Rho-associated coiled-coil-containing protein kinase(RoCK)belongs to the serine-threonine family,and RoCK is involved in a variety of biological processes including cell migration,adhesion,proliferation and differenti...Rho-associated coiled-coil-containing protein kinase(RoCK)belongs to the serine-threonine family,and RoCK is involved in a variety of biological processes including cell migration,adhesion,proliferation and differentiation through phosphorylation of different downstream substrates.The aberrant activation of ROCK is associated with the pathological conditions in different systems including various diseases,including cancer,neurological diseases,inflammation,cardiovascular diseases and glaucoma.Therefore,the ROCK inhibitors have potential applicability for treating the aforementioned diseases.Four small molecule ROCK inhibitors have been approved for clinical use:fasudil,ripasudil,netarsudil and belumosudil.In recent years,more small molecule ROCK inhibitors have been identified.This paper reviews the ROCK inhibitors reported in past seven years.We mainly focused on the summarization of the structure-activity relationships,inhibitory efficacy,pharmacological mechanisms and the relevant clinical studies of the reported ROCK inhibitors.Besides the small molecular inhibitors,the peptides and biological extracts which exhibit ROCK inhibitory effects are also included.We also provide suggestions for the future development of the potent ROCK inhibitors.展开更多
Y-27632为嘧啶衍生物,是一种近年来合成的特异性Rho相关螺旋卷曲蛋白激酶(Rho associated coiled-coil forming protein kinase,R O C K)抑制剂,能通过调控R O C K介导的多种生物效应从而抑制肝纤维化的形成.研究发现,转化生长因子β1(t...Y-27632为嘧啶衍生物,是一种近年来合成的特异性Rho相关螺旋卷曲蛋白激酶(Rho associated coiled-coil forming protein kinase,R O C K)抑制剂,能通过调控R O C K介导的多种生物效应从而抑制肝纤维化的形成.研究发现,转化生长因子β1(transforming growth factorβ1,TGF-β1)/结缔组织生长因子(connective tissue growth factor,CTGF)通路参与肝纤维化的形成,TGF-β1诱导其下游效应分子CTGF表达,促使细胞外基质生成增多,导致肝纤维化.Y-27632具有抑制TGF-β1和CTGF表达的作用,本文从ROCK抑制剂Y-27632对TGF-β1/CTGF通路的影响来阐述Y-27632的抗纤维化作用,借此更深入的了解Y-27632的作用靶点,为肝纤维化的靶向治疗提供理论依据.展开更多
目的:探讨RHO/ROCK信号通路在人精子抗冷冻损伤中的作用,为高效精液冷冻保护剂的研制提供理论依据。方法:选取健康精液25份,每份精液分为新鲜组、对照组与RHO通路抑制剂组(抑制剂组)。检测冷冻前后各组精液精子活力、精子存活率、精子...目的:探讨RHO/ROCK信号通路在人精子抗冷冻损伤中的作用,为高效精液冷冻保护剂的研制提供理论依据。方法:选取健康精液25份,每份精液分为新鲜组、对照组与RHO通路抑制剂组(抑制剂组)。检测冷冻前后各组精液精子活力、精子存活率、精子膜完整率、正常形态精子百分率、精子DNA碎片指数(DFI)、精子顶体酶活性及精子线粒体膜电位变化;免疫荧光染色检测RHOa/ROCK蛋白在精子中的表达。结果:抑制剂组精液冷冻复苏后精子活力[(57.50±6.83)%vs(51.20±7.70)%,P=0.002]、精子存活率[(60.24±5.53)%vs(52.87±5.07)%,P=0.001]、精子膜完整率[(67.10±4.43)%vs(59.78±5.56)%,P=0.001]、正常形态精子百分率[(7.46±1.28)%vs(4.83±1.11)%,P=0.001]、精子DFI[(18.87±4.07)%vs(27.64±6.64)%,P=0.001]、精子线粒体膜电位(63.11±2.97 vs 56.30±4.28,P=0.001)指标均明显优于对照组;抑制剂组冷冻后精子顶体酶活性与对照组差异无统计学意义(98.30±11.33 vs 97.65±9.31,P>0.05)。免疫荧光染色显示RHOa/ROCK蛋白在精子头、颈部广泛表达。结论:RHO/ROCK信号通路在精子冷冻损伤中具有一定作用,抑制其通路活性可明显提高精子抗冷冻损伤的能力。展开更多
基金supported by the National Natural Science Foundation of China(Nos.82073311 and 81973866)Natural Science Foundation of Sichuan Province(No.2022JDTD0025)Science and Technology Research Project of Sichuan Traditional Chinese Medicine Administration(No.2021ZD016).
文摘Rho-associated coiled-coil-containing protein kinase(RoCK)belongs to the serine-threonine family,and RoCK is involved in a variety of biological processes including cell migration,adhesion,proliferation and differentiation through phosphorylation of different downstream substrates.The aberrant activation of ROCK is associated with the pathological conditions in different systems including various diseases,including cancer,neurological diseases,inflammation,cardiovascular diseases and glaucoma.Therefore,the ROCK inhibitors have potential applicability for treating the aforementioned diseases.Four small molecule ROCK inhibitors have been approved for clinical use:fasudil,ripasudil,netarsudil and belumosudil.In recent years,more small molecule ROCK inhibitors have been identified.This paper reviews the ROCK inhibitors reported in past seven years.We mainly focused on the summarization of the structure-activity relationships,inhibitory efficacy,pharmacological mechanisms and the relevant clinical studies of the reported ROCK inhibitors.Besides the small molecular inhibitors,the peptides and biological extracts which exhibit ROCK inhibitory effects are also included.We also provide suggestions for the future development of the potent ROCK inhibitors.
文摘Y-27632为嘧啶衍生物,是一种近年来合成的特异性Rho相关螺旋卷曲蛋白激酶(Rho associated coiled-coil forming protein kinase,R O C K)抑制剂,能通过调控R O C K介导的多种生物效应从而抑制肝纤维化的形成.研究发现,转化生长因子β1(transforming growth factorβ1,TGF-β1)/结缔组织生长因子(connective tissue growth factor,CTGF)通路参与肝纤维化的形成,TGF-β1诱导其下游效应分子CTGF表达,促使细胞外基质生成增多,导致肝纤维化.Y-27632具有抑制TGF-β1和CTGF表达的作用,本文从ROCK抑制剂Y-27632对TGF-β1/CTGF通路的影响来阐述Y-27632的抗纤维化作用,借此更深入的了解Y-27632的作用靶点,为肝纤维化的靶向治疗提供理论依据.
文摘目的:探讨RHO/ROCK信号通路在人精子抗冷冻损伤中的作用,为高效精液冷冻保护剂的研制提供理论依据。方法:选取健康精液25份,每份精液分为新鲜组、对照组与RHO通路抑制剂组(抑制剂组)。检测冷冻前后各组精液精子活力、精子存活率、精子膜完整率、正常形态精子百分率、精子DNA碎片指数(DFI)、精子顶体酶活性及精子线粒体膜电位变化;免疫荧光染色检测RHOa/ROCK蛋白在精子中的表达。结果:抑制剂组精液冷冻复苏后精子活力[(57.50±6.83)%vs(51.20±7.70)%,P=0.002]、精子存活率[(60.24±5.53)%vs(52.87±5.07)%,P=0.001]、精子膜完整率[(67.10±4.43)%vs(59.78±5.56)%,P=0.001]、正常形态精子百分率[(7.46±1.28)%vs(4.83±1.11)%,P=0.001]、精子DFI[(18.87±4.07)%vs(27.64±6.64)%,P=0.001]、精子线粒体膜电位(63.11±2.97 vs 56.30±4.28,P=0.001)指标均明显优于对照组;抑制剂组冷冻后精子顶体酶活性与对照组差异无统计学意义(98.30±11.33 vs 97.65±9.31,P>0.05)。免疫荧光染色显示RHOa/ROCK蛋白在精子头、颈部广泛表达。结论:RHO/ROCK信号通路在精子冷冻损伤中具有一定作用,抑制其通路活性可明显提高精子抗冷冻损伤的能力。
