目的观察盐酸法舒地尔注射液联合丁苯酞软胶囊治疗急性脑梗死14d的美国国立卫生研究院卒中量表(National Institute of Health Stroke Scale,NIHSS)评分改善及对血清基质金属蛋白酶2(matrix metalloproteinase-2,MMP-2)、基质金属蛋白酶...目的观察盐酸法舒地尔注射液联合丁苯酞软胶囊治疗急性脑梗死14d的美国国立卫生研究院卒中量表(National Institute of Health Stroke Scale,NIHSS)评分改善及对血清基质金属蛋白酶2(matrix metalloproteinase-2,MMP-2)、基质金属蛋白酶9(matrix metalloproteinase-9,MMP-9)表达水平的影响。方法将78例急性脑梗死患者随机分为观察组和对照组各39例。对照组采用常规对症治疗,观察组在对照组治疗基础上加用盐酸法舒地尔注射液静脉滴注和丁苯酞软胶囊口服,2组均连续治疗14d。分别于治疗前后采用NIHSS评分对2组进行神经功能测定,并对治疗前后MMP-2、MMP-9水平进行比较。结果经过14d的治疗,观察组总有效率优于对照组(P<0.05),2组NIHSS评分及血清MMP-2、MMP-9水平均较治疗前显著降低(P<0.05),但观察组降低幅度更大,治疗后观察组NIHSS评分及血清MMP-2、MMP-9水平均低于对照组,差异有统计学意义(P<0.05)。结论盐酸法舒地尔注射液联合丁苯酞软胶囊可降低急性脑梗死患者的NIHSS评分,显著下调血清中MMP-2、MMP-9的表达。其机制可能与抑制炎症反应、减轻卒中后继发性脑损伤有关。展开更多
Constraint-induced movement therapy after cerebral ischemia stimulates axonal growth by decreasing expression levels of Nogo-A,RhoA,and Rho-associated kinase(ROCK)in the ischemic boundary zone.However,it remains uncle...Constraint-induced movement therapy after cerebral ischemia stimulates axonal growth by decreasing expression levels of Nogo-A,RhoA,and Rho-associated kinase(ROCK)in the ischemic boundary zone.However,it remains unclear if there are any associations between the Nogo-A/RhoA/ROCK pathway and angiogenesis in adult rat brains in pathological processes such as ischemic stroke.In addition,it has not yet been reported whether constraint-induced movement therapy can promote angiogenesis in stroke in adult rats by overcoming Nogo-A/RhoA/ROCK signaling.Here,a stroke model was established by middle cerebral artery occlusion and reperfusion.Seven days after stroke,the following treatments were initiated and continued for 3 weeks:forced limb use in constraint-induced movement therapy rats(constraint-induced movement therapy group),intraperitoneal infusion of fasudil(a ROCK inhibitor)in fasudil rats(fasudil group),or lateral ventricular injection of NEP1-40(a specific antagonist of the Nogo-66 receptor)in NEP1-40 rats(NEP1-40 group).Immunohistochemistry and western blot assay results showed that,at 2 weeks after middle cerebral artery occlusion,expression levels of RhoA and ROCK were lower in the ischemic boundary zone in rats treated with NEP1-40 compared with rats treated with ischemia/reperfusion or constraint-induced movement therapy alone.However,at 4 weeks after middle cerebral artery occlusion,expression levels of RhoA and ROCK in the ischemic boundary zone were markedly decreased in the NEP1-40 and constraint-induced movement therapy groups,but there was no difference between these two groups.Compared with the ischemia/reperfusion group,modified neurological severity scores and foot fault scores were lower and time taken to locate the platform was shorter in the constraint-induced movement therapy and fasudil groups at 4 weeks after middle cerebral artery occlusion,especially in the constraint-induced movement therapy group.Immunofluorescent staining demonstrated that fasudil promoted an immune response of nerve-regene展开更多
Background RhoA/ Rho kinase （ROCK） pathway is involved in pulmonary arterial hypertension （PAH） and pulmonary artery smooth muscle cell （PASMC） proliferation. Inhibition of ROCK has been proposed as a treatment ...Background RhoA/ Rho kinase （ROCK） pathway is involved in pulmonary arterial hypertension （PAH） and pulmonary artery smooth muscle cell （PASMC） proliferation. Inhibition of ROCK has been proposed as a treatment for PAH. But the mechanism of RhoA/ROCK pathway and its downstream signaling in proliferation of human PASMCs is unclear. We investigated the effect of fasudil, a selective ROCK inhibitor, on platelet-derived growth factor （PDGF） induced human PASMC proliferation, and the possible association between RhoA/ROCK and extracellular signal-regulated kinase （ERK）,p27KiP1.Methods Human PASMCs were cultured with the stimulation of 10 ng/ml PDGF, and different concentrations of fasudil were added before the addition of mitogen. Cell viability and cell cycle were determined with MTT and flow cytometry respectively. ROCK activity, ERK activity and protein expression of proliferating cell nuclear angigen （PCNA） and p27Kip1 were measured by immunoblotting.Results By MTT assay, PDGF significantly increased the OD value that represented human PASMC proliferation, and pretreatment with fasudil significantly reversed this effect in a dose-dependent manner. After PDGF stimulation, the percentage of cells in S phase increased dramatically from 15.6% to 24.3%, while the percentage in G0/G1 phase was reduced from 80.6% to 59%. And pretreatment with fasudil reversed the cell cycle effect of PDGF significantly in a dose-dependent manner. PDGF markedly induced ROCK activity and ERK activity with a peak at 15 minutes, which were significantly inhibited by fasudil. In addition, fasudil significantly inhibited PDGF-induced PCNA expression and fasudil also upregulated p27Kip1 expression in human PASMCs, which decreased after PDGF stimulation.Conclusion RhoA/ROCK is vital for PDFG-induced human PASMC proliferation, and fasudil effectively inhibited PDGF-induced human PASMC proliferation by up-regulation of p27Kip1, which may be associated with inhibition of ERK activity.展开更多
目的分析无创通气联合法舒地尔应用于老年慢性肺源性心脏病（肺心病）合并呼吸衰竭患者的临床价值。方法选取2010年9月至2013年8月在四川大学华西医院呼吸内科进行住院治疗的老年慢性肺心病合并呼吸衰竭患者70例,依据随机数字表法分为...目的分析无创通气联合法舒地尔应用于老年慢性肺源性心脏病（肺心病）合并呼吸衰竭患者的临床价值。方法选取2010年9月至2013年8月在四川大学华西医院呼吸内科进行住院治疗的老年慢性肺心病合并呼吸衰竭患者70例,依据随机数字表法分为两组：联合治疗组（37例）采用无创通气联合法舒地尔治疗,无创通气呼吸频率为15次/min,氧浓度为30%~40%,呼吸压力调制为4 cm H2O（1 cm H2O=0.098 k Pa）,吸气压力调制为8 cm H2O,法舒地尔每12小时30 mg静脉滴注;无创机械通气组（33例）采用无创通气治疗,方法同联合治疗组。比较两组患者的呼吸频率、心率、肺动脉压、动脉血氧分压（Pa O2）、动脉血二氧化碳分压（Pa CO2）、动脉血氧饱和度（Sa O2）、血浆脑钠肽（BNP）和临床疗效。结果联合治疗组呼吸频率、心率和肺动脉压分别为（23±5）次/min、（93±8）次/min、（43±3）mm Hg（1 mm Hg=0.133 k Pa）,均显著低于无创机械通气组的（28±3）次/min、（99±8）次/min、（52±4）mm Hg（P〈0.05）;联合治疗组的Pa O2、Pa CO2和Sa O2分别为（78±7）mm Hg、（45±6）mm Hg、（91±6）%,无创机械通气组分别为（69±6）mm Hg、（55±8）mm Hg、（85±9）%,两组比较差异均有统计学意义（P〈0.05）;联合治疗组治疗后血浆BNP为（118±31）ng/L,显著低于无创机械通气组的（136±34）ng/L（P〈0.05）;联合治疗组的临床疗效优于无创机械通气组（P〈0.05）。结论无创通气联合法舒地尔能快速、有效地治疗老年慢性肺心病合并呼吸衰竭患者。展开更多
Background Hyperglycemia may accelerate liver fibrosis.Currently,there is no effective treatment for liver fibrosis induced by type 2 diabetes.The study aim was to investigate whether RhoA/Rho kinase （ROCK） pathway ...Background Hyperglycemia may accelerate liver fibrosis.Currently,there is no effective treatment for liver fibrosis induced by type 2 diabetes.The study aim was to investigate whether RhoA/Rho kinase （ROCK） pathway is involved in liver fibrosis in the rats with type 2 diabetes and define the protective effects of fasudil on livers.Methods A rat model of type 2 diabetes was established by high fat diet combined with streptozotocin （30 mg/kg,intraperitoneal injection）.Animals were randomly assigned to 3 groups：control rats,untreated diabetic rats that received vehicle and fasudil-treated diabetic rats that received ROCK inhibitor fasudil hydrochloride hydrate （10 mg/kg per day,intraperitoneal injection,for 14 weeks）.The morphological features of liver were observed by HE staining.Accumulation of collagen in livers was determined by Masson staining and the measurement of hydroxyproline.The mRNA expression of transforming growth factor-β1 （TGFβ1）,connective tissue growth factor （CTGF）,type-Ⅰ,and type-Ⅲ procollagen was assessed with real-time polymerase chain reaction.The phosphorylation of myosin phosphatase target subunit-1 （MYPT1）and the protein levels of TGFβ1 and α-smooth muscle actin （α-SMA） were evaluated by Western blotting.Results Compared with control rats,untreated diabetic rats showed higher values of collagen and hydroxyproline in livers （P ＜0.01）,the phosphorylation of MYPT1 and the protein levels of TGFβ1 and α-SMA were increased （P ＜0.01）,and the mRNA expression of TGFβ1,CTGF,type-Ⅰ,and type-Ⅲ procollagen was upregulated （P ＜0.01）; compared with untreated diabetic rats,treatment with fasudil signifcantly reduced values of collagen and hydroxyproline （P ＜0.01）,and decreased the phosphorylation of MYPT1 and the levels of TGFβ1 and α-SMA （P ＜0.01）,concomitant with the downregulation of TGFβ1/CTGF,type-Ⅰ,and type-Ⅲ procollagen mRNA expression （P ＜0.01）.Conclusions Fasudil ameliorates liver fibrosis in rats with type 2 展开更多
文摘目的观察盐酸法舒地尔注射液联合丁苯酞软胶囊治疗急性脑梗死14d的美国国立卫生研究院卒中量表(National Institute of Health Stroke Scale,NIHSS)评分改善及对血清基质金属蛋白酶2(matrix metalloproteinase-2,MMP-2)、基质金属蛋白酶9(matrix metalloproteinase-9,MMP-9)表达水平的影响。方法将78例急性脑梗死患者随机分为观察组和对照组各39例。对照组采用常规对症治疗,观察组在对照组治疗基础上加用盐酸法舒地尔注射液静脉滴注和丁苯酞软胶囊口服,2组均连续治疗14d。分别于治疗前后采用NIHSS评分对2组进行神经功能测定,并对治疗前后MMP-2、MMP-9水平进行比较。结果经过14d的治疗,观察组总有效率优于对照组(P<0.05),2组NIHSS评分及血清MMP-2、MMP-9水平均较治疗前显著降低(P<0.05),但观察组降低幅度更大,治疗后观察组NIHSS评分及血清MMP-2、MMP-9水平均低于对照组,差异有统计学意义(P<0.05)。结论盐酸法舒地尔注射液联合丁苯酞软胶囊可降低急性脑梗死患者的NIHSS评分,显著下调血清中MMP-2、MMP-9的表达。其机制可能与抑制炎症反应、减轻卒中后继发性脑损伤有关。
基金supported by the National Natural Science Foundation of China(General Program),No.81771271(to JF)
文摘Constraint-induced movement therapy after cerebral ischemia stimulates axonal growth by decreasing expression levels of Nogo-A,RhoA,and Rho-associated kinase(ROCK)in the ischemic boundary zone.However,it remains unclear if there are any associations between the Nogo-A/RhoA/ROCK pathway and angiogenesis in adult rat brains in pathological processes such as ischemic stroke.In addition,it has not yet been reported whether constraint-induced movement therapy can promote angiogenesis in stroke in adult rats by overcoming Nogo-A/RhoA/ROCK signaling.Here,a stroke model was established by middle cerebral artery occlusion and reperfusion.Seven days after stroke,the following treatments were initiated and continued for 3 weeks:forced limb use in constraint-induced movement therapy rats(constraint-induced movement therapy group),intraperitoneal infusion of fasudil(a ROCK inhibitor)in fasudil rats(fasudil group),or lateral ventricular injection of NEP1-40(a specific antagonist of the Nogo-66 receptor)in NEP1-40 rats(NEP1-40 group).Immunohistochemistry and western blot assay results showed that,at 2 weeks after middle cerebral artery occlusion,expression levels of RhoA and ROCK were lower in the ischemic boundary zone in rats treated with NEP1-40 compared with rats treated with ischemia/reperfusion or constraint-induced movement therapy alone.However,at 4 weeks after middle cerebral artery occlusion,expression levels of RhoA and ROCK in the ischemic boundary zone were markedly decreased in the NEP1-40 and constraint-induced movement therapy groups,but there was no difference between these two groups.Compared with the ischemia/reperfusion group,modified neurological severity scores and foot fault scores were lower and time taken to locate the platform was shorter in the constraint-induced movement therapy and fasudil groups at 4 weeks after middle cerebral artery occlusion,especially in the constraint-induced movement therapy group.Immunofluorescent staining demonstrated that fasudil promoted an immune response of nerve-regene
基金This study was supported by grants from the National Natural Science Foundation of China （No. 30972958）, Beijing Natural Science Foundation （No. 7112046）, Beijing Municipal Education Commission （No. PXM2011_014226 07 000060）.
文摘Background RhoA/ Rho kinase （ROCK） pathway is involved in pulmonary arterial hypertension （PAH） and pulmonary artery smooth muscle cell （PASMC） proliferation. Inhibition of ROCK has been proposed as a treatment for PAH. But the mechanism of RhoA/ROCK pathway and its downstream signaling in proliferation of human PASMCs is unclear. We investigated the effect of fasudil, a selective ROCK inhibitor, on platelet-derived growth factor （PDGF） induced human PASMC proliferation, and the possible association between RhoA/ROCK and extracellular signal-regulated kinase （ERK）,p27KiP1.Methods Human PASMCs were cultured with the stimulation of 10 ng/ml PDGF, and different concentrations of fasudil were added before the addition of mitogen. Cell viability and cell cycle were determined with MTT and flow cytometry respectively. ROCK activity, ERK activity and protein expression of proliferating cell nuclear angigen （PCNA） and p27Kip1 were measured by immunoblotting.Results By MTT assay, PDGF significantly increased the OD value that represented human PASMC proliferation, and pretreatment with fasudil significantly reversed this effect in a dose-dependent manner. After PDGF stimulation, the percentage of cells in S phase increased dramatically from 15.6% to 24.3%, while the percentage in G0/G1 phase was reduced from 80.6% to 59%. And pretreatment with fasudil reversed the cell cycle effect of PDGF significantly in a dose-dependent manner. PDGF markedly induced ROCK activity and ERK activity with a peak at 15 minutes, which were significantly inhibited by fasudil. In addition, fasudil significantly inhibited PDGF-induced PCNA expression and fasudil also upregulated p27Kip1 expression in human PASMCs, which decreased after PDGF stimulation.Conclusion RhoA/ROCK is vital for PDFG-induced human PASMC proliferation, and fasudil effectively inhibited PDGF-induced human PASMC proliferation by up-regulation of p27Kip1, which may be associated with inhibition of ERK activity.
文摘目的分析无创通气联合法舒地尔应用于老年慢性肺源性心脏病（肺心病）合并呼吸衰竭患者的临床价值。方法选取2010年9月至2013年8月在四川大学华西医院呼吸内科进行住院治疗的老年慢性肺心病合并呼吸衰竭患者70例,依据随机数字表法分为两组：联合治疗组（37例）采用无创通气联合法舒地尔治疗,无创通气呼吸频率为15次/min,氧浓度为30%~40%,呼吸压力调制为4 cm H2O（1 cm H2O=0.098 k Pa）,吸气压力调制为8 cm H2O,法舒地尔每12小时30 mg静脉滴注;无创机械通气组（33例）采用无创通气治疗,方法同联合治疗组。比较两组患者的呼吸频率、心率、肺动脉压、动脉血氧分压（Pa O2）、动脉血二氧化碳分压（Pa CO2）、动脉血氧饱和度（Sa O2）、血浆脑钠肽（BNP）和临床疗效。结果联合治疗组呼吸频率、心率和肺动脉压分别为（23±5）次/min、（93±8）次/min、（43±3）mm Hg（1 mm Hg=0.133 k Pa）,均显著低于无创机械通气组的（28±3）次/min、（99±8）次/min、（52±4）mm Hg（P〈0.05）;联合治疗组的Pa O2、Pa CO2和Sa O2分别为（78±7）mm Hg、（45±6）mm Hg、（91±6）%,无创机械通气组分别为（69±6）mm Hg、（55±8）mm Hg、（85±9）%,两组比较差异均有统计学意义（P〈0.05）;联合治疗组治疗后血浆BNP为（118±31）ng/L,显著低于无创机械通气组的（136±34）ng/L（P〈0.05）;联合治疗组的临床疗效优于无创机械通气组（P〈0.05）。结论无创通气联合法舒地尔能快速、有效地治疗老年慢性肺心病合并呼吸衰竭患者。
文摘Background Hyperglycemia may accelerate liver fibrosis.Currently,there is no effective treatment for liver fibrosis induced by type 2 diabetes.The study aim was to investigate whether RhoA/Rho kinase （ROCK） pathway is involved in liver fibrosis in the rats with type 2 diabetes and define the protective effects of fasudil on livers.Methods A rat model of type 2 diabetes was established by high fat diet combined with streptozotocin （30 mg/kg,intraperitoneal injection）.Animals were randomly assigned to 3 groups：control rats,untreated diabetic rats that received vehicle and fasudil-treated diabetic rats that received ROCK inhibitor fasudil hydrochloride hydrate （10 mg/kg per day,intraperitoneal injection,for 14 weeks）.The morphological features of liver were observed by HE staining.Accumulation of collagen in livers was determined by Masson staining and the measurement of hydroxyproline.The mRNA expression of transforming growth factor-β1 （TGFβ1）,connective tissue growth factor （CTGF）,type-Ⅰ,and type-Ⅲ procollagen was assessed with real-time polymerase chain reaction.The phosphorylation of myosin phosphatase target subunit-1 （MYPT1）and the protein levels of TGFβ1 and α-smooth muscle actin （α-SMA） were evaluated by Western blotting.Results Compared with control rats,untreated diabetic rats showed higher values of collagen and hydroxyproline in livers （P ＜0.01）,the phosphorylation of MYPT1 and the protein levels of TGFβ1 and α-SMA were increased （P ＜0.01）,and the mRNA expression of TGFβ1,CTGF,type-Ⅰ,and type-Ⅲ procollagen was upregulated （P ＜0.01）; compared with untreated diabetic rats,treatment with fasudil signifcantly reduced values of collagen and hydroxyproline （P ＜0.01）,and decreased the phosphorylation of MYPT1 and the levels of TGFβ1 and α-SMA （P ＜0.01）,concomitant with the downregulation of TGFβ1/CTGF,type-Ⅰ,and type-Ⅲ procollagen mRNA expression （P ＜0.01）.Conclusions Fasudil ameliorates liver fibrosis in rats with type 2
