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Regulation of microglia related neuroinflammation contributes to the protective effect of Gelsevirine on ischemic stroke

Stroke, especially ischemic stroke, is an important cause of neurological morbidity and mortality worldwide. Growing evidence suggests that the immune system plays an intricate function in the pathophysiology of stroke. Gelsevirine (Gs), an alkaloid from Gelsemium elegans, has been proven to decreas...

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Autores principales: Xing, Chunlei, Lv, Juan, Zhu, Zhihui, Cong, Wei, Bian, Huihui, Zhang, Chenxi, Gu, Ruxin, Chen, Dagui, Tan, Xiying, Su, Li, Zhang, Yu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10098192/
https://www.ncbi.nlm.nih.gov/pubmed/37063929
http://dx.doi.org/10.3389/fimmu.2023.1164278
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author Xing, Chunlei
Lv, Juan
Zhu, Zhihui
Cong, Wei
Bian, Huihui
Zhang, Chenxi
Gu, Ruxin
Chen, Dagui
Tan, Xiying
Su, Li
Zhang, Yu
author_facet Xing, Chunlei
Lv, Juan
Zhu, Zhihui
Cong, Wei
Bian, Huihui
Zhang, Chenxi
Gu, Ruxin
Chen, Dagui
Tan, Xiying
Su, Li
Zhang, Yu
author_sort Xing, Chunlei
collection PubMed
description Stroke, especially ischemic stroke, is an important cause of neurological morbidity and mortality worldwide. Growing evidence suggests that the immune system plays an intricate function in the pathophysiology of stroke. Gelsevirine (Gs), an alkaloid from Gelsemium elegans, has been proven to decrease inflammation and neuralgia in osteoarthritis previously, but its role in stroke is unknown. In this study, the middle cerebral artery occlusion (MCAO) mice model was used to evaluate the protective effect of Gs on stroke, and the administration of Gs significantly improved infarct volume, Bederson score, neurobiological function, apoptosis of neurons, and inflammation state in vivo. According to the data in vivo and the conditioned medium (CM) stimulated model in vitro, the beneficial effect of Gs came from the downregulation of the over-activity of microglia, such as the generation of inflammatory factors, dysfunction of mitochondria, production of ROS and so on. By RNA-seq analysis and Western-blot analysis, the JAK-STAT signal pathway plays a critical role in the anti-inflammatory effect of Gs. According to the results of molecular docking, inhibition assay, and thermal shift assay, the binding of Gs on JAK2 inhibited the activity of JAK2 which inhibited the over-activity of JAK2 and downregulated the phosphorylation of STAT3. Over-expression of a gain-of-function STAT3 mutation (K392R) abolished the beneficial effects of Gs. So, the downregulation of JAK2-STAT3 signaling pathway by Gs contributed to its anti-inflammatory effect on microglia in stroke. Our study revealed that Gs was benefit to stroke treatment by decreasing neuroinflammation in stroke as a potential drug candidate regulating the JAK2-STAT3 signal pathway.
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spelling pubmed-100981922023-04-14 Regulation of microglia related neuroinflammation contributes to the protective effect of Gelsevirine on ischemic stroke Xing, Chunlei Lv, Juan Zhu, Zhihui Cong, Wei Bian, Huihui Zhang, Chenxi Gu, Ruxin Chen, Dagui Tan, Xiying Su, Li Zhang, Yu Front Immunol Immunology Stroke, especially ischemic stroke, is an important cause of neurological morbidity and mortality worldwide. Growing evidence suggests that the immune system plays an intricate function in the pathophysiology of stroke. Gelsevirine (Gs), an alkaloid from Gelsemium elegans, has been proven to decrease inflammation and neuralgia in osteoarthritis previously, but its role in stroke is unknown. In this study, the middle cerebral artery occlusion (MCAO) mice model was used to evaluate the protective effect of Gs on stroke, and the administration of Gs significantly improved infarct volume, Bederson score, neurobiological function, apoptosis of neurons, and inflammation state in vivo. According to the data in vivo and the conditioned medium (CM) stimulated model in vitro, the beneficial effect of Gs came from the downregulation of the over-activity of microglia, such as the generation of inflammatory factors, dysfunction of mitochondria, production of ROS and so on. By RNA-seq analysis and Western-blot analysis, the JAK-STAT signal pathway plays a critical role in the anti-inflammatory effect of Gs. According to the results of molecular docking, inhibition assay, and thermal shift assay, the binding of Gs on JAK2 inhibited the activity of JAK2 which inhibited the over-activity of JAK2 and downregulated the phosphorylation of STAT3. Over-expression of a gain-of-function STAT3 mutation (K392R) abolished the beneficial effects of Gs. So, the downregulation of JAK2-STAT3 signaling pathway by Gs contributed to its anti-inflammatory effect on microglia in stroke. Our study revealed that Gs was benefit to stroke treatment by decreasing neuroinflammation in stroke as a potential drug candidate regulating the JAK2-STAT3 signal pathway. Frontiers Media S.A. 2023-03-30 /pmc/articles/PMC10098192/ /pubmed/37063929 http://dx.doi.org/10.3389/fimmu.2023.1164278 Text en Copyright © 2023 Xing, Lv, Zhu, Cong, Bian, Zhang, Gu, Chen, Tan, Su and Zhang https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Xing, Chunlei
Lv, Juan
Zhu, Zhihui
Cong, Wei
Bian, Huihui
Zhang, Chenxi
Gu, Ruxin
Chen, Dagui
Tan, Xiying
Su, Li
Zhang, Yu
Regulation of microglia related neuroinflammation contributes to the protective effect of Gelsevirine on ischemic stroke
title Regulation of microglia related neuroinflammation contributes to the protective effect of Gelsevirine on ischemic stroke
title_full Regulation of microglia related neuroinflammation contributes to the protective effect of Gelsevirine on ischemic stroke
title_fullStr Regulation of microglia related neuroinflammation contributes to the protective effect of Gelsevirine on ischemic stroke
title_full_unstemmed Regulation of microglia related neuroinflammation contributes to the protective effect of Gelsevirine on ischemic stroke
title_short Regulation of microglia related neuroinflammation contributes to the protective effect of Gelsevirine on ischemic stroke
title_sort regulation of microglia related neuroinflammation contributes to the protective effect of gelsevirine on ischemic stroke
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10098192/
https://www.ncbi.nlm.nih.gov/pubmed/37063929
http://dx.doi.org/10.3389/fimmu.2023.1164278
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