Gamma-tocopherol, a major form of vitamin E in diets: Insights into antioxidant and anti-inflammatory effects, mechanisms, and roles in disease management

Qing Jiang, Suji Im, James G Wagner, Michelle L Hernandez, David B Peden

Free Radic Biol Med . 2022 Jan;178:347-359. doi: 10.1016/j.freeradbiomed.2021.12.012. Epub 2021 Dec 9.

Abstract

γ-Tocopherol (γT) is a major form of vitamin E in the US diet and the second most abundant vitamin E in the blood and tissues, while α-tocopherol (αT) is the predominant vitamin E in tissues. During the last >25 years, research has revealed that γT has unique antioxidant and anti-inflammatory activities relevant to disease prevention compared to αT. While both compounds are potent lipophilic antioxidants, γT but not αT can trap reactive nitrogen species by forming 5-nitro-γT, and appears to show superior protection of mitochondrial function. γT inhibits ionophore-stimulated leukotrienes by blocking 5-lipoxygenase (5-LOX) translocation in leukocytes, decreases cyclooxygenase-2 (COX-2)-catalyzed prostaglandins in macrophages and blocks the growth of cancer cells but not healthy cells. For these activities, γT is stronger than αT. Moreover, γT is more extensively metabolized than αT via cytochrome P-450 (CYP4F2)-initiated side-chain oxidation, which leads to formation of metabolites including 13′-carboxychromanol (13′-COOH) and carboxyethyl-hydroxychroman (γ-CEHC). 13′-COOH and γ-CEHC are shown to be the predominant metabolites found in feces and urine, respectively. Interestingly, γ-CEHC has natriuretic activity and 13′-COOH inhibits both COX-1/-2 and 5-LOX activity. Consistent with these mechanistic findings of γT and metabolites, studies show that supplementation of γT mitigates inflammation and disease symptoms in animal models with induced inflammation, asthma and cancer. In addition, supplementation of γT decreased inflammation markers in patients with kidney diseases and mild asthma. These observations support that γT may be useful against inflammation-associated diseases.

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The α-tocopherol-derived long-chain metabolite α-13′-COOH mediates endotoxin tolerance and modulates the inflammatory response via MAPK and NFκB pathways

Martin Schubert, Stefan Kluge, Elena Brunner, Simona Pace, Marc Birringer, Oliver Werz, Stefan Lorkowski

Free Radic Biol Med . 2022 Jan;178:83-96. doi: 10.1016/j.freeradbiomed.2021.11.032. Epub 2021 Nov 27.

Abstract

Scope: The long-chain metabolites of (LCM) vitamin E are proposed as the active regulatory metabolites of vitamin E providing, with their anti-inflammatory properties, an explanatory approach for the inconsistent effects of vitamin E on inflammatory-driven diseases. We examined the modulation of cytokine expression and release from macrophages, a fundamental process in many diseases, to gain insights into the anti-inflammatory mechanisms of the α-tocopherol-derived LCM α-13′-COOH.

Methods and results: Suppressed gene expression of C-C motif chemokine ligand 2 (Ccl2), tumor necrosis factor (Tnf), and interleukin (Il) 6 in response to lipopolysaccharides by 24 h pre-treatment with α-13′-COOH in RAW264.7 macrophages was revealed using quantitative reverse transcription PCR. Further, reduced secretion of IL1β and CCL2 was found in this setup using flow cytometry. In contrast, 1 h pre-treatment suppressed only CCL2. Consequent gene expression analysis within 24 h of α-13′-COOH treatment revealed the induction of mitogen-activated protein kinases (MAPK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) negative feedback regulators including the ‘master regulators’ dual-specificity phosphatase 1 (Dusp1/Mkp1) and tumor necrosis factor induced protein 3 (Tnfaip3/A20). Approaches with immunoblots and chemical antagonists suggest a feedback induction via activation of extracellular-signal regulated kinase (ERK), p38 MAPK and NFκB pathways.

Conclusions: CCL2 is suppressed in murine macrophages by α-13′-COOH and the indirect suppression of MAPK and NFκB pathways is likely a relevant process contributing to anti-inflammatory actions of α-13′-COOH. These results improve the understanding of the effects of α-13′-COOH and provide a basis for new research strategies in the context of inflammatory diseases.

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Label-Free Electrochemical Biosensors to Evaluate the Antioxidant Effect of Tocopherol in Ultraviolet Radiation

Lixia Gao, Yong Teng

Methods Mol Biol . 2022;2343:241-246. doi: 10.1007/978-1-0716-1558-4_16.

Abstract

Electrochemical biosensors offer a sensitive, specific, and rapid detection platform for in situ real-time monitoring of intracellular and extracellular metabolites. These sensors have been widely used to evaluate the efficacy of preclinical drugs, especially for natural products with antioxidant potency. Ultraviolet (UV) radiation causes oxidative stress in cells and induces cells to release reactive oxygen species. Tocopherol is a fat-soluble vitamin found in vegetable oils as well as in grains, seeds, and nuts, which plays an important protective role as an antioxidant in resisting oxidative stress caused by UV radiation. Here, we describe a protocol using a glass carbon electrode functionalized with nanotube@DNA-Mn3(PO4)2 composite to monitor and quantify the production of superoxide ions in UV-irradiated melanoma cells in the presence or absence of tocopherol. This study demonstrates the advantages and potential application of label-free electrochemical sensors in the measurement of natural antioxidants from plant materials.

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Genotoxicity of nedaplatin in cultured lymphocytes: modulation by vitamin E

Muntaha S Al-Khdour, Omar F Khabour, Laith N Al-Eitan, Karem H Alzoubi

Drug Chem Toxicol . 2021 Dec 29;1-5. doi: 10.1080/01480545.2021.2015369. Online ahead of print.

Abstract

Nedaplatin is a chemotherapeutic agent used widely in cancer therapy. Nedaplatin has been shown to cause DNA damage to cells via the induction of oxidative stress. Vitamin E (Vit E) has an anti-mutagenic activity that can protect cells from DNA damaging agents. The objective of this study is to examine the genotoxic and cytotoxic effects of nedaplatin in human cultured lymphocytes. In addition, modulation of such effects by Vit E was also examined. The frequencies of sister chromatid exchange (SCE) and chromosomal aberrations (CAs) were used as an indicator for genotoxicity. The mitotic and proliferative indices were used to examine the cytotoxic effects of nedaplatin. The results showed that nedaplatin significantly elevated SCE and CA frequencies in human lymphocytes (p ˂ 0.01). The increases in the frequencies of SCE and CA caused by nedaplatin were lowered by pretreatment treatment with Vit E (p < 0.05). Nedaplatin significantly lowered mitotic index but Vit E pretreatment did not modulate this effect. These results suggest that Vit E has the potential to ameliorate the genotoxicity of nedaplatin in cultured lymphocytes.

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γ-Tocotrienol Protects against Mitochondrial Dysfunction, Energy Deficits, Morphological Damage, and Decreases in Renal Functions after Renal Ischemia

Grazyna Nowak, Judit Megyesi

Int J Mol Sci . 2021 Nov 24;22(23):12674. doi: 10.3390/ijms222312674.

Abstract

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 F0F1-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.

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Paclitaxel-loaded polymeric nanoparticles based on α-tocopheryl succinate for the treatment of head and neck squamous cell carcinoma: in vivo murine model

Juan Riestra-Ayora, Carolina Sánchez-Rodríguez, Raquel Palao-Suay, Joaquín Yanes-Díaz, Ana Martín-Hita, María Rosa Aguilar, Ricardo Sanz-Fernández

Drug Deliv . 2021 Dec;28(1):1376-1388. doi: 10.1080/10717544.2021.1923863.

Abstract

The prognosis of patients with recurrent or metastatic head and neck squamous cell cancer (HNSCC) is generally poor. New treatments are required to supplement the current standard of care. Paclitaxel (PTX), an effective chemotherapeutic for HNSCC, has serious side effects. A polymeric nanocarrier system was developed for the delivery of PTX to improve HNSCC treatment. This study aimed to evaluate the antitumor efficacy of PTX-loaded polymeric nanoparticles based on α-TOS (PTX-NPs) administered by direct intratumoral injection into a Hypopharynx carcinoma squamous cells (FaDu) tumor xenograft mouse model. The nanocarrier system based on block copolymers of polyethylene glycol (PEG) and a methacrylic derivative of α-TOS was synthesized and PTX was loaded into the delivery system. Tumor volume was measured to evaluate the antitumor effect of the PTX-NPs. The relative mechanisms of apoptosis, cell proliferation, growth, angiogenesis, and oxidative and nitrosative stress were detected by Western blotting, fluorescent probes, and immunohistochemical analysis. The antitumor activity results showed that compared to free PTX, PTX-NPs exhibited much higher antitumor efficacy and apoptosis-inducing in a FaDu mouse xenograft model and demonstrated an improved safety profile. Ki-67, EGFR, and angiogenesis markers (Factor VIII, CD31, and CD34) expression were significantly lower in the PTX-NPs group compared with other groups (p < .05). Also, PTX-NPs induced oxidative and nitrosative stress in tumor tissue. Direct administration of PTX-loaded polymeric nanoparticles based on α-Tocopheryl Succinate at the tumor sites, proved to be promising for HNSCC therapy.

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Delta-tocotrienol enhances the antitumor effects of interferon alpha through ROS and Erk/MAPK signaling pathways in hepatocellular carcinoma cells

Alvaro Lucci, Marina C Vera, Carla G Comanzo, Florencia Lorenzetti, Anabela C Ferretti, María Paula Ceballos, Ariel D Quiroga, Maria de Lujan Alvarez, María Cristina Carrillo

Can J Physiol Pharmacol . 2021 Dec 21. doi: 10.1139/cjpp-2021-0606. Online ahead of print.

Abstract

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 to single therapies. Combining δ-tocotrienol and IFN α enhanced the decrease in proliferating cell nuclear antigen (PCNA) and matrix metalloproteinases MMP-7 and MMP-9. The combination also produced an enhancement of apoptosis together with increased Bax/Bcl-xL ratio and 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 anticancer effects of the combined treatment. In conclusion, the combination of δ-tocotrienol with IFN α therapy showed promising results for HCC cells treatment, which makes the combination of cytokine-based immunotherapy with natural products a potential strategy against liver cancer.

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δ-tocotrienol suppresses the migration and angiogenesis of trophoblasts in preeclampsia and promotes their apoptosis via miR-429/ ZEB1 axis

Mei Shi, Xiuyun Chen, Hui Li, Lixia Zheng

Bioengineered . 2021 Dec;12(1):1861-1873. doi: 10.1080/21655979.2021.1923238.

Abstract

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.

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The Vitamin E Isoform α-Tocopherol is Not Effective as a Complementary Treatment in Cancer Treatment: A Systematic Review

Dorothee Retzlaff, Jennifer Dörfler, Sabine Kutschan, Maren Freuding, Jens Büntzel, Jutta Hübner

Nutr Cancer . 2021 Dec 17;1-24. doi: 10.1080/01635581.2021.2014905. Online ahead of print

Abstract

The term vitamin E describes tocopherols and tocotrienols, whose chemical variations result in different biological activities including antioxidants. Neuroprotective effects of alpha-tocopherol against different toxins are assumed, therefore, it is discussed as a possible protective factor for adverse effects in cancer treatment. In July 2020, a systematic search was conducted searching five databases (Embase, Cochrane, PsychInfo, Cinahl, Medline) to find studies concerning the impact of α-tocopherol application and its potential harm on cancer patients. From 7546 search results, 22 publications referring to 20 studies with 1941 patients were included. Included patients were diagnosed with various cancer types and stages. Outcome variables were overall survival of cancer, symptom management of mucositis and chemotherapy-induced peripheral neuropathy (CIPN). The studies had different methodological qualities (mainly acceptable) and reported heterogeneous results: some reported significant improvement of mucositis and CIPN while others did not find changes concerning these endpoints. Due to heterogeneous results and methodical limitations of the included studies, a clear statement regarding the effectiveness of α-tocopherol as complementary treatment for cancer patients is not possible. Despite findings regarding reduction of oral side effects, usage of α-tocopherol during therapy must be discouraged because of potential negative influence on survival rates.

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