A Redox-Silent Analogue of Tocotrienol May Break the Homeostasis of Proteasomes in Human Malignant Mesothelioma Cells by Inhibiting STAT3 and NRF1

Kyota Ishii, Momoka Fusegi, Tatsuki Mori, Kosuke Teshima, Nanako Ninomiya, Kakeru Kohno, Ayami Sato, Tatsuya Ishida, Yuichi Miyakoshi, Tomohiro Yano

Int J Mol Sci . 2022 Feb 28;23(5):2655. doi: 10.3390/ijms23052655.

Abstract

6-O-Carboxypropyl-alpha-tocotrienol (α-T3E) is a multi-target redox-silent analogue of tocotrienol that exhibits cytotoxicity against many cancer cells, including malignant mesothelioma (MM) cells. α-T3E has several molecular targets to effectively induce cytotoxicity against MM cells; however, the mechanisms underlying this cytotoxicity remain unclear. In the present study, we demonstrated that the α-T3E-dependent disruption of the homeostasis of proteasomes strongly induced endoplasmic reticulum (ER) stress, which resulted in effective cytotoxicity against MM cells. The α-T3E-dependent disruption of the homeostasis of proteasomes depended on decreases in proteasome subunits via the inactivation of signal transducer and activator of transcription 3 (STAT3) and nuclear factor erythroid 2 related factor-1 (NRF1), which inhibited protease activity, such as chymotrypsin-like activity, in proteasomes. The α-T3E-dependent inhibition of this activity also induced severe ER stress and ultimately resulted in effective cytotoxicity against MM cells with chemoresistance. The present results indicate that α-T3E acts as an effective anti-mesothelioma agent by disrupting the homeostasis of proteasomes through the simultaneous inactivation of STAT3 and NRF1.

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Potential of the Compounds from Bixa orellana Purified Annatto Oil and Its Granules (Chronic ®) against Dyslipidemia and Inflammatory Diseases: In Silico Studies with Geranylgeraniol and Tocotrienols

Mateus Alves Batista, Abrahão Victor Tavares de Lima Teixeira Dos Santos, Aline Lopes do Nascimento, Luiz Fernando Moreira, Indira Ramos Senna Souza, Heitor Ribeiro da Silva, Arlindo César Matias Pereira, Lorane Izabel da Silva Hage-Melim, José Carlos Tavares Carvalho

Molecules . 2022 Feb 28;27(5):1584. doi: 10.3390/molecules27051584.

Abstract

Some significant compounds present in annatto are geranylgeraniol and tocotrienols. These compounds have beneficial effects against hyperlipidemia and chronic diseases, where oxidative stress and inflammation are present, but the exact mechanism of action of such activities is still a subject of research. This study aimed to evaluate possible mechanisms of action that could be underlying the activities of these molecules. For this, in silico approaches such as ligand topology (PASS and SEA servers) and molecular docking with the software GOLD were used. Additionally, we screened some pharmacokinetic and toxicological parameters using the servers PreADMET, SwissADME, and ProTox-II. The results corroborate the antidyslipidemia and anti-inflammatory activities of geranylgeraniol and tocotrienols. Notably, some new mechanisms of action were predicted to be potentially underlying the activities of these compounds, including inhibition of squalene monooxygenase, lanosterol synthase, and phospholipase A2. These results give new insight into new mechanisms of action involved in these molecules from annatto and Chronic®.

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Drug release, stability and efficiency of vitamin e loaded in liposomes for bovine sperm protection in cryopreservation medium

L Taouzinet, S Fatmi, A Khellouf, M Lahianl-Skiba, M Skiba, M Iguer-Ouada

Cryo Letters . Jan-Feb 2022;43(1):50-57.

Abstract

Background: It is known that a considerable number of drugs in clinical use or under development are water-insoluble drugs with poor bioavailability. The liposomal delivery system has drawn attention as one of the noteworthy approaches to increase both dissolution and absorption because of its biocompatibility and ability to encapsulate hydrophobic molecules in the lipid domain. However, several drawbacks have been reported, the most common is liposome structural instability.

Objective: To encapsulate alpha tocopherol into liposomes, to determine the new formulation stability and to study the drug-release of alpha tocopherol into the sperm cryopreservation medium.

Materials and methods: The liposomes prepared by an ethanol injection method were characterized for size stability, alpha tocopherol release and sperm motility tests.

Results: The prepared unilamellar vesicles had both narrow size distribution (around 99 nm) and a good physical and chemical stability at 4°C during 12 months. The liposomes did not release the vitamin E immediately, but retained the protectant for 24 hours, probably due to the rigidity of the liposomal fence which was reinforced by adding cholesterol. Then, all vitamin E molecules were released by 48 hours. Release was potentially by Fickian diffusion probably by the creation of mini-ducts due to both agitation and fence hydration. Moreover, semen motility treated with vitamin E liposome preparations was significantly improved compared to all other treatments (including commonly used sperm conservation media).

Conclusion: The stable vitamin E liposomes formulated in this work are a promising alternative for semen cryopreservation protection.

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A 28-year prospective analysis of serum vitamin E, vitamin E-related genetic variation and risk of prostate cancer

Wayne R Lawrence, Jung-Eun Lim, Jiaqi Huang, Stephanie J Weinstein, Satu Mӓnnistӧ, Demetrius Albanes

Prostate Cancer Prostatic Dis . 2022 Feb 23. doi: 10.1038/s41391-022-00511-y. Online ahead of print.

Abstract

Objective: Investigate the relationship between serum α-tocopherol concentration and long-term risk of prostate cancer, and evaluate the interaction with vitamin E-related genetic variants and their polygenic risk score (PRS).

Methods: We conducted a biochemical analysis of 29,102 male Finnish smokers in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Serum α-tocopherol was measured at baseline using high-performance liquid chromatography, and 2724 prostate cancer cases were identified during 28 years of follow-up. Cox proportional hazards models examined whether serum α-tocopherol concentrations were associated with prostate cancer risk. Among 8383 participants, three SNPs related to vitamin E status (rs964184, rs2108622, and rs11057830) were examined to determine whether they modified the relationship between serum α-tocopherol concentrations and prostate cancer risk, both individually and as a PRS using logistic regression models.

Results: No association was observed between serum α-tocopherol and prostate cancer risk (fifth quintile (Q5) vs. Q1 hazard ratio (HR) = 0.87, 95% confidence interval (95% CI) 0.75, 1.02; P-trend = 0.57). Though no interactions were seen by population characteristics, high α-tocopherol concentration was associated with reduced prostate cancer risk among the trial α-tocopherol supplementation group (Q5 quintile vs. Q1 HR = 0.79, 95% CI 0.64, 0.99). Finally, no associated interaction between the three SNPs or their PRS and prostate cancer risk was observed.

Conclusion: Although there was a weak inverse association between α-tocopherol concentration and prostate cancer risk over nearly three decades, our findings suggest that men receiving the trial α-tocopherol supplementation who had higher baseline serum α-tocopherol concentration experienced reduced prostate cancer risk. Vitamin E-related genotypes did not modify the serum α-tocopherol-prostate cancer risk association.

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δ-Tocotrienol is the most potent vitamin E form in inhibiting prostate cancer cell growth and inhibits prostate carcinogenesis in Ptenp-/- mice

Hong Wang, William Yan, Yuhai Sun, Chung S Yang

Cancer Prev Res (Phila) . 2022 Feb 10;canprevres.0508.2021. doi: 10.1158/1940-6207.CAPR-21-0508. Online ahead of print.

Abstract

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 immunohistochemistry. 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.

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α-Tocopherol Prevents Sperm Apoptosis and Necrosis in Rats Exposed to 2,3,7,8-Tetrachlorodibenzo-p-dioxin

Dewa Ketut Meles, Kadek Rachmawati, Iwan Sahrial Hamid, Imam Mustofa, Wurlina Wurlina, Niluh Suwasanti, Desak Ketut Sekar Cempaka Putri, Suzanita Utama

Vet Med Int . 2022 Feb 21;2022:3685686. doi: 10.1155/2022/3685686. eCollection 2022.

Abstract

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a persistent organic pollutant that induces overproduction of reactive oxygen species (ROS). Studies on avoiding the adverse effects of dioxin pollution exposure are needed in all aspects, including reproductive health. This study aimed to determine the effect of α-tocopherol on superoxide dismutase (SOD) and malondialdehyde (MDA) levels, live spermatozoa, apoptosis, and necrosis in male rats exposed to dioxin as a model. Thirty healthy 12-week-old male rats were randomly divided into five groups. Rats in the control group were given corn oil twice daily at 4-hour intervals. The remaining rats were given TCDD 700 mg/kg BW daily, followed by administration of corn oil and α-tocopherol at doses of 77, 140, and 259 mg/kg BW/d for T0, T1, T2, and T3 groups, respectively. The treatments were conducted for 45 days; all rats were euthanized to collect blood and testicular samples on day 46. The results showed that exposure of TCDD resulted in a decrease in SOD activity and live spermatozoa and increased MDA level and death, apoptosis, and necrosis of spermatozoa (T0) compared to the control (C) group (p < 0.05). The administration of α-tocopherol, starting from the doses of 77 (T1), 149 (T2), and 259 mg (T3) per kg BW, was sequentially followed by returning MDA levels, recovering SOD activities, and restoration in the percentage of living, dead, apoptotic, and necrotic spermatozoa, similar (p > 0.05) to those of the control group. It could be concluded that the administration of α-tocopherol resolves the harmful effects of TCDD on the viability of spermatozoa in rats as a model.

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Vitamin E: Where Are We Now in Vascular Diseases?

Anahita Garg, Jetty Chung-Yung Lee

Life (Basel) . 2022 Feb 18;12(2):310. doi: 10.3390/life12020310.

Abstract

Vitamin E is one of the most popular fat-soluble vitamins in pathological research and has been under scrutiny since the 1980s as a vital dietary component of food. The antioxidant effect of vitamin E has been widely studied due to its benefits in the prevention of various cardiovascular diseases. In recent years, alternative effects of vitamin E, in terms of anti-inflammatory pathways and gene regulation, have also been of interest to researchers. This review examines the role of dietary vitamin E (α-tocopherol) as an antioxidant and bioactive molecule in promoting vascular health. While the antioxidant effect of vitamin E is well established, knowledge about its capacity as a promising regulatory molecule in the control of the vascular system is limited. The aim of this review is to discuss some of these mechanisms and summarize their role in the prevention of cardiovascular diseases (CVD). Here, we also briefly discuss foods rich in vitamin E, and deliberate some potential toxicological effects of excessive supplemental vitamin E in the body.

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Vitamin E in foodstuff: Nutritional, analytical, and food technology aspects

Farah Zaaboul, YuanFa Liu

Compr Rev Food Sci Food Saf . 2022 Feb 18. doi: 10.1111/1541-4337.12924. Online ahead of print.

Abstract

Vitamin E is a group of isoprenoid chromanols with different biological activities. It comprises eight oil-soluble compounds: four tocopherols, namely, α-, β-, γ-, and δ-tocopherols; and four tocotrienols, namely, α-, β-, γ, and δ-tocotrienols. Vitamin E isomers are well-known for their antioxidant activity, gene-regulation effects, and anti-inflammatory and nephroprotective properties. Considering that vitamin E is exclusively synthesized by photosynthetic organisms, animals can only acquire it through their diet. Plant-based food is the primary source of vitamin E; hence, oils, nuts, fruits, and vegetables with high contents of vitamin E are mostly consumed after processing, including industrial processes and home-cooking, which involve vitamin E profile and content alteration during their preparation. Accordingly, it is essential to identify the vitamin E content and profile in foodstuff to match daily intake requirements. This review summarizes recent advances in vitamin E chemistry, metabolism and metabolites, current knowledge on their contents and profiles in raw and processed plant foods, and finally, their modern developments in analytical methods.

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α-Tocopherol phosphate as a photosensitizer in the reaction of nucleosides with UV light: formation of 5,6-dihydrothymidine

Toshinori Suzuki, Chiaki Ono

Genes Environ . 2022 Feb 15;44(1):6. doi: 10.1186/s41021-022-00237-2.

Abstract

Introduction: α-Tocopherol phosphate, a natural water-soluble α-tocopherol analog, exists in biological tissues and fluids. Synthesized α-tocopherol phosphate is used as an ingredient of cosmetics.

Findings: When a neutral mixed solution of 2′-deoxycytidine, 2′-deoxyguanosine, thymidine, and 2′-deoxyadenosine was irradiated with UV light at wavelengths longer than 300 nm in the presence of α-tocopherol phosphate, thymidine was markedly consumed in an α-tocopherol phosphate dose-dependent manner, whereas other nucleosides only slightly decreased. Two major product peaks were detected in an HPLC chromatogram. The products were identified as diastereomers of 5,6-dihydrothymidine. The addition of radical scavengers had almost no effects on the generation of 5,6-dihydrothymidine, whereas the reactions of nucleosides other than thymidine were suppressed. Trolox, another water-soluble α-tocopherol analog, did not generate 5,6-dihydrothymidine, although all nucleosides were slightly consumed. When UV irradiation of thymidine with α-tocopherol phosphate was conducted in D2O, two deuterium atoms were added to 5 and 6 positions of thymidine with both syn and anti configurations. The ratio of syn and anti configurations alternated depending on pD of the solution.

Conclusions: The results indicate that α-tocopherol phosphate is a photosensitizer of nucleosides, especially thymidine, and that it introduces two hydrogen atoms to thymidine from H2O, generating 5,6-dihydrothymidine.

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Tocotrienol in Pre-Eclampsia Prevention: A Mechanistic Analysis in Relation to the Pathophysiological Framework

Zaleha Abdullah Mahdy, Kok-Yong Chin, Nik Lah Nik-Ahmad-Zuky, Aida Kalok, Rahana Abdul Rahman

Cells . 2022 Feb 10;11(4):614. doi: 10.3390/cells11040614.

Abstract

The pathophysiology of pre-eclampsia involves two major pathways, namely systemic oxidative stress and subsequent generalised inflammatory response, which eventually culminates in endothelial cell injury and the syndrome of pre-eclampsia with multi-organ dysfunction. Aspirin has been used to reduce the risk of pre-eclampsia, but it only possesses anti-inflammatory properties without any antioxidant effect. Hence, it can only partially alleviate the problem. Tocotrienols are a unique form of vitamin E with strong antioxidant and anti-inflammatory properties that can be exploited as a preventive agent for pre-eclampsia. Many preclinical models showed that tocotrienol can also prevent hypertension and ischaemic/reperfusion injury, which are the two main features in pre-eclampsia. This review explores the mechanism of action of tocotrienol in relation to the pathophysiology of pre-eclampsia. In conclusion, the study provides sufficient justification for the establishment of a large clinical trial to thoroughly assess the capability of tocotrienol in preventing pre-eclampsia.

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