Open-label, single-arm, single-center clinical study on the effectiveness and safety of a moisturizer containing tocotrienol-rich composition in children with mild to moderate atopic dermatitis.

BACKGROUND: Little is known about antioxidant efficacy of topical vitamin E on atopic dermatitis (AD) due to lack of controlled clinical studies. AIM: The study evaluates the effectiveness and safety of a topical moisturizer containing tocotrienol-rich composition over 12 weeks on patients aged between 1 month and 12 years with mild to moderate AD. METHODS: We conducted a 12 weeks, prospective, open-label clinical study on the effect of tocotrienol as an adjunct to conventional treatment. This study was approved by the Ethics Committee for Research Involving Human Subject. JKEUPM-2019-274 (NMMR-19-1588-49234). RESULTS: Thirty AD patients with a mean age of 2.77 ± 3.05 were enrolled in the study. At week-12, significant reduction of investigator global assessment (63.4%), Patient-Oriented Scoring Atopic Dermatitis Index (PO-SCORAD) (65%), and SCORAD (52.3%) was noted (p < 0.05). There was also a significant decreased in pruritus intensity (46%, p < 0.05). Similarly at week-12, Infant's Dermatitis Quality of Life Index and Children's Dermatology Life Quality Index were found to improve significantly compared to baseline (p < 0.05). Instrumental assessment revealed improvement in TEWL and erythema index, 49.7% and 17.4%, respectively. No adverse reaction was observed. 95% of patients were satisfied with the moisturizer and 90% perceived it to be better than the one in the market. There was a 55.07% reduction in the use of hydrocortisone 1% cream toward the end of the study (p < 0.05). CONCLUSIONS: The results suggested that tocotrienol-rich moisturizer is safe and effective in the management of AD in young children.

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

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-ß/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-ß1/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.

Potential Role of Tocotrienols on Non-Communicable Diseases: A Review of Current Evidence.

Tocotrienol (T3) is a subfamily of vitamin E known for its wide array of medicinal properties. This review aimed to summarize the health benefits of T3, particularly in prevention or treatment of non-communicable diseases (NCDs), including cardiovascular, musculoskeletal, metabolic, gastric, and skin disorders, as well as cancers. Studies showed that T3 could prevent various NCDs, by suppressing 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) in the mevalonate pathway, inflammatory response, oxidative stress, and alternating hormones. The efficacy of T3 in preventing/treating these NCDs is similar or greater compared to tocopherol (TF). TF may lower the efficacy of T3 because the efficacy of the combination of TF and T3 was lower than T3 alone in some studies. Data investigating the effects of T3 on osteoporosis, arthritis, and peptic ulcers in human are limited. The positive outcomes of T3 treatment obtained from the preclinical studies warrant further validation from clinical trials.

Delta tocotrienol in recurrent ovarian cancer. A phase II trial.

Delta tocotrienol has anti-neoplastic activity as demonstrated in several in-vitro and in-vivo investigations. The effect relies on inhibition of different pathways. It also has antiangiogenic activity, and an additive effect to bevacizumab may be expected. The present study was a phase II trial of bevacizumab combined with tocotrienol in chemotherapy refractory ovarian cancer. The study also included analysis of circulating tumor specific HOXA9 methylated DNA (HOXA9 meth-ctDNA) during treatment. The study included 23 patients. The rate of disease stabilization was 70% with very low toxicity. The median PFS was 6.9 months and the median OS 10.9 months, which is rather high compared to the current literature. A division of the patients according to level of HOXA9 meth-ctDNA already after the first cycle of chemotherapy resulted in two groups of patients with different prognoses. Patients with an increasing level of HOXA9 meth-ctDNA had a median PFS and OS of 1.4 and 4.3 months, respectively, compared to 7.8 and 12 months in the group with stable or decreasing levels. The combination of bevacizumab and tocotrienol is potent in chemotherapy refractory ovarian cancer. The level of HOXA9 meth-ctDNA after one cycle of chemotherapy holds important prognostic information.

Anticancer properties of tocotrienols: A review of cellular mechanisms and molecular targets.

Vitamin E is composed of two groups of compounds: α-, ß-, γ-, and δ-tocopherols (TPs), and the corresponding unsaturated tocotrienols (TTs). TTs are found in natural sources such as red palm oil, annatto seeds, and rice bran. In the last decades, TTs (specifically, γ-TT and δ-TT) have gained interest due to their health benefits in chronic diseases, based on their antioxidant, neuroprotective, cholesterol-lowering, anti-inflammatory activities. Several in vitro and in vivo studies pointed out that TTs also exert a significant antitumor activity in a wide range of cancer cells. Specifically, TTs were shown to exert antiproliferative/proapoptotic effects and to reduce the metastatic or angiogenic properties of different cancer cells; moreover, these compounds were reported to specifically target the subpopulation of cancer stem cells, known to be deeply involved in the development of resistance to standard therapies. Interestingly, recent studies pointed out that TTs exert a synergistic antitumor effect on cancer cells when given in combination with either standard antitumor agents (i.e., chemotherapeutics, statins, "targeted" therapies) or natural compounds with anticancer activity (i.e., sesamin, epigallocatechin gallate (EGCG), resveratrol, ferulic acid). Based on these observations, different TT synthetic derivatives and formulations were recently developed and demonstrated to improve TT water solubility and to reduce TT metabolism in cancer cells, thus increasing their biological activity. These promising results, together with the safety of TT administration in healthy subjects, suggest that these compounds might represent a new chemopreventive or anticancer treatment (i.e., in combination with standard therapies) strategy. Clinical trials aimed at confirming this antitumor activity of TTs are needed.

Tocotrienol-Rich Vitamin E from Palm Oil (Tocovid) and Its Effects in Diabetes and Diabetic Nephropathy: A Pilot Phase II Clinical Trial.

Tocotrienol-rich vitamin E from palm oil (Tocovid) has been shown to ameliorate diabetes through its superior antioxidant, antihyperglycemic, and anti-inflammatory properties in diabetic rats. This study aimed to investigate the effects of Tocovid on diabetic nephropathy in patients with type 2 diabetes. Baseline parameters of potential subjects such as HbA1c, blood pressure, Advanced Glycation Endproduct (AGE), soluble receptor for AGE (sRAGE), Nε-Carboxymethyllysine (Nε-CML), and Cystatin C were assessed for possible correlation with diabetic nephropathy. Only subjects with diabetic nephropathy or urine microalbuminuria-positive defined as Urine Albumin to Creatinine Ratio (UACR) >10 mg/mmol were recruited into a prospective, randomized, double-blinded, placebo-controlled trial. The intervention group (n = 22) received Tocovid 200 mg twice a day while the control group (n = 23) received placebo twice a day for 8 weeks. Changes in Hemoglobin A1c (HbA1c), blood pressure, serum biomarkers and renal parameters such as UACR, serum creatinine, and estimated Glomerular Filtration Rate (eGFR) were compared between the two groups. It was found that serum Nε-CML significantly correlated to the severity of microalbuminuria. For every 1 ng/mL increase in serum Nε-CML, the odds of diabetic nephropathy increased by 1.476 times. Tocovid, compared to placebo, significantly reduced serum creatinine but not eGFR, UACR, HbA1c, blood pressure, and serum biomarkers. In conclusion, serum Nε-CML is a potential biomarker for diabetic nephropathy. Treatment with Tocovid significantly reduced serum creatinine; therefore Tocovid may be a useful addition to the current treatment for diabetic nephropathy.

A Review on the Relationship between Tocotrienol and Alzheimer Disease.

Alzheimer’s disease (AD) is plaguing the aging population worldwide due to its tremendous health care and socioeconomic burden. Current treatment of AD only offers symptomatic relief to patients. Development of agents targeting specific pathologies of AD is very slow. Tocotrienol, a member of the vitamin E family, can tackle many aspects of AD, such as oxidative stress, mitochondrial dysfunction and abnormal cholesterol synthesis. This review summarizes the current evidence on the role of tocotrienol as a neuroprotective agent. Preclinical studies showed that tocotrienol could reduce oxidative stress by acting as a free-radical scavenger and promoter of mitochondrial function and cellular repair. It also prevented glutamate-induced neurotoxicity in the cells. Human epidemiological studies showed a significant inverse relationship between tocotrienol levels and the occurrence of AD. However, there is no clinical trial to support the claim that tocotrienol can delay or prevent the onset of AD. As a conclusion, tocotrienol has the potential to be developed as an AD-preventing agent but further studies are required to validate its efficacy in humans.

Tocotrienol Treatment in Familial Dysautonomia: Open-Label Pilot Study.

Familial dysautonomia (FD) is an autosomal recessive congenital neuropathy, primarily presented in Ashkenazi Jews. The most common mutation in FD patients results from a single base pair substitution of an intronic splice site in the IKBKAP gene which disrupts normal mRNA splicing and leads to tissue-specific reduction of IKBKAP protein (IKAP). To date, treatment of FD patients remains preventative, symptomatic and supportive. Based on previous in vitro evidence that tocotrienols, members of the vitamin E family, upregulate transcription of the IKBKAP gene, we aimed to investigate whether a similar effects was observed in vivo. In the current study, we assessed the effects of tocotrienol treatment on FD patients' symptoms and IKBKAP expression in white blood cells. The initial daily doses of 50 or 100 mg tocotrienol, doubled after 3 months, was administered to 32 FD patients. Twenty-eight FD patients completed the 6-month study. The first 3 months of tocotrienol treatment was associated with a significant increase in IKBKAP expression level in FD patients' blood. Despite doubling the dose after the initial 3 months of treatment, IKBKAP expression level returned to baseline by the end of the 6-month treatment. Clinical improvement was noted in the reported clinical questionnaire (with regard to dizziness, bloching, sweating, number of pneumonia, cough episodes, and walking stability), however, no significant effect was observed in any clinical measurements (weight, height, oxygen saturation, blood pressure, tear production, histamine test, vibration threshold test, nerve conduction, and heart rate variability) following Tocotrienol treatment. In conclusion, tocotrienol treatment appears significantly beneficial by clinical evaluation for some FD patients in a few clinical parameters; however it was not significant by clinical measurements. This open-label study shows the complexity of effect of tocotrienol treatment on FD patients' clinical outcomes and on IKBKAP expression level compared to in vitro results. A longitudinal study with an increased sample size is required in the future to better understand tocotrienol affect on FD patients.

The biological effects of tocotrienol on bone: a review on evidence from rodent models.

Osteoporosis causes significant health care and economic burden to society, leading to a relentless search for effective preventive agents. Tocotrienol, a member of the vitamin E family, has demonstrated promising potential as an osteoporosis-preventing agent. This review summarizes evidence on the effects of tocotrienol on bone in animal models. Techniques used to examine the effects of tocotrienol on bone in animals included bone histomorphometry, X-ray microtomography, dual-energy X-ray absorptiometry, bone turnover markers, bone calcium content, and biomechanical strength. Tocotrienol was shown to improve osteoblast number, bone formation, mineral deposition, and bone microarchitecture in osteopenic rats. It also decreased osteoclast number and bone erosion in the rats. Tocotrienol supplementation resulted in an improvement in bone mineral density, although biomechanical strength was not significantly altered in the rats. The beneficial effects of tocotrienol on bone can be attributed to its role as an antioxidant, anti-inflammatory agent, suppressor of the mevalonate pathway, and modulator of genes favorable to bone formation.

Autophagy inhibitor 3-methyladenine potentiates apoptosis induced by dietary tocotrienols in breast cancer cells.

INTRODUCTION: Tocomin® represents commercially available mixture of naturally occurring tocotrienols (T3s) and tocopherols extracted from palm oil/palm fruits that possess powerful antioxidant, anticancer, neuro/cardioprotective and cholesterol-lowering properties. Cellular autophagy represents a defense mechanism against oxidative stress and several anticancer compounds. Recently, we reported that T3s induce apoptosis and endoplasmic reticulum stress in breast cancer cells. METHODOLOGY: We studied the effects of Tocomin® on MCF-7 and MDA-MB 231 breast cancer cells and non-tumor MCF-10A cells. RESULTS: Tocomin® inhibited cell proliferation and induced apoptosis in both MCF-7 and MDA-MB 231 breast cancer cell lines without affecting the viability of MCF-10A cells. We also showed that Tocomin® negatively modulates phosphoinositide 3-kinase and mTOR pathways and induces cytoprotective autophagic response in triple negative MDA-MB 231 cells. Lastly, we demonstrate that autophagy inhibitor 3-methyladenine (3-MA) potentiated the apoptosis induced by Tocomin® in MDA-MB 231 cells. CONCLUSION: Together, our data indicate anticancer effects of Tocomin® in breast cancer cells, which is potentiated by the autophagy inhibitor 3-MA.

Clinical investigation of the protective effects of palm vitamin E tocotrienols on brain white matter.

BACKGROUND AND PURPOSE: Previous cell-based and animal studies showed mixed tocotrienols are neuroprotective, but the effect is yet to be proven in humans. Thus, the present study aimed to evaluate the protective activity of mixed tocotrienols in humans with white matter lesions (WMLs). WMLs are regarded as manifestations of cerebral small vessel disease, reflecting varying degrees of neurodegeneration and tissue damage with potential as a surrogate end point in clinical trials. METHODS: A total of 121 volunteers aged ≥35 years with cardiovascular risk factors and MRI-confirmed WMLs were randomized to receive 200 mg mixed tocotrienols or placebo twice a day for 2 years. The WML volumes were measured from MRI images taken at baseline, 1 year, and 2 years using a validated software and were compared. Fasting blood samples were collected for full blood chemistry investigation. RESULTS: According to per-protocol (88 volunteers) and intention-to-treat (121 volunteers) analyses, the mean WML volume of the placebo group increased after 2 years, whereas that of the tocotrienol-supplemented group remained essentially unchanged. The mean WML volume change between the 2 groups was not significantly different (P=0.150) at the end of 1 year but was significant at the end of 2 years for both per-protocol and intention-to-treat analyses (P=0.019 and P=0.018). No significant difference was observed in the blood chemistry parameters between the 2 groups. CONCLUSIONS: Mixed tocotrienols were found to attenuate the progression of WMLs. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00753532.

A review on the use of statins and tocotrienols, individually or in combination for the treatment of osteoporosis.

Skeletal tissue undergoes continuous remodeling which makes it unique among other body tissues. Osteoporosis is a common bone metabolic disorder affecting both men and women. Osteoporosis and its complications mainly osteoporotic fractures, have a high impact on health and economy. Current approved medications are associated with numerous side effects, which limit their use. Identification of a new and safe therapy is mandatory. Statins, also known as HMGCoA reductase inhibitors, are frequently used for the treatment of hypercholesterolemia and for the prevention of morbidity and mortality associated with cardiovascular disease. Statins improved bone health status in intact and ovariectomised rodents following high clinically intolerable oral doses. However, this beneficial effect of statins could not be significantly demonstrated in humans. The reason behind this discrepancy might be due to the safety and bioavailability of the currently used oral statins. Vitamin E, especially the tocotrienols at the dose 60 mg/kg/day provided significant antiosteoporotic effects in different animal models of osteoporosis. The use of the aforementioned dose of tocotrienols was shown to be safe in both humans and animals. Enhancement of bone formation and reduction of bone resorption were achieved more effectively by a combination of tocotrienols and statins than by either treatment when supplemented separately at clinically tolerable doses. Therefore, the adverse effects associated with high statin doses might be avoided with the coadministration of tocotrienols. Moreover, the combination therapy strategy might be useful for patients who are at high risk of osteoporosis, cardiovascular events and hypercholesterolaemia.

Tocotrienols: the lesser known form of natural vitamin E.

A recent and growing body of research has shown that members of this vitamin E family posses unique biologic functions. Tocotrienols have garnered much of this recent attention, and in particular alpha-tocotrienol has been shown to be the most potent neuroprotective form of vitamin E. Protection exclusively mediated through tocotrienols has been arbitrated to many mechanisms including inhibition of 12-LOX, c-Src, PLA2 and through up-regulation of MRP1. Further, tocotrienols have recently been shown to induce arteriogenesis through induction of TIMP1 and decreased activation of MMP2. However, the unique therapeutic potential of tocotrienols is not limited to neuroprotection. Tocotrienols have been shown to have molecular targets including: apoptotic regulators, cytokines, adhesion molecules, enzymes, kinases, receptors, transcription factors, and growth factors. In spite of this large and unique therapeutic potential, scientific literature on tocotrienols only accounts for approximately 1% of vitamin E research. Given the potential of tocotrienols and relatively scant literature, further investigation is warranted.

Tocotrienols and cardiovascular health.

This review emphasizes the effects of tocotrienols on the risk factors for atherosclerosis, plaque instability and thrombogenesis, and compares these effects with tocopherol. Tocotrienols reduce serum lipids and raise serum HDL-C. Alpha-tocopherol, on the other hand, has no effect on serum lipids. Tocotrienols have greater antioxidant activity than tocopherols. Both reduce the serum levels of C-reactive protein (CRP) and advanced glycation end products, and expression of cell adhesion molecules. The CRP-lowering effects of tocotrienols are greater than tocopherol. Tocotrienols reduce inflammatory mediators, δ-tocotrienol being more potent, followed by γ- and α-tocotrienol. Tocotrienols are antithrombotic and suppress the expression of matrix metalloproteinases. They suppress, regress and slow the progression of atherosclerosis, while tocopherol only suppresses, and has no effect on regression and slowing of progression of atherosclerosis. Tocotrienol reduces risk factors for destabilization of atherosclerotic plaques. There are no firm data to suggest that tocotrienols are effective in reducing the risk of cardiac events in established ischemic heart disease. Alpha-tocopherol is effective in primary prevention of coronary artery disease (CAD), but has no conclusive evidence that it has beneficial effects in patients with established ischemic heart disease. Tocotrienols are effective in reducing ischemia-reperfusion cardiac injury in experimental animals and has the potential to be used in patients undergoing angioplasty, stent implantation and aorto-coronary bypass surgery. In conclusion, experimental data suggest that tocotrienols have a potential for cardiovascular health, but long-term randomized clinical trials are needed to establish their efficacy in primary and secondary prevention of CAD.

Retraction Notice: Tocotrienols and its Role in Cardiovascular Health- a Lead for Drug Design

The article has been retracted by the Editorial office of the journal Current Pharmaceutical Design, due to some inconsistencies in the article [1]. The article appeared to be copied verbatim from published papers. Upon checking these facts, we have established that considerable portions of this review are made up of text copied verbatim from other published material. The Publisher has retracted this article in accordance with good ethical practices. REFERENCE: [1] Vasanthi HR, Parameswari RP and Das DK. Tocotrienols and its Role in Cardiovascular Health- a Lead for Drug Design. Curr Pharm Des 2011; 17(21): 2170-5. Bentham Science apologizes to the readers of the journal for any inconvenience this may have caused. The Bentham Editorial Policy on Article Retraction can be found at https://benthamscience.com/editorial-policies-main.php. Bentham Science Disclaimer: It is a condition of publication that manuscripts submitted to this journal have not been published and will not be simultaneously submitted or published elsewhere. Furthermore, any data, illustration, structure or table that has been published elsewhere must be reported, and copyright permission for reproduction must be obtained. Plagiarism is strictly forbidden, and by submitting the article for publication the authors agree that the publishers have the legal right to take appropriate action against the authors, if plagiarism or fabricated information is discovered. By submitting a manuscript, the authors agree that the copyright of their article is transferred to the publishers if and when the article is accepted for publication.