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Cancer Research Jul 2023Ferroptosis is an iron-dependent form of regulated cell death induced by the lethal overload of lipid peroxides in cellular membranes. In recent years, modulating...
UNLABELLED
Ferroptosis is an iron-dependent form of regulated cell death induced by the lethal overload of lipid peroxides in cellular membranes. In recent years, modulating ferroptosis has gained attention as a potential therapeutic approach for tumor suppression. In the current study, retinol saturase (RETSAT) was identified as a significant ferroptosis mediator using a publicly accessible CRISPR/Cas9 screening dataset. RETSAT depletion protected tumor cells from lipid peroxidation and subsequent cell death triggered by various ferroptosis inducers. Furthermore, exogenous supplementation with retinoids, including retinol (the substrate of RETSAT) and its derivatives retinal and retinoic acid, also suppressed ferroptosis, whereas the product of RETSAT, 13, 14-dihydroretinol, failed to do so. As effective radical-trapping antioxidant, retinoids protected the lipid membrane from autoxidation and subsequent fragmentation, thus terminating the cascade of ferroptosis. Pseudotargeted lipidomic analysis identified an association between retinoid regulation of ferroptosis and lipid metabolism. Retinoic acid, but not 13, 14-dihydroretinoic acid, interacted with its nuclear receptor and activated transcription of stearoyl-CoA desaturase, which introduces the first double bond into saturated fatty acid and thus catalyzes the generation of monounsaturated fatty acid, a known ferroptosis suppressor. Therefore, RETSAT promotes ferroptosis by transforming retinol to 13, 14-dihydroretinol, thereby turning a strong anti-ferroptosis regulator into a relatively weak one.
SIGNIFICANCE
Retinoids have ferroptosis-protective properties and can be metabolized by RETSAT to promote ferroptosis, suggesting the possibility of targeting retinoid metabolism in cancer as a treatment strategy to trigger ferroptosis.
Topics: Humans; Vitamin A; Retinoids; Tretinoin; Ferroptosis; Lipid Metabolism; Neoplasms
PubMed: 37184371
DOI: 10.1158/0008-5472.CAN-22-3977 -
Molecules (Basel, Switzerland) Mar 2021Vitamin A is a fat-soluble micronutrient essential for growth, immunity, and good vision. The preformed retinol is commonly found in food of animal origin whereas... (Review)
Review
Vitamin A is a fat-soluble micronutrient essential for growth, immunity, and good vision. The preformed retinol is commonly found in food of animal origin whereas provitamin A is derived from food of plant origin. This review summarises the current evidence from animal, human and cell-culture studies on the effects of vitamin A towards bone health. Animal studies showed that the negative effects of retinol on the skeleton were observed at higher concentrations, especially on the cortical bone. In humans, the direct relationship between vitamin A and poor bone health was more pronounced in individuals with obesity or vitamin D deficiency. Mechanistically, vitamin A differentially influenced the stages of osteogenesis by enhancing early osteoblastic differentiation and inhibiting bone mineralisation via retinoic acid receptor (RAR) signalling and modulation of osteocyte/osteoblast-related bone peptides. However, adequate vitamin A intake through food or supplements was shown to maintain healthy bones. Meanwhile, provitamin A (carotene and β-cryptoxanthin) may also protect bone. In vitro evidence showed that carotene and β-cryptoxanthin may serve as precursors for retinoids, specifically all-trans-retinoic acid, which serve as ligand for RARs to promote osteogenesis and suppressed nuclear factor-kappa B activation to inhibit the differentiation and maturation of osteoclasts. In conclusion, we suggest that both vitamin A and provitamin A may be potential bone-protecting agents, and more studies are warranted to support this hypothesis.
Topics: Animals; Bone and Bones; Humans; Obesity; Osteogenesis; Receptors, Retinoic Acid; Vitamin A; Vitamin D Deficiency
PubMed: 33801011
DOI: 10.3390/molecules26061757 -
Cleveland Clinic Journal of Medicine Feb 2022Vitamin A, like many things in life, should be consumed in appropriate amounts. Excessive intake of preformed vitamin A, such as that found in supplements and animal... (Review)
Review
Vitamin A, like many things in life, should be consumed in appropriate amounts. Excessive intake of preformed vitamin A, such as that found in supplements and animal sources (animal liver, fish liver oil, dairy, and eggs), is associated with multisystem effects that can include bone resorption and hypercalcemia. Hence, vitamin A toxicity should be explored in unexplained cases of parathyroid hormone-independent hypercalcemia. Serum retinol levels can be helpful in the diagnosis, but the results must be interpreted with caution since they do not always reflect total body levels. Treatment involves supportive care and withdrawal of vitamin A sources, especially preformed ones. Given the long half-life of retinol, normalization of serum levels can take several months.
Topics: Animals; Dietary Supplements; Humans; Hypercalcemia; Parathyroid Hormone; Vitamin A; Vitamin D; Vitamins
PubMed: 35105698
DOI: 10.3949/ccjm.89a.21056 -
The British Journal of Nutrition Dec 2021SARS-CoV2 infects respiratory epithelial cells via its cellular receptor angiotensin-converting enzyme 2, causing a viral pneumonia with pronounced inflammation... (Review)
Review
SARS-CoV2 infects respiratory epithelial cells via its cellular receptor angiotensin-converting enzyme 2, causing a viral pneumonia with pronounced inflammation resulting in significant damage to the lungs and other organ systems, including the kidneys, though symptoms and disease severity are quite variable depending on the intensity of exposure and presence of underlying conditions that may affect the immune response. The resulting disease, coronavirus disease 2019 (COVID-19), can cause multi-organ system dysfunction in patients requiring hospitalisation and intensive care treatment. Serious infections like COVID-19 often negatively affect nutritional status, and the resulting nutritional deficiencies may increase disease severity and impair recovery. One example is the viral infection measles, where associated vitamin A (VA) deficiency increases disease severity and appropriately timed supplementation during recovery reduces mortality and hastens recovery. VA may play a similar role in COVID-19. First, VA is important in maintaining innate and adaptive immunity to promote clearance of a primary infection as well as minimise risks from secondary infections. Second, VA plays a unique role in the respiratory tract, minimising damaging inflammation, supporting repair of respiratory epithelium and preventing fibrosis. Third, VA deficiency may develop during COVID-19 due to specific effects on lung and liver stores caused by inflammation and impaired kidney function, suggesting that supplements may be needed to restore adequate status. Fourth, VA supplementation may counteract adverse effects of SARS-CoV2 on the angiotensin system as well as minimises adverse effects of some COVID-19 therapies. Evaluating interactions of SARS-CoV2 infection with VA metabolism may thus provide improved COVID-19 therapy.
Topics: Adaptive Immunity; COVID-19; Humans; Immunity, Innate; Inflammation; RNA, Viral; Vitamin A
PubMed: 33468263
DOI: 10.1017/S0007114521000246 -
Blood Mar 2024
Topics: Child; Humans; Young Adult; Vitamin A; Graft vs Host Disease
PubMed: 38512262
DOI: 10.1182/blood.2024023828 -
Annual Review of Nutrition Sep 2020The history of vitamin A goes back over one hundred years, but our realization of its importance for the brain and cognition is much more recent. The brain is more... (Review)
Review
The history of vitamin A goes back over one hundred years, but our realization of its importance for the brain and cognition is much more recent. The brain is more efficient than other target tissues at converting vitamin A to retinoic acid (RA), which activates retinoic acid receptors (RARs). RARs regulate transcription, but their function in the cytoplasm to control nongenomic actions is also crucial. Controlled synthesis of RA is essential for regulating synaptic plasticity in regions of the brain involved in learning and memory, such as the hippocampus. Vitamin A deficiency results in a deterioration of these functions, and failure of RA signaling is perhaps associated with normal cognitive decline with age as well as with Alzheimer's disease. Further, several psychiatric and developmental disorders that disrupt cognition are also linked with vitamin A and point to their possible treatment with vitamin A or RA.
Topics: Animals; Cognition; Cognitive Dysfunction; Humans; Tretinoin; Vitamin A
PubMed: 32966186
DOI: 10.1146/annurev-nutr-122319-034227 -
Annual Review of Nutrition Oct 2021Vitamin A, acting through its metabolite, all--retinoic acid, is a potent transcriptional regulator affecting expression levels of hundreds of genes through retinoic... (Review)
Review
Vitamin A, acting through its metabolite, all--retinoic acid, is a potent transcriptional regulator affecting expression levels of hundreds of genes through retinoic acid response elements present within these genes. However, the literature is replete with claims that consider vitamin A to be an antioxidant vitamin, like vitamins C and E. This apparent contradiction in the understanding of how vitamin A acts mechanistically within the body is a major focus of this review. Vitamin E, which is generally understood to act as a lipophilic antioxidant protecting polyunsaturated fatty acids present in membranes, is often proposed to be a transcriptional regulator. The evaluation of this claim is another focus of the review. We conclude that vitamin A is an indirect antioxidant, whose indirect function is to transcriptionally regulate a number of genes involved in mediating the body's canonical antioxidant responses. Vitamin E, in addition to being a direct antioxidant, prevents the increase of peroxidized lipids that alter both metabolic pathways and gene expression profiles within tissues and cells. However, there is little compelling evidence that vitamin E has a direct transcriptional mechanism like that of vitamin A. Thus, we propose that the term antioxidant not be applied to vitamin A, and we discourage the use of the term transcriptional mediator when discussing vitamin E.
Topics: Antioxidants; Humans; Tretinoin; Vitamin A; Vitamin E; Vitamins
PubMed: 34115520
DOI: 10.1146/annurev-nutr-082018-124228 -
Frontiers in Endocrinology 2021Vitamin A (VA), which is stored in several forms in most tissues, is required to maintain metabolite homeostasis and other processes, including the visual cycle, energy... (Review)
Review
Vitamin A (VA), which is stored in several forms in most tissues, is required to maintain metabolite homeostasis and other processes, including the visual cycle, energy balance, epithelial cell integrity, and infection resistance. In recent years, VA molecules, also known as retinoids, have been extensively explored and used in the treatment of skin disorders and immune-related tumors. To date, several observational and interventional studies have explored the relationship between VA status and the pathogenesis of diabetes. In particular, VA micronutrients have been shown to regulate pancreatic development, β-cell function, pancreatic innate immune responses, and pancreatic stellate cells phenotypes through multiple mechanisms. However, there are still many problems to be proven or resolved. In this review, we summarize and discuss recent and available evidence on VA biological metabolism in the pancreas. Analysis of the effects of VA on metabolism in the pancreas will contribute to our understanding of the supportive physiological roles of VA in pancreas protection.
Topics: Animals; Glucose; Homeostasis; Humans; Lipid Metabolism; Pancreas; Vitamin A
PubMed: 33679618
DOI: 10.3389/fendo.2021.620941 -
Nutrients Jan 2021Animal studies as early as the 1920s suggested that vitamin A deficiency leads to squamous cell metaplasia in numerous epithelial tissues including the skin. However,... (Review)
Review
Animal studies as early as the 1920s suggested that vitamin A deficiency leads to squamous cell metaplasia in numerous epithelial tissues including the skin. However, humans usually die from vitamin A deficiency before cancers have time to develop. A recent long-term cohort study found that high dietary vitamin A reduced the risk of cutaneous squamous cell carcinoma (cSCC). cSCC is a form of nonmelanoma skin cancer that primarily occurs from excess exposure to ultraviolet light B (UVB). These cancers are expensive to treat and can lead to metastasis and death. Oral synthetic retinoids prevent the reoccurrence of cSCC, but side effects limit their use in chemoprevention. Several proteins involved in vitamin A metabolism and signaling are altered in cSCC, which may lead to retinoid resistance. The expression of vitamin A metabolism proteins may also have prognostic value. This article reviews what is known about natural and synthetic retinoids and their metabolism in cSCC.
Topics: Animals; Antineoplastic Agents; Biological Products; Carcinoma, Squamous Cell; Clinical Studies as Topic; Disease Management; Drug Evaluation, Preclinical; Drug Resistance; Humans; Metabolic Networks and Pathways; Retinoids; Skin Neoplasms; Treatment Outcome; Vitamin A
PubMed: 33466372
DOI: 10.3390/nu13010153 -
Journal of Molecular Endocrinology Oct 2022Vitamin A (retinol) is an essential, fat-soluble vitamin that plays critical roles in embryonic development, vision, immunity, and reproduction. Severe vitamin A... (Review)
Review
Vitamin A (retinol) is an essential, fat-soluble vitamin that plays critical roles in embryonic development, vision, immunity, and reproduction. Severe vitamin A deficiency results in profound embryonic dysgenesis, blindness, and infertility. The roles of bioactive vitamin A metabolites in regulating cell proliferation, cellular differentiation, and immune cell function form the basis of their clinical use in the treatment of dermatologic conditions and hematologic malignancies. Increasingly, vitamin A also has been recognized to play important roles in cardiometabolic health, including the regulation of adipogenesis, energy partitioning, and lipoprotein metabolism. While these roles are strongly supported by animal and in vitro studies, they remain poorly understood in human physiology and disease. This review briefly introduces vitamin A biology and presents the key preclinical data that have generated interest in vitamin A as a mediator of cardiometabolic health. The review also summarizes clinical studies performed to date, highlighting the limitations of many of these studies and the ongoing controversies in the field. Finally, additional perspectives are suggested that may help position vitamin A metabolism within a broader biological context and thereby contribute to enhanced understanding of vitamin A's complex roles in clinical cardiometabolic disease.
Topics: Adipogenesis; Animals; Cardiovascular Diseases; Female; Homeostasis; Humans; Pregnancy; Vitamin A; Vitamin A Deficiency
PubMed: 35900842
DOI: 10.1530/JME-22-0078