bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2022–06–12
101 papers selected by
Yasmin Elkabani, Egyptian Foundation for Research and Community Development
  1. Pimozide inhibits the growth of breast cancer cells by alleviating the Warburg effect through the P53 signaling pathway.
  2. A novel pH-responsive nanoniosomal emulsion for sustained release of curcumin from a chitosan-based nanocarrier: emphasis on the concurrent improvement of loading, sustained release, and apoptosis induction.
  3. Isobavachalcone: A comprehensive review of its plant sources, pharmacokinetics, toxicity, pharmacological activities and related molecular mechanisms.
  4. Enhancing the Release Efficiency of Molecular Chemotherapeutic Prodrug by Photodynamic Therapy.
  5. NIR-Mediated drug release and tumor theranostics using melanin-loaded liposomes.
  6. Scalable Manufacture of Curcumin-Loaded Chitosan Nanocomplex for pH-Responsive Delivery by Coordination-Driven Flash Nanocomplexation.
  7. Tumor Microenvironment Triggered the In Situ Synthesis of an Excellent Sonosensitizer in Tumor for Sonodynamic Therapy.
  8. Presenting a bioactive nanotherapeutic agent for colon cancer treatment.
  9. Nanotechnological Approaches for the Treatment of Triple-Negative Breast Cancer: A Comprehensive Review.
  10. pH-responsive hybrid platelet membrane-coated nanobomb with deep tumor penetration ability and enhanced cancer thermal/chemodynamic therapy.
  11. The Potential of Epigallocatechin Gallate (EGCG) in Targeting Autophagy for Cancer Treatment: A Narrative Review.
  12. Hypoxia-Reinforced Antitumor RNA Interference Mediated by Micelleplexes with Programmed Disintegration.
  13. Synergistic effects of natural compounds and conventional chemotherapeutic agents: recent insights for the development of cancer treatment strategies.
  14. Crosstalk of Epigenetic and Metabolic Signaling Underpinning Glioblastoma Pathogenesis.
  15. Oxygen-Generating Hydrogels Overcome Tumor Hypoxia to Enhance Photodynamic/Gas Synergistic Therapy.
  16. Delivery of an ectonucleotidase inhibitor with ROS-responsive nanoparticles overcomes adenosine-mediated cancer immunosuppression.
  17. Design and evaluation of hyaluronic acid coated plga nanoparticles of raloxifene hydrochloride for treatment of breast cancer.
  18. Lipid-based nanoparticles for treatment of cancer.
  19. Nano Drug Delivery System for Tumor Immunotherapy: Next-Generation Therapeutics.
  20. Injectable and Self-Healing Polysaccharide Hydrogel Loading Molybdenum Disulfide Nanoflakes for Synergistic Photothermal-Photodynamic Therapy of Breast Cancer.
  21. Dual-targeted and controlled release delivery of doxorubicin to breast adenocarcinoma: In vitro and in vivo studies.
  22. Injectable alginate hydrogels for synergistic tumor combination therapy through repolarization of tumor-associated macrophages.
  23. Insights into Aptamer-Drug Delivery Systems against Prostate Cancer.
  24. Zeolitic imidazolate framework-based nanoparticles for the cascade enhancement of cancer chemodynamic therapy by targeting glutamine metabolism.
  25. Preparation and application of pH-responsive drug delivery systems.
  26. Curcumin and Related Compounds in Cancer Cells: New Avenues for Old Molecules.
  27. A Review of Twenty Years of Research on the Regulation of Signaling Pathways by Natural Products in Breast Cancer.
  28. Multifunction in One Nanoparticle for Anticancer Therapy: Bowl-Shaped Au@PDA Yolk-Shell NPs.
  29. Phytochemistry and Biological Activity of Medicinal Plants in Wound Healing: An Overview of Current Research.
  30. Gastroretentive Drug Delivery System in Cancer Chemotherapy.
  31. An Overview of the Neuropharmacological Potential of Thymoquinone and its Targeted Delivery Prospects for CNS Disorder.
  32. Targeting cancer signaling pathways by natural products: Exploring promising anti-cancer agents.
  33. Biomimetic smart mesoporous carbon nanozyme as a dual-GSH depletion agent and O2 generator for enhanced photodynamic therapy.
  34. The Potential of Plant-Derived Extracts and Compounds to Augment Anticancer Effects of Chemotherapeutic Drugs.
  35. A Mini-Review on Solid Lipid Nanoparticles and Nanostructured Lipid Carriers: Topical Delivery of Phytochemicals for the Treatment of Acne Vulgaris.
  36. Anticancer therapeutic effect of cerium-based nanoparticles: known and unknown molecular mechanisms.
  37. 3-O-Ethyl-L-Ascorbic Acid Doped Enteric-Coated Gelatin Capsules towards the Advanced Oral Curcumin Delivery for Cancers.
  38. Enzymatic Synthesis of Peptide Nanofibers for Self-Delivery of Indomethacin and Tyroservatide in Cancer Therapy.
  39. Aconiti Lateralis Radix Praeparata as Potential Anticancer Herb: Bioactive Compounds and Molecular Mechanisms.
  40. Eryngium Species as a Potential Ally for Treating Metabolic Syndrome and Diabetes.
  41. The Combination of a Novel GLUT1 Inhibitor and Cisplatin Synergistically Inhibits Breast Cancer Cell Growth By Enhancing the DNA Damaging Effect and Modulating the Akt/mTOR and MAPK Signaling Pathways.
  42. Therapeutic effects of ginseng and ginsenosides on colorectal cancer.
  43. Selenium nanoparticles coupling with Astragalus Polysaccharides exert their cytotoxicities in MCF-7 cells by inhibiting autophagy and promoting apoptosis.
  44. Bioactive Compounds and Functional Properties of Herbal Preparations of Cystus creticus L. Collected From Rhodes Island.
  45. Photodynamic Therapy in Combination with the Hepatitis B Core Virus-like Particles (HBc VLPs) to Prime Anticancer Immunity for Colorectal Cancer Treatment.
  46. Novel Insights in the Regulatory Mechanisms of Ferroptosis in Hepatocellular Carcinoma.
  47. Multifunctional Hybrid Hydrogel System Enhanced the Therapeutic Efficacy of Treatments for Postoperative Glioma.
  48. Sinomenium acutum: A Comprehensive Review of its Botany, Phytochemistry, Pharmacology and Clinical Application.
  49. The Comparison of the Efficiency of Emodin and Aloe-Emodin in Photodynamic Therapy.
  50. Calixarene-modified albumin for stoichiometric delivery of multiple drugs in combination-chemotherapy.
  51. Nutritional Value, Phytochemical Potential, and Therapeutic Benefits of Pumpkin (Cucurbita sp.).
  52. Antineoplastic activity of biogenic silver and gold nanoparticles to combat leukemia: Beginning a new era in cancer theragnostic.
  53. Microalgae Bioactive Compounds to Topical Applications Products-A Review.
  54. Zein Microparticles and Nanoparticles as Drug Delivery Systems.
  55. Involvement of Phytochemical-Encapsulated Nanoparticles' Interaction with Cellular Signalling in the Amelioration of Benign and Malignant Brain Tumours.
  56. Differential Effects of Dietary Macronutrients on the Development of Oncogenic KRAS-Mediated Pancreatic Ductal Adenocarcinoma.
  57. Enzyme-Powered Micro/Nanomotors for Cancer Treatment.
  58. Combined regimens of cisplatin and metformin in cancer therapy: A systematic review and meta-analysis.
  59. An Update to Hallmarks of Cancer.
  60. Novel Lysosome-Targeting Fluorescence Off-On Photosensitizer for Near-Infrared Hypoxia Imaging and Photodynamic Therapy In Vitro and In Vivo.
  61. The Regulatory Roles of Polysaccharides and Ferroptosis-Related Phytochemicals in Liver Diseases.
  62. pH and Redox-Dual Sensitive Chitosan Nanoparticles Having Methyl Ester and Disulfide Linkages for Drug Targeting against Cholangiocarcinoma Cells.
  63. Dual-Responsive multifunctional "core-shell" magnetic nanoparticles promoting Fenton reaction for tumor ferroptosis therapy.
  64. Drug in Drug: A host-guest formulation of azocalixarene with hydroxychloroquine for synergistic anti-inflammation.
  65. Magnetite Nanoparticles in Magnetic Hyperthermia and Cancer Therapies: Challenges and Perspectives.
  66. Beyond Genetics: The Role of Metabolism in Photoreceptor Survival, Development and Repair.
  67. Repurposing Vitamin C for Cancer Treatment: Focus on Targeting the Tumor Microenvironment.
  68. Nanocurcumin in Oral Squamous Cancer Cells and Its Efficacy as a Chemo-Adjuvant.
  69. Construction of D-A-Conjugated Covalent Organic Frameworks with Enhanced Photodynamic, Photothermal, and Nanozymatic Activities for Efficient Bacterial Inhibition.
  70. Ultrasound-Assisted Extraction of Natural Pigments From Food Processing By-Products: A Review.
  71. Vitamin D, the Vitamin D Receptor, Calcitriol Analogues and Their Link with Ocular Diseases.
  72. Annonaceous Acetogenin Mimic AA005 Inhibits the Growth of TNBC MDA-MB-468 Cells by Altering Cell Energy Metabolism.
  73. The powerful Solanaceae: Food and nutraceutical applications in a sustainable world.
  74. The Effect of Dual Bioactive Compounds Artemisinin and Metformin Co-loaded in PLGA-PEG Nano-particles on Breast Cancer Cell lines: Potential Apoptotic and Anti-proliferative Action.
  75. Core-shell Pluronic F127/chitosan based nanoparticles for effective delivery of methotrexate in the management of rheumatoid arthritis.
  76. Ultrasound-triggered drug delivery for glioma therapy through gambogic acid-loaded nanobubble-microbubble complexes.
  77. A small-molecule self-assembled nanodrug for combination therapy of photothermal-differentiation-chemotherapy of breast cancer stem cells.
  78. Self-assembled hydrogel nanocube for stimuli responsive drug delivery and tumor ablation by phototherapy against breast cancer.
  79. Phytochemistry and bioactivities of the main constituents of Polyporus umbellatus (Pers.) Fries.
  80. Curcuma aeruginosa Roxb. exhibits cytotoxicity in A-549 and HeLa cells by inducing apoptosis through caspase-dependent pathways.
  81. Recent Advances in Antimicrobial Nano-Drug Delivery Systems.
  82. Combination therapy of bioactive compounds with acarbose: A proposal to control hyperglycemia in type 2 diabetes.
  83. Live Macrophage-Delivered Doxorubicin-Loaded Liposomes Effectively Treat Triple-Negative Breast Cancer.
  84. Folate Decorated Multifunctional Biodegradable Nanoparticles for Gastric Carcinoma Active Targeting Theranostics.
  85. Possible Nonneurological Health Benefits of Ketogenic Diet: Review of Scientific Reports over the Past Decade.
  86. Green decoration of graphene oxide Nano sheets with gelatin and gum Arabic for targeted delivery of doxorubicin.
  87. Citrus maxima (Brum.) Merr. (Rutaceae): Bioactive Chemical Constituents and Pharmacological Activities.
  88. Dietary phytochemicals/nutrients as promising protector of breast cancer development: a comprehensive analysis.
  89. Ionic Liquids Assisted Topical Drug Delivery for Permeation Enhancement: Formulation Strategies, Biomedical Applications, and Toxicological Perspective.
  90. Traditional Uses, Phytochemistry and Biological Activities of Alocasia Species: A Systematic Review.
  91. Modified Titanium Dioxide as a Potential Visible-Light-Activated Photosensitizer for Bladder Cancer Treatment.
  92. Nanoparticle classification, physicochemical properties, characterization, and applications: a comprehensive review for biologists.
  93. Effects of polyallylamine-coated nanoparticles on the optical and photochemical properties of rose bengal.
  94. Zinc Oxide Nanoparticles: A Review on Its Applications in Dentistry.
  95. Unraveling the Phytochemistry, Traditional Uses, and Biological and Pharmacological Activities of Thymus algeriensis Boiss. & Reut.
  96. Mammary adipocytes protect triple-negative breast cancer cells from ferroptosis.
  97. Mucoadhesive meloxicam-loaded nanoemulsions: Development, characterization and nasal applicability studies.
  98. Brain Drug Delivery and Neurodegenerative Diseases: Polymeric PLGA-Based Nanoparticles as a Forefront Platform.
  99. Rational construction of polycystine-based nanoparticles for biomedical applications.
  100. Polymer nanotherapeutics: A versatile platform for effective rheumatoid arthritis therapy.
  101. A comprehensive insight into the antineoplastic activities and molecular mechanisms of deoxypodophyllotoxin: Recent trends, challenges, and future outlook.
  1. Biomed Pharmacother. 2022 Jun;pii: S0753-3322(22)00452-8. [Epub ahead of print]150 113063
    Pimozide inhibits the growth of breast cancer cells by alleviating the Warburg effect through the P53 signaling pathway.
    Jiao Li, Peng Qu, Xing-Zhi Zhou, Yun-Xia Ji, Shuo Yuan, Shuang-Ping Liu, Qing-Gao Zhang.
      The Warburg effect is a promising target for the diagnosis and treatment of cancer, referring to the ability of cancer cells to generate energy through high levels of glycolysis even in the presence of oxygen, allowing them to grow and proliferate rapidly. The antipsychotic Pimozide has strong anti-breast cancer effects both in vivo and in vitro, whether Pimozide has an inhibitory effect on aerobic glycolysis has not been elucidated. In this study, Pimozide inhibited the Warburg effect of breast cancer cells by hindering glucose uptake, ATP level and lactate production; reducing the extracellular acidification rate (ECAR); suppressing the expression of PKM2, a rate-limiting enzyme in glycolysis. Intriguingly, Pimozide was significantly involved in reprogramming glucose metabolism in breast cancer cells through a p53-dependent manner. Mechanistic studies demonstrated Pimozide increased the expression of p53 through inhibition of the PI3K/Akt/MDM2 signaling pathway, which in turn downregulated the expression of PKM2. In sum, our results suggest that Pimozide mediates the p53 signaling pathway through PI3K/AKT/MDM2 to inhibit the Warburg effect and breast cancer growth, and it may be a potential aerobic glycolysis inhibitor for the treatment of breast cancer.
    Keywords:  Breast cancer; P53; PI3K/Akt/MDM2; PKM2; Pimozide; Warburg effect
    DOI:  https://doi.org/10.1016/j.biopha.2022.113063
  2. Biotechnol Prog. 2022 Jun 09. e3280
    A novel pH-responsive nanoniosomal emulsion for sustained release of curcumin from a chitosan-based nanocarrier: emphasis on the concurrent improvement of loading, sustained release, and apoptosis induction.
    Shabnam Haseli, Mehrab Pourmadadi, Amirmasoud Samadi, Fatemeh Yazdian, Majid Abdouss, Hamid Rashedi, Mona Navaei-Nigjeh.
      Curcumin application as an anti-cancer drug is faced with several impediments. This study has developed a platform that facilitates the sustained release of curcumin, improves loading efficiency, and anti-cancer activity. Montmorillonite (MMT) nanoparticles were added to chitosan (CS)-agarose (Aga) hydrogel and then loaded with curcumin (Cur) to prepare a curcumin-loaded nanocomposite hydrogel. The loading capacity increased from 63% to 76% by adding MMT nanoparticles to a chitosan-agarose hydrogel. Loading the fabricated nanocomposite in the nanoniosomal emulsion resulted in sustained release of curcumin under acidic conditions. Release kinetics analysis showed diffusion and erosion are the dominant release mechanisms, indicating non-fickian (or anomalous) transport based on the Korsmeyer-Peppas model. FTIR spectra confirmed that all nanocomposite components were present in the fabricated nanocomposite. Besides, XRD results corroborated the amorphous structure of the prepared nanocomposite. Zeta potential results corroborated the stability of the fabricated nanocarrier. Cytotoxicity of the prepared CS-Aga-MMT-Cur on MCF-7 cells was comparable to that of curcumin-treated cells (p <0.001). Moreover, the percentage of apoptotic cells increased due to the enhanced release profile resulting from the addition of MMT to the hydrogel and the incorporation of the fabricated nanocomposite into the nanoniosomal emulsion. To recapitulate, the current delivery platform improved loading, sustained release, and curcumin anti-cancer effect. Hence, this platform could be a potential candidate to mitigate cancer therapy restrictions with curcumin. This article is protected by copyright. All rights reserved.
    Keywords:  Cancer therapy; Chitosan; Curcumin; Montmorillonite; Niosome; pH-sensitive nanocarrier
    DOI:  https://doi.org/10.1002/btpr.3280
  3. Phytother Res. 2022 Jun 09.
    Isobavachalcone: A comprehensive review of its plant sources, pharmacokinetics, toxicity, pharmacological activities and related molecular mechanisms.
    Nan Xing, Xianli Meng, Shaohui Wang.
      Isobavachalcone (IBC), also known as isobapsoralcone, is a natural flavonoid widely derived from many medicinal plants, including Fabaceae, Moraceae, and so forth. IBC has been paid more and more attention by researchers in recent years due to its pharmacological activity in many diseases. This review aims to describe in detail the plant sources, pharmacokinetics, toxicity, pharmacological activities, and molecular mechanisms of IBC on various diseases. We found that IBC can be obtained not only by extraction but also by chemical synthesis. Pharmacokinetic studies have shown that IBC has low bioavailability, but can penetrate the blood-brain barrier and is widely distributed in the brain. Its pharmacological activities mainly include anticancer, antibacterial, anti-inflammatory, antiviral, neuroprotective, bone protection, and other activities. In particular, IBC shows strong anti-tumor and anti-inflammatory therapeutic potential due to its anti-cancer and anti-inflammatory activities. However, due to its hepatotoxicity, there may be more drug interactions. Therefore, more and more in-depth studies are needed for its clinical application. Mechanically, IBC can induce the production of reactive oxygen species (ROS), inhibit AKT, ERK, and Wnt pathways, and promote apoptosis of cancer cells through mitochondrial or endoplasmic reticulum pathways. IBC can inhibit the NF-κB pathway and the production of multiple inflammatory mediators by activating NRF2/HO-1 pathway, thus producing anti-inflammatory effects. Moreover, we discussed the limitations of current research on IBC and put forward some new perspectives and challenges, which provide a strong basis for clinical application and new drug development of IBC in the future.
    Keywords:  isobavachalcone; molecular mechanisms; pharmacokinetics; pharmacological activity; plant sources; toxicity
    DOI:  https://doi.org/10.1002/ptr.7520
  4. Angew Chem Int Ed Engl. 2022 Jun 10.
    Enhancing the Release Efficiency of Molecular Chemotherapeutic Prodrug by Photodynamic Therapy.
    Jie Yuan, Qian-Hui Zhou, Shuai Xu, Qing-Ping Zuo, Wei Li, Xing-Xing Zhang, Tian-Bing Ren, Lin Yuan, Xiao-Bing Zhang.
      Tumor-specific, hypoxia-activated prodrugs have been developed to alleviate the side effects of chemotherapy drugs. However, the release efficiency of hypoxia-activated prodrugs is restricted by the degree of tumor hypoxia, which further leads to poor cancer treatment effects. On the other hand, oxygen is consumed gradually in photodynamic therapy (PDT), which aggravates hypoxia at the tumor site. In this study, we combined hypoxia-activated prodrugs with PDT agents to promote the prodrugs release, thereby improving their bioavailability and therapeutic effects. As a proof of concept, a mitochondria-targeted molecular prodrug, CS-P, was designed and synthesized. It can be selectively activated by tumor hypoxia to release chemotherapeutic drugs and photosensitizers, and then further discharge drugs after light irradiation. The design strategy proposed in this paper provides a new idea for enhancing hypoxia-activated prodrug release and real-time monitoring prodrug release.
    Keywords:  fluorescent probe; hypoxia-activated prodrug; photoacoustic imaging; photodynamic therapy; tumour
    DOI:  https://doi.org/10.1002/anie.202206169
  5. Biomater Res. 2022 Jun 03. 26(1): 22
    NIR-Mediated drug release and tumor theranostics using melanin-loaded liposomes.
    Min Ah Kim, Chang-Moon Lee.
       BACKGROUND: Heat generation in a drug delivery carrier by exposure to near-infrared (NIR) light with excellent tissue transmittance is an effective strategy for drug release and tumor therapy. Because liposomes have amphiphilic properties, they are useful as drug carriers. Liposomes are also very suitable for drug delivery strategies using heat generation by NIR laser because lipid bilayers are easily broken by heat. Thermally generated bubbles from liposomes not only induce drug release, but also enable ultrasound imaging.
    METHODS: Melanin, perfluorohexane (PFH), and 5-fluorouracil (5-FU)-loaded liposomes (melanin@PFH@5-FU-liposomes) that can generate heat and bubble by NIR laser irradiation were prepared by a thin film method. Conversion of light to heat and bubble generation of melanin@PFH@5-FU-liposomes were evaluated using an infrared (IR) thermal imaging camera and an ultrasound imaging system both in vitro and in vivo. To investigate tumor therapeutic effect, NIR laser of 808 nm was used to irradiate tumor site for 10 min after injecting melanin@PFH@5-FU-liposome into tail veins of CT26-bearing mice.
    RESULTS: Melanin@PFH@5-FU-liposomes showed a spherical shape with a size of 209.6 ± 4.3 nm. Upon NIR laser irradiation, melanin@PFH@5-FU-liposomes exhibited effective temperature increase both in vitro and in vivo. In this regard, temperature increase caused a phase transition of PFH to induce bubble generation dramatically, resulting in effective drug release behavior and ultrasound imaging. The temperature of the tumor site was increased to 52 t and contrast was greatly enhanced during ultrasound imaging due to the generation of bubble. More importantly, tumor growth was effectively inhibited by injection of melanin@PFH@5-FU-liposomes with laser irradiation.
    CONCLUSIONS: Based on intrinsic photothermal properties of melanin and phase transition properties of PFH, melanin@PFH@5-FU-liposomes exhibited effective heat and bubble generation upon NIR laser irradiation. The elevated temperature induced bubble generation, resulting in contrast enhancement of ultrasound imaging. Melanin@PFH@5-FU-liposomes under NIR laser irradiation induced the death of cancer cells, thereby effectively inhibiting tumor growth. These results suggest that melanin@PFH@5-FU-liposomes can be utilized as a promising agent for photothermal tumor therapy and ultrasound imaging.
    Keywords:  Liposome; Melanin; Perfluorohexane; Photothermal cancer therapy; Ultrasound imaging
    DOI:  https://doi.org/10.1186/s40824-022-00270-w
  6. Polymers (Basel). 2022 May 24. pii: 2133. [Epub ahead of print]14(11):
    Scalable Manufacture of Curcumin-Loaded Chitosan Nanocomplex for pH-Responsive Delivery by Coordination-Driven Flash Nanocomplexation.
    Ziwei Xia, Zhinan Fu, Li Li, Enguang Ma, Liang Sun, Qinyu Ma, Xuhong Guo.
      Metal coordination-driven nanocomplexes are known to be responsive to physiologically relevant stimuli such as pH, redox, temperature or light, making them well-suited for antitumor drug delivery. The ever-growing demand for such nanocomplexes necessitates the design of a scalable approach for their production. In this study, we demonstrate a novel coordination self-assembly strategy, termed flash nanocomplexation (FNC), which is rapid and efficient for the fabrication of drug-loaded nanoparticles (NPs) in a continuous manner. Based on this strategy, biocompatible chitosan (CS) and Cu2+ can be regarded anchors to moor the antitumor drug (curcumin, Cur) through coordination, resulting in curcumin-loaded chitosan nanocomplex (Cur-loaded CS nanocomplex) with a narrow size distribution (PDI &lt; 0.124) and high drug loading (up to 41.75%). Owing to the excellent stability of Cur-loaded CS nanocomplex at neutral conditions (&gt;50 days), premature Cur leakage was limited to lower than 1.5%, and pH-responsive drug release behavior was realized in acidic tumor microenvironments. An upscaled manufacture of Cur-loaded CS nanocomplex is demonstrated with continuous FNC, which shows an unprecedented method toward practical applications of nanomedicine for tumor therapy. Furthermore, intracellular uptake study and cytotoxicity experiments toward H1299 cells demonstrates the satisfied anticancer efficacy of the Cur-loaded CS nanocomplex. These results confirm that coordination-driven FNC is an effective method that enables the rapid and scalable fabrication of antitumor drugs.
    Keywords:  chitosan; coordination-driven; curcumin; flash nanocomplexation
    DOI:  https://doi.org/10.3390/polym14112133
  7. ACS Appl Mater Interfaces. 2022 Jun 07.
    Tumor Microenvironment Triggered the In Situ Synthesis of an Excellent Sonosensitizer in Tumor for Sonodynamic Therapy.
    Wei-Qiang Huang, Ya-Qi Zhu, Wei You, Jing Chen, Fan Gao, Xuan Nie, Ze Zhang, Guang Chen, Yue Yu, Lei Xia, Chun-Yan Hong, Long-Hai Wang, Zong-Yao Hao, Ye-Zi You.
      An ultrasound-triggered sonodynamic therapy has shown great promise for cancer therapy. However, its clinical applications are very limited because the traditional sonosensitizers tend to suffer from very poor efficiency combined with low retention in cancer cells and low tumor selectivity. Therefore, sonosensitizers with higher effectivity, higher tumor cell retention, and higher tumor cell specificity are highly required. Herein, we constructed a Ti2C(OH)X nanosheet, which was a poor sonosensitizer but had a long circulation in the blood system. However, it was very interesting to find that the tumor microenvironment could in situ turn Ti2C(OH)X nanosheet into a novel and excellent sonosensitizer with a nanofiber structure in tumors, exhibiting excellent ability to generate reactive oxygen species (ROS) under ultrasound. Moreover, the nanofiber structure made it very difficult to get out of cancer cells, highly enhancing the retention of the sonosensitizer in the tumor, thereby enabling it to effectively and selectively kill cancer cells in vivo. Our findings demonstrate that the strategy of the tumor microenvironment triggering the in situ synthesis of an effective sonosensitizer in tumor provided a promising means to simultaneously increase the efficiency, sonosensitizer retention in cancer cells, and cancer selectivity, thereby effectively killing cancer cells but causing little damage to healthy tissues via the sonodynamic therapy.
    Keywords:  cancer selectivity; in situ synthesis; sonosensitizer; tumor microenvironment; ultrasound
    DOI:  https://doi.org/10.1021/acsami.2c05369
  8. Eur J Pharmacol. 2022 Jun 06. pii: S0014-2999(22)00345-4. [Epub ahead of print] 175084
    Presenting a bioactive nanotherapeutic agent for colon cancer treatment.
    Parichehr Hassanzadeh, Elham Arbabi.
      Colon cancer (CC) is one of the major causes of death worldwide. Insufficient drug concentration, non-specificity, or serious adverse effects of the conventional chemotherapeutic agents necessitate application of more effective treatment options. Herein, poly-ursolic acid, a polymer with anticancer effect, has been self-assembled for producing nanoparticles (NPs) for delivery of irinotecan (IRN) which is usually associated with poor solubility and severe adverse effects. NPs showed therapeutic efficiency by themselves in vivo and in vitro. IRN-loaded NPs with appropriate physicochemical characteristics, released IRN in a controlled fashion and demonstrated more efficient cytotoxicity, lower clearance rate and distribution volume, higher Cmax and AUC, prolonged t1/2, increased accumulation in tumor, and therapeutic effects in vivo as compared to free drug. There was no significant alteration of body weight or damage to the major organs. The prepared bioactive nanoplatform via improvement of IRN efficiency could be applied for inducing synergistic toxicity against CC.
    Keywords:  Colon cancer; Irinotecan; Nanomedicine; Poly ursolic acid
    DOI:  https://doi.org/10.1016/j.ejphar.2022.175084
  9. Curr Drug Metab. 2022 Jun 08.
    Nanotechnological Approaches for the Treatment of Triple-Negative Breast Cancer: A Comprehensive Review.
    Lahanya Guha, Ishfaq Ahmad Bhat, Aasiya Bashir, Jawad Ur Rahman, Faheem Hyder Pottoo.
      Breast cancer is the most prevalent cancer in women around the world, having a sudden spread nowadays because of the poor sedentary lifestyle of people. Comprising of several subtypes, one of the most dangerous and aggressive ones is triple-negative breast cancer or TNBC. Even though conventional surgical approaches like single and double mastectomy and preventive chemotherapeutic approaches are there, but they are not selective to cancer cells and are only for symptomatic treatment. A new branch called nanotechnology has emerged in the last few decades that offer various novel characteristics such as size in nanometric scale, enhanced adherence to multiple targeting moieties, active and passive targeting, controlled release, and site-specific targeting. Among various nanotherapeutic approaches like dendrimers, lipid-structured nanocarriers, carbon nanotubes, etc. nanoparticle targeted therapeutics can be termed the best among all for their specific cytotoxicity to cancer cells and increased bioavailability to a target site. This review focuses on the types and molecular pathways involving TNBC, existing treatment strategies, various nanotechnological approaches like exosomes, carbon nanotubes, dendrimers, lipid, and carbon-based nanocarriers, and especially various nanoparticles (NPs) like polymeric, photodynamic, peptide conjugated, antibody-conjugated, metallic, inorganic, natural product capped and CRISPR based nanoparticles already approved for treatment or are under clinical and pre-clinical trials for TNBC.
    Keywords:  Estrogen receptor (ER); Human epidermal growth factor receptor 2 (HER2); Nanoparticles; Nanotechnology; Progesterone receptor (PR); Targeted therapy.; Triple-negative breast cancer
    DOI:  https://doi.org/10.2174/1389200223666220608144551
  10. Theranostics. 2022 ;12(9): 4250-4268
    pH-responsive hybrid platelet membrane-coated nanobomb with deep tumor penetration ability and enhanced cancer thermal/chemodynamic therapy.
    Huang Yang, Yuan Ding, Zongrui Tong, Xiaohui Qian, Hao Xu, Fenghao Lin, Guoping Sheng, Liangjie Hong, Weilin Wang, Zhengwei Mao.
      Background: Despite their outstanding properties in high surface-to-volume ratio and deep penetration, the application of ultrasmall nanoparticles for tumor theranostics remains limited because of their dissatisfied targeting performance and short blood circulation lifetime. Various synthetic materials with complex structures have been prepared as a multifunctional platform for loading ultrasmall nanoparticles. However, their use in nanomedicine is restricted because of unknown metabolic processes and potential physiological toxicity. Therefore, versatile and biocompatible nanoplatforms need to be designed through a simple yet effective method for realizing specific delivery and responsible release of ultrasmall nanoparticles. Methods: Iron-gallic acid coordination polymer nanodots (FeCNDs) exhibits outstanding photothermal ability and Fenton catalytic performance, which can be applied for tumor inhibition via hyperthermia and reactive oxygen species. A pH-responsive platelet-based hybrid membrane (pH-HCM) was prepared via co-extrusion and acted as a safe nanoplatform to load FeCNDs (pH-HCM@FeCNDs). Subsequently, their responsive performance and penetration ability were valued considering the multicellular sphere (MCS) model in an acidic or neutral environment. Thereafter, in vivo fluorescence image was performed to assess targeting capability of pH-HCM@FeCNDs. Finally, the corresponding antitumor and antimetastatic effects on orthotropic breast cancer were investigated. Results: In 4T1 MCS model, pH-HCM@FeCNDs group exhibited higher penetration efficiency (72.84%) than its non-responsive counterparts (17.77%) under an acidic environment. Moreover, the fluorescence intensity in pH-HCM@FeCNDs group was 3.18 times higher than that in group without targeting performance in the in vivo fluorescence image experiment. Finally, through in vivo experiments, pH-HCM@FeCNDs was confirmed to exhibit the best antitumor effect (90.33% tumor reduction) and antimetastatic effects (only 0.29% tumor coverage) on orthotropic breast cancer. Conclusions: Hybrid cell membrane was an ideal nanoplatform to deliver nanodots because of its good responsibility, satisfactory targeting ability, and excellent biocompatibility. Consequently, this study provides novel insights into the delivery and release of nanodots in a simple but effect method.
    Keywords:  combined therapy; hybrid cell membrane; nanodots; platelet membrane; tumor penetration
    DOI:  https://doi.org/10.7150/thno.68996
  11. Int J Mol Sci. 2022 May 28. pii: 6075. [Epub ahead of print]23(11):
    The Potential of Epigallocatechin Gallate (EGCG) in Targeting Autophagy for Cancer Treatment: A Narrative Review.
    Elena Ferrari, Saverio Bettuzzi, Valeria Naponelli.
      Autophagy is an evolutionarily conserved process for the degradation of redundant or damaged cellular material by means of a lysosome-dependent mechanism, contributing to cell homeostasis and survival. Autophagy plays a multifaceted and context-dependent role in cancer initiation, maintenance, and progression; it has a tumor suppressive role in the absence of disease and is upregulated in cancer cells to meet their elevated metabolic demands. Autophagy represents a promising but challenging target in cancer treatment. Green tea is a widely used beverage with healthy effects on several diseases, including cancer. The bioactive compounds of green tea are mainly catechins, and epigallocatechin-gallate (EGCG) is the most abundant and biologically active among them. In this review, evidence of autophagy modulation and anti-cancer effects induced by EGCG treatment in experimental cancer models is presented. Reviewed articles reveal that EGCG promotes cytotoxic autophagy often through the inactivation of PI3K/Akt/mTOR pathway, resulting in apoptosis induction. EGCG pro-oxidant activity has been postulated to be responsible for its anti-cancer effects. In combination therapy with a chemotherapy drug, EGCG inhibits cell growth and the drug-induced pro-survival autophagy. The selected studies rightly claim EGCG as a valuable agent in cancer chemoprevention.
    Keywords:  autophagy; autophagy activator; autophagy modulator; cancer therapy; epigallocatechin gallate
    DOI:  https://doi.org/10.3390/ijms23116075
  12. Acta Biomater. 2022 Jun 02. pii: S1742-7061(22)00326-9. [Epub ahead of print]
    Hypoxia-Reinforced Antitumor RNA Interference Mediated by Micelleplexes with Programmed Disintegration.
    Xudong Li, Xiangnan Xu, Ke Huang, Yuchen Wu, Zhifeng Lin, Lichen Yin.
      The performance of polycation-mediated siRNA delivery is often hurdled by the multiple systemic and cellular barriers that pose conflicting requirements for materials properties. Herein, micelleplexes (MPs) capable of programmed disintegration were developed to mediate efficient delivery of siRNA against XIAP (siXIAP) in a hypoxia-reinforced manner. MPs were assembled from azobenzene-crosslinked oligoethylenimine (AO), acid-transformable diblock copolymer PPDHP with conjugated photosensitizer, and siXIAP. AO efficiently condensed siXIAP via electrostatic interaction, and PPDHP rendered additional hydrophobic interaction with AO to stabilize the MPs against salt. The hydrophilic PEG corona enhanced the serum stability of MPs to prolong blood circulation and promote tumor accumulation. After internalization into cancer cells, the endolysosomal acidity triggered shedding of PPDHP, exposing AO to induce endolysosomal escape. Then, light irradiation generated lethal amount of ROS, and concurrently aggravated intracellular hypoxia level to degrade AO into low-molecular weight segments, release siXIAP, and potentiate the XIAP silencing efficiency. Thus, siXIAP-mediated pro-apoptosis cooperated with generated ROS to provoke pronounced anti-cancer efficacy against Skov-3 tumors in vitro and in vivo. This study provides a hypoxia-instructed strategy to overcome the multiple barriers against anti-cancer siRNA delivery in a programmed manner. STATEMENT OF SIGNIFICANCE: : The success of RNA interference (RNAi) heavily depends on delivery systems that can enable spatiotemporal control over siRNA delivery. Herein, we developed micelleplexes (MPs) constructed from hypoxia-degradable, azobenzene-crosslinked oligoethylenimine (AO) and acid-responsive, photosensitizer-conjugated diblock copolymer PPDHP, to mediate efficient anti-tumor siRNA (siXIAP) delivery via programmed disintegration. MPs possessed high salt/serum stability and underwent acid-triggered PPDHP detachment to promote endolysosomal escape. Then, light irradiation aggravated hypoxia to trigger AO degradation and intracellular siXIAP release, which cooperated with photodynamic therapy to eradicate tumor cells. This study presents a new example of hypoxia-degradable polycation to mediate hypoxia-reinforced RNAi, and it also renders an effective strategy to overcome the complicated extracellular/intracellular barriers against systemic siRNA delivery.
    Keywords:  RNA interference; hypoxia responsiveness; intracellular siRNA release; micelleplexes; photodynamic therapy
    DOI:  https://doi.org/10.1016/j.actbio.2022.05.050
  13. Heliyon. 2022 Jun;8(6): e09519
    Synergistic effects of natural compounds and conventional chemotherapeutic agents: recent insights for the development of cancer treatment strategies.
    Ana María Castañeda, Carlos Mario Meléndez, Diego Uribe, Johanna Pedroza-Díaz.
      Cancer is one of the leading causes of death in the world. Chemotherapy is presented as an option for treatment of this disease, however, low specificity, high resistance rates, toxicity and hypersensitivity reactions, make it necessary to search for therapeutic alternatives that increase the selectivity of treatment, reduce the side effects and enhance its antitumor potential. Natural products are accessible, inexpensive and less toxic sources; in addition, they have multiple mechanisms of action that can potentiate the outcome of chemotherapeutics. In this review, we present evidence on the beneficial effect of the interaction of dietary phytochemicals with chemotherapeutical agents for cancer treatment. This effect is generated by different mechanisms of action such as, increased tumoricidal effect via sensitization of cancer cells, reversing chemoresistance through inhibition of several targets involved in the development of drug resistance and, decreasing chemotherapy-induced toxicity in non-tumoral cells by the promotion of repair mechanisms. Studies discussed in this review will provide a solid basis for the exploration of the potential use of natural products in combination with chemotherapeutical agents, to overcome some of the difficulties that arise in the management of cancer patients.
    Keywords:  Chemotherapy; Natural products; Reversal of chemoresistance; Selectivity for cancer cells; Tumoricidal effect
    DOI:  https://doi.org/10.1016/j.heliyon.2022.e09519
  14. Cancers (Basel). 2022 May 27. pii: 2655. [Epub ahead of print]14(11):
    Crosstalk of Epigenetic and Metabolic Signaling Underpinning Glioblastoma Pathogenesis.
    Mariam Markouli, Dimitrios Strepkos, Kostas A Papavassiliou, Athanasios G Papavassiliou, Christina Piperi.
      Metabolic alterations in neoplastic cells have recently gained increasing attention as a main topic of research, playing a crucial regulatory role in the development and progression of tumors. The interplay between epigenetic modifications and metabolic pathways in glioblastoma cells has emerged as a key pathogenic area with great potential for targeted therapy. Epigenetic mechanisms have been demonstrated to affect main metabolic pathways, such as glycolysis, pentose phosphate pathway, gluconeogenesis, oxidative phosphorylation, TCA cycle, lipid, and glutamine metabolism by modifying key regulatory genes. Although epigenetic modifications can primarily promote the activity of metabolic pathways, they may also exert an inhibitory role. In this way, they participate in a complex network of interactions that regulate the metabolic behavior of malignant cells, increasing their heterogeneity and plasticity. Herein, we discuss the main epigenetic mechanisms that regulate the metabolic pathways in glioblastoma cells and highlight their targeting potential against tumor progression.
    Keywords:  DNA; Krebs cycle; TCA cycle; acetylation; glioblastoma; glioma; gluconeogenesis; glutamine; glycolysis; histones; methylation; microRNAs; oxidative phosphorylation; pentose phosphate pathway
    DOI:  https://doi.org/10.3390/cancers14112655
  15. ACS Appl Mater Interfaces. 2022 Jun 10.
    Oxygen-Generating Hydrogels Overcome Tumor Hypoxia to Enhance Photodynamic/Gas Synergistic Therapy.
    Mi Zhang, Xiaoguang Liu, Yinghua Mao, Yuhang He, Juan Xu, Feng Zheng, Weilong Tan, Shu Rong, Yonghong Chen, Xuemei Jia, Hong Li.
      Hypoxic environment is a bottleneck of photodynamic therapy (PDT) in tumor treatment, as oxygen is the critical substrate for photosensitivity reaction. Herein, a sustained oxygen supply system based on cerium nanoparticles and hydrogel (GHCAC) was explored for enhanced synergistic PDT and gas therapy. Ceria nanoparticles were prepared as a drug carrier by self-assembly mediated by hyaluronic acid (HA), a targeting for CD44 on cervical cancer cells, followed by photosensitizer and l-arginine (l-Arg) loading. Then, the GHCAC system was developed by incorporating a prepared nanocarrier (HCePA) and O2-evolving agent calcium peroxide (CaO2) into the hydrogel (Gel) developed by a poloxamer. Gel in the system could moderately infiltrate H2O to react with CaO2 and generate sustained oxygen using the catalase-like activity of HCePA. The system could efficiently alleviate hypoxia in tumor environments for up to 7 days, meeting the "once injection, repeat irradiation" strategy and enhanced PDT efficacy. Besides, the generated singlet oxygen (1O2) in the PDT process could also oxidize l-Arg into high concentrations of nitric oxide for synergistic gas therapy. The developed oxygen supplied and drug delivery Gel system is a new strategy for synergistic PDT/gas therapy to overcome cervical cancer.
    Keywords:  ceria nanoparticles; gas therapy; hydrogel; photodynamic therapy; tumor hypoxia
    DOI:  https://doi.org/10.1021/acsami.2c02949
  16. Sci Transl Med. 2022 Jun 08. 14(648): eabh1261
    Delivery of an ectonucleotidase inhibitor with ROS-responsive nanoparticles overcomes adenosine-mediated cancer immunosuppression.
    Chengqiong Mao, Stacy Yeh, Juan Fu, Mercedes Porosnicu, Alexandra Thomas, Gregory L Kucera, Konstantinos I Votanopoulos, Shaomin Tian, Xin Ming.
      Tumor evasion of immune destruction is associated with the production of immunosuppressive adenosine in the tumor microenvironment (TME). Anticancer therapies can trigger adenosine triphosphate (ATP) release from tumor cells, causing rapid formation of adenosine by the ectonucleotidases CD39 and CD73, thereafter exacerbating immunosuppression in the TME. The goal of this study was to develop an approach to facilitate cancer therapy-induced immunogenic cell death including ATP release and to limit ATP degradation into adenosine, in order to achieve durable antitumor immune response. Our approach was to construct reactive oxygen species (ROS)-producing nanoparticles that carry an ectonucleotidase inhibitor ARL67156 by electronic interaction and phenylboronic ester. Upon near-infrared irradiation, nanoparticle-produced ROS induced ATP release from MOC1 cancer cells in vitro and triggered the cleavage of phenylboronic ester, facilitating the release of ARL67156 from the nanoparticles. ARL67156 prevented conversion of ATP to adenosine and enhanced anticancer immunity in an MOC1-based coculture model. We tested this approach in mouse tumor models. Nanoparticle-based ROS-responsive drug delivery reprogramed the immunogenic landscape in tumors, eliciting tumor-specific T cell responses and tumor regression, conferring long-term survival in mouse models. We demonstrated that TME reprograming sets the stage for response to anti-programmed cell death protein 1 (PD1) immunotherapy, and the combination resulted in tumor regression in a 4T1 breast cancer mouse model that was resistant to PD1 blockade. Furthermore, our approach also induced immunological effects in patient-derived organotypic tumor spheroid model, suggesting potential translation of our nanoparticle approach for treating human cancers.
    DOI:  https://doi.org/10.1126/scitranslmed.abh1261
  17. Drug Dev Ind Pharm. 2022 Jun 10. 1-17
    Design and evaluation of hyaluronic acid coated plga nanoparticles of raloxifene hydrochloride for treatment of breast cancer.
    Kajol Bhatt, Pravin Patil, Parva Jani, Parth Thakkar, Krutika Sawant.
       CONTEXT: In the present study, Hyaluronic acid coated Raloxifene loaded PLGA nanoparticles have been developed to improve the anticancer potential and reduce side effects associated with the drug.
    AIM AND OBJECTIVES: The investigation was aimed to formulate and optimize Raloxifene hydrochloride loaded PLGA nanoparticles with surface modification using hyaluronic acid as a targeting moiety. To perform physicochemical characterization, in vitro cytotoxicity study (using MCF-7), in vitro drug release study and in vivo pharmacodynamic study of optimized formulation.
    METHODOLOGY: Raloxifene hydrochloride (RALH) loaded PLGA nanoparticles were prepared by nanoprecipitation technique, followed by surface modification with hyaluronic acid. Formulation was optimized by using 23 factorial design and characterized by physicochemical, in vitro drug release, in vitro cytotoxicity studies and in vivo pharmacokinetics.
    RESULTS AND DISCUSSION: The particle size, PDI, zeta potential, entrapment efficiency and loading capacity of spherically shaped RALH loaded nanoparticles was 207.3 ± 4.2 d.nm, 0.218 ± 0.127, -28.3 mV, 43.75 ± 1.2% and 7.55 ± 1.14% respectively. The in-vitro drug release showed sustained release and followed Korsemeyer-Peppas model with non fickian release pattern. The in-vitro cytotoxicity study of drug loaded NPs by MTT assay on MCF-7 breast carcinoma cell showed anti-cancer activity after 48 hrs of treatment.
    CONCLUSION: The results of the present investigation suggested that RALH loaded HA modified PLGA nanoparticles showed sustained drug release with anticancer activity and can be promising approach for treatment of breast cancer.
    Keywords:  Breast cancer; Factorial design; Hyaluronic acid; Optimization; PLGA nanoparticles; Raloxifene hydrochloride; sustained release
    DOI:  https://doi.org/10.1080/03639045.2022.2088784
  18. Heliyon. 2022 May;8(5): e09403
    Lipid-based nanoparticles for treatment of cancer.
    Sumit Sheoran, Swati Arora, R Samsonraj, Pilli Govindaiah, Sugunakar Vuree.
      Investigators were continuously creating novel nanotechnologies to address unmet requirements throughout the administration of therapeutic medicines & imaging agents for cancer treatment & diagnostics, appropriately. LNPs(Lipid nanoparticles) are legitimate particulates (approx. 100 nm in size) gathered from various lipid as well as other biochemical compounds which overall functionality to resolve biological barriers (biobarriers), allowing LNPs to selectively collect somewhere outside of disease-target cells again for responsive therapeutics. Most pharmaceutically important compounds were insoluble throughout water solutions, were chemical & physiologically unstable, or have toxicities. Among the most potential drug carrier for bioactive organic compounds is LBNPs (Lipid based nanoparticles) technologies. Its present use in chemotherapy have transformed treatment for cancer by increasing the antitumor effect of a number of chemotherapeutics. Because they may be created using naturally occurring sources, LBNPs have great temporal and thermal stability, maximum load potential, simplicity of preparations, cheap manufacturing costs, & big manufacturing output. Furthermore, combining chemotherapeutic drugs with LNPs reduces active therapeutic dosage and toxicities, lowers treatment resistance, & raises drug concentration in tumour cells while reducing concentrations in normal tissue. LBNPs were widely studied in cancer treatment, both in vitro and in vivo, with encouraging outcomes in certain clinical trials. This study provides an overview of the many types of LBNPs which have been created in latest years and their applications and contributions in different types of cancers.
    Keywords:  Clinical trials; Lipid based Nanopartcles; Liposomes; Solid lipid nanoparticles; Tumour
    DOI:  https://doi.org/10.1016/j.heliyon.2022.e09403
  19. Front Oncol. 2022 ;12 864301
    Nano Drug Delivery System for Tumor Immunotherapy: Next-Generation Therapeutics.
    Lili Zhou, Manshu Zou, Yilin Xu, Peng Lin, Chang Lei, Xinhua Xia.
      Tumor immunotherapy is an artificial stimulation of the immune system to enhance anti-cancer response. It has become a powerful clinical strategy for treating cancer. The number of immunotherapy drug approvals has been increasing in recent years, and many treatments are in clinical and preclinical stages. Despite this progress, the special tumor heterogeneity and immunosuppressive microenvironment of solid tumors made immunotherapy in the majority of cancer cases difficult. Therefore, understanding how to improve the intratumoral enrichment degree and the response rate of various immunotherapy drugs is key to improve efficacy and control adverse reactions. With the development of materials science and nanotechnology, advanced biomaterials such as nanoparticle and drug delivery systems like T-cell delivery therapy can improve effectiveness of immunotherapy while reducing the toxic side effects on non-target cells, which offers innovative ideas for improving immunity therapeutic effectiveness. In this review, we discuss the mechanism of tumor cell immune escape and focus on current immunotherapy (such as cytokine immunotherapy, therapeutic monoclonal antibody immunotherapy, PD-1/PD-L1 therapy, CAR-T therapy, tumor vaccine, oncolytic virus, and other new types of immunity) and its challenges as well as the latest nanotechnology (such as bionic nanoparticles, self-assembled nanoparticles, deformable nanoparticles, photothermal effect nanoparticles, stimuli-responsive nanoparticles, and other types) applications in cancer immunotherapy.
    Keywords:  drug delivery; nanomedicine; nanotechnology; tumor immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2022.864301
  20. Macromol Biosci. 2022 Jun 08. e2200161
    Injectable and Self-Healing Polysaccharide Hydrogel Loading Molybdenum Disulfide Nanoflakes for Synergistic Photothermal-Photodynamic Therapy of Breast Cancer.
    Yujie Qi, Yifeng Yuan, Zhiyi Qian, Xiaodie Ma, Weizhong Yuan, Ye Song.
      In order to overcome the limitation of traditional therapies of cancer and improve the accuracy of treatment, more advantageous cancer treatment methods need to be explored and studied. As a result, photothermal photodynamic therapy of breast cancer using bovine serum albumin (BSA) modified molybdenum disulfide nanoflakes. Then the well-dispersed BSA-MoS2 NFs are loaded in the injectable and self-healing polysaccharide hydrogel which is prepared by the reaction of oxidized sodium alginate (OSA) and hydroxypropyl chitosan (HPCS) through the formation of Schiff base bonds. The injection and self-healing properties of the nanocomposite hydrogel are investigated. In vitro photothermal and photodynamic investigations demonstrated that BSA-MoS2 NFs possess obvious photothermal conversion and production of reactive oxygen species (ROS) under the irradiation of near infrared (NIR) laser (808 nm). In vivo anticancer investigation indicates that the nanocomposite hydrogel can be directly injected and remain in the tumor sites and achieve the synergistic photothermal-photodynamic therapy of cancer. This article is protected by copyright. All rights reserved.
    Keywords:  injectable and self-healing polysaccharide hydrogel; molybdenum disulfide nanoflakes; synergistic photothermal-photodynamic therapy
    DOI:  https://doi.org/10.1002/mabi.202200161
  21. Int J Pharm. 2022 Jun 04. pii: S0378-5173(22)00447-1. [Epub ahead of print]623 121892
    Dual-targeted and controlled release delivery of doxorubicin to breast adenocarcinoma: In vitro and in vivo studies.
    Zahra Jamshidi, Taraneh Sadat Zavvar, Mohammad Ramezani, Mona Alibolandi, Farzin Hadizadeh, Khalil Abnous, Seyed Mohammad Taghdisi.
      Doxorubicin (DOX) is a chemotherapeutic drug that belongs to the anthracyclines family. Cardiotoxicity is one of the main limiting factor of prescribing DOX. To reduce its side effects and enhance the drug delivery to the targeted tissues, we aimed to establish a new targeted and controlled release drug delivery system for treatment of breast cancer. In this article, we tried to synthesize a new nanoplatform consisted of DOX conjugate with hydrazide and disulfide bonds to the hyaluronic acid (HA). Firstly, 4,4'-Dithiodibutyric acid (DTBH) was conjugated with HA. Then, 3-aminophenyl boronic acid monohydrate (APBA) was conjugated with DTBH-HA. Subsequently, DOX was added to DTBH-HA-APBA. HA is a natural polymer with the ability to target CD44, a cell surface adhesion receptor, which are highly overexpressed on the surface of variety of cancer cells. Other targeting agent, APBA can target sialic acid on the cancer cells surface and improve the tumor uptake. Formation of The DTBH-HA-APBA conjugate was confirmed by proton nuclear magnetic resonance (1H NMR) spectroscopy. Scanning emission electron microscopy (SEM) images of the DOX-DTBH-HA-APBA displayed a spherical shape with an average diameter of about 70 nm. In vitro drug release study showed considerably different release pattern of DOX from the formulation at acidic pH (5.4) which was higher than normal pH (7.4). Cellular uptake and cellular cytotoxicity analysis were examined in human breast adenocarcinoma cell line (MCF-7) and mouse breast cancer cells (4T1) as positive cell lines and Chinese Hamster Ovary cells (CHO) as negative cell line. Results confirmed that there is a remarkable difference between dual-targeted (DOX-DTBH-HA-APBA) and single targeted (DOX-DTBH-HA) formulations in both positive cell lines regarding internalization and cytotoxicity. In vivo studies indicated that dual-targeted formulation has the best efficacy with minimum side effects in mouse model. Fluorescence imaging of organs revealed that DOX-DTBH-HA-APBA showed greater DOX accumulation compared with DOX-DTBH-HA and free DOX in tumor site. Also, pathological evaluation indicated that there is no observable cardiotoxicity with final formulation.
    Keywords:  3-Aminophenyl boronic acid; Breast cancer; Controlled release; Hyaluronic acid; Targeted delivery
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.121892
  22. J Control Release. 2022 Jun 07. pii: S0168-3659(22)00320-0. [Epub ahead of print]348 239-249
    Injectable alginate hydrogels for synergistic tumor combination therapy through repolarization of tumor-associated macrophages.
    Tingting Xiao, Jianzhi Zhu, Liang Jia, Hailong Che, Jie Liu, J Deckers, Jan C M van Hest, Xiangyang Shi.
      Locally administered drug delivery systems are promising as they allow to circumvent the side effects associated with systematic administration. In this study, we constructed multifunctional hydrogels by simply mixing commercial alginate (ALG) sols with glucose oxidase (GOx)-conjugated polyacrylic acid-stabilized iron oxide nanoparticles (GPI NPs) and Toll-like receptor 7/8 agonist resiquimod (R848). The injectable sols were able to transform into hydrogels (GPI/R848@ALG) by the ionic cross-linking between ALG and physiological Ca2+ to trap the therapeutic components within the hydrogel framework. Upon intratumoral injection, the hydrogels were employed for starvation therapy, promoted chemodynamic therapy and tumor-associated macrophages (TAMs) repolarization. The energy supply was blocked by consuming the intratumoral glucose via the GOx-catalyzed conversion of glucose into gluconic acid and hydrogen peroxide (H2O2).In vitro results showed that the generated H2O2 could be further converted into highly cytotoxic hydroxyl radicals (·HO) by the Fenton reaction to induce enhanced chemodynamic therapy. The TAMs repolarization studies in vitro exhibited that the GPI/R848@ALG hydrogels up-regulated the expression of CD86 by 63% and down-regulated the proportion of CD206 by 14% with a synergistic effect of the presence of Fe3O4 and R848, suggesting that the multifunctional hydrogels exert functions to direct the remodeling of TAMs from the tumor supportive M2-like phenotype to the tumor destructive M1-like phenotype to further contribute to the antitumor effect. Moreover, both in vitro and in vivo experiments demonstrate that the multifunctional hydrogels exhibit admirable antitumor performance towards 4T1 tumors. This work thereby provides a promising multifunctional nanoplatform for synergistic cancer starvation therapy, chemodynamic therapy and TAMs repolarization.
    Keywords:  Combination therapy; Ferromagnetic nanoparticles; Glucose oxidase; Injectable hydrogels; Resiquimod; Tumor-associated macrophages repolarization
    DOI:  https://doi.org/10.1016/j.jconrel.2022.05.049
  23. Molecules. 2022 May 26. pii: 3446. [Epub ahead of print]27(11):
    Insights into Aptamer-Drug Delivery Systems against Prostate Cancer.
    Xueni Wang, Qian Zhou, Xiaoning Li, Xia Gan, Peng Liu, Xiaotao Feng, Gang Fang, Yonghong Liu.
      Prostate cancer is a common cancer in elderly males. Significant progress has been made in the drug therapies for prostate cancer in recent years. However, side effects are still problems that have not been overcome by the currently used anti-prostate cancer drugs. Novel technologies can be applied to reduce or even eliminate the side effects of drugs. An aptamer may be a sequence of nucleic acids or peptides that can specifically recognize proteins or cells. Taking advantage of this feature, scientists have designed aptamer-drug delivery systems for the development of anti-prostate cancer agents. Theoretically, these aptamer-drug delivery systems can specifically recognize prostate cancer cells and then induce cell death without attacking normal cells. We collected the relevant literature in this field and found that at least nine compounds have been prepared as aptamer-drug delivery systems to evaluate their precise anti-prostate cancer effects. However, the currently studied aptamer-drug delivery systems have not yet entered the market due to defects. Here, we analyze the published data, summarize the characteristics of these delivery systems, and propose ways to promote their application, thus promoting the development of the aptamer-drug delivery systems against prostate cancer.
    Keywords:  aptamer; curcumin; docetaxel; doxorubicin; drug delivery systems; paclitaxel; prostate cancer; thymoquinone
    DOI:  https://doi.org/10.3390/molecules27113446
  24. Nanoscale. 2022 Jun 08.
    Zeolitic imidazolate framework-based nanoparticles for the cascade enhancement of cancer chemodynamic therapy by targeting glutamine metabolism.
    Hui Jian, Yun Zhang, Junyue Wang, Zhenxiang Chen, Tingyi Wen.
      The reprogrammed amino acid metabolism maintains the powerful antioxidant defense and DNA damage repair capacity of cancer cells, which could promote their escape from reactive oxygen species (ROS)-induced damage and inevitably diminish the efficacy of ROS-based therapies. Herein, we propose a strategy to enhance the effect of chemodynamic therapy (CDT) via glutaminolysis-targeted inhibition for cancer cells dependent on abnormal glutamine metabolism. To screen optimum drugs targeting glutamine metabolism, transcriptomic analysis is performed to identify predictive biomarkers. Eventually, telaglenastat (CB-839) is used to block mitochondrial glutaminase 1 (GLS 1) in basal-like breast cancer and loaded into the developed iron-doped zeolitic imidazolate frameworks (ZIF(Fe) NPs) to form ZIF(Fe)&CB nanoparticles, which are able to co-deliver Fe2+ and CB-839 into the tumor. CB-839 induced-glutaminolysis inhibition not only reduces intracellular antioxidants (glutathione, taurine) to amplify Fe2+-induced oxidative stress, but also decreases nucleotide pools (e.g., adenosine, dihydroorotate) to incur the deficiency of building blocks for DNA damage repair, thereby promoting the cell-killing effect of CDT. In vivo assessments further confirm the enhanced anticancer performance and good biocompatibility of ZIF(Fe)&CB nanoparticles. This study provides a promising strategy for the development and improvement of ROS-based anticancer nanosystems.
    DOI:  https://doi.org/10.1039/d2nr01736a
  25. J Control Release. 2022 Jun 07. pii: S0168-3659(22)00327-3. [Epub ahead of print]348 206-238
    Preparation and application of pH-responsive drug delivery systems.
    Haitao Ding, Ping Tan, Shiqin Fu, Xiaohe Tian, Hu Zhang, Xuelei Ma, Zhongwei Gu, Kui Luo.
      Microenvironment-responsive drug delivery systems (DDSs) can achieve targeted drug delivery, reduce drug side effects and improve drug efficacies. Among them, pH-responsive DDSs have gained popularity since the pH in the diseased tissues such as cancer, bacterial infection and inflammation differs from a physiological pH of 7.4 and this difference could be harnessed for DDSs to release encapsulated drugs specifically to these diseased tissues. A variety of synthetic approaches have been developed to prepare pH-sensitive DDSs, including introduction of a variety of pH-sensitive chemical bonds or protonated/deprotonated chemical groups. A myriad of nano DDSs have been explored to be pH-responsive, including liposomes, micelles, hydrogels, dendritic macromolecules and organic-inorganic hybrid nanoparticles, and micron level microspheres. The prodrugs from drug-loaded pH-sensitive nano DDSs have been applied in research on anticancer therapy and diagnosis of cancer, inflammation, antibacterial infection, and neurological diseases. We have systematically summarized synthesis strategies of pH-stimulating DDSs, illustrated commonly used and recently developed nanocarriers for these DDSs and covered their potential in different biomedical applications, which may spark new ideas for the development and application of pH-sensitive nano DDSs.
    Keywords:  Controlled drug release; Drug delivery systems; Drug-loading/conjugate; Nanomedicine; pH-sensitive
    DOI:  https://doi.org/10.1016/j.jconrel.2022.05.056
  26. Front Pharmacol. 2022 ;13 889816
    Curcumin and Related Compounds in Cancer Cells: New Avenues for Old Molecules.
    Matteo Costantino, Cristina Corno, Diego Colombo, Paola Perego.
      Curcumin and related compounds are known for the large spectrum of activities. The chemical features of these compounds are important for their biological effects with a key role for the thiol-reactive α-β unsaturated carbonyl groups. Curcumin derivatives may overcome the limitation of the bioavailability of the parent compound, while maintaining the key chemical features responsible for biological activities. Curcumin and related compounds show anti-viral, anti-fungal, anti-microbial and anti-tumor activities. The therapeutic effects of curcumin, used as a supplement in cancer therapy, have been documented in various cancer types, in which inhibition of cell growth and survival pathways, induction of apoptosis and other cell death pathways have been reported. Curcumin-induced apoptosis has been linked both to the intrinsic and extrinsic apoptotic pathways. Necroptosis has also been involved in curcumin-induced toxicity. Among curcumin-induced effects, ferroptosis has also been described. The mechanism of curcumin toxicity can be triggered by reactive oxygen species-mediated endoplasmic reticulum stress. Curcumin targets have been identified in the context of the ubiquitin-proteasome system with evidence of inhibition of the proteasome proteolytic activities and cellular deubiquitinases. Curcumin has recently been shown to act on the tumor microenvironment with effects on cancer-associated fibroblasts and immune cells. The related product caffeic acid phenethyl ester has shown promising preclinical results with an effect on the inflammatory microenvironment. Here, we review the mechanisms underlying curcumin and derivatives toxicity towards cancer cells with particular emphasis on cell death pathways and the ubiquitin-proteasome system.
    Keywords:  cancer; cell death; curcumin; deubiquitinases; proteasome
    DOI:  https://doi.org/10.3389/fphar.2022.889816
  27. Molecules. 2022 May 25. pii: 3412. [Epub ahead of print]27(11):
    A Review of Twenty Years of Research on the Regulation of Signaling Pathways by Natural Products in Breast Cancer.
    Muhammad Naeem, Muhammad Omer Iqbal, Humaira Khan, Muhammad Masood Ahmed, Muhammad Farooq, Muhammad Moeen Aadil, Mohamad Ikhwan Jamaludin, Abu Hazafa, Wan-Chi Tsai.
      Breast cancer (BC) is the second leading cause of death among women, and it has become a global health issue due to the increasing number of cases. Different treatment options, including radiotherapy, surgery, chemotherapy and anti-estrogen therapy, aromatase inhibitors, anti-angiogenesis drugs, and anthracyclines, are available for BC treatment. However, due to its high occurrence and disease progression, effective therapeutic options for metastatic BC are still lacking. Considering this scenario, there is an urgent need for an effective therapeutic strategy to meet the current challenges of BC. Natural products have been screened as anticancer agents as they are cost-effective, possess low toxicity and fewer side effects, and are considered alternative therapeutic options for BC therapy. Natural products showed anticancer activities against BC through the inhibition of angiogenesis, cell migrations, proliferations, and tumor growth; cell cycle arrest by inducing apoptosis and cell death, the downstream regulation of signaling pathways (such as Notch, NF-κB, PI3K/Akt/mTOR, MAPK/ERK, and NFAT-MDM2), and the regulation of EMT processes. Natural products also acted synergistically to overcome the drug resistance issue, thus improving their efficacy as an emerging therapeutic option for BC therapy. This review focused on the emerging roles of novel natural products and derived bioactive compounds as therapeutic agents against BC. The present review also discussed the mechanism of action through signaling pathways and the synergistic approach of natural compounds to improve their efficacy. We discussed the recent in vivo and in vitro studies for exploring the overexpression of oncogenes in the case of BC and the current status of newly discovered natural products in clinical investigations.
    Keywords:  breast cancer; combination therapy; natural products; signaling pathways; therapeutic agents; transcription factors; treatment
    DOI:  https://doi.org/10.3390/molecules27113412
  28. ACS Appl Mater Interfaces. 2022 Jun 08.
    Multifunction in One Nanoparticle for Anticancer Therapy: Bowl-Shaped Au@PDA Yolk-Shell NPs.
    Xin Ding, Tianyu Wang, Shiwei Bai, Yunfeng Wan, Shuai Zhu, Tao Li, Na Peng, Tao Qiu, Yi Liu.
      Multifunctional nanoparticles (NPs) with simultaneous multimodal therapeutic and imaging capabilities are very necessary for biomedical applications. We successfully prepared bowl-shaped gold@polydopamine yolk-shell NPs (bowl-shaped Au@PDA YNPs) by a novel and facile method. The unique bowl-like structure enables a drug loading rate of 92% (920 μg mg-1). The bowl-shaped Au@PDA YNPs are biocompatible, have good photothermal conversion and strong near-infrared (NIR) absorption, and can control drug release under pH/NIR dual response. Bowl-shaped Au@PDA YNPs can also be employed as contrast agents for computed tomography/photoacoustic imaging for dual-modal imaging-guided chemotherapy and photothermal therapy due to the presence of Au NPs.
    Keywords:  CT/PA imaging; bowl-shaped nanoparticles; chemotherapy; pH/NIR dual-responsive properties; photothermal therapy
    DOI:  https://doi.org/10.1021/acsami.2c07671
  29. Molecules. 2022 Jun 01. pii: 3566. [Epub ahead of print]27(11):
    Phytochemistry and Biological Activity of Medicinal Plants in Wound Healing: An Overview of Current Research.
    Stefania Vitale, Sara Colanero, Martina Placidi, Giovanna Di Emidio, Carla Tatone, Fernanda Amicarelli, Anna Maria D'Alessandro.
      Wound healing is a complicated process, and the effective management of wounds is a major challenge. Natural herbal remedies have now become fundamental for the management of skin disorders and the treatment of skin infections due to the side effects of modern medicine and lower price for herbal products. The aim of the present study is to summarize the most recent in vitro, in vivo, and clinical studies on major herbal preparations, their phytochemical constituents, and new formulations for wound management. Research reveals that several herbal medicaments have marked activity in the management of wounds and that this activity is ascribed to flavonoids, alkaloids, saponins, and phenolic compounds. These phytochemicals can act at different stages of the process by means of various mechanisms, including anti-inflammatory, antimicrobial, antioxidant, collagen synthesis stimulating, cell proliferation, and angiogenic effects. The application of natural compounds using nanotechnology systems may provide significant improvement in the efficacy of wound treatments. Increasing the clinical use of these therapies would require safety assessment in clinical trials.
    Keywords:  herbs; medicinal plants; natural wound dressing; secondary metabolites; skin disorders; wound healing
    DOI:  https://doi.org/10.3390/molecules27113566
  30. Curr Drug Deliv. 2022 Jun 08.
    Gastroretentive Drug Delivery System in Cancer Chemotherapy.
    Pooja Anothra, Deepak Pradhan, Jitu Halder, Goutam Ghosh, Goutam Rath.
       BACKGROUND: Chemotherapy for stomach cancer often includes several side effects. The primary reasons for the failure of such treatment approaches are low drug concentrations in target tissues and a short stomach residence time.
    OBJECTIVE: Gastroretentive controlled drug delivery systems because of the longer gastric retention time improves the therapeutic performance of chemotherapeutic drugs following oral administration. The goal of this study was to find suitable gastroretentive formulations that might be used for localized treatment of stomach cancer.
    METHOD: The purpose of this study is to summarize current advances in gastro-retentive drug administration for oral chemotherapy, with a focus on floating, mucoadhesive, and swellable systems. This article also discusses the potentials and limitations of existing gastroretentive drug delivery systems used in cancer chemotherapy.
    RESULT: Due to increased stomach retention and modified drug release properties, gastroretentive controlled drug delivery systems improve the therapeutic performance of anti-cancer drugs used to treat stomach cancer.
    CONCLUSION: Gastroretentive drug delivery systems appear to be a promising carrier for localized chemotherapy with smaller doses and better patient compliance. However, selection of drug candidates, drug-food interactions and chemotherapy induced gastric discomfort remain the key characteristics that must be addressed to improve treatment outcomes.
    Keywords:  Gastroretentive; chemotherapy.; floating; gastric cancer; mucoadhesive; swellable
    DOI:  https://doi.org/10.2174/1567201819666220608141124
  31. Curr Drug Metab. 2022 Jun 08.
    An Overview of the Neuropharmacological Potential of Thymoquinone and its Targeted Delivery Prospects for CNS Disorder.
    Rishabh Verma, Ali Sartaj, Farheen Fatima Qizilbash, Mohammed M Ghoneim, Sultan Alshehri, Syed Sarim Imam, Chandra Kala, Md Shamsher Alam, Sadaf Jamal Gilani, Mohamad Taleuzzaman.
      At present, people and patients worldwide are relying on the medicinal plant as a therapeutic agent over pharmaceuticals because the medicinal plant is considered safer, especially for chronic disorders. Several medicinal plants and their components are being researched and explored for their possible therapeutic contribution to CNS disorders. Thymoquinone (TQ) is one such molecule. Thymoquinone, one of the constituents of Plant Nigella Sativa, is effective against several neurodegenerative diseases like; Alzheimer's, Depression, Encephalomyelitis, Epilepsy, Ischemia, Parkinson's, and Traumatic. This review article presents the neuropharmacological potential of TQ's, their challenges, and delivery prospects, explicitly focusing on neurological disorders along with their chemistry, pharmacokinetics, and toxicity. Since TQ has some pharmacokinetic challenges, scientists have focused on novel formulations and delivery systems to enhance bioavailability and ultimately increase its therapeutic value. In the present work, the role of nanotechnology in neurodegenerative disease and how it improves bioavailability and delivery of a drug to the site of action has been discussed. There are a few limitations for developing novel drug formulation, including solubility, pH, and compatibility of nanomaterials. Since here we are targeting CNS disorders, the blood-brain barrier (BBB) becomes an additional challenge Hence, the review summarized the novel aspects of delivery and biocompatible nanoparticles-based approaches for targeted drug delivery into CNS, enhancing TQ bioavailability and its neurotherapeutic effects.
    Keywords:  BBB.; Bioavailability; CNS disorder; Neuropharmacological; Thymoquinone
    DOI:  https://doi.org/10.2174/1389200223666220608142506
  32. Biomed Pharmacother. 2022 Jun;pii: S0753-3322(22)00443-7. [Epub ahead of print]150 113054
    Targeting cancer signaling pathways by natural products: Exploring promising anti-cancer agents.
    Sheema Hashem, Tayyiba Akbar Ali, Sabah Akhtar, Sabah Nisar, Geetanjali Sageena, Shahid Ali, Sharefa Al-Mannai, Lubna Therachiyil, Rashid Mir, Imadeldin Elfaki, Mohammad Muzaffar Mir, Farrukh Jamal, Tariq Masoodi, Shahab Uddin, Mayank Singh, Mohammad Haris, Muzafar Macha, Ajaz A Bhat.
      Cancer is one of the leading causes of death and significantly burdens the healthcare system. Due to its prevalence, there is undoubtedly an unmet need to discover novel anticancer drugs. The use of natural products as anticancer agents is an acceptable therapeutic approach due to accessibility, applicability, and reduced cytotoxicity. Natural products have been an incomparable source of anticancer drugs in the modern era of drug discovery. Along with their derivatives and analogs, natural products play a major role in cancer treatment by modulating the cancer microenvironment and different signaling pathways. These compounds are effective against several signaling pathways, mainly cell death pathways (apoptosis and autophagy) and embryonic developmental pathways (Notch pathway, Wnt pathway, and Hedgehog pathway). The historical record of natural products is strong, but there is a need to investigate the current role of natural products in the discovery and development of cancer drugs and determine the possibility of natural products being an important source of future therapeutic agents. Many target-specific anticancer drugs failed to provide successful results, which accounts for a need to investigate natural products with multi-target characteristics to achieve better outcomes. The potential of natural products to be promising novel compounds for cancer treatment makes them an important area of research. This review explores the significance of natural products in inhibiting the various signaling pathways that serve as drivers of carcinogenesis and thus pave the way for developing and discovering anticancer drugs.
    Keywords:  Apoptosis; Natural products; Proliferation; Signaling pathways; Tumor
    DOI:  https://doi.org/10.1016/j.biopha.2022.113054
  33. Acta Biomater. 2022 Jun 05. pii: S1742-7061(22)00338-5. [Epub ahead of print]
    Biomimetic smart mesoporous carbon nanozyme as a dual-GSH depletion agent and O2 generator for enhanced photodynamic therapy.
    Junya Lu, Yuling Mao, Shuaipeng Feng, Xian Li, Yikun Gao, Qinfu Zhao, Siling Wang.
      Photodynamic therapy (PDT) has been thriving in the theranostics of cancer in recent years. However, due to a series of problems such as high concentration of GSH and insufficient O2 partial pressure in the tumor micro-environment, it is difficult to achieve the desired therapeutic effects with single PDT. Mesoporous carbon (MC-COOH) has been widely used in photothermal therapy (PTT) due to its high photothermal conversion efficiency and drug loading. In addition, we have discovered that MC-COOH owned high-efficiency glutathione oxidase-like activity for intracellular lasting GSH consumption. Hence, a smart mesoporous carbon nanozyme (CCM) was designed as a dual-GSH depletion agent and O2 generator combined with PTT to overcome the dilemma of PDT. MnO2-doped carbon nanozyme (MC-Mn) was developed as the photothermal vehicles for the efficient loading of photosensitizer (Ce6). Subsequently, 4T1 membrane-coated nanozyme (Ce6/CCM) was constructed to achieve homologous targeting capability. The carbon nanozyme owned the sustained dual-GSH depletion function through MC-COOH and MnO2, which greatly destroyed the antioxidant system of the tumor. Meanwhile, MnO2 could produce affluent O2 in the presence of H2O2, thereby alleviating the hypoxic state of tumor tissues and further promoting the generation of ROS. In addition, the novel carbon nanozyme was designed as photoacoustic imaging (PAI) agent and magnetic resonance imaging (MRI) contrast for real-time imaging during tumor therapy. In summary, this work showed that the biomimetic carbon nanozyme could be used as dual-GSH depletion agent and O2 generator for dual-mode imaging-guided PTT-PDT. STATEMENT OF SIGNIFICANCE: - MC-COOH with highly efficient GSH-OXD activity was first discovered and applied in PDT. - MnO2 acted as an O2 generator and GSH depletion agent to enhance PDT. - The tumor-targeting ability of the nanozyme was improved by cell membrane camouflage. - CCM nanozyme possesses both PAI and MRI dual-mode imaging modalities to guide PDT/PTT.
    Keywords:  Mesoporous carbon nanozyme; O(2) generator; dual-mode imaging; glutathione oxidase-like activity; photodynamic therapy
    DOI:  https://doi.org/10.1016/j.actbio.2022.06.001
  34. Nutr Cancer. 2022 Jun 08. 1-19
    The Potential of Plant-Derived Extracts and Compounds to Augment Anticancer Effects of Chemotherapeutic Drugs.
    Chu Xin Ng, Muzaira Mazrul Affendi, Pei Pei Chong, Sau Har Lee.
      Plant extracts comprise a complex mixture of natural compounds with diverse biological activities including anticancer activities. This has made the use of plant extracts a trending strategy in cancer treatment. In addition, plants' active constituents such as polyphenols could confer protective effects on normal cells against damage by free radicals as well as lessen the toxicity of chemotherapeutic drugs. Recently, many emerging studies revealed the combinatory uses of plant extracts and individual therapeutic compounds that could be a promising panacea in hampering multiple signaling pathways involved in cancer development and progression. Besides enhancing the therapeutic efficacy, this has also been proven to reduce the dosage of chemotherapeutic drugs used, and hence overcome multiple drug resistance and minimize treatment side effects. Notably, combined use of plant extracts with chemotherapeutics drugs was shown to enhance anticancer effects through modulating various signaling pathways, such as P13K/AKT, NF-κB, JNK, ERK, WNT/β-catenin, and many more. Hence, this review aims to comprehensively summarize both In Vitro and In Vivo mechanisms of actions of well-studied plant extracts, such as Ganoderma Lucidum, Korean red ginseng, Garcinia sp., curcumin, and luteolin extracts in augmenting anticancer properties of the conventional chemotherapeutic drugs from an extensive literature search of recent publications.
    DOI:  https://doi.org/10.1080/01635581.2022.2069274
  35. Molecules. 2022 May 27. pii: 3460. [Epub ahead of print]27(11):
    A Mini-Review on Solid Lipid Nanoparticles and Nanostructured Lipid Carriers: Topical Delivery of Phytochemicals for the Treatment of Acne Vulgaris.
    Romchat Chutoprapat, Peerawas Kopongpanich, Lai Wah Chan.
      Acne vulgaris (acne) is one of the most common dermatological problems affecting adolescents and young adults. Although acne may not lead to serious medical complications, its psychosocial effects are tremendous and scientifically proven. The first-line treatment for acne is topical medications composed of synthetic compounds, which usually cause skin irritation, dryness and itch. Therefore, naturally occurring constituents from plants (phytochemicals), which are generally regarded as safe, have received much attention as an alternative source of treatment. However, the degradation of phytochemicals under high temperature, light and oxygen, and their poor penetration across the skin barrier limit their application in dermatology. Encapsulation in lipid nanoparticles is one of the strategies commonly used to deliver drugs and phytochemicals because it allows appropriate concentrations of these substances to be delivered to the site of action with minimal side effects. Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) are promising delivery systems developed from the combination of lipid and emulsifier. They have numerous advantages that include biocompatibility and biodegradability of lipid materials, enhancement of drug solubility and stability, ease of modulation of drug release, ease of scale-up, feasibility of incorporation of both hydrophilic and lipophilic drugs and occlusive moisturization, which make them very attractive carriers for delivery of bioactive compounds for treating skin ailments such as acne. In this review, the concepts of SLNs and NLCs, methods of preparation, characterization, and their application in the encapsulation of anti-acne phytochemicals will be discussed.
    Keywords:  acne vulgaris; nanostructured lipid carriers; phytochemicals; solid lipid nanoparticles; topical application
    DOI:  https://doi.org/10.3390/molecules27113460
  36. Biomater Sci. 2022 Jun 10.
    Anticancer therapeutic effect of cerium-based nanoparticles: known and unknown molecular mechanisms.
    Maria John Newton Amaldoss, Rashid Mehmood, Jia-Lin Yang, Pramod Koshy, Naresh Kumar, Ashwin Unnikrishnan, Charles C Sorrell.
      Cerium-based nanoparticles (CeNPs), particularly cerium oxide (CeO2), have been studied extensively for their antioxidant and prooxidant properties. However, their complete redox and enzyme-mimetic mechanisms of therapeutic action at the molecular level remain elusive, constraining their potential for clinical translation. Although the therapeutic effects of both antioxidant and prooxidant mechanisms generally are attributed to Ce3+ ↔ Ce4+ redox switching mediation, some studies have hinted at the involvement of unknown pathways in therapeutic effects. While redox switching is recognised increasingly as playing a key role in ROS-dependent cancer therapy, ROS-independent cytotoxicity mechanisms, such as Ce4+ dissolution and autophagy, also are emerging as being of importance. Although ROS-mediated prooxidant therapies are the most intensively studied, particularly in the context of cancer, the antioxidant activity deriving from the redox switching, particularly during radiation therapy, also plays an important role in the protection of normal cells during radiation therapy, hence reducing adverse effects. Since cancer cell proliferation results in aberrant behaviour of the tumour microenvironment (TME), then CeNP-based therapies are being used to address a multiplicity of known and unknown factors that aim to normalise the TME and thus prevent this aberrant behaviour. Although it is perceived that the pH plays a key role in the therapeutic performance of cerium-based nanoparticles, this is not conclusive because the relative importances of other factors, particularly Ce dissolution, Ce3+/Ce4+ ratio, cellular H2O2 level, and the role of anions, remain poorly understood. Consequently, the present work explores these multiple chemistry-driven mechanisms, which are both ROS-dependent and ROS-independent, in cancer therapy.
    DOI:  https://doi.org/10.1039/d2bm00334a
  37. Polymers (Basel). 2022 May 29. pii: 2207. [Epub ahead of print]14(11):
    3-O-Ethyl-L-Ascorbic Acid Doped Enteric-Coated Gelatin Capsules towards the Advanced Oral Curcumin Delivery for Cancers.
    Dong-Jin Lim.
      Among plant-derived polyphenols, curcumin has been recognized as a therapeutically potent nutrient presenting pleiotropic pharmacological effects on various cancers. However, the poor absorption and bioavailability of curcumin limit the use of this excellent naturally occurring polyphenol. 3-O-ethyl-L-ascorbic acid (EA) doped enteric-coated gelatin capsules were studied in the search for advanced oral curcumin delivery. The EA doped enteric-coated gelatin capsules were successfully created based on a developed inner dual enteric coating technique. When placed in four buffer solutions with different pHs (pH 2.0, 5.0, 6.0, and 7.3), the coated gelatin capsules showed delayed-release profiles of curcumin below pH 6.0. In contrast, both pristine and fabricated gelatin capsules showed similar curcumin release profiles at pH 7.3, which is a common pH observed in the lower gastrointestinal tract, especially intestinal regions. In conclusion, these results demonstrated the potential of the EA doped enteric-coated gelatin capsules in developing advanced oral delivery of curcumin targeting intestinal-specific regions.
    Keywords:  3-O-ethyl-L-ascorbic acid; cancer prevention; curcumin; gastrointestinal drug delivery; oral drug delivery
    DOI:  https://doi.org/10.3390/polym14112207
  38. ACS Biomater Sci Eng. 2022 Jun 09.
    Enzymatic Synthesis of Peptide Nanofibers for Self-Delivery of Indomethacin and Tyroservatide in Cancer Therapy.
    Chunlu Wang, Yaoyao Zheng, Yaxin Zheng, Can Wu, Xiujie Wang, Menghua Huang, Xiaoxing Wu, Wenying Zhong, Keming Xu.
      Non-steroidal anti-inflammatory drugs (NSAIDs) have drawn considerable attention in the field of cancer treatment, yet these drugs display limited potency and selectivity against cancer cells. To address these problems, we designed a peptide-based self-delivery system [Indomethacin-Phe-Phe-Tyr (H2PO3)-Ser-Val, IDM-FFpYSV] that combines an NSAID molecule (indomethacin, or IDM) and a segment of anticancer tripeptide (tyroservatide, or YSV). IDM-FFpYSV is capable of self-assembling in an aqueous solution to afford nanofibrillar hydrogels under the catalysis of alkaline phosphatases (ALPs), which are overexpressed on the plasma membrane of cancer cells. The IDM-FFpYSV + ALP hydrogel displays a continuous release profile of peptide drugs, whereas a solution mixture of pure drugs (IDM-OH + pYSV + ALP) shows burst release of drug moieties. The treatment of IDM-FFpYSV selectively inhibits the proliferation of HeLa cells in vitro, with precise regulations of intracellular targeting proteins (COX-2 and AC-H3). The enhanced potency and selectivity of IDM-FFpYSV are found to be attributed to enhanced cellular uptake of peptide drugs, which involves a caveolae-mediated endocytosis pathway. Furthermore, intravenous administration of the IDM-FFpYSV formulation significantly inhibits the tumor growth in a HeLa-xenografted mouse model, whereas treatment of solution mixtures of pure drugs (IDM-OH + pYSV) fails to do so. Taken together, the study provides a viable strategy to augment anticancer efficacies of self-delivery system through molecular integration of multiple anticancer elements with an enzyme-instructed self-assembly process.
    Keywords:  cancer; enzyme; hydrogel; indomethacin; self-assembly
    DOI:  https://doi.org/10.1021/acsbiomaterials.2c00574
  39. Front Pharmacol. 2022 ;13 870282
    Aconiti Lateralis Radix Praeparata as Potential Anticancer Herb: Bioactive Compounds and Molecular Mechanisms.
    Wen Zhang, Chaoying Lu, Shuhui Cai, Yaru Feng, Jinjun Shan, Liuqing Di.
      Aconiti Lateralis Radix Praeparata (Fuzi in Chinese) is a traditional herbal medicine widely used in China and other Asian countries. In clinical practice, it is often used to treat heart failure, rheumatoid arthritis, and different kinds of pains. Fuzi extract and its active ingredients exert considerable anticancer, anti-inflammatory, and analgesic effects. The main chemical substances of Fuzi include alkaloids, polysaccharides, flavonoids, fatty acids, and sterols. Among of them, alkaloids and polysaccharides are responsible for the anticancer efficacy. Most bioactive alkaloids in Fuzi possess C19 diterpenoid mother nucleus and these natural products show great potential for cancer therapy. Moreover, polysaccharides exert extraordinary tumor-suppressive functions. This review comprehensively summarized the active ingredients, antineoplastic effects, and molecular mechanisms of Fuzi by searching PubMed, Web of Science, ScienceDirect, and CNKI. The anticancer effects are largely attributed to inducing apoptosis and autophagy, inhibiting proliferation, migration and invasion, regulating body immunity, affecting energy metabolism, as well as reversing multidrug resistance. Meanwhile, several signaling pathways and biological processes are mainly involved, such as NF-κB, EMT, HIF-1, p38 MAPK, PI3K/AKT/mTOR, and TCA cycle. Collectively, alkaloids and polysaccharides in Fuzi might serve as attractive therapeutic candidates for the development of anticancer drugs. This review would lay a foundation and provide a basis for further basic research and clinical application of Fuzi.
    Keywords:  Aconiti Lateralis Radix Praeparata; Fuzi; alkaloid; anticancer; mechanism; polysaccharide
    DOI:  https://doi.org/10.3389/fphar.2022.870282
  40. Front Nutr. 2022 ;9 878306
    Eryngium Species as a Potential Ally for Treating Metabolic Syndrome and Diabetes.
    Eréndira Patricia Pérez-Muñoz, Marilena Antunes-Ricardo, Mariana Martínez-Ávila, Daniel Guajardo-Flores.
      Medicinal plants possess natural compounds that can be used as an alternative for synthetic medicines that may cause long-term side effects on patients such as neurocognitive effects, muscular and hepatic toxicity. Metabolic Syndrome is associated with increased risk of several diseases such as diabetes, cardiovascular disease, dyslipidemia, and hypertension thus, becoming the greatest challenge as a growing public health concern worldwide. Latin-American countries possess a wide diversity of medicinal plants that have been used to treat different health conditions since pre-Hispanic times. Eryngium spp. has been studied due to their beneficial properties mainly to treat diabetes, dyslipidemia, blood pressure, and digestive problems. This review gives an update mainly on the pharmacological activities of the Eryngium spp., summarizing the biological activities and plausible mechanism of action of their bioactive components toward metabolic syndrome. For instance, flavonoids and tannins proved to increase the levels of HDL and reduced the levels of VLDL, LDL. On the other hand, phenolic acids improved glucose metabolism through the inhibition of phosphoenolpyruvate carboxykinase and glucose 6-phosphatase (G6Pase) and reestablished the impaired activity of enzymes related to glucose oxidation and glycogen synthesis. The terpenes and sesquiterpenes like β-farnese, β-pinene, and calamenene exhibited a protective effect by reducing the oxidizing damage by the regulation of the Reactive Oxygen Species (ROS). Saponins controlled the dyslipidemia by reducing the serum concentrations of lipids, triglycerides and total cholesterol. Finally, the aerial parts of Eryngium had the capacity of inhibiting dietary carbohydrate digestive enzymes, thus controlling glucose levels. The Eryngium plant is normally consumed as an infusion to obtain the benefits of the plants, however novel technologies such as cavitation, ultrasound assisted, microwave assisted, and supercritical fluid have been applied to improve the extraction yields and selectivity of bioactive compounds. The common treatment to control diabetic dyslipidemia are synthetic medicines such as metformin and ezetimibe, which allows the regulation of glucose, cholesterol and insulin resistance. However, patients that take these medications may present side effects such as muscular toxicity, hepatic toxicity, neurocognitive effects, just to name a few. More studies regarding the efficacy and safety of the use of traditional medicinal herbs are required. However, these materials may be used in the treatment of diabetes related conditions to ensure life quality and reduce side effects among the diabetic population.
    Keywords:  Eryngium; diabetes; dyslipidemia; medicinal plant; metabolic syndrome
    DOI:  https://doi.org/10.3389/fnut.2022.878306
  41. Front Pharmacol. 2022 ;13 879748
    The Combination of a Novel GLUT1 Inhibitor and Cisplatin Synergistically Inhibits Breast Cancer Cell Growth By Enhancing the DNA Damaging Effect and Modulating the Akt/mTOR and MAPK Signaling Pathways.
    Hao-Cheng Weng, Chieh-Ju Sung, Jui-Ling Hsu, Wohn-Jenn Leu, Jih-Hwa Guh, Fan-Lu Kung, Lih-Ching Hsu.
      Breast cancer is the most prevalent cancer and the second leading cause of cancer death in women. Cisplatin is a commonly used chemotherapeutic drug for breast cancer treatment. Owing to serious side effects, the combination of cisplatin with other drugs is an effective strategy to simultaneously reduce side effects and increase the anticancer efficacy. GLUT1 is an emerging target for cancer treatment since cancer cells usually consume more glucose, a phenomenon called the Warburg effect. In this study, we found that the combination of cisplatin and a novel GLUT1 inhibitor #43 identified from our previous high-throughput screening exerted a synergistic anticancer effect in MCF-7 and MDA-MB-231 breast cancer cells. Mechanism studies in MCF-7 cells revealed that combination of cisplatin and #43 significantly induced apoptosis, intracellular reactive oxygen species, and loss of mitochondrial membrane potential. Furthermore, #43 enhanced the DNA damaging effect of cisplatin. Akt/mTOR downstream signaling and the ERK signaling pathway usually involved in cell growth and survival were inhibited by the combination treatment. On the other hand, phosphorylation of p38 and JNK, which may be associated with apoptosis, was induced by the combination treatment. Altogether, our data indicate that oxidative stress, DNA damage, the Akt/mTOR and MAPK signaling pathways, and apoptosis may be involved in the synergism of cisplatin and #43 in breast cancer cells.
    Keywords:  Akt/mTOR and MAPK signaling pathways; DNA damage; GLUT1 inhibitor; breast cancer; cisplatin; oxidative stress
    DOI:  https://doi.org/10.3389/fphar.2022.879748
  42. Food Funct. 2022 Jun 06.
    Therapeutic effects of ginseng and ginsenosides on colorectal cancer.
    Linxian Zhao, Yueming Zhang, Yajuan Li, Chen Li, Kai Shi, Kai Zhang, Ning Liu.
      Colorectal cancer (CRC) is among the most common malignant diseases with high morbidity and mortality rates. Ginseng and its major extracts, ginsenosides, have been used in medical fields for thousands of years. In particular, their huge anti-cancer potential has drawn a great deal of attention in recent years. There is a large body of evidence that has shown that ginseng and its extracts could significantly inhibit tumor development and progression by suppressing cell proliferation, tumor growth, invasion and metastasis, inducing tumor cell apoptosis, regulating tumor-associated immune responses, and improving the therapeutic effect of chemotherapy. Notably, different subtypes of ginsenosides, even those extracted from the same ginseng, have exhibited distinct anti-cancer functions through different mechanisms. Over the past few years, a large number of studies have focused on how ginseng or various ginsenosides influence CRC development. Therefore, the roles and the potential of ginseng and ginsenosides in the treatment of CRC are summarized in this review. In addition, the biochemical properties of ginseng and ginsenosides are also briefly described.
    DOI:  https://doi.org/10.1039/d2fo00899h
  43. J Trace Elem Med Biol. 2022 May 24. pii: S0946-672X(22)00086-4. [Epub ahead of print]73 127006
    Selenium nanoparticles coupling with Astragalus Polysaccharides exert their cytotoxicities in MCF-7 cells by inhibiting autophagy and promoting apoptosis.
    Zhiyu Duan, Madan Liang, Congcong Yang, Chaoqun Yan, Liwei Wang, Jiaqi Song, Lingling Han, Yuzhu Fan, Wen Li, Taigang Liang, Qingshan Li.
       BACKGROUND: Astragalus Polysaccharides (APS) had been reported to exhibit antitumor activities. Given that nanoparticles possessed unique advantages in cancer treatment, APS was used as the modifier to prepare gold, silver and selenium nanoparticles (APS-Au, APS-Ag and APS-Se NPs) in the present study.
    METHODS: The three nanoparticles were synthesized via a green approach and characterized by DLS, TEM, XRD, FT-IR and UV-Vis. The inhibitory effects of these nanoparticles on various tumor cells proliferation were examined by MTT assay in vitro. Reactive oxygen species (ROS), mitochondrial membrane potential (MMP) and the expression of apoptosis and autophagy-related proteins were also detected.
    RESULTS: Among these, APS-Se NPs displayed the most potent antitumor activities against MCF-7 cells in vitro. Flow cytometric analysis suggested that after cells were exposed to elevated concentrations of APS-Se NPs (10, 20 and 40 μmol/L), the rate of apoptosis was increasing (16.63 ± 0.89, 38.60 ± 3.46 and 44.38 ± 2.62%, respectively). Further analysis by immunofluorescence revealed an increase in intracellular ROS and a loss of MMP. This was accompanied by increased LC3-I to LC3-II conversion. Also, western blot analysis demonstrated that the ratios of Bax/Bcl-2 and cleaved caspase9/caspase 9 rose, and LC3-II and p62 protein levels increased. The addition of chloroquine, an inhibitor of autophagy, further enhanced protein expression of p62 and LC3-II.
    CONCLUSION: APS-Se NPs exerted their cytotoxic activity in MCF-7 cells by blocking autophagy and facilitating mitochondrial pathway-mediated apoptosis.
    Keywords:  Apoptosis; Astragalus Polysaccharides; Autophagy; MCF-7 cells; Selenium nanoparticles
    DOI:  https://doi.org/10.1016/j.jtemb.2022.127006
  44. Front Nutr. 2022 ;9 881210
    Bioactive Compounds and Functional Properties of Herbal Preparations of Cystus creticus L. Collected From Rhodes Island.
    Andrei Mocan, Ângela Fernandes, Ricardo C Calhelha, Laura Gavrilaş, Isabel C F R Ferreira, Marija Ivanov, Marina Sokovic, Lillian Barros, Mihai Babotă.
      The members of Cystus genus are perenial shrubs with a well-established use in traditional medicine. Among these, C. creticus is the most popular, herbal preparations obtained from its aerial parts being recognized as antimicrobial, antitumor and anti-inflammatory agents. The present study aimed to evaluate phytochemical profile and bioactive potential of aqueous and hydroethanolic extracts of C. creticus aerial parts harvested from two different areas of Rhodes island. LC-DAD-ESI/MSn analysis revealed the presence of myricetin and quercetin glycosides as main compounds, especially in aqueous extracts, being probably responsible for their enhanced antioxidant and antimicrobial potential. On the other side, hydroethanolic preparations exerted a strong anti-inflammatory and anti-biofilm activity. Our findings suggest that the use of solvents with intermediate polarity can assure the best recovery of bioactive compounds from C. creticus, increasing the extraction yield for other non-phenolic compounds which can enhance therapeutic potential of the extract through a synergistic action.
    Keywords:  Cystus creticus; antimicrobial compounds; bioactive compounds; herbal preparations; natural antioxidant
    DOI:  https://doi.org/10.3389/fnut.2022.881210
  45. Cancers (Basel). 2022 May 31. pii: 2724. [Epub ahead of print]14(11):
    Photodynamic Therapy in Combination with the Hepatitis B Core Virus-like Particles (HBc VLPs) to Prime Anticancer Immunity for Colorectal Cancer Treatment.
    Yang Hao, Zili Gu, Zhenfeng Yu, Timo Schomann, Sana Sayedipour, Julio C Aguilar, Peter Ten Dijke, Luis J Cruz.
      Photodynamic therapy (PDT), which combines light and oxygen with a photosensitizer to induce reactive oxygen species (ROS)-mediated killing of primary tumor cells, benefits from non-invasive properties and its negligible toxicity to surrounding healthy tissues. In this study, we have shown that the second-generation photosensitizer FOSCAN can be internalized by tumor cells and effectively induce tumor cell death when exposed to laser irradiation in vitro. In addition, these dying tumor cells can be phagocytosed by dendritic cells and lead to their activation and maturation as assessed by in vitro co-culture models. While PDT induces immunogenic tumor cell apoptosis, its application for the treatment of tumors located in deep tissues and advanced malignancies has been limited. In this study, we demonstrate that hepatitis B core virus-like particles (HBc VLPs) can serve as a vaccine to enhance PDT-induced anti-cancer immunity by priming humoral immune responses and inducing CD8+ T cell responses. The combination of PDT and HBc VLPs increased the survival rate of MC-38 tumor-bearing mice to 55%, compared to 33% in PDT alone and no tumor-free mice in vaccine alone. Moreover, the combination effectively prevented tumor recurrence in vivo through enhanced immune memory T cells after therapy. Therefore, as both are clinically approved techniques, this combination provides a promising strategy for cancer therapy.
    Keywords:  TLR-based immunotherapies; cancer treatment; combined therapy strategy; photodynamic therapy; vaccination; viral core particles
    DOI:  https://doi.org/10.3390/cancers14112724
  46. Front Cell Dev Biol. 2022 ;10 873029
    Novel Insights in the Regulatory Mechanisms of Ferroptosis in Hepatocellular Carcinoma.
    Shiwen Ma, Yao Mawulikplimi Adzavon, Xiaohu Wen, Pengxiang Zhao, Fei Xie, Mengyu Liu, Xuemei Ma.
      Ferroptosis is a newly defined programmed cell death, which by its mechanism differs from other programmed cell death processes such as apoptosis, necrosis, and autophagy. It has a unique morphology and biological properties that antioxidants and iron-chelating agents can regulate. Ferroptosis has the characteristics of iron ion deposition and dependence on lipid peroxidation. It can affect the progression of many cancers, including liver cancer, by inducing an intracellular iron-dependent accumulation of reactive oxygen species, providing new possibilities for cancer treatment. At present, great progress has been made in exploring the molecular mechanism of ferroptosis. In this review, we summarize the characteristics, mechanisms, and regulatory factors of ferroptosis in detail, discuss the progress of ferroptosis research in liver cancer, and provide directions and new ideas for the treatment of hepatocellular carcinoma.
    Keywords:  ferroptosis; hepatocellular carcinoma; iron; iron homeostasis; lipid peroxidation
    DOI:  https://doi.org/10.3389/fcell.2022.873029
  47. ACS Appl Mater Interfaces. 2022 Jun 08.
    Multifunctional Hybrid Hydrogel System Enhanced the Therapeutic Efficacy of Treatments for Postoperative Glioma.
    Xiang Cao, Shengnan Li, Wenli Chen, Hongdan Lu, Lu Ye, Zhiyi Min, Shanbo Sun, Chuanhui Teng, Haoyuan Yin, Qi Zhang, Weichong He, Xiuzhen Wang, Wei Lv, Lingyan Lv, Hongliang Xin.
      Glioma is the most lethal brain tumor with a poor prognosis, and a combination of multiple therapeutic strategies is critical for postoperative glioma treatment. Herein, a multifunctional hybrid hydrogel system (designated as CP&CL@RNPPTX-Gel) was developed for local treatment of postoperative glioma. The system was composed of self-illuminating chlorin e6 (Ce6) conjugated with luminol molecule (CL)-loaded glioma-targeting paclitaxel prodrug nanoparticles and copper peroxide nanodots (CP NDs) coembedded into a three-dimensional thermosensitive hydroxypropyl chitin hydrogel frame. After injection of CP&CL@RNPPTX-Gel into the cavity of postoperative glioma, the solution could be cross-linked into the gel as a drug reservoir under body temperature stimulation. Then, the sustained-released CP NDs decomposed into Cu2+ and H2O2 in the acidic microenvironment of the glioma cells to exert chemodynamic therapy (CDT). Meanwhile, Cu2+ could catalyze the self-luminescence of CL to induce photodynamic therapy (PDT) without external excitation light. Moreover, paclitaxel prodrug nanoparticles degraded into paclitaxel to restrain residual glioma cells in response to intracellular reduced glutathione (GSH). The in vitro and in vivo results showed that CP&CL@RNPPTX-Gel had great potential as a multifunctional hybrid hydrogel system with remarkable therapeutic effects for postoperative glioma treatment via a combination of chemotherapy, CDT, and PDT.
    Keywords:  chemodynamic therapy; drug delivery; glioma; self-illuminating; thermosensitive hydrogel
    DOI:  https://doi.org/10.1021/acsami.2c05147
  48. Am J Chin Med. 2022 Jun 08. 1-35
    Sinomenium acutum: A Comprehensive Review of its Botany, Phytochemistry, Pharmacology and Clinical Application.
    Chao Ding, Yuze Li, Yu Sun, Ying Wu, Fengrui Wang, Chenwang Liu, Huawei Zhang, Yi Jiang, Dongdong Zhang, Xiaomei Song.
      Sinomenium acutumis the dry stem of Sinomenium acutum (Thunb.) Rehd et Wils. (S. acutum) and Sinomenium acutum(Thunb.) Rehd. et Wils. var. cinereumRehd. et Wils and is mainly distributed in China and Japan. As a traditional Chinese medicine (TCM) for dispelling wind and dampness in China, it is widely distributed and has a long history of drug use. In recent years, with the increase of the incidence of rheumatoid disease, S. acutum has become the focus of research. This paper reviews the literature on the chemical constituents, pharmacological effects, clinical applications and pharmacokinetics and safety of S. acutum from the past 60 years. At present, more than 210 natural compounds have been isolated from S. acutum, including alkaloids, lignans, triterpenoid saponins, steroids, and other structures. Pharmacological activities of S. acutum were mainly reported on anti-inflammatory, analgesic, anti-allergic, immunosuppressive, anti-tumor, liver-protective, anti-oxidative, and other effects, and clinical applications were mainly recorded on rheumatoid arthritis, ankylosing spondylitis, and other diseases. The clinical use of SIN has fewer side effects and more safety; only a small number of gastrointestinal reactions occurred, and the symptoms disappeared after the drug stopped. The purpose of this paper is to lay a foundation and provide reference for the follow-up research and wide application of S. acutum.
    Keywords:  Alkaloids; Clinical Application; Pharmacological Activities; Review; Sinomenium acutum
    DOI:  https://doi.org/10.1142/S0192415X22500501
  49. Int J Mol Sci. 2022 Jun 03. pii: 6276. [Epub ahead of print]23(11):
    The Comparison of the Efficiency of Emodin and Aloe-Emodin in Photodynamic Therapy.
    Martyna Nowak-Perlak, Mariusz A Bromke, Piotr Ziółkowski, Marta Woźniak.
      Skin cancer (melanoma and non-melanoma) is the most frequent type of malignancy in the Caucasian population. Photodynamic therapy (PDT) as an interesting and unique strategy may potentially boost standard therapeutic approaches. In the present study, the potential of emodin and aloe-emodin as photosensitizers in photodynamic therapy has been investigated. The conducted research presents for the first-time comparison of the phototoxic and anti-cancerous effects of emodin and aloe-emodin on skin cancer cell lines, including SCC-25 representing cutaneous squamous cell carcinoma, MUG-Mel2 representing a melanoma cell line, and normal human keratinocytes HaCaT representing control normal skin cells. To assess the effectiveness of emodin and aloe-emodin as a photosensitizer in PDT on different skin cell lines, we performed MTT assay measuring cytotoxicity of natural compounds, cellular uptake, apoptosis with flow cytometry, and a wound-healing assay. Although emodin and aloe-emodin are isomers and differ only in the position of one hydroxyl group, our phototoxicity and apoptosis detection results show that both substances affect skin cancer cells (SSC-25 squamous cell carcinoma and MUG-Mel2 melanoma) and normal keratinocytes (HaCaT cell line) in other ways. In conclusion, our study provides evidence suggesting that emodin and aloe-emodin mediated PDT exhibits the potential for clinical development as a new effective and safe photosensitizer to treat skin cancer.
    Keywords:  aloe-emodin; emodin; natural compound; photodynamic therapy; skin cancer
    DOI:  https://doi.org/10.3390/ijms23116276
  50. Theranostics. 2022 ;12(8): 3747-3757
    Calixarene-modified albumin for stoichiometric delivery of multiple drugs in combination-chemotherapy.
    Ying Wang, Zhanzhan Zhang, Xinzhi Zhao, Lina Xu, Yadan Zheng, Hua-Bin Li, Dong-Sheng Guo, Linqi Shi, Yang Liu.
      Rationale: In combination chemotherapy, the molar ratio of drugs is a critical parameter that determines the synergistic effects. However, most co-delivery vectors are incapable of maintaining the optimal molar ratio of drugs throughout the delivery process. Herein, a calixarene-modified albumin (CaMA), which can co-deliver multiple drugs with precise control of the drug ratio, is presented. Methods: CaMA was prepared by chemically conjugating multiple sulfonate azocalix[4]arenes (SAC4A) onto the surface of bovine serum albumin (BSA). The precise drug loading and synchronous drug release were measured using fluorescence spectroscopy. Mouse tumor cell 4T1 and 4T1-bearing mice were used to evaluate the combined effects of mitomycin C (MMC) and doxorubicin (DOX) in vitro and in vivo. Results: With multiple hypoxia-responsive calixarenes conjugated onto a single albumin molecule, CaMA achieved precise drug loading and synchronous release of multiple drugs into the tumor microenvironment. This unique drug loading and release mechanism ensures that CaMA maintains the drug ratio from the initial drug loading to the release site, providing a solid foundation for multi-drug combination therapy with the goal of achieving predictable therapeutic outcomes in vivo. The delivery of the model drug combination MMC and DOX at a prescreened ratio via CaMA achieved significantly enhanced tumor suppression and reduced systemic toxicity. Conclusions: This stoichiometric delivery feature makes CaMA a powerful tool for the development of combination chemotherapy and personalized medications for cancer treatment.
    Keywords:  co-delivery; combination chemotherapy; host-guest interaction; hypoxia-responsive; stoichiometric
    DOI:  https://doi.org/10.7150/thno.72559
  51. Plants (Basel). 2022 May 24. pii: 1394. [Epub ahead of print]11(11):
    Nutritional Value, Phytochemical Potential, and Therapeutic Benefits of Pumpkin (Cucurbita sp.).
    Maria Batool, Muhammad Modassar Ali Nawaz Ranjha, Ume Roobab, Muhammad Faisal Manzoor, Umar Farooq, Hafiz Rehan Nadeem, Muhammad Nadeem, Rabia Kanwal, Hamada AbdElgawad, Soad K Al Jaouni, Samy Selim, Salam A Ibrahim.
      Pumpkin is a well-known multifunctional ingredient in the diet, full of nutrients, and has opened new vistas for scientists during the past years. The fruit of pumpkin including the flesh, seed, and peel are a rich source of primary and secondary metabolites, including proteins, carbohydrates, monounsaturated fatty acids, polyunsaturated fatty acids, carotenoids, tocopherols, tryptophan, delta-7-sterols, and many other phytochemicals. This climber is traditionally used in many countries, such as Austria, Hungary, Mexico, Slovenia, China, Spain, and several Asian and African countries as a functional food and provides health promising properties. Other benefits of pumpkin, such as improving spermatogenesis, wound healing, antimicrobial, anti-inflammatory, antioxidative, anti-ulcerative properties, and treatment of benign prostatic hyperplasia have also been confirmed by researchers. For better drug delivery, nanoemulsions and niosomes made from pumpkin seeds have also been reported as a health promising tool, but further research is still required in this field. This review mainly focuses on compiling and summarizing the most relevant literature to highlight the nutritional value, phytochemical potential, and therapeutic benefits of pumpkin.
    Keywords:  bioactive compounds; phytochemicals; pumpkin; therapeutic potential
    DOI:  https://doi.org/10.3390/plants11111394
  52. Biotechnol Rep (Amst). 2022 Jun;34 e00714
    Antineoplastic activity of biogenic silver and gold nanoparticles to combat leukemia: Beginning a new era in cancer theragnostic.
    Ebrahim Mostafavi, Atefeh Zarepour, Hamed Barabadi, Ali Zarrabi, Linh B Truong, David Medina-Cruz.
      The American Cancer Society estimated around 61,090 new cases of leukemia were diagnosed, and around 23,660 people died from this disease in the United States alone in 2021. Due to its burden on society, there is an unmet need to explore innovative approaches to overcome leukemia. Among different strategies that have been explored, nanotechnology appears to be a promising and effective approach for therapeutics. Specifically, biogenic silver and gold nanoparticles (NPs) have attracted significant attention for their antineoplastic activity toward leukemia cancer cells due to their unique physicochemical properties. Indeed, these nanostructures have emerged as useful approaches in anti-leukemic applications, either as carriers to enhance drug bioavailability and its targeted delivery to a specific organ or as a novel therapeutic agent. This review explores recent advances in green synthesized nanomaterials and their potential use against leukemia, especially focusing on silver (Ag) and gold (Au) nanostructures. In detail, we have reviewed various eco-friendly methods of bio-synthesized NPs, their analytical properties, and toxicity effects against leukemic models. This overview confirms the satisfactory potency of biogenic NPs toward leukemic cells and desirable safety profiles against human native cells, which opens a promising door toward commercializing these types of nontherapeutic agents if challenges involve clinical validations, reproducibility, and scalability could be resolved.
    Keywords:  Biosynthesis; Gold NPss; Leukemia; Metallic nanomaterials; Silver NPs; Therapeutic
    DOI:  https://doi.org/10.1016/j.btre.2022.e00714
  53. Molecules. 2022 May 30. pii: 3512. [Epub ahead of print]27(11):
    Microalgae Bioactive Compounds to Topical Applications Products-A Review.
    Manuel Martínez-Ruiz, Carlos Alberto Martínez-González, Dong-Hyun Kim, Berenice Santiesteban-Romero, Humberto Reyes-Pardo, Karen Rocio Villaseñor-Zepeda, Edgar Ricardo Meléndez-Sánchez, Diana Ramírez-Gamboa, Ana Laura Díaz-Zamorano, Juan Eduardo Sosa-Hernández, Karina G Coronado-Apodaca, Ana María Gámez-Méndez, Hafiz M N Iqbal, Roberto Parra-Saldivar.
      Microalgae are complex photosynthetic organisms found in marine and freshwater environments that produce valuable metabolites. Microalgae-derived metabolites have gained remarkable attention in different industrial biotechnological processes and pharmaceutical and cosmetic industries due to their multiple properties, including antioxidant, anti-aging, anti-cancer, phycoimmunomodulatory, anti-inflammatory, and antimicrobial activities. These properties are recognized as promising components for state-of-the-art cosmetics and cosmeceutical formulations. Efforts are being made to develop natural, non-toxic, and environmentally friendly products that replace synthetic products. This review summarizes some potential cosmeceutical applications of microalgae-derived biomolecules, their mechanisms of action, and extraction methods.
    Keywords:  antioxidants; bioactive compounds; biomass; immunomodulator; microalgae; photoprotectants
    DOI:  https://doi.org/10.3390/molecules27113512
  54. Polymers (Basel). 2022 May 27. pii: 2172. [Epub ahead of print]14(11):
    Zein Microparticles and Nanoparticles as Drug Delivery Systems.
    Iolanda De Marco.
      Zein is a natural, biocompatible, and biodegradable polymer widely used in the pharmaceutical, biomedical, and packaging fields because of its low water vapor permeability, antibacterial activity, and hydrophobicity. It is a vegetal protein extracted from renewable resources (it is the major storage protein from corn). There has been growing attention to producing zein-based drug delivery systems in the recent years. Being a hydrophobic biopolymer, it is used in the controlled and targeted delivery of active principles. This review examines the present-day landscape of zein-based microparticles and nanoparticles, focusing on the different techniques used to obtain particles, the optimization of process parameters, advantages, disadvantages, and final applications.
    Keywords:  controlled release; drug delivery systems; microparticles; nanoparticles; zein
    DOI:  https://doi.org/10.3390/polym14112172
  55. Molecules. 2022 Jun 01. pii: 3561. [Epub ahead of print]27(11):
    Involvement of Phytochemical-Encapsulated Nanoparticles' Interaction with Cellular Signalling in the Amelioration of Benign and Malignant Brain Tumours.
    Sidharth Mehan, Navneet Arora, Sonalika Bhalla, Andleeb Khan, Muneeb U Rehman, Badrah S Alghamdi, Torki Al Zughaibi, Ghulam Md Ashraf.
      Brain tumours have unresolved challenges that include delay prognosis and lower patient survival rate. The increased understanding of the molecular pathways underlying cancer progression has aided in developing various anticancer medications. Brain cancer is the most malignant and invasive type of cancer, with several subtypes. According to the WHO, they are classified as ependymal tumours, chordomas, gangliocytomas, medulloblastomas, oligodendroglial tumours, diffuse astrocytomas, and other astrocytic tumours on the basis of their heterogeneity and molecular mechanisms. The present study is based on the most recent research trends, emphasising glioblastoma cells classified as astrocytoma. Brain cancer treatment is hindered by the failure of drugs to cross the blood-brain barrier (BBB), which is highly impregnableto foreign molecule entry. Moreover, currently available medications frequently fail to cross the BBB, whereas chemotherapy and radiotherapy are too expensive to be afforded by an average incomeperson and have many associated side effects. When compared to our current understanding of molecularly targeted chemotherapeutic agents, it appears that investigating the efficacy of specific phytochemicals in cancer treatment may be beneficial. Plants and their derivatives are game changers because they are efficacious, affordable, environmentally friendly, faster, and less toxic for the treatment of benign and malignant tumours. Over the past few years, nanotechnology has made a steady progress in diagnosing and treating cancers, particularly brain tumours. This article discusses the effects of phytochemicals encapsulated in nanoparticles on molecular targets in brain tumours, along with their limitations and potential challenges.
    Keywords:  astrocytoma; blood–brain barrier; brain tumour; glioblastoma; nanoparticles; phytochemicals
    DOI:  https://doi.org/10.3390/molecules27113561
  56. Cancers (Basel). 2022 May 31. pii: 2723. [Epub ahead of print]14(11):
    Differential Effects of Dietary Macronutrients on the Development of Oncogenic KRAS-Mediated Pancreatic Ductal Adenocarcinoma.
    Liang Zhu, Juntao Ji, Jianjia Ma, Dan Wang, Muyun Liu, James Xianxing Du, Rong Chen, Wei Hou, James L Abbruzzese, Craig D Logsdon, Vincent W Yang, Yongde Luo, Weiqin Lu.
      KRAS mutations are prevalent in patients with pancreatic ductal adenocarcinoma (PDAC) and are critical to fostering tumor growth in part by aberrantly rewiring glucose, amino acid, and lipid metabolism. Obesity is a modifiable risk factor for pancreatic cancer. Corroborating this epidemiological observation, mice harboring mutant KRAS are highly vulnerable to obesogenic high-fat diet (HFD) challenges leading to the development of PDAC with high penetrance. However, the contributions of other macronutrient diets, such as diets rich in carbohydrates that are regarded as a more direct source to fuel glycolysis for cancer cell survival and proliferation than HFD, to pancreatic tumorigenesis remain unclear. In this study, we compared the differential effects of a high-carbohydrate diet (HCD), an HFD, and a high-protein diet (HPD) in PDAC development using a mouse model expressing an endogenous level of mutant KRASG12D specifically in pancreatic acinar cells. Our study showed that although with a lower tumorigenic capacity than chronic HFD, chronic HCD promoted acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) lesions with increased inflammation, fibrosis, and cell proliferation compared to the normal diet (ND) in KrasG12D/+ mice. By contrast, chronic HPD showed no significant adverse effects compared to the ND. Furthermore, ablation of pancreatic acinar cell cyclooxygenase 2 (Cox-2) in KrasG12D/+ mice abrogated the adverse effects induced by HCD, suggesting that diet-induced pancreatic inflammation is critical for promoting oncogenic KRAS-mediated neoplasia. These results indicate that diets rich in different macronutrients have differential effects on pancreatic tumorigenesis in which the ensuing inflammation exacerbates the process. Management of macronutrient intake aimed at thwarting inflammation is thus an important preventive strategy for patients harboring oncogenic KRAS.
    Keywords:  KRAS; high-carbohydrate diet; high-protein diet; inflammation; macronutrients; pancreatic cancer
    DOI:  https://doi.org/10.3390/cancers14112723
  57. Chem Asian J. 2022 Jun 08.
    Enzyme-Powered Micro/Nanomotors for Cancer Treatment.
    Xi Wang, Dang Zhang, Yu Bai, Jian Zhang, Lei Wang.
      The incidence and lethal rate of cancers are rapidly rising recently, however current treatments of cancers, such as surgical resection, radiotherapy, chemotherapy and targeted therapy, usually require long treatment period and have more side effects and high recurrence rate. Enzyme-powered micro/nanomotors (EMNMs), with powerful self-propulsion, enhanced permeability and good biocompatibility, have shown great potential in crossing biological barrier and targeted drug transportation for cancer treatment; moreover, advanced approaches based on EMNMs such as photothermal therapy and starvation therapy have also been widely explored in cancer treatment. Although there are several review works discussing the progress of micro/nanomotors for biomedical applications, there is not one review paper with the focus on the cancer treatment. Therefore, in this review, we try to concisely and timely summarize the recent progress of cancer treatment based on enzyme-driven micro/nanomotors, such as brain tumors, bladder cancer, breast cancer and others. Finally, the challenges and outlook of cancer therapy based on EMNMs are discussed, hoping to provide fundamental guidance for the future development.
    Keywords:  Catalysis; Micro/nanomotors; Self propulsion; cancer therapy; enzyme
    DOI:  https://doi.org/10.1002/asia.202200498
  58. Life Sci. 2022 Jun 01. pii: S0024-3205(22)00380-0. [Epub ahead of print] 120680
    Combined regimens of cisplatin and metformin in cancer therapy: A systematic review and meta-analysis.
    Emad Jafarzadeh, Vahideh Montazeri, Shima Aliebrahimi, Ahmad Habibian Sezavar, Mohammad H Ghahremani, Seyed Nasser Ostad.
       INTRODUCTION: Cancer cell resistance to chemotherapy agents is a challenging issue in treating patients with cancer. Findings suggest that a combination of drugs may have synergistic or additive effects. in the present study, we systematically reviewed the combined regimens of metformin with cisplatin in various treating cancers.
    METHODS: A comprehensive systematic search was performed in PubMed, Scopus, Embase, and other relevant databases with the following keyword "metformin", "cisplatin", "combination", "using all their equivalents and similar terms. Pooled odds ratio (OR) and 95% confidence intervals of cell viability and tumor volume as primary outcomes were calculated using Der-Simonian and Laird method while random effects meta-analysis was used, taking into account clinical and statistical heterogeneity.
    RESULTS: Overall, 44 studies were retrieved, Findings of the present meta-analysis showed that combined regimens of metformin plus cisplatin was significantly associated with decreased odds of tumor volume and cell viability for all cancers compared with cisplatin alone (pooled OR: 0.40; 95% CI: 0.27, 0.58) and (pooled OR: 0.49; 95% CI: 0.42, 0.58) respectively. The result was same for cell viability in lung cancer (pooled OR: 0.59; 95% CI: 0.49, 0.70). The tumor size reduction and the response rate were evident in the animal xenografts model.
    CONCLUSION: Findings indicated that combining metformin with cisplatin is a practical therapeutic approach to increase treatment efficacy in the case of cell viability and tumor volume and minimize side effects. A combination of metformin with cisplatin could enhance treatment efficacy through synergistic inhibitory effects on the growth of cancer cells.
    Keywords:  Cancer therapy; Chemotherapy; Cisplatin; Cisplatin-resistance; Metformin; meta-analysis
    DOI:  https://doi.org/10.1016/j.lfs.2022.120680
  59. Cureus. 2022 May;14(5): e24803
    An Update to Hallmarks of Cancer.
    Swapna Ravi, Antonio M Alencar, Jemma Arakelyan, Weihao Xu, Roberta Stauber, Cheng-Chi I Wang, Ruzanna Papyan, Narine Ghazaryan, Rosalina M Pereira.
      In the last decade, there has been remarkable progress in research toward understanding and refining the hallmarks of cancer. In this review, we propose a new hallmark - "pro-survival autophagy." The importance of pro-survival autophagy is well established in tumorigenesis, as it is related to multiple steps in cancer progression and vital for some cancers. Autophagy is a potential anti-cancer therapeutic target. For this reason, autophagy is a good candidate as a new hallmark of cancer. We describe two enabling characteristics that play a major role in enabling cells to acquire the hallmarks of cancer - "tumor-promoting microenvironment and macroenvironment" and "cancer epigenetics, genome instability and mutation." We also discuss the recent updates, therapeutic and prognostic implications of the eight hallmarks of cancer described by Hanahan et al. in 2011. Understanding these hallmarks and enabling characteristics is key not only to developing new ways to treat cancer efficiently but also to exploring options to overcome cancer resistance to treatment.
    Keywords:  autophagy; cancer; genome instability; hallmark; macroenvironment; microenvironment; tumor
    DOI:  https://doi.org/10.7759/cureus.24803
  60. Molecules. 2022 May 27. pii: 3457. [Epub ahead of print]27(11):
    Novel Lysosome-Targeting Fluorescence Off-On Photosensitizer for Near-Infrared Hypoxia Imaging and Photodynamic Therapy In Vitro and In Vivo.
    Shangli Ding, Mingyan Yang, Jiajia Lv, Hongyu Li, Gang Wei, Jie Gao, Zeli Yuan.
      Photodynamic therapy (PDT) has emerged as a new antitumor modality. Hypoxia, a vital characteristic of solid tumors, can be explored to stimulate the fluorescence response of photosensitizers (PSs). Considering the characteristics of PDT, the targeting of organelles employing PS would enhance antitumor effects. A new multifunctional cyanine-based PS (CLN) comprising morpholine and nitrobenzene groups was prepared and characterized. It generated fluorescence in the near-infrared (NIR) region in the presence of sodium dithionite (Na2S2O4) and nitroreductase (NTR). The response mechanism of CLN was well investigated, thus revealing that its obtained reduction product was CLNH. The obtained fluorescence and singlet oxygen quantum yield of CLNH were 8.65% and 1.60%, respectively. Additionally, the selective experiment for substrates indicated that CLN exhibited a selective response to NTR. Thus, CLN fluorescence could be selectively switched on and its fluorescence intensity increased, following a prolonged stay in hypoxic cells. Furthermore, fluorescence colocalization demonstrated that CLN could effectively target lysosomes. CLN could generate reactive oxygen species and kill tumor cells (IC50 for 4T1 cells was 7.4 μM under a hypoxic condition), following its response to NTR. NIR imaging and targeted PDT were finally applied in vivo.
    Keywords:  cyanine; hypoxia; lysosome; near-infrared; nitroreductase; photodynamic therapy
    DOI:  https://doi.org/10.3390/molecules27113457
  61. Nutrients. 2022 May 30. pii: 2303. [Epub ahead of print]14(11):
    The Regulatory Roles of Polysaccharides and Ferroptosis-Related Phytochemicals in Liver Diseases.
    Yijing Ren, Siyue Li, Zixuan Song, Qiuping Luo, Yingying Zhang, Hao Wang.
      Liver disease is a global health burden with high morbidity and mortality worldwide. Liver injuries can develop into severe end-stage diseases, such as cirrhosis or hepatocellular carcinoma, without valid treatment. Therefore, identifying novel drugs may promote liver disease treatment. Phytochemicals, including polysaccharides, flavonoids, alkaloids, and terpenes, are abundant in foods and medicinal plants and have various bioactivities, such as antioxidation, immunoregulation, and tumor killing. Recent studies have shown that many natural polysaccharides play protective roles in liver disease models in vitro and in vivo, such as fatty liver disease, alcoholic liver disease, drug-induced liver injury, and liver cancer. The mechanisms of liver disease are complex. Notably, ferroptosis, a new type of cell death driven by iron and lipid peroxidation, is considered to be the key mechanism in many hepatic pathologies. Therefore, polysaccharides and other types of phytochemicals with activities in ferroptosis regulation provide novel therapeutic strategies for ferroptosis-related liver diseases. This review summarizes our current understanding of the mechanisms of ferroptosis and liver injury and compelling preclinical evidence of natural bioactive polysaccharides and phytochemicals in treating liver disease.
    Keywords:  ferroptosis; liver injury; phytochemical; polysaccharide
    DOI:  https://doi.org/10.3390/nu14112303
  62. Materials (Basel). 2022 May 26. pii: 3795. [Epub ahead of print]15(11):
    pH and Redox-Dual Sensitive Chitosan Nanoparticles Having Methyl Ester and Disulfide Linkages for Drug Targeting against Cholangiocarcinoma Cells.
    Ju-Il Yang, Hye Lim Lee, Je-Jung Yun, Jungsoo Kim, Kyoung-Ha So, Young-Il Jeong, Dae-Hwan Kang.
      The aim of this study is to prepare pH- and redox-sensitive nanoparticles for doxorubicin (DOX) delivery against DOX-resistant HuCC-T1 human cholangiocarcinoma (CCA) cells. For this purpose, L-histidine methyl ester (HIS) was attached to chitosan oligosaccharide (COS) via dithiodipropionic acid (abbreviated as ChitoHISss). DOX-incorporated nanoparticles of ChitoHISss conjugates were fabricated by a dialysis procedure. DOX-resistant HuCC-T1 cells were prepared by repetitive exposure of HuCC-T1 cells to DOX. ChitoHISss nanoparticles showed spherical morphology with a small diameter of less than 200 nm. The acid pH and glutathione (GSH) addition induced changes in the size distribution pattern of ChitoHISss nanoparticles from a narrow/monomodal distribution pattern to a wide/multimodal pattern and increased the fluorescence intensity of the nanoparticle solution. These results indicate that a physicochemical transition of nanoparticles can occur in an acidic pH or redox state. The more acidic the pH or the higher the GSH concentration the higher the drug release rate was, indicating that an acidic environment or higher redox states accelerated drug release from ChitoHISss nanoparticles. Whereas free DOX showed decreased anticancer activity at DOX-resistant HuCC-T1 cells, DOX-incorporated ChitoHISss nanoparticles showed dose-dependent anticancer activity. Intracellular delivery of DOX-incorporated ChitoHISss nanoparticles was relatively increased at an acidic pH and in the presence of GSH, indicating that DOX-incorporated ChitoHISss nanoparticles have superior acidic pH- and redox-sensitive behavior. In an in vivo tumor xenograft model, DOX-incorporated ChitoHISss nanoparticles were specifically delivered to tumor tissues and then efficiently inhibited tumor growth. We suggest that ChitoHISss nanoparticles are a promising candidate for treatment of CCA.
    Keywords:  acidic pH sensitive; cholangiocarcinoma; drug targeting; nanoparticles; redox sensitive
    DOI:  https://doi.org/10.3390/ma15113795
  63. Int J Pharm. 2022 Jun 07. pii: S0378-5173(22)00453-7. [Epub ahead of print] 121898
    Dual-Responsive multifunctional "core-shell" magnetic nanoparticles promoting Fenton reaction for tumor ferroptosis therapy.
    Hao Chi, Guang Zhu, Yalin Yin, He Diao, Zicheng Liu, Shibo Sun, Zhaoming Guo, Weiping Xu, Jianqiang Xu, Changhao Cui, Xiao-Jin Xing, Kun Ma.
      Ferroptosis is a newly found promising cell death pathway, which bypasses apoptosis and overcomes multidrug resistance of tumor. In this study, acid and redox dual-responsive multifunctional magnetic nanoparticles loading with Sorafenib (Sor), namely FMMHG/Sor, were prepared for tumor ferroptosis therapy. Fe3O4 nanoparticles as the core provided sufficient iron ion for ferroptosis and magnetic targeting. Mesoporous organosilica nanoparticles (MON) was coated on the outside of Fe3O4 to form "core-shell" structure, which contained the disulfidebond with redox-responsive. MnO2 was dropped on the surface of MON as gatekeeper, which was decomposed at low pH into O2 to promote drug release. Glucose oxidase (GOD) catalyzed glucose to produce H2O2, which reacted with iron ion to generate hydroxylradical (OH•) vie Fenton reaction. OH• inhibited GPX4 expression to induce ferroptosis with Sor as a synergistic inducer. Hyaluronic acid (HA) protected nanoparticles from removed by immune system and actively targeted to tumor cells. Overall, pH and redox dual-responsive FMMHG/Sor is a promising antitumor nanomedicine with magnetic targeting and active targeting for efficient tumor ferroptosis therapy.
    Keywords:  Fe(3)O(4) nanoparticles; Ferroptosis; Manganese oxide; Redox-responsive; Targeted drug delivery; pH-responsive
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.121898
  64. Adv Mater. 2022 Jun 09. e2203765
    Drug in Drug: A host-guest formulation of azocalixarene with hydroxychloroquine for synergistic anti-inflammation.
    Shihui Li, Rong Ma, Xin-Yue Hu, Hua-Bin Li, Wen-Chao Geng, Xianglei Kong, Chao Zhang, Dong-Sheng Guo.
      Macrocyclic delivery and therapeutics are two significant topics in supramolecular biomedicine. The functional integration of these topics would open new avenues for treating diseases synergistically. However, these two individual topics have been occasionally merged, probably because of the lack of functionalized design of macrocyclic host and the lack of efficient recognition between host and guest drugs. Herein, we proposed a "drug-in-drug" strategy in which an active drug is encapsulated by a macrocycle possessing therapeutic activity to form a multi-functional supramolecular active pharmaceutical ingredient. As a proof-of-concept, we prepared a complex of hydroxychloroquine (HCQ) with sulfonated azocalix[4]arene (HCQ@SAC4A) to treat rheumatoid arthritis (RA) combinedly. SAC4A is a therapeutic agent that exhibits scavenging capacity for reactive oxygen species and exerts an anti-inflammatory effect. It is also a hypoxia-responsive carrier that could deliver HCQ directly to the inflammatory articular cavity. Consequently, HCQ@SAC4A achieved the synergistic anti-inflammatory effect on both inflamed RAW 264.7 cells and RA rats. This effect is attributed to the temporal and spatial consistency of the two active ingredients of the complex. As a new paradigm for combinational therapy, the drug-in-drug strategy advances in easy preparation, mix-and-match combination, and precise ratiometric control. This article is protected by copyright. All rights reserved.
    Keywords:  anti-inflammation; biomedical materials; combinational therapy; macrocycle; supramolecular chemistry
    DOI:  https://doi.org/10.1002/adma.202203765
  65. Nanomaterials (Basel). 2022 May 25. pii: 1807. [Epub ahead of print]12(11):
    Magnetite Nanoparticles in Magnetic Hyperthermia and Cancer Therapies: Challenges and Perspectives.
    Agnieszka Włodarczyk, Szymon Gorgoń, Adrian Radoń, Karolina Bajdak-Rusinek.
      Until now, strategies used to treat cancer are imperfect, and this generates the need to search for better and safer solutions. The biggest issue is the lack of selective interaction with neoplastic cells, which is associated with occurrence of side effects and significantly reduces the effectiveness of therapies. The use of nanoparticles in cancer can counteract these problems. One of the most promising nanoparticles is magnetite. Implementation of this nanoparticle can improve various treatment methods such as hyperthermia, targeted drug delivery, cancer genotherapy, and protein therapy. In the first case, its feature makes magnetite useful in magnetic hyperthermia. Interaction of magnetite with the altered magnetic field generates heat. This process results in raised temperature only in a desired part of a patient body. In other therapies, magnetite-based nanoparticles could serve as a carrier for various types of therapeutic load. The magnetic field would direct the drug-related magnetite nanoparticles to the pathological site. Therefore, this material can be used in protein and gene therapy or drug delivery. Since the magnetite nanoparticle can be used in various types of cancer treatment, they are extensively studied. Herein, we summarize the latest finding on the applicability of the magnetite nanoparticles, also addressing the most critical problems faced by smart nanomedicine in oncological therapies.
    Keywords:  hyperthermia; magnetite nanoparticles; smart nanomedicine
    DOI:  https://doi.org/10.3390/nano12111807
  66. Front Cell Dev Biol. 2022 ;10 887764
    Beyond Genetics: The Role of Metabolism in Photoreceptor Survival, Development and Repair.
    Joseph Hanna, Luke Ajay David, Yacine Touahri, Taylor Fleming, Robert A Screaton, Carol Schuurmans.
      Vision commences in the retina with rod and cone photoreceptors that detect and convert light to electrical signals. The irreversible loss of photoreceptors due to neurodegenerative disease leads to visual impairment and blindness. Interventions now in development include transplanting photoreceptors, committed photoreceptor precursors, or retinal pigment epithelial (RPE) cells, with the latter protecting photoreceptors from dying. However, introducing exogenous human cells in a clinical setting faces both regulatory and supply chain hurdles. Recent work has shown that abnormalities in central cell metabolism pathways are an underlying feature of most neurodegenerative disorders, including those in the retina. Reversal of key metabolic alterations to drive retinal repair thus represents a novel strategy to treat vision loss based on cell regeneration. Here, we review the connection between photoreceptor degeneration and alterations in cell metabolism, along with new insights into how metabolic reprogramming drives both retinal development and repair following damage. The potential impact of metabolic reprogramming on retinal regeneration is also discussed, specifically in the context of how metabolic switches drive both retinal development and the activation of retinal glial cells known as Müller glia. Müller glia display latent regenerative properties in teleost fish, however, their capacity to regenerate new photoreceptors has been lost in mammals. Thus, re-activating the regenerative properties of Müller glia in mammals represents an exciting new area that integrates research into developmental cues, central metabolism, disease mechanisms, and glial cell biology. In addition, we discuss this work in relation to the latest insights gleaned from other tissues (brain, muscle) and regenerative species (zebrafish).
    Keywords:  Müller glia regeneration; glycolysis; metabolic reprogramming; mitochondria; oxidative phosphorylation; photoreceptor development; retinal degeneration
    DOI:  https://doi.org/10.3389/fcell.2022.887764
  67. Cancers (Basel). 2022 May 25. pii: 2608. [Epub ahead of print]14(11):
    Repurposing Vitamin C for Cancer Treatment: Focus on Targeting the Tumor Microenvironment.
    Wen-Ning Li, Shi-Jiao Zhang, Jia-Qing Feng, Wei-Lin Jin.
      Based on the enhanced knowledge on the tumor microenvironment (TME), a more comprehensive treatment landscape for targeting the TME has emerged. This microenvironment provides multiple therapeutic targets due to its diverse characteristics, leading to numerous TME-targeted strategies. With multifaced activities targeting tumors and the TME, vitamin C is renown as a promising candidate for combination therapy. In this review, we present new advances in how vitamin C reshapes the TME in the immune, hypoxic, metabolic, acidic, neurological, mechanical, and microbial dimensions. These findings will open new possibilities for multiple therapeutic avenues in the fight against cancer. We also review the available preclinical and clinical evidence of vitamin C combined with established therapies, highlighting vitamin C as an adjuvant that can be exploited for novel therapeutics. Finally, we discuss unresolved questions and directions that merit further investigation.
    Keywords:  anti-immunity; dietary intervention; drug repurposing; tumor microenvironment; vitamin C
    DOI:  https://doi.org/10.3390/cancers14112608
  68. Cureus. 2022 May;14(5): e24678
    Nanocurcumin in Oral Squamous Cancer Cells and Its Efficacy as a Chemo-Adjuvant.
    Diptasree Mukherjee, Prakruti Dash, Balamurugan Ramadass, Manaswini Mangaraj.
      Oral squamous cell carcinoma is the sixth most common cancer worldwide. Despite the available treatment, the survival rate is poor. The addition of agents to make chemotherapeutics safer and more effective is important. Curcumin is a common Indian spice that has shown anticarcinogenic properties. It has been possible to overcome its poor bio-availability using nanotechnology. We aimed to investigate the adjuvant effect of nanocurcumin (NC ~ 200 nm size) treatment on cetuximab (epidermal growth factor receptor inhibitor) in oral squamous cancer cells (KB 3-1 cell). Cancer cells were cultured and treated for 24 hours with cetuximab and NC, in various doses to find the drugs' half-maximal inhibitory concentration (IC50). Experiments were conducted with a combination dose of both and sensitization treatment with NC before cetuximab with cytotoxicity assessment by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. One-way analysis of variance (ANOVA) was used to compare different treatment groups. We found a concentration-dependent cancer cell death with NC, which was significant compared to cetuximab (p <0.001). The combination treatment group had highly significant cell death (p <0.0001) compared to a single drug, and the NC sensitization caused substantial cell death compared to a single cetuximab treatment (p<0.01). Our study findings indicate the potential chemo-adjuvant effect of NC in oral cancer.
    Keywords:  adjuvant therapy; cetuximab; curcumin; cytotoxicity; nanocurcumin; oral cancer
    DOI:  https://doi.org/10.7759/cureus.24678
  69. ACS Appl Mater Interfaces. 2022 Jun 08.
    Construction of D-A-Conjugated Covalent Organic Frameworks with Enhanced Photodynamic, Photothermal, and Nanozymatic Activities for Efficient Bacterial Inhibition.
    Gui-Ping Yang, Xiao-Lin Meng, Sai-Jin Xiao, Qiong-Qing Zheng, Quan-Gen Tan, Ru-Ping Liang, Li Zhang, Pu Zhang, Jian-Ding Qiu.
      Bacterial infection causes serious threats to human life, especially with the appearance of antibiotic-resistant bacteria. Phototherapeutic approaches have become promising due to their noninvasiveness, few adverse effects, and high efficiency. Herein, a covalent organic framework (TAPP-BDP) with a conjugated donor-acceptor (D-A) structure has been constructed for efficient photoinduced bacteriostasis. Under the irradiation with a single near-infrared (NIR) light (λ = 808 nm), TAPP-BDP alone involves triple and synergistic bacterial inhibition based on the integration of photodynamic, photothermal, and peroxidase-like enzymatic activities. The unique D-A structure endows TAPP-BDP with a narrow energy band gap, improving its photodynamic and nanozyme activities to generate reactive oxygen species (ROS) to realize the broad-spectrum bactericidal activity. The extended π-conjugated skeleton of TAPP-BDP results in enhanced absorption in NIR, and the remarkable photothermal activity can increase the temperature up to 65 °C to cause efficient bacterial degeneration. TAPP-BDP shows excellent antibacterial efficiency against both Gram-negative and Gram-positive bacteria. Animal experiments further suggest that TAPP-BDP can effectively heal wounds infected with Staphylococcus aureus in living systems.
    Keywords:  covalent organic framework; peroxidase-like nanozyme activity; photodynamic therapy; photothermal therapy; synergistic antimicrobial activities
    DOI:  https://doi.org/10.1021/acsami.2c05953
  70. Front Nutr. 2022 ;9 891462
    Ultrasound-Assisted Extraction of Natural Pigments From Food Processing By-Products: A Review.
    Guillermo Linares, Meliza Lindsay Rojas.
      Ultrasound is an emerging technology, which has been highly explored in the food area to improve processes and products. When ultrasound is applied to a product with solid or fluid characteristics, the passage of acoustic waves and acoustic cavitation generates different mechanisms responsible for modifications in the original matrix of the sample. These effects of ultrasound can also be used to take advantage of by-products, for example by extracting compounds of interest, including natural pigments. Natural pigments or colorants are being highly demanded by different industries not only for color purposes but also due to their healthy properties, the greater demands in regulations and new consumer preferences. This review presents an updated critical analysis of the application of ultrasound-assisted extraction (UAE) to obtain natural pigments from food processing by-products. Initially, the ultrasound effects and mechanisms that improve the extraction of natural pigments in a fluid medium, as well as the factors that influence the extraction and the energy consumption of UAE are analyzed and described. Subsequently, the UAE application to obtain pigments belonging to the groups of carotenoids, chlorophyll, anthocyanins and betalains is evaluated. These sections detail the processing conditions, positive and negative effects, as well as possible applications of the extracted pigments. This review presents relevant information that may be useful to expand and explore new applications of ultrasound technology as well as promote the revaluation of by-products to obtain pigments that can be used in food, pharmaceutical or cosmetic industries.
    Keywords:  by-products; emerging technology; extraction; high-power ultrasound (HPU); natural pigments
    DOI:  https://doi.org/10.3389/fnut.2022.891462
  71. Nutrients. 2022 Jun 05. pii: 2353. [Epub ahead of print]14(11):
    Vitamin D, the Vitamin D Receptor, Calcitriol Analogues and Their Link with Ocular Diseases.
    Miłosz Caban, Urszula Lewandowska.
      The global prevalence of eye diseases continues to grow, bringing with it a reduction in the activity levels and quality of life of patients, and partial or complete blindness if left untreated. As such, there is considerable interest in identifying more effective therapeutic options and preventive agents. One such agent is vitamin D, known to have a range of anti-cancer, anti-angiogenic, anti-inflammatory and anti-oxidative properties, and whose deficiency is linked to the pathogenesis of a range of cardiovascular, cancer, and inflammatory diseases. This review presents the current stage of knowledge concerning the link between vitamin D and its receptor and the occurrence of eye disease, as well as the influence of analogues of calcitriol, an active metabolite of vitamin D. Generally, patients affected by various ocular disorders have vitamin D deficiency. In addition, previous findings suggest that vitamin D modulates the course of eye diseases and may serve as a marker, and that its supplementation could mitigate some disorders. However, as these studies have some limitations, we recommend further randomized trials to clarify the link between vitamin D and its activity with eye disease.
    Keywords:  25-hydroxyvitamin D; calcitriol; eye diseases; vitamin D
    DOI:  https://doi.org/10.3390/nu14112353
  72. Chembiochem. 2022 Jun 08.
    Annonaceous Acetogenin Mimic AA005 Inhibits the Growth of TNBC MDA-MB-468 Cells by Altering Cell Energy Metabolism.
    Bao-Bao Yu, Hao Yuan, Yun-Cong Chen, Dan-Xia Zhou, Zhen-Ji Gan, Jie Wang, Jian-Xin Li, Zhu-Jun Yao.
      AA005, a structurally simplified mimic of natural Annonaceous acetogenins, presents outstanding properties with impressive cytotoxicity and cell-type selective actions. The present study aimed at evaluating the potential of AA005 as a therapeutic agent for Triple-negative breast cancer (TNBC). AA005 potently inhibited the growth of TNBC cells at 50 nM level. Inspired by the finding of the phosphatase and tensin homolog (PTEN) tumor suppressor, the effect of AA005 on aerobic glycolysis was investigated in TNBC MDA-MB-468 cells. Of note, a short-term AA005 exposure markedly suppressed the mitochondrial function in MDA-MB-468 cells, thus activating the aerobic glycolysis to lessen the risk of decreased ATP generation in mitochondria. While, prolonging the incubation time of AA005 obviously weakened the aerobic glycolysis in the cells. This was in part attributed to the PI3K-AKT pathway inactivation and subsequent declined glucose uptake. As a consequence, the energy supply was completely cut down from the two major energy-producing pathways. Further experiments also showed that AA005 resulted in irreversible damage on cell activity including cell cycle and growth, inducing mitochondrial oxidative stress and ultimately leading to cell death. In addition, the in vivo therapeutic efficacy of AA005 was proved on 4T1 xenograft tumor mice model. Our data demonstrated that AA005 exhibited a great potential for future clinical applications in TNBC therapy.
    Keywords:  AA005, TNBC, MDA-MB-468, aerobic glycolysis, energy crisis
    DOI:  https://doi.org/10.1002/cbic.202200250
  73. Adv Food Nutr Res. 2022 ;pii: S1043-4526(22)00009-2. [Epub ahead of print]100 131-172
    The powerful Solanaceae: Food and nutraceutical applications in a sustainable world.
    Mikel Añibarro-Ortega, José Pinela, Alexios Alexopoulos, Spyridon A Petropoulos, Isabel C F R Ferreira, Lillian Barros.
      The Solanaceae family is considered one of the most important families among plant species because, on one hand encompasses many staple food crops of the human diet while, on the other hand, it includes species rich in powerful secondary metabolites that could be valorized in medicine or drug formulation as well as nutraceuticals and food supplements. The main genera are Solanum, Capsicum, Physalis, and Lycium which comprise several important cultivated crops (e.g., tomato, pepper, eggplant, tomatillo, and goji berry), as well as genera notable for species with several pharmaceutical properties (e.g., Datura, Nicotiana, Atropa, Mandragora, etc.). This chapter discusses the nutritional value of the most important Solanaceae species commonly used for their edible fruit, as well as those used in the development of functional foods, food supplements, and nutraceuticals due to their bioactive constituents. The toxic and poisonous effects are also discussed aiming to highlight possible detrimental consequences due to irrational use. Finally, considering the high amount of waste and by-products generated through the value chain of the main crops, the sustainable management practices implemented so far are presented with the aim to increase the added-value of these crops.
    Keywords:  Agroindustry by-products; Alkaloids; Bioactive compounds; Capsicum; Drugs; Food crops; Food supplements; Lycium; Nutraceuticals; Physalis; Solanum; Withanolides
    DOI:  https://doi.org/10.1016/bs.afnr.2022.03.004
  74. Appl Biochem Biotechnol. 2022 Jun 08.
    The Effect of Dual Bioactive Compounds Artemisinin and Metformin Co-loaded in PLGA-PEG Nano-particles on Breast Cancer Cell lines: Potential Apoptotic and Anti-proliferative Action.
    Nasim Hassani, Davoud Jafari-Gharabaghlou, Mehdi Dadashpour, Nosratollah Zarghami.
      The most prevalent malignancy among women is breast cancer. Phytochemicals and their derivatives are rapidly being recognized as possible cancer complementary therapies because they can modify signaling pathways that lead to cell cycle control or directly alter cell cycle regulatory molecules. The phytochemicals' poor bioavailability and short half-life make them unsuitable as anticancer drugs. Applying PLGA-PEG NPs improves their solubility and tolerance while also reducing drug adverse effects. According to the findings, combining anti-tumor phytochemicals can be more effective in regulating several signaling pathways linked to tumor cell development. The point of the study was to compare the anti-proliferative impacts of combined artemisinin and metformin on cell cycle arrest and expression of cyclin D1 and apoptotic genes (bcl-2, Bax, survivin, caspase-7, and caspase-3), and also hTERT genes in breast cancer cells. T-47D breast cancer cells were treated with different concentrations of metformin (MET) and artemisinin (ART) co-loaded in PLGA-PEG NPs and free form. The MTT test was applied to assess drug cytotoxicity in T47D cells. The cell cycle distribution was investigated using flow cytometry and the expression levels of cyclin D1, hTERT, Bax, bcl-2, caspase-3, and caspase-7, and survivin genes were then determined using real-time PCR. The findings of the MTT test and flow cytometry revealed that each state was cytotoxic to T47D cells in a time and dose-dependent pattern. Compared to various state of drugs (free and nano state, pure and combination state) Met-Art-PLGA/PEG NPs demonstrated the strongest anti-proliferative impact and considerably inhibited the development of T-47D cells; also, treatment with nano-formulated forms of Met-Art combination resulted in substantial downregulation of hTERT, Bcl-2, cyclin D1, survivin, and upregulation of caspase-3, caspase-7, and Bax, in the cells, as compared to the free forms, as indicated by real-time PCR findings. The findings suggested that combining an ART/MET-loaded PLGA-PEG NP-based therapy for breast cancer could significantly improve treatment effectiveness.
    Keywords:  Apoptosis; Artemisinin; Breast cancer; Metformin; PLGA/PEG; Synergistic effect
    DOI:  https://doi.org/10.1007/s12010-022-04000-9
  75. Int J Biol Macromol. 2022 May 31. pii: S0141-8130(22)01182-5. [Epub ahead of print]213 465-477
    Core-shell Pluronic F127/chitosan based nanoparticles for effective delivery of methotrexate in the management of rheumatoid arthritis.
    Afifa Shafiq, Asadullah Madni, Shahzeb Khan, Humaira Sultana, Sumaira, Hassan Shah, Safiullah Khan, Sadia Rehman, Mehwish Nawaz.
      This study was designed to improve oral bioavailability of the methotrexate (MTX) by sustaining its release profile and integration into core-shell polymeric nanoparticles. The self-micellization and ionotropic gelation technique was employed which resulted into spherical shaped nanoparticles (181-417 nm) with encapsulation efficiency of 80.14% to 85.54%. Furthermore, Fourier Transform Infrared Spectroscopy and Differential Scanning Calorimetry analyses were carried out to investigate physicochemical and thermal stability of the produced engineered core shell nanoparticles of the methotrexate. . Entrapment of drug in polymeric core was confirmed by X-ray diffraction analysis. In-vitro sustained release behavior of nanoparticles was observed at pH 6.8 for 48 h while low drug release was observed at pH 1.2 due to pH-responsive nature of Pluronic F127. Acute toxicity study confirmed safety and biocompatible profile of nanoparticles. MTX loaded polymeric nanoparticles ameliorated the pharmacokinetic profile (8 folds greater half-life, 6.26 folds higher AUC0-t and 3.48 folds higher mean residence time). In vivo study conducted in rat model depicted the improved therapeutic efficacy and healing of arthritis through MTX loaded polymeric nanoparticles, preferentially attributable to high accretion of MTX in the inflamed site. In conclusion, MTX loaded polymeric nanoparticles is an attractive drug delivery strategy for an effective management and treatment of rheumatoid arthritis.
    Keywords:  Methotrexate; Oral drug delivery system; Pluronic F127; Polymeric nanoparticles; Rheumatoid arthritis
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.05.192
  76. Biomed Pharmacother. 2022 Jun;pii: S0753-3322(22)00431-0. [Epub ahead of print]150 113042
    Ultrasound-triggered drug delivery for glioma therapy through gambogic acid-loaded nanobubble-microbubble complexes.
    Feng Wang, Lei Dong, Simin Liang, Xixi Wei, Yongling Wang, Liansheng Chang, Kang Guo, Hongwei Wu, Yuqiao Chang, Yaling Yin, Lu Wang, Yu Shi, Fei Yan, Nana Li.
      Glioma is one of the most common primary brain tumors. Gambogic acid (GA) is widely used in tumor chemotherapy. However, GA has poor water solubility, low bioavailability, and difficult permeability across the blood-brain barrier (BBB), leading to poor efficacy against brain tumors. In our study, we developed negatively charged GA-loaded PLGA nanobubbles [GA/poly(lactic-co-glycolic acid) (PLGA)] and conjugated them onto the surface of cationic lipid microbubbles (CMBs) through electrostatic interactions. The resulting GA/PLGA-CMB complex was characterized for its particle size, distribution, drug encapsulation efficiency, and ultrasound imaging property, revealing a high drug encapsulation efficiency and excellent contrast imaging capability. Importantly, significantly enhanced GA delivery into the brain could be observed after the intravenous administration of GA/PLGA-CMBs combined with low-intensity focused ultrasound (FUS) due to the cavitation from CMBs, which mediated blood-brain barrier (BBB) opening. Taking advantage of the opened BBB, GA/PLGA nanobubbles could be delivered into the tumor. Then, the second FUS irradiation at higher energy was used to induce the cavitation of GA/PLGA nanobubbles, producing the second cavitation on tumor cells, significantly enhancing the ability of GA to enter tumor cells and inhibit tumor growth inhibition efficacy.
    Keywords:  Blood–brain barrier; Focused ultrasound; Gambogic acid; Glioma
    DOI:  https://doi.org/10.1016/j.biopha.2022.113042
  77. Biomaterials. 2022 May 24. pii: S0142-9612(22)00238-1. [Epub ahead of print]286 121598
    A small-molecule self-assembled nanodrug for combination therapy of photothermal-differentiation-chemotherapy of breast cancer stem cells.
    Xin Xie, Kailong Jiang, Bowen Li, Shenglei Hou, Honglin Tang, Baihao Shao, Yuan Ping, Qiqing Zhang.
      The combination therapy with different treatment modalities has been widely applied in the clinical applications of cancer treatment. However, it stills a considerable challenge to achieve co-delivery of different drugs because of distinct drug encapsulation mechanisms, low drug loading, and high excipient-related toxicity. Cancer stem cells (CSCs) are closely related to tumor metastasis and recurrence due to high chemoresistance. Herein, we report a stimuli-responsive and tumor-targeted small-molecule self-assembled nanodrug for the combination therapy against CSCs and normal cancer cells. The hydrophobic differentiation-inducing agent (all-trans retinoic acid, ATRA) and hydrophilic anticancer drug (irinotecan, IRI) constitute this amphiphilic nanodrug, which could self-assemble into stable nanoparticles and encapsulate the photothermal agent IR825. Upon cellular uptake, this nanodrug display good release profiles in response to acid and esterase microenvironments by ester linkage. The released drugs not only increase chemotherapy sensitivity by the differentiation of CSCs into non-CSCs, but also exhibit superior cytotoxicity in cancer cells. In addition, IR825 within this nanodrug enables in vivo fluorescence/photoacoustic (PA) imaging allowing for tracking drug distribution. Moreover, the DSPE-PEG-RGD-functionalized nanodrug displayed high tumor accumulation and good biocompatibility, enabling efficient inhibition of tumor growth and tumor metastasis in tumor-bearing mice.
    Keywords:  Breast cancer; Cancer stem cells; Combination therapy; Nanodrug; Small-molecule self-assemble
    DOI:  https://doi.org/10.1016/j.biomaterials.2022.121598
  78. Int J Biol Macromol. 2022 Jun 01. pii: S0141-8130(22)01180-1. [Epub ahead of print]213 435-446
    Self-assembled hydrogel nanocube for stimuli responsive drug delivery and tumor ablation by phototherapy against breast cancer.
    Mukherjee Arjama, Sivaraj Mehnath, Murugaraj Jeyaraj.
      The shape and responsiveness of nanoengineered delivery carriers are crucial characteristics for the rapid and efficient delivery of therapeutics. We report on a novel type of micrometer-sized hydrogel particles of controlled shape with dual pH and redox sensitivity for intracellular delivery of anticancer drugs and phototherapy. The cubical HA-DOP-CS-PEG networks with disulfide links are obtained by cross-linking HA-DOP-CS-PEG with cystamine. The pH-triggered hydrogel swelling/shrinkage was not only affords effective doxorubicin release. It also actively provides the endosomal/lysosomal escape, redox-triggered drug release. The hydrogels degrade rapidly to low molecular weight chains in the presence of the typical intracellular concentration of glutathione. Drug-loaded cube particles found to be 12% more cytotoxic. ICG and DOX-loaded hydrogel cubes demonstrate 90% cytotoxicity when incubated with MCF-7 cancer cells for 24 and 48 h, respectively. This approach integrates the advantages of pH sensitivity, enzymatic degradation, and shape-regulated internalization for novel types of "intelligent" three-dimensional networks with programmable behavior for controlled delivery of therapeutics.
    Keywords:  Glutathione; Intracellular delivery; Multilayer hydrogel; Nanocube; Phototherapy; pH-responsive
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.05.190
  79. Phytomedicine. 2022 May 30. pii: S0944-7113(22)00274-4. [Epub ahead of print]103 154196
    Phytochemistry and bioactivities of the main constituents of Polyporus umbellatus (Pers.) Fries.
    Di He, Yafei Ren, Xin Hua, Jiao Zhang, Bin Zhang, Juane Dong, Thomas Efferth, Pengda Ma.
       BACKGROUND: Edible fungi resources have good application prospects in the research and development of food, medicine, and health products. Polyporus umbellatus (Pers.) Fries, as a precious edible and medicinal fungus, has long been used by Chinese medicine to treat urinary systems and related kidney diseases.
    PURPOSE: In recent years, researchers have discovered and isolated a variety of active compounds from P. umbellatus. Modern phytochemical and pharmacological experiments showed that the crude extract of P. umbellatus had many biological functions and could be widely used in the fields of food, pharmaceutical and cosmetics. This paper summarizes the active components of P. umbellatus, through elaborating its mechanism of action, further clarify the action substances, in order to improve the utilization rate of P. umbellatus, promote the development and application of P. umbellatus in food, pharmaceutical and cosmetics industry.
    METHODS: In this paper, the literatures related to P. umbellatus were summarized and classified by "China National Knowledge Instructure (CNKI)", "Google Scholar" and "Web of Science". Compared with other articles, this work systematically sorted out all the active substances with clear structures in P. umbellatus. On this basis, combined with the chemical composition of P. umbellatus, its functional efficacy was expounded, and the effects of different types of active substances in P. umbellatus were further presented.
    RESULTS: The main chemical constituents of P. umbellatus include polysaccharide and sterol, and the secondary compounds include fatty acids, phenols and other small molecules. These active substances endowed P. umbellatus anti-cancer, antibacterial, diuretic, antioxidant, enhance immune system, promote hair growth and other pharmacological activities, which has been verified many times in vivo and in vitro experiments.
    CONCLUSION: Modern in vitro or in vivo pharmacological experiments and clinical practice for the efficacy of P. umbellatus provides a strong support, and the separation of compounds in P. umbellatus has also deepened people's understanding of this traditional Chinese medicine, greatly promoted the development and application of P. umbellatus. However, the complex active substances of poring also hinder the research of P. umbellatus to some extent, and the mechanism of action and potential synergistic or antagonistic effect of the mixture of various active ingredients have not been clearly analyzed. How to use the bioactivity-guided separation strategy to identify more bioactive components and analyze the molecular mechanism of the main active components have become the main problems of P. umbellatus research, but also provides a direction for the further study of it.
    Keywords:  Edible fungus; Functional food; Mechanism of action; Pathophysiology; Phytochemistry; Phytotherapy
    DOI:  https://doi.org/10.1016/j.phymed.2022.154196
  80. Biomed Pharmacother. 2022 Jun;pii: S0753-3322(22)00428-0. [Epub ahead of print]150 113039
    Curcuma aeruginosa Roxb. exhibits cytotoxicity in A-549 and HeLa cells by inducing apoptosis through caspase-dependent pathways.
    Alex Zohmachhuana, Malsawmdawngliana, F Lalnunmawia, Vabeiryureilai Mathipi, K Lalrinzuali, N Senthil Kumar.
      The aim of the current study was to examine the efficacy of the leaf, stem and rhizome of Curcuma aeruginosa Roxb. for their phytochemical content, antioxidant and anti-cancer activities. The different parts of C. aeruginosa were subjected to sequential extraction to give three fractions viz., hexane, ethyl acetate and methanol extract. The cytotoxic effect and the mode of action against A-549 human lung adenocarcinoma and HeLa cell lines were examined. C. aeruginosa presented no significant toxic effect in normal human lung cells (L-132). The methanol extracts were found to be the most cytotoxic and further investigation was carried out to understand the effects. The methanol extracts induced DNA damage after 24 h with significant increase in tail DNA and tail moment when compared to untreated control. Up-regulation in the expression of the caspase - 8 and - 3 activity was observed after 48 h of treatment. The mechanism of cell death and apoptosis induced by the methanol extracts on A549 and HeLa cells were studied using fluorescent staining. Bioactive compounds detected from the HPLC revealed phenol and flavonoid compounds: Gallic acid, quercetin, caffeic acid, kaempferol, rutin, coumaric acid and naringenin. GC-MS results identified the presence of sesquiterpenoids: α-curcumene, curzerene curcumenol, curzerenone epicurzerenone, caryophyllene oxide and diterpenoid, andrographolide. These compounds are known for inducing apoptosis in human cancer cells through caspase - dependent pathways. Therefore, C. aeruginosa and its potential to induce apoptosis in cancer cells suggest that they have potential in medical applications.
    Keywords:  Antioxidant; Apoptosis; Caspase; Comet assay; MTT
    DOI:  https://doi.org/10.1016/j.biopha.2022.113039
  81. Nanomaterials (Basel). 2022 May 29. pii: 1855. [Epub ahead of print]12(11):
    Recent Advances in Antimicrobial Nano-Drug Delivery Systems.
    Tong-Xin Zong, Ariane Pandolfo Silveira, José Athayde Vasconcelos Morais, Marina Carvalho Sampaio, Luis Alexandre Muehlmann, Juan Zhang, Cheng-Shi Jiang, Shan-Kui Liu.
      Infectious diseases are among the major health issues of the 21st century. The substantial use of antibiotics over the years has contributed to the dissemination of multidrug resistant bacteria. According to a recent report by the World Health Organization, antibacterial (ATB) drug resistance has been one of the biggest challenges, as well as the development of effective long-term ATBs. Since pathogens quickly adapt and evolve through several strategies, regular ATBs usually may result in temporary or noneffective treatments. Therefore, the demand for new therapies methods, such as nano-drug delivery systems (NDDS), has aroused huge interest due to its potentialities to improve the drug bioavailability and targeting efficiency, including liposomes, nanoemulsions, solid lipid nanoparticles, polymeric nanoparticles, metal nanoparticles, and others. Given the relevance of this subject, this review aims to summarize the progress of recent research in antibacterial therapeutic drugs supported by nanobiotechnological tools.
    Keywords:  antimicrobial; antimicrobial resistance; drug delivery systems; nanocarriers; nanoparticles
    DOI:  https://doi.org/10.3390/nano12111855
  82. J Food Biochem. 2022 Jun 03. e14268
    Combination therapy of bioactive compounds with acarbose: A proposal to control hyperglycemia in type 2 diabetes.
    Jonatan Jafet Uuh Narvaez, Maira Rubí Segura Campos.
      Type 2 diabetes (T2D) is a chronic metabolic disease with a high impact on public health and social welfare. Hyperglycemia is a characteristic of T2D that leads to different complications. Acarbose (ACB) reduces hyperglycemia by inhibiting α-amylase (AMY) and α-glucosidase (GLU) enzymes. However, ACB causes low adherence to treatment by patients with diabetes due to its side effects. Consequently, reducing the side effects produced by ACB without compromising its efficacy is a challenge in treating T2D. Bioactive compounds (BC) are safe and could decrease the side effects compared to antidiabetic drugs such as ACB. Nevertheless, their efficacy alone concerning that drug is unknown. The scientific advances have been directed toward searching for new approaches, such as combination therapies between BC and ACB. This review analyzes the combined therapy of BC (extracts or isolates) with ACB in inhibiting AMY and GLU as a proposal to control hyperglycemia in T2D. PRACTICAL APPLICATION: Postprandial hyperglycemia is one most typical signs of type 2 diabetes, and it can have significant consequences, including cardiovascular problems. Acarbose has side effects that lead to the abandonment of treatment. Bioactive compounds in extracts or isolated forms have become a viable option for controlling hyperglycemia without side effects, but their administration alone is insufficient. The scientific advances of acarbose/bioactive compound combination therapy as a proposal for controlling hyperglycemia in T2D were analyzed. The findings suggested that bioactive compounds combined with acarbose are effective when they function synergistically or additively; however, they are not recommended in therapy when they have an antagonistic effect.
    Keywords:  acarbose; bioactive compounds; combination therapy; hyperglycemia; type 2 diabetes
    DOI:  https://doi.org/10.1111/jfbc.14268
  83. ACS Nano. 2022 Jun 09.
    Live Macrophage-Delivered Doxorubicin-Loaded Liposomes Effectively Treat Triple-Negative Breast Cancer.
    Lan Yang, Yongshun Zhang, Yu Zhang, Yani Xu, Yuai Li, Zhiqiang Xie, Hairui Wang, Yunzhu Lin, Qing Lin, Tao Gong, Xun Sun, Zhirong Zhang, Ling Zhang.
      Triple-negative breast cancer is often aggressive and resistant to various cancer therapies, especially corresponding targeted drugs. It is shown that targeted delivery of chemotherapeutic drugs to tumor sites could enhance treatment outcome against triple-negative breast cancer. In this study, we exploited the active tumor-targeting capability of macrophages by loading doxorubicin-carrying liposomes on their surfaces via biotin-avidin interactions. Compared with conventional liposomes, this macrophage-liposome (MA-Lip) system further increased doxorubicin accumulation in tumor sites, penetrated deeper into tumor tissue, and enhanced antitumor immune response. As a result, the MA-Lip system significantly lengthened the survival rate of 4T1 cell-bearing mice with low toxicity. Besides, the MA-Lip system used highly biocompatible and widely approved materials, which ensured its long-term safety. This study provides a system for triple-negative breast cancer treatment and offers another macrophage-based strategy for tumor delivery.
    Keywords:  biotin; drug delivery; liposomes; macrophages; streptavidin; triple-negative breast cancer
    DOI:  https://doi.org/10.1021/acsnano.2c03573
  84. Int J Nanomedicine. 2022 ;17 2493-2502
    Folate Decorated Multifunctional Biodegradable Nanoparticles for Gastric Carcinoma Active Targeting Theranostics.
    Xin Zhang, Ronglin Yan, Ziran Wei, Dejun Yang, Zunqi Hu, Yu Zhang, Xin Huang, Hejing Huang, Weijun Wang.
       Introduction: Gastric cancer remains a major clinical issue and little progress has been made in the treatment of gastric cancer patients during recent decades. Nanoparticles provide a versatile platform for the diagnosis and treatment of gastric cancer.
    Methods: We prepared 7-ethyl-10-hydroxycamptothecin (SN-38) 125I-radiolabelled biodegradable nanoparticles with folate surface modification (125I-SN-38-FA-NPs) as a novel nanoplatform for targeted gastric carcinoma theranostics. We characterized this system in terms of particle size, morphology, radiostability, and release properties and examined the in vitro cytotoxicity and cellular uptake properties of 125I-SN-38-FA-NPs in MNK 7 and NCI-N7 cells. The pharmacokinetics and biodistribution of 125I-SN-38-FA-NPs were imaged by single photon emission computer tomography (SPECT). An MNK7 tumor-bearing model were established and the in vivo antitumor activity of 125I-SN-38-FA-NPs was evaluated.
    Results: SN-38 was readily radiolabeled with 125I and exhibited high radiostability. Poly-lactic-co-glycolic acid (PLGA) nanoparticles (NPs) were formed by solvent exchange, and displayed spherical morphology of 100 nm in diameter as characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM). A 2.5-fold greater uptake of 125I-radiolabelled SN-38-loaded folate-decorated PLGA nanoparticles (125I-SN-38-FA-NPs) than 125I-radiolabelled SN-38-loaded PLGA nanoparticles (125I-SN-38-NPs) were record in MKN7 tumor cells. NPs and folate-decorated PLGA nanoparticles (FA-NPs) also had good biocompatibility in methyl thiazolyl tetrazolium (MTT) assays. Pharmacokinetic, biodistribution and SPECT imaging studies showed that 125I-SN-38-FA-NPs had prolonged circulation, were distributed in the reticuloendothelial system, and had high uptake in tumors with a higher tumor accumulation of 125I-SN-38-FA-NPs than 125I-SN-38-NPs recorded at 24 h postinjection. In vivo SN-38-FA-NPs significantly inhibited tumor growth without causing obvious side effects.
    Conclusion: Folate receptor alpha (FOLR1) targeted drug-loaded nanoparticles enable SPECT imaging and chemotherapy, and provide a novel nanoplatform for gastric carcinoma active targeting theranostics.
    Keywords:  SN-38; SPECT; active targeting; biodegradable nanoparticles; folate
    DOI:  https://doi.org/10.2147/IJN.S348380
  85. J Obes. 2022 ;2022 7531518
    Possible Nonneurological Health Benefits of Ketogenic Diet: Review of Scientific Reports over the Past Decade.
    Katarzyna Daria Gołąbek, Bożena Regulska-Ilow.
      The ketogenic diet (KD) has been used since the 1920s as a therapy for drug-resistant epilepsy. Due to the beneficial effects of this diet on the nervous system and the proposed multifaceted effects of ketones on health and disease, researchers have evaluated its use in other nonneurological conditions. The objective of this review was to analyze the most recent papers, which is why meta-analyses were used in which 75% of the studies were from 2012 to 2022. Authors also cited single studies from the last decade that lasted longer than 12 months to assess the long-term benefits of KD. Reports from the past decade have highlighted several significant areas regarding the impact of KD. One of these is the use of very low-calorie ketogenic diet (VLCKD) as an effective possibly safe and patient-motivating component of a long-term weight loss plan. Reports on the positive influence of KD on the health of obese individuals, and the possible resulting validity of its use, should be verified by patients' physical activity levels. A significant number of studies from the last decade evaluate the effect of KD on improving the health of individuals with type 2 diabetes as an effective tool in lowering glycated hemoglobin (Hb1Ac) and required doses of hypoglycemic drugs. The long-term studies indicate a possible beneficial effect of KD on cardiovascular function due to improvement lipid profile, changes in apolipoprotein (Apo) A1, adiponectin, and intercellular adhesion molecule-1 (ICAM-1).
    DOI:  https://doi.org/10.1155/2022/7531518
  86. Biotechnol Rep (Amst). 2022 Jun;34 e00722
    Green decoration of graphene oxide Nano sheets with gelatin and gum Arabic for targeted delivery of doxorubicin.
    Mohamed Hasanin, Nesrin Fouad Taha, Aya Rashad Abdou, Laila Hasanin Emara.
      Tri-nanocomposite system of biocompatible polymers (gelatin/gum arabic) functionalized onto graphene-oxide nanosheets for controlling the release of an anticancer, doxorubicin (DOX), was fabricated via green-biosynthesis. Biocompatibility and nano-size stability of the tri-nanocomposite was characterized by SEM, TEM, FTIR, XRD, and zeta-potential. Loading-efficiency, release-behavior and cytotoxic-activity of DOX-loaded-composite in WI-38 normal-lung-fibroblast and A549 lung-carcinoma cells were investigated. High DOX-loading (at pH 9.5), with pH-sensitive release from loaded-composite was achieved, with 25% and 77% DOX released, at physiological pH 7.4 and cancerous pH 5.3, respectively. Stability of tri-nanocomposite system was confirmed over 3-months storage at accelerated conditions, as presented by FTIR, XRD, TEM, zeta-potential and in-vitro release assays. High proliferative inhibitory effect of DOX loaded-composite, on A549-cells, with minimal toxicity on WI-38-cells, with IC50 values of 51.9 ± 0.46 and 185±1.08 µg/mL, against A549 and WI-38, respectively. Proposed tri-nanocomposite offers a novel combination of gelatin/gum arabic with graphene-oxide for targeted drug-delivery and efficient anti-cancer therapy.
    Keywords:  Doxorubicin; Gelatin/gum arabic/graphene oxide tri-nanocomposite
    DOI:  https://doi.org/10.1016/j.btre.2022.e00722
  87. Evid Based Complement Alternat Med. 2022 ;2022 8741669
    Citrus maxima (Brum.) Merr. (Rutaceae): Bioactive Chemical Constituents and Pharmacological Activities.
    Biswash Sapkota, Hari Prasad Devkota, Prakash Poudel.
      Citrus maxima (Burm). Merr. (family Rutaceae), commonly known as Pomelo, is an ethnomedicinally, pharmacologically, and phytochemically valued species. Various ethnomedicinal reports have revealed the use of C. maxima for cough, fever, asthma, diarrhea, ulcer, and diabetes and as a sedative. Numerous phytochemicals have been reported from C. maxima such as polyphenols, terpenoids, sterols, carotenoids, vitamins, and amino acids. The plant possesses significant bioactivities like antioxidant, antimicrobial, anti-inflammatory, analgesic, anticancer, antidiabetic, anti-Alzheimer's disease, insecticidal, anxiolytic, hepatoprotective, antimalarial, and antiobesity. Extensive research is necessary to explore the detailed mechanism of action of extracts and compounds to design effective medicines, herbal products, and functional foods.
    DOI:  https://doi.org/10.1155/2022/8741669
  88. Pharmacol Rep. 2022 Jun 04.
    Dietary phytochemicals/nutrients as promising protector of breast cancer development: a comprehensive analysis.
    Suman Kumar Samanta, Paramita Choudhury, Partha Pratim Sarma, Bhaskarjyoti Gogoi, Neelutpal Gogoi, Rajlakshmi Devi.
      Genetic change, particularly epigenetic alteration, is one of the imperative factors for sporadic breast cancer development in the worldwide population of women. The DNA methylation process is essential and natural for human cellular renewal and tissue homeostasis, but its dysregulation contributes to many pathological changes, including breast tumorigenesis. Chemopreventive agents mainly protect the abnormal DNA methylation either by hindering the division of pre-malignant cells or looming the DNA damage, which leads to malignancy. The present review article is about understanding the potential role of dietary phytochemicals in breast cancer prevention. Accordingly, a literature search of the published article until August 2021 has been performed. Further, we have investigated the binding affinity of different phytochemicals isolated from diverse dietary sources against the various oncogenic proteins related to breast cancer initiation to understand the common target(s) in breast cancer prevention mechanisms. Various small phytochemicals, especially dietary phytochemicals including sulforaphane, mahanine, resveratrol, linolenic acid, diallyl sulfide, benzyl/phenethyl isothiocyanate, etc. are being investigated as the chemopreventive agent to manage breast cancer development, and some of them have shown promising outcomes in the cited research. In this present review, we discuss the recent advancement in acceptance of such types of potential dietary phytochemicals as a chemopreventive agent against breast cancer development and their inner lining mechanism. The critical clinical trials and cohort studies have also been considered to understand the progress in contemporary perspectives.
    Keywords:  Breast cancer; Breast cancer targets; Chemoprevention; DNA methylation; Dietary phytochemicals
    DOI:  https://doi.org/10.1007/s43440-022-00373-0
  89. AAPS PharmSciTech. 2022 Jun 08. 23(5): 161
    Ionic Liquids Assisted Topical Drug Delivery for Permeation Enhancement: Formulation Strategies, Biomedical Applications, and Toxicological Perspective.
    Prerana D Navti, Abhijeet Pandey, Ajinkya Nitin Nikam, Bharath Singh Padya, Guruprasad Kalthur, Kunnatur B Koteshwara, Srinivas Mutalik.
      Topical drug delivery provides several benefits over other conventional routes by providing localizing therapeutic effects and also avoids the gastrointestinal tract circumventing the first-pass metabolism and enzymatic drug degradation. Being painless, the topical route also prevents the difficulties linked with the parenteral route. However, there are limitations to the current topical systems which necessitate the need for further research to find functional excipients to overcome these limitations. This review deals in depth with the ionic liquids concerning their physicochemical properties and applicability as well as their role in the arena of topical drug delivery in permeation enhancement, bioavailability enhancement of the drugs by solvation, and drug moiety modification. The review gives a detailed insight into the recent literature on ionic liquid-based topical formulations like ionic liquid-based emulsions, active pharmaceutical ingredient-ionic liquids, ionic liquid-based bacterial cellulose membranes, topical small interfering RNA (siRNA) delivery, and ionogels as a possible solutions for overcoming the challenges associated with the topical route. This review also takes into account the toxicological aspects and biomedical applications of ionic liquids.
    Keywords:  biomedical applications; ionic liquids; permeation; skin; topical delivery; toxicological aspects
    DOI:  https://doi.org/10.1208/s12249-022-02313-w
  90. Front Pharmacol. 2022 ;13 849704
    Traditional Uses, Phytochemistry and Biological Activities of Alocasia Species: A Systematic Review.
    Dayar Arbain, Lorenskia Maria Regina Sinaga, Muhammad Taher, Deny Susanti, Zainul Amiruddin Zakaria, Junaidi Khotib.
      The genus Alocasia (Schott) G. Don consists of 113 species distributed across Asia, Southeast Asia, and Australia. Alocasia plants grow in tropical and subtropical forests with humid lowlands. Featuring their large green heart-shaped or arrow-shaped ear leaves and occasionally red-orange fruit, they are very popular ornamental plants and are widely used as traditional medicines to treat various diseases such as jaundice, snake bite, boils, and diabetes. This manuscript critically analysed the distribution, traditional uses, and phytochemical contents of 96 species of Alocasia. The numerous biological activities of Alocasia species were also presented, which include anti-cancer, antidiabetic and antihyperglycaemic, antioxidant, antidiarrhoea, antimicrobial and antifungal, antiparasitic (antiprotozoal and anthelminthic), antinociceptive and anti-inflammatory, brine shrimp lethality, hepatoprotective, anti-hemagglutinin, anti-constipation and diuretic, and radioprotective activities as well as acute toxicity studies. Research articles were acquired by the accessing three scientific databases comprising PubMed, Scopus, and Google Scholar. For this review, specific information was obtained using the general search term "Alocasia", followed by the "plant species names" and "phytochemical" or "bioactivity" or "pharmacological activity". The accepted authority of the plant species was referred from theplantlist.org. Scientific studies have revealed that the genus is mainly scattered throughout Asia. It has broad traditional benefits, which have been associated with various biological properties such as cytotoxic, antihyperglycaemic, antimicrobial, and anti-inflammatory. Alocasia species exhibit diverse biological activities that are very useful for medical treatment. The genus Alocasia was reported to be able to produce a strong and high-quality anti-cancer compound, namely alocasgenoside B, although information on this compound is currently limited. Therefore, it is strongly recommended to further explore the relevant use of natural compounds present in the genus Alocasia, particularly as an anti-cancer agent. With only a few Alocasia species that have been scientifically studied so far, more attention and effort is required to establish the link between traditional uses, active compounds, and pharmacological activities of various species of this genus.
    Keywords:  Alocasia; bioactivities; giant taro; keladi liar; talas liar
    DOI:  https://doi.org/10.3389/fphar.2022.849704
  91. ACS Omega. 2022 May 31. 7(21): 17563-17574
    Modified Titanium Dioxide as a Potential Visible-Light-Activated Photosensitizer for Bladder Cancer Treatment.
    Thaiane Robeldo, Lucas S Ribeiro, Lida Manrique, Andressa Mayumi Kubo, Elson Longo, Emerson Rodrigues Camargo, Ricardo Carneiro Borra.
      Low oxygen concentration inside the tumor microenvironment represents a major barrier for photodynamic therapy of many malignant tumors, especially urothelial bladder cancer. In this context, titanium dioxide, which has a low cost and can generate high ROS levels regardless of local O2 concentrations, could be a potential type of photosensitizer for treating this type of cancer. However, the use of UV can be a major disadvantage, since it promotes breakage of the chemical bonds of the DNA molecule on normal tissues. In the present study, we focused on the cytotoxic activities of a new material (Ti(OH)4) capable of absorbing visible light and producing high amounts of ROS. We used the malignant bladder cell line MB49 to evaluate the effects of multiple concentrations of Ti(OH)4 on the cytotoxicity, proliferation, migration, and production of ROS. In addition, the mechanisms of cell death were investigated using FACS, accumulation of lysosomal acid vacuoles, caspase-3 activity, and mitochondrial electrical potential assays. The results showed that exposure of Ti(OH)4 to visible light stimulates the production of ROS and causes dose-dependent necrosis in tumor cells. Also, Ti(OH)4 was capable of inhibiting the proliferation and migration of MB49 in low concentrations. An increase in the mitochondrial membrane potential associated with the accumulation of acid lysosomes and low caspase-3 activity suggests that type II cell death could be initiated by autophagic dysfunction mechanisms associated with high ROS production. In conclusion, the characteristics of Ti(OH)4 make it a potential photosensitizer against bladder cancer.
    DOI:  https://doi.org/10.1021/acsomega.1c07046
  92. J Nanobiotechnology. 2022 Jun 07. 20(1): 262
    Nanoparticle classification, physicochemical properties, characterization, and applications: a comprehensive review for biologists.
    Nadeem Joudeh, Dirk Linke.
      Interest in nanomaterials and especially nanoparticles has exploded in the past decades primarily due to their novel or enhanced physical and chemical properties compared to bulk material. These extraordinary properties have created a multitude of innovative applications in the fields of medicine and pharma, electronics, agriculture, chemical catalysis, food industry, and many others. More recently, nanoparticles are also being synthesized 'biologically' through the use of plant- or microorganism-mediated processes, as an environmentally friendly alternative to the expensive, energy-intensive, and potentially toxic physical and chemical synthesis methods. This transdisciplinary approach to nanoparticle synthesis requires that biologists and biotechnologists understand and learn to use the complex methodology needed to properly characterize these processes. This review targets a bio-oriented audience and summarizes the physico-chemical properties of nanoparticles, and methods used for their characterization. It highlights why nanomaterials are different compared to micro- or bulk materials. We try to provide a comprehensive overview of the different classes of nanoparticles and their novel or enhanced physicochemical properties including mechanical, thermal, magnetic, electronic, optical, and catalytic properties. A comprehensive list of the common methods and techniques used for the characterization and analysis of these properties is presented together with a large list of examples for biogenic nanoparticles that have been previously synthesized and characterized, including their application in the fields of medicine, electronics, agriculture, and food production. We hope that this makes the many different methods more accessible to the readers, and to help with identifying the proper methodology for any given nanoscience problem.
    Keywords:  Biogenic nanoparticles; Bionanoparticles; Characterization of nanomaterials; Metal nanoparticles; Nanobiotechnology; Nanomaterials
    DOI:  https://doi.org/10.1186/s12951-022-01477-8
  93. J Chin Med Assoc. 2022 Jun 06.
    Effects of polyallylamine-coated nanoparticles on the optical and photochemical properties of rose bengal.
    Kai-Ying Lin, Yeou-Guang Tsay, C Allen Chang.
       BACKGROUND: Inasmuch as optical and photochemical properties of a photosensitizer can be modified upon association with the nanoparticle (NP), we wondered whether the effectiveness of phototherapeutic rose bengal (RB) was affected upon tethering to the sodium lanthanide fluoride NP with an outer polyallylamine (PAH) coat.
    METHODS: RB molecules were electrostatically bound to the NaYF4:Gd3+:Nd3+ NPs with inner silica and outer PAH coats. The products were analyzed for their size, shape and zeta potential using transmission electron microscopy and dynamic light scattering instrument. UV-Vis absorption spectrometry and fluorescence spectrometry were used to examine the spectral properties. Photodynamic effect in terms of singlet oxygen generation was quantitatively determined using the indicator 1,3-diphenylisobenzofuran (DPBF). Photocytotoxicity mediated by NP-bound RB was tested using A549 cells. (Student's t test was used for statistical evaluation.).
    RESULTS: NP-bound RB had the major absorbance peak at 561 nm, in comparison with 549 nm for free RB, accompanied with a significant decrease in absorptivity. The molar extinction coefficient becomes 36,000 M-1 cm-1, only ~35% of that for free RB. Fluorescence spectral analyses showed a paradoxical decrease in the emission with higher NP concentrations even at very low dilutions. Most importantly, the association of RB with these NPs drastically increased its singlet oxygen production upon irradiation. The interaction of RB with PAH coat could partly account for this enhancement, given our finding that PAH in solution also caused a drastic rise in DPBF reactivity by free RB. These NPs exhibited strong photocytotoxic effects, and their promise in photodynamic therapy was addressed.
    CONCLUSION: Our findings provide evidence that the PAH coat plays a key role in enhanced biological activities of RB delivered via nanoparticles, including the increase in singlet oxygen production and photocytotoxic effects.
    DOI:  https://doi.org/10.1097/JCMA.0000000000000762
  94. Front Bioeng Biotechnol. 2022 ;10 917990
    Zinc Oxide Nanoparticles: A Review on Its Applications in Dentistry.
    C Pushpalatha, Jithya Suresh, V S Gayathri, S V Sowmya, Dominic Augustine, Ahmed Alamoudi, Bassam Zidane, Nassreen Hassan Mohammad Albar, Shankargouda Patil.
      Nanotechnology in modern material science is a research hot spot due to its ability to provide novel applications in the field of dentistry. Zinc Oxide Nanoparticles (ZnO NPs) are metal oxide nanoparticles that open new opportunities for biomedical applications that range from diagnosis to treatment. The domains of these nanoparticles are wide and diverse and include the effects brought about due to the anti-microbial, regenerative, and mechanical properties. The applications include enhancing the anti-bacterial properties of existing restorative materials, as an anti-sensitivity agent in toothpastes, as an anti-microbial and anti-fungal agent against pathogenic oral microflora, as a dental implant coating, to improve the anti-fungal effect of denture bases in rehabilitative dentistry, remineralizing cervical dentinal lesions, increasing the stability of local drug delivery agents and other applications.
    Keywords:  biomedical application; dental applications; nanodentistry; restorative material; zinc oxide nanoparticles
    DOI:  https://doi.org/10.3389/fbioe.2022.917990
  95. Oxid Med Cell Longev. 2022 ;2022 6487430
    Unraveling the Phytochemistry, Traditional Uses, and Biological and Pharmacological Activities of Thymus algeriensis Boiss. & Reut.
    Ismail Mahdi, Widad Ben Bakrim, Gabin Thierry M Bitchagno, Hassan Annaz, Mona F Mahmoud, Mansour Sobeh.
      Growing concern for public health has increased the need to change the paradigm towards a healthcare system that advocates holistic practices while reducing adverse effects. Herbal therapy is becoming an integral part of the therapeutic arsenal, and several successful plant-derived compounds/molecules are being introduced into the market. The medicinal plants belonging to the genus Thymus are among the most important species within the Lamiaceae family. One of them is Thymus algeriensis which is mainly distributed in the Mediterranean region. For a long time, this species has been used in traditional medicine to treat several disorders and diseases including inflammation, diabetes, rheumatism, digestive, and respiratory affections. This review describes the traditional uses, phytochemical composition, and biological and pharmacological activities of T. algeriensis extracts. Data were obtained using electronic databases such as SciFindern, ScienceDirect, Scopus, and Web of Science. Several plant-based extracts and a broad spectrum of identified secondary metabolites were highlighted and discussed with respective activities and modes of action. T. algeriensis represents a promising natural resource for the pharmaceutical industry mainly for antioxidant, anti-inflammatory, antimicrobial, and anticancer activities. Considering these findings, more research is needed to transmute the conventional uses of T. algeriensis into scientifically sound information. Moreover, extensive preclinical, clinical, toxicological, and pharmacokinetic trials on this species and its derivatives compounds are required to underpin the mechanisms of action and ensure its biosafety and efficiency. This comprehensive review provides a scientific basis for future investigations on the use of T. algeriensis and derived compounds in health maintenance and promotion and disease prevention.
    DOI:  https://doi.org/10.1155/2022/6487430
  96. J Hematol Oncol. 2022 Jun 03. 15(1): 72
    Mammary adipocytes protect triple-negative breast cancer cells from ferroptosis.
    Yizhao Xie, Biyun Wang, Yannan Zhao, Zhonghua Tao, Ye Wang, Guangliang Chen, Xichun Hu.
      Ferroptosis, a novel non-apoptotic form of cell death, can induce tumor cell death and treatment resistance. Lipid metabolism is closely related to ferroptosis; however, the effect of mammary adipocytes on breast cancer ferroptosis remains to be elucidated. Here, we established the co-culture system of adipocyte-breast cancer cells and revealed the protection of triple-negative breast cancer from ferroptosis by adipocytes. Then, we performed the lipidomics analysis comparing lipid metabolites of co-cultured and normal-cultured cells. Mechanistically, oleic acid secreted from adipocytes inhibited lipid peroxidation and ferroptosis of triple-negative breast cancer cells in the presence of ACSL3. Taken together, mammary adipocytes can protect breast cancer cells from ferroptosis through oleic acid in the presence of ACSL3. These findings could provide new ideas and targets for tumor treatment.
    Keywords:  Adipocytes; Breast cancer; Cell death; Ferroptosis; Lipid metabolism
    DOI:  https://doi.org/10.1186/s13045-022-01297-1
  97. Eur J Pharm Sci. 2022 Jun 01. pii: S0928-0987(22)00114-2. [Epub ahead of print]175 106229
    Mucoadhesive meloxicam-loaded nanoemulsions: Development, characterization and nasal applicability studies.
    Bence Sipos, Ildikó Csóka, Nimród Szivacski, Mária Budai-Szűcs, Zsuzsanna Schelcz, István Zupkó, Piroska Szabó-Révész, Balázs Volk, Gábor Katona.
      Intranasally administered non-steroidal anti-inflammatory drugs (NSAIDs) offer an innovative opportunity in the field of pain management. Combination of the nasal physiological advantages such as the rich vascularization and large absorption area along with novel nanomedical formulations can fulfill all the necessary criteria of an advanced drug delivery system. Nanoemulsions represent a versatile formulation approach suitable for nasal drug delivery by increasing the absorption and the bioavailability of many drugs for systemic and nose-to-brain delivery due to their stability, small droplet size and optimal solubilization properties. In this study we aimed to develop meloxicam (MX)-loaded mucoadhesive nanoemulsions and to investigate the nasal applicability of the optimized formulations. Our results indicated the optimized nanoemulsion formulation (MX-NE3) had a droplet size of 158.5 nm in monodisperse droplet size distribution (polydispersity index of 0.211). The surface charge was -11.2 mV, which helped with the colloidal stability upon dilution at simulated nasal conditions and storage. The high encapsulation efficiency (79.2%) mediated a 15-fold drug release and a 3-fold permeability increase at nasal conditions compared to the initial MX. Proper wetting properties associated with high mucoadhesion prosper the increased residence time on the surface of the nasal mucosa. No cytotoxic effect of the formulations was observed on NIH/3T3 mouse embryonic fibroblast cell lines, which supports the safe nasal applicability.
    Keywords:  Factorial design; Meloxicam; Mucoadhesion; Nanoemulsion; Nasal drug delivery; Permeation enhancement
    DOI:  https://doi.org/10.1016/j.ejps.2022.106229
  98. Ageing Res Rev. 2022 Jun 02. pii: S1568-1637(22)00100-3. [Epub ahead of print] 101658
    Brain Drug Delivery and Neurodegenerative Diseases: Polymeric PLGA-Based Nanoparticles as a Forefront Platform.
    Miguel Pinto, Vera Silva, Sandra Barreiro, Renata Silva, Fernando Remião, Fernanda Borges, Carlos Fernandes.
      The discovery of effective drugs for the treatment of neurodegenerative disorders (NDs) is a deadlock. Due to their complex etiology and high heterogeneity, progresses in the development of novel NDs therapies have been slow, raising social/economic and medical concerns. Nanotechnology and nanomedicine evolved exponentially in recent years and presented a panoply of tools projected to improve diagnosis and treatment. Drug-loaded nanosystems, particularly nanoparticles (NPs), were successfully used to address numerous drug glitches, such as efficacy, bioavailability and safety. Polymeric nanoparticles (PNPs), mainly based on polylactic-co-glycolic acid (PLGA), have been already validated and approved for the treatment of cancer, neurologic dysfunctions and hormonal-related diseases. Despite promising no PNPs-based therapy for neurodegenerative disorders is available up to date. To stimulate the research in the area the studies performed so far with polylactic-co-glycolic acid (PLGA) nanoparticles as well as the techniques aimed to improve PNPs BBB permeability and drug targeting were revised. Bearing in mind NDs pharmacological therapy landscape huge efforts must be done in finding new therapeutic solutions along with the translation of the most promising results to the clinic, which hopefully will converge in the development of effective drugs in a foreseeable future.
    Keywords:  Neurodegenerative diseases; Poly(lactide-co-glycolide) acid nanoparticles; blood-brain barrier; brain targeting; drug delivery
    DOI:  https://doi.org/10.1016/j.arr.2022.101658
  99. J Mater Chem B. 2022 Jun 06.
    Rational construction of polycystine-based nanoparticles for biomedical applications.
    Jinjin Chen, Jiazhen Yang, Jianxun Ding.
      Polypeptide-based nanoparticles are one of the promising excipients of nanomedicines due to their excellent biosafety and flexible modification. Among all the types of polypeptide nanoparticles, polycystine (PCys2)-based ones draw increasing attention due to their unique properties. On the one hand, the uniformed nanogels can be easily obtained through the crosslinking of two active centers during polymerization without additional step of self-assembly. On the other hand, the Cys2-based nanoparticles always showed reduction-responsiveness owing to the inherent disulfide bond. With the development of advanced diagnostic and therapeutic technologies, the multi-functional PCys2-based nanoparticles were achieved via rational construction of the polymer structure. This review summarizes the overall development of Cys2-based polypeptide nanoparticles, especially the structural design for the generation of multi-functional nanoparticles, along with their corresponding biomedical applications.
    DOI:  https://doi.org/10.1039/d2tb00581f
  100. J Control Release. 2022 Jun 02. pii: S0168-3659(22)00326-1. [Epub ahead of print]
    Polymer nanotherapeutics: A versatile platform for effective rheumatoid arthritis therapy.
    Rimsha Nooreen, Shweta Nene, Harsha Jain, Velpula Prasannanjaneyulu, Palak Chitlangya, Shivam Otavi, Dharmendra Khatri, Rajeev Singh Raghuvanshi, Shashi Bala Singh, Saurabh Srivastava.
      Rheumatoid arthritis is an aggressive and severely debilitating disorder that is characterized by joint pain and cartilage damage. It restricts mobility in patients, leaving them unable to carry out simple tasks. RA presents itself with severe lasting pain, swelling and stiffness in the joints and may cause permanent disability in patients. Treatment regimens currently employed for rheumatoid arthritis revolve around keeping clinical symptoms like joint pain, inflammation, swelling and stiffness at bay. The current therapeutic interventions in rheumatoid arthritis involve the use of non-steroidal anti-inflammatory drugs, glucocorticoids, disease-modifying anti-rheumatic drugs and newer biological drugs that are engineered for inhibiting the expression of pro-inflammatory mediators. These conventional drugs are plagued with severe adverse effects because of their higher systemic distribution, lack of specificity and higher doses. Oral, intra-articular, and intravenous routes are routinely used for drug delivery which is associated with decreased patient compliance, high cost, poor bioavailability and rapid systemic clearance. All these drawbacks have enticed researchers to create novel strategies for drug delivery, the main approach being nanocarrier-based systems. In this article, we aim to consolidate the remarkable contributions of polymeric carrier systems including microneedle technology and smart trigger-responsive polymeric carriers in the management of rheumatoid arthritis along with its detailed pathophysiology. This review also briefly describes the safety and regulatory aspects of polymer therapeutics.
    Keywords:  Dendrimers; Microneedles; Polymeric micelles; Polymeric nanoparticles; Rheumatoid arthritis; Stimuli-responsive nanocarriers
    DOI:  https://doi.org/10.1016/j.jconrel.2022.05.054
  101. Eur J Pharmacol. 2022 Jun 07. pii: S0014-2999(22)00350-8. [Epub ahead of print] 175089
    A comprehensive insight into the antineoplastic activities and molecular mechanisms of deoxypodophyllotoxin: Recent trends, challenges, and future outlook.
    Sayeh Mottaghi, Hassan Abbaszadeh.
      Lignans constitute an important group of polyphenols, which have been demonstrated to potently suppress cancer cell proliferation. Numerous in vitro and in vivo studies indicate that deoxypodophyllotoxin as a natural lignan possesses potent anticancer activities against various types of human cancer. The purpose of current review is to provide the reader with the latest findings in understanding the anticancer effects and molecular mechanisms of deoxypodophyllotoxin. This review comprehensively describes the influence of deoxypodophyllotoxin on signaling cascades and molecular targets implicated in cancer cell proliferation and invasion. A number of various signaling molecules and pathways, including apoptosis, necroptosis, cell cycle, angiogenesis, vascular disruption, ROS, MMPs, glycolysis, and microtubules as well as NF-κB, PI3K/Akt/mTOR, and MAPK cascades have been reported to be responsible for the anticancer activities of deoxypodophyllotoxin. The results of present review suggest that the cyclolignan deoxypodophyllotoxin can be developed as a novel and potent anticancer agent, especially as an alternative option for treatment of resistant tumors to chemotherapy.
    Keywords:  Anticancer activities; Deoxypodophyllotoxin; Lignans; Molecular mechanisms
    DOI:  https://doi.org/10.1016/j.ejphar.2022.175089
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