Neruoprotection is considered as one of important therapeutic approaches for ischemic stroke.Inflammation plays an important role in the pathogenesis of ischemic stroke,and the inhibition of inflammation in the ischem...Neruoprotection is considered as one of important therapeutic approaches for ischemic stroke.Inflammation plays an important role in the pathogenesis of ischemic stroke,and the inhibition of inflammation in the ischemic brain tissue may provide neuroprotective effect.In this study,we observed the influence of permanent middle cerebral artery occlussion（pMCAO） and transient MCAO（tMCAO） on NF-κB level and production of several inflammatory cytokines in injured hemisphere in mice,investigated the regulative effect of a new compound W026 B on these influences in the two MCAO models.In pMCAO model,10 μg/kg and 100 μg/kg of W026 B（i.v.） significantly reduced infarct volumes,100 μg/kg of W026 B significantly decreased neurologic deficit scores and brain water contents,and 10 μg/kg and 100 μg/kg of W026 B reduced Evans blue exudation from ischemic brain tissue.The level of NF-κB was elevated by 17.6 times in injured hemisphere,and the levels of TNF-α,IL-1β and IL-17 were elevated by 2.3 times,2.2 times and 3.8 times compared with the sham operation group,respectively,100 μg/kg of W026 B significantly reduced these inflammatory cytokines.In tMCAO model,the elevation of NF-κB,TNF-α,IL-1β and IL-17 was 2.3 times,1.4 times,1.5 times and 1.4 times compared with the sham operation group,respectively.Moreover,100 μg/kg of W026 B significantly decreased the levels of these inflammatory cytokines.In embolic MCAO mice model,W026 B alone significantly reduced infarct volumes,and combined application with tPA further reduced infarct volume.In conclusion,W026 B displayed significant protecive effect on three brain ischemia models.It could protect brain against injury induced by ischmia and ischemia-reperfusion through inhibiting the production of NF-κB,TNF-α,IL-1β and IL-17.These results suggest that W026 B has a value for further study.展开更多
W026B is a new compound that has a protective effect on cerebral ischemia reperfusion(I-R)injury in mice,while its specific mechanism is still unknown.In this study,proteomics was used to observe the effect of W026B o...W026B is a new compound that has a protective effect on cerebral ischemia reperfusion(I-R)injury in mice,while its specific mechanism is still unknown.In this study,proteomics was used to observe the effect of W026B on protein expression in brain I-R tissue,and to reveal its potential target.A total of 42 significantly altered proteins were identified in both brain I-R model and W026B treatment from 4852 proteins detected by proteomics,and most of these proteins were related to immunity and inflammation,metabolism,neuroprotection as well as cell proliferation and cell structure.Western blotting analysis showed that three out of five selected proteins showed consistent alteration with the proteomics.Regulator of G protein signaling 17(RGS17)was selected for further study,and its knockdown by siRNA RGS17 aggravated brain injury and abolished the protective effect of W026B.W026B could bind with RGS17(KD:6.04×10–6 mol/L).The knockdown of RGS17 aggravated Neuro-2 a cell damage induced by group I metabotropic glutamate receptors(mGluRs)agonist,and abolished the protective effect of W026B.In conclusion,W026B protected brain against I-R injury by affecting diverse proteins.RGS17 might be one of its targets and a potential therapeutic target of brain I-R injury.The upstream receptor of G protein,which was regulated by RGS17 and affected by W026B,might be group I m GluRs.This study provided useful evidence for the further R&D and the potential clinical application of W026B.展开更多
As a newly synthesized lignan derivative,W026B has been proved to be a neuroprotective agent,and it can significantly reduce cerebral infarct volume,improve behavioral scores and protect blood brain barrier in differe...As a newly synthesized lignan derivative,W026B has been proved to be a neuroprotective agent,and it can significantly reduce cerebral infarct volume,improve behavioral scores and protect blood brain barrier in different models.However,its exact mechanism is still unclear.In the present study,a protein named B55γ,one of candidate targets of W026 B screened by proteomic study,was investigated to explore its influence on the effect of W026B in t-MCAO mice.siRNA PPP2R2C was used to knockdown the expression of protein B55γin t-MCAO mice.The results showed that the knockdown of B55γsignificantly suppressed the neuroprotective effect of W026B.Further results showed that the knockdown of PPP2R2C,B55γgene,abolished the effect of W026B on reducing the level of NF-κB p65 in ischemic brain tissue,and knockdown of PPP2R2C also reversed the effect of W026B on decreasing the activity of caspase-3 in ischemic brain tissue.In conclusion,protein B55γmight be an important mediator of the protective effect of W026B.B55γactively participated in the brain protective effect of W026B by affecting the inflammatory response and apoptotic pathway during ischemia reperfusion.These results revealed a new mechanism underlying the neuroprotective effect of W026B.展开更多
基金National Natural Science Foundation of China(Grant No.81573333,81503060)
文摘Neruoprotection is considered as one of important therapeutic approaches for ischemic stroke.Inflammation plays an important role in the pathogenesis of ischemic stroke,and the inhibition of inflammation in the ischemic brain tissue may provide neuroprotective effect.In this study,we observed the influence of permanent middle cerebral artery occlussion（pMCAO） and transient MCAO（tMCAO） on NF-κB level and production of several inflammatory cytokines in injured hemisphere in mice,investigated the regulative effect of a new compound W026 B on these influences in the two MCAO models.In pMCAO model,10 μg/kg and 100 μg/kg of W026 B（i.v.） significantly reduced infarct volumes,100 μg/kg of W026 B significantly decreased neurologic deficit scores and brain water contents,and 10 μg/kg and 100 μg/kg of W026 B reduced Evans blue exudation from ischemic brain tissue.The level of NF-κB was elevated by 17.6 times in injured hemisphere,and the levels of TNF-α,IL-1β and IL-17 were elevated by 2.3 times,2.2 times and 3.8 times compared with the sham operation group,respectively,100 μg/kg of W026 B significantly reduced these inflammatory cytokines.In tMCAO model,the elevation of NF-κB,TNF-α,IL-1β and IL-17 was 2.3 times,1.4 times,1.5 times and 1.4 times compared with the sham operation group,respectively.Moreover,100 μg/kg of W026 B significantly decreased the levels of these inflammatory cytokines.In embolic MCAO mice model,W026 B alone significantly reduced infarct volumes,and combined application with tPA further reduced infarct volume.In conclusion,W026 B displayed significant protecive effect on three brain ischemia models.It could protect brain against injury induced by ischmia and ischemia-reperfusion through inhibiting the production of NF-κB,TNF-α,IL-1β and IL-17.These results suggest that W026 B has a value for further study.
基金National Natural Science Foundation of China(Grant No.81503060,81573333)
文摘W026B is a new compound that has a protective effect on cerebral ischemia reperfusion(I-R)injury in mice,while its specific mechanism is still unknown.In this study,proteomics was used to observe the effect of W026B on protein expression in brain I-R tissue,and to reveal its potential target.A total of 42 significantly altered proteins were identified in both brain I-R model and W026B treatment from 4852 proteins detected by proteomics,and most of these proteins were related to immunity and inflammation,metabolism,neuroprotection as well as cell proliferation and cell structure.Western blotting analysis showed that three out of five selected proteins showed consistent alteration with the proteomics.Regulator of G protein signaling 17(RGS17)was selected for further study,and its knockdown by siRNA RGS17 aggravated brain injury and abolished the protective effect of W026B.W026B could bind with RGS17(KD:6.04×10–6 mol/L).The knockdown of RGS17 aggravated Neuro-2 a cell damage induced by group I metabotropic glutamate receptors(mGluRs)agonist,and abolished the protective effect of W026B.In conclusion,W026B protected brain against I-R injury by affecting diverse proteins.RGS17 might be one of its targets and a potential therapeutic target of brain I-R injury.The upstream receptor of G protein,which was regulated by RGS17 and affected by W026B,might be group I m GluRs.This study provided useful evidence for the further R&D and the potential clinical application of W026B.
基金National Natural Science Foundation of China(Grant No.8150306081573333)。
文摘As a newly synthesized lignan derivative,W026B has been proved to be a neuroprotective agent,and it can significantly reduce cerebral infarct volume,improve behavioral scores and protect blood brain barrier in different models.However,its exact mechanism is still unclear.In the present study,a protein named B55γ,one of candidate targets of W026 B screened by proteomic study,was investigated to explore its influence on the effect of W026B in t-MCAO mice.siRNA PPP2R2C was used to knockdown the expression of protein B55γin t-MCAO mice.The results showed that the knockdown of B55γsignificantly suppressed the neuroprotective effect of W026B.Further results showed that the knockdown of PPP2R2C,B55γgene,abolished the effect of W026B on reducing the level of NF-κB p65 in ischemic brain tissue,and knockdown of PPP2R2C also reversed the effect of W026B on decreasing the activity of caspase-3 in ischemic brain tissue.In conclusion,protein B55γmight be an important mediator of the protective effect of W026B.B55γactively participated in the brain protective effect of W026B by affecting the inflammatory response and apoptotic pathway during ischemia reperfusion.These results revealed a new mechanism underlying the neuroprotective effect of W026B.
