OBJECTIVE To investigate the vasorelaxant effect of pinocembrin(5,7-dihydroxyflavanone),one of the main flavonoids in propolis,on angiotensinⅡ(AngⅡ)induced vasoconstriction and the molecular mechanism of action.METH...OBJECTIVE To investigate the vasorelaxant effect of pinocembrin(5,7-dihydroxyflavanone),one of the main flavonoids in propolis,on angiotensinⅡ(AngⅡ)induced vasoconstriction and the molecular mechanism of action.METHODS The isometric vascular tone was measured in thoracic aortic rings from SD rat,and the effects of pinocembrin on the single dose and concentration cumulative response curves of AngⅡ were recorded.The binding of pinocembrin to the angiotensin type 1 receptor(AT1R)was studied by using molecule docking analysis.Intracellular[Ca2+]([Ca2+]i)was measured with Fura2/AM in VSMCs.The phosphorylation levels of myosin light chain 2(MLC2)and myosin phosphatase target unit 1(MYPT1),and protein level of Rho kinase 1(ROCK1)in the rat aortic rings were detected by Western blotting.RESULTS Pinocembrin was observed to inhibit AngⅡ-induced vasoconstriction in rat aortic rings with either intact or denuded endothelium.In endothelium-denuded tissues,pinocembrin(pD′2 4.28±0.15)counteracted the contractions evoked by cumulative concentrations of AngⅡ.In a docking model,pinocembrin showed effective binding at the active site of AT1R.Pinocembrin was shown to inhibit both AngⅡ-induced Ca2+ release from internal stores and Ca2+ influx.Moreover,the increase in the phosphorylation of MLC2 and MYPT1,and the increased protein level of ROCK1 induced by AngⅡ was blocked by pinocembrin.CONCLUSION Pinocembrin inhibits AngⅡ-induced rat aortic ring contraction in a Ca2+-dependent and Ca2+-independent manner via blocking AT1R.展开更多
AIM： TO evaluate the safety and efficacy of chronic administration of Iosartan on hepatic fibrosis in chronic hepatitis C patients.METHODS： Fourteen patients with chronic hepatitis C non-responders （n = 10）, with ...AIM： TO evaluate the safety and efficacy of chronic administration of Iosartan on hepatic fibrosis in chronic hepatitis C patients.METHODS： Fourteen patients with chronic hepatitis C non-responders （n = 10）, with contraindications （n = 2） or lack of compliance （n = 2） to interferon plus ribavirin therapy and liver fibrosis were enrolled. Liver and renal function test, clinical evaluation, and liver biopsies were performed at baseline and after Iosartan administration at a dose of 50 mg/d during the 6 mo. The control group composed of nine patients with the same inclusion criteria and paired liver biopsies （interval 6-14 mo）. Histological activity index （HAI） with fibrosis stage was assessed under blind conditions by means of Ishak＇s score. Subendothelial fibrosis was evaluated by digital image analyses.RESULTS： The changes in the fibrosis stage were significantly different between Iosartan group （decrease of 0.5±1.3） and controls （increase of 0.89±1.27; P〈0.03）. In the treated patients, a decrease in fibrosis stage was observed in 7/14 patients vs 1/9 control patients （P〈0.04）. A decrease in sub-endothelial fibrosis was observed in the Iosartan group. No differences were found in HAI after Iosartan administration. Acute and chronic decreases in systolic arterial pressures （P〈0.05） were observed after the Iosartan administration, without changes in mean arterial pressure or renal function.CONCLUSION： Chronic AT-Ⅱ type 1 receptor （AT1R） blockade may reduce liver fibrosis in patients with chronic hepatitis C.展开更多
Background:Macrophages are involved in the pathogenesis of idiopathic pulmonary fibrosis,partially by activating lung fibroblasts.However,how macrophages communicate with lung fibroblasts is largely unexplored.Exosome...Background:Macrophages are involved in the pathogenesis of idiopathic pulmonary fibrosis,partially by activating lung fibroblasts.However,how macrophages communicate with lung fibroblasts is largely unexplored.Exosomes can mediate intercellular communication,whereas its role in lung fibrogenesis is unclear.Here we aim to investigate whether exosomes can mediate the crosstalk between macrophages and lung fibroblasts and subsequently induce fibrosis.Methods:In vivo,bleomycin(BLM)-induced lung fibrosis model was established and macrophages infiltration was examined.The effects of GW4869,an exosomes inhibitor,on lung fibrosis were assessed.Moreover,macrophage exosomes were injected into mice to observe its pro-fibrotic effects.In vitro,exosomes derived from angiotensin Ⅱ(Ang Ⅱ)-stimulated macrophages were collected.Then,lung fibroblasts were treated with the exosomes.Twenty-four hours later,protein levels ofα-collagen I,angiotensin Ⅱ type 1 receptor(AT1R),transforming growth factor-β(TGF-β),and phospho-Smad2/3(p-Smad2/3)in lung fibroblasts were examined.The Student's t test or analysis of variance were used for statistical analysis.Results:In vivo,BLM-treated mice showed enhanced infiltration of macrophages,increased fibrotic alterations,and higher levels of Ang Ⅱ and AT1R.GW4869 attenuated BLM-induced pulmonary fibrosis.Mice with exosomes injection showed fibrotic features with higher levels of Ang Ⅱ and AT1R,which was reversed by irbesartan.In vitro,we found that macrophages secreted a great number of exosomes.The exosomes were taken by fibroblasts and resulted in higher levels of AT1R(0.22±0.02 vs.0.07±0.02,t=8.66,P=0.001),TGF-β(0.54±0.05 vs.0.09±0.06,t=10.00,P<0.001),p-Smad2/3(0.58±0.06 vs.0.07±0.03,t=12.86,P<0.001)andα-collagen I(0.27±0.02 vs.0.16±0.01,t=7.01,P=0.002),and increased Ang Ⅱ secretion(62.27±7.32 vs.9.56±1.68,t=12.16,P<0.001).Interestingly,Ang Ⅱ increased the number of macrophage exosomes,and the protein levels of Alix(1.45±0.15 vs.1.00±0.10,t=4.32,P=0.012),AT1R(4.05±0.64 vs.1.00±0.09,t=8.17,P=0.001),and glyceraldehyde-3-phosphate dehydrogenase(2.13±0.36 vs.1.00±0.10,t=5.28,P=0.006)were increased in exosomes secreted by the same number of macrophages,indicating a positive loop between Ang Ⅱ and exosomes production.Conclusions:Exosomes mediate intercellular communication between macrophages and fibroblasts plays an important role in BLM-induced pulmonary fibrosis.展开更多
血管紧张素II(Angiotensin II,AngII)是一种重要的心血管活性物质,其受体亚型的作用及信号途径各有特点,不同受体经同一信号途径的作用意义也不同。丝裂原激活的蛋白激酶(Mitogen-activated protein kinase,MAPK)是广泛存在于哺乳动物...血管紧张素II(Angiotensin II,AngII)是一种重要的心血管活性物质,其受体亚型的作用及信号途径各有特点,不同受体经同一信号途径的作用意义也不同。丝裂原激活的蛋白激酶(Mitogen-activated protein kinase,MAPK)是广泛存在于哺乳动物体内的信号途径,在各种应激反应中可被激活。AngII经其不同受体激活MAPK信号途径在心血管系统中可发挥重要的病理生理作用。展开更多
基金The project supported by National Natural Science Foundation of China(81102444)the Major Scientific and Technological Special Project for"Significant New Drugs Creation"(2009ZX09302-003,2013ZX09508104)the Central Public Scientific Research Institution Fundamental Project(2014CX05)
文摘OBJECTIVE To investigate the vasorelaxant effect of pinocembrin(5,7-dihydroxyflavanone),one of the main flavonoids in propolis,on angiotensinⅡ(AngⅡ)induced vasoconstriction and the molecular mechanism of action.METHODS The isometric vascular tone was measured in thoracic aortic rings from SD rat,and the effects of pinocembrin on the single dose and concentration cumulative response curves of AngⅡ were recorded.The binding of pinocembrin to the angiotensin type 1 receptor(AT1R)was studied by using molecule docking analysis.Intracellular[Ca2+]([Ca2+]i)was measured with Fura2/AM in VSMCs.The phosphorylation levels of myosin light chain 2(MLC2)and myosin phosphatase target unit 1(MYPT1),and protein level of Rho kinase 1(ROCK1)in the rat aortic rings were detected by Western blotting.RESULTS Pinocembrin was observed to inhibit AngⅡ-induced vasoconstriction in rat aortic rings with either intact or denuded endothelium.In endothelium-denuded tissues,pinocembrin(pD′2 4.28±0.15)counteracted the contractions evoked by cumulative concentrations of AngⅡ.In a docking model,pinocembrin showed effective binding at the active site of AT1R.Pinocembrin was shown to inhibit both AngⅡ-induced Ca2+ release from internal stores and Ca2+ influx.Moreover,the increase in the phosphorylation of MLC2 and MYPT1,and the increased protein level of ROCK1 induced by AngⅡ was blocked by pinocembrin.CONCLUSION Pinocembrin inhibits AngⅡ-induced rat aortic ring contraction in a Ca2+-dependent and Ca2+-independent manner via blocking AT1R.
文摘AIM： TO evaluate the safety and efficacy of chronic administration of Iosartan on hepatic fibrosis in chronic hepatitis C patients.METHODS： Fourteen patients with chronic hepatitis C non-responders （n = 10）, with contraindications （n = 2） or lack of compliance （n = 2） to interferon plus ribavirin therapy and liver fibrosis were enrolled. Liver and renal function test, clinical evaluation, and liver biopsies were performed at baseline and after Iosartan administration at a dose of 50 mg/d during the 6 mo. The control group composed of nine patients with the same inclusion criteria and paired liver biopsies （interval 6-14 mo）. Histological activity index （HAI） with fibrosis stage was assessed under blind conditions by means of Ishak＇s score. Subendothelial fibrosis was evaluated by digital image analyses.RESULTS： The changes in the fibrosis stage were significantly different between Iosartan group （decrease of 0.5±1.3） and controls （increase of 0.89±1.27; P〈0.03）. In the treated patients, a decrease in fibrosis stage was observed in 7/14 patients vs 1/9 control patients （P〈0.04）. A decrease in sub-endothelial fibrosis was observed in the Iosartan group. No differences were found in HAI after Iosartan administration. Acute and chronic decreases in systolic arterial pressures （P〈0.05） were observed after the Iosartan administration, without changes in mean arterial pressure or renal function.CONCLUSION： Chronic AT-Ⅱ type 1 receptor （AT1R） blockade may reduce liver fibrosis in patients with chronic hepatitis C.
基金supported by the Science and Technology Project in Guangzhou(No.201904010482)the National Natural Science Foundation of China(Nos.81570064,81870068,and 82070063).
文摘Background:Macrophages are involved in the pathogenesis of idiopathic pulmonary fibrosis,partially by activating lung fibroblasts.However,how macrophages communicate with lung fibroblasts is largely unexplored.Exosomes can mediate intercellular communication,whereas its role in lung fibrogenesis is unclear.Here we aim to investigate whether exosomes can mediate the crosstalk between macrophages and lung fibroblasts and subsequently induce fibrosis.Methods:In vivo,bleomycin(BLM)-induced lung fibrosis model was established and macrophages infiltration was examined.The effects of GW4869,an exosomes inhibitor,on lung fibrosis were assessed.Moreover,macrophage exosomes were injected into mice to observe its pro-fibrotic effects.In vitro,exosomes derived from angiotensin Ⅱ(Ang Ⅱ)-stimulated macrophages were collected.Then,lung fibroblasts were treated with the exosomes.Twenty-four hours later,protein levels ofα-collagen I,angiotensin Ⅱ type 1 receptor(AT1R),transforming growth factor-β(TGF-β),and phospho-Smad2/3(p-Smad2/3)in lung fibroblasts were examined.The Student's t test or analysis of variance were used for statistical analysis.Results:In vivo,BLM-treated mice showed enhanced infiltration of macrophages,increased fibrotic alterations,and higher levels of Ang Ⅱ and AT1R.GW4869 attenuated BLM-induced pulmonary fibrosis.Mice with exosomes injection showed fibrotic features with higher levels of Ang Ⅱ and AT1R,which was reversed by irbesartan.In vitro,we found that macrophages secreted a great number of exosomes.The exosomes were taken by fibroblasts and resulted in higher levels of AT1R(0.22±0.02 vs.0.07±0.02,t=8.66,P=0.001),TGF-β(0.54±0.05 vs.0.09±0.06,t=10.00,P<0.001),p-Smad2/3(0.58±0.06 vs.0.07±0.03,t=12.86,P<0.001)andα-collagen I(0.27±0.02 vs.0.16±0.01,t=7.01,P=0.002),and increased Ang Ⅱ secretion(62.27±7.32 vs.9.56±1.68,t=12.16,P<0.001).Interestingly,Ang Ⅱ increased the number of macrophage exosomes,and the protein levels of Alix(1.45±0.15 vs.1.00±0.10,t=4.32,P=0.012),AT1R(4.05±0.64 vs.1.00±0.09,t=8.17,P=0.001),and glyceraldehyde-3-phosphate dehydrogenase(2.13±0.36 vs.1.00±0.10,t=5.28,P=0.006)were increased in exosomes secreted by the same number of macrophages,indicating a positive loop between Ang Ⅱ and exosomes production.Conclusions:Exosomes mediate intercellular communication between macrophages and fibroblasts plays an important role in BLM-induced pulmonary fibrosis.
文摘血管紧张素II(Angiotensin II,AngII)是一种重要的心血管活性物质,其受体亚型的作用及信号途径各有特点,不同受体经同一信号途径的作用意义也不同。丝裂原激活的蛋白激酶(Mitogen-activated protein kinase,MAPK)是广泛存在于哺乳动物体内的信号途径,在各种应激反应中可被激活。AngII经其不同受体激活MAPK信号途径在心血管系统中可发挥重要的病理生理作用。
