bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2022‒04‒03
104 papers selected by
Yasmin Elkabani
Egyptian Foundation for Research and Community Development
  1. Delivering Singlet Oxygen in Dark Condition With an Anthracene-Functionalized Semiconducting Compound for Enhanced Phototheranostics.
  2. GSH-Responsive and Hypoxia-Activated Multifunctional Nanoparticles for Synergetically Enhanced Tumor Therapy.
  3. Efficacy of Sirna-Loaded Nanoparticles in the Treatment of k-ras Mutant Lung Cancer in vitro.
  4. Lipid metabolic reprogramming by hypoxia-inducible factor-1 in the hypoxic tumour microenvironment.
  5. Comprehensive comparison of theranostic nanoparticles in breast cancer.
  6. Design and Development of Nanostructured Co Delivery of Artemisinin and Chrysin for Targeting hTERT Gene Expression in Breast Cancer Cell Line: Possible Clinical Application in Cancer Treatment.
  7. Potential Therapeutic Implications of Caffeic Acid in Cancer Signaling: Past, Present, and Future.
  8. Targeting Mitochondria for Cancer Photodynamic Therapy.
  9. The metabolic basis of epilepsy.
  10. Sequential Ultrasound-Triggered and Hypoxia-Sensitive Nanoprodrug for Cascade Amplification of Sonochemotherapy.
  11. Selective delivery of curcumin to breast cancer cells by self-targeting apoferritin nanocages with pH-responsive and low toxicity.
  12. Listening to Drug Delivery and Responses via Photoacoustic Imaging.
  13. Multiple stimuli-responsive nanosystem for potent, ROS-amplifying, chemo-sonodynamic antitumor therapy.
  14. Two-Pronged Anti-Tumor Therapy by a New Polymer-Paclitaxel Conjugate Micelle with an Anti-Multidrug Resistance Effect.
  15. Synergistic Effect of Quercetin Magnetite Nanoparticles and Targeted Radiotherapy in Treatment of Breast Cancer.
  16. Role and regulation of autophagy in cancer.
  17. Development of poly(p-coumaric acid) as a self-anticancer nanocarrier for efficient and biosafe cancer therapy.
  18. Biodegradable and biocompatible subcutaneous implants consisted of pH-sensitive mebendazole-loaded/folic acid-targeted chitosan nanoparticles for murine triple-negative breast cancer treatment.
  19. Design and Characterization of Paclitaxel-Loaded Polymeric Nanoparticles Decorated With Trastuzumab for the Effective Treatment of Breast Cancer.
  20. Synthesis and evaluation of chitosan based controlled release nanoparticles for the delivery of ticagrelor.
  21. The Influence of Oncogenic RAS on Chemotherapy and Radiotherapy Resistance Through DNA Repair Pathways.
  22. In situ Co-Delivery of Doxorubicin and Cisplatin by Injectable Thermosensitive Hydrogels for Enhanced Osteosarcoma Treatment.
  23. Transsulfuration, minor player or crucial for cysteine homeostasis in cancer.
  24. Fungal Endophytes: an Accessible Source of Bioactive Compounds with Potential Anticancer Activity.
  25. Cancer Chemotherapy via Natural Bioactive Compounds.
  26. Cu-Chelated polydopamine nanoparticles as a photothermal medium and "immunogenic cell death" inducer for combined tumor therapy.
  27. Comparison of the Impact of the Mediterranean Diet, Anti-Inflammatory Diet, Seventh-Day Adventist Diet, and Ketogenic Diet Relative to Cognition and Cognitive Decline.
  28. Indomethacin-based near-infrared photosensitizer for targeted photodynamic cancer therapy.
  29. Natural approach in osteoarthritis therapy.
  30. Synergistic effect of antimetabolic and chemotherapy drugs in triple-negative breast cancer.
  31. Therapeutic Implications of Caffeic Acid in Cancer and Neurological Diseases.
  32. Tumor-targeted hyaluronic acid-based oxidative stress nanoamplifier with ROS generation and GSH depletion for antitumor therapy.
  33. Anti-cancer activity of sustained release capsaicin formulations.
  34. Complexation of phytochemicals with cyclodextrins and their derivatives- an update.
  35. The impact of bioactive compounds derived from marine fish on cancer.
  36. Dual Roles of Coconut Oil and Its Major Component Lauric Acid on Redox Nexus: Focus on Cytoprotection and Cancer Cell Death.
  37. Photothermal therapy-mediated autophagy in breast cancer treatment: Progress and trends.
  38. Curcumin and Its Analogs as a Therapeutic Strategy in Infections Caused by RNA Genome Viruses.
  39. Injectable in situ intelligent thermo-responsive hydrogel with glycyrrhetinic acid-conjugated nano graphene oxide for chemo-photothermal therapy of malignant hepatocellular tumor.
  40. KRAS Mutation in Rare Tumors: A Landscape Analysis of 3453 Chinese Patients.
  41. Gemcitabine cationic polymeric nanoparticles against ovarian cancer: formulation, characterization, and targeted drug delivery.
  42. Rational design of iridium-porphyrin conjugates for novel synergistic photodynamic and photothermal therapy anticancer agents.
  43. Epigallocatechin-3-gallate suppresses the growth of human osteosarcoma by inhibiting the Wnt/β-catenin signalling pathway.
  44. Advancement and Applications of Platelet-Inspired Nanoparticles: A Paradigm for Cancer Targeting.
  45. The optical research progress of nanophosphors composed of transition elements in the fourth period of near-infrared windows I and II for deep-tissue theranostics.
  46. pH-redox responsive cascade-targeted liposomes to intelligently deliver doxorubicin prodrugs and lonidamine for glioma.
  47. Potential application of Helicobacter pylori against cancer: carcinogenic pathogen or therapeutic agent?
  48. Research progress on antineoplastic, antibacterial, and anti-inflammatory activities of seven-membered heterocyclic derivatives.
  49. A discursive review of recent development and patents on glycerosomes.
  50. Targeted delivery and controlled released of essential oils using nanoencapsulation: A review.
  51. Targeting Transporters for Drug Delivery to the Brain: Can We Do Better?
  52. The ethnobotany, phytochemistry, and biological properties of Nigella damascena - A review.
  53. All-stage targeted therapy for glioblastoma based on lipid membrane coated cabazitaxel nanocrystals.
  54. Postbiotics as the new frontier in food and pharmaceutical research.
  55. Physical & Chemical Microwave Ablation (MWA) Enabled by Nonionic MWA Nanosensitizers Repress Incomplete MWA-Arised Liver Tumor Recurrence.
  56. Improving the Therapeutic Efficiency of Hypoxic-Activated Prodrugs by Enhancing Hypoxia in Solid Tumors.
  57. A Systemic Review on the Synthesis, Characterization, and Applications of Palladium Nanoparticles in Biomedicine.
  58. Advances and Applications of Metal-Organic Framework Nanomaterials as Oral Delivery Carriers: A Review.
  59. Melanoma and Nanotechnology-Based Treatment.
  60. Glutathione-Depleting Organic Metal Adjuvants for Effective NIR-II Photothermal Immunotherapy.
  61. A review on the design, synthesis, and structure-activity relationships of benzothiazole derivatives against hypoxic tumors.
  62. pH/Enzyme dual sensitive and nucleus-targeting dendrimer nanoparticles to enhance the antitumour activity of doxorubicin.
  63. Applications of algae to obtain healthier meat products: A critical review on nutrients, acceptability and quality.
  64. A Facile Way To Improve the Bioavailability of Nanomedicine Based on the Threshold Theory.
  65. Prunus mira Koehne in Sichuan, China: Recorded History as a Medicine and Food, Modern Applications, Distribution, and Ethnobotanical Investigations.
  66. Ultrasmall iron oxide nanoparticles cause significant toxicity by specifically inducing acute oxidative stress to multiple organs.
  67. Research progress of anti-glioma chemotherapeutic drugs (Review).
  68. Advances in the stimuli-responsive injectable hydrogel for controlled release of drugs.
  69. Spiky Cascade Biocatalysts as Peroxisome-Mimics for Ultrasound-Augmented Tumor Ablation.
  70. 5-Aminolevulinic acid overcomes hypoxia-induced radiation resistance by enhancing mitochondrial reactive oxygen species production in prostate cancer cells.
  71. Alteration in glucose metabolism in the brain associated with tamoxifen treatment: Study in postmenopausal animal model.
  72. Recent Advances and Mechanistic Insights into Antibacterial Activity, Antibiofilm Activity, and Cytotoxicity of Silver Nanoparticles.
  73. Nanomaterials-based drug delivery approaches for wound healing.
  74. Recent advances in nuclear receptors-mediated health benefits of blueberry.
  75. Biomimetic GBM-targeted drug delivery system boosting ferroptosis for immunotherapy of orthotopic drug-resistant GBM.
  76. Vinblastine Loaded On Graphene Quantum Dots And Its Anticancer Applications.
  77. Review on NAD(P)H dehydrogenase quinone 1 (NQO1) pathway.
  78. [Applications and perspectives of ketone body D-β-hydroxybutyrate in the medical fields].
  79. Hispolon-Loaded Liquid Crystalline Nanoparticles: Development, Stability, In Vitro Delivery Profile, and Assessment of Hepatoprotective Activity in Hepatocellular Carcinoma.
  80. CD44/Folate Dual Targeting Receptor Reductive Response PLGA-Based Micelles for Cancer Therapy.
  81. Skin-Permeable Nano-Lithocholic Lipidoid Efficiently Alleviates Psoriasis-like Chronic Skin Inflammations.
  82. Targeted delivery of quercetin by biotinylated mixed micelles for non-small cell lung cancer treatment.
  83. Imaging Sub-Cellular Methionine and Insulin Interplay in Triple Negative Breast Cancer Lipid Droplet Metabolism.
  84. The pathogenesis and treatment mechanism of Parkinson's disease from the perspective of traditional Chinese medicine.
  85. Glutamate blunts cell-killing effects of neutrophils in tumor microenvironment.
  86. Phytochemical compositions, health-promoting properties and food applications of crabapples: A review.
  87. Supramolecular organic frameworks improve the safety of clinically used porphyrin photodynamic agents and maintain their antitumor efficacy.
  88. [Research progress on effective components and mechanisms of anti-depressive Chinese medicine].
  89. Lecithins: A comprehensive review of their properties and their use in formulating microemulsions.
  90. A Mini-Review of Flavone Isomers Apigenin and Genistein in Prostate Cancer Treatment.
  91. Tumor-oriented mathematical models in hydrogel regulation for precise topical administration regimens.
  92. Investigating the role of peptides in effective therapies against cancer.
  93. Nanotechnology: A Promising Targeted Drug Delivery System for Brain Tumours and Alzheimer's Disease.
  94. Elderberry (Sambucus nigra L.): Bioactive Compounds, Health Functions, and Applications.
  95. Advances and prospects of ultrasound targeted drug delivery systems using biomaterial-modified micro/nanobubbles for tumor therapy.
  96. Treat more than heat-New therapeutic implications of Cimicifuga racemosa through AMPK-dependent metabolic effects.
  97. Fermented Jussara: Evaluation of Nanostructure Formation, Bioaccessibility, and Antioxidant Activity.
  98. DNA Nanobots - Emerging Customized Nanomedicine in Oncology.
  99. Dynamic Surface Wrinkles for In Situ Light-Driven Dynamic Gratings.
  100. Brain-targeting biomimetic nanoparticles for codelivery of celastrol and LY2157299 for reversing glioma immunosuppression.
  101. Design and Characterization of Liposomal Methotrexate and Its Effect on BT-474 Breast Cancer Cell Line.
  102. Neuroanatomical, Biochemical, and Functional Modifications in Brain Induced by Treatment with Antidepressants.
  103. The potential mechanism of Chebulae Fructus in the treatment of hepatocellular carcinoma on the basis of network pharmacology.
  104. Marine Polysaccharides in Tailor- Made Drug Delivery.
  1. Front Bioeng Biotechnol. 2022 ;10 781766
    Delivering Singlet Oxygen in Dark Condition With an Anthracene-Functionalized Semiconducting Compound for Enhanced Phototheranostics.
    Jian Shen, Liuhong Pan, Xujing Zhang, Zhenyuan Zou, Bo Wei, Yongchang Chen, Xiaoyan Tang, Dengfeng Zou.
      Photodynamic therapy (PDT) utilizes the photogeneration of reactive oxygen species (ROS) with high cytotoxicity to kill cancer cells, holding great promise for cancer treatment. Fractionated delivery of singlet oxygen (1O2) is a wise approach to relieving hypoxia, thus enhancing the therapeutic efficacy. In this article, an anthracene-functionalized semiconducting compound (DPPA) has been designed and synthesized. With irradiation, the compound is able to undergo efficient intersystem crossing (ISC) and non-radioactive decay for photodynamic/photothermal synergistic therapy. In addition, the anthracene module is able to capture and release 1O2 reversibly with or without irradiation. DPPA nanoparticles (NPs) obtained by nanoprecipitation with DSPE-PEG exhibit considerable high phototoxicity on human kidney cancer cells (A498), and the half maximum inhibitory concentration (IC50) is 15.8 μg/ml. Furthermore, an in vivo study demonstrates that complete tumor suppression was observed when the mice were administered DPPA NPs with the help of laser, compared with the control and dark groups. The H&E analysis of the normal tissues (the heart, liver, spleen, lungs, and kidney) indicates that such NPs cause no side effects, indicating the biosafety of DPPA NPs. The results provide a strategy to design a heavy-atom-free photosensitizer for photothermal and fractionated PDT against kidney tumors.
    Keywords:  DPPA; fractionated PDT; heavy-atom–free; human kidney cancer; synergistic therapy
    DOI:  https://doi.org/10.3389/fbioe.2022.781766
  2. ACS Biomater Sci Eng. 2022 Mar 31.
    GSH-Responsive and Hypoxia-Activated Multifunctional Nanoparticles for Synergetically Enhanced Tumor Therapy.
    Chunyang Liu, Sihan Jia, Li Tu, Peiyan Yang, Yange Wang, Sunkui Ke, Wei Shi, Shefang Ye.
      The integration of reactive oxygen species (ROS)-based chemodynamic therapy (CDT) and photodynamic therapy (PDT) has attracted enormous attention for synergistic antitumor therapies. However, the strategy is severely hampered by tumor hypoxia and overproduced antioxidant glutathione (GSH) in the tumor microenvironment. Inspired by the concept of metal coordination-based nanomedicines, we proposed an effective strategy for synergistic cancer treatment in response to the special tumor microenvironmental properties. Herein, we present novel metal-coordinated multifunctional nanoparticles (NPs) by the Cu2+-triggered assembly of photosensitizer indocyanine green (ICG) and hypoxia-activated anticancer prodrug tirapazamine (TPZ) (Cu-ICG/TPZ NPs). After accumulating within tumor sites via the enhanced permeability and retention (EPR) effect, the Cu-ICG/TPZ NPs were capable of triggering a cascade of combinational therapeutic reactions, including hyperthermia, GSH elimination, and Cu+-mediated •OH generation and the subsequent hypoxia-triggered chemotherapeutic effect of TPZ, thus achieving synergistic tumor therapy. Both in vitro and in vivo evaluations suggested that the multifunctional Cu-ICG/TPZ NPs could realize satisfactory therapeutic efficacy with excellent biosafety. These results thus suggested the great potential of Cu-ICG/TPZ NPs to serve as a metallodrug nanoagent for synergetically enhanced tumor treatment.
    Keywords:  GSH depletion; chemodynamic therapy; combined therapy; metal coordination; photodynamic therapy
    DOI:  https://doi.org/10.1021/acsbiomaterials.2c00076
  3. J Microencapsul. 2022 Mar 31. 1-19
    Efficacy of Sirna-Loaded Nanoparticles in the Treatment of k-ras Mutant Lung Cancer in vitro.
    Ayse Gencer, Ipek Baysal, Emirhan Nemutlu, Samiye Yabanoglu-Ciftci, Betul Arica.
      AIM: To design and develop K-RAS silencing small interfering RNA (siRNA)-loaded poly (D, L-lactic-co-glycolic acid) nanoparticles and evaluate their efficacy in the treatment of K-RAS mutant lung cancer.METHODS: The nanoparticles prepared by the double emulsion solvent evaporation method were characterized by TEM, FTIR and XPS analyzes and evaluated in vitro by XTT, PCR, ELISA, and Western-Blot. Metabolomic analyzes were performed to evaluate the changes in metabolic profiles of the cells after nanoparticles treatment.
    RESULTS: The nanoparticles were obtained with a particle size less than 250 nm, a polydispersity index around 0.1, a surface charge of (-12) - (+14) mV, and 80% of the siRNA encapsulation. The nanoparticles didn't affect cell viability of the cells after 72 hours. In cancer cells, KRAS expression was decreased by up to 50%, protein levels were decreased by more than 90%.
    CONCLUSION: The formulated siRNA delivery nanoparticles can be promising treatment in lung cancer.
    Keywords:  K-RAS; L-lactic-co-glycolic acid); lung cancer; metabolomic; poly (D; polymeric nanoparticle; siRNA
    DOI:  https://doi.org/10.1080/02652048.2022.2061058
  4. Pflugers Arch. 2022 Mar 28.
    Lipid metabolic reprogramming by hypoxia-inducible factor-1 in the hypoxic tumour microenvironment.
    Jieun Seo, Jeong-Eun Yun, Sung Joon Kim, Yang-Sook Chun.
      Cancer cells rewire metabolic processes to adapt to the nutrient- and oxygen-deprived tumour microenvironment, thereby promoting their proliferation and metastasis. Previous research has shown that modifying glucose metabolism, the Warburg effect, makes glycolytic cancer cells more invasive and aggressive. Lipid metabolism has also been receiving attention because lipids function as energy sources and signalling molecules. Because obesity is a risk factor for various cancer types, targeting lipid metabolism may be a promising cancer therapy. Here, we review the lipid metabolic reprogramming in cancer cells mediated by hypoxia-inducible factor-1 (HIF-1). HIF-1 is the master transcription factor for tumour growth and metastasis by transactivating genes related to proliferation, survival, angiogenesis, invasion, and metabolism. The glucose metabolic shift (the Warburg effect) is mediated by HIF-1. Recent research on HIF-1-related lipid metabolic reprogramming in cancer has confirmed that HIF-1 also modifies lipid accumulation, β-oxidation, and lipolysis in cancer, triggering its progression. Therefore, targeting lipid metabolic alterations by HIF-1 has therapeutic potential for cancer. We summarize the role of the lipid metabolic shift mediated by HIF-1 in cancer and its putative applications for cancer therapy.
    Keywords:  Cancer therapy; Hypoxia-inducible factor-1; Lipid metabolism; Tumour microenvironment
    DOI:  https://doi.org/10.1007/s00424-022-02683-x
  5. Am J Clin Exp Immunol. 2022 ;11(1): 1-27
    Comprehensive comparison of theranostic nanoparticles in breast cancer.
    Amin Nikdouz, Nima Namarvari, Ramin Ghasemi Shayan, Arezoo Hosseini.
      Breast cancer is the most frequently happening cancer and the most typical cancer death among females. Despite the crucial progress in breast cancer therapy by using Chemotherapeutic agents, most anti-tumor drugs are insufficient to destroy exactly the breast cancer cells. The noble method of drug delivery using nanoparticles presents a great promise in treating breast cancer most sufficiently and with the least harm to the patient. Nanoparticles, with their spectacular characteristics, help overcome problems of this kind. Unique features of nanoparticles such as biocompatibility, bioavailability, biodegradability, sustained release, and, most importantly, site-specific targeting enables the Chemotherapeutic agents loaded in nanocarriers to differentiate between healthy tissue and cancer cells, leading to low toxicity and fewer side effects. This review focuses on evaluating and comprehending nanoparticles utilized in breast cancer treatment, including the most recent data related to the drugs they can carry. Also, this review covers all information related to each nanocarrier, such as their significant characteristics, subtypes, advantages, disadvantages, and chemical modification methods with recently published studies. This article discusses over 21 nanoparticles used in breast cancer treatment with possible chemical ligands such as monoclonal antibodies and chemotherapeutic agents binding to these carriers. These different nanoparticles and the unique features of each nanocarrier give the researchers all the data and insight to develop and use the brand-new drug delivery system.
    Keywords:  Breast cancer; chemotherapeutic agents; immunotherapy; nanoparticles; site-specific tumor targeting; targeted therapy
  6. Asian Pac J Cancer Prev. 2022 Mar 01. pii: 90025. [Epub ahead of print]23(3): 919-927
    Design and Development of Nanostructured Co Delivery of Artemisinin and Chrysin for Targeting hTERT Gene Expression in Breast Cancer Cell Line: Possible Clinical Application in Cancer Treatment.
    Leila Khoshravan, Mehdi Dadashpour, Mehrdad Hashemi, Nosratollah Zarghami.
      BACKGROUND: Breast cancer is one of the most significant causes of female cancer death worldwide. To explore the possibility of a novel chemo-preventive strategy for improving breast cancer treatment, the anticancer effects of two natural compounds, Artemisinin (Art) and Chrysin (Chr), against T47D breast cancer cells were investigated.METHODS: For this purpose, Art and Chr were co-encapsulated in PEGylated PLGA nanoparticles (NPs) and the synthesized NPs were characterized by FE-SEM, FTIR, and DLS and then, MTT assay was used to assess and compare the cytotoxicity of various concentrations of the chemotheruptic molecules in pure and nanoformulated forms as well as in alone and combination state after 48 h exposure time. Drug release study was performed using the dialysis method. Also, the mRNA levels of hTERT genes expression were studied by quantitative real-time PCR.
    RESULTS: The results showed that pure and formulations drugs exhibited dose-dependent cytotoxicity against T47D cells and especially, Art/Chr-PLGA/PEG NPs had a more synergistic anti-proliferative effect and significantly arrested the growth of cancer cells than the other groups. Moreover, Real-time PCR results revealed that Art, Chr and combination of Art-Chr in pure and encapsulated forms inhibited hTERT gene expression.
    CONCLUSIONS: It was found that Art/Chr-PLGA/PEG NPs relative to pure combination could further decline hTERT expression in all concentrations. Our study demonstrated that Art/Chr-PLGA/PEG NPs based combinational therapy holds promising potential for the treatment of breast cancer.
    Keywords:  Artimicinin; Chrysin; Combination therapy; breast cancer; hTERT
    DOI:  https://doi.org/10.31557/APJCP.2022.23.3.919
  7. Front Pharmacol. 2022 ;13 845871
    Potential Therapeutic Implications of Caffeic Acid in Cancer Signaling: Past, Present, and Future.
    Manzar Alam, Ghulam Md Ashraf, Kayenat Sheikh, Anish Khan, Sabeeha Ali, Md Meraj Ansari, Mohd Adnan, Visweswara Rao Pasupuleti, Md Imtaiyaz Hassan.
      Caffeic acid (CA) has been present in many herbs, vegetables, and fruits. CA is a bioactive compound and exhibits various health advantages that are linked with its anti-oxidant functions and implicated in the therapy and prevention of disease progression of inflammatory diseases and cancer. The anti-tumor action of CA is attributed to its pro-oxidant and anti-oxidant properties. CA's mechanism of action involves preventing reactive oxygen species formation, diminishing the angiogenesis of cancer cells, enhancing the tumor cells' DNA oxidation, and repressing MMP-2 and MMP-9. CA and its derivatives have been reported to exhibit anti-carcinogenic properties against many cancer types. CA has indicated low intestinal absorption, low oral bioavailability in rats, and pitiable permeability across Caco-2 cells. In the present review, we have illustrated CA's therapeutic potential, pharmacokinetics, and characteristics. The pharmacological effects of CA, the emphasis on in vitro and in vivo studies, and the existing challenges and prospects of CA for cancer treatment and prevention are discussed in this review.
    Keywords:  anti-cancer; anti-oxidant activity; bioavailability; caffeic acid; cancer; clinical trials
    DOI:  https://doi.org/10.3389/fphar.2022.845871
  8. Photodiagnosis Photodyn Ther. 2022 Mar 24. pii: S1572-1000(22)00119-3. [Epub ahead of print] 102830
    Targeting Mitochondria for Cancer Photodynamic Therapy.
    Muhammad Danish Yaqoob, Long Xu, Chuanfeng Li, Merrin Man Long Leong, Dan Dan Xu.
      Cancer remains a health-related concern globally from the ancient times till to date. The application of light to be used as therapeutic potential/agent has been used for several thousands of years. Photodynamic therapy (PDT) is a modern, non-invasive therapeutic modality for the treatment of various infections by bacteria, fungi, and viruses. Mitochondria are subcellular, double-membrane organelles that have the role in cancer and anticancer therapy. Mitochondria play a key role in regulation of apoptosis and these organelles produce most of the cell's energy which enhance its targeting objective. The role of mitochondria in anticancer approach is achieved by targeting its metabolism (glycolysis and TCA cycle) and apoptotic and ROS homeostasis. The role of mitochondria-targeted cancer therapies in photodynamic therapy have proven to be more effective than other similar non-targeting techniques. Particularly in PDT, mitochondria-targeting sensitizers are important as they have a crucial role in overcoming the hypoxia factor, resulting in high efficacy. IR-730 and IR-Pyr are the indocyine derivatives photosensitizers that play a crucial role in targeting mitochondria because of their better photostability during laser irradiation. Clinical and pre-clinical trials are going on this approach to target different solid tumors using mitochondrial targeted photodynamic therapy.
    Keywords:  Photodynamic therapy; cancer; mitochondria
    DOI:  https://doi.org/10.1016/j.pdpdt.2022.102830
  9. Nat Rev Neurol. 2022 Mar 31.
    The metabolic basis of epilepsy.
    Jong M Rho, Detlev Boison.
      The brain is a highly energy-demanding organ and requires bioenergetic adaptability to balance normal activity with pathophysiological fuelling of spontaneous recurrent seizures, the hallmark feature of the epilepsies. Recurrent or prolonged seizures have long been known to permanently alter neuronal circuitry and to cause excitotoxic injury and aberrant inflammation. Furthermore, pathological changes in bioenergetics and metabolism are considered downstream consequences of epileptic seizures that begin at the synaptic level. However, as we highlight in this Review, evidence is also emerging that primary derangements in cellular or mitochondrial metabolism can result in seizure genesis and lead to spontaneous recurrent seizures. Basic and translational research indicates that the relationships between brain metabolism and epileptic seizures are complex and bidirectional, producing a vicious cycle that compounds the deleterious consequences of seizures. Metabolism-based treatments such as the high-fat, antiseizure ketogenic diet have become mainstream, and metabolic substrates and enzymes have become attractive molecular targets for seizure prevention and recovery. Moreover, given that metabolism is crucial for epigenetic as well as inflammatory changes, the idea that epileptogenesis can be both negatively and positively influenced by metabolic changes is rapidly gaining ground. Here, we review evidence that supports both pathophysiological and therapeutic roles for brain metabolism in epilepsy.
    DOI:  https://doi.org/10.1038/s41582-022-00651-8
  10. ACS Nano. 2022 Mar 31.
    Sequential Ultrasound-Triggered and Hypoxia-Sensitive Nanoprodrug for Cascade Amplification of Sonochemotherapy.
    Fan Zhuang, Qiong Ma, Caihong Dong, Huijing Xiang, Yujia Shen, Pei Sun, Cuixian Li, Yixin Chen, Beilei Lu, Yu Chen, Beijian Huang.
      Hypoxia, the typical and conspicuous characteristic of most solid tumors, worsens the tumor invasiveness and metastasis. Here, we engineered a sequential ultrasound (US)/hypoxia-sensitive sonochemotherapeutic nanoprodrug by initially synthesizing the hypoxia-activated azo bond-containing camptothecin (CPT) prodrug (CPT2-Azo) and then immobilizing it into the mesopores of sonosensitizer-integrated metal organic frameworks (MOF NPs). Upon entering the hypoxic tumor microenvironment (TME), the structure of CPT2-Azo immobilized MOFs (denoted as MCA) was ruptured and the loaded nontoxic CPT2-Azo prodrug was released from the MOF NPs. Under US actuation, this sonochemotherapeutic nanoprodrug not only promoted sonosensitizer-mediated sonodynamic therapy (SDT) via the conversion of oxygen into cytotoxic reactive oxygen species (ROS) but also aggravated hypoxia in the TME by elevating oxygen consumption. The exacerbated hypoxia in turn served as a positive amplifier to boost the activation of CPT2-Azo, and the controllable release of toxic chemotherapeutic drug (CPT), and compensated the insufficient treatment efficacy of SDT. In vitro and in vivo evaluations confirmed that sequential SDT and tumor hypoxia-activated sonochemotherapy promoted the utmost of tumor hypoxia and thereby contributed to the augmented antitumor efficacy, resulting in conspicuous apoptotic cell death and noteworthy tumor suppression in vivo. Our work provides a distinctive insight into the exploitation of the hypoxia-activated sonochemotherapeutic nanoprodrug that utilizes the hypoxic condition in TME, a side effect of SDT, to initiate chemotherapy, thus causing a significantly augmented treatment outcome compared to conventional SDT.
    Keywords:  ROS generation; camptothecin release; hypoxia-sensitive nanoprodrug; sonochemotherapy; synergistic therapy
    DOI:  https://doi.org/10.1021/acsnano.1c09505
  11. Drug Deliv. 2022 Dec;29(1): 986-996
    Selective delivery of curcumin to breast cancer cells by self-targeting apoferritin nanocages with pH-responsive and low toxicity.
    Peng Ji, Xianglong Wang, Jiabing Yin, Yi Mou, Haiqin Huang, Zhenkun Ren.
      Breast cancer is prevalent and diverse with significantly high incidence and mortality rates. Curcumin (Cur), a polyphenol component of turmeric, has been widely recognized as having strong anti-breast cancer activity. However, its anti-cancer efficiency is largely impaired by some of its concomitant negative properties, including its poor solubility, low cellular uptake, and severe reported side effects. Hence, the necessity arises to develop a novel low-toxic and high-efficiency targeting drug delivery system (DDS). In this study, we developed a pH-sensitive tumor self-targeting DDS (Cur@HFn) based on self-assembled HFn loaded with Cur, in which Cur was encapsulated into HFn cavity by using a disassembly/reassembly strategy, and the Cur@HFn was characterized by ultraviolet-visible (UV-vis), dynamic light scattering (DLS), and transmission electron microscope (TEM). A variety of breast cancer cell models were built to evaluate cytotoxicity, apoptosis, targeting properties, and uptake mechanism of the Cur@HFn. The pharmacodynamics was also evaluated in tumor (4T1) bearing mice after intravenous injection. In vitro release experiments showed that Cur@HFn is pH sensitive and shows sustained drug release under slightly acidic conditions. Compared with Cur, Cur@HFn has stronger cytotoxicity, cellular uptake, and targeting performance. Our study supported that Cur@HFn has a higher in vivo therapeutic effect and lower systemic toxicity. The safety evaluation results indicated that Cur@HFn has no hematotoxicity, hepatotoxicity, and nephrotoxicity. The findings of the present study showed that the Cur@HFn has been successfully prepared and has potential application value in the treatment of breast cancer.
    Keywords:  Human heavy chain apoferritin drug carrier (HFn); ROS; anti-tumor; curcumin; tumor self-targeting
    DOI:  https://doi.org/10.1080/10717544.2022.2056662
  12. Adv Drug Deliv Rev. 2022 Mar 25. pii: S0169-409X(22)00125-9. [Epub ahead of print] 114235
    Listening to Drug Delivery and Responses via Photoacoustic Imaging.
    Byullee Park, Sinyoung Park, Jeesu Kim, Chulhong Kim.
      Administrating pharmaceutic agents efficiently to achieve the therapeutic effect is the aim of all drug delivery techniques. Recent drug delivery systems aim to deliver high doses of drugs to disease sites accurately while maximizing therapeutic effects and minimizing potential side effects. Key approaches apply image guidance techniques for the quantification of drug biodistribution and pharmacokinetic parameters during drug delivery. This review highlights recent research on image-guided drug delivery systems based on photoacoustic imaging, which has been attracting attention for its non-invasiveness, non-ionizing radiation, and real-time imaging functions. Photoacoustic imaging based on the photothermal conversion efficiency of agents can be easily combined with various phototherapeutics, making them highly suitable for drug delivery therapy platforms. Here, we summarize and compare the characteristics of various types of photoacoustic imaging systems, focus on contrast-enhanced photoacoustic imaging and controlled release of therapeutics in drug delivery systems for synergistic therapies.
    Keywords:  Drug delivery; agents; nanoparticle; photoacoustic imaging; synergistic therapy
    DOI:  https://doi.org/10.1016/j.addr.2022.114235
  13. Bioact Mater. 2022 Sep;15 355-371
    Multiple stimuli-responsive nanosystem for potent, ROS-amplifying, chemo-sonodynamic antitumor therapy.
    JunJie Tang, Xiaoge Zhang, Lili Cheng, Yadong Liu, You Chen, Zhaozhong Jiang, Jie Liu.
      Although sonodynamic therapy (SDT) is a promising non-invasive tumor treatment strategy due to its safety, tissue penetration depth and low cost, the hypoxic tumor microenvironment limits its therapeutic effects. Herein, we have designed and developed an oxygen-independent, ROS-amplifying chemo-sonodynamic antitumor therapy based on novel pH/GSH/ROS triple-responsive PEG-PPMDT nanoparticles. The formulated artemether (ART)/Fe3O4-loaded PEG-PPMDT NPs can rapidly release drug under the synergistic effect of acidic endoplasmic pH and high intracellular GSH/ROS levels to inhibit cancer cell growth. Besides, the ROS level in the NPs-treated tumor cells is magnified by ART via interactions with both Fe2+ ions formed in situ at acidic pH and external ultrasound irradiation, which is not affected by hypoxia tumor microenvironment. Consequently, the enriched intracellular ROS level can cause direct necrosis of ROS-stressed tumor cells and further accelerate the drug release from the ROS-responsive PEG-PPMDT NPs, achieving an incredible antitumor potency. Specifically, upon the chemo-sonodynamic therapy by ART/Fe3O4-loaded PEG-PPMDT NPs, all xenotransplants of human hepatocellular carcinoma (HepG2) in nude mice shrank significantly, and 40% of the tumors were completely eliminated. Importantly, the Fe3O4 encapsulated in the NPs is an efficient MRI contrast agent and can be used to guide the therapeutic procedures. Further, biosafety analyses show that the PEG-PPMDT NPs possess minimal toxicity to main organs. Thus, our combined chemo-sonodynamic therapeutic method is promising for potent antitumor treatment by controlled release of drug and facile exogenous generation of abundant ROS at target tumor sites.
    Keywords:  Chemodynamic therapy; MRI imaging; Nanoparticle; Sonodynamic therapy; pH/GSH/ROS triple-Responsive
    DOI:  https://doi.org/10.1016/j.bioactmat.2021.12.002
  14. Int J Nanomedicine. 2022 ;17 1323-1341
    Two-Pronged Anti-Tumor Therapy by a New Polymer-Paclitaxel Conjugate Micelle with an Anti-Multidrug Resistance Effect.
    Juan Du, Lanlan Zong, Mengmeng Li, Keke Yu, Yonghui Qiao, Qi Yuan, Xiaohui Pu.
      Introduction: Cancerous tumors are still a major disease that threatens human life, with tumor multidrug resistance (MDR) being one of the main reasons for the failure of chemotherapy. Thus, reversing tumor MDR has become a research focus of medical scientists.Methods: Here, a reduction-sensitive polymer prodrug micelle, mPEG-DCA-SS-PTX (PDSP), was manufactured with a new polymer inhibitor of drug resistance as a carrier to overcome MDR and improve the anti-tumor effect of PTX.
    Results: The PDSP micelles display good stability, double-responsive drug release, and excellent biocompatibility. The PDSP micelles reduced the cytotoxicity of PTX to normal HL-7702 cells and enhanced that to SMMC-7721 and MCF-7 cells in vitro. Improved sensitivity of A549/ADR to PDSP was also observed in vitro. Furthermore, in vivo experiments show reduced systemic toxicity and enhanced therapeutic efficacy of PTX to H22 subcutaneous tumor-bearing mice.
    Conclusion: This work proves that the reduction-sensitive polymer prodrug micelles carried by the new polymer inhibitor can be used as an alternative delivery system to target tumors and reverse MDR for paclitaxel and other tumor-resistant drugs.
    Keywords:  anti-multidrug resistance; liver targeting; paclitaxel; polymer prodrug micelles; reduction sensitivity
    DOI:  https://doi.org/10.2147/IJN.S348598
  15. Breast Cancer (Auckl). 2022 ;16 11782234221086728
    Synergistic Effect of Quercetin Magnetite Nanoparticles and Targeted Radiotherapy in Treatment of Breast Cancer.
    Mostafa A Askar, Heba As El-Nashar, Mahmood A Al-Azzawi, Sahar S Abdel Rahman, Omama E Elshawi.
      Quercetin is a potent cancer therapeutic agent present in fruits and vegetables. The pharmaceutical uses of quercetin are limited due to many problems associated with low solubility, bioavailability, permeability, and instability. In addition, the high doses of quercetin show toxic effects in clinical and experimental studies. Therefore, a new strategy is warranted to overcome these problems without the use of toxic doses. The iron oxide nanoparticles can be used as a drug delivery system. This study aimed to prepare quercetin-conjugated magnetite nanoparticles (QMNPs) using biological simple nanoprecipitation and mediated by fungus Aspergillus oryzae. Also, we initiated in vitro and in vivo studies to determine whether QMNPs might sensitize breast cancer to radiotherapy treatment. The structural, morphological, and magnetic properties of the prepared nanoparticles were studied. The results indicated that QMNPs were spherical in shape and 40 nm in diameter. The in vitro studies showed that the incubation of MCF-7, HePG-2, and A459 cancer cells with QMNPs for 24 h effectively inhibited the growth of cancer cell lines in a concentration-dependent manner with IC50 values of 11, 77.5, and104 nmol/mL, respectively. The combination of QMNPs with irradiation (IR) potently blocked MCF-7 cancer cell proliferation and showed significant changes in the morphology of these cells as observed by bright-field inverted light microscopy. Focusing on the long-term toxicity of QMNPs (20 ml/kg), the assessment of hematological, hepatic, and renal markers indicated no toxic effect. Besides, QMNPs inhibited tumor growth and potently enhanced the lateral radiotherapy treatment in N-methyl-N-nitrosourea (MNU)-induced breast cancer in female white albino rats. These anticancer and radiosensitizing activities were ascribed to cytotoxicity, cell cycle arrest, immunomodulation, and efficiency through induction of apoptosis. In a conclusion, these observations suggest that the QMNPs combined with LRT could act as a potential targeted therapy in breast cancer.
    Keywords:  Nanoparticles; apoptosis; breast cancer; magnetic oxide; methyl-N-nitrosourea; quercetin; radiotherapy
    DOI:  https://doi.org/10.1177/11782234221086728
  16. Biochim Biophys Acta Mol Basis Dis. 2022 Mar 25. pii: S0925-4439(22)00070-9. [Epub ahead of print]1868(7): 166400
    Role and regulation of autophagy in cancer.
    Ravichandran Rakesh, Loganathan Chandramani PriyaDharshini, Kunnathur Murugesan Sakthivel, Rajan Radha Rasmi.
      Autophagy is an intracellular self-degradative mechanism which responds to cellular conditions like stress or starvation and plays a key role in regulating cell metabolism, energy homeostasis, starvation adaptation, development and cell death. Numerous studies have stipulated the participation of autophagy in cancer, but the role of autophagy either as tumor suppressor or tumor promoter is not clearly understood. However, mechanisms by which autophagy promotes cancer involves a diverse range of modifications of autophagy associated proteins such as ATGs, Beclin-1, mTOR, p53, KRAS etc. and autophagy pathways like mTOR, PI3K, MAPK, EGFR, HIF and NFκB. Furthermore, several researches have highlighted a context-dependent, cell type and stage-dependent regulation of autophagy in cancer. Alongside this, the interaction between tumor cells and their microenvironment including hypoxia has a great potential in modulating autophagy response in favour to substantiate cancer cell metabolism, self-proliferation and metastasis. In this review article, we highlight the mechanism of autophagy and their contribution to cancer cell proliferation and development. In addition, we discuss about tumor microenvironment interaction and their consequence on selective autophagy pathways and the involvement of autophagy in various tumor types and their therapeutic interventions concentrated on exploiting autophagy as a potential target to improve cancer therapy.
    Keywords:  Autophagy; Cancer; Homeostasis; Hypoxia
    DOI:  https://doi.org/10.1016/j.bbadis.2022.166400
  17. Biomater Sci. 2022 Apr 01.
    Development of poly(p-coumaric acid) as a self-anticancer nanocarrier for efficient and biosafe cancer therapy.
    Liying Wang, Xinru You, Chunlei Dai, Yifen Fang, Jun Wu.
      Using biocompatible polymers with potential therapeutic activity is an appealing strategy for the development of new functional drug carriers. In this study, we report the synthesis of therapeutic poly(p-coumaric acid) (PCA) from p-coumaric acid, a common plant phenolic acid with multiple bioactivities. The prepared PCA was formulated into nanoparticles (NPs) using the nanoprecipitation method and docetaxel (DTX) was encapsulated to form DTX-loaded PCA NPs (DTX@PCA NPs). Their potential as a nanocarrier for anticancer drug delivery was systematically evaluated. The DTX@PCA NPs not only had a small particle size and good stability, but also exhibited superior in vitro anticancer activity, anti-metastasis ability compared with free drugs, and preferable cellular uptake by tumor cells. In addition, the three-dimensional tumor spheroid assay revealed the effective tumor penetration and anticancer activity of the DTX@PCA NPs. Importantly, the DTX@PCA NPs preferentially accumulated in tumors and prolonged systemic circulation, significantly inhibiting tumor growth in vivo and simultaneously attenuating the side effects of DTX. Interestingly, the blank PCA NPs themselves also exhibited additional tumor suppression activity to some extent with high biosafety, further indicating the significant potential of PCA as a novel self-therapeutic nanocarrier for anticancer drug delivery and enhanced cancer therapy.
    DOI:  https://doi.org/10.1039/d2bm00027j
  18. J Nanobiotechnology. 2022 Mar 31. 20(1): 169
    Biodegradable and biocompatible subcutaneous implants consisted of pH-sensitive mebendazole-loaded/folic acid-targeted chitosan nanoparticles for murine triple-negative breast cancer treatment.
    Amirhosein Kefayat, Maryam Hosseini, Fatemeh Ghahremani, Nafise Arbab Jolfaie, Mohammad Rafienia.
      BACKGROUND: Mebendazole (MBZ) is a well-known anti-parasite drug with significant anti-cancer properties. However, MBZ exhibits low solubility, limited absorption efficacy, extensive first-pass effect, and low bioavailability. Therefore, multiple oral administration of high dose MBZ is required daily for achieving the therapeutic serum level which can cause severe side effects and patients' non-compliance.METHOD: In the present study, MBZ-loaded/folic acid-targeted chitosan nanoparticles (CS-FA-MBZ) were synthesized, characterized, and used to form cylindrical subcutaneous implants for 4T1 triple-negative breast tumor (TNBC) treatment in BALB/c mice. The therapeutic efficacy of the CS-FA-MBZ implants was investigated after subcutaneous implantation in comparison with Control, MBZ (40 mg/kg, oral administration, twice a week for 2 weeks), and CS-FA implants, according to 4T1 tumors' growth progression, metastasis, and tumor-bearing mice survival time. Also, their biocompatibility was evaluated by blood biochemical analyzes and histopathological investigation of vital organs.
    RESULTS: The CS-FA-MBZ implants were completely degraded 15 days after implantation and caused about 73.3%, 49.2%, 57.4% decrease in the mean tumors' volume in comparison with the Control (1050.5 ± 120.7 mm3), MBZ (552.4 ± 76.1 mm3), and CS-FA (658.3 ± 88.1 mm3) groups, respectively. Average liver metastatic colonies' number per microscope field at the CS-FA-MBZ group (2.3 ± 0.7) was significantly (P < 0.05) lower than the Control (9.6 ± 1.7), MBZ (5.0 ± 1.5), and CS-FA (5.2 ± 1) groups. In addition, the CS-FA-MBZ treated mice exhibited about 52.1%, 27.3%, and 17% more survival days after the cancer cells injection in comparison with the Control, MBZ, and CS-FA groups, respectively. Moreover, the CS-FA-MBZ implants were completely biocompatible based on histopathology and blood biochemical analyzes.
    CONCLUSION: Taking together, CS-FA-MBZ implants were completely biodegradable and biocompatible with high therapeutic efficacy in a murine TNBC model.
    Keywords:  Chitosan nanoparticles; Folic acid; Mebendazole; Subcutaneous implants; Triple-negative breast cancer
    DOI:  https://doi.org/10.1186/s12951-022-01380-2
  19. Front Pharmacol. 2022 ;13 855294
    Design and Characterization of Paclitaxel-Loaded Polymeric Nanoparticles Decorated With Trastuzumab for the Effective Treatment of Breast Cancer.
    Mirina Sakhi, Abad Khan, Zafar Iqbal, Ismail Khan, Abida Raza, Asmat Ullah, Fazli Nasir, Saeed Ahmad Khan.
      The aim of the study was to design and formulate an antibody-mediated targeted, biodegradable polymeric drug delivery system releasing drug in a controlled manner to achieve a therapeutic goal for the effective treatment of breast cancer. Antibody-mediated paclitaxel-loaded PLGA polymeric nanoformulations were prepared by the solvent evaporation method using different experimental parameters and compatibility studies. The optimized formulations were selected for in vitro and in vivo evaluation and cytotoxicity studies. The in vitro drug release studies show a biphasic release pattern for the paclitaxel-loaded PLGA nanoparticles showing a burst release for 24 h followed by an extended release for 14 days; however, a more controlled and sustained release was observed for antibody-conjugated polymeric nanoparticles. The cytotoxicity of reference drug and paclitaxel-loaded PLGA nanoparticles with and without antibody was determined by performing MTT assay against MCF-7 cells. Rabbits were used as experimental animals for the assessment of various in vivo pharmacokinetic parameters of selected formulations. The pharmacokinetic parameters such as Cmax (1.18-1.33 folds), AUC0-t (39.38-46.55 folds), MRT (10.04-12.79 folds), t1/2 (3.06-4.6 folds), and Vd (6.96-8.38 folds) have been increased significantly while clearance (4.34-4.61 folds) has been decreased significantly for the selected nanoformulations as compared to commercially available paclitaxel formulation (Paclixil®). The surface conjugation of nanoparticles with trastuzumab resulted in an increase in in vitro cytotoxicity as compared to plain nanoformulations and commercially available conventional brand (Paclixil®). The developed PLGA-paclitaxel nanoformulations conjugated with trastuzumab have the desired physiochemical characteristics, surface morphology, sustained release kinetics, and enhanced targeting.
    Keywords:  PLGA; biodegradable; breast cancer; cytotoxicity; drug-delivery; paclitaxel; polymeric; trastuzumab
    DOI:  https://doi.org/10.3389/fphar.2022.855294
  20. Des Monomers Polym. 2022 ;25(1): 55-63
    Synthesis and evaluation of chitosan based controlled release nanoparticles for the delivery of ticagrelor.
    Nariman Shahid, Alia Erum, Muhammad Zaman, Ume Ruqia Tulain, Qurat-Ul-Ain Shoaib, Nadia Shamshad Malik, Rizwana Kausar, Ayesha Rashid, Umaira Rehman.
      The aim of this contemporary work was to formulate a controlled release mucoadhesive nanoparticle formulation for enhancing the oral bioavailability of Ticagrelor (TG), a BCS class IV drug, having low oral bioavailability of about 36%. The nanoparticles can act as efficient carriers for hydrophobic drugs, due to having high surface area and hence can improve their aqueous solubility due to their hydrophilic nature. The nanoparticles (NPs) of TG were formulated using chitosan (CH) as polymer and sodium tripolyphosphate (TPP) as cross-linker, by ionic gelation technique with varying concentrations of polymer with respect to TG and TPP. Characterization of prepared nanoparticles was carried out to assess zeta potential, size, shape, entrapment efficiency (EE) and loading capacity (LC), using zeta sizer, surface morphology and chemical compatibility analysis. Drug release was observed using UV-Spectrophotometer. By increasing concentration of CH the desired size of particles (106.9 nm), zeta potential (22.6 mv) and poly dispersity index (0.364) was achieved. In vitro profiles showed a controlled and prolonged release of TG in both lower pH-1.2 and neutral pH-7.4 mediums, with effective protection of entrapped TG in simulated gastric conditions. X-ray diffraction patterns (XRD) showed the crystalline nature of formed NPs. Hence, this effort showed that hydrophobic drugs can be effectively encapsulated in nanoparticulate systems to enhance their solubility and stability, ultimately improving their bioavailability and effectiveness with better patient compliance by reducing dosing frequencies as well.
    Keywords:  Nanoparticles; bioavailability; chitosan; hydrophilic; hydrophobic; ionic gelation; ticagrelor
    DOI:  https://doi.org/10.1080/15685551.2022.2054117
  21. Front Cell Dev Biol. 2022 ;10 751367
    The Influence of Oncogenic RAS on Chemotherapy and Radiotherapy Resistance Through DNA Repair Pathways.
    Rodrigo E Cáceres-Gutiérrez, Yair Alfaro-Mora, Marco A Andonegui, José Díaz-Chávez, Luis A Herrera.
      RAS oncogenes are chief tumorigenic drivers, and their mutation constitutes a universal predictor of poor outcome and treatment resistance. Despite more than 30 years of intensive research since the identification of the first RAS mutation, most attempts to therapeutically target RAS mutants have failed to reach the clinic. In fact, the first mutant RAS inhibitor, Sotorasib, was only approved by the FDA until 2021. However, since Sotorasib targets the KRAS G12C mutant with high specificity, relatively few patients will benefit from this therapy. On the other hand, indirect approaches to inhibit the RAS pathway have revealed very intricate cascades involving feedback loops impossible to overcome with currently available therapies. Some of these mechanisms play different roles along the multistep carcinogenic process. For instance, although mutant RAS increases replicative, metabolic and oxidative stress, adaptive responses alleviate these conditions to preserve cellular survival and avoid the onset of oncogene-induced senescence during tumorigenesis. The resulting rewiring of cellular mechanisms involves the DNA damage response and pathways associated with oxidative stress, which are co-opted by cancer cells to promote survival, proliferation, and chemo- and radioresistance. Nonetheless, these systems become so crucial to cancer cells that they can be exploited as specific tumor vulnerabilities. Here, we discuss key aspects of RAS biology and detail some of the mechanisms that mediate chemo- and radiotherapy resistance of mutant RAS cancers through the DNA repair pathways. We also discuss recent progress in therapeutic RAS targeting and propose future directions for the field.
    Keywords:  DNA damage response; cancer; chemotherapy and radiotherapy resistance; double strand breaks; oncogene-induced senescence; ras; reactive oxygen species
    DOI:  https://doi.org/10.3389/fcell.2022.751367
  22. Int J Nanomedicine. 2022 ;17 1309-1322
    In situ Co-Delivery of Doxorubicin and Cisplatin by Injectable Thermosensitive Hydrogels for Enhanced Osteosarcoma Treatment.
    Meng Si, Yanni Xia, Menglin Cong, Dandan Wang, Yong Hou, Hecheng Ma.
      Purpose: Osteosarcoma is considered as the most common primary malignant bone tumor in children and adolescents, and the treatments including chemotherapy and surgery were far from satisfactory. Localized tumor treatments by hydrogels incorporating combined chemotherapeutic drugs have recently emerged as superior approaches for enhanced anti-tumor effects and reduced systemic toxicity.Methods: A novel injectable thermosensitive poly (lactide-co- glycolide)-poly (ethylene glycol)-poly(lactide-co-glycolide) triblock copolymer hydrogel containing doxorubicin and cisplatin for the localized chemotherapy of osteosarcoma were synthesized and characterized. The in vitro drug release properties of the drugs-loaded hydrogels were investigated. To study the anti-tumor efficacy of hydrogels depots in vitro, the cytotoxicity and apoptosis rate against Saos-2 and MG-63 cells were evaluated by MTT, Annexin V and PCR methods. The in vivo synergistic anti-tumor efficacy of the multi-drugs co-loaded hydrogels was investigated by human osteosarcoma xenografts. Additionally, the systemic toxic side effects were evaluated by ex vivo histological analysis of the major organs of the mice.
    Results: The PLGA-PEG-PLGA copolymer solution underwent a sol-gel transition at appropriate temperature and degraded in the PBS, presenting a friendly biocompatibility in vitro. The in vitro cell viability tests demonstrated that DOX and CDDP co-loaded hydrogels exhibited synergistic anti-proliferation effect, due to the sustained release of drugs from the drugs-loaded hydrogel. The treatment with DOX and CDDP co-loaded hydrogel led to the highest efficiency in inhibiting the tumor growth, enhanced tumor necrosis rate and increased regulation of the apoptosis-related gene expressions, indicating a synergistic anti-tumor efficacy in vivo. Additionally, ex vivo histological analysis of the nude mice exhibited low systemic toxicity.
    Conclusion: The combination treatment of osteosarcoma by localized, sustained co-delivery of DOX and CDDP by PLGA-PEG-PLGA hydrogel may serve as a promising strategy for efficient clinical treatment of osteosarcoma.
    Keywords:  combination therapy; hydrogels; localized delivery; osteosarcoma; synergistic therapy
    DOI:  https://doi.org/10.2147/IJN.S356453
  23. Trends Cell Biol. 2022 Mar 29. pii: S0962-8924(22)00060-5. [Epub ahead of print]
    Transsulfuration, minor player or crucial for cysteine homeostasis in cancer.
    Hai-Feng Zhang, Ramon I Klein Geltink, Seth J Parker, Poul H Sorensen.
      Cysteine, a thiol-containing amino acid, is crucial for the synthesis of sulfur-containing biomolecules that control multiple essential cellular activities. Altered cysteine metabolism has been linked to numerous driver oncoproteins and tumor suppressors, as well as to malignant traits in cancer. Cysteine can be acquired from extracellular sources or synthesized de novo via the transsulfuration (TSS) pathway. Limited availability of cystine in tumor interstitial fluids raises the possible dependency on de novo cysteine synthesis via TSS. However, the contribution of TSS to cancer metabolism remains highly contentious. Based on recent findings, we provide new perspectives on this crucial but understudied metabolic pathway in cancer.
    Keywords:  cancer; cysteine metabolism; ferroptosis; glutathione; redox homeostasis; transsulfuration
    DOI:  https://doi.org/10.1016/j.tcb.2022.02.009
  24. Appl Biochem Biotechnol. 2022 Mar 29.
    Fungal Endophytes: an Accessible Source of Bioactive Compounds with Potential Anticancer Activity.
    Nilesh Rai, Priyamvada Gupta, Priyanka Kumari Keshri, Ashish Verma, Pradeep Mishra, Deepak Kumar, Ajay Kumar, Santosh Kumar Singh, Vibhav Gautam.
      Endophytes either be bacteria, fungi, or actinomycetes colonize inside the tissue of host plants without showing any immediate negative effects on them. Among numerous natural alternative sources, fungal endophytes produce a wide range of structurally diverse bioactive metabolites including anticancer compounds. Considering the production of bioactive compounds in low quantity, genetic and physicochemical modification of the fungal endophytes is performed for the enhanced production of bioactive compounds. Presently, for the treatment of cancer, chemotherapy is majorly used, but the side effects of chemotherapy are of prime concern in clinical practices. Also, the drug-resistant properties of carcinoma cells, lack of cancer cells-specific medicine, and the side effects of drugs are the biggest obstacles in cancer treatment. The interminable requirement of potential drugs has encouraged researchers to seek alternatives to find novel bioactive compounds, and fungal endophytes seem to be a probable target for the discovery of anticancer drugs. The present review focuses a comprehensive literature on the major fungal endophyte-derived bioactive compounds which are presently been used for the management of cancer, biotic factors influencing the production of bioactive compounds and about the challenges in the field of fungal endophyte research.
    Keywords:  Anticancer activity; Bioactive compound; Epigenetic modifier; Fungal endophytes; Paclitaxel; Podophyllotoxin
    DOI:  https://doi.org/10.1007/s12010-022-03872-1
  25. Curr Drug Discov Technol. 2022 Mar 31.
    Cancer Chemotherapy via Natural Bioactive Compounds.
    Kalyani Pathak, Manash Pratim Pathak, Riya Saikia, Urvashee Gogoi, Jon Jyoti Sahariah, James H Zothantluanga, Abhishek Samanta, Aparoop Das.
      BACKGROUND: Cancer-induced mortality is increasingly prevalent globally which skyrocketed the necessity to discover new/novel safe and effective anticancer drugs. Cancer is characterized by the continuous multiplication of cells in the human which is unable to control. Scientific research is drawing its attention towards naturally-derived bioactive compounds as they have fewer side effects compared to the current synthetic drugs used for chemotherapy.OBJECTIVE: Drugs isolated from natural sources and their role in the manipulation of epigenetic markers in cancer are discussed briefly in this review article.
    METHODS: With advancing medicinal plant biotechnology and microbiology in the past century, several anticancer phytomedicines were developed. Modern pharmacopeia contains at least 25% herbal-based remedy including clinically used anticancer drugs. These drugs mainly include the podophyllotoxin derivatives vinca alkaloids, curcumin, mistletoe plant extracts, taxanes, camptothecin, combretastatin, and others including colchicine, artesunate, homoharringtonine, ellipticine, roscovitine, maytanasin, tapsigargin,andbruceantin.
    RESULTS: Compounds (psammaplin, didemnin, dolastin, ecteinascidin,and halichondrin) isolated from marine sources and animals such as microalgae, cyanobacteria, heterotrophic bacteria, invertebrates. They have been evaluated for their anticancer activity on cells and experimental animal models and used chemotherapy.Drug induced manipulation of epigenetic markers plays an important role in the treatment of cancer.
    CONCLUSION: The development of a new drug from isolated bioactive compounds of plant sources has been a feasible way to lower the toxicity and increase their effectiveness against cancer. Potential anticancer therapeutic leads obtained from various ethnomedicinal plants, foods, marine, and microorganisms are showing effective yet realistically safe pharmacological activity. This review will highlight important plant-based bioactive compounds like curcumin, stilbenes, terpenes, other polyphenolic phyto-compounds, and structurally related families that are used to prevent/ ameliorate cancer. However, a contribution from all possible fields of science is still a prerequisite for discovering safe and effective anticancer drugs.
    Keywords:  Bioactive; cancer; chemotherapy; curcumin; neoplasm; vincristine
    DOI:  https://doi.org/10.2174/1570163819666220331095744
  26. J Mater Chem B. 2022 Mar 29.
    Cu-Chelated polydopamine nanoparticles as a photothermal medium and "immunogenic cell death" inducer for combined tumor therapy.
    Na Xu, Ao Hu, Ximing Pu, Juan Wang, Xiaoming Liao, Zhongbing Huang, Guangfu Yin.
      Chemodynamic therapy (CDT) and photothermal therapy (PTT) have been powerful technologies for tumor ablation. However, how to realize efficient CDT and PTT synergetic tumor ablation through a safe and intelligent system, remains a topic of great research value. Herein, a novel Cu-chelated polydopamine nano-system (Cu-PDA) with surface PEGylation and folate (FA) targeting modification (Cu-PDA-FA) was presented as a photothermal agent (PTA), Fenton-like reaction initiator and "immunogenic cell death" inducer to mediate PTT/CDT synergistical tumor therapy and antitumor immune activation. Primarily, the prepared Cu-PDA NPs possessed elevated photothermal conversion efficiency (46.84%) under the near-infrared (NIR) irradiation, bringing about hyperthermic death of tumor cells. Secondly, Cu-PDA catalyzed the generation of toxic hydroxyl radicals (˙OH) in response to the specific tumor microenvironment (TME) with the depletion of GSH, killing tumor cells with high specificity. Interestingly, the increase in local tumor temperature caused by PTT availed the production of ˙OH, and then the produced toxic ˙OH further led the tumor cells to be more sensitive to heat via impeding the expression of heat shock protein, so the synergistically enhanced PTT/CDT in tumor therapy could be achieved. Most importantly, the synergistical PTT/CDT could cause tumor cell death in an immunogenic way to generate in situ tumor vaccine-like functions, which were able to trigger a systemic antitumor immune response, preventing recurrence and metastasis without any other adjuvant supplementation. Overall, these Cu-PDA NPs will provide inspiration for the construction of a versatile nanoplatform for tumor therapy.
    DOI:  https://doi.org/10.1039/d2tb00025c
  27. Curr Nutr Rep. 2022 Mar 26.
    Comparison of the Impact of the Mediterranean Diet, Anti-Inflammatory Diet, Seventh-Day Adventist Diet, and Ketogenic Diet Relative to Cognition and Cognitive Decline.
    Jennifer To, Zi Yi Shao, Monique Gandawidjaja, Tara Tabibi, Noam Grysman, George T Grossberg.
      PURPOSE OF REVIEW: Increasing evidence points toward the importance of diet and its impact on cognitive decline. This review seeks to clarify the impact of four diets on cognition: the Mediterranean diet, the anti-inflammatory diet, the Seventh Day Adventist diet, and the Ketogenic diet.RECENT FINDINGS: Of the diets reviewed, the Mediterranean diet provides the strongest evidence for efficacy. Studies regarding the anti-inflammatory diet and Seventh Day Adventist diet are sparse, heterogeneous in quality and outcome measurements, providing limited reliable data. There is also minimal research confirming the cognitive benefits of the Ketogenic diet. Increasing evidence supports the use of the Mediterranean diet to reduce cognitive decline. The MIND-diet, a combination of the Mediterranean and DASH diets, seems especially promising, likely due to its anti-inflammatory properties. The Ketogenic diet may also have potential efficacy; however, adherence in older populations may be difficult given frequent adverse effects. Future research should focus on long-term, well-controlled studies confirming the impact of various diets, as well as the combination of diets and lifestyle modification.
    Keywords:  Adventist Health Study; Anti-inflammatory diet; Cognitive function; Cognitive impairment; Dementia; Inflammation; Ketogenic diet; Ketone bodies; MIND diet; Mediterranean diet; Medium chain triglycerides; Seventh Day Adventist diet
    DOI:  https://doi.org/10.1007/s13668-022-00407-2
  28. Bioorg Chem. 2022 Mar 24. pii: S0045-2068(22)00163-8. [Epub ahead of print]122 105758
    Indomethacin-based near-infrared photosensitizer for targeted photodynamic cancer therapy.
    Siriwalee Siriwibool, Sirilak Wangngae, Kantapat Chansaenpak, Sirawit Wet-Osot, Rung-Yi Lai, Parinya Noisa, Mongkol Sukwattanasinitt, Anyanee Kamkaew.
      Near-IR fluorescent sensitizers based on heptamethine cyanine (Cy820 and Cy820-IMC) were synthesized and their abilities to target and abolish tumor cells via photodynamic therapy (PDT) were explored. Some hepthamethine cyanine dyes can be transported into cancer cells via the organic anion transporting polypeptides (OATPs). In this study, we aimed to enhance the target ability of the sensitizer by conjugation Cy820 with indomethacin, a non-steroidal anti-inflammatory drug (NSAID), to obtain Cy820-IMC that aimed to target cyclooxygenase-2 (COX-2) which overexpresses in cancer cells. The results showed that Cy820-IMC internalized the cancer cells faster than Cy820 which was verified to be related to COX-2 level and OATPs. Based on PDT experiments, Cy820-IMC has higher photocytotoxicity index than Cy820, >7.13 and 4.90, respectively, implying that Cy820-IMC showed better PDT property than Cy820. However, Cy820 exhibits slightly higher normal-to-cancer cell toxicity ratio than Cy820-IMC, 6.58 and 3.63, respectively. Overall, Cy820-IMC has superior cancer targetability and enhanced photocytoxicity. These characteristics can be further improved towards clinically approved sensitizers for PDT.
    Keywords:  COX-2; Cancer targeting; Cy820; Heptamethine cyanine; NIR photosensitizer; Photodynamic therapy
    DOI:  https://doi.org/10.1016/j.bioorg.2022.105758
  29. Recent Adv Inflamm Allergy Drug Discov. 2022 Mar 31.
    Natural approach in osteoarthritis therapy.
    Alice Grigore, Virginia Vulturescu.
      Osteoarthritis (OA) is the most common joint disease worldwide and its rising prevalence is supported by factors such as obesity and sedentariness. At molecular level, it is considered an inflammatory disease that leads to destruction of articular cartilage. An effective therapy to end the degenerative process of arthritis remains elusive, and most of the therapeutic tools prevent the progress or alleviate the symptoms. By now, medicines for OA are available for oral, topical or intra-articular (IA) therapy and include analgesics, nonsteroidal anti-inflammatory drugs, corticosteroids, hyaluronic acid. Compared with the conventional oral administration, IA therapy has multiple advantages in terms of bioavailability, efficacy and toxicity. This review aims at underlying the beneficial effect of herbal medicine in OA therapy and to open new research perspectives. Herbal medicine administered orally or topically exhibit pharmacological properties that could be relevant for their beneficial effect in OA, mainly anti-inflammatory and antioxidant effects. There are few studies regarding IA injections of plant extracts/ compounds and none related to any combination with agents used already in clinic. Designing natural pharmaceutical formulations with increased bioavailability, safe and lack of side effects, specifically tested, would be a plus for medicinal plant areas of research and a novelty for clinic.
    Keywords:  antioxidant degeneration; inflammation; intra-articular hyaluronic acid
    DOI:  https://doi.org/10.2174/2772270816666220331163707
  30. Biomed Pharmacother. 2022 Mar 23. pii: S0753-3322(22)00232-3. [Epub ahead of print]149 112844
    Synergistic effect of antimetabolic and chemotherapy drugs in triple-negative breast cancer.
    Elena López-Camacho, Lucía Trilla-Fuertes, Angelo Gámez-Pozo, Irene Dapía, Rocío López-Vacas, Andrea Zapater-Moros, María Isabel Lumbreras-Herrera, Pedro Arias, Pilar Zamora, Juan Ángel Fresno Vara, Enrique Espinosa.
      The triple-negative breast cancer (TNBC) subtype comprises approximately 15% of all breast cancers and is associated with poor long-term outcomes. Classical chemotherapy remains the standard of treatment, with toxicity and resistance being major limitations. TNBC is a high metabolic group, and antimetabolic drugs are effective in inhibiting TNBC cell growth. We analyzed the combined effect of chemotherapy and antimetabolic drug combinations in MDA-MB-231, MDA-MB-468 and HCC1143 human TNBC cell lines. Cells were treated with each drug or with drug combinations at a range of concentrations to establish the half-maximal inhibitory concentrations (IC50). The dose-effects of each drug or drug combination were calculated, and the synergistic or antagonistic effects of drug combinations were defined. Chemotherapy and antimetabolic drugs exhibited growth inhibitory effects on TNBC cell lines. Antimetabolic drugs targeting the glycolysis pathway had a synergistic effect with chemotherapy drugs, and antiglycolysis drug combinations also had a synergistic effect. The use of these drug combinations could lead to new therapeutic strategies that reduce chemotherapy drug doses, decreasing their toxic effect, or that maintain the doses but enhance their efficacy by their synergistic effect with other drugs.
    Keywords:  Antimetabolic drugs; Chemotherapy drugs; Synergism; Triple-negative breast cancer
    DOI:  https://doi.org/10.1016/j.biopha.2022.112844
  31. Front Oncol. 2022 ;12 860508
    Therapeutic Implications of Caffeic Acid in Cancer and Neurological Diseases.
    Manzar Alam, Sarfraz Ahmed, Abdelbaset Mohamed Elasbali, Mohd Adnan, Shoaib Alam, Md Imtaiyaz Hassan, Visweswara Rao Pasupuleti.
      Caffeic acid (CA) is found abundantly in fruits, vegetables, tea, coffee, oils, and more. CA and its derivatives have been used for many centuries due to their natural healing and medicinal properties. CA possesses various biological and pharmacological activities, including antioxidant, anti-inflammatory, anticancer, and neuroprotective effects. The potential therapeutic effects of CA are mediated via repression and inhibition of transcription and growth factors. CA possesses potential anticancer and neuroprotective effects in human cell cultures and animal models. However, the biomolecular interactions and pathways of CA have been described highlighting the target binding proteins and signaling molecules. The current review focuses on CA's chemical, physical, and pharmacological properties, including antioxidant, anti-inflammatory, anticancer, and neuroprotective effects. We further described CA's characteristics and therapeutic potential and its future directions.
    Keywords:  caffeic acid; clinical trials; diabetic neuropathy; inflammatory diseases; inhibitors; targeted therapy
    DOI:  https://doi.org/10.3389/fonc.2022.860508
  32. Int J Biol Macromol. 2022 Mar 26. pii: S0141-8130(22)00609-2. [Epub ahead of print]
    Tumor-targeted hyaluronic acid-based oxidative stress nanoamplifier with ROS generation and GSH depletion for antitumor therapy.
    Qiuxing Liu, Xin Ding, Xiaoyu Xu, Hualu Lai, Zishan Zeng, Ting Shan, Tao Zhang, Meixu Chen, Yanjuan Huang, Zeqian Huang, Xiuling Dai, Meng Xia, Shengmiao Cui.
      Tumor cells with innate oxidative stress are more susceptible to exogenous ROS-mediated oxidative damage than normal cells. However, the generated ROS could be scavenged by the overexpressed GSH in cancer cells, thus causing greatly restricted efficiency of ROS-mediated antitumor therapy. Herein, using cinnamaldehyde (CA) as a ROS generator while β-phenethyl isothiocyanate (PEITC) as a GSH scavenger, we designed a tumor-targeted oxidative stress nanoamplifier to elevate intracellular ROS level and synchronously suppress antioxidant systems, for thorough redox imbalance and effective tumor cells killing. First, an amphiphilic acid-sensitive cinnamaldehyde-modified hyaluronic acid conjugates (HA-CA) were synthesized, which could self-assemble into nano-assembly in aqueous media via strong hydrophobic interaction and π-π stacking. Then, aromatic PEITC was appropriately encapsulated into HA-CA nano-assembly to obtain HA-CA/PEITC nanoparticles. Through enhanced permeability retention (EPR) effect and specific CD44 receptor-mediated endocytosis, HA-CA/PEITC nanoparticles could accumulate in tumor tissues and successfully release CA and PEITC under acidic lysosomal environment. Both in vitro and in vivo results showed that the nanoparticles could efficiently boost oxidative stress of tumor cells via generating ROS and depleting GSH, and finally achieve superior antitumor efficacy. This nanoamplifier with good biosafety provides a potential strategy to augment ROS generation and suppress GSH for enhanced oxidation therapy.
    Keywords:  Cinnamaldehyde; GSH depletion; Oxidation therapy; Oxidative stress; β-Phenethyl isothiocyanate
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.03.139
  33. Pharmacol Ther. 2022 Mar 26. pii: S0163-7258(22)00071-7. [Epub ahead of print] 108177
    Anti-cancer activity of sustained release capsaicin formulations.
    Justin C Merritt, Stephen D Richbart, Emily G Moles, Ashley J Cox, Kathleen C Brown, Sarah L Miles, Paul T Finch, Joshua A Hess, Maria T Tirona, Monica A Valentovic, Piyali Dasgupta.
      Capsaicin (trans-8-methyl-N-vanillyl-6-noneamide) is a hydrophobic, lipophilic vanilloid phytochemical abundantly found in chili peppers and pepper extracts. Several convergent studies show that capsaicin displays robust cancer activity, suppressing the growth, angiogenesis and metastasis of several human cancers. Despite its potent cancer-suppressing activity, the clinical applications of capsaicin as a viable anti-cancer drug have remained problematic due to its poor bioavailability and aqueous solubility properties. In addition, the administration of capsaicin is associated with adverse side effects like gastrointestinal cramps, stomach pain, nausea and diarrhea and vomiting. All these hurdles may be circumvented by encapsulation of capsaicin in sustained release drug delivery systems. Most of the capsaicin-based the sustained release drugs have been tested for their pain-relieving activity. Only a few of these formulations have been investigated as anti-cancer agents. The present review describes the physicochemical properties, bioavailability, and anti-cancer activity of capsaicin-sustained release agents. The asset of such continuous release capsaicin formulations is that they display better solubility, stability, bioavailability, and growth-suppressive activity than the free drug. The encapsulation of capsaicin in sustained release carriers minimizes the adverse side effects of capsaicin. In summary, these capsaicin-based sustained release drug delivery systems have the potential to function as novel chemotherapies, unique diagnostic imaging probes and innovative chemosensitization agents in human cancers.
    Keywords:  Cancer; Capsaicin; Liposomes; Nanoparticles; Signaling; Solid dispersion
    DOI:  https://doi.org/10.1016/j.pharmthera.2022.108177
  34. Biomed Pharmacother. 2022 Mar 24. pii: S0753-3322(22)00251-7. [Epub ahead of print]149 112862
    Complexation of phytochemicals with cyclodextrins and their derivatives- an update.
    Vasanti Suvarna, Bhunesh Bore, Chaitanya Bhawar, Rashmi Mallya.
      Bioactive phytochemicals from natural source have gained tremendous interest over several decades due to their wide and diverse therapeutic activities playing key role as functional food supplements, pharmaceutical and nutraceutical products. Nevertheless, their application as therapeutically active moieties and formulation into novel drug delivery systems are hindered due to major drawbacks such as poor solubility, bioavailability and dissolution rate and instability contributing to reduction in bioactivity. These drawbacks can be effectively overcome by their complexation with different cyclodextrins. Present article discusses complexation of phytochemicals varying from flavonoids, phenolics, triterpenes, and tropolone with different natural and synthetic cyclodextrins. Moreover, the article summarizes complexation methods, complexation efficiency, stability, stability constants and enhancement in rate and extent of dissolution, bioavailability, solubility, in vivo and in vitro activities of reported complexed phytochemicals. Additionally, the article presents update of published patent details comprising of complexed phytochemicals of therapeutic significance. Thus, phytochemical cyclodextrin complexes have tremendous potential for transformation into drug delivery systems as substantiated by significant outcome of research findings.
    Keywords:  Cyclodextrin; Inclusion complex; Phytochemical; Solubility
    DOI:  https://doi.org/10.1016/j.biopha.2022.112862
  35. Anticancer Agents Med Chem. 2022 Mar 30.
    The impact of bioactive compounds derived from marine fish on cancer.
    Mirunalini Sankaran, V L Maruthanila.
      Cancer persists as the world's leading cause of mortality, thereby making it a compelling condition to research and potentially develop prevention options. Anticancer therapies such as chemotherapy, surgery and radiation therapy are becoming highly futile and tend to have achieved a clinical deficit, due to massive side effects, toxicities, and limited specificity. Anticancer agents from natural sources, such as aquatic fishes, terrestrial mammals, animal venoms, and amphibians, have mainly been focused on in recent researches. Edible marine fishes contain high contents of fatty acids, vitamins, and proteins, also having bioactive compounds. Fish derivatives are naturally having the potential to target cancer cells while being less hazardous to normal tissues, making them a better choice for cancer prevention and therapy. In this review, we mainly focused on the bioactive compounds identified from marine fishes which have significant biological properties including anticancer effects, also discuss the mechanism of action.
    Keywords:  Anticancer activity; Bioactive peptides; Marine fish; Mechanism of action
    DOI:  https://doi.org/10.2174/1871520622666220330142442
  36. Front Neurosci. 2022 ;16 833630
    Dual Roles of Coconut Oil and Its Major Component Lauric Acid on Redox Nexus: Focus on Cytoprotection and Cancer Cell Death.
    Venkatesan Ramya, Karuppiah Prakash Shyam, Eshwaran Kowsalya, Chelladurai Karthikeyan Balavigneswaran, Balamuthu Kadalmani.
      It has been reported that coconut oil supplementation can reduce neuroinflammation. However, coconut oils are available as virgin coconut oil (VCO), crude coconut oil (ECO), and refined coconut oil (RCO). The impact of coconut oil extraction process (and its major fatty acid component lauric acid) at cellular antioxidant level, redox homeostasis and inflammation in neural cells is hitherto unexplained. Herein, we have shown the antioxidant levels and cellular effect of coconut oil extracted by various processes in human neuroblastoma cells (SH-SY5Y) cultured in vitro. Results indicate VCO and ECO treated cells displayed better mitochondrial health when compared to RCO. Similar trend was observed for the release of reactive oxygen species (ROS), key oxidative stress response genes (GCLC, HO-1, and Nqo1) and inflammatory genes (IL6, TNFα, and iNOS) in SH-SY5Y cells. Our results signified that both VCO and ECO offer better neural health primarily by maintaining the cellular redox balance. Further, RCO prepared by solvent extraction and chemical refining process lacks appreciable beneficial effect. Then, we extended our study to find out the reasons behind maintaining the cellular redox balance in neuroblastoma cells by VCO and ECO. Our GC-MS results showed that lauric acid (C14:0) (LA) content was the major difference in the fatty acid composition extracted by various processes. Therefore, we evaluated the efficacy of LA in SH-SY5Y cells. The LA showed dose-dependent effect. At IC50 concentration (11.8 μM), LA down regulated the oxidative stress response genes and inflammatory genes. The results clearly indicate that the LA inhibited the neuroinflammation and provided an efficient cellular antioxidant activity, which protects the cells. The efficiency was also evaluated in normal cell line such as fibroblasts (L929) to cross-validate that the results were not false positive. Different concentration of LA on L929 cells showed high compatibility. From our observation, we conclude that VCO and ECO offers better cellular protection owing to their powerful antioxidant system. Therefore, we advocate the inclusion of either VCO and/or ECO in the diet for a healthy lifestyle.
    Keywords:  antioxidants; cellular redox homeostasis; coconut oil (CO); extraction process; lauric acid (LA); neuroinflammation; reactive oxygen species
    DOI:  https://doi.org/10.3389/fnins.2022.833630
  37. Life Sci. 2022 Mar 25. pii: S0024-3205(22)00199-0. [Epub ahead of print]298 120499
    Photothermal therapy-mediated autophagy in breast cancer treatment: Progress and trends.
    Jamileh Kadkhoda, Ali Tarighatnia, Mohammad Reza Tohidkia, Nader D Nader, Ayuob Aghanejad.
      Breast cancer (BC) has different clinical manifestations due to its diverse mechanism of action that has created many challenges to choosing appropriate treatment. Recent findings of the biology of breast cancer including the mechanisms of survival and metastasis, understanding the effective signaling pathways in tumor formation and modeling of cancer cell responses to the therapeutic approaches provided significant advances in BC treatment. In this regard, the use of phototherapy-based approaches such as photothermal therapy (PTT) would be an encouraging alternative for tumor suppression through activating autophagy or suppressing cell signaling that influences the cell cycle to induce cell death. Since autophagy has a dual opposite role consisting of pro-survival and growth inhibition in breast cancer microenvironments, the regulation of autophagy would be playing promising roles in the treatment of BC using PTT. This review updates the molecular mechanisms that PTT could evoke autophagic cell death in breast cancer. Moreover, this article provides insights into the biological effects of autophagy-targeted-PTT as a promising strategy for breast cancer therapy.
    Keywords:  Autophagy; Breast cancer; Cell death; Photothermal therapy; Signaling pathway
    DOI:  https://doi.org/10.1016/j.lfs.2022.120499
  38. Food Environ Virol. 2022 Mar 29.
    Curcumin and Its Analogs as a Therapeutic Strategy in Infections Caused by RNA Genome Viruses.
    Leide Lene C Ferreira, Marina P Abreu, Camila B Costa, Paulo O Leda, Maria Dutra Behrens, Elisabete Pereira Dos Santos.
      The use of natural resources for the prevention and treatment of diseases considered fatal to humanity has evolved. Several medicinal plants have nutritional and pharmacological potential in the prevention and treatment of viral infections, among them, turmeric, which is recognized for its biological properties associated with curcuminoids, mainly represented by curcumin, and found mostly in rhizomes. The purpose of this review was to compile the pharmacological activities of curcumin and its analogs, aiming at stimulating their use as a therapeutic strategy to treat infections caused by RNA genome viruses. We revisited its historical application as an anti-inflammatory, antioxidant, and antiviral agent that combined with low toxicity, motivated research against viruses affecting the population for decades. Most findings concentrate particularly on arboviruses, HIV, and the recent SARS-CoV-2. As one of the main conclusions, associating curcuminoids with nanomaterials increases solubility, bioavailability, and antiviral effects, characterized by blocking the entry of the virus into the cell or by inhibiting key enzymes in viral replication and transcription.
    Keywords:  Antiviral activity; Curcuma longa L.; Curcumin; RNA virus; Viral infections
    DOI:  https://doi.org/10.1007/s12560-022-09514-3
  39. J Biomater Appl. 2022 Mar 27. 8853282221078107
    Injectable in situ intelligent thermo-responsive hydrogel with glycyrrhetinic acid-conjugated nano graphene oxide for chemo-photothermal therapy of malignant hepatocellular tumor.
    Huahua Wang, Baiyan Wang, Shasha Wang, Jiaqi Chen, Weiwei Zhi, Yanbin Guan, Bangrong Cai, Yanhui Zhu, Yongyan Jia, Shengnan Huang, Xiali Zhu.
      Malignant tumor is one of the major diseases with high morbidity and mortality. The purpose of this study is to prepare berberine hydrochloride (BH) in situ thermo-sensitive hydrogel based on glycyrrhetinic acid (GA) modified nano graphene oxide (NGO) (GA-BH-NGO-gel). NGO was taken as the photosensitizer, GA was taken as the target molecule, and BH was taken as the model drug. The physicochemical properties and anti-tumor activity in vivo and in vitro were also studied. This subject could provide a certain theoretical basis for the chemo-photothermal therapy combined treatment of malignant tumor. The release behavior of GA-BH-NGO-gel in vitro presented sustained and temperature-dependent drug release effect. The anti-tumor activity studies in vivo and in vitro had shown that GA-BH-NGO-gel had stronger anti-tumor activity, which could be targeting distributed to the tumor tissues. Moreover, the inhibitory effect of GA-BH-NGO-gel was enhanced when combined with 808 nm of laser irradiation. In this research, the chemo-photothermal combination therapy was applied into the tumor treatment, which may provide certain research ideas for the clinical treatment of malignant tumor.
    Keywords:  berberine hydrochloride; chemo-photothermal therapy; glycyrrhetinic acid; nano graphene oxide; thermo-sensitive hydrogel; tumor
    DOI:  https://doi.org/10.1177/08853282221078107
  40. Front Mol Biosci. 2022 ;9 831382
    KRAS Mutation in Rare Tumors: A Landscape Analysis of 3453 Chinese Patients.
    Shuhang Wang, Qin Li, Peiwen Ma, Yuan Fang, Yue Yu, Ning Jiang, Huilei Miao, Qiyu Tang, Yuqi Yang, Shujun Xing, Rongrong Chen, Xin Yi, Ning Li.
      KRAS is the most commonly mutated oncogene in human cancers. Targeted therapy and immunotherapy for this gene have made remarkable progress in recent years. However, comprehensive molecular landscape analysis of KRAS in rare tumors is lacking. Retrospective analysis was performed on clinical samples from patients with rare tumors collected between September 2015 and September 2021, using hybrid-capture-based next-generation sequencing for genomic profiling and immunohistochemistry assay for PD-L1. Of the 3,453 patients included in analysis, KRAS mutations were identified in 8.7% patients in overall; mutation rate and mutation subtypes varied widely across tumor systems and subtypes. KRAS mutations included 21 missense mutations, of which G12D (29.2%), G12V (24.6%), and G13D (10.8%) were most common. Interestingly, KRAS G12C was observed in 0.6% patients overall, and in 5.7% of sarcomatoid carcinoma of the lung and 5.4% of clear cell ovarian cancer tumors, but none in small-bowel cancer tumors. 31.8% KRAS mutations and 36.4% KRAS G12C mutations co-occurred with other targetable alterations. No significant correlation was observed between TMB-H, MSI-H, PD-L1 status, and KRAS mutation status, which may be related to the high proportion of G12D. This study is the first KRAS mutation landscape study in rare tumors of large sample size in China and worldwide. Our results suggest that targeted therapy and immunotherapy are both feasible, albeit complex, in these patients. This information may have significant impact on the operation of clinical trials for rare tumor patients with KRAS mutations in China.
    Keywords:  G12C; KRAS; immunotherapy; rare tumors; targeted therapy
    DOI:  https://doi.org/10.3389/fmolb.2022.831382
  41. Drug Deliv. 2022 Dec;29(1): 1060-1074
    Gemcitabine cationic polymeric nanoparticles against ovarian cancer: formulation, characterization, and targeted drug delivery.
    Sankha Bhattacharya, Md Meraj Anjum, Krishna Kumar Patel.
      This study focused on gemcitabine (GTB) delivery of cationic polymeric nanoparticles to treat ovarian cancer in order to promote effective localized delivery and drug retention during biological discharge. To begin, four GTB-loaded polymer nanoparticles were prepared: chitosan nanoparticles (CS-NPs), polysarcosin nanoparticles (PSar-NPs), poly-l-lysine & polysarcosin nanoparticles (PLL-PSar-NPs), and chitosan & polysarcosin nanoparticles (CS-PSar-NPs). Based on preliminary particle size, zeta potential, encapsulation efficiency, DSC, surface morphology, release profiling, and cellular internalization studies using rhodamine 123 and Nile red fluorescent markers, it was hypothesized that CS-PSar-NPs could be the best cationic formulation with strong biocompatibility and anticancer activity against the OVCAR-8 ovarian cancer cell line. To improve effective targeting, cellular penetration, and in vitro cytotoxicity, epidermal growth factor receptor variation III (EGFRvIII) is attached over all four polymeric nanoparticles. Confocal imaging revealed that EGFRvIII-conjugated cationic GTB polymeric nanoparticles had a greater cellular uptake and double internalization capabilities than unconjugated nanoparticles, as well as time-dependent cell entrance. GTB and EGFRvIII-conjugated polymer nanoparticles would have a stronger potential to infiltrate ovarian cancer cells during the first hour of incubation. According to TEM and FTIR findings, EGFRvIII conjugation across the non-target CS-PSar-NP surface was successful, making CS-PSar-NPS-EGFRvIII more target-specific and thus a safer drug delivery candidate for ovarian cancer treatment.HighlightsGTB loaded non-target CS-PSar-NPs & active targeted CS-PSar-NPs-EGFRvII developed.SEM, AFM, DSC, particle size, zeta potential, internalization performed for CS-PSar-NPs.MTT & CLSM study confirmed CS-PSar-NPS-EGFRvII was binding specific to OVCAR-8 cellsFabrication of EGFRvII over nanoparticles confirmed by TEM.CS-PSar-NPS-EGFRvII safer candidate for ovarian cancer.
    Keywords:  EGFR vIII; Gemcitabine; OVCAR-8; confocal microscopy; polysarcosin
    DOI:  https://doi.org/10.1080/10717544.2022.2058645
  42. Chem Sci. 2021 Apr 28. 12(16): 5918-5925
    Rational design of iridium-porphyrin conjugates for novel synergistic photodynamic and photothermal therapy anticancer agents.
    Liping Zhang, Yun Geng, Lijuan Li, Xiaofan Tong, Shi Liu, Xingman Liu, Zhongmin Su, Zhigang Xie, Dongxia Zhu, Martin R Bryce.
      Near-infrared (NIR) emitters are important probes for biomedical applications. Nanoparticles (NPs) incorporating mono- and tetranuclear iridium(iii) complexes attached to a porphyrin core have been synthesized. They possess deep-red absorbance, long-wavelength excitation (635 nm) and NIR emission (720 nm). TD-DFT calculations demonstrate that the iridium-porphyrin conjugates herein combine the respective advantages of small organic molecules and transition metal complexes as photosensitizers (PSs): (i) the conjugates retain the long-wavelength excitation and NIR emission of porphyrin itself; (ii) the conjugates possess highly effective intersystem crossing (ISC) to obtain a considerably more long-lived triplet photoexcited state. These photoexcited states do not have the usual radiative behavior of phosphorescent Ir(iii) complexes, and they play a very important role in promoting the singlet oxygen (1O2) and heat generation required for photodynamic therapy (PDT) and photothermal therapy (PTT). The tetranuclear 4-Ir NPs exhibit high 1O2 generation ability, outstanding photothermal conversion efficiency (49.5%), good biocompatibility, low half-maximal inhibitory concentration (IC50) (0.057 μM), excellent photothermal imaging and synergistic PDT and PTT under 635 nm laser irradiation. To our knowledge this is the first example of iridium-porphyrin conjugates as PSs for photothermal imaging-guided synergistic PDT and PTT treatment in vivo.
    DOI:  https://doi.org/10.1039/d1sc00126d
  43. Bioengineered. 2022 Apr;13(4): 8490-8502
    Epigallocatechin-3-gallate suppresses the growth of human osteosarcoma by inhibiting the Wnt/β-catenin signalling pathway.
    Chaoqun Dong, Zhigang Wang, Peng Shen, Yingguo Chen, Jinshu Wang, Hongbo Wang.
      Osteosarcoma (OS) is one of the most common malignant tumors in adolescents. Due to local invasion, distant metastasis and drug resistance, the clinical treatment efficacy and prognosis of OS have remained almost unchanged for decades. Epigallocatechin-3-gallate (EGCG) is a unique catechin from tea leaves, and some studies have confirmed its antitumour effects on various tumors. Here, cellular experiments showed that EGCG significantly promoted OS cell apoptosis and inhibited proliferation, migration and invasion, and cell and animal experiments demonstrated that the Wnt/β-catenin pathway played an indispensable role in the antitumour effects of EGCG. Moreover, EGCG inhibited the growth of OS cells in vitro while suppressing tumor cell damage to the bone in situ and distant lung metastasis. The results indicate that the antitumour effect of EGCG on human OS may be mediated by regulating the Wnt/β-catenin pathway and that EGCG can be used alone or in combination with other regimens as a potentially effective anticancer treatment.
    Keywords:  Osteosarcoma; Wnt/β-catenin pathways; anticancer effect; epigallocatechin-3-gallate
    DOI:  https://doi.org/10.1080/21655979.2022.2051805
  44. Curr Pharm Biotechnol. 2022 Mar 29.
    Advancement and Applications of Platelet-Inspired Nanoparticles: A Paradigm for Cancer Targeting.
    Debashish Ghose, Suryakanta Swain, Chinam Niranjan Patra, Bikash Ranjan Jena, Muddana Eswara Bhanoji Rao.
      Platelet-inspired nanoparticles ignited the potential of new opportunities that can be effectively applied to produce similar biological particulates, such as the structural cellular and vesicular components and varied viral forms, to improve biocompatible features that could enhance the nature of biocompatible elements promote effectiveness in therapy. The simplicity and more effortless adaptability of such biomimetic techniques uplift the delivery of the carriers laden with cellular structures, which has created varied opportunities and scope of merits like; prolongation in circulation and alleviating immunogenicity improvement of the site-specific active targeting. Platelet-inspired nanoparticles or medicines are the most recent nanotechnology-based drug targeting systems used mainly to treat blood-related disorders, tumors, and cancer. The present review encompasses the current approach of platelet-inspired nanoparticles or medicines that have boosted the scientific community from versatile fields to advance biomedical sciences. Surprisingly, this knowledge has streamlined to development of newer diagnostic methods, imaging techniques, and novel nanocarriers, which might further help in the treatment protocol of the diseased conditions. The basis of the review primarily focuses on the novel advancements and recent patents in nanoscience and nanomedicine that could be streamlined in the future for the management of progressive cancers and tumor targeting. Rigorous technological advancements like biomimetic stem cells, pH-sensitive drug delivery of nanoparticles, DNA origami devices, virosomes, nano cells like exosomes mimicking nanovesicles, DNA nanorobots, microbots, etc., can be implemented effectively for target-specific drug delivery.
    Keywords:  Adenosine diphosphate receptors; Artificial blood components; CLEC-2 inhibitors; Hemoglobin-based oxygen-carrier systems; Thrombocytosis; Tumor therapy
    DOI:  https://doi.org/10.2174/1389201023666220329111920
  45. Nanoscale. 2022 Mar 30.
    The optical research progress of nanophosphors composed of transition elements in the fourth period of near-infrared windows I and II for deep-tissue theranostics.
    Ming-Hsien Chan, Wen-Tse Huang, Kuan-Chun Chen, Ting-Yi Su, Yung-Chieh Chan, Michael Hsiao, Ru-Shi Liu.
      Research in the field of nano-optics is advancing by leaps and bounds, among which near-infrared (NIR) light optics have attracted much attention. NIR light has a longer wavelength than visible light, such that it can avoid shielding caused by biological tissues. This advantage has driven its importance and practicality in human treatment applications and has attracted significant attention from researchers in academia and industry. In the broad spectrum of infrared light wavelengths, the most noticeable ones are the NIR biological window I of 700-900 nm and window II of 1000-1700 nm. Luminescent materials can effectively cover the NIR biological window with different doping strategies. These doped elements are mostly transition elements with multielectron orbitals. Several nanomaterials based on narrow-spectrum lanthanides have been developed to correspond to biological applications of different wavelengths. However, this review explicitly introduces the absorption and reflection/luminescence interactions between NIR light and biological tissues independently. Unlike the adjustment of the wavelength of the lanthanide series, this review analyzes the NIR optical properties of the fourth-period element ions in transition elements (such as Cr3+ and Ni2+). These elements have a broadband wavelength of NIR light emission and higher quantum efficiency, corresponding to the absorption and emission spectrum and photobiological absorption of different NIR windows for therapeutic diagnosis. Finally, this review lists and explores other broadband NIR phosphors and has tried to discover the possibility of non-invasive precision medicine in the future.
    DOI:  https://doi.org/10.1039/d2nr00343k
  46. Eur J Med Chem. 2022 Mar 21. pii: S0223-5234(22)00183-0. [Epub ahead of print]235 114281
    pH-redox responsive cascade-targeted liposomes to intelligently deliver doxorubicin prodrugs and lonidamine for glioma.
    Yi Zhao, Yao Peng, Zhongzhen Yang, Jiaqi Lu, Ru Li, Yuesen Shi, Yaxin Du, Ze Zhao, Li Hai, Yong Wu.
      To synergistically treat glioma with a combination chemotherapy, we design and prepare novel cascade-targeted liposomes (Lip-TPGS) using glucose and triphenylphosphonium (TPP) as targeting moieties, which could intelligently deliver redox-sensitive doxorubicin (DOX) prodrugs (SDOX) and chemotherapeutic sensitizer lonidamine (LND). The pH-responsive ligand Chol-TPG modified by PEGylated glucose can overcome the blood-brain barrier and reach tumor cells. Combined with the modification of mitochondria targeting ligand (Chol-TPP), Lip-TPGS are endowed with pH-responsive charge regulation function and multi-stage targeting abilities. After triggered by the excessive glutathione in tumor cells, Lip-TPGS could sufficiently release the parent drugs DOX, which would significantly reduce side effects without compromising anti-glioma efficacy. Therefore, Lip-TPGS possess these characteristics: good pharmacokinetic behavior, superior brain targeting ability, specific tumor recognition and internalization capability, and strong endo/lysosome escaping and mitochondria targeting potential. Furthermore, Lip-TPGS exhibit significant advantages on anti-glioma by inhibiting proliferation, promoting apoptosis, inducing mitochondria dysfunction, inhibiting migration and invasion, prolonging the survival time, narrowing tumor areas, limiting lung metastasis, and reducing toxicity to normal organs. In summary, Lip-TPGS, with cascade targeting abilities from tissue/cell to organelle levels and highly controlled drug release properties, would become a promising drug delivery system for glioma treatment.
    Keywords:  Doxorubicin; Glioma; Liposome; Lonidamine; Multi-functional; pH/redox responsive
    DOI:  https://doi.org/10.1016/j.ejmech.2022.114281
  47. Bratisl Lek Listy. 2022 ;123(3): 205-213
    Potential application of Helicobacter pylori against cancer: carcinogenic pathogen or therapeutic agent?
    Soleimani Neda, Ebrahimi Askari Razieh, Rommasi Foad.
      The repeated exposure of normal cells to carcinogenic agents may lead to mutations in their genetic material, changing them into cancerous cells. In this case, the structure and function of these cells would alter, and they would not behave like a normal cell. Treatment of cancer by bacteria is a promising and new strategy. Recently, scientists demonstrated that bacteria could induce apoptosis in cancerous cells. Cell death was identified by cellular cytotoxicity assays when bacterial structures were utilized, and these observations proved bacterial capability for apoptosis induction. Helicobacter pylori (or H. pylori) is known as a pathogenic and carcinogenic bacterium that can cause various problems. Recently, practical therapeutic applications of this bacterium has drawn attention. Here, we analyzed the advantages and merits of bacterial compounds of H. pylori as active remedial agents for cancer treatment. Besides describing H. pylori virulent factors and their role in cancer incidence, we also discuss how their potentials can significantly be strengthened and used for cancer treatment. This review results suggest that some factors of H. pylori can be exploited as therapeutic agents for cancer therapy in future (Tab. 1, Fig. 3, Ref. 77). Keywords: apoptosis induction, bacteriotherapy, cancer treatment, Helicobacter pylori.
    DOI:  https://doi.org/10.4149/BLL_2022_034
  48. Curr Med Chem. 2022 Mar 28.
    Research progress on antineoplastic, antibacterial, and anti-inflammatory activities of seven-membered heterocyclic derivatives.
    Bin Li, Chen Chen, Jingjing Jia, Ling He.
      Seven-membered heterocyclic compounds are important drug scaffolds, because of their unique chemical structures. They widely exist in natural products and show a variety of biological activities. They have commonly been used in central nervous system drugs in the past 30 years. In the past decade, there are many studies on the activities of antitumor, antibacterial, etc. Herein, we summarize the research advances in different kinds of seven-membered heterocyclic compounds containing nitrogen, oxygen, and sulfur heteroatoms with antitumor, antisepsis, and anti-inflammation activities in the past ten years, which is expected to be beneficial to the development and design of novel drugs for the corresponding indications.
    Keywords:  Seven-membered ring; anti-inflammation.; antisepsis; antitumor; biological activities; heterocyclic compounds
    DOI:  https://doi.org/10.2174/0929867329666220328123953
  49. Recent Pat Nanotechnol. 2022 Mar 28.
    A discursive review of recent development and patents on glycerosomes.
    Singh Ragini, Fatima Zeeshan, Srivastava Dipti, Awasthi Himani.
      BACKGROUND: To achieve a target-based drug delivery with minimal side effects, novel drug delivery systems are being continuously explored. Vesicular systems are one such system that can ameliorate the bioavailability of the encapsulated drug by delivering the drug at the targeted site and can minimize the side effect.OBJECTIVE: The objective of this review is to provide a vivid description of glycerosomes and their applications. Glycerosomes are sphere-shaped versatile vesicles consisting of one or more phospholipid bilayers similar to liposomes but contain a high concentration of glycerol, which modifies the liposome bilayer fluidity. Glycerosomes can encapsulate both hydrophobic and hydrophilic drugs, which makes them the promising vehicle in the field of drug delivery.
    CONCLUSION: Most of the glycerosome formulations prepared were targeted for topical delivery and in particular, a cutaneous route where they have shown promising results. These vesicles are biocompatible and due to the high glycerol concentration, they have improved spreadability and penetrability. It is therefore imperative to explore the other topical routes such as ocular, vaginal, nasal, and rectal for delivery of drugs.
    Keywords:  Glycerol; Glycerosomes; Phospholipid vesicles; Topical delivery; Vesicular systems; bilayer fluidity
    DOI:  https://doi.org/10.2174/1872210516666220328124450
  50. Adv Colloid Interface Sci. 2022 Mar 26. pii: S0001-8686(22)00057-4. [Epub ahead of print]303 102655
    Targeted delivery and controlled released of essential oils using nanoencapsulation: A review.
    Weria Weisany, Shima Yousefi, Nawroz Abdul-Razzak Tahir, Nassim Golestanehzadeh, David Julian McClements, Benu Adhikari, Mehran Ghasemlou.
      Essential oils (EOs) contain a complex mixture of volatile and non-volatile molecules with diverse biological activities, including flavoring, antioxidant, antimicrobial, and nutraceutical properties. As a result, EOs have numerous potential applications in the agriculture, food, and pharmaceutical industries. However, their hydrophobicity, chemical instability, and volatility pose a challenge for many of their applications. These challenges can often be overcome by encapsulation EOs in colloidal delivery systems. Over the last decade or so, nanoencapsulation and microencapsulation technologies have been widely explored for their potential to improve the handling, dispersibility, and stability of hydrophobic substances, as well as to control their release profiles (e.g., targeted, triggered, sustained, or burst release). These technologies include emulsification, coacervation, precipitation, spray-drying, spray-cooling, freeze-drying, fluidized bed coating, and extrusion. This article reviews some of the most important developments in EOs encapsulation, the physicochemical mechanisms underlying the behavior of encapsulated EOs, current challenges, and potential applications in the food and biomedical sciences. This review has found that nanoencapsulation has countless of potential advantages for the utilization of EOs in the food industry and can improve their water-dispersibility, food matrix compatibility, chemical stability, volatility, and bioactivity.
    Keywords:  Encapsulation; Essential oils; Microencapsulation; Nanoencapsulation; Nanotechnology
    DOI:  https://doi.org/10.1016/j.cis.2022.102655
  51. Pharm Res. 2022 Mar 31.
    Targeting Transporters for Drug Delivery to the Brain: Can We Do Better?
    Elena Puris, Gert Fricker, Mikko Gynther.
      Limited drug delivery to the brain is one of the major reasons for high failure rates of central nervous system (CNS) drug candidates. The blood-brain barrier (BBB) with its tight junctions, membrane transporters, receptors and metabolizing enzymes is a main player in drug delivery to the brain, restricting the entrance of the drugs and other xenobiotics. Current knowledge about the uptake transporters expressed at the BBB and brain parenchymal cells has been used for delivery of CNS drugs to the brain via targeting transporters. Although many transporter-utilizing (pro)drugs and nanocarriers have been developed to improve the uptake of drugs to the brain, their success rate of translation from preclinical development to humans is negligible. In the present review, we provide a systematic summary of the current progress in development of transporter-utilizing (pro)drugs and nanocarriers for delivery of drugs to the brain. In addition, we applied CNS pharmacokinetic concepts for evaluation of the limitations and gaps in investigation of the developed transporter-utilizing (pro)drugs and nanocarriers. Finally, we give recommendations for a rational development of transporter-utilizing drug delivery systems targeting the brain based on CNS pharmacokinetic principles.
    Keywords:  CNS; drug delivery; nanocarriers; prodrugs; transporter
    DOI:  https://doi.org/10.1007/s11095-022-03241-x
  52. Phytochemistry. 2022 Mar 23. pii: S0031-9422(22)00081-4. [Epub ahead of print]198 113165
    The ethnobotany, phytochemistry, and biological properties of Nigella damascena - A review.
    Natale Badalamenti, Aurora Modica, Giuseppe Bazan, Pasquale Marino, Maurizio Bruno.
      This review is a systematic scientific work on medicinal and traditional use, on the chemical composition of specialized metabolites, volatile and non-volatile, on aspects related to toxicology and phytotherapy of Nigella damascena L. The genus Nigella (Ranunculaceae) is distributed throughout the Mediterranean basin, extending to northern India, and has been divided into three sections. Nigella damanscena L. is traditionally used as an ingredient in food, for example, as flavouring agents in bread and cheese, but is also known in folk medicine, used to regulate menstruation; for catarrhal affections and amenorrhea; as a diuretic and sternutatory; as an analgesic, anti-oedematous, and antipyretic; and for vermifuge and its disinfectant effects. This paper reviews the most dated to the latest scientific research on this species, highlighting the single isolated metabolites and exploring their biological activity. Fifty-seven natural compounds have been isolated and characterised from the seeds, roots, and aerial parts of the plant. Among these constituents, alkaloids, flavonoids, diterpenes, triterpenes, and aromatic compounds are the main constituents. The isolated compounds and the various extracts obtained with solvents of different polarities presented a diverse spectrum of biological activities such as antibacterial, antifungal, antitumour, antioxidant, anti-inflammatory, antipyretic, anti-oedema, and antiviral activities. Various in vitro and in vivo tests have demonstrated the pharmacological potential of β-elemene and alkaloid damascenin. Unfortunately, the largest number of biological studies on this species and its metabolites have been conducted in vitro; therefore, further investigation is necessary to evaluate the toxicological aspects and real mechanisms of action of crude extracts to confirm the therapeutic potential of N. damascena.
    Keywords:  Anti-inflammatory aspects; Anticancer properties; Dolabellane diterpenes; Fixed oils; Nigella damascena; Ranunculaceae; β-elemene
    DOI:  https://doi.org/10.1016/j.phytochem.2022.113165
  53. J Control Release. 2022 Mar 25. pii: S0168-3659(22)00181-X. [Epub ahead of print]
    All-stage targeted therapy for glioblastoma based on lipid membrane coated cabazitaxel nanocrystals.
    Sunyi Wu, Linwei Lu, Jianfen Zhou, Danni Ran, Songli Wang, Qianzhu Xu, Weixia Xu, Jun Wang, Yu Liu, Cao Xie, Zimiao Luo, Weiyue Lu.
      Glioblastoma (GBM) is the most aggressive brain tumor with poor prognosis and frequent recurrence. The blood-brain barrier (BBB), blood-brain tumor barrier (BBTB) hinder the entry of therapeutics into the glioma region. Vasculogenic mimicry (VM) formed by invasive glioma cells is also related to recurrence of GBM. VAP is a D-peptide ligand of GRP78 protein overexpressed on BBTB, VM, and glioma cells but not on normal tissues. Besides, p-hydroxybenzoic acid (pHA) can effectively traverse the BBB. Herein we developed an all-stage glioma-targeted cabazitaxel (CBZ) nanocrystal loaded liposome modified with a "Y" shaped targeting ligand composed of pHA and VAP (pV-Lip/cNC). The pure drug nanocrystal core provided high drug loading, while lipid membrane promoted the stability and circulation time. pV-Lip/cNC exhibited excellent glioma homing, barriers crossing, and tumor spheroid penetrating capability in vitro. Treatment of pV-Lip/cNC displayed enhanced CBZ accumulation in glioma and anti-glioma effect with a median survival time (53 days) significantly longer than that of cNC loaded liposomes modified with either single ligand (42 days for VAP and 45 days for pHA) in the murine orthotopic GBM model. These results indicated pV-Lip/cNC could traverse the BBB and BBTB, destruct VM, and finally kill glioma cells to realize all-stage glioma therapy.
    Keywords:  All-stage targeted delivery; Cabazitaxel; Glioma; Liposome; Nanocrystal
    DOI:  https://doi.org/10.1016/j.jconrel.2022.03.047
  54. Crit Rev Food Sci Nutr. 2022 Mar 29. 1-28
    Postbiotics as the new frontier in food and pharmaceutical research.
    Sahar Sabahi, Aziz Homayouni Rad, Leili Aghebati-Maleki, Narges Sangtarash, Mahdi Asghari Ozma, Atefeh Karimi, Hedayat Hosseini, Amin Abbasi.
      Food is the essential need of human life and has nutrients that support growth and health. Gastrointestinal tract microbiota involves valuable microorganisms that develop therapeutic effects and are characterized as probiotics. The investigations on appropriate probiotic strains have led to the characterization of specific metabolic byproducts of probiotics named postbiotics. The probiotics must maintain their survival against inappropriate lethal conditions of the processing, storage, distribution, preparation, and digestion system so that they can exhibit their most health effects. Conversely, probiotic metabolites (postbiotics) have successfully overcome these unfavorable conditions and may be an appropriate alternative to probiotics. Due to their specific chemical structure, safe profile, long shelf-life, and the fact that they contain various signaling molecules, postbiotics may have anti-inflammatory, immunomodulatory, antihypertensive properties, inhibiting abnormal cell proliferation and antioxidative activities. Consequently, present scientific literature approves that postbiotics can mimic the fundamental and clinical role of probiotics, and due to their unique characteristics, they can be applied in an oral delivery system (pharmaceutical/functional foods), as a preharvest food safety hurdle, to promote the shelf-life of food products and develop novel functional foods or/and for developing health benefits, and therapeutic aims. This review addresses the latest postbiotic applications with regard to pharmaceutical formulations and commercial food-based products. Potential postbiotic applications in the promotion of host health status, prevention of disease, and complementary treatment are also reviewed.
    Keywords:  Postbiotic; food safety; functional foods; gut microbiota; health promotion; immunomodulation; pharmaceutical products
    DOI:  https://doi.org/10.1080/10408398.2022.2056727
  55. ACS Nano. 2022 Mar 30.
    Physical & Chemical Microwave Ablation (MWA) Enabled by Nonionic MWA Nanosensitizers Repress Incomplete MWA-Arised Liver Tumor Recurrence.
    Qidi Hou, Kun Zhang, Sitong Chen, Jie Chen, Yan Zhang, Ningqiang Gong, Weisheng Guo, Chao Fang, Luo Wang, Jian Jiang, Jianping Dou, Xingjie Liang, Jie Yu, Ping Liang.
      Ionic liquid (IL)-loaded or metal ions-enriched nanoparticles have been witnessed to assist microwave ablation (MWA) and heighten heat utilization for tumor treatment, which, however, inevitably brings about cell dys-homeostasis and severely endangers normal cells or tissues. In this report, a nonionic MWA sensitizer that encapsulates ethyl formate (EF) and doxorubicin (DOX) in liposomes (EF-DOX-Lips) was constructed to reinforce MWA and combined therapy against incomplete MWA-induced tumor recurrence. EF in EF-DOX-Lips as the nonionic liquid can perform like IL to accelerate energy transformation from electromagnetic energy to heat for strengthening MWA. More significantly, EF metabolite, that is, ethanol, also enables chemical ablation, which further enhances MWA. As well, the EF gasification-enhanced lipid rupture and cavitation can promote DOX delivery into a liver tumor for magnifying MWA & chemotherapy combined therapy. By virtue of these contributions, this nonionic MWA nanosensitizer exerts robust antitumor effects to inhibit tumor proliferation and angiogenesis for repressing tumor growth and recurrence or metastasis via downregulating the Epha2 gene and unconventional PI3K/Akt & MAPK signal pathways that the incomplete MWA activated, which provides an avenue to elevate an MWA-based antitumor outcome.
    Keywords:  Cell dyshomeostasis; Ethyl formate metabolism; Incomplete microwave ablation (MWA); Nonionic MWA nanosensitizers; Physical & chemical ablation
    DOI:  https://doi.org/10.1021/acsnano.1c10714
  56. ACS Biomater Sci Eng. 2022 Mar 29.
    Improving the Therapeutic Efficiency of Hypoxic-Activated Prodrugs by Enhancing Hypoxia in Solid Tumors.
    Gaoqian Zhao, Yan Jin, Shutao Gao, Tingshan Xiao, Miao Fan, Dandan Liu, Jinchao Zhang, Zhenhua Li, Xiaohan Zhou, Huifang Liu.
      The low sensitivity of hypoxic regions in solid tumors to radiotherapy and chemotherapy remains a major obstacle to cancer treatment. By taking advantage of hypoxic-activated prodrugs, tirapazamine (TPZ), generating cytotoxic reductive products and the glucose oxidase (GOx)-based glucose oxidation reaction, we designed a nanodrug-loading system that combined TPZ-induced chemotherapy with GOx-mediated cancer-orchestrated starvation therapy and cancer oxidation therapy. In this work, we first prepared mesoporous silica (MSN) loaded with TPZ. Then, in order to prevent the leakage of TPZ in advance, the surface was coated with a layer of carMOF formed by Fe3+ and carbenicillin (car), and GOx was adsorbed on the outermost layer to form the final nanosystem MSN-TPZ@carMOF-GOx (MT@c-G). GOx could effectively consume oxygen and catalyzed glucose into gluconic acid and hydrogen peroxide. First, the generated gluconic acid lowered the pH of tumor tissues, promoted the decomposition of carMOF, and released TPZ. Second, oxygen consumption could improve the degree of hypoxia in tumor tissues, so that enhanced the activity of TPZ. Furthermore, GOx could generate cancer-orchestrated starvation/oxidation therapy. Therefore, our study provided a new strategy that TPZ combined with GOx achieved starvation/oxidation/chemotherapy for enhancing anticancer effects in hypoxic regions.
    Keywords:  glucose oxidase; hypoxic region; hypoxic-activated prodrugs; mesoporous silica; tirapazamine
    DOI:  https://doi.org/10.1021/acsbiomaterials.2c00104
  57. Appl Biochem Biotechnol. 2022 Mar 29.
    A Systemic Review on the Synthesis, Characterization, and Applications of Palladium Nanoparticles in Biomedicine.
    Davoodbasha MubarakAli, Hoekun Kim, Perumalsamy Sundara Venkatesh, Jung-Wan Kim, Sang-Yul Lee.
      Palladium nanoparticles (Pd NPs) have been considered as a potential candidate in the field of biomedical applications due to its unique properties such as huge catalytic, hydrogen storage, and sensing behavior. Therefore, Pd NPs have shown to have a significant potential for the development of antimicrobials, wound healing, antioxidant, and anticancer property in recent days. There are plenty of reports that showed superior properties of noble metals. However, only very few studies have been undertaken to explore the advantage of Pd NPs in the field of biomedical applications. This review reports detailed and comprehensive studies comprising of the synthesis, characterization, and potential applications of Pd NPs in biomedicine. This report provides evidences in the literature documented by early researchers to understand the potential applications of Pd NPs to be explored in various fields.
    Keywords:  Anticancer; Antimicrobial; Biomedicine; Palladium nanoparticles; Synthesis
    DOI:  https://doi.org/10.1007/s12010-022-03840-9
  58. Mini Rev Med Chem. 2022 Mar 30.
    Advances and Applications of Metal-Organic Framework Nanomaterials as Oral Delivery Carriers: A Review.
    Li Li, Zhaorui Qi, Shasha Han, Xurui Li, Bingmi Liu, Yu Liu.
      Oral administration is a commonly used, safe, and patient-compliant method of drug delivery. However, due to the multiple absorption barriers in the gastrointestinal tract (GIT), the oral bioavailability of many drugs is low, resulting in a limited range of applications for oral drug delivery. Nanodrug delivery systems have unique advantages in overcoming the multiple barriers to oral absorption and improving the oral bioavailability of encapsulated drugs. Metal-organic frameworks (MOFs) are composed of metal ions and organic linkers assembled by coordination chemistry. Unlike other nanomaterials, nanoscale metal-organic frameworks (nano-MOFs, NMOFs) are increasingly popular for drug delivery systems (DDSs) due to their tunable pore size and easily modified surfaces. This paper summarizes the literature on MOFs in pharmaceutics included in SCI for the past ten years. Then, the GIT structure and oral drug delivery systems are reviewed, and the advantages, challenges, and solution strategies possessed by oral drug delivery systems are discussed. Importantly, two major classes of MOFs suitable for oral drug delivery systems are summarized, and various representative MOFs as oral drug carriers are evaluated in the context of oral drug delivery systems. Finally, the challenges faced by DDSs in the development of MOFs, such as biostability, biosafety, and toxicity, are examined.
    Keywords:  Metal-organic frameworks; drug delivery; medical application of MOFs.; nanocarriers; nanoparticles; oral administration
    DOI:  https://doi.org/10.2174/1389557522666220330152145
  59. Front Oncol. 2022 ;12 858185
    Melanoma and Nanotechnology-Based Treatment.
    Hong Zeng, Jia Li, Kai Hou, Yiping Wu, Hongbo Chen, Zeng Ning.
      Melanoma is a malignant tumor arising in melanocytes from the basal layer of the epidermis and is the fifth most commonly diagnosed cancer in the United States. Melanoma is aggressive and easily metastasizes, and the survival rate is low. Nanotechnology-based diagnosis and treatment of melanoma have attracted increasing attention. Importantly, nano drug delivery systems have the advantages of increasing drug solubility, enhancing drug stability, prolonging half-life, optimizing bioavailability, targeting tumors, and minimizing side effects; thus, these systems can facilitate tumor cytotoxicity to achieve effective treatment of melanoma. In this review, we discuss current nanosystems used in the diagnosis and treatment of melanoma, including lipid systems, inorganic nanoparticles, polymeric systems, and natural nanosystems. The excellent characteristics of novel and effective drug delivery systems provide a basis for the broad applications of these systems in the diagnosis and treatment of melanoma, particularly metastatic melanoma.
    Keywords:  cytotoxicity; drug delivery; melanoma; metastasis; nanotechnology
    DOI:  https://doi.org/10.3389/fonc.2022.858185
  60. Adv Mater. 2022 Mar 31. e2201706
    Glutathione-Depleting Organic Metal Adjuvants for Effective NIR-II Photothermal Immunotherapy.
    Yun Chen, Peiying He, Deblin Jana, Dongdong Wang, Menghao Wang, Peiyuan Yu, Wei Zhu, Yanli Zhao.
      Although photothermal immunotherapy (PTI) is a compelling strategy for tumor therapy, the development of promising photothermal agents to overcome the insufficient immunogenicity of tumor cells and the poor immune response encountered in PTI is still challenging. Herein, we present commercial small-molecule-based organic metal adjuvants (OMAs) with second near-infrared photoacoustic and photothermal properties as well as the ability to perturb redox homeostasis to potentiate immunogenicity and immune responsiveness. OMAs, assembled from charge-transfer complexes and characterized by a broad substrate scope, high accessibility, and flexibly tuned optical properties, demonstrate strong phototherapeutic and adjuvant abilities via the depletion of glutathione and cysteine, and subsequently elicit systemic immunity by evoking immunogenic cell death, promoting dendritic cell maturation, and increasing T cell infiltration. Furthermore, programmed cell death protein 1 antibody can be employed to synergize with OMAs to suppress tumor immune evasion and ultimately improve the treatment outcomes. This study unlocks new paradigms to provide a versatile OMA-based scaffold for future practical applications. This article is protected by copyright. All rights reserved.
    Keywords:  cancer treatment; glutathione depletion; organic metal adjuvants; photoacoustic imaging; photothermal immunotherapy
    DOI:  https://doi.org/10.1002/adma.202201706
  61. Curr Org Synth. 2022 Mar 29.
    A review on the design, synthesis, and structure-activity relationships of benzothiazole derivatives against hypoxic tumors.
    Akif Hakan Kurt, Lokman Ayaz, Furkan Ayaz, Zeynel Seferoglu, Yahya Nural.
      There has been a growing body of studies on benzothiazoles and benzothiazole derivatives as strong and effective antitumor agents against lung, liver, pancreas, breast, and brain tumors. Due to highly proliferative nature of the tumor cells, the oxygen levels get lower than that of a normal tissue in the tumor microenvironment. This situation is called as hypoxia and has been associated with increased ability for carcinogenesis. For the drug design and development strategies, hypoxic nature of the tumor tissues has been exploited more aggressively. Hypoxia itself acts as a signal initiating system to activate the pathways that eventually lead to the spread of the tumor cells into the different tissues, increases the rate of DNA damage and eventually ends up with more mutation levels that may increase the drug resistance. As one of the major mediators of hypoxic response, hypoxia inducible factors (HIFs) has been shown to activate to angiogenesis, metastasis, apoptosis resistance, and many other protumorigenic responses in cancer development. In the current review, we will be discussing the design, synthesis and structure-activity relationships of benzothiazole derivatives against hypoxic tumors such lung, liver, pancreas, breast and brain as potential anticancer drug candidates. The focus points of the study will be the biology behind carcinogenesis and how hypoxia contributes to the process, recent studies on benzothiazole and its derivatives as anti-cancer agents against hypoxic cancers, conclusions and future perspectives. We believe that this review will be useful for the researchers in the field of drug design during their studies to generate novel benzothiazole-containing hybrids against hypoxic tumors with higher efficacies.
    Keywords:  Anticancer activity; Benzothiazole; Heterocyclic compounds; Hypoxia; Organic Synthesis.
    DOI:  https://doi.org/10.2174/1570179419666220330001036
  62. Pharm Dev Technol. 2022 Mar 30. 1-21
    pH/Enzyme dual sensitive and nucleus-targeting dendrimer nanoparticles to enhance the antitumour activity of doxorubicin.
    Zi-Yan Wu, Jian-Min Shen, Hao Lang, Ting Yue, Chan Sun.
      Direct delivery of drugs into the nucleus is a promising nanotechnology therapy, since the nucleus is one of the most important organelles controlling cell proliferation and apoptosis. Here, we report a nucleus-targeting nanocarrier for nuclear drug delivery using a pH/enzyme dual sensitive strategy. The specific ligand PGM (PKKKRKV-GFLG-Mp), composed of nuclear localization sequence (PKKKRKV), enzyme-sensitive tetrapeptide (Gly-Phe-Leu-Gly, GFLG), and pH-sensitive molecules morpholine (Mp), was modified on poly (amidoamine) (PAMAM) by maleimide active polyethylene glycol ester (NHS-PEG-MAL) to form PAMAM-PEG-PGM. Doxorubicin (DOX) was loaded into the cavity of PAMAM to prepare DOX/PAMAM-PEG-PGM. In vitro release study suggested DOX release from DOX/PAMAM-PEG-PGM nanoparticles followed pH and enzyme-triggered manner. In vitro studies showed DOX/PAMAM-PEG-PGM nanoparticles could not only promote cell internalization through the charge switching of morpholine, but also achieve nuclear internalization by the mediation of composite formed by NLS and importin α/β receptor. Further, employing H22 tumour-bearing BALB/c mice as a model, the systemic distribution and anticancer effects of nanoparticles were studied in vivo. The results indicated the nanoparticles could preferentially accumulate in the tumour site in vivo, and the tumour inhibition rate was 88.47%. In short, the nanoparticles developed could be promising in application to nucleus-targeting therapy to enhance antitumour activity.
    Keywords:  Drug delivery; Nanotechnology therapy; Nucleus targeting; Poly (amidoamine); pH/Enzyme dual sensitive
    DOI:  https://doi.org/10.1080/10837450.2022.2055569
  63. Crit Rev Food Sci Nutr. 2022 Mar 31. 1-18
    Applications of algae to obtain healthier meat products: A critical review on nutrients, acceptability and quality.
    Min Wang, Jianjun Zhou, Jéssica Tavares, Carlos A Pinto, Jorge A Saraiva, Miguel A Prieto, Hui Cao, Jianbo Xiao, Jesus Simal-Gandara, Francisco J Barba.
      Meat constitutes one the main protein sources worldwide. However, ethical and health concerns have limited its consumption over the last years. To overcome this negative impact, new ingredients from natural sources are being applied to meat products to obtain healthier proteinaceous meat products. Algae is a good source of unsaturated fatty acids, proteins, essential amino acids, and vitamins, which can nutritionally enrich several foods. On this basis, algae have been applied to meat products as a functional ingredient to obtain healthier meat-based products. This paper mainly reviews the bioactive compounds in algae and their application in meat products. The bioactive ingredients present in algae can give meat products functional properties such as antioxidant, neuroprotective, antigenotoxic, resulting in healthier foods. At the same time, algae addition to foods can also contribute to delay microbial spoilage extending shelf-life. Additionally, other algae-based applications such as for packaging materials for meat products are being explored. However, consumers' acceptance for new products (particularly in Western countries), namely those containing algae, not only depends on their knowledge, but also on their eating habits. Therefore, it is necessary to further explore the nutritional properties of algae-containing meat products to overcome the gap between new meat products and traditional products, so that healthier algae-containing meat can occupy a significant place in the market.
    Keywords:  Algae; bioactive compounds; healthier meat product; nutritional
    DOI:  https://doi.org/10.1080/10408398.2022.2054939
  64. Mol Pharm. 2022 Mar 29.
    A Facile Way To Improve the Bioavailability of Nanomedicine Based on the Threshold Theory.
    Huihui Zhang, Pengfei Cui, Zihan Gao, Shuwen Zhou, Cheng Wang, Pengju Jiang, Xinye Ni, Jianhao Wang, Lin Qiu.
      One of the most significant barriers to the clinical transformation of nanomedicines is low drug distribution in solid tumors due to quick clearance of nanomedicine after injection. Studies have revealed that the distribution of nanomedicine in tumor sites can be considerably improved when the number of nanoparticles supplied in a short period surpasses the threshold. Most routinely employed nanomaterials have dose-related safety concerns. To resolve this problem, we use highly biocompatible albumin to construct blank nanoparticles and doxorubicin loading nanoparticles. Under the guidance of the threshold theory, when the quantity of drug loading nanoparticles is constant, the drug delivery effectiveness improves with the addition of blank nanoparticles. This enhanced impact was verified both in vitro and in vivo. The area under the curve of the high dose group (19.5 × 1011) is 2.5 times higher than that of the low dose group (6.5 × 1011). In addition, the drug distribution of the high dose group at the tumor site was also improved by 1.5 times compared with the low dose group. The results of histopathological sections also showed that the administration of excess blank nanoparticles within 24 h has no damage to the animals. This study contributes to the clinical transition of nanomedicine by providing fresh ideas for anticancer nanomedicine research.
    Keywords:  bioavailability; nanomedicine; threshold theory
    DOI:  https://doi.org/10.1021/acs.molpharmaceut.2c00137
  65. Front Pharmacol. 2022 ;13 826712
    Prunus mira Koehne in Sichuan, China: Recorded History as a Medicine and Food, Modern Applications, Distribution, and Ethnobotanical Investigations.
    Jingwen Zhang, Wanyue Chen, Weijun Sun, You Zhou, Xiaoli Li, Jing Zhang, Gang Fan, Hongxiang Yin, Ju Qin, Yongcui Yuan, Wei Xu, Zhang Wang.
      Prunus mira Koehne, a Prunus plant in the Rosaceae family, is named ཁམབུ། in Tibetan and "Guang he tao" in Chinese. It is mainly distributed in Tibet Autonomous Region, Yunnan Province, and Sichuan Province in China. It is also a rare "living fossil group" of peach genetic resources in the world. It is used in traditional Chinese medicine for the treatment of dysmenorrhea, injury, intestinal dryness, constipation, and other diseases, and is used in Tibetan medicine for the treatment of hair, eyebrows, and beard shedding. In this article, the botanical characteristics, medicinal history, modern applied research, and ethnobotanical investigation of P. mira were recorded and evaluated. P. mira was first recorded in Dumu Materia Medica. P. mira in Sichuan Province is mainly distributed in Ganzi Tibetan Autonomous Prefecture, and has certain economic and medicinal value. P. mira has high nutritional composition. It is made into high-quality edible oil, cosmetic base oil, fruit juice, fruit wine, fruit vinegar, "Liang guo", and other products. Oleic acid and linoleic acid are the main fat-soluble components of P. mira, which has an anti-inflammatory medicinal value and promotes hair growth. Its longevity and cold resistance can bring great genetic value and play an important role in maintaining peach genetic diversity. At present, there are few studies on the pharmacological effects of specific active components of P. mira and there are also few clinical studies. We can continue to study these aspects in the future. At the same time, products of P. mira have great market potential. All in all, P. mira is very worthy of further research and development.
    Keywords:  Prunus mira Koehne; botanical charateristics; ethnobotanical investigation; medicinal and edible; medicinal record history; modern research and application; traditional Chinese medicine
    DOI:  https://doi.org/10.3389/fphar.2022.826712
  66. Part Fibre Toxicol. 2022 Mar 29. 19(1): 24
    Ultrasmall iron oxide nanoparticles cause significant toxicity by specifically inducing acute oxidative stress to multiple organs.
    Lin Wu, Wen Wen, Xiaofeng Wang, Danhua Huang, Jin Cao, Xueyong Qi, Song Shen.
      BACKGROUND: Iron oxide nanoparticles have been approved by food and drug administration for clinical application as magnetic resonance imaging (MRI) and are considered to be a biocompatible material. Large iron oxide nanoparticles are usually used as transversal (T2) contrast agents to exhibit dark contrast in MRI. In contrast, ultrasmall iron oxide nanoparticles (USPIONs) (several nanometers) showed remarkable advantage in longitudinal (T1)-weighted MRI due to the brighten effect. The study of the toxicity mainly focuses on particles with size of tens to hundreds of nanometers, while little is known about the toxicity of USPIONs.RESULTS: We fabricated Fe3O4 nanoparticles with diameters of 2.3, 4.2, and 9.3 nm and evaluated their toxicity in mice by intravenous injection. The results indicate that ultrasmall iron oxide nanoparticles with small size (2.3 and 4.2 nm) were highly toxic and were lethal at a dosage of 100 mg/kg. In contrast, no obvious toxicity was observed for iron oxide nanoparticles with size of 9.3 nm. The toxicity of small nanoparticles (2.3 and 4.2 nm) could be reduced when the total dose was split into 4 doses with each interval for 5 min. To study the toxicology, we synthesized different-sized SiO2 and gold nanoparticles. No significant toxicity was observed for ultrasmall SiO2 and gold nanoparticles in the mice. Hence, the toxicity of the ultrasmall Fe3O4 nanoparticles should be attributed to both the iron element and size. In the in vitro experiments, all the ultrasmall nanoparticles (< 5 nm) of Fe3O4, SiO2, and gold induced the generation of the reactive oxygen species (ROS) efficiently, while no obvious ROS was observed in larger nanoparticles groups. However, the ·OH was only detected in Fe3O4 group instead of SiO2 and gold groups. After intravenous injection, significantly elevated ·OH level was observed in heart, serum, and multiple organs. Among these organs, heart showed highest ·OH level due to the high distribution of ultrasmall Fe3O4 nanoparticles, leading to the acute cardiac failure and death.
    CONCLUSION: Ultrasmall Fe3O4 nanoparticles (2.3 and 4.2 nm) showed high toxicity in vivo due to the distinctive capability in inducing the generation of ·OH in multiple organs, especially in heart. The toxicity was related to both the iron element and size. These findings provide novel insight into the toxicology of ultrasmall Fe3O4 nanoparticles, and also highlight the need of comprehensive evaluation for their clinic application.
    Keywords:  Iron oxide; Oxidative stress; ROS; Toxicity; Ultrasmall nanoparticles
    DOI:  https://doi.org/10.1186/s12989-022-00465-y
  67. Oncol Rep. 2022 May;pii: 101. [Epub ahead of print]47(5):
    Research progress of anti-glioma chemotherapeutic drugs (Review).
    Yi-Shu Zhou, Wei Wang, Na Chen, Li-Cui Wang, Jin-Bai Huang.
      Glioma is the most common primary intracranial malignancy in the central nervous system. At present, the most important treatment option is surgical resection of the tumor combined with radiotherapy and chemotherapy. The principle of operation is to remove the tumor to the maximal extent on the basis of preserving brain function. However, prominent invasive and infiltrative proliferation of glioma tumor cells into the surrounding normal tissues frequently reduces the efficacy of treatment. This in turn worsens the prognosis, because the tumor cannot be completely removed, which can readily relapse. Chemotherapeutic agents when applied individually have demonstrated limited efficacy for the treatment of glioma. However, multiple different chemotherapeutic agents can be used in combination with other treatment modalities to improve the efficacy while circumventing systemic toxicity and drug resistance. Therefore, it is pivotal to unravel the inhibitory mechanism mediated by the different chemotherapeutic drugs on glioma cells in preclinical studies. The aim of the present review is to provide a summary for understanding the effects of different chemotherapeutic drugs in glioma, in addition to providing a reference for the preclinical research into novel chemotherapeutic agents for future clinical application.
    Keywords:  action mechanism; brain; chemotherapeutic drugs; combination therapy; glioma
    DOI:  https://doi.org/10.3892/or.2022.8312
  68. Macromol Rapid Commun. 2022 Mar 28. e2200007
    Advances in the stimuli-responsive injectable hydrogel for controlled release of drugs.
    Chunxiang Mo, Rui Luo, Yuping Chen.
      The stimuli-responsiveness of injectable hydrogel has been drastically developed for the controlled release of drugs and achieved encouraging curative effects in a variety of diseases including wounds, cardiovascular diseases and tumors. The gelation, swelling and degradation of such hydrogels respond to endogenous biochemical factors (such as pH, reactive oxygen species, glutathione, enzymes, glucose) and/or to exogenous physical stimulations (like light, magnetism, electricity and ultrasound), thereby accurately releasing loaded drugs in response to specifically pathological status and as desired for treatment plan and thus improving therapeutic efficacy effectively. In this paper, we give a detailed introduction of recent progresses in responsive injectable hydrogels and focus on the design strategy of various stimuli-sensitivities and their resultant alteration of gel dissociation and drug liberation behaviour. Their application in disease treatment is also discussed. This article is protected by copyright. All rights reserved.
    Keywords:  drug delivery; injectable hydrogel; stimuli-responsive
    DOI:  https://doi.org/10.1002/marc.202200007
  69. ACS Appl Mater Interfaces. 2022 Mar 29.
    Spiky Cascade Biocatalysts as Peroxisome-Mimics for Ultrasound-Augmented Tumor Ablation.
    Hongmei Yuan, Lingyan Zhang, Tian Ma, Jianbo Huang, Chuanxiong Nie, Sujiao Cao, Xi Xiang, Lang Ma, Chong Cheng, Li Qiu.
      Ultrasound (US)-augmented tumor ablation with sono-catalysts has emerged as a promising therapeutic modality due to high tissue penetration, nonionizing performance, and low cost of US-based therapies. Developing peroxisome-mimetic cascade biocatalysts for US-augmented synergistic treatment would further effectively reduce the dependence of the microenvironment H2O2 and enhance the tumor-localized reactive oxygen species (ROS) generation. Here, we proposed and synthesized a novel spiky cascade biocatalyst as peroxisome-mimics that consist of multiple enzyme-mimics, i.e., glucose oxidase-mimics (Au nanoparticles for producing H2O2) and heme-mimetic atomic catalytic centers (Fe-porphyrin for ROS generation), for US-augmented cascade-catalytic tumor therapy. The synthesized spiky cascade biocatalysts exhibit an obvious spiky structure, uniform nanoscale size, independent of endogenous H2O2, and efficient US-responsive biocatalytic activities. The enzyme-mimetic biocatalytic experiments show that the spiky cascade biocatalysts can generate abundant ·OH via a cascade chemodynamic path and also 1O2 via US excitation. Then, we demonstrate that the spiky cascade biocatalysts show highly efficient ROS production to promote melanoma cell apoptosis under US irradiation without extra H2O2. Our in vivo animal data further reveal that the proposed US-assisted chemodynamic cascade therapies can significantly augment the therapy efficacy of malignant melanoma. We suggest that these efficient peroxisome-mimetic cascade-catalytic strategies will be promising for clinical tumor therapies.
    Keywords:  cascade biocatalysts; nanocatalytic tumor therapy; reactive oxygen species; sonodynamic therapy; spiky nanostructures
    DOI:  https://doi.org/10.1021/acsami.1c25072
  70. Br J Cancer. 2022 Apr 01.
    5-Aminolevulinic acid overcomes hypoxia-induced radiation resistance by enhancing mitochondrial reactive oxygen species production in prostate cancer cells.
    Takuya Owari, Nobumichi Tanaka, Yasushi Nakai, Makito Miyake, Satoshi Anai, Shingo Kishi, Shiori Mori, Rina Fujiwara-Tani, Yudai Hojo, Takuya Mori, Masaomi Kuwada, Tomomi Fujii, Masatoshi Hasegawa, Kiyohide Fujimoto, Hiroki Kuniyasu.
      BACKGROUND: The naturally occurring amino acid 5-aminolevulinic acid (5-ALA) is a precursor of protoporphyrin IX (PpIX) biosynthesised in the mitochondria. When accumulated PpIX is excited by light (wavelength of 625-635 nm), reactive oxygen species (ROS) are generated. Here, we investigated whether 5-ALA may increase the sensitisation of prostate cancer (PCA) cells to radiotherapy through the generation of ROS via its metabolite, PpIX.METHODS: Effect of 5-ALA on PC-3 and DU-145 PCA cell lines treated with ionising radiation (IR) was examined in vitro and in vivo with assessment by clonogenic assay, mitochondrial function and ROS production under normoxia or hypoxia condition.
    RESULTS: 5-ALA enhanced intra-mitochondrial ROS production immediately after exposure to IR and decreased mitochondrial membrane potential via increase of intra-cellular PpIX. IR with 5-ALA induced mitochondrial dysfunction and increased ATP production, switching energy metabolism to the quiescence. Under hypoxic condition, ROS burst and mitochondrial dysfunction were induced by IR with 5-ALA resulting reducing cancer stemness and radiation resistance.
    CONCLUSION: These results suggest that combined therapy with 5-ALA and radiation therapy is a novel strategy to improve the anti-cancer effects of radiation therapy for PCA.
    DOI:  https://doi.org/10.1038/s41416-022-01789-4
  71. Toxicol Appl Pharmacol. 2022 Mar 27. pii: S0041-008X(22)00147-8. [Epub ahead of print] 116002
    Alteration in glucose metabolism in the brain associated with tamoxifen treatment: Study in postmenopausal animal model.
    Suélyn Koerich, Fernanda Coleraus Silva, Ana Maria Itinose, Paula Maria Quaglio Bellozi, Fabiano Sandrini, Sara Cristina Sagae Schneider, Carla Brugin Marek.
      Tamoxifen is an effective breast cancer therapy in postmenopausal women. However, it can induce hyperglycemia through different mechanisms, such as the impairment of mitochondrial metabolism. Quercetin, a flavonoid with antioxidant potential, has beneficial effects on tamoxifen-induced adverse effects. Therefore, this study aimed to (1) investigate glucose concentration in blood, cerebrospinal fluid, cerebellum, cortex, and hippocampus of tamoxifen-treated ovariectomized female rats, non-treated and treated with quercetin; and (2) establish the metabolic profile of these regions. For that purpose, ovariectomized female rats were divided into four groups: canola oil 1 mL/kg (CONT); tamoxifen 5 mg/kg (TAM); quercetin 22.5 mg/kg (QUER); and tamoxifen 5 mg/kg + quercetin 22.5 mg/kg (TAM + Q); and were treated for 14 days orally. Subsequently, glucose levels were measured in blood, cerebrospinal fluid, cerebellum, cortex, and hippocampus. Pyruvate and lactate concentrations were analyzed in the three brain regions. Tamoxifen-induced hyperglycemia significantly increased glucose concentrations in the cerebrospinal fluid, cortex, and hippocampus, as well as lactate production in the hippocampus. Quercetin significantly prevented the tamoxifen-induced increase in glucose concentrations in all analyzed samples. Besides, quercetin decreased cortical pyruvate production. The copper content decreased only in the hippocampus of group TAM + Q animals. In addition, it is important to highlight that this study also observed that fourteen days of tamoxifen treatment strongly affects brain glucose metabolism, potentially disrupting normal brain functions. Therefore, this drug might represent a risk factor for postmenopausal women undergoing chemoprevention. Meanwhile, quercetin represents a potential intervention to promote metabolic regulation of glucose in tamoxifen-treated women.
    Keywords:  Flavonoids; Hyperglycemia; Neurodegeneration; Postmenopausal women; Quercetin; Tamoxifen
    DOI:  https://doi.org/10.1016/j.taap.2022.116002
  72. ACS Appl Bio Mater. 2022 Mar 31.
    Recent Advances and Mechanistic Insights into Antibacterial Activity, Antibiofilm Activity, and Cytotoxicity of Silver Nanoparticles.
    Neetu Tripathi, Manoj Kumar Goshisht.
      The substantial increase in multidrug-resistant (MDR) pathogenic bacteria is a major threat to global health. Recently, the Centers for Disease Control and Prevention reported possibilities of greater deaths due to bacterial infections than cancer. Nanomaterials, especially small-sized (size ≤10 nm) silver nanoparticles (AgNPs), can be employed to combat these deadly bacterial diseases. However, high reactivity, instability, susceptibility to fast oxidation, and cytotoxicity remain crucial shortcomings for their uptake and clinical application. In this review, we discuss various AgNPs-based approaches to eradicate bacterial infections and provide comprehensive mechanistic insights and recent advances in antibacterial activity, antibiofilm activity, and cytotoxicity (both in vitro and in vivo) of AgNPs. The mechanistic of antimicrobial activity involves four steps: (i) adhesion of AgNPs to cell wall/membrane and its disruption; (ii) intracellular penetration and damage; (iii) oxidative stress; and (iv) modulation of signal transduction pathways. Numerous factors affecting the bactericidal activity of AgNPs such as shape, size, crystallinity, pH, and surface coating/charge have also been described in detail. The review also sheds light on antimicrobial photodynamic therapy and the role of AgNPs versus Ag+ ions release in bactericidal activities. In addition, different methods of synthesis of AgNPs have been discussed in brief.
    Keywords:  antibacterial/antibiofilm activity; bacteria; bacterial infections; biofilm; cytotoxicity; membrane; reactive oxygen species; silver nanoparticles/ions
    DOI:  https://doi.org/10.1021/acsabm.2c00014
  73. Curr Pharm Des. 2022 Mar 28.
    Nanomaterials-based drug delivery approaches for wound healing.
    Aswathy Ravindran Girija, Sivakumar Balasubramanian, Allison J Cowin.
      Wound healing is a complex and dynamic process that requires intricate synchronization between multiple cell types within appropriate extracellular microenvironment. Wound healing process involves four overlapping phases in a precisely regulated manner, consisting of hemostasis, inflammation, proliferation, and maturation. For an effective wound healing all four phases must follow in a sequential pattern within a time frame. Several factors might interfere with one or more of these phases in healing process, thus causing improper or impaired wound healing resulting in non-healing chronic wounds. The complications associated with chronic non-healing wounds, along with the limitations of existing wound therapies, have led to the development and emergence of novel and innovative therapeutic interventions. Nanotechnology presents unique and alternative approaches to accelerate the healing of chronic wounds by the interaction of nanomaterials during different phases of wound healing. This review focuses on recent innovative nanotechnology-based strategies for wound healing and tissue regeneration based on nanomaterials, including nanoparticles, nanocomposites and scaffolds. The efficacy of the intrinsic therapeutic potential of nanomaterials (including silver, gold, zinc oxide, copper, cerium oxide, etc.) and the ability of nanomaterials as carriers (liposomes, hydrogels, polymeric nanomaterials, nanofibers) as therapeutic agents associated with wound-healing applications have also been addressed. The significance of these nanomaterial-based therapeutic interventions for wound healing needs to be highlighted to engage researchers and clinicians towards this new and exciting area of bio-nanoscience. We believe that these recent developments will offer researchers an updated source on the use of nanomaterials as an advanced approach to improve wound healing.
    Keywords:  Wound healing; chronic wounds; drug delivery; nano-scaffolds.; nanocarriers; nanoparticles; nanotechnology; polymeric nanoparticles
    DOI:  https://doi.org/10.2174/1381612828666220328121211
  74. Phytomedicine. 2022 Mar 21. pii: S0944-7113(22)00141-6. [Epub ahead of print]100 154063
    Recent advances in nuclear receptors-mediated health benefits of blueberry.
    Haoyang Zou, Haiqing Ye, Jie Zhang, Li Ren.
      BACKGROUND: Blueberry is rich in bioactive substances and has anti-oxidant, anti-inflammatory, anti-obesity, anti-cancer, neuroprotective, and other activities. Blueberry has been shown to treat diseases by mediating the transcription of nuclear receptors. However, evidence for nuclear receptor-mediated health benefits of blueberry has not been systematically reviewed.PURPOSE: This review aims to summarize the nuclear receptor-mediated health benefits of blueberry.
    METHODS: This study reviews all relevant literature published in NCBI PubMed, Scopus, Web of Science, and Google Scholar by January 2022. The relevant literature was extracted from the databases with the following keyword combinations: "biological activities" OR "nuclear receptors" OR "phytochemicals" AND "blueberry" OR "Vaccinium corymbosum" as well as free-text words.
    RESULTS: In vivo and in vitro experimental results and clinical evidence have demonstrated that blueberry has health-promoting effects. Supplementing blueberry is beneficial to the treatment of cancer, the alleviation of metabolic syndrome, and liver protection. Blueberry can regulate the transcription of PPARs, ERs, AR, GR, MR, LXRs, and FXR and mediate the expressions of Akt, CYP 1Al, p53, and Bcl-2.
    CONCLUSION: Blueberry can be targeted to treat various diseases by mediating the transcription of nuclear receptors. Nevertheless, further human research is needed.
    Keywords:  Active ingredients; Blueberry; Health benefits; Nuclear receptors
    DOI:  https://doi.org/10.1016/j.phymed.2022.154063
  75. J Nanobiotechnology. 2022 Mar 27. 20(1): 161
    Biomimetic GBM-targeted drug delivery system boosting ferroptosis for immunotherapy of orthotopic drug-resistant GBM.
    Bao Liu, Qifeng Ji, Ying Cheng, Miao Liu, Bangle Zhang, Qibing Mei, Daozhou Liu, Siyuan Zhou.
      BACKGROUND: Clinical studies have shown that the efficacy of programmed cell death receptor-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitors on glioblastoma (GBM) is much lower than what is expected because of the low immunogenicity of GBM. Ferroptosis of cancer cells can induce the maturation of dendritic cells (DC cells) and increase the activity of T cell. The activated T cells release IFN-γ, which subsequently induces the ferroptosis of cancer cells. Thus, the aim of this paper is to set up a new GBM-targeted drug delivery system (Fe3O4-siPD-L1@M-BV2) to boost ferroptosis for immunotherapy of drug-resistant GBM.RESULTS: Fe3O4-siPD-L1@M-BV2 significantly increased the accumulation of siPD-L1 and Fe2+ in orthotopic drug-resistant GBM tissue in mice. Fe3O4-siPD-L1@M-BV2 markedly decreased the protein expression of PD-L1 and increased the ratio between effector T cells and regulatory T cells in orthotopic drug-resistant GBM tissue. Moreover, Fe3O4-siPD-L1@M-BV2 induced ferroptosis of GBM cells and maturation of DC cell, and it also increased the ratio between M1-type microglia and M2-type microglia in orthotopic drug-resistant GBM tissue. Finally, the growth of orthotopic drug-resistant GBM in mice was significantly inhibited by Fe3O4-siPD-L1@M-BV2.
    CONCLUSION: The mutual cascade amplification effect between ferroptosis and immune reactivation induced by Fe3O4-siPD-L1@M-BV2 significantly inhibited the growth of orthotopic drug-resistant GBM and prolonged the survival time of orthotopic drug-resistant GBM mice.
    Keywords:  Drug-resistant glioblastoma; Ferroptosis; Glioblastoma; Immunotherapy; Microglia; siPD-L1
    DOI:  https://doi.org/10.1186/s12951-022-01360-6
  76. J Microencapsul. 2022 Mar 30. 1-27
    Vinblastine Loaded On Graphene Quantum Dots And Its Anticancer Applications.
    Thi Hang Au, Bich Ngoc Nguyen, Phuong Hoa Nguyen, Stephanie Pethe, Vo-Thanh Giang, Thi Vu Thu Ha.
      AIMS: The aim of our work is to load Vinblastine drug loaded on graphene quantum dots to improve its cytotoxicity on cancer cells and reduce it on normal cell in the composites. Moreover, GQDs-Vin composite significantly inhibited the tumor growth in animals.METHODS: GQDs-Vin composites were prepared by homogenization of GQDs and Vin solutions. The loading of Vin on GQDs in the composites were characterized by FTIR, PL, UV-vis spectra, and TEM. The cytotoxicity of GQDs, Vin, and GQDs-Vin composites was investigated on the Hela, HGC-27, A549, MCF-7, CCF-STTG1 cells and Vero by in vitro and in vivo methods. The difference in cellular structure and organelles in mice's livers in comparison between control group and GQDs-Vin (1:5) groups was characterized by TEM.
    RESULTS: The diameter of the nanoparticles of GQDs-Vin composites in weight ratios 1:1, 1:3 and 1:5 w/w of 50-70 nm, 100-150 nm and ∼500nm, respectively, is larger than that of GQDs of 10-50nm. The in vitro results showed that GQDs not only improved the cytotoxicity of Vin to cancer cells, but also decreased its cytotoxicity towards normal cells in the composites. The GQDs-Vin (1:5) composite exhibited a stronger tumor inhibition effect than Vin alone. The morphology of mice's livers showed the absence GQDs-Vin nanoparticles in the mice's livers suggests the lack of storage and the leakage from the liver without any toxicity.
    CONCLUSIONS: Results of the improved cytotoxicity of GQDs-Vin composite on cancer cells, its reduced cytotoxicity on normal cell and the significant inhibition on tumor growth of GQDs-Vin composite compared with Vin and GQDs alone may indicate a synergistic effect of Vin and GQDs in their composites for anticancer application.
    Keywords:  Vinblastine; cancer cell; composite; cytotoxicity; graphene quantum dots
    DOI:  https://doi.org/10.1080/02652048.2022.2060361
  77. Mol Biol Rep. 2022 Mar 28.
    Review on NAD(P)H dehydrogenase quinone 1 (NQO1) pathway.
    S Preethi, K Arthiga, Amit B Patil, Asha Spandana, Vikas Jain.
      NQO1 is an enzyme present in humans which is encoded by NQO1 gene. It is a protective antioxidant agent, versatile cytoprotective agent and regulates the oxidative stresses of chromatin binding proteins for DNA damage in cancer cells. The oxidization of cellular pyridine nucleotides causes structural alterations to NQO1 and changes in its capacity to binding of proteins. A strategy based on NQO1 to have protective effect against cancer was developed by organic components to enhance NQO1 expression. The quinone derivative compounds like mitomycin C, RH1, E09 (Apaziquone) and β-lapachone causes cell death by NQO1 reduction of two electrons. It was also known to be overexpressed in various tumor cells of breast, lung, cervix, pancreas and colon when it was compared with normal cells in humans. The mechanism of NQO1 by the reduction of FAD by NADPH to form FADH2 is by two ways to inhibit cancer cell development such as suppression of carcinogenic metabolic activation and prevention of carcinogen formation. The NQO1 exhibit suppression of chemical-mediated carcinogenesis by various properties of NQO1 which includes, detoxification of quinone scavenger of superoxide anion radical, antioxidant enzyme, protein stabilizer. This review outlines the NQO1 structure, mechanism of action to inhibit the cancer cell, functions of NQO1 against oxidative stress, drugs acting on NQO1 pathways, clinical significance.
    Keywords:  Cancer; DNA damage; FAD; NADPH; NQO1; Quinone
    DOI:  https://doi.org/10.1007/s11033-022-07369-2
  78. Sheng Wu Gong Cheng Xue Bao. 2022 Mar 25. 38(3): 976-989
    [Applications and perspectives of ketone body D-β-hydroxybutyrate in the medical fields].
    Liya A, Zihua Li, Jinyan Lü, Liusong Yu, Wei Situ, Lingyun Xue, Hui Wang, Guoqiang Chen.
      Human body can obtain energy from either carbohydrate or fat digestion. Although glucose metabolism derived from carbohydrate-based diets has long been utilized for energy supply, it has been recently discovered that shifting from glucose to fatty acid metabolism may become a novel way for improving human health especially when carbohydrate is deprived. In recent years, intermittent fasting and ketogenic diets have received a lot of attention in respect to favoring fatty acid metabolism. In all cases, fatty acid metabolism produces D-β-hydroxybutyrate (D3HB), which is a natural ketone body, as well as, a monomer of microbial poly-D-β-hydroxybutyrate (PHB). D3HB can be utilized by different cells of the body as an alternative energy fuel or an intracellular signaling molecule with multiple downstream signaling pathways. Usually, the serum level of D3HB is increased during ketogenic diets, however, requires a very long period of adaptation (over 3-months) and exhibits unwanted adverse effects. Hence, exogenous ketone supplements using D3HB have become a more effective approach to induce and maintain nutritional ketosis for subsequent functional effects. This review describes how D3HB is produced and metabolized within the body, the functional roles played by D3HB, and a detailed summary of the different applications of exogenous ketones that have been explored to date in both nutritional and therapeutical context.
    Keywords:  D-β-hydroxybutyrate; D3HB; PHB; biosynthesis; exogenous ketones; ketone metabolism; nutritional ketosis
    DOI:  https://doi.org/10.13345/j.cjb.210343
  79. ACS Omega. 2022 Mar 22. 7(11): 9452-9464
    Hispolon-Loaded Liquid Crystalline Nanoparticles: Development, Stability, In Vitro Delivery Profile, and Assessment of Hepatoprotective Activity in Hepatocellular Carcinoma.
    Mohammad Javed Ansari, Mahfoozur Rahman, Khalid S Alharbi, Waleed M Altowayan, Ahmed Mahmoud Abdelhaleem Ali, Waleed H Almalki, Md Abul Barkat, Tanuja Singh, Shehla Nasar, Md Habban Akhter, Sarwar Beg, Hani Choudhry.
      The present work describes the development and characterization of liquid crystalline nanoparticles of hispolon (HP-LCNPs) for treating hepatocellular carcinoma. HP-LCNPs were prepared by a top-down method utilizing GMO as the lipid and Pluronic F-127 as the polymeric stabilizer. The prepared formulations (HP1-HP8) were tested for long-term stability, where HP5 showed good stability with a particle size of 172.5 ± 0.3 nm, a polydispersity index (PDI) of 0.38 ± 0.31 nm, a zeta potential of -10.12 mV ± 0.05, an entrapment efficiency of 86.81 ± 2.5%, and a drug loading capacity of 12.51 ± 1.12%. Optical photomicrography and transmission electron microscopy images demonstrated a consistent, low degree of aggregation and a spherical shape of LCNPs. The effect of temperature and pH on the optimized formulation (HP5) indicated good stability at 45 °C and at pH between 2 and 5. In vitro gastrointestinal stability indicated no significant change in the particle size, PDI, and entrapment efficiency of the drug. The drug release study exhibited a biphasic pattern in simulated gastric fluid (pH 1.2) for 2 h and simulated intestinal fluid (pH 7.4) for up to 24 h, while the best fitting of the profile was observed with the Higuchi model, indicating the Fickian diffusion mechanism. The in vivo pharmacokinetic study demonstrated nearly 4.8-fold higher bioavailability from HP5 (AUC: 1774.3 ± 0.41 μg* h/mL) than from the HP suspension (AUC: 369.11 ± 0.11 μg* h/mL). The anticancer activity evaluation revealed a significant improvement in antioxidant parameters and serum hepatic biomarkers (SGOT, SGPT, ALP, total bilirubin, and GGT) in the diethyl nitrosamine-treated group of rats with the optimized LCNP formulation (HP5) vis-à-vis HP suspension.
    DOI:  https://doi.org/10.1021/acsomega.1c06796
  80. Front Pharmacol. 2022 ;13 829590
    CD44/Folate Dual Targeting Receptor Reductive Response PLGA-Based Micelles for Cancer Therapy.
    Ru Zhang, Yunying Jiang, Linkun Hao, Yang Yang, Ying Gao, Ningning Zhang, Xuecheng Zhang, Yimin Song.
      In this study, a novel poly (lactic-co-glycolic acid) (PLGA)-based micelle was synthesized, which could improve the therapeutic effect of the antitumor drug doxorubicin hydrochloride (DOX) and reduce its toxic and side effects. The efficient delivery of DOX was achieved by active targeting mediated by double receptors and stimulating the reduction potential in tumor cells. FA-HA-SS-PLGA polymer was synthesized by amidation reaction, and then DOX-loaded micelles were prepared by dialysis method. The corresponding surface method was used to optimize the experimental design. DOX/FA-HA-SS-PLGA micelles with high drug loading rate and encapsulation efficiency were prepared. The results of hydrophilic experiment, critical micelle concentration determination, and hemolysis test all showed that DOX/FA-HA-SS-PLGA micelles had good physicochemical properties and biocompatibility. In addition, both in vitro reduction stimulus response experiment and in vitro release experiment showed that DOX/FA-HA-SS-PLGA micelles had reduction sensitivity. Molecular docking experiments showed that it can bind to the target protein. More importantly, in vitro cytology studies, human breast cancer cells (MCF-7), human non-small cell lung cancer cells (A549), and mouse colon cancer cells (CT26) were used to demonstrate that the dual receptor-mediated endocytosis pathway resulted in stronger cytotoxicity to tumor cells and more significant apoptosis. In and in vivo antitumor experiment, tumor-bearing nude mice were used to further confirm that the micelles with double targeting ligands had better antitumor effect and lower toxicity. These experimental results showed that DOX/FA-HA-SS-PLGA micelles have the potential to be used as chemotherapeutic drugs for precise tumor treatment.
    Keywords:  antitumor; doxorubicin hydrochloride (DOX); dual target; micelles; reduction sensitive; tumor actively targeted
    DOI:  https://doi.org/10.3389/fphar.2022.829590
  81. ACS Appl Mater Interfaces. 2022 Mar 29.
    Skin-Permeable Nano-Lithocholic Lipidoid Efficiently Alleviates Psoriasis-like Chronic Skin Inflammations.
    Hari Krishnareddy Rachamalla, Chandrashekhar Voshavar, Porkizhi Arjunan, Gokulnath Mahalingam, Rashmi Praksash Chowath, Rajkumar Banerjee, Praveen Kumar Vemula, Srujan Marepally.
      Long-term application of topical therapeutics for psoriasis has a plethora of side effects. Additionally, skin-permeating agents used in their formulations for deeper dermal delivery damage the skin. To address these limitations, we developed novel lithocholic acid analogues that could form lipid nanoparticles (nano-LCs) spontaneously in the aqueous milieu, permeate through the skin, penetrate the deeper dermal layers, and exert anti-inflammatory effects against psoriasis-like chronic skin inflammations. Prior findings demonstrated that lithocholic acid acts as a vitamin D receptor agonist without affecting the Ca+2 metabolism and also as an antagonist for ephrin type-A receptor 2 (EphA2). Taking cues from the previous findings, lithocholic acid derivatives with twin alkyl chains (LC6, LC8, LC10, and LC-12) were synthesized, nanoparticles (nano-LCs) were prepared, and they were evaluated for their skin permeability and anti-inflammatory properties. Among these nano-LCs, nano-LC10 demonstrated superior anti-inflammatory properties and inhibition of keratinocyte proliferation in various cell-based evaluations. Furthermore, the therapeutic efficiency of nano-LC10 was evaluated in an imiquimod-induced psoriasis-like mouse model and demonstrated comparable efficiency with the standard topical formulation, Sorvate, in reducing skin inflammations. Nano-LC10 also reduced systemic inflammation, organ toxicity, and also proinflammatory serum cytokine levels. Overall, nano-lithocholic lipidoid (nano-LC10) can be a potential novel class of therapeutics for topical application in treating psoriasis.
    Keywords:  lipid nanoparticles; lithocholic acid analogues; psoriasis; skin permeation; topical applications
    DOI:  https://doi.org/10.1021/acsami.1c19180
  82. Drug Deliv. 2022 Dec;29(1): 970-985
    Targeted delivery of quercetin by biotinylated mixed micelles for non-small cell lung cancer treatment.
    Kangkang Li, Xinlong Zang, Xiangjun Meng, Yanfeng Li, Yi Xie, Xuehong Chen.
      Lung cancer is the leading cause of cancer death world-wide and its treatment remains a challenge in clinic, especially for non-small cell lung cancer (NSCLC). Thus, more effective therapeutic strategies are required for NSCLC treatment. Quercetin (Que) as a natural flavonoid compound has gained increasing interests due to its anticancer activity. However, poor water solubility, low bioavailability, short half-life, and weak tumor accumulation hinder in vivo applications and antitumor effects of Que. In this study, we developed Que-loaded mixed micelles (Que-MMICs) assembled from 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene glycol)-biotin (DSPE-PEG-biotin) and poly(ethylene glycol) methyl ether methacrylate-poly[2-(dimethylamino) ethyl acrylate]-polycaprolactone (PEGMA-PDMAEA-PCL) for NSCLC treatment. The results showed that Que was efficiently encapsulated into the mixed micelles and the encapsulation efficiency (EE) was up to 85.7%. Cellular uptake results showed that biotin conjugation significantly improved 1.2-fold internalization of the carrier compared to that of non-targeted mixed micelles. In vitro results demonstrated that Que-MMICs could improve cytotoxicity (IC50 = 7.83 μg/mL) than Que-MICs (16.15 μg/mL) and free Que (44.22 μg/mL) to A549 cells, which efficiently induced apoptosis and arrested cell cycle. Furthermore, Que-MMICs showed satisfactory tumor targeting capability and antitumor efficacy possibly due to the combination of enhanced permeability and retention (EPR) and active targeting effect. Collectively, Que-MMICs demonstrated high accumulation at tumor site and exhibited superior anticancer activity in NSCLC bearing mice model.
    Keywords:  Mixed micelles; NSCLC; biotin; quercetin; targeted delivery
    DOI:  https://doi.org/10.1080/10717544.2022.2055225
  83. Front Oncol. 2022 ;12 858017
    Imaging Sub-Cellular Methionine and Insulin Interplay in Triple Negative Breast Cancer Lipid Droplet Metabolism.
    Anthony A Fung, Khang Hoang, Honghao Zha, Derek Chen, Wenxu Zhang, Lingyan Shi.
      Triple negative breast cancer (TNBC) is a particularly aggressive cancer subtype that is difficult to diagnose due to its discriminating epidemiology and obscure metabolome. For the first time, 3D spatial and chemometric analyses uncover the unique lipid metabolome of TNBC under the tandem modulation of two key metabolites - insulin and methionine - using non-invasive optical techniques. By conjugating heavy water (D2O) probed Raman scattering with label-free two-photon fluorescence (TPF) microscopy, we observed altered de novo lipogenesis, 3D lipid droplet morphology, and lipid peroxidation under various methionine and insulin concentrations. Quantitative interrogation of both spatial and chemometric lipid metabolism under tandem metabolite modulation confirms significant interaction of insulin and methionine, which may prove to be critical therapeutic targets, and proposes a powerful optical imaging platform with subcellular resolution for metabolic and cancer research.
    Keywords:  DO-SRS; TPF; breast cancer; heavy water; insulin; lipid metabolism; methionine; stimulated Raman scattering
    DOI:  https://doi.org/10.3389/fonc.2022.858017
  84. Phytomedicine. 2022 Mar 15. pii: S0944-7113(22)00122-2. [Epub ahead of print]100 154044
    The pathogenesis and treatment mechanism of Parkinson's disease from the perspective of traditional Chinese medicine.
    Peng Chen, Jie Zhang, Chen Wang, Yi-Hui Chai, An-Guo Wu, Ning-Yu Huang, Long Wang.
      BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disease with no treatment currently available to modify its progression. Traditional Chinese medicine (TCM) has gained attention for its unique theoretical basis and clinical effects. Many studies have reported on the clinical effects and pharmacological mechanisms of Chinese herbs in PD. However, few studies have focused on the treatment mechanisms of anti-PD TCM drugs from the perspective of TCM itself.PURPOSE: To elaborate the treatment mechanisms of anti-PD TCM drugs in the perspective of TCM.
    METHODS: We performed a literature survey using traditional books of Chinese medicine and online scientific databases including PubMed, Web of Science, Google Scholar, China National Knowledge Infrastructure (CNKI), and others up to July 2021.
    RESULTS: TCM theory states that PD is caused by a dysfunction of the zang-fu organs (liver, spleen, kidney, and lung) and subsequent pathogenic factors (wind, fire, phlegm, and blood stasis). Based on the pathogenesis, removing pathogenic factors and restoring visceral function are two primary treatment principles for PD in TCM. The former includes dispelling wind, clearing heat, resolving phlegm, and promoting blood circulation, while the latter involves nourishing the liver and kidney and strengthening the spleen. The anti-PD mechanisms of the active ingredients of TCM compounds and herbs at different levels include anti-apoptosis, anti-inflammation, and anti-oxidative stress, as well as the restoration of mitochondrial function and the regulation of autophagy and neurotransmitters.
    CONCLUSION: Chinese herbs and prescriptions can be used to treat PD by targeting multiple pharmacological mechanisms.
    Keywords:  Chinese medicine; Parkinson's disease; pathogenesis; treatment mechanism
    DOI:  https://doi.org/10.1016/j.phymed.2022.154044
  85. Cancer Sci. 2022 Apr 01.
    Glutamate blunts cell-killing effects of neutrophils in tumor microenvironment.
    Tiantian Xiong, Ping He, Mi Zhou, Dan Zhong, Teng Yang, Wenhui He, Zhizhen Xu, Zongtao Chen, Yang-Wuyue Liu, Shuang-Shuang Dai.
      Neutrophils are the first defenders of innate system for injury and infection. It is gradually recognized as important participants in tumor initiation and development due to heterogeneity and plasticity of neutrophils. In tumor microenvironment (TME), neutrophils might exert anti-tumor and pro-tumor functions depending on its surroundings. Tumor cells systemically alter intracellular amino acid (AA) metabolism and extracellular AA distribution to meet their proliferation need, leading to metabolic reprogramming and TME reshaping. However, the underlying mechanisms about how altered AAs affect neutrophils in TME are less-explored. Here, we identified that abundant glutamate releasing from tumor cells blunted neutrophils' cell-killing effects toward tumor cells in vitro and in vivo. Mass spectrometric detection, tumor flow and western experiments proved that increased level of pSTAT3/RAB10/ARF4 mediated by glutamate, were accompanied with immunosuppressive phenotypes of neutrophils in TME. We also discovered that Riluzole, FDA-approved glutamate release inhibitor, significantly inhibited tumor growth by restoring neutrophils' cell-killing effects though decreasing glutamate secretion from tumor cells. These findings highlight the importance of tumor-released glutamate on neutrophils transformation in TME, providing new possible cancer treatment targeting at altered glutamate metabolism.
    Keywords:  Glutamate; Neutrophil; Riluzole; STAT3; Tumor microenvironment
    DOI:  https://doi.org/10.1111/cas.15355
  86. Food Chem. 2022 Mar 23. pii: S0308-8146(22)00751-8. [Epub ahead of print]386 132789
    Phytochemical compositions, health-promoting properties and food applications of crabapples: A review.
    Xiangquan Zeng, He Li, Weibo Jiang, Qianqian Li, Yu Xi, Xiaomei Wang, Jian Li.
      Crabapples belong to the genus Malus (Rosaceae), which are small sized edible fruits with unique aroma and taste. According to previous studies, crabapples are rich in bioactive compounds and possess a series of health-promoting properties. Various crabapple-based food products and additives have also been developed by different research groups in recent years. In this paper, we aim to summarize the current knowledge about the phytochemical compositions, health-promoting properties and food applications of crabapples for the first time. It is shown that crabapples are good sources of polyphenols, terpenoids, vitamins, lipids, fibers, soluble sugars, microelements, organic acids and amino acids, which exhibit antioxidant, anticancer, lipid-lowering, anti-diabetic and anti-inflammatory activities in vitro and/or in vivo. Nowadays, the crabapple fruits have been successfully utilized to produce vinegar, jam, mixed beverage, fruit bar/gelatinized layers and lipophilic antioxidant. In a word, crabapples may have great potential in the development of new functional food and drinks.
    Keywords:  Bioactive compounds; Crabapples; Food applications; Health-promoting properties; Phytochemical composition
    DOI:  https://doi.org/10.1016/j.foodchem.2022.132789
  87. Biomaterials. 2022 Mar 18. pii: S0142-9612(22)00106-5. [Epub ahead of print]284 121467
    Supramolecular organic frameworks improve the safety of clinically used porphyrin photodynamic agents and maintain their antitumor efficacy.
    Yamin Liu, Chuan-Zhi Liu, Ze-Kun Wang, Wei Zhou, Hui Wang, Yun-Chang Zhang, Dan-Wei Zhang, Da Ma, Zhan-Ting Li.
      Despite that photodynamic therapy (PDT) has been applied for the treatment of cancer and skin diseases for more than two decades, all clinically used photodynamic agents (PDAs) suffer the drawback of skin phototoxicity of PDAs, which requires patients to avoid exposure to natural light for weeks after treatment, but has so far lacked effective suppression methods. Here, we report that three-dimensional diamondoid supramolecular organic frameworks (SOFs), that possess well-defined 2.1-nm porosity, can be used to suppress the skin phototoxicity of Photofrin, HiPorfin and Talaporfin, three porphyrin-based PDAs which clinically receive the most wide applications by injecting SOF after PDT, via an adsorption and retention mechanism. Fluorescence and dynamic light scattering experiments confirm that the SOFs have strong interaction with PDAs, and can adsorb PDAs at a micromolar concentration, whereas dialysis experiments support that the adsorption leads to an important retention effect. In vitro and in vivo experiments reveal that SOFs have high biocompatibility. Studies with healthy and tumor-bearing mouse models demonstrate that, when the PDAs are administrated at a dose comparable with the clinical one, SOF can remarkably suppress sunlight-induced skin phototoxicity, whereas the PDT efficacy of mice treated with SOF post-PDT is maintained. This work provides an efficient strategy for the improvement of the safety of clinically used PDAs.
    Keywords:  Host-guest chemistry; Photodynamic therapy; Phototoxicity suppression; Supramolecular organic framework; cucurbit[8]uril
    DOI:  https://doi.org/10.1016/j.biomaterials.2022.121467
  88. Zhongguo Zhong Yao Za Zhi. 2022 Mar;47(5): 1184-1189
    [Research progress on effective components and mechanisms of anti-depressive Chinese medicine].
    Zhen-Guang Song, Xiao-Qing Zhou, Dong-Mei Yan, Li-Ping Tang, Fei Wang, Bin Li.
      Since the pathogenesis of depression is complicated, the therapeutic effects of western medicine are poor accompanied by severe side effects. Chinese medicine has unique advantages in the treatment based on syndrome differentiation and contains many effective components against depression, including flavonoids, terpenes, phenylpropanoids, quinones, and alkaloids. These chemical components can delay the course of the disease, improve the curative effect, and reduce side effects of western medicine by regulating the biochemical abnormalities of monoamine neurotransmitters, brain tissue protein content, and internal environment as well as energy metabolism to make the treatment of Chinese medicine highlighted and recognized. This study systematically reviewed the effective components and mechanisms of anti-depressive Chinese medicine to inspire the rational development and utilization of new Chinese medicines against depression.
    Keywords:  Chinese medicine; depression; effective components; mechanism; research progress
    DOI:  https://doi.org/10.19540/j.cnki.cjcmm.20211122.202
  89. J Food Biochem. 2022 Mar 30. e14157
    Lecithins: A comprehensive review of their properties and their use in formulating microemulsions.
    Néstor Gutiérrez-Méndez, Dely R Chavez-Garay, Martha Y Leal-Ramos.
      Lecithins are a phospholipid-rich mixture recovered from the degumming process of crude vegetable oils. Since the nineteenth century, this by-product of oil processing has been used as a food and pharmaceutical ingredient. Lecithins' popularity as an ingredient in the pharmaceutical and food industries arises from their particular properties, such as their hydrophilic-lipophilic balance, critical micellar concentration, and assembly properties. However, there is limited knowledge of the use of lecithins to formulate pharmaceutical- and food-grade microemulsions. Unlike conventional emulsions, microemulsions are thermodynamically stable systems that offer long-term stability. Besides, microemulsions show nano-sized droplets, transparency, ease of preparation and scale-up, and do not require expensive equipment. This review aims to provide a comprehensive overview of lecithins, their properties, and their use in formulating microemulsions, a promising method to incorporate, protect, and deliver bioactive compounds in pharmaceutical and food products. PRACTICAL APPLICATIONS: Lecithins are a phospholipid-rich mixture recovered from the degumming process of crude vegetable oils. Since the nineteenth century, this by-product of oil processing has been used as a food ingredient. Lecithin phospholipids are commonly used as emulsifier agents in the food and pharmaceutical industries because of their particular properties. However, there is limited knowledge of the use of lecithins to formulate pharmaceutical- or food-grade microemulsions. Unlike conventional emulsions, microemulsions are stable systems that offer long-term stability, nano-sized droplets, transparency, ease of preparation and scale-up, and do not require expensive equipment. This review aims to provide a comprehensive overview of lecithins, their properties, and their use in formulating microemulsions, a promising method to incorporate, protect, and deliver bioactive compounds such as vitamins, flavors, antioxidants, nutrients, colors, antimicrobials, and polyphenols.
    Keywords:  food-grade microemulsions; lecithins; phospholipids
    DOI:  https://doi.org/10.1111/jfbc.14157
  90. Front Pharmacol. 2022 ;13 851589
    A Mini-Review of Flavone Isomers Apigenin and Genistein in Prostate Cancer Treatment.
    Xiaozhen Ji, Kai Liu, Qingyue Li, Qun Shen, Fangxuan Han, Qingmei Ye, Caijuan Zheng.
      The initial responses to standard chemotherapies among prostate cancer (PCa) patients are usually significant, while most of them will finally develop drug resistance, rendering them with limited therapies. To discover new regimens for the treatment of PCa including resistant PCa, natural products, the richest source of bioactive compounds, can serve as a library for screening and identifying promising candidates, and flavones such as apigenin and genistein have been used in lab and clinical trials for treating PCa over decades. In this mini-review, we take a look into the progress of apigenin and genistein, which are isomers, in treating PCa in the past decade. While possessing very similar structure, these two isomers can both target the same signaling pathways; they also are found to work differently in PCa cells. Given that more combinations are being developed and tested, genistein appears to be the more promising option to be approved. The anticancer efficacies of these two flavones can be confirmed by in-vitro and in-vivo studies, and their applications remain to be validated in clinical trials. Information gained in this work may provide important information for new drug development and the potential application of apigenin and genistein in treating PCa.
    Keywords:  apigenin; flavone; genistein; prostate cancer; resistance
    DOI:  https://doi.org/10.3389/fphar.2022.851589
  91. J Control Release. 2022 Mar 24. pii: S0168-3659(22)00168-7. [Epub ahead of print]
    Tumor-oriented mathematical models in hydrogel regulation for precise topical administration regimens.
    Zhen Wang, Bixi Ding, Yuanpei Zhao, Yue Han, Yu Sheng, Ling Tao, Xiangchun Shen, Jianping Zhou, Lei Jiang, Yang Ding.
      Increasing knowledge of drug delivery properties, tumor profiles and their relationship promotes precise administration regimens, representing a promising pattern to personalized tumor treatment. Herein, we propose a regulatory hydrogel depot toward metastatic cancer by establishing mathematical models between tumor characteristics and administration regimens. Specifically, a thermo-sensitive PLGA-PEG-PLGA polymer is introduced as injectable hydrogel matrix, of which the administration volume and frequency are manipulated elaborately according to tumor size and gel-degradation kinetics. Structurally, doxorubicin (Dox) and arginine-terminated nanoparticles containing KIAA1199 specific shRNA (shKIAARPDNs) are incorporated into hydrogels, thereby formulating a topical and sustained drug depot to achieve synergy treatment. For dual-targeting therapy, Dox interdicts DNA replication/transcription, and shKIAA persistently silences KIAA1199 protein to modulate aggressive phenotypes. After individual peritumoral injection, Gel/shKIAARPDNs/Dox demonstrates desirable distribution patterns and gel degradation kinetics with enhanced tumor penetration. Moreover, a preferable inhibition of tumor proliferation and metastasis is confirmed after twice treatment in 12 days, indicating better therapeutic efficacy with less dosage and frequency. Consequently, the controllable administration regimen inspired mathematical models of thermosensitive hydrogel provides an intelligent platform for personalized treatment to metastatic cancer.
    Keywords:  Hydrogel regulation; KIAA1199 specific shRNA; Personalized synergy treatment; Redox-sensitive arginine-terminated dendrimers; Tumor-oriented mathematical models
    DOI:  https://doi.org/10.1016/j.jconrel.2022.03.042
  92. Cancer Cell Int. 2022 Mar 27. 22(1): 139
    Investigating the role of peptides in effective therapies against cancer.
    Reza Naeimi, Asrin Bahmani, Saeid Afshar.
      Early diagnosis and effective treatment of cancer are challenging. To diagnose and treat cancer effectively and to overcome these challenges, fundamental innovations in traditional diagnosis and therapy are necessary. Peptides can be very helpful in this regard due to their potential and diversity. To enhance the therapeutic potential of peptides, their limitations must be properly identified and their structures engineered and modified for higher efficiency. Promoting the bioavailability and stability of peptides is one of the main concerns. Peptides can also be effective in different areas of targeting, alone or with the help of other therapeutic agents. There has been a lot of research in this area, and the potential for variability of peptides will continue to improve this process. Another promising area in which peptides can help treat cancer is peptide vaccines, which are undergoing promising research, and high throughput technologies can lead to fundamental changes in this area. Peptides have been effective in almost all areas of cancer treatment, and some have even gone through clinical phases. However, many barriers need to be overcome to reach the desired point. The purpose of this review is to evaluate the mechanisms associated with peptides in the diagnosis and treatment of cancer. Therefore, related studies in this area will be discussed.
    Keywords:  Cancer; Peptides; Therapeutic effect; Vaccines
    DOI:  https://doi.org/10.1186/s12935-022-02553-7
  93. Curr Med Chem. 2022 Mar 28.
    Nanotechnology: A Promising Targeted Drug Delivery System for Brain Tumours and Alzheimer's Disease.
    Aziz Unnisa, Nigel H Greig, Mohammad Amjad Kamal.
      Nanotechnology is the process of modulating shape and size at the nanoscale to design and manufacture structures, devices, and systems. Nanotechnology's prospective breakthroughs are incredible, and some cannot even be comprehended right now. The blood-brain barrier, which is a prominent physiological barrier in the brain, limits the adequate elimination of malignant cells by preventing the concentration of therapeutic drugs at the target tissue. Nanotechnology has sparked interest in recent years as a way to solve these issues and improve drug delivery. Inorganic and organic nanomaterials were found to be beneficial for bioimaging approaches and controlled drug delivery systems. Brain cancer (BC) and Alzheimer's disease (AD) are two of the prominent disorders of the brain. Even though the pathophysiology and pathways for both disorders are different, nanotechnology with common features can deliver drugs over the BBB, advancing the treatment of both disorders. This innovative technology could provide a foundation for combining diagnostics, treatments, and delivery of targeted drugs to the tumour site, with further supervising the response, by designing and delivering materials by employing atomic and molecular elements. There is currently limited treatment for Alzheimer's disease, and reversing further progression is difficult. Recently, various nanocarriers have been investigated to improve the bioavailability and efficacy of many AD treatment drugs. Nanotechnology-assisted drugs can penetrate the BBB and reach the target tissue. However, further research is required in this field, to ensure the safety and efficacy of drug-loaded nanoparticles. The application of nanotechnology in the diagnosis and treatment of brain tumours and Alzheimer's disease is briefly discussed in this review.
    Keywords:  Alzheimer's disease; Brain tumour; Nanotechnology; blood-brain barrier; drug delivery; nanoparticles
    DOI:  https://doi.org/10.2174/0929867329666220328125206
  94. J Agric Food Chem. 2022 Mar 29.
    Elderberry (Sambucus nigra L.): Bioactive Compounds, Health Functions, and Applications.
    Dan Liu, Xiao-Qin He, Ding-Tao Wu, Hua-Bin Li, Yi-Bin Feng, Liang Zou, Ren-You Gan.
      Elderberry (Sambucus nigra L.) is rich in many bioactive compounds and exhibits diverse health functions, of which an understanding can be helpful for its better utilization in the food industry. This review mainly summarizes recent studies about the bioactive compounds and health functions of elderberry, highlighting the potential mechanism of action. In addition, the applications of elderberry in foods are also discussed. Elderberry contains diversely bioactive ingredients, such as (poly)phenolic compounds and terpenoid compounds. Recent studies report that some food processing methods can affect the content of bioactive compounds in elderberry. Additionally, elderberry exhibits various health functions in vitro and in vivo, including antioxidant, anti-inflammatory, anticancer, anti-influenza, antimicrobial, antidiabetic, cardiovascular protective, and neuroprotective activities, and their potential molecular mechanisms are associated with regulating some key signaling pathways and molecular targets. Up to now, there have been limited clinical trials supporting the health benefits of elderberry. Overall, elderberry is a promising dietary source of bioactive ingredients and has the potential to be developed into functional foods or nutraceuticals for preventing and treating certain chronic diseases.
    Keywords:  (poly)phenolics; applications; elderberry; health benefits; mechanism of action
    DOI:  https://doi.org/10.1021/acs.jafc.2c00010
  95. Curr Med Chem. 2022 Mar 31.
    Advances and prospects of ultrasound targeted drug delivery systems using biomaterial-modified micro/nanobubbles for tumor therapy.
    Chen Lin, Ye-Zi Chen, Bo Wu, Meng-Ting Yang, Chao-Qi Liu, Yun Zhao.
      The incidence of malignant tumors is rising rapidly and tends to be in the younger, which has been one of the most important factors endangering the safety of human life. Ultrasound micro/nanobubbles, as a noninvasive and highly specific antitumor strategy, can reach and destroy tumor tissue through their effects of cavitation and acoustic perforation under the guidance of ultrasound. Meanwhile, micro/nanobubbles are now used as a novel drug carrier, releasing drugs at a target region, especially on the prospects of biomaterial-modified micro/nanobubbles as a dual modality for drug delivery and therapeutic monitoring. and successful evaluation of the sonoporation mechanism(s), ultrasound parameters, drug type and dose will need to be addressed before translating this technology for clinical use. Therefore, this paper collects the literature on the experimental and clinical studies of ultrasound biomaterial-modified micro/nanobubbles therapy in vitro and in vivo in recent years.
    Keywords:  Ultrasound; micro nanobubble; drug delivery system; molecule delivery; targeting; tumor therapy
    DOI:  https://doi.org/10.2174/0929867329666220331110315
  96. Phytomedicine. 2022 Mar 19. pii: S0944-7113(22)00138-6. [Epub ahead of print]100 154060
    Treat more than heat-New therapeutic implications of Cimicifuga racemosa through AMPK-dependent metabolic effects.
    Jürgen Drewe, Georg Boonen, Carsten Culmsee.
      BACKGROUND: Cimicifuga racemosa extracts (CRE) have obtained a "well-established use status" in the treatment of postmenopausal (i.e., climacteric) complaints, which predominantly include vasomotor symptoms such as hot flushes and sweating, as well as nervousness, irritability, and metabolic changes. Although characteristic postmenopausal complaints are known for a very long time and the beneficial effects of CRE on climacteric symptoms are well accepted, both the pathophysiology of postmenopausal symptoms and the mechanism of action of CREs are not yet fully understood. In particular, current hypotheses suggest that changes in the α-adrenergic and serotonergic signaling pathways secondary to estrogen depletion are responsible for the development of hot flushes.PURPOSE: Some of the symptoms associated with menopause cannot be explained by these hypotheses. Therefore, we attempted to extend our classic understanding of menopause by integrating of partly age-related metabolic impairments.
    METHODS: A comprehensive literature survey was performed using the PubMed database for articles published through September 2021. The following search terms were used: (cimicifuga OR AMPK) AND (hot flush* OR hot flash* OR menopaus* OR osteoporos* OR cancer OR antioxida* OR cardiovasc*). No limits were set with respect to language, and the references cited in the articles retrieved were used to identify additional publications.
    RESULTS: We found that menopause is a manifestation of the general aging process, with specific metabolic changes that aggravate menopausal symptoms, which are accelerated by estrogen depletion and associated neurotransmitter dysregulation. Cimicifuga extracts with their metabolic effects mitigate climacteric symptoms but may also modulate the aging process itself. Central to these effects are effects of CRE on the metabolic key regulator, the AMP-activated protein kinase (AMPK).
    CONCLUSIONS: As an extension of this effect dimension, other off-label indications may appear attractive in the sense of repurposing of this herbal treatment.
    Keywords:  Cimicifuga racemosa; Herbal drug; Mechanism of action; Menopause; Metabolism
    DOI:  https://doi.org/10.1016/j.phymed.2022.154060
  97. Front Bioeng Biotechnol. 2022 ;10 814466
    Fermented Jussara: Evaluation of Nanostructure Formation, Bioaccessibility, and Antioxidant Activity.
    Michele Amendoeira Giaconia, Sergiana Dos Passos Ramos, Camilly Fratelli, Marcelo Assis, Tatiana Martelli Mazzo, Elson Longo, Veridiana Vera de Rosso, Anna Rafaela Cavalcante Braga.
      Among the species of plants present in the Atlantic Forest, the jussara (Euterpe edulis Mart.) stands out for the contents of bioactive compounds present in its composition. Fermentation processes can be essential in converting bioproducts and bioactive compounds, improving their biological properties. In addition, the improvement of procedures for the maintenance of the features of bioactive compounds has been a research focus in recent years, and the nanotechnology features that can potentially solve this issue have been highlighted among the most reviewed paths. The present work focused on tailoring nanostructures applying polyethylene oxide, assembling fermented jussara pulp nanofibers, and assessing their characteristics. The results revealed the formation of fermented jussara nanofibers with a diameter of 101.2 ± 26.2 nm. Also, the obtained results allow us to state that it is possible to maintain or even increase the antioxidant activity of anthocyanins and their metabolites after fermentation processes.
    Keywords:  Anthocyanins; antioxidant activity; bioaccessibility; bioactive compounds; electrospinning; nanofibers
    DOI:  https://doi.org/10.3389/fbioe.2022.814466
  98. Curr Drug Deliv. 2022 Mar 31.
    DNA Nanobots - Emerging Customized Nanomedicine in Oncology.
    Rajesh Singh, Rohitas Deshmukh.
      Cancer is one of the most lethal diseases of the twenty-first century. Many medicines, including antitumor antibiotics, are used to deliver tedious and severe chemotherapy and radiation treatment, both of which have significant side effects. DNA nanorobots, as an alternative, might be used as a cancer treatment method that is both safer and more precise than current treatments. DNA nanobots are being praised as a major milestone in medical research. The major goal of these nanobots is to find and destroy malignant cells in the human body. A unique strand of DNA is folded into the systematic form to create these nanobots. DNA origami has magnified tumor passive targeting and prolonged properties at the tumour location. The triangle-like DNA origami, in particular, shows excellent accumulation on passive targeting of tumor. Self-built DNA origami nanostructures were utilized to deliver the anticancer drug doxorubicin into tumors, and the approach was found to be highly successful in vivo. In another demonstration, a robot was made with the help of DNA origami and aptamer for folding a 90nm long tube-like apparatus. It was carried out to transport the blood coagulation protease thrombin in the interior portion which is guarded against blood plasma protein and circulating platelets. The robot unfolded once the aptamer was identified and attached to its tumor-specific target molecule, delivering thrombin to the circulation, stimulating coagulation of the regional malignant cells, proceeding to tumor necrosis and tumor growth inhibition. Various studies revealed the effectiveness of DNA nanobots in cancer therapy.
    Keywords:  Cancer; DNA nanobot; doxorubicin; nanobot; nanotechnology; thrombin
    DOI:  https://doi.org/10.2174/1567201819666220331094812
  99. ACS Appl Mater Interfaces. 2022 Apr 01.
    Dynamic Surface Wrinkles for In Situ Light-Driven Dynamic Gratings.
    Tianjiao Ma, Liangwei Zhou, Jianyu Hua, Jin Li, Xiaodong Ma, Wen Qiao, Jie Yin, Xuesong Jiang.
      Dynamic diffraction gratings (DDGs) are considered as one of the most promising technologies for application in smart optical devices because of their in situ dynamic regulation of light propagation on demand; however, it is still a challenge to fabricate dynamic periodic micro/nanostructures due to limited materials and processes. Here, a facile and feasible strategy to construct a near-infrared (NIR) radiation-driven DDG is developed based on a double-sided surface pattern, which is fabricated by dynamic wrinkles and/or soft-imprinted static wrinkles. Poly(dimethylsiloxane) (PDMS) containing carbon nanotubes (CNTs) serves as the substrate, and wrinkles are formed on both sides. The resulting double-sided wrinkle pattern can be used as a DDG to generate various adjustable two-dimensional (2D) diffraction patterns driven by NIR light. Furthermore, with various combinations of wrinkles, we demonstrated a single-sided responsive DDG and a double-sided responsive DDG to realize the evolution of diffraction patterns from 2D to one-dimensional (1D) and 2D to zero-dimensional (0D), respectively. The results provide an alternative for DDGs that will have wide applications in smart display, sensing, and imaging systems.
    Keywords:  double-sided grating; dynamic diffraction grating; in situ regulating light; micro/nanostructure; reversible wrinkle
    DOI:  https://doi.org/10.1021/acsami.2c03235
  100. Int J Pharm. 2022 Mar 29. pii: S0378-5173(22)00264-2. [Epub ahead of print] 121709
    Brain-targeting biomimetic nanoparticles for codelivery of celastrol and LY2157299 for reversing glioma immunosuppression.
    Siqi Zhu, Feifei Sun, Pengfei Zhao, Gang Liang, Xiaoyi Sun, Linghui Zeng, Yongzhuo Huang.
      The treatment of glioblastoma remains a huge challenge due to the lack of an efficient way to deliver drugs across the blood-brain barrier (BBB), and the pharmacotherapy options are very limited. In this work, a biomimetic albumin BBB-penetrating system modified by a brain-targeting peptide was designed for co-delivering a TGF-β receptor I (TGFβRI) inhibitor (LY2157299) and an mTOR inhibitor (celastrol). The albumin delivery system can target nAChRs overexpressed both on the BBB and glioma cells, thereby promoting drug delivery into the glioma. The biomimetic nanoparticles could repolarize tumor-associated macrophages (TAMs) from M2 to M1 phenotype by suppressing the STAT6 pathway, thereby reducing TGF-β1 secretion and inducing cell apoptosis. In addition, the treatment also blocked TGF-β/SMAD2 signaling pathway. The glioma-targeting ability and therapeutic efficacy were confirmed in an orthotopic glioma mouse model. The biomimetic nanoparticles significantly prolonged the survival rate, showing a decrease in the proportion of M2-like TAMs and the levels of TGF-β1 and lactic acid in the glioma tissues. This delivery and treatment strategy provides a new approach for the treatment of gliomas.
    Keywords:  albumin nanoparticles; brain-targeted delivery; celastrol; glioblastoma; tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.121709
  101. Med J Islam Repub Iran. 2021 ;35 158
    Design and Characterization of Liposomal Methotrexate and Its Effect on BT-474 Breast Cancer Cell Line.
    Niloufar Tavakoli Dastjerd, Nematollah Gheibi, Hossein Ahmadpour Yazdi, Hanifeh Shariatifar, Alireza Farasat.
      Background: Breast cancer is the most common type of cancer among women worldwide. Traditional treatments, including chemotherapy, surgery, mastectomy, and radiotherapy, are commonly used. Because of the limitation of the aforementioned methods, novel treatment strategies are needed. Methotrexate is a chemotherapeutic drug, which is commonly used to treat breast cancer. Because of the side effects of the free drug, the liposomal form of the drug is suggested. Methods: Liposomal methotrexate was prepared and the encapsulation efficiency was measured. Moreover, the particle size and the zeta potential were measured. The liposome morphology was confirmed using transmission electron microscopy. The MTT assay was done to examine the cytotoxicity of free and encapsulated methotrexate on BT-474 cell line. The Annexin-V/PI dual staining assay was performed to assess the apoptosis in BT-474 breast cancer cells via the flow cytometry method. Results: The transmission electron microscopy results confirmed the integrated and spherical structure of the nanoparticles. The results of drug release showed that in acidic pH (5.4), more than 90% of the drug was released after 24 hours, which was higher than 2 other pHs. Furthermore, the IC50 value of liposomal methotrexate was determined as 2.15 and 0.82 mg/mL for 24 and 48 hours. The flow cytometry results confirmed that liposomal methotrexate had a greater cytotoxic effect on cancer cells compared with free methotrexate. Conclusion: Because of the advantages of liposomal based nanocarriers, in this study, liposomal methotrexate could be suggested as an appropriate candidate to treat breast cancer.
    Keywords:  BT-474; Breast Cancer; Liposome; Methotrexate; Nanocarriers
    DOI:  https://doi.org/10.47176/mjiri.35.158
  102. Mol Neurobiol. 2022 Mar 29.
    Neuroanatomical, Biochemical, and Functional Modifications in Brain Induced by Treatment with Antidepressants.
    Khushboo, Nikhat J Siddiqi, Maria de Lourdes Pereira, Bechan Sharma.
      Depression is a psychosomatic disorder. The pharmacological treatment of depression has been based on the pathophysiology of deficiency in monoamines, mainly serotonin and noradrenaline. All approved antidepressants designed to enhance central monoaminergic tone possess many limitations such as 2 to 5 weeks delay in response, a limited clinical efficacy, and severe side effects. Since the pathophysiological aberrations associated to depression go beyond monoamines, the development of better antidepressants would depend on the identification and understanding of new cellular targets. The pharmacological studies of antidepressants, however, indicate the involvement of the blockade of neuronal uptake systems for norepinephrine and serotonin (5-hydroxytryptamine) including receptors for neurotransmitters. Many preclinical studies have suggested that hippocampus containing abundant agonists such as5-HT1A and 5-HT4 receptor subtypes in the dentate gyrus (DG) is critically involved in the mechanism of action of antidepressants. DG being a part of hippocampus possibly contributes to the brain functions such as formation of new sporadic memories. It is reported that antidepressants cause significant alterations in the structure and function of different brain regions in order to finally lead to their therapeutic effects. This review presents an overview of structural changes in the brain during depression; different neurobiological theories and novel drug development; strategy of augmentation with combinatorial therapy; receptors and targets of actions of antidepressants; and involvement of key signaling factors in the regulation of depression, pharmacology, metabolism, and the underlying principles involved in displaying how the application of antidepressants modulates the structure and function of the brain.
    Keywords:  Antidepressants; Depression; Metabolism; Neurotransmitters; Receptors
    DOI:  https://doi.org/10.1007/s12035-022-02780-z
  103. Ann Hepatol. 2022 Mar 26. pii: S1665-2681(22)00043-6. [Epub ahead of print] 100701
    The potential mechanism of Chebulae Fructus in the treatment of hepatocellular carcinoma on the basis of network pharmacology.
    Jialu Jiang, Zhiping Yang, Guoxin Hou, Xuming Yao, Jin Jiang.
      INTRODUCTION AND OBJECTIVES: Hepatocellular carcinoma (HCC) ranks third on the list of the leading cause for cancer death globally. The treatment of HCC patients is unsatisfactory. However, the traditional Chinese medicine Chebulae Fructus has potential efficacy in the treatment of HCC.PATIENTS OR MATERIALS AND METHODS: We mined the active ingredients of Chebulae Fructus and its main targets from the Traditional Chinese Medicine Systems Pharmacology database. HCC-related datasets were downloaded from The Cancer Genome Atlas database and differentially expressed genes (DEGs) in HCC were obtained by differential expression analysis. Top10 small molecule compounds capable of reversing HCC pathology were screened by the Connectivity Map database based on DEGs. Ellipticine, an extract of Chebulae Fructus, had the potential to reverse HCC pathology. Protein-Protein Interaction (PPI) networks of DEGs in HCC were constructed using STRING. Eighteen potential targets of Chebulae Fructus for the treatment of HCC were obtained by taking intersection of DEGs in HCC with targets corresponding to the active constituents of Chebulae Fructus. In addition, MTT assay was also employed to examine the effect of ellipticine on HCC cell viability.
    RESULTS: It has been shown that ellipticine and ellagic acid have antitumor activity. Random Walk with Restart analysis of PPI networks was performed using potential targets as seeds, and the genes with the top 50 affinity coefficients were selected to construct a drug-active constituent-gene interaction network. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses of key genes involved in the treatment of HCC with Chebulae Fructus demonstrated that these genes were mainly enriched in signaling pathways related to tumor metabolism such as cAMP signaling pathway and Ras signaling pathway. Finally, it was verified by MTT assay that proliferation of HCC cells could be remarkably hindered.
    CONCLUSIONS: We excavated ellipticine, a key active constituent of Chebulae Fructus, by network pharmacology, and elucidated the signaling pathways involved in Chebulae Fructus, providing a theoretical basis for the use of Chebulae Fructus for HCC clinical application.
    Keywords:  Chebulae Fructus; PPI network; ellipticine; hepatocellular carcinoma; network pharmacology
    DOI:  https://doi.org/10.1016/j.aohep.2022.100701
  104. Curr Pharm Des. 2022 Mar 28.
    Marine Polysaccharides in Tailor- Made Drug Delivery.
    Sreejan Manna, Sougata Jana.
      Marine sources have attracted much interest as an emerging source of biomaterials in drug delivery applications. Amongst all other marine biopolymers, polysaccharides have been the mostly investigated class of biomaterials. The low cytotoxic behavior, in combination with the newly explored health benefits of marine polysaccharides has made it one of the prime research areas in the pharmaceutical and biomedical fields. In this review, we focused on all available marine polysaccharides, including their classification based on biological sources. The applications of several marine polysaccharides in recent years for tissue-specific novel drug delivery including gastrointestinal, brain tissue, transdermal, ocular, liver, and lung have also been discussed here. The abundant availability in nature, cost-effective extraction, and purification process along with a favorable biodegradable profile will encourage researchers to continue investigating marine polysaccharides for exploring newer applications in targeting specific delivery of therapeutics.
    Keywords:  Alginate; Carrageenan; Chitosan; Drug delivery applications; Hyaluronic acid; Marine polysaccharides
    DOI:  https://doi.org/10.2174/1381612828666220328122539
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