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A review of the possible mechanisms of action of tocotrienol - a potential antiosteoporotic agent

Chin KY, Mo H, Soelaiman IN

Curr Drug Targets, 2013 Dec;14(13):1533-41.
PMID: 23859472

Osteoporosis is posing a tremendous healthcare problem globally. Much effort has been invested in finding novel antiosteoporotic agents to stop the progression of this disease. Tocotrienol, one of the isoforms of vitamin E, is poised as a potential antiosteoporotic agent. Previous studies showed that tocotrienol as a single isomer or as a mixture demonstrated both anabolic and antiresorptive effects in various rodent models of osteoporosis. In vitro experiments further demonstrated that tocotrienol could up-regulate genes related to osteoblastogenesis and modify receptor activator of nuclear factor kappa B signaling against osteoclastogenesis. Additionally, tocotrienol was also shown to be a strong 3- hydroxy-3-methyl-glutaryl-CoA reductase down-regulator with a mechanism different from that of statins. Inhibition of the mevalonate pathway affects both osteoblast and osteoclast formation in favor of the former. Tocopherol, a more commonly used isoform of vitamin E does not possess similar effects. Tocotrienol is also a potent antioxidant. It can scavenge free radicals and prevent oxidative damage on osteoblast thus promoting its survival. It may also up-regulate the antioxidant defense network in osteoclast and indirectly act against free radical signaling essential in osteoclastogenesis. The effects of tocotrienol on Wnt/β-catenin signaling essential in osteoblastogenesis have not been determined. More mechanistic studies need to be conducted to illustrate the antiosteoporotic effects of tocotrienol. Clinical trials are also required to confirm its effects in humans. In conclusion, tocotrienol demonstrates great potential as an antiosteoporotic agent and much research effort should be invested to develop it as an agent to curb osteoporosis.
Fulltext Use of medicinal plants and natural products for treatment of osteoporosis and its complications

Soelaiman IN, Das S, Shuid AN, Mo H, Mohamed N

Evid Based Complement Alternat Med, 2013;2013:764701.
PMID: 23476703 DOI: 10.1155/2013/764701
Fulltext Safety and efficacy of tocotrienol supplementation for bone health in postmenopausal women: protocol for a dose-response double-blinded placebo-controlled randomised trial

Shen CL, Mo H, Yang S, Wang S, Felton CK, Tomison MD, et al.

BMJ Open, 2016 12 23;6(12):e012572.
PMID: 28011809 DOI: 10.1136/bmjopen-2016-012572

INTRODUCTION: Osteoporosis is a major health concern in postmenopausal women, and oxidative stress contributes to the development of bone loss. Cellular studies and ovariectomised rat model mimicking bone loss in postmenopausal women show the bone-protective effect of tocotrienols (TTs) with antioxidant capability. We aim to access the safety and efficacy of TT consumption for bone health in postmenopausal women.
METHODS AND ANALYSIS: In this 12-week randomised double-blinded placebo-controlled trial for the effects of dietary TT supplementation in postmenopausal women, postmenopausal women aged 45 years and older with at least 1 year after menopause and bone mineral density T-score at the spine and/or hip 2.5 or more below the reference values will be randomly assigned to 3 daily supplements: (1) placebo group receiving 860 mg olive oil, (2) low TT group receiving 430 mg of 70% pure TTs (containing 300 mg TT) and (3) high TT group receiving 860 mg of 70% pure TTs (600 mg TT). The primary outcome measure will be urinary N-terminal telopeptide. The secondary outcome measures will be serum bone-specific alkaline phosphatase, receptor activator of nuclear factor-κB ligand, osteoprotegerin, urinary 8-hydroxy-2'-deoxyguanosine and quality of life. At 0, 6 and 12 weeks, the following will be assessed: (1) primary and secondary outcome measures; (2) serum TT and tocopherol concentrations; (3) physical activity and food frequency questionnaires. Liver function will be monitored every 6 weeks for safety. 'Intent-to-treat' principle will be employed for data analysis. A model of repeated measurements with random effect error terms will be applied. Analysis of covariance, χ2 analysis and regression will be used for comparisons.
ETHICS AND DISSEMINATION: This study was approved by the Bioethics Committee of the Texas Tech University Health Sciences Center. The findings of this trial will be submitted to a peer-reviewed journal in the areas of bone or nutrition and international conferences.
TRIAL REGISTRATION NUMBER: NCT02058420; results.
Structure identification of a polysaccharide purified from Lycium barbarium fruit

Yuan Y, Wang YB, Jiang Y, Prasad KN, Yang J, Qu H, et al.

Int J Biol Macromol, 2016 Jan;82:696-701.
PMID: 26505952 DOI: 10.1016/j.ijbiomac.2015.10.069

The water-soluble bioactive polysaccharides can contribute to the health benefits of Lycium barbarium fruit. However, the structure characteristics of these polysaccharides remain unclear yet. An important polysaccharide (LBPA) was isolated and purified from L. barbarium in this work. It was identified by chemical and spectroscopic methods as arabinogalactan with β-d-(1→6)-galactan as backbone, which was different to any reported polysaccharides from this species before. This arabinogalactan was comprised of Araf, Galp, GlcpA and Rhap with a molar ratio of 9.2:6.6:1.0:0.9. The side chains, including α-l-Araf-(1→, α-l-Araf-(1→5)-α-l-Araf-(1→, β-l-Araf-(1→5)-α-l-Araf-(1→ and α-l-Rhap-(1→4)-β-d-GlcpA-(1→6)-β-d-Galp-(1→, were linked to β-d-(1→6)-galactan at O-3. The putative structure was drawn as below. The molecular weight was determined to be 470,000g/mol by gel permeation chromatography.
Tocotrienols for bone health: a translational approach

Shen CL, Klein A, Chin KY, Mo H, Tsai P, Yang RS, et al.

Ann N Y Acad Sci, 2017 Aug;1401(1):150-165.
PMID: 28891093 DOI: 10.1111/nyas.13449

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.
Sofosbuvir-velpatasvir for treatment of chronic hepatitis C virus infection in Asia: a single-arm, open-label, phase 3 trial

Wei L, Lim SG, Xie Q, Văn KN, Piratvisuth T, Huang Y, et al.

Lancet Gastroenterol Hepatol, 2019 02;4(2):127-134.
PMID: 30555048 DOI: 10.1016/S2468-1253(18)30343-1

BACKGROUND: Treatment with combined sofosbuvir and velpatasvir has resulted in high sustained virological response rates in patients chronically infected with hepatitis C virus (HCV) with genotypes 1-6 in clinical trials and real-world settings, but its efficacy and safety has not been assessed in Asia, a region with diverse HCV genotypes.
METHODS: In this single-arm, open-label, phase 3 trial, we recruited patients from 38 sites across China, Thailand, Vietnam, Singapore, and Malaysia, who were chronically infected with HCV genotypes 1-6, and were HCV treatment-naive or treatment-experienced, either without cirrhosis or with compensated cirrhosis. Patients self-administered a combined sofosbuvir (400 mg) and velpatasvir (100 mg) tablet once daily for 12 weeks. The primary efficacy endpoint was sustained virological response, defined as HCV RNA less than 15 IU/mL at 12 weeks after completion of treatment (SVR12), assessed in all patients who received at least one dose of study drug. The primary safety endpoint was the proportion of adverse events leading to premature discontinuation of study drug. This trial is registered with ClinicalTrials.gov, number NCT02671500, and is completed.
FINDINGS: Between April 14, 2016, and June 30, 2017, 375 patients were enrolled in the study, of whom 374 completed the full treatment course and one discontinued treatment. Overall, 362 (97% [95% CI 94-98]) of 375 patients achieved SVR12. Among 42 patients with HCV genotype 3b, all of whom had baseline resistance-associated substitutions in NS5A, 25 (89% [95% CI 72-98]) of 28 patients without cirrhosis and seven (50% [23-77]) of 14 patients with cirrhosis achieved SVR12. The most common adverse events were upper respiratory tract infection (36 [10%] patients) and headache (18 [5%] patients). There were no discontinuations due to adverse events. Serious adverse events were reported in three (1%) patients, none of which was judged to be related to sofosbuvir-velpatasvir treatment.
INTERPRETATION: Consistent with data from other phase 3 studies, single-tablet sofosbuvir-velpatasvir for 12 weeks is an efficacious and safe treatment for Asian patients with chronic HCV infection, but might have lower efficacy in those infected with HCV genotype 3b and with cirrhosis.
FUNDING: Gilead Sciences.