bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2022–02–13
85 papers selected by
Yasmin Elkabani, Egyptian Foundation for Research and Community Development
  1. Harnessing GLUT1 Targeted Pro-oxidant Ascorbate for Synergistic Phototherapeutics.
  2. Photolytic Removal of Red Blood Cell Membranes Camouflaged on Nanoparticles for Enhanced Cellular Uptake and Combined Chemo-Photodynamic Inhibition of Cancer Cells.
  3. Targeting fuel pocket of cancer cell metabolism: A focus on glutaminolysis.
  4. Multifunctional Doxorubicin@Hollow-Cu9S8 nanoplatforms for Photothermally-Augmented Chemodynamic-Chemo therapy.
  5. Curcumin nanoformulations: Beneficial nanomedicine against cancer.
  6. Multi-responsive nanotheranostics with enhanced tumor penetration and oxygen self-producing capacities for multimodal synergistic cancer therapy.
  7. Bioinspired nanocatalysts as hydrogen peroxide homeostasis regulators for tumor-specific synergistic therapy.
  8. A mechanistic modeling framework reveals the key principles underlying tumor metabolism.
  9. Molecular evidences on anti-inflammatory, anticancer, and memory-boosting effects of frankincense.
  10. Light-controllable charge-reversal nanoparticles with polyinosinic-polycytidylic acid for enhancing immunotherapy of triple negative breast cancer.
  11. Bioactive food components for colorectal cancer prevention and treatment: A good match.
  12. GSH-sensitive polymeric prodrug: Synthesis and loading with photosensitizers as nanoscale chemo-photodynamic anti-cancer nanomedicine.
  13. Methylglyoxal produced by tumor cells through formaldehyde-enhanced Warburg effect potentiated polarization of tumor-associated macrophages.
  14. Photodynamic therapy of melanoma with new, structurally similar, NIR-absorbing ruthenium (II) complexes promotes tumor growth control via distinct hallmarks of immunogenic cell death.
  15. Chitosan derivatives functionalized dual ROS-responsive nanocarriers to enhance synergistic oxidation-chemotherapy.
  16. Pure drug nano-assemblies: A facile carrier-free nanoplatform for efficient cancer therapy.
  17. Indocyanine green assembled free oxygen-nanobubbles towards enhanced near-infrared induced photodynamic therapy.
  18. Light-triggered nitric oxide release and structure transformation of peptide for enhanced intratumoral retention and sensitized photodynamic therapy.
  19. Engineering macrophage exosome disguised biodegradable nanoplatform for enhanced sonodynamic therapy of glioblastoma.
  20. Combination of Photothermal Therapy with Anti-Inflammation Therapy Attenuates the Inflammation Tumor Microenvironment and Weakens Immunosuppression for Enhancement Antitumor Treatment.
  21. Acceleration of antibacterial activity of curcumin loaded biopolymers against methicillin-resistant Staphylococcus aureus: Synthesis, optimization, and evaluation.
  22. Cellular and molecular mechanisms of curcumin on thyroid gland disorders.
  23. Destruction of tumor vasculature by vascular disrupting agents in overcoming the limitation of EPR effect.
  24. Hybrid in situ- forming injectable hydrogels for local cancer therapy.
  25. An insight into anticancer, antioxidant, antimicrobial, antidiabetic and anti-inflammatory effects of quercetin: a review.
  26. Bioresponsive immune-booster-based prodrug nanogel for cancer immunotherapy.
  27. Targeting OXPHOS and the electronic transport chain in cancer; molecular and therapeutic implications.
  28. pH-Responsive, Adorned Nanoniosomes for Codelivery of Cisplatin and Epirubicin: Synergistic Treatment of Tumorigenesis Breast Cancer.
  29. Potential Role of Curcumin for the Treatment of Major Depressive Disorder.
  30. Magnetic Nanoparticle-Mediated Heating for Biomedical Applications.
  31. Construction of heteroaryl-bridged NIR AIEgens for specific imaging of lipid droplets and its application in photodynamic therapy.
  32. The nanocomposites designs of phytomolecules from medicinal and aromatic plants: promising anticancer-antiviral applications.
  33. Polyphenol-modified nanovesicles for synergistically enhanced in vitro tumor cell targeting and apoptosis.
  34. The potential of Graphene Oxide and reduced Graphene Oxide in diagnosis and treatment of Cancer.
  35. Resveratrol-loaded chitosan-pectin core-shell nanoparticles as novel drug delivery vehicle for sustained release and improved antioxidant activities.
  36. Personalized Medicine for Prostate Cancer: Is Targeting Metabolism a Reality?
  37. Intravesical delivery of KDM6A-mRNA via mucoadhesive nanoparticles inhibits the metastasis of bladder cancer.
  38. PLGA+Fe₃O₄+PFP Nanoparticles Drug-Delivery Demonstrates Potential Anti-Tumor Effects on Tumor Cells.
  39. Doxorubicin-loaded polypyrrole nanovesicles for suppressing tumor metastasis through combining photothermotherapy and lymphatic system-targeted chemotherapy.
  40. Water-Soluble Porphyrin-Based Nanoparticles Derived from Electrostatic Interaction for Enhanced Photodynamic Therapy.
  41. Tumor microenvironment-responsive fenton nanocatalysts for intensified anticancer treatment.
  42. The hallmarks of cancer metabolism: Still emerging.
  43. Evoking Highly Immunogenic Ferroptosis Aided by Intramolecular Motion-Induced Photo-Hyperthermia for Cancer Therapy.
  44. Genistein: A Review on its Anti-Inflammatory Properties.
  45. Salvia miltiorrhiza Bge. (Danshen) for Inflammatory Bowel Disease: Clinical Evidence and Network Pharmacology-Based Strategy for Developing Supplementary Medical Application.
  46. Pediatric acute lymphoblastic leukemia management using multitargeting bioactive natural compounds: A systematic and critical review.
  47. Near-Infrared Fluorescent Heptamethine Cyanine Dyes for COX-2 Targeted Photodynamic Cancer Therapy.
  48. Optimized Nanoparticles for Enhanced Oral Bioavailability of a Poorly Soluble Drug: Solid lipid nanoparticles versus Nanostructured lipid carriers.
  49. Skin cancer biology and barriers to treatment: Recent applications of polymeric micro/nanostructures.
  50. Symphony of nanomaterials and immunotherapy based on the cancer-immunity cycle.
  51. Nanotherapeutics in autophagy: a paradigm shift in cancer treatment.
  52. Black soybean (Glycine max (L.) Merr.): paving the way toward new nutraceutical.
  53. Chemotherapeutic potential of hesperetin for cancer treatment, with mechanistic insights: A comprehensive review.
  54. Deferoxamine Counteracts Cisplatin Resistance in A549 Lung Adenocarcinoma Cells by Increasing Vulnerability to Glutamine Deprivation-Induced Cell Death.
  55. Synergic fabrication of multifunctional liposomes nanocomposites for improved radiofrequency ablation combination for liver metastasis cancer therapy.
  56. Satiety associated with calorie restriction and time-restricted feeding: Central neuroendocrine integration.
  57. Targeting Regulated Cell Death with Pharmacological Small Molecules: An Update on Autophagy-Dependent Cell Death, Ferroptosis, and Necroptosis in Cancer.
  58. Blocking EP4 downregulates tumor metabolism and synergizes with anti-PD-1 therapy to activate natural killer cells in a lung adenocarcinoma model.
  59. Nanocapsules: An Emerging Drug Delivery System.
  60. A Nuclear-Targeted AIE Photosensitizer for Enzyme Inhibition and Photosensitization in Cancer Cell Ablation.
  61. A scintillating nanoplatform with upconversion function for the synergy of radiation and photodynamic therapies for deep tumors.
  62. A Systemic Review for Ethnopharmacological Studies on Isatis indigotica Fortune: Bioactive Compounds and their Therapeutic Insights.
  63. Cannabis with breast cancer treatment: propitious or pernicious?
  64. The effect of lactate dehydrogenase-A inhibition on intracellular nucleotides and mitochondrial respiration in pancreatic cancer cells.
  65. Versatile ginsenoside Rg3 liposomes inhibit tumor metastasis by capturing circulating tumor cells and destroying metastatic niches.
  66. Current Nano-therapeutic Approaches Ameliorating Inflammation in Cancer Progression.
  67. Jackfruit (Artocarpus heterophyllus Lam.) in health and disease: a critical review.
  68. Anticancer Effect of Tanshinones on Female Breast Cancer and Gynecological Cancer.
  69. Rhenium-guanidine complex as photosensitizer: trigger HeLa cell apoptosis through death receptor-mediated, mitochondria-mediated and cell cycle arrest pathways.
  70. Anticancer potential of allicin: A review.
  71. Oxamate targeting aggressive cancers with special emphasis to brain tumors.
  72. Determining the factors affecting energy metabolism and energy requirement in cancer patients.
  73. A comprehensive and current review on the role of flavonoids in lung cancer-Experimental and theoretical approaches.
  74. Combretastatin A4-loaded poly(lactic-co-glycolic acid)/soybean lecithin nanoparticles with enhanced drug dissolution rate and antiproliferation activity.
  75. Photodynamic therapy in the treatment of denture stomatitis: A systematic review and meta-analysis.
  76. Mineral medicine: from traditional drugs to multifunctional delivery systems.
  77. Novel Glucose-Responsive Antioxidant Hybrid Hydrogel for Enhanced Diabetic Wound Repair.
  78. CRAF dimerization with ARAF regulates KRAS-driven tumor growth.
  79. The bioactivity and applications of pomegranate peel extract: A review.
  80. Can dietary patterns prevent cognitive impairment and reduce Alzheimer's disease risk: exploring the underlying mechanisms of effects.
  81. Cyanobacteria-based self-oxygenated photodynamic therapy for anaerobic infection treatment and tissue repair.
  82. The osteogenic niche-targeted arsenic nanoparticles prevent colonization of disseminated breast tumor cells in the bone.
  83. A cyclodextrin-based nanoformulation achieves co-delivery of ginsenoside Rg3 and quercetin for chemo-immunotherapy in colorectal cancer.
  84. Characterization of the physicochemical properties, antioxidant activity, and antiproliferative activity of natural melanin from S. reiliana.
  85. Chemical investigation and screening of anti-cancer potential of Syzygium aromaticum L. bud (clove) essential oil nanoemulsion.
  1. Angew Chem Int Ed Engl. 2022 Feb 09.
    Harnessing GLUT1 Targeted Pro-oxidant Ascorbate for Synergistic Phototherapeutics.
    Seyoung Koo, Min-Goo Lee, Amit Sharma, Mingle Li, Xingcai Zhang, Kanyi Pu, Sung-Gil Chi, Jong Seung Kim.
      Despite extensive efforts to realize effective photodynamic therapy (PDT), there is still a lack of therapeutic approaches concisely-structured to mitigate major obstacles of PDT in clinical applications. Herein, we report a molecular strategy exploiting ascorbate chemistry to enhance the efficacy of PDT in cancer cells overexpressing glucose transporter 1 (GLUT1). AA-EtNBS, a 5-O-substituted ascorbate-photosensitizer (PS) conjugate, undergoes a reversible structural conversion of the ascorbate moiety in the presence of reactive oxygen species (ROS) and glutathione (GSH), thereby promoting its uptake in GLUT1-overexpressed KM12C colon cancer cells and perturbing tumor redox homeostasis, respectively. Due to the peculiar pro-oxidant role of ascorbate in tumour environments, AA-EtNBS effectively sensitised KM12C cancer cells prior to PS-mediated superoxide radical generation under near-infrared (NIR) illumination. AA-EtNBS successfully exhibited GLUT1-targeted synergistic therapeutic efficacy during PDT both in vitro and in vivo. Therefore, this study outlines a promising strategy employing ascorbate both as a targeting unit for GLUT1-overexpressed cancer cells and redox homeostasis destruction agent, thereby enhancing therapeutic responses towards anticancer treatment when used in conjunction with conventional PDT.
    Keywords:  GLUT1; photodynamic therapy; phototherapeutics; targeted therapy
    DOI:  https://doi.org/10.1002/anie.202110832
  2. Mol Pharm. 2022 Feb 11.
    Photolytic Removal of Red Blood Cell Membranes Camouflaged on Nanoparticles for Enhanced Cellular Uptake and Combined Chemo-Photodynamic Inhibition of Cancer Cells.
    Yanfei Liu, Nachuan Wen, Ke Li, Minquan Li, Shengnan Qian, Shiran Li, Ting Jiang, Ting Wang, Yuwei Wu, Zhenbao Liu.
      Biomimetic therapeutics offer great potential for drug delivery that avoids immune recognition. However, the coated cell membrane usually hinders the cellular uptake of nanoparticles; thus, structure-changeable formulations have attracted increasing attention. Herein, we report photolytic pyropheophorbide a (PA)-inserted red blood cell (RBC) membrane-camouflaged curcumin dimeric prodrug (CUR2-TK)-poly(lactic-co-glycolic acid) (PLGA) nanoparticles [(CUR2-TK)-PLGA@RBC-PA] for enhanced cancer therapy. In these nanoparticles, the inner core was constructed using PLGA and loaded with our synthesized reactive oxygen species (ROS)-responsive cleavable curcumin dimeric prodrug (CUR2-TK). The nanoparticles generated ROS in response to the light irradiation attributed to the incorporated PA. The ROS further triggered the lysis of the cell membrane and exposed the nanoparticles for enhanced tumor cellular uptake, and the ROS also cleaved CUR2-TK for controlled CUR drug release. Moreover, the ROS performed photodynamic therapy (PDT). The chemotherapy and PDT produced a combined effect in the treatment of cancer cells, thus enhancing anticancer therapeutic efficacy.
    Keywords:  cancer therapy; curcumin dimeric prodrug; photosensitizer; red blood cell membrane
    DOI:  https://doi.org/10.1021/acs.molpharmaceut.1c00720
  3. Biochem Pharmacol. 2022 Feb 04. pii: S0006-2952(22)00037-5. [Epub ahead of print] 114943
    Targeting fuel pocket of cancer cell metabolism: A focus on glutaminolysis.
    Shagun Sharma, Navneet Agnihotri, Sandeep Kumar.
      Advances in cell metabolism over the past few decades have demonstrated glutamine as an essential nutrient for cancer cell survival and proliferation. Glutamine offers a remarkable capacity to fuel diverse metabolic pathways in cancer cells including the Krebs cycle, maintenance of redox homeostasis, and synthesis of cellular building blocks such as nucleic acids, fatty acids, glutathione, and other amino acids. The increase in glutaminolysis has further been linked to the accumulation of oncometabolites such as 2HG (2-Hydroxyglutarate), succinate, fumarate, etc., thereby contributing to tumorigenesis via regulating epigenetic modification of imprinted genes. Therefore, therapeutic targeting of glutaminolysis in cancer cells is worth exploring for possible treatment strategies for cancer management. In this review, we have discussed the detailed mechanism of glutamine uptake, transport, and its instrumental role in rewiring the metabolic adaptation of cancer cells in the tumor microenvironment under nutrient deprivation and hypoxia. Furthermore, we have attempted to provide an updated therapeutic intervention of glutamine metabolism as a treatment strategy for cancer management.
    Keywords:  Cancer Cell Metabolism; Glutamine; Glutaminolysis; Tumor Microenvironment, Chemotherapy
    DOI:  https://doi.org/10.1016/j.bcp.2022.114943
  4. J Colloid Interface Sci. 2022 Jan 29. pii: S0021-9797(22)00176-X. [Epub ahead of print]615 38-49
    Multifunctional Doxorubicin@Hollow-Cu9S8 nanoplatforms for Photothermally-Augmented Chemodynamic-Chemo therapy.
    Xiaohan Liu, Peng Geng, Nuo Yu, Zheng Xie, Yirou Feng, Qin Jiang, Maoquan Li, Ye Song, Weishuai Lian, Zhigang Chen.
      Multimodal therapy has attracted increasing interests in tumor treatment due to its high anti-cancer efficacy, and the key is to develop multifunctional nanoagents. The classic multifunctional nanoagents are made up of expensive and complex components, leading to limited practical applications. To solve these problems, we have developed the polyethylene glycol (PEG) coated hollow Cu9S8 nanoparticles (H-Cu9S8/PEG NPs), whose H-Cu9S8 component exhibits the photothermal effect for near-infrared (NIR) photothermal therapy (PTT), the Fenton-like catalytic activity for chemodynamic therapy (CDT), and the drug-loading capacity for chemotherapy. The H-Cu9S8/PEG NPs with a diameter of ∼ 100 nm have been synthesized by sulfurizing cuprous oxide (Cu2O) nanoparticles through "Kirkendall effect", and they exhibit high photothermal conversion efficiency of 40.9%. Meanwhile, the H-Cu9S8/PEG NPs are capable of a Fenton-like reaction, which can be augmented by 2 times under the NIR irradiation. The hollow structure gives the H-Cu9S8/PEG high doxorubicin (DOX) loading capacity (21.1%), and then the DOX release can be further improved by pH and photothermal effect. When the DOX@H-Cu9S8/PEG dispersions are injected into the tumor-bearing mice, the tumor growth can be efficiently inhibited due to the synergistic effect of photothermally-augmented CDT-chemo therapy. Therefore, the DOX@H-Cu9S8/PEG can serve as a multifunctional nanoplatform for photothermally-augmented CDT-chemo treatment of malignant tumors.
    Keywords:  Chemodynamic therapy; Chemotherapy; CuS; Near infrared; Photothermal effect
    DOI:  https://doi.org/10.1016/j.jcis.2022.01.156
  5. Phytother Res. 2022 Feb 07.
    Curcumin nanoformulations: Beneficial nanomedicine against cancer.
    Solmaz Maleki Dizaj, Mahdieh Alipour, Elaheh Dalir Abdolahinia, Elham Ahmadian, Aziz Eftekhari, Haleh Forouhandeh, Yalda Rahbar Saadat, Simin Sharifi, Sepideh Zununi Vahed.
      Curcumin is a phytochemical achieved from the plant turmeric. It is extensively utilized for the treatment of several types of diseases such as cancers. Nevertheless, its efficiency has been limited because of rapid metabolism, low bioavailability, poor water solubility, and systemic elimination. Scientists have tried to solve these problems by exploring novel drug delivery systems such as lipid-based nanoparticles (NPs) (e.g., solid lipid NPs, nanostructured lipid carriers, and liposomes), polymeric NPs, micelles, nanogels, cyclodextrin, gold, and mesoporous silica NPs. Among these, liposomes have been the most expansively studied. This review mainly focuses on the different curcumin nanoformulations and their use in cancer therapy in vitro, in vivo, and clinical studies. Despite the development of curcumin-containing NPs for the treatment of cancer, potentially serious side effects, including interactions with other drugs, some toxicity aspects of NPs may occur that require more high-quality investigations to firmly establish the clinical efficacy.
    Keywords:  cancer; curcumin; nanoformulations
    DOI:  https://doi.org/10.1002/ptr.7389
  6. Acta Pharm Sin B. 2022 Jan;12(1): 406-423
    Multi-responsive nanotheranostics with enhanced tumor penetration and oxygen self-producing capacities for multimodal synergistic cancer therapy.
    Shuangquan Gou, Nanxi Chen, Xiaoai Wu, Menghang Zu, Shixiong Yi, Binwu Ying, Fangyin Dai, Bowen Ke, Bo Xiao.
      Incorporation of multiple functions into one nanoplatform can improve cancer diagnostic efficacy and enhance anti-cancer outcomes. Here, we constructed doxorubicin (DOX)-loaded silk fibroin-based nanoparticles (NPs) with surface functionalization by photosensitizer (N770). The obtained nanotheranostics (N770-DOX@NPs) had desirable particle size (157 nm) and negative surface charge (-25 mV). These NPs presented excellent oxygen-generating capacity and responded to a quadruple of stimuli (acidic solution, reactive oxygen species, glutathione, and hyperthermia). Surface functionalization of DOX@NPs with N770 could endow them with active internalization by cancerous cell lines, but not by normal cells. Furthermore, the intracellular NPs were found to be preferentially retained in mitochondria, which were also efficient for near-infrared (NIR) fluorescence imaging, photothermal imaging, and photoacoustic imaging. Meanwhile, DOX could spontaneously accumulate in the nucleus. Importantly, a mouse test group treated with N770-DOX@NPs plus NIR irradiation achieved the best tumor retardation effect among all treatment groups based on tumor-bearing mouse models and a patient-derived xenograft model, demonstrating the unprecedented therapeutic effects of trimodal imaging-guided mitochondrial phototherapy (photothermal therapy and photodynamic therapy) and chemotherapy. Therefore, the present study brings new insight into the exploitation of an easy-to-use, versatile, and robust nanoplatform for programmable targeting, imaging, and applying synergistic therapy to tumors.
    Keywords:  Cancer; Chemotherapy; Mitochondrial targeting; Nanotheranostic; Oxygen self-generation; Phototherapy; Quadruple responsibility; Silk fiborin
    DOI:  https://doi.org/10.1016/j.apsb.2021.07.001
  7. Biomater Sci. 2022 Feb 07.
    Bioinspired nanocatalysts as hydrogen peroxide homeostasis regulators for tumor-specific synergistic therapy.
    Yajie Zhao, Xiao Xiao, Fan Jiang, Binbin Ding, Ziyong Cheng, Ping'an Ma, Jun Lin.
      Tailored to the special tumor microenvironment (TME), chemodynamic therapy (CDT) has been introduced to generate hydroxyl radicals (˙OH) primarily for the tumor via Fenton and Fenton-like reactions. However, deficient hydrogen peroxide (H2O2) levels and low reaction efficiency severely limit the development of CDT, which have attracted tremendous efforts to alleviate. Inspired by the H2O2 homeostasis in cancer cells, here, hollow Cu2-xS nanocatalysts (CS NCs) loaded with doxorubicin (DOX) (named CSD NCs) are engineered. As biometric enzyme-like reactive oxygen species (ROS) regulators, the CS NCs were fabricated to cyclically take advantage of H2O2 for enhanced CDT and synergistic photothermal therapy (PTT) and photodynamic therapy (PDT). According to the conception here, CDT is strengthened due to the H2O2 generation step, which is dependent on superoxide radical (O2˙-) conversion by the superoxide dismutase-mimicking activity of the nanoparticles. Meanwhile, catalase-like activity promotes O2 levels, which overcome the hypoxia limitation in the TME and further promote ˙OH and O2˙- creation and augmentation through PDT/PTT under NIR II laser stimulation. Moreover, DOX released in the acidic environment can activate nicotinamide adenine dinucleotide phosphate oxidases (NOXs), which increase O2˙- generation and successively participates in the next H2O2 supply in the cycle. Overall, this work paves the way to construct synergistic therapy agents with H2O2 cyclic utilization ability for PDT/PTT/chemotherapy and intensive CDT.
    DOI:  https://doi.org/10.1039/d1bm02000e
  8. PLoS Comput Biol. 2022 Feb 11. 18(2): e1009841
    A mechanistic modeling framework reveals the key principles underlying tumor metabolism.
    Shubham Tripathi, Jun Hyoung Park, Shivanand Pudakalakatti, Pratip K Bhattacharya, Benny Abraham Kaipparettu, Herbert Levine.
      While aerobic glycolysis, or the Warburg effect, has for a long time been considered a hallmark of tumor metabolism, recent studies have revealed a far more complex picture. Tumor cells exhibit widespread metabolic heterogeneity, not only in their presentation of the Warburg effect but also in the nutrients and the metabolic pathways they are dependent on. Moreover, tumor cells can switch between different metabolic phenotypes in response to environmental cues and therapeutic interventions. A framework to analyze the observed metabolic heterogeneity and plasticity is, however, lacking. Using a mechanistic model that includes the key metabolic pathways active in tumor cells, we show that the inhibition of phosphofructokinase by excess ATP in the cytoplasm can drive a preference for aerobic glycolysis in fast-proliferating tumor cells. The differing rates of ATP utilization by tumor cells can therefore drive heterogeneity with respect to the presentation of the Warburg effect. Building upon this idea, we couple the metabolic phenotype of tumor cells to their migratory phenotype, and show that our model predictions are in agreement with previous experiments. Next, we report that the reliance of proliferating cells on different anaplerotic pathways depends on the relative availability of glucose and glutamine, and can further drive metabolic heterogeneity. Finally, using treatment of melanoma cells with a BRAF inhibitor as an example, we show that our model can be used to predict the metabolic and gene expression changes in cancer cells in response to drug treatment. By making predictions that are far more generalizable and interpretable as compared to previous tumor metabolism modeling approaches, our framework identifies key principles that govern tumor cell metabolism, and the reported heterogeneity and plasticity. These principles could be key to targeting the metabolic vulnerabilities of cancer.
    DOI:  https://doi.org/10.1371/journal.pcbi.1009841
  9. Phytother Res. 2022 Feb 10.
    Molecular evidences on anti-inflammatory, anticancer, and memory-boosting effects of frankincense.
    Mina Khajehdehi, Mohammad Khalaj-Kondori, Behzad Baradaran.
      Chemical diversity of natural products with drug-like features has attracted much attention from medicine to develop more safe and effective drugs. Their anti-inflammatory, antitumor, analgesic, and other therapeutic properties are sometimes more successful than chemical drugs in controlling disease due to fewer drug resistance and side effects and being more tolerable in a long time. Frankincense, the oleo gum resin extracted from the Boswellia species, contains some of these chemicals. The anti-inflammatory effect of its main ingredient, boswellic acid, has been traditionally used to treat many diseases, mainly those target memory functions. In this review, we have accumulated research evidence from the beneficial effect of Frankincense consumption in memory improvement and the prevention of inflammation and cancer. Besides, we have discussed the molecular pathways mediating the therapeutic effects of this natural supplement.
    Keywords:  boswellic acid; cancer; frankincense; inflammation; memory improvement; nutraceutical
    DOI:  https://doi.org/10.1002/ptr.7399
  10. Acta Pharm Sin B. 2022 Jan;12(1): 353-363
    Light-controllable charge-reversal nanoparticles with polyinosinic-polycytidylic acid for enhancing immunotherapy of triple negative breast cancer.
    Lei Fang, Zitong Zhao, Jue Wang, Ping Xiao, Xiangshi Sun, Yaping Ding, Pengcheng Zhang, Dangge Wang, Yaping Li.
      Nucleic acid drugs are highly applicable for cancer immunotherapy with promising therapeutic effects, while targeting delivery of these drugs to disease lesions remains challenging. Cationic polymeric nanoparticles have paved the way for efficient delivery of nucleic acid drugs, and achieved stimuli-responsive disassembly in tumor microenvironment (TME). However, TME is highly heterogeneous between individuals, and most nanocarriers lack active-control over the release of loaded nucleic acid drugs, which will definitely reduce the therapeutic efficacy. Herein, we have developed a light-controllable charge-reversal nanoparticle (LCCN) with controlled release of polyinosinic-polycytidylic acid [Poly(I:C)] to treat triple negative breast cancer (TNBC) by enhanced photodynamic immunotherapy. The nanoparticles keep suitably positive charge for stable loading of Poly(I:C), while rapidly reverse to negative charge after near-infrared light irradiation to release Poly(I:C). LCCN-Poly(I:C) nanoparticles trigger effective phototoxicity and immunogenic cell death on 4T1 tumor cells, elevate antitumor immune responses and inhibit the growth of primary and abscopal 4T1 tumors in mice. The approach provides a promising strategy for controlled release of various nucleic acid-based immune modulators, which may enhance the efficacy of photodynamic immunotherapy against TNBC.
    Keywords:  Cancer immunotherapy; Charge-reversal; Nanoparticles; Photodynamic therapy; Polyinosinic-polycytidylic acid; ROS-responsive; Triple negative breast cancer; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.apsb.2021.06.006
  11. Crit Rev Food Sci Nutr. 2022 Feb 06. 1-15
    Bioactive food components for colorectal cancer prevention and treatment: A good match.
    Samuel Amintas, Charles Dupin, Julian Boutin, Pauline Beaumont, François Moreau-Gaudry, Aurélie Bedel, Stéphanie Krisa, Véronique Vendrely, Sandrine Dabernat.
      Colorectal cancer (CRC) is the third most frequent cancer worldwide, accounts for about 10% of the total cancer cases, and ranks as the second cause of death by cancer. CRC is more prevalent in developed countries in close causal relation with occidental diets. Due to anatomy, the diet has a strong impact on CRC. High contents in meat are acknowledged risk factors whereas a diet rich in fruits and vegetables is an established CRC protective factor. Fruits and vegetables contain numerous Bioactive Food Components (BFCs), physiologically active food compounds, beneficial on health. Preventive and therapeutic benefits of BFCs in cancer have increasingly been reported over the past 20 years. BFCs show both chemopreventive and anti-tumor properties in CRC but more interestingly, abundant research describes BFCs as enhancers of conventional cancer treatments. Despite these promising results, their clinical transferability is slowed down by bioavailability interrogations and their poorly understood hormetic effect. In this review, we would like to reposition BFCs as well-fitted for applications in CRC. We provide a synthetic overview of trustworthy BFC applications in CRC, with a special highlight on combinatory approaches and conventional cancer treatment potentiation strategies.
    Keywords:  Bioactive food; cancer prevention; combination cancer treatment; curcumin; natural compounds; resveratrol
    DOI:  https://doi.org/10.1080/10408398.2022.2036095
  12. Acta Pharm Sin B. 2022 Jan;12(1): 424-436
    GSH-sensitive polymeric prodrug: Synthesis and loading with photosensitizers as nanoscale chemo-photodynamic anti-cancer nanomedicine.
    Lei Luo, Yiming Qi, Hong Zhong, Shinan Jiang, Hu Zhang, Hao Cai, Yahui Wu, Zhongwei Gu, Qiyong Gong, Kui Luo.
      Precisely delivering combinational therapeutic agents has become a crucial challenge for anti-tumor treatment. In this study, a novel redox-responsive polymeric prodrug (molecular weight, MW: 93.5 kDa) was produced by reversible addition-fragmentation chain transfer (RAFT) polymerization. The amphiphilic block polymer-doxorubicin (DOX) prodrug was employed to deliver a hydrophobic photosensitizer (PS), chlorin e6 (Ce6), and the as-prepared nanoscale system [NPs(Ce6)] was investigated as a chemo-photodynamic anti-cancer agent. The glutathione (GSH)-cleavable disulfide bond was inserted into the backbone of the polymer for biodegradation inside tumor cells, and DOX conjugated onto the polymer with a disulfide bond was successfully released intracellularly. NPs(Ce6) released DOX and Ce6 with their original molecular structures and degraded into segments with low MWs of 41.2 kDa in the presence of GSH. NPs(Ce6) showed a chemo-photodynamic therapeutic effect to kill 4T1 murine breast cancer cells, which was confirmed from a collapsed cell morphology, a lifted level in the intracellular reactive oxygen species, a reduced viability and induced apoptosis. Moreover, ex vivo fluorescence images indicated that NPs(Ce6) retained in the tumor, and exhibited a remarkable in vivo anticancer efficacy. The combinational therapy showed a significantly increased tumor growth inhibition (TGI, 58.53%). Therefore, the redox-responsive, amphiphilic block polymeric prodrug could have a great potential as a chemo-photodynamic anti-cancer agent.
    Keywords:  Combinational therapy; Nanomedicine; Photodynamic therapy; Polymeric prodrug; Stimuli responsiveness
    DOI:  https://doi.org/10.1016/j.apsb.2021.05.003
  13. Toxicol Appl Pharmacol. 2022 Feb 05. pii: S0041-008X(22)00055-2. [Epub ahead of print] 115910
    Methylglyoxal produced by tumor cells through formaldehyde-enhanced Warburg effect potentiated polarization of tumor-associated macrophages.
    Huijuan Ma, Zhaoqian Ding, Ying Xie, Linyi Li, Dan Li, Kaiyan Lou, Wei Wang, Huan Xu.
      Environmental exposure to formaldehyde is known to be associated with cancers and many other diseases. Although formaldehyde has been classified as a group I carcinogen, the molecular mechanisms of its carcinogenicity are still not fully understood. Formaldehyde is also involved in the folate-driven one‑carbon metabolism, and excess amount of formaldehyde was found to interfere with other metabolic pathways including glycolysis, which can enhance Warburg effect and induce immunosuppression in tumor microenvironment. Therefore, different tumor cells and THP-1 derived macrophages were utilized to explore the metabolism-related effects induced by formaldehyde at environmentally relevant concentrations. Significant increases of glucose uptake, glycolysis levels, HIF-1α signaling and methylglyoxal production were observed in tumor cells treated with 20 and 50 μM formaldehyde for 24 h, and the overproduced methylglyoxal in the conditioned medium collected from the tumor cells treated with formaldehyde triggered macrophage polarization towards M2 cells. Myricetin, a flavonol scavenging methylglyoxal, reversed the polarization of macrophages induced by methylglyoxal at 50 μM. These results not only provided essential evidences to reveal the molecular mechanisms of Warburg effect and metabolism-related immunosuppression related to formaldehyde exposure, but also indicated that methylglyoxal could be utilized as a target for therapeutic treatment or prevention of formaldehyde-induced immunotoxicity.
    Keywords:  Formaldehyde; HIF-1α; Methylglyoxal; Polarization; Tumor-associated macrophages; Warburg effect
    DOI:  https://doi.org/10.1016/j.taap.2022.115910
  14. Am J Cancer Res. 2022 ;12(1): 210-228
    Photodynamic therapy of melanoma with new, structurally similar, NIR-absorbing ruthenium (II) complexes promotes tumor growth control via distinct hallmarks of immunogenic cell death.
    Prathyusha Konda, John A Roque Iii, Liubov M Lifshits, Angelita Alcos, Eissa Azzam, Ge Shi, Colin G Cameron, Sherri A McFarland, Shashi Gujar.
      Cancer therapies that generate T cell-based anti-cancer immune responses are critical for clinical success and are favored over traditional therapies. One way to elicit T cell immune responses and generate long-lasting anti-cancer immunity is through induction of immunogenic cell death (ICD), a form of regulated cell death that promotes antigenicity and adjuvanticity within dying cells. Therefore, research in the last decade has focused on developing cancer therapies which stimulate ICD. Herein, we report novel photodynamic therapy (PDT) compounds with immunomodulatory and ICD inducing properties. PDT is a clinically approved, minimally invasive anti-cancer treatment option and has been extensively investigated for its tumor-destroying properties, lower side effects, and immune activation capabilities. In this study, we explore two structurally related ruthenium compounds, ML19B01 and ML19B02, that can be activated with near infrared light to elicit superior cytotoxic properties. In addition to its direct cell killing abilities, we investigated the effect of our PSs on immunological pathways upon activation. PDT treatment with ML19B01 and ML19B02 induced differential expression of reactive oxygen species, proinflammatory response-mediating genes, and heat shock proteins. Dying melanoma cells induced by ML19B01-PDT and ML19B02-PDT contained ICD hallmarks such as calreticulin, ATP, and HMGB1, initiated activation of antigen presenting cells, and were efficiently phagocytosed by bone marrow-derived dendritic cells. Most importantly, despite the distinct profiles of ICD hallmark inducing capacities, vaccination with both PDT-induced dying cancer cells established anti-tumor immunity that protected mice against subsequent challenge with melanoma cells.
    Keywords:  Immunogenic cell death; T cells; cancer immunotherapies; dendritic cells; melanoma; photodynamic therapy
  15. Carbohydr Polym. 2022 Apr 15. pii: S0144-8617(21)01474-0. [Epub ahead of print]282 119087
    Chitosan derivatives functionalized dual ROS-responsive nanocarriers to enhance synergistic oxidation-chemotherapy.
    Jia-Xin Liao, Qun-Fa Huang, Yan-Hong Li, Da-Wei Zhang, Guan-Hai Wang.
      The efficient triggering of prodrug release has become a challengeable task for stimuli-responsive nanomedicine utilized in cancer therapy due to the subtle differences between normal and tumor tissues and heterogeneity. In this work, a dual ROS-responsive nanocarriers with the ability to self-regulate the ROS level was constructed, which could gradually respond to the endogenous ROS to achieve effective, hierarchical and specific drug release in cancer cells. In brief, DOX was conjugated with MSNs via thioketal bonds and loaded with β-Lapachone. TPP modified chitosan was then coated to fabricate nanocarriers for mitochondria-specific delivery. The resultant nanocarriers respond to the endogenous ROS and release Lap specifically in cancer cells. Subsequently, the released Lap self-regulated the ROS level, resulting in the specific DOX release and mitochondrial damage in situ, enhancing synergistic oxidation-chemotherapy. The tumor inhibition Ratio was achieved to 78.49%. The multi-functional platform provides a novel remote drug delivery system in vivo.
    Keywords:  Chemotherapy; Oxidative stress; Prodrug; ROS-responsive; Self-regulation
    DOI:  https://doi.org/10.1016/j.carbpol.2021.119087
  16. Acta Pharm Sin B. 2022 Jan;12(1): 92-106
    Pure drug nano-assemblies: A facile carrier-free nanoplatform for efficient cancer therapy.
    Shuwen Fu, Guanting Li, Wenli Zang, Xinyu Zhou, Kexin Shi, Yinglei Zhai.
      Nanoparticulate drug delivery systems (Nano-DDSs) have emerged as possible solution to the obstacles of anticancer drug delivery. However, the clinical outcomes and translation are restricted by several drawbacks, such as low drug loading, premature drug leakage and carrier-related toxicity. Recently, pure drug nano-assemblies (PDNAs), fabricated by the self-assembly or co-assembly of pure drug molecules, have attracted considerable attention. Their facile and reproducible preparation technique helps to remove the bottleneck of nanomedicines including quality control, scale-up production and clinical translation. Acting as both carriers and cargos, the carrier-free PDNAs have an ultra-high or even 100% drug loading. In addition, combination therapies based on PDNAs could possibly address the most intractable problems in cancer treatment, such as tumor metastasis and drug resistance. In the present review, the latest development of PDNAs for cancer treatment is overviewed. First, PDNAs are classified according to the composition of drug molecules, and the assembly mechanisms are discussed. Furthermore, the co-delivery of PDNAs for combination therapies is summarized, with special focus on the improvement of therapeutic outcomes. Finally, future prospects and challenges of PDNAs for efficient cancer therapy are spotlighted.
    Keywords:  ABC, accelerated blood clearance; ACT, adoptive cell transfer; ATO, atovaquone; ATP, adenosine triphosphate; BV, Biliverdin; Ber, berberine; CI, combination index; CPT, camptothecin; CTLs, cytotoxic T lymphocytes; Cancer treatment; Carrier-free; Ce6, chlorine e6; Combination therapy; DBNP, DOX-Ber nano-assemblies; DBNP@CM, DBNP were cloaked with 4T1 cell membranes; DCs, dendritic cells; DOX, doxorubicin; DPDNAs, dual pure drug nano-assemblies; EGFR, epithelial growth factor receptor; EPI, epirubicin; EPR, enhanced permeability and retention; FRET, Forster Resonance Energy Transfer; GEF, gefitinib; HCPT, hydroxycamptothecin; HMGB1, high-mobility group box 1; IC50, half maximal inhibitory concentration; ICB, immunologic checkpoint blockade; ICD, immunogenic cell death; ICG, indocyanine green; ITM, immunosuppressive tumor microenvironment; MDS, molecular dynamics simulations; MPDNAs, multiple pure drug nano-assemblies; MRI, magnetic resonance imaging; MTX, methotrexate; NIR, near-infrared; NPs, nanoparticles; NSCLC, non-small cell lung cancer; Nano-DDSs, nanoparticulate drug delivery systems; Nanomedicine; Nanotechnology; PAI, photoacoustic imaging; PD-1, PD receptor 1; PD-L1, PD receptor 1 ligand; PDNAs, pure drug nano-assemblies; PDT, photodynamic therapy; PPa, pheophorbide A; PTT, photothermal therapy; PTX, paclitaxel; Poly I:C, polyriboinosinic:polyribocytidylic acid; Pure drug; QSNAP, quantitative structure-nanoparticle assembly prediction; RBC, red blood cell; RNA, ribonucleic acid; ROS, reactive oxygen species; SPDNAs, single pure drug nano-assemblies; Self-assembly; TA, tannic acid; TEM, transmission electron microscopy; TLR4, Toll-like receptor 4; TME, tumor microenvironment; TNBC, triple negative breast; TTZ, trastuzumab; Top I & II, topoisomerase I & II; UA, ursolic acid; YSV, tripeptide tyroservatide; ZHO, Z-Histidine-Obzl; dsRNA, double-stranded RNA; α-PD-L1, anti-PD-L1 monoclonal antibody
    DOI:  https://doi.org/10.1016/j.apsb.2021.08.012
  17. Nano Res. 2022 Jan 29. 1-9
    Indocyanine green assembled free oxygen-nanobubbles towards enhanced near-infrared induced photodynamic therapy.
    Li Yang, Bin Huang, Shiqi Hu, Yuan An, Jingyi Sheng, Yan Li, Yuxin Wang, Ning Gu.
      Photodynamic therapy (PDT) has shown a promising capability for cancer treatment with minimal side effects. Indocyanine green (ICG), the only clinically approved near-infrared (NIR) fluorophore, has been used as a photosensitizer for PDT in clinical application. However, the main obstacle of directly utilizing ICG in the clinic lies in its low singlet oxygen (1O2) quantum yield (QY) and instability in aqueous solution. To improve the PDT efficacy of ICG, free ICG molecules were assembled with free oxygen nanobubbles (NBs-O2) to fabricate ICG-NBs-O2 by hydrophilic-hydrophobe interactions on the gas-liquid interface. Interestingly, 1O2 QY of ICG-NBs-O2 solution was significantly increased to 1.6%, which was estimated to be 8 times as high as that of free ICG solution. Meanwhile, ICG-NBs-O2 exhibited better aqueous solution stability compared with free ICG. Furthermore, through establishing tumor models in nude mice, the therapeutic efficacy of ICG-NBs-O2 was also assessed in the PDT treatment of oral cancer. The tumor volume in ICG-NBs-O2 treated group on day 14 decreased to 0.56 of the initial tumor size on day 1, while the tumor volume in free ICG treated group increased to 2.4 times. The results demonstrated that ICG-NBs-O2 showed excellent tumor ablation in vivo. Therefore, this facile method provided an effective strategy for enhanced PDT treatment of ICG and showed great potential in clinical application.
    Electronic Supplementary Material: Supplementary material (measurements of the singlet oxygen quantum yield of ICG-NBs-O2, time-dependent temperature changes during the laser irradiation, photographs of Cal27 tumor-bearing nude mice and complete blood count of health male balb/c mice analysis) is available in the online version of this article at 10.1007/s12274-022-4085-0.
    Keywords:  aqueous solution stability; free oxygen-nanobubbles; indocyanine green; photodynamic therapy; singlet oxygen quantum yield
    DOI:  https://doi.org/10.1007/s12274-022-4085-0
  18. Bioact Mater. 2022 Jun;12 303-313
    Light-triggered nitric oxide release and structure transformation of peptide for enhanced intratumoral retention and sensitized photodynamic therapy.
    Lingdong Jiang, Danyang Chen, Zhaokui Jin, Chao Xia, Qingqing Xu, Mingjian Fan, Yunlu Dai, Jia Liu, Yuanpei Li, Qianjun He.
      Tumor-targeted delivery of nanomedicine is of great importance to improve therapeutic efficacy of cancer and minimize systemic side effects. Unfortunately, nowadays the targeting efficiency of nanomedicine toward tumor is still quite limited and far from clinical requirements. In this work, we develop an innovative peptide-based nanoparticle to realize light-triggered nitric oxide (NO) release and structural transformation for enhanced intratumoral retention and simultaneously sensitizing photodynamic therapy (PDT). The designed nanoparticle is self-assembled from a chimeric peptide monomer, TPP-RRRKLVFFK-Ce6, which contains a photosensitive moiety (chlorin e6, Ce6), a β-sheet-forming peptide domain (Lys-Leu-Val-Phe-Phe, KLVFF), an oligoarginine domain (RRR) as NO donor and a triphenylphosphonium (TPP) moiety for targeting mitochondria. When irradiated by light, the constructed nanoparticles undergo rapid structural transformation from nanosphere to nanorod, enabling to achieve a significantly higher intratumoral accumulation by 3.26 times compared to that without light irradiation. More importantly, the conversion of generated NO and reactive oxygen species (ROS) in a light-responsive way to peroxynitrite anions (ONOO-) with higher cytotoxicity enables NO to sensitize PDT in cancer treatment. Both in vitro and in vivo studies demonstrate that NO sensitized PDT based on the well-designed transformable nanoparticles enables to eradicate tumors efficiently. The light-triggered transformable nanoplatform developed in this work provides a new strategy for enhanced intratumoral retention and improved therapeutic outcome.
    Keywords:  Enhanced intratumoral retention; Nanomedicine; Nitric oxide; Peptide; Photodynamic therapy; Structural transformation
    DOI:  https://doi.org/10.1016/j.bioactmat.2021.09.035
  19. Adv Mater. 2022 Feb 08. e2110364
    Engineering macrophage exosome disguised biodegradable nanoplatform for enhanced sonodynamic therapy of glioblastoma.
    Tingting Wu, Ying Liu, Yu Cao, Zhihong Liu.
      Sonodynamic therapy (SDT) exhibits high tissue penetration and negligible radiation damage to normal tissues, and thus emerges as a promising cancer therapeutic modality for glioblastoma (GBM). However, the blood-brain barrier (BBB) and hypoxic microenvironment greatly limit the SDT efficiency. In this work, a biodegradable nanoplatform (termed as CSI) was fabricated by encapsulating catalase (CAT) into silica nanoparticles (CAT@SiO2 ) for tumor hypoxia relief, and then loaded with the sonosensitizer indocyanine green (ICG). Inspired by the ability of macrophages to cross the BBB, CSI was further coated with AS1411 aptamer-modified macrophage exosomes to form CSI@Ex-A, which possessed efficient BBB penetration and good cancer cell-targeting capability. After tumor cell endocytosis, highly expressed glutathione (GSH) triggeres biodegradation of the nanoplatform and the released CAT catalyzes hydrogen peroxide (H2 O2 ) to produce O2 to relieve tumor hypoxia. The GSH depletion and O2 self-supplying effectively enhanced the SDT efficiency both in vitro and in vivo. In addition, the resulting CSI@Ex-A exhibited good biocompatibility and long circulation time. These findings demonstrate that CSI@Ex-A may serve as a competent nanoplatform for GBM therapy, with potential for clinical translation. This article is protected by copyright. All rights reserved.
    Keywords:  Sonodynamic therapy; biodegradable nanoplatform; blood-brain barrier; exosomes; glioblastoma
    DOI:  https://doi.org/10.1002/adma.202110364
  20. Small. 2022 Feb 06. e2107071
    Combination of Photothermal Therapy with Anti-Inflammation Therapy Attenuates the Inflammation Tumor Microenvironment and Weakens Immunosuppression for Enhancement Antitumor Treatment.
    Di Zhang, Jinghong Yang, Sheng Ye, Yutong Wang, Chuang Liu, Qianbing Zhang, Ruiyuan Liu.
      Photothermal therapy has gained widespread attention in cancer treatment, although its efficacy is suppressed due to the inflammatory response and immunosuppression, resulting in a discounted therapeutic effect. In this contribution, a high-performance NIR absorption organic small chromophore is developed, which is encapsulated into Pluronic F-127 to fabricate NIR absorption organic nanoparticles (TTM NPs) with excellent photothermal conversion efficiency (51.49%) for photothermal therapy. TTM NPs based photothermal therapy are combined with Aspisol, a kind of nonsteroidal anti-inflammatory drug, to weaken the inflammation and immunosuppression tumor microenvironment and enhance the antitumor effect. The results prove that the combination therapy realizes effective thermal elimination of primary tumors, inhibition of distant tumors, and suppression of tumor metastasis. The data show that combination therapy can suppress the expression of inflammatory factors, enhance dendritic cell activation and maturation, reverse the immunosuppression, facilitate T cell infiltration, and restore antitumor cytotoxic T lymphocyte activity. This study provides a paradigm to extend the development of photothermal therapy.
    Keywords:  NIR absorption organic nanoparticles; anti-inflammation therapy; inflammation tumor microenvironment; photothermal therapy; suppression metastasis; weaken immunosuppression
    DOI:  https://doi.org/10.1002/smll.202107071
  21. Eng Life Sci. 2022 Feb;22(2): 58-69
    Acceleration of antibacterial activity of curcumin loaded biopolymers against methicillin-resistant Staphylococcus aureus: Synthesis, optimization, and evaluation.
    Hamoun Anbari, Amir Maghsoudi, Mohammadreza Hosseinpour, Fatemeh Yazdian.
      Curcumin is a polyphenolic molecule with antibacterial, antioxidant, anti-inflammatory, and antimicrobial properties. This study aimed to prepare nanocurcumin by encapsulating in biopolymers to improve its stability, bioavailability, water-solubility, antibacterial efficiency against methicillin-resistant Staphylococcus aureus. Three effective variables of curcumin concentration, polymer concentration, and water volume on curcumin-loaded polymer nanoparticles, were optimized. The average size of polyacrylic acid (PAA), polyvinyl alcohol (PVA), and polyethyleneimine (PEI) nanoparticles were obtained 75.2, 77.1, 86.4 nm, respectively. The nanoparticles had a spherical shape, a smooth and uniform surface morphology. The MIC of PAA, PVA, and PEI nanoparticles was 0.480, 0.390, and 0.340 mg/mL, respectively and the MIC of PAA, PVA, and PEI combined with methicillin was 0.330, 0.260, and 0.200 mg/mL, respectively. According to the results, curcumin-loaded PEI nanoparticles had the highest inhibitory effect against methicillin-resistant S. aureus among the synthesized nanoparticles. The results showed that solvent volume, polymer concentration and curcumin concentration had a significant effect on particle size. The inhibitory properties of curcumin nanoparticles significantly increased due to the smaller particle size and increased penetration into the bacterium. Curcumin-loaded nanoparticles can be promising drug carriers for the treatment of infections, cancer, and other diseases.
    Keywords:  Staphylococcus aureus; curcumin; methicillin; nanocurcumin
    DOI:  https://doi.org/10.1002/elsc.202100050
  22. Curr Med Chem. 2022 Feb 10.
    Cellular and molecular mechanisms of curcumin on thyroid gland disorders.
    Farzaneh Shakeri, Bahram Bibak, Mohammad Reza Safdari, Zakieh Keshavarzi, Tannaz Jamialahmadi, Thozhukat Sathyapalan, Amirhossein Sahebkar.
      There is growing literature on the positive therapeutic potentials of curcumin. Curcumin or diferuloylmethane is a polyphenol obtained from the plant Curcuma longa. Curcumin has been used widely in Ayurvedic and Chinese medicine for various conditions. The role of curcumin on thyroid glands has been shown by its effects on various biological pathways, including anti-inflammatory, antioxidant, anti-proliferative, apoptosis, angiogenesis, cell cycle and metastasis. We reviewed the recent literature on curcumin applications for thyroid dysfunction, including hyperthyroidism and hypothyroidism, and discussed the molecular mechanisms of these effects. This review aims to summarize the wealth of research related to the thyroid gland therapeutic effect of curcumin.
    Keywords:  Curcumin; Molecular mechanisms; Thyroid gland
    DOI:  https://doi.org/10.2174/0929867329666220210145033
  23. Adv Drug Deliv Rev. 2022 Feb 07. pii: S0169-409X(22)00028-X. [Epub ahead of print] 114138
    Destruction of tumor vasculature by vascular disrupting agents in overcoming the limitation of EPR effect.
    Zhilin Liu, Yu Zhang, Na Shen, Jiali Sun, Zhaohui Tang, Xuesi Chen.
      Nanomedicine greatly improves the efficiency in the delivery of antitumor drugs into the tumor, but insufficient tumoral penetration impairs the therapeutic efficacy of most nanomedicines. Vascular disrupting agent (VDA) nanomedicines are distributed around the tumor vessels due to the low tissue penetration in solid tumors, and the released drugs can selectively destroy immature tumor vessels and block the supply of oxygen and nutrients, leading to the internal necrosis of the tumors. VDAs can also improve the vascular permeability of the tumor, further increasing the extravasation of VDA nanomedicines in the tumor site, markedly reducing the dependence of nanomedicines on the enhanced permeability and retention effect (EPR effect). This review highlights the progress of VDA nanomedicines in recent years and their application in cancer therapy. First, the mechanisms of different VDAs are introduced. Subsequently, different strategies of delivering VDAs are described. Finally, multiple combination strategies with VDA nanomedicines in cancer therapy are described in detail.
    Keywords:  Tumor enrichment; Tumor internal necrosis; Vascular disrupting agents; Vascular permeability changes
    DOI:  https://doi.org/10.1016/j.addr.2022.114138
  24. Int J Pharm. 2022 Feb 03. pii: S0378-5173(22)00088-6. [Epub ahead of print]616 121534
    Hybrid in situ- forming injectable hydrogels for local cancer therapy.
    Marzieh Mohammadi, Malihe Karimi, Bizhan Malaekeh-Nikouei, Mohammad Torkashvand, Mona Alibolandi.
      Injectable in situ forming hydrogels are amongst the efficient local drug delivery systems for cancer therapy. Providing a 3D hydrogel network within the target tissue capable of sustained release of the chemotherapeutics made them attractive candidates for increasing the therapeutic index. Remarkable swelling properties, mechanical strength, biocompatibility, wide composition variety and tunable polymeric moieties have led to preparation of injectable hydrogels which also could be used as cavity adaptive chemotherapeutic-loaded implants to prevent post -surgical cancer recurrence. Implementation of various polymers, nanoparticles, peptide and proteins and different crosslinking chemistry facilitated the fabrication of hybrid hydrogels with favorable characteristics such as stimuli sensitive platforms or multifunctional systems. In the current review, we focused on design and fabrication strategies of injectable in situ forming hydrogels and summarized recent hybrid hydrogels used for local cancer therapy.
    Keywords:  Cancer; Cancer local therapy; Hybrid materials; Hydrogel; Sustained release
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.121534
  25. Polym Bull (Berl). 2022 Jan 30. 1-22
    An insight into anticancer, antioxidant, antimicrobial, antidiabetic and anti-inflammatory effects of quercetin: a review.
    Muhammad Azeem, Muhammad Hanif, Khalid Mahmood, Nabeela Ameer, Fazal Rahman Sajid Chughtai, Usman Abid.
      Flavonoids are present naturally in many fruits and vegetables including onions, apples, tea, cabbage, cauliflower, berries and nuts which provide us with quercetin, a powerful natural antioxidant and cytotoxic compound. Due to antioxidant property, many nutraceuticals and cosmeceuticals products contain quercetin as a major ingredient nowadays. Current review enlightened sources and quercetin's role as an antioxidant, antimicrobial, antidiabetic, anticancerous and anti-inflammatory agent in medical field during last 5 to 6 years. Literature search was systematically done using scientific for the published articles of quercetin. A total of 345 articles were reviewed, and it was observed that more than 40% of articles were about quercetin's use as an antioxidant agent, more than 25% of studies were about its use as an anticancer agent, and articles on antimicrobial activity were more than 15%. 10% of the articles showed anti-inflamamatory effects of quercetin. Literature search also revealed that quercetin alone and its complexes with chitosan, metal ions and polymers possessed good antidiabetic properties. Thus, the review focuses on new therapeutic interventions and drug delivery system of quercetin in medical field for the benefit of mankind.
    Keywords:  Anti-inflammatory; Anticancer; Antidiabetic; Antimicrobial; Antioxidant; Quercetin
    DOI:  https://doi.org/10.1007/s00289-022-04091-8
  26. Acta Pharm Sin B. 2022 Jan;12(1): 451-466
    Bioresponsive immune-booster-based prodrug nanogel for cancer immunotherapy.
    Xianbin Ma, Shaochen Yang, Tian Zhang, Shuo Wang, Qichao Yang, Yao Xiao, Xiaoxiao Shi, Peng Xue, Yuejun Kang, Gang Liu, Zhi-Jun Sun, Zhigang Xu.
      The combination of chemotherapy and immunotherapy motivates a potent immune system by triggering immunogenic cell death (ICD), showing great potential in inhibiting tumor growth and improving the immunosuppressive tumor microenvironment (ITM). However, the therapeutic effectiveness has been restricted by inferior drug bioavailability. Herein, we reported a universal bioresponsive doxorubicin (DOX)-based nanogel to achieve tumor-specific co-delivery of drugs. DOX-based mannose nanogels (DM NGs) was designed and choosed as an example to elucidate the mechanism of combined chemo-immunotherapy. As expected, the DM NGs exhibited prominent micellar stability, selective drug release and prolonged survival time, benefited from the enhanced tumor permeability and prolonged blood circulation. We discovered that the DOX delivered by DM NGs could induce powerful anti-tumor immune response facilitated by promoting ICD. Meanwhile, the released mannose from DM NGs was proved as a powerful and synergetic treatment for breast cancer in vitro and in vivo, via damaging the glucose metabolism in glycolysis and the tricarboxylic acid cycle. Overall, the regulation of tumor microenvironment with DOX-based nanogel is expected to be an effectual candidate strategy to overcome the current limitations of ICD-based immunotherapy, offering a paradigm for the exploitation of immunomodulatory nanomedicines.
    Keywords:  5-ALA, 5-aminolevulinic acid; 5-FU, 5-fluorouracil; ALKP, alkaline phosphatase; ALT, alanine aminotransferase; APCs, antigen-presenting cells; AST, aminotransferase; ATP, adenosine triphosphate; AUC, area under curves; Bioresponsive; CLSM, confocal laser scanning microscope; CPT-11, irinotecan; CRE, creatinine; CRT, calreticulin; Ce6, chlorin e6; Chemotherapy; DAMPs, damage-associated molecular patterns; DCs, dendritic cells; DDSs, drug delivery systems; DLN, draining lymph nodes; DM NGs, doxorubicin-based mannose nanogel; DOC, docetaxel; DOX, doxorubicin; DTT, d,l-dithiothreitol; Doxorubicin; FCM, flow cytometry; FDA, Fluorescein diacetate; GEM, gemcitabine; GSH, glutathione; H&E, hematoxylin-eosin; HCPT, 10-hydroxy camptothecin; HCT, hematocrit; HGB, hemoglobin concentration; HMGB1, high migrating group box 1; ICB, immune checkpoint blockade; ICD, immunogenic cell death; ICG, indocyanine Green; IHC, immunohistochemistry; ITM, immunosuppressive tumor microenvironment; Immunogenic cell death; Immunotherapy; LDH, lactate dehydrogenase; LYM, lymphocyte ratio; MAN, mannose; MCHC, mean corpuscular hemoglobin concentration; MCSs, multicellular spheroids; MFI, mean fluorescence intensity; MPV, mean platelet volume; Mannose; NGs, nanogels; Nanogel; OXA, oxaliplatin; P18, purpurin 18; PDI, polydispersity index; PLT, platelets; PTX, paclitaxel; Prodrug; RBC, red blood cell count; RDW, variation coefficient of red blood cell distribution width; TAAs, tumor-associated antigens; TAM, tumor-associated macrophages; TGF-β, transforming growth factor-β; TMA, tissue microarrays; TME, tumor microenvironment; Urea, urea nitrogen; WBC, white blood cell count; irAEs, immune-related adverse events
    DOI:  https://doi.org/10.1016/j.apsb.2021.05.016
  27. Semin Cancer Biol. 2022 Feb 02. pii: S1044-579X(22)00023-2. [Epub ahead of print]
    Targeting OXPHOS and the electronic transport chain in cancer; molecular and therapeutic implications.
    John Greene, Ashvina Segaran, Simon Lord.
      Oxidative phosphorylation (OXPHOS) takes place in mitochondria and is the process whereby cells use carbon fuels and oxygen to generate ATP. Formerly OXPHOS was thought to be reduced in tumours and that glycolysis was the critical pathway for generation of ATP but it is now clear that OXPHOS, at least in many tumour types, plays a critical role in delivering the bioenergetic and macromolecular anabolic requirements of cancer cells. There is now great interest in targeting the OXPHOS and the electron transport chain for cancer therapy and in this review article we describe current therapeutic approaches and challenges.
    Keywords:  OXPHOS; cancer drugs; cancer metabolism; complex I; electron transport chain
    DOI:  https://doi.org/10.1016/j.semcancer.2022.02.002
  28. ACS Appl Bio Mater. 2022 Feb 07.
    pH-Responsive, Adorned Nanoniosomes for Codelivery of Cisplatin and Epirubicin: Synergistic Treatment of Tumorigenesis Breast Cancer.
    Ali Moammeri, Koorosh Abbaspour, Alireza Zafarian, Elham Jamshidifar, Hamidreza Motasadizadeh, Farnaz Dabbagh Moghaddam, Zeinab Salehi, Pooyan Makvandi, Rassoul Dinarvand.
      Combination chemotherapy has become a treatment modality for breast cancer. However, serious side effects and high cytotoxicity associated with this combination therapy make it a high-risk method for breast cancer treatment. This study evaluated the anticancer effect of decorated niosomal nanocarriers loaded with cisplatin (CIS) and epirubicin (EPI) in vitro (on SKBR3 and 4T1 breast cancer cells) and in vivo on BALB/c mice. For this purpose, polyethylene glycol (PEG) and folic acid (FA) were employed to prepare a functionalized niosomal system to improve endocytosis. FA-PEGylated niosomes exhibited desired encapsulation efficiencies of ∼91.2 and 71.9% for CIS and EPI, respectively. Moreover, cellular assays disclosed that a CIS and EPI-loaded niosome (NCE) and FA-PEGylated niosomal CIS and EPI (FPNCE) enhanced the apoptosis rate and cell migration in SKBR3 and 4T1 cells compared to CIS, EPI, and their combination (CIS+EPI). For FPNCE and NCE groups, the expression levels of Bax, Caspase3, Caspase9, and Mfn1 genes increased, whereas the expression of Bcl2, Drp1, MMP-2, and MMP-9 genes was downregulated. Histopathology results showed a reduction in the mitosis index, invasion, and pleomorphism in BALB/c inbred mice with NCE and FPNCE treatment. In this paper, for the first time, we report a niosomal nanocarrier functionalized with PEG and FA for codelivery of CIS and EPI to treat breast cancer. The results demonstrated that the codelivery of CIS and EPI through FA-PEGylated niosomes holds great potential for breast cancer treatment.
    Keywords:  breast cancer; cisplatin; endocytosis; epirubicin; folic acid; niosome
    DOI:  https://doi.org/10.1021/acsabm.1c01107
  29. CNS Drugs. 2022 Feb 07.
    Potential Role of Curcumin for the Treatment of Major Depressive Disorder.
    Adrian L Lopresti.
      Curcumin is the major biologically active polyphenolic constituent in the turmeric plant (Curcuma longa) that has been shown to have antioxidant, anti-inflammatory, neuroprotective, anticancer, antimicrobial, and cardioprotective effects. Interest in curcumin as a treatment for mental health conditions has increased and there is an expanding body of preclinical and clinical research examining its antidepressant and anxiolytic effects. In this narrative review, human trials investigating the effects of curcumin for the treatment of depression or depressive symptoms are summarised. Using findings from in vitro, animal, and human trials, possible biological mechanisms associated with the antidepressant effects of curcumin are also explored. To increase the understanding of curcumin for the treatment of depression, directions for future research are proposed.
    DOI:  https://doi.org/10.1007/s40263-022-00901-9
  30. J Heat Transfer. 2022 Mar;pii: 030801. [Epub ahead of print]144(3):
    Magnetic Nanoparticle-Mediated Heating for Biomedical Applications.
    Elyahb Allie Kwizera, Samantha Stewart, Md Musavvir Mahmud, Xiaoming He.
      Magnetic nanoparticles, especially superparamagnetic nanoparticles (SPIONs), have attracted tremendous attention for various biomedical applications. Facile synthesis and functionalization together with easy control of the size and shape of SPIONS to customize their unique properties, have made it possible to develop different types of SPIONs tailored for diverse functions/applications. More recently, considerable attention has been paid to the thermal effect of SPIONs for the treatment of diseases like cancer and for nanowarming of cryopreserved/banked cells, tissues, and organs. In this mini-review, recent advances on the magnetic heating effect of SPIONs for magnetothermal therapy and enhancement of cryopreservation of cells, tissues, and organs, are discussed, together with the non-magnetic heating effect (i.e., high Intensity focused ultrasound or HIFU-activated heating) of SPIONs for cancer therapy. Furthermore, challenges facing the use of magnetic nanoparticles in these biomedical applications are presented.
    Keywords:  HIFU; Magnetic nanoparticles; SPIONs; cancer; cryopreservation; hyperthermia; magnetothermal; nanowarming
    DOI:  https://doi.org/10.1115/1.4053007
  31. Spectrochim Acta A Mol Biomol Spectrosc. 2022 Jan 25. pii: S1386-1425(22)00094-4. [Epub ahead of print]272 120946
    Construction of heteroaryl-bridged NIR AIEgens for specific imaging of lipid droplets and its application in photodynamic therapy.
    Zhanguo Sun, Shuman Shi, Pengli Guan, Bin Liu.
      As a kind of subcellular organelle, lipid droplets (LDs) play a critical role in the body's normal metabolism. LDs have gained increasing attention as a fluorescent photodynamic target site. Near-infrared (NIR) organic light-emitting luminescent materials, with aggregation-induced emission (AIE)-active feature, preeminent LD-imaging ability, and effective reactive oxygen species (ROS) production property, have been widely used for photodynamic therapy (PDT) in diagnostic therapeutics, but its application remains challenging. In the present work, three novel NIR organic compounds with AIE-active feature, namely, TPET-Is, TPET-Fu, and TPEF-Is, were developed and synthesized. These heteroaryl-bridged molecules possess a donor-donor-π-acceptor structure and strong intramolecular charge transfer character. These AIEgens are capable of high-fidelity LD imaging in living cells (Pearson's coefficient values: 0.94, 0.96, 0.97) due to their biocompatibility, good photostability, and strong lipophilicity (LogP values: 9.39, 7.89, 8.03), respectively. Moreover, they can be also applied in bright imaging the LDs of oil-rich plant tissues, such as those of sunflower seeds. The respective AIEgens TPET-Fu of these compounds can also produce ROS in the condition of white light to effectively kill live Hela cells. The present study thus provides a potential strategy through heteroaryl-bridged molecular engineering for LD-targeted imaging and PDT application.
    Keywords:  AIEgens; Lipid droplets; Near-infrared emission; Photodynamic therapy
    DOI:  https://doi.org/10.1016/j.saa.2022.120946
  32. Beni Suef Univ J Basic Appl Sci. 2022 ;11(1): 17
    The nanocomposites designs of phytomolecules from medicinal and aromatic plants: promising anticancer-antiviral applications.
    Ayse Kaplan.
       Background: Nowadays, researchers are moving toward a herbal approach to cancer treatment because of the harmful effects of synthetic anti-tumor drugs. The evaluation of active compounds with plant origin may help in the remedy of human illnesses in the future. These active compounds have direct or indirect curative efficacies on difficult to cure diseases such as cancer. Investigation of nanoforms of these active compounds is one of the curious topics of the scientific community.
    Main body: Saffron and its components obtained from Crocus sativa, essential oils obtained from lavender, Syzygium aromaticum called cloves and Beta vulgaris are known for their anticancer effects. Nano-drugs are designed to increase the anticancer activity of plant-derived drugs. Herbal extracts operate very great in the production of nanoparticles. The aim is to ensure that only the nano-drug is delivered to the tumor site. Furthermore, nanoparticles have hazardous effects when analyzed at elevated doses, but this issue can be doped together with plant extracts.
    Short conclusions: The nanocomposites (graphene oxide, solid lipid nano and nanoemulsion) of phytomolecules obtained from saffron, clove, lavender and red beet may be effective in minimizing these toxic effects. In the near future, detecting the anticancer molecular mechanisms of these naturally derived compounds and nanocomposites could contribute to further cancer research. Apart from these, these compounds and its nanocomposites could have antiviral effects against today's threat covid-19 virus. Consequently, more promising anticancer and antiviral agents would be discovered.
    Graphical abstract:
    Keywords:  Anticancer-antiviral activity; Clove; Lavender; Phytonanocomposite; Red beet; Saffron
    DOI:  https://doi.org/10.1186/s43088-022-00198-z
  33. J Mater Chem B. 2022 Feb 07.
    Polyphenol-modified nanovesicles for synergistically enhanced in vitro tumor cell targeting and apoptosis.
    Jihye Seo, Seulgi Kim, Yousong Lee, Jiwon Kim, Youngbok Lee, Mikyung Shin, Jin Woong Kim.
      Tannic acid (TA) not only prevents drug carriers from sticking to the glycocalyx layer of vascular endothelial cells but also has anti-cancer properties, thereby improving drug delivery efficiency in cancer treatment. This study proposes a TANNylated nanovesicle-based cancer treatment approach by utilizing the aforementioned advantages of TA. We fabricated cancer cell-targeting BC71 peptide-conjugated TANNylated nanovesicles (TANVBC71) by covalently bonding the TA derivative and BC71 (cyclo[βA-kRK(3-maleimidopropionyl)-D-(D-2-naphthyl)]) with thiol-modified phospholipids through the thiol-maleimide reaction. We demonstrated that TANVBC71 was absorbed faster in high amounts by cancer cells than nanovesicles owing to its high affinity for the epidermal growth factor receptor and extracellular matrix components that are driven by van der Waals attraction as well as hydrogen bonding and hydrophobic interactions in a complex manner. These complex attractions of TANVBC71 for cancer cells led to the effective induction of cancer cell apoptosis. The findings obtained in this study highlight that the TANVBC71 system has the potential for intelligent high-efficacy cancer cell drug delivery.
    DOI:  https://doi.org/10.1039/d1tb02509k
  34. Curr Med Chem. 2022 Feb 08.
    The potential of Graphene Oxide and reduced Graphene Oxide in diagnosis and treatment of Cancer.
    Akram X Akram Keramat, Jamileh Kadkhoda, Raheleh Farahzadi, Ezzatollah Fathi, Soodabeh Davaran.
      Nanotechnology is a pioneer field of study; for engineering smart nanosystems in targeted diagnosis and treatment in cancer therapy. The potent therapy for different kinds of solid tumors should ideally target individually the cancerous cells and tissue with no impact on healthy cells in the body. Nano-sized graphene oxide (GO) and reduced graphene oxide (rGO) have phenomenal chemical versatility, high surface area ratio, and supernatural physical properties. The synergistic effects caused by the well-defined assembly of GO and rGO surface generate not only essential optical, mechanical, but also electronic behaviors. Developing novel multifunctional hybrid nanoparticles with great potential is highly considered in multimodal cancer treatment. GO, and rGO are engineered as a programmable targeting delivery system and combed with photonic energy they utilize in photothermal therapy. Its remarkable properties indicated its applications as a biosensor, bio-imaging for cancer diagnosis. In this current review, we show a remarkable highlight about GO, rGO, and discuss the notable applications for cancer diagnosis and treatment, and an overview of possible cellular signaling pathways that are affected by GO, rGO in cancer treatment.
    Keywords:  Graphene Oxide/reduced Graphene Oxide; bioimaging; biosensor; cancer diagnosis; cell signaling; photothermal; targeted delivery
    DOI:  https://doi.org/10.2174/0929867329666220208092157
  35. R Soc Open Sci. 2022 Feb;9(2): 210784
    Resveratrol-loaded chitosan-pectin core-shell nanoparticles as novel drug delivery vehicle for sustained release and improved antioxidant activities.
    Shruti Sarma, Sangeeta Agarwal, Pranjal Bhuyan, Jnyandeep Hazarika, Mausumi Ganguly.
      Resveratrol, chemically known as 3,5,4'-trihydroxy-trans-stilbene, is a natural polyphenol with promising multi-targeted health benefits. The optimal therapeutic uses of resveratrol are limited due to its poor solubility, rapid metabolism and low bioavailability. To address the issues, we have encapsulated resveratrol inside the nanosized core made of chitosan and coated this core with pectin-shell in order to fabricate a drug delivery vehicle which can entrap resveratrol for a longer period of time. The core-shell nanoparticles fabricated in this way were characterized with the help of Fourier transform infrared spectrometer, field-emission scanning electron microscope, field-emission transmission electron microscopy/selected area electron diffraction, high-resolution transmission electron microscope, dynamic light scattering and zeta potential measurements. In vitro drug release study showed the ability of the core-shell nanoparticles to provide sustained release of resveratrol for almost 30 h. The release efficiency of the drug was found to be pH dependent, and a sequential control over drug release can be obtained by varying the shell thickness. The resveratrol encapsulated in a nanocarrier was found to have a better in vitro antioxidant activity than free resveratrol as determined by 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging method. This work finally offers a novel nano-based drug delivery system.
    Keywords:  antioxidant activity; bioavailability; core–shell nanoparticles; drug delivery; resveratrol
    DOI:  https://doi.org/10.1098/rsos.210784
  36. Front Oncol. 2021 ;11 778761
    Personalized Medicine for Prostate Cancer: Is Targeting Metabolism a Reality?
    Gio Fidelito, Matthew J Watt, Renea A Taylor.
      Prostate cancer invokes major shifts in gene transcription and metabolic signaling to mediate alterations in nutrient acquisition and metabolic substrate selection when compared to normal tissues. Exploiting such metabolic reprogramming is proposed to enable the development of targeted therapies for prostate cancer, yet there are several challenges to overcome before this becomes a reality. Herein, we outline the role of several nutrients known to contribute to prostate tumorigenesis, including fatty acids, glucose, lactate and glutamine, and discuss the major factors contributing to variability in prostate cancer metabolism, including cellular heterogeneity, genetic drivers and mutations, as well as complexity in the tumor microenvironment. The review draws from original studies employing immortalized prostate cancer cells, as well as more complex experimental models, including animals and humans, that more accurately reflect the complexity of the in vivo tumor microenvironment. In synthesizing this information, we consider the feasibility and potential limitations of implementing metabolic therapies for prostate cancer management.
    Keywords:  lipid metabolism; metabolic heterogeneity; metabolic targeting; metabolism; obesity; patient-derived xenograft; prostate neoplasia
    DOI:  https://doi.org/10.3389/fonc.2021.778761
  37. Proc Natl Acad Sci U S A. 2022 Feb 15. pii: e2112696119. [Epub ahead of print]119(7):
    Intravesical delivery of KDM6A-mRNA via mucoadhesive nanoparticles inhibits the metastasis of bladder cancer.
    Na Kong, Ruonan Zhang, Gongwei Wu, Xinbing Sui, Junqing Wang, Na Yoon Kim, Sara Blake, Diba De, Tian Xie, Yihai Cao, Wei Tao.
      Lysine-specific demethylase 6A (KDM6A), also named UTX, is frequently mutated in bladder cancer (BCa). Although known as a tumor suppressor, KDM6A's therapeutic potential in the metastasis of BCa remains elusive. It also remains difficult to fulfill the effective up-regulation of KDM6A levels in bladder tumor tissues in situ to verify its potential in treating BCa metastasis. Here, we report a mucoadhesive messenger RNA (mRNA) nanoparticle (NP) strategy for the intravesical delivery of KDM6A-mRNA in mice bearing orthotopic Kdm6a-null BCa and show evidence of KDM6A's therapeutic potential in inhibiting the metastasis of BCa. Through this mucoadhesive mRNA NP strategy, the exposure of KDM6A-mRNA to the in situ BCa tumors can be greatly prolonged for effective expression, and the penetration can be also enhanced by adhering to the bladder for sustained delivery. This mRNA NP strategy is also demonstrated to be effective for combination cancer therapy with other clinically approved drugs (e.g., elemene), which could further enhance therapeutic outcomes. Our findings not only report intravesical delivery of mRNA via a mucoadhesive mRNA NP strategy but also provide the proof-of-concept for the usefulness of these mRNA NPs as tools in both mechanistic understanding and translational study of bladder-related diseases.
    Keywords:  KDM6A; bladder cancer; elemene; intravesical delivery; mRNA nanoparticles
    DOI:  https://doi.org/10.1073/pnas.2112696119
  38. Ann Transplant. 2022 Feb 11. 27 e933246
    PLGA+Fe₃O₄+PFP Nanoparticles Drug-Delivery Demonstrates Potential Anti-Tumor Effects on Tumor Cells.
    Dayan Yang, Qiqing Chen, Min Zhang, Lin Xie, Yan Chen, Tingting Zhong, Fang Tian, Guiying Feng, Xiangxiang Jing, Ling Lin.
      BACKGROUND Nanoparticles are proven as a potential tool for treating various disorders. However, efficient nanoparticle delivery of anti-tumor drugs is urgently needed for tumor treatment. This study aimed to generate a drug-delivery nanoparticle with higher efficacy and safety. MATERIAL AND METHODS We developed a poly-(lactide-co-glycolide) (PLGA) nanoparticle (FLGA-Fe₃O₄+PFP) embedded with super-paramagnetic iron oxide (Fe₃O₄) and perfluoropentane (PFP). Characteristics of FLGA-Fe₃O₄+PFP nanoparticles were observed using optical microscopy, scanning electron microscopy, and transmission electron microscopy. HNE1 and HepG2 cells were cultured and used for experiments. MTT was used to evaluate cytotoxic effects of FLGA-Fe₃O₄+PFP nanoparticles on HNE1 and HepG2 cells. Cell engulfment capacity was examined and a cell targeting experiment was conducted to evaluate invasive capability and binding efficiency of PLGA+Fe₃O₄+PFP nanoparticles, respectively. Biological toxicity of PLGA+Fe₃O₄+PFP nanoparticles in rats was evaluated by determining CK, LDH, creatinine, and UA levels, and ALT and AST activities. RESULTS PLGA+Fe₃O₄+PFP nanoparticles demonstrated well-defined spherical and dispersed morphology with smooth surfaces. There were scattered black spots on shells of PLGA+Fe₃O₄+PFP nanoparticles. PLGA+Fe₃O₄+PFP nanoparticles did not trigger obvious effects on cell viability of HNE1 and HepG2 cells. HNE1 and HepG2 cells demonstrated higher engulfment capacity for PLGA+ Fe₃O₄+PFP nanoparticles. PLGA+Fe₃O₄+PFP nanoparticles demonstrated higher targeting CDDP delivery efficacy and promoted binding efficiency of targeting CDDP with cells. PLGA+Fe₃O₄+PFP nanoparticles demonstrated no obvious toxic effects on heart, kidney, liver (without effects on CK, LDH, creatinine, UA levels, and ALT and AST activities). CONCLUSIONS PLGA+Fe₃O₄+PFP nanoparticles were safe, with higher invasive ability and binding efficiency of targeting CDDP with tumor cells. Therefore, PLGA+Fe₃O₄+PFP nanoparticles demonstrated potential anti-tumor effects after transplantation.
    DOI:  https://doi.org/10.12659/AOT.933246
  39. Nanoscale. 2022 Feb 10.
    Doxorubicin-loaded polypyrrole nanovesicles for suppressing tumor metastasis through combining photothermotherapy and lymphatic system-targeted chemotherapy.
    Lu Wang, Genhua Liu, Yunping Hu, Shuangquan Gou, Tingting He, Qian Feng, Kaiyong Cai.
      The lymphatic system provides a main route for the dissemination of most malignancies, which was related to high mortality in cancer patients. Traditional intravenous chemotherapy is of limited effectiveness on lymphatic metastasis due to the difficulty in accessing the lymphatic system. Herein, a novel lymphatic-targeting nanoplatform is prepared by loading doxorubicin (DOX) into sub-50 nm polypyrrole nanovesicles (PPy NVs). The PPy NVs possessed hollow spherical morphologies and a negative surface charge, leading to high drug loading capacity. These vesicles can also convert near-infrared (NIR) light into heat and thus can be used for tumor thermal ablation. DOX loaded PPy NVs (PPy@DOX NVs) along with NIR illumination are highly effective against 4T1 breast cancer cells in vitro. More importantly, following subcutaneous (SC) injection, a direct lymphatic migration of PPy@DOX NVs is confirmed through fluorescence observation of the isolated draining nodes. The acidic conditions in metastatic nodes might subsequently trigger the release of the encapsulated DOX NVs based on their pH-sensitive release profile. In a mouse model bearing 4T1 breast cancer, lymphatic metastases, as well as lung metastases, are significantly inhibited by nanocarrier-mediated trans-lymphatic drug delivery in combination with photothermal ablation. In conclusion, this platform holds great potential in impeding tumor growth and metastasis.
    DOI:  https://doi.org/10.1039/d2nr00186a
  40. ACS Appl Bio Mater. 2022 Feb 07.
    Water-Soluble Porphyrin-Based Nanoparticles Derived from Electrostatic Interaction for Enhanced Photodynamic Therapy.
    Yu-Xin Li, Yamin Liu, Hui Wang, Zhan-Ting Li, Dan-Wei Zhang.
      Pyrrole and porphyrin-derived nanoparticles have great potential use in bioimaging and therapy because of their unique magnetic, optical, and other photophysical properties, whereas the poor solubility in aqueous solution is one of the drawbacks of current photosensitizers for their photodynamic therapy (PDT) applications. Here, we developed a kind of water-soluble porphyrin-based nanoparticles that are coassembled mainly by the electrostatic interaction of anionic porphyrins and cationic tetraphenylmethane derivative. No aggregation-caused quenching (ACQ) was detected for these nanoparticles. In addition, the simple porphyrin transformation into nanoparticles improved their ability to generate reactive oxygen species singlet oxygen (1O2), which is an important factor causing apoptosis. The coassembled water-soluble porphyrin-based nanoparticles exhibited enhanced antitumor efficiency via PDT both in vitro and in vivo.
    Keywords:  coassembled nanoparticles; electrostatic interactions; photodynamic therapy (PDT); porphyrin derivatives; singlet oxygen; water soluble
    DOI:  https://doi.org/10.1021/acsabm.1c01262
  41. J Nanobiotechnology. 2022 Feb 05. 20(1): 69
    Tumor microenvironment-responsive fenton nanocatalysts for intensified anticancer treatment.
    Yandong Wang, Fucheng Gao, Xiaofeng Li, Guiming Niu, Yufei Yang, Hui Li, Yanyan Jiang.
      Chemodynamic therapy (CDT) based on Fenton or Fenton-like reactions is an emerging cancer treatment that can both effectively fight cancer and reduce side effects on normal cells and tissues, and it has made important progress in cancer treatment. The catalytic efficiency of Fenton nanocatalysts(F-NCs) directly determines the anticancer effect of CDT. To learn more about this new type of therapy, this review summarizes the recent development of F-NCs that are responsive to tumor microenvironment (TME), and detailedly introduces their material design and action mechanism. Based on the deficiencies of them, some effective strategies to significantly improve the anticancer efficacy of F-NCs are highlighted, which mainly includes increasing the temperature and hydrogen peroxide concentration, reducing the pH, glutathione (GSH) content, and the dependence of F-NCs on acidic environment in the TME. It also discusses the differences between the effect of multi-mode therapy with external energy (light and ultrasound) and the single-mode therapy of CDT. Finally, the challenges encountered in the treatment process, the future development direction of F-NCs, and some suggestions are analyzed to promote CDT to enter the clinical stage in the near future.
    Keywords:  Cancer treatment; Fenton reaction; Multi-mode therapy; Nanocatalyst; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s12951-022-01278-z
  42. Cell Metab. 2022 Feb 01. pii: S1550-4131(22)00022-5. [Epub ahead of print]
    The hallmarks of cancer metabolism: Still emerging.
    Natalya N Pavlova, Jiajun Zhu, Craig B Thompson.
      Metabolism of cancer cells is geared toward biomass production and proliferation. Since the metabolic resources within the local tissue are finite, this can lead to nutrient depletion and accumulation of metabolic waste. To maintain growth in these conditions, cancer cells employ a variety of metabolic adaptations, the nature of which is collectively determined by the physiology of their cell of origin, the identity of transforming lesions, and the tissue in which cancer cells reside. Furthermore, select metabolites not only serve as substrates for energy and biomass generation, but can also regulate gene and protein expression and influence the behavior of non-transformed cells in the tumor vicinity. As they grow and metastasize, tumors can also affect and be affected by the nutrient distribution within the body. In this hallmark update, recent advances are incorporated into a conceptual framework that may help guide further research efforts in exploring cancer cell metabolism.
    DOI:  https://doi.org/10.1016/j.cmet.2022.01.007
  43. Adv Sci (Weinh). 2022 Feb 08. e2104885
    Evoking Highly Immunogenic Ferroptosis Aided by Intramolecular Motion-Induced Photo-Hyperthermia for Cancer Therapy.
    Chao Chen, Zaiyu Wang, Shaorui Jia, Yuan Zhang, Shenglu Ji, Zheng Zhao, Ryan T K Kwok, Jacky W Y Lam, Dan Ding, Yang Shi, Ben Zhong Tang.
      Immunogenic cell death (ICD) through apoptosis or necroptosis is widely adopted to improve the therapeutic effect in cancer treatment by triggering a specific antitumor immunity. However, the tumor resistance to apoptosis/necroptosis seriously impedes the therapeutic effect. Recently, ferroptosis featured with excessive lipid peroxidation is demonstrated capable of bypassing the apoptosis/necroptosis resistance to kill cancer cells. To date, numerous efficient ferroptosis inducers are developed and successfully utilized for sensitizing cancer cells to ferroptosis. Unfortunately, these inducers can hardly generate adequate immunogenicity during induction of ferroptotic cancer cell death, which distinctly attenuates the efficacy of triggering antitumor immune response, therefore leads to unsatisfactory therapeutic effect. Herein, a novel high-performance photothermal nanoparticle (TPA-NDTA NP) is designed by exploiting energy via excited-state intramolecular motion and employed for immensely assisting ferroptosis inducer to evoke highly efficient ICD through ferroptosis pathway. Tumor models with poor immunogenicity are used to demonstrate the tremendously enhanced therapeutic effect endowed by highly enhanced immunogenic ferroptosis in vitro and in vivo by virtue of the NPs. This study sheds new light on a previously unrecognized facet of boosting the immunogenicity of ferroptosis for achieving satisfactory therapeutic effect in cancer therapy.
    Keywords:  aggregate; ferroptosis; immunogenic cell death; intramolecular motion; photothermal therapy
    DOI:  https://doi.org/10.1002/advs.202104885
  44. Front Pharmacol. 2022 ;13 820969
    Genistein: A Review on its Anti-Inflammatory Properties.
    Yu Xian Goh, Juriyati Jalil, Kok Wai Lam, Khairana Husain, Chandini Menon Premakumar.
      Nowadays, non-resolving inflammation is becoming a major trigger in various diseases as it plays a significant role in the pathogenesis of atherosclerosis, asthma, cancer, obesity, inflammatory bowel disease, chronic obstructive pulmonary disease, neurodegenerative disease, multiple sclerosis, and rheumatoid arthritis. However, prolonged use of anti-inflammatory drugs is usually accompanied with undesirable effects and hence more patients tend to seek for natural compounds as alternative medicine. Considering the fact above, there is an urgency to discover and develop potential novel, safe and efficacious natural compounds as drug candidates for future anti-inflammatory therapy. Genistein belongs to the flavonoid family, in the subgroup of isoflavones. It is a phytoestrogen that is mainly derived from legumes. It is a naturally occurring chemical constituent with a similar chemical structure to mammalian estrogens. It is claimed to exert many beneficial effects on health, such as protection against osteoporosis, reduction in the risk of cardiovascular disease, alleviation of postmenopausal symptoms and anticancer properties. In the past, numerous in vitro and in vivo studies have been conducted to investigate the anti-inflammatory potential of genistein. Henceforth, this review aims to summarize the anti-inflammatory properties of genistein linking with the signaling pathways and mediators that are involved in the inflammatory response as well as its toxicity profile. The current outcomes are analysed to highlight the prospect as a lead compound for drug discovery. Data was collected using PubMed, ScienceDirect, SpringerLink and Scopus databases. Results showed that genistein possessed strong anti-inflammatory activities through inhibition of various signaling pathways such as nuclear factor kappa-B (NF-κB), prostaglandins (PGs), inducible nitric oxide synthase (iNOS), proinflammatory cytokines and reactive oxygen species (ROS). A comprehensive assessment of the mechanism of action in anti-inflammatory effects of genistein is included. However, evidence for the pharmacological effects is still lacking. Further studies using various animal models to assess pharmacological effects such as toxicity, pharmacokinetics, pharmacodynamics, and bioavailability studies are required before clinical studies can be conducted. This review will highlight the potential use of genistein as a lead compound for future drug development as an anti-inflammatory agent.
    Keywords:  anti-inflammatory; genistein; nitric oxide production; nuclear factor kappa B; pro-inflammatory cytokines; prostaglandin; reactive oxygen species
    DOI:  https://doi.org/10.3389/fphar.2022.820969
  45. Front Pharmacol. 2021 ;12 741871
    Salvia miltiorrhiza Bge. (Danshen) for Inflammatory Bowel Disease: Clinical Evidence and Network Pharmacology-Based Strategy for Developing Supplementary Medical Application.
    Siyuan Zhang, Hua Luo, Shiyi Sun, Yating Zhang, Jiaqi Ma, Yuting Lin, Lin Yang, Dechao Tan, Chaomei Fu, Zhangfeng Zhong, Yitao Wang.
      Inflammatory bowel disease (IBD) is a non-specific colorectal disease caused by multifaceted triggers. Although conventional treatments are effective in the management of IBD, high cost and frequent side effects limit their applications and have turned sufferers toward alternative and complementary approaches. Salvia miltiorrhiza Bge (Danshen) is an herbal medicine that reportedly alleviates the symptoms of IBD. A large body of research, including clinical trials in which Danshen-based products or botanical compounds were used, has unmasked its multiple mechanisms of action, but no review has focused on its efficacy as a treatment for IBD. Here, we discussed triggers of IBD, collected relevant clinical trials and analyzed experimental reports, in which bioactive compounds of Danshen attenuated rodent colitis in the management of intestinal integrity, gut microflora, cell death, immune conditions, cytokines, and free radicals. A network pharmacology approach was applied to describe sophisticated mechanisms in a holistic view. The safety of Danshen was also discussed. This review of evidence will help to better understand the potential benefits of Danshen for IBD treatment and provide insights for the development of innovative applications of Danshen.
    Keywords:  Salvia miltiorrhiza bge; clinical trial; danshen; inflammatory bowel disease; network pharmacology
    DOI:  https://doi.org/10.3389/fphar.2021.741871
  46. Pharmacol Res. 2022 Feb 03. pii: S1043-6618(22)00061-5. [Epub ahead of print]177 106116
    Pediatric acute lymphoblastic leukemia management using multitargeting bioactive natural compounds: A systematic and critical review.
    Fatemeh Nabizadeh, Saeideh Momtaz, Maryam Ghanbari-Movahed, Farshad Qalekhani, Hadi Mohsenpour, Ina Yosifova Aneva, Anusha Bishayee, Mohammad Hosein Farzaei, Anupam Bishayee.
      Pediatric acute lymphoblastic leukemia (pALL), a malignancy of the lymphoid line of blood cells, accounts for a large percentage of all childhood leukemia cases. Although the 5-year survival rate for children with ALL has greatly improved over years, using chemotherapeutics as its first-line treatment still causes short- and long-term side effects. Furthermore, induction of toxicity and resistance, as well as the high cost, limit their application. Phytochemicals, with remarkable cancer preventive and chemotherapeutic characteristics, may serve as old solutions to new challenges. Bioactive plant secondary metabolites have exhibited promising antileukemic and adjunctive effects by targeting various molecular processes, including autophagy, cell cycle, angiogenesis, and extrinsic/intrinsic apoptotic pathways. Although numerous reports have shown that various plant secondary metabolites can interfere with the progression of malignancies, including leukemia, there was no comprehensive review article on the effect of phytochemicals on pALL. This systematic review aims to provide critical and cohesive analysis of the potential of various naturally-occurring plant secondary metabolites in the management of pALL with the understanding of underlying molecular and cellular mechanisms of action.
    Keywords:  Cancer; Molecular mechanisms; Pediatric acute lymphoblastic leukemia; Phytochemicals; Secondary metabolites; Treatment
    DOI:  https://doi.org/10.1016/j.phrs.2022.106116
  47. ChemMedChem. 2022 Feb 07.
    Near-Infrared Fluorescent Heptamethine Cyanine Dyes for COX-2 Targeted Photodynamic Cancer Therapy.
    Sirilak Wangngae, Siriwalee Siriwibool, Kantapat Chansaenpak, Sirawit Wet-Osot, Rung-Yi Lai, Anyanee Kamkaew.
      We designed and synthesized two heptamethine cyanine based theranostic probes that aimed to target COX-2 in cancer cells. One is I-IR799-CXB which I-IR799 was conjugated to COX-2 specific inhibitor, celecoxib, and another is I-IR799-IMC , where the non-selective COX inhibitor, indomethacin, was used. I-IR799 is a heptamethine cyanine derivative that can be activated by near infrared light for photodynamic therapy (PDT) purposes. I-IR799-CXB and I-IR799-IMC were tested for their cancer targeting and photodynamic efficiency towards liver hepatocellular carcinoma cells (HepG2) compared to normal liver cell, alpha mouse liver 12 cells (AML12). Interestingly, after conjugation, I-IR799-IMC exhibited superior tumour targetability and PDT efficiency than I-IR799-CXB .
    Keywords:  COX-2; Heptamethine cyanine; cancer targeting; photodynamic therapy; small molecule targeting
    DOI:  https://doi.org/10.1002/cmdc.202100780
  48. Pharm Nanotechnol. 2022 Feb 10.
    Optimized Nanoparticles for Enhanced Oral Bioavailability of a Poorly Soluble Drug: Solid lipid nanoparticles versus Nanostructured lipid carriers.
    Manal K M Darwish, Amal S M Abu El-Enin, Kamilia H A Mohammed.
      Rosuvastatin calcium (ROSCa) is an anti-hyperlipidemic drug with only 20% oral bioavailability due to its low solubility and high first-pass metabolism. Therefore, the main purpose of this work was to compare solid lipid nanoparticles to nanostructured lipid carriers and evaluate their effect on solubility improvement and hence the bioavailability of a model insoluble drug.
    METHODOLOGY: Different nanosuspensions were formulated using high-speed homogenization and ultrasonication techniques, using Apifil as solid lipid and maisine as liquid lipid. The effect of different variables on quality attributes (particle size, entrapment efficiency (EE), and in vitro release) was studied using the Box-Behnken design. Then, the optimized nanoparticles were lyophilized, filled into capsules, and evaluated. Finally, the optimized formula was clinically evaluated in six healthy human volunteers.
    RESULTS: It was observed that the variables had a great impact on EE and particle size. Nanoparticles showed maximum particles of 180.3 nm, and % EE ranged from 40.77% to 91.67%. Capsules loaded with NLCs were found to be more stable than those loaded with SLNs. The clinical study of NLCs-ROSCa showed an enhancement in the C max (8.92 ng/ml) compared to the commercial product (2.56 ng/ml) with approximately 349% relative bioavailability.
    CONCLUSION: ROSCa was successfully encapsulated in SLNs and NLCs. The optimized NLCs formulation showed improved quality attributes compared to SLNs. Thus, NLCs loaded formulations could be an effective oral drug delivery system to enhance the bioavailability of insoluble drugs.
    Keywords:  Box-Behnken design; Entrapment efficiency; Rosuvastatin; and clinical evaluation; nanostructured lipid carriers; optimization; oral bioavailability; particle size; solid lipid nanoparticle
    DOI:  https://doi.org/10.2174/2211738510666220210110003
  49. J Adv Res. 2022 Feb;36 223-247
    Skin cancer biology and barriers to treatment: Recent applications of polymeric micro/nanostructures.
    Nazeer Hussain Khan, Maria Mir, Lei Qian, Mahnoor Baloch, Muhammad Farhan Ali Khan, Asim-Ur- Rehman, Ebenezeri Erasto Ngowi, Dong-Dong Wu, Xin-Ying Ji.
       Background: Skin cancer has been the leading type of cancer worldwide. Melanoma and non-melanoma skin cancers are now the most common types of skin cancer that have been reached to epidemic proportion. Based on the rapid prevalence of skin cancers, and lack of efficient drug delivery systems, it is essential to surge the possible ways to prevent or cure the disease.
    Aim of review: Although surgical modalities and therapies have been made great progress in recent years, however, there is still an urgent need to alleviate its increased burden. Hence, understanding the precise pathophysiological signaling mechanisms and all other factors of such skin insults will be beneficial for the development of more efficient therapies.
    Key scientific concepts of review: In this review, we explained new understandings about onset and development of skin cancer and described its management via polymeric micro/nano carriers-based therapies, highlighting the current key bottlenecks and future prospective in this field. In therapeutic drug/gene delivery approaches, polymeric carriers-based system is the most promising strategy. This review discusses that how polymers have successfully been exploited for development of micro/nanosized systems for efficient delivery of anticancer genes and drugs overcoming all the barriers and limitations associated with available conventional therapies. In addition to drug/gene delivery, intelligent polymeric nanocarriers platforms have also been established for combination anticancer therapies including photodynamic and photothermal, and for theranostic applications. This portfolio of latest approaches could promote the blooming growth of research and their clinical availability.
    Keywords:  5-ALA, 5-aminolevulinic acid; 5-FU, 5-fluorouracil; AIDS, Acquired immune deficiency syndrome; BCC, Basal cell carcinoma; BCCs, Basal cell carcinomas; Basal cell carcinoma; CREB, response element-binding protein; DDS, Drug delivery system; DIM-D, Di indolyl methane derivative; Drug delivery; GNR-PEG-MN, PEGylated gold nanorod microneedle; Gd, Gadolinium; Gene delivery; HH, Hedgehog; HPMC, Hydroxypropyl methylcellulose; IPM, Isopropyl myristate; MCIR, Melanocortin-1 receptor; MNPs, Magnetic nanoparticle; MNs, Microneedles; MRI, Magnetic Resonance Imaging; MSC, Melanoma skin cancer; Microneedles; Mn, Manganese; NMSC, Non melanoma skin cancer; NPs, Nano Particles; OTR, Organ transplant recipients; PAMAM, Poly-amidoamines; PAN, Polyacrylonitrile; PATCH1, Patch; PCL, Poly (ε-caprolactone); PDT, Photodynamic therapy; PEG, Polyethylene glycol; PLA, Poly lactic acid; PLA-HPG, Poly (d-l-lactic acid)-hyperbranched polyglycerol; PLGA, Poly (lactide-co-glycolide) copolymers; PLL, Poly (L-lysine); Polymeric nanocarriers; QDs, Quantum dots; SC, Skin cancer; SCC, Squamous cell Carcinoma; SMO, Smoothen; SPIO, Superparamagnetic iron oxide; Squamous cell carcinoma; UV, Ultra Violet; cAMP, Cyclic adenosine monophosphate; dPG, Dendritic polyglycerol; hTERT, Human telomerase reverse transcriptase
    DOI:  https://doi.org/10.1016/j.jare.2021.06.014
  50. Acta Pharm Sin B. 2022 Jan;12(1): 107-134
    Symphony of nanomaterials and immunotherapy based on the cancer-immunity cycle.
    Qianqian Li, Zhaoqing Shi, Fan Zhang, Weiwei Zeng, Dunwan Zhu, Lin Mei.
      The immune system is involved in the initiation and progression of cancer. Research on cancer and immunity has contributed to the development of several clinically successful immunotherapies. These immunotherapies often act on a single step of the cancer-immunity cycle. In recent years, the discovery of new nanomaterials has dramatically expanded the functions and potential applications of nanomaterials. In addition to acting as drug-delivery platforms, some nanomaterials can induce the immunogenic cell death (ICD) of cancer cells or regulate the profile and strength of the immune response as immunomodulators. Based on their versatility, nanomaterials may serve as an integrated platform for multiple drugs or therapeutic strategies, simultaneously targeting several steps of the cancer-immunity cycle to enhance the outcome of anticancer immune response. To illustrate the critical roles of nanomaterials in cancer immunotherapies based on cancer-immunity cycle, this review will comprehensively describe the crosstalk between the immune system and cancer, and the current applications of nanomaterials, including drug carriers, ICD inducers, and immunomodulators. Moreover, this review will provide a detailed discussion of the knowledge regarding developing combinational cancer immunotherapies based on the cancer-immunity cycle, hoping to maximize the efficacy of these treatments assisted by nanomaterials.
    Keywords:  Cancer immunotherapy; Cancer‒immunity cycle; Drug delivery; ICD inducers; Immunomodulators; Nanomaterials; Photodynamic therapy; Photothermal therapy; Radio sensitizer
    DOI:  https://doi.org/10.1016/j.apsb.2021.05.031
  51. Drug Deliv Transl Res. 2022 Feb 11.
    Nanotherapeutics in autophagy: a paradigm shift in cancer treatment.
    Shloka Negi, Aiswarya Chaudhuri, Dulla Naveen Kumar, Deepa Dehari, Sanjay Singh, Ashish Kumar Agrawal.
      Autophagy is a catabolic process in which an organism responds to its nutrient or metabolic emergencies. It involves the degradation of cytoplasmic proteins and organelles by forming double-membrane vesicles called "autophagosomes." They sequester cargoes, leading them to degradation in the lysosomes. Although autophagy acts as a protective mechanism for maintaining homeostasis through cellular recycling, it is ostensibly a cause of certain cancers, but a cure for others. In other words, insufficient autophagy, due to genetic or cellular dysfunctions, can lead to tumorigenesis. However, many autophagy modulators are developed for cancer therapy. Diverse nanoparticles have been documented to induce autophagy. Also, the highly stable nanoparticles show blockage to autophagic flux. In this review, we revealed a general mechanism by which autophagy can be induced or blocked via nanoparticles as well as several studies recently performed to prove the stated fact. In addition, we have also elucidated the paradoxical roles of autophagy in cancer and how their differential role at different stages of various cancers can affect its treatment outcomes. And finally, we summarize the breakthroughs in cancer disease treatments by using metallic, polymeric, and liposomal nanoparticles as potent autophagy modulators.
    Keywords:  Apoptosis; Autophagosomes; Autophagy; Cancer; Chemotherapeutic agents; Nanoparticles
    DOI:  https://doi.org/10.1007/s13346-022-01125-6
  52. Crit Rev Food Sci Nutr. 2022 Feb 10. 1-27
    Black soybean (Glycine max (L.) Merr.): paving the way toward new nutraceutical.
    Manoj Kumar, Rajat Suhag, Muzaffar Hasan, Sangram Dhumal, Radha, R Pandiselvam, Marisennayya Senapathy, Vellaikumar Sampathrajan, Sneh Punia, Ali A S Sayed, Surinder Singh, John F Kennedy.
      Black soybean (BS) is a nutritious legume that is high in proteins, essential amino acids, dietary fiber, vitamins, minerals, anthocyanins, phenolic acids, isoflavones, and flavones. Traditional approaches for extracting BS bioactive compounds are commonly employed because they are simple and inexpensive, but they use toxic solvents and have lower yields. As a result, new extraction techniques have been developed, such as microwave, ultrasound, and enzyme-assisted extraction. Modern approaches are less harmful to the environment, are faster, and produce higher yields. The major anthocyanin in the BS seed coat was discovered as cyanidin-3-O-glucoside, accounting for nearly 75% of the total anthocyanins. BS and its seed coat also contains phenolic acids (p-hydroxybenzoic, gallic, vanillin, syringic acid), isoflavones (daidzein, glycitein and genistein), flavones, flavonols, flavanones, and flavanols. Bioactive compounds present in BS exhibit antioxidant, anti-cancerous, anti-diabetic, anti-obesity, anti-inflammatory, cardio and neuroprotective activities. The characterization and biological activity investigation of these bioactive compounds has provided researchers and food manufacturers with valuable information for developing functional food products and nutraceutical ingredients. In this review, the nutritional makeup of BS is reviewed, and the paper seeks to provide an insight of bioactive compound extraction methods as well as bioactive compounds identified by various researchers. The biological activities of BS extracts and their potential applications in food products (noodles), biodegradable films (pH sensitive film), and therapeutic applications (wound healing and anti-inflammation) are also discussed in the study. Therefore, BS have enormous potential for use in developing functional foods and nutraceutical components. This is the first review of its sort to describe and explain various extraction methodologies and characterization of bioactives, as well as their biological activity recorded in diverse works of literature, making it possible for food manufacturers and scientists to get a quick overview.
    Keywords:  Extraction methods; anthocyanins; antioxidant; biological activity; food application
    DOI:  https://doi.org/10.1080/10408398.2022.2029825
  53. Heliyon. 2022 Jan;8(1): e08815
    Chemotherapeutic potential of hesperetin for cancer treatment, with mechanistic insights: A comprehensive review.
    Md Sohel, Habiba Sultana, Tayeba Sultana, Md Al Amin, Suraiya Aktar, Md Chayan Ali, Zahed Bin Rahim, Md Arju Hossain, Abdullah Al Mamun, Mohammad Nurul Amin, Raju Dash.
       Background: Cancer has become a significant concern in the medical sector with increasing disease complexity. Although some available conventional treatments are still a blessing for cancer patients, short-and long-term adverse effects and poor efficiency make it more difficult to treat cancer patients, demonstrating the need for new potent and selective anticancer drugs. In search of potent anticancer agents, naturally occurring compounds have always been admired due to their structural diversity, where Hesperetin (HSP) may be one of the potent candidates.
    Purpose: We aimed to summarize all sources, pharmacological properties, anticancer activities of HSP against numerous cancers types through targeting multiple pathological processes, mechanism of HSP on sensitizing the current anti-cancer agents and other phytochemicals, overcoming resistance pattern and determining absorption, distribution, metabolism, excretion, and toxicity (ADME/Tox).
    Methods: Information was retrieved from PubMed, Science Direct, and Google Scholar based on some key points like Hesperetin, cancer name, anticancer resistance, nanoformulation, and ADME/Tox was determined by in silico approaches.
    Result: HSP is a phytoestrogen present in citrus fruits in a high concentration (several hundred mg/kg) and exhibited anti-cancer activities through interfering at several pathways. HSP can suppress tumor formation by targeting several cellular proteins such as cell cycle regulatory, apoptosis, metastatic, tyrosine kinase, growth factor receptor, estrogen metabolism, and antioxidant-related protein.HSP has shown remarkable synergistic properties in combination therapy and has been reported to overcome multidrug cancer resistance drugs, leading to an improved defensive mechanism. These anticancer activities of HSP may be due to proper structural chemistry.
    Conclusion: Overall, HSP showed potential anticancer activities against all cancer and possess better pharmacokinetic properties. So this phytochemical alone or combination with other agents can be an effective alternative drug for cancer treatment.
    Keywords:  ADME/Tox; Anticancer agents; Cancer; Hesperetin
    DOI:  https://doi.org/10.1016/j.heliyon.2022.e08815
  54. Front Oncol. 2021 ;11 794735
    Deferoxamine Counteracts Cisplatin Resistance in A549 Lung Adenocarcinoma Cells by Increasing Vulnerability to Glutamine Deprivation-Induced Cell Death.
    Wen-Jun Liu, Peng-Yu Pan, Ye Sun, Jian-Bo Wang, Huan Zhou, Xin Xie, Zhi-Yuan Duan, Han-Yu Dong, Wen-Na Chen, Li-de Zhang, Chun Wang.
      Glutamine, like glucose, is a major nutrient consumed by cancer cells, yet these cells undergo glutamine starvation in the cores of tumors, forcing them to evolve adaptive metabolic responses. Pharmacologically targeting glutamine metabolism or withdrawal has been exploited for therapeutic purposes, but does not always induce cancer cell death. The mechanism by which cancer cells adapt to resist glutamine starvation in cisplatin-resistant non-small-cell lung cancer (NSCLC) also remains uncertain. Here, we report the potential metabolic vulnerabilities of A549/DDP (drug-resistant human lung adenocarcinoma cell lines) cells, which were more easily killed by the iron chelator deferoxamine (DFO) during glutamine deprivation than their parental cisplatin-sensitive A549 cells. We demonstrate that phenotype resistance to cisplatin is accompanied by adaptive responses during glutamine deprivation partly via higher levels of autophagic activity and apoptosis resistance characteristics. Moreover, this adaptation could be explained by sustained glucose instead of glutamine-dominant complex II-dependent oxidative phosphorylation (OXPHOS). Further investigation revealed that cisplatin-resistant cells sustain OXPHOS partly via iron metabolism reprogramming during glutamine deprivation. This reprogramming might be responsible for mitochondrial iron-sulfur [Fe-S] cluster biogenesis, which has become an "Achilles' heel," rendering cancer cells vulnerable to DFO-induced autophagic cell death and apoptosis through c-Jun N-terminal kinase (JNK) signaling. Finally, in vivo studies using xenograft mouse models also confirmed the growth-slowing effect of DFO. In summary, we have elucidated the adaptive responses of cisplatin-resistant NSCLC cells, which balanced stability and plasticity to overcome metabolic reprogramming and permitted them to survive under stress induced by chemotherapy or glutamine starvation. In addition, for the first time, we show that suppressing the growth of cisplatin-resistant NSCLC cells via iron chelator-induced autophagic cell death and apoptosis was possible with DFO treatment. These findings provide a solid basis for targeting mitochondria iron metabolism in cisplatin-resistant NSCLC for therapeutic purposes, and it is plausible to consider that DFO facilitates in the improvement of treatment responses in cisplatin-resistant NSCLC patients.
    Keywords:  NSCLC; cell death; cisplatin resistance; deferoxamine; glutamine deprivation; metabolic reprogramming
    DOI:  https://doi.org/10.3389/fonc.2021.794735
  55. Drug Deliv. 2022 Dec;29(1): 506-518
    Synergic fabrication of multifunctional liposomes nanocomposites for improved radiofrequency ablation combination for liver metastasis cancer therapy.
    Ning Zhang, Yibin Wu, Weiqi Xu, Zhenjian Li, Lu Wang.
      The field of biomedical research has recently been interested in nanoplatforms with various functionalities, such as cancer drug carriers and MRI and optical imaging, as well as thermal treatment, among other things. As a result of the present investigation, a unique multifunctional liposome (MFL) was established in this investigation. Using radiofrequency-induced imaging and drug release based on magnetic field impact, a dual drug delivery targeted with tumor multi-mechanism treatment was made more effective. The C60 (fullerene) surface was coated with iron nanocomposites to establish the proposed nanosystems, and PEGylation was used (Fe3O4-C60-PEG2000). For fullerene radiofrequency-triggered drug release, thermosensitive DPPC liposomes with folate-DSPE-PEG2000 enveloped the binary nanosystems and doxorubicin (DOX). The in vitro cytotoxicity of the nanocomposites was confirmed by the liver metastasis in HT-29 colon cancer cells using radiofrequency. The flow cytometry analysis confirmed the apoptosis cell death mechanism. The thermal treatment combined chemotherapeutic MFL nano framework transformed radiofrequency radiation from thermoresponsive liposomes, which was noticed both in vivo and in vitro. Due to their superior active tumor targeting and magnetic targeting characteristics, the MFL could also selectively destroy cancerous liver cells in highly co-localized targets.
    Keywords:  Liposome; apoptosis; doxorubicin; in vivo tumor model; liver cancer
    DOI:  https://doi.org/10.1080/10717544.2021.2008056
  56. Adv Nutr. 2022 Feb 04. pii: nmac011. [Epub ahead of print]
    Satiety associated with calorie restriction and time-restricted feeding: Central neuroendocrine integration.
    Debra K M Tacad, Ashley P Tovar, Christine E Richardson, William F Horn, Nancy L Keim, Giri P Krishnan, Sridevi Krishnan.
      This review focuses on summarizing current knowledge on how time-restricted feeding (TRF) and continuous caloric restriction (CR) affect central neuro-endocrine systems involved in regulating satiety. Several interconnected regions of the hypothalamus, brainstem, and cortical areas of the brain are involved in the regulation of satiety. Following CR and TRF, the increase in hunger and reduction of satiety signals of the melanocortin system (NPY, POMC, and AgRP) appear similar between CR and TRF protocols, as do the dopaminergic responses in the mesocorticolimbic circuit. However, ghrelin and leptin signaling via the melanocortin system appears to improve energy balance signals and reduce hyperphagia following TRF, which has not been reported in CR. In addition to satiety systems, CR and TRF also influence circadian rhythms. CR influences the SCN (suprachiasmatic nucleus) or the primary circadian clock as seen by increased clock gene expression. In contrast, TRF appears to affect both the SCN and the peripheral clocks, as seen by phasic changes in the non-SCN (potentially the elusive food entrainable oscillator) and metabolic clocks. The peripheral clocks are influenced by the primary circadian clock but are also entrained by food timing, sleep timing, and other lifestyle parameters, which can supersede the metabolic processes that are regulated by the primary circadian clock. Taken together, TRF influences hunger/satiety, energy balances systems, and circadian rhythms, suggesting a role for adherence to CR in the long run if implemented using the TRF approach. However, these suggestions are based on only a few studies, and future investigations that use standardized protocols for the evaluation of the effect of these diet patterns (time, duration, meal composition, sufficiently powered) are necessary to verify these preliminary observations.
    Keywords:  calorie restriction; circadian rhythms; hypothalamus; light-entrainable oscillator; peripheral oscillators; satiety; time-restricted feeding
    DOI:  https://doi.org/10.1093/advances/nmac011
  57. J Med Chem. 2022 Feb 07.
    Targeting Regulated Cell Death with Pharmacological Small Molecules: An Update on Autophagy-Dependent Cell Death, Ferroptosis, and Necroptosis in Cancer.
    Junhao Wu, Jing Ye, Qiang Xie, Bo Liu, Ming Liu.
      Regulated cell death is a widely attractive subject among the topics of cancer therapy and has gained some advances for discovery of targeted anticancer drugs. In the past decade, nonapoptotic regulated cell death has been implicated in the development and therapeutic responses of a variety of human cancers. Hitherto, targeting autophagy-dependent cell death (ADCD), ferroptosis, and necroptosis with small molecules has been emerging as a hopeful strategy for the improvement of potential cancer therapy, which may have an advantage to bypass the apoptosis-resistance machinery. Thus, in this perspective, we concentrate on the key molecular insights into ADCD, ferroptosis, and necroptosis and summarize the corresponding small molecules in potential cancer therapy. Moreover, the relationships between the three subroutines and small molecules modulating the crosstalk are discussed. We believe that these inspiring findings would be advantageous to exploiting more potential targets and pharmacological small molecules in future cancer treatment.
    DOI:  https://doi.org/10.1021/acs.jmedchem.1c01572
  58. Int Immunol. 2022 Feb 08. pii: dxac004. [Epub ahead of print]
    Blocking EP4 downregulates tumor metabolism and synergizes with anti-PD-1 therapy to activate natural killer cells in a lung adenocarcinoma model.
    Miho Tokumasu, Mikako Nishida, Takamasa Kawaguchi, Ikuru Kudo, Tohru Kotani, Kazuhiko Takeda, Takao Yoshida, Heiichiro Udono.
      Prostaglandin E2 (PGE2), a product of the cyclooxygenase (COX) pathway, is produced by tumors and surrounding stromal cells. It stimulates tumor progression, promotes angiogenesis, and suppresses the antitumor response. Pharmacological inhibition of PGE2 synthesis has been shown to suppress tumor initiation and growth in vivo. In the current study, we demonstrated that the growth of the Ptgs2-deficient the 3LL lung adenocarcinoma cell line was downregulated in vivo through natural killer (NK) cell activation and a reduction in the population of polymorphonuclear leukocyte-myeloid-derived suppressor cells (PMN-MDSCs) and tumor associated macrophages (TAMs). Based on these results, the therapeutic effect of ONO-AE3-208 (EP4i), an inhibitor of EP4 (a PGE2 receptor), combined with anti-PD-1Ab was evaluated. EP4i, but not anti-PD-1 Ab, decreased tumor metabolism including glycolysis, fatty acid oxidation, and oxidative phosphorylation. EP4i induced IFNγ production from only NK cells (not from T cells) and a shift from M2- to M1-like macrophages in TAMs. These effects were further enhanced by anti-PD-1 Ab treatment. Although CD8T cell infiltration was increased, IFNγ production was not significantly altered, even with combination therapy. Tumor hypoxia was ameliorated by either EP4i or anti-PD-1 Ab treatment, which was further affected by the combination. Normalization of tumor vessels was significant only for the combination therapy. The results indicate a novel effect of EP4i for the metabolic reprogramming of tumors, revealed unique features of EP4i that can synergize with anti-PD-1Ab to promote IFNγ production of NK cells, polarize TAMs into the M1-phenotype, and reduce hypoxia through normalization of the tumor vasculature. (250 words).
    Keywords:  NK cells; Prostaglandin; tumor immunity; tumor metabolism; tumor vessels
    DOI:  https://doi.org/10.1093/intimm/dxac004
  59. Recent Pat Nanotechnol. 2022 Feb 10.
    Nanocapsules: An Emerging Drug Delivery System.
    Deepika Purohit, Pawan Jalwal, Deeksha Manchanda, Sapna Saini, Ravinder Verma, Deepak Kaushik, Vineet Mittal, Manish Kumar, Tanima Bhattacharya, Md Habibur Rahman, Rohit Dutt, Parijat Pandey.
       BACKGROUND: Controlled drug release and site-specific delivery of drugs make nanocapsules the most approbative drug delivery system for various kinds of drugs, bioactive, protein, and peptide compounds. Nanocapsules (NCs) are spherical shape microscopic shells consisting of a core (solid or liquid) in which the drug is positioned in a cavity enclosed by a distinctive polymeric membrane.
    OBJECTIVES: The main objective of the present study is to elaborate on various formulation techniques and methods of nanocapsules (NCs). The review also spotlights various biomedical applications as well as on the patents of NCs till date.
    METHODS: The review was extracted from the searches performed using various search engines such as PubMed, Google Patents, Medline, and Google Scholars, etc. In order to emphasize the importance of NCs, some published patents of NCs have been also reported in the review.
    RESULTS: NCs are tiny magical shells having incredible reproducibility. Various techniques can be used to formulate NCs. The pharmaceutical performance of the formulated NCs can be judged by evaluating their shape, size, entrapment efficiency, loading capacity, etc. using different analytical techniques. Their main applications are found in the field of agrochemicals, genetic manipulation, cosmetics, hygiene items, strategic distribution of drugs to tumors, nanocapsule bandages to combat infection, and radiotherapy.
    CONCLUSION: In the present review, our team made a deliberate effort to summarize the recent advances in the field of NCs and focus on new patents related to the implementation of NCs delivery systems in the area of some life-threatening disorders like diabetes, cancer, and cardiovascular diseases.
    Keywords:  Applications; Characterization; Nanocapsules; Nanoparticles; Patents
    DOI:  https://doi.org/10.2174/1872210516666220210113256
  60. Angew Chem Int Ed Engl. 2022 Feb 08.
    A Nuclear-Targeted AIE Photosensitizer for Enzyme Inhibition and Photosensitization in Cancer Cell Ablation.
    Kang-Nan Wang, Liu-Yi Liu, Duo Mao, Ming-Xuan Hou, Cai-Ping Tan, Zong-Wan Mao, Bin Liu.
      The nucleus is considered the ideal target for anti-tumor therapy because DNA and some enzymes in the nucleus are the main causes of cell canceration and malignant proliferation. However, nuclear target drugs with good biosafety and high efficiency in cancer treatment are rare. Herein, a nuclear-targeted material MeTPAE with aggregation-induced emission (AIE) characteristics was developed based on a triphenylamine structure skeleton. MeTPAE can not only interact with histone deacetylases (HDACs) to inhibit cell proliferation but also damage telomere and nucleic acids precisely through photodynamic treatment (PDT). The cocktail strategy of MeTPAE caused obvious cell cycle arrest and showed excellent PDT antitumor activity, which offered new opportunities for the effective treatment of malignant tumors.
    Keywords:  histone deacetylase inhibition; nuclear targeting; nucleic acid damage; photosensitizer; telomerase inhibition
    DOI:  https://doi.org/10.1002/anie.202114600
  61. J Mater Chem C Mater. 2022 Jan 07. 10(2): 688-695
    A scintillating nanoplatform with upconversion function for the synergy of radiation and photodynamic therapies for deep tumors.
    Yansong Feng, Xiaomeng Liu, Qiqing Li, Shilin Mei, Kefan Wu, Jun Yuan, Langping Tu, Ivo Que, Filippo Tamburini, Fabio Baldazzi, Alan Chan, Luis J Cruz, Jing Zuo, Changjiang Yao, Hong Zhang.
      Collaborative therapy is regarded as an effective approach in increasing the therapeutic efficacy of cancer. In this work, we have proposed and validated the concept of upconversion lumienscence image guided synergy of photodynamic therapy (PDT) and radiotherapy (RT) for deep cancer, via a specially designed nanoplatform integrating near infrared (NIR) light activated luminescence upconversion and X-ray induced scintillation. Upon NIR light irradiation, the nanoplatform emits highly monochromatic red light solely for imaging the targeted cancer cells without triggering therapy; however, when the irradiation turns to a low dose of X-rays, scintillation will occur which induces effectively the PDT destroying the cancer cells together with X-ray induced RT. The novel theranostic nanoplatform is constructed in such a way that the interactions between the upconversion core and the outmost scintillating shell are blocked effectively by an inert layer between them. This structural design not only enables a nearly perfect excitation energy delivery (∼100% at a spectral overlapping wavelength of ∼540 nm) from the outermost scintellating layer to the surface-anchored photosensitizers and so a maximum yield of radical oxygen species, but also achieves a strong NIR induced upconversion luminescence for imaging. Since PDT and RT attack different parts of a cancer cell, this synergy is more effective in destroying cancer than a single therapy, resulting in the reduction of the X-ray irradiation dosage. As a proof of principle, the theranostic effect is validated by in vitro and in vivo experiments, exhibiting the great potential of this sort of nanoplatform in deep cancer treatment.
    DOI:  https://doi.org/10.1039/d1tc04930e
  62. Am J Chin Med. 2022 Feb 09. 1-47
    A Systemic Review for Ethnopharmacological Studies on Isatis indigotica Fortune: Bioactive Compounds and their Therapeutic Insights.
    Li Wen Wong, Calvin Bok Sun Goh, Joash Ban Lee Tan.
      Isatis indigotica Fortune is a biennial Chinese woad of the Cruciferae family. It is primarily cultivated in China, where it was a staple in indigo dye manufacture till the end of the 17th century. Today, I. indigotica is used primarily as a therapeutic herb in traditional Chinese medicine (TCM). The medicinal use of the plant is separated into its leaves (Da-Qing-Ye) and roots (Ban-Lan-Gen), whereas its aerial components can be processed into a dried bluish-spruce powder (Qing-Dai), following dehydration for long-term preservation. Over the past several decades, I. indigotica has been generally utilized for its heat-clearing effects and bodily detoxification in TCM, attributed to the presence of several classes of bioactive compounds, including organic acids, alkaloids, terpenoids, and flavonoids, as well as lignans, anthraquinones, glucosides, glucosinolates, sphingolipids, tetrapyrroles, and polysaccharides. This paper aims to delineate I. indigotica from its closely-related species (Isatis tinctoria and Isatis glauca) while highlighting the ethnomedicinal uses of I. indigotica from the perspectives of modern and traditional medicine. A systematic search of PubMed, Embase, PMC, Web of Science, and Google Scholar databases was done for articles on all aspects of the plant, emphasizing those analyzing the bioactivity of constituents of the plant. The various key bioactive compounds of I. indigotica that have been found to exhibit anti-inflammatory, antimicrobial, anticancer, and anti-allergic properties, along with the protective effects against neuronal injury and bone fracture, will be discussed. Collectively, the review hopes to draw attention to the therapeutic potential of I. indigotica not only as a TCM, but also as a potential source of bioactive compounds for disease management and treatment.
    Keywords:   Anti-Inflammation; Antiviral; Chinese Woad; Complementary Medicine; Ethnopharmacology; Isatis indigotica Fortune
    DOI:  https://doi.org/10.1142/S0192415X22500069
  63. 3 Biotech. 2022 Feb;12(2): 54
    Cannabis with breast cancer treatment: propitious or pernicious?
    Recardia Schoeman, Amy de la Harpe, Natasha Beukes, Carminita L Frost.
      Cannabis has been used for various medicinal applications including, but not limited to, cancer: most commonly to treat chemotherapy-associated side effects. Cannabis is often used for its palliative effects in the form of purified cannabinoids, or as extracts. This study was conducted using two breast cancer cell lines and aimed to evaluate potential anti-proliferative "intra-entourage effects" between purified phytocannabinoids resembling the THC and CBD ratios of medicinal and recreational cannabis strains, as well as to investigate potential "inter-entourage effects" between the different ratios and the phytochemicals found in a Cannabis sativa extract. This study also aimed to evaluate the potential interaction between cannabinoids and chemotherapeutic agents. The data identified an intra-entourage effect present in the MCF-7 cells when treated with a recreational, but not a medicinal, cannabis formulation. This effect may be due to THC partially exerting its anti-proliferative effects through the estrogen receptor (ER), present in the MCF-7 cell line. Little to no intra-entourage effects were observed in the MDA-MB-231 cell line and no inter-entourage effects were observed in either cell line. The simultaneous treatment of the MCF-7 cell line with various cannabinoid formulations and the common breast cancer treatment, tamoxifen, resulted in the diminished anti-proliferative activity of tamoxifen, an effect that was more evident when combined with recreational cannabis formulations. Since cannabis is commonly used in palliative care to treat chemotherapy-associated side effects, further research is required to investigate the potential interference of various cannabis formulations to ensure that the efficacy of chemotherapeutic agents is not compromised.
    Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-021-03102-1.
    Keywords:  Breast cancer; Cannabinoids; Cannabis extract; Combination therapy
    DOI:  https://doi.org/10.1007/s13205-021-03102-1
  64. Nucleosides Nucleotides Nucleic Acids. 2022 Feb 07. 1-11
    The effect of lactate dehydrogenase-A inhibition on intracellular nucleotides and mitochondrial respiration in pancreatic cancer cells.
    Marika Franczak, Barbara Kutryb-Zajac, Btissame El Hassouni, Elisa Giovannetti, Carlotta Granchi, Filippo Minutolo, Ryszard T Smolenski, Godefridus J Peters.
      Pancreatic cancer (PC) is one of the most lethal malignancies. PC is characterized by a high expression of the glucose transporter GLUT-1 and of lactate dehydrogenase A (LDH-A). The novel LDH-A inhibitor NHI-Glc-2 was designed for a better uptake via GLUT-1 and was shown to be cytotoxic against the PC cell line PANC-1. Using RP-HPLC we investigated its effect on adenine nucleotides and NADH/NAD+, while the Seahorse analyzer was used to determine its effect on glycolysis and mitochondrial function. A 24 hour exposure to 10 µM NHI-Glc-2 (around the IC50) decreased the ATP concentration by about 10%, but at 25 µM this decrease was 38%, while NAD+ decreased by 26%, associated with a 35% decrease in the NADH/NAD+ ratio. A 10 µM NHI-Glc-2 decreased extracellular acidification and oxygen consumption (about 75%), as well as the mitochondrial respiration parameters by 50%. In conclusion, LDH-A inhibition markedly affected the energy supply of PANC-1 cells. The respiration data indicated a dependency of the cells on glycolysis and fatty acid oxidation.Supplemental data for this article is available online at https://doi.org/10.1080/15257770.2022.2031215 .
    Keywords:  Pancreatic cancer; glucose transporter 1; lactate dehydrogenase A; mitochondrial function; nucleotides
    DOI:  https://doi.org/10.1080/15257770.2022.2031215
  65. Sci Adv. 2022 Feb 11. 8(6): eabj1262
    Versatile ginsenoside Rg3 liposomes inhibit tumor metastasis by capturing circulating tumor cells and destroying metastatic niches.
    Jiaxuan Xia, Shaojie Ma, Xi Zhu, Chen Chen, Ru Zhang, Zhonglian Cao, Xing Chen, Longlong Zhang, Ying Zhu, Shuya Zhang, Shiyi Li, Guolong Gu, Xunbin Wei, Kunqian Yu, Jianxin Wang.
      Limited circulating tumor cells (CTCs) capturing efficiency and lack of regulation capability on CTC-supportive metastatic niches (MNs) are two main obstacles hampering the clinical translation of conventional liposomes for the treatment of metastatic breast cancers. Traditional delivery strategies, such as ligand modification and immune modulator co-encapsulation for nanocarriers, are inefficient and laborious. Here, a multifunctional Rg3 liposome loading with docetaxel (Rg3-Lp/DTX) was developed, in which Rg3 was proved to intersperse in the phospholipid bilayer and exposed its glycosyl on the liposome surface. Therefore, it exhibited much higher CTC-capturing efficiency via interaction with glucose transporter 1 (Glut1) overexpressed on CTCs. After reaching the lungs with CTCs, Rg3 inhibited the formation of MNs by reversing the immunosuppressive microenvironment. Together, Rg3-Lp/DTX exhibited excellent metastasis inhibition capacity by CTC ("seeds") neutralization and MN ("soil") inhibition. The strategy has great clinical translation prospects for antimetastasis treatment with enhanced therapeutic efficacy and simple preparation process.
    DOI:  https://doi.org/10.1126/sciadv.abj1262
  66. Semin Cancer Biol. 2022 Feb 07. pii: S1044-579X(22)00027-X. [Epub ahead of print]
    Current Nano-therapeutic Approaches Ameliorating Inflammation in Cancer Progression.
    Muneeb U Rehman, Andleeb Khan, Zuha Imtiyaz, Shafat Ali, Hafiz Antar Makeen, Summya Rashid, Azher Arafah.
      Cancer is one of the biggest causes of mortality in the world. The advances in cancer research have taken us to distance in understanding the disease, which helps develop therapeutic strategies. Surgery and chemotherapy are the two main chosen routes of combat for cancer. These chemotherapeutic agents are good at targeting cancer, but many lack the specificity to make the distinction between healthy cells. Also, the toxicity of these chemotherapeutic agents is very high. This gap makes it quintessential to either look for better and safe agents or makes it possible for existing agents to meet these needs. Nanotechnology has the potential to deal with these unmet needs. Nanotechnology has been a hot topic recently due to its applications, one of these being nanomedicine. Studies have proven that cancer nanomedicine has a scope of being revolutionary. With the help of nanoparticles, we can make drugs specific for the cancer tissue; it can also help in increasing the bioavailability of the drug. A nanoparticle can be modified as such that it can carry the drug load that is required and delivers it to the specific target. In this review article, we have discussed the advances in nanomedicine and the current clinical status of various nanomedicines. We have extensively explored various strategies used to develop cancer nanomedicine while also discussing their mechanism of action.
    Keywords:  Cancer progression; Nanotechnology; Nanotoxicity; inflammation
    DOI:  https://doi.org/10.1016/j.semcancer.2022.02.006
  67. Crit Rev Food Sci Nutr. 2022 Feb 10. 1-35
    Jackfruit (Artocarpus heterophyllus Lam.) in health and disease: a critical review.
    Ashutosh Gupta, Alexis R Marquess, Abhay Kumar Pandey, Anupam Bishayee.
      Artocarpus heterophyllus Lam. (Family Moraceae), is a tropical tree, native to India and common in Asia, Africa, and several regions in South America. The fruit is commonly known as jackfruit which is one of the largest edible fruits in the world. Jackfruits comprises a wide range of nutrients, including minerals, carbohydrates, volatile compounds, proteins, and vitamins. The fruit, bark, leaves, and roots are endowed with therapeutic attributes and are utilized in the many traditional medicinal systems for the management of various ailments. Fruit and seeds are commonly used to prepare various food items, including sauce, ice creams, jams, jellies, and marmalades. Due to unique texture, jackfruit is becoming a popular meat substitute. Based on preclinical studies, jackfruit exhibits antimicrobial, antioxidant, anti-melanin, antidiabetic, anti-inflammatory, immunomodulatory, antiviral, anthelmintic, wound-healing, and antineoplastic activities. Clinical studies reveal that the leaves possess antidiabetic action in healthy and insulin-independent diabetic individuals. Despite numerous health benefits, regrettably, jackfruit has not been properly utilized in a marketable scale in areas where it is produced. This review delivers an updated, comprehensive, and critical evaluation on the nutritional value, phytochemical profiling, pharmacological attributes and underlying mechanisms of action to explore the full potential of jackfruit in health and disease.
    Keywords:   Artocarpus heterophyllus ; lectins; pharmacological activities; phytochemistry; prenylated compounds; value-added products
    DOI:  https://doi.org/10.1080/10408398.2022.2031094
  68. Front Pharmacol. 2021 ;12 824531
    Anticancer Effect of Tanshinones on Female Breast Cancer and Gynecological Cancer.
    Zhou Jin, Yu Chenghao, Peng Cheng.
      Female breast cancer, ovarian cancer, cervical cancer, and endometrial cancer are the most common tumors and the most common causes of cancer-related mortality worldwide in women. Drugs derived from natural plants play important roles in malignant tumor therapy. Salvia miltiorrhiza is a commonly used Chinese herb which has been used in the treatment of liver diseases and cardiovascular diseases because of its positive effect of promoting blood circulation, increasing oxidative stress, and removing blood stasis. Recently, studies have found that fat-soluble components of Salvia miltiorrhiza such as tanshinone II, tanshinone I, cryptotanshinone, and dihydrotanshinone I displayed good antitumor activity in vivo and in vitro for gynecological cancer by different molecular mechanisms. In this study, the latest research progress on the antitumor effect and mechanism of tanshinone compounds in breast cancer and gynecological cancer was reviewed to provide references for the research and clinical application of these compounds (tanshinone II, tanshinone I, cryptotanshinone, and dihydrotanshinone I).
    Keywords:  female breast cancer; gynecological cancer; molecular mechanism; tanshinones; traditional Chinese medicine
    DOI:  https://doi.org/10.3389/fphar.2021.824531
  69. Metallomics. 2022 Feb 12. pii: mfac008. [Epub ahead of print]
    Rhenium-guanidine complex as photosensitizer: trigger HeLa cell apoptosis through death receptor-mediated, mitochondria-mediated and cell cycle arrest pathways.
    Shu-Fen He, Jia-Xin Liao, Min-Ying Huang, Yu-Qing Zhang, Yi-Min Zou, Ci-Ling Wu, Wen-Yuan Lin, Jia-Xi Chen, Jing Sun.
      During the last decades, growing evidence indicates that the photodynamic antitumor activity of transition metal complexes, and Re(I) compounds are potential candidates for photodynamic therapy (PDT). This study reports the synthesis, characterization, and anti-tumor activity of three new Re(I)-guadinium complexes. Cytotoxicity tests reveal that complex Re1 increased cytotoxicity by 145-fold from IC50 > 180 μM in the dark to 1.3 ± 0.7 μM following 10 min of light irradiation (425 nm) in HeLa cells. Further, the mechanism by which Re1 induces apoptosis in the presence or absence of light irradiation was investigated, and results indicate that cell death was caused through different pathways. Upon irradiation, Re1 first accumulates on the cell membrane and interacts with death receptors to activate the extrinsic death receptor-mediated signaling pathway, then is transported into the cell cytoplasm. Most of the intracellular Re1 locates within mitochondria, improving the ROS level, and decreasing MMP and ATP levels, and inducing the activation of caspase-9 and, thus, apoptosis. Subsequently, the residual Re1 can translocate into the cell nucleus, and activates the p53 pathway, causing cell-cycle arrest and eventually cell death.
    Keywords:  Re(I) complex; apoptosis; cytotoxicity; mechanism; membrane receptors; phototoxicity
    DOI:  https://doi.org/10.1093/mtomcs/mfac008
  70. Pharmacol Res. 2022 Feb 05. pii: S1043-6618(22)00063-9. [Epub ahead of print] 106118
    Anticancer potential of allicin: A review.
    Elena Catanzaro, Donatella Canistro, Valentina Pellicioni, Fabio Vivarelli, Carmela Fimognari.
      Phytochemicals have attracted attention in the oncological field because they are biologically friendly and have relevant pharmacological activities. Thanks to the intense and unique spicy aroma, garlic is one of the most used plants for cooking. Its consumption is correlated to health beneficial effects towards several chronic diseases, such as cancer, mainly attributable to allicin, a bioactive sulfur compound stored in different plant parts in a precursor form. The objective of this review is to present and critically discuss the chemistry and biosynthesis of allicin, its pharmacokinetic profile, its anticancer mechanisms and molecular targets, and its selectivity towards tumor cells. The research carried out so far revealed that allicin suppresses the growth of different types of tumors. In particular, it targets many signaling pathways associated with cancer development. Future research directions are also outlined to further characterize this promising natural product.
    Keywords:  Allicin; Anticancer Drugs; Cancer; Cytotoxicity; Pharmacokinetics; Selectivity
    DOI:  https://doi.org/10.1016/j.phrs.2022.106118
  71. Biomed Pharmacother. 2022 Feb 04. pii: S0753-3322(22)00074-9. [Epub ahead of print]147 112686
    Oxamate targeting aggressive cancers with special emphasis to brain tumors.
    Meric A Altinoz, Aysel Ozpinar.
      Cancer is one of the main causes of human mortality and brain tumors, including invasive pituitary adenomas, medulloblastomas and glioblastomas are common brain malignancies with poor prognosis. Therefore, the development of innovative management strategies for refractory cancers and brain tumors is important. In states of mitochondrial dysfunction - commonly encountered in malignant cells - cells mostly shift to anaerobic glycolysis by increasing the expression of LDHA (Lactate Dehydrogenase-A) gene. Oxamate, an isosteric form of pyruvate, blocks LDHA activity by competing with pyruvate. By blocking LDHA, it inhibits protumorigenic cascades and also induces ROS (reactive oxygen species)-induced mitochondrial apoptosis of cancer cells. In preclinical studies, oxamate blocked the growth of invasive pituitary adenomas, medulloblastomas and glioblastomas. Oxamate also increases temozolomide and radiotherapy sensitivity of glioblastomas. Oxamate is highly polar, which may preclude its clinical utilization due to low penetrance through cell membranes. However, this obstacle could be overcome with nanoliposomes. Moreover, different oxamate analogs were developed which inhibit LDHC4, an enzyme also involved in cancer progression and germ cell physiology. Lastly, phenformin, an antidiabetic agent, exerts anticancer effects via complex I inhibition in the mitochondria and leading the overproduction of ROS. Oxamate combination with phenformin reduces the lactic acidosis-causing side effect of phenformin while inducing synergistic anticancer efficacy. In sum, oxamate as a single agent and more efficiently with phenformin has high potential to slow the progression of aggressive cancers with special emphasis to brain tumors.
    Keywords:  Glioblastoma; Invasive pituitary adenoma; Medulloblastoma; Oxamate; Phenformin; Warburg effect
    DOI:  https://doi.org/10.1016/j.biopha.2022.112686
  72. J Res Med Sci. 2021 ;26 124
    Determining the factors affecting energy metabolism and energy requirement in cancer patients.
    Tuğçe Bulmuş Tüccar, Nilüfer Acar Tek.
      Cancer is the second most common cause of death worldwide. It is a generic name for a large group of diseases that can affect any part of the body. Cancer affects both energy intake through the diet and the total energy expenditure (TEE) through the changes in energy metabolism, resulting in negative or positive energy balance. Determining daily energy requirement is very important in the regulation of the nutrition therapy in a cancer patients. Due to the difficulty in directly measuring the TEE, resting energy expenditure, which is the largest component of the TEE, is often used in the determination of the energy requirement. In this study, the effects of disease-specific factors such as tumor burden, inflammation, weight loss and cachexia on energy metabolism in cancer patients were investigated.
    Keywords:  Cancer; cancer cachexia; cancer care; energy metabolism; nutrition; resting metabolic rate
    DOI:  https://doi.org/10.4103/jrms.JRMS_844_20
  73. Phytomedicine. 2022 Jan 17. pii: S0944-7113(22)00016-2. [Epub ahead of print]98 153938
    A comprehensive and current review on the role of flavonoids in lung cancer-Experimental and theoretical approaches.
    Şeyda Berk, Savaş Kaya, Esra Küpeli Akkol, Hilal Bardakçı.
       BACKGROUND: It is well-known that flavonoids, which can be easily obtained from many fruits and vegetables are widely preferred in the treatment of some important diseases. Some researchers noted that these chemical compounds exhibit high inhibition effect against various cancer types. Many experimental studies proving this ability of the flavonoids with high antioxidant activity are available in the literature.
    PUROPOSE: The main aim of this review is to summarize comprehensively anticancer properties of flavonoids against the lung cancer in the light of experimental studies and well-known theory and electronic structure principles. In this review article, more detailed and current information about the using of flavonoids in the treatment of lung cancer is presented considering theoretical and experimental approaches.
    STUDY DESIGN: In addition to experimental studies including the anticancer effects of flavonoids, we emphasized the requirement of the well-known electronic structure principle in the development of anticancer drugs. For this aim, Conceptual Density Functional Theory should be considered as a powerful tool. Searching the databases including ScienceDirect, PubMed and Web of Science, the suitable reference papers for this project were selected.
    METHODS: Theoretical tools like DFT and Molecular Docking provides important clues about anticancer behavior and drug properties of molecular systems. Conceptual Density Functional Theory and CDFT based electronic structure principles and rules like Hard and Soft Acid-Base Principle (HSAB), Maximum Hardness Principle, Minimum Polarizability, Minimum Electrophilicity Principles and Maximum Composite Hardness Rule introduced by one of the authors of this review are so useful to predict the mechanisms and powers of chemical systems. Especially, it cannot be ignored the success of HSAB Principle in the explanations and highlighting of biochemical interactions.
    RESULTS: Both theoretical analysis and experimental studies confirmed that flavonoids have higher inhibition effect against lung cancer. In addition to many superior properties like anticancer activity, antimicrobial activity, antioxidant activity, antidiabetic effect of flavonoids, their toxicities are also explained with the help of published popular papers. Action modes of the mentioned compounds are given in detail.
    CONCLUSION: The review includes detailed information about the mentioned electronic structure principles and rules and their applications in the cancer research. In addition, the epidemiology and types of lung cancer anticancer activity of flavonoids in lung cancer are explained in details.
    Keywords:  Anticancer drugs; CDFT; Flavonoids; HSAB principle; Lung cancer
    DOI:  https://doi.org/10.1016/j.phymed.2022.153938
  74. Curr Drug Deliv. 2022 Feb 09.
    Combretastatin A4-loaded poly(lactic-co-glycolic acid)/soybean lecithin nanoparticles with enhanced drug dissolution rate and antiproliferation activity.
    Yue Cao, Atef M Ohammed Qasem Ahmed, Huan-Huan Du, Wei Sun, Xiaojuan Lu, Zhao Xu, Jing Tao, Qing-Ri Cao.
      Purpose：This study aimed to prepare combretastatin A4 (CA4)-loaded nanoparticles (CA4 NPs) using poly(lactic-co-glycolic acid) (PLGA) and soybean lecithin (Lipoid S100) as carriers, and further evaluate the physicochemical properties and cytotoxicities of CA4 NPs against cancer cells. Methods：CA4 NPs were prepared using a solvent evaporation technique. The effects of formulations on CA4 NPs were investigated in terms of particle size, zeta potential, encapsulation efficacy and drug loading. The physicochemical properties of CA4 NPs were characterized using transmission electron microscopy, X-ray powder diffraction, differential scanning calorimetry, and fourier transform infrared spectra. The drug release from CA4 NPs was performed using a dialysis method. In addition, the cytotoxicity of CA4 NPs against human alveolar basal epithelial (A549) cells was also evaluated. Results：CA4 NPs prepared with a low organic/water phase ratio (1:20) and high drug/PLGA mass ratio (1:2.5) exhibited a uniform hydrodynamic particle size of 142 nm; zeta potential of -1.66 mV; and encapsulation efficacy and drug loading of 92.1% and 28.3%, respectively. CA4 NPs show a significantly higher release rate than pure CA4 in pH 7.4 phosphate-buffered solution with 0.5% Tween 80. The drug molecules can change from the crystal state to an amorphous form when they are loaded into the PLGA/Lipoid S100 matrix, and some molecular interactions could also occur between the drug and PLGA. Importantly, CA4 NPs show a remarkably higher antiproliferation activity against A549 cancer cells compared with pure CA4. Conclusion：These results suggest the promising potential of PLGA/Lipoid S100 nanoparticles as the drug delivery system of CA4 for effective cancer therapy.
    Keywords:  PLGA/Lipoid S100; combretastatin A4; cytotoxicity.; dissolution; antiproliferation activity; nanoparticles; physiochemical characteristics
    DOI:  https://doi.org/10.2174/1567201819666220209093443
  75. J Prosthet Dent. 2022 Feb 04. pii: S0022-3913(21)00697-1. [Epub ahead of print]
    Photodynamic therapy in the treatment of denture stomatitis: A systematic review and meta-analysis.
    Taciana Emília Leite Vila-Nova, Rafaella de Souza Leão, Joel Ferreira Santiago Junior, Eduardo Piza Pellizzer, Belmiro Cavalcanti do Egito Vasconcelos, Sandra Lúcia Dantas Moraes.
       STATEMENT OF PROBLEM: Photodynamic therapy is widely used in dentistry, but limited evidence exists regarding its effectiveness in treating denture stomatitis. High resistance to antifungals has been reported, and photodynamic therapy could be an alternative treatment.
    PURPOSE: The purpose of this systematic review and meta-analysis was to evaluate whether photodynamic therapy is effective in reducing denture stomatitis.
    MATERIAL AND METHODS: A systematic review was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist and recorded in the prospective register of systematic reviews (PROSPERO) (CRD42020205589) to answer the population, intervention, control, outcome (PICO) question: "Is photodynamic therapy effective in the treatment of denture stomatitis when compared with the use of antifungal agents?" Electronic searches were performed in databases PubMed/MEDLINE, Cochrane library, and Web of Science for articles published until February 2021 by using the following terms: (denture stomatitis OR oral candidiasis) AND (low-level light therapy OR laser therapy OR lasers OR photodynamic therapies OR photochemotherapy) AND (antifungal drugs OR antifungal agents OR antimicrobial OR treatment). Clinical trials and randomized clinical trials, studies in the English language, and studies comparing antifungal agents with photodynamic therapy were included.
    RESULTS: In total, 5 articles were selected for the qualitative analysis and 3 for the meta-analysis. No significant difference was detected between antifungal therapy and photodynamic therapy in the reduction of colony-forming units on the palate. In a subgroup analysis, a significant difference was found in the reduction of colony-forming units on the palate at 15 days and at the denture surface at 30 days.
    CONCLUSIONS: Photodynamic therapy is effective in the treatment of denture stomatitis, but after 30 days and 15 days, the antifungals demonstrated better performance.
    DOI:  https://doi.org/10.1016/j.prosdent.2021.11.028
  76. Chin Med. 2022 Feb 10. 17(1): 21
    Mineral medicine: from traditional drugs to multifunctional delivery systems.
    Xiaoqing Zhong, Zhenning Di, Yuanxin Xu, Qifan Liang, Kuanhan Feng, Yuting Zhang, Liuqing Di, Ruoning Wang.
      Mineral drugs are an important constituent of traditional Chinese medicine (TCM). Taking minerals that contain heavy metals as drugs is a very national characteristic part of TCM. However, the safety and scientific nature of mineral drugs are controversial owing to their heavy metals and strong toxicity. In 2000, the Food and Drug Administration (FDA) authorized arsenic trioxide (ATO) as first-line therapy for acute promyelocytic leukemia. This makes the development and utilization of mineral drugs become a research hotspot. The development of nanomedicine has found a great prospect of mineral drugs in nano-delivery carriers. And that will hold promise to address the numerous biological barriers facing mineral drug formulations. However, the studies on mineral drugs in the delivery system are few at present. There is also a lack of a detailed description of mineral drug delivery systems. In this review, the advanced strategies of mineral drug delivery systems in tumor therapy are summarized. In addition, the therapeutic advantages and research progress of novel mineral drug delivery systems are also discussed. Here, we hope that this will provide a useful reference for the design and application of new mineral drug delivery systems.
    Keywords:  Active ingredient; Mineral drug; Novel drug delivery system; Traditional preparation
    DOI:  https://doi.org/10.1186/s13020-022-00577-9
  77. ACS Appl Mater Interfaces. 2022 Feb 07.
    Novel Glucose-Responsive Antioxidant Hybrid Hydrogel for Enhanced Diabetic Wound Repair.
    Zejun Xu, Guiting Liu, Jun Huang, Jun Wu.
      Antioxidant hydrogel has exhibited great potential for diabetic wound treatment. However, it is still a difficult challenge to realize reactive oxygen species (ROS) scavenging in an intelligent manner. Herein, we designed a novel glucose-responsive antioxidant hybrid hydrogel for enhanced diabetic wound repair. In this study, phenylboronic acid (PBA) with unique glucose-sensitivity was modified onto a hyaluronic acid (HA) chain by one-step synthesis, which was then incorporated into a polyethylene glycol diacrylates (PEG-DA) hydrogel matrix to obtain a novel hybrid hydrogel (PEG-DA/HA-PBA). Then, myricetin (MY) molecules with strong antioxidant activity were immobilized into the hybrid hydrogel by the formation of a dynamic borate bond between the polyphenol group of MY and the phenylboronic acid group of HA-PBA. The PEG-DA/HA-PBA/MY (PHM) hybrid hydrogel achieved glucose-triggered MY release, efficient ROS-scavenging (>80.0%), and also reshaped the hostile oxidative wound microenvironment (reduced MDA activity and increased SOD and GSH/GSSG levels). Furthermore, in vitro and in vivo results indicated that the PHM hydrogel platform effectively ameliorated the inflammatory response (decreased IL-6 and increased Il-10 expression), accelerated angiogenesis (increased VEGF and CD 31 expression), and increased tissue remodeling within 20 days, which was better than the nonresponsive PEG-DA/MY (PM) hydrogel platform in promoting diabetic wound healing. All results strongly suggested that this novel glucose-responsive antioxidant hybrid hydrogel platform has great potential in diabetic wound repair.
    Keywords:  antioxidation; diabetic wound; glucose-responsive; hydrogel; reactive oxygen species
    DOI:  https://doi.org/10.1021/acsami.1c23461
  78. Cell Rep. 2022 Feb 08. pii: S2211-1247(22)00067-5. [Epub ahead of print]38(6): 110351
    CRAF dimerization with ARAF regulates KRAS-driven tumor growth.
    Avinashnarayan Venkatanarayan, Jason Liang, Ivana Yen, Frances Shanahan, Benjamin Haley, Lilian Phu, Erik Verschueren, Trent B Hinkle, David Kan, Ehud Segal, Jason E Long, Tony Lima, Nicholas P D Liau, Jawahar Sudhamsu, Jason Li, Christiaan Klijn, Robert Piskol, Melissa R Junttila, Andrey S Shaw, Mark Merchant, Matthew T Chang, Donald S Kirkpatrick, Shiva Malek.
      KRAS, which is mutated in ∼30% of all cancers, activates the RAF-MEK-ERK signaling cascade. CRAF is required for growth of KRAS mutant lung tumors, but the requirement for CRAF kinase activity is unknown. Here, we show that subsets of KRAS mutant tumors are dependent on CRAF for growth. Kinase-dead but not dimer-defective CRAF rescues growth inhibition, suggesting that dimerization but not kinase activity is required. Quantitative proteomics demonstrates increased levels of CRAF:ARAF dimers in KRAS mutant cells, and depletion of both CRAF and ARAF rescues the CRAF-loss phenotype. Mechanistically, CRAF depletion causes sustained ERK activation and induction of cell-cycle arrest, while treatment with low-dose MEK or ERK inhibitor rescues the CRAF-loss phenotype. Our studies highlight the role of CRAF in regulating MAPK signal intensity to promote tumorigenesis downstream of mutant KRAS and suggest that disrupting CRAF dimerization or degrading CRAF may have therapeutic benefit.
    Keywords:  ARAF; BRAF; CRAF; ERK; KRAS; MAPK; MEK; cancer; dimerization; kinase
    DOI:  https://doi.org/10.1016/j.celrep.2022.110351
  79. J Food Biochem. 2022 Feb 06. e14105
    The bioactivity and applications of pomegranate peel extract: A review.
    Qiwen Xiang, Meifeng Li, Jiayu Wen, Fajian Ren, Zhou Yang, Xingyue Jiang, Yan Chen.
      Pomegranate peel (PP) is a by-product in the processing of pomegranate products, which is usually discarded as a waste. However, a large number of researches have shown that pomegranate peel extract (PPE) is rich in a variety of phenolic substances, among which ellagic acid (EA), as one of the main active components, has significant biological activities, such as anti-oxidation, anti-tumor, anti-inflammatory, neuroprotection, anti-viral, and anti-bacterial. We analyzed the mechanism of EA's biological activity, and discussed its application in the food industry, for instance, food preservation, food additives, and functional foods. Combined with the research status of PPE, we discussed the limitations and development potential of PPE, in order to provide theoretical reference and scientific basis for the development and utilization of pomegranate by-products. PRACTICAL APPLICATIONS: Pomegranate peel (PP), the inedible part of the fruit, is usually treated as waste. In recent years, researchers have been committed to exploring various bioactive ingredients in PP and exploring its potential benefits to human health, which has far-reaching significance. In this paper, the chemical constituents of polyphenols in PP were reviewed, mainly focusing on the biological activity and mechanism of ellagic acid (EA). We reviewed the applications and invention patents of pomegranate peel extract (PPE) in food field, including food preservation, food additive, and functional foods, providing reference for the recycling and reuse of PP.
    Keywords:  applications; bioactivity; ellagic acid; pomegranate peel extract
    DOI:  https://doi.org/10.1111/jfbc.14105
  80. Neurosci Biobehav Rev. 2022 Feb 02. pii: S0149-7634(22)00045-8. [Epub ahead of print] 104556
    Can dietary patterns prevent cognitive impairment and reduce Alzheimer's disease risk: exploring the underlying mechanisms of effects.
    Chuan-Qi Chu, Lei-Lei Yu, Guo-Yuan Qi, Ya-Shi Mi, Wan-Qiang Wu, Yuan-Kun Lee, Qi-Xiao Zhai, Feng-Wei Tian, Wei Chen.
      Alzheimer's disease (AD) is one of the fastest growing cognitive decline-related neurological diseases. To date, effective curative strategies have remained elusive. A growing body of evidence indicates that dietary patterns have significant effects on cognitive function and the risk of developing AD. Previous studies on the association between diet and AD risk have mainly focused on individual food components and specific nutrients, and the mechanisms responsible for the beneficial effects of dietary patterns on AD are not well understood. This article provides a comprehensive overview of the effects of dietary patterns, including the Mediterranean diet (MedDiet), dietary approaches to stop hypertension (DASH) diet, Mediterranean-DASH diet intervention for neurological delay (MIND), ketogenic diet, caloric restriction, intermittent fasting, methionine restriction, and low-protein and high-carbohydrate diet, on cognitive impairment and summarizes the underlying mechanisms by which dietary patterns attenuate cognitive impairment, especially highlighting the modulation of dietary patterns on cognitive impairment through gut microbiota. Furthermore, considering the variability in individual metabolic responses to dietary intake, we put forward a framework to develop personalized dietary patterns for people with cognitive disorders or AD based on individual gut microbiome compositions.
    Keywords:  Alzheimer’s disease; Cognitive impairment; DASH; Dietary patterns; Gut microbiome; MIND; Mediterranean; Personalized nutrition; dietary restriction; ketogenic diet
    DOI:  https://doi.org/10.1016/j.neubiorev.2022.104556
  81. Bioact Mater. 2022 Jun;12 314-326
    Cyanobacteria-based self-oxygenated photodynamic therapy for anaerobic infection treatment and tissue repair.
    Bailiang Wang, Liyang Zhou, Yishun Guo, Hanwen Guo, Yiming Zhong, Xiaomin Huang, Yifan Ge, Qingying Wang, Xiaoying Chu, Yingying Jin, Kaiyue Lan, Mei Yang, Jia Qu.
      Photodynamic therapy (PDT) is an important technique to deal with drug-resistant bacterial infections in the post-antibiotic era. However, the hypoxic environment in intractable infections such as refractory keratitis and periodontitis, makes PDT more difficult. In this work, spontaneous oxygen-producing cyanobacteria were used as the carrier of photosensitizer (Ce6), and ultrasmall Cu5.4O nanoparticles (Cu5.4O USNPs) with catalase activity for infection and inflammation elimination and rapid tissue repair (CeCycn-Cu5.4O). The loading of Ce6 and Cu5.4O USNPs onto cyanobacteria surface were confirmed by transmission electron microscopy, nano particle size analyzer, scanning electron microscopy. In vitro sterilization and biofilm removal experiments demonstrated that the restriction of hypoxic environment to PDT was significantly alleviated due to the oxygen production of cyanobacteria. Under laser irradiation, the close transfer of energy photons to oxygen produced by cyanobacteria reduced more than 90% of Ce6 dosages (660 nm, 200 mW/cm2, 2 min). It is worth mentioning that both rapid sterilization through PDT and long-term oxidized free radicals elimination were achieved by adjusting the ratio of Ce6 and Cu5.4O USNPs. Both periodontitis and refractory keratitis animal models proved the excellent self-oxygenation enhanced antibacterial property and promotion of tissue repair.
    Keywords:  Anaerobic infection; Periodontitis; Photodynamic therapy; Refractory keratitis; Self-oxygenated
    DOI:  https://doi.org/10.1016/j.bioactmat.2021.10.032
  82. Acta Pharm Sin B. 2022 Jan;12(1): 364-377
    The osteogenic niche-targeted arsenic nanoparticles prevent colonization of disseminated breast tumor cells in the bone.
    Cong Liu, Anzhi Hu, Huijuan Chen, Jing Liang, Mancang Gu, Yang Xiong, Chao-Feng Mu.
      Up to 70% of patients with late-stage breast cancer have bone metastasis. Current treatment regimens for breast cancer bone metastasis are palliative with no therapeutic cure. Disseminated tumor cells (DTCs) colonize inside the osteogenic niches in the early stage of bone metastasis. Drug delivery into osteogenic niches to inhibit DTC colonization can prevent bone metastasis from entering its late stage and therefore cure bone metastasis. Here, we constructed a 50% DSS6 peptide conjugated nanoparticle to target the osteogenic niche. The osteogenic niche was always located at the endosteum with immature hydroxyapatite. Arsenic-manganese nanocrystals (around 14 nm) were loaded in osteogenic niche-targeted PEG-PLGA nanoparticles with an acidic environment-triggered arsenic release. Arsenic formulations greatly reduced 4T1 cell adhesion to mesenchymal stem cells (MSCs)/preosteoblasts (pre-OBs) and osteogenic differentiation of osteoblastic cells. Arsenic formulations also prevented tumor cell colonization and dormancy via altering the direct interaction between 4T1 cells and MSCs/pre-OBs. The chemotactic migration of 4T1 cells toward osteogenic cells was blocked by arsenic in mimic 3D osteogenic niche. Systemic administration of osteogenic niche-targeted arsenic nanoparticles significantly extended the survival of mice with 4T1 syngeneic bone metastasis. Our findings provide an effective approach for osteogenic niche-specific drug delivery and suggest that bone metastasis can be effectively inhibited by blockage of tumor cell colonization in the bone microenvironment.
    Keywords:  Arsenic trioxide; Arsenic-manganese nanocrystal; Bone colonization; Bone marrow; Bone metastasis; Breast cancer; Immature hydroxyapatite; Osteogenic niche
    DOI:  https://doi.org/10.1016/j.apsb.2021.06.012
  83. Acta Pharm Sin B. 2022 Jan;12(1): 378-393
    A cyclodextrin-based nanoformulation achieves co-delivery of ginsenoside Rg3 and quercetin for chemo-immunotherapy in colorectal cancer.
    Dandan Sun, Yifang Zou, Liu Song, Shulan Han, Hao Yang, Di Chu, Yun Dai, Jie Ma, Caitriona M O'Driscoll, Zhuo Yu, Jianfeng Guo.
      The immune checkpoint blockade therapy has profoundly revolutionized the field of cancer immunotherapy. However, despite great promise for a variety of cancers, the efficacy of immune checkpoint inhibitors is still low in colorectal cancer (CRC). This is mainly due to the immunosuppressive feature of the tumor microenvironment (TME). Emerging evidence reveals that certain chemotherapeutic drugs induce immunogenic cell death (ICD), demonstrating great potential for remodeling the immunosuppressive TME. In this study, the potential of ginsenoside Rg3 (Rg3) as an ICD inducer against CRC cells was confirmed using in vitro and in vivo experimental approaches. The ICD efficacy of Rg3 could be significantly enhanced by quercetin (QTN) that elicited reactive oxygen species (ROS). To ameliorate in vivo delivery barriers associated with chemotherapeutic drugs, a folate (FA)-targeted polyethylene glycol (PEG)-modified amphiphilic cyclodextrin nanoparticle (NP) was developed for co-encapsulation of Rg3 and QTN. The resultant nanoformulation (CD-PEG-FA.Rg3.QTN) significantly prolonged blood circulation and enhanced tumor targeting in an orthotopic CRC mouse model, resulting in the conversion of immunosuppressive TME. Furthermore, the CD-PEG-FA.Rg3.QTN achieved significantly longer survival of animals in combination with Anti-PD-L1. The study provides a promising strategy for the treatment of CRC.
    Keywords:  ATF6, activating transcription factor 6; ATP, adenosine triphosphate; CI, combination index; CRC, colorectal cancer; CRT, calreticulin; CTLA-4, cytotoxic T lymphocyte antigen 4; CXCL10, C-X-C motif chemokine 10; CXCL9, C-X-C motif chemokine 9; Chemotherapy; Colorectal cancer; Combination therapy; DAMPs, damage-associated molecular patterns; DCs, dendritic cells; ECL, enhanced chemiluminescence; EE, encapsulation efficiency; ER, endoplasmic reticulum; FA, folate; HMGB1, high-mobility group box 1; ICD, immunogenic cell death; IFN-γ, interferon-gamma; IL-10, interleukin-10; IL-12, interleukin-12; IL-4, interleukin-4; IL-6, interleukin-6; IRE1, inositol-requiring enzyme 1; Immunogenic cell death; Immunotherapy; LC, loading capacity; MDSCs, myeloid derived suppressor cells; MMR, mismatch repair; MR, molar ratio; NAC, N-acetyl-l-cysteine; NP, nanoparticle; Nano drug delivery system; PD-L1, programmed death-ligand 1; PEG, polyethylene glycol; PERK, PKR-like ER kinase; PFA, paraformaldehyde; PVDF, polyvinylidene fluoride; QTN, quercetin; ROS, reactive oxygen species; Reactive oxygen species; TAAs, tumor-associated antigens; TME, tumor microenvironment; Tumor microenvironment; UPR, unfolded protein response; p-IRE1, phosphorylation of IRE1; p-PERK, phosphorylation of PERK
    DOI:  https://doi.org/10.1016/j.apsb.2021.06.005
  84. Sci Rep. 2022 Feb 08. 12(1): 2110
    Characterization of the physicochemical properties, antioxidant activity, and antiproliferative activity of natural melanin from S. reiliana.
    Xin Fu, Mengxi Xie, Ming Lu, Lin Shi, Taiyuan Shi, Miao Yu.
      This study aimed to characterize the physicochemical properties and stability of L-25 melanin extracted from Sporisorium reilianum (S. reiliana). The results showed that the maximum absorption wavelength of melanin was 215 nm. Reducing agents, heat, light, microwaving, oxidants, and common food additives did not affect the melanin. Additionally, it has a good metal stability except Mn2+. The IR spectra revealed the presence of O-H, N-H, C=O, and C=C bonds as well as carboxyl, alcohol hydroxyl, and phenolic hydroxyl groups and a pyran ring. L-25 melanin could be defined as DL-hydroxy phenylalanine (DOPA)-melanin. The antioxidant and antiproliferative were also measured. The melanin has a specific stability and high antioxidant activity, including a strong DPPH free radical scavenging ability, and protected damaged HepG2 cells by reducing reactive oxygen species, malondialdehyde, and lactate dehydrogenase content. In conclusion, S. reilianum represents a novel source of melanin, that could be applied to health food or food additives. Our results show that melanin from S. reilianum is a natural pigment with good stability that has a great prospect of development and application, providing a theoretical basis and methods for its further processing and development as a functional food.
    DOI:  https://doi.org/10.1038/s41598-022-05676-z
  85. 3 Biotech. 2022 Feb;12(2): 49
    Chemical investigation and screening of anti-cancer potential of Syzygium aromaticum L. bud (clove) essential oil nanoemulsion.
    Atena Vafaei Malek Abadi, Ehsan Karimi, Ehsan Oskoueian, Ghasem Rahimi Kalateh Shah Mohammad, Negin Shafaei.
      This study was done to improve the medicinal properties of Syzygium Aromaticum L by processing S. Aromaticum L. bud essential oil (SABE) to the Nanoemulsion drug delivery system (SABE-NE) and investigating its anti-tumor and apoptotic impacts against the human HT-29 colon cancer cells. Applying the ultra-sonication method and characterization by DLS and FESEM analysis facilitates the nanoemulsification procedure. Human cancer (HT-29) and normal (HFF) cell lines were then evaluated based on the SABE-NE apoptotic and cytotoxic effects. In an in vitro section, flow cytometry method, Cas3 gene profile, AO/PI cell staining, and MTT assays are used to analyze the apoptotic and cytotoxic activities. In further analysis, liver lipid peroxidation and antioxidant genes expression (SOD, CAT, and GPx) investigate alterations in mice organs. As a result, produced 131.2 nm SABE-NE induces apoptosis response and cellular death (Cas3 up-regulation and enhanced SubG1 peaks). Subsequently, the HT-29 cells' viability can reduce significantly, while HFF cells indicate confined cytotoxic impacts. Moreover, in vivo test results on mice livers demonstrate the cytoprotective properties of SABE-NE (reduced lipid peroxidation and increased antioxidant enzymes gene expression and nondetectable cytotoxic impacts). We produced a novel nanoemulsion drug delivery system called SABE-NE, a cell-specific apoptotic inducer. We thus can be utilized as an efficient anti-cancer compound for human colon cancer treatment. However, further supplementary studies are required to verify and approve its cell-specific anti-tumor activity.
    Keywords:  Anti-cancer; Apoptotic activity; Syzygium aromaticum L. bud essential oil nanoemulsion (SABE-NE)
    DOI:  https://doi.org/10.1007/s13205-022-03117-2
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