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The EMBO Journal Jan 2023The cellular activation of the NLRP3 inflammasome is spatiotemporally orchestrated by various organelles, but whether lysosomes contribute to this process remains...
The cellular activation of the NLRP3 inflammasome is spatiotemporally orchestrated by various organelles, but whether lysosomes contribute to this process remains unclear. Here, we show the vital role of the lysosomal membrane-tethered Ragulator complex in NLRP3 inflammasome activation. Deficiency of Lamtor1, an essential component of the Ragulator complex, abrogated NLRP3 inflammasome activation in murine macrophages and human monocytic cells. Myeloid-specific Lamtor1-deficient mice showed marked attenuation of NLRP3-associated inflammatory disease severity, including LPS-induced sepsis, alum-induced peritonitis, and monosodium urate (MSU)-induced arthritis. Mechanistically, Lamtor1 interacted with both NLRP3 and histone deacetylase 6 (HDAC6). HDAC6 enhances the interaction between Lamtor1 and NLRP3, resulting in NLRP3 inflammasome activation. DL-all-rac-α-tocopherol, a synthetic form of vitamin E, inhibited the Lamtor1-HDAC6 interaction, resulting in diminished NLRP3 inflammasome activation. Further, DL-all-rac-α-tocopherol alleviated acute gouty arthritis and MSU-induced peritonitis. These results provide novel insights into the role of lysosomes in the activation of NLRP3 inflammasomes by the Ragulator complex.
Topics: Mice; Humans; Animals; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Inflammation; Histone Deacetylase 6; alpha-Tocopherol; Uric Acid; Peritonitis; Lysosomes; Mice, Inbred C57BL
PubMed: 36444797
DOI: 10.15252/embj.2022111389 -
Free Radical Biology & Medicine Nov 2021α-Tocopherol transfer protein (α-TTP) is so far the only known protein that specifically recognizes α-tocopherol (α-Toc), the most abundant and most biologically... (Review)
Review
α-Tocopherol transfer protein (α-TTP) is so far the only known protein that specifically recognizes α-tocopherol (α-Toc), the most abundant and most biologically active form of vitamin E, in higher animals. α-TTP is highly expressed in the liver where α-TTP selects α-Toc among vitamin E forms taken up via plasma lipoproteins and promotes its secretion to circulating lipoproteins. Thus, α-TTP is a major determinant of plasma α-Toc concentrations. Familial vitamin E deficiency, also called Ataxia with vitamin E deficiency, is caused by mutations in the α-TTP gene. More than 20 different mutations have been found in the α-TTP gene worldwide, among which some missense mutations provided valuable clues to elucidate the molecular mechanisms underlying intracellular α-Toc transport. In hepatocytes, α-TTP catalyzes the vectorial transport of α-Toc from the endocytotic compartment to the plasma membrane (PM) by targeting phosphatidylinositol phosphates (PIPs) such as PI(4,5)P. By binding PIPs at the PM, α-TTP opens the lid covering the hydrophobic pocket, thus facilitating the release of bound α-Toc to the PM.
Topics: Animals; Carrier Proteins; Vitamin E; Vitamin E Deficiency; alpha-Tocopherol
PubMed: 34563650
DOI: 10.1016/j.freeradbiomed.2021.09.021 -
Nutrients Jul 2023The relationship between vitamin E intake or circulating α-tocopherol and various health outcomes is still debatable and uncertain. We conducted an umbrella review to... (Review)
Review
The relationship between vitamin E intake or circulating α-tocopherol and various health outcomes is still debatable and uncertain. We conducted an umbrella review to identify the relationships between vitamin E intake or circulating tocopherol and health outcomes by merging and recalculating earlier meta-analyses. The connections that were found to be statistically significant were then classified into different evidence levels based on values, between-study heterogeneity, prediction intervals, and small study effects. We finally included 32 eligible meta-analyses with four vitamin E sources and 64 unique health outcomes. Only the association between circulating α-tocopherol and wheeze or asthma in children was substantiated by consistent evidence. Suggestive evidence was suggested for seven results on endothelial function (supplemental vitamin E): serum C-reactive protein (CRP) concentrations (supplemental vitamin E), cervical cancer (dietary vitamin E), esophageal cancer (dietary vitamin E), cervical intraepithelial neoplasia (CIN, dietary vitamin E), pancreatic cancer (total vitamin E intake), and colorectal cancer (circulating α-tocopherol levels); all of these showed a protective effect consistent with the vitamin E source. In conclusion, our work has indicated that vitamin E is protective for several particular health outcomes. Further prospective studies are required when other factors that may contribute to bias are considered.
Topics: Child; Humans; Vitamin E; alpha-Tocopherol; Antioxidants; Tocopherols; Diet
PubMed: 37571239
DOI: 10.3390/nu15153301 -
Current Opinion in Plant Biology Aug 2023Among the eight forms of vitamin E, only tocopherols are essential compounds that are distributed throughout the entire plant kingdom, with α-tocopherol being the most... (Review)
Review
Among the eight forms of vitamin E, only tocopherols are essential compounds that are distributed throughout the entire plant kingdom, with α-tocopherol being the most predominant form in photosynthetic tissues. At the cellular level, α-tocopherol is of special relevance inside the chloroplast, where it eliminates singlet oxygen and modulates lipid peroxidation. This is of utmost relevance since tocopherols are the only antioxidants that counteract lipid peroxidation. Moreover, at the whole-plant level, α-tocopherol appears to modulate several physiological processes from germination to senescence. The antioxidant role of α-tocopherol at the cellular level can have profound effects at the whole-plant level, including the modulation of physiological processes that are apparently not related to redox processes and could be considered non-antioxidant functions. Here, we discuss whether non-antioxidant functions of α-tocopherol at the whole-plant level are mediated by its antioxidant role in chloroplasts and the regulation of redox processes at the cellular level.
Topics: Antioxidants; alpha-Tocopherol; Vitamin E; Tocopherols; Chloroplasts
PubMed: 37311290
DOI: 10.1016/j.pbi.2023.102400 -
Molecules (Basel, Switzerland) Apr 2023Microglia, the resident macrophage-like population in the central nervous system, play a crucial role in the pathogenesis of many neurodegenerative disorders by...
Microglia, the resident macrophage-like population in the central nervous system, play a crucial role in the pathogenesis of many neurodegenerative disorders by triggering an inflammatory response that leads to neuronal death. Neuroprotective compounds to treat or prevent neurodegenerative diseases are a new field of study in modern medicine. Microglia are activated in response to inflammatory stimuli. The pathogenesis of various neurodegenerative diseases is closely related to the constant activation of microglia due to their fundamental role as a mediator of inflammation in the brain environment. α-Tocopherol, also known as vitamin E, is reported to possess potent neuroprotective effects. The goal of this study was to investigate the biological effects of vitamin E on BV2 microglial cells, as a possible neuroprotective and anti-inflammatory agent, following stimulation with lipopolysaccharide (LPS). The results showed that the pre-incubation of microglia with α-tocopherol can guarantee neuroprotective effects during microglial activation induced by LPS. α-Tocopherol preserved the branched morphology typical of microglia in a physiological state. It also reduced the migratory capacity; the production of pro-inflammatory and anti-inflammatory cytokines such as TNF-α and IL-10; and the activation of receptors such as TRL4 and CD40, which modulate the PI3K-Akt signaling pathway. The results of this study require further insights and research, but they present new scenarios for the application of vitamin E as an antioxidant for the purpose of greater neuroprotection in vivo for the prevention of possible neurodegenerative diseases.
Topics: Humans; Lipopolysaccharides; Microglia; alpha-Tocopherol; Neuroprotective Agents; Phosphatidylinositol 3-Kinases; Macrophages; Anti-Inflammatory Agents; Vitamin E; Neurodegenerative Diseases; Nitric Oxide; NF-kappa B
PubMed: 37110573
DOI: 10.3390/molecules28083340 -
Chemico-biological Interactions Oct 2021Acetylcholinesterase (AChE) is reversibly inhibited by α-tocopherol (α-T). Steady state kinetic analysis shows that α-T is a mixed slow-binding inhibitor of type A of...
Acetylcholinesterase (AChE) is reversibly inhibited by α-tocopherol (α-T). Steady state kinetic analysis shows that α-T is a mixed slow-binding inhibitor of type A of human enzyme (K = 0.49 μM; K = 1.6 μM) with a residence time of 2 min on target. Molecular dynamics (MD) simulations support this mechanism, and indicate that α-T first forms multiple non-specific interactions with AChE surface near the gorge entrance, then binds to the peripheral side with alkylene chain slowly sliding down the gorge, inducing no significant conformational change. α-T slightly modulates the progressive inhibition of AChE by the cyclic organophosphorus, cresyl saligenylphosphate, accelerating the fast pseudo-first order process of phosphorylation. A moderate accelerating effect of α-T on phosphorylation by paraoxon was also observed after pre-incubation of AChE in the presence of α-T. This accelerating effect of α-T on ex vivo paraoxon-induced diaphragm muscle weakness was also observed. The effect of α-T on AChE phosphylation was interpreted in light of molecular modeling results. From all results it is clear that α-T does not protect AChE against phosphylation by organophosphorus.
Topics: Acetylcholinesterase; Cholinesterase Inhibitors; Humans; Kinetics; Models, Molecular; Phosphorylation; Protein Conformation; alpha-Tocopherol
PubMed: 34506764
DOI: 10.1016/j.cbi.2021.109646 -
Scientific Reports May 2024The causal association between vitamin E status and osteoarthritis (OA) remains controversial in previous epidemiological studies. We employed a Mendelian randomization...
The causal association between vitamin E status and osteoarthritis (OA) remains controversial in previous epidemiological studies. We employed a Mendelian randomization (MR) analysis to explore the causal relationship between circulating alpha-tocopherol levels (main forms of vitamin E in our body) and OA. The instrumental variables (IVs) of circulating alpha-tocopherol levels were obtained from a Genome-wide association study (GWAS) dataset of 7781 individuals of European descent. The outcome of OA was derived from the UK biobank. Two-sample MR analysis was used to estimate the causal relationship between circulating alpha-tocopherol levels and OA. The inverse-variance weighted (IVW) method was the primary analysis in this analysis. We used the MR-Egger method to determine horizontal pleiotropic in this work. The heterogeneity effect of instrumental IVs was detected by MR-Egger and IVW analyses. Sensitivity analysis was performed by removing single nucleotide polymorphism (SNP) one by one. Three SNPs (rs964184, rs2108622, and rs11057830) (P < 5E-8) strongly associated with circulating alpha-tocopherol levels were used in this analysis. The IVW-random effect indicated no causal relationship between circulating alpha-tocopherol levels and clinically diagnosed OA (OR = 0.880, 95% CI 0.626, 1.236, P = 0.461). Similarly, IVW analysis showed no causal association between circulating alpha-tocopherol levels and self-reported OA (OR = 0.980, 95% CI 0.954, 1.006, P = 0.139). Other methods of MR analyses and sensitivity analyses revealed consistent findings. MR-Egger and IVW methods indicated no significant heterogeneity between IVs. The MR-Egger intercept showed no horizontal pleiotropic. The results of this linear Mendelian randomization study indicate no causal association between genetically predicted alpha-tocopherol levels and the progression of OA. Alpha-tocopherol may not provide beneficial and more favorable outcomes for the progression of OA. Further MR analysis based on updated GWASs with more IVs is required to verify the results of our study.
Topics: Humans; alpha-Tocopherol; Mendelian Randomization Analysis; Osteoarthritis; Polymorphism, Single Nucleotide; Genome-Wide Association Study; Male; Female; Genetic Predisposition to Disease
PubMed: 38698019
DOI: 10.1038/s41598-024-60676-5 -
Free Radical Biology & Medicine Dec 2021α-Tocopherol (α-T) is a required dietary nutrient for humans and thus is a vitamin. This narrative review focuses on vitamin E structures, functions, biological... (Review)
Review
α-Tocopherol (α-T) is a required dietary nutrient for humans and thus is a vitamin. This narrative review focuses on vitamin E structures, functions, biological determinants and its deficiency symptoms in humans. The mechanisms for the preferential α-T tissue enrichment in the human body include the α-T transfer protein (TTPA) and the preferential metabolism of non-α-T forms. Potential new α-T biomarkers, pharmacokinetic data, and whether there are better approaches to evaluate and set the α-T dietary requirement are discussed. Finally, the possible role of α-T supplements in delay of chronic diseases and the evaluation of vitamin E safety are considered.
Topics: Diet; Dietary Supplements; Humans; Vitamin E; Vitamin E Deficiency; alpha-Tocopherol
PubMed: 34699937
DOI: 10.1016/j.freeradbiomed.2021.10.028 -
International Journal For Vitamin and... Jan 2021Contrast-induced nephropathy (CIN) is a relevant cause of acute renal dysfunction and is associated with an increased morbidity and mortality. Purpose: Verify the... (Meta-Analysis)
Meta-Analysis
Contrast-induced nephropathy (CIN) is a relevant cause of acute renal dysfunction and is associated with an increased morbidity and mortality. Purpose: Verify the effect of α-tocopherol pre-treatment on CIN prevention in subjects with chronic kidney disease. A Medline/Embase and clinicaltrials.gov were searched up to May 1st, 2017. Randomized controlled trials recruiting patients undergoing diagnostic or therapeutic radiocontrast infusion comparing the effect of either oral or i.v. multiple administration of pharmacological dose of α-tocopherol in preventing CIN versus placebo were included. A random-effects model, calculating Mantel-Haenszel odds ratio with 95% confidence interval, was applied to study the effect of α-tocopherol on CIN occurrence. Funnel plot analysis was used to assess publication bias, while agreement within studies was measured by the I index and tested with the Q-Cochran test. Out of 242 studies, 4 trials were selected. CIN incidence resulted significantly lower in α-tocopherol compared to placebo group (5.8% vs. 15.4%, MH-OR [95% C.I.] 0.34 [0.19 - 0.59]). Alpha-tocopherol treatment was associated with both a tendential higher eGFR (mean difference 2.19 [95% C.I. -0.41; 4.79] mL/min) and lower creatinine level (mean difference -0.06 [95% C.I. -0.21; 0.09] mg/dl) compared to placebo. No relevant publication bias (p = 0.48) and heterogeneity (I = 0%; χ = 1.01, df = 3 [p = 0.80], I = 0%) were evident. Alpha-tocopherol pre-treatment is associated with reduction of incidence of CIN. Its administration deserves to be further explored as a simple and inexpensive tool for CIN prevention.
Topics: Contrast Media; Humans; Kidney Diseases; Randomized Controlled Trials as Topic; alpha-Tocopherol
PubMed: 31017554
DOI: 10.1024/0300-9831/a000573 -
Turkish Neurosurgery 2021To evaluate the functional and histopathological results of alpha-tocopherol (vitamin E) and vitamin B12 on an experimental rat model of peripheral nerve injury.
AIM
To evaluate the functional and histopathological results of alpha-tocopherol (vitamin E) and vitamin B12 on an experimental rat model of peripheral nerve injury.
MATERIAL AND METHODS
This research included 32 Wistar Hannover rats. The sciatic nerves of the animals were crushed using an aneurysm clamp. The rats were divided into 4 groups, as group 0 (the controls; no treatment), and groups B12, E, and B12+E, respectively. The rats were analyzed functionally, using the sciatic functional index (SFI), and histopathologically.
RESULTS
In the functional analysis, it was determined that vitamin E was as influential as B12. Concomitant use of these 2 vitamins was found to be more beneficial. The SFI was significantly higher in the B12+E group when compared with that of the B12 group, which indicated that vitamin E improved the healing effects of vitamin B12. In the histopathological evaluation, vitamin E was not effective in the treatment of axonal degeneration (AxD) or edema/inflammation (EI) by itself. Although vitamin B12 was effective in the treatment of EI, it was ineffective in the treatment of AxD. However, the combination of these vitamins decreased both AxD and EI, which showed that the additive effects of these vitamins could reverse neurological injury when used together.
CONCLUSION
Vitamins B12 and E were effective in the functional recovery of peripheral nerve injury (PNI). Neither vitamin B12 nor E was effective in the treatment AxD; however, their combination was effective in the treatment of AxD. The results suggested that vitamin E was effective in the treatment of PNI, especially when combined with vitamin B12. It is our belief that the combination of these vitamins could be used in the treatment of PNI, especially after future studies have been conducted on humans.
Topics: Animals; Antioxidants; Drug Therapy, Combination; Male; Peripheral Nerve Injuries; Rats; Rats, Wistar; Recovery of Function; Sciatic Nerve; Vitamin B 12; Vitamin B Complex; alpha-Tocopherol
PubMed: 33575997
DOI: 10.5137/1019-5149.JTN.30784-20.3