Search

Elaeagnus mollis is an important newly developing woody oil plant species and the vitamin E (VitE) content in its kernel oil is relatively high. In the present study, the VitE component content and functional genes involving in VitE biosynthesis in E. mollis kernel at different developmental stage were investigated. The VitE content increased with kernel development, reaching up to ~ 7.96 mg/g oil in kernel mature stage. The content of tocopherol was much higher than that of tocotrienol and γ-tocopherol became the dominant component. E. mollis kernel extracts had relatively strong antioxidant capacity. We identified 17 genes (16 VTEs and 1 homogentisic acid geranylgeranyl transferase (HGGT)) directly involving in VitE biosynthesis in RNA-Seq data. Phylogenetic and qRT-PCR results indicated that the annotation and reliability of the RNA-Seq were accurate. Transient overexpression of EmVTE3 and EmWRKY13 in tobacoo leaves increased and decreased the VitE content to 192.18 and 118.29 µg/g, respectively. Weighted gene co-expression analysis elucidated that the blue module showed significant correlation with tocopherol content. Co-expression network analysis revealed that 2-methyl-6-phytobenzoquinone methyltransferase (MPBQ-MT/VTE3) played a vital role and EmWRKY13 may be a key negative regulator in E. mollis VitE biosynthesis. This study not only revealed the traditional VitE biosynthesis pathway in E. mollis, but also set a solid foundation for future genetic breeding of this species., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Cancer is a disease resulting from uncontrolled cell division, which significantly contributes to human mortality rates. An alternative approach to cancer treatment, such as cancer immunotherapy, is needed as the existing chemotherapy and radiotherapy approaches target the cancer cells and healthy dividing cells. Vitamin E is a plant-derived lipid-soluble antioxidant with numerous health-promoting benefits, including anticancer and immunomodulatory properties. Vitamin E comprises eight natural isoforms: tocopherols ( α , β , δ , and γ ) and tocotrienols ( α , β , δ , and γ ). While initial research focused on the anticancer properties of α -tocopherol, there is growing interest in other natural forms and modified synthetic analogues of vitamin E due to their unique properties and enhanced anticancer effects. Hence, this review is aimed at outlining the effect of vitamin E and its analogues at various steps of the cancer-immunity cycle that can be used to stimulate anticancer immune responses., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Nevvin Raaj Morgan et al.)

γ-Tocotrienol (γ-T3) is a major subtype of vitamin E, mainly extracted from palm trees, barley, walnuts, and other plants. γ-T3 has effects on anti-inflammation, anti-oxidation, and potential chemoprevention against malignancies. It is still uncompleted to understand the effect of γ-T3 on the inhibitory mechanism of cancer. This study aimed to investigate whether γ-T3 enhanced autophagy in gastric cancer and the underlying molecular mechanism. The results showed that γ-T3 (0-90 μmol/L) inhibited the proliferation of gastric cancer MKN45 cells and AGS cells, and arrested the cell cycle at the G0/G1 phase in a dose-dependent manner. Autophagy was increased in MKN45 cells treated with γ-T3 (0-45 μmol/L), especially at a dose of 30 μmol/L for 24 h. These effects were reversed by 3-methyladenine pretreatment. Furthermore, γ-T3 (30 μmol/L) also significantly downregulated the expression of pGSK-3β (ser9) and β-catenin protein in MKN45 cells, and γ-T3 (20 mg/kg b.w.) effectively decreased the growth of MKN45 cell xenografts in BABL/c mice. GSK-3β inhibitor-CHIR-99021 reversed the negative regulation of GSK-3β/β-Catenin signaling and autophagy. Our findings indicated that γ-T3 enhances autophagy in gastric cancer cells mediated by GSK-3β/β-Catenin signaling, which provides new insights into the role of γ-T3 enhancing autophagy in gastric cancer., (© 2024 Wiley Periodicals LLC.)

Purpose: Corneal fibroblasts are involved in the wound healing of the cornea with proliferation, migration, and differentiation processes. Coenzyme Q10 (CoQ10) and vitamin E can enhance corneal wound healing when applied after a corneal lesion as an eye drop. Thus, this study was performed to determine the potential efficiency of a CoQ10 ophthalmical solution containing a CoQ10 and vitamin E D-α-tocopherol polyethylene glycol 1000 succinate (TPGS)-derived formulation in human corneal fibroblasts (HCFs) in vitro . Methods: Primary HCFs were obtained from cadaveric corneal tissue, and cell viability was determined using MTT assay at 24 and 72 h. Cell migration was evaluated using an in vitro wound healing assay, and mRNA expressions of collagen type I (COL-I), collagen type III (COL-III), lumican, hyaluronan, matrix metalloproteinase (MMP)-1, MMP-2, MMP-9, tissue inhibitors of MMP (TIMP)-1, TIMP-2, interleukin (IL)-1β, IL-6, IL-8, and IL-10 were assessed using reverse transcription polymerase chain reaction at 24 and 72 h. Results: At various concentrations of CoQ10 ophthalmical solution (CoQ10-os), cell viability and wound healing rates of HCFs increased compared with the control group. The expressions of COL-I , COL-III , lumican, and hyaluronan were increased by CoQ10-os, whereas those of MMP-1 , MMP-2 , MMP-9 , TIMP-1 , TIMP-2 , and TIMP-3 were not affected by CoQ10-os at 24 and 72 h. In treating HCFs with a CoQ10-os medium, IL-1β , IL-6 , and IL-8 decreased, whereas IL-10 was significantly increased in a time- and dose-dependent manner. Conclusions: The findings indicate that CoQ10 and vitamin E-TPGS are potent regulators of the bioactivity of HCFs, thus supporting their potential application as ophthalmical solutions in therapies aimed at the fast regeneration of damaged cornea tissues.

Aceclofenac (ACE) is a drug that was precisely devised to circumvent the shortcomings associated with diclofenac. However, ACE too corresponds to nonsteroidal anti-inflammatory drug (NSAID)-related adverse effects, but with a lower amplitude. The present investigation seeks to develop liposomes loaded with ACE adopting a central composite design (CCD) and formulate a chitosan-based hydrogel for synergistic anti-inflammatory efficacy and improved ACE dermal administration. On the basis of preliminary vesicle size, Poly Dispersity Index (PDI), and drug entrapment, the composition of lipid, cholesterol, and vitamin E TPGS were chosen as independent variables. The formulation composition met the specifications for an optimum liposomal formulation, with total lipid concentration (13.5% w/w), cholesterol concentration (10% w/w), and surfactant concentration (2% w/w). With particle size and PDI of 174.22 ± 5.46 nm and 0.285 ± 0.01 respectively, the optimised formulation achieved an entrapment effectiveness of 92.08 ± 3.56%. Based on the CCD design, the optimised formulation Acec-Lipo opt was chosen and was subsequently transformed to a chitosan-based gel formulation for in vitro drug release, penetration through the skin, in vivo analgesic therapeutic activity, and skin irritation testing. % age oedema inhibition was found to be greatest with the Acec-Lipo opt gel formulation, followed by Acec gel. These results reinforce the notion that the inclusion of chitosan resulted in a synergistic effect despite the same strength of the drug. The findings suggested that Acec-Lipo incorporated in chitosan gel for skin targeting might be an effective formulation for topical ACE administration in clinical subjects., (© 2024. Controlled Release Society.)

In the pathological process of Alzheimer's disease, neuronal cell death is closely related to the accumulation of reactive oxygen species. Our previous studies have found that oxidative stress can activate microtubule affinity-regulating kinases, resulting in elevated phosphorylation levels of tau protein specifically at the Ser262 residue in N1E-115 cells that have been subjected to exposure to hydrogen peroxide. This process may be one of the pathogenic mechanisms of Alzheimer's disease. Vitamin E is a fat-soluble, naturally occurring antioxidant that plays a crucial role in biological systems. This study aimed to examine the probable processes that contribute to the inhibiting effect on the abnormal phosphorylation of tau protein and the neuroprotective activity of a particular type of vitamin E, α-tocotrienol. The experimental analysis revealed that α-tocotrienol showed significant neuroprotective effects in the N1E-115 cell line. Our data further suggest that one of the mechanisms underlying the neuroprotective effects of α-tocotrienol may be through the inhibition of microtubule affinity-regulated kinase activation, which significantly reduces the oxidative stress-induced aberrant elevation of p-Tau (Ser262) levels. These results indicate that α-tocotrienol may represent an intriguing strategy for treating or preventing Alzheimer's disease.

Exposure to high, marginally lethal doses or higher of ionizing radiation, either intentional or accidental, results in injury to various organs. Currently, there is only a limited number of safe and effective radiation countermeasures approved by US Food and Drug Administration for such injuries. These approved agents are effective for only the hematopoietic component of the acute radiation syndrome and must be administered only after the exposure event: currently, there is no FDA-approved agent that can be used prophylactically. The nutraceutical, gamma-tocotrienol (GT3) has been found to be a promising radioprotector of such exposure-related injuries, especially those of a hematopoietic nature, when tested in either rodents or nonhuman primates. We investigated the nature of injuries and the possible protective effects of GT3 within select organ systems/tissues caused by both non-lethal level (4.0 Gy), as well as potentially lethal level (5.8 Gy) of ionizing radiation, delivered as total-body or partial-body exposure. Results indicated that the most severe, dose-dependent injuries occurred within those organ systems with strong self-renewing capacities (e.g., the lymphohematopoietic and gastrointestinal systems), while in other tissues (e.g., liver, kidney, lung) endowed with less self-renewal, the pathologies noted tended to be less pronounced and less dependent on the level of exposure dose or on the applied exposure regimen. The prophylactic use of the test nutraceutical, GT3, appeared to limit the extent of irradiation-associated pathology within blood forming tissues and, to some extent, within the small intestine of the gastrointestinal tract. No distinct, global pattern of bodily protection was noted with the agent's use, although a hint of a possible radioprotective benefit was suggested not only by a lessening of apparent injury within select organ systems, but also by way of noting the lack of early onset of moribundity within select GT3-treated animals., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

The aim is to investigate the possible pulmonary protective effect of vanillic acid (VA) in liposome-TPGS nanoparticles, to overcome VA's poor bioavailability. VA was successfully extracted. Liposomes were prepared using thin film hydration. Central composite design was adopted for optimisation of liposomes to get the maximum entrapment efficiency (EE%) and the minimum mean diameter, where the liposomes were further modified with TPGS, and tested for PDI, zeta-potential, and in-vitro drug release. In-vivo study on mice with LPS-acute pulmonary toxicity was tested. TPGS-modified VA-liposomes showed EE% of 69.35 ± 1.23%, PS of 201.7 ± 3.23 nm, PDI of 0.19 ± 0.02, and zeta-potential of -32.2 ± 0.32 mv. A sustained drug release of the TPGS-modified VA-liposomes was observed compared to standard VA, and a pulmonary-protective effect through decreasing miR-217 expression with subsequent anti-inflammatory effect through suppression of MAPK and PI3K/NF-κB pathways was also demonstrated in the current study. TPGS-modified VA-liposomes showed an enhanced bioavailability and a sustained drug release with promising pulmonary protective effects against acute pulmonary injury diseases.

Scope: Tocomonoenols (T1) are little-known vitamin E derivatives naturally occurring in foods. Limited knowledge exists regarding the cellular uptake and metabolism of α-tocomonoenol (αT1) and none about that of γ-tocomonoenol (γT1)., Methods and Results: The study investigates the cytotoxicity, uptake, and metabolism of αT1 and γT1 in HepG2 cells compared to the α- and γ-tocopherols (T) and -tocotrienols (T3). None of the studied tocochromanols are cytotoxic up to 100 µmol L -1 . The uptake of the γ-congeners is significantly higher than that of the corresponding α-forms, whereas no significant differences are observed based on the degree of saturation of the sidechain. Carboxymethylbutyl-hydroxychromans (CMBHC) are the predominant short-chain metabolites of all tocochromanols and conversion is higher for γT1 than αT1 as well as for the γ-congeners of T and T3. The rate of metabolism increases with the number of double bonds in the sidechain. The rate of metabolic conversion of the T1 is more similar to tocopherols than to that of the tocotrienols., Conclusion: This is the first evidence that both αT1 and γT1 follow the same sidechain degradation pathway and exert similar rates of metabolism than tocopherols. Therefore, investigation into the biological activities of tocomonoenols is warranted., (© 2024 The Authors. Molecular Nutrition & Food Research published by Wiley‐VCH GmbH.)

A complex cascade of systemic and tissue-specific responses induced by exposure to ionizing radiation can lead to functional impairment over time in the surviving population. Current methods for management of survivors of unintentional radiation exposure episodes rely on monitoring individuals over time for the development of adverse clinical symptoms due to the lack of predictive biomarkers for tissue injury. In this study, we report on changes in metabolomic and lipidomic profiles in multiple tissues of nonhuman primates (NHPs) that received either 4.0 Gy or 5.8 Gy total-body irradiation (TBI) of 60Co gamma rays, and 4.0 or 5.8 Gy partial-body irradiation (PBI) from LINAC-derived photons and were treated with a promising radiation countermeasure, gamma-tocotrienol (GT3). These include small molecule alterations that correlate with radiation effects in the jejunum, lung, kidney, and spleen of animals that either survived or succumbed to radiation toxicities over a 30-day period. Radiation-induced metabolic changes in tissues were observed in animals exposed to both doses and types of radiation, but were partially alleviated in GT3-treated and irradiated animals, with lung and spleen being most responsive. The majority of the pathways protected by GT3 treatment in these tissues were related to glucose metabolism, inflammation, and aldarate metabolism, suggesting GT3 may exert radioprotective effects in part by sparing these pathways from radiation-induced dysregulation. Taken together, the results of our study demonstrate that the prophylactic administration of GT3 results in metabolic and lipidomic shifts that likely provide an overall advantage against radiation injury. This investigation is among the first to highlight the use of a molecular phenotyping approach in a highly translatable NHP model of partial- and total-body irradiation to determine the underlying physiological mechanisms involved in the radioprotective efficacy of GT3., (©2024 by Radiation Research Society. All rights of reproduction in any form reserved.)

To date only four recombinant growth factors, including Filgrastim (rhG-CSF), have been approved by FDA as radiomitigators to ameliorate hematopoietic acute radiation syndrome (H-ARS). These approved agents are not stable under room-temperature, needing to be stored at 2-8 °C, and would not be feasible in a mass casualty scenario where rapid and cost-effective intervention is crucial. Delta-tocotrienol (δ-T3H), the most potent G-CSF-inducing agent among vitamin E isoforms, exhibited efficiency and selectivity on G-CSF production in comparison with TLR and STING agonists in mice. Five-dose δ-T3H was utilized as the optimal therapeutic regimen due to long-term G-CSF production and the best peripheral blood (PB) recovery of irradiated mice. Comparable with rhG-CSF, sequential administration of δ-T3H post-irradiation improved hematologic recovery and accelerated the regeneration of hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) in the bone marrow (BM) and spleen of 6.5Gy irradiated mice; and consistently enhanced repopulation of BM-HSCs. In 4.0Gy irradiated nonhuman primates, δ-T3H exhibited comparable efficacy as rhG-CSF to promote PB recovery and colony-formation of BM-HPCs. Altogether, we demonstrated that sequential administration of delta-tocotrienol ameliorates radiation-induced myelosuppression in mice and non-human primates through inducing G-CSF production, indicated δ-T3H as a promising radiomitigator for the management of H-ARS, particularly in a mass casualty scenario., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Considering the increasing risk of nuclear attacks worldwide, the development of develop potent and safe radioprotective agents for nuclear emergencies is urgently needed. γ-tocotrienol (GT3) and δ-tocotrienol (DT3) have demonstrated a potent radioprotective effect by inducing the production of granulocyte-colony stimulating factor (G-CSF) in vivo. However, their application is limited because of their low bioavailability. The utilization of ester prodrugs can be an effective strategy for modifying the pharmacokinetic properties of drug molecules. In this study, we initially confirmed that DT3 exhibited the most significant potential for inducing G-CSF effects among eight natural vitamin E homologs. Consequently, we designed and synthesized a series of DT3 ester and ether derivatives, leading to improved radioprotective effects. The metabolic study conducted in vitro and in vivo has identified DT3 succinate 5b as a prodrug of DT3 with an approximately seven-fold higher bioavailability compared to DT3 alone. And DT3 ether derivative 8a were relatively stable and approximately 4 times more bioavailable than DT3 prototype. Furthermore, 5b exhibited superior ability to mitigate radiation-induced pancytopenia, enhance the recovery of bone marrow hematopoietic stem and progenitor cells, and promote splenic extramedullary hematopoiesis in sublethal irradiated mice. Similarly, 8a shown potential radiation protection, but its radiation protection is less than DT3. Based on these findings, we identified 5b as a DT3 prodrug, and providing an attractive candidate for further drug development., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Despite remarkable scientific progress over the past six decades within the medical arts and in radiobiology in general, limited radiation medical countermeasures (MCMs) have been approved by the United States Food and Drug Administration for the acute radiation syndrome (ARS). Additional effort is needed to develop large animal models for improving the prediction of clinical safety and effectiveness of MCMs for acute and delayed effects of radiation in humans. Nonhuman primates (NHPs) are considered the animal models that reproduce the most appropriate representation of human disease and are considered the gold standard for drug development and regulatory approval. The clinical and histopathological effects of supralethal, total- or partial-body irradiations (12 Gy) of NHPs were assessed, along with possible protective actions of a promising radiation MCM, gamma-tocotrienol (GT3). Results show that these supralethal radiation exposures induce severe injuries that manifest both clinically as well as pathologically, as evidenced by the noted functionally crippling lesions within various major organ systems of experimental NHPs. The MCM, GT3, has limited radioprotective efficacy against such supralethal radiation doses., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Everolimus is a drug approved for the treatment of breast cancer with HR+ and advanced breast cancer reoccurring in postmenopausal women. The oral administration of EVE has been observed to have low oral bioavailability and severe epithelial cutaneous events that include rashes and lip ulceration followed by mouth ulceration after oral administration., Aim: The present research aimed to enhance the bioavailability by loading the EVE into a stealth liposomal formulation (S-EVE-LIPO) intended for intravenous administration., Methods: The surface of the liposomes was modified with vitamin E TPGS, which prolongs the systemic circulation of the drug and provides additional benefits like inhibition of the P-gp efflux pump and acting synergistically with EVE., Results: The formulation was prepared using the thin film hydration method and optimized using a D-optimal mixture design. ANOVA suggested the significance of the proposed mathematic model, and the optimized formulation was generated by design expert software. The optimized formulation (S-EVE-LIPO) was observed with nanometric size (99.5 ± 3.70 nm) with higher encapsulation efficacy (81.5 ± 2.86 %). The S-EVELIPO formulation indicated a sustained release profile as 90.22% drug release was observed in 48 h, whereas the formulation without vitamin E TPGS (EVE-LIPO) released only 74.15 drugs in 24 hours. In vitro cytotoxicity study suggested that the presence of vitamin E TPGS lowers the IC 50 value (54.2 ± 1.69), increases the cellular uptake of the formulation, also increases the generation of ROS, and shows better hemocompatibility., Conclusion: Vitamin E TPGS could be set as a vital additive to improve therapeutic efficacy and reduce offsite toxicity and dosing frequency., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

γ-Tocotrienol (GT3), a member of the vitamin E family, is well known for its medicinal value in clinical treatments. However, the role of GT3 in T helper 17 (Th17)/regulatory T cell (Treg) differentiation and function is not fully understood. Here, we demonstrated that GT3 suppressed Th17 differentiation in vitro by inhibiting signal transducer and activator of transcription 3 (STAT3) phosphorylation in the interleukin 6 (IL-6)/Janus kinase (JAK)/STAT3 signaling pathway. GT3 also inhibited HIF1A expression in Th17 metabolism. Additionally, we showed that GT3 treatment inhibited disease aggravation in an imiquimod (IMQ)-induced psoriasis-like mouse model by reducing the percentage of Th17 cells in the spleen in vivo. The findings of this study demonstrated the effects of GT3 on Th17 cells through the STAT3 signaling pathway., Competing Interests: Declaration of interest None., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective: We aimed to compare the efficacy of δ-tocotrienol with α-tocopherol in the treatment of patients with non-alcoholic fatty liver disease (NAFLD)., Design and Interventions: This study was a double-blinded, active-controlled trial. The patients with NAFLD were randomly assigned to receive either δ-tocotrienol 300 mg or α-tocopherol 268 mg twice daily for 48 weeks., Endpoints: The primary endpoints were change from baseline in fatty liver index (FLI), liver-to-spleen attenuation ratio (L/S ratio), and homeostatic model assessment for insulin resistance (HOMA-IR) at 48 weeks. Key secondary endpoints were change in markers of inflammation, oxidative stress, and hepatocyte apoptosis. Clinical assessment, biochemical analysis, and computed tomography scan of the liver were conducted at baseline, 24 and 48 weeks., Results: A total of 100 patients (δ-tocotrienol = 50, α-tocopherol = 50) were randomized and included in the intention to treat analysis. Compared with baseline, there was a significant improvement (p < .001) in FLI, L/S ratio, HOMA-IR, and serum malondialdehyde in both groups at 48 weeks that was not significant between the two groups. However, there was a significantly greater decrease in body weight, serum interleukin-6, tumor necrosis factor-alpha, leptin, cytokeratin-18, and increase in adiponectin in the δ-tocotrienol group compared to the α-tocopherol group at 48 weeks (p < .05). No adverse events were reported., Conclusion: δ-tocotrienol and α-tocopherol exerted equally beneficial effects in terms of improvement in hepatic steatosis, oxidative stress, and insulin resistance in patients with NAFLD. However, δ-tocotrienol was more potent than α-tocopherol in reducing body weight, inflammation, and apoptosis associated with NAFLD. TRIAL REGISTRATION: Sri Lankan Clinical Trials Registry (https://slctr.lk/SLCTR/2019/038)., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The influence of pumpkin seed roasting conditions (110-140 °C) and screw-pressing on the formation of previously undescribed Δ 7 -phytosterol oxidation products and tocopherylquinone adducts with nucleophilic phosphatidylethanolamine species was investigated. The roasting process of pumpkin seed paste at a temperature above 120 °C for 30 min considerably enhanced the formation of Δ 7 -oxysterols. Targeted analysis [electron impact mass spectrometry (MS), 1D-nuclear magnetic resonance] led to the identification of five novel markers of pumpkin paste roasting, among which (3β,5α,22 E ,24 S )-stigmasta-7,22-dien-6-one-3-ol (6-oxo-α-spinasterol), stereoisomers of (3β,5α,22 E )-7,8-epoxystigmast-22-en-3-ol (7,8-epoxy-α-spinasterol), and (3β,5α)-22,23-epoxystigmast-7-en-3-ol (7,8-epoxy-α-spinasterol) were reported in edible oils for the first time. Simulated culinary processing provided novel stereoisomers of (3β,5α,22 E )-stigmasta-7,22-dien-3,6-diol, unusual (3β,5α,22 E )-stigmasta-7,22-dien-6,15-dione-3-ol, and (5α,22 E )-stigmasta-7,22-dien-3-one accompanied by minor stereoisomers of (3β,5α)-7,8;22,23-diepoxystigmastan-3-ol. Moreover, a clear relationship between the pumpkin seed oil stability index and synergistic effect of glycerophospholipids with present tocochromanols was found. High-resolution atmospheric pressure chemical ionization-MS experiments clearly demonstrated the formation of various γ-tocopherylquinone adducts with primary amines, namely, octylamine. The mitigation strategy of potentially detrimental oxysterols from pumpkin seed oil included optimization of processing parameters while maintaining the formation of desirable sensory-active compounds.

Chemical investigation of Allophylus africanus P. Beauv fruits led to the isolation of a new δ -tocotrienol, 3 α -hydroxy-δ-tocotrienol ( 1 ) together with eight known compounds ( 2 - 9 ). Compound ( 1) was allylated ( 1a ) and prenylated ( 1 b and 1c ) to give three new semi-synthesized derivatives which were fully characterized as: 6- O -allyl-3 α -hydroxy-δ-tocotrienol ( 1a ), 6- O -prenyl-3 α -hydroxy-δ-tocotrienol ( 1 b ) and 6- O ,5-C-diprenyl-3 α -hydroxy-δ-tocotrienol ( 1c ). The structures of compounds were established using comprehensive spectroscopic analysis including UV, MS, 1 D NMR, 2 D NMR and by comparison with the corresponding literature data. Compound ( 1 ) and its semi-synthetic derivatives ( 1a-c ) were tested for their antioxydant activity using DPPH radical scavenging assay and also for their cytotoxicity using human cervix carcinoma KB-3-1 cell lines. The results showed that compound ( 1) exhibited antioxidant activity with an IC 50 value of 0.25  μ M compared to the reference control trolox (26  µ M); and good cytotoxic activity with IC 50 values of 97  μ M compared to the reference (+)-griseofulvin (IC 50 between17-21  μ M).

Programmed death-ligand 1 (PD-L1), a critical immune checkpoint ligand, is commonly overexpressed on the surface of many tumor types including lung and prostate cancer. PD-L1 can exert cancer-promoting activity through either suppressing T cell-mediated immune response or activating tumor-intrinsic signaling. Here, we demonstrated that β-tocotrienol (β-T3), an isomer of vitamin E, effectively inhibited PD-L1 expression both in vitro and in vivo, which was mechanistically associated inactivating JAK2/STAT3 pathway. Down-regulating PD-L1 expression by β-T3 led to enhanced immune response and inactivation of PD-L1-induced tumor-intrinsic signaling, which in turn contributed to its anticancer activity. This study uncovered a novel mechanism involved in the anticancer effect of β-T3., Competing Interests: Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The Warburg effect is commonly recognized as a hallmark of nearly all tumors. In prostate cancer (PCa), it has been shown to be driven by PTEN loss- and Akt hyperactivation-associated upregulation of hexokinase 2 (HK2). δ-Tocotrienol (δ-TT) is an extensively studied antitumor compound; however, its role in affecting PCa glycolysis is still unclear. Herein, we demonstrated that δ-TT inhibits glucose uptake and lactate production in PTEN-deficient LNCaP and PC3 PCa cells, by specifically decreasing HK2 expression. Notably, this was accompanied by the inhibition of the Akt pathway. Moreover, the nutraceutical could synergize with the well-known hypoglycemic agent metformin in inducing PCa cell death, highlighting the crucial role of the above metabolic phenotype in δ-TT-mediated cytotoxicity. Collectively, these results unravel novel inhibitory effects of δ-TT on glycolytic reprogramming in PCa, thus providing new perspectives into the mechanisms of its antitumor activity and into its use in combination therapy.

The complexity of hepatocellular carcinoma (HCC) signaling and the failure of pharmacological therapeutics reveal the significance of establishing new anti-cancer strategies. Interferon alpha (IFN-α) has been used as adjuvant therapy for reducing HCC recurrence and improving survival. Delta-tocotrienol (δ-tocotrienol), a natural unsaturated isoform of vitamin E, is a promising candidate for cancer treatment. In this study, we evaluated whether the combination of δ-tocotrienol with IFN-α displays significant advantages in the treatment of HCC cells. Results showed that the combination significantly decreased cell viability, migration and invasion of HCC cells compared with single therapies. Combining δ-tocotrienol and IFN-α enhanced the decrease in proliferating cell nuclear antigen (PCNA) and matrix metalloproteinase (MMP) 7 and MMP-9. The combination also produced an enhancement of apoptosis together with increased Bax/Bcl-xL ratio and reactive oxygen species (ROS) generation. δ-tocotrienol induced Notch1 activation and changes in Erk and p38 MAPK signaling status. Blocking experiments confirmed that ROS and Erk are involved, at least in part, in the anti-cancer effects of the combined treatment. In conclusion, the combination of δ-tocotrienol with IFN-α therapy showed promising results for HCC cell treatment, which makes the combination of cytokine-based immunotherapy with natural products a potential strategy against liver cancer.

The gastrointestinal (GI) system is highly susceptible to irradiation. Currently, there is no Food and Drug Administration (FDA)-approved medical countermeasures for GI radiation injury. The vitamin E analog gamma-tocotrienol (GT3) is a promising radioprotector in mice and nonhuman primates (NHP). We evaluated GT3-mediated GI recovery in total-body irradiated (TBI) NHPs. Sixteen rhesus macaques were divided into two groups; eight received vehicle and eight GT3 24 h prior to 12 Gy TBI. Proximal jejunum was assessed for structural injuries and crypt survival on day 4 and 7. Apoptotic cell death and crypt cell proliferation were assessed with TUNEL and Ki-67 immunostaining. Irradiation induced significant shortening of the villi and reduced mucosal surface area. GT3 induced an increase in crypt depth at day 7, suggesting that more stem cells survived and proliferated after irradiation. GT3 did not influence crypt survival after irradiation. GT3 treatment caused a significant decline in TUNEL-positive cells at both day 4 (p < 0.03) and 7 (p < 0.0003). Importantly, GT3 induced a significant increase in Ki-67-positive cells at day 7 (p < 0.05). These data suggest that GT3 has radioprotective function in intestinal epithelial and crypt cells. GT3 should be further explored as a prophylactic medical countermeasure for radiation-induced GI injury.

Vitamin E compounds, consisting of α, β, γ, and δ forms of tocopherols and tocotrienols, display different cancer preventive activities in experimental models. Tocotrienols may have higher potential for clinical use due to their lower effective doses in laboratory studies. However, most studies on tocotrienols have been carried out using cancer cell lines. Strong data from animal studies may encourage the use of tocotrienols for human cancer prevention research. To examine the cancer inhibitory activity of different vitamin E forms, we first investigated their inhibitory activities of different vitamin E forms in prostate cancer cell lines. We found that δ-tocotrienol (δT3) was the most effective form in inhibiting cell growth at equivalent doses. Because of this in vitro potency, δT3 was further studied using prostate-specific Pten-/- (Ptenp-/-) mice. We found that 0.05% δT3 in diet reduced prostate adenocarcinoma multiplicity by 32.7%, featuring increased apoptosis and reduced cell proliferation. The inhibitory effect of 0.05% δT3 in diet was similar to that of 0.2% δ-tocopherol (δT) in diet reported previously. Our further study on the δT3-induced transcriptome changes indicated that δT3 inhibited genes in blood vessel development in the prostate of Ptenp-/- mice, which was confirmed by IHC. Together, our results demonstrate that δT3 effectively inhibits the development of prostate adenocarcinoma in Ptenp-/- mice, which involves inhibition of proliferation and angiogenesis and promotion of apoptosis., Prevention Relevance: We demonstrated that δ-tocotrienol is the most active vitamin E form in inhibiting the growth of several prostate cancer cell lines. In transgenic Ptenp-/- mice, δ-tocotrienol inhibited the formation of prostate cancer. This result would encourage and help design clinical studies for the application of δ-tocotrienol for prostate cancer prevention., (©2022 American Association for Cancer Research.)

Radiological incidents or terrorist attacks would likely expose civilians and military personnel to high doses of ionizing radiation, leading to the development of acute radiation syndrome. We examined the effectiveness of prophylactic administration of a developmental radiation countermeasure, γ-tocotrienol (GT3), in a total-body irradiation (TBI) mouse model. CD2F1 mice received GT3 24 h prior to 11 Gy cobalt-60 gamma-irradiation. This dose of radiation induces severe hematopoietic acute radiation syndrome and moderate gastrointestinal injury. GT3 provided 100% protection, while the vehicle control group had 100% mortality. Two-dimensional differential in-gel electrophoresis was followed by mass spectrometry and Ingenuity Pathway Analysis (IPA). Analysis revealed a change in expression of 18 proteins in response to TBI, and these changes were reversed with prophylactic treatment of GT3. IPA revealed a network of associated proteins involved in cellular movement, immune cell trafficking, and inflammatory response. Of particular interest, significant expression changes in beta-2-glycoprotein 1, alpha-1-acid glycoprotein 1, alpha-2-macroglobulin, complement C3, mannose-binding protein C, and major urinary protein 6 were noted after TBI and reversed with GT3 treatment. This study reports the untargeted approach, the network, and specific serum proteins which could be translated as biomarkers of both radiation injury and protection by countermeasures., (© 2022. The Author(s).)

γ-Tocotrienol (γ-T3), an isoprenoid phytochemical, has shown the promotion of osteoblast proliferation and differentiation in our previous study. In this study, its underlying mechanism was investigated through regulating the Wnt/β-catenin signaling pathway in MC3T3-E1 cells. Comparative experiment results showed that γ-T3, not α-tocopherol (α-TOC) increased more significantly the viability and differentiation in MC3T3-E1 cells. After that, the cells were incubated with 10 mM LiCl, or 4 μM γ-T3 with or without 1 μM XAV-939. γ-T3 at 4 μM stimulated the Wnt/β-catenin signaling pathway by increasing the expression and nuclear accumulation of β-catenin, and the expressions of their downstream factors, such as cyclin-D1, c-Myc, BMP2 and BMP-4 in MC3T3-E1 cells. γ-T3 not only upregulated the viability, induced G0/G1 to the S phase, and promoted the expressions of PCNA (Proliferating Cell Nuclear Antigen) and Ki-67, but also increased ALP activity and the expressions of ON, OPN and OCN. Moreover, the effects of γ-T3 on the MC3T3-E1 cells resembled the actions of LiCl, an activator of the Wnt/β-catenin signaling pathway. Notably, all these effects of γ-T3 on the MC3T3-E1 cells were completely blocked by the Wnt/β-catenin signaling pathway inhibitor XAV-939. Our data demonstrated that γ-T3 can target β-catenin to enhance the Wnt/β-catenin signaling pathway, which led to increased expressions of the downstream cell proliferation and cell cycle-associated (cyclin D1 and c-myc), and cell differentiation-associated (BMP-2 and BMP-4) target genes, and ultimately promoted MC3T3-E1 cell proliferation and differentiation. Therefore, γ-T3 may be a potential agent to prevent and reverse osteoporosis due to its safety and powerful abilities of osteogenesis.

2-Prenylated benzopyrans represent a class of natural and synthetic compounds showing a wide range of significant activities. Polycerasoidol is a natural prenylated benzopyran isolated from the stem bark of Polyalthia cerasoides (Annonaceae) that exhibits dual PPARα/γ agonism and an anti-inflammatory effect by inhibiting mononuclear leukocyte adhesion to the dysfunctional endothelium. Herein, we report the synthesis of three new series of prenylated benzopyrans containing one (series 1), two (series 2, "polycerasoidol" analogs) and three (series 3, "trans-δ-tocotrienolic acid" analogs) isoprenoid units in the hydrocarbon side chain at the 2-position of the chroman-6-ol (6-hydroxy-dihydrobenzopyran) scaffold. Isoprenoid moieties were introduced through a Grignard reaction sequence, followed by Johnson-Claisen rearrangement and subsequent Wittig olefination. hPPAR transactivation activity and the structure activity relationships (SAR) of eleven novel synthesized 2-prenylated benzopyrans were explored. PPAR transactivation activity demonstrated that the seven-carbon side chain analogs (series 1) displayed selectivity for hPPARα, while the nine-carbon side chain analogs (polycerasoidol analogs, series 2) did so for hPPARγ. The side chain elongation to 11 or 13 carbons (series 3) resulted in weak dual PPARα/γ activation. Therefore, 2-prenylated benzopyrans of seven- and nine-carbon side chain (polycerasoidol analogs) are good lead compounds for developing useful candidates to prevent cardiovascular diseases associated with metabolic disorders., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: To study the effects of delta-tocotrienol on glycaemic control parameters in individuals with pre-diabetes., Methods: The randomised control trial was conducted at the Armed Forces Institute of Pathology, Rawalpindi, Pakistan, from July 15 to November 15, 2019, and comprised individuals aged 18-60 years having fasting plasma glucose of 5.6 to 6.9 mmol/L or glycosylated haemoglobin of 5.7 to 6.4%. They were randomised into group A receiving 300mg delta-tocotrienol and group B receiving a placebo once daily for 12 weeks. Weight, height, waist circumference, fasting plasma glucose, insulin and glycosylated haemoglobin were measured at the beginning and end of the trial to assess any change. Body mass index and homeostatic model assessment-insulin resistance were also calculated. Data was analysed using SPSS 21., Results: Of the 77participants, 40(52%) were in group A and 37(48%) in group B. Group A showed significantly greater reduction in terms of fasting plasma glucose, glycosylated haemoglobin, insulin and homeostatic model assessment-insulin resistance index (p≤0.001) post-intervention., Conclusions: Delta-tocotrienol supplementation was found to have a significant effect in improving glycaemic control parameters in persons with pre-diabetes. Futures larger scale clinical trials are needed to confirm these findings., Clinical Trial Number: SLCTR/2019/024.

Background: Breast Cancer is one of the most commonly diagnosed cancers worldwide and a major cause of death among women. Although chemotherapeutic agents remain the keystones in cancer therapy, significant side effects have failed to provide a safe and tolerable treatment for cancer patients. Dietary antioxidant vitamins were extensively investigated over the past years and their relevance in cancer chemotherapy remains to be elucidated., Objective: In the current study, we aimed to investigate the anti-proliferative and apoptotic effects of combining γ-tocotrienol, a member of the vitamin E family, with the chemotherapeutic drug etoposide in MCF-7 and MDA-MB-231 breast cancer cell lines., Methods: The antiproliferative effect of etoposide combined with γ-tocotrienol was measured using MTS viability reagent. The pro-apoptotic effect was elucidated through Cell Death ELISA and dual Annexin V/PI staining followed by flow cytometric analysis., Results: Our results showed that etoposide significantly decreased the cell growth of both cell lines, with MDA-MB-231 cells being more sensitive to etoposide treatment than MCF-7. Moreover, simultaneous treatment of both breast cancer cell lines with low doses of γ-tocotrienol and etoposide induced a synergistic antiproliferative effect (CI<1). Furthermore, the combination therapy significantly increased the percentage of total apoptotic cells in the MDA-MB-231 cell line and the degree of DNA fragmentation as compared to treatment with either compound alone., Conclusion: In conclusion, our results provide evidence for the profound anti-tumorigenic effect of combined etoposide and γ-tocotrienol in the breast cancer cell lines., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Contrary to the major vitamin E congener α-tocopherol, which carries a saturated sidechain, and α-tocotrienol, with a threefold unsaturated sidechain, little is known about the intracellular fate of α-tocomonoenol, a minor vitamin E derivative with a single double bond in C11'-position of the sidechain. We hypothesized that, due to structural similarities, the uptake and metabolism of α-tocomonoenol will resemble that of α-tocopherol. Cytotoxicity, cellular uptake of α-tocomonoenol, α-tocopherol and α-tocotrienol and conversion into the short-chain metabolites αCEHC and αCMBHC were studied in HepG2 cells. α-Tocomonoenol did not show significant effects on cell viability and its uptake was similar to that observed for α-tocopherol and significantly lower than for α-tocotrienol. α-Tocomonoenol was mainly metabolized to αCMBHC in liver cells, but to a lower extent than α-tocotrienol, while α-tocopherol was not metabolized in quantifiable amounts at all. In summary, the similarities in the cytotoxicity, uptake and metabolism of α-tocomonoenol and α-tocopherol suggest that this minor vitamin E congener deserves more attention in future research with regard to its potential vitamin E activity., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Context: Glucagon-like peptide 1 (GLP-1) and α-tocopheryl quinone can promote the growth of intestinal flora and affect the pathogenesis of non-alcoholic steatohepatitis (NASH)., Objective: This study determines the molecular mechanism of the effect of tocopheryl quinone in the treatment of high cholesterol and cholate diet (HFCC)-induced NASH., Materials and Methods: Thirty-two male Sprague Dawley (SD) rats grouped as lean control (LC), LC + tocopheryl quinone (1 mL of 3 × 10 6 dpm tocopheryl quinone via i.p. injection), HFCC (5.1 kcal/g of fat diet), and HFCC + tocopheryl quinone. Profiles of intestinal flora were assessed by 16S ribosomal ribonucleic acid-based analysis. Levels and activity of GLP-1, interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF-α) in intestinal tissues were detected by immunohistochemistry (IHC), Western blot and enzyme-linked immunosorbent assay (ELISA)., Results: HFCC rats presented higher levels of cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein (HDL), while tocopheryl quinone reversed the effects of HFCC. HFCC dysregulated malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), Vitamin E, 12-hydroxyeicosatetraenoic acid (12-HETE), 13-hydroxyoctadecadienoic acid (13-HODE) and nuclear factor kappa B (NF-κB), and the effects of HFCC were reversed by the treatment of tocopheryl quinone. Also, GLP-1 in the HFCC group was down-regulated while the IL-6 and TNF-α activity and endotoxins were all up-regulated. HFCC significantly decreased the number and diversity of bacteria, whereas tocopheryl quinone substantially restored the balance of intestinal flora and promoted the growth of both Bacteroides and Lactobacilli in vitro ., Discussion and Conclusions: α-Tocopheryl quinone relieves HFCC-induced NASH via regulating oxidative stress, GLP-1 expression, intestinal flora imbalance, and the metabolism of glucose and lipids.

Preeclampsia (PE) is a severe medical disorder during pregnancy and there has been controversy about the effects of vitamin E on PE. This research intended to explore if δ-tocotrienol (δ-TT), an isomer of vitamin E, could impact PE. Preeclamptic and normal placentas were obtained and total RNA was extracted. The expression of different genes was analyzed through quantitative real-time polymerase chain reaction (qRT-PCR) and Pearson correlation analysis was conducted. After that, HTR-8/SVneo cells (human trophoblasts) were chosen and they were subjected to δ-tocotrienol treatment and then Cell Counting Kit-8 was used to test cell viability. To assess the effects of δ-TT on trophoblasts, wound healing assay and Transwell invasion assay were performed. How miR-429 interacts with ZEB1 was examined via dual luciferase reporter assay. Also, protein expression was evaluated via Western blotting. Our results have shown that δ-TT can impair the viability of trophoblasts and induce their apoptosis. Additionally, it can repress the growth, migration, epithelial-mesenchymal transition (EMT), invasion and angiogenesis in trophoblasts. Mechanistically, δ-TT exerts these effects on trophoblasts via downregulating miR-429 and upregulating ZEB1. Furthermore, miR-429 can bind ZEB1 directly. Clinical sample analysis has revealed that miR-429 expression in preeclamptic placenta is higher than that in normal placenta, but ZEB1 expression in preeclamptic placenta is downregulated. Also, there is a negative association between miR-429 and ZEB1 expression in preeclamptic placentas. These discoveries imply that δ-TT may be hazardous to pregnancy and should not be used in preeclamptic patients. In addition, targeting miR-429 might treat PE.

Ischemia-induced mitochondrial dysfunction and ATP depletion in the kidney result in disruption of primary functions and acute injury of the kidney. This study tested whether γ-tocotrienol (GTT), a member of the vitamin E family, protects mitochondrial function, reduces ATP deficits, and improves renal functions and survival after ischemia/reperfusion injury. Vehicle or GTT (200 mg/kg) were administered to mice 12 h before bilateral kidney ischemia, and endpoints were assessed at different timepoints of reperfusion. GTT treatment reduced decreases in state 3 respiration and accelerated recovery of this function after ischemia. GTT prevented decreases in activities of complexes I and III of the respiratory chain, and blocked ischemia-induced decreases in F 0 F 1 -ATPase activity and ATP content in renal cortical tissue. GTT improved renal morphology at 72 h after ischemia, reduced numbers of necrotic proximal tubular and inflammatory cells, and enhanced tubular regeneration. GTT treatment ameliorated increases in plasma creatinine levels and accelerated recovery of creatinine levels after ischemia. Lastly, 89% of mice receiving GTT and 70% of those receiving vehicle survived ischemia. Conclusions: Our data show novel observations that GTT administration improves mitochondrial respiration, prevents ATP deficits, promotes tubular regeneration, ameliorates decreases in renal functions, and increases survival after acute kidney injury in mice.

Bio-catalytic reactions involving ene-reductases (EREDs) in tandem with chemo-catalysis in water can be greatly enhanced by the presence of nanomicelles derived from the surfactant TPGS-750-M. Transformations are provided that illustrate the variety of sequences now possible in 1-pot as representative examples of this environmentally attractive approach to organic synthesis.

Purpose: While there is concern about degenerative tissue effects of exposure to space radiation during deep-space missions, there are no pharmacological countermeasures against these adverse effects. γ-Tocotrienol (GT3) is a natural form of vitamin E that has anti-oxidant properties, modifies cholesterol metabolism, and has anti-inflammatory and endothelial cell protective properties. The purpose of this study was to test whether GT3 could mitigate cardiovascular effects of oxygen ion ( 16 O) irradiation in a mouse model., Materials and Methods: Male C57BL/6 J mice were exposed to whole-body 16 O (600 MeV/n) irradiation (0.26-0.33 Gy/min) at doses of 0 or 0.25 Gy at 6 months of age and were followed up to 9 months after irradiation. Animals were administered GT3 (50 mg/kg/day s.c.) or vehicle, on Monday - Friday starting on day 3 after irradiation for a total of 16 administrations. Ultrasonography was used to measure in vivo cardiac function and blood flow parameters. Cardiac tissue remodeling and inflammatory infiltration were assessed with histology and immunoblot analysis at 2 weeks, 3 and 9 months after radiation., Results: GT3 mitigated the effects of 16 O radiation on cardiac function, the expression of a collagen type III peptide, and markers of mast cells, T-cells and monocytes/macrophages in the left ventricle., Conclusions: GT3 may be a potential countermeasure against late degenerative tissue effects of high-linear energy transfer radiation in the heart., (Copyright © 2021 The Committee on Space Research (COSPAR). Published by Elsevier B.V. All rights reserved.)

Objectives: Among gynaecologic malignancies, ovarian cancer (OC) represents the leading cause of death for women worldwide. Current OC treatment involves cytoreductive surgery followed by platinum-based chemotherapy, which is associated with severe side effects and development of drug resistance. Therefore, new therapeutic strategies are urgently needed. Herein, we evaluated the anti-tumour effects of Vitamin E-derived δ-tocotrienol (δ-TT) in two human OC cell lines, IGROV-1 and SKOV-3 cells., Materials and Methods: MTT and Trypan blue exclusion assays were used to assess δ-TT cytotoxicity, alone or in combination with other molecules. δ-TT effects on cell cycle, apoptosis, ROS generation and MAPK phosphorylation were investigated by flow cytometry, Western blot and immunofluorescence analyses. The synergism between δ-TT and chemotherapy was evaluated by isobologram analysis., Results: We demonstrated that δ-TT could induce cell cycle block at G1-S phase and mitochondrial apoptosis in OC cell lines. In particular, we found that the proapoptotic activity of δ-TT correlated with mitochondrial ROS production and subsequent JNK and p38 activation. Finally, we observed that the compound was able to synergize with cisplatin, not only enhancing its cytotoxicity in IGROV-1 and SKOV-3 cells but also re-sensitizing IGROV-1/Pt1 cell line to its anti-tumour effects., Conclusions: δ-TT triggers G1 phase cell cycle arrest and ROS/MAPK-mediated apoptosis in OC cells and sensitizes them to platinum treatment, thus representing an interesting option for novel chemopreventive/therapeutic strategies for OC., (© 2021 The Authors. Cell Proliferation published by John Wiley & Sons Ltd.)

Nasopharyngeal carcinoma has a notably high incidence rate in Southern China, Southeast Asia, North Africa, Middle East, and the Arctic. δ-Tocotrienol is abundant in cereal and has some health benefits. In our recent study, we showed that δ-tocotrienol exerted anti-inflammatory effects in murine macrophages in vitro. The aim of this study was to further investigate the chemopreventive effects of δ-tocotrienol on human CNE1 cells. We showed that δ-tocotrienol induced apoptosis and cell cycle arrest at G 0 /G 1 and M phases in nasopharyngeal carcinoma cells. Microarray analysis revealed that after CNE1 cells were treated with δ-tocotrienol, 169 genes were up-regulated and 167 down-regulated. ERK1/2 was shown to play a vital role in cell cycle arrest by gene chips. The results suggest that δ-tocotrienol induces cell cycle arrest in CNE1 cells via the p16/CDK4/cyclin D1 signaling pathway. Western blots showed that CNE1 apoptosis was related to dysregulated expression of Bax-2 and Bcl-2. Furthermore, caspase-3, -8, -9 up-regulation was related to the apoptotic effect of δ-tocotrienol; therefore, δ-tocotrienol triggers apoptosis in CNE1 cells through caspase-3 signaling. δ-Tocotrienol may potentially be developed as an anti-cancer agent in the management of nasopharyngeal carcinoma.

Nutrition can modulate host immune responses as well as promote anticancer effects. In this study, two nutritional supplements, namely gamma-tocotrienol (γT3) and Spirulina, were evaluated for their immune-enhancing and anticancer effects in a syngeneic mouse model of breast cancer (BC). Five-week-old female BALB/c mice were fed Spirulina , γT3, or a combination of Spirulina and γT3 ( Spirulina + γT3) for 56 days. The mice were inoculated with 4T1 cells into their mammary fat pad on day 28 to induce BC. The animals were culled on day 56 for various analyses. A significant reduction ( p < 0.05) in tumor volume was only observed on day 37 and 49 in animals fed with the combination of γT3 + Spirulina . There was a marked increase ( p < 0.05) of CD4/CD127 + T-cells and decrease ( p < 0.05) of T-regulatory cells in peripheral blood from mice fed with either γT3 or Spirulina. The breast tissue of the combined group showed abundant areas of necrosis, but did not prevent metastasis to the liver. Although there was a significant increase ( p < 0.05) of MIG-6 and Cadherin 13 expression in tumors from γT3-fed animals, there were no significant ( p > 0.05) differences in the expression of MIG-6, Cadherin 13, BIRC5, and Serpine1 upon combined feeding. This showed that combined γT3 + Spirulina treatment did not show any synergistic anticancer effects in this study model.

The study aimed to ascertain the effects of delta-tocotrienol (δT3) supplementation on glycemic control, oxidative stress, inflammation and related micro-ribonucleic acid (miRNA) expression in patients with type 2 diabetes mellitus (T2DM). Total 110 patients of T2DM on oral hypoglycemic agents, were randomly divided into tocotrienol and placebo groups and given 250 mg δT3 or cellulose soft gel capsule once daily respectively for 24 weeks. Glycemic control, oxidative stress, inflammatory biomarkers, and miRNAs expression were measured in serum at baseline and end of the intervention by using standard laboratory methods. Compared to the placebo, δT3 supplementation resulted in a significant (p ≤ .05) reduction [mean difference (95% confidence interval)] in plasma glucose [-0.48 (-0.65, -0.30)], insulin [-1.19 (-1.51, -0.87)], homeostatic model assessment of insulin resistance [-0.67 (-0.86, -0.49)], glycosylated hemoglobin [-0.53 (-0.79, -0.28)], malondialdehyde [-0.34 (-0.45, -0.22)], high sensitive-C-reactive protein[-0.35 (-0.54, -0.16)], tumor necrosis factor-alpha [-1.22 (-1.62, -0.83)], and interleukin-6[-2.30 (-2.91, -1.68)]. More than twofold downregulation in miRNA-375, miRNA-34a, miRNA-21, and upregulation in miRNA-126, miRNA-132 expression was observed in the δT3 group compared to the placebo. The study demonstrated that δT3 supplementation in addition to oral hypoglycemic agents, improved glycemic control, inflammation, oxidative stress, and miRNA expression in T2DM without any adverse effect. Thus, δT3 might be considered as an effective dietary supplement to prevent long-term diabetic complications., (© 2021 John Wiley & Sons Ltd.)

The vitamin E derivative with side chain modification (TC6OAc) has been shown to possess anticancer activity in our earlier in vivo studies. It was hypothesized that, as Vitamin E (VE) and VE derivative are fat soluble lipophilic molecules, they exert their function by modulating the lipid metabolism and related pathways. This study aimed to evaluate the cellular impact of this VE derivative (2,5,7,8-Tetramethyl-2-(4'-Methyl-3'-Pentenyl)-6-Acetoxy Chromane-TC6OH), using α-tocopherol as a reference compound throughout the experiments. Their effects on the cellular metabolism, the biophysical properties of cellular lipids and the functional characteristics of cells were monitored in human estrogen receptor (ER) positive breast cancer cells. It has been documented that TC6OH treatment induces tumor cell apoptosis by dissipating the mitochondrial membrane potential, modulating the lipid, transportation and degradation as well as downregulating certain anti-apoptotic and growth factor related proteins. Due to resistance of ER positive cells to the established therapies, the findings of this study are of translational value.

Background & Aims: Damage induced by lipid peroxidation has been associated with impaired glucose homeostasis. Vitamin E (α-tocopherol, α-TOH) competitively reacts with lipid peroxyl radicals to mitigate oxidative damage, and forms oxidized vitamin E metabolites. Accordingly, we aimed to investigate the associations between α-TOH metabolites (oxidized and enzymatic) in both circulation and urine and measures of glucose homeostasis in the general middle-aged population., Methods: This cross-sectional study was embedded in the population-based Netherlands Epidemiology of Obesity (NEO) Study. α-TOH metabolites in blood (α-TOH and α-CEHC-SO 3 ) and urine [sulfate (SO 3 ) and glucuronide (GLU) of both α-TLHQ (oxidized) and α-CEHC (enzymatic)] were quantified by liquid chromatography coupled with tandem mass spectrometry (LC/MS-MS). Measures of glucose homeostasis (HOMA-B, HOMA-IR, Insulinogenic index and Matsuda index) were obtained from fasting and postprandial blood samples. Multivariable linear regression analyses were performed to assess the associations of α-TOH metabolites and measures of glucose homeostasis., Results: We included 498 participants (45% men) with mean (SD) age of 55.8 (6.1) years who did not use glucose-lowering medication. While blood α-TOH was not associated with measures of glucose homeostasis, urinary oxidized metabolites (α-TLHQ-SO 3 /GLU) were associated with HOMA-IR and Matsuda index. For example, a one-SD higher α-TLHQ-SO 3 was associated with 0.92 (95% CI: 0.87, 0.97) fold lower HOMA-IR and 1.06 (1.01, 1.11) fold higher Matsuda index, respectively. Similar results were obtained for the urinary α-TLHQ to α-CEHC ratio as a measure of oxidized-over-enzymatic conversion of α-TOH., Conclusion: Higher urinary levels of oxidized α-TOH metabolites as well as higher oxidized-to-enzymatic α-TOH metabolite ratio, but not circulating α-TOH or enzymatic metabolites, were associated with lower insulin resistance. Rather than circulating α-TOH, estimates of the conversion of α-TOH might be informative in relation to health and disease., Competing Interests: Conflicts of interest Dr. Mook-Kanamori is a part time research consultant for Metabolon, Inc. The other authors declare no conflict of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Melanoma is an aggressive tumor with still poor therapy outcomes. δ-tocotrienol (δ-TT) is a vitamin E derivative displaying potent anti-cancer properties. Previously, we demonstrated that δ-TT triggers apoptosis in human melanoma cells. Here, we investigated whether it might also activate paraptosis, a non-canonical programmed cell death. In accordance with the main paraptotic features, δ-TT was shown to promote cytoplasmic vacuolization, associated with endoplasmic reticulum/mitochondrial dilation and protein synthesis, as well as MAPK activation in A375 and BLM cell lines. Moreover, treated cells exhibited a significant reduced expression of OXPHOS complex I and a marked decrease in oxygen consumption and mitochondrial membrane potential, culminating in decreased ATP synthesis and AMPK phosphorylation. This mitochondrial dysfunction resulted in ROS overproduction, found to be responsible for paraptosis induction. Additionally, δ-TT caused Ca 2+ homeostasis disruption, with endoplasmic reticulum-derived ions accumulating in mitochondria and activating the paraptotic signaling. Interestingly, by using both IP3R and VDAC inhibitors, a close cause-effect relationship between mitochondrial Ca 2+ overload and ROS generation was evidenced. Collectively, these results provide novel insights into δ-TT anti-melanoma activity, highlighting its ability to induce mitochondrial dysfunction-mediated paraptosis. δ-tocotrienol induces paraptotic cell death in human melanoma cells, causing endoplasmic reticulum dilation and mitochondrial swelling. These alterations induce an impairment of mitochondrial function, ROS production and calcium overload.

The problem of multidrug resistance (MDR) presents a major obstacle in the chemotherapy of cancer. The MDR phenotype is often linked to the overexpression of ATP-binding cassette (ABC) transporters, that pumps out and decreased intracellular drug accumulation. γ-Tocotrienol, an unsaturated tocopherol belonging to the vitamin E family, has been shown to reverse the MDR of MCF-7/Adr cell. To reveal the role of γ-tocotrienol-NF-κB-P-gp axis in the reversal process, the expression level of mdr1/P-gp was determined by real-time PCR and western blot, while NF-κB activity was detected by immunofluorescence and NF-κB transcriptional activity reporter assay. Besides, mdr1 promoter activity and P-gp transport capacity were measured with the effect of γ-tocotrienol and NF-κB agonist/antagonist. Results showed that γ-tocotrienol effectively inhibited the expression levels of mdr1 mRNA and P-gp protein. It is demonstrated that γ-tocotrienol also suppressed mdr1 promoter activity and the efflux activity of P-gp. In addition, the activation of NF-κB signaling pathway and the transcriptional activity of NF-κB were both reduced by γ-tocotrienol. Evidences also showed that the NF-κB pathway is really involved in the regulation of the expression and function of mdr1/P-gp. Taken together, we confirmed that γ-tocotrienol reversed the MDR of MCF-7/Adr through the signaling pathway of NF-κB and P-gp., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The onset of many degenerative diseases related to aging has been associated with a decrease in the activity of antistress systems, and pharmacological interventions increasing stress resistance could be effective to prevent the development of such diseases. Achiote is a valuable source of carotenoid and tocotrienols, which have antioxidant activity. In this work, we explore the capacity of an achiote seed extract and its main compounds to modulate the lifespan and antistress responses on Caenorhabditis elegans , as well as the mechanisms involved in these effects. Achiote lipophilic extract, bixin, and δ -tocotrienol were applied on nematodes to carry out lifespan, stress resistance, and fertility assays. The achiote seed extract increased the median and maximum lifespan up to 35% and 27% and increased resistance against oxidative and thermal stresses without adverse effects on fertility. The beneficial effects were mimicked by a bixin+ δ -tocotrienol mixture. All the effects on lifespan and stress resistance were independent of caloric restriction but dependent on the insulin/insulin growth factor-1 pathway. This study could provide insights for further research on a new beneficial use of this important crop in health and nutraceutical applications beyond its use as a source of natural pigments., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Vitamin E acts as essential antioxidant against detrimental oxidation of biological molecules induced by multiple reactive species. To gain more insight into the physiological role of vitamin E, the levels of its oxidation products in humans under normal and pathological conditions were compared. α-Tocopherol quinone (α-TQ) and 5-nitro-γ-tocopherol (5-NgT) were focused. α-TQ is produced by multiple oxidants including oxygen radicals, peroxynitrite, hypochlorite, singlet oxygen, and ozone, while 5-NgT is produced by nitrogen dioxide radical derived from peroxynitrite and the reaction of nitrite and hypochlorite. The reported concentrations of α-TQ and 5-NgT in healthy human plasma are highly variable ranging from 15 to 360 and 4 to 170 nM, respectively. In general, the molar ratio 5-NgT/γ-tocopherol was higher than the ratio α-TQ/α-tocopherol. Both absolute concentrations of α-TQ and 5-NgT and the molar ratios to the parent tocopherols were elevated significantly in the plasma of patients with various diseases compared with healthy subjects except neurological diseases. The molar ratios of the products to the respective parent compounds decreased in the order of 5-NgT/γ-tocopherol > α-TQ/α-tocopherol > hydroxyoctadecadienoate/linoleate > 3-nitrotyrosine/tyrosine > isoprostane/arachidonate. The molar ratios of nitrated products to the respective parent compounds in human plasma are approximately 10 -2 for 5-NgT and 10 -5 for 3-nitrotyrosine, nitro-oleic acid, and 8-nitroguaine. These data indicate that vitamin E acts as an important physiological antioxidant and that α-TQ and 5-NgT represent biomarker for oxidative stress and nitrative stress respectively.

With the successful development and increased use of targeted radionuclide therapy for treating cancer comes the increased risk of radiation injury to bone marrow-both direct suppression and stochastic effects, leading to neoplasia. Herein, we report a novel radioprotector drug, a liposomal formulation of γ-tocotrienol (GT3), or GT3-Nano for short, to mitigate bone marrow radiation damage during targeted radionuclide therapy. Methods: GT3 was loaded into liposomes using passive loading. 64 Cu-GT3-Nano and 3 H-GT3-Nano were synthesized to study the in vivo biodistribution profile of the liposome and GT3 individually. The radioprotection efficacy of GT3-Nano was assessed after acute 137 Cs whole-body irradiation at a sublethal (4 Gy), a lethal (9 Gy), or a single high-dose administration of 153 Sm-ethylenediamine- N,N,N',N' -tetrakis(methylene phosphonic acid) (EDTMP). Flow cytometry and fluorescence microscopy were used to analyze hematopoietic cell population dynamics and the cellular site of GT3-Nano localization in the spleen and bone marrow, respectively. Results: Bone marrow uptake and retention (percentage injected dose per gram of tissue) at 24 h was 6.98 ± 2.34 for 64 Cu-GT3-Nano and 7.44 ± 2.52 for 3 H-GT3-Nano. GT3-Nano administered 24 h before or after 4 Gy of total-body irradiation (TBI) promoted rapid and complete hematopoietic recovery, whereas recovery of controls stalled at 60%. GT3-Nano demonstrated dose-dependent radioprotection, achieving 90% survival at 50 mg/kg against lethal 9-Gy TBI. Flow cytometry of the bone marrow indicated that progenitor bone marrow cells MPP2 and CMP were upregulated in GT3-Nano-treated mice. Immunohistochemistry showed that GT3-Nano accumulates in CD105-positive sinusoid epithelial cells. Conclusion: GT3-Nano is highly effective in mitigating the marrow-suppressive effects of sublethal and lethal TBI in mice. GT3-Nano can facilitate rapid recovery of hematopoietic components in mice treated with the endoradiotherapeutic agent 153 Sm-EDTMP., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

New 5-substituted vitamin E derivatives were semisynthesized, and their antibacterial activity against human Gram-positive and Gram-negative pathogens was evaluated. Several vitamin E analogues were active against methicillin-resistant Staphylococcus aureus (MRSA) and/or methicillin-resistant Staphylococcus epidermidis (MRSE); structure-activity relationships (SARs) are discussed. As a result, it is shown that the presence of a carboxylic acid function at the C-5 position and/or at the end of the side chain is crucial for the antibacterial activity. The bactericidal or bacteriostatic action of three compounds against MRSA and MRSE was confirmed in a time-kill kinetics study, and the cytotoxicity on human cells was evaluated. The preliminary mechanism study by confocal microscopy indicated that those vitamin E analogues led to bacterial cell death through membrane disruption., (© 2020 Wiley-VCH GmbH.)

Singlet oxygen ( 1 O 2 ) is the major reactive oxygen species ROS causing photooxidative stress in plants which is formed predominantly in the reaction center of photosystem II during photosynthesis. To avoid deleterious effects of 1 O 2 oxygen on photosynthetic membrane components, plant synthesize a variety of 1 O 2 quenchers of lipophilic character, such as carotenoids or phenolic prenyllipids (tocopherols, plastochromanol-8, plastoquinol). In the process of chemical quenching of 1 O 2 by the antioxidants, both short-lived products, such as oxidized carotenoids, or relative long-lived compounds, such as oxidized phenolic prenyllipids are formed. The other target of 1 O 2 are unsaturated fatty acids of membrane lipids that undergo peroxidation as a result of the reaction. Some of the 1 O 2 oxidation products, like β-cyclocitral can be components of 1 O 2 -signallingsignaling pathway leading to acclimatory responses of plants, while some others further fulfill antioxidant functions, like hydroxy-plastochromanol or hydroxy-plastoquinol. As most of the 1 O 2 oxidation products are specific compounds formed only as a results of 1 O 2 action, they can be very useful, specific molecular markers of 1 O 2 -dependent oxidative stress in vivo., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The gut microbiota play important roles in colon cancer. Vitamin E δ-tocotrienol (δTE) and its metabolite δTE-13'-carboxychromanol (δTE-13') are known to have cancer-preventive effects, but their impact on gut flora during tumorigenesis and the role of the metabolite in δTE's beneficial effects remain to be determined. In the murine colitis-associated colon cancer (CAC) induced by azoxymethane (AOM) and dextran sulfate sodium (DSS), we show that δTE and δTE-13' inhibited the multiplicity of large adenomas (>2 mm 2 ) by 34% (P<.05) and 55% (P<.01), respectively, compared to the control diet. δTE-13' diminished AOM/DSS-increased GM-CSF and MCP-1, and δTE decreased IL-1β. Using 16S rRNA gene sequencing of fecal DNAs, we observe that δTE and δTE-13' modulated the composition but not the richness of gut microbes compared to the control. Both δTE and δTE-13' enhanced potentially beneficial Lactococcus and Bacteroides. The elevation of Lactococcus positively correlated with fecal concentrations of δTE-13' and its hydrogenated metabolite, suggesting that the metabolite may contribute to δTE's modulation of gut microbes. Furthermore, δTE-13' counteracted AOM/DSS-induced depletion of Roseburia that is known to be decreased in patients with inflammatory bowel diseases. δTE uniquely elevated (Eubacterium) coprostanoloigenes. Our study demonstrates that δTE and δTE-13' inhibited tumorigenesis, suppressed pro-inflammatory cytokines and modulated gut microbiota in a murine CAC model. These findings uncover new and distinct activities of δTE and δTE-13' and support the notion that the metabolite may play a role in δTE's anticancer and modulation of gut microbes., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Senescence is an irreversible permanent cell cycle arrest accompanied by changes in cell morphology and physiology. Bioactive compounds including tocotrienols (vitamin E) can affect important biological functions. The aim of this study was to investigate how γ- and δ-tocotrienols can affect stress-induced premature senescence. We established two different models of premature stress senescence by induction of senescence with either hydrogen peroxide or etoposide in human lung fibroblasts MRC-5 (ECACC, England). We observed increased percentage of cells with increased SA-β-galactosidase activity, decreased cell viability/proliferation and increased level of p21 in both models. In addition, γ-tocotrienol or δ-tocotrienol (both at concentrations of 150, 200 and 300 μM) were added to the cells along with the inductor of senescence (cotreatment). We have found that this cotreatment led to the decrease of cell viability/proliferation in both models of premature stress senescence, but did not change the percentage of senescent cells. Moreover, we detected no expression of caspase-3 or apoptotic DNA fragmentation in any models of premature stress senescence after the cotreatment with γ- as well as δ-tocotrienols. However, an increased level of autophagic protein LC-3 II was detected in cells with hydrogen peroxide-induced senescence after the cotreatment with γ-tocotrienol as well as δ-tocotrienol. In case of etoposide-induced senescence only δ-tocotrienol cotreatment led to an increased level of LC-3 II protein in cells. According to our work δ-tocotrienol is more effective compound than γ-tocotrienol.