Myrrh extract alleviated ROS-mediated ferroptosis through regulating TXNIP/NLRP3 axis in ischemic stroke  

作　　者：LIU Tian-long WANG Wen-jun DING Yi WEN Ai-dong ZHANG Ru-xue 

机构地区：[1]Department of Pharmacy,Key Laboratory of Prevention and Cure for the Plateau Environmental Damage of PLA,940 Hospital of PLA Joint Logistics Support Forces,Lanzhou 730050,China [2]Department of Pharmacy,Xijing Hospital,Fourth Military Medical University,Xi′an 710032,China

出　　处：《中国药理学与毒理学杂志》2019年第9期667-668,共2页Chinese Journal of Pharmacology and Toxicology

基　　金：National Natural Science Foundation of China(81673631;81603385);China Postdoctoral Science Foundation(2018M643843);Natural Science Foundation of Shaanxi Province(2017JM8056);Key Research and Development Foundation of Shaanxi province(2018SF-241)

摘　　要：OBJECTIVE To investigate the neuroprotective effects and exact mechanisms of myrrh extract following cerebral ischemic stroke.METHODS Male rats were randomly divided into three groups:sham group,middle cerebral artery occlusion(MCAO)group and myrrh group.Morphological changes were assessed after 7 d of myrrh treatment.Microarray analysis with circulating mRNA was performed to identify differential gene expression profile,gene ontology and pathway enrichment analyses were carried out to predict the gene function.Gene co-expression and pathway networks were constructed to identify the potential targets.The markers of oxidative stress,inflammatory reaction and ferroptosis in the cerebral cortex were detected by ELISA assays.The identified hub pathways and genes were validated by western blotting,immunofluorescence and immunohistochemistry analyses.Neurons were exposed to transient oxygen-glucose deprivation(OGD)to model ischemia-like conditions.siRNA-TXNIP were transfected in OGD-induced neurons to explore the mechanism.RESULTS Myrrh extract significantly alleviated neurological deficits,infarct volume and histo⁃pathological damage in MCAO rats.A total of 2200 differentially expressed genes were identified among the three groups.Oxidation-reduction process,inflammatory response,ferroptosis were enriched as the significant gene ontology items.NOD-like receptor signaling were identified as the hub pathway based on the pathway relation network.TXNIP and NLRP3 were screened as the potential targets by a time sequence profile analysis.The levels of IL-1β,IL-18,TNF-α,MDA and TFR in brain tissues were increased while the CAT,SOD,GSH-px and GPX4 levels were significantly decreased in MCAO group.As expected,myrrh extract greatly reversed these changes.The similarly results were also observed in OGD treated neuron cells.The elevated expressions of TXNIP and NLRP3 induced by OGD were success⁃fully inhibited by myrrh treatment.Knockdown of TXNIP significantly alleviated OGD-induced ROS accumulation and oxidative stress,buOBJECTIVE To investigate the neuroprotective effects and exact mechanisms of myrrh extract following cerebral ischemic stroke. METHODS Male rats were randomly divided into three groups: sham group, middle cerebral artery occlusion（MCAO） group and myrrh group. Morphological changes were assessed after 7 d of myrrh treatment.Microarray analysis with circulating mRNA was performed to identify differential gene expression profile, gene ontology and pathway enrichment analyses were carried out to predict the gene function. Gene co-expression and pathway networks were constructed to identify the potential targets. The markers of oxidative stress, inflammatory reaction and ferroptosis in the cerebral cortex were detected by ELISA assays. The identified hub pathways and genes were validated by western blotting, immunofluorescence and immunohistochemistry analyses. Neurons were exposed to transient oxygen-glucose deprivation（OGD） to model ischemia-like conditions. si RNA-TXNIP were transfected in OGD-induced neurons to explore the mechanism. RESULTS Myrrh extract significantly alleviated neurological deficits, infarct volume and histopathological damage in MCAO rats. A total of 2200 differentially expressed genes were identified among the three groups. Oxidation-reduction process, inflammatory response, ferroptosis were enriched as the significant gene ontology items. NOD-like receptor signaling were identified as the hub pathway based on the pathway relation network. TXNIP and NLRP3 were screened as the potential targets by a time sequence profile analysis. The levels of IL-1β, IL-18, TNF-α,MDA and TFR in brain tissues were increased while the CAT, SOD, GSH-px and GPX4 levels were significantly decreased in MCAO group. As expected, myrrh extract greatly reversed these changes. The similarly results were also observed in OGD treated neuron cells. The elevated expressions of TXNIP and NLRP3 induced by OGD were successfully inhibited by myrrh treatment. Knockdown of TXNIP significantly alleviated OGD-induced ROS a

关 键 词：myrrh extract ischemic stroke ferroptosis NLRP3 inflammasome thioredoxin-interacting protein reac⁃tive oxygen species 

分 类 号：R74[医药卫生—神经病学与精神病学]