Gamma-Tocotrienol Inhibits Proliferation and Growth of HSD17B4-Overexpressing HepG2 Liver Cancer Cells.

INTRODUCTION: Hydroxysteroid 17-beta dehydrogenase 4 (HSD17B4) is involved in the progression of hepatocellular carcinoma (HCC). AIMS: This study aimed to investigate the inhibitory effect of gamma-tocotrienol (γ-T3) on the proliferation and growth of HSD17B4-overexpressing HepG2 cells. METHODS: HepG2 cells were transfected with empty or HSD17B4-overexpressing plasmids, followed by vitamin E (VE) or γ-T3 treatment. MTS assay, Western blotting, qRT-PCR, and flow cytometry were employed to assess cell proliferation, protein expression, mRNA levels, and apoptosis. HSD17B4 interaction with γ-T3 was assessed by quantifying γ-T3 in the collected precipitate of HSD17B4 using anti-flag magnetic beads. Tumor xenografts were established in NSG mice, and tumor growth was monitored. RESULTS: HSD17B4 overexpression significantly promoted HepG2 cell proliferation, which was effectively counteracted by VE or γ-T3 treatment in a dose-dependent manner. VE and γ-T3 did not exert their effects through direct regulation of HSD17B4 expression. Instead, γ-T3 was found to interact with HSD17B4, inhibiting its activity in catalyzing the conversion of estradiol (E2) into estrone. Moreover, γ-T3 treatment led to a reduction in cyclin D1 expression and suppressed key proliferation signaling pathways, such as ERK, MEK, AKT, and STAT3. Additionally, γ-T3 promoted apoptosis in HSD17B4-overexpressing HepG2 cells. In an in vivo model, γ-T3 effectively reduced the growth of HepG2 xenograft tumors. CONCLUSION: In conclusion, our study demonstrates that γ-T3 exhibits potent anti-proliferative and anti-tumor effects against HepG2 cells overexpressing HSD17B4. These findings highlight the therapeutic potential of γ-T3 in HCC treatment and suggest its role in targeting HSD17B4-associated pathways to inhibit tumor growth and enhance apoptosis.

Obtaining Bixin- and Tocotrienol-Rich Extracts from Peruvian Annatto Seeds Using Supercritical CO2 Extraction: Experimental and Economic Evaluation.

Currently, Bixa orellana L. extracts are used as a color source in the food, pharmaceutical, and cosmetic industries because they are important as a potential source of antioxidant activity. The extraction is carried out by conventional methods, using alkaline solutions or organic solvents. These extraction methods do not take advantage of the lipid fraction of annatto (Bixa orellana L.) seeds, and the process is not friendly to the environment. In this work, the objective was to obtain an extract rich in nutraceuticals (bixin and tocols) of high antioxidant power from Peruvian annatto seeds as a potential source for a functional food or additive in the industry using supercritical fluid extraction (SFE). Experiments related to extraction yield, bixin, tocotrienols, tocopherols, and antioxidant activity were carried out. The SFE was performed at 40 °C, 50 °C, and 60 °C, and 100, 150, and 250 bar with 0.256 kg/h carbon dioxide as the supercritical solvent (solvent-to-feed ratio of 10.2). Supercritical extraction at 60 °C and 250 bar presented the best results in terms of global extraction yield of 1.40 ± 0.01 g/100 g d.b., extract concentration of 0.564 ± 0.005 g bixin/g extract, 307.8 mg α-tocotrienol/g extract, 39.2 mg ß-tocotrienol/g extract, 2 mg γ-tocopherol/g extract, and IC50 of 989.96 µg extract/mL. Economical evaluation showed that 60 °C, 250 bar, and 45 min presented the lowest cost of manufacturing (2 × 2000 L, COM of USD 212.39/kg extract). This extract is a potential source for functional food production.

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.

Topical Nanoemulsion Hydrogel Formulated from Supercritical Fluid Extracted Palm-Pressed Fiber Oil and Virgin Coconut Oil with Antioxidant and Antibacterial Effects.

Skincare industries are growing rapidly around the globe but most products are formulated using synthetic chemicals and organic solvent extracted plant extracts, thus may be hazardous to the users and incur higher cost for purification that eventually leads to phytonutrient degradation. Therefore, this study aimed to formulate a stable natural formulation with antioxidant and antimicrobial activities by using supercritical carbon dioxide (SC-CO 2 ) extracted palm-pressed fiber oil (PPFO) as an active ingredient with virgin coconut oil (VCO) as a formulation base. PPFO was extracted from fresh palm-pressed fiber (PPF) while VCO was from dried grated coconut copra using SC-CO 2 before being subjected to the analyses of physicochemical properties, phytonutrient content and biological activities including antioxidant and antimicrobial. The nanoemulgel formulations were then developed and examined for their stability through accelerated stability study for 3 months by measuring their pH, particle size, polydispersity index and zeta potential. The results showed that PPFO contained a high amount of phytonutrients, especially total carotenoid (1497 ppm) and total tocopherol and tocotrienol (2269 ppm) contents. The newly developed nanoemulgels maintained their particles in nano size and showed good stability with high negative zeta potentials. Sample nanoemulgel formulated with 3% PPFO diluted in VCO as effective concentration showed significantly stronger antioxidant activity than the control which was formulated from 3% tocopheryl acetate diluted in mineral oil, towards DPPH and ABTS radicals, with IC 50 values of 67.41 and 44.28 µL/mL, respectively. For the antibacterial activities, the sample nanoemulgel was found to inhibit Gram positive bacteria S. aureus and S. epidermidis growth but not the Gram negative strain E. coli. Overall, this study revealed the potential of SF-extracted PPFO as an active ingredient in the antioxidant topical formulations thus future study on in vitro skin cell models is highly recommended for validation.

Palm-based tocotrienol-rich fraction (TRF) supplementation modulates cardiac sod1 expression, fxr target gene expression, and tauro-conjugated bile acid levels in aleptinemic mice fed a high-fat diet.

Tocotrienol-rich fraction (TRF) has been reported to protect the heart from oxidative stress-induced inflammation. It is, however, unclear whether the protective effects of TRF against oxidative stress involve the activation of farnesoid X receptor (fxr), a bile acid receptor, and the regulation of bile acid metabolites. In the current study, we investigated the effects of TRF supplementation on antioxidant activities, expression of fxr and its target genes in cardiac tissue, and serum untargeted metabolomics of high-fat diet-fed mice. Mice were divided into high-fat diet (HFD) with or without TRF supplementation (control) for 6 weeks. At the end of the intervention, body weight (BW), waist circumference (WC), and random blood glucose were measured. Heart tissues were collected, and the gene expression of sod1, sod2, gpx, and fxr and its target genes shp and stat3 was determined. Serum was subjected to untargeted metabolomic analysis using UHPLC-Orbitrap. In comparison to the control, the WC of the TRF-treated group was higher (p >0.05) than that of the HFD-only group, in addition there was no significant difference in weight or random blood glucose level. Downregulation of sod1, sod2, and gpx expression was observed in TRF-treated mice; however, only sod1 was significant when compared to the HFD only group. The expression of cardiac shp (fxr target gene) was significantly upregulated, but stat3 was significantly downregulated in the TRF-treated group compared to the HFD-only group. Biochemical pathways found to be influenced by TRF supplementation include bile acid secretion, primary bile acid biosynthesis, and biotin and cholesterol metabolism. In conclusion, TRF supplementation in HFD-fed mice affects antioxidant activities, and more interestingly, TRF also acts as a signaling molecule that is possibly involved in several bile acid-related biochemical pathways accompanied by an increase in cardiac fxr shp expression. This study provides new insight into TRF in deregulating bile acid receptors and metabolites in high-fat diet-fed mice.

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.

Vitamin E and conflicting understandings in noncommunicable diseases: Is it worth supplementing?

Vitamin E is a lipid-soluble nutrient found mainly in vegetable oils and oilseeds. It is divided into eight homologous compounds; however, only α-tocopherol exhibits vitamin activity. Many advantages are related to these compounds, including cellular protection through antioxidant and anti-inflammatory activity, and improving lipid metabolism. Physiopathology of many diseases incepts with reduced antioxidant defense, characterized by an increased reactive oxygen species production and activation of transcription factors involved in inflammation, such as nuclear factor-kappa B (NF-κB), that can be linked to oxidative stress. Moreover, disorders of lipid metabolism can increase the risk of cardiovascular diseases. In addition, intestinal dysbiosis plays a vital role in developing chronic non-communicable diseases. In this regard, vitamin E can be considered to mitigate those disorders, but data still needs to be more conclusive. This narrative review aims to elucidate the mechanisms of action of vitamin E and if supplementation can be beneficial in a disease scenario regarding non-communicable diseases.

A multiplex approach of MS, 1D-, and 2D-NMR metabolomics in plant ontogeny: A case study on Clusia minor L. organs (leaf, flower, fruit, and seed).

INTRODUCTION: The genus Clusia L. is mostly recognised for the production of prenylated benzophenones and tocotrienol derivatives. OBJECTIVES: The objective of this study was to map metabolome variation within Clusia minor organs at different developmental stages. MATERIAL AND METHODS: In total 15 organs/stages (leaf, flower, fruit, and seed) were analysed by UPLC-MS and 1H- and heteronuclear multiple-bond correlation (HMBC)-NMR-based metabolomics. RESULTS: This work led to the assignment of 46 metabolites, belonging to organic acids(1), sugars(2) phenolic acids(1), flavonoids(3) prenylated xanthones(1) benzophenones(4) and tocotrienols(2). Multivariate data analyses explained the variability and classification of samples, highlighting chemical markers that discriminate each organ/stage. Leaves were found to be rich in 5-hydroxy-8-methyltocotrienol (8.5 µg/mg f.w.), while flowers were abundant in the polyprenylated benzophenone nemorosone with maximum level detected in the fully mature flower bud (43 µg/mg f.w.). Nemorosone and 5-hydroxy tocotrienoloic acid were isolated from FL6 for full structural characterisation. This is the first report of the NMR assignments of 5-hydroxy tocotrienoloic acid, and its maximum level was detected in the mature fruit at 50 µg/mg f.w. Seeds as typical storage organ were rich in sugars and omega-6 fatty acids. CONCLUSION: To the best of our knowledge, this is the first report on a comparative 1D-/2D-NMR approach to assess compositional differences in ontogeny studies compared with LC-MS exemplified by Clusia organs. Results derived from this study provide better understanding of the stages at which maximal production of natural compounds occur and elucidate in which developmental stages the enzymes responsible for the production of such metabolites are preferentially expressed.

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.

Tocotrienols Provide Radioprotection to Multiple Organ Systems through Complementary Mechanisms of Antioxidant and Signaling Effects.

Tocotrienols have powerful radioprotective properties in multiple organ systems and are promising candidates for development as clinically effective radiation countermeasures. To facilitate their development as clinical radiation countermeasures, it is crucial to understand the mechanisms behind their powerful multi-organ radioprotective properties. In this context, their antioxidant effects are recognized for directly preventing oxidative damage to cellular biomolecules from ionizing radiation. However, there is a growing body of evidence indicating that the radioprotective mechanism of action for tocotrienols extends beyond their antioxidant properties. This raises a new pharmacological paradigm that tocotrienols are uniquely efficacious radioprotectors due to a synergistic combination of antioxidant and other signaling effects. In this review, we have covered the wide range of multi-organ radioprotective effects observed for tocotrienols and the mechanisms underlying it. These radioprotective effects for tocotrienols can be characterized as (1) direct cytoprotective effects, characteristic of the classic antioxidant properties, and (2) other effects that modulate a wide array of critical signaling factors involved in radiation injury.

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.

The Effect of Vitamin E Supplementation on Serum Aminotransferases in Non-Alcoholic Fatty Liver Disease (NAFLD): A Systematic Review and Meta-Analysis.

Νon-alcoholic fatty liver disease (NAFLD) is a common cause of end-stage liver disease in developed countries. Oxidative stress plays a key role during the course of the disease and vitamin E supplementation has shown to be beneficial due to its antioxidative properties. We aim to investigate the effect of vitamin E supplementation on serum aminotransferase levels in patients with NAFLD. Three electronic databases (MEDLINE, CENTRAL, and Embase) were reviewed for randomized trials that tested vitamin E supplementation versus placebo or no intervention in patients with NAFLD, published until April 2023. A total of 794 patients from 12 randomized trials were included in this meta-analysis. Notwithstanding the studies' heterogeneity and moderate internal validity in certain cases, among studies testing vitamin E supplementation at 400 IU/day and above, the values of alanine aminotransferase (ALT) were reduced compared with placebo or no intervention [ALT Mean Difference (MD) = -6.99 IU/L, 95% CI (-9.63, -4.35), for studies conducted in Asian countries and MD = -9.57 IU/L, 95% CI (-12.20, -6.95) in non-Asian countries]. Regarding aspartate aminotransferase (AST), patients in the experimental group experienced a reduction in serum levels, though smaller in absolute values [AST MD = -4.65 IU/L, 95% CI (-7.44, -1.86) in studies conducted in Asian populations] and of lower precision in non-Asian studies [MD = -5.60 IU/L, 95% CI (-11.48, 0.28)].

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.

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.

Anti-inflammatory and antioxidant properties of rice bran oil extract in copper sulfate-induced inflammation in zebrafish (Danio rerio).

Tocotrienols have strong antioxidant properties; however, tocotrienol has not been investigated in detail in aquatic products. In this study, the anti-inflammatory and antioxidant activities of the tocotrienol-rich fraction from rice bran oil and its potential mechanism were verified in a zebrafish CuSO4 inflammation model. The in vitro antioxidant activity was evaluated using the 2,2-Diphenyl-1-picrylhydrazyl (DPPH) stable radical method. The copper chelating activity was determined using the pyrocatechol violet method. Intracellular reactive oxygen species in zebrafish were detected using a fluorescent ROS probe. Transgenic Tg (lyz: DsRed2) zebrafish were used for neutrophil transmigration assays. The mRNA expression levels of antioxidant and pro-inflammatory factor genes were measured using quantitative real-time reverse transcription PCR. In the concentration range tested, 100 µg/mL TRF had the highest copper chelating activity (10%). TRF showed DPPH-free radical scavenging ability, which was 53% at 100 µg/mL TRF. TRF effectively repressed ROS generation and inhibited neutrophil migration to the inflamed site. Moreover, TRF upregulated the expression of antioxidant genes sod and gpx4b, inhibited the expression of pro-inflammatory factors tnfa and il8, and suppressed CuSO4-induced inflammation. In conclusion, TRF has significant anti-inflammatory and antioxidant properties, which supports the use of TRF as an aquatic feed additive to improve the anti-inflammatory and antioxidant capacity of aquatic products.

Tocotrienols-enriched Self-nanoemulsifying Drug Delivery System Enhances the Antileukemic Activity of All-trans Retinoic Acid but not Electrocardiogram Alterations Evoked by Its Combination with Arsenic Trioxide.

All-trans retinoic acid and arsenic trioxide are the leading choices for the treatment of acute promyelocytic leukemia. Notwithstanding the impressive differentiative properties of all-trans retinoic acid and the apoptotic properties of arsenic trioxide, some problems still occur in acute promyelocytic leukemia treatment. These problems are due to patients' relapses, mainly related to changes in the ligand-binding domain of RARα (retinoic acid receptor α) and the cardiotoxic effects caused by arsenic trioxide. We previously developed a self-nanoemulsifying drug delivery system enriched with tocotrienols to deliver all-trans retinoic acid (SNEDDS-TRF-ATRA). Herein, we have evaluated if tocotrienols can help revert ATRA resistance in an APL cell line (NB4-R2 compared to sensitive NB4 cells) and mitigate the cardiotoxic effects of arsenic trioxide in a murine model. SNEDDS-TRF-ATRA enhanced all-trans retinoic acid cytotoxicity in NB4-R2 (resistant) cells but not in NB4 (sensitive) cells. Moreover, SNEDDS-TRF-ATRA did not significantly change the differentiative properties of all-trans retinoic acid in both NB4 and NB4-R2 cells. Combined administration of SNEDDS-TRF-ATRA and arsenic trioxide could revert QTc interval prolongation caused by ATO but evoked other electrocardiogram alterations in mice, such as T wave flattening. Therefore, SNEDDS-TRF-ATRA may enhance the antileukemic properties of all-trans retinoic acid but may influence ECG changes caused by arsenic trioxide administration. SNEDDS-TRF-ATRA presents cytotoxicity in resistant APL cells (NB4-R2). Combined administration of ATO and SNEDDS-TRF-ATRA in mice prevented the prolongation of the QTc interval caused by ATO but evoked ECG abnormalities such as T wave flattening.

Composition, Microbiota, Mechanisms, and Anti-Obesity Properties of Rice Bran.

Rice is a major cereal crop and a staple food for nearly 50% of people worldwide. Rice bran (RB) is a nutrient-rich by-product of rice processing. RB is rich in carbohydrates, fibers, proteins, lipids, minerals, and several trace elements (phosphorus, calcium, magnesium, potassium, and manganese). The extraction process and storage have influenced RB extracts and RB oil's quality. The RB composition has also varied on the rice cultivars. The color of RB indicates the richness of the bioactive compounds, especially anthocyanins. γ-oryzanol, tocopherols, tocotrienols, and unsaturated fatty acids are major components of RB oil. It has been established that RB supplementation could improve the host's health status. Several preclinical and clinical studies have reported that RB has antioxidant, anticancer, anti-inflammatory, anticolitis, and antidiabetic properties. The beneficial biological properties of RB are partially attributed to its ability to alter the host microbiome and help to maintain and restore eubiosis. Non-communicable diseases (NCDs), including heart disease, diabetes, cancer, and lung disease, account for 74% of deaths worldwide. Obesity is a global health problem and is a major reason for the development of NCDs. The medical procedures for managing obesity are expensive and long-term health supplements are required to maintain a healthy weight. Thus, cost-effective natural adjuvant therapeutic strategy is crucial to treat and manage obesity. Several studies have revealed that RB could be a complementary pharmacological candidate to treat obesity. A comprehensive document with basic information and recent scientific results on the anti-obesity activity of RB and RB compounds is obligatory. Thus, the current manuscript was prepared to summarize the composition of RB and the influence of RB on the host microbiome, possible mechanisms, and preclinical and clinical studies on the anti-obesity properties of RB. This study suggested that the consumption of RB oil and dietary RB extracts might assist in managing obesity-associated health consequences. Further, extended clinical studies in several ethnic groups are required to develop dietary RB-based functional and nutritional supplements, which could serve as an adjuvant therapeutic strategy to treat obesity.

Intramuscular compatibility of an injectable anti-inflammatory nanodispersion from a standardized Bixa orellana oil (Chronic®): a toxicological study in Wistar rats.

Bixa orellana L. is a plant popularly known as "ucurum", "annatto", and "achiote". It is native to South America, and its seeds are an abundant source of geranylgeraniol and tocotrienols. Nanoencapsulation is a valuable technique that can decrease the drug needed to achieve an effect, decreasing potential toxicity, side effects and potentiate the anti-inflammatory effect. This study aimed to evaluate the acute toxicity of an intramuscular application of a nanodispersion containing a standardized extract from the seeds of Bixa orellana (NBO) in Wistar rats. The chemical evaluation showed δ-tocotrienol at 0.725 ± 0.062 mg/mL (72.6 ± 0.9%). The stability study showed the nanoparticles had an average size from 53.15 ± 0.64 to 59.9 ± 3.63 nm, with a polydispersity index ranging from 0.574 ± 0.032 to 0.574 ± 0.32, Zeta potential from 18.26 ± 0.59 to 19.66 ± 1.45 mV. After testing the intramuscular application of NBO with doses from 1 to 5 mg/kg in animals, it was observed that the acute treatment did not elicit any toxic effects within this range. The dose of 10 mg/kg, although not affecting hematological and biochemical parameters (CPK, LDH, myoglobin, AST, ALT, TC, TG, glucose levels, creatinine, and urea), could induce some muscle tissue changes, including leukocyte infiltration, morphological chances, and potentially necrosis. In conclusion, the results showed that the treatments devoided toxicity between 1 and 5 mg/kg.

Chemopreventive and anti-tumor potential of vitamin E in preclinical breast cancer studies: A systematic review.

BACKGROUND: Vitamin E has been investigated for its antitumor potential, including the ability to change cancer gene pathways as well as promote antioxidant and pro-oxidant activity. OBJECTIVE: Therefore, this systematic review aimed to evaluate antitumor and chemopreventive activity of different vitamin E isoforms (tocopherols and tocotrienols) through in vitro and in vivo studies. METHOD: The systematic review was registered in PROSPERO (No. CRD4202126207) and the search was carried out in four electronic databases (PubMed, Science Direct, Scopus and Web of Science) in June 2021 by three independent reviewers. The search equation used was: "Supplementation" AND ("Vitamin E" OR Tocopherol OR Tocotrienol) AND "breast cancer" AND (chemotherapy OR therapy OR prevention). In vitro studies and animal models of breast cancer supplemented with tocopherol or tocotrienol vitamers, alone or in combination, were included. RESULTS: The results revealed 8546 relevant studies that were initially identified in our search. After analysis, a total of 12 studies were eligible for this systematic review. All studies included animal models, and 5 of them also performed in vitro experiments on cancer cell lines. The studies performed supplementation with tocopherols, mixtures (tocopherols and tocotrienols) and synthetic vitamin E forms. There was an significant association of estradiol, dendritic cells and pterostilbene in combined therapy with vitamin E. Vitamin E delayed tumor development, reduced tumor size, proliferation, viability, expression of anti-apoptotic and cell proliferation genes, and upregulated pro-apoptotic genes, tumor suppressor genes and increased immune response. The effects on oxidative stress markers and antioxidant activity were conflicting among studies. Only one study with synthetic vitamin E reported cardiotoxicity, but it did not show vitamin E genotoxicity. CONCLUSION: In conclusion, vitamin E isoforms, isolated or associated, showed antitumor and chemopreventive activity. However, due to studies heterogeneity, there is a need for further analysis to establish dose, form, supplementation time and breast cancer stage.