OBJECTIVE To investigate the role of chemokine-like factor 1(CKLF1),a novel C-C chemokine,on brain-blood barrier(BBB)integrity in rat focal cerebral ischemia and reperfusion model.METHODS Antibodies against CKLF1 was ...OBJECTIVE To investigate the role of chemokine-like factor 1(CKLF1),a novel C-C chemokine,on brain-blood barrier(BBB)integrity in rat focal cerebral ischemia and reperfusion model.METHODS Antibodies against CKLF1 was applied to the rightcerebral ventricle immediately after transient middle cerebral artery occlusion.Brain water content,Evans blue leakage and the expression of aquaporin-4(AQP-4),matrix metalloproteinase-9(MMP-9),zonula occludens-1(ZO-1)and occludin were measured.RESULTS After treatment with antiCKLF1 antibody,brain water content and Evans blue leakage in ipsilateral hemisphere were decreased in a dose-dependent manner at 24 h after reperfusion,but not changed in contralateral hemisphere.Anti-CKLF1 antibody reduced the expression of AQP-4 and MMP-9,and upregulated the expression of ZO-1 and Occludin.These results suggest that CKLF1 is involved in BBB disruption after reperfusion.CONCLUSION Inhibition of CKLF1 protects against cerebral ischemia by maintaining BBB integrity,possibly via inhibiting the expression of AQP-4 and MMP-9,and increasing the expression of tight junction protein.展开更多
To improve aqueous solubility and anti-ischemic activity of 3-n-butylphthalide(NBP),we designed and synthesized the ring-opened derivative of NBP-ferulic acid-glucose trihybrids(S1-S8).These hybrids inhibited adenosin...To improve aqueous solubility and anti-ischemic activity of 3-n-butylphthalide(NBP),we designed and synthesized the ring-opened derivative of NBP-ferulic acid-glucose trihybrids(S1-S8).These hybrids inhibited adenosine diphosphate(ADP)-or arachidonic acid(AA)-induced platelet aggregation,among them,S2 was 30-fold more water-soluble,and over 10-fold more potent in inhibition of platelet aggregation,as well as reduced ROS generation and protected primary neuronal cells from OGD/Rinduced damage,in comparison with NB P.Additionally,S2 was more active than its three moieties alone or in combination,suggesting that the activity of S2 may be attributed to the synergistic effects of these moieties.Importantly,in vivo studies indicated that S2 not only possessed good pharmacokinetic profile,but also improved NBP distribution in rodent brain,suggesting that the glucose moiety in S2 may be recognized by glucose transporter 1(GLUT1)on blood-brain barrier(BBB),promoting it to penetrate through BBB.Our findings suggest that S2 may be a promising candidate for the intervention of ischemic stroke,warranting further study.展开更多
基金The project supported by National Natural Science Foundation of China(81302760)the Chinese Postdoctoral Science Foundation Project(2013M542510)
文摘OBJECTIVE To investigate the role of chemokine-like factor 1(CKLF1),a novel C-C chemokine,on brain-blood barrier(BBB)integrity in rat focal cerebral ischemia and reperfusion model.METHODS Antibodies against CKLF1 was applied to the rightcerebral ventricle immediately after transient middle cerebral artery occlusion.Brain water content,Evans blue leakage and the expression of aquaporin-4(AQP-4),matrix metalloproteinase-9(MMP-9),zonula occludens-1(ZO-1)and occludin were measured.RESULTS After treatment with antiCKLF1 antibody,brain water content and Evans blue leakage in ipsilateral hemisphere were decreased in a dose-dependent manner at 24 h after reperfusion,but not changed in contralateral hemisphere.Anti-CKLF1 antibody reduced the expression of AQP-4 and MMP-9,and upregulated the expression of ZO-1 and Occludin.These results suggest that CKLF1 is involved in BBB disruption after reperfusion.CONCLUSION Inhibition of CKLF1 protects against cerebral ischemia by maintaining BBB integrity,possibly via inhibiting the expression of AQP-4 and MMP-9,and increasing the expression of tight junction protein.
基金the National Natural Science Foundation of China(Nos.81773573,81822041,21977116 and 81673305)National Science&Technology Major Project“Key New Drug Creation and Manufacturing Program”(No.2018ZX09711002006-013)+2 种基金the open project of State Key Laboratory of Natural Medicines(No.SKLNMZZCX201824)State Key Laboratory of Pathogenesis,Prevention and Treatment of High Incidence Diseases in Central Asia Fund(No.SKL-HIDCA-2018-1)Part of the work was supported by Postgraduate Research&Practice Innovation Program of Jiangsu Province(No.KYCX18_0795)。
文摘To improve aqueous solubility and anti-ischemic activity of 3-n-butylphthalide(NBP),we designed and synthesized the ring-opened derivative of NBP-ferulic acid-glucose trihybrids(S1-S8).These hybrids inhibited adenosine diphosphate(ADP)-or arachidonic acid(AA)-induced platelet aggregation,among them,S2 was 30-fold more water-soluble,and over 10-fold more potent in inhibition of platelet aggregation,as well as reduced ROS generation and protected primary neuronal cells from OGD/Rinduced damage,in comparison with NB P.Additionally,S2 was more active than its three moieties alone or in combination,suggesting that the activity of S2 may be attributed to the synergistic effects of these moieties.Importantly,in vivo studies indicated that S2 not only possessed good pharmacokinetic profile,but also improved NBP distribution in rodent brain,suggesting that the glucose moiety in S2 may be recognized by glucose transporter 1(GLUT1)on blood-brain barrier(BBB),promoting it to penetrate through BBB.Our findings suggest that S2 may be a promising candidate for the intervention of ischemic stroke,warranting further study.
