Protective Effect of Tocotrienol on In Vitro and In Vivo Models of Parkinson’s Disease.

Matsura T.

J Nutr Sci Vitaminol (Tokyo). 2019;65(Supplement):S51-S53. doi: 10.3177/jnsv.65.S51.

Abstract

Parkinson’s disease (PD) is a common progressive neurodegenerative disease. It has been reported that oxidative stress contributes, at least in part, to its pathogenesis. Although dietary epidemiological studies suggest that sufficient intake of vitamin E may prevent the onset of PD, antioxidative therapy for PD with exogenous antioxidants involving α-tocopherol has not been successful in the clinical setting thus far. In recent years, the non-antioxidant activities of vitamin E have been given attention to. In the present study, to determine the antioxidant-independent cytoprotective activity of vitamin E, we investigated whether tocotrienols (T3s), another members of vitamin E family, exhibit the neuroprotective effect in cell and mouse models of PD independently of their antioxidant activities. Treatment with T3s, especially γ- and δ-T3s, exhibited cytoprotective effects via activation of PI3K/Akt signaling pathway in a cellular PD model. We also identified estrogen receptor (ER) β as an upstream mediator of PI3K/Akt signaling and demonstrated the direct binding of T3 to ERβ in vitro. Silencing expression of caveolin suppressed the cytoprotective effects of T3, indicating that caveola formation plays an important role in the cytoprotection by T3 via ERβ/PI3K/Akt signaling pathway. Thus it has been shown that T3 exerts cytoprotective function by a novel mechanism, which includes membrane ERβ/PI3K/Akt signaling via caveola formation as well as its antioxidant activity. Furthermore, we revealed that δ-T3 treatment relieved PD-related symptoms in PD model mice. These results suggest that T3 elicits the cytoprotective effects via ERβ/PI3K/Akt signaling pathway in cellular and murine PD models.

Hosseini M, Sarveazad A, Babahajian A, Baikpour M, Vaccaro AR, Chapman JR, Yousefifard M, Rahimi-Movaghar V

Nutr Rev. 2019 Dec 4. pii: nuz076. doi: 10.1093/nutrit/nuz076.

Abstract

CONTEXT:

Many animal studies have evaluated the role of vitamins in the recovery of motor function after spinal cord injury, but their results have been contradictory and no consensus has been reached.

OBJECTIVE:

This meta-analysis aimed to investigate the effects of vitamin C and vitamin E on recovery of motor function after spinal cord injury in animal models.

DATA SOURCES:

Two authors independently collected the records of relevant articles published in MEDLINE, Embase, Scopus, and Web of Science through November 2018.

STUDY SELECTION:

All studies conducted in animal models to evaluate the therapeutic effects of vitamin C or vitamin E or both on recovery of motor function after spinal cord injury were included. Studies that lacked a control group or a standard treatment, lacked an assessment of motor function, included genetically modified/engineered animals, included animals pretreated with vitamin C or vitamin E, or combined vitamin treatment with other methods, such as cell therapies, were excluded.

DATA EXTRACTION:

Data from 10 articles met the inclusion criteria for meta-analysis, conducted in accordance with PRISMA guidelines.

RESULTS:

Daily supplementation with vitamin C (P < 0.0001) and vitamin E (P < 0.0001) significantly improved the recovery of motor function in animals affected by spinal cord injury. Vitamin C supplementation is effective only when administered intraperitoneally (P < 0.0001). Concurrent supplementation with both vitamins does not show better efficacy than treatment with either one alone.

CONCLUSION:

Administration of vitamin C and vitamin E in animal models of spinal cord injury significantly improves the recovery of motor function.

Ishida Y, Hino S, Morita T, Ikeda S, Nishimura N

Br J Nutr. 2019 Dec 3:1-25. doi: 10.1017/S0007114519003118.

Abstract

We investigated whether non-digestible saccharide fermentation-derived hydrogen molecules (H2) in rat colon could improve the in vivo reduction-oxidation balance via regeneration of α-tocopherol, by assessing their effect on hydroxyl radicals, the α-tocopherol concentration and the reduction-oxidation balance. In experiment 1, a Fenton reaction with phenylalanine (0 or 1.37 mmol/L of H2) was conducted. In experiment 2, rats received intraperitoneally 400 mg/kg of corn oil containing phorone, 7 days after drinking ad libitum water containing 0 or 4% fructooligosaccharides (groups CP and FP, respectively). In experiment 3, rats unable to synthesise ascorbic acid, drank ad libitum for 14 days, water with 240 mg/L (group AC), 20 mg of ascorbic acid/L (group DC) or 20 mg of ascorbic acid/L and 4% fructooligosaccharides (group DCF). In the Fenton reaction, H2 reduced tyrosine produced from phenylalanine to 72% when platinum was added and to 92% when platinum was excluded. In experiment 2, liver glutathione was depleted by administration of phorone to rats. However, compared with CP, no change in the m-tyrosine concentration in the liver of FP was detected. In experiment 3, net H2 excretion was higher in DCF than in the other rats, 3 days after the experiment ended. Furthermore, the concentrations of H2 and α-tocopherol and the reduction-oxidation glutathione ratio in perirenal adipose tissue of rats were significantly higher and lower, respectively, in DCF than in DC. To summarise, in rat colon, fermentation-derived H2 further reduced the reduction-oxidation balance in perirenal adipose tissue through increased regeneration of α-tocopherol.

Bolotta A, Pini A, Abruzzo PM, Ghezzo A, Modesti A, Gamberi T, Ferreri C, Bugamelli F, Fortuna F, Vertuani S, Manfredini S, Zucchini C, Marini M

Exp Biol Med (Maywood). 2019 Dec 3:1535370219890873. doi: 10.1177/1535370219890873.

Abstract Friedreich’s ataxia is an autosomal recessive disorder characterized by impaired mitochondrial function, resulting in oxidative stress. In this study, we aimed at evaluating whether tocotrienol, a phytonutrient that diffuses easily in tissues with saturated fatty layers, could complement the current treatment with idebenone, a quinone analogue with antioxidant properties. Five young Friedreich’s ataxia patients received a low-dose tocotrienol supplementation (5 mg/kg/day), while not discontinuing idebenone treatment. Several oxidative stress markers and biological parameters related to oxidative stress were evaluated at the time of initiation of treatment and 2 and 12 months post-treatment. Some oxidative stressrelated parameters and some inflammation indices were altered in Friedreich’s ataxia patients taking idebenone alone and tended to be normal values following tocotrienol supplementation; likewise, a cardiac magnetic resonance study showed some improvement following one-year tocotrienol treatment. The pathway by which tocotrienol affects the Nrf2 modulation of hepcidin gene expression, a peptide involved in iron handling and in inflammatory responses, is viewed in the light of the disruption of the iron intracellular distribution and of the Nrf2 anergy characterizing Friedreich’s ataxia. This research provides a suitable model to analyze the efficacy of therapeutic strategies able to counteract the excess free radicals in Friedreich’s ataxia, and paves the way to long-term clinical studies.

Napolitano G, Fasciolo G, Di Meo S, Venditti P

Nutrients. 2019 Dec 1;11(12). pii: E2900. doi: 10.3390/nu11122900.

Abstract

Mitochondria are both the main sites of production and the main target of reactive oxygen species (ROS). This can lead to mitochondrial dysfunction with harmful consequences for the cells and the whole organism, resulting in metabolic and neurodegenerative disorders such as type 2 diabetes, obesity, dementia, and aging. To protect themselves from ROS, mitochondria are equipped with an efficient antioxidant system, which includes low-molecular-mass molecules and enzymes able to scavenge ROS or repair the oxidative damage. In the mitochondrial membranes, a major role is played by the lipid-soluble antioxidant vitamin E, which reacts with the peroxyl radicals faster than the molecules of polyunsaturated fatty acids, and in doing so, protects membranes from excessive oxidative damage. In the present review, we summarize the available data concerning the capacity of vitamin E supplementation to protect mitochondria from oxidative damage in hyperthyroidism, a condition that leads to increased mitochondrial ROS production and oxidative damage. Vitamin E supplementation to hyperthyroid animals limits the thyroid hormone-induced increases in mitochondrial ROS and oxidative damage. Moreover, it prevents the reduction of the high functionality components of the mitochondrial population induced by hyperthyroidism, thus preserving cell function.

Panachan J, Chokchaichamnankit D, Weeraphan C, Srisomsap C, Masaratana P, Hatairaktham S, Panichkul N, Svasti J, Kalpravidh RW

Hematology. 2019 Dec;24(1):300-307. doi: 10.1080/16078454.2019.1568354.

Abstract

OBJECTIVE:

Iron overload and oxidative stress are the major causes of serious complications and mortality in thalassemic patients. Our previous work supports the synergistic effects of antioxidant cocktails (curcuminoids or vitamin E, N-acetylcysteine, and deferiprone) in treatment of β-thalassemia/Hb E patients. This further 2-DE-based proteomic study aimed to identify the plasma proteins that expressed differentially in response to antioxidant cocktails.

METHODS:

Frozen plasma samples of ten normal subjects and ten β-thalassemia/Hb E patients at three-time points (baseline, month 6, and month 12) were reduced the dynamic range of proteome using ProteoMiner kit and separated proteins by two-dimensional gel electrophoresis. Differentially expressed proteins were identified using tandem mass spectrometry. Several plasma proteins were validated by ELISA and Western blot analysis.

RESULTS:

Thirteen and 11 proteins were identified with altered expression levels in the curcuminoids- and vitamin E cocktail groups, respectively. The associations between vitronectin (VTN) expression and total bilirubin levels, as well as between serum paraoxonase/arylesterase 1 (PON1) expression and blood reactive oxygen species were observed. Validation results were consistent with proteomics results.

DISCUSSION AND CONCLUSIONS:

These plasma proteins may provide better understanding of the mechanisms underlying the therapeutic effects of antioxidant cocktails in thalassemic patients.

Bazzaz R, Bijanpour H, Pirouzpanah SMB, Yaghmaei P, Rashtchizadeh N

J Biochem Mol Toxicol. 2019 Nov;33(11):e22399. doi: 10.1002/jbt.22399.

Abstract

Resistance to chemotherapy with 5-fluorouracil (5-FU) in patients with colorectal cancer (CRC) is the major obstacle to reach the maximum efficiency of CRC treatment. Combination therapy has emerged as a novel anticancer strategy. The present study evaluates the cotreatment of γ-tocopherol and 5-FU in enhancing the efficacy of chemotherapy against HT-29 colon cancer cells. Cytotoxic effect of this combination was examined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and a synergistic effect was evaluated by a combination index technique. Nuclear morphology was studied via 4′,6-diamidino-2-phenylindole staining and flow cytometric assays were conducted to identify molecular mechanisms of apoptosis and cell cycle progression. We investigated the expression of Cyclin D1, Cyclin E, Bax, and Bcl-2 by a quantitative real-time polymerase chain reaction. The IC₅₀ values for 5-FU and γ-tocopherol were 21.8 ± 2.5 and 14.4 ± 2.6 μM, respectively, and also this combination therapeutic increased the percentage of apoptotic cells from 35% ± 2% to 40% ± 4% (P < .05). Furthermore, incubation HT-29 colon cells with combined concentrations of two drugs caused significant accumulation of cells in the subGsubG1 phase. Our results presented the combination therapy with 5-FU and γ-tocopherol as a novel therapeutic approach, which can enhance the efficacy of chemotherapy.

Long Y, Liu X, Tan XZ, Jiang CX, Chen SW, Liang GN, He XM, Wu J, Chen T, Xu Y

Ecotoxicol Environ Saf. 2019 Nov 27:109937. doi: 10.1016/j.ecoenv.2019.109937.

Abstract

Growing epidemiological evidence has shown that exposure to polychlorinated biphenyls (PCBs) is harmful to the cardiovascular system. However, how PCB 118-induced oxidative stress mediates endothelial dysfunction is not fully understood. Here, we explored whether and how PCB 118 exposure-induced oxidative stress leads to NLRP3 inflammasome-dependent pyroptosis in endothelial cells. As expected, PCB 118 was cytotoxic to HUVECs and induced caspase-1 activation and cell membrane disruption, which are characteristics of pyroptosis. Moreover, PCB 118-induced pyroptosis may have been due to the activation of the NLRP3 infammasomes. PCB 118 also induced excessive reactive oxygen species (ROS) in HUVECs. The ROS scavenger (±)-α-tocopherol and the NFκB inhibitor BAY11-7082 reversed the upregulation of NLRP3 expression and the increase in NLRP3 inflammasome activation induced by PCB 118 exposure in HUVECs. Additionally, PCB 118-induced oxidative stress and pyroptosis were dependent on Aryl hydrocarbon receptor (AhR) activation and subsequent cytochrome P450 1A1 upregulation, which we confirmed by using the AhR selective antagonist CH 223191. These data suggest that PCB 118 exposure induces NLRP3 inflammasome activation and subsequently leads to pyroptosis in endothelial cells in vitro and in vivo. AhR-mediated ROS production play a central role in PCB 118-induced pyroptosis by priming NFκB-dependent NLRP3 expression and promoting inflammasome activation.