OBJECTIVE To investigate the neuroprotective effect and possible mechanisms of lute.olin-7-O-β-D-glucuronide(LGU) against focalcerebral ischemic injury.METHODS The focal cerebral ischemic injury model was established...OBJECTIVE To investigate the neuroprotective effect and possible mechanisms of lute.olin-7-O-β-D-glucuronide(LGU) against focalcerebral ischemic injury.METHODS The focal cerebral ischemic injury model was established by middle cerebral artery occlusion(MCAO).Male Sprague Dawley rats were randomly divided into sham group,model group(MCAO),LGU group(0.24,0.72 and2.16 mg·kg^(-1)) and positive control group(Edaravone at 5 mg·kg^(-1)).LGU was injected intravenously 30 min after MCAO.Neurological severity score,infarct volume and brain water content were detected 24 h after MCAO and the levels of Na+-K+ ATPase,Ca2 + ATPase,TNF-α and IL-1β were detected to explore the possible mechanisms.For the therapeutic time window test,LGU(0.72 mg·kg^(-1)) was injected intrave.nously 0.5,2,4,6,8,10 and 12 h respectively after MCAO.To evaluate motion behavior,LGU were injected intravenously 30 min after MCAO and once per day during detection period.The changes of motor coordination were detected by rotating rod method and grip strength analysis,and the changes of gaits were detected using DigiGait Imaging System.RESULTS LGU improved the neurological severity score,infarct volume ratio and brain water content.The therapeutic time window of LGU for cerebral infarction and brain edema was at least 6 h and for neurological dysfunction was 12 h.LGU also prolonged the latency on rotarod,increased the forelimb tension and improved 8 gait parameters,including stance duration,stride length,stance width,paw area,paw area variability,gait symmetry,ataxia coefficient and tau propulsion.Furthermore,LGU increased Na^+-K^+-ATPase and Ca^(2+)-ATPase levels in the cortex and hippocampus in the ischemic side,reduced the levels of TNF-α and IL-1β in the serum.CONCLUSION LGU has a significant neuroprotective effect against cerebral ischemic injury via improving energy metabolism and reducing inflammation.展开更多
OBJECTIVE E-cadherin is a major component of tubular adherent proteins which maintain intercellular contacts and cell polarity in epithelial tissue,it is involved in the pathological process of renal cell carcinoma an...OBJECTIVE E-cadherin is a major component of tubular adherent proteins which maintain intercellular contacts and cell polarity in epithelial tissue,it is involved in the pathological process of renal cell carcinoma and fibrotic diseases via epithelial-mesenchymal transition.Although we and others found that expression of E-cadherin was significantly down-regulated in kidney suffered acute kidney injury(AKI),its function in AKI was still unknown,which was explored in the current study.METHODS We disrupted E-cadherin or restored E-cadherin with compound 8J in cisplatin-stimulated tubular epithelial cell lines,the cell damage and inflammation were evaluated,additionally,the therapeutic potential of E-cadherin restoration was also determined in vivo.RESULTS We found that cisplatin reduced E-cadherin expression both in mouse kidney and tubular epithelial cell lines(m TECs).Administration of compound 8J restored the level of E-cadherin,thereby increased cell viability while attenuating programmed cell death,which may be mediated by deactivation of RIPK/MLKL axis,reduced membrane translocation of phosphor-MLKL and decreased cleavage of caspase 3.Compound 8J also suppressed inflammatory response in cisplatin-treated m TECs,which was correlated with suppressed NF-κB phorsphorylation and promoter activity.In contrast,disruption of E-cadherin enhanced cell damage and inflammation.Treatment of compound 8J failed to further attenuate kidney damage in E-cadherin knockdown cells,indicating compound 8J protected against mT ECs mainly through restoring E-cadherin.We also found that peritoneal injection of compound 8J protected against renal function and tubular damage by preventing NF-κB-driven renal inflammation and RIPK/MLKL-regulated programmed cell death,which was led by restoration of E-cadherin in cisplatin nephropathy.CONCLUSION More than a victim degraded after kidney injury,E-cadherin also has functional role in controlling tubule integrity,programmed cel death and renal inflammation.In this regard,restoration of E-cadherin by compound 8J should be considered as a novel therapeutic strategy for acute kidney injury.展开更多
基金supported by Young and Middle-aged Teacher Career Development Support Plan of Shenyang Pharmaceutical University(ZQN2016002) and Science and Technology Funds from Department of Education of Liaoning province(2016101633L3)
文摘OBJECTIVE To investigate the neuroprotective effect and possible mechanisms of lute.olin-7-O-β-D-glucuronide(LGU) against focalcerebral ischemic injury.METHODS The focal cerebral ischemic injury model was established by middle cerebral artery occlusion(MCAO).Male Sprague Dawley rats were randomly divided into sham group,model group(MCAO),LGU group(0.24,0.72 and2.16 mg·kg^(-1)) and positive control group(Edaravone at 5 mg·kg^(-1)).LGU was injected intravenously 30 min after MCAO.Neurological severity score,infarct volume and brain water content were detected 24 h after MCAO and the levels of Na+-K+ ATPase,Ca2 + ATPase,TNF-α and IL-1β were detected to explore the possible mechanisms.For the therapeutic time window test,LGU(0.72 mg·kg^(-1)) was injected intrave.nously 0.5,2,4,6,8,10 and 12 h respectively after MCAO.To evaluate motion behavior,LGU were injected intravenously 30 min after MCAO and once per day during detection period.The changes of motor coordination were detected by rotating rod method and grip strength analysis,and the changes of gaits were detected using DigiGait Imaging System.RESULTS LGU improved the neurological severity score,infarct volume ratio and brain water content.The therapeutic time window of LGU for cerebral infarction and brain edema was at least 6 h and for neurological dysfunction was 12 h.LGU also prolonged the latency on rotarod,increased the forelimb tension and improved 8 gait parameters,including stance duration,stride length,stance width,paw area,paw area variability,gait symmetry,ataxia coefficient and tau propulsion.Furthermore,LGU increased Na^+-K^+-ATPase and Ca^(2+)-ATPase levels in the cortex and hippocampus in the ischemic side,reduced the levels of TNF-α and IL-1β in the serum.CONCLUSION LGU has a significant neuroprotective effect against cerebral ischemic injury via improving energy metabolism and reducing inflammation.
基金supported by National Natural Science Foundation of China(81570623)Science and Technological Fund of Anhui Province for Outstanding Youth of China(1608085J07)
文摘OBJECTIVE E-cadherin is a major component of tubular adherent proteins which maintain intercellular contacts and cell polarity in epithelial tissue,it is involved in the pathological process of renal cell carcinoma and fibrotic diseases via epithelial-mesenchymal transition.Although we and others found that expression of E-cadherin was significantly down-regulated in kidney suffered acute kidney injury(AKI),its function in AKI was still unknown,which was explored in the current study.METHODS We disrupted E-cadherin or restored E-cadherin with compound 8J in cisplatin-stimulated tubular epithelial cell lines,the cell damage and inflammation were evaluated,additionally,the therapeutic potential of E-cadherin restoration was also determined in vivo.RESULTS We found that cisplatin reduced E-cadherin expression both in mouse kidney and tubular epithelial cell lines(m TECs).Administration of compound 8J restored the level of E-cadherin,thereby increased cell viability while attenuating programmed cell death,which may be mediated by deactivation of RIPK/MLKL axis,reduced membrane translocation of phosphor-MLKL and decreased cleavage of caspase 3.Compound 8J also suppressed inflammatory response in cisplatin-treated m TECs,which was correlated with suppressed NF-κB phorsphorylation and promoter activity.In contrast,disruption of E-cadherin enhanced cell damage and inflammation.Treatment of compound 8J failed to further attenuate kidney damage in E-cadherin knockdown cells,indicating compound 8J protected against mT ECs mainly through restoring E-cadherin.We also found that peritoneal injection of compound 8J protected against renal function and tubular damage by preventing NF-κB-driven renal inflammation and RIPK/MLKL-regulated programmed cell death,which was led by restoration of E-cadherin in cisplatin nephropathy.CONCLUSION More than a victim degraded after kidney injury,E-cadherin also has functional role in controlling tubule integrity,programmed cel death and renal inflammation.In this regard,restoration of E-cadherin by compound 8J should be considered as a novel therapeutic strategy for acute kidney injury.
