproliferative effect of etoposide combined with γ-tocotrienol was measured using MTS viability reagent. The pro-apoptotic effect was elucidated through Cell Death ELISA and dual Annexin V/PI staining followed by flow cytometric analysis.
    RESULTS: Our results showed that etoposide significantly decreased the cell growth of both cell lines with MDA-MB-231 cells being more sensitive to etoposide treatment than MCF-7. Moreover, the simultaneous treatment of both breast cancer cell lines with low doses of γ-tocotrienol and etoposide induced a synergistic antiproliferative effect (CI<1). Furthermore, the combination therapy significantly increased the percentage of total apoptotic cells in the MDA-MB-231 cell line and the degree of DNA fragmentation as compared to treatment with either compound alone.
    CONCLUSION: In conclusion, our results provide evidence for the profound anti-tumorigenic effect of combined etoposide and γ-tocotrienol in the breast cancer cell lines.
    Keywords:  : apoptosis; chemotherapeutic drugs; combination therapy; gamma-tocotrienol; mammary carcinoma; vitamin E derivatives
    DOI:  https://doi.org/10.2174/1874467215666220131095611
  95. Nat Cancer. 2021 Jan;2(1): 49-65
    Mutant Kras co-opts a proto-oncogenic enhancer network in inflammation-induced metaplastic progenitor cells to initiate pancreatic cancer.
    Yong Li, Yi He, Junya Peng, Zhendong Su, Zeyao Li, Bingjie Zhang, Jing Ma, Meilian Zhuo, Di Zou, Xinde Liu, Xinhong Liu, Wenze Wang, Dan Huang, Mengyue Xu, Jianbin Wang, Haiteng Deng, Jing Xue, Wei Xie, Xun Lan, Mo Chen, Yupei Zhao, Wenming Wu, Charles J David.
      Kras-activating mutations display the highest incidence in pancreatic ductal adenocarcinoma. Pancreatic inflammation accelerates mutant Kras-driven tumorigenesis in mice, suggesting high selectivity in the cells that oncogenic Kras transforms, although the mechanisms dictating this specificity are poorly understood. Here we show that pancreatic inflammation is coupled to the emergence of a transient progenitor cell population that is readily transformed in the presence of mutant KrasG12D. These progenitors harbor a proto-oncogenic transcriptional program driven by a transient enhancer network. KrasG12D mutations lock this enhancer network in place, providing a sustained Kras-dependent oncogenic program that drives tumors throughout progression. Enhancer co-option occurs through functional interactions between the Kras-activated transcription factors Junb and Fosl1 and pancreatic lineage transcription factors, potentially accounting for inter-tissue specificity of oncogene transformation. The pancreatic ductal adenocarcinoma cell of origin thus provides an oncogenic transcriptional program that fuels tumor progression beyond initiation, accounting for the intra-tissue selectivity of Kras transformation.
    DOI:  https://doi.org/10.1038/s43018-020-00134-z
  96. Front Genet. 2021 ;12 768130
    Chrysin Modulates Aberrant Epigenetic Variations and Hampers Migratory Behavior of Human Cervical (HeLa) Cells.
    Ritu Raina, Abdulmajeed G Almutary, Sali Abubaker Bagabir, Nazia Afroze, Sharmila Fagoonee, Shafiul Haque, Arif Hussain.
      Purpose: Plant-derived phytochemicals have shown epigenetic modulatory effect in different types of cancer by reversing the pattern of DNA methylation and chromatin modulation, thereby restoring the function of silenced tumor-suppressor genes. In the present study, attempts have been made to explore chrysin-mediated epigenetic alterations in HeLa cells. Methods: Colony formation and migration assays followed by methylation-specific PCR for examining the methylation status of CpG promoters of various tumor-suppressor genes (TSGs) and the expression of these TSGs at the transcript and protein levels were performed. Furthermore, global DNA methylation; biochemical activities of DNA methyltransferases (DNMTs), histone methyl transferases (HMTs), histone deacetylases (HDACs), and histone acetyl transferases (HATs) along with the expression analysis of chromatin-modifying enzymes; and H3 and H4 histone modification marks analyses were performed after chrysin treatment. Results: The experimental analyses revealed that chrysin treatment encourages cytostatic behavior as well as inhibits the migration capacity of HeLa cells in a time- and dose-dependent manner. Chrysin reduces the methylation of various tumor-suppressor genes, leading to their reactivation at mRNA and protein levels. The expression levels of various chromatin-modifying enzymes viz DNMTs, HMTs, HDACs, and HATS were found to be decreased, and H3 and H4 histone modification marks were modulated too. Also, reduced global DNA methylation was observed following the treatment of chrysin. Conclusion: This study concludes that chrysin can be used as a potential epigenetic modifier for cancer treatment and warrants for further experimental validation.
    Keywords:  DNA methylation; chrysin; epigenetic modification; epigenome; phytochemicals
    DOI:  https://doi.org/10.3389/fgene.2021.768130
  97. Front Pharmacol. 2021 ;12 811724
    A GSH/CB Dual-Controlled Self-Assembled Nanomedicine for High-Efficacy Doxorubicin-Resistant Breast Cancer Therapy.
    Yang Yang, Quanfeng Zhao, Zhe Peng, Yunjiang Zhou, Miao-Miao Niu, Lin Chen.
      Chemoresistance is a major therapeutic obstacle in the treatment of breast cancer. Therefore, how to overcome chemoresistance is a problem to be solved. Here, a glutathione (GSH)/cathepsin B (CB) dual-controlled nanomedicine formed by cyclic disulfide-bridged peptide (cyclic-1a) as a potent anticancer agent is reported. Under the sequential treatment of GSH and CB, cyclic-1a can efficiently self-assemble into nanofibers. In vitro studies show that cyclic-1a promotes the apoptosis of MCF-7/DOX cells by inducing the cleavages of caspase-3 and PARP. In vivo studies confirm that cyclic-1a significantly inhibits the progression of MCF-7/DOX cells-derived xenograft in nude mice, with no obvious adverse reactions. This study provides a paradigm of GSH/CB dual-controlled nanomedicine for high-efficacy and low-toxic DOX-resistant breast cancer therapy.
    Keywords:  GSH; breast cancer; cathepsin B; cyclic peptide; drug-resistance
    DOI:  https://doi.org/10.3389/fphar.2021.811724
  98. Oxid Med Cell Longev. 2022 ;2022 2910411
    Nutraceutical Profiling, Bioactive Composition, and Biological Applications of Lepidium sativum L.
    Sakshi Painuli, Cristina Quispe, Jesús Herrera-Bravo, Prabhakar Semwal, Miquel Martorell, Zainab M Almarhoon, Ainur Seilkhan, Alibek Ydyrys, Javad Sharifi Rad, Mohammed M Alshehri, Sevgi Durna Daştan, Yasaman Taheri, Daniela Calina, William C Cho.
      The roots, leaves, and seeds of Lepidium sativum L., popularly known as Garden cress in different regions, have high economic importance; although, the crop is particularly cultivated for the seeds. In traditional medicine, this plant has been reported to possess various biological activities. This review is aimed at providing updated and critical scientific information about the traditional, nutritional, phytochemical, and biological activities of L. sativum. In addition, the geographic distribution is also reviewed. The comprehensive literature search was carried out with the help of different search engines PubMed, Web of Science, and Science Direct. This review highlighted the importance of L. sativum as an edible herb that possesses a wide range of therapeutic properties along with high nutritional values. Preclinical studies (in vitro and in vivo) displayed anticancer, hepatoprotective, antidiabetic, hypoglycemic, antioxidant, antimicrobial, gastrointestinal, and fracture/bone healing activities of L. sativum and support the clinical importance of plant-derived bioactive compounds for the treatment of different diseases. Screening of literature revealed that L. sativum species and their bioactive compounds may be a significant source for new drug compounds and also could be used against malnutrition. Further clinical trials are needed to effectively assess the actual potential of the species and its bioactive compounds.
    DOI:  https://doi.org/10.1155/2022/2910411
  99. Alzheimers Dement. 2021 Dec;17 Suppl 7 e054164
    Association between cancer treatment and progression of all-cause dementia.
    Mackenzie E Fowler, Richard E Kennedy, Nicole C Wright, Marguerite R Irvin, Kristen L Triebel, Gabrielle B Rocque.
      BACKGROUND: Cancer treatments have been associated with cancer-related cognitive impairment (CRCI). CRCI exhibits symptoms similar to those experienced with dementia syndromes, and could result from the cancer itself or as a consequence of cancer therapies. No studies have examined the potential effect of cancer treatments on cognition in dementia.METHOD: Electronic health record data from the University of Alabama at Birmingham were extracted July 2003 to February 2020. Baseline cognition and cognitive progression on the Alabama Brief Cognitive screener (ABCs) among dementia patients based on receipt of various cancer treatments were evaluated using adjusted linear mixed effects models.
    RESULT: Hormone therapies were associated with faster decline on the ABCs compared to other treatments (b: -1.39, 95% CI: -2.73, -0.04). Similar results were seen for hormone therapies compared to neither hormone nor immunotherapy (b: -1.55, 95% CI: -3.02, -0.08). No cognitive differences were detected for other cancer treatments.
    CONCLUSION: Hormone therapies may lead to faster cognitive decline in cancer survivors who develop dementia later in life. Larger studies of long-term effects of cancer therapies are needed to allow for stratification by cancer type and cancer staging and evaluate modification by race and socioeconomic status.
    DOI:  https://doi.org/10.1002/alz.054164
  100. IUBMB Life. 2022 Feb 03.
    Evaluating the Therapeutic Efficacy of Radiolabeled BSA@CuS Nanoparticle-induced Radio-photothermal Therapy against Anaplastic Thyroid Cancer.
    Chunmei Zhang, Jinyan Chai, Qiang Jia, Jian Tan, Zhaowei Meng, Ning Li, Menghui Yuan.
      PURPOSE: Bovine serum albumin (BSA) has been employed as a mild biological template in nanoscale particles. Copper sulfide (CuS) has been used for photothermal therapy (PTT) in several studies. In this study, we aimed to synthesize the 131 I-labeled BSA-modified CuS nanoparticles (131 I-BSA@CuS), with attributes of both radiotherapy and PTT, as a therapeutic agent against anaplastic thyroid carcinoma (ATC).METHOD: BSA@CuS nanoparticles were prepared using the solvothermal reaction and then labeled with Na131 I by the chloramine-T method. The products were characterized and their cytotoxicity was investigated in vitro and in vivo. The therapeutic efficacy of 131 I-BSA@CuS was evaluated in ARO cell (an ATC cell line) subcutaneous tumors.
    RESULTS: The nanoparticles showed good biocompatibility and low toxicity in vitro and in vivo. BSA@CuS rapidly and effectively converted the light energy from an 808 nm laser into thermal energy with a conversion efficiency of 28.07%. SPECT/CT imaging demonstrated that the accumulation of radioactivity peaked within 24 h and resided in the tumors for 5 days post intratumoral injection. In vivo assays indicated that, compared to monotherapy, the synthesized nanoparticles employing both PTT and radiotherapy possess better therapeutic efficacy against tumors.
    CONCLUSION: The synthesized nanomaterial showed uniform dispersion, good stability and aqueous solubility, excellent photothermal properties, and long-term retention in ATC. Hence, combined radiotherapy and PTT can significantly inhibit tumor growth compared to monotherapy, and can be applied in clinical settings.
    Keywords:  near infrared region laser; photothermal therapy; radioiodine; radiotherapy; single-photon emission computed tomography
    DOI:  https://doi.org/10.1002/iub.2601
  101. Pharm Dev Technol. 2022 Feb 02. 1-31
    mPEG-Cholic acid/TPGS mixed micelles for combined delivery of paclitaxel and bufalin to treat hepatocellular carcinoma.
    Yujia Liu, Xiaoyu Lu, Zhenhai Zhang, Shulong Jiang, Huixia Lv.
      In this study, amphiphilic block copolymer mPEG-cholic acid was synthesized in conjunction with TPGS as stabilizer to prepare multifunctional micelles. The formed polymeric micelles (PCTm) were used for the delivery of paclitaxel (PTX) and bufalin (BF). PEG group could enhance solubility and extend circulation time, while cholic acid groups achieved the liver targeted function. Combinations of these approaches could realize a synergistic therapeutic effect in the treatment of advanced hepatocellular carcinoma. CLSM in vitro results demonstrated that drug capsulation into PCTm could enhance cellular uptake. FCM results confirmed the uptake amount of C6/PCTm was 7.5-fold higher than that of free C6 after incubation for 2 h. Competitive inhibition test proved the Na+-taurocholate co-transporting polypeptide (NTCP) involved in the uptake mechanism of PCTm. Meanwhile, in vivo imaging assays demonstrated that the fluorescence intensity of Cy5.5/PCTm was higher than that of free Cy5.5 on liver and tumor with extended circulation time to 48 h. In addition, in vivo studies confirmed that the combined therapy exhibited the strongest tumor inhibition rate of 82.29% with lower systemic toxicity. Hence, these results indicated that PCTm could provide a promising strategy for targeting hepatocellular carcinoma and achieve the goal of the synergism and attenuation.
    Keywords:  Bufalin; Cholic acid; Combination therapy; Hepatocellular carcinoma; Micelle; Paclitaxel
    DOI:  https://doi.org/10.1080/10837450.2022.2037140
  102. Phytomedicine. 2022 Jan 17. pii: S0944-7113(22)00014-9. [Epub ahead of print]98 153936
    Combinatorial effect of thymoquinone with chemo agents for tumor therapy.
    Shah Jehan, Jiaxin Huang, Umar Farooq, Irum Basheer, Wenhu Zhou.
      BACKGROUND: Most chemotherapeutics used in cancer therapies exhibit considerable side effects to the patients. Thus, developing new chemo agents to treat cancer patients with minimal toxic and side effects is urgently needed. Recently, the combination of different chemotherapeutics has become a promising strategy to treat malignancies. Thymoquinone (TQ) is a primary bioactive compound derived from the folk medicinal plant Nigella sativa, which has been found an antitumor, chemopreventive and chemopotentiating agent against human neoplastic diseases.PURPOSE: We briefly summarize the current research of the biomolecular mechanisms of TQ and evaluate the existing literature on TQ adjuvant therapies against various cancers.
    METHOD: The data in this review were gathered by several search engines including, Google Scholar, PubMed and ScienceDirect. We highlighted and classified the outcomes of both in vitro and in vivo experiments of TQ adjuvant therapies against human cancers and their chemopreventive activities on vital organs.
    RESULTS: Several studies have shown that TQ synergistically potentiated the antitumor activity of numerous chemo agents against human neoplastic disease, including lung, breast, liver, colorectal, skin, prostate, stomach, bone and blood cancers. TQ also acted as a chemopreventive agent and reduced the toxicity of many chemo agents to vital organs, such as the heart, liver, kidneys and lungs.
    CONCLUSION: In summary, we highly recommend an advanced evaluation of TQ adjuvant therapies at the level of preclinical and clinical trials, which could lead to a novel combinatorial therapy for cancer treatment with low or tolerable adverse effects on patients.
    Keywords:  Chemoprevention; Chemotherapeutic; Combinatorial treatment; Cytotoxicity; Synergistic effect; Thymoquinone
    DOI:  https://doi.org/10.1016/j.phymed.2022.153936
  103. Biomed Pharmacother. 2022 Jan 29. pii: S0753-3322(22)00060-9. [Epub ahead of print]147 112672
    SiRNA-circFARSA-loaded porous silicon nanomaterials for pancreatic cancer treatment via inhibition of CircFARSA expression.
    Huixiao Yuan, Xin Huang, Qingqing Li, Cici Luo, Chenyu Lin, Shuxian Zhang, Yaguang Zhang, Zhilin Yan, Ning Du, Zhongmin Liu, Hua Jiang, Bingdi Chen.
      Novel functions and involvement of circFARSA have not been reported in pancreatic cancer; in addition, its inhibitor screening has not yet been conducted. The purpose of this study was to (1) verify circFARSA as a novel anti-cancer target for pancreatic cancer and (2) to prepare a novel anti-pancreatic cancer agent targeting circFARSA. In this study, we designed and synthesized a small interfering RNA (siRNA, named siRNA-circFARSA), which specifically inhibits circFARSA expression. Using liposomes and porous silicon nanoparticles (pSiNPs) as siRNA delivery system, we prepared liposome-siRNA-circFARSA and pSiNP-PEI-siRNA-circFARSA and investigated their anti-cancer mechanism by quantitative real-time PCR and western blotting. Cell proliferation curves and transwell migration assays were performed to investigate the effect of siRNAs proliferation and migration capabilities of cancer cells. Patient-derived tumor xenograft mouse models were used to investigate the anti-cancer effects in vivo. The data showed that both liposome-siRNA-circFARSA and pSiNP-PEI-siRNA-circFARSA (Si: 0.7 µg/mL) significantly inhibited the proliferation and migration of pancreatic cancer cells in vitro. However, the biological safety and in vivo anti-cancer effects of pSiNP-PEI-siRNA-circFARSA (Si: 22.4 µg/mL) were higher than those of liposome-siRNA-circFARSA. The results showed that siRNA-circFARSA could inhibit the expression of circFARSA and then BCL-2 protein expression, thereby leading to pancreatic cancer cell apoptosis after transportation into pancreatic cancer cells. Therefore, this study provides tools for pancreatic cancer treatment in the future, as it (1) verified circFARSA as a novel target for pancreatic cancer treatment, and (2) prepared a novel anti-pancreatic cancer agent (pSiNP-PEI-siRNA-circFARSA).
    Keywords:  CircFARSA; Liposome; Pancreatic cancer; Porous silicon; SiRNA
    DOI:  https://doi.org/10.1016/j.biopha.2022.112672
  104. Int Arch Otorhinolaryngol. 2022 Jan;26(1): e119-e124
    Antioxidant Effect of Curcumin on the Prevention of Oxidative Damage to the Cochlea in an Ototoxic Rat Model Based on Malondialdehyde Expression.
    Tengku Siti Hajar Haryuna, Dyah Fauziah, Sari Anggraini, M Pahala Hanafi Harahap, Juliandi Harahap.
      Introduction  Aminoglycoside, as an antimicrobial medication, also has side-effects on the inner ears, bringing about hearing disorders. Curcumin has been proven to be a strong scavenger against various reactive oxygen species (ROS), and the increase in ROS production is considered to play an important role in the process of hearing disorder. Objective  To prove that curcumin is an effective antioxidant to prevent cochlear damage based on malondialdehyde (MDA) expression. Methods  The present research used 32 Rattus norvegicus , of the Wistar lineage, randomly divided into 8 groups: negative control, ototoxic control (a single dose of 40 mg/ml of gentamicin via intratympanic injection), 2 groups submitted to ototoxic control + curcumin treatment (100 mg/kg, 200 mg/kg), 2 groups who iunderwent ototoxic control + curcumin treatment for 7 days, and two groups submitted to curcumin treatment as prevention for 3 days + ototoxic induction. Results  The results showed that the lowest dosage of curcumin (100 mg/kg) could decrease MDA expression on the cochlear fibroblastic wall of the ototoxic model; however using greater doses of curcumin (200 mg/kg) for 7 days would provide a better effect. Curcumin could also significantly decrease MDA expression when it was administered during the preototoxic exposure. Conclusion  Curcumin can be used as a therapy for ototoxic prevention based on the decrease in MDA expression.
    Keywords:  cochlear fibroblast; curcumin; gentamicin; malondialdehyde; ototoxicity; reactive oxygen species
    DOI:  https://doi.org/10.1055/s-0040-1722161
  105. J Drug Target. 2022 Feb 03. 1-14
    Her-2 directed systemic delivery of fatty acid synthase (FASN) siRNA with novel liposomal carrier systems in the breast cancer mouse model.
    Arif Khan, Ahmed N Aljarbou, Shamshir Khan, Masood A Khan.
      Despite the current advancements in the gene silencing therapy in vitro, the systemic delivery of siRNA still remains a challenging task for its transition into clinics. We have previously developed the Her2-targeted fatty acid synthase (FASN) siRNA-encapsulating immunoliposomes (ILs) with a great stability in the presence of serum. We report here the therapeutic potential of the lipid-based novel formulations in the breast cancer mouse model. The growth inhibitory and gene silencing effects of various formulations were determined by measuring the size of the tumor, cell proliferation, apoptotic index and immunoassays against Her2-over expressed tumor xenografts in nude mice. The pegylated DSPC/Chol and DOPE/CHEMS immunoliposomes containing FASN-siRNA significantly decreased the tumor growth relative to non-targeted liposomes. They induced the 1.5-fold increase in cellular apoptosis and several fold decrease in proliferation as compared to non-targeted liposomal formulations of FASN-siRNA. Moreover, FASN-siRNA-ILs produced several fold increase in the ratios of p53/p21 and Bax/Bcl-2. The gene silencing effects of targeted FASN-liposomes were found significantly superior, resulting in 30%-40% downregulation in FASN as compared to non-targeted similar formulations. Both types of FASN immunoliposomes provided a highly efficient approach for targeted delivery in Her-2-expressed breast cancer and thus offered a promising anticancer strategy in the clinical therapy.
    Keywords:  FASN; Her-2 targeting; pH-sensitive immunoliposomes; siRNA Delivery
    DOI:  https://doi.org/10.1080/1061186X.2022.2038613
  106. Tetrahedron. 2022 Jan 22. pii: 132501. [Epub ahead of print]105
    Recent total syntheses of anthraquinone-based natural products.
    Jackson A Gartman, Uttam K Tambar.
      The scientific community has found deep interest in anthraquinone-based compounds due to their therapeutic properties and challenging structural elements. Various architecturally beautiful natural products have been successfully synthesized in recent decades utilizing two main strategies: either an early-stage synthesis of the anthraquinone and further elongation of the system, or a late-stage introduction of the anthraquinone ring moiety. Select syntheses of complex anthraquinone monomers and dimers within the past 20 years are described with an emphasis on the retrosynthetic disconnections that shape the anthraquinone-installation strategy.
    Keywords:  Annulation; Anthraquinones; Cyclization; Cycloaddition; Natural products; Total synthesis
    DOI:  https://doi.org/10.1016/j.tet.2021.132501
  107. Transl Cancer Res. 2021 Nov;10(11): 4680-4693
    Exploring the molecular targets and mechanisms of [10]-Gingerol for treating triple-negative breast cancer using bioinformatics approaches, molecular docking, and in vivo experiments.
    Ping Huang, Peijuan Zhou, Yuqi Liang, Jiahua Wu, Guosong Wu, Rui Xu, Yan Dai, Qianqian Guo, Hai Lu, Qianjun Chen.
      Background: Triple-negative breast cancer (TNBC) is the most aggressive among breast cancer subtypes with the worst prognosis. Ginger is widely used in pharmaceuticals and as food. Its anticancer properties are known, but the mechanism is still unclear. [10]-Gingerol is one of the main phenolic compounds isolated from ginger. Studying the biological effects of [10]-Gingerol is of great significance to understand the efficacy of ginger.Methods: In this study, the therapeutic effects of [10]-Gingerol on TNBC cells were studied using network pharmacology, molecular docking, and in vitro experiments, and the target and mechanism of action were explained.
    Results: A total of 48 targets of ginger for the treatment of TNBC were found. These targets might interfere with the growth of TNBC by participating in many pathways, such as endocrine resistance, progesterone-mediated oocyte maturation, estrogen signaling pathway, and cellular senescence. Prognostic analyses indicated that the JUN, FASN, ADRB2, ADRA2A, and PGR were the hub genes, while molecular docking predicted the stable binding of ADRB2 protein with drug compounds. Additionally, [10]-Gingerol could induce apoptosis by regulating the caspase activation.
    Conclusions: [10]-Gingerol affects the growth of TNBC through multiple action targets and participating in multiple action pathways. ADRB2 and apoptosis pathways might be important target pathways for [10]-Gingerol in the treatment of TNBC.
    Keywords:  Triple-negative breast cancer (TNBC); [10]-Gingerol; apoptosis; molecular docking; natural product; network pharmacology
    DOI:  https://doi.org/10.21037/tcr-21-1138
  108. Nanomedicine. 2022 Jan 29. pii: S1549-9634(22)00012-0. [Epub ahead of print] 102526
    CAQK modification enhances the targeted accumulation of metformin-loaded nanoparticles in rats with spinal cord injury.
    Ting Li, Pei Jing, Lingling Yang, Yujie Wan, Xingjie Du, Jun Wei, Meiling Zhou, Zhongbing Liu, Yan Lin, Zhirong Zhong.
      Spinal cord injury (SCI) often causes neuronal membrane rupture and immediate death of neurons, followed by complicated secondary injuries. Treatment of SCI still remains a major challenge in clinical practice; thus, a great advance is urgently needed in this field. Metformin (MET) has anti-oxidant, anti-inflammatory, anti-apoptotic and neuroprotective properties, which may exert a potential therapeutic effect on SCI. In this study, we established a zein-based MET-loaded nanodrug system (CAQK-MET-NPs) for the targeted drug delivery for SCI. The results showed that MET could be effectively encapsulated into zein to obtain the zein-based spherical nanoparticles. Pharmacokinetic analysis indicated that CAQK-MET-NPs exhibited sustained-release and long-term therapeutic effects. The fluorescence imaging and tissue distribution experiments showed that CAQK-MET-NPs could efficiently accumulate at the lesion site of SCI rats. In conclusion, CAQK-MET-NPs may be a promising nanodrug for the treatment of SCI.
    Keywords:  CAQK; Metformin; Spinal cord injury; Targeted accumulation; Zein-based nanoparticles
    DOI:  https://doi.org/10.1016/j.nano.2022.102526
  109. Biomater Sci. 2022 Feb 01.
    MnO2 coated nanotheranostic LDH for synergistic cascade chemo/chemodynamic cancer therapy under the guidance of MRI-targeted diagnosis.
    Bengao Zhu, Xuefei Lv, Mengmeng Zhang, Huiying Wang, Senbin Chen, Jintao Zhu.
      Integrating magnetic resonance imaging (MRI)-targeted diagnosis with synergistic cascade treatments, such as chemo/chemodynamic therapy (CT/CDT), is highly desired for promoting the antitumor performance; however, the rational design of such "all-in-one" nanomedicine is still in its infancy. In this report, using MnO2 coated layered dihydroxide (LDH) as a carrier to load chemotherapy molecule 5-flurouracil (5-FU), a novel tumor microenvironment (TME) regulating nanodrug is formed: LDH/5-FU@MnO2. Combined guidance of CT/CDT and MRI is used to realize synergistic diagnosis and enhanced anti-tumor efficacy. MnO2 is converted into Mn2+ in the presence of reducing agent GSH, the in situ generated Mn2+, not only serves as the chemical fuel for the Fenton reaction, combining H2O2 depletion and ˙OH generation, but can also be used as a nuclear magnetic contrast agent for MRI. Moreover, the tumor acidic environment is able to trigger 5-FU release for initiating chemotherapy in the tumor zone. This "all-in-one" LDH/5-FU@MnO2 nanomedicine integrating multiple treatment modalities and magnetic resonance imaging properties, causes persistent modulation of the TME and exhibits effective antitumor theranostic performance. Such a sophisticated nanomedicine design not only achieves improved CT/CDT antitumor efficiency, but also realizes the activatable magnetic resonance imaging. This strategy combines the merits of each treatment, significantly enhancing the anticancer efficacy, and is anticipated to display promising potentials in the clinical translation plans.
    DOI:  https://doi.org/10.1039/d1bm01806j
  110. Transl Cancer Res. 2021 Feb;10(2): 656-668
    The anti-tumoral effects of the oxygen carrier YQ23 in a triple-negative breast cancer syngeneic model.
    Elysian Chow, Jonathan S H Lau, Terence Wai, Ian P Y Lam.
      Background: Triple-negative breast cancer (TNBC), an aggressive breast cancer subtype, is associated with poor prognosis and high mortality rate. In the search for effective therapeutic options, preclinical studies have suggested using systemic oxygenation to inhibit tumor growth and metastasis in various cancer models, including TNBC, by weakening the hypoxia-A2A adenosine receptors (A2AR)-driven immunosuppression in the tumor microenvironment (TME). In our present study, a hemoglobin-based oxygen carrier (HBOC) "YQ23" was tested for its role in modulating the TME and tumor inhibition.Methods: A syngeneic TNBC mouse model was established by inoculating 4T1 cells subcutaneously in BALB/c mice. Tumor (~100 mm3) bearing mice were treated either with saline or YQ23 (400 mg/kg) i.v. once weekly. To prove the immune-regulatory role of YQ23, CD4+ and CD8+ cells were depleted from a group of mice prior to treatment. Tumor growth was monitored for four weeks while xenografts were isolated at the end of the treatment for ex vivo immunohistological examination.
    Results: YQ23 significantly inhibited the tumor growth, and this suppressive effect was abolished by depleting the host immune cells. Immunohistochemical staining of xenograft sections showed YQ23 reduced the level of hypoxia and adenosine producing ecto-enzyme CD73. Although there was no significant difference in the make up of the intra-tumoral immune populations, we observed a down-regulation of the immune checkpoint PD-1. In concordance with the weakened immunosuppression, the inflammatory cytokine interferon γ and cytolytic granzyme B were upregulated.
    Conclusions: YQ23 treatment may be a potential therapeutic strategy to modulate the TME in TNBC.
    Keywords:  Adenosine; hypoxia; triple-negative breast cancer (TNBC); xenograft
    DOI:  https://doi.org/10.21037/tcr-20-2768
  111. Nat Rev Cancer. 2022 Jan 31.
    The role of ROS in tumour development and progression.
    Eric C Cheung, Karen H Vousden.
      Eukaryotic cells have developed complex systems to regulate the production and response to reactive oxygen species (ROS). Different ROS control diverse aspects of cell behaviour from signalling to death, and deregulation of ROS production and ROS limitation pathways are common features of cancer cells. ROS also function to modulate the tumour environment, affecting the various stromal cells that provide metabolic support, a blood supply and immune responses to the tumour. Although it is clear that ROS play important roles during tumorigenesis, it has been difficult to reliably predict the effect of ROS modulating therapies. We now understand that the responses to ROS are highly complex and dependent on multiple factors, including the types, levels, localization and persistence of ROS, as well as the origin, environment and stage of the tumours themselves. This increasing understanding of the complexity of ROS in malignancies will be key to unlocking the potential of ROS-targeting therapies for cancer treatment.
    DOI:  https://doi.org/10.1038/s41568-021-00435-0
  112. Adv Cancer Res. 2022 ;pii: S0065-230X(21)00065-8. [Epub ahead of print]153 1-27
    A brief history of RAS and the RAS Initiative.
    Frank McCormick.
      In this review, I provide a brief history of the discovery of RAS and the GAPs and GEFs that regulate its activity from a personal perspective. Much of this history has been driven by technological breakthroughs that occurred concurrently, such as molecular cloning, cDNA expression to analyze RAS proteins and their structures, and application of PCR to detect mutations. I discuss the RAS superfamily and RAS proteins as therapeutic targets, including recent advances in developing RAS inhibitors. I also describe the role of the RAS Initiative at Frederick National Laboratory for Cancer Research in advancing development of RAS inhibitors and providing new insights into signaling complexes and interaction of RAS proteins with the plasma membrane.
    Keywords:  GAP; HRAS; KRAS; NRAS; RAS superfamily; SOS
    DOI:  https://doi.org/10.1016/bs.acr.2021.07.003
  113. Adv Cancer Res. 2022 ;pii: S0065-230X(21)00063-4. [Epub ahead of print]153 169-203
    Targeting RAS oncogenesis with SOS1 inhibitors.
    Roman Christian Hillig, Benjamin Bader.
      RAS proteins play major roles in many human cancers, but programs to develop direct RAS inhibitors so far have only been successful for the oncogenic KRAS mutant G12C. As an alternative approach, inhibitors for the RAS guanine nucleotide exchange factor SOS1 have been investigated by several academic groups and companies, and major progress has been achieved in recent years in the optimization of small molecule activators and inhibitors of SOS1. Here, we review the discovery and development of small molecule modulators of SOS1 and their molecular binding modes and modes of action. As targeting the RAS pathway is expected to result in the development of resistance mechanisms, SOS1 inhibitors will most likely be best applied in vertical combination approaches where two nodes of the RAS signaling pathway are hit simultaneously. We summarize the current understanding of which combination partners may be most beneficial for patients with RAS driven tumors.
    Keywords:  Activator; Cancer; Combination therapy; GEF; Guanine nucleotide exchange factor; KRAS; RASopathies; SOS1; Small molecule inhibitor; Son of sevenless
    DOI:  https://doi.org/10.1016/bs.acr.2021.07.001
  114. Int J Pharm. 2022 Feb 01. pii: S0378-5173(22)00087-4. [Epub ahead of print] 121533
    PEGylated dendritic polyurethane as unimolecular micelles for tumor chemotherapy: Effect of molecular architecture.
    Wei Chen, Peng Liu.
      Unimolecular micelles have attracted intense interests as drug carriers for tumor chemotherapy owing to their superior stability in comparison with the self-assembled supramolecular ones. Among them, the dendritic polymers with the polar frameworks could favour the loading of chemotherapeutic drugs rather than the hyperbranched polymers via radical polymerization, by enhancing the interaction with drugs. While the tedious synthesis procedure for dendritic polymers could be simplified with the construction principle on urethane chemistry. Here, the PEGylated dendritic polyurethanes, Ph-DPUGly-PEG and Ph-DPUTEA-PEG, were designed with glycerol or triethanolamine as monomer, respectively. The effect of the molecular architecture of the Ph-DPU-PEGs unimolecular micelles on the controlled drug releasing performance was compared. It was found that the Ph-DPUTEA-PEG with tertiary amine as branching points could efficiently endow the pH-triggered drug release, due to its protonation.
    Keywords:  Drug carriers; dendritic polyurethane; molecular design; pH-triggered drug release; unimolecular micelles
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.121533
  115. Adv Inorg Chem. 2022 Jan 25.
    Photodynamic inactivation (PDI) as a promising alternative to current pharmaceuticals for the treatment of resistant microorganisms.
    Barbara Pucelik, Janusz M Dąbrowski.
      Although the whole world is currently observing the global battle against COVID-19, it should not be underestimated that in the next 30 years, approximately 10 million people per year could be exposed to infections caused by multi-drug resistant bacteria. As new antibiotics come under pressure from unpredictable resistance patterns and relegation to last-line therapy, immediate action is needed to establish a radically different approach to countering resistant microorganisms. Among the most widely explored alternative methods for combating bacterial infections are metal complexes and nanoparticles, often in combination with light, but strategies using monoclonal antibodies and bacteriophages are increasingly gaining acceptance. Photodynamic inactivation (PDI) uses light and a dye termed a photosensitizer (PS) in the presence of oxygen to generate reactive oxygen species (ROS) in the field of illumination that eventually kill microorganisms. Over the past few years, hundreds of photomaterials have been investigated, seeking ideal strategies based either on single molecules (e.g., tetrapyrroles, metal complexes) or in combination with various delivery systems. The present work describes some of the most recent advances of PDI, focusing on the design of suitable photosensitizers, their formulations, and their potential to inactivate bacteria, viruses, and fungi. Particular attention is focused on the compounds and materials developed in our laboratories that are capable of killing in the exponential growth phase (up to seven logarithmic units) of bacteria without loss of efficacy or resistance, while being completely safe for human cells. Prospectively, PDI using these photomaterials could potentially cure infected wounds and oral infections caused by various multidrug-resistant bacteria. It is also possible to treat the surfaces of medical equipment with the materials described, in order to disinfect them with light, and reduce the risk of nosocomial infections.
    Keywords:  Antibiotics; Bacteriochlorins; Delivery systems; Metal complexes; Photochemical mechanism; Photodynamic inactivation (PDI); Photosensitizers; Porphyrins; Reactive oxygen species (ROS)
    DOI:  https://doi.org/10.1016/bs.adioch.2021.12.003
  116. Am J Chin Med. 2022 Feb 03. 1-19
    Anticancer Effects of Taraxacum via Cell Cycle Arrest, Necrosis, Apoptosis, and Endoplasmic Reticulum Stress.
    Chien-Jung Lin, Shu-Ting Liu, Rong-Chi Yang, Li-Hsiang Wang, Chen-Chen Tsai, Teng-Wei Chen, Shih-Ming Huang.
      Dandelion (Taraxacum species) is a wild plant with over 2500 species. Flavonoids, phenolic compounds, saponins, sesquiterpenes, and sugars have been detected in the organs of Taraxacum, and for centuries it has been used in traditional medicine for the relief and treatment of various diseases. However, details of its working mechanism remain unclear. Bioactive compounds in herbal extracts generally have low yields, which makes their isolation and purification intensive in terms of time and cost. Here, to assess their versatility and safety, we applied aqueous extracts of two species of Taraxacum, T. mongolicum and T. formosanum, including extracts of both fresh and dried T. formosanum, to compare their potential antitumor effects on HeLa human cervical cancer cells, three liver cancer cell lines, and one normal liver cell line. After being treated with a lower dose of Taraxacum, the upregulation of subG1 and S populations, as well as increased levels of p-eIF2[Formula: see text]-to-eIF2[Formula: see text] ratio, were observed in HeLa cells, whereas the downregulation of S population and the absence of mRNA expressions were detected in HeLa cells when being treated with a higher dose of Taraxacum. These results indicated that Taraxacumcould induce apoptosis and endoplasmic reticulum stress while suppressing proliferation, transcription, colony formation, migration, and invasion. What's more, we also found that the effects of fresh T. formosanum were much stronger than that of T. mongolicumin HeLa cells. Based on these results, we suggest that T. formosanum may contain specific compound(s) that are potentially useful for cancer therapy. However, much work remains to identify these effective compounds for the future application of Taraxacumto cancer therapy.
    Keywords:  Endoplasmic Reticulum Stress; Robotic Stress; T. Formosanum; Taraxacum
    DOI:  https://doi.org/10.1142/S0192415X22500227
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