Gamma tocotrienol, a potent radioprotector, preferentially upregulates expression of anti-apoptotic genes to promote intestinal cell survival

Suman, Shubhankar; Datta, Kamal; Chakraborty, Kushal; Kulkarni, S.; Doiron, Kathryn; Fornace, Albert J.; Kumar, Krishna B.; Hauer‐Jensen, Martin; Ghosh, Sanchita

doi:10.1016/j.fct.2013.08.011

Cited by 39 publications

(38 citation statements)

References 52 publications

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“…38 In addition, numerous studies have demonstrated that tocopherols can be either antiapoptotic or proapoptotic, depending upon cell types. 42 Our data also showed that HUVECs treated for 24 h with αand δ-tocopherols alone did not cause cell death (Fig. [39][40][41] Suman et al reported that γ-tocotrienol upregulated the expression of anti-apoptotic genes to promote intestinal cell survival.…”

Section: Discussionsupporting

confidence: 65%

δ-Tocopherol prevents methylglyoxal-induced apoptosis by reducing ROS generation and inhibiting apoptotic signaling cascades in human umbilical vein endothelial cells

Kim

Seo

et al. 2015

Food Funct.

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Methylglyoxal (MGO) is a highly reactive metabolite of glucose, which is known to cause damage and induce apoptosis in endothelial cells. Endothelial cell damage is implicated in the progression of diabetes-associated complications and atherosclerosis. Nuts are high in vitamin E. Consumption of nuts has been recommended for the prevention of cardiovascular disease. However, different nuts contain different forms of vitamin E, which can have different effects on endothelial cells. In this work, we investigated the protective effect of different isoforms of vitamin E on MGO-induced apoptosis in human umbilical vein endothelial cells (HUVECs). Among all forms of vitamin E, δ-tocopherol showed the highest effect on apoptosis of HUVECs. We also compared the anti-apoptotic activity of δ-tocopherol with that of α-tocopherol in MGO-treated HUVECs. Pretreatment with α- or δ-tocopherol significantly inhibited MGO-induced changes in cell morphology, cell death, and production of intracellular reactive oxygen species. δ-Tocopherol prevented MGO-induced apoptosis in HUVECs by increasing Bcl-2 expression and decreasing Bax expression. Interestingly, α-tocopherol also inhibited these factors but to a lesser extent than δ-tocopherol. MGO was found to activate mitogen-activated protein kinases (MAPKs). Compared to pretreatment with α-tocopherol, pretreatment with δ-tocopherol more strongly inhibited the activation of MAPKs, such as JNK and ERK1/2. These findings suggest that δ-tocopherol may be a more effective regulator of MGO-induced apoptosis than α-tocopherol.

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Section: Discussionsupporting

confidence: 65%

δ-Tocopherol prevents methylglyoxal-induced apoptosis by reducing ROS generation and inhibiting apoptotic signaling cascades in human umbilical vein endothelial cells

Kim

Seo

et al. 2015

Food Funct.

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“…GT3 induces multiple changes in functional genetic pathways known to be of critical importance in the cellular responses to radiation exposure, such as oxidative stress, DNA damage, cell cycle phase, regulation of cell death, cell proliferation, hematopoiesis and blood vessel development (45). Recently, it has been reported that GT3-mediated protection of intestinal cells occurs via up-regulation of anti-apoptotic and downregulation of pro-apoptotic factors (46). GT3 treatment combined with pentoxifylline increased postirradiation survival over that of GT3 alone by a mechanism that may depend on induction of hematopoietic stimuli (47).…”

Section: Discussionmentioning

confidence: 99%

Radioprotective Efficacy of Gamma-Tocotrienol in Nonhuman Primates

Singh

Kulkarni²,

Fatanmi³

et al. 2016

Radiation Research

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105

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The search for treatments to counter potentially lethal radiation-induced injury over the past several decades has led to the development of multiple classes of radiation countermeasures. However, to date only granulocyte colony-stimulating factor (G-CSF; filgrastim, Neupogen)and pegylated G-CSF (pegfilgrastim, Neulasta) have been approved by the United States Food and Drug Administration (FDA) for the treatment of hematopoietic acute radiation syndrome (ARS). Gamma-tocotrienol (GT3) has demonstrated strong radioprotective efficacy in the mouse model, indicating the need for further evaluation in a large animal model. In this study, we evaluated GT3 pharmacokinetics (PK) and efficacy at different doses of cobalt-60 gamma radiation (0.6 Gy/min) using the nonhuman primate (NHP) model. The PK results demonstrated increased area under the curve with increasing drug dose and half-life of GT3. GT3 treatment resulted in reduced group mean neutropenia by 3-5 days and thrombocytopenia by 1-5 days. At 5.8 and 6.5 Gy total-body irradiation, GT3 treatment completely prevented thrombocytopenia. The capability of GT3 to reduce severity and duration of neutropenia and thrombocytopenia was dose dependent; 75 mg/kg treatment was more effective than 37.5 mg/kg treatment after a 5.8 Gy dose. However, the higher GT3 dose (75 mg/kg) was associated with higher frequency of adverse skin effects (small abscess) at the injection site. GT3 treatment of irradiated NHPs caused no significant difference in animal survival at 60 days postirradiation, however, low mortality was observed in irradiated, vehicle-treated groups as well. The data from this pilot study further elucidate the role and pharmacokinetics of GT3 in hematopoietic recovery after irradiation in a NHP model, and demonstrate the potential of GT3 as a promising radioprotector.

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“…Ten microliters of protein was electrophoresed on a 12% sodium dodecyl sulfate (SDS)–polyacrylamide gel and transferred to membranes. Blots were probed with goat anti- sodium dodecyl sulfate (SOD) (1:1000) and rabbit anti-catalase (1:8000) and visualized with a 1:5000 dilution of IgG conjugated to horseradish peroxidase [50]. …”

Section: Methodsmentioning

confidence: 99%

The Protective Effects of Clams on Hypercholesterolemia in Late-Stage Triple-Transgenic Alzheimer’s Diseased Mice Hearts

et al. 2018

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To investigate a high cholesterol diet in Alzheimer’s disease (AD) mice, they were fed with (2% cholesterol) in five groups with a control group, AD mice group, AD mice plus Meretrix lusoria group, AD mice plus Geloina eros group, and, AD mice plus Corbicula fluminea group for three months, and treated with the fatty acid profiles of clams by gas chromatography (GC). The results showed that treatment with clams for three months reduced Fas/L and Caspase-3 in the Meretrix lusoria and Geloina eros groups, but Fas-associated death domain (FADD) and Caspase-8 were strongly reduced in the Geloina eros group. For the mitochondria-dependent apoptotic pathway, the reduction of apoptosis proteins were observed in the hearts of clams-treated AD mice. BAK and Caspase-9 was reduced in the Meretrix lusoria group, but Caspase-3 and Cytochrome-c were reduced in Geloina eros group. Enhancement of survival proteins p-AKT, p-IGF1R, p-PI3K, Bcl-XL, Bcl2, and the longevity SIRT1 signaling proteins, p-AMPK-α, SIRT1, PGC1-α, p-FOXO3 were observed in clams-treated mice and even more strongly enhanced in the Meretrix lusoria, Geloina eros and Corbicula fluminea groups. This study observed that the ingestion of clams caused a reduction of apoptosis proteins and enhancement of survival and SIRT1 signaling proteins in the hearts.

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Gamma tocotrienol, a potent radioprotector, preferentially upregulates expression of anti-apoptotic genes to promote intestinal cell survival

Cited by 39 publications

References 52 publications

δ-Tocopherol prevents methylglyoxal-induced apoptosis by reducing ROS generation and inhibiting apoptotic signaling cascades in human umbilical vein endothelial cells

δ-Tocopherol prevents methylglyoxal-induced apoptosis by reducing ROS generation and inhibiting apoptotic signaling cascades in human umbilical vein endothelial cells

Radioprotective Efficacy of Gamma-Tocotrienol in Nonhuman Primates

The Protective Effects of Clams on Hypercholesterolemia in Late-Stage Triple-Transgenic Alzheimer’s Diseased Mice Hearts

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