Vitamin E (VitE) has important antioxidant and anti-inflammatory effects and is necessary for normal physiological fuction. α-Tocopherol (α-T), the predominant form of VitE in human tissues, has been extensively studied, yet therapeutic trials of VitE have been uniformly negative. We postulate that a nanoparticle approach might provide effective delivery and therapeutic effect.
Chronic exposure to stress factors contributes to the development of depression by generating excess of reactive oxygen species which leads to oxidative stress and inflammatory processes. The aim of the study was to assess the potential protective properties of α–tocopherolsupplementation on the rats exposed to chronic variable stress (CVS). Male Wistar rats (50-55 days old, weighing 200-250 g) were divided into three groups (n=10): control, stressed, and stressed and receiving (+)-α–tocopherol solution in a dose of 100 mg/kg/day. Rats in the stressed groups were exposed to CVS for 40 days. Markers of redox disorders (glutathione reduced and oxidized levels, GSH/GSSG ratio, glutathione peroxidase, glutathione reductase activities, total antioxidant status, and lipid peroxidation) and inflammatory response (IL-1β, IL6, and TNF-α) were determined in the blood. Additionally, molecular biomarkers of depression (expression of Fkbp5 and Tph2) were studied in hippocampus. The biochemical analysis was inconclusive about the presence of oxidative stress in the blood of rats exposed to CVS. However, changes in all parameters suggest presence of redox equilibrium disorders. Similarly, activation of inflammatory processes was observed as a result of CVS. Molecular effects of environmental stress in hippocampus were also observed. Generally, α–tocopherolameliorated redox equilibrium disorders, tempered inflammatory response, and protected from changes in determined molecular markers of depression.
Smoking is an extremely lethal act and is associated with many illnesses. Lately, major concerns that passive smokers face the same health risks as (if not higher than) active smokers have been raised. Some studies have shown that active smoking is associated with low serum levels of vitamins and testosterone. Are these facts also valid in passive smokers? This study investigated the levels of cotinine, testosterone, follicle stimulating (FSH), Luteinizing Hormone (LH), prolactin and vitamin E in male active smokers and compare these with male passive smokers. Serum levels of cotinine, testosterone, FSH, LH, prolactin and vitamin E were determined in 60 cigarette smokers, 60 passive smokers and 60 non-smokers recruited from Calabar metropolis. The hormones were assayed using ELISA and Vitamin E using high performance liquid chromatography. Socio-demographic and anthropometric indices were obtained and data analyzed using PAWstatistic 18. Cotinine levels were significantly (p<0.05) higher in active smokers than in passive smokers and controls. Vitamin E and testosterone were significantly lower in both active (p<0.05) and passive smokers (p<0.05) when compared to non-smokers. The FSH of the active smokers was significantly higher (p = 0.034) than that of the controls while the passive smokers had the highest LH values (p = 0.0001). However, there were no significant variations in the prolactin levels among the three groups. Both passive and active smoking depletes serum vitamins E and lowers testosterone levels. Lower serum vitamin E is pointer to increased oxidative stress which in conjunction with lower testosterone levels may lead to increased incidence of infertility in both active and passive male smokers.
Nuclear factor-κB (NF-κB) regulates inflammation and cell survival, and is considered a potential target for anti-inflammatory and anti-cancer therapy. δ-Tocotrienol (δTE), a vitamin E form, has been shown to inhibit NF-κB, but the mechanism underlying this action is not clear. In the present study, we show that δTE inhibited TNF-α-induced activation of NF-κB and LPS-stimulated IL-6 in a dose- and time-dependent manner in Raw 264.7 macrophages. δTE potently inhibited TNF-α-induced phosphorylation of transforming growth factor β-activated kinase 1 (TAK1), an upstream kinase essential for the activation of NF-κB. Interestingly, δTE significantly increased the expression of A20 and to a less extent, cylindromatosis (CYLD), both of which are inhibitors of NF-κB. The importance of induction of A20 in δTE’s anti-NF-κB effect is validated in A20 knockout cells where δTE’s inhibition of NF-κB was largely diminished. In pursuit of the cause for A20 induction, we found that δTE treatment caused rapid and persistent elevation of dihydroceramides, while decreased ceramides initially but increased ceramides during prolonged treatment. These changes of sphingolipids were accompanied by increased cellular stress markers. Importantly, δTE’s induction of A20 and inhibition of NF-κB activation were partially counteracted by myriocin, a potent inhibitor of de novo synthesis of sphingolipids, indicating a critical role of sphingolipid modulation in δTE-mediated effects. Since dihydroceramide has been shown to induce A20 and inhibit NF-κB in RAW cells, we conclude that that δTE inhibits NF-κB activation by enhancing its negative regulator A20 as a result of modulating sphingolipids especially elevation of dihydroceramides.
The imbalance between antioxidant system and reactive oxygen species (ROS) generation is related to epileptogenesis, neuronal death, and seizure frequency. Treatment with vitamin E has been associated with neuroprotection and control of seizures. In most experimental studies, vitamin E treatment has short duration. Therefore, the aim of this study was to verify the role of long-term treatment with vitamin E in rats submitted to the pilocarpine model of epilepsy. Rats were divided into two main groups: control (Ctr) and pilocarpine (Pilo). Each one was subdivided according to treatment: vehicle (Ctr V and Pilo V) or vitamin E at dosages of 6 IU/kg/day (Ctr E6 and Pilo E6) or 60 IU/kg/day (Ctr E60 and Pilo E60). Treatment lasted 120 days from status epilepticus (SE). There were no statistical differences concerning treatment in the Ctr group for all variables, so the data were grouped. Carbonyl content in the hippocampus of Pilo V and Pilo E6 was higher compared with that of the Ctr group (8 ± 1.5, 7.1 ± 1, and 3.1 ± 0.3 nmol carbonyl/mg protein, respectively for Pilo V, Pilo E6, and Ctr; p < 0.05). Carbonyl content was restored to control values in Pilo E60 rats (4.2 ± 1.1 and 3.1 ± 0.3 nmol carbonyl/mg protein, respectively for Pilo E60 and Ctr; p > 0.05). The volume of the hippocampal formation (6.5 ± 0.3, 6.6 ± 0.4, 6.3 ± 0.3, and 7.4 ± 0.2, respectively for Pilo V, Pilo E6, Pilo E60, and Ctr) and subfields CA1 (1.6 ± 0.1, 1.4 ± 0.2, 1.5 ± 0.1, and 2 ± 0.05, respectively for Pilo V, Pilo E6, Pilo E60, and Ctr) and CA3 (1.7 ± 0.1, 1.5 ± 0.2, 1.4 ± 0.1, and 2 ± 0.1, respectively for Pilo V, Pilo E6, Pilo E60, and Ctr) was reduced in the Pilo group regardless of treatment. Parvalbumin immunostaining was increased in the hilus of the Pilo E60 group compared with that in the Ctr group (26 ± 2 and 39.6 ± 8.3 neurons, respectively for Ctr and Pilo E60). No difference was found in seizure frequency and Neo-Timm staining. Therefore, long-term treatment with 60 IU/kg/day of vitamin E prevented oxidative damage in the hippocampus and increased hilar parvalbumin expression in rats with epilepsy without a reduction in seizure frequency.
α-Tocopherol (α-TOH) is the primary lipophilic radical trapping antioxidant in human tissues. Oxidative catabolism of α-tocopherol (αTOH) is initiated by ω-hydroxylation of the terminal carbon (C-13) of the isoprenoid sidechain followed by oxidative transformations that sequentially truncate the chain to yield the 2,5,7,8-tetramethyl(3’carboxyethyl)-6-hydroxychroman (α-CEHC). After conjugation to glucuronic acid, 3′-carboxyethyl-6-hydroxychroman glucuronide is excreted in urine. We report here that the same enzyme that accomplishes this task, the cytochrome P450 monooxygenase CYP-4F2, can also ω-hydroxylate the terminal carbon of α-tocopheryl quinone. A standard sample of ω-OH-α-tocopheryl quinone (ω-OH-α-TQ) was synthesized as a mixture of stereoisomers by allylic oxidation of α-tocotrienol using SeO2followed by double-bond reduction and oxidation to the quinone. After incubating human liver microsomes or insect cell microsomes expressing only recombinant human CYP-4F2, cytochrome b5, and NADPH P450 reductase with d6-α-tocopheryl quinone (d6-αTQ), we showed that the ω-hydroxylated (13-OH) d6-α-TQ was produced. We further identified the production of the terminal carboxylic acid d6-13-COOH-αTQ. The ramifications of this discovery to the understanding of tocopherol utilization and metabolism, including the quantitative importance of the αTQ-ω-hydroxylase pathway in humans, are discussed.
Vitamin E is a fat-soluble antioxidant that can protect the polyunsaturated fatty acids (PUFAs) in the membrane from oxidation, regulate the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), and modulate signal transduction. Immunomodulatory effects of vitamin E have been observed in animal and human models under normal and disease conditions. With advances in understating of the development, function, and regulation of dendritic cells (DCs), macrophages, natural killer (NK) cells, T cells, and B cells, recent studies have focused on vitamin E‘s effects on specific immune cells. This review will summarize the immunological changes observed with vitamin Eintervention in animals and humans, and then describe the cell-specific effects of vitamin E in order to understand the mechanisms of immunomodulation and implications of vitamin E for immunological diseases.
To investigate the possibility of mitochondria-dependent apoptosis as a mechanism of early steroid-induced avascular necrosis of femoral head (SANFH) in rats and vitamin E as a possible prevention strategy.
Seventy-two male Sprague Dawley rats were randomly divided into control group, model group, and intervention group, with 24 rats in each group. The rats in control group were not treated as normal control. The rats in model group and intervention group were established early SANFH models by lipopolysaccharide combined with methylprednisolone injection. At the same time, the rats in intervention group were injected with vitamin E (40 mg/kg) every day for 7 days. At 2, 4, and 8 weeks after the final injection, the bilateral femoral heads were harvested and observed by HE staining, TUNEL assay, immunohistochemical staining, and Western blot. The rate of empty lacunae, apoptotic index, and the expressions of Caspase-9, Caspase-3, and cytochrome-c (Cyt-c) proteins were calculated.
According to histological staining, there were significant differences in the rate of empty lacunae between intervention group and control group at 8 weeks ( P<0.05) and between intervention group and model group at 4 and 8 weeks ( P<0.05). The apoptotic index of intervention group was significantly lower than that of model group at each time point ( P<0.05). And there was significant difference between the intervention group and the control group at 8 weeks ( P<0.05). According to immunohistochemistry staining and Western blot, the expressions of Cyt-c, Caspase-9, and Caspase-3 all significantly decreased in intervention group than those in model group at each time point ( P<0.05); and the differences were significant between intervention group and control group at 8 weeks ( P<0.05).
Vitamin E can delay the progression of early SANFH by reducing mitochondrial dependent osteocyte apoptosis.
The current study aimed to evaluate the mechanisms involved in protection against doxorubicin-induced cardiac and renal toxicities upon treatment with eicosapentaenoic acid and vitamin E.
Rats were randomly assigned to 4 groups: normal control, doxorubicin inducted control, eicosapentaenoic acid treated group and a final group pretreated with vitamin E. Lipid peroxidation, reduced glutathione (GSH) and tumor necrosis factor-alpha (TNF-α) contents as well as glutathione peroxidase (GPx), superoxide dismutase (SOD) and myeloperoxidase (MPO) activities were assessed. Moreover, hearts were used for immunohistochemical detection of the pro-apoptotic protein cytochrome c expression, while the kidneys were used for detection of inducible nitric oxide synthase (iNOS) expression.
Eicosapentaenoic acid and vitamin E produced significant protection from doxorubicin-induced cardiac and renal toxicities. The suggested mechanisms for protection included decreased cytochrome c and iNOS expression as well as markedly decreased lipid peroxides and TNF-α contents accompanied with increased GSH content as compared to the doxorubicin control group. Moreover, there was marked increase in GPx and SOD activities accompanied by significant suppression of MPO activity.
The present study demonstrated the potent protective effects of eicosapentaenoic acid and vitamin E from doxorubicin induced cardiac and renal toxicities through their potent anti-oxidant, anti-inflammatory and anti-apoptotic properties. Hence, eicosapentaenoic acid and vitamin E could be promising protective agents against doxorubicintoxicity.
Phenytoin is one of the most well-known antiepileptic drugs that cause cognitive impairment which is closely related to cAMP response element-binding protein (CREB) brain-derived neurotrophic factor (BDNF) signaling pathway. Moreover, vascular endothelial growth factor (VEGF), an endothelial growth factor, has a documented role in neurogenesis and neuronal survival and cognitive impairment. Therefore, this study aimed to investigate the influence of powerful antioxidants: α-Toc and CoQ10 alone or combined in the preservation of brain tissues and the maintenance of memory formation in phenytoin-induced cognitive impairment in rats. The following behavioral test novel object recognition and elevated plus maze were assessed after 14 days of treatment. Moreover, VEGF, BDNF, TrkB, and CREB gene expression levels in the hippocampus and prefrontal cortex were estimated using RT-PCR. Both α-Toc and CoQ10 alone or combined with phenytoin showed improvement in behavioral tests compared to phenytoin. Mechanistically, α-Toc and/or CoQ10 decreases the VEGF mRNA expression, while increases BDNF-TrKB-CREB mRNA levels in hippocampus and cortex of phenytoin-treated rats. Collectively, α-Toc and/or CoQ10 alleviated the phenytoin-induced cognitive impairment through suppressing oxidative damage. The underlying molecular mechanism of the treating compounds is related to the VEGF and enhancing BDNF-TrkB-CREB signaling pathway. Our study indicated the usefulness α-Toc or CoQ10 as an adjuvant to antiepileptic drugs with an advantage of preventing cognitive impairment and oxidative stress.