Vitamin E reduces radiation injury of hippocampal neurons in mice by inhibiting ferroptosis

Chen Ren, Xuanzi Li, Shasha Du

Nan Fang Yi Ke Da Xue Xue Bao . 2020 Aug 30;40(8):1097-1102. doi: 10.12122/j.issn.1673-4254.2020.08.05.

Abstract

Objective: To explore the protective effect of vitamin E (VE) against radiation injury of hippocampal neurons in mice and explore the possible mechanism.

Methods: Cultured HT-22 and U251 cells with or without exposure to 8 Gy irradiation were treated with VE (200 μmol/L for 24 h), ferroptosis inhibitor (ferrostatin-1, 5 μmol/L for 24 h), apoptosis inhibitor (ZVAD-FMK, 2 μmol/L), or necroptosis inhibitor (100 μmol/L). MTT assay was used to evaluate the cell viability after the treatments, and reduced glutathione (GSH), malondialdehyde (MDA), lipid reactive oxygen species (lipid ROS), and intracellular iron ion levels were detected for assessment of ferroptosis. The mice exposed to 16 Gy irradiation with or without vitamin E (500 U/kg) treatment for 6 weeks were assessed for behavioral changes and cognitive functions using Morris water maze test.

Results: Treatment with VE significantly promoted the cell survival following irradiation in HT-22 cells (P < 0.05) but not in U251 cells (P > 0.05). Ferrostatin-1, but not ZVAD or the necroptosis inhibitor, promoted the survival of HT-22 cells following the irradiation. Exposure to irradiation significantly increased ferroptosis-related oxidative stress level in HT-22 cells, manifested by decreased GSH level and increased MDA, lipid ROS and intracellular iron ion levels (P < 0.05); treatment with VE and ferrostatin-1 both obviously reversed radiation-induced ferroptosis-related oxidative stress in the cells (P < 0.05). In Morris water maze test, the mice with radiation exposure showed obviously increased exploration time and distance (P < 0.05), which were significantly decreased after treatment with VE (P < 0.05).

Conclusions: Vitamin E reduces radiation injury by inhibiting ferroptosis in the hippocampal neurons in mice.

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The wonders of palm oil

Ahmad Parveez Ghulam Kadir

The Malaysian Palm Oil Board (MPOB)’s research and collaborations with local and overseas institutions have scientifically proven that palm-derived Vitamin E tocotrienols are important for human health as they can prevent many non-communicable diseases. Through the continuous and dedicated research conducted by MPOB, the health benefits of palm oil and its phyto-nutrients are being explored extensively.

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Corneal UV Protective Effects of a Topical Antioxidant Formulation: A Pilot Study on In Vivo Rabbits

Marisa Palazzo, Francesco Vizzarri, Lubomir Ondruška, Michele Rinaldi, Luigi Pacente, Germano Guerra, Francesco Merolla, Ciro Caruso, Ciro Costagliola

Int J Mol Sci . 2020 Jul 30;21(15):E5426. doi: 10.3390/ijms21155426.

Abstract

This study aimed to evaluate the protective effect of a topical antioxidant and ultraviolet (UV) shielding action formulation containing riboflavin and D-α-tocopherol polyethylene glycol succinate (TPGS) vitamin E against corneal UV-induced damage in vivo rabbit eyes. In vivo experiments were performed using male albino rabbits, which were divided into four groups. The control group (CG) did not receive any UV irradiation; the first group (IG) was irradiated with a UV-B-UV-A lamp for 30 min; the second (G30) and third (G60) groups received UV irradiation for 30 and 60 min, respectively, and were topically treated with one drop of the antioxidant and shielding formulation every 15 min, starting one hour before irradiation, until the end of UV exposure. The cornea of the IG group showed irregular thickening, detachment of residual fragments of the Descemet membrane, stromal fluid swelling with consequent collagen fiber disorganization and disruption, and inflammation. The cornea of the G30 group showed edema, a mild thickening of the Descemet membrane without fibrillar collagen disruption and focal discoloration, or inflammation. In the G60 group, the cornea showed a more severe thickening, a more abundant fluid accumulation underneath the Descemet membrane with focal detachment, and no signs of severe tissue alterations, as were recorded in the IG group. Our results demonstrate that topical application of eye drops containing riboflavin and TPGS vitamin E counteracts UV corneal injury in exposed rabbits.

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The effect of aging and antioxidants on photoreactivity and phototoxicity of human melanosomes: An in vitro study

Magdalena M Olchawa, Grzegorz M Szewczyk, Andrzej C Zadlo, Olga I Krzysztynska-Kuleta, Tadeusz J Sarna

Pigment Cell Melanoma Res . 2020 Jul 23. doi: 10.1111/pcmr.12914. Online ahead of print.

Abstract

Aging may significantly modify antioxidant and photoprotective properties of melanin in retinal pigment epithelium (RPE). Here, photoreactivity of melanosomes (MS), isolated from younger and older human donors with and without added zeaxanthin and α-tocopherol, was analyzed by electron paramagnetic resonance oximetry, time-resolved singlet oxygen phosphorescence, and protein oxidation assay. The phototoxic potential of ingested melanosomes was examined in ARPE-19 cells exposed to blue light. Phagocytosis of FITC-labeled photoreceptor outer segments (POS) isolated from bovine retinas was determined by flow cytometry. Irradiation of cells fed MS induced significant inhibition of the specific phagocytosis with the effect being stronger for melanosomes from older than from younger human cohorts, and enrichment of the melanosomes with antioxidants reduced the inhibitory effect. Cellular protein photooxidation was more pronounced in samples containing older melanosomes, and it was diminished by antioxidants. This study suggests that blue light irradiated RPE melanosomes could induce substantial inhibition of the key function of the cells-their specific phagocytosis. The data indicate that while photoreactivity of MS and their phototoxic potential increase with age, they could be reduced by selected natural antioxidants.

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Tocol Prophylaxis for Total-body Irradiation: A Proteomic Analysis in Murine Model

Elliot Rosen, Oluseyi O Fatanmi, Stephen Y Wise, V Ashutosh Rao, Vijay K Singh

Health Phys . 2020 Jul;119(1):12-20. doi: 10.1097/HP.0000000000001221.

Abstract

The aim of this study was to analyze the changes in mouse jejunum protein expression in response to prophylactic administration of two promising tocols, γ-tocotrienol (GT3) and α-tocopherol succinate (TS), as radiation countermeasures before irradiation to elucidate the molecular mechanism(s) of their radioprotective efficacy. Mice were administered GT3 or TS (200 mg kg) subcutaneously 24 h prior to exposure to 11 Gy Co γ-radiation, a supralethal dose for mice. Jejunum was harvested 24 h post-irradiation. Results of the two-dimensional differential in-gel electrophoresis (2D-DIGE), coupled with mass spectrometry, and advanced bioinformatics tools suggest that the tocols have a corresponding impact on expression of 13 proteins as identified by mass spectrometry. Ingenuity Pathway Analysis (IPA) reveals a network of associated proteins involved in inflammatory response, organismal injury and abnormalities, and cellular development. Relevant signaling pathways including actin cytoskeleton signaling, RhoA signaling, and Rho family GTPase were identified. This study reveals the major proteins, pathways, and networks involved in preventing the radiation-induced injury in gut that may be contributing to enhanced survival.

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Deuteration of the Farnesyl Terminal Methyl Groups of δ-Tocotrienol and Its Effects on the Metabolic Stability and Ability of Inducing G-CSF Production

Xingui Liu, Zhengya Gao, Qiang Fu, Lin Song, Peiyi Zhang, Xuan Zhang, Howard Hendrickson, Peter A Crooks, Daohong Zhou, Guangrong Zheng

Bioorg Med Chem . 2020 Jun 1;28(11):115498. doi: 10.1016/j.bmc.2020.115498. Epub 2020 Apr 8.

Abstract

δ-tocotrienol (DT3), a member of vitamin E family, has been shown to have a potent radio-protective effect. However, its application as a radioprotectant is limited, at least in part, by its short plasma elimination half-life and low bioavailability. In an effort to increase the metabolic stability of DT3, a deuterium substituted DT3 derivative, d6-DT3, was designed and synthesized. d6-DT3 showed improved in vitro and in vivo metabolic stability compared to DT3. The unexpected lower potency of d6-DT3 in inducing granulocyte-colony stimulating factor (G-CSF) production in mouse revealed that the metabolite(s) of DT3 might play a major role in inducing G-CSF induction.

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Suppression of Menthyl Anthranilate (UV-A Sunscreen)-Sensitized Singlet Oxygen Generation by Trolox and α-tocopherol

Shogo Kitasaka, Mikio Yagi, Azusa Kikuchi

Photochem Photobiol Sci . 2020 Jun 2. doi: 10.1039/d0pp00023j. Online ahead of print.

Abstract

Menthyl anthranilate (MA, tradename meradimate) is a UV-A absorber. The interactions of ground-state molecular oxygen with the long-lived triplet state of MA produce singlet oxygen through energy transfer. The quantum yield of singlet oxygen generation is 0.12 in air-saturated ethanol. Kinetic traces of the near-IR phosphorescence of singlet oxygen generated by MA-photosensitization have been measured in the absence and presence of Trolox (a water-soluble analogue of vitamin E and a quencher of singlet oxygen) and α-tocopherol (vitamin E, a natural antioxidant) in ethanol. Fluorescence and transient absorption measurements suggest that Trolox and α-tocopherol quench the lowest excited singlet and triplet states of MA. As a result, Trolox and α-tocopherol suppress MA-photosensitized singlet oxygen generation. Not only the quenching of singlet oxygen but also the suppression of singlet oxygen generation is the mechanism of antioxidant properties of Trolox and α-tocopherol for MA. The ability of α-tocopherol to suppress the MA-photosensitized singlet oxygen generation in isododecane, used as a solvent for an oil-soluble UV absorber, is close to that in ethanol. Suppression of sunscreen-photosensitized singlet oxygen generation is an important method for the formulation of safe cosmetic sunscreens.

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Randomized, Placebo-Controlled Clinical Trial Combining Pentoxifylline-Tocopherol and Clodronate in the Treatment of Radiation-Induced Plexopathy

Delanian SE, Lenglet T, Maisonobe T, Resche-Rigon M, Pradat PF

Int J Radiat Oncol Biol Phys. 2020 May 1;107(1):154-162. doi: 10.1016/j.ijrobp.2020.01.002. Epub 2020 Jan 24.

Abstract

PURPOSE:

Radiation-induced (RI) plexopathy is a rare peripheral nerve injury after radiation therapy for cancer. No treatment has been shown to slow its progression. A pentoxifylline-vitamin E combination significantly reduced RI fibrosis, and its association with clodronate (PENTOCLO) allowed healing of osteoradionecrosis and reduction of neurologic symptoms in phase 2 trials.

METHODS AND MATERIALS:

A placebo-controlled, double-blind trial conducted in adults with RI limb plexopathy without cancer recurrence, randomized in 2 arms to PENTOCLO (pentoxifylline 800 mg, tocopherol 1000 mg, clodronate 1600 mg 5 days per week) or triple placebo. The primary outcome measure after 18 months of treatment was the neurologic Subjective Objective Management Analytic (SOMA) score evaluating pain, paresthesia, and motor disability.

RESULTS:

Between 2011 and 2015, 59 patients were included: 1 false inclusion (neoplastic plexopathy), 29 treated with placebo (group P), and 29 treated with the active drugs (group A); 46 patients presented an upper-limb and 12 a lower-limb plexopathy. The mean delay after irradiation was 26 ± 8 years, for patients with neurologic symptoms for 5 ± 5 years. The median global SOMA scores in the P and A groups, respectively, were 9 (range, 6-11) versus 9 (range, 8-11) at M0 and 9 (range, 5-12) versus 10 (range, 6-11) at M18 without any significant difference. Analysis of the secondary outcomes showed that SOMA score subdomains for pain and paresthesia were more affected in group A (not significant). The frequency of adverse events was similar in the 2 groups (81% of patients): slight expected vascular-gastrointestinal symptoms in A, but a large excess of RI complications (arterial stenosis).

CONCLUSIONS:

This first randomized drug trial in RI plexopathy failed to show a beneficial effect. More studies are needed in patients with less advanced disease and fewer confounding comorbidities and with a more sensitive measure to detect a therapeutic effect.

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Tocol Prophylaxis for Total-body Irradiation: A Proteomic Analysis in Murine Model.

Rosen E, Fatanmi OO, Wise SY, Rao VA, Singh VK

Health Phys. 2020 Mar 20. doi: 10.1097/HP.0000000000001221. [Epub ahead of print]

Abstract

The aim of this study was to analyze the changes in mouse jejunum protein expression in response to prophylactic administration of two promising tocols, γ-tocotrienol (GT3) and α-tocopherol succinate (TS), as radiation countermeasures before irradiation to elucidate the molecular mechanism(s) of their radioprotective efficacy. Mice were administered GT3 or TS (200 mg kg) subcutaneously 24 h prior to exposure to 11 Gy Co γ-radiation, a supralethal dose for mice. Jejunum was harvested 24 h post-irradiation. Results of the two-dimensional differential in-gel electrophoresis (2D-DIGE), coupled with mass spectrometry, and advanced bioinformatics tools suggest that the tocols have a corresponding impact on expression of 13 proteins as identified by mass spectrometry. Ingenuity Pathway Analysis (IPA) reveals a network of associated proteins involved in inflammatory response, organismal injury and abnormalities, and cellular development. Relevant signaling pathways including actin cytoskeleton signaling, RhoA signaling, and Rho family GTPase were identified. This study reveals the major proteins, pathways, and networks involved in preventing the radiation-induced injury in gut that may be contributing to enhanced survival.

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Beneficial effects of vitamin E on radioiodine induced gastrointestinal damage: an experimental and pathomorphological study.

Yumusak N, Sadic M, Akbulut A, Aydinbelge FN, Koca G, Korkmaz M

Bratisl Lek Listy. 2019;120(4):263-269. doi: 10.4149/BLL_2019_048.

Abstract

OBJECTIVES:

The aim of the present study was to investigate the radioprotective effect of vitamin E in the prevention of radioiodine (RAI) induced gastrointestinal damage.

METHOD:

Twenty-four rats were randomly divided into three groups as follows: Group-1 was untreated control group, Group-2 was orally administered single dose of 111 MBq RAI, and Group-3 was orally administered 111 MBq RAI and 1 mL of oral vitamin EVitamin E was started two days before RAI administration and was continued for five days once daily after RAI. Pathomorphological parameters of gastrointestinal tissues (stomach, small intestines and bowels) were measured using Hematoxylin-Eosin and Masson’s trichrome staining.

RESULTS:

Varying degrees of inflammation, edema, ulcer, mucosal degeneration, necrosis and fibrosis were seen in the stomach, small intestine and bowel tissues of the rats in both study groups and not in the control group. The differences were statistically significant between these groups for all parameters (p < 0.05). The histopathological damage in the vitamin E treated group was significantly less than the damage in the RAI only group (p < 0.05 for all pathomorphological parameters).

CONCLUSION:

The results of this study showed that vitamin E has a radioprotective property with antiinflammatory and antifibrotic effects protecting against gastrointestinal damage caused by radioiodine.

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