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1.
Int J Mol Sci ; 23(6)2022 Mar 10.
Article in English | MEDLINE | ID: covidwho-1742487

ABSTRACT

The published literature makes a very strong case that a wide range of disease morbidity associates with and may in part be due to epithelial barrier leak. An equally large body of published literature substantiates that a diverse group of micronutrients can reduce barrier leak across a wide array of epithelial tissue types, stemming from both cell culture as well as animal and human tissue models. Conversely, micronutrient deficiencies can exacerbate both barrier leak and morbidity. Focusing on zinc, Vitamin A and Vitamin D, this review shows that at concentrations above RDA levels but well below toxicity limits, these micronutrients can induce cell- and tissue-specific molecular-level changes in tight junctional complexes (and by other mechanisms) that reduce barrier leak. An opportunity now exists in critical care-but also medical prophylactic and therapeutic care in general-to consider implementation of select micronutrients at elevated dosages as adjuvant therapeutics in a variety of disease management. This consideration is particularly pointed amidst the COVID-19 pandemic.


Subject(s)
Inflammatory Bowel Diseases/metabolism , Intestinal Mucosa/metabolism , Micronutrients/metabolism , Vitamin A/metabolism , Vitamin D/metabolism , Zinc/metabolism , Animals , COVID-19/epidemiology , COVID-19/metabolism , COVID-19/virology , Humans , Micronutrients/pharmacology , Pandemics/prevention & control , SARS-CoV-2/physiology , Tight Junctions/drug effects , Tight Junctions/metabolism , Vitamin A/pharmacology , Vitamin D/pharmacology , Vitamins/metabolism , Vitamins/pharmacology , Zinc/pharmacology
2.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1867(2): 159070, 2022 02.
Article in English | MEDLINE | ID: covidwho-1596012

ABSTRACT

N-[4-hydroxyphenyl]retinamide, commonly known as fenretinide, a synthetic retinoid with pleiotropic benefits for human health, is currently utilized in clinical trials for cancer, cystic fibrosis, and COVID-19. However, fenretinide reduces plasma vitamin A levels by interacting with retinol-binding protein 4 (RBP4), which often results in reversible night blindness in patients. Cell culture and in vitro studies show that fenretinide binds and inhibits the activity of ß-carotene oxygenase 1 (BCO1), the enzyme responsible for endogenous vitamin A formation. Whether fenretinide inhibits vitamin A synthesis in mammals, however, remains unknown. The goal of this study was to determine if the inhibition of BCO1 by fenretinide affects vitamin A formation in mice fed ß-carotene. Our results show that wild-type mice treated with fenretinide for ten days had a reduction in tissue vitamin A stores accompanied by a two-fold increase in ß-carotene in plasma (P < 0.01) and several tissues. These effects persisted in RBP4-deficient mice and were independent of changes in intestinal ß-carotene absorption, suggesting that fenretinide inhibits vitamin A synthesis in mice. Using Bco1-/- and Bco2-/- mice we also show that fenretinide regulates intestinal carotenoid and vitamin E uptake by activating vitamin A signaling during short-term vitamin A deficiency. This study provides a deeper understanding of the impact of fenretinide on vitamin A, carotenoid, and vitamin E homeostasis, which is crucial for the pharmacological utilization of this retinoid.


Subject(s)
Fenretinide/pharmacology , Vitamin A/pharmacology , beta Carotene/metabolism , Animals , Body Weight/drug effects , Dioxygenases/metabolism , Intestinal Absorption/drug effects , Intestines/drug effects , Liver/drug effects , Liver/pathology , Mice, Inbred C57BL , Models, Biological , Retinol-Binding Proteins, Plasma/deficiency , Retinol-Binding Proteins, Plasma/metabolism , Vitamin A/blood , Vitamin A Deficiency/blood , Vitamin A Deficiency/pathology , Vitamin E/blood , Vitamin E/metabolism , beta Carotene/blood
3.
Aging (Albany NY) ; 13(12): 15785-15800, 2021 06 27.
Article in English | MEDLINE | ID: covidwho-1285613

ABSTRACT

Recent reports indicate that patients with hepatocholangiocarcinoma (CHOL) have a higher morbidity and mortality rate for coronavirus disease (COVID-19). Anti-CHOL/COVID-19 medicines are inexistent. Vitamin A (VA) refers to a potent nutrient with anti-cytotoxic and anti-inflammatory actions. Therefore, this study aimed to determine the potential functions and molecular mechanisms of VA as a potential treatment for patients with both CHOL and COVID-19 (CHOL/COVID-19). The transcriptome data of CHOL patients were obtained from the Cancer Genome Analysis database. Furthermore, the network pharmacology approach and bioinformatics analysis were used to identify and reveal the molecular functions, therapeutic biotargets, and signaling of VA against CHOL/COVID-19. First, clinical findings identified the medical characteristics of CHOL patients with COVID-19, such as susceptibility gene, prognosis, recurrence, and survival rate. Anti-viral and anti-inflammatory pathways, and immunopotentiation were found as potential targets of VA against CHOL/COVID-19. These findings illustrated that VA may contribute to the clinical management of CHOL/COVID-19 achieved by induction of cell repair, suppression of oxidative stress and inflammatory reaction, and amelioration of immunity. Nine vital therapeutic targets (BRD2, NOS2, GPT, MAPK1, CXCR3, ICAM1, CDK4, CAT, and TMPRSS13) of VA against CHOL/COVID-19 were identified. For the first time, the potential pharmacological biotargets, function, and mechanism of action of VA in CHOL/COVID-19 were elucidated.


Subject(s)
COVID-19/drug therapy , Immunity/drug effects , SARS-CoV-2/drug effects , Vitamin A/pharmacology , Anti-Inflammatory Agents/pharmacology , Antiviral Agents/pharmacology , COVID-19/virology , Carcinoma, Hepatocellular/genetics , Cholangiocarcinoma/genetics , Computational Biology , Female , Humans , Inflammation/drug therapy , Inflammation/etiology , Liver Neoplasms/genetics , Male , Molecular Docking Simulation , Proportional Hazards Models , Signal Transduction/drug effects
4.
Drug Dev Res ; 82(7): 883-895, 2021 11.
Article in English | MEDLINE | ID: covidwho-1168846

ABSTRACT

The current pandemic forced us to introspect and revisit our armamentarium of medicinal agents which could be life-saving in emergency situations. Oxygen diffusion-enhancing compounds represent one such class of potential therapeutic agents, particularly in ischemic conditions. As rewarding as the name suggests, these agents, represented by the most advanced and first-in-class molecule, trans-sodium crocetinate (TSC), are the subject of intense clinical investigation, including Phase 1b/2b clinical trials for COVID-19. Being a successor of a natural product, crocetin, TSC is being investigated for various cancers as a radiosensitizer owing to its oxygen diffusion enhancement capability. The unique properties of TSC make it a promising therapeutic agent for various ailments such as hemorrhagic shock, stroke, heart attack, among others. The present review outlines various (bio)synthetic strategies, pharmacological aspects, clinical overview and potential therapeutic benefits of crocetin and related compounds including TSC. The recent literature focusing on the delivery aspects of these compounds is covered as well to paint the complete picture to the curious reader. Given the potential TSC holds as a first-in-class agent, small- and/or macromolecular therapeutics based on the core concept of improved oxygen diffusion from blood to the surrounding tissues where it is needed the most, will be developed in future and satisfy the unmet medical need for many diseases and disorders.


Subject(s)
COVID-19/therapy , Carotenoids/therapeutic use , Oxygen Consumption/drug effects , Oxygen Inhalation Therapy/methods , Vitamin A/analogs & derivatives , Animals , Carotenoids/chemical synthesis , Carotenoids/pharmacology , Clinical Trials, Phase I as Topic , Clinical Trials, Phase II as Topic , Diffusion , Humans , Vitamin A/chemical synthesis , Vitamin A/pharmacology , Vitamin A/therapeutic use
5.
Med Hypotheses ; 144: 110250, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-753092

ABSTRACT

This study presents two new concepts and definitions to the medical literature. One of those is "endogenous retinoic acid theory" and the other "retinoic acid depletion syndrome". A new classification will be provided for the immune system: "retinoic acid-dependent component" and "retinoic acid non-dependent component". If this theory is verified, all the diseases where the retinoic acid metabolism is defective and retinoic acid levels are low will be identified and new approaches will be developed fortreating such diseases. When the need for retinoic acids increases, such as acute infection, high fever, severe catabolic process, or chronic antigenic stimulation, cytochrome oxidase enzymes are inhibited by drugs or internal mechanisms. Metabolism and excretion of retinoic acids stored in the liver are prevented. In this way, retinoic acid levels in the blood are raised to therapeutic levels. This is called "Endogenous Retinoic Acid Theory". Retinoic acids also manage their metabolism through feedback mechanisms. Despite compensatory mechanisms, causes such as high fever, serious catabolic process and excessively large viral genome (SARS-CoV-2), excessive use of RIG-I and Type I interferon synthesis pathway using retinoic acid causes emptying of retinoic acid stores. As a result, the RIG-I pathway becomes ineffective, Type I IFN synthesis stops, and the congenital immune system collapses. Then the immune mechanism passes to TLR3, TLR7, TLR8, TLR9, MDA5 and UPS pathways in the monocyte, macrophage, neutrophil and dendritic cells of the adaptive immune defense system that do not require retinoic acid. This leads to excessive TNFα and cytokine discharge from the pathway. With the depletion of retinoic acid stores as a result of this overuse, the immune defense mechanism switches from the congenital immune system to the adaptive immune system, where retinoic acids cannot be used. As a result of this depletion of retinoic acids, the shift of the immune system to the NFκB arm, which causes excessive cytokine release, is called "retinoic acid depletion syndrome". COVID-19 and previously defined sepsis, SIRS and ARDS are each retinoic acid depletion syndrome. We claim that retinoic acid metabolism is defective in most inflammatory diseases, particularly COVID-19 (cytokine storm) sepsis, SIRS and ARDS. Finding a solution to this mechanism will bring a new perspective and treatment approach to such diseases.


Subject(s)
COVID-19/immunology , COVID-19/therapy , Tretinoin/metabolism , Autoimmunity , COVID-19/metabolism , Carotenoids/metabolism , DEAD Box Protein 58/immunology , Humans , Immune System , Interferon Type I/metabolism , Interferons/metabolism , Liver/metabolism , Models, Theoretical , Nervous System/metabolism , Receptors, Immunologic , Syndrome , Viral Load , Vitamin A/pharmacology , Vitamin A Deficiency/metabolism , Zinc/metabolism
6.
Aging Clin Exp Res ; 32(10): 2115-2131, 2020 Oct.
Article in English | MEDLINE | ID: covidwho-738008

ABSTRACT

BACKGROUND: In December 2019, a novel human-infecting coronavirus, SARS-CoV-2, had emerged. The WHO has classified the epidemic as a "public health emergency of international concern". A dramatic situation has unfolded with thousands of deaths, occurring mainly in the aged and very ill people. Epidemiological studies suggest that immune system function is impaired in elderly individuals and these subjects often present a deficiency in fat-soluble and hydrosoluble vitamins. METHODS: We searched for reviews describing the characteristics of autoimmune diseases and the available therapeutic protocols for their treatment. We set them as a paradigm with the purpose to uncover common pathogenetic mechanisms between these pathological conditions and SARS-CoV-2 infection. Furthermore, we searched for studies describing the possible efficacy of vitamins A, D, E, and C in improving the immune system function. RESULTS: SARS-CoV-2 infection induces strong immune system dysfunction characterized by the development of an intense proinflammatory response in the host, and the development of a life-threatening condition defined as cytokine release syndrome (CRS). This leads to acute respiratory syndrome (ARDS), mainly in aged people. High mortality and lethality rates have been observed in elderly subjects with CoV-2-related infection. CONCLUSIONS: Vitamins may shift the proinflammatory Th17-mediated immune response arising in autoimmune diseases towards a T-cell regulatory phenotype. This review discusses the possible activity of vitamins A, D, E, and C in restoring normal antiviral immune system function and the potential therapeutic role of these micronutrients as part of a therapeutic strategy against SARS-CoV-2 infection.


Subject(s)
Betacoronavirus/immunology , Betacoronavirus/pathogenicity , Coronavirus Infections/diet therapy , Coronavirus Infections/prevention & control , Cytokines/immunology , Pandemics/prevention & control , Pneumonia, Viral/diet therapy , Pneumonia, Viral/prevention & control , Vitamins/immunology , Vitamins/therapeutic use , Aged , Ascorbic Acid/immunology , Ascorbic Acid/pharmacology , Ascorbic Acid/therapeutic use , Betacoronavirus/drug effects , COVID-19 , Coronavirus Infections/immunology , Coronavirus Infections/virology , Humans , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , SARS-CoV-2 , Th17 Cells/drug effects , Th17 Cells/immunology , Vitamin A/immunology , Vitamin A/pharmacology , Vitamin A/therapeutic use , Vitamin D/immunology , Vitamin D/pharmacology , Vitamin D/therapeutic use , Vitamin E/immunology , Vitamin E/pharmacology , Vitamin E/therapeutic use , Vitamins/pharmacology
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