The antioxidant effects of Hydroxytyrosol and Vitamin E on pediatric NAFLD, in a clinical trial: a new treatment?

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.

Suzuki H, Kume A, Herbas MS

nt J Mol Sci. 2018 Dec 24;20(1). pii: E64. doi: 10.3390/ijms20010064.

Abstract

Although epidemiological and experimental studies have suggested beneficial effects of vitamin E deficiency on malaria infection, it has not been clinically applicable for the treatment of malaria owing to the significant content of vitamin E in our daily food. However, since α-tocopherol transfer protein (α-TTP) has been shown to be a determinant of vitamin E level in circulation, manipulation of α-tocopherol levels by α-TTP inhibition was considered as a potential therapeutic strategy for malaria. Knockout studies in mice indicated that inhibition of α-TTP confers resistance against malaria infections in murines, accompanied by oxidative stress-induced DNA damage in the parasite, arising from vitamin E deficiency. Combination therapy with chloroquine and α-TTP inhibition significantly improved the survival rates in murines with malaria. Thus, clinical application of α-tocopherol deficiency could be possible, provided that α-tocopherol concentration in circulation is reduced. Probucol, a recently found drug, induced α-tocopherol deficiency in circulation and was effective against murine malaria. Currently, treatment of malaria relies on the artemisinin-based combination therapy (ACT); however, when mice infected with malarial parasites were treated with probucol and dihydroartemisinin, the beneficial effect of ACT was pronounced. Protective effects of vitamin E deficiency might be extended to manage other parasites in future.

Sarkisyan VA, Kodentsova VM, Bessonov VV, Kochetkova AA

Vopr Pitan. 2018;87(3):5-11. doi: 10.24411/0042-8833-2018-10025. Epub 2018 May 11.

Abstract

The molecular docking method was used to study the structural characteristics determining the competitive transport in the blood, and also the subsequent binding with enzymes of tocopherols and their metabolites to yield a specific biological activity. The target proteins were α-tocopherol-transport protein (α-TTP), tocopherol-associated protein 1 (TAP1), cyclooxygenase-2 (COX-2), protein phosphatase 2A (PP2A) and 3-hydroxy- 3-methylglutaryl-Coenzyme A (HMG-CoA) reductase. RRR-tocopherol (α-, β-, γ- and δ-forms), RRR-13′-carboxychromanol (α-, β-, γ- and δ-forms) and carboxyethyl hydroxychromanol (α-, β-, γ- and δ-forms) were used as ligands in this research. The conducted studies confirmed that among all homologues the α-tocopherol had the greatest affinity for the transport proteins α-TTP and TAP1 (ΔG=-11.40 and ΔG=-10.28 kcal/mol, respectively). It was shown that in all cases carboxyethyl hydroxychromanol metabolites had the greatest free binding energy (ΔG>-8 kcal/mol), that was why it has been concluded that they were not effective ligands for the proteins under study. In contrast, the metabolites of 13′-carboxychromanol, when bound to both α-TTP and TAP1 proteins, preferentially formed more stable complexes than their precursors. It was shown for the first time that γ-13′-carboxychromanol with TAP1 has less free binding energy (ΔG=-10.64 kcal/mol) in comparison to the α-tocopherol complex (ΔG=-10.28 kcal/mol). It has also been shown that 13′-carboxychromanole metabolites were more efficiently bound to COX-2 enzymes (ΔG=-9.56 kcal/mol for α-13′-carboxychromanol complex) and HMG-CoA reductase (ΔG=-9.46 kcal/mol for the complex with δ-13′-carboxychromanol). In relation to the PP2A protein, 13′-carboxychromanol metabolites had similar affinities as their precursors. The results of the work indicate the possibility of 13′-carboxychromanols to competitively bind to α-tocopherol transporters and act as effective ligands of COX-2 and HMG-CoA, that can be used to correct nutritional status in conditions accompanied by deficiency of tocopherols.

Sayyahi A, Jahanshahi M, Amini H, Sepehri H

Folia Neuropathol. 2018;56(3):215-228. doi: 10.5114/fn.2018.78703.

Abstract

M1 muscarinic receptor plays a fundamental role in memory and is closely associated with Alzheimer’s disease (AD); it has long been assumed as a therapeutic goal. By activating of the cholinergic receptor vitamin E helps with memory retention. But effects of vitamin E on density of M1 muscarinic receptor-immunoreactive (ir) neurons remain poorly understood. The present research aimed to examine the chronic administration effect of vitamin E against scopolamine-induced memory loss and the number of M1 muscarinic receptor-ir neurons of the hippocampus in male rats. Randomly, 42 adult male Wistar rats were divided to six groups: control, Sham-saline: receiving scopolamine + saline, Sham-sesame oil: receiving scopolamine + sesame oil and three experimental groups: receiving scopolamine + vitamin E with different doses (25, 50, and 100 mg/kg/day, i.p.) for 14 days. The passive avoidance task was used for the memory test. Twenty-four hours after behavioral tests, rats’ brains were taken and fixed, and after tissue processing, sections were stained using the immunohistochemical technique for M1 muscarinic receptor-ir neurons and cresyl violet for neurons. The injection of scopolamine to rats caused memory impairment and vitamin E treatment could ameliorate it. In the scopolamine-treated groups, the number of CA1 and CA3 pyramidal and dentate gyrus (DG) granular neurons was decreased significantly as compared to the control group. Vitamin E treatment significantly increased neuron numbers in the CA1 and CA3 areas of the hippocampus and DG area. Treatment with vitamin E for 14 days could compensate the loss of M1 muscarinic receptor-immunoreactive neuron numbers induced by scopolamine in the hippocampus. The most effective vitamin E dose was 50 mg/kg/day in this study. In conclusion, vitamin E can compensate the neuronal loss in the hippocampal formation and also it can raise the density of M1 receptor-ir muscarinic neurons after an injection of scopolamine.

Birringer M, Lorkowski S

IUBMB Life. 2018 Dec 22. doi: 10.1002/iub.1988. [Epub ahead of print]

Abstract

Vitamin E plays an important role as a lipophilic antioxidant in cellular redox homeostasis. Besides this function, numerous non-antioxidant properties of this vitamin have been discovered in the past. DNA microarray technology revealed a complex regulatory network influenced by the different vitamin E forms (Rimbach et al., Molecules, 15, 1746 (2010); Galli et al., Free Radic. Biol. Med., 102, 16 (2017)); however, little is known about the biological activity of vitamin E metabolites. A new chapter of vitamin E research was been opened when endogenous long-chain tocopherol metabolites were identified and their high biological activity in vitro and in vivo was recognized (Schmölz et al., World J. Biol. Chem., 7, 14 (2016); Torquato et al., J. Pharm. Biomed. Anal., 124, 399 (2016)). Just recently, it was shown that an endogenous metabolite of vitamin E inhibits 5-lipoxygenase at nanomolar concentrations, thereby limiting inflammation (Pein et al., Nat. Commun., 9, 3834 (2018)). Furthermore, long-chain vitamin E metabolites (LCM) exhibit hormone-like activities similar to the lipid soluble vitamins A and D (Galli et al., Free Radic. Biol. Med., 102, 16 (2017); Schubert et al., Antioxidants, 7 (2018)). This review aims at summarizing recent findings on the regulatory activities of vitamin E metabolites, especially of LCMs.

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.

Huang X, Zhang H, Zhen J, Dong S, Guo Y, Van Halm-Lutterodt N, Yuan L

Aging (Albany NY). 2018 Dec 20;10(12):4066-4083. doi: 10.18632/aging.101694.

Abstract

OBJECTIVE:

The current study evaluated the relationship between circulating fat soluble vitamin status and cognition in aging Chinese population.

METHODS:

A cross-sectional study was carried out in 1754 community residents aged 55-80 years aiming to evaluate the relationship between circulating α-tocopherol and retinol status and cognition. The effect of ApoE genetic polymorphism on the relationship between vitamins and cognition was also explored.

RESULTS:

Our results indicated that serum retinol status positively correlated with cognitive performance; while, serum α-tocopherol (α-TOH)/retinol ratio negatively correlated with cognitive performance. Mild cognitive impairment (MCI) subject demonstrated higher serum α-TOH status (P < 0.05), α-TOH/retinol ratio (P < 0.01) and lower retinol status (P < 0.01) than normal subjects. Subjects with ApoE4 genotype have lower serum retinol level (P < 0.05) and higher α-TOH/retinol ratio (P < 0.01) than subjects with ApoE3 genotype. MCI-ApoE4 carriers demonstrated the worst cognitive performance (P < 0.05) and exhibited higher serum TC, α-TOH and α-TOH/retinol ratio levels (P < 0.05), and lower LDL-C, retinol and lipid-adjusted retinol status (P < 0.05). MCI-ApoE2 subjects showed higher serum TC, HDL-C content and α-TOH/retinol ratio (P < 0.05); and lower serum retinol and lipid-adjusted retinol status (P < 0.05).

CONCLUSION:

Lower circulating retinol and higher α-TOH/retinol ratio potentially predicts an increased risk for the development of cognitive decline in aging Chinese adults. ApoE2 or E4 carriers with higher circulating α-TOH/retinol ratio infer poor cognitive performance and an increased risk of developing MCI.

Sun WG, Song RP, Wang Y, Ge S, Zhang YH, Wang HX, Liu J, Liu LX

J Agric Food Chem. 2018 Dec 18. doi: 10.1021/acs.jafc.8b05832. [Epub ahead of print]

Abstract

γ-Tocotrienol (γ-T3) exhibits the activity of anti-cancer via regulating cell signaling pathways. Nuclear factor-kB (NF-kB), one of crucial pro-inflammatory factors, involved in the regulation of cell proliferation, apoptosis, invasion and migration of tumor. In the present study, NF-kB activity inhibited by γ-T3 was investigated in gastric cancer cells. Cell proliferation, NF-kB activity, active protein phosphatase type 2A (PP2A), and ataxia-telangiectasia mutated (ATM) protein were explored using MTT, methylene blue, ELISA, malachite green, luciferase and Western blotting assays. The effects of γ-T3 on tumor growth, the expression of NF-kB and PP2A proteins were also further examined by implanting human gastric cancer cells in a BALB/c nude mouse model. The results showed that γ-T3 significantly inhibited the cell proliferation and attenuated the NF-kB activity in vitro and in vivo. γ-T3 dramatically increased PP2A activity and protein expression, which suppressed ATM phosphorylation and its translocation to the cytoplasm in gastric cancer cells. Thus, our findings may provide mechanistic insight into effects of γ-T3 on the regulation of NF-kB activity by a PP2A-dependent mechanism and suggest that PP2A may serve as a molecular target for a potential chemopreventive agent.