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In vivo conversion of ?-tocopherol to its quinone metabolite and quantification of intracellular concentrations of vitamin E and its metabolites in cells in vitro. (A) To assess the in vivo conversion of ?T to its quinone metabolite, stable deuterium-labelled ?-tocopherol (d 4-?T) was dosed orally to Sprague-Dawley male rats. Four hours after the final dose, plasma and tissues were collected for bioanalytical quantification of d 4-?T and d 4-?TQ by LC-MS/MS. While <1% of deuteriumlabeled ?T was detected as the quinone in the plasma fraction, varying levels of quinone conversion were observed in the tissues assessed, ranging from ~2% (liver) to ~50% (small intestine). (B) Vitamin E (?T) and its metabolites, vitamin E quinone (?TQ) and vitamin E hydroquinone (?THQ), were detected simultaneously in Q7 striatal cells under basal growth conditions or supplementation with ?T or ?TQ (10 ?M, 24 h). Results displayed are mean ? SD, n = 6; results from 1 experiment representative of 3 similar experiments. (C) Stacked bar graphs showing the mean proportions of ?T, ?TQ, and ?THQ quantified simultaneously under basal, ?T-or ?TQ-supplemented conditions using the succinate capping methodology described in Methods.
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Ferroptosis is a form of programmed cell death associated with inflammation, neurodegeneration, and ischemia. Vitamin E (alpha-tocopherol) has been reported to prevent ferroptosis, but the mechanism by which this occurs is controversial. To elucidate the biochemical mechanism of vitamin E activity, we systematically investigated the effects of its...
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Background:
Ferroptosis is a newly identified form of programmed cell death caused by iron-dependent lipid peroxidation. Our study was designed to determine the expression patterns and role of 15-lipoxygenase-1 (ALOX15) in subarachnoid hemorrhage (SAH) and to investigate whether cepharanthine (CEP) can inhibit ferroptosis by inhibiting ALOX15 in s...
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... It prevents the formation of lipid hydroperoxides produced from lipoxygenase; other antioxidants also participate in detoxifying lipids to avert ferroptosis. In cases of glutathione peroxidase 4 deficiency, vitamin E compensates for detoxification, as alpha-tocopherol hydroquinone has higher antioxidant properties than alpha-tocopherol [96]. In cases of neurodegeneration in COVID-19, the anti-ferroptosis effect of vitamin E at doses of 500 mg/kg may prevent neural damage [6,95]. ...
This review summarizes the scientific knowledge concerning the impact of vitamins, magnesium, and trace elements on various mechanisms contributing to the possible treatment and prevention of COVID-19, including its delayed consequences. A search was conducted in various databases, including PubMed, Scopus, ClinicalTrials.- gov, and Web of Science. Among the main mechanisms involved in the effects of the studied micronutrients, immune-boosting, antioxidant and anti-inflammatory effects were also highlighted. The analyzed clinical trials confirmed that supplementation with higher daily doses of some micronutrients can reduce SARS-CoV-2 viral load and hospitalization time. The potential role of most known vitamins in preventing, treating COVID-19, and rehabilitating patients was considered. The most promising agents for combating COVID-19 and its consequences might be the following vitamins: vitamin D, ascorbic acid, polyunsaturated fatty acids (PUFAs), and some B complex vitamins. Inorganic elements deserving attention include magnesium and trace elements, such as zinc, selenium, copper, and iron. Some associations were found between micronutrient deficiencies and COVID-19 severity in children, adults, and older people. Patients can obtain the aforementioned micronutrients from natural food sources or as supplements/- drugs in various dosage forms. The reviewed micronutrients might be considered adjunctive treatment strategies for COVID-19 patients.
... Colorectal cancer (CRC) is one of the leading causes of death among cancers worldwide [82]. IMCA, a benzopyran derivative, was discovered to control apoptosis through ferroptosis [83]. On the one hand, it has been found that IMCA can reduce GPX4 synthesis by downregulating SLC7A11. ...
Ferroptosis is a novel form of programmed death, dependent on iron ions and oxidative stress, with a predominant intracellular form of lipid peroxidation. In recent years, ferroptosis has gained more and more interest of people in the treatment mechanism of targeted tumors. mTOR, always overexpressed in the tumor, and controlling cell growth and metabolic activities, has an important role in both autophagy and ferroptosis. Interestingly, the selective types of autophay plays an important role in promoting ferroptosis, which is related to mTOR and some metabolic pathways (especially in iron and amino acids). In this paper, we list the main mechanisms linking ferroptosis with mTOR signaling pathway and further summarize the current compounds targeting ferroptosis in these ways. There are growing experimental evidences that targeting mTOR and ferroptosis may have effective impact in many tumors, and understanding the mechanisms linking mTOR to ferroptosis could provide a potential therapeutic approach for tumor treatment.
... The different forms of VE metabolites and derivatives also exhibit physiological activities, which are associated with various diseases and have attracted much attention recently 28 . VE hydroquinone TQH 2 metabolites, which are formed by the reduction of TQ, are now postulated to be as an endogenous regulators responsible for the cytoprotective activity associated with a programmed cell death associated with inflammation, neurodegeneration, and ischemia 29 . Further studies with improved study designs are required to better understand the complexity. ...
Vitamin E (VE) is a lipophilic vitamin, and Evans and Bishop demonstrated the existence of a hitherto unrecognized dietary factor essential for normal reproduction in rat. During 100 years after the discovery, α-tocopherol (α-Toc) has been the representative species in VE homologues, and both naturally occurring and synthetically prepared α-Toc have been widely used and studied. Although it is indicated by a single-word VE, research on VE involves various chemical species. It is important to understand the fine structure and accurate characteristics of individual VE species when using VE. Each VE sample has compositional and/or isomer issues, and furthermore, the usability greatly varies depending on the modified species of esterification. The VE industry involves many interdisciplinary fields. Improvements in formulation technology and confirmation of the novel biological activity of VE greatly owns its utility and opens up new applications. As the interim period between the start and end of the agenda for Sustainable Development Goals (SDGs), in this minireview, the recent trends and future guidelines of VE, especially α- Toc, in relation to the SDGs have been demonstrated.
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... The significant increase in the concentration of enzymatic antioxidants and the decrease in the concentration of MDA in the group treated with 50 mg/kg vitamin E are mainly due to its antioxidant properties [62] by suppressing the production of free radicals resulting from lipid peroxidation, especially Brussels radical ROO• which oxidizes unsaturated fatty acids (PUFAs) in cell membranes [63] through its removal of these radicals and the formation of alpha-tocopheroxyl radicals -α as an intermediate [64], which are reduced directly to tocopherol-α as a result of its interaction with vitamin C, which regenerates its antioxidant properties and contributes to maintaining its levels in tissues within the normal range [65]. The work of vitamin E as an antioxidant is through several important mechanisms, including its absorption of free radicals and its conversion to harmless vehicles, and its interaction with the oxidizing fat, which protects the cells from the harmful effects of the oxidation process [64], as well as its contribution to preventing the occurrence of a kind of programmed death known Ferroptosis through its effect on the Lipoxygenase -15 it was found that there is a final future for vitamin E called the α -Tocopherol Hydroquinone it works as an effective inhibitor of this enzyme [66]. ...
The current study aimed to evaluate the effect of propolis (aquatic, alcoholic) and vitamin E on the state of experimentally induced oxidative stress status in the male white rats. The animals were distributed into five groups: The first group (negative control) was given only water and food until the end of the study period. The second group (positive control) was dosed with H2O2 through drinking water at a concentration of 0.5% for 21 days. The third group was dosed with H2O2 at a concentration of 0.5% and treated with aqueous extract of propolis at a concentration of 4% for 21 days. The fourth group was dosed with H2O2 with drinking water at a concentration of 0.5% and treated with an alcoholic extract of propolis at a concentration of 1% for 21 days. The fifth group was dosed with H2O2with drinking water at a concentration of 0.5%. It was treated with vitamin E at a concentration of 50 mg/kg for 21 days. The results showed that the treatment with the water and alcoholic extract of propolis and vitamin E has led to a significant increase (p≤0.05) in the concentrations of the antioxidants enzyme (superoxide dismutase, catalase, glutathione peroxidase) and a moral decrease in the Malmondialdehyde compared to the negative control.
... The significant increase in the concentration of enzymatic antioxidants and the decrease in the concentration of MDA in the group treated with 50 mg/kg vitamin E are mainly due to its antioxidant properties [62] by suppressing the production of free radicals resulting from lipid peroxidation, especially Brussels radical ROO• which oxidizes unsaturated fatty acids (PUFAs) in cell membranes [63] through its removal of these radicals and the formation of alpha-tocopheroxyl radicals -α as an intermediate [64], which are reduced directly to tocopherol-α as a result of its interaction with vitamin C, which regenerates its antioxidant properties and contributes to maintaining its levels in tissues within the normal range [65]. The work of vitamin E as an antioxidant is through several important mechanisms, including its absorption of free radicals and its conversion to harmless vehicles, and its interaction with the oxidizing fat, which protects the cells from the harmful effects of the oxidation process [64], as well as its contribution to preventing the occurrence of a kind of programmed death known Ferroptosis through its effect on the Lipoxygenase -15 it was found that there is a final future for vitamin E called the α -Tocopherol Hydroquinone it works as an effective inhibitor of this enzyme [66]. ...
The current study aimed to evaluate the effect of propolis (aquatic, alcoholic) and vitamin E on the state of experimentally induced oxidative stress status in the male white rats. The animals were distributed into five groups: The first group (negative control) was given only water and food until the end of the study period. The second group (positive control) was dosed with H2O2 through drinking water at a concentration of 0.5% for 21 days. The third group was dosed with H2O2 at a concentration of 0.5% and treated with aqueous extract of propolis at a concentration of 4% for 21 days. The fourth group was dosed with H2O2 with drinking water at a concentration of 0.5% and treated with an alcoholic extract of propolis at a concentration of 1% for 21 days. The fifth group was dosed with H2O2with drinking water at a concentration of 0.5%. It was treated with vitamin E at a concentration of 50 mg/kg for 21 days. The results showed that the treatment with the water and alcoholic extract of propolis and vitamin E has led to a significant increase (p≤0.05) in the concentrations of the antioxidants enzyme (superoxide dismutase, catalase, glutathione peroxidase) and a moral decrease in the Malmondialdehyde compared to the negative control.
... To the best of our knowledge, no published data supports the contention that vitamin E may also function through a lncRNA-dependent pathway. However, alpha-tocopherol can prevent ferroptosis, a type of irondependent programmed cell death associated with blood and neurological diseases, ischemia-reperfusion injury, kidney injury, inflammation, and cancer [74]. Ferroptosis-related lncRNAs have been reported in a wide range of cancers, including hepatocellular carcinoma [75], head and neck squamous cell carcinoma [76], colorectal cancer [77], and stomach adenocarcinoma [78]. ...
A major revelation of genome-scale biological studies in the post-genomic era has been that two-thirds of human genes do not encode proteins. The majority of non-coding RNA transcripts in humans are long non-coding RNA (lncRNA) molecules, non-protein-coding regulatory transcripts with sizes greater than 500 nucleotides. LncRNAs are involved in nearly every aspect of cellular physiology, playing fundamental regulatory roles both in normal cells and in disease. As result, they are functionally linked to multiple human diseases, from cancer to autoimmune, inflammatory, and neurological disorders. Numerous human conditions and diseases stem from gene-environment interactions; in this regard, a wealth of reports demonstrate that the intake of specific and essential nutrients, including vitamins, shapes our transcriptome, with corresponding impacts on health. Vitamins command a vast array of biological activities, acting as coenzymes, antioxidants, hormones, and regulating cellular proliferation and coagulation. Emerging evidence suggests that vitamins and lncRNAs are interconnected through several regulatory axes. This type of interaction is expected, since lncRNA has been implicated in sensing the environment in eukaryotes, conceptually similar to riboswitches and other RNAs that act as molecular sensors in prokaryotes. In this review, we summarize the peer-reviewed literature to date that has reported specific functional linkages between vitamins and lncRNAs, with an emphasis on mammalian models and humans, while providing a brief overview of the source, metabolism, and function of the vitamins most frequently investigated within the context of lncRNA molecular mechanisms, and discussing the published research findings that document specific connections between vitamins and lncRNAs.
... Studies have shown that the inhibition of mitochondrial ferroptosis is a potential therapeutic target to combat ferroptosis-related cardiac disease. Some of the compounds that have demonstrated anti-ferroptosis properties by targeting mitochondria include vitamin E and several plant-derived extracts, such as EGCG from green tea extract (Fig. 2) [24][25][26][27][28]. ...
... These include the use of ferroptosis inhibitors such as ferrostatins, liproxstatins, or iron chelators to reduce iron-mediated oxidative stress and lipid peroxidation [35,47,78]. Additionally, compounds that enhance the antioxidant defense system, such as vitamin E, EGCG, ACSL4 inhibition, curcumin, sulforaphane, and Nrf2 activators, have shown potential in mitigating ferroptosis-induced heart damage [9,27,28,66,78,86]. Further research is needed to validate these therapeutic approaches and evaluate their clinical effectiveness. ...
Ferroptosis is a newly recognized type of regulated cell death that is characterized by the accumulation of iron and lipid peroxides in cells. Studies have shown that ferroptosis plays a significant role in the pathogenesis of various diseases, including cardiovascular diseases. In cardiovascular disease, ferroptosis is associated with ischemia–reperfusion injury, myocardial infarction, heart failure, and atherosclerosis. The molecular mechanisms underlying ferroptosis include the iron-dependent accumulation of lipid peroxidation products, glutathione depletion, and dysregulation of lipid metabolism, among others. This review aims to summarize the current knowledge of the molecular mechanisms of ferroptosis in cardiovascular disease and discuss the potential therapeutic strategies targeting ferroptosis as a treatment for cardiovascular disease.
... Agonists Erastin System Xc − (direct), VDAC2/3 (direct), p53 (enhances ferroptosis by activating p53) [23,98] RSL3 GPX4 (direct) [14] Sulfasalazine System Xc − (a novel, potent inhibitor of System Xc − ) [99] Interleukin-6 System Xc − (activates System Xc − via the JAK2/STAT3 pathway) [100] Sorafenib System Xc − (Inhibit System Xc − by upstream) [101] (R)-DCPP GSH (unknown), GPX4 (unknown) [102] Acetaminophen GSH (direct) [103] Cisplatin GSH (direct) [104] FINO2 GPX4 (indirect), Fe 2+ (direct) [105] Lipopolysaccharide SLC7A11 (unknown), GPX4 (unknown) [106] Legumain GPX4 (promotes chaperone-mediated autophagy of GPX4) [107] DPI2 GSH (unknown) [41] Dexamethasone GSH (indirect) [108] Siramesine FPN (unknown), FT (unknown) [109] Dihydroartemisinin FT (degradation of ferritin in an autophagy-independent manner) [110] FIN56 GPX4, CoQ10 (GPX4 degradation and squalene synthase activation inhibit coenzyme Q10 through acetyl-CoA carboxylase activity) [111] Manganese ROS (direct), Lipid peroxidation (direct) [112] Inhibitors Fer-1 ROS (direct) [113] SRS 11-92 ROS (direct) [114] Vitamin E ROS (direct) [115] Nuciferine ROS (direct) [116] Liproxstatin-1 ROS (direct) [117] Irisin Nrf2 (unknown), GPX4 (unknown) [118] Platycodin D GPX4 (unknown) regulates ferroptosis through GPX4 [119] Ginkgolide B GPX4 (inhibiting the ubiquitination of GPX4.) [120] Canagliflozin system Xc − (unknown), GPX4 (unknown), GSH (unknown) [121] BRD4770 System Xc − -GPX4 (unknown), FSP1-CoQ10 (unknown), GCH1-BH4 (unknown) [122] Quercetin ROS (unknown), GSH (unknown) [123] Hydropersulfides ROS (direct) [124] Ginsenoside Rg1 GPX4 (unknown), GSH (unknown), FSP1 (unknown) its antiferroptosis activity was dependent on FSP1 [125] MCTR1 Nrf2 (suppresses ferroptosis the Nrf2 signaling) [126] Entacapone Nrf2 (affects the p62-KEAP1-NRF2 pathway, thereby upregulatin NRF2) [127] Astragaloside-IV Nrf2 (inhibited miR-138-5p expression, subsequently increasing Sirt1/Nrf2 activity) [128] Forsythoside A Nrf2 (unknown), GPX4 (unknown) Nrf2/GPX4 axis plays a key role [129] Rosiglitazone ACSL4 (direct) [130] Pioglitazone ACSL4 (direct) [130] Troglitazone ACSL4 (direct) [130] nephropathy [159]. By promoting the KLF15/Nrf2 signaling pathway, sirtuin7 (Sirt7) attenuated renal ferroptosis, lipid peroxidation, and epithelial mesenchymal transition (EMT) in the hypertensive state, thereby attenuating renal fibrosis [160]. ...
Chronic kidney disease (CKD) has historically been a significant global health concern, profoundly impacting both life and well-being. In the process of CKD, with the gradual loss of renal function, the incidence of various life-threatening complications, such as cardiovascular diseases, cerebrovascular accident, infection and stroke, is also increasing rapidly. Unfortunately, existing treatments exhibit limited ability to halt the progression of kidney injury in CKD, emphasizing the urgent need to delve into the precise molecular mechanisms governing the occurrence and development of CKD while identifying novel therapeutic targets. Renal fibrosis, a typical pathological feature of CKD, plays a pivotal role in disrupting normal renal structures and the loss of renal function. Ferroptosis is a recently discovered iron-dependent form of cell death characterized by lipid peroxide accumulation. Ferroptosis has emerged as a potential key player in various diseases and the initiation of organ fibrosis. Substantial evidence suggests that ferroptosis may significantly contribute to the intricate interplay between CKD and its progression. This review comprehensively outlines the intricate relationship between CKD and ferroptosis in terms of iron metabolism and lipid peroxidation, and discusses the current landscape of pharmacological research on ferroptosis, shedding light on promising avenues for intervention. It further illustrates recent breakthroughs in ferroptosis-related regulatory mechanisms implicated in the progression of CKD, thereby providing new insights for CKD treatment.
... Recently, exosomes extracted from mesenchymal stem cells (MSCs) were found to exert cardioprotective Kang et al., 2019Fisher et al., 2013aFisher et al., 2013bZhang et al., 2021Fisher et al., 2013bZhang et al., 2021Ding et al., 2006Baba et al., 2018Fang et al., 2020Bai et al., 2020Shizukuda et al., 2005Feng et al., 2019Hinman et al., 2018Liu Y et al., 2015Jiang et al., 2022Liu et al., 2018 DFO: deferoxamine; HF: heart failure; LV: left ventricular; DIC: DOX-induced cardiomyopathy; DXZ: dexrazoxane; C3G: cyanidin-3glucoside; MIRI: myocardial ischemia-reperfusion injury; mTOR: mammalian target of rapamycin; Fer-1: ferrostatin-1; ROS: reactive oxygen species; SLC7A11: solute carrier family 7 member 11; GPX4: glutathione peroxidase 4; Lip-1: liproxstatin-1; I/R: ischemia/reperfusion; VDAC1: voltage-dependent anion channel 1; TEMPO: 2,2,6,6-tetramethylpiperidine-1-oxyl. effects by inhibiting ferroptosis (Song et al., 2021). ...
Cardiovascular diseases (CVDs) are a leading factor driving mortality worldwide. Iron, an essential trace mineral, is important in numerous biological processes, and its role in CVDs has raised broad discussion for decades. Iron-mediated cell death, namely ferroptosis, has attracted much attention due to its critical role in cardiomyocyte damage and CVDs. Furthermore, ferritinophagy is the upstream mechanism that induces ferroptosis, and is closely related to CVDs. This review aims to delineate the processes and mechanisms of ferroptosis and ferritinophagy, and the regulatory pathways and molecular targets involved in ferritinophagy, and to determine their roles in CVDs. Furthermore, we discuss the possibility of targeting ferritinophagy-induced ferroptosis modulators for treating CVDs. Collectively, this review offers some new insights into the pathology of CVDs and identifies possible therapeutic targets.
... Antioxidant natural products such as vitamins [138] can effectively suppress the ferroptosis and have a myocardial protection effect. For example, vitamin E can prevent atherosclerosis, and its potential mechanism may be involved in the prevention of ferroptosis by reducing the oxidation of LDL (Fig. 3, Table 1) [139][140][141][142]. ...
... Reduce the oxidation of LDL. [139][140][141][142] ...
The term cardiomyopathy refers to a group of heart diseases that cause severe heart failure over time. Cardiomyopathies have been proven to be associated with ferroptosis, a non-apoptotic form of cell death. It has been shown that some small molecule drugs and active ingredients of herbal medicine can regulate ferroptosis, thereby alleviating the development of cardiomyopathy. This article reviews recent discoveries about ferroptosis, its role in the pathogenesis of cardiomyopathy, and the therapeutic options for treating ferroptosis-associated cardiomyopathy. The article aims to provide insights into the basic mechanisms of ferroptosis and its treatment to prevent cardiomyopathy and related diseases.
