The effects of vitamin E on non-proliferative diabetic retinopathy in type 2 diabetes mellitus: Are they sustainable with 12 months of therapy

J-Ian Ho, En Yng Ng, Yilynn Chiew, Yan Yi Koay, Pei Fen Chuar, Sonia Chew Wen Phang, Badariah Ahmad, Khalid Abdul Kadir

SAGE Open Med . 2022 May 26;10:20503121221095324. doi: 10.1177/20503121221095324. eCollection 2022.


Introduction: Prolonged uncontrolled hyperglycaemia has shown to cause oxidative stress, inflammation, thrombosis and upregulation of angiogenesis in diabetics, which all contributes to diabetic retinopathy development and progression. Vitamin E is found to have anti-inflammatory, anti-oxidative, anti-thrombogenic and anti-angiogenesis which could play an important role in early treatment of diabetic retinopathy. This study aims to investigate the effect of Tocotrienol-rich vitamin E (Tocovid) on the progression of retinal microhaemorrhages and diabetic macular oedema in patients with diabetic retinopathy.

Method: This is a multi-centred, randomized, double-blinded, placebo-controlled trial which involved 55 eligible participants. The participants in the treatment group (n = 22) received Tocovid 200 mg twice daily while those in the placebo group (n = 23) would receive placebo twice daily. Both groups will be on the treatment for a total duration of 12 months. Both retinal signs will be assessed at baseline, 2 months, 6 months and 12 months of treatment to determine the progression of diabetic retinopathy. Serum vascular endothelial growth factor which reflects on the angiogenesis process in the eye was analysed as well at similar time points as the retinal findings.

Results: After 12 months of treatment, the placebo group had a significant increase of 23.42% in retinal microhaemorrhages (p < 0.05), but the Tocovid group had no significant changes. Moreover, the Tocovid group showed a significant decrease of 48.38% in area of diabetic macular oedema over the 12 months period (p < 0.05), but the placebo group had no significant changes. Meanwhile, there was no significant difference in serum vascular endothelial growth factor level when comparing between both groups.

Conclusion: These findings could indicate that Tocovid has an important role in preventing early diabetic retinopathy progression.

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Vitamin E supplementation improves testosterone, glucose- and lipid-related metabolism in women with polycystic ovary syndrome: a meta-analysis of randomized clinical trials

Sebastián Yalle-Vásquez, Karem Osco-Rosales, Wendy Nieto-Gutierrez, Vicente Benites-Zapata, Faustino R Pérez-López, Christoper A Alarcon-Ruiz

Gynecol Endocrinol . 2022 May 25;1-10. doi: 10.1080/09513590.2022.2079629. Online ahead of print


Aim: This systematic review and meta-analysis assessed the effect of vitamin E supplementation on testosterone, glucose, lipid profile, pregnancy rate, hirsutism, and body mass index (BMI) in women with polycystic ovary syndrome (PCOS).

Methods: A multi-database search was performed from inception to January 2022 for randomized controlled trials (RCTs) reporting the effects of vitamin E supplementation with or without another nutritional supplement on women with PCOS. A random-effects model was used to obtain mean differences (MDs) and its 95% confidence intervals (95%CI). Evidence certainty was assessed with GRADE methodology.

Results: We meta-analyzed eight RCTs reporting vitamin E supplementation alone or combined with other individual substances like omega-3, vitamin D3, or magnesium oxide in adult women ≤40 years old with PCOS. Vitamin E supplementation reduced fasting glucose (MD: -1.92 mg/dL, 95%CI: -3.80 to -0.05), fasting insulin (MD: -2.24 µIU/mL, 95%CI: -3.34 to -1.14), HOMA-IR (MD: -0.42, 95%CI: -0.65 to -0.19), total cholesterol (MD: -18.12 mg/dL, 95%CI: -34.37 to -1.86), LDL-cholesterol (MD: -15.92 mg/dL, 95%CI: -29.93 to -1.90), triglycerides (MD: -20.95 mg/dL, 95%CI: -37.31 to -4.58), total testosterone (MD: -0.42 ng/mL, 95%CI: -0.55 to -0.29), and increased sex hormone-binding globulin (MD: 7.44 nmol/L, 95%CI: 2.68 to 12.20). However, it had no impact on female sex hormones, HDL-cholesterol, BMI, and hirsutism. Two RCTs assessed pregnancy and implantation rates with inconsistent results. The certainty of the evidence was very low to moderate.

Conclusion: Vitamin E supplementation improves glucose, lipid, and androgenic-related biomarkers in women with PCOS.

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In-vitro and in-vivo evaluations of tocotrienol-rich nanoemulsified system on skin wound healing

Wai Ting Chong, Chin Ping Tan, Yoke Kqueen Cheah, Oi Ming Lai

PLoS One . 2022 May 25;17(5):e0267381. doi: 10.1371/journal.pone.0267381. eCollection 2022


Proper wound healing is vital for the survival of higher organisms. Responses to skin injury can lead to complications such as scar formation that can affect the quality of life. In this study, keratinocytes migration (scratch assay) and zebrafish tail regeneration experiments were used to evaluate the wound healing effect of a tocotrienol-based nanoemulsified (NE) system against ascorbic acid and phosphate-buffered saline (PBS) as positive and negative controls, respectively. MTT assay provided a concentration range of 0.35-8.75 μg/ml of nanoemulsion that produced cell viability more than 100%. After 24 hours of treatment, the wound closure of keratinocytes were found to be significantly faster by 73.76%, 63.37% and 35.56%, respectively when treated with 3.50 μg/ml and 1.75 μg/ml of NE compared to the blank. The lethal concentration at 50% (LC50 value) obtained from acute and prolonged toxicity was almost similar, which was 4.6 mg/ml and 5.0 mg/ml, respectively. Growth of zebrafish tail regeneration treated with NE at a concentration of 2.5 mg/ml was significantly faster than the untreated zebrafish, which regenerated to 40% on the fifth day, more than 60% on the tenth day of treatment and fully recovered at the twentieth day. In conclusion, these results showed the potential of the tocotrienols-based nanoemulsified system in enhancing wound healing through accelerated wound closure.

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Vitamin E (Alpha-Tocopherol) Metabolism and Nutrition in Chronic Kidney Disease

Francesco Galli, Mario Bonomini, Desirée Bartolini, Linda Zatini, Gianpaolo Reboldi, Giada Marcantonini, Giorgio Gentile, Vittorio Sirolli, Natalia Di Pietro

Antioxidants (Basel) . 2022 May 18;11(5):989. doi: 10.3390/antiox11050989


Vitamin E (alpha-tocopherol) is an essential micronutrient and fat-soluble antioxidant with proposed role in protecting tissues from uncontrolled lipid peroxidation. This vitamin has also important protein function and gene modulation effects. The metabolism of vitamin E depends on hepatic binding proteins that selectively retain food alpha-tocopherol for incorporation into nascent VLDL and tissue distribution together with esterified cholesterol and triglycerides. Chronic kidney disease (CKD) is a condition of oxidative stress and increased lipid peroxidation, that are associated with alterations of alpha-tocopherol metabolism and function. Specific changes have been reported for the levels of its enzymatic metabolites, including both short-chain and long-chain metabolites, the latter being endowed with regulatory functions on enzymatic and gene expression processes important for the metabolism of lipids and xenobiotics detoxification, as well as for the control of immune and inflammatory processes. Vitamin E therapy has been investigated in CKD using both oral vitamin E protocols and vitamin E-coated hemodialyzers, showing promising results in the secondary prevention of cardiovascular disease, as well as of immune and hematological complications. These therapeutic approaches are reviewed in the present article, together with a narrative excursus on the main findings indicating CKD as a condition of relative deficiency and impaired metabolism of vitamin E.

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RHR: The Health Benefits of Tocotrienols, with Dr. Barrie Tan

Dr. Barrie Tan, one of the world’s foremost experts in vitamin E, joins Chris Kresser in this episode of Revolution Health Radio to discuss tocotrienols and their health benefits. Dr. Tan talks about his discovery of the tocotrienol content in the annatto plant, explains how tocotrienols differ from and interact with tocopherols (the more commonly-known form of vitamin E), and discusses research showing the potential benefits of tocotrienols on everything from osteoporosis and bone health to inflammatory conditions, cardiovascular risk, metabolic conditions, and cancer prevention.

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Exploiting the Metabolic Consequences of PTEN Loss and Akt/Hexokinase 2 Hyperactivation in Prostate Cancer: A New Role for δ-Tocotrienol

Fabrizio Fontana, Martina Anselmi, Patrizia Limonta

Int J Mol Sci . 2022 May 9;23(9):5269. doi: 10.3390/ijms23095269.


The Warburg effect is commonly recognized as a hallmark of nearly all tumors. In prostate cancer (PCa), it has been shown to be driven by PTEN loss- and Akt hyperactivation-associated upregulation of hexokinase 2 (HK2). δ-Tocotrienol (δ-TT) is an extensively studied antitumor compound; however, its role in affecting PCa glycolysis is still unclear. Herein, we demonstrated that δ-TT inhibits glucose uptake and lactate production in PTEN-deficient LNCaP and PC3 PCa cells, by specifically decreasing HK2 expression. Notably, this was accompanied by the inhibition of the Akt pathway. Moreover, the nutraceutical could synergize with the well-known hypoglycemic agent metformin in inducing PCa cell death, highlighting the crucial role of the above metabolic phenotype in δ-TT-mediated cytotoxicity. Collectively, these results unravel novel inhibitory effects of δ-TT on glycolytic reprogramming in PCa, thus providing new perspectives into the mechanisms of its antitumor activity and into its use in combination therapy.

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Antioxidant effects of vitamin E and risk of cardiovascular disease in women with obesity – A narrative review

Anna Maria Rychter, Szymon Hryhorowicz, Ryszard Słomski, Agnieszka Dobrowolska, Iwona Krela-Kaźmierczak

Clin Nutr . 2022 May 6;41(7):1557-1565. doi: 10.1016/j.clnu.2022.04.032. Online ahead of print.


Proper dietary habits are a vital element of cardiovascular (CV) treatment, and – according to the current guidelines – a diet rich in antioxidants is generally recommended. It remains, however, inconclusive whether antioxidant nutrients should be supplemented for CV health, and if so, in which form and dosage. Currently available data suggest that vitamin E may be essential in preventing CVD, especially in coronary heart disease and atherosclerosis – nevertheless, vitamin E supplementation may be questionable and may even be associated with adverse outcomes. Further, current studies highlight a strong need for identifying sex-specific strategies, which could improve guidelines for both the prevention and management of cardiovascular disease (CVD). It should also be emphasized that understanding the role of genetic variants in genes involved in VE metabolism may also be crucial for more precise nutritional recommendations for patients suffering from CVD. Therefore, we summarize the current knowledge regarding vitamin E antioxidant properties, which could be essential from CV perspective, and aim to assess whether vitamin E supplementation can be beneficial in CV prevention, especially in the high-risk group of women with obesity.

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Alpha- and Gamma-Tocopherol Modulates the Amyloidogenic Pathway of Amyloid Precursor Protein in an in vitro Model of Alzheimer’s Disease: A Transcriptional Study

Aslina Pahrudin Arrozi, Siti Nur Syazwani Shukri, Nuraqila Mohd Murshid, Ahmad Baihaqi Ahmad Shahzalli, Wan Zurinah Wan Ngah, Hanafi Ahmad Damanhuri, Suzana Makpol

Front Cell Neurosci . 2022 May 5;16:846459. doi: 10.3389/fncel.2022.846459. eCollection 2022.


The amyloid precursor protein (APP) processing pathway was altered in Alzheimer’s disease (AD) and contributed to abnormal amyloid-beta (Aβ) production, which forms insoluble interneuron protein aggregates known as amyloid plaques in the brain. Targeting the APP processing pathway is still fundamental for AD modifying therapy. Extensive research has evaluated the protective effects of vitamin E as an antioxidant and as a signaling molecule. The present study aimed to investigate the modulatory effects of different tocopherol isomers on the expression of genes involved in regulating the APP processing pathway in vitro. The screening for the effective tocopherol isomers in reducing APP expression and Aβ-42 was carried out in SH-SY5Y stably overexpressed APP Swedish. Subsequently, quantitative one-step real-time PCR was performed to determine the modulatory effects of selected tocopherol isomers on the expression of genes in SH-SY5Y stably overexpressed three different types of APP (wild-type, APP Swedish, and APP Swedish/Indiana). Our results showed that all tocopherol isomers, especially at higher concentrations (80-100 μM), significantly increased (p < 0.05) the cell viability in all cells group, but only α-tocopherol (ATF) and γ-tocopherol (GTF) significantly decreased (p < 0.05) the APP mRNA level without statistically significant APP protein level, accompanied with a reduced significance (p < 0.05) on the level of Aβ-42 in SH-SY5Y APP Swedish. On the other hand, β- and δ-tocopherol (BTF and DTF) showed no effects on the level of APP expression and Aβ-42. Subsequent results demonstrated that ATF and GTF significantly decreased (p < 0.05) the expression of gene beta-site APP cleaving enzyme (BACE1), APH1B, and Nicastrin (NCSTN), but significantly increased (p < 0.05) the expression of Sirtuin 1 (SIRT1) in SH-SY5Y stably expressed the mutant APP form. These findings suggested that ATF and GTF could modulate altered pathways and may help ameliorate the burden of amyloid load in AD.

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Molecular Mechanisms Underlying the Therapeutic Role of Vitamin E in Age-Related Macular Degeneration

Genea Edwards, Caroline G Olson, Carlyn P Euritt, Peter Koulen

Front Neurosci . 2022 May 4;16:890021. doi: 10.3389/fnins.2022.890021. eCollection 2022.


The eye is particularly susceptible to oxidative stress and disruption of the delicate balance between oxygen-derived free radicals and antioxidants leading to many degenerative diseases. Attention has been called to all isoforms of vitamin E, with α-tocopherol being the most common form. Though similar in structure, each is diverse in antioxidant activity. Preclinical reports highlight vitamin E’s influence on cell physiology and survival through several signaling pathways by activating kinases and transcription factors relevant for uptake, transport, metabolism, and cellular action to promote neuroprotective effects. In the clinical setting, population-based studies on vitamin E supplementation have been inconsistent at times and follow-up studies are needed. Nonetheless, vitamin E’s health benefits outweigh the controversies. The goal of this review is to recognize the importance of vitamin E’s role in guarding against gradual central vision loss observed in age-related macular degeneration (AMD). The therapeutic role and molecular mechanisms of vitamin E’s function in the retina, clinical implications, and possible toxicity are collectively described in the present review.

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Vitamin E rescues valproic acid-induced testicular injury in rats: Role of autophagy

Amira Ebrahim Alsemeh, Marwa Mahmood Ahmed, Amal Fawzy, Walaa Samy, Marwa Tharwat, Samar Rezq

Life Sci . 2022 May 1;296:120434. doi: 10.1016/j.lfs.2022.120434. Epub 2022 Feb 25.


Aims: Valproic acid (VPA), a commonly used antiepileptic drug, can induce testicular oxidative stress and injury. Altered autophagic response usually follows testicular injury. The study aims to evaluate the role of autophagy in the protective effect of the antioxidant vitamin E (Vit E) against VPA-induced testicular injury.

Materials and methods: VPA (100, 300, and 500 mg/kg/day) was administered for 8 days. The protective group received both Vit E (50 mg/kg) and VPA (500 mg/kg). The testicular weight, sperm analysis, and serum testosterone concentration, as well as testicular histopathology, steroidogenic gene expression, and oxidative stress markers were evaluated. The mRNA or protein expression of autophagy-related proteins [adenosine monophosphate-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), microtubule-associated protein light chain 3 (LC3), Beclin1, and p62] were measured using RT-PCR or immunohistochemistry.

Key findings: VPA resulted in lower testes weight and sperm quality with aberrant morphology. VPA dose-dependently induced testicular oxidative stress, which was associated with decreased steroidogenic gene expression and serum testosterone levels, as well as deteriorated histopathology. These biochemical and histological changes were also associated with autophagy induction (higher LC3 and Beclin1, and lower p62) that was lost with the highest toxic dose (500 mg/kg). The attenuated autophagy with the highest dose was accompanied by AMPK downregulation and mTOR upregulation. Vit E protected against VPA-mediated oxidative stress and toxicity while also restoring autophagic response and AMPK/mTOR levels.

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