The Protective Effects of γ-Tocotrienol on Muscle Stem Cells Through Inhibiting Reactive Oxidative Stress Production

Shuo Yang, Juan Yang, Huiwen Zhao, Rong Deng, Hancheng Fan, Jinfu Zhang, Zihao Yang, Huihong Zeng, Bohai Kuang, Lijian Shao

Front Cell Dev Biol . 2022 Mar 15;10:820520. doi: 10.3389/fcell.2022.820520. eCollection 2022.

Abstract

Pseudotrophic muscular dystrophy is a common clinical skeletal muscle necrotic disease, among which Duchenne muscular dystrophy (DMD) is the predominant. For such diseases, there is no clinically effective treatment, which is only symptomatic or palliative treatment. Oxidative stress and chronic inflammation are common pathological features of DMD. In recent years, it has been found that the pathophysiological changes of skeletal muscle in DMD mice are related to muscle stem cell failure. In the present study, we established a DMD mice model and provided tocotrienol (γ-tocotrienol, GT3), an antioxidant compound, to explore the relationship between the physiological state of muscle stem cells and oxidative stress. The results showed that the application of GT3 can reduce ROS production and cellular proliferation in the muscle stem cells of DMD mice, which is beneficial to promote the recovery of muscle stem cell function in DMD mice. GT3 treatment improved the differentiation ability of muscle stem cells in DMD mice with increasing numbers of MyoD+ cells. GT3 application significantly decreased percentages of CD45+ cells and PDGFRα+ fibro-adipogenic progenitors in the tibialis anterior of DMD mice, indicating that the increased inflammation and fibro-adipogenic progenitors were attenuated in GT3-treated DMD mice. These data suggest that increased ROS production causes dysfunctional muscle stem cell in DMD mice, which might provide a new avenue to treat DMD patients in the clinic.

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Dietary Vitamin E intake is associated with a reduced risk of developing digestive diseases and NAFLD

Eleonora Scorletti, Kate Townsend Creasy, Marijana Vujkovic, Mara Vell, Inuk Zandvakili, Daniel J Rader, Kai Markus Schneider, Carolin V Schneider

Am J Gastroenterol . 2022 Mar 14. doi: 10.14309/ajg.0000000000001726. Online ahead of print.

Abstract

Introduction: Vitamin E supplementation is recommended for the treatment of non-alcoholic fatty liver disease (NAFLD) for nondiabetic patients, but its preventative effects are unclear.

Methods: We assessed dietary Vitamin E intake with disease phenotypes and evaluated Vitamin E levels with the development of NAFLD.

Results: Data from >210,000 participants demonstrate that increased dietary Vitamin E associates with reduced rates of several gastrointestinal diseases and reduced overall mortality. Diabetic and overweight subjects with increased Vitamin E intake have fewer NAFLD diagnoses.

Conclusion: Our findings reveal the relevance of Vitamin E consumption for several gastrointestinal diseases and warrant further mechanistic and therapeutic investigations.

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Alpha-tocotrienol enhances arborization of primary hippocampal neurons via upregulation of Bcl-xL

Han-A Park, Kristi M Crowe-White, Lukasz Ciesla, Madison Scott, Sydni Bannerman, Abigail U Davis, Bishnu Adhikari, Garrett Burnett, Katheryn Broman, Khondoker Adeba Ferdous, Kimberly H Lackey, Pawel Licznerski, Elizabeth A Jonas

Nutr Res . 2022 Mar 7;101:31-42. doi: 10.1016/j.nutres.2022.02.007. Online ahead of print.

Abstract

Alpha-tocotrienol (α-TCT) is a member of the vitamin E family. It has been reported to protect the brain against various pathologies including cerebral ischemia and neurodegeneration. However, it is still unclear if α-TCT exhibits beneficial effects during brain development. We hypothesized that treatment with α-TCT improves intracellular redox homeostasis supporting normal development of neurons. We found that primary hippocampal neurons isolated from rat feti grown in α-TCT-containing media achieved greater levels of neurite complexity compared to ethanol-treated control neurons. Neurons were treated with 1 μM α-TCT for 3 weeks, and media were replaced with fresh α-TCT every week. Treatment with α-TCT increased α-TCT levels (26 pmol/mg protein) in the cells, whereas the control neurons did not contain α-TCT. α-TCT-treated neurons produced adenosine triphosphate (ATP) at a higher rate and increased ATP retention at neurites, supporting formation of neurite branches. Although treatment with α-TCT alone did not change neuronal viability, neurons grown in α-TCT were more resistant to death at maturity. We further found that messenger RNA and protein levels of B-cell lymphoma-extra large (Bcl-xL) are increased by α-TCT treatment without inducing posttranslational cleavage of Bcl-xL. Bcl-xL is known to enhance mitochondrial energy production, which improves neuronal function including neurite outgrowth and neurotransmission. Therefore α-TCT-mediated Bcl-xL upregulation may be the central mechanism of neuroprotection seen in the α-TCT-treated group. In summary, treatment with α-TCT upregulates Bcl-xL and increases ATP levels at neurites. This correlates with increased neurite branching during development and with protection of mature neurons against oxidative stress.

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Potential “Therapeutic” Effects of Tocotrienol-Rich Fraction (TRF) and Carotene “Against” Bleomycin-Induced Pulmonary Fibrosis in Rats via TGF-β/Smad, PI3K/Akt/mTOR and NF-κB Signaling Pathways

Yifei Lu, Yihan Zhang, Zhenyu Pan, Chao Yang, Lin Chen, Yuanyuan Wang, Dengfeng Xu, Hui Xia, Shaokang Wang, Shiqing Chen, Yoong Jun Hao, Guiju Sun

Nutrients . 2022 Mar 5;14(5):1094. doi: 10.3390/nu14051094.

Abstract

Background: Pulmonary fibrosis (PF) is a chronic, progressive, and, ultimately, terminal interstitial disease caused by a variety of factors, ranging from genetics, bacterial, and viral infections, to drugs and other influences. Varying degrees of PF and its rapid progress have been widely reported in post-COVID-19 patients and there is consequently an urgent need to develop an appropriate, cost-effective approach for the prevention and management of PF.

Aim: The potential “therapeutic” effect of the tocotrienol-rich fraction (TRF) and carotene against bleomycin (BLM)-induced lung fibrosis was investigated in rats via the modulation of TGF-β/Smad, PI3K/Akt/mTOR, and NF-κB signaling pathways.

Design/methods: Lung fibrosis was induced in Sprague-Dawley rats by a single intratracheal BLM (5 mg/kg) injection. These rats were subsequently treated with TRF (50, 100, and 200 mg/kg body wt/day), carotene (10 mg/kg body wt/day), or a combination of TRF (200 mg/kg body wt/day) and carotene (10 mg/kg body wt/day) for 28 days by gavage administration. A group of normal rats was provided with saline as a substitute for BLM as the control. Lung function and biochemical, histopathological, and molecular alterations were studied in the lung tissues.

Results: Both the TRF and carotene treatments were found to significantly restore the BLM-induced alterations in anti-inflammatory and antioxidant functions. The treatments appeared to show pneumoprotective effects through the upregulation of antioxidant status, downregulation of MMP-7 and inflammatory cytokine expressions, and reduction in collagen accumulation (hydroxyproline). We demonstrated that TRF and carotene ameliorate BLM-induced lung injuries through the inhibition of apoptosis, the induction of TGF-β1/Smad, PI3K/Akt/mTOR, and NF-κB signaling pathways. Furthermore, the increased expression levels were shown to be significantly and dose-dependently downregulated by TRF (50, 100, and 200 mg/kg body wt/day) treatment in high probability. The histopathological findings further confirmed that the TRF and carotene treatments had significantly attenuated the BLM-induced lung injury in rats.

Conclusion: The results of this study clearly indicate the ability of TRF and carotene to restore the antioxidant system and to inhibit proinflammatory cytokines. These findings, thus, revealed the potential of TRF and carotene as preventive candidates for the treatment of PF in the future.

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Supercritical fluid chromatography with post-column addition of supporting electrolyte solution for electrochemical determination of tocopherol and tocotrienol isomers

Kazuhiro Yamamoto, Takuma Nishimura, Koichi Machida, Akira Kotani, Hideki Hakamata

J Sep Sci . 2022 Mar 5. doi: 10.1002/jssc.202100923. Online ahead of print.

Abstract

A supercritical fluid chromatography with electrochemical detection system was developed for the simultaneous determination of tocopherol and tocotrienol isomers. The supercritical fluid chromatography with electrochemical detection system was connected with an additional pump to create a flow path to add a supporting electrolyte solution. The supporting electrolyte solution was mixed with a mobile phase in a post-column fashion, enabling the independent control of the separation and detection. After optimization of the measurement conditions, vitamin E isomers and an internal standard substance (2,2,5,7,8-pentamethyl-6-hydroxychroman) were separated within 30 min using a mixture of supercritical carbon dioxide and methanol (99:1, v/v) as a mobile phase and a cyanopropyl column (4.6 mm inner diameter × 250 mm length, 5 μm). For the electrochemical detection, methanol containing 1.0 mol/L ammonium acetate was used as a supporting electrolyte solution, and the applied potential was set at +0.8 V. This analytical method showed good linearity (5-100 μg/mL) and repeatability (less than 2.5% relative standard deviation, n = 6) and was applicable to the determination of tocopherol and tocotrienol isomers in nutrition supplements.

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Effect of tocotrienol on the primary progression of nonalcoholic steatohepatitis in a mouse model

Jun Noichi, Tomoko Ishiakawa, Ikuyo Ichi, Yoko Fujiwara

J Clin Biochem Nutr . 2022 Mar;70(2):140-146. doi: 10.3164/jcbn.21-69. Epub 2021 Oct 2.

Abstract

Tocotrienol (T3), a vitamin E (Vit E) isoform, is known to have both biological and antioxidant effects. Although alpha-tocopherol (α-Toc), another isoform of Vit E is suggested to be a useful treatment against nonalcoholic steatohepatitis (NASH), the effect of T3 on NASH is unclear. This study aimed to comparatively evaluate the effects of T3 and α-Toc on NASH in the early stage of NASH progression, using a recently established NASH mouse model induced by a choline-deficient l-amino acid-defined high-fat diet (CDAHFD). Six-week-old male mice were divided into four groups (n = 6 per group) and fed the CDAHFD for 1 week. The first group was given no other treatment (Pre). The other three groups continued the CDAHFD plus daily oral administration of Vit E-free corn oil (Control), corn oil containing α-Toc, or corn oil containing T3 for additional 2 weeks. Neither Vit E treatment changed the histologic features of NASH, but T3 significantly reduced the mRNA expression of several genes related to inflammation and fibrosis and α-Toc did not. These results suggested that oral T3 treatment was more effective than α-Toc at suppressing hepatic inflammation and fibrosis in the early stage of NASH progression in CDAHFD model mice.

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The tocopherol transfer protein mediates vitamin E trafficking between cerebellar astrocytes and neurons

L Ulatowski, Mikel Ghelfi, Ryan West, J Atkinson, C J Finno, D Manor

J Biol Chem . 2022 Mar;298(3):101712. doi: 10.1016/j.jbc.2022.101712. Epub 2022 Feb 9.

Abstract

Alpha-tocopherol (vitamin E) is an essential nutrient that functions as a major lipid-soluble antioxidant in humans. The alpha-tocopherol transfer protein (TTP) binds α-tocopherol with high affinity and selectivity and regulates whole-body distribution of the vitamin. Heritable mutations in the TTPA gene result in familial vitamin E deficiency, elevated indices of oxidative stress, and progressive neurodegeneration that manifest primarily in spinocerebellar ataxia. Although the essential role of vitamin E in neurological health has been recognized for over 50 years, the mechanisms by which this essential nutrient is transported in the central nervous system are poorly understood. Here we found that, in the murine cerebellum, TTP is selectively expressed in glial fibrillary acidic protein-positive astrocytes, where it facilitates efflux of vitamin E to neighboring neurons. We also show that induction of oxidative stress enhances the transcription of the TtpA gene in cultured cerebellar astrocytes. Furthermore, secretion of vitamin E from astrocytes is mediated by an ABC-type transporter, and uptake of the vitamin into neurons involves the low-density lipoprotein receptor-related protein 1. Taken together, our data indicate that TTP-expressing astrocytes control the delivery of vitamin E from astrocytes to neurons, and that this process is homeostatically responsive to oxidative stress. These are the first observations that address the detailed molecular mechanisms of vitamin E transport in the central nervous system, and these results have important implications for understanding the molecular underpinnings of oxidative stress-related neurodegenerative diseases.

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Vitamin E in the treatment of tardive dyskinesia: a meta-analysis

Hongyan Xu, Haoqiang Qin, Shaohua Chen, Mingjian Guan

Int Clin Psychopharmacol . 2022 Mar 1;37(2):60-66. doi: 10.1097/YIC.0000000000000387.

Abstract

Long-term use of antipsychotic drugs is associated with tardive dyskinesia. At present, there is no satisfactory treatment for tardive dyskinesia. Some randomized trials suggested that vitamin E can improve tardive dyskinesia. This study was undertaken to evaluate the effects of vitamin E treatment for tardive dyskinesia. We searched internet databases for randomized controlled trials. A total of 21 studies including 854 patients with tardive dyskinesia were included in this meta-analysis. Eighteen studies reported the Abnormal Involuntary Movements Scale (AIMS) as the primary outcome. After vitamin E treatment, a decrease of 2.36 (95% CI = -3.27 to -1.45; P < 0.00001) in the AIMS was observed in the treatment group, compared with the control group. Vitamin E may offer a new avenue treatment for tardive dyskinesia.

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Gamma-tocotrienol, a radiation countermeasure, reverses proteomic changes in serum following total-body gamma irradiation in mice

Elliot Rosen, Oluseyi O Fatanmi, Stephen Y Wise, V Ashutosh Rao, Vijay K Singh

Sci Rep . 2022 Mar 1;12(1):3387. doi: 10.1038/s41598-022-07266-5.

Abstract

Radiological incidents or terrorist attacks would likely expose civilians and military personnel to high doses of ionizing radiation, leading to the development of acute radiation syndrome. We examined the effectiveness of prophylactic administration of a developmental radiation countermeasure, γ-tocotrienol (GT3), in a total-body irradiation (TBI) mouse model. CD2F1 mice received GT3 24 h prior to 11 Gy cobalt-60 gamma-irradiation. This dose of radiation induces severe hematopoietic acute radiation syndrome and moderate gastrointestinal injury. GT3 provided 100% protection, while the vehicle control group had 100% mortality. Two-dimensional differential in-gel electrophoresis was followed by mass spectrometry and Ingenuity Pathway Analysis (IPA). Analysis revealed a change in expression of 18 proteins in response to TBI, and these changes were reversed with prophylactic treatment of GT3. IPA revealed a network of associated proteins involved in cellular movement, immune cell trafficking, and inflammatory response. Of particular interest, significant expression changes in beta-2-glycoprotein 1, alpha-1-acid glycoprotein 1, alpha-2-macroglobulin, complement C3, mannose-binding protein C, and major urinary protein 6 were noted after TBI and reversed with GT3 treatment. This study reports the untargeted approach, the network, and specific serum proteins which could be translated as biomarkers of both radiation injury and protection by countermeasures.

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Oil-based vitamin E oral spray for oral health in pregnancy

Sabrina Reppuccia, Felice Crocetto, Elisabetta Gragnano, Pietro D'Alessandro, Martin Vetrella, Gabriele Saccone, Bruno Arduino

Future Sci OA . 2022 Mar 1;8(4):FSO790. doi: 10.2144/fsoa-2021-0095. eCollection 2022 Apr.

Abstract

Aim: To assess the efficacy of vitamin E oral spray in pregnancy.

Materials & methods: This was a retrospective study aimed to evaluate efficacy of vitamin E oral spray (vitamin E acetate in a medium chain tryglicerides vehicle – patented formulation) starting from the first trimester of pregnancy, with a control group.

Results: A total of 100 women were included in the study and were compared with a matched control group. Only 25/200 women reported to have at least one teeth cleaning during pregnancy. Women who received the oral spray had a significantly lower risk of preterm birth compared with the control group, and lower risk of periodontal diseases.

Conclusion: Use of oil-based vitamin E oral spray in pregnancy is associated with a decreased risk of periodontal diseases and therefore preterm birth.

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