Effects of vitamin A and vitamin E on attenuation of titanium dioxide nanoparticles-induced toxicity in the liver of male Wistar rats

Moradi A, Ziamajidi N, Ghafourikhosroshahi A, Abbasalipourkabir R

Mol Biol Rep. 2019 Jun;46(3):2919-2932. doi: 10.1007/s11033-019-04752-4. Epub 2019 Mar 18.

Abstract

The increasing application of titanium dioxide nanoparticles (NTiO₂) in life and the toxicity potential of these nanoparticles have raised concerns about their detrimental effects on human health. This study was conducted to investigate the hepatoprotective effects of vitamin Eand vitamin A against hepatotoxicity induced by NTiO₂ in rats. Thirty-six male Wistar rats were randomly divided into six groups of six rats each. Intoxicated group received 300 mg/kg NTiO₂ for two weeks by gavage. Groups treated with vitamin E (100 IU/kg), vitamin A (100 IU/kg) and mixture of these vitamins were orally administered for 3 weeks (started 7 days before NTiO₂ administration). In order to investigate the redox changes, total antioxidant capacity, total oxidant status, and lipid peroxidation were determined in liver tissue as well as activity of antioxidant enzymes including superoxide dismutase, glutathione peroxidase, and catalase. In addition, inflammatory responses were assessed by measuring the expression of NF-κB (mRNA) and TNF-α (mRNA and protein). Histopathological analysis and measurement of liver enzymes (ALP, ALT, AST, and LDH in serum) were also done to determine hepatic injury. In liver, NTiO₂ caused hepatic injury, redox perturbation, and reduction of antioxidant enzymes and elevation of inflammatory mediators, significantly. However, treatment with vitamins was able to significantly ameliorate these alterations. This study highlights the antioxidant and anti-inflammatory properties of vitamins A and E against toxicity of NTiO₂ and poses the use of these vitamins to mitigate the toxic effects of this nanoparticles in NTiO₂-contained products.

He W, Xu Y, Ren X, Xiang D, Lei K, Zhang C, Liu D

Dig Dis Sci. 2019 May 10. doi: 10.1007/s10620-019-05657-9. [Epub ahead of print]

Abstract

BACKGROUND:

Vitamin E has been reported to have a beneficial effect on nonalcoholic fatty liver disease (NAFLD); however, the underlying mechanism of action has not yet been clearly defined.

AIM:

We aimed to evaluate the effects and mechanisms of vitamin E on lipid and glucose homeostasis both in vivo and in vitro.

METHODS:

An NAFLD model was established in C57BL/6 mice fed a 30% fructose solution for 8 weeks. Subsequently, NAFLD mice were given vitamin E (70 mg/kg) for 2 weeks. In addition, L02 cells were treated with 5 mM fructose and 100 nM vitamin E to explore the potential mechanisms of action.

RESULTS:

Vitamin E reversed the impaired glucose tolerance of fructose-treated mice. Histopathological examination showed that liver steatosis was significantly relieved in vitamin E-treated mice. These effects may be attributed to the upregulation of nuclear factor erythroid-2-related factor 2 (Nrf2), carboxylesterase 1 (CES1), and downregulated proteins involved in lipid synthesis by vitamin E treatment. In vivo, vitamin E also significantly reduced lipid accumulation in fructose-treated L02 cells, and the Nrf2 inhibitor ML385 reversed the protective effects of vitamin E.

CONCLUSION:

These data indicated that the therapeutic effects of vitamin E on lipid and glucose homeostasis may be associated with activation of the Nrf2/CES1 signaling pathway.

Jian H, Ai-Min L

Hepatology. 2019 Mar 18. doi: 10.1002/hep.30603. [Epub ahead of print]

Abstract

According to the article conducted by Eduardo et al.(1), the non-transplant survival rate of nonalcoholic steatohepatitis (NASH) patients with bridging necrosis and cirrhosis, which is a subtype of non-alcoholic fatty liver disease (NAFLD), was found to be improved by vitamin E, who will reduce the occurrence of liver decompensation. However, combined with the literature we have reviewed and the clinical experience we have achieved, two important factors that may affect the study results will be proposed in the article. This article is protected by copyright. All rights reserved.

Nobili V, Alisi A, Mosca A, Crudele A, Zaffina S, Denaro M, Smeriglio A, Trombetta D

Antioxid Redox Signal. 2019 Feb 11. doi: 10.1089/ars.2018.7704. [Epub ahead of print]

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in children. Several studies suggest that the improvement of oxidative stress is suggested as a possible therapeutic strategy for pediatric nonalcoholic steatohepatitis. We performed a randomized, double-blind placebo-controlled trial to test the potential efficacy, assessed by improvement of oxidative stress parameters and liver ultrasound, and tolerability of a mixture of vitamin E and hydroxytyrosol (HXT) in adolescents with biopsy-proven NAFLD. Four hundred forty consecutive patients were screened, 80 of these with biopsy-proven NAFLD were enrolled. Forty patients received an oral dose of HXT and vitamin E and 40 children received the capsules of placebo for 4 months. Seventy patients completed the study. Patients in the treatment arm showed a decrease of insulin resistance (IR), triglyceride levels, oxidative stress parameters, and steatosis grade. Noteworthy, the steatosis improvement correlates with the levels of advanced glycation end products and carbonylated proteins. The HXT and vitamin Etreatment improved the main oxidative stress parameters, IR, and steatosis in children with NAFLD. The use of two natural molecules that may have antioxidant effects seems a promising strategy that could be easily diet integrated to improve NAFLD-related liver damage in children.

Zeb A, Khan AA

Front Nutr. 2019 Jan 10;5:137. doi: 10.3389/fnut.2018.00137. eCollection 2018.

Abstract

Dietary oxidized olive oil, alone or in combination with different doses of α-tocopherol, were given to Swiss albino rats for 30 days; in order to determine its role in oxidative stress and fatty liver, induced by the oxidized olive oils. Serum biochemical parameters and hematological indices of blood were analyzed. The liver was analyzed for histopathological changes, lipid peroxidation, and polar triacylglycerols composition. Results revealed that there was a significant decline in the serum total cholesterol, triglycerides, LDL, glucose and ALT; while a significant increase occurred in the serum HDL levels through the supplementation of α-tocopherol in male and female rats. Hematological parameters were almost in the normal reference range in the groups that were fed α-tocopherol, alone or in combination with oxidized oil, while being significantly altered by the oxidized olive oil. There were acute hepatitis and necrosis in the liver with no fatty changes after feeding with oxidized olive oil, along with varying doses of α-tocopherol. Higher amounts of polar compounds were present in female rats (15.2-93.1 μg/g) compared to male rats (12.2-82.3%) that correspond to the supplementation of α-tocopherol in combination with oxidized oil. Lipid oxidation in liver was minimized by tocopherol, while an increase occurred in the accumulation of oxidized lipids in the liver. These findings revealed that tocopherol is beneficial against the oxidized oil induced biochemical and hematological changes and lipid peroxidation but causes fatty accumulation in the liver. Therefore, the role of tocopherol in patients with fatty liver disease may be considered, as tocopherol may increase the chance of survival.

Nobili V, Alisi A, Mosca A, Crudele A, Zaffina S, Denaro M, Smeriglio A, Trombetta D

Antioxid Redox Signal. 2018 Dec 27. doi: 10.1089/ars.2018.7704. [Epub ahead of print]

Abstract

TRIAL DESIGN:

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in children. Several studies suggest that the improvement of oxidative stress is suggested as a possible therapeutic strategy for paediatric NASH. We performed a randomized double-blind placebo-controlled trial to test the potential efficacy, assessed by improvement of oxidative-stress parameters and liver ultrasound, and tolerability of a mixture of vitamin E and Hydroxytyrosol (HXT) in adolescents with biopsy-proven NAFLD.

METHODS:

440 consecutive patients were screened, 80 of these with biopsy-proven NAFLD were enrolled. Forty patients received an oral dose of HXT and vitamin E and 40 children received the capsules of placebo, for 4 months.

RESULTS:

Seventy patients completed the study. Patients in the treatment arm showed a decrease of insulin-resistance, triglyceride levels, oxidative-stress parameters and steatosis grade. Noteworthy, the steatosis improvement correlates with the levels of advanced glycation end products and carbonylated proteins.

CONCLUSION:

The HXT and vitamin E treatment improved the main oxidative-stress parameters, insulin resistance and steatosis in children with NAFLD. The use of two natural molecules that may have antioxidant effects seems a promising strategy that could be easily diet integrated to improve NAFLD related liver damage in children.

Nagashimada M, Ota T

IUBMB Life. 2018 Dec 27. doi: 10.1002/iub.1991. [Epub ahead of print]

Abstract

Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide. NAFLD manifests as hepatic lipid accumulation, insulin resistance, and inflammation, and can progress to nonalcoholic steatohepatitis (NASH) and cirrhosis. However, the underlying mechanisms of NAFLD, including those that drive its progression, are unclear. Both liver-resident (Kupffer cells) and recruited macrophages play a crucial role in the development of insulin resistance and NASH. Therefore, NALFD could potentially be ameliorated by modifying the polarization of macrophages/Kupffer cells. Reactive oxygen species induce oxidative stress, which is implicated in the progression of NASH. Micronutrients, including vitamins, are potent antioxidants that exert anti-inflammatory effects, and are used in the treatment of NAFLD. We review here the molecular mechanisms of the pathogenesis of NAFLD and the potential utility of vitamin E in its prevention and/or treatment.

Banini BA, Cazanave SC1,, Yates KP, Asgharpour A, Vincent R, Mirshahi F, Le P, Contos MJ, Tonascia J, Chalasani NP, Kowdley KV, McCullough AJ, Behling CA, Schwimmer JB, Lavine JE1, Sanyal AJ

J Clin Gastroenterol. 2018 Dec 21. doi: 10.1097/MCG.0000000000001142. [Epub ahead of print]

Abstract

BACKGROUND:

Haptoglobin (Hp) genotype has been linked to oxidative stress and cardiovascular outcomes in response to vitamin E (VitE) among patients with diabetes mellitus. Its effect on histologic response to VitE in nonalcoholic steatohepatitis (NASH) is unknown.

GOALS:

Our objective was to determine if Hp genotype associates with response to VitE in patients with NASH.

STUDY:

A post hoc analysis of 228 patients receiving VitE or placebo in 2 clinical trials was performed. Regression analysis was used to assess the effect of VitE versus placebo, by Hp genotype (1-1, 2-1, or 2-2), on histologic features and laboratory markers of nonalcoholic fatty liver disease, comparing baseline to end of treatment values. An interaction term was included in the regression models to assess differential treatment effect across Hp genotype.

RESULTS:

Hp 2-2 patients treated with VitE versus placebo showed significant histologic improvement (51% vs. 20%; OR=4.2; P=0.006), resolution of steatohepatitis (44% vs. 12%; OR=6.2; P=0.009), decrease in nonalcoholic fatty liver disease Activity Score (NAS) (-2.2 vs. -0.6; P=0.001), and decrease in liver enzymes alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and γ-glutamyl transpeptidase. Hp 2-1 patients on VitE versus placebo showed improved resolution of steatohepatitis, NAS and liver enzymes. Hp 1-1 patients showed no significant improvement in histology or liver enzymes. VitE had no effect on fibrosis stage in any group. Regression analysis showed incremental benefit of having Hp 2-2 or 2-1 versus 1-1 for all liver enzyme.

CONCLUSIONS:

Hp 2 allele is associated with greater histologic and biological improvement in NASH with VitE treatment compared with the Hp 1 allele.

Zingg JM

IUBMB Life. 2018 Dec 17. doi: 10.1002/iub.1986. [Epub ahead of print]

Abstract

Vitamin E modulates signal transduction pathways by several molecular mechanisms. As a hydrophobic molecule located mainly in membranes it contributes together with other lipids to the physical and structural characteristics such as membrane stability, curvature, fluidity, and the organization into microdomains (lipid rafts). By acting as the main lipid-soluble antioxidant, it protects other lipids such as mono- and poly-unsaturated fatty acids (MUFA and PUFA, respectively) against chemical reactions with reactive oxygen and nitrogen species (ROS and RNS, respectively) and prevents membrane destabilization and cellular dysfunction. In cells, vitamin E affects signaling in redox-dependent and redox-independent molecular mechanisms by influencing the activity of enzymes and receptors involved in modulating specific signal transduction and gene expression pathways. By protecting and preventing depletion of MUFA and PUFA it indirectly enables regulatory effects that are mediated by the numerous lipid mediators derived from these lipids. In recent years, some vitamin E metabolites have been observed to affect signal transduction and gene expression and their relevance for the regulatory function of vitamin E is beginning to be elucidated. In particular, the modulation of the CD36/FAT scavenger receptor/fatty acids transporter by vitamin E may influence many cellular signaling pathways relevant for lipid homeostasis, inflammation, survival/apoptosis, angiogenesis, tumorigenesis, neurodegeneration, and senescence. Thus, vitamin E has an important role in modulating signal transduction and gene expression pathways relevant for its uptake, distribution, metabolism, and molecular action that when impaired affect physiological and patho-physiological cellular functions relevant for the prevention of a number of diseases.

Khadangi F, Azzi A

IUBMB Life. 2018 Dec 14. doi: 10.1002/iub.1990. [Epub ahead of print]

Abstract

α-Tocopherol is the only tocopherol that has been shown to prevent the human deficiency disease Ataxia with Isolated Vitamin E Deficiency (AVED), and thus it is the only one that, for humans, can be called vitamin E. Vitamin E in addition to preventing AVED has documented immune boosting properties and an activity against nonalcoholic hepatosteatosis and low-grade inflammation. Epidemiological studies indicating that vitamin E could prevent cardiovascular events, neurodegenerative disease, macular degeneration, and cancer were in general not confirmed by clinical intervention studies. Vitamin E and some of its metabolites modulate cell signaling and gene transcription. Future research is needed to achieve a better understanding of the molecular events leading to gene regulation by vitamin E, especially in its phosphorylated form. Isolation and characterization of the vitamin E kinase and vitamin E phosphate phosphatase will help in the understanding of cell regulation processes modulated by vitamin E. A clarification of the pathogenesis of AVED remains an important goal to be achieved.