Ginkgo biloba L.leaf(GBL)has been reported to protect against ischemic stroke(IS),one of the leading causes of death and longterm disability worldwide,while there is a lack of systematic study on the exact mechanism.H...Ginkgo biloba L.leaf(GBL)has been reported to protect against ischemic stroke(IS),one of the leading causes of death and longterm disability worldwide,while there is a lack of systematic study on the exact mechanism.Here,network pharmacology and bioinformatics were used to predict the active components,important targets,and potential mechanisms of GBL in the treatment of IS.Active compounds of GBL were screened based on drug-like index and oral bioavailability,key target genes were screened based on network pharmacology and gene chip,downstream pathways for the regulation of key target genes were predicted based on gene set enrichment analysis,and the interaction between key targets and active compounds was verified based on molecular docking.The results showed that GBL played a protective role in cerebral ischemia with mainly 14 active compounds,such as isoquercitrin,luteolin-4’-glucoside,beta-sitosterol,campesterol,diosmetin,ginkgolide B,ginkgolide C,ginkgolide J,ginkgolide M,isogoycyrol,laricitrin,luteolin,sesamin,and stigmasterol.Further studies revealed that GBL played important role in immunomodulation and inflammation inhibition after cerebral ischemia by acting on its peripheral targets ARG1 and MMP9 to regulate Toll-like receptor,Chemokine and Notch signaling pathway.Meanwhile,GBL played important role in reducing neuroinflammation and blood-brain barrier damage after cerebral ischemia by acting on its central targets,CCL2,PTGS2,IL6,IL1B and MMP9 to regulate the Cytokine-cytokine receptor interaction,Jak-STAT,and Toll-like receptor signaling pathway.Additionally,molecular docking verified that the active compounds mentioned above could bind to ARG1,MMP9,CCL2,PTGS2,IL6,and IL1B.The present study shows the multicomponent,multitarget and multichannel pharmacological effects of GBL on cerebral ischemia and provides a new strategy for the treatment of IS.展开更多
AIM: To determine the role of leukocyte functionassociated antigen-1(LFA-1) in polymicrobial sepsis model in mice.METHODS: Cecal ligation and puncture model was used to study polymicrobial sepsis in wild type and LFA-...AIM: To determine the role of leukocyte functionassociated antigen-1(LFA-1) in polymicrobial sepsis model in mice.METHODS: Cecal ligation and puncture model was used to study polymicrobial sepsis in wild type and LFA-1 knockout(KO)(= CD11 a KO) mice. Their survivals were examined. Neutrophil recruitment to the abdominal cavity, bacterial tissue load and bacterial killing by neutrophils, tissue cytokine profiles, and serum cytokines were examined. Apoptosis of tissues was assessed using cleaved-caspase 3 and TUNNEL staining. The recruitment of neutrophils to various tissues was assessed using myeloperoxidase staining or measuring myeloperoxidase activity. RESULTS: LFA-1 deficiency significantly decreased survival(P = 0.0024) with the reduction of neutrophil recruitment to the abdominal cavity and higher bacterial load in blood. It was also associated with increased apoptosis in spleen and more organ injuries probed by interleukin-6 m RNA level. However, the deficiency of LFA-1 did not prevent neutrophil recruitment to lung, liver, spleen or kidney, which suggested the existence of LFA-1 independent recruitment mechanism in these organs. CONCLUSION: LFA-1 deficiency did not attenuate neutrophil recruitment to various organs to adequately mitigate secondary tissue injury in sepsis. It was associated with decreased neutrophil recruitment to the abdominal cavity, higher bacterial load, leading to increased mortality in an abdominal, polymicrobial sepsis.展开更多
Resistance multi-spot welding (MSW) in column, triangle and tetragonal symmetry arrangements was prepared using cold-rolled 301L high-strength sheets, and their static and fatigue properties were in- vestigated. The...Resistance multi-spot welding (MSW) in column, triangle and tetragonal symmetry arrangements was prepared using cold-rolled 301L high-strength sheets, and their static and fatigue properties were in- vestigated. The effects of spot welds on the fracture strengths and fatigue limits were discussed. The results show that the static strengths can be estimated using an inherent linear relationship formula of the load versus the welding area. It was based on the 28%-33% volume fraction of α′ martensite induced at the interfacial spot weld fracture because of the failure deformation. The fatigue limits of the MSW nonlin- early increase with the number of spot welds. The arrangement of spot welds in the MSW significantly affects the average fatigue limit of each spot weld; its 26% maximum reduction occurred in the triangle, and the interaction stress between spot welds led to its 18% reduction in the tetragonal symmetry. The calculated fatigue stress of all MSW loadings with their mean fatigue limits was 230-270 MPa.展开更多
基金supported by the National Natural Science Foundation of China(82074056).
文摘Ginkgo biloba L.leaf(GBL)has been reported to protect against ischemic stroke(IS),one of the leading causes of death and longterm disability worldwide,while there is a lack of systematic study on the exact mechanism.Here,network pharmacology and bioinformatics were used to predict the active components,important targets,and potential mechanisms of GBL in the treatment of IS.Active compounds of GBL were screened based on drug-like index and oral bioavailability,key target genes were screened based on network pharmacology and gene chip,downstream pathways for the regulation of key target genes were predicted based on gene set enrichment analysis,and the interaction between key targets and active compounds was verified based on molecular docking.The results showed that GBL played a protective role in cerebral ischemia with mainly 14 active compounds,such as isoquercitrin,luteolin-4’-glucoside,beta-sitosterol,campesterol,diosmetin,ginkgolide B,ginkgolide C,ginkgolide J,ginkgolide M,isogoycyrol,laricitrin,luteolin,sesamin,and stigmasterol.Further studies revealed that GBL played important role in immunomodulation and inflammation inhibition after cerebral ischemia by acting on its peripheral targets ARG1 and MMP9 to regulate Toll-like receptor,Chemokine and Notch signaling pathway.Meanwhile,GBL played important role in reducing neuroinflammation and blood-brain barrier damage after cerebral ischemia by acting on its central targets,CCL2,PTGS2,IL6,IL1B and MMP9 to regulate the Cytokine-cytokine receptor interaction,Jak-STAT,and Toll-like receptor signaling pathway.Additionally,molecular docking verified that the active compounds mentioned above could bind to ARG1,MMP9,CCL2,PTGS2,IL6,and IL1B.The present study shows the multicomponent,multitarget and multichannel pharmacological effects of GBL on cerebral ischemia and provides a new strategy for the treatment of IS.
基金Supported by CHMC Anesthesia Foundation(Soriano SG and Yuki K)William F.Milton Fund(Yuki K)BCH Endowed Chair in Pediatric Neuroanesthesia(Soriano SG)
文摘AIM: To determine the role of leukocyte functionassociated antigen-1(LFA-1) in polymicrobial sepsis model in mice.METHODS: Cecal ligation and puncture model was used to study polymicrobial sepsis in wild type and LFA-1 knockout(KO)(= CD11 a KO) mice. Their survivals were examined. Neutrophil recruitment to the abdominal cavity, bacterial tissue load and bacterial killing by neutrophils, tissue cytokine profiles, and serum cytokines were examined. Apoptosis of tissues was assessed using cleaved-caspase 3 and TUNNEL staining. The recruitment of neutrophils to various tissues was assessed using myeloperoxidase staining or measuring myeloperoxidase activity. RESULTS: LFA-1 deficiency significantly decreased survival(P = 0.0024) with the reduction of neutrophil recruitment to the abdominal cavity and higher bacterial load in blood. It was also associated with increased apoptosis in spleen and more organ injuries probed by interleukin-6 m RNA level. However, the deficiency of LFA-1 did not prevent neutrophil recruitment to lung, liver, spleen or kidney, which suggested the existence of LFA-1 independent recruitment mechanism in these organs. CONCLUSION: LFA-1 deficiency did not attenuate neutrophil recruitment to various organs to adequately mitigate secondary tissue injury in sepsis. It was associated with decreased neutrophil recruitment to the abdominal cavity, higher bacterial load, leading to increased mortality in an abdominal, polymicrobial sepsis.
基金funded by the Scientific Research and Development Projects of China Railway Corporation(2011J105-B)
文摘Resistance multi-spot welding (MSW) in column, triangle and tetragonal symmetry arrangements was prepared using cold-rolled 301L high-strength sheets, and their static and fatigue properties were in- vestigated. The effects of spot welds on the fracture strengths and fatigue limits were discussed. The results show that the static strengths can be estimated using an inherent linear relationship formula of the load versus the welding area. It was based on the 28%-33% volume fraction of α′ martensite induced at the interfacial spot weld fracture because of the failure deformation. The fatigue limits of the MSW nonlin- early increase with the number of spot welds. The arrangement of spot welds in the MSW significantly affects the average fatigue limit of each spot weld; its 26% maximum reduction occurred in the triangle, and the interaction stress between spot welds led to its 18% reduction in the tetragonal symmetry. The calculated fatigue stress of all MSW loadings with their mean fatigue limits was 230-270 MPa.