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2 results on '"NUCLEAR TRANSLOCATOR"'

1. Withaferin A inhibits ferroptosis and protects against intracerebral hemorrhage

Author

Zi-Xian Zhou, Qi Cui, Ying-Mei Zhang, Jia-Xin Yang, Wen-Jing Xiang, Ning Tian, Yan-Lin Jiang, Mei-Ling Chen, Bin Yang, Qing-Hua Li, and Ru-Jia Liao

Subjects
behavior, brain injuries, hemorrhagic stroke, ferroptosis, heme oxygenase-1, neuroprotection, nuclear factor e2-related factor 2, nuclear translocator, oxidative stress, stroke, Neurology. Diseases of the nervous system, RC346-429
Abstract

Recent studies have indicated that suppressing oxidative stress and ferroptosis can considerably improve the prognosis of intracerebral hemorrhage (ICH). Withaferin A (WFA), a natural compound, exhibits a positive effect on a number of neurological diseases. However, the effects of WFA on oxidative stress and ferroptosis-mediated signaling pathways to ICH remain unknown. In this study, we investigated the neuroprotective effects and underlying mechanism for WFA in the regulation of ICH-induced oxidative stress and ferroptosis. We established a mouse model of ICH by injection of autologous tail artery blood into the caudate nucleus and an in vitro cell model of hemin-induced ICH. WFA was injected intracerebroventricularly at 0.1, 1 or 5 µg/kg once daily for 7 days, starting immediately after ICH operation. WFA markedly reduced brain tissue injury and iron deposition and improved neurological function in a dose-dependent manner 7 days after cerebral hemorrhage. Through in vitro experiments, cell viability test showed that WFA protected SH-SY5Y neuronal cells against hemin-induced cell injury. Enzyme-linked immunosorbent assays in vitro and in vivo showed that WFA markedly decreased the level of malondialdehyde, an oxidative stress marker, and increased the activities of anti-oxidative stress markers superoxide dismutase and glutathione peroxidase after ICH. Western blot assay, quantitative polymerase chain reaction and immunofluorescence results demonstrated that WFA activated the nuclear factor E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling axis, promoted translocation of Nrf2 from the cytoplasm to nucleus, and increased HO-1 expression. Silencing Nrf2 with siRNA completely reversed HO-1 expression, oxidative stress and protective effects of WFA. Furthermore, WFA reduced hemin-induced ferroptosis. However, after treatment with an HO-1 inhibitor, the neuroprotective effects of WFA against hemin-induced ferroptosis were weakened. MTT test results showed that WFA combined with ferrostatin-1 reduced hemin-induced SH-SY5Y neuronal cell injury. Our findings reveal that WFA treatment alleviated ICH injury-induced ferroptosis and oxidative stress through activating the Nrf2/HO-1 pathway, which may highlight a potential role of WFA for the treatment of ICH.

Published
2023
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2. Male and female mice show significant differences in hepatic transcriptomic response to 2,3,7,8-tetrachlorodibenzo-p-dioxin

Author

John D. Watson, Stephenie D. Prokopec, Raimo Pohjanvirta, Jamie Lee, Paul C. Boutros, Ren X. Sun, Departments of Faculty of Veterinary Medicine, Food Hygiene and Environmental Health, and Raimo Pohjanvirta / Principal Investigator

Subjects
Male, NUCLEAR TRANSLOCATOR, TCDD, Polychlorinated Dibenzodioxins, Cytoplasmic and Nuclear, AHR, Receptors, Cytoplasmic and Nuclear, 010501 environmental sciences, 413 Veterinary science, 01 natural sciences, Medical and Health Sciences, 8-tetrachlorodibenzo-p-dioxin, Transcriptome, C57BL/6 MICE, Mice, Receptors, ABNORMAL LIVER DEVELOPMENT, 2.1 Biological and endogenous factors, heterocyclic compounds, Aetiology, Receptor, AH RECEPTOR, reproductive and urinary physiology, Aryl hydrocarbon receptor, GENE-EXPRESSION, Regulation of gene expression, 0303 health sciences, biology, FLAVIN-CONTAINING MONOOXYGENASE, Liver Disease, Sex hormone receptor, Biological Sciences, Phenotype, 3. Good health, Liver, MOUSE-LIVER, Female, Research Article, Biotechnology, ARYL-HYDROCARBON RECEPTOR, medicine.medical_specialty, endocrine system, Bioinformatics, 03 medical and health sciences, Sex Factors, Internal medicine, Information and Computing Sciences, Sex differences, medicine, Genetics, Animals, 2,3,7,8-tetrachlorodibenzo-p-dioxin, SPRAGUE-DAWLEY RATS, Constitutive Androstane Receptor, 030304 developmental biology, 0105 earth and related environmental sciences, Gene Expression Profiling, Gene expression profiling, stomatognathic diseases, Endocrinology, Gene Expression Regulation, Agent Orange & Dioxin, biology.protein, Digestive Diseases, Hormone
Abstract

Background 2,3,7,8–tetrachlorodibenzo-p-dixion (TCDD) is the most potent of the dioxin congeners, capable of causing a wide range of toxic effects across numerous animal models. Previous studies have demonstrated that males and females of the same species can display divergent sensitivity phenotypes to TCDD toxicities. Although it is now clear that most TCDD-induced toxic outcomes are mediated by the aryl hydrocarbon receptor (AHR), the mechanism of differential responses to TCDD exposure between sexes remains largely unknown. To investigate the differential sensitivities in male and female mice, we profiled the hepatic transcriptomic responses 4 days following exposure to various amounts of TCDD (125, 250, 500 or 1000 μg/kg) in adult male and female C57BL/6Kuo mice. Results Several key findings were revealed by our study. 1) Hepatic transcriptomes varied significantly between the sexes at all doses examined. 2) The liver transcriptome of males was more dysregulated by TCDD than that of females. 3) The alteration of “AHR-core” genes was consistent in magnitude, regardless of sex. 4) A subset of genes demonstrated sex-dependent TCDD-induced transcriptional changes, including Fmo3 and Nr1i3, which were significantly induced in livers of male mice only. In addition, a meta-analysis was performed to contrast transcriptomic profiles of various organisms and tissues following exposure to equitoxic doses of TCDD. Minimal overlap was observed in the differences between TCDD-sensitive or TCDD-resistant models. Conclusions Sex-dependent sensitivities to TCDD exposure are associated with a set of sex-specific TCDD-responsive genes. In addition, complex interactions between the aryl hydrocarbon and sex hormone receptors may affect the observable differences in sensitivity phenotypes between the sexes. Further work is necessary to better understand the roles of those genes altered by TCDD in a sex-dependent manner, and their association with changes to sex hormones and receptors. Electronic supplementary material The online version of this article (doi:10.1186/s12864-015-1840-6) contains supplementary material, which is available to authorized users.

Published
2015

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