bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2021–12–12
89 papers selected by
Yasmin Elkabani, Egyptian Foundation for Research and Community Development
  1. Targeting ferroptosis for cancer therapy: iron metabolism and anticancer immunity.
  2. Porphyrin/Chlorin Derivatives as Promising Molecules for Therapy of Colorectal Cancer.
  3. Anticancer Properties of Eugenol: A Review.
  4. Dual anticancer role of metformin: an old drug regulating AMPK dependent/independent pathways in metabolic, oncogenic/tumorsuppresing and immunity context.
  5. Drugs repurposed: An advanced step towards the treatment of breast cancer and associated challenges.
  6. Biological Effects of Gyrophoric Acid and Other Lichen Derived Metabolites, on Cell Proliferation, Apoptosis and Cell Signaling pathways.
  7. Anti-cancer Research on Arnebiae Radix-derived Naphthoquinone in Recent Five Years.
  8. Breast Cancer: A Global Concern, Diagnostic and Therapeutic Perspectives, Mechanistic Targets in Drug Development.
  9. Chalcones against the hallmarks of cancer: a mini-review.
  10. The role of dietary polyphenols in osteosarcoma: A possible clue about the molecular mechanisms involved in a process that is just in its infancy.
  11. Sonodynamic Therapy with Metal Complexes: A New Promise in Cancer Therapy.
  12. Biodegradable mesoporous nanocomposites with dual-targeting function for enhanced anti-tumor therapy.
  13. Drug Delivery of Natural Products Through Nanocarriers for Effective Breast Cancer Therapy: A Comprehensive Review of Literature.
  14. Effects of Nigella sativa, Camellia sinensis, and Allium sativum as Food Additives on Metabolic Disorders, a Literature Review.
  15. Capsaicin inhibits HIF-1α accumulation through suppression of mitochondrial respiration in lung cancer cells.
  16. A two-front nutritional environment fuels colorectal cancer: perspectives for dietary intervention.
  17. Oxygenic Enrichment in Hybrid Ruthenium Sulfide Nanoclusters for an Optimized Photothermal Effect.
  18. Insight Into Nicotinamide Adenine Dinucleotide Homeostasis as a Targetable Metabolic Pathway in Colorectal Cancer.
  19. Natural Products Targeting Cancer Stem Cells for Augmenting Cancer Therapeutics.
  20. Synergistic Cascade Strategy Based on Modifying Tumor Microenvironment for Enhanced Breast Cancer Therapy.
  21. Integrated or Independent Actions of Metformin in Target Tissues Underlying Its Current Use and New Possible Applications in the Endocrine and Metabolic Disorder Area.
  22. Evaluation of anti-cancer effect of zerumbone and cisplatin on N-nitrosodiethylamine induced hepatic cancer in freshwater fish (Danio rerio).
  23. Receptor Tyrosine Kinases and Their Signaling Pathways as Therapeutic Targets of Curcumin in Cancer.
  24. Hesperidin and its aglycone hesperetin in breast cancer therapy: A review of recent developments and future prospects.
  25. Enhanced Anti-Tumor Effect of Folate-Targeted FA-AMA-hyd-DOX Conjugate in a Xenograft Model of Human Breast Cancer.
  26. Systematic Review of Cancer Targeting by Nanoparticles Revealed a Global Association between Accumulation in Tumors and Spleen.
  27. Combinations of Calcitriol with Anticancer Treatments for Breast Cancer: An Update.
  28. Photodynamic effect of Protoporphyrin IX in gliosarcoma 9l/lacZ cell line.
  29. Biotinylated curcumin as a novel chemosensitizer enhances naphthalimide-induced autophagic cell death in breast cancer cells.
  30. Anti-tumour potential and selectivity of caffeic acid phenethyl ester in osteosarcoma cells.
  31. The Multifaceted Role of Curcumin in Advanced Nanocurcumin Form in the Treatment and Management of Chronic Disorders.
  32. Cancer-Targeted Azo Dye for Two-Photon Photodynamic Therapy in Human Colon Tissue.
  33. Enhanced Platelet-Rich Plasma (ePRP) Stimulates Wound Healing through Effects on Metabolic Reprogramming in Fibroblasts.
  34. Carbonic anhydrase inhibitors: an update on experimental agents for the treatment and imaging of hypoxic tumors.
  35. Mitochondria-Targeted Nanocarriers Promote Highly Efficient Cancer Therapy: A Review.
  36. PEGylated Doxorubicin Prodrug-Forming Reduction-Sensitive Micelles With High Drug Loading and Improved Anticancer Therapy.
  37. FC-BBR/IND-induced glucose oxidase nanodrugs for targeted combination therapy.
  38. A pH-Responsive Nanoplatform Based on Fluorescent Conjugated Polymer Dots for Imaging-Guided Multitherapeutics Delivery and Combination Cancer Therapy.
  39. Recent advances in in situ oxygen-generating and oxygen-replenishing strategies for hypoxic-enhanced photodynamic therapy.
  40. Development of Polymer-Based Nanoformulations for Glioblastoma Brain Cancer Therapy and Diagnosis: An Update.
  41. A branched small molecule-drug conjugate nanomedicine strategy for the targeted HCC chemotherapy.
  42. Nanoparticles for Cancer Therapy: Current Progress and Challenges.
  43. Hybrid Nanoplatform: Enabling a Precise Antitumor Strategy via Dual-Modal Imaging-Guided Photodynamic/Chemo-/Immunosynergistic Therapy.
  44. Xanthohumol reduces inflammation and cell metabolism in HT29 primary colon cancer cells.
  45. Photodynamic therapy – significance in oncology
  46. Theranostic near-infrared-IIb emitting nanoprobes for promoting immunogenic radiotherapy and abscopal effects against cancer metastasis.
  47. Biomimetic Nanomaterials Triggered Ferroptosis for Cancer Theranostics.
  48. Development of oral curcumin based on pH-responsive transmembrane peptide-cyclodextrin derivative nanoparticles for hepatoma.
  49. Precise Diagnosis and Therapy of Bone Cancer Using Near-Infrared Lights.
  50. Biomacromolecule-Functionalized Nanoparticle-Based Conjugates for Potentiation of Anticancer Therapy.
  51. A MXene-Based Bionic Cascaded-Enzyme Nanoreactor for Tumor Phototherapy/Enzyme Dynamic Therapy and Hypoxia-Activated Chemotherapy.
  52. Editorial: Stimuli-Responsive Nanoparticles for Anti-cancer Therapy.
  53. Exploring the Antiglioma Mechanisms of Luteolin Based on Network Pharmacology and Experimental Verification.
  54. The Disulfiram/Copper Complex Induces Autophagic Cell Death in Colorectal Cancer by Targeting ULK1.
  55. Recent Advancements in Serum Albumin-Based Nanovehicles Toward Potential Cancer Diagnosis and Therapy.
  56. Noscapine, an Emerging Medication for Different Diseases: A Mechanistic Review.
  57. Artemisia santolinifolia-Mediated Chemosensitization via Activation of Distinct Cell Death Modes and Suppression of STAT3/Survivin-Signaling Pathways in NSCLC.
  58. Auriculasin enhances ROS generation to regulate colorectal cancer cell apoptosis, ferroptosis, oxeiptosis, invasion and colony formation.
  59. Berberine as a Potential Anticancer Agent: A Comprehensive Review.
  60. Virus-inspired hollow mesoporous gadolinium-bismuth nanotheranostics for magnetic resonance imaging-guided synergistic photodynamic-radiotherapy.
  61. Tripterygium hypoglaucum (Lévl.) Hutch and Its Main Bioactive Components: Recent Advances in Pharmacological Activity, Pharmacokinetics and Potential Toxicity.
  62. Old Habits Die Hard: Dietary Habits of Migraine Patients Challenge our Understanding of Dietary Triggers.
  63. Design and Synthesis of a Star-Like Polymeric Micelle Modified with AS1411 Aptamer for Targeted Delivery of Camptothecin for Cancer Therapy.
  64. Hunger Training as a self-regulation strategy in a comprehensive weight loss program for breast cancer prevention: a randomized feasibility study.
  65. Neuroprotection by the Ketogenic Diet: Evidence and Controversies.
  66. Chitosan oligosaccharide regulates AMPK and STAT1 pathways synergistically to mediate PD-L1 expression for cancer chemoimmunotherapy.
  67. Dietary and Supplemental Vitamin C Intake and Risk of Breast Cancer: Results from the Nurses' Health Studies.
  68. The Use of Herbal Medicines for the Prevention of Glucocorticoid-Induced Osteoporosis.
  69. Resveratrol-Induced Signal Transduction in Wound Healing.
  70. Stimuli-responsive nanomaterials for cancer treatment: boundaries, opportunities and applications.
  71. Misregulation of the expression and activity of DNA methyltransferases in cancer.
  72. Responsive nanomedicines enhanced by or enhancing physical modalities to treat solid cancer tumors: Preclinical and Clinical evidence of safety and efficacy.
  73. TPGS2000-DOX Prodrug Micelles for Improving Breast Cancer Therapy.
  74. Catalase deficiency facilitates the shuttling of free fatty acid to brown adipose tissue through lipolysis mediated by ROS during sustained fasting.
  75. Emerging Application of Magnetic Nanoparticles for Diagnosis and Treatment of Cancer.
  76. The Ketogenic Effect of Medium-Chain Triacylglycerides.
  77. Aptamer-modified DNA tetrahedra-gated metal-organic framework nanoparticle carriers for enhanced chemotherapy or photodynamic therapy.
  78. Recent advances in industrial applications of seaweeds.
  79. Blood-brain barrier penetrating liposomes with synergistic chemotherapy for glioblastoma treatment.
  80. The Effect of Organoselenium Compounds on Histone Deacetylase Inhibition and Their Potential for Cancer Therapy.
  81. Photodynamic therapy with mitochondria-targeted biscyclometallated Ir(III) complexes. Multi-action mechanism and strong influence of the cyclometallating ligand.
  82. Transdermal Drug Delivery Systems and Their Use in Obesity Treatment.
  83. Tocopherols as antioxidants in lipid-based systems: The combination of chemical and physicochemical interactions determines their efficiency.
  84. Intracellular Enzyme-Responsive Profluorophore and Prodrug Nanoparticles for Tumor-Specific Imaging and Precise Chemotherapy.
  85. A Multiscale Model to Identify Limiting Factors in Nanoparticle-Based miRNA Delivery for Tumor Inhibition.
  86. Epigenetic Reprogramming and Landscape of Transcriptomic Interactions: Impending Therapeutic Interference of Triple-Negative Breast Cancer in Molecular Medicine.
  87. Phytosterols in Seaweeds: An Overview on Biosynthesis to Biomedical Applications.
  88. Stimuli-responsive Polymeric nanosystems for therapeutic applications.
  89. A Critical Analysis of Quercetin as the Attractive Target for the Treatment of Parkinson's Disease.
  1. Am J Cancer Res. 2021 ;11(11): 5508-5525
    Targeting ferroptosis for cancer therapy: iron metabolism and anticancer immunity.
    Lianxiang Luo, Han Wang, Wen Tian, Jiayan Zeng, Yuru Huang, Hui Luo.
      Ferroptosis is a new form of programmed cell death characterized by iron-dependent accumulation of lipid peroxidation, which plays an important role in cancer biology. Ferroptosis is involved in many biological processes, such as amino acid metabolism, glutathione metabolism, iron metabolism, and lipid metabolism. Iron is an essential trace element in a variety of normal cell processes, such as DNA synthesis and repair, cell respiration, metabolism and signal transduction, etc., and iron metabolism disorder has been considered as one of the metabolic markers of malignant cancer cells. In addition, iron is involved in the regulation of innate and adaptive immune responses, suggesting that targeted regulation of iron metabolism may contribute to anti-tumor immunity and cancer therapy. In this review, the regulatory mechanism of ferroptosis, the interaction between ferroptosis on tumor cell metabolism, and anti-tumor immunity were systematically reviewed. Immunotherapy combined with targeted regulation of iron and iron-dependent regulation of ferroptosis should be the focus of future ferroptosis research.
    Keywords:  Ferroptosis; anti-tumor immunity; cancer; lipid peroxidation; metabolism
  2. Molecules. 2021 Nov 30. pii: 7268. [Epub ahead of print]26(23):
    Porphyrin/Chlorin Derivatives as Promising Molecules for Therapy of Colorectal Cancer.
    Fatima Dandash, David Y Leger, Mona Diab-Assaf, Vincent Sol, Bertrand Liagre.
      Colorectal cancer (CRC) is a leading cause of cancer-related death. The demand for new therapeutic approaches has increased attention paid toward therapies with high targeting efficiency, improved selectivity and few side effects. Porphyrins are powerful molecules with exceptional properties and multifunctional uses, and their special affinity to cancer cells makes them the ligands par excellence for anticancer drugs. Porphyrin derivatives are used as the most important photosensitizers (PSs) for photodynamic therapy (PDT), which is a promising approach for anticancer treatment. Nevertheless, the lack of solubility and selectivity of the large majority of these macrocycles led to the development of different photosensitizer complexes. In addition, targeting agents or nanoparticles were used to increase the efficiency of these macrocycles for PDT applications. On the other hand, gold tetrapyrrolic macrocycles alone showed very interesting chemotherapeutic activity without PDT. In this review, we discuss the most important porphyrin derivatives, alone or associated with other drugs, which have been found effective against CRC, as we describe their modifications and developments through substitutions and delivery systems.
    Keywords:  chlorin; colorectal cancer; photodynamic therapy; porphyrin
    DOI:  https://doi.org/10.3390/molecules26237268
  3. Molecules. 2021 Dec 06. pii: 7407. [Epub ahead of print]26(23):
    Anticancer Properties of Eugenol: A Review.
    Ali T Zari, Talal A Zari, Khalid Rehman Hakeem.
      Conventional cancer treatments have shown several unfavourable adverse effects, as well as an increase in anticancer drug resistance, which worsens the impending cancer therapy. Thus, the emphasis is currently en route for natural products. There is currently great interest in the natural bioactive components from medicinal plants possessing anticancer characteristics. For example, clove (Syzygium aromaticum L.) (Family Myrtaceae) is a highly prized spice that has been historically utilized as a food preservative and for diverse medical uses. It is reckoned amongst the valued sources of phenolics. It is indigenous to Indonesia but currently is cultivated in various places of the world. Among diverse active components, eugenol, the principal active component of S. aromaticum, has optimistic properties comprising antioxidant, anti-inflammatory, and anticancer actions. Eugenol (4-allyl-2-methoxyphenol) is a musky oil that is mainly obtained from clove. It has long been utilized all over the world as a result of its broad properties like antioxidant, anticancer, anti-inflammatory, and antimicrobial activities. Eugenol continues to pique investigators' interest because of its multidirectional activities, which suggests it could be used in medications to treat different ailments. Anticancer effects of eugenol are accomplished by various mechanisms like inducing cell death, cell cycle arrest, inhibition of migration, metastasis, and angiogenesis on several cancer cell lines. Besides, eugenol might be utilized as an adjunct remedy for patients who are treated with conventional chemotherapy. This combination leads to a boosted effectiveness with decreased toxicity. The present review focuses on the anticancer properties of eugenol to treat several cancer types and their possible mechanisms.
    Keywords:  anti-inflammatory; anticancer properties; antioxidant; apoptosis; autophagy; clove oil; eugenol; invasion; metastasis; migration; proliferation
    DOI:  https://doi.org/10.3390/molecules26237407
  4. Am J Cancer Res. 2021 ;11(11): 5625-5643
    Dual anticancer role of metformin: an old drug regulating AMPK dependent/independent pathways in metabolic, oncogenic/tumorsuppresing and immunity context.
    Maja S Misirkic Marjanovic, Ljubica M Vucicevic, Ana R Despotovic, Marina M Stamenkovic, Kristina D Janjetovic.
      Metformin has been known to treat type 2 diabetes for decades and is widely prescribed antidiabetic drug. Recently, its anticancer potential has also been discovered. Moreover, metformin has low cost thus it has attained profound research interest. Comprehensing the complexity of the molecular regulatory networks in cancer provides a mode for advancement of research in cancer development and treatment. Metformin targets many pathways that play an important role in cancer cell survival outcome. Here, we described anticancer activity of metformin on the AMPK dependent/independent mechanisms regulating metabolism, oncogene/tumor suppressor signaling pathways together with the issue of clinical studies. We also provided brief overwiev about recently described metformin's role in cancer immunity. Insight in these complex molecular networks, will simplify application of metformin in clinical trials and contribute to improvement of anti-cancer therapy.
    Keywords:  AMPK; Metformin; cancer; immunity; metabolism; oncogenes; tumor suppressors
  5. Biomed Pharmacother. 2021 Dec 01. pii: S0753-3322(21)01159-8. [Epub ahead of print] 112375
    Drugs repurposed: An advanced step towards the treatment of breast cancer and associated challenges.
    Jonaid Ahmad Malik, Sakeel Ahmed, Bisma Jan, Onur Bender, Turki Al Hagbani, Aali Alqarni, Sirajudheen Anwar.
      Breast cancer (BC) is mostly observed in women and is responsible for huge mortality in women subjects globally. Due to the continued development of drug resistance and other contributing factors, the scientific community needs to look for new alternatives, and drug repurposing is one of the best opportunities. Here we light upon the drug repurposing with a major focus on breast cancer. BC is a division of cancer known as the leading cause of death of 2.3 million women globally, with 685,000 fatalities. This number is steadily rising, necessitating the development of a treatment that can extend survival time. All available treatments for BC are very costly as well as show side effects. This unfulfilled requirement of the anti-cancer drugs ignited an enthusiasm for drug repositioning, which means finding out the anti-cancer use of already marketed drugs for other complications. With the advancement in proteomics, genomics, and computational approaches, the drug repurposing process hastens. So many drugs are repurposed for the BC, including alkylating agents, antimetabolite, anthracyclines, an aromatase inhibitor, mTOR, and many more. The drug resistance in breast cancer is rising, so reviewing how the challenges in breast cancer can be combated with drug repurposing. This paper provides the updated information on all the repurposed drugs candidates for breast cancer with the molecular mechanism responsible for their anti-tumor activity. Additionally, all the challenges that occur during the repurposing of the drugs are discussed.
    Keywords:  Breast cancer; Drug repurposing; Drug resistance; Molecular mechanism; Repurposing challenges
    DOI:  https://doi.org/10.1016/j.biopha.2021.112375
  6. Chem Biol Interact. 2021 Dec 03. pii: S0009-2797(21)00406-3. [Epub ahead of print]351 109768
    Biological Effects of Gyrophoric Acid and Other Lichen Derived Metabolites, on Cell Proliferation, Apoptosis and Cell Signaling pathways.
    Mahshid Mohammadi, Leila Bagheri, Amr Badreldin, Pedram Fatehi, Leila Pakzad, Zacharias Suntres, Andre J van Wijnen.
      Secondary metabolites from fungi, algae and lichens have remarkable biological activities as antibiotics, fungicides, antiviral drugs, and cancer therapeutics. This review focuses on the lichen-derived metabolite gyrophoric acid and other select secondary metabolites (e.g., usnic acid, salazinic acid, physodic acid, vulpinic acid ceratinalone, flavicansone, ramalin, physciosporin, tumidulin, atranorin, parmosidone) that modulate a number of cellular pathways relevant to several biomedical diseases and disorders, including cancer, diabetes and cardiovascular disease. We discuss the chemical structure and biochemical activities of gyrophoric acid and other compounds relative to the molecular mechanisms and cellular processes that these metabolites target in a distinct human and rodent cell types. The therapeutic promise of gyrophoric acid and similar lichen derived metabolites is associated with the chemical versatility of these compounds as polyaromatic depsides with functional carboxyl and hydroxyl side-groups that may permit selective interactions with distinct enzymatic active sites. Gyrophoric acid has been examined in a series of studies as an effective anticancer drug because it impinges on topoisomerase 1 activity, as well as causes cell cycle arrest, comprises cell survival, and promotes apoptosis. Because gyrophoric acid has cytostatic properties, its biological roles and possible medicinal utility may extend beyond effects on cancer cells and be relevant to any process that is controlled by cell growth and differentiation.
    Keywords:  Anticancer; Apoptosis; Cancer cytostatic; Cardiovascular diseases; Cytotoxic; Depside; Diabetes; Gyrophoric acid; Lichens; Mechanism of action; Proliferation; Secondary metabolite; Topoisomerase
    DOI:  https://doi.org/10.1016/j.cbi.2021.109768
  7. Recent Pat Anticancer Drug Discov. 2021 Dec 09.
    Anti-cancer Research on Arnebiae Radix-derived Naphthoquinone in Recent Five Years.
    Lian Zhu, Kailin Li, Mingjuan Liu, Kexin Liu, Shengjun Ma, Wei Cai.
       BACKGROUND: In recent years, many naphthoquinone compounds with anticancer activity have been identified in Arnebiae Radix, and some of them have the potential to be developed into anticancer drugs.
    OBJECTIVE: This article aimed to provide a comprehensive overview of the anticancer effects of naphthoquinone compounds through a detailed review of literature and Chinese patents, and discuss their potential to be developed as anticancer drugs for clinical application.
    METHODS: Research papers were collected through the databases of PubMed, Cnki and SciDirect using keyword searches "naphthoquinone compounds" and "anticancer". The keywords of "shikonin" and "shikonin derivatives" were also used in PubMed, Cnki and SciDirect databases to collect research articles. The Chinese patents were collected using the Cnki patent database.
    RESULTS: Naphthoquinone compounds have been found to possess anti-cancer activity, and their modes of action are associated with inducing apoptosis, inhibiting cancer cell proliferation, promoting autophagy in cancer cells, anti-cancer angiogenesis and inhibition of cell adhesion, invasion and metastasis, inhibiting glycolysis and inhibiting DNA topoisomerase activity.
    CONCLUSION: Most of the naphthoquinone compounds show effective anti-cancer activity in vitro. The structure modification of naphthoquinone aims to develop anti-cancer drugs with high efficacy and low toxicity.
    Keywords:  Arnebiae Radix; anti-cancer; naphthoquinone compounds; shikonin
    DOI:  https://doi.org/10.2174/1574892816666211209164745
  8. Adv Pharm Bull. 2021 Sep;11(4): 580-594
    Breast Cancer: A Global Concern, Diagnostic and Therapeutic Perspectives, Mechanistic Targets in Drug Development.
    Gul-E-Saba Chaudhry, Rehmat Jan, Abdah Akim, Muhammad Naveed Zafar, Yeong Yik Sung, Tengku Sifzizul Tengku Muhammad.
      Cancer is a complex multifactorial process, unchecked and abrupt division, and cell growth-conventional chemotherapy, along with radiotherapy, is used to treat breast cancer. Due to reduce efficacy and less survival rate, there is a particular need for the discovery of new active anticancer agents. Natural resources such as terrestrial/marine plants or organisms are a promising source for the generation of new therapeutics with improving efficacy. The screening of natural plant extracts and fractions, isolations of phytochemicals, and mechanistic study of those potential compounds play a remarkable role in the development of new therapeutic drugs with increased efficacy. Cancer is a multistage disease with complex signaling cascades. The initial study of screening whole extracts or fractions and later the isolation of secondary compounds and their mechanism of action study gives a clue of potential therapeutic agents for future drug development. The phytochemicals present in extracts/fractions produce remarkable effects due to synergistically targeting multiple signals. In this review, the molecular targets of extracts/ fractions and isolated compounds highlighted. The therapeutic agent's mechanistic targets in drug development focused involves; i) Induction of Apoptosis, ii) modulating cell cycle arrest, iii) Inhibition or suppression of invasion and metastasis and iv) various other pro-survival signaling pathways. The phytochemicals and their modified analogs identified as future potential candidates for anticancer chemotherapy.
    Keywords:  Apoptosis; Breast cancer; Cell cycle arrest; Drug development; Mechanism of action; Natural products; Phytochemicals; Plant anticancer drugs
    DOI:  https://doi.org/10.34172/apb.2021.068
  9. Nat Prod Res. 2021 Dec 06. 1-18
    Chalcones against the hallmarks of cancer: a mini-review.
    Paloma Silva de Souza, Geysa Cristina Caldas Bibá, Evelynn Dalila do Nascimento Melo, Michelle Frazão Muzitano.
      Chalcones (1,3-diphenylpropen-1-ones) are a class of flavonoids that have been shown a broad spectrum of biological activities with therapeutic potential. Naturally occurring chalcones or synthetic chalcone derivatives have been extensively investigated as anticancer compounds. Cancer is still among the leading causes of death globally, although cancer treatments have improved over the past decades. Most of chemotherapeutic drugs target proliferating tumor cells; however, the cancer cells capabilities are also associated to tumor surround microenvironment. Thereby, the search of new compounds with a broad antitumor activity is still a great challenge. The cytotoxicity mechanisms of chalcones are beyond apoptosis induction in tumor cells, which make them promising compound for cancer therapy. In this mini-review we summarized recent studies that describe the anticancer potential of chalcones related to some of hallmarks of cancer. We shed a light on sustaining proliferative signaling, tumor-promoting inflammation, activating invasion and metastasis, inducing angiogenesis and resisting cell death.
    Keywords:  Chalcone; cancer; chemotherapy; flavonoid; hallmarks
    DOI:  https://doi.org/10.1080/14786419.2021.2000980
  10. J Food Biochem. 2021 Dec 07. e14026
    The role of dietary polyphenols in osteosarcoma: A possible clue about the molecular mechanisms involved in a process that is just in its infancy.
    Ana Carolina Silveira Rabelo, Jéssica Borghesi, Giuliana D Noratto.
      Osteosarcoma (OS) is a primary malignant bone tumor mainly affecting children, teenagers and young adults, being associated with early metastasis and poor prognosis. The beneficial effects of polyphenols have been investigated in different areas, including their potential to fight OS. Polyphenols are believed to reduce morbidity and/or slow down the development of cancer. This review aimed to assess the effect of polyphenols in OS and investigate their molecular mechanisms. It was observed that the broad spectrum of health-promoting properties of plant polyphenols in OS occurs mainly due to modulation of reactive oxygen species, anti-inflammatory activity, anti-angiogenesis, apoptosis inducer, inhibition of invasion and metastasis. However, it is worth mentioning that although the promising effects of polyphenols in the fight against OS, most of the studies have been performed using in vitro and in vivo animal models. Therefore, studies in humans are needed to validate the effectiveness of polyphenols in OS treatment. PRACTICAL APPLICATIONS: Polyphenols are widely used for various diseases, however, until now, their real role in the treatment of osteosarcoma remains unknown. This review provides a broad spectrum of research conducted with polyphenols and their potential as adjuvant therapy in the treatment of osteosarcoma. However, prior to their clinical application for osteosarcoma treatment, there is a need to isolate and identify specific polyphenolic compounds with high antitumor activity, increase their oral bioavailability, and to investigate their interactions with chemotherapeutic drugs being used in clinical practice.
    Keywords:  cancer; molecular basis; osteosarcoma; pathway; polyphenols
    DOI:  https://doi.org/10.1111/jfbc.14026
  11. ChemMedChem. 2021 Dec 08.
    Sonodynamic Therapy with Metal Complexes: A New Promise in Cancer Therapy.
    Ashish Kumar Yadav, Narendra Kumar, Abdul Talim Khan, Rajesh Kushwaha, Samya Banerjee.
      In recent years, to overcome the problem of low tissue penetration power of light in photodynamic therapy (PDT), sonodynamic therapy (SDT) with ultrasound (US) as the drug stimulus has emerged as a potential alternative to PDT. The significantly higher tissue penetration capacity of US is reported to allow the treatment of deep-seated tumours. In general, organic molecules and nanomaterials dominate as the sonosensitizers in this area of research, and the potential of metal complexes in SDT is not yet well explored. In this highlight, we have summarized two recent literature reports in which researchers have explored the efficiency of metal complexes as sonosensitizers for the first time. These reports indicate the high potential of metal complexes in SDT.
    Keywords:  Metal complex; Singlet oxygen; Sono-cytotoxicity; Sonodynamic therapy; Ultrasound
    DOI:  https://doi.org/10.1002/cmdc.202100615
  12. J Control Release. 2021 Dec 01. pii: S0168-3659(21)00639-8. [Epub ahead of print]341 383-398
    Biodegradable mesoporous nanocomposites with dual-targeting function for enhanced anti-tumor therapy.
    Shan Gao, Yuli Liu, Meng Liu, Dongjuan Yang, Mingming Zhang, Kai Shi.
      Tumor-associated macrophages (TAMs), the main components of infiltrating leukocytes in tumors, often play a key role in promoting cancer development and progression. The tumor-specific microenvironment forces the phenotype of tumor-infiltrating to evolve in a direction favorable to tumor development, that is, the generation of M2-like TAMs. Consequently, the dual intervention of cancer cells and tumor microenvironment has become a research hotspot in the field of tumor immunotherapy. In this contribution, we developed pH-sensitive mesoporous calcium silicate nanocomposites (MCNs) encapsulated with indocyanine green (ICG) to enable the effective combination of photothermal therapy (PTT) and photodynamic therapy (PDT) triggered by the 808 nm near-infrared (NIR) light. The mannose and hyaluronic acid-grafted MCNs specifically targeted TAMs and tumor cells and promoted cell apoptosis both in vitro and in vivo. This paper revealed that irradiation of ICG loaded MCNs with NIR can produce a potent hyperthermia and induce abundant intracellular singlet oxygen generation in the target cells. These results suggest that the novel nanoplatform is believed to facilitate the delivery of chemotherapeutic agents to the tumor microenvironment (TME) to enhance the effects of tumor treatment.
    Keywords:  Biodegradable; Indocyanine green; Ordered mesoporous nanocomposites; Photodynamic therapy; Photothermal therapy; Tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.jconrel.2021.11.044
  13. Int J Nanomedicine. 2021 ;16 7891-7941
    Drug Delivery of Natural Products Through Nanocarriers for Effective Breast Cancer Therapy: A Comprehensive Review of Literature.
    Kah Min Yap, Mahendran Sekar, Shivkanya Fuloria, Yuan Seng Wu, Siew Hua Gan, Nur Najihah Izzati Mat Rani, Vetriselvan Subramaniyan, Chandrakant Kokare, Pei Teng Lum, M Yasmin Begum, Shankar Mani, Dhanalekshmi Unnikrishnan Meenakshi, Kathiresan V Sathasivam, Neeraj Kumar Fuloria.
      Despite recent advances in the diagnosis and treatment of breast cancer (BC), it remains a global health issue affecting millions of women annually. Poor prognosis in BC patients is often linked to drug resistance as well as the lack of effective therapeutic options for metastatic and triple-negative BC. In response to these unmet needs, extensive research efforts have been devoted to exploring the anti-BC potentials of natural products owing to their multi-target mechanisms of action and good safety profiles. Various medicinal plant extracts/essential oils and natural bioactive compounds have demonstrated anti-cancer activities in preclinical BC models. Despite the promising preclinical results, however, the clinical translation of natural products has often been hindered by their poor stability, aqueous solubility and bioavailability. There have been attempts to overcome these limitations, particularly via the use of nano-based drug delivery systems (NDDSs). This review highlights the tumour targeting mechanisms of NDDSs, the advantages and disadvantages of the major classes of NDDSs and their current clinical status in BC treatment. Besides, it also discusses the proposed anti-BC mechanisms and nanoformulations of nine medicinal plants' extracts/essential oils and nine natural bioactive compounds; selected via the screening of various scientific databases, including PubMed, Scopus and Google Scholar, based on the following keywords: "Natural Product AND Nanoparticle AND Breast Cancer". Overall, these nanoformulations exhibit improved anti-cancer efficacy against preclinical BC models, with some demonstrating biocompatibility with normal cell lines and mouse models. Further clinical studies are, however, warranted to ascertain their efficacy and biocompatibility in humans.
    Keywords:  breast cancer; drug delivery; molecular mechanisms; nanoparticles; natural products; phytomedicine
    DOI:  https://doi.org/10.2147/IJN.S328135
  14. Front Pharmacol. 2021 ;12 762182
    Effects of Nigella sativa, Camellia sinensis, and Allium sativum as Food Additives on Metabolic Disorders, a Literature Review.
    Akbar Anaeigoudari, Hamidreza Safari, Mohammad Reza Khazdair.
      Objective: Metabolic disorders (MD) can disturb intracellular metabolic processes. A metabolic disorder can be resulted from enzyme deficits or disturbances in function of various organs including the liver, kidneys, pancreas, cardiovascular system, and endocrine system. Some herbs were used traditionally for spices, food additives, dietary, and medicinal purposes. Medicinal plants possess biological active compounds that enhance human health. We aimed to provide evidence about therapeutic effects of some medicinal herbs on MD. Data Sources: PubMed, Scopus, and Google Scholar were explored for publications linked to MD until February 2021. The most literature reports that were published in the last 10 years were used. All types of studies such as animal studies, clinical trials, and in vitro studies were included. The keywords included "Metabolic disorders," "Nigella sativa L.," "Thymoquinone," "White tea"OR "Camellia sinensis L." "catechin," and "Allium sativum L." OR "garlic" were searched. Results: Based on the results of scientific studies, the considered medicinal plants and their active components in this review have been able to exert the beneficial therapeutic effects on obesity, diabetes mellitus and non-alcoholic fatty liver disease. Conclusions: These effects are obvious by inhibition of lipid peroxidation, suppression of inflammatory reactions, adjustment of lipid profile, reduction of adipogenesis and regulation of blood glucose level.
    Keywords:  Garlic; Nigella sativa L.; anti-diabetic effects; anti-inflammatory effects; anti-obesity effects; metabolic disorders; white tea
    DOI:  https://doi.org/10.3389/fphar.2021.762182
  15. Biomed Pharmacother. 2021 Dec 06. pii: S0753-3322(21)01286-5. [Epub ahead of print]146 112500
    Capsaicin inhibits HIF-1α accumulation through suppression of mitochondrial respiration in lung cancer cells.
    Tae-Hee Han, Min Kyung Park, Hiroyuki Nakamura, Hyun Seung Ban.
      Hypoxia inducible factor (HIF)-1α is an important transcription factor regulating cancer metabolism in hypoxic environment. Capsaicin is known to inhibit hypoxia-induced HIF activity in lung cancer. Hence, in this study we tried to elucidate its inhibitory mechanism of action. In lung cancer cells, including H1299, H23, A549, and H2009 cells, capsaicin inhibited cell growth and HIF activation. Under hypoxic conditions, capsaicin reduced the accumulation of HIF-1α protein and the expression of its target genes, including pyruvate dehydrogenase kinase 1 (PDK1) and glucose transporter 1 (GLUT1), with no effect on overall HIF-1α mRNA levels in the H1299 cells. In addition, capsaicin increased intracellular oxygen levels by suppressing mitochondrial respiration, resulting in a reduction of HIF-1α accumulation. Furthermore, mitochondrial ATP production was reduced by capsaicin through the inhibition of mitochondrial respiration in the H1299, H23, A549, and H2009 cells. These results indicate that capsaicin potentially exhibits anticancer therapeutic effects in lung cancer under hypoxic conditions.
    Keywords:  Capsaicin; HIF-1α; Hypoxia; Lung cancer; Mitochondrial respiration
    DOI:  https://doi.org/10.1016/j.biopha.2021.112500
  16. Trends Endocrinol Metab. 2021 Dec 06. pii: S1043-2760(21)00261-7. [Epub ahead of print]
    A two-front nutritional environment fuels colorectal cancer: perspectives for dietary intervention.
    Elien Alderweireldt, Charlotte Grootaert, Olivier De Wever, John Van Camp.
      Colorectal cancer (CRC) develops and progresses in a nutritional environment comprising a continuously changing luminal cocktail of external dietary and microbial factors on the apical side, and a dynamic host-related pool of systemic factors on the serosal side. In this review, we highlight how this two-front environment influences the bioenergetic status of colonocytes throughout CRC development from (cancer) stem cells to cancer cells in nutrient-rich and nutrient-poor conditions, and eventually to metastatic cells, which, upon entry to the circulation and during metastatic seeding, are forced to metabolically adapt. Furthermore, given the influence of diet on the two-front nutritional environment, we discuss dietary strategies that target the specific metabolic preferences of these cells, with a possible impact on colon cancer cell bioenergetics and CRC outcome.
    Keywords:  bioenergetics; colorectal cancer; dietary intervention; metabolism; nutritional environment
    DOI:  https://doi.org/10.1016/j.tem.2021.11.002
  17. ACS Appl Mater Interfaces. 2021 Dec 07.
    Oxygenic Enrichment in Hybrid Ruthenium Sulfide Nanoclusters for an Optimized Photothermal Effect.
    Houjuan Zhu, Zibiao Li, Enyi Ye, David Tai Leong.
      Transition-metal dichalcogenide (TMD)-based nanomaterials have been extensively explored for the photonic therapy. To the best of our knowledge, near-infrared (NIR) light is a requirement for the photothermal therapy (PTT) to achieve the feature of deep-tissue penetration, whereas no obvious absorption peaks existing in the NIR region for existing TMD nanomaterials limit their therapeutic efficacy. As one category of TMD nanomaterials, ruthenium sulfide-based nanomaterials have been less exploited in biomedical applications including tumor therapy so far. Here, we develop a facile biomineralization-assisted bottom-up strategy to synthesize oxygenic hybrid ruthenium sulfide nanoclusters (RuSx NCs) by regulating the oxygen amounts and sulfur defects for the optimized PTT. By regulating the increasing initial molar ratios of Ru to S, RuSx NCs with small sizes were endowed with increasing oxygen contents and sulfur defects, leading to the photothermal conversion efficiency (PCE) increasing from 32.8 to 41.9%, which were higher than that of most small-sized inorganic photothermal nanoagents. In contrast to commercial indocyanine green, these RuSx NCs exhibited higher photostability under NIR laser irradiation. The high PCE and superior photostability allowed RuSx NCs to effectively and completely ablate cancer cells. Thus, the proposed defect engineering strategy endows RuSx NCs with an excellent photothermal effect for the PTT of tumors of living mice, which also proves the potential of further exploring the properties of RuSx NCs for future biomedical applications.
    Keywords:  oxygen enrichment; photothermal effect; photothermal therapy; ruthenium sulfide nanoclusters; sulfur defect
    DOI:  https://doi.org/10.1021/acsami.1c17608
  18. Front Pharmacol. 2021 ;12 758320
    Insight Into Nicotinamide Adenine Dinucleotide Homeostasis as a Targetable Metabolic Pathway in Colorectal Cancer.
    Giorgia Colombo, Edoardo Luigi Maria Gelardi, Federica Carolina Balestrero, Marianna Moro, Cristina Travelli, Armando A Genazzani.
      Tumour cells modify their cellular metabolism with the aim to sustain uncontrolled proliferation. Cancer cells necessitate adequate amounts of NAD and NADPH to support several enzymes that are usually overexpressed and/or overactivated. Nicotinamide adenine dinucleotide (NAD) is an essential cofactor and substrate of several NAD-consuming enzymes, such as PARPs and sirtuins, while NADPH is important in the regulation of the redox status in cells. The present review explores the rationale for targeting the key enzymes that maintain the cellular NAD/NADPH pool in colorectal cancer and the enzymes that consume or use NADP(H).
    Keywords:  ALDH = aldehyde dehydrogenase; CD38; NAD; NADPH; NAMPT (nicotinamide phosphoribosyltransferase); PARP; isocitrate dehydrogenase (IDH); sirtuins
    DOI:  https://doi.org/10.3389/fphar.2021.758320
  19. Int J Mol Sci. 2021 Dec 02. pii: 13044. [Epub ahead of print]22(23):
    Natural Products Targeting Cancer Stem Cells for Augmenting Cancer Therapeutics.
    Ari Meerson, Soliman Khatib, Jamal Mahajna.
      Cancer stem cells (CSC) have been identified in several types of solid tumors. In some cases, CSC may be the source of all the tumor cells, the cause of the tumor's resistance to chemotherapeutic agents, and the source of metastatic cells. Thus, a combination therapy targeting non-CSC tumor cells as well as specifically targeting CSCs holds the potential to be highly effective. Natural products (NPs) have been a historically rich source of biologically active compounds and are known for their ability to influence multiple signaling pathways simultaneously with negligible side effects. In this review, we discuss the potential of NPs in targeting multiple signaling pathways in CSC and their potential to augment the efficacy of standard cancer therapy. Specifically, we focus on the anti-CSC activities of flavonoids, FDA-approved drugs originating from natural sources. Additionally, we emphasize the potential of NPs in targeting microRNA-mediated signaling, given the roles of microRNA in the maintenance of the CSC phenotype.
    Keywords:  cancer stem cells; cancer therapy; flavonoids; natural products
    DOI:  https://doi.org/10.3390/ijms222313044
  20. Front Pharmacol. 2021 ;12 750847
    Synergistic Cascade Strategy Based on Modifying Tumor Microenvironment for Enhanced Breast Cancer Therapy.
    Huan Zhang, Jinshun Xu, Binyang Gao, Hong Wang, Jianbo Huang, Jie Zhou, Rui Yang, Feng Yan, Yulan Peng.
      Background: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with very few treatment options. Although tumor-targeted nanomedicines hold great promise for the treatment of TNBC, the tumor microenvironment (TME) continues to be a major cause of failure in nanotherapy and immunotherapy. To overcome this barrier, we designed a new synergistic cascade strategy (SCS) that uses mild hyperthermia and smart drug delivery system (SDDS) to alter TME resistance in order to improve drug delivery and therapeutic efficacy of TNBC. Methods: Mild hyperthermia was produced by microwave (MW) irradiation. SDDS were formulated with thermosensitive polymer-lipid nanoparticles (HA-BNPs@Ptx), composed of polymer PLGA, phospholipid DPPC, hyaluronic acid (HA, a differentiation-44-targeted molecule, also known as CD44), 1-butyl-3-methylimidazolium-L-lactate (BML, a MW sensitizer), and paclitaxel (Ptx, chemotherapy drug). 4T1 breast tumor-bearing mice were treated with two-step MW combined with HA-BNPs@Ptx. Tumors in mice were pretreated with first MW irradiation prior to nanoparticle injection to modify and promote TME and promoting nanoparticle uptake and retention. The second MW irradiation was performed on the tumor 24 h after the injection of HA-BNPs@Ptx to produce a synergistic cascade effect through activating BML, thus, enhancing a hyperthermia effect, and instantly releasing Ptx at the tumor site. Results: Multifunctional CD44-targeted nanoparticles HA-BNPs@Ptx were successfully prepared and validated in vitro. After the first MW irradiation of tumors in mice, the intratumoral perfusion increased by two times, and the nanoparticle uptake was augmented by seven times. With the second MW irradiation, remarkable antitumor effects were obtained with the inhibition rate up to 88%. In addition, immunohistochemical analysis showed that SCS therapy could not only promote tumor cell apoptosis but also significantly reduce lung metastasis. Conclusion: The SCS using mild hyperthermia combined with SDDS can significantly improve the efficacy of TNBC treatment in mice by modifying TME and hyperthermia-mediated EPR effects.
    Keywords:  breast cancer; drug delivery; hyperthermia; nanoparticles; tumor microenvironment
    DOI:  https://doi.org/10.3389/fphar.2021.750847
  21. Int J Mol Sci. 2021 Dec 02. pii: 13068. [Epub ahead of print]22(23):
    Integrated or Independent Actions of Metformin in Target Tissues Underlying Its Current Use and New Possible Applications in the Endocrine and Metabolic Disorder Area.
    Giovanni Tulipano.
      Metformin is considered the first-choice drug for type 2 diabetes treatment. Actually, pleiotropic effects of metformin have been recognized, and there is evidence that this drug may have a favorable impact on health beyond its glucose-lowering activity. In summary, despite its long history, metformin is still an attractive research opportunity in the field of endocrine and metabolic diseases, age-related diseases, and cancer. To this end, its mode of action in distinct cell types is still in dispute. The aim of this work was to review the current knowledge and recent findings on the molecular mechanisms underlying the pharmacological effects of metformin in the field of metabolic and endocrine pathologies, including some endocrine tumors. Metformin is believed to act through multiple pathways that can be interconnected or work independently. Moreover, metformin effects on target tissues may be either direct or indirect, which means secondary to the actions on other tissues and consequent alterations at systemic level. Finally, as to the direct actions of metformin at cellular level, the intracellular milieu cooperates to cause differential responses to the drug between distinct cell types, despite the primary molecular targets may be the same within cells. Cellular bioenergetics can be regarded as the primary target of metformin action. Metformin can perturb the cytosolic and mitochondrial NAD/NADH ratio and the ATP/AMP ratio within cells, thus affecting enzymatic activities and metabolic and signaling pathways which depend on redox- and energy balance. In this context, the possible link between pyruvate metabolism and metformin actions is extensively discussed.
    Keywords:  cell metabolism; cell signaling; endocrinology; metabolic diseases; metformin; neuroendocrine tumors; pituitary tumors; pyruvate; pyruvate dehydrogenase complex
    DOI:  https://doi.org/10.3390/ijms222313068
  22. Nat Prod Res. 2021 Dec 09. 1-5
    Evaluation of anti-cancer effect of zerumbone and cisplatin on N-nitrosodiethylamine induced hepatic cancer in freshwater fish (Danio rerio).
    Jegannathan Srimathi Devi, Dayalan Haripriya, Santhosh Arul, Konda Mani Saravanan, Giridharan Bupesh.
      Cancer is the uncontrolled proliferation of abnormal cells in the body. There is a foreseeable need for an effective anti-carcinogenic drug. In this regard, zerumbone (ZER) is identified as one such therapeutic herbal compound that has been shown to enhance the anticancer activity of cisplatin (CIS), with negligible side effects. Yet, the fundamental mechanisms of co-treatment of ZER and CIS on Hepatocellular carcinoma remain indefinable. The current study is endeavored to evaluate the anti-cancer effect of the individual and co-treatment of ZER, CIS and its combination on Diethyl nitrosamine induced hepatic cancer in wild-type zebra fish (Danio Rerio) models. Our careful analysis on treated and untreated fishes shows that CIS + ZER combination group restricted further progression of hepatocellular carcinoma cells significantly, which concludes that co-treatment of ZER with CIS was therapeutically effective for treating human HCC cancer cells which were induced into zebra fish.
    Keywords:  Anti-cancer; cisplatin; combination therapy; nitrosodiethylamine; zebra fish; zerumbone
    DOI:  https://doi.org/10.1080/14786419.2021.2012672
  23. Front Pharmacol. 2021 ;12 772510
    Receptor Tyrosine Kinases and Their Signaling Pathways as Therapeutic Targets of Curcumin in Cancer.
    Sareshma Sudhesh Dev, Syafiq Asnawi Zainal Abidin, Reyhaneh Farghadani, Iekhsan Othman, Rakesh Naidu.
      Receptor tyrosine kinases (RTKs) are transmembrane cell-surface proteins that act as signal transducers. They regulate essential cellular processes like proliferation, apoptosis, differentiation and metabolism. RTK alteration occurs in a broad spectrum of cancers, emphasising its crucial role in cancer progression and as a suitable therapeutic target. The use of small molecule RTK inhibitors however, has been crippled by the emergence of resistance, highlighting the need for a pleiotropic anti-cancer agent that can replace or be used in combination with existing pharmacological agents to enhance treatment efficacy. Curcumin is an attractive therapeutic agent mainly due to its potent anti-cancer effects, extensive range of targets and minimal toxicity. Out of the numerous documented targets of curcumin, RTKs appear to be one of the main nodes of curcumin-mediated inhibition. Many studies have found that curcumin influences RTK activation and their downstream signaling pathways resulting in increased apoptosis, decreased proliferation and decreased migration in cancer both in vitro and in vivo. This review focused on how curcumin exhibits anti-cancer effects through inhibition of RTKs and downstream signaling pathways like the MAPK, PI3K/Akt, JAK/STAT, and NF-κB pathways. Combination studies of curcumin and RTK inhibitors were also analysed with emphasis on their common molecular targets.
    Keywords:  combination therapy; curcumin; polyphenol; receptor tyrosine kinase; signaling pathway; tyrosine kinase inhibitor
    DOI:  https://doi.org/10.3389/fphar.2021.772510
  24. Saudi J Biol Sci. 2021 Dec;28(12): 6730-6747
    Hesperidin and its aglycone hesperetin in breast cancer therapy: A review of recent developments and future prospects.
    Kah Min Yap, Mahendran Sekar, Yuan Seng Wu, Siew Hua Gan, Nur Najihah Izzati Mat Rani, Lay Jing Seow, Vetriselvan Subramaniyan, Neeraj Kumar Fuloria, Shivkanya Fuloria, Pei Teng Lum.
      Breast cancer (BC) has high incidence and mortality rates, making it a major global health issue. BC treatment has been challenging due to the presence of drug resistance and the limited availability of therapeutic options for triple-negative and metastatic BC, thereby urging the exploration of more effective anti-cancer agents. Hesperidin and its aglycone hesperetin, two flavonoids from citrus species, have been extensively evaluated for their anti-cancer potentials. In this review, available literatures on the chemotherapeutic and chemosensitising activities of hesperidin and hesperetin in preclinical BC models are reported. The safety and bioavailability of hesperidin and hesperetin as well as the strategies to enhance their bioavailability are also discussed. Overall, hesperidin and hesperetin can inhibit cell proliferation, migration and BC stem cells as well as induce apoptosis and cell cycle arrest in vitro. They can also inhibit tumour growth, metastasis and neoplastic changes in tissue architecture in vivo. Moreover, the co-administration of hesperidin or hesperetin with doxorubicin, letrozole or tamoxifen can enhance the efficacies of these clinically available agents. These chemotherapeutic and chemosensitising activities of hesperidin and hesperetin have been linked to several mechanisms, including the modulation of signalling pathways, glucose uptake, enzymes, miRNA expression, oxidative status, cell cycle regulatory proteins, tumour suppressor p53, plasma and liver lipid profiles as well as DNA repair mechanisms. However, poor water solubility, extensive phase II metabolism and apical efflux have posed limitations to the bioavailability of hesperidin and hesperetin. Various strategies for bioavailability enhancement have been studied, including the utilisation of nano-based drug delivery systems and the co-administration of hesperetin with other flavonoids. In particular, nanoformulated hesperidin and hesperetin possess greater chemotherapeutic and chemosensitising activities than free compounds. Despite promising preclinical results, further safety and efficacy evaluation of hesperidin and hesperetin as well as their nanoformulations in clinical trials is required to ascertain their potentials to be developed as clinically useful agents for BC treatment.
    Keywords:  Bioavailability; Biosafety; Breast cancer; Hesperetin; Hesperidin; Nanoformulation
    DOI:  https://doi.org/10.1016/j.sjbs.2021.07.046
  25. Molecules. 2021 Nov 24. pii: 7110. [Epub ahead of print]26(23):
    Enhanced Anti-Tumor Effect of Folate-Targeted FA-AMA-hyd-DOX Conjugate in a Xenograft Model of Human Breast Cancer.
    Tian-Tian Liao, Jiang-Fan Han, Fei-Yue Zhang, Ren Na, Wei-Liang Ye.
      Folate-aminocaproic acid-doxorubicin (FA-AMA-hyd-DOX) was firstly synthesized by our group. It was indicated that FA-AMA-hyd-DOX was pH-responsive, and had strong cytotoxicity on a folate receptor overexpressing cell line (KB cells) in vitro. The aim of our study was to further explore the potential use of FA-AMA-hyd-DOX as a new therapeutic drug for breast cancer. The cellular uptake and the antiproliferative activity of the FA-AMA-hyd-DOX in MDA-MB-231 cells were measured. Compared with DOX, FA-AMA-hyd-DOX exhibited higher targeting ability and cytotoxicity to FR-positive tumor cells. Subsequently, the tissue distribution of FA-AMA-hyd-DOX was studied, and the result confirmed that DOX modified by FA can effectively increase the selectivity of drugs in vivo. After determining the maximum tolerated dose (MTD) of FA-AMA-hyd-DOX in MDA-MB-231 tumor-bearing nude mice, the antitumor effects and the in vivo safety of FA-AMA-hyd-DOX were systematically evaluated. The data showed that FA-AMA-hyd-DOX could effectively increase the dose of DOX tolerated by tumor-bearing nude mice and significantly inhibit MDA-MB-231 tumor growth in vivo. Furthermore, FA-AMA-hyd-DOX treatment resulted in almost no obvious damage to the mice. All the positive data suggest that FA-targeted FA-AMA-hyd-DOX is a promising tumor-targeted compound for breast cancer therapy.
    Keywords:  biosafety; breast cancer; cancer targeted therapy; doxorubicin; prodrug delivery
    DOI:  https://doi.org/10.3390/molecules26237110
  26. Int J Mol Sci. 2021 Dec 01. pii: 13011. [Epub ahead of print]22(23):
    Systematic Review of Cancer Targeting by Nanoparticles Revealed a Global Association between Accumulation in Tumors and Spleen.
    Andrey S Drozdov, Petr I Nikitin, Julian M Rozenberg.
      Active targeting of nanoparticles toward tumors is one of the most rapidly developing topics in nanomedicine. Typically, this strategy involves the addition of cancer-targeting biomolecules to nanoparticles, and studies on this topic have mainly focused on the localization of such formulations in tumors. Here, the analysis of the factors determining efficient nanoparticle targeting and therapy, various parameters such as types of targeting molecules, nanoparticle type, size, zeta potential, dose, and the circulation time are given. In addition, the important aspects such as how active targeting of nanoparticles alters biodistribution and how non-specific organ uptake influences tumor accumulation of the targeted nanoformulations are discussed. The analysis reveals that an increase in tumor accumulation of targeted nanoparticles is accompanied by a decrease in their uptake by the spleen. There is no association between targeting-induced changes of nanoparticle concentrations in tumors and other organs. The correlation between uptake in tumors and depletion in the spleen is significant for mice with intact immune systems in contrast to nude mice. Noticeably, modulation of splenic and tumor accumulation depends on the targeting molecules and nanoparticle type. The median survival increases with the targeting-induced nanoparticle accumulation in tumors; moreover, combinatorial targeting of nanoparticle drugs demonstrates higher treatment efficiencies. Results of the comprehensive analysis show optimal strategies to enhance the efficiency of actively targeted nanoparticle-based medicines.
    Keywords:  biodistribution; cancer targeting; functionalization; nanoparticle therapy; nanoparticles for drug delivery
    DOI:  https://doi.org/10.3390/ijms222313011
  27. Int J Mol Sci. 2021 Nov 25. pii: 12741. [Epub ahead of print]22(23):
    Combinations of Calcitriol with Anticancer Treatments for Breast Cancer: An Update.
    Mariana Segovia-Mendoza, Janice García-Quiroz, Lorenza Díaz, Rocío García-Becerra.
      Preclinical, clinical, and epidemiological studies indicate that vitamin D3 (VD) deficiency is a risk factor for the development of breast cancer. Underlying mechanisms include the ability of calcitriol to induce cell differentiation, inhibit oncogenes expression, and modify different signaling pathways involved in the control of cell proliferation. In addition, calcitriol combined with different kinds of antineoplastic drugs has been demonstrated to enhance their beneficial effects in an additive or synergistic fashion. However, a recognized adjuvant regimen based on calcitriol for treating patients with breast cancer has not yet been fully established. Accordingly, in the present work, we review and discuss the preclinical and clinical studies about the combination of calcitriol with different oncological drugs, aiming to emphasize its main therapeutic benefits and opportunities for the treatment of this pathology.
    Keywords:  breast cancer; calcitriol; drug combination; efficacy
    DOI:  https://doi.org/10.3390/ijms222312741
  28. Photodiagnosis Photodyn Ther. 2021 Dec 01. pii: S1572-1000(21)00486-5. [Epub ahead of print] 102669
    Photodynamic effect of Protoporphyrin IX in gliosarcoma 9l/lacZ cell line.
    Letícia Corrêa Fontana, Juliana Guerra Pinto, Gabrielle Dos Santos Vitorio, Rainara Moreno Sanches, André Henrique Correia Pereira, Cristina Pacheco-Soares, Leandro Ariel Mamone, Juliana Ferreira Strixino.
      Photodynamic Therapy (PDT) is a promising therapy for treating cancer, producing reactive oxygen species (ROS) to induce the death of cancer cells. This study aimed to evaluate the action of PDT on gliosarcoma cells, using protoporphyrin IX as PS by incubation with the precursor aminolevulinic acid (ALA). An LED device was used with a light dose of 10 J/cm². The success of the therapy proved to be dependent on the concentration of ALA, and an incubation time of 4 hours required for an effective response. Cell death was prevalent due to necrosis when assessed 18 hours post-PDT. ALA proved to be an option to PDT in cells of the 9L/lacZ, with the protocol tested.
    Keywords:  5-ALA; Photodynamic therapy; aminolevulinic acid; brain cancer; gliosarcoma
    DOI:  https://doi.org/10.1016/j.pdpdt.2021.102669
  29. Eur J Med Chem. 2021 Nov 29. pii: S0223-5234(21)00878-3. [Epub ahead of print]228 114029
    Biotinylated curcumin as a novel chemosensitizer enhances naphthalimide-induced autophagic cell death in breast cancer cells.
    Chenwen Shao, Jian Wu, Siqi Han, Yani Liu, Zhi Su, Hai-Liang Zhu, Hong-Ke Liu, Yong Qian.
      Achieving selective release of chemical anticancer agents and improving therapeutic efficacy has always been a hot spot in the field of cancer research, yet how to achieve this remains a great challenge. In this work, we constructed a novel chemical anticancer agent (named MCLOP) by introducing naphthalimide into the skeleton of methylene blue (MB). Under the stimulation by cellular hypochlorous acid (HClO) and visible light, selective release of active naphthalimide can be achieved within breast cancer cell lines, the release process of which can be tracked visually using near-infrared fluorescence of MB (685 nm). More importantly, we developed biotinylated curcumin (Cur-Bio) as a new chemosensitizer, which significantly enhanced the ability of MCLOP to induce autophagic cell death of breast cancer cells. This synergistic treatment strategy exhibited an excellent anti-proliferation effect on breast cancer cells in vitro, three-dimensional (3D) cell sphere model, and mouse tumor model in vivo. This work provides a new strategy for the treatment of breast cancer and also opens new opportunities for the efficient treatment of cancer with curcumin-based chemosensitizer.
    Keywords:  Autophagic cell death; Biotinylated-curcumin; Breast cancer; Chemosensitizer; Methylene blue; Near-infrared fluorescence
    DOI:  https://doi.org/10.1016/j.ejmech.2021.114029
  30. Tissue Cell. 2021 Nov 27. pii: S0040-8166(21)00221-4. [Epub ahead of print]74 101705
    Anti-tumour potential and selectivity of caffeic acid phenethyl ester in osteosarcoma cells.
    Ana Lígia Pagnan, Adriano Souza Pessoa, Cintia Kazuko Tokuhara, Vanessa Svizzero Fakhoury, Gabriela Silva Neubern Oliveira, Mariana Liessa Rovis Sanches, Kelly Karina Inacio, Valdecir Farias Ximenes, Rodrigo Cardoso Oliveira.
      Osteosarcoma is the most common type of bone cancer, and metastasis is widespread decreasing the survival rate. The search for new therapeutic strategies has increased for phytochemicals due to their potential as antioxidants and anticancer properties. Thus, we evaluated the caffeic acid phenethyl ester (CAPE) and caffeic acid's (CA) anticancer properties on UMR-106 murine osteosarcoma cells. The IC25 and IC50 were 1.3 and 2.7 μM for CAPE and 91.0 and 120.0 μM for CA, respectively. This study shows the potential anticancer properties of CAPE and highlights how a phenethyl ester component addition can improve the pharmacological potency in relation to its precursor CA. Our results showed that CAPE was more efficient and selective in reducing the viability of tumor cells compared to the control osteoblasts (MC3T3-E1) (p < 0.05). In addition, CAPE was 44-fold (IC25) and 70-fold (IC50) more cytotoxic than CA. CAPE also decreased ROS generation and cell migration. In summary, CAPE was more selective for tumor cells, preserving normal ones, suggesting its potential role as an anticancer drug.
    Keywords:  Antioxidants; Cancer; Cytotoxicity; Phenolic compounds; Phytochemicals
    DOI:  https://doi.org/10.1016/j.tice.2021.101705
  31. Molecules. 2021 Nov 24. pii: 7109. [Epub ahead of print]26(23):
    The Multifaceted Role of Curcumin in Advanced Nanocurcumin Form in the Treatment and Management of Chronic Disorders.
    Priti Tagde, Pooja Tagde, Fahadul Islam, Sandeep Tagde, Muddaser Shah, Zareen Delawar Hussain, Md Habibur Rahman, Agnieszka Najda, Ibtesam S Alanazi, Mousa O Germoush, Hanan R H Mohamed, Mardi M Algandaby, Mohammed Z Nasrullah, Natalia Kot, Mohamed M Abdel-Daim.
      Curcumin is the primary polyphenol in turmeric's curcuminoid class. It has a wide range of therapeutic applications, such as anti-inflammatory, antioxidant, antidiabetic, hepatoprotective, antibacterial, and anticancer effects against various cancers, but has poor solubility and low bioavailability. Objective: To improve curcumin's bioavailability, plasma concentration, and cellular permeability processes. The nanocurcumin approach over curcumin has been proven appropriate for encapsulating or loading curcumin (nanocurcumin) to increase its therapeutic potential. Conclusion: Though incorporating curcumin into nanocurcumin form may be a viable method for overcoming its intrinsic limitations, and there are reasonable concerns regarding its toxicological safety once it enters biological pathways. This review article mainly highlights the therapeutic benefits of nanocurcumin over curcumin.
    Keywords:  anti-inflammatory action; anticancer; antioxidant effect; nanocurcumin; neurodegenerative disease; solubility
    DOI:  https://doi.org/10.3390/molecules26237109
  32. Anal Chem. 2021 Dec 09.
    Cancer-Targeted Azo Dye for Two-Photon Photodynamic Therapy in Human Colon Tissue.
    Dong Joon Lee, Vinayak Juvekar, Hyo Won Lee, Eun Seo Kim, Choong-Kyun Noh, Sung Jae Shin, Hwan Myung Kim.
      Inappropriate cancer management can be prevented by simultaneous cancer diagnosis, treatment, and real-time assessment of therapeutic processes. Here, we describe the design of a two-photon (TP) photosensitizer (PS), ACC-B, for high temporal and spatioselective near-infrared cancer therapy. ACC-B consisting of a biotin unit significantly enhanced the cancer sensitivity of the PS. Upon TP irradiation, ACC-B generated reactive oxygen species (ROS) through the type I photodynamic therapy (PDT) process and triggered highly selective cancer ablation. In addition, fluorescence microscopy images revealed that ACC-B-loaded live human colon tissues showed a marked difference in ACC-B uptake between normal and cancer tissues, and this property was used for real-time imaging. Upon 770 nm TP treatment, ACC-B generated ROS efficiently in live colon cancer tissues with high spatial selectivity. During PDT, ACC-B can provide in situ spatioselective visualization of cellular behavior and molecular information for therapeutic assessment in specific regions.
    DOI:  https://doi.org/10.1021/acs.analchem.1c03429
  33. Int J Mol Sci. 2021 Nov 23. pii: 12623. [Epub ahead of print]22(23):
    Enhanced Platelet-Rich Plasma (ePRP) Stimulates Wound Healing through Effects on Metabolic Reprogramming in Fibroblasts.
    Hsin-Pei Weng, Yuan-Yang Cheng, Hsin-Lun Lee, Tai-Yi Hsu, Yu-Tang Chang, Yao-An Shen.
      As a source of growth factors for expediting wound healing and tissue regeneration, plasma-rich plasma (PRP) has been extensively applied in diverse fields including orthopaedics, ophthalmology, oral and maxillofacial surgery, dentistry, and gynaecology. However, the function of PRP in metabolic regulations remains enigmatic. A standardized method was devised herein to enrich growth factors and to lyophilize it as enhanced PRP (ePRP) powder, which could become ubiquitously available without mechanical centrifugation in clinical practice. To identify metabolic reprogramming in human dermal fibroblasts under ePRP treatment, putative metabolic targets were identified by transcriptome profiling and validated for their metabolic effects and mechanism. ePRP does not only promote wound healing but re-aligns energy metabolism by shifting to glycolysis through stimulation of glycolytic enzyme activity in fibroblasts. On the contrary, oxygen consumption rates and several mitochondrial respiration activities were attenuated in ePRP-treated fibroblasts. Furthermore, ePRP treatment drives the mitochondrial resetting by hindering the mitochondrial biogenesis-related genes and results in a dampened mitochondrial mass. Antioxidant production was further increased by ePRP treatment to prevent reactive oxygen species formation. Besides, ePRP also halts the senescence progression of fibroblasts by activating SIRT1 expression. Importantly, the glycolytic inhibitor 2-DG can completely reverse the ePRP-enhanced wound healing capacity, whereas the mitochondrial inhibitor oligomycin cannot. This is the first study to utilize PRP for comprehensively investigating its effects on the metabolic reprogramming of fibroblasts. These findings indicate that PRP's primary metabolic regulation is to promote metabolic reprogramming toward glycolytic energy metabolism in fibroblasts, preserving redox equilibrium and allowing anabolic pathways necessary for the healing and anti-ageing process.
    Keywords:  ageing; glycolysis; metabolic reprogramming; platelet-rich plasma; regenerative medicine
    DOI:  https://doi.org/10.3390/ijms222312623
  34. Expert Opin Investig Drugs. 2021 Dec 04.
    Carbonic anhydrase inhibitors: an update on experimental agents for the treatment and imaging of hypoxic tumors.
    Claudiu T Supuran.
       INTRODUCTION: Hypoxic tumors, unlike normal tissues, overexpress proteins involved in oxygen sensing, metabolism, pH regulation, angiogenesis, immunological response and other survival mechanisms, which are under investigation as antitumor drug targets.
    AREAS COVERED: Carbonic anhydrase (CA) isoforms CA IX and XII are among these validated antitumor/antimetastatic drug targets, with several of their inhibitors undergoing preclinical or clinical stage investigations. Alone or in combination with other chemotherapeutic agents or radiotherapy, CA IX/XII inhibitors such as SLC-0111, SLC-149, S4, 6A10, etc., were shown to inhibit the growth of the primary tumor, metastases and invasiveness of many tumor types, being also amenable for the development of imaging agents.
    EXPERT OPINION: SLC-0111 is the most investigated agent, being in Phase Ib/II clinical trials. In addition to its interference with extracellular acidifications, it has been shown to promote ferroptosis in cancer cells, another antitumor mechanism of this compound and the entire class. A large number sulfonamide and non-sulfonamide inhibitors have been developed using SLC-0111 as lead in the last three years, together with hybrid agents incorporating CA inhibitors and other anticancer chemotypes, including cytotoxins, telomerase, thioredoxin or P-glycoprotein inhibitors, adenosine A2A receptor antagonists, pyrophosphatase/phosphodiesterase-3 inhibitors or antimetabolites. All of them showed significant antitumor activity.
    Keywords:  SLC-0111; antitumor drug; carbonic anhydrase; hypoxia; inhibitors; sulfonamide; theragnostic agent
    DOI:  https://doi.org/10.1080/13543784.2021.2014813
  35. Front Bioeng Biotechnol. 2021 ;9 784602
    Mitochondria-Targeted Nanocarriers Promote Highly Efficient Cancer Therapy: A Review.
    Zeng Zeng, Chao Fang, Ying Zhang, Cong-Xian Chen, Yi-Feng Zhang, Kun Zhang.
      Mitochondria are the primary organelles which can produce adenosine triphosphate (ATP). They play vital roles in maintaining normal functions. They also regulated apoptotic pathways of cancer cells. Given that, designing therapeutic agents that precisely target mitochondria is of great importance for cancer treatment. Nanocarriers can combine the mitochondria with other therapeutic modalities in cancer treatment, thus showing great potential to cancer therapy in the past few years. Herein, we summarized lipophilic cation- and peptide-based nanosystems for mitochondria targeting. This review described how mitochondria-targeted nanocarriers promoted highly efficient cancer treatment in photodynamic therapy (PDT), chemotherapy, combined immunotherapy, and sonodynamic therapy (SDT). We further discussed mitochondria-targeted nanocarriers' major challenges and future prospects in clinical cancer treatment.
    Keywords:  chemotherapy; combined immunotherapy; mitochondria; nanocarriers; phototherapy
    DOI:  https://doi.org/10.3389/fbioe.2021.784602
  36. Front Bioeng Biotechnol. 2021 ;9 781982
    PEGylated Doxorubicin Prodrug-Forming Reduction-Sensitive Micelles With High Drug Loading and Improved Anticancer Therapy.
    Dongdong Wang, Xiaoyi Zhang, Bingbing Xu.
      Significant efforts on the design and development of advanced drug delivery systems for targeted cancer chemotherapy continue to be a major challenge. Here, we reported a kind of reduction-responsive PEGylated doxorubicin (DOX) prodrug via the simple esterification and amidation reactions, which self-assembled into the biodegradable micelles in solutions. Since there was an obvious difference in the reduction potentials between the oxidizing extracellular milieu and the reducing intracellular fluids, these PEG-disulfide-DOX micelles were localized intracellularly and degraded rapidly by the stimulus to release the drugs once reaching the targeted tumors, which obviously enhanced the therapeutic efficacy with low side effects. Moreover, these reduction-sensitive micelles could also physically encapsulate the free DOX drug into the polymeric cargo, exhibiting a two-phase programmed drug release behavior. Consequently, it showed a potential to develop an intelligent and multifunctional chemotherapeutic payload transporter for the effective tumor therapy.
    Keywords:  biocompatible; disulfide; drug delivery; micelles; reduction-sensitive
    DOI:  https://doi.org/10.3389/fbioe.2021.781982
  37. Int J Pharm. 2021 Dec 03. pii: S0378-5173(21)01155-8. [Epub ahead of print] 121349
    FC-BBR/IND-induced glucose oxidase nanodrugs for targeted combination therapy.
    Yu Cheng, Yuanhui Ji, Defang Ouyang.
      Targeted therapy from cells to mitochondria can improve the bioavailability and therapeutic effects of drugs. Combination therapy by combining two or more therapeutic methods comes to be seen a hopeful strategy to overcome the emergence of resistance. Ferrocene (FC) derivatives of the sandwich structure can not only directly inhibit the proliferation of cancer cells but also catalyze the Fenton reaction to enhance chemodynamic therapy. Berberine (BBR) is a Chinese herbal extract with mitochondria-targeted anticancer activity. In our work, glucose oxidase (GOD) was induced to self-assemble by ferrocene-berberine conjugate (FC-BBR) and indomethacin (IND), which was then encapsulated by hyaluronic acid (HA) and formed nanodrugs (FC-BBR/IND@GOD@HA NPs). Molecular simulation results showed that the drugs could be bound to multiple sites of GOD and induce its self-assembly. The prepared nanoassembly could inhibit the proliferation and induce the apoptosis of HepG2 cells, which might be the result of targeted chemodynamic therapy and starvation therapy. Moreover, the FC-BBR/IND@GOD@HA NPs could also promote the production of reactive oxygen species and the loss of mitochondrial membrane potential and block the cells in S phase. More importantly, it could inhibit the movement and migration of cancer cells, which gave it the potential to prevent tumor metastasis.
    Keywords:  chemodynamic therapy; ferrocene; glucose oxidase; starvation therapy; targeted therapy
    DOI:  https://doi.org/10.1016/j.ijpharm.2021.121349
  38. ACS Biomater Sci Eng. 2021 Dec 06.
    A pH-Responsive Nanoplatform Based on Fluorescent Conjugated Polymer Dots for Imaging-Guided Multitherapeutics Delivery and Combination Cancer Therapy.
    Yilin Wang, Xuefan Xiong, Yanxi Zhu, Xinyue Song, Qiong Li, Shusheng Zhang.
      For cancer treatment, nanocarriers were designed with cationic lipids and polymers to improve the cytosolic delivery efficiency of siRNA. Though the positively charged nanocarriers showed great potential for RNA therapy, it was inevitable to generate the potential cytotoxicity. We constructed a pH-responsive nanoplatform, which co-carried siRNA and anticancer drug (hydroxycamptothecine, HCPT), to integrate gene therapy and chemotherapy for combination cancer therapy. The fluorescent conjugated polymer nanoparticles (CPNPs) modified with cell-penetrating peptides were employed as cores to carry siRNA molecules (siRNA-CPNPs) and track the biodistribution of nanotherapeutics by virtue of fluorescence. Calcium phosphate (CaP) nanocoatings were deposited on the surface of siRNA-CPNPs, followed by loading with HCPT and aptamers targeting cancer cells to obtain a targeted and tumor acid-responsive biocompatible nanoplatform. After the uptake of cancer cells, the CaP nanocoatings were decomposed in the acidic endo/lysosomes to release HCPT, and the siRNA-CPNPs were exposed to facilitate the siRNA endo/lysosome escape and cytoplasm delivery. Results obtained from both in vitro and in vivo studies in tumor inhibition expressed that the combined therapy exhibited a better therapeutic efficacy than any monotherapy.
    Keywords:  combination cancer therapy; endo/lysosome escape; responsive release; siRNA delivery; tumor microenvironment (TME)
    DOI:  https://doi.org/10.1021/acsbiomaterials.1c01244
  39. Biomater Sci. 2021 Aug 19.
    Recent advances in in situ oxygen-generating and oxygen-replenishing strategies for hypoxic-enhanced photodynamic therapy.
    Shuheng Qin, Yue Xu, Hua Li, Haiyan Chen, Zhenwei Yuan.
      Cancer is a leading cause of death worldwide, accounting for an estimated 10 million deaths by 2020. Over the decades, various strategies for tumor therapy have been developed and evaluated. Photodynamic therapy (PDT) has attracted increasing attention due to its unique characteristics, including low systemic toxicity and minimally invasive nature. Despite the excellent clinical promise of PDT, hypoxia is still the Achilles' heel associated with its oxygen-dependent nature related to increased tumor proliferation, angiogenesis, and distant metastases. Moreover, PDT-mediated oxygen consumption further exacerbates the hypoxia condition, which will eventually lead to the poor effect of drug treatment and resistance and irreversible tumor metastasis, even limiting its effective application in the treatment of hypoxic tumors. Hypoxia, with increased oxygen consumption, may occur in acute and chronic hypoxia conditions in developing tumors. Tumor cells farther away from the capillaries have much lower oxygen levels than cells in adjacent areas. However, it is difficult to change the tumor's deep hypoxia state through different ways to reduce the tumor tissue's oxygen consumption. Therefore, it will become more difficult to cure malignant tumors completely. In recent years, numerous investigations have focused on improving PDT therapy's efficacy by providing molecular oxygen directly or indirectly to tumor tissues. In this review, different molecular oxygen supplementation methods are summarized to alleviate tumor hypoxia from the innovative perspective of using supplemental oxygen. Besides, the existing problems, future prospects and potential challenges of this strategy are also discussed.
    DOI:  https://doi.org/10.1039/d1bm00317h
  40. Polymers (Basel). 2021 Nov 26. pii: 4114. [Epub ahead of print]13(23):
    Development of Polymer-Based Nanoformulations for Glioblastoma Brain Cancer Therapy and Diagnosis: An Update.
    Bijuli Rabha, Kaushik Kumar Bharadwaj, Siddhartha Pati, Bhabesh Kumar Choudhury, Tanmay Sarkar, Zulhisyam Abdul Kari, Hisham Atan Edinur, Debabrat Baishya, Leonard Ionut Atanase.
      Brain cancers, mainly high-grade gliomas/glioblastoma, are characterized by uncontrolled proliferation and recurrence with an extremely poor prognosis. Despite various conventional treatment strategies, viz., resection, chemotherapy, and radiotherapy, the outcomes are still inefficient against glioblastoma. The blood-brain barrier is one of the major issues that affect the effective delivery of drugs to the brain for glioblastoma therapy. Various studies have been undergone in order to find novel therapeutic strategies for effective glioblastoma treatment. The advent of nanodiagnostics, i.e., imaging combined with therapies termed as nanotheranostics, can improve the therapeutic efficacy by determining the extent of tumour distribution prior to surgery as well as the response to a treatment regimen after surgery. Polymer nanoparticles gain tremendous attention due to their versatile nature for modification that allows precise targeting, diagnosis, and drug delivery to the brain with minimal adverse side effects. This review addresses the advancements of polymer nanoparticles in drug delivery, diagnosis, and therapy against brain cancer. The mechanisms of drug delivery to the brain of these systems and their future directions are also briefly discussed.
    Keywords:  blood–brain barrier (BBB)/blood brain tumour barrier (BBTB); drug delivery and imaging; glioma/glioblastoma; nanodiagnostics; polymer nanoparticles
    DOI:  https://doi.org/10.3390/polym13234114
  41. Eur J Med Chem. 2021 Dec 02. pii: S0223-5234(21)00886-2. [Epub ahead of print]228 114037
    A branched small molecule-drug conjugate nanomedicine strategy for the targeted HCC chemotherapy.
    Sha-Sha Li, Cheng-Mei Zhang, Jing-De Wu, Chao Liu, Zhao-Peng Liu.
      Off-target toxicity is one of the main challenges faced by anticancer chemotherapeutics. For tumor targeted and precision chemotherapy, we take the advantages of the ligand directed tumor active targeting of small molecule drug conjugates (SMDCs) and the passive tumor targeting of nanoparticles via the enhanced penetration and retention (EPR) effects, put forward a branched small molecule drug conjugate (BSMDC) nanomedicine design concept. In a proof of concept, we used pentaerythritol as the branched moiety, galactosamine (GalN) as the hepatocellular carcinoma (HCC) directing ligands, PTX as a payload, and a stearoyl moiety as the amphiphilic property adjusting group, designed and synthesized BSMDC 1 and prepared its NPs. In cellular level, the BSMDC 1 NPs targeted asialoglycoprotein receptor (ASGPR)-overexpressing HepG2 cells, were effectively taken up in the cells and released in tumor microenvironments, inhibited the HepG2 cell proliferation, arrested HepG2 cell in G2/M phase and induced tumor cell apoptosis. In HepG2 xenograft nude mice, the BSMDC 1 NPs were high specific to target the tumor and demonstrated a higher antitumor efficiency than BSMDC 1, having no apparent influences on mice body weights and major organs, supporting our BSMDC nanomedicine design concept. Therefore, this new strategy may find applications for cancer targeted and precision chemotherapy.
    Keywords:  Hepatocellular carcinoma; Nanomedicine; Paclitaxel; Small molecule-drug conjugate; Targeted therapy
    DOI:  https://doi.org/10.1016/j.ejmech.2021.114037
  42. Nanoscale Res Lett. 2021 Dec 05. 16(1): 173
    Nanoparticles for Cancer Therapy: Current Progress and Challenges.
    Shreelaxmi Gavas, Sameer Quazi, Tomasz M Karpiński.
      Cancer is one of the leading causes of death and morbidity with a complex pathophysiology. Traditional cancer therapies include chemotherapy, radiation therapy, targeted therapy, and immunotherapy. However, limitations such as lack of specificity, cytotoxicity, and multi-drug resistance pose a substantial challenge for favorable cancer treatment. The advent of nanotechnology has revolutionized the arena of cancer diagnosis and treatment. Nanoparticles (1-100 nm) can be used to treat cancer due to their specific advantages such as biocompatibility, reduced toxicity, more excellent stability, enhanced permeability and retention effect, and precise targeting. Nanoparticles are classified into several main categories. The nanoparticle drug delivery system is particular and utilizes tumor and tumor environment characteristics. Nanoparticles not only solve the limitations of conventional cancer treatment but also overcome multidrug resistance. Additionally, as new multidrug resistance mechanisms are unraveled and studied, nanoparticles are being investigated more vigorously. Various therapeutic implications of nanoformulations have created brand new perspectives for cancer treatment. However, most of the research is limited to in vivo and in vitro studies, and the number of approved nanodrugs has not much amplified over the years. This review discusses numerous types of nanoparticles, targeting mechanisms, and approved nanotherapeutics for oncological implications in cancer treatment. Further, we also summarize the current perspective, advantages, and challenges in clinical translation.
    Keywords:  Cancer; Cellular targeting; Chemotherapy; Cryosurgery; Multidrug resistance; Nanoparticles; Scale-up
    DOI:  https://doi.org/10.1186/s11671-021-03628-6
  43. ACS Nano. 2021 Dec 08.
    Hybrid Nanoplatform: Enabling a Precise Antitumor Strategy via Dual-Modal Imaging-Guided Photodynamic/Chemo-/Immunosynergistic Therapy.
    Haoran Chen, Fengxia Wu, Xiaoyu Xie, Wang Wang, Qiqing Li, Langping Tu, Bin Li, Xianggui Kong, Yulei Chang.
      Photodynamic therapy (PDT) has been widely used in tumor therapy due to its high spatial-temporal control and noninvasiveness. However, its clinical application is limited by weak efficacy, shallow tissue penetration, and phototoxicity. Herein, a facile theranostic nanoplatform based on photoswitchable lanthanide-doped nanoparticles was designed. Typically, these nanoparticles had UV-blue and 1525 nm emission upon 980 nm excitation and 1525 nm emission upon 800 nm excitation. We further used these nanoparticles for achieving real-time near-infrared (NIR)-IIb imaging (800 nm) with a high signal-to-noise ratio and imaging-guided PDT (980 nm). Moreover, such a photoswitchable nanoplatform capping with pH-sensitive calcium phosphate for coloading doxorubicin (a chemotherapeutic immunogenic cell death [ICD] inducer) and paramagnetic Mn2+ ions enhances T1-magnetic resonance imaging in the tumor microenvironment. Our results suggest that this theranostic nanoplatform could not only kill tumor cells directly through dual-modal image-guided PDT/chemotherapy but also inhibit distant tumor and lung metastasis through ICD. Therefore, it has great potential for clinical application .
    Keywords:  NIR-IIb imaging guidance; immunogenic cell death; lanthanide-doped nanoparticles; photodynamic therapy; photoswitch; theranostics; upconversion
    DOI:  https://doi.org/10.1021/acsnano.1c09635
  44. Int J Food Sci Nutr. 2021 Dec 08. 1-9
    Xanthohumol reduces inflammation and cell metabolism in HT29 primary colon cancer cells.
    Margalida Torrens-Mas, Marina Alorda-Clara, Maria Martínez-Vigara, Pilar Roca, Jorge Sastre-Serra, Jordi Oliver, Daniel Gabriel Pons.
      Xanthohumol (XN) is a prenylated flavonoid known for its antioxidant and anti-inflammatory effects and has been studied as an anti-cancer agent. In this study, we aimed at analysing the effect of XN on a primary colorectal adenocarcinoma cell line, HT29, on cell viability, inflammatory and antioxidant gene expression, and metabolism. For this purpose, cells were treated with 10 nM and 10 µM XN, and cell viability, H2O2 production, lipid peroxidation and gene expression of inflammatory, antioxidant, and mitochondrial-related genes, as well as protein levels of metabolic enzymes, were determined. Results showed no significant effects on cell viability and a general decrease in pro-inflammatory, antioxidant and mitochondrial biogenesis gene expression with the lower concentration of XN. Furthermore, glucose and oxidative metabolism enzymes were also reduced. These results suggest that XN treatment, at low doses, could stop the proliferation and progression of HT29 cells by downregulating inflammatory signals and cell metabolism.
    Keywords:  Colon cancer; inflammation; oxidative metabolism; xanthohumol
    DOI:  https://doi.org/10.1080/09637486.2021.2012561
  45. Postepy Biochem. 2021 09 30. 67(3): 236-247
    Photodynamic therapy – significance in oncology
    Beata Mossakowska, Anna Fabisiewicz, Janusz Siedlecki.
      Photodynamic therapy (PDT) is one of the least toxic methods causing the death of cancer cells. Photosensitizer (PS) applied to a patient accumulates in the tumor, where under the appropriate wavelength and insensitivity of light is activated. Activated PS in the presence of oxygen produces reactive oxygen species (ROS), which make significant damage leading to the destruction of cancer cells by apoptosis, necrosis or autophagic process. Moreover, PDT causes an acute local inflammatory response that is involved in removing dead cells, restoring normal tissue homeostasis, and sometimes leads to the development of systemic immunity. However, some cells may survive treatment and develop resistance. Mechanisms, which lead to decrease of the level of PS in cells may be involved in the cytoprotection of cancer cells from PDT. Furthermore, increased activity of antioxidant mechanisms, overexpression of molecular chaperones and activation of survival pathways can protect cells from PDT.
    DOI:  https://doi.org/10.18388/pb.2021_394
  46. Nat Commun. 2021 Dec 09. 12(1): 7149
    Theranostic near-infrared-IIb emitting nanoprobes for promoting immunogenic radiotherapy and abscopal effects against cancer metastasis.
    Hao Li, Meng Wang, Biao Huang, Su-Wen Zhu, Jun-Jie Zhou, De-Run Chen, Ran Cui, Mingxi Zhang, Zhi-Jun Sun.
      Radiotherapy is an important therapeutic strategy for cancer treatment through direct damage to cancer cells and augmentation of antitumor immune responses. However, the efficacy of radiotherapy is limited by hypoxia-mediated radioresistance and immunosuppression in tumor microenvironment. Here, we construct a stabilized theranostic nanoprobe based on quantum dots emitting in the near-infrared IIb (NIR-IIb, 1,500-1,700 nm) window modified by catalase, arginine-glycine-aspartate peptides and poly(ethylene glycol). We demonstrate that the nanoprobes effectively aggregate in the tumor site to locate the tumor region, thereby realizing precision radiotherapy with few side-effects. In addition, nanoprobes relieve intratumoral hypoxia and reduce the tumor infiltration of immunosuppressive cells. Moreover, the nanoprobes promote the immunogenic cell death of cancer cells to trigger the activation of dendritic cells and enhance T cell-mediated antitumor immunity to inhibit tumor metastasis. Collectively, the nanoprobe-mediated immunogenic radiotherapy can boost the abscopal effect to inhibit tumor metastasis and prolong survival.
    DOI:  https://doi.org/10.1038/s41467-021-27485-0
  47. Front Chem. 2021 ;9 768248
    Biomimetic Nanomaterials Triggered Ferroptosis for Cancer Theranostics.
    Xinyu Zhang, Yanling Ma, Jipeng Wan, Jia Yuan, Diqing Wang, Weiyi Wang, Xiao Sun, Qingwei Meng.
      Ferroptosis, as a recently discovered non-apoptotic programmed cell death with an iron-dependent form, has attracted great attention in the field of cancer nanomedicine. However, many ferroptosis-related nano-inducers encountered unexpected limitations such as immune exposure, low circulation time, and ineffective tumor targeting. Biomimetic nanomaterials possess some unique physicochemical properties which can achieve immune escape and effective tumor targeting. Especially, certain components of biomimetic nanomaterials can further enhance ferroptosis. Therefore, this review will provide a comprehensive overview on recent developments of biomimetic nanomaterials in ferroptosis-related cancer nanomedicine. First, the definition and character of ferroptosis and its current applications associated with chemotherapy, radiotherapy, and immunotherapy for enhancing cancer theranostics were briefly discussed. Subsequently, the advantages and limitations of some representative biomimetic nanomedicines, including biomembranes, proteins, amino acids, polyunsaturated fatty acids, and biomineralization-based ferroptosis nano-inducers, were further spotlighted. This review would therefore help the spectrum of advanced and novice researchers who are interested in this area to quickly zoom in the essential information and glean some provoking ideas to advance this subfield in cancer nanomedicine.
    Keywords:  biomimetic modification; cancer therapy; diagnosis; ferroptosis; nanomedicine
    DOI:  https://doi.org/10.3389/fchem.2021.768248
  48. Carbohydr Polym. 2022 Feb 01. pii: S0144-8617(21)01279-0. [Epub ahead of print]277 118892
    Development of oral curcumin based on pH-responsive transmembrane peptide-cyclodextrin derivative nanoparticles for hepatoma.
    Tiantian Wei, Yin Zhang, Meng Lei, Yanru Qin, Zhongjie Wang, Zhimeng Chen, Liefeng Zhang, Yongqiang Zhu.
      Herein, a pH-responsive cyclodextrin derivative (R6H4-CMβCD) with cell-penetrating ability was successfully synthesized, and curcumin-loaded nanoparticles (R6H4-CMβCD@CUR NPs, RCCNPs) were developed to improve its efficacy in hepatoma. RCCNPs could improve the cell uptake compared with CMβCD@CUR NPs (CCNPs) and were internalized into cells mainly through endocytosis mediated by reticulin and macropinocytosis. Furthermore, the accumulation of RCCNPs in hepatoma cells at pH 6.4 was higher than that at pH 7.4, indicating a pH-responsive uptake. Additionally, RCCNPs could escape from the lysosomes via the "proton sponge effect", and a high apoptosis rate was detected. Importantly, in vivo experiments revealed that orally administered RCCNPs could exert excellent anti-cancer effects in tumor-bearing mice. Hematoxylin-eosin staining did not show significant histological changes in the major organs. Thus, our findings indicate the potential of R6H4-CMβCD as a nanopharmaceutical material, and RCCNPs as an effective delivery system for oral curcumin in cancer management.
    Keywords:  Curcumin nanoparticles; Cyclodextrin derivative; Hepatocellular carcinoma; pH-responsive transmembrane peptide
    DOI:  https://doi.org/10.1016/j.carbpol.2021.118892
  49. Front Bioeng Biotechnol. 2021 ;9 771153
    Precise Diagnosis and Therapy of Bone Cancer Using Near-Infrared Lights.
    Qing Cai, Zuntai Li, Baosheng Li, Jiayang Jiang, Xiaoyu Li, Weiyan Meng, Shoujun Zhu.
      Bone is a preferred site for both primary and metastasis tumors. Current diagnosis of osteopathia typically relies on noninvasive skeleton radiography technology. However, due to the limited resolution of ionizing radiation, accurate diagnosis and effective identification impairment areas are still lacking. Near-infrared (NIR) bioimaging, especially in the NIR-II (1000-1700 nm) regions, can provide high sensitivity and spatiotemporal resolution bioimaging compared to the conventional radiography. Thus, NIR bioimaging affords intraoperative visualization and imaging-guided surgery, aiming to overcome challenges associated with theranostics of osteopathia and bone tumors. The present review aimed to summarize the latest evidence on the use of NIR probes for the targeting bone imaging. We further highlight the recent advances in bone photoX (X presents thermal, dynamic, and immuno) therapy through NIR probes, in particular combination with other customized therapeutic agents could provide high-efficiency treatment for bone tumors.
    Keywords:  bone tumor; diagnosis; near-infrared probe; osteopathia; photoX therapy
    DOI:  https://doi.org/10.3389/fbioe.2021.771153
  50. Curr Cancer Drug Targets. 2021 Dec 05.
    Biomacromolecule-Functionalized Nanoparticle-Based Conjugates for Potentiation of Anticancer Therapy.
    Priyank Shah, Pravin Shende.
      Cancer is a rapidly growing life-threatening disease that affected 18.1 million people worldwide in 2018. Various conventional techniques like surgery, radiation, and chemotherapy are considered as a mainstream treatment for patients but show some limitations like cytotoxicity due to off-targeted action, poor intra-tumor localization, development of multi-drug resistance by tumor cells, physical and psychological stresses, etc. Such limitations have motivated the scientists to work towards more patient-centric and precision therapy using advanced drug delivery systems like liposomes, nanoparticles, nanoconjugates, etc. However, these carriers also face limitations like poor biocompatibility, lesser payload capacity, leakage of encapsulated drug, and short-term stability. So, this review article explores the profound insights for the development of biomacromolecule-functionalized nanoconjugates to potentiate the anticancer activity of therapeutic agents for various cancers like lung, colorectal, ovarian, breast and liver cancer. Researchers have shown interest in biofunctionalized nanoconjugates because of advantages like biocompatibility, site-specificity with better localization, higher entrapment with long-term stability and lesser off-target toxicity. The progressive trend of biomacromolecule nanoconjugates will encourage further research for the development of effective transport of drugs, nutraceuticals and phytoconstituents for on-site effect at cancer microenvironment and tumor cells with higher safety profile.
    Keywords:  Bioconjugates; biotherapy; cancer; nanocarriers; nanoconjugates; nanoparticles; therapeutic
    DOI:  https://doi.org/10.2174/1568009621666211206102942
  51. Nanomicro Lett. 2021 Dec 09. 14(1): 22
    A MXene-Based Bionic Cascaded-Enzyme Nanoreactor for Tumor Phototherapy/Enzyme Dynamic Therapy and Hypoxia-Activated Chemotherapy.
    Xiaoge Zhang, Lili Cheng, Yao Lu, Junjie Tang, Qijun Lv, Xiaomei Chen, You Chen, Jie Liu.
      The enzyme-mediated elevation of reactive oxygen species (ROS) at the tumor sites has become an emerging strategy for regulating intracellular redox status for anticancer treatment. Herein, we proposed a camouflaged bionic cascaded-enzyme nanoreactor based on Ti3C2 nanosheets for combined tumor enzyme dynamic therapy (EDT), phototherapy and deoxygenation-activated chemotherapy. Briefly, glucose oxidase (GOX) and chloroperoxidase (CPO) were chemically conjugated onto Ti3C2 nanosheets, where the deoxygenation-activated drug tirapazamine (TPZ) was also loaded, and the Ti3C2-GOX-CPO/TPZ (TGCT) was embedded into nanosized cancer cell-derived membrane vesicles with high-expressed CD47 (meTGCT). Due to biomimetic membrane camouflage and CD47 overexpression, meTGCT exhibited superior immune escape and homologous targeting capacities, which could effectively enhance the tumor preferential targeting and internalization. Once internalized into tumor cells, the cascade reaction of GOX and CPO could generate HClO for efficient EDT. Simultaneously, additional laser irradiation could accelerate the enzymic-catalytic reaction rate and increase the generation of singlet oxygen (1O2). Furthermore, local hypoxia environment with the oxygen depletion by EDT would activate deoxygenation-sensitive prodrug for additional chemotherapy. Consequently, meTGCT exhibits amplified synergistic therapeutic effects of tumor phototherapy, EDT and chemotherapy for efficient tumor inhibition. This intelligent cascaded-enzyme nanoreactor provides a promising approach to achieve concurrent and significant antitumor therapy.
    Keywords:  CD47; Cascaded-enzyme nanoreactor; Deoxygenation-sensitive prodrugs; Phototherapy; Tumor enzyme dynamic therapy
    DOI:  https://doi.org/10.1007/s40820-021-00761-w
  52. Front Bioeng Biotechnol. 2021 ;9 797619
    Editorial: Stimuli-Responsive Nanoparticles for Anti-cancer Therapy.
    Saji Uthaman, In-Kyu Park, Kang Moo Huh, James Lai, Mitsuhiro Ebara.
      
    Keywords:  drug delivery; molecular Imaging; nanoparticle; photothermal therapy; ultra sound
    DOI:  https://doi.org/10.3389/fbioe.2021.797619
  53. Evid Based Complement Alternat Med. 2021 ;2021 7765658
    Exploring the Antiglioma Mechanisms of Luteolin Based on Network Pharmacology and Experimental Verification.
    Renxuan Huang, Rui Dong, Nan Wang, Beiwu Lan, Hongyang Zhao, Yufei Gao.
      Luteolin, a natural flavone compound, exists in a variety of fruits and vegetables, and its anticancer effect has been shown in many studies. However, its use in glioma treatment is hampered due to the fact that the underlying mechanism of action has not been fully explored. Therefore, we elucidated the potential antiglioma targets and pathways of luteolin systematically with the help of network pharmacology and molecular docking technology. The druggability of luteolin, including absorption, excretion, distribution, and metabolism, was assessed via the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). The potential targets of luteolin and glioma were extracted from public databases, and the intersecting targets between luteolin and glioma were integrated and visualized by a Venn diagram. In addition, GO and KEGG pathway analysis was engaged in Metascape. The network of the luteolin-target-pathway was visualized by Cytoscape. Ultimately, the interactions between luteolin and predicted key targets were confirmed by Discovery studio software. According to the ADME results, luteolin shows great potential for development into a drug. 4860 glioma-associated targets and 280 targets of luteolin were identified, of which 205 were intersection targets. 6 core targets of luteolin against glioma, including AKT1, JUN, ALB, MAPK3, MAPK1, and TNF, were identified via PPI network analysis of which AKT1, JUN, ALB, MAPK1, and TNF harbor diagnostic value. The biological processes of luteolin are mainly involved in the response to inorganic substances, response to oxidative stress, and apoptotic signaling pathway. The essential pathways of luteolin against glioma involve pathways in cancer, the PI3K-Akt signaling pathway, the TNF signaling pathway, and more. Meanwhile, luteolin's interaction with six core targets was verified by molecular docking simulation and its antiglioma effect was verified by in vitro experiments. This study suggests that luteolin has a promising potential for development into a drug and, moreover, it displays preventive effects against glioma by targeting various genes and pathways.
    DOI:  https://doi.org/10.1155/2021/7765658
  54. Front Pharmacol. 2021 ;12 752825
    The Disulfiram/Copper Complex Induces Autophagic Cell Death in Colorectal Cancer by Targeting ULK1.
    Yeting Hu, Yucheng Qian, Jingsun Wei, Tian Jin, Xiangxing Kong, Hongfeng Cao, Kefeng Ding.
      Colorectal cancer (CRC) is highly prevalent worldwide, but there has been limited development of efficient and affordable treatment. Induced autophagy has recently been recognized as a novel therapeutic strategy in cancer treatment, and disulfiram (DSF), a well-known antialcohol drug, is also found to inhibit tumor growth in various malignancies. Recently, DSF has been reported to induce excessive autophagy in oral squamous cells; however, little is known about whether it can induce autophagy and suppress proliferation in CRC. In this study, we investigate the effect of DSF with copper (DSF/Cu) on CRC both in vitro and in vivo and find that the combination significantly inhibits CRC cell viability and mainly induces autophagy instead of apoptosis. Furthermore, we use whole genome CRISPR library screening and identify a new mechanism by which DSF triggers autophagy by ULK1. Overall, these findings provide a potential CRC treatment.
    Keywords:  CRISPR library; ULK1; autophagy; colorectal cancer; disulfiram
    DOI:  https://doi.org/10.3389/fphar.2021.752825
  55. Front Chem. 2021 ;9 746646
    Recent Advancements in Serum Albumin-Based Nanovehicles Toward Potential Cancer Diagnosis and Therapy.
    Xue Shen, Xiyang Liu, Tingting Li, Yin Chen, Yang Chen, Pan Wang, Lin Zheng, Hong Yang, Chunhui Wu, Shengqi Deng, Yiyao Liu.
      Recently, drug delivery vehicles based on nanotechnology have significantly attracted the attention of researchers in the field of nanomedicine since they can achieve ideal drug release and biodistribution. Among the various organic or inorganic materials that used to prepare drug delivery vehicles for effective cancer treatment, serum albumin-based nanovehicles have been widely developed and investigated due to their prominent superiorities, including good biocompatibility, high stability, nontoxicity, non-immunogenicity, easy preparation, and functionalization, allowing them to be promising candidates for cancer diagnosis and therapy. This article reviews the recent advances on the applications of serum albumin-based nanovehicles in cancer diagnosis and therapy. We first introduce the essential information of bovine serum albumin (BSA) and human serum albumin (HSA), and discuss their drug loading strategies. We then discuss the different types of serum albumin-based nanovehicles including albumin nanoparticles, surface-functionalized albumin nanoparticles, and albumin nanocomplexes. Moreover, after briefly discussing the application of serum albumin-based nanovehicles used as the nanoprobes in cancer diagnosis, we also describe the serum albumin-based nanovehicle-assisted cancer theranostics, involving gas therapy, chemodynamic therapy (CDT), phototherapy (PTT/PDT), sonodynamic therapy (SDT), and other therapies as well as cancer imaging. Numerous studies cited in our review show that serum albumin-based nanovehicles possess a great potential in cancer diagnostic and therapeutic applications.
    Keywords:  cancer therapy; diagnostic nanoprobes; drug loading; serum albumin-based nanovehicles; theranostics
    DOI:  https://doi.org/10.3389/fchem.2021.746646
  56. Evid Based Complement Alternat Med. 2021 ;2021 8402517
    Noscapine, an Emerging Medication for Different Diseases: A Mechanistic Review.
    Pouria Rahmanian-Devin, Vafa Baradaran Rahimi, Mahmoud Reza Jaafari, Shiva Golmohammadzadeh, Zahra Sanei-Far, Vahid Reza Askari.
      Noscapine is a benzylisoquinoline alkaloid isolated from poppy extract, used as an antitussive since the 1950s, and has no addictive or euphoric effects. Various studies have shown that noscapine has excellent anti-inflammatory effects and potentiates the antioxidant defences by inhibiting nitric oxide (NO) metabolites and reactive oxygen species (ROS) levels and increasing total glutathione (GSH). Furthermore, noscapine has indicated antiangiogenic and antimetastatic effects. Noscapine induces apoptosis in many cancerous cell types and provides favourable antitumour activities and inhibitory cell proliferation in solid tumours, even drug-resistant strains, via mitochondrial pathways. Moreover, this compound attenuates the dynamic properties of microtubules and arrests the cell cycle in the G2/M phase. Noscapine can reduce endothelial cell migration in the brain by inhibiting endothelial cell activator interleukin 8 (IL-8). In fact, this study aimed to elaborate on the possible mechanisms of noscapine against different disorders.
    DOI:  https://doi.org/10.1155/2021/8402517
  57. Molecules. 2021 Nov 27. pii: 7200. [Epub ahead of print]26(23):
    Artemisia santolinifolia-Mediated Chemosensitization via Activation of Distinct Cell Death Modes and Suppression of STAT3/Survivin-Signaling Pathways in NSCLC.
    Uyanga Batbold, Jun-Jen Liu.
      Conventional chemotherapy remains an integral part of lung cancer therapy, regardless of its toxicity and drug resistance. Consequently, the discovery of an alternative to conventional chemotherapy is critical. Artemisia santolinifolia ethanol extract (AS) was assessed for its chemosensitizer ability when combined with the conventional anticancer drug, docetaxel (DTX), against non-small cell lung cancer (NSCLC). SRB assay was used to determine cell viability for A549 and H23 cell lines. The potential for this combination was examined by the combination index (CI). Further cell death, analyses with Annexin V/7AAD double staining, and corresponding protein expressions were analyzed. Surprisingly, AS synergistically enhanced the cytotoxic effect of DTX by inducing apoptosis in H23 cells through the caspase-dependent pathway, whereas selectively increased necrotic cell population in A549 cells, following the decline in GPX4 level and reactive oxygen species (ROS) activation with the highest rate in the combination treatment group. Furthermore, our results highlight the chemosensitization ability of AS when combined with DTX. It was closely associated with synergistic inhibition of oncogenesis signaling molecule STAT3 in both cell lines and concurrently downregulating prosurvival protein Survivin. Conclusively, AS could enhance DTX-induced cancer cells apoptosis by abrogating substantial prosurvival proteins' expressions and triggering two distinct cell death pathways. Our data also highlight that AS might serve as an adjunctive therapeutic option along with a conventional chemotherapeutic agent in the management of NSCLC patients.
    Keywords:  Artemisia santolinifolia; STAT3/survivin; docetaxel
    DOI:  https://doi.org/10.3390/molecules26237200
  58. Biochem Biophys Res Commun. 2021 Dec 01. pii: S0006-291X(21)01626-0. [Epub ahead of print]587 99-106
    Auriculasin enhances ROS generation to regulate colorectal cancer cell apoptosis, ferroptosis, oxeiptosis, invasion and colony formation.
    Chun-Xiao Wang, Li-Hua Chen, Hai-Bin Zhuang, Ze-Sheng Shi, Zhi Chuan Chen, Jian-Peng Pan, Zhong-Shi Hong.
      Colorectal cancer (CRC) is one of the most common malignant tumors in the digestive system, and Chinese herbal medicine plays an important role in tumor treatment. The in-depth study of auriculasin isolated from Flemingia philippinensis showed that auriculasin promoted reactive oxygen species (ROS) generation in a concentration-dependent manner; when ROS scavenger NAC was added, the effects of auriculasin in promoting ROS generation and inhibiting cell viability were blocked. Auriculasin induced CRC cell apoptosis, led to mitochondrial shrinkage, and increased the intracellular accumulation of Fe2+ and MDA. When auriculasin and NAC were added simultaneously, the levels of apoptosis, Fe2+ and MDA returned to the control group levels, indicating that auriculasin activated apoptosis and ferroptosis by inducing ROS generation. In addition, auriculasin promoted the expression of Keap1 and AIFM1, but significantly reduced the phosphorylation level of AIFM1, while NAC significantly blocked the regulation of Keap1 and AIFM1 by auriculasin, which indicates that auriculasin can also induce oxeiptosis through ROS. When Z-VAD-FMK, Ferrostatin-1, Keap1 siRNA, PGAM5 siRNA and AIFM1 siRNA were added respectively, the inhibitory effect of auriculasin on cell viability was significantly weakened, indicating that auriculasin inhibits cell viability by inducing apoptosis, ferroptosis and oxeiptosis. Auriculasin also inhibited the invasion and clone forming ability of CRC cells, while NAC blocked the above effects of auriculasin. Therefore, auriculasin can promote CRC cell apoptosis, ferroptosis and oxeiptosis by inducing ROS generation, thereby inhibiting cell viability, invasion and clone formation, indicating that auriculasin has a significant antitumor effect.
    Keywords:  Auriculasin; Colorectal cancer; Ferroptosis; Oxeiptosis; ROS
    DOI:  https://doi.org/10.1016/j.bbrc.2021.11.101
  59. Molecules. 2021 Dec 04. pii: 7368. [Epub ahead of print]26(23):
    Berberine as a Potential Anticancer Agent: A Comprehensive Review.
    Abdur Rauf, Tareq Abu-Izneid, Anees Ahmed Khalil, Muhammad Imran, Zafar Ali Shah, Talha Bin Emran, Saikat Mitra, Zidan Khan, Fahad A Alhumaydhi, Abdullah S M Aljohani, Ishaq Khan, Md Mominur Rahman, Philippe Jeandet, Tanweer Aslam Gondal.
      Berberine (BBR), a potential bioactive agent, has remarkable health benefits. A substantial amount of research has been conducted to date to establish the anticancer potential of BBR. The present review consolidates salient information concerning the promising anticancer activity of this compound. The therapeutic efficacy of BBR has been reported in several studies regarding colon, breast, pancreatic, liver, oral, bone, cutaneous, prostate, intestine, and thyroid cancers. BBR prevents cancer cell proliferation by inducing apoptosis and controlling the cell cycle as well as autophagy. BBR also hinders tumor cell invasion and metastasis by down-regulating metastasis-related proteins. Moreover, BBR is also beneficial in the early stages of cancer development by lowering epithelial-mesenchymal transition protein expression. Despite its significance as a potentially promising drug candidate, there are currently no pure berberine preparations approved to treat specific ailments. Hence, this review highlights our current comprehensive knowledge of sources, extraction methods, pharmacokinetic, and pharmacodynamic profiles of berberine, as well as the proposed mechanisms of action associated with its anticancer potential. The information presented here will help provide a baseline for researchers, scientists, and drug developers regarding the use of berberine as a promising candidate in treating different types of cancers.
    Keywords:  alkaloids; berberine; cancer; cancer preventive agents; pharmacokinetic study
    DOI:  https://doi.org/10.3390/molecules26237368
  60. Adv Healthc Mater. 2021 Dec 10. e2102060
    Virus-inspired hollow mesoporous gadolinium-bismuth nanotheranostics for magnetic resonance imaging-guided synergistic photodynamic-radiotherapy.
    Zongjunlin Liu, Peiyuan Wang, Fang Xie, Jianhao Chen, Meimei Cai, Yang Li, Jianghua Yan, Qin Lin, Fanghong Luo.
      The anti-tumor efficacy of single photodynamic therapy (PDT) and radiotherapy (RT) has been greatly affected by inadequate tumor uptake of photo/radiation sensitizers, limited laser penetration depth, and radiation sickness caused by high doses of X-rays. Here, we report a biomimetic coronavirus-inspired hollow mesoporous gadolinium/bismuth nanocarrier loaded with a new NIR photosensitizer HB (referred to as HB@VHMBi-Gd) for magnetic resonance imaging (MRI)-guided synergistic photodynamic-RT. HB@VHMBi-Gd displayed a faster cellular uptake rate than the conventional spherical HMBi-Gd loaded with HB (HB@SHMBi-Gd) because of the rough surface-enhanced adhesion. After intravenous injection, HB@VHMBi-Gd was efficiently delivered to the tumor and rapidly invaded the tumor cells by surface spikes. Interestingly, lysosomal acidity could trigger the degradation of VHMBi-Gd to produce ultrasmall nanoparticles to amplify the X-ray attenuation ability and enhance MRI contrast and radiosensitization. Under laser and X-ray irradiation, HB@VHMBi-Gd significantly enhanced 1 O2 generation from HB to induce activation of caspase 9/3 and inhibition of C-myc, while enhancing hydroxyl radical generation from Bi2 O3 to induce intense DNA breakage. By synergistically inducing cell apoptosis by distinct reactive oxygen species (ROS), HB@VHMBi-Gd exhibited superior anticancer efficacy with ∼90% tumor inhibition. We envision that biomimetic virus-inspired hollow hybrid metal nanoparticles could provide a promising strategy for imaging-guided synergistic photodynamic-RT. This article is protected by copyright. All rights reserved.
    DOI:  https://doi.org/10.1002/adhm.202102060
  61. Front Pharmacol. 2021 ;12 715359
    Tripterygium hypoglaucum (Lévl.) Hutch and Its Main Bioactive Components: Recent Advances in Pharmacological Activity, Pharmacokinetics and Potential Toxicity.
    Junqi Zhao, Fangling Zhang, Xiaolin Xiao, Zhao Wu, Qichao Hu, Yinxiao Jiang, Wenwen Zhang, Shizhang Wei, Xiao Ma, Xiaomei Zhang.
      Tripterygium hypoglaucum (Lévl.) Hutch (THH) is believed to play an important role in health care and disease treatment according to traditional Chinese medicine. Moreover, it is also the representative of medicine with both significant efficacy and potential toxicity. This characteristic causes THH hard for embracing and fearing. In order to verify its prospect for clinic, a wide variety of studies were carried out in the most recent years. However, there has not been any review about THH yet. Therefore, this review summarized its characteristic of components, pharmacological effect, pharmacokinetics and toxicity to comprehensively shed light on the potential clinical application. More than 120 secondary metabolites including terpenoids, alkaloids, glycosides, sugars, organic acids, oleanolic acid, polysaccharides and other components were found in THH based on phytochemical research. All these components might be the pharmacological bases for immunosuppression, anti-inflammatory and anti-tumour effect. In addition, recent studies found that THH and its bioactive compounds also demonstrated remarkable effect on obesity, insulin resistance, fertility and infection of virus. The main mechanism seemed to be closely related to regulation the balance of immune, inflammation, apoptosis and so on in various disease. Furthermore, the study of pharmacokinetics revealed quick elimination of the main component triptolide. The feature of celastrol was also investigated by several models. Finally, the side effect of THH was thought to be the key for its limitation in clinical application. A series of reports indicated that multiple organs or systems including liver, kidney and genital system were involved in the toxicity. Its potential serious problem in liver was paid specific attention in recent years. In summary, considering the significant effect and potential toxicity of THH as well as its components, the combined medication to inhibit the toxicity, maintain effect might be a promising method for clinical conversion. Modern advanced technology such as structure optimization might be another way to reach the efficacy and safety. Thus, THH is still a crucial plant which remains for further investigation.
    Keywords:  Tripterygium hypoglaucum (Lévl.) Hutch.; pharmacokinetics; pharmacology; phytochemistry; toxicity
    DOI:  https://doi.org/10.3389/fphar.2021.715359
  62. Front Neurol. 2021 ;12 748419
    Old Habits Die Hard: Dietary Habits of Migraine Patients Challenge our Understanding of Dietary Triggers.
    Marco Lisicki, Jean Schoenen.
      Introduction: Migraine is a multifactorial neurological disorder with a major metabolic facet. Dietary approaches represent a commonly implemented lifestyle modifying strategy in headache clinics, yet the precise relationship between diet and migraine is still a matter of debate. Materials and Methods: The study consisted of two parts: first, in a cross-sectional design, we compared alimentary habits of migraine subjects and a control group of healthy volunteers. For the second part, we prospectively evaluated patients' daily consumption of various potentially migraine-triggering foods over a two-month period in order to examine their possible association with the occurrence of a migraine attack. Results: Most migraine patients reported avoiding at least one potentially migraine-triggering food/drink from their diet. In spite of that, with the sole exemption of citrus fruits, there were no statistically significant differences with respect to consumption patterns between migraine patients and controls (including wine and chocolate). Consumption frequency over time was proportional to intake of potentially migraine-triggering foods the day before a migraine attack. Conclusion: Our results underline the need of performing trigger challenges in order to avoid falling into an association-causation fallacy when attempting to identify possible alimentary migraine triggers. Indeed, it is possible that intake of certain foods like chocolate before attacks is a consequence of pre-attack cravings or a simple coincidence facilitated by previously established dietary habits.
    Keywords:  diet; headache; metabolism; prospective; survey
    DOI:  https://doi.org/10.3389/fneur.2021.748419
  63. Int J Pharm. 2021 Dec 03. pii: S0378-5173(21)01152-2. [Epub ahead of print] 121346
    Design and Synthesis of a Star-Like Polymeric Micelle Modified with AS1411 Aptamer for Targeted Delivery of Camptothecin for Cancer Therapy.
    Atena Jabbari, Elnaz Yaghoobi, Hamid Azizollahi, Saeed Shojaee, Mohammad Ramezani, Mona Alibolandi, Khalil Abnous, Seyed Mohammad Taghdisi.
      Improving of tumor targeting and decreasing side effects at normal cells of antitumor drugs are necessary to promote the cancer chemotherapy efficacy. Herein, we have synthesized a novel 21-arm star like diblock polymer of β-cyclodextrin-{poly(ε-caprolactone)-poly(2-aminoethylmethacrylate)}21 which decorated with nucleolin aptamer (AS1411). The diblock polymer was prepared by combined ROP with electron transfer atom transfer radical polymerization (ARGET ATRP) methods followed camptothecin (CPT) encapsulation with high entrapment efficiency (65%). Subsequently, the attachment of AS1411 aptamer via covalent bond led to the formation of the final product β-CD-(PCL-PAEMA)21/AS1411/CPT. In vitro drug release experiment demonstrated almost 50% of CPT was released in 72 h at acidic tumoral environment. The data of cellular toxicity (MTT) showed that the final product remarkably enhanced cell death in MCF-7 and 4T1 cells while normal cells (L929) showed high viability toward the prepared complex. Also, the finding of flow cytometry analysis and fluorescence imaging indicated successful internalization of complex into the target cells but not the nontarget cells. The in vivo experiments revealed the fact that β-CD-(PCL-PAEMA)21/AS1411/CPT micelles showed high tumor inhibitory potential in comparison with free CPT. These findings exhibited the excellent ability of the novel star-like polymeric micelle with targeting agent for the targeted and effective delivery of CPT in cancer treatment.
    Keywords:  AS1411 aptamer; Camptothecin; Drug delivery; Star-like micelle; Supramolecular technology; β-cyclodextrin
    DOI:  https://doi.org/10.1016/j.ijpharm.2021.121346
  64. Cancer Prev Res (Phila). 2021 Dec 09. pii: canprevres.0298.2021. [Epub ahead of print]
    Hunger Training as a self-regulation strategy in a comprehensive weight loss program for breast cancer prevention: a randomized feasibility study.
    Susan M Schembre, Michelle R Jospe, Edward J Bedrick, Liang Li, Abenaa M Brewster, Erma Levy, Danika D Dirba, Morgan Campbell, Rachael W Taylor, Karen M Basen-Engquist.
      Weight losses >10% favorably modulate biomarkers of breast cancer risk but are not typically achieved by comprehensive weight loss programs, including the Diabetes Prevention Program (DPP). Combining the DPP with Hunger Training (HT), an evidence-based self-regulation strategy that uses self-monitored glucose levels to guide meal timing, has potential to enhance weight losses and cancer-related biomarkers, if proven feasible. This 2-arm RCT examined the feasibility of adding HT to the DPP and explored effects on weight and metabolic and breast cancer risk biomarkers. Fifty postmenopausal women (BMI > 27 kg/m2) at risk of breast cancer were randomized to the DPP+HT or DPP-only arm. Both arms followed a 16-week version of the DPP delivered weekly by a trained registered dietitian. Those in the DPP+HT also wore a continuous glucose monitor during weeks 4-6 of the program. Feasibility criteria were accrual rates > 50%, retention rates > 80%, and adherence to the HT protocol >75%. All a priori feasibility criteria were achieved. The accrual rate was 67%; retention rate was 81%; and adherence to HT was 90%. Weight losses and BMI reductions were significant over time as were changes in metabolic and breast cancer risk biomarkers but did not vary by group. This trial demonstrated that HT was feasible to add to comprehensive weight management program targeted towards postmenopausal women at high risk of breast cancer, though upon preliminary examination it does not appear to enhance weight loss or metabolic changes.
    DOI:  https://doi.org/10.1158/1940-6207.CAPR-21-0298
  65. Front Nutr. 2021 ;8 782657
    Neuroprotection by the Ketogenic Diet: Evidence and Controversies.
    Sarah M Gough, Alicia Casella, Kristen Jasmin Ortega, Abigail S Hackam.
      The ketogenic diet (KD) is a high-fat low-carbohydrate diet that has been used for decades as a non-pharmacologic approach to treat metabolic disorders and refractory pediatric epilepsy. In recent years, enthusiasm for the KD has increased in the scientific community due to evidence that the diet reduces pathology and improves various outcome measures in animal models of neurodegenerative disorders, including multiple sclerosis, stroke, glaucoma, spinal cord injury, retinal degenerations, Parkinson's disease and Alzheimer's disease. Clinical trials also suggest that the KD improved quality of life in patients with multiple sclerosis and Alzheimer's disease. Furthermore, the major ketone bodies BHB and ACA have potential neuroprotective properties and are now known to have direct effects on specific inflammatory proteins, transcription factors, reactive oxygen species, mitochondria, epigenetic modifications and the composition of the gut microbiome. Neuroprotective benefits of the KD are likely due to a combination of these cellular processes and other potential mechanisms that are yet to be confirmed experimentally. This review provides a comprehensive summary of current evidence for the effectiveness of the KD in humans and preclinical models of various neurological disorders, describes molecular mechanisms that may contribute to its beneficial effects, and highlights key controversies and current gaps in knowledge.
    Keywords:  inflammation; ketogenic diet; ketone bodies; mitochondria; neurodegeneration
    DOI:  https://doi.org/10.3389/fnut.2021.782657
  66. Carbohydr Polym. 2022 Feb 01. pii: S0144-8617(21)01256-X. [Epub ahead of print]277 118869
    Chitosan oligosaccharide regulates AMPK and STAT1 pathways synergistically to mediate PD-L1 expression for cancer chemoimmunotherapy.
    Jiashe Chen, Zaigang Zhou, Chunjuan Zheng, Yu Liu, Ruiqi Hao, Xiaolin Ji, Qiaoer Xi, Jianliang Shen, Zhiming Li.
      After regular chemotherapy, the expression of programmed cell death ligand 1 (PD-L1) in almost all kinds of cancers is significantly increased, leading to reduced efficacy of T cell mediated immune killing in tumors. To solve this, a lot of PD-L1 antibodies were produced and used, but their high cost and serious toxic side effects still limit its usage. Recently, small molecule compounds that could effectively regulate PD-L1 expression possess the edges to solve the problems of PD-L1 antibodies. Chitosan oligosaccharide (COS), a biomaterial derived from the N-deacetylation product of chitin, has a broad spectrum of biological activities in treating tumors. However, the mechanism of its anti-cancer effect is still not well understood. Here, for the first time, we clearly identified that COS could inhibit the upregulated PD-L1 expression induced by interferon γ (IFN-γ) in various tumors via the AMPK activation and STAT1 inhibition. Besides, COS itself significantly restricted the growth of CT26 tumors by enhancing the T cell infiltration in tumors. Furthermore, we observed that combining COS with Gemcitabine (GEM), one of the typical chemotherapeutic drugs, leaded to a more remarkable tumor remission. Therefore, it was demonstrated that COS could be used as a useful way to improve the efficacy of existing chemotherapies by effective PD-L1 downregulation.
    Keywords:  AMP-activated protein kinase; Chemotherapy; Chitosan oligosaccharide; PD-L1; STAT1 signaling
    DOI:  https://doi.org/10.1016/j.carbpol.2021.118869
  67. J Nutr. 2021 Dec 03. pii: nxab407. [Epub ahead of print]
    Dietary and Supplemental Vitamin C Intake and Risk of Breast Cancer: Results from the Nurses' Health Studies.
    Claire Cadeau, Maryam S Farvid, Bernard A Rosner, Walter C Willett, A Heather Eliassen.
       BACKGROUND: Some previous studies suggested that high supplemental vitamin C intake may be associated with an increased risk of breast cancer, although evidence is inconsistent.
    OBJECTIVE: Our objective was to study the association between vitamin C intake and breast cancer risk using regularly updated assessments of intake over a long follow-up.
    METHODS: We prospectively followed 88,041 women aged 33 to 60 years from the Nurses' Health Study (NHS; 1980-2014) and 93,372 women aged 26 to 45 years from the Nurses' Health Study II (NHSII; 1991-2013). A total of 11,258 incident invasive breast cancers among 181,413 women were diagnosed. Data on vitamin C intake were collected every 2-4 years via a validated food frequency questionnaire and specific questions on dietary supplement use. Multivariate hazard ratios (HRs) and 95% confidence intervals (CIs) for incident invasive breast cancer were estimated with Cox models.
    RESULTS: During follow-up, 82% of participants ever used supplements containing vitamin C, including multivitamins. Cumulative total vitamin C intake (HR for quintile 5 vs. 1 = 0.97, 95%CI: 0.91, 1.03, Ptrend = 0.81), dietary vitamin C intake (HR for quintile 5 vs. 1 = 0.98, 95%CI: 0.92, 1.04, Ptrend = 0.57) and supplemental vitamin C intake (HR for quintile 5 vs. 1 in users = 1.02, 95%CI: 0.94, 1.09, Ptrend = 0.77) were not associated with breast cancer risk. Results were unchanged when different exposure latencies were considered. The results did not differ by menopausal status; postmenopausal hormone therapy use or BMI. No differences were observed by estrogen receptor status of the tumor.
    CONCLUSIONS: Our results do not support any important association between total, dietary or supplemental vitamin C intake and breast cancer risk.
    Keywords:  breast cancer; dietary supplements; nutrition; prospective study; vitamin C
    DOI:  https://doi.org/10.1093/jn/nxab407
  68. Front Endocrinol (Lausanne). 2021 ;12 744647
    The Use of Herbal Medicines for the Prevention of Glucocorticoid-Induced Osteoporosis.
    Leiming Zhang, Xiaoli Li, Tianhao Ying, Tian Wang, Fenghua Fu.
      Glucocorticoids are drugs that are widely used to suppress inflammation and the activation of the immune system. However, the prolonged use or at high doses of glucocorticoid can result in adverse side effects including osteoporosis, bone loss, and an increased risk of fracture. A number of compounds derived from natural plant sources have been reported to exert anti-inflammatory activity by interacting with the glucocorticoid receptor (GR), likely owing to their chemical similarity to glucocorticoids, or by regulating GR, without a concomitant risk of treatment-related side effects such as osteoporosis. Other herbal compounds can counteract the pathogenic processes underlying glucocorticoid-induced osteoporosis (GIOP) by regulating homeostatic bone metabolic processes. Herein, we systematically searched the PubMed, Embase, and Cochrane library databases to identify articles discussing such compounds published as of May 01, 2021. Compounds reported to exert anti-inflammatory glucocorticoid-like activity without inducing GIOP include escin, ginsenosides, and glycyrrhizic acid, while compounds reported to alleviate GIOP by improving osteoblast function or modulating steroid hormone synthesis include tanshinol and icariin.
    Keywords:  escin; ginsenoside; glucocorticoid-induced osteoporosis; glycyrrhizic acid; herb medicine; icariin
    DOI:  https://doi.org/10.3389/fendo.2021.744647
  69. Int J Mol Sci. 2021 Nov 23. pii: 12614. [Epub ahead of print]22(23):
    Resveratrol-Induced Signal Transduction in Wound Healing.
    Anna-Lisa Pignet, Marlies Schellnegger, Andrzej Hecker, Michael Kohlhauser, Petra Kotzbeck, Lars-Peter Kamolz.
      Resveratrol is a well-known polyphenol that harbors various health benefits. Besides its well-known anti-oxidative potential, resveratrol exerts anti-inflammatory, pro-angiogenic, and cell-protective effects. It seems to be a promising adjuvant for various medical indications, such as cancer, vascular, and neurodegenerative diseases. Additionally, resveratrol was shown to display beneficial effects on the human skin. The polyphenol is discussed to be a feasible treatment approach to accelerate wound healing and prevent the development of chronic wounds without the drawback of systemic side effects. Despite resveratrol's increasing popularity, its molecular mechanisms of action are still poorly understood. To take full advantage of resveratrol's therapeutic potential, a profound knowledge of its interactions with its targets is needed. Therefore, this review highlights the resveratrol-induced molecular pathways with particular focus on the most relevant variables in wound healing, namely inflammation, oxidative stress, autophagy, collagen proliferation and angiogenesis.
    Keywords:  SIRT1 signaling; molecular pathway; resveratrol; skin; wound healing
    DOI:  https://doi.org/10.3390/ijms222312614
  70. Chem Commun (Camb). 2021 Dec 07.
    Stimuli-responsive nanomaterials for cancer treatment: boundaries, opportunities and applications.
    Nuria Lafuente-Gómez, Ana Latorre, Paula Milán-Rois, Ciro Rodriguez Diaz, Álvaro Somoza.
      Small molecule drugs, including most chemotherapies, are rapidly degraded and/or eliminated from the body, which is why high doses of these drugs are necessary, potentially producing toxic effects. Several types of nanoparticles loaded with anti-cancer drugs have been designed to overcome the disadvantages of conventional therapies. Modified nanoparticles can circulate for a long time, thus improving the solubility and biodistribution of drugs. Furthermore, they also allow the controlled release of the payload once its target tissue has been reached. These mechanisms can reduce the exposure of healthy tissues to chemotherapeutics, since the drugs are only released in the presence of specific tumour stimuli. Overall, these properties can improve the effectiveness of treatments while reducing undesirable side effects. In this article, we review the recent advances in stimuli-responsive albumin, gold and magnetic nanostructures for controlled anti-cancer drug delivery. These nanostructures were designed to release drugs in response to different internal and external stimuli of the cellular environment, including pH, redox, light and magnetic fields. We also describe various examples of applications of these nanomaterials. Overall, we shed light on the properties, potential clinical translation and limitations of stimuli-responsive nanoparticles for cancer treatment.
    DOI:  https://doi.org/10.1039/d1cc05056g
  71. NAR Cancer. 2021 Dec;3(4): zcab045
    Misregulation of the expression and activity of DNA methyltransferases in cancer.
    Isaiah K Mensah, Allison B Norvil, Lama AlAbdi, Sarah McGovern, Christopher J Petell, Ming He, Humaira Gowher.
      In mammals, DNA methyltransferases DNMT1 and DNMT3's (A, B and L) deposit and maintain DNA methylation in dividing and nondividing cells. Although these enzymes have an unremarkable DNA sequence specificity (CpG), their regional specificity is regulated by interactions with various protein factors, chromatin modifiers, and post-translational modifications of histones. Changes in the DNMT expression or interacting partners affect DNA methylation patterns. Consequently, the acquired gene expression may increase the proliferative potential of cells, often concomitant with loss of cell identity as found in cancer. Aberrant DNA methylation, including hypermethylation and hypomethylation at various genomic regions, therefore, is a hallmark of most cancers. Additionally, somatic mutations in DNMTs that affect catalytic activity were mapped in Acute Myeloid Leukemia cancer cells. Despite being very effective in some cancers, the clinically approved DNMT inhibitors lack specificity, which could result in a wide range of deleterious effects. Elucidating distinct molecular mechanisms of DNMTs will facilitate the discovery of alternative cancer therapeutic targets. This review is focused on: (i) the structure and characteristics of DNMTs, (ii) the prevalence of mutations and abnormal expression of DNMTs in cancer, (iii) factors that mediate their abnormal expression and (iv) the effect of anomalous DNMT-complexes in cancer.
    DOI:  https://doi.org/10.1093/narcan/zcab045
  72. Adv Drug Deliv Rev. 2021 Dec 06. pii: S0169-409X(21)00468-3. [Epub ahead of print] 114075
    Responsive nanomedicines enhanced by or enhancing physical modalities to treat solid cancer tumors: Preclinical and Clinical evidence of safety and efficacy.
    Ligeri Papaioannou, Konstantinos Avgoustakis.
      Nanomedicine has improved cancer treatment but not to the extent anticipated. Responsive nanomedicines enhanced by physical modalities (radiation, ultrasounds, alternating magnetic fields) or enhancing the activity of physical modalities such as radiotherapy to kill cancer represents an important approach in improving the safety and anticancer effectiveness. Importantly, the combined treatments have shown promise for the treatment of difficult to treat tumors, such as tumors that are resistant to chemotherapy (multi drug resistant, MDR) or radiotherapy and hypoxic tumors, and for the prevention of tumor metastasis. In this review, the mechanisms of responsive nanomedicines activity enhancement by physical means and vice versa are presented and preclinical and, most importantly, clinical evidence of the safety and efficacy of nanomedicines enhanced by or enhancing by physical modalities in treating solid tumors are critically discussed.
    Keywords:  AFM; cancer; focused ultrasounds; nanomedicines; photodynamic therapy; photothermal ablation; radiotherapy
    DOI:  https://doi.org/10.1016/j.addr.2021.114075
  73. Int J Nanomedicine. 2021 ;16 7875-7890
    TPGS2000-DOX Prodrug Micelles for Improving Breast Cancer Therapy.
    Lan Tang, Wenhui Jiang, Lan Wu, Xiaolan Yu, Zheng He, Weiguang Shan, Lulu Fu, Zhenhai Zhang, Yunchun Zhao.
       Background: Doxorubicin (DOX) is an anthracycline antibiotic that inhibits the growth of several solid and hematologic malignant tumors. Increasing the targeting ability of DOX and reducing the multi-drug resistance (MDR) of tumor cells to DOX are major aims for researchers.
    Purpose: In this study, to increase therapeutic efficiency, reduce the side effects and the MDR of tumor cells to DOX, D-alpha-tocopheryl polyethylene glycol 2000 succinate monoester (TPGS2000)-DOX prodrug micelles were developed by grafting DOX to TPGS2000 via an amide bond that release DOX in the slightly acidic conditions in tumor tissue.
    Materials and Methods: The TPGS2000-DOX micelles were constructed using polyethylene glycol 12-hydroxy stearate (Solutol HS15) as the carrier. The in vitro drug release profile and dilution stability of the nanomicelles were determined. The in vitro cytotoxicity and distribution of the nanomicelles in the tumor cells were also investigated. Moreover, we explored the therapeutic outcomes using the MCF-7/ADR tumor-bearing murine model.
    Results: The average particle size was approximately 30 nm with a narrow distribution, which was conducive for solid tumor accumulation. The results of in vivo imaging and in vitro cellular uptake assays demonstrated that the TPGS2000-DOX micelles increased the tumor-targeting ability and cellular uptake of DOX. The anticancer potential of TPGS2000-DOX micelles was higher than that of DOX, as revealed by in vitro cytotoxic assays with MCF-7/ADR cells and in vivo antitumor assays with MCF-7 tumor-bearing nude mice.
    Conclusion: TPGS2000-DOX prodrug micelles reverse the MDR of tumor cells, achieve passive targeting by forming nanomicelles, and subsequently enhance the efficacy and reduce the toxicity of DOX.
    Keywords:  D-alpha-tocopheryl polyethylene glycol 2000 succinate monoester; breast cancer; doxorubicin; multi-drug resistance; polymer prodrug nanomedicine
    DOI:  https://doi.org/10.2147/IJN.S335405
  74. Cell Biosci. 2021 Dec 07. 11(1): 201
    Catalase deficiency facilitates the shuttling of free fatty acid to brown adipose tissue through lipolysis mediated by ROS during sustained fasting.
    Raghbendra Kumar Dutta, Joon No Lee, Yunash Maharjan, Channy Park, Seong-Kyu Choe, Ye-Shih Ho, Raekil Park.
       BACKGROUND: Fatty acids (FA) derived from adipose tissue and liver serve as the main fuel in thermogenesis of brown adipose tissue (BAT). Catalase, a peroxisomal enzyme, plays an important role in maintaining intracellular redox homeostasis by decomposing hydrogen peroxide to either water or oxygen that oxidize and provide fuel for cellular metabolism. Although the antioxidant enzymatic activity of catalase is well known, its role in the metabolism and maintenance of energy homeostasis has not yet been revealed. The present study investigated the role of catalase in lipid metabolism and thermogenesis during nutrient deprivation in catalase-knockout (KO) mice.
    RESULTS: We found that hepatic triglyceride accumulation in KO mice decreased during sustained fasting due to lipolysis through reactive oxygen species (ROS) generation in adipocytes. Furthermore, the free FA released from lipolysis were shuttled to BAT through the activation of CD36 and catabolized by lipoprotein lipase in KO mice during sustained fasting. Although the exact mechanism for the activation of the FA receptor enzyme, CD36 in BAT is still unclear, we found that ROS generation in adipocytes mediated the shuttling of FA to BAT.
    CONCLUSIONS: Taken together, our findings uncover the novel role of catalase in lipid metabolism and thermogenesis in BAT, which may be useful in understanding metabolic dysfunction.
    Keywords:  Catalase; Lipolysis; Reactive Oxygen species (ROS); Sustained fasting; Thermogenesis
    DOI:  https://doi.org/10.1186/s13578-021-00710-5
  75. Polymers (Basel). 2021 Nov 27. pii: 4146. [Epub ahead of print]13(23):
    Emerging Application of Magnetic Nanoparticles for Diagnosis and Treatment of Cancer.
    Dalal A Alromi, Seyed Yazdan Madani, Alexander Seifalian.
      Cancer is a disease that has resulted in millions of deaths worldwide. The current conventional therapies utilized for the treatment of cancer have detrimental side effects. This led scientific researchers to explore new therapeutic avenues with an improved benefit to risk profile. Researchers have found nanoparticles, particles between the 1 and 100 nm range, to be encouraging tools in the area of cancer. Magnetic nanoparticles are one of many available nanoparticles at present. Magnetic nanoparticles have increasingly been receiving a considerable amount of attention in recent years owing to their unique magnetic properties, among many others. Magnetic nanoparticles can be controlled by an external magnetic field, signifying their ability to be site specific. The most popular approaches for the synthesis of magnetic nanoparticles are co-precipitation, thermal decomposition, hydrothermal, and polyol synthesis. The functionalization of magnetic nanoparticles is essential as it significantly increases their biocompatibility. The most utilized functionalization agents are comprised of polymers. The synthesis and functionalization of magnetic nanoparticles will be further explored in this review. The biomedical applications of magnetic nanoparticles investigated in this review are drug delivery, magnetic hyperthermia, and diagnosis. The diagnosis aspect focuses on the utilization of magnetic nanoparticles as contrast agents in magnetic resonance imaging. Clinical trials and toxicology studies relating to the application of magnetic nanoparticles for the diagnosis and treatment of cancer will also be discussed in this review.
    Keywords:  cancer; diagnosis; drug delivery; functionalization; magnetic hyperthermia; magnetic nanoparticles; synthesis; toxicity
    DOI:  https://doi.org/10.3390/polym13234146
  76. Front Nutr. 2021 ;8 747284
    The Ketogenic Effect of Medium-Chain Triacylglycerides.
    Ting-Yu Lin, Hung-Wen Liu, Tsung-Min Hung.
      Medium-chain triacylglycerides (MCTs) are dietary supplements that can induce ketosis without the need for a traditional ketogenic diet or prolonged fasting. They have the potential to marginally delay the progression of neurodegenerative diseases, such as Alzheimer's disease. However, there have been inconsistencies in reports of the MCT dose-response relationship, which may be due to differences in MCT composition, participant characteristics, and other factors that can influence ketone generation. To resolve these discrepancies, we reviewed studies that investigated the ketogenic effect of MCTs in healthy adults. Aside from the treatment dose, other factors that can influence the ketogenic response, such as accompanying meals, fasting duration, and caffeine intake, were assessed. Based on the available literature, four practical recommendations are made to optimize the ketogenic effect of MCTs and reduce unwanted side effects (primarily gastrointestinal discomfort and diarrhea). First, the starting dose should be either 5 g of octanoic acid [caprylic acid (C8); a component of MCTs] or 5 g of a combination of C8 and decanoic or capric acid (C10; another component of MCTs), and the dose should be progressively increased to 15-20 g of C8. Second, MCTs should be consumed after an overnight fast, without an accompanying meal if tolerable, or with a low-carbohydrate meal. Third, the addition of caffeine may slightly increase the ketogenic response. Fourth, emulsifying the MCTs might increase their ketogenic effect and alleviate side effects.
    Keywords:  Tricaprin – Captex® 1000 (PubChem CID: 69310); Tricaprylin – Captex® 8000 (PubChem CID: 10850); aging - old age - seniors; beta-hydroxybutyrate; cognition; decanoic acid (PubChem CID 2969); ketone bodies; octanoic acid (caprylic acid) (PubChem CID: 379)
    DOI:  https://doi.org/10.3389/fnut.2021.747284
  77. Chem Sci. 2021 Nov 10. 12(43): 14473-14483
    Aptamer-modified DNA tetrahedra-gated metal-organic framework nanoparticle carriers for enhanced chemotherapy or photodynamic therapy.
    Pu Zhang, Amit Fischer, Yu Ouyang, Jianbang Wang, Yang Sung Sohn, Rachel Nechushtai, Eli Pikarsky, Chunhai Fan, Itamar Willner.
      UiO-66 metal-organic framework nanoparticles (NMOFs) gated by aptamer-functionalized DNA tetrahedra provide superior biomarker-responsive hybrid nano-carriers for biomedical applications. Hybrid nano-carriers consisting of ATP-aptamer or VEGF-aptamer functionalized tetrahedra-gated NMOFs are loaded with the chemotherapeutic drug, doxorubicin (DOX). In the presence of ATP or VEGF, both abundant in cancer cells, the tetrahedra-gated NMOFs are unlocked to release the drug. Enhanced and selective permeation of the DOX-loaded ATP/VEGF-responsive tetrahedra-gated NMOFs into MDA-MB-231 breast cancer cells as compared to the reference ATP/VEGF-responsive duplex-gated NMOFs or non-malignant MCF-10A epithelial breast cells is observed. This results in enhanced and selective cytotoxicity of the tetrahedra-gated DOX-loaded NMOFs toward the malignant cells. Additional nano-carriers, consisting of photosensitizer Zn(ii) protoporphyrin IX (Zn(ii)-PPIX)-loaded VEGF-responsive tetrahedra-gated NMOFs, are introduced. The VEGF-triggered unlocking of the NMOFs yields separated G-quadruplex-VEGF aptamer complexes conjugated to the tetrahedra, resulting in the release of loaded Zn(ii)-PPIX. Association of the released Zn(ii)-PPIX to the G-quadruplex structures generates highly fluorescent supramolecular Zn(ii)-PPIX/G-quadruplex VEGF aptamer-tetrahedra structures. The efficient and selective generation of the highly fluorescent Zn(ii)-PPIX/G-quadruplex VEGF aptamer-tetrahedra nanostructures in malignant cells allows the light-induced photosensitized generation of reactive oxygen species (ROS), leading to high-efficacy PDT treatment of the malignant cells.
    DOI:  https://doi.org/10.1039/d1sc04229g
  78. Crit Rev Food Sci Nutr. 2021 Dec 08. 1-30
    Recent advances in industrial applications of seaweeds.
    Sevim Polat, Monica Trif, Alexandru Rusu, Vida Šimat, Martina Čagalj, Gonca Alak, Raciye Meral, Yesim Özogul, Abdurahman Polat, Fatih Özogul.
      Seaweeds have been generally utilized as food and alternative medicine in different countries. They are specifically used as a raw material for wine, cheese, soup, tea, noodles, etc. In addition, seaweeds are potentially good resources of protein, vitamins, minerals, carbohydrates, essential fatty acids and dietary fiber. The quality and quantity of biologically active compounds in seaweeds depend on season and harvesting period, seaweed geolocation as well as ecological factors. Seaweeds or their extracts have been studied as innovative sources for a variety of bioactive compounds such as polyunsaturated fatty acids, polyphenols, carrageenan, fucoidan, etc. These secondary metabolites have been shown to have antioxidant, antimicrobial, antiviral, anticancer, antidiabetic, anti-inflammatory, anti-aging, anti-obesity and anti-tumour properties. They have been used in pharmaceutical/medicine, and food industries since bioactive compounds from seaweeds are regarded as safe and natural. Therefore, this article provides up-to-date information on the applications of seaweed in different industries such as pharmaceutical, biomedical, cosmetics, dermatology and agriculture. Further studies on innovative extraction methods, safety issue and health-promoting properties should be reconsidered. Moreover, the details of the molecular mechanisms of seaweeds and their bioactive compounds for physiological activities are to be clearly elucidated.
    Keywords:  Bioactive compounds; functional properties; health benefits; industrial utilization; seaweeds
    DOI:  https://doi.org/10.1080/10408398.2021.2010646
  79. Biomater Sci. 2021 Dec 07.
    Blood-brain barrier penetrating liposomes with synergistic chemotherapy for glioblastoma treatment.
    Ying Zhang, Haijing Qu, Xiangdong Xue.
      Glioblastoma multiforme (GBM) is an aggressive and malignant brain tumor with high mortality. The current treatment strategies are still unsatisfactory for this devastating disease. Here, we developed a glucose-functionalized liposome (gLTP) that co-loads temozolomide (TMZ) and pro-apoptotic peptide (PAP) to achieve synergistic efficacy towards GBM. The gLTP can readily penetrate the blood-brain barrier via the glucose-GLUT1 pathway and release the TMZ and PAP in the cells. The PAP destroys the mitochondria and subsequently depletes ATP generation, making the GBM cells more sensitive to TMZ-mediated chemotherapy. gLTP exhibits the best anti-tumor effect on the subcutaneous brain tumor model compared to other treatments, including a single drug (TMZ or PAP) liposome and TMZ and PAP physical mixture. On the highly aggressive intracranial tumor model, gLTP can readily penetrate the BBB and efficiently deliver the drugs into the brain tumor, leading to striking improvements in total survival compared to the other treatments. This strategy potentially inspires new attempts to design more effective anti-GBM formulations.
    DOI:  https://doi.org/10.1039/d1bm01506k
  80. Int J Mol Sci. 2021 Nov 30. pii: 12952. [Epub ahead of print]22(23):
    The Effect of Organoselenium Compounds on Histone Deacetylase Inhibition and Their Potential for Cancer Therapy.
    Theolan Adimulam, Thilona Arumugam, Ashmika Foolchand, Terisha Ghazi, Anil A Chuturgoon.
      Genetic and epigenetic changes alter gene expression, contributing to cancer. Epigenetic changes in cancer arise from alterations in DNA and histone modifications that lead to tumour suppressor gene silencing and the activation of oncogenes. The acetylation status of histones and non-histone proteins are determined by the histone deacetylases and histone acetyltransferases that control gene transcription. Organoselenium compounds have become promising contenders in cancer therapeutics. Apart from their anti-oxidative effects, several natural and synthetic organoselenium compounds and metabolites act as histone deacetylase inhibitors, which influence the acetylation status of histones and non-histone proteins, altering gene transcription. This review aims to summarise the effect of natural and synthetic organoselenium compounds on histone and non-histone protein acetylation/deacetylation in cancer therapy.
    Keywords:  cancer; histone deacetylation; methylselenocysteine; organoselenium compounds; selenocysteine; selenomethionine
    DOI:  https://doi.org/10.3390/ijms222312952
  81. Dalton Trans. 2021 Dec 07.
    Photodynamic therapy with mitochondria-targeted biscyclometallated Ir(III) complexes. Multi-action mechanism and strong influence of the cyclometallating ligand.
    Elisenda Zafon, Igor Echevarría, Sílvia Barrabés, Blanca R Manzano, Félix A Jalón, Ana M Rodríguez, Anna Massaguer, Gustavo Espino.
      Photodynamic therapy is an alternative to classical chemotherapy due to its potential to reduce side effects by a controlled activation of a photosensitizer through local irradiation with light. The photosensitizer then interacts with oxygen and generates reactive oxygen species. Iridium biscyclometallated complexes are very promising photosensitizers due to their exceptional photophysical properties and their ability to target mitochondria. Four Ir(III) biscyclometallated complexes of formula [Ir(C^N)2(N^N')]Cl, where N^N' is a ligand containing a benzimidazolyl fragment, have been synthesized and characterized. The C^N ligands were 2-phenylpyridinate (ppy) and 2-(2,4-difluorophenyl)pyridinate (dfppy). The complexes exhibited high photostability. The electrochemical and photophysical properties were modulated by both the cyclometallating and the ancillary ligands. The dfppy derivatives yielded the highest emission energy values, quantum yields of phosphorescence and excited state lifetimes. All complexes generated 1O2 in aerated solutions upon irradiation. Biological studies revealed that these complexes have a moderate cytotoxicity in the dark against different human cancer cell lines: prostate (PC-3), colon (CACO-2) and melanoma (SK-MEL-28), and against non-malignant fibroblasts (CCD-18Co). However, derivatives with ppy ligands ([1a]Cl, [2a]Cl) yielded a relevant photodynamic activity upon light irradiation (450 nm, 24.1 J cm-2), with phototoxicity indexes (EC50,dark/EC50,light) of 20.8 and 17.3, respectively, achieved in PC-3 cells. Mechanistic studies showed that these complexes are taken up by the cells through endocytosis and preferentially accumulate in mitochondria. Upon photoactivation, the complexes induced mitochondrial membrane depolarization and DNA damage, thus triggering cell death, mainly by apoptosis. Complex [1a]Cl is also able to oxidize NADH. This mitochondria-targeted photodynamic mechanism greatly inhibited the reproductive capacity of cancer cells and provides a valuable alternative to traditional chemotherapy for the controlled treatment of cancer.
    DOI:  https://doi.org/10.1039/d1dt03080a
  82. Int J Mol Sci. 2021 Nov 25. pii: 12754. [Epub ahead of print]22(23):
    Transdermal Drug Delivery Systems and Their Use in Obesity Treatment.
    Zhiguo Li, Xuexun Fang, Dahai Yu.
      Transdermal drug delivery (TDD) has recently emerged as an effective alternative to oral and injection administration because of its less invasiveness, low rejection rate, and excellent ease of administration. TDD has made an important contribution to medical practice such as diabetes, hemorrhoids, arthritis, migraine, and schizophrenia treatment, but has yet to fully achieve its potential in the treatment of obesity. Obesity has reached epidemic proportions globally and posed a significant threat to human health. Various approaches, including oral and injection administration have widely been used in clinical setting for obesity treatment. However, these traditional options remain ineffective and inconvenient, and carry risks of adverse effects. Therefore, alternative and advanced drug delivery strategies with higher efficacy and less toxicity such as TDD are urgently required for obesity treatment. This review summarizes current TDD technology, and the main anti-obesity drug delivery system. This review also provides insights into various anti-obesity drugs under study with a focus on the recent developments of TDD system for enhanced anti-obesity drug delivery. Although most of presented studies stay in animal stage, the application of TDD in anti-obesity drugs would have a significant impact on bringing safe and effective therapies to obese patients in the future.
    Keywords:  drug delivery; obesity; transdermal drug delivery; treatment
    DOI:  https://doi.org/10.3390/ijms222312754
  83. Compr Rev Food Sci Food Saf. 2021 Dec 09.
    Tocopherols as antioxidants in lipid-based systems: The combination of chemical and physicochemical interactions determines their efficiency.
    Nathalie Barouh, Claire Bourlieu-Lacanal, Maria Cruz Figueroa-Espinoza, Erwann Durand, Pierre Villeneuve.
      Lipid oxidation is a major concern in the food, cosmetic, and pharmaceutical sectors. The degradation of unsaturated lipids affects the nutritional, physicochemical, and organoleptic properties of products and can lead to off-flavors and to the formation of potentially harmful oxidation compounds. To prevent or slow down lipid oxidation, different antioxidant additives are used alone or in combination to achieve the best possible efficiency with the minimum possible quantities. In manufactured products, that is, heterogeneous systems containing lipids as emulsions or bulk phase, the efficiency of an antioxidant is determined not only by its chemical reactivity, but also by its physical properties and its interaction with other compounds present in the products. The antioxidants most widely used on the industrial scale are probably tocopherols, either as natural extracts or pure synthetic molecules. Considerable research has been conducted on their antioxidant activity, but results regarding their efficiency are contradictory. Here, we review the known mechanisms behind the antioxidant activity of tocopherols and discuss the chemical and physical features that determine their efficacy. We first describe their chemical reactivity linked with the main factors that modulate it between efficient antioxidant capacity and potential prooxidant effects. We then describe their chemical interactions with other molecules (phenolic compounds, metals, vitamin C, carotenes, proteins, and phospholipids) that have potential additive, synergistic, or antagonist effects. Finally, we discuss other physical parameters that influence their activity in complex systems including their specific interactions with surfactants in emulsions and their behavior in the presence of association colloids in bulk oils.
    Keywords:  antioxidant; bulk oil; emulsion; prooxidant; tocopherols
    DOI:  https://doi.org/10.1111/1541-4337.12867
  84. ACS Appl Mater Interfaces. 2021 Dec 08.
    Intracellular Enzyme-Responsive Profluorophore and Prodrug Nanoparticles for Tumor-Specific Imaging and Precise Chemotherapy.
    Qing Pei, Shaojin Lu, Junli Zhou, Bowen Jiang, Chaonan Li, Zhigang Xie, Xiabin Jing.
      Responsive drug delivery systems possess great potential in disease diagnosis and treatment. Herein, we develop an activatable prodrug and fluorescence imaging material by engineering the endogenous NAD(P)H:quinone oxidoreductase-1 (NQO1) responsive linker. The as-prepared nanomaterials possess the NQO1-switched drug release and fluorescence enablement, which realizes the tumor-specific chemotherapy and imaging in living mice. The enzyme-sensitive prodrug nanoparticles exhibit selectively potent anticancer performance to NQO1-positive cancer and ignorable off-target toxicity. This work provides an alternative strategy for constructing smart prodrug nanoplatforms with precision, selectivity, and practicability for advanced cancer imaging and therapy.
    Keywords:  NQO1; enzyme; near-infrared imaging.; precise therapy; prodrug
    DOI:  https://doi.org/10.1021/acsami.1c19058
  85. Annu Int Conf IEEE Eng Med Biol Soc. 2021 Nov;2021 4230-4233
    A Multiscale Model to Identify Limiting Factors in Nanoparticle-Based miRNA Delivery for Tumor Inhibition.
    Prashant Dogra, Javier Ruiz Ramirez, Joseph D Butner, Maria J Pelaez, Vittorio Cristini, Zhihui Wang.
      MicroRNA-based gene therapy for cancer treatment via nanoparticles (NPs) requires navigation of multiple physical and physiological barriers in order to efficiently deliver the miRNAs to the cancer cell cytoplasm. We here present a mathematical model to investigate the variability associated with tumor, NP, and miRNA characteristics, and identify the limiting factors in miRNA delivery to tumors. Through global parameter analysis, the miRNA release rate from NPs and NP degradability were found to have the most significant impact on cytosolic accumulation of miRNAs. These NP properties can be fine-tuned in order to optimize the delivery system for enhancing the efficacy of miRNA-based therapy.Clinical Relevance-Understanding the effect of nanoparticle, tumor, and miRNA characteristics in governing the efficacy of miRNA-based cancer therapy will support its clinical translation.
    DOI:  https://doi.org/10.1109/EMBC46164.2021.9630862
  86. Curr Mol Med. 2021 Dec 05.
    Epigenetic Reprogramming and Landscape of Transcriptomic Interactions: Impending Therapeutic Interference of Triple-Negative Breast Cancer in Molecular Medicine.
    Suman Kumar Ray, Sukhes Mukherjee.
      The mechanisms governing the development and progression of cancers are believed to be the consequence of hereditary deformities and epigenetic modifications. Accordingly, epigenetics has become an incredible and progressively explored field of research to discover better prevention and therapy for neoplasia, especially triple-negative breast cancer (TNBC). It represents 15-20% of all invasive breast cancers and will, in general, have bellicose histological highlights and poor clinical outcomes. In the early phases of triple-negative breast carcinogenesis, epigenetic deregulation modifies chromatin structure and influences the plasticity of cells. It up-keeps the oncogenic reprogramming of malignant progenitor cells with the acquisition of unrestrained selfrenewal capacities. Genomic impulsiveness in TNBC prompts mutations, copy number variations, as well as genetic rearrangements, while epigenetic remodeling includes an amendment by DNA methylation, histone modification, and noncoding RNAs of gene expression profiles. It is currently evident that epigenetic mechanisms assume a significant part in the pathogenesis, maintenance, and therapeutic resistance of TNBC. Although TNBC is a heterogeneous malaise that is perplexing to describe and treat, the ongoing explosion of genetic and epigenetic research will help to expand these endeavors. Latest developments in transcriptome analysis have reformed our understanding of human diseases, including TNBC at the molecular medicine level. It is appealing to envision transcriptomic biomarkers to comprehend tumor behavior more readily regarding its cellular microenvironment. Understanding these essential biomarkers and molecular changes will propel our capability to treat TNBC adequately. This review will depict the different aspects of epigenetics and the landscape of transcriptomics in triple-negative breast carcinogenesis and their impending application for diagnosis, prognosis, and treatment decision with the view of molecular medicine.
    Keywords:  Epigenetic reprogramming; biomarkers; genomic impulsiveness; transcriptome; treatment decision; triple negative breast cancer
    DOI:  https://doi.org/10.2174/1566524021666211206092437
  87. Int J Mol Sci. 2021 Nov 24. pii: 12691. [Epub ahead of print]22(23):
    Phytosterols in Seaweeds: An Overview on Biosynthesis to Biomedical Applications.
    Soo-In Sohn, Periyasamy Rathinapriya, Sekaran Balaji, Devasahayam Jaya Balan, Thirukannamangai Krishnan Swetha, Ravindran Durgadevi, Selvaraj Alagulakshmi, Patchiappan Singaraj, Subramani Pandian.
      Seaweed extracts are considered effective therapeutic alternatives to synthetic anticancer, antioxidant, and antimicrobial agents, owing to their availability, low cost, greater efficacy, eco-friendliness, and non-toxic nature. Since the bioactive constituents of seaweed, in particular, phytosterols, possess plenty of medicinal benefits over other conventional pharmaceutical agents, they have been extensively evaluated for many years. Fortunately, recent advances in phytosterol-based research have begun to unravel the evidence concerning these important processes and to endow the field with the understanding and identification of the potential contributions of seaweed-steroidal molecules that can be used as chemotherapeutic drugs. Despite the myriad of research interests in phytosterols, there is an immense need to fill the void with an up-to-date literature survey elucidating their biosynthesis, pharmacological effects, and other biomedical applications. Hence, in the present review, we summarize studies dealing with several types of seaweed to provide a comprehensive overview of the structural determination of several phytosterol molecules, their properties, biosynthetic pathways, and mechanisms of action, along with their health benefits, which could significantly contribute to the development of novel drugs and functional foods.
    Keywords:  antimicrobials; antioxidants; functional foods; phytosterols; seaweeds; β-sitosterol
    DOI:  https://doi.org/10.3390/ijms222312691
  88. Curr Pharm Des. 2021 Dec 08.
    Stimuli-responsive Polymeric nanosystems for therapeutic applications.
    Mayank Handa, Ajit Singh, S J S Flora, Rahul Shukla.
       BACKGROUND: Recent past decades have reported emerging of polymeric nanoparticles as a promising technique for controlled and targeted drug delivery. As nanocarriers, they have high drug loading and delivery to the specific site or targeted cells with an advantage of no drug leakage within en route and unloading of a drug in a sustained fashion at the site. These stimuli-responsive systems are functionalized in dendrimers, metallic nanoparticles, polymeric nanoparticles, liposomal nanoparticles, quantum dots.
    PURPOSE OF REVIEW: The authors reviewed the potential of smart stimuli-responsive carriers for therapeutic application and their behavior in external or internal stimuli like pH, temperature, redox, light, and magnet. These stimuli-responsive drug delivery systems behave differently in In vitro and In vivo drug release patterns. Stimuli-responsive nanosystems include both hydrophilic and hydrophobic systems. This review highlights the recent development of the physical properties and their application in specific drug delivery.
    CONCLUSION: The stimuli (smart, intelligent, programmed) drug delivery systems provide site-specific drug delivery with potential therapy for cancer, neurodegenerative, lifestyle disorders. As development and innovation, the stimuli-responsive based nanocarriers are moving at a fast pace and huge demand for biocompatible and biodegradable responsive polymers for effective and safe delivery.
    Keywords:  Drug delivery; cancer; neurodegeneration; pH responsive; polymeric nanoparticles; temperature responsive
    DOI:  https://doi.org/10.2174/1381612827666211208150210
  89. CNS Neurol Disord Drug Targets. 2021 Dec 06.
    A Critical Analysis of Quercetin as the Attractive Target for the Treatment of Parkinson's Disease.
    Ozlem Bahadır Acıkara, Gökçe Şeker Karatoprak, Çiğdem Yücel, Esra Küpeli Akkol, Eduardo Sobarzo-Sánchez, Maryam Khayatkashani, Mohammad Amjad Kamal, Hamid Reza Khayat Kashani.
      Parkinson's disease (PD) is a multifaceted disorder with various factors that have been suggested to play a synergistic pathophysiological role, such as oxidative stress, autophagy, pro-inflammatory events, and neurotransmitter abnormalities. While it is crucial to discover new treatments in addition to preventing PD, recent studies have focused on determining whether nutraceuticals will exert neuroprotective actions and pharmacological functions in PD. Quercetin, a flavonol- type flavonoid, is found in many fruits and vegetables and has been recognized as a complementary therapy for PD. The neuroprotective effect of quercetin is directly associated with its antioxidant activity, in addition to stimulating cellular defense against oxidative stress. Other related mechanisms are activating sirtuins (SIRT1) and inducing autophagy, in addition to induction of Nrf2-ARE and paraoxonase 2 (PON2). Quercetin, whose neuroprotective activity has been demonstrated in many studies, unfortunately, has a disadvantage because of its poor water solubility, chemical instability, and low oral bioavailability. It has been reported that the disadvantages of quercetin have been eliminated in studies with nanocarriers loaded with quercetin. The role of nanotechnology and nanodelivery systems in reducing oxidative stress during PD provides an indisputable advantage. Accordingly, the aim of the present review is to shed light on the beneficial effects and underlying mechanisms of quercetin in neuroprotection. In addition, the contribution of nanodelivery systems to the neuroprotective effect of quercetin will be discussed.
    Keywords:  Parkinson's disease; Quercetin; antioxidant activity; nanodelivery systems; natural compound; neuroprotective
    DOI:  https://doi.org/10.2174/1871527320666211206122407
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