Tocotrienols Prevent the Decline of Learning Ability in High-Fat, High-Sucrose Diet-Fed C57BL/6 Mice.

Obesity has been increasing worldwide and is well-known as a risk factor for cognitive decline. It has been reported that oxidative stress in the brain is deeply involved in cognitive dysfunction in rodent models. While there are many studies on oxidation in the liver and adipose tissue of obese mice, the relationship between obesity-induced cognitive dysfunction and brain oxidation has not been elucidated. Here, we show that obesity induced by a high-fat, high-sucrose diet (HFSD) alters cognitive function in C57BL/6 male mice, and it may involve the acceleration of brain oxidation. Tocotrienols (T3s), which are members of the vitamin E family, can prevent HFSD-induced cognitive changes. To elucidate these mechanisms, respiratory metabolism, locomotor activity, temperature around brown adipose tissue, and protein profiles in the cerebrum cortex were measured. Contrary to our expectation, respiratory metabolism was decreased, and temperature around brown adipose tissue was increased in the feeding of HFSD. The proteins that regulate redox balance did not significantly change, but 12 proteins, which were changed by HFSD feeding and not changed by T3s-treated HFSD compared to control mice, were identified. Our results indicated that HFSD-induced obesity decreases mouse learning ability and that T3s prevent its change. Additionally, feeding of HFSD significantly increased brain oxidation. However, further study is needed to elucidate the mechanisms of change in oxidative stress in the brain by obesity.

Hypolipidemic Effect of Rice Bran Oil Extract Tocotrienol in High-Fat Diet-Induced Hyperlipidemia Zebrafish (Danio Rerio) Induced by High-Fat Diet.

In recent years, the potent influence of tocotrienol (T3) on diminishing blood glucose and lipid concentrations in both Mus musculus (rats) and Homo sapiens (humans) has been established. However, the comprehensive exploration of tocotrienol's hypolipidemic impact and the corresponding mechanisms in aquatic species remains inadequate. In this study, we established a zebrafish model of a type 2 diabetes mellitus (T2DM) model through high-fat diet administration to zebrafish. In the T2DM zebrafish, the thickness of ocular vascular walls significantly increased compared to the control group, which was mitigated after treatment with T3. Additionally, our findings demonstrate the regulatory effect of T3 on lipid metabolism, leading to the reduced synthesis and storage of adipose tissue in zebrafish. We validated the expression patterns of genes relevant to these processes using RT-qPCR. In the T2DM model, there was an almost two-fold upregulation in pparγ and cyp7a1 mRNA levels, coupled with a significant downregulation in cpt1a mRNA (p < 0.01) compared to the control group. The ELISA revealed that the protein expression levels of Pparγ and Rxrα exhibited a two-fold elevation in the T2DM group relative to the control. In the T3-treated group, Pparγ and Rxrα protein expression levels consistently exhibited a two-fold decrease compared to the model group. Lipid metabolomics showed that T3 could affect the metabolic pathways of zebrafish lipid regulation, including lipid synthesis and decomposition. We provided experimental evidence that T3 could mitigate lipid accumulation in our zebrafish T2DM model. Elucidating the lipid-lowering effects of T3 could help to minimize the detrimental impacts of overfeeding in aquaculture.

Unveiling the antioxidant superiority of α-tocopherol: Implications for vitamin E nomenclature and classification.

Since the discovery of tocopherols a century ago, α-tocopherol has been distinguished for its unique biological functions. In this study, we aim to elucidate the unique characteristics of α-tocopherol from a chemical perspective. Utilizing density functional theory (DFT) calculations, we evaluated the thermodynamic and kinetic properties of tocopherols, tocotrienols and their oxidation products. Our findings highlight the superior thermodynamic and kinetic properties of α-tocopherol. Although tocopherol substrates generally exhibit similar reactivities, α-tocopherol is distinguished by a larger gap between the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) in intermediates, indicating a potential for greater energy release and favoring reaction progression. Moreover, α-tocopherol shows enhanced efficiency in quenching radical intermediates, especially when combined with vitamin C. All these dates provide valuable support for the naming of vitamin E.

Tocotrienol isoforms: The molecular mechanisms underlying their effects in cancer therapy and their implementation in clinical trials.

Tocotrienols are found in a variety of natural sources, like rice bran, annatto seeds and palm oil, and have been shown to have several health-promoting properties, particularly against chronic diseases such as cancer. The incidence of cancer is rapidly increasing around the world, not only a result of continued aging and population growth, but also due to the adoption of aspects of the Western lifestyle, such as high-fat diets and low-physical activity. The literature provides strong evidence that tocotrienols are able to inhibit the growth of various cancers, including breast, lung, ovarian, prostate, liver, brain, colon, myeloma and pancreatic cancers. These findings, along with the reported safety profile of tocotrienols in healthy human volunteers, encourage further research into these compounds' potential use in cancer prevention and treatment. The current review provided detailed information about the molecular mechanisms of action of different tocotrienol isoforms in various cancer models and evaluated the potential therapeutic effects of different vitamin E analogues on important cancer hallmarks, such as cellular proliferation, apoptosis, angiogenesis and metastasis. MEDLINE/PubMed and Scopus databases were used to identify recently published articles that investigated the anticancer effects of vitamin E derivatives in various types of cancer in vitro and in vivo along with clinical evidence of adjuvant chemopreventive benefits. Following an overview of pre-clinical studies, we describe several completed and ongoing clinical trials that are paving the way for the successful implementation of tocotrienols in cancer chemotherapy.

Coordinated Transcriptome and Metabolome Analyses of a Barley hvhggt Mutant Reveal a Critical Role of Tocotrienols in Endosperm Starch Accumulation.

Tocotrienols and tocopherols (vitamin E) are potent antioxidants that are synthesized in green plants. Unlike ubiquitous tocopherols, tocotrienols predominantly accumulate in the endosperm of monocot grains, catalyzed by homogentiate geranylgeranyl transferase (HGGT). Previously, we generated a tocotrienol-deficient hvhggt mutant with shrunken barley grains. However, the relationship between tocotrienols and grain development remains unclear. Here, we found that the hvhggt lines displayed hollow endosperms with defective transfer cells and reduced aleurone layers. The carbohydrate and starch contents of the hvhggt endosperm decreased by approximately 20 and 23%, respectively. Weighted gene coexpression network analyses identified a critical gene module containing HvHGGT, which was strongly associated with the hvhggt mutation and enriched with gene functions in starch and sucrose metabolism. Metabolome measurements revealed an elevated soluble sugar content in the hvhggt endosperm, which was significantly associated with the identified gene modules. The hvhggt endosperm had significantly higher NAD(H) and NADP(H) contents and lower levels of ADPGlc (regulated by redox balance) than the wild-type, consistent with the absence of tocotrienols. Interestingly, exogenous α-tocotrienol spraying on developing hvhggt spikes partially rescued starch accumulation and endosperm defects. Our study supports a potential novel function of tocotrienols in grain starch accumulation and endosperm development in monocot crops.

Effects of emulsified and non-emulsified palm tocotrienol on bone and joint health in ovariectomised rats with monosodium iodoacetate-induced osteoarthritis.

Postmenopausal women are susceptible to osteoporosis and osteoarthritis. Tocotrienol, a bone-protective nutraceutical, is reported to prevent osteoarthritis in male rats. However, its efficacy on joint health in oestrogen deficiency has not been validated. Besides, data on the use of emulsification systems in enhancing bioavailability and protective effects of tocotrienol are limited. Ovariectomised adult female Sprague-Dawley rats (3 months old) were treated with refined olive oil, emulsified (EPT, 100 mg/kg/day with 25% vitamin E content), non-emulsified palm tocotrienol (NEPT, 100 mg/kg/day with 50% vitamin E content) and calcium carbonate (1% w/v in drinking water) plus glucosamine sulphate (250 mg/kg/day) for 10 weeks. Osteoarthritis was induced with monosodium iodoacetate four weeks after ovariectomy. Baseline control was sacrificed upon receipt, while the sham group was not ovariectomised and treated with refined olive oil. EPT and NEPT prevented femoral metaphyseal and subchondral bone volume decline caused by ovariectomy. EPT decreased subchondral trabecular separation compared to the negative control. EPT preserved stiffness and Young's Modulus at the femoral mid-shaft of the rats. Circulating RANKL was reduced post-treatment in the EPT group. Joint width was reduced in all the treatment groups vs the negative control. The EPT group's grip strength was significantly improved over the negative control and NEPT group. EPT also preserved cartilage histology based on several Mankin's subscores. EPT performed as effectively as NEPT in preventing osteoporosis and osteoarthritis in ovariectomised rats despite containing less vitamin E content. This study justifies clinical trials for the use of EPT in postmenopausal women with both conditions.

α-Tocotrienol in rice bran enhances steroidogenesis in mouse Leydig cell via increased gene expression of steroidogenic acute regulatory protein and induction of its mitochondrial translocation.

Rice is a staple food in the Asian region and one of the world's major energy sources. Testosterone is a steroid hormone that maintains physical, sexual, and cognitive ability, and its decline causes health problems like late-onset hypogonadism. Evaluation of various grain extracts showed rice bran to stimulate testosterone secretion from Leydig model cells. α-Tocotrienol was found as a bioactive compound in rice bran, and mechanistic analysis showed the stimulation of steroid hormone synthesis through enhanced gene expression of steroidogenic acute regulatory protein as well as inducing mitochondrial localization of the protein. Preliminary study showed an increasing trend in serum testosterone levels in mice by oral intake of α-tocotrienol. These results suggest that α-tocotrienol intake may be effective in preventing symptoms caused by low testosterone levels.

Tocotrienol monomers and dimers from the roots of Litchi chinensis with tyrosinase inhibition activity.

Four undescribed modified tocotrienols, including two monomers, litchinols A (1) and B (2), and two walsurol dimers, δ,δ-walsurol (3) and γ,δ-bi-O-walsurol (4), as well as seven known compounds (5-11) were isolated from the roots of Litchi chinensis. The structures of the undescribed compounds were elucidated based on analyses of spectroscopic data and ECD spectra. All tocotrienol derivatives (1-6) were evaluated for their tyrosinase inhibition activity. Only monomers 1-2 and 5-6 displayed potent inhibitory activity and greater than kojic acid. Kinetic analysis revealed that the representative compound 2 was uncompetitive inhibitor with the inhibition constant value of 5.70 µM.

Carotenoids and tocols comparison in different Subspecies of Triticum turgidum and aestivum.

Carotenoids and Tocols in six genotypes of Triticum turgidum ssp. durum, five of Triticum turgidum ssp. dicoccum, four of Triticum aestivum ssp. aestivum, and six of Triticum aestivum ssp. spelta were investigated. The aim of the present study was to identify, quantify, and compare the content of tocopherols, tocotrienols, and carotenoids in different primitive and modern genotypes of wheat species in order to evaluate the lines with the highest content and possibly use them for selection and breeding programs. The Triticum durum group showed the highest mean content of total carotenoids, with lutein being the most abundant, accounting for 80.12 % (Triticum spelta) to 86.65 % (Triticum turgidum) of total carotenoids. Among the genotypes, Line 6 (Triticum durum) had the highest lutein content (12.17 µg g-1), significantly differing from the lines within its group and the other groups of dicoccum, aestivum, and spelta.Triticum dicoccum exhibited a lower average content of total tocols compared to other Triticum species. The tocols profile showed a prevalence of tocotrienols over tocopherols. ß + Î³-T3 was the most abundant individual tocol isomer in all Triticum genotypes, contributing for 50.40 % (Triticum ssp. aestivum) and 42.50 % (Triticum spelta) of the total content, respectively. The highest ß + Î³-T3 content (23.83 µg/g) was found in Line 6 of Triticum durum. Correlation, principal component, and cluster analyses revealed positive correlations between total tocols and ß/γ tocotrienols, significant differences between various groups of the same species, formation of six clusters labeled as I to VI, and the identification of genotypes from the same species grouped in different clusters.

Tocotrienol-Rich Fraction Attenuates Blue Light-Induced Oxidative Stress and Melanogenesis in B16-F1 Melanocytes via Anti-Oxidative and Anti-Tyrosinase Properties.

Our skin is constantly exposed to blue light (BL), which is abundant in sunlight and emitted by digital devices. Prolonged exposure to BL can lead to oxidative stress-induced damages and skin hyperpigmentation. For this study, we used a cell line-based model to examine the protective effects of tocotrienol-rich fraction (TRF) on BL-induced oxidative stress and hyperpigmentation in B16-F1 melanocytes. Alpha-tocopherol (αTP) was used as a comparator. Molecular assays such as cell viability assay, flow cytometry, western blotting, fluorescence imaging, melanin and tyrosinase analysis were performed. Our results showed that TRF effectively suppressed the formation of reactive oxygen species and preserved the mitochondrial membrane potential. Additionally, TRF exhibited anti-apoptotic properties by reducing the activation of the p38 mitogen-activated protein kinase molecule and downregulating the expression of cleaved caspase-3. Moreover, TRF modulated tyrosinase activity, resulting in a lowered rate of melanogenesis and reduced melanin production. In contrast, αTP did not exhibit significant protective effects against skin damages and pigmentation in BL-induced B16-F1 cells. Therefore, this study indicates that TRF may offer superior protective effects over αTP against the effects of BL on melanocytes. These findings demonstrate the potential of TRF as a protective natural ingredient that acts against BL-induced skin damages and hyperpigmentation via its anti-oxidative and anti-melanogenic properties.

Dietary Vitamin E Isoforms Intake: Development of a New Tool to Assess Tocopherols and Tocotrienols Intake in Adults.

Due to the documented health benefits of tocopherols and tocotrienols as bioactive compounds, it seems important to assess their intake. The aim of this study was to develop a new tool and its application for assessment of tocopherol and tocotrienol intake in adults. Dietary data were collected by semiquantitative FFQ (VitE-FFQ) and by a 1-day dietary record in a group of 447 subjects. The database of the US Department of Agriculture (USDA) was used to calculate the individual isoforms of vitamin E and develop the tool-VIT_E.CAL. The assessment of measuring agreement between the two methods was conducted by analysis of the correlations and Bland-Altman plots. The average α-tocopherol intake was 11.3 mg/day for the data obtained using the FFQ method and 12.8 mg/day for the results obtained using the 1-day dietary record. Depending on the adopted recommendation, only 40-57% of the subjects had adequate vitamin E intake. The intake of α-tocopherol did not exceed the UL value in any of the respondents. The dominant forms of vitamin E in the diet of the studied group were α- and γ- forms (55% and 38% of the total sum) among tocopherols and ß- and γ- forms (49% and 24% of the total sum) among tocotrienols. VIT_E.CAL allows us to calculate not only the total amount of vitamin E but also its eight isoforms. It can be a useful tool to assess individual and group intake of various forms of vitamin E in the diet. The use of VIT_E.CAL enables the proper assessment of vitamin E (as α-tocopherol and not α-tocopherol equivalent) in the diet of Poles, and most likely also in the European diet. The obtained results indicate the need to take into account the content of individual forms of vitamin E in food/diet, which will allow for a reliable assessment of its consumption. It also seems necessary to standardize the nomenclature regarding the name of vitamin E and its use for correct nutritional assessment.

Delta tocotrienol as a supplement to FOLFOXIRI in first-line treatment of metastatic colorectal cancer. A randomized, double-blind, placebo-controlled phase II study.

PURPOSE: Triplet chemotherapy might be more effective than doublet chemotherapy in metastatic colorectal cancer (mCRC), but it may also be marked by increased toxicity. To investigate whether δ-tocotrienol, a vitamin E analogue, with possible neuroprotective and anti-inflammatory effects, reduces the toxicity of triplet chemotherapy, we conducted a randomized, double-blind, placebo-controlled trial in mCRC patients receiving first-line 5-fluorouracil, oxaliplatin and irinotecan (FOLFOXIRI). MATERIAL AND METHODS: Seventy patients with mCRC were randomly assigned (1:1) to receive FOLFOXIRI plus either δ-tocotrienol or placebo at the Department of Oncology, Vejle Hospital, Denmark. Eligibility criteria were adenocarcinoma in the colon or rectum, age 18-75 years and ECOG performance status 0-1. FOLFOXIRI was given in eight cycles followed by four cycles of 5-fluorouracil. δ-tocotrienol 300 mg or placebo × 3 daily was added during chemotherapy and for a maximum of two years. The primary endpoint was time to hospitalization or death during treatment with chemotherapy. RESULTS: Median time to first hospitalization or death was 3.7 months in the placebo group (95% CI 1.93-not reached (NR)), and was NR in the δ-tocotrienol group (95% CI 1.87-NR) with a hazard ratio of 0.70 (95% CI 0.36-1.36). Grade 3-4 toxicities were uncommon in both groups, except for neutropenia, which occurred in 19 patients (58%) in the placebo group and 17 patients (50%) in the δ-tocotrienol group. There were no grade 3 or 4 peripheral sensory neuropathy. In the placebo group, 24 patients (71%) had oxaliplatin dose reductions compared to 17 patients (47%) in the δ-tocotrienol group (p = 0.047). CONCLUSION: The addition of δ-tocotrienol to FOLFOXIRI did not statistically significant prolong the time to first hospitalization or death compared to FOLFOXIRI plus placebo. Toxicity was manageable and not statistically different. There was a statistically significant difference in dose reductions of oxaliplatin pointing to a possible neuroprotective effect of δ-tocotrienol.

Vitamin E biofortification: Maximizing oilseed tocotrienol and total vitamin E tocochromanol production by use of metabolic bypass combinations.

Vitamin E tocochromanols are generated in plants by prenylation of homogentisate using geranylgeranyl diphosphate (GGDP) for tocotrienol biosynthesis and phytyl diphosphate (PDP) for tocopherol biosynthesis. Homogentisate geranylgeranyl transferase (HGGT), which uses GGDP for prenylation, is a proven target for oilseed tocochromanol biofortification that effectively bypasses the chlorophyll-linked pathway that limits PDP for vitamin E biosynthesis. In this report, we explored the feasibility of maximizing tocochromanol production in the oilseed crop camelina (Camelina sativa) by combining seed-specific HGGT expression with increased biosynthesis and/or reduced homogentisate catabolism. Plastid-targeted Escherichia coli TyrA-encoded chorismate mutase/prephenate dehydrogenase and Arabidopsis hydroxyphenylpyruvate dioxygenase (HPPD) cDNA were co-expressed in seeds to bypass feedback-regulated steps and increase flux into homogentisate biosynthesis. Homogentisate catabolism was also suppressed by seed-specific RNAi of the gene for homogentisate oxygenase (HGO), which initiates homogentisate degradation. In the absence of HGGT expression, tocochromanols were increased by ∼2.5-fold with HPPD/TyrA co-expression, and ∼1.4-fold with HGO suppression compared to levels in non-transformed seeds. No further increase in tocochromanols was observed in HPPD/TyrA lines with the addition of HGO RNAi. HGGT expression alone increased tocochromanol concentrations in seeds by âˆ¼four-fold to ≤1400 µg/g seed weight. When combined with HPPD/TyrA co-expression, we obtained an additional three-fold increase in tocochromanol concentrations indicating that homogentisate concentrations limit HGGT's capacity for maximal tocochromanol production. The addition of HGO RNAi further increased tocochromanol concentrations to 5000 µg/g seed weight, an unprecedented tocochromanol concentration in an engineered oilseed. Metabolomic data obtained from engineered seeds provide insights into phenotypic changes associated with "extreme" tocochromanol production.

Bioaccessibility of Tocols in Commercial Maize Hybrids Determined by an In Vitro Digestion Model for Poultry.

Despite the high proportion of maize grain in animal diets, the contribution made by maize phytochemicals is neglected. Tocols and their contribution to the vitamin E content of animal diets are one example, exacerbated by sparse information on the tocol bioaccessibility of commercial hybrids. In this study, the contents of individual and total tocols and their bioaccessibility were determined in the grain samples of 103 commercial hybrids using a standardized INFOGEST digestion procedure. In the studied hybrids, total tocol content ranged from 19.24 to 54.44 µg/g of dry matter. The contents of micellar α-, γ-, δ-tocopherols, γ-tocotrienol, and total tocols correlated positively with the corresponding contents in the grain samples of the studied hybrids. In contrast, a negative correlation was observed between the bioaccessibility of γ- tocopherol, α- and γ-tocotrienol, and total tocols, along with the corresponding contents in the grain of studied hybrids. The highest bioaccessibility was exhibited by γ-tocotrienol (532.77 g/kg), followed by δ-tocopherol (529.88 g/kg), γ-tocopherol (461.76 g/kg), α-tocopherol (406.49 g/kg), and α-tocotrienol (359.07 g/kg). Overall, there are significant differences in the content and bioaccessibility of total and individual tocols among commercial maize hybrids, allowing the selection of hybrids for animal production based not only on crude chemical composition but also on the content of phytochemicals.

Vitamin E discussion forum position paper on the revision of the nomenclature of vitamin E.

This position paper opens a discussion forum of this Journal dedicated to a scientific debate on Vitamin E nomenclature. With this article we provide the scientific and medical communities with what we consider relevant information in favor of revising the nomenclature of vitamin E. To our knowledge, only RRR-α-tocopherol has been medically used to protect against a deficiency disease in humans, and therefore, it would be appropriate to restrict the term vitamin to this molecule. The direct demonstration of a vitamin function to other tocochromanols (including other tocopherols, tocotrienols and eventually tocomonoenols), has not yet been scientifically shown. In fact, the medical prescription of a molecule against the deficiency disease only because it has been included in the "Vitamin E family", but not tested as vitamin E, could lead to ineffective therapy and potentially dangerous consequences for patients. The idea of this revision launched during the recent 3rd Satellite Symposium on Vitamin E of the 2022 SFRR-Europe meeting, offers a open platform of discussion for the scientists involved in vitamin E research and scientific societies interested to this subject.

Rice Bran: From Waste to Nutritious Food Ingredients.

Rice (Oryza sativa L.) is a principal food for more than half of the world's people. Rice is predominantly consumed as white rice, a refined grain that is produced during the rice milling process which removes the bran and germ and leaves the starchy endosperm. Rice bran is a by-product produced from the rice milling process, which contains many bioactive compounds, for instance, phenolic compounds, tocotrienols, tocopherols, and γ-oryzanol. These bioactive compounds are thought to protect against cancer, vascular disease, and type 2 diabetes. Extraction of rice bran oil also generates various by-products including rice bran wax, defatted rice bran, filtered cake, and rice acid oil, and some of them exert bioactive substances that could be utilized as functional food ingredients. However, rice bran is often utilized as animal feed or discarded as waste. Therefore, this review aimed to discuss the role of rice bran in metabolic ailments. The bioactive constituents and food product application of rice bran were also highlighted in this study. Collectively, a better understanding of the underlying molecular mechanism and the role of these bioactive compounds exerted in the rice bran would provide a useful approach for the food industry and prevent metabolic ailments.

Tocotrienol-rich fraction reduces retinal inflammation and angiogenesis in rats with streptozotocin-induced diabetes.

BACKGROUND: Diabetic retinopathy (DR) is the second commonest microvascular complication of diabetes mellitus. It is characterized by chronic inflammation and angiogenesis. Palm oil-derived tocotrienol-rich fraction (TRF), a substance with anti-inflammatory and anti-angiogenic properties, may provide protection against DR development. Therefore, in this study, we investigated the effect of TRF on retinal vascular and morphological changes in diabetic rats. The effects of TRF on the retinal expression of inflammatory and angiogenic markers were also studied in the streptozotocin (STZ)-induced diabetic rats. METHODS: Male Sprague Dawley rats weighing 200-250 g were grouped into normal rats (N) and diabetic rats. Diabetes was induced by intraperitoneal injection of streptozotocin (55 mg/kg body weight) whereas N similarly received citrate buffer. STZ-injected rats with blood glucose of more than 20 mmol/L were considered diabetic and were divided into vehicle-treated (DV) and TRF-treated (DT) groups. N and DV received vehicle, whereas DT received TRF (100 mg/kg body weight) via oral gavage once daily for 12 weeks. Fundus images were captured at week 0 (baseline), week 6 and week 12 post-STZ induction to estimate vascular diameters. At the end of experimental period, rats were euthanized, and retinal tissues were collected for morphometric analysis and measurement of NFκB, phospho-NFκB (Ser536), HIF-1α using immunohistochemistry (IHC) and enzyme-linked immunosorbent assay (ELISA). Retinal inflammatory and angiogenic cytokines expression were measured by ELISA and real-time quantitative PCR. RESULTS: TRF preserved the retinal layer thickness (GCL, IPL, INL and OR; p < 0.05) and retinal venous diameter (p < 0.001). TRF also lowered the retinal NFκB activation (p < 0.05) as well as expressions of IL-1ß, IL-6, TNF-α, IFN-γ, iNOS and MCP-1 (p < 0.05) compared to vehicle-treated diabetic rats. Moreover, TRF also reduced retinal expression of VEGF (p < 0.001), IGF-1 (p < 0.001) and HIF-1α (p < 0.05) compared to vehicle-treated rats with diabetes. CONCLUSION: Oral TRF provided protection against retinal inflammation and angiogenesis in rats with STZ-induced diabetes by suppressing the expression of the markers of retinal inflammation and angiogenesis.

Efficient Secretory Production of δ-Tocotrienol by Combining Pathway Modularization and Transportation Engineering.

The vitamin E component δ-tocotrienol has shown impressive activities in radioprotection, neuroprotection, and cholesterol reduction. Its production is limited by the low content in plants and difficulty in separation from other tocotrienols. Fermentative production using a microbial cell factory that exclusively produces and secretes δ-tocotrienol is a promising alternative approach. Assembly of the δ-tocotrienol synthetic pathway in Saccharomyces cerevisiae followed by comprehensive pathway engineering led to the production of 73.45 mg/L δ-tocotrienol. Subsequent addition of 2-hydroxypropyl-ß-cyclodextrin (CD) and overexpression of the transcription factor PDR1 significantly elevated δ-tocotrienol titer to 241.7 mg/L (63.65 mg/g dry cell weight) in shake flasks, with 30.4% secreted. By properly adding CD and the in situ extractant olive oil, 181.12 mg/L of δ-tocotrienol was collected as an extracellular product, accounting for 85.6% of the total δ-tocotrienol production. This process provides not only a promising δ-tocotrienol cell factory but also insights into yeast engineering toward secretory production of other terpenoids.

Effect of nano-delivery systems on the bioavailability and tissue biodistribution of vitamin E tocotrienols.

Vitamin E is one of the most important essential vitamins to support the regulation of oxidative stress in human body. Tocotrienols are part of the vitamin E family. The potentials of tocotrienols as nutraceutical ingredient are largely understated due to low oral bioavailability, which is a common problem associated with fat-soluble bioactive compounds. Nanoencapsulation technology offers innovative solutions to enhance the delivery mechanisms of these compounds. In this study, the effect of nanoencapsulation on the oral bioavailability and tissue distribution of tocotrienols were investigated using two types of formulations, i.e. nanovesicles (NV-T3) and solid lipid nanoparticles (NP-T3). At least 5-fold increment in maximum plasma concentrations, evident with dual-peak pharmacokinetic profiles, were observed after oral administration of nano-encapsulated tocotrienols. Plasma tocotrienol composition showed a shift from α-tocotrienol dominant in control group (Control-T3) to γ-tocotrienol dominant after nanoencapsulation. Tissue distribution of tocotrienols was found to be strongly influenced by the type of nanoformulation. Both nanovesicles (NV-T3) and nanoparticles (NP-T3) showed elevated accumulation in the kidneys and liver (5-fold) compared to control group while selectivity for α-tocotrienol was evident for NP-T3. In brain and liver of rats given NP-T3, α-tocotrienol emerged as the dominant congener (>80%). Acute oral administration of nanoencapsulated tocotrienols did not show signs of toxicity. The study concluded enhanced bioavailability and selective tissue accumulation of tocotrienol congeners when delivered via nanoencapsulation.

Effects of Tocotrienol-Rich Fraction Supplementation in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

There are a large number of studies that have reported benefits of tocotrienol-rich fraction (TRF) in various populations with different health status. To date, no systematic reviews have examined randomized controlled trials (RCTs) on the effect of TRF supplementations specifically in patients with type 2 diabetes mellitus (T2DM). This systematic review and meta-analysis aim to examine the changes in HbA1c (glycated hemoglobin), blood pressure, and serum Hs-CRP (C-reactive protein high sensitivity) levels at post-TRF supplementation. Online databases including PubMed, Scopus, OVID Medline, and Cochrane Central Register of Controlled Trials were searched from inception until March 2023 for RCTs supplementing TRF in patients with T2DM. A total of 10 studies were included in the meta-analysis to estimate the pooled effect size. The Cochrane Risk-of-Bias (RoB) Assessment Tool was utilized to evaluate the RoB in individual studies. The meta-analysis revealed that TRF supplementation at a dosage of 250-400 mg significantly decreased HbA1c (-0.23, 95% CI: -0.44, -0.02, P < 0.05, n = 754), particularly where the intervention duration is less than 6 mo (-0.47%, 95% CI: -0.90, -0.05, P < 0.05, n = 126) and where duration of diabetes is less than 10 y (-0.37, 95% CI: -0.68, -0.07, P < 0.05, n = 83). There was no significant reduction in systolic and diastolic blood pressure and serum Hs-CRP (P > 0.05). The present meta-analysis demonstrated that supplementing with TRF in patients with T2DM decreased HbA1c but does not decrease systolic and diastolic blood pressure and serum Hs-CRP.