Effects of Delta-tocotrienol Supplementation on Liver Enzymes, Inflammation, Oxidative stress and Hepatic Steatosis in Patients with Nonalcoholic Fatty Liver Disease

Pervez MA, Khan DA, Ijaz A, Khan S.

Turk J Gastroenterol. 2018 Mar;29(2):170-176. doi: 10.5152/tjg.2018.17297.

Abstract

BACKGROUND/AIMS:

Non-alcoholic fatty liver disease (NAFLD) is a growing public health problem worldwide and is associated with increased morbidity and mortality. Currently, there is no definitive treatment for this disease. δ-Tocotrienol has potent anti-inflammatory and antioxidant properties and may reduce liver injury in NAFLD. The present study aims to evaluate the efficacy and safety of δ-tocotrienol in the treatment of NAFLD.

MATERIALS AND METHODS:

The present study was a randomized, double-blind, placebo-controlled pilot study conducted in patients aged > 20 years, belonging to both sexes, having ultrasound-proven fatty liver disease, having a fatty liver index (FLI) of ≥ 60, and persistent elevation of alanine transaminase. A total of 71 patients were assigned to receive either oral δ-tocotrienol (n=35, 300 mg twice daily) or placebo (n=36) for 12 weeks. At the baseline and at the end of the study, clinical and biochemical parameters, including lipid profile, liver function tests, high-sensitivity C-reactive protein (hs-CRP), and malondialdehyde (MDA) were measured. Body mass index and FLI were calculated, and ultrasound grading of hepatic steatosis was performed.

RESULTS:

Out of 71 enrolled patients, 64 patients, 31 in the δ-tocotrienol group and 33 in the placebo group, completed the study. After 12 weeks of supplementation, δ-tocotrienol showed greater efficacy than placebo by decreasing serum aminotransferases, hs-CRP, MDA, and FLI score (p<0.001). However, it did not improve hepatic steatosis on ultrasound examination. No adverse effects were reported.

CONCLUSION:

δ-Tocotrienol was safe, and it effectively improved aminotransferase levels and inflammatory and oxidative stress markers in patients with NAFLD. Large-scale randomized clinical trials are warranted to further support these findings.

Abubakar IB, Lim SW, Loh HS.

Trop Life Sci Res. 2018 Mar;29(1):229-238. doi: 10.21315/tlsr2018.29.1.15. Epub 2018 Mar 2.

Abstract

Kajian terbaru mencadangkan bahawa pendekatan gabungan rawatan boleh digunakan untuk meningkatkan potensi antikanser dan menghindari batasan pemberian tocotrienol dos tinggi. Acalypha wilkesiana adalah tumbuhan ubatan yang telah digunakan sebagai rawatan tambahan untuk kanser dalam perubatan tradisional. Di sini, kesan rawatan tunggal dan gabungan β-, γ-dan δ-tocotrienols dan ekstrak etil asetat (9EA) daripada Acalypha wilkesiana pada paru-paru (A549) dan sel-sel kanser otak (U87MG) telah disiasat. γ-dan δ-tocotrienols menunjukkan kesan antiproliferatif yang lebih tinggi terhadap A549 (12.1 μg/ml dan 13.6 μg/ml) dan sel U87MG (3.3 μg/ml dan 5.2 μg/ml) berbanding β-tocotrienols (9.4 μg/ml), masing-masing. Sedangkan, 9EA merangsang kesan antiproliferatif yang kuat terhadap sel U87MG sahaja (2.0 μg/ml). Rawatan terapi tocotrienols dan 9EA mencetuskan perencatan pertumbuhan sinergis sehingga pengurangan 8.4 kali ganda dalam dos yang kuat dari β-, γ-dan δ-tocotrienols pada sel A549. Ciri-ciri apoptotik juga dibuktikan pada sel-sel A549 yang menerima rawatan tunggal dan gabungan. Sinergi ini boleh meningkatkan hasil terapeutik untuk kanser paru-paru.

Recent studies suggested that combined treatment approaches can be used to improve anticancer potency and circumvent the limitations of high-dose tocotrienols administration. Acalypha wilkesiana is a medicinal plant that has been used as an adjunct treatment for cancers in traditional medicine. Herein, the effects of single and combined treatments of β-, γ- and δ-tocotrienols and ethyl acetate extract (9EA) of Acalypha wilkesiana on lung (A549) and brain (U87MG) cancer cells were investigated. γ- and δ-tocotrienols exhibited higher potent antiproliferative effects against A549 (12.1 μg/ml and 13.6 μg/ml) and U87MG cells (3.3 μg/ml and 5.2 μg/ml) compared to β-tocotrienols (9.4 μg/ml and 92.4 μg/ml), respectively. Whereas, 9EA induced potent antiproliferative effects against U87MG cells only (2.0 μg/ml). Combined treatments of tocotrienols and 9EA induced a synergistic growth inhibition with up to 8.4-fold reduction in potent doses of β-, γ- and δ-tocotrienols on A549 cells. Apoptotic features were also evidenced on A549 cells receiving single and combined treatments. The synergism may greatly improve the therapeutic outcome for lung cancer.

KEYWORDS:

Acalypha wilkesiana; Apoptosis; Synergism; Tocotrienol

Kumar MR, Reddy GR

Hum Exp Toxicol. 2018 Mar;37(3):295-308. doi: 10.1177/0960327117698540. Epub 2017 Mar 23.

Abstract

This study was planned to determine arsenic (As) (10 mg/kg body weight given through oral gavage) induced behavioral and cholinergic perturbations in three different age groups of rats; young (postnatal day 21), adult (3 months), and aged (18 months) at 7 days post-acute exposure ( n = 6 for each of the four groups of all three age points). Further, we also evaluated the ameliorative effect of essential metal zinc (Zn; 0.02% through drinking water) and an antioxidant, α-tocopherol (vitamin E; 125 mg/kg body weight through oral gavage) against As-induced neurotoxicity. As exposure showed significant alterations in behavioral functions (open-field behavior, total locomotor activity, grip strength, exploratory behavior, and water maze learning). Cholinergic studies in three brain regions (cerebral cortex, cerebellum, and hippocampus) of different age groups also showed significant increase in acetylcholine levels and a decrease in acetylcholinesterase activity. These effects were more pronounced in hippocampus followed by cerebral cortex and cerebellum. Among the three different age points, aged animals were found to be more vulnerable to the As-induced toxicity as compared to young and adult animals suggesting that As neurotoxicity is age dependent. These As-induced alterations were significantly reversed following supplementation with Zn or vitamin E. However, vitamin E was found to elicit greater protection as compared to Zn in restoring the altered behavioral and cholinergic perturbations, providing evidence for As-induced oxidative damage.

Pourafshar S, Johnson SA, Keshavarz B, Feresin RG, Khalil DA, Chai SC, Arjmandi BH

Menopause. 2018 Mar;25(3):336-342. doi: 10.1097/GME.0000000000001003.

Abstract

OBJECTIVE:

Menopause is associated with adverse changes in hematological parameters. Although the antioxidative and anti-inflammatory properties of vitamin E have been previously demonstrated, the effects of vitamin E on hematopoietic parameters are not well-documented. This study investigated the effects of supplemental vitamin E on hematological parameters in a rat model of ovarian hormone deficiency.

METHODS:

Twelve-month-old female Sprague-Dawley rats were either sham-operated (Sham) or ovariectomized (Ovx). Animals were randomly divided among five treatment groups (n = 12/group) as follows: Sham; Ovx; Ovx + 300, Ovx + 525, or Ovx + 750 mg/kg diet of vitamin E for 100 days.

RESULTS:

Compared with Sham, ovariectomy increased leukocyte subpopulation counts including lymphocytes (2.01 × 10/mm; 95% confidence interval [CI] 0.11, 4.03; P = 0.03), monocytes (0.35 × 10/mm; 95% CI 0.60, 0.11; P = 0.01), neutrophils (0.72 × 10/mm; 95% CI 0.26, 1.19; P = 0.01), eosinophils (0.07 × 10/mm; 95% CI 0.12, 0.30; P = 0.00), and basophils (0.13 × 10/mm; 95% CI 0.04, 0.21; P = 0.02). Medium dose (MD) (-0.26 × 10/mm; 95% CI -0.47, -0.05; P = 0.007) and high dose (HD) (-0.22 × 10/mm; 95% CI -0.43, -0.01; P = 0.037) supplemental vitamin E attenuated Ovx-induced increases in monocyte counts. Low dose (LD) (-0.55 × 10/mm; 95% CI -0.95, -0.15; P = 0.003), MD (-0.61 × 10/mm; P = 0.001), and HD (-0.54 × 10/mm; 95% CI -0.95, -0.14; P = 0.004) supplemental vitamin E attenuated Ovx-induced increases in neutrophil counts. LD (-0.05 × 10/mm; 95% CI -0.08, -0.11; P = 0.006), MD (-0.05 × 10/mm; 95% CI -0.08, -0.11; P = 0.005), and HD (-0.05 × 10/mm; 95% CI -0.09, -0.01; P = 0.004) supplemental vitamin E also attenuated the Ovx-induced increase in eosinophil counts. Only LD (-0.09 × 10/mm; 95% CI -0.17, -0.02; P = 0.009) supplemental vitamin E attenuated the Ovx-induced increase in basophil counts. The remaining hematological parameters assessed were not significantly affected by ovariectomy or supplemental vitamin E.

CONCLUSION:

These findings suggest that vitamin E in the form of α-tocopherol acetate may provide protection against ovarian hormone deficiency-associated adverse changes in hematological parameters.

Sailo BL, Banik K, Padmavathi G, Javadi M, Bordoloi D, Kunnumakkara AB

Pharmacol Res. 2018 Feb 27. pii: S1043-6618(17)31460-3

Abstract

Despite the significant advancements in the diagnosis and treatment of cancer, it still remains one of the most fatal diseases in the world due to the lack of sensitive diagnosis methods and effective drugs. Therefore, discovering novel therapies that are safe, efficacious and affordable are required for the better management of this disease. Tocotrienols, analogues of vitamin E have gained increased attention due to their safety and efficacy. Extensive research over the past several years has strongly indicated that tocotrienols can efficiently prevent/inhibit the growth of different cancers such as cancers of blood, brain, breast, cervical, colon, liver, lung, pancreas, prostate, skin, stomach etc. This is mainly accredited to their ability to modulate various molecular targets involved in cancer cell proliferation, survival, invasion, angiogenesis, and metastasis such as NF-κB, STAT3, Akt/mTOR, etc. In addition, increasing lines of evidence has shown that tocotrienols can sensitize cancer cells to chemotherapeutic agents such as celecoxib, doxorubicin, erlotinib, gefitinib, gemcitabine, paclitaxel, statin etc. Moreover, several clinical trials have confirmed the safety and tolerability of tocotrienols in humans. This review summarizes the potential of tocotrienols for the prevention and treatment of different cancers based on the available in vitro, in vivo and clinical studies.

Zang S, Chen J, Song Y, Bai L, Chen J, Chi X, He F, Sheng H, Wang J, Xie S, Xie W, Yang Y, Zhang J, Zheng M, Zou Z, Wang B, Shi J

Adv Ther. 2018 Feb;35(2):218-231. doi: 10.1007/s12325-018-0670-8. Epub 2018 Feb 6.

Abstract

INTRODUCTION:

Vitamin E is one of the most promising agents for nonalcoholic steatohepatitis (NASH) treatment, and its drug responsiveness may be closely associated with haptoglobin (Hp) genotype. However, its efficacy and safety remain unknown in China. This clinical trial of vitamin E versus placebo for the treatment of nondiabetic patients with nonalcoholic steatohepatitis (VENS) is conducted to evaluate (a) the efficacy and safety of treatment with vitamin E softgel (300 mg/day) determined from standardized histologic scoring of liver biopsies, (b) whether treatment with vitamin E improves biochemical parameters, cytokines, anthropometric parameters, controlled attenuation parameter (CAP), and transient elastography (TE) values determined by Fibroscan and health-related quality of life (SF-36), (c) whether the efficacy of vitamin E treatment is associated with the Hp genotype in nondiabetic adults with NASH.

METHODS:

VENS is a multicenter, randomized, double-masked, placebo parallel controlled trial to evaluate the efficacy and safety of treatment with vitamin E softgel in nondiabetic adults with NASH versus treatment with placebo in China. Liver biopsies are read by a pathological evaluation committee independently according to the NASH Clinical Research Network (CRN) scoring system. The NAFLD activity score (NAS) represents the sum of scores for steatosis, lobular inflammation, and hepatocyte ballooning. The definition of histologic improvement requires all three of the following criteria to be met: (a) either improvement in NAS by at least 2 points or post-treatment NAS score no higher than 3, (b) at least 1-point improvement in the score for ballooning, and (c) no worsening of fibrosis stages. We plan to recruit 120 biopsy-proven NASH patients from13 centers in China. Participants will be randomly assigned to groups treated with either with vitamin E (100 mg, tid) or placebo for 96 weeks then followed by 24 weeks of post-treatment observation. Biochemical parameters, cytokines, anthropometric parameters, CAP and TE values, Hp genotype, and several questionnaires will be collected as per the schedule. This protocol was approved by the Ethics Committee of Hangzhou Normal University Affiliated Hospital to ensure patients safety, and R&G Pharmastudies Co., Ltd. was established for monitoring the accumulated interim data to review efficacy and quality of data collection and overall study management.

RESULTS:

As a preliminary study, a mobile phone application (app) for lifestyle modification and database recording ( http://laiyivens.365hy.com ) was exploited for every participant. The percentage of NAFLD patients with Hp 2-2 allele is much higher than that of Western patients (65.71% vs 36%, respectively), which suggests that the Chinese benefit more from vitamin E treatment.

CONCLUSION:

VENS is the first randomized controlled trial (RCT) to evaluate the efficacy of Vitamin E in treating nondiabetic NASH patients in China.

Dass AS, Narayana S, Venkatarathnamma PN

J Adv Pharm Technol Res. 2018 Jan-Mar;9(1):32-36. doi: 10.4103/japtr.JAPTR_309_17.

Abstract

Diabetes mellitus (DM) and its complications have been implicated in hyperglycemia-induced oxidative stress. Antioxidants can improve glycemic control, lipid profile, and cognitive functions. We assessed the effect of Vitamin E and omega 3 fatty acids (OFA) on the above parameters. One hundred patients with type 2 DM receiving metformin 500 mg and glimepiride 1 mg were randomized to receive add-on therapy of Vitamin E 400 mg or OFA once daily for 12 weeks and the third group served as control. Fasting blood sugar (FBS), postprandial blood sugar (PPBS), glycated hemoglobin (HbA1c), body mass index (BMI), waist-hip ratio (WHR), lipid profile, and mini-mental state examination were done at baseline and 12 weeks. Eighty-seven patients completed the study. A significant reduction in FBS, PPBS, and HbA1c was observed in all the three groups at 12 weeks. There was significant reduction in total cholesterol and triglycerides (TG) in patients receiving either of the antioxidants and also significant reduction in low-density lipoprotein in patients receiving OFA at 12 weeks compared to baseline. BMI and WHR were significantly increased in control group. Intergroup analysis showed that in patients receiving Vitamin E and OFA, the reduction of FBS, PPBS, and HbA1c were similar. The patients receiving OFA had significant reduction in TG compared to control. There was no significant effect on cognitive function. Vitamin E and OFA had beneficial effects on lipid profile and anthropometric measurements; however, the glycemic control was similar to the patients in control group.

Ghlissi Z, Hakim A, Mnif H, Kallel R, Zeghal K, Boudawara T, Sahnoun Z

Saudi J Kidney Dis Transpl. 2018 Jan-Feb;29(1):10-18. doi: 10.4103/1319-2442.225205.

Abstract

This study was carried out to evaluate spontaneous renal regeneration after stopping colistin methanesulfonate (CMS), which induces tubular damage, and the curative effect of Vitamin E (vit E) in rats. Animals were given the following: sterile saline (n = 6), 300,000 IU/kg/ day of CMS (n = 24), or 450,000 IU/kg/day of CMS (n = 24) for seven days. Each CMS group was subdivided into four subgroups (n = 6) and sacrificed as follows: (i) 12 h after stopping CMS, (ii) two weeks after stopping CMS, (iii) two weeks after stopping treatment with vit E, and (iv) two weeks after stopping treatment with olive oil. Subsequently, plasma creatinine (pCr), urine N-acetyl-b-D-glucosaminidase (NAG), renal tissue level of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione reductase (GSH), and renal histology were tested. CMS-induced tubular damage increased the NAG and MDA levels and decreased the SOD and GSH activities. After two weeks of stopping CMS, there was no significant renal recovery. However, treatment with vit E improved tubular regeneration and reduced the biochemical impairments. Two weeks might not be long enough for significant spontaneous renal regeneration. Improvement of renal parameters by vit E could be explained by the reduction of oxidative stress damage.

Nukala U, Thakkar S, Krager KJ, Breen PJ, Compadre CM, Aykin-Burns N

Antioxidants (Basel). 2018 Feb 23;7(2). pii: E33. doi: 10.3390/antiox7020033.

Abstract

Radiation countermeasures fall under three categories, radiation protectors, radiation mitigators, and radiation therapeutics. Radiation protectors are agents that are administered before radiation exposure to protect from radiation-induced injuries by numerous mechanisms, including scavenging free radicals that are generated by initial radiochemical events. Radiation mitigators are agents that are administered after the exposure of radiation but before the onset of symptoms by accelerating the recovery and repair from radiation-induced injuries. Whereas radiation therapeutic agents administered after the onset of symptoms act by regenerating the tissues that are injured by radiation. Vitamin E is an antioxidant that neutralizes free radicals generated by radiation exposure by donating H atoms. The vitamin E family consists of eight different vitamers, including four tocopherols and four tocotrienols. Though alpha-tocopherol was extensively studied in the past, tocotrienols have recently gained attention as radiation countermeasures. Despite several studies performed on tocotrienols, there is no clear evidence on the factors that are responsible for their superior radiation protection properties over tocopherols. Their absorption and bioavailability are also not well understood. In this review, we discuss tocopherol’s and tocotrienol‘s efficacy as radiation countermeasures and identify the challenges to be addressed to develop them into radiation countermeasures for human use in the event of radiological emergencies.

Su M, Wang D, Chang W, Liu L, Cui M, Xu T

Assay Drug Dev Technol. 2018 Feb 22. doi: 10.1089/adt.2017.831. [Epub ahead of print]

Abstract

Atherosclerosis is a major cause for cardiovascular diseases. High-density lipoprotein (HDL) may reduce atherosclerosis through several different mechanisms. HDL is composed of lipids, cholesterol, cholesteryl esters, triglycerides, and phospholipids, mainly phosphatidylcholine plus specialized proteins called apolipoproteins (apos). In this study, we prepared vitamin E containing HDL (V_E-HDL) that contains egg phosphatidylcholine, cholesterol, vitamin E, and two kinds of recombinant human apolipoproteins (rhapo)-rhapoA-I and rhapoE in vitro by the facilitation of cholate. After that, we studied the effects of V_E-HDL on foam cell formation, cellular cholesterol efflux, oxidative low-density lipoprotein (oxLDL)-stimulated oxidative stress, and apoptosis of macrophages to evaluate the protective efficacy of V_E-HDL on macrophages. As the results showed, we prepared a new type of reconstituent HDL with apolipoproteins and vitamin E for the first time. V_E-HDL has protective efficacy on macrophages. It has the prospect of becoming a therapeutic agent on atherosclerosis in the future.