The Ameliorative Effects of a Tocotrienol-Rich Fraction on the AGE-RAGE Axis and Hypertension in High-Fat-Diet-Fed Rats with Metabolic Syndrome.

Cheng HS, Ton SH, Tan JBL, Abdul Kadir K

Nutrients. 2017 Sep 7;9(9). pii: E984. doi: 10.3390/nu9090984.

Abstract

The clinical value of tocotrienols is increasingly appreciated because of the unique therapeutic effects that are not shared by tocopherols. However, their effect on metabolic syndrome is not well-established. This study aimed to investigate the effects of a tocotrienol-rich fraction (TRF) from palm oil in high-fat-diet-treated rats. Male, post-weaning Sprague Dawley rats were provided high-fat (60% kcal) diet for eight weeks followed by a TRF (60 mg/kg) treatment for another four weeks. Physical, metabolic, and histological changes were compared to those on control and high-fat diets respectively. High-fat feeding for eight weeks induced all hallmarks of metabolic syndrome. The TRF reversed systolic and diastolic hypertension, hypercholesterolemia, hepatic steatosis, impaired antioxidant defense, and myeloperoxidase hyperactivity triggered by the high-fat diet. It also conferred an inhibitory effect on protein glycation to reduce glycated hemoglobin A1c and advanced glycation end products (AGE). This was accompanied by the suppression of the receptor for advanced glycation end product (RAGE) expression in the liver. The treatment effects on visceral adiposity, glycemic control, triglyceride level, as well as peroxisome proliferator-activated receptor α and γ expression were negligible. To conclude, treatment with a TRF exhibited protective effects on the cardiovascular and liver health in addition to the amelioration of plasma redox imbalance and AGE-RAGE activation. Further investigation as a therapy for metabolic syndrome is therefore worthwhile.

Peh HY, Tan WSD, Chan TK, Pow CW, Foster PS, Wong WSF.

Free Radic Biol Med. 2017 Sep;110:332-344. doi: 10.1016/j.freeradbiomed.2017.06.023. Epub 2017 Jul 3.

Abstract

Inflammation and oxidative stress contribute to emphysema in COPD. Although corticosteroids are the standard of care for COPD, they do not reduce oxidative stress, and a subset of patients is steroid-resistant. Vitamin E isoform γ-tocotrienol possesses both anti-inflammatory and anti-oxidative properties that may protect against emphysema. We aimed to establish the therapeutic potential of γ-tocotrienol in cigarette smoke-induced COPD models in comparison with prednisolone. BALB/c mice were exposed to cigarette smoke for 2 weeks or 2 months. γ-Tocotrienol and prednisolone were given orally. Bronchoalveolar lavage (BAL) fluid and lung tissues were assessed for inflammation, oxidative damage, and regulation of transcription factor activities. Emphysema and lung function were also evaluated. γ-Tocotrienol dose-dependently reduced cigarette smoke-induced BAL fluid neutrophil counts and levels of cytokines, chemokines and oxidative damage biomarkers, and pulmonary pro-inflammatory and pro-oxidant gene expression, but restored lung endogenous antioxidant activities. γ-Tocotrienol acted by inhibiting nuclear translocation of STAT3 and NF-κB, and up-regulating Nrf2 activation in the lungs. In mice exposed to 2-month cigarette smoke, γ-tocotrienol ameliorated bronchial epithelium thickening and destruction of alveolar sacs in lungs, and improved lung functions. In comparison with prednisolone, γ-tocotrienol demonstrated better anti-oxidative efficacy, and protection against emphysema and lung function in COPD. We revealed for the first time the anti-inflammatory and antioxidant efficacies of γ-tocotrienol in cigarette smoke-induced COPD models. In addition, γ-tocotrienol was able to attenuate emphysematous lesions and improve lung function in COPD. γ-Tocotrienol may have therapeutic potential for the treatment of COPD.

Kalantari A, Saremi A, Shavandi N, Foroutan Nia A

Urol J. 2017 Aug 29;14(5):5023-5026.

Abstract

PURPOSE:

The aim of this study was to evaluate the effect of 4 week intensive swimming exercise and alpha-tocopherol supplementation on testicular oxidative stress and spermatogenesis in rats.

MATERIALS AND METHODS:

40 male rats were randomly assigned to Control (C), Sham (S), Exercise (E) and Exercise + supplement (ES) groups. Exercise training performed for 4 weeks (1session/day, 6days/week). Each session included 180 minutes of swimming. In ES group, alpha-ocopherol was injected at a dose of 50 mg/kg/day. 48 hours after last training session, all rats were killed and gonads of them were removed from their body for histological and biochemical assays. All statistical analysis was performed by SPSS 16. P values less than 0.05 were considered as statistically significant.

RESULTS:

Total testicular antioxidant capacity increased significantly in E (P = .003) and ES groups (P = .001) whereas there was no significant difference between C and E group in testicle Malondialdehyde (a lipid peroxidation marker) level (P = .999) and spermatogenesis quality (P = .381). Testicle Malondialdehyde level decreased (P = .009) and spermatogenesis quality was improved significantly in ES group (P = .001).

CONCLUSION:

Alpha-tocopherol supplementation is effective in order to improve spermatogenesis process in athletes who exercise with high intensity.

Nur Azlina MF, Qodriyah HMS, Chua KH, Kamisah Y

World J Gastroenterol. 2017 Aug 28;23(32):5887-5894. doi: 10.3748/wjg.v23.i32.5887.

Abstract

AIM:

To investigate and compare the effects of tocotrienol and omeprazole on gastric growth factors in rats exposed to water-immersion restraint stress (WIRS).

METHODS:

Twenty-eight male Wistar rats were randomly assigned to four groups of seven rats. The two control groups were administered vitamin-free palm oil (vehicle) and the two treatment groups were given omeprazole (20 mg/kg) or tocotrienol (60 mg/kg) by oral gavage. After 28 d of treatment, rats from one control group and both treated groups were subjected to WIRS one time for 3.5 h. Gastric lesions were measured and gastric tissues were obtained to measure vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), and transforming growth factor-alpha (TGF-α) mRNA expression.

RESULTS:

Rats exposed to WIRS for 3.5 h demonstrated the presence of considerable ulcers in the form of gastric erosion. The lesion index in the stressed control (S) group was increased (P < 0.001) compared to the tocotrienol treated and omeprazole treated groups. Stress led to a decrease in gastric VEGF (P < 0.001), bFGF (P < 0.001) and TGF-α (P < 0.001) mRNA levels and caused an increase in EGF mRNA (P < 0.001) that was statistically significant compared to the non-stressed control group. Although both treatment agents exerted similar ulcer reducing ability, only treatment with tocotrienol led to increased expression of VEGF (P = 0.008), bFGF (P = 0.001) and TGF-α (P = 0.002) mRNA.

CONCLUSION:

Tocotrienol provides gastroprotective effects in WIRS-induced ulcers. Compared to omeprazole, tocotrienol exerts a similar protective effect, albeit through multiple mechanisms of protection, particularly through up-regulation of growth factors that assist in repair of gastric tissue injuries.

Jang Y, Rao X, Jiang Q

J Nutr Biochem. 2017 Aug;46:49-56. doi: 10.1016/j.jnutbio.2017.04.003. Epub 2017 Apr 12.

Abstract

Vitamin E gamma-tocotrienol (γTE) is known to have anticancer effects, but mechanisms underlying these actions are not clear. Here using liquid chromatography tandem mass spectrometry, we show that γTE induced marked changes of sphingolipids including rapid elevation of dihydrosphingosine and dihydroceramides (dhCers) in various types of cancer cells. The elevation of dihydrosphingolipids coincided with increased cellular stress, as indicated by JNK phosphorylation, and was prior to any sign of induction of apoptosis. Chemically blocking de novo synthesis of sphingolipids partially counteracted γTE-induced apoptosis and autophagy. Experiments using ¹³C₃, ¹⁵N-labeled l-serine together with enzyme assays indicate that γTE inhibited cellular dihydroceramide desaturase (DEGS) activity without affecting its protein expression or de novo synthesis of sphingolipids. Unlike the effect on dhCers, γTE decreased ceramides (Cers) after 8-h treatment but increased C_18:0-Cer and C_16:0-Cer after 16 and 24 h, respectively. The increase of Cers coincides with γTE-induced apoptosis and autophagy. Since γTE inhibits DEGS and decreases de novo Cer synthesis, elevation of Cers during prolonged γTE treatment is likely caused by sphingomeylinase-mediated hydrolysis of sphingomyelin. This idea is supported by the observation that an acid sphingomeylinase inhibitor partially reversed γTE-induced cell death. Our study demonstrates that γTE altered sphingolipid metabolism by inhibiting DEGS activity and possibly by activating SM hydrolysis during prolonged treatment in cancer cells.

Shen CL, Klein A, Chin KY, Mo H, Tsai P, Yang RS, Chyu MC, Ima-Nirwana S

Ann N Y Acad Sci. 2017 Aug;1401(1):150-165. doi: 10.1111/nyas.13449.

Abstract

Osteoporosis, a degenerative bone disease, is characterized by low bone mass and microstructural deterioration of bone tissue resulting in aggravated bone fragility and susceptibility to fractures. The trend of extended life expectancy is accompanied by a rise in the prevalence of osteoporosis and concomitant complications in the elderly population. Epidemiological evidence has shown an association between vitamin E consumption and the prevention of age-related bone loss in elderly women and men. Animal studies show that ingestion of vitamin E, especially tocotrienols, may benefit bone health in terms of maintaining higher bone mineral density and improving bone microstructure and quality. The beneficial effects of tocotrienols on bone health appear to be mediated via antioxidant/anti-inflammatory pathways and/or 3-hydroxy-3-methylglutaryl coenzyme A mechanisms. We discuss (1) an overview of the prevalence and etiology of osteoporosis, (2) types of vitamin E (tocopherols versus tocotrienols), (3) findings of tocotrienols and bone health from published in vitro and animal studies, (4) possible mechanisms involved in bone protection, and (5) challenges and future direction for research.

Ikegami H, Kawawa R, Ichi I, Ishikawa T, Koike T, Aoki Y, Fujiwara Y

J Nutr. 2017 Aug 23. pii: jn248575. doi: 10.3945/jn.117.248575. [Epub ahead of print]

Abstract

Background: Animal studies on the effects of vitamin E on bone health have yielded conflicting and inconclusive results, and to our knowledge, no studies have addressed the effect of vitamin E on bone in animals consuming a high-fat diet (HFD).Objective: This study aimed to evaluate the effect of excessive vitamin E on bone metabolism in normal male mice and ovariectomized female mice fed a normal diet (ND) or HFD.Methods: In the first 2 experiments, 7-wk-old male mice were fed an ND (16% energy from fat) containing 75 (control), 0 (vitamin E-free), or 1000 (high vitamin E) mg vitamin E/kg (experiment 1) or an HFD (46% energy from fat) containing 0, 200, 500, or 1000 mg vitamin E/kg (experiment 2) for 18 wk. In the third experiment, 7-wk-old sham-operated or ovariectomized female mice were fed the ND (75 mg vitamin E/kg) or HFD containing 0 or 1000 mg vitamin E/kg for 8 wk. At the end of the feeding period, blood and femurs were collected to measure bone turnover markers and analyze histology and microcomputed tomography.Results: In experiments 1 and 2, vitamin E intake had no effect on plasma alkaline phosphatase (ALP), tartrate-resistant acid phosphatase (TRAP) activity, or bone formation, resorption, or volume in femurs in mice fed the ND or HFDs. In experiment 3, bone volume was significantly reduced (85%) in ovariectomized mice compared with that in sham-operated mice (P < 0.05), but it did not differ among mice fed the 3 diets. Plasma ALP and TRAP activities and bone formation and resorption in femur were similar among ovariectomized mice fed the HFD containing 0 or 1000 mg vitamin E/kg.Conclusions: The results suggest that excess vitamin E intake does not cause bone loss in normal male mice or in ovariectomized or sham-operated female mice, regardless of dietary fat content.

Dong Y, Chen X, Liu Y, Shu Y, Chen T, Xu L, Li M, Guan X

Int J Geriatr Psychiatry. 2017 Aug 23. doi: 10.1002/gps.4780. [Epub ahead of print]

Abstract

OBJECTIVE:

Whether low-serum vitamin E increases the risk of Alzheimer disease (AD) in older people remains inconclusive. This meta-analysis aims to synthesize evidence-based case-control studies to evaluate the association between serum vitamin E and the risk of AD.

METHODS:

Potentially relevant studies were selected through PubMed, Embase, Wanfang, Chongqing VIP, and China National Knowledge Infrastructure databases by using the core terms Vitamin E/alpha-tocopherol and Alzheime’s disease/senile dementia/AD in the titles, abstracts, and keywords of the articles. The association between serum vitamin E levels and AD was estimated by using the weighted mean difference (WMD) and 95% confidence interval by adopting a random effects model. Heterogeneity was assessed by using Cochran Q test and I² statistic. Forest plot was used to present the results graphically from meta-analysis. Publication bias was evaluated by using funnel plots and Egger test.

RESULTS:

We identified 17 studies that met the eligibility criteria. The studies included 2057 subjects with 904 AD patients and 1153 controls. The results indicated that AD patients had a lower concentration of serum vitamin E compared with healthy controls among older people (WMD = -6.811 μmol/L, 95% confidence interval -8.998 to -4.625; Z = -6.105, P < .001). Publication bias was not detected and sensitivity analysis performed by omitting each study, and calculating the pooled WMD again for the remaining studies indicated the results stable.

CONCLUSIONS:

Alzheimer disease is associated with a low concentration of serum vitamin E in older people. However, necessary prospective cohort studies should be conducted to determine the risk of serum vitamin E for AD in the future.

Uchihara Y, Ueda F, Tago K, Nakazawa Y, Ohe T, Mashino T, Yokota S, Kasahara T, Tamura H, Funakoshi-Tago M

PLoS One. 2017 Aug 14;12(8):e0183003. doi: 10.1371/journal.pone.0183003. eCollection 2017.

Abstract

Anaplastic large cell lymphomas (ALCL) are mainly characterized by harboring the fusion protein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). The ALK inhibitor, crizotinib specifically induced apoptosis in Ba/F3 cells expressing NPM-ALK by inhibiting the activation of NPM-ALK and its downstream molecule, signal transducer and activator of transcription factor 3 (STAT3). We found that α-tocopherol, a major component of vitamin E, attenuated the effects of crizotinib independently of its anti-oxidant properties. Although α-tocopherolsuppressed the inhibitory effects of crizotinib on the signaling axis including NPM-ALK and STAT3, it had no influence on the intake of crizotinib into cells. Crizotinib also directly inhibited the kinase activity of NPM-ALK; however, this inhibitory effect was not altered by the co-treatment with α-tocopherol. Whereas the nuclear localization of NPM-ALK was disappeared by the treatment with crizotinib, the co-treatment with α-tocopherol swept the effect of crizotinib and caused the localization of NPM-ALK in nucleus. The administration of α-tocopherolattenuated the anti-tumor activity of crizotinib against NPM-ALK-provoked tumorigenesis in vivo. Furthermore, the α-tocopherol-induced inhibition of crizotinib-caused apoptosis was also observed in NPM-ALK-positive cells derived from ALCL patients, namely, SUDHL-1 and Ki-JK. Collectively, these results not only revealed the novel mechanism underlying crizotinib-induced apoptosis in NPM-ALK-positive cells, but also suggest that the anti-tumor effects of crizotinib are attenuated when it is taken in combination with vitamin E.

Chia LL, Jantan I, Chua KH

Curr Pharm Biotechnol. 2017 Aug 8. doi: 10.2174/1389201018666170808144703. [Epub ahead of print]

Abstract

BACKGROUND:

Tocotrienols (T3) are the natural occurring vitamin E derivatives that possess antioxidant properties and therapeutic potential in diabetic complications. The bioactivities of the derivatives are determined by the number and arrangement of methyl substitution on the structure.

OBJECTIVE:

The objective of this study was to determine the effects of T3 derivatives, δ-T3, γ-T3 and α-T3 on insulin secretion of rat pancreatic islets in a dynamic culture.

METHOD:

Pancreatic islets isolated from male Wistar rats were treated with T3 for 1 h at 37 oC in a microfluidic system with continuous operation that provided a stable cell culture environment. Glucose (2.8 mM and 16.7 mM, as basal and stimulant, respectively) and potassium chloride (KCl) (30 mM) were added to the treatment in calcium free medium. The supernatant were collected for insulin measurements.

RESULTS:

Short-term exposure (1 h) of δ-T3 to β cells in the stimulant glucose condition significantly potentiated insulin secretion in a dose-dependent manner. γ-T3 and α-T3 also displayed dose-dependent effect but less effective in the activation of insulin secretion. Essentially, KCl, a pancreatic β cell membrane depolarizing agent, added into the treatment further enhanced the insulin secretion of δ-T3, γ-T3 and α-T3 with ED50 values of 504, 511 and 588 µM, respectively.

CONCLUSION:

The findings suggest the potential of δ-T3 in regulating glucose-stimulated insulin secretion (GSIS) in response to the intracellular calcium especially in the presence of KCl.