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.

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.

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.

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.

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.

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.

γ-tocotrienol regulates gastric cancer by targeting notch signaling pathway.

BACKGROUND: Gastric cancer is a common cause of death from cancer and an important global health care issue. Consequently, there is an urgent need to find new drugs and therapeutic targets for the treatment of gastric cancer. Recent studies have shown that tocotrienols (T3) have significant anticancer ability in cancer cell lines. Our previous study found that γ-tocotrienol (γ-T3) induced apoptosis in gastric cancer cells. We further explored the possible mechanisms of γ-T3 therapy for gastric cancer. METHODS: In this study, we treated gastric cancer cells with γ-T3, collect and deposit the cells. γ-T3-treated gastric cancer cells group and untreated group were subjected to RNA-seq assay, and analysis of sequencing results. RESULTS: Consistent with our previous findings, the results suggest that γ-T3 can inhibit mitochondrial complexes and oxidative phosphorylation. Analysis reveals that γ-T3 has altered mRNA and ncRNA in gastric cancer cells. Significantly altered signaling pathways after γ-T3 treatment were enriched for human papillomavirus infection (HPV) pathway and notch signaling pathway. The same significantly down-regulated genes notch1 and notch2 were present in both pathways in γ-T3-treated gastric cancer cells compared to controls. CONCLUSIONS: It is indicated that γ-T3 may cure gastric cancer by inhibiting the notch signaling pathway. To provide a new and powerful basis for the clinical treatment of gastric cancer.

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.

Molecular Mechanism of Tocotrienol-Mediated Anticancer Properties: A Systematic Review of the Involvement of Endoplasmic Reticulum Stress and Unfolded Protein Response.

BACKGROUND: Tocotrienol, a type of vitamin E, is well known for its anti-cancer and other biological activities. This systematic review aims to summarize the involvement of endoplasmic reticulum stress (ERS) and subsequent unfolded protein response (UPR) as the underlying molecular mechanisms for the anticancer properties of tocotrienol. METHOD: A comprehensive literature search was performed in March 2023 using the PubMed, Scopus, Web of Science, and EMBASE databases. In vitro, in vivo, and human studies were considered. RESULT: A total of 840 articles were retrieved during the initial search, and 11 articles that fit the selection criteria were included for qualitative analysis. The current mechanistic findings are based solely on in vitro studies. Tocotrienol induces cancer cell growth arrest, autophagy, and cell death primarily through apoptosis but also through paraptosis-like cell death. Tocotrienol-rich fractions, including α-, γ- and δ-tocotrienols, induce ERS, as evidenced by upregulation of UPR markers and/or ERS-related apoptosis markers. Early endoplasmic reticulum calcium ion release, increased ceramide level, proteasomal inhibition, and upregulation of microRNA-190b were suggested to be essential in modulating tocotrienol-mediated ERS/UPR transduction. Nevertheless, the upstream molecular mechanism of tocotrienol-induced ERS is largely unknown. CONCLUSION: ERS and UPR are essential in modulating tocotrienol-mediated anti-cancer effects. Further investigation is needed to elucidate the upstream molecular mechanism of tocotrienol-mediated ERS.

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.

The effect of palm oil-derived tocotrienol-rich fraction in preserving normal retinal vascular diameter in streptozotocin-induced diabetic rats.

PURPOSE: Angiogenesis in diabetic retinopathy (DR) is associated with increased retinal expression of angiopoietin-2 (Ang-2) and protein kinase C (PKC). Tocotrienol-rich fraction (TRF) has been shown to reduce the expression vascular endothelial growth factor (VEGF) in several experimental models. However, its effect against other angiogenic markers such as Ang-2 and PKC in rat model of diabetes remains unknown. Therefore, we investigated the effect of TRF on the retinal vascular changes and Ang-2 and PKC expressions in rats with streptozotocin (STZ)-induced DR. METHODS: Sprague-Dawley rats were divided into normal control rats (N) which received vehicle, and diabetic rats which either received vehicle (DV) or 100 mg/kg of TRF (DT). Diabetes was induced with intraperitoneal injection of STZ (60 mg/kg body weight). Treatments were given orally, once daily, for 12 weeks after confirmation of hyperglycaemia. Fundus photographs were captured at baseline, 6- and 12-week post-STZ injection and average diameter of retinal veins and arteries were measured. At 12-week post-STZ injection, rats were euthanised, and retinae were collected for measurement of Ang-2 and PKC gene and protein expressions. RESULTS: Retinal venous and arterial diameters were significantly greater in DV compared to DT at week 12 post-STZ injection (p < 0.001 and < 0.05, respectively). The vessel diameter measurements in DT were comparable to N and this effect of TRF was associated with significantly lower Ang-2 and PKC gene and protein expressions compared to DV. CONCLUSION: Oral TRF reduces the expression of retinal angiogenic markers and preserves the retinal vascular diameter of rats with STZ-induced DR.

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.

Tocotrienol-Rich Fraction and Levodopa Regulate Proteins Involved in Parkinson's Disease-Associated Pathways in Differentiated Neuroblastoma Cells: Insights from Quantitative Proteomic Analysis.

Tocotrienol-rich fraction (TRF), a palm oil-derived vitamin E fraction, is reported to possess potent neuroprotective effects. However, the modulation of proteomes in differentiated human neuroblastoma SH-SY5Y cells (diff-neural cells) by TRF has not yet been reported. This study aims to investigate the proteomic changes implicated by TRF in human neural cells using a label-free liquid-chromatography-double mass spectrometry (LC-MS/MS) approach. Levodopa, a drug used in the treatment of Parkinson's disease (PD), was used as a drug control. The human SH-SY5Y neuroblastoma cells were differentiated for six days and treated with TRF or levodopa for 24 h prior to quantitative proteomic analysis. A total of 81 and 57 proteins were differentially expressed in diff-neural cells following treatment with TRF or levodopa, respectively. Among these proteins, 32 similar proteins were detected in both TRF and levodopa-treated neural cells, with 30 of these proteins showing similar expression pattern. The pathway enrichment analysis revealed that most of the proteins regulated by TRF and levodopa are key players in the ubiquitin-proteasome, calcium signalling, protein processing in the endoplasmic reticulum, mitochondrial pathway and axonal transport system. In conclusion, TRF is an essential functional food that affects differential protein expression in human neuronal cells at the cellular and molecular levels.

Tocotrienol-Rich Fractions Offer Potential to Suppress Pulmonary Fibrosis Progression.

Although pulmonary fibrosis (PF) is considered a rare disease, the incidence thereof has increased steadily in recent years, while a safe and effective cure remains beyond reach. In this study, the potential of tocotrienol-rich fractions (TRF) and carotene to alleviate PF was explored. PF was induced in Sprague-Dawley rats via a single intratracheal bleomycin (BLM) (5 mg/kg) instillation. These rats were subsequently treated with TRF, carotene, pirfenidone (Pir) and nintedanib (Nin) for 28 days via gavage administration, whereafter histopathological performance, biochemical functions and molecular alterations were studied in the lung tissues. Our results showed that TRF, carotene, Nin and Pir all ameliorated PF by reducing inflammation and resisting oxidative stress to varying degrees. The related mechanisms involved the TGF-ß1/Smad, PI3K/Akt and NF-κB signaling pathways. Ultimately, our findings revealed that, when combined with TRF, the therapeutic effects of Nin and Pir on PF were enhanced, indicating that TRF may, indeed, provide promising potential for use in combination therapy in the treatment of PF.

Palm Oil Derived Tocotrienol-Rich Fraction Attenuates Vascular Dementia in Type 2 Diabetic Rats.

Vascular dementia (VaD) is a serious global health issue and type 2 diabetes mellitus (T2DM) patients are at higher risk. Palm oil tocotrienol-rich fraction (TRF) exhibits neuroprotective properties; however, its effect on VaD is not reported. Hence, we evaluated TRF effectiveness in T2DM-induced VaD rats. Rats were given a single dose of streptozotocin (STZ) and nicotinamide (NA) to develop T2DM. Seven days later, diabetic rats were given TRF doses of 30, 60, and 120 mg/kg orally for 21 days. The Morris water maze (MWM) test was performed for memory assessment. Biochemical parameters such as blood glucose, plasma homocysteine (HCY) level, acetylcholinesterase (AChE) activity, reduced glutathione (GSH), superoxide dismutase (SOD) level, and histopathological changes in brain hippocampus and immunohistochemistry for platelet-derived growth factor-C (PDGF-C) expression were evaluated. VaD rats had significantly reduced memory, higher plasma HCY, increased AChE activity, and decreased GSH and SOD levels. However, treatment with TRF significantly attenuated the biochemical parameters and prevented memory loss. Moreover, histopathological changes were attenuated and there was increased PDGF-C expression in the hippocampus of VaD rats treated with TRF, indicating neuroprotective action. In conclusion, this research paves the way for future studies and benefits in understanding the potential effects of TRF in VaD rats.

Transcriptomic Analysis of the Anticancer Effects of Annatto Tocotrienol, Delta-Tocotrienol and Gamma-Tocotrienol on Chondrosarcoma Cells.

Previous studies have demonstrated the anticancer activities of tocotrienol on several types of cancer, but its effects on chondrosarcoma have never been investigated. Therefore, this study aims to determine the anticancer properties of annatto tocotrienol (AnTT), γ-tocotrienol (γ-T3) and δ-tocotrienol (δ-T3) on human chondrosarcoma SW1353 cells. Firstly, the MTT assay was performed to determine the half-maximal inhibitory concentration (IC50) of tocotrienol on SW1353 cells after 24 h treatment. The mode of cell death, cell cycle analysis and microscopic observation of tocotrienol-treated SW1353 cells were then conducted according to the respective IC50 values. Subsequently, RNAs were isolated from tocotrienol-treated cells and subjected to RNA sequencing and transcriptomic analysis. Differentially expressed genes were identified and then verified with a quantitative PCR. The current study demonstrated that AnTT, γ-T3 and δ-T3 induced G1 arrest on SW1353 cells in the early phase of treatment (24 h) which progressed to apoptosis upon 48 h of treatment. Furthermore, tocotrienol-treated SW1353 cells also demonstrated large cytoplasmic vacuolation. The subsequent transcriptomic analysis revealed upregulated signalling pathways in endoplasmic reticulum stress, unfolded protein response, autophagy and transcription upon tocotrienol treatment. In addition, several cell proliferation and cancer-related pathways, such as Hippo signalling pathway and Wnt signalling pathway were also significantly downregulated upon treatment. In conclusion, AnTT, γ-T3 and δ-T3 possess promising anticancer properties against chondrosarcoma cells and further study is required to confirm their effectiveness as adjuvant therapy for chondrosarcoma.

Antioxidant and anti-apoptotic effects of tocotrienol-rich fraction against streptozotocin-induced diabetic retinopathy in rats.

Oxidative stress, a key player in diabetic retinopathy (DR), is associated with retinal cell apoptosis. This study investigated the effect of tocotrienol-rich fraction (TRF), a potent antioxidant, towards visual behaviour, retinal morphology, cells apoptosis and redox status in streptozotocin (STZ)-induced DR rats. Sprague-Dawley rats were divided into 3 groups: non-diabetic (N), was injected with citrate buffer intraperitoneally, diabetic treated with vehicle (DV), and diabetic treated with TRF (DT), were injected with STZ intraperitoneally (55 mg/kg) to induce diabetes. DT received 100 mg of TRF/kg orally for 12-weeks, whereas DV and N received vehicle. The general and visual-behaviour responses were assessed at week 12 in an open field arena. Rats were then sacrificed, and retinae were processed for haematoxylin and eosin (H&E) and terminal transferase-mediated dUTP nick end-labelling (TUNEL) staining. Retinal antioxidant, lipid peroxidation and anti-apoptotic markers were measured. The general and visual-behaviour responses in DT were comparable to N. Retinal thickness and cell counts were lower in DV and DT compared to N. Lower number of TUNEL-positive cells were observed in DT compared to DV (1.48-fold, p < 0.001) which correlated with retinal caspase-3 expression (2.31-fold, p < 0.001). The retinal oxidative stress in DT was lower than DV as indicated by higher reduced glutathione (2.10-fold, p < 0.05), superoxide dismutase (1.12-fold, p < 0.05) and catalase (1.40-fold, p < 0.001), and lower malondialdehyde (2.54-fold, p < 0.001). In conclusion, oral TRF (100 mg/kg) supplementation for 12-weeks reduces retinal oxidative stress in STZ-induced DR rats, which in turn reduces retinal cell apoptosis and protects retinal morphology. These findings were associated with preservation of the visual-behaviour responses.

Tocotrienol as a Protecting Agent against Glucocorticoid-Induced Osteoporosis: A Mini Review of Potential Mechanisms.

Glucocorticoid-induced osteogenic dysfunction is the main pathologyical mechanism underlying the development of glucocorticoid-induced osteoporosis. Glucocorticoids promote adipogenic differentiation and osteoblast apoptosis through various pathways. Various ongoing studies are exploring the potential of natural products in preventing glucocorticoid-induced osteoporosis. Preclinical studies have consistently shown the bone protective effects of tocotrienol through its antioxidant and anabolic effects. This review aims to summarise the potential mechanisms of tocotrienol in preventing glucocorticoid-induced osteoporosis based on existing in vivo and in vitro evidence. The current literature showed that tocotrienol prevents oxidative damage on osteoblasts exposed to high levels of glucocorticoids. Tocotrienol reduces lipid peroxidation and increases oxidative stress enzyme activities. The reduction in oxidative stress protects the osteoblasts and preserves the bone microstructure and biomechanical strength of glucocorticoid-treated animals. In other animal models, tocotrienol has been shown to activate the Wnt/ß-catenin pathway and lower the RANKL/OPG ratio, which are the targets of glucocorticoids. In conclusion, tocotrienol enhances osteogenic differentiation and bone formation in glucocorticoid-treated osteoblasts while improving structural integrity in glucocorticoid-treated rats. This is achieved by preventing oxidative stress and osteoblast apoptosis. However, these preclinical results should be validated in a randomised controlled trial.

Polyprenylated Benzophenones and Tocotrienol Derivatives from the Edible Fruits of Garcinia oblongifolia Champ. ex Benth. and Their Cytotoxicity Activity.

The fruits of Garcinia oblongifolia Champ. ex Benth. were famous as an edible fruit in tropical regions of China. Because of its unique taste and great nutritional value, the ripe fresh fruits of G. oblongifolia could be eaten directly or used as raw materials for natural beverages and food supplements. In this work, six new polyprenylated benzophenones (1-6) and one new dimeric tocotrienol derivative (7), together with 18 known ones (8-25), were isolated from the fruits of G. oblongifolia. Compounds 1-4 were peculiar polycyclic polyprenylated acylphloroglucinols (PPAPs) featuring the rare carbon skeleton of a bicyclo[3.4.1]decane-1,3-diketone. Moreover, all isolates (1-25) were evaluated for their cytotoxicity activities against nasopharyngeal carcinoma (NPC) cell lines (CNE1 and CNE2). Among these isolates, compound 6 exhibited the strongest cytotoxicity activity on CNE1 and CNE2 cells with the IC50 values of 7.8 ± 0.2 and 9.1 ± 0.3 µM, respectively. Further mechanistic investigation demonstrated that 6 could induce mitophagy to promote Caspase-9/GSDME-mediated pyroptosis through triggering ROS in NPC cells.

Therapeutic potential of palm oil vitamin E-derived tocotrienols in inflammation and chronic diseases: Evidence from preclinical and clinical studies.

Palm oil is rich in tocotrienols (T3s), a type of vitamin E that has garnered considerable research interest as it exhibits anti-inflammatory as well as antioxidant characteristics that are comparable to or exceed those of tocopherols (Toc). Notably, T3 must be consumed as it cannot be produced by the human body. Here, we reviewed the anti-inflammatory activities of T3s in the prevention and treatment of various inflammatory disorders; focusing on recent preclinical and clinical studies. There is compelling data from experimental models and human studies that shows that T3 administration can inhibit the release of various inflammatory mediators that contribute to age-related disease by enhancing oxidative stress, reducing melanin production and skin damage, and preventing cardiovascular disease and stroke. There is evidence to show that T3s possess neuroprotective, anticancer, and anti-osteoporosis properties. In addition, T3s also protect the gastrointestinal tract, facilitate blood glucose control in people with diabetes, and prevent fatty liver disease. Furthermore, results from some clinical studies suggest that T3s are beneficial nutritional supplements with no evident side-effects when administered to patients with neurological or cardiovascular disorders. There is growing evidence from clinical trials that shows that T3s can help prevent dementia and Alzheimer's disease. More well-designed clinical trials, as well as human intervention studies, are required to confirm the health benefits of palm T3.