Idiopathic pulmonary fibrosis（IPF） is characterized by progressive lung scarring, reduced median survival, poor prognosis and limited therapeutic options, leading to great need for new pharmacologic therapies. In re...Idiopathic pulmonary fibrosis（IPF） is characterized by progressive lung scarring, reduced median survival, poor prognosis and limited therapeutic options, leading to great need for new pharmacologic therapies. In recent years, researchers have found that Rho-ROCK signaling pathway may be a new drug target in the prevention of IPF. This article reviewed the role of Rho-ROCK pathway in pulmonary fibrosis and the application of ROCK inhibitors in experimental models of IPF. Multiple lines of evidence therefore indicated that ROCK inhibition has great potential to be a powerful therapeutic tool in the prevention and treatment of IPF in clinic.展开更多
Left ventricular non-compaction(LVNC),is a hereditary cardiomyopathy with limited treatments.Our previous study linked phosphodiesterase 4D interacting protein(PDE4DIP)to LVNC development.To explore the functional rol...Left ventricular non-compaction(LVNC),is a hereditary cardiomyopathy with limited treatments.Our previous study linked phosphodiesterase 4D interacting protein(PDE4DIP)to LVNC development.To explore the functional role of PDE4DIP activation in regulating cell polarity,skeleton,and energy metabolism,and to elucidate its mechanisms driving LVNC development,bioinformatics analysis was performed to compare its expression in LVNC patients and normal subjects.Overexpression and knockdown of PDE4DIP were constructed in H9C2 cells and neonatal Sprague–Dawley rat primary cardiomyocytes,respectively.Electron microscopy,MitoTracker-Green staining,and an ATP kit were employed to assess mitochondria's morphology and functional status.Real-time quantitative PCR,western blotting,and immunofluorescence assays were employed to detect the expression of cell polarity-,skeleton-,and Rho-ROCK signaling-related genes and proteins.Cell scratching and CCK-8 assays were employed to detect cell migration and proliferation abilities of H9C2,respectively.We found that PDE4DIP expression was increased in the LVNC-derived human-induced pluripotent stem cell-derived cardiomyocytes compared with normal subjects.Furthermore,overexpression of PDE4DIP induced cytoskeletal disorganization,decreased ATP content and cell migration,and increased cell proliferation and mitochondrial vacuolation.Moreover,the knockdown of PDE4DIP promoted cytoskeleton formation and contributed to increased ATP content and elevated cell migration.Mechanically,overexpression of PDE4DIP inhibited cell polarity-,skeleton-,and Rho-ROCK signaling-related genes and proteins,which could be increased by knockdown of PDE4DIP,suggesting that a critical regulation of PDE4DIP to Rho-ROCK pathway.This discovery suggests that PDE4DIP contributes to the development of LVNC by regulating cell polarity,skeleton,and energy metabolism through the Rho-ROCK pathway.展开更多
Rho/ROCK信号通路是细胞内一条重要的信号转导通路,其中Rho蛋白和ROCK(Rho-associated protein kinase)是其关键组成部分。Rho蛋白是一类小型GTP酶,参与调控细胞骨架的关键过程。ROCK作为Rho蛋白的下游效应蛋白激酶,能够调节细胞的形态...Rho/ROCK信号通路是细胞内一条重要的信号转导通路,其中Rho蛋白和ROCK(Rho-associated protein kinase)是其关键组成部分。Rho蛋白是一类小型GTP酶,参与调控细胞骨架的关键过程。ROCK作为Rho蛋白的下游效应蛋白激酶,能够调节细胞的形态、迁移和增殖等多种生物学过程。近年来,Rho/ROCK信号通路在各种病毒复制中的作用逐渐受到重视,研究发现一些病毒通过Rho/ROCK通路干扰细胞的收缩、黏附和迁移,参与调节病毒感染引发的免疫反应,并影响细胞间的紧密连接。现主要综述Rho/ROCK信号通路及其关键信号分子Rho和ROCK的活化与调控在病毒复制及细胞间紧密连接蛋白研究中的进展。展开更多
Background After injury,axonal regeneration of the adult central nervous system （CNS） is inhibited by myelin-derived growth-suppressing proteins.These axonal growth inhibitory proteins are mediated via activation of...Background After injury,axonal regeneration of the adult central nervous system （CNS） is inhibited by myelin-derived growth-suppressing proteins.These axonal growth inhibitory proteins are mediated via activation of Rho,a small GTP-binding protein.The activated form of Rho,which is bound to GTP,is the direct activator of Rho kinase （ROCK） through serial downstream effector proteins to inhibit axonal regeneration.The objective of this study was to observe the therapeutic effect of inactivation of the Rho-ROCK signaling pathway to promote neurologic recovery after spinal cord injuries in rats.Methods One hundred and twenty adult female Sprague-Dawley rats were randomly divided into three groups.Laminectomies alone were conducted in 40 rats in the sham group.Laminectomies and spinal cord transections were performed in 40 rats in the control group （treated with normal saline administered intraperitoneally）.Laminectomies and spinal cord transections were performed in 40 rats in the fasudil-treated group （treated with fasudil administered intraperitoneally）.Neurologic recovery was evaluated before surgery and 3 days,and 1,2,3,and 4 weeks after surgery using the Basso-Beattie-Bresnahan （BBB） scale of hind limb movement.At the same time,the expression of RhoA mRNA was determined with RT-PCR.Histopathologic examinations and immunofiuorescence staining of NF were performed 1 month after surgery.Results Compared with the control group,the BBB scores of the fasudil-treated group were significantly increased and the expression of RhoA mRNA was significantly decreased.In the fasudil-treated group,a large number of NF-positive regenerating fibers was observed; some fibers crossed the slit of the lesion.Conclusion Inactivation of the Rho-ROCK signaling pathway promotes CNS axonal regeneration and neurologic recovery after spinal cord injuries in rats.展开更多
基金Zhejiang Provincial Natural Science Foundation of China(Grant No.LQ15H280007)National Natural Science Foundation of China(Grant No.81202977)project of Traditional Chinese Medicine Science of Zhejiang province(Grant No.2013ZA026 and 2016ZA042)
文摘Idiopathic pulmonary fibrosis（IPF） is characterized by progressive lung scarring, reduced median survival, poor prognosis and limited therapeutic options, leading to great need for new pharmacologic therapies. In recent years, researchers have found that Rho-ROCK signaling pathway may be a new drug target in the prevention of IPF. This article reviewed the role of Rho-ROCK pathway in pulmonary fibrosis and the application of ROCK inhibitors in experimental models of IPF. Multiple lines of evidence therefore indicated that ROCK inhibition has great potential to be a powerful therapeutic tool in the prevention and treatment of IPF in clinic.
基金supported by the National Natural Science Foundation of China(No.81570218,82170244)the Program for Youth Innovation in Future Medicine of Chongqing Medical University(No.W0176)the National Clinical Key Specialty Construction Project(China)(No.010140).
文摘Left ventricular non-compaction(LVNC),is a hereditary cardiomyopathy with limited treatments.Our previous study linked phosphodiesterase 4D interacting protein(PDE4DIP)to LVNC development.To explore the functional role of PDE4DIP activation in regulating cell polarity,skeleton,and energy metabolism,and to elucidate its mechanisms driving LVNC development,bioinformatics analysis was performed to compare its expression in LVNC patients and normal subjects.Overexpression and knockdown of PDE4DIP were constructed in H9C2 cells and neonatal Sprague–Dawley rat primary cardiomyocytes,respectively.Electron microscopy,MitoTracker-Green staining,and an ATP kit were employed to assess mitochondria's morphology and functional status.Real-time quantitative PCR,western blotting,and immunofluorescence assays were employed to detect the expression of cell polarity-,skeleton-,and Rho-ROCK signaling-related genes and proteins.Cell scratching and CCK-8 assays were employed to detect cell migration and proliferation abilities of H9C2,respectively.We found that PDE4DIP expression was increased in the LVNC-derived human-induced pluripotent stem cell-derived cardiomyocytes compared with normal subjects.Furthermore,overexpression of PDE4DIP induced cytoskeletal disorganization,decreased ATP content and cell migration,and increased cell proliferation and mitochondrial vacuolation.Moreover,the knockdown of PDE4DIP promoted cytoskeleton formation and contributed to increased ATP content and elevated cell migration.Mechanically,overexpression of PDE4DIP inhibited cell polarity-,skeleton-,and Rho-ROCK signaling-related genes and proteins,which could be increased by knockdown of PDE4DIP,suggesting that a critical regulation of PDE4DIP to Rho-ROCK pathway.This discovery suggests that PDE4DIP contributes to the development of LVNC by regulating cell polarity,skeleton,and energy metabolism through the Rho-ROCK pathway.
文摘Rho/ROCK信号通路是细胞内一条重要的信号转导通路,其中Rho蛋白和ROCK(Rho-associated protein kinase)是其关键组成部分。Rho蛋白是一类小型GTP酶,参与调控细胞骨架的关键过程。ROCK作为Rho蛋白的下游效应蛋白激酶,能够调节细胞的形态、迁移和增殖等多种生物学过程。近年来,Rho/ROCK信号通路在各种病毒复制中的作用逐渐受到重视,研究发现一些病毒通过Rho/ROCK通路干扰细胞的收缩、黏附和迁移,参与调节病毒感染引发的免疫反应,并影响细胞间的紧密连接。现主要综述Rho/ROCK信号通路及其关键信号分子Rho和ROCK的活化与调控在病毒复制及细胞间紧密连接蛋白研究中的进展。
文摘Background After injury,axonal regeneration of the adult central nervous system （CNS） is inhibited by myelin-derived growth-suppressing proteins.These axonal growth inhibitory proteins are mediated via activation of Rho,a small GTP-binding protein.The activated form of Rho,which is bound to GTP,is the direct activator of Rho kinase （ROCK） through serial downstream effector proteins to inhibit axonal regeneration.The objective of this study was to observe the therapeutic effect of inactivation of the Rho-ROCK signaling pathway to promote neurologic recovery after spinal cord injuries in rats.Methods One hundred and twenty adult female Sprague-Dawley rats were randomly divided into three groups.Laminectomies alone were conducted in 40 rats in the sham group.Laminectomies and spinal cord transections were performed in 40 rats in the control group （treated with normal saline administered intraperitoneally）.Laminectomies and spinal cord transections were performed in 40 rats in the fasudil-treated group （treated with fasudil administered intraperitoneally）.Neurologic recovery was evaluated before surgery and 3 days,and 1,2,3,and 4 weeks after surgery using the Basso-Beattie-Bresnahan （BBB） scale of hind limb movement.At the same time,the expression of RhoA mRNA was determined with RT-PCR.Histopathologic examinations and immunofiuorescence staining of NF were performed 1 month after surgery.Results Compared with the control group,the BBB scores of the fasudil-treated group were significantly increased and the expression of RhoA mRNA was significantly decreased.In the fasudil-treated group,a large number of NF-positive regenerating fibers was observed; some fibers crossed the slit of the lesion.Conclusion Inactivation of the Rho-ROCK signaling pathway promotes CNS axonal regeneration and neurologic recovery after spinal cord injuries in rats.
