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Advantages of Rho-associated kinases and their inhibitor fasudil for the treatment of neurodegenerative diseases 被引量:7
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作者 Qing Wang Li-Juan Song +4 位作者 Zhi-Bin Ding Zhi Chai Jie-Zhong Yu Bao-Guo Xiao Cun-Gen Ma 《Neural Regeneration Research》 SCIE CAS CSCD 2022年第12期2623-2631,共9页
Ras homolog(Rho)-associated kinases(ROCKs)belong to the serine-threonine kinase family,which plays a pivotal role in regulating the damage,survival,axon guidance,and regeneration of neurons.ROCKs are also involved in ... Ras homolog(Rho)-associated kinases(ROCKs)belong to the serine-threonine kinase family,which plays a pivotal role in regulating the damage,survival,axon guidance,and regeneration of neurons.ROCKs are also involved in the biological effects of immune cells and glial cells,as well as the development of neurodegenerative disorders such as Alzheimer’s disease,Parkinson’s disease,and multiple sclerosis.Previous studies by us and others confirmed that ROCKs inhibitors attenuated the symptoms and progression of experimental models of the abovementioned neurodegenerative diseases by inhibiting neuroinflammation,regulating immune imbalance,repairing the blood-brain barrier,and promoting nerve repair and myelin regeneration.Fasudil,the first ROCKs inhibitor to be used clinically,has a good therapeutic effect on neurodegenerative diseases.Fasudil increases the activity of neural stem cells and mesenchymal stem cells,thus optimizing cell therapy.This review will systematically describe,for the first time,the effects of abnormal activation of ROCKs on T cells,B cells,microglia,astrocytes,oligodendrocytes,and pericytes in neurodegenerative diseases of the central nervous system,summarize the therapeutic potential of fasudil in several experimental models of neurodegenerative diseases,and clarify the possible cellular and molecular mechanisms of ROCKs inhibition.This review also proposes that fasudil is a novel potential treatment,especially in combination with cell-based therapy.Findings from this review add support for further investigation of ROCKs and its inhibitor fasudil for the treatment of neurodegenerative diseases. 展开更多
关键词 Alzheimer’s disease cell-based therapy central nervous system cells FASUDIL IMMUNOCYTES multiple sclerosis Parkinson’s disease PERICYTES Rho kinase inhibitor rho-associated kinases
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Tolerance of neurite outgrowth to Rho kinase inhibitors decreased by cyclooxygenase-2 inhibitor 被引量:1
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作者 Weigang Duan Ling Que +3 位作者 Xiaoman Lv Qifeng Li Hua Yin Luyong Zhang 《Neural Regeneration Research》 SCIE CAS CSCD 2012年第34期2705-2712,共8页
In this study, PC12 Adh cells and Neuro-2a cells were treated with Rho-associated kinase inhibitors (Y27632 and Fasudil), a cyclooxygenase-1 selective inhibitor (SC560), and a cyclooxygenase-2 inhibitor (NS398).... In this study, PC12 Adh cells and Neuro-2a cells were treated with Rho-associated kinase inhibitors (Y27632 and Fasudil), a cyclooxygenase-1 selective inhibitor (SC560), and a cyclooxygenase-2 inhibitor (NS398). We found that these cells became tolerant to Rho-associated kinase inhibitors, as neurite outgrowth induced by these inhibitors diminished following more than 3 days of exposure in either cell line. The proteins cyclooxygenase-2 and cytosolic prostaglandin E synthetase were upregulated at day 3. NS398 decreased the tolerance to neurite outgrowth induction in both cell lines, whereas SC560 had almost no effect. These findings indicate that cells become tolerant to neurite outgrowth induced by Rho-associated kinase inhibitors, this is at least partly associated with upregulation of proteins involved in the cyclooxygenase-2 pathway, and cyclooxygenases-2 inhibition prevents this tolerance. 展开更多
关键词 rho-associated kinase inhibitors Y27632 FASUDIL NEURITE cyclooxygenase 2 inhibitors drugtolerance
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Inhibition of RhoA/Rho-kinase pathway suppresses the expression of extracellular matrix induced by CTGF or TGF-β in ARPE-19 被引量:22
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作者 Jing Zhu Duy Nguyen +3 位作者 Hong Ouyang Xiao-Hui Zhang Xiao-Ming Chen Kang Zhang 《International Journal of Ophthalmology(English edition)》 SCIE CAS 2013年第1期8-14,共7页
AIM:To investigate the role of Rho-associated protein kinase (ROCK) inhibitor, Y27632, in mediating the production of extracellular matrix (ECM) components including fibronectin, matrix metallo-proteinase-2 (MMP-2) an... AIM:To investigate the role of Rho-associated protein kinase (ROCK) inhibitor, Y27632, in mediating the production of extracellular matrix (ECM) components including fibronectin, matrix metallo-proteinase-2 (MMP-2) and type I collagen as induced by connective tissue growth factor(CTGF) or transforming growth factor-β (TGF-β) in a human retinal pigment epithelial cell line, ARPE-19. METHODS:The effect of Y27632 on the CTGF or TGF-β induced phenotype in ARPE-19 cells was measured with immunocytochemistry as the change in F-actin. ARPE-19 cells were treated with CTGF (1, 10, 100ng/mL)and TGF-β (10ng/mL) in serum free media, and analyzed for fibronectin, laminin, and MMP-2 and type I collagen by RT-qPCR and immunocytochemistry. Cells were also pretreated with an ROCK inhibitor, Y27632, to analyze the signaling contributing to ECM production. ·RESULTS:Treatment of ARPE-19 cells in culture with TGF-β or CTGF induced an ECM change from a cobblestone morphology to a more elongated swirl pattern indicating a mesenchymal phenotype. RT-qPCR analysis and different gene expression analysis demonstrated an upregulation in expression of genes associated with cytoskeletal structure and motility. CTGFor TGF-β significantly increased expression of fibronectin mRNA (P =0.006, P =0.003 respectively), laminin mRNA (P =0.006, P =0.005), MMP-2 mRNA (P =0.006, P =0.001), COL1A1 mRNA (P =0.001, P =0.001), COL1A2 mRNA (P = 0.001, P =0.001). Preincubation of ARPE-19 with Y27632 (10mmol/L) significantly prevented CTGF or TGF-β induced fibronectin (P=0.005, P=0.003 respectively), MMP-2 (P = 0.003, P =0.002), COL1A1 (P =0.006, P =0.003), and COL1A2 (P =0.006, P =0.004) gene expression, but not laminin (P =0.375, P =0.516). CONCLUSION:Our study demonstrated that both TGF-β and CTGF upregulate the expression of ECM components including fibronectin, laminin, MMP-2 and type I collagen by activating the RhoA/ROCK signaling pathway. During this process, ARPE-19 cells were shown to change from an epithelial to a mesenchymal phenotype in vitro. Y27632, a ROCK inhibitor, inhibited the transcription of fibronectin, MMP-2 and type I collagen, but not laminin. The data from our work suggest a role for CTGF as a profibrotic mediator. Inhibiting the RhoA/ROCK pathway represents a potential target to prevent the fibrosis of retinal pigment epithelial (RPE) cells. This might lead to a novel therapeutic approach to preventing the onset of early proliferative vitreoretinopathy(PVR). 展开更多
关键词 rho-associated protein kinase inhibitor Connective tissue growth factor transforming growth factor-β proliferative vitreoretinopathy
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Axonal growth inhibitors and their receptors in spinal cord injury:from biology to clinical translation 被引量:2
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作者 Sílvia Sousa Chambel Célia Duarte Cruz 《Neural Regeneration Research》 SCIE CAS CSCD 2023年第12期2573-2581,共9页
Axonal growth inhibitors are released during traumatic injuries to the adult mammalian central nervous system, including after spinal cord injury. These molecules accumulate at the injury site and form a highly inhibi... Axonal growth inhibitors are released during traumatic injuries to the adult mammalian central nervous system, including after spinal cord injury. These molecules accumulate at the injury site and form a highly inhibitory environment for axonal regeneration. Among these inhibitory molecules, myelinassociated inhibitors, including neurite outgrowth inhibitor A, oligodendrocyte myelin glycoprotein, myelin-associated glycoprotein, chondroitin sulfate proteoglycans and repulsive guidance molecule A are of particular importance. Due to their inhibitory nature, they represent exciting molecular targets to study axonal inhibition and regeneration after central injuries. These molecules are mainly produced by neurons, oligodendrocytes, and astrocytes within the scar and in its immediate vicinity. They exert their effects by binding to specific receptors, localized in the membranes of neurons. Receptors for these inhibitory cues include Nogo receptor 1, leucine-rich repeat, and Ig domain containing 1 and p75 neurotrophin receptor/tumor necrosis factor receptor superfamily member 19(that form a receptor complex that binds all myelin-associated inhibitors), and also paired immunoglobulin-like receptor B. Chondroitin sulfate proteoglycans and repulsive guidance molecule A bind to Nogo receptor 1, Nogo receptor 3, receptor protein tyrosine phosphatase σ and leucocyte common antigen related phosphatase, and neogenin, respectively. Once activated, these receptors initiate downstream signaling pathways, the most common amongst them being the Rho A/ROCK signaling pathway. These signaling cascades result in actin depolymerization, neurite outgrowth inhibition, and failure to regenerate after spinal cord injury. Currently, there are no approved pharmacological treatments to overcome spinal cord injuries other than physical rehabilitation and management of the array of symptoms brought on by spinal cord injuries. However, several novel therapies aiming to modulate these inhibitory proteins and/or their receptors are under investigation in ongoing clinical trials. Investigation has also been demonstrating that combinatorial therapies of growth inhibitors with other therapies, such as growth factors or stem-cell therapies, produce stronger results and their potential application in the clinics opens new venues in spinal cord injury treatment. 展开更多
关键词 chondroitin sulphate proteoglycans collapsin response mediator protein 2 inhibitory molecules leucine-rich repeat and Ig domain containing 1 leucocyte common antigen related myelin-associated glycoprotein neurite outgrowth inhibitor A Nogo receptor 1 Nogo receptor 3 oligodendrocyte myelin glycoprotein p75 neurotrophin receptor Plexin A2 Ras homolog family member A/rho-associated protein kinase receptor protein tyrosine phosphataseσ repulsive guidance molecule A spinal cord injury tumour necrosis factor receptor superfamily member 19
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Ras同源基因家族蛋白A/Rho相关卷曲螺旋蛋白激酶信号通路调控缺血性卒中的研究进展
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作者 张展 姜德龙 +1 位作者 王庆谚 王鹏琴 《中国脑血管病杂志》 CAS CSCD 北大核心 2024年第10期700-707,共8页
Ras同源基因家族蛋白A(RhoA)是一种小的鸟苷三磷酸酶蛋白,在缺血性卒中发生发展过程中可激活Rho相关卷曲螺旋蛋白激酶(ROCK)。RhoA/ROCK信号通路是缺血性卒中病理过程中的重要调节因子,调控该信号通路已成为促进缺血性卒中后神经细胞恢... Ras同源基因家族蛋白A(RhoA)是一种小的鸟苷三磷酸酶蛋白,在缺血性卒中发生发展过程中可激活Rho相关卷曲螺旋蛋白激酶(ROCK)。RhoA/ROCK信号通路是缺血性卒中病理过程中的重要调节因子,调控该信号通路已成为促进缺血性卒中后神经细胞恢复和改善脑缺血-再灌注损伤的研究热点,然而目前RhoA/ROCK抑制剂仅有法舒地尔上市,其余仍处于研发或临床试验阶段。作者对RhoA/ROCK信号通路对缺血性卒中发挥的调控作用及机制进行总结,并对抑制剂及调控药物的应用进行阐述,旨在为缺血性卒中防治提供新的思路。 展开更多
关键词 缺血性卒中 RhoA GTP结合蛋白质 RHO相关激酶类 RhoA/rock信号通路 抑制剂 综述
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Rho/ROCK2通路在阿尔茨海默病病理进程中的重要作用 被引量:4
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作者 张天弼 张云龙 +1 位作者 胡警文 张应玖 《国际药学研究杂志》 CAS CSCD 北大核心 2016年第1期33-38,共6页
Rho/Rho相关卷曲螺旋形成蛋白激酶(ROCK)通路是生物体中广泛存在的经典信号通路,参与多种生理调节过程。ROCK有2种亚型,即ROCK1和ROCK2。在阿尔茨海默病(AD)患者脑中,Rho/ROCK2表现为活性上调,并伴有Aβ42水平升高,以及神经细胞突起的... Rho/Rho相关卷曲螺旋形成蛋白激酶(ROCK)通路是生物体中广泛存在的经典信号通路,参与多种生理调节过程。ROCK有2种亚型,即ROCK1和ROCK2。在阿尔茨海默病(AD)患者脑中,Rho/ROCK2表现为活性上调,并伴有Aβ42水平升高,以及神经细胞突起的形态与功能异常,推测AD的发生、发展与Rho或ROCK2的高表达或过度激活有关。目前Rho/ROCK2通路被认为是预防和治疗AD的一个有效的靶通路,而Rho或ROCK2,也成为药物研发的重要靶点。研究发现,降低Rho或ROCK2的表达,或者抑制Rho或ROCK2的活性均可减少Aβ42诱导的神经毒性,保护神经元,减缓AD的发展。因此,Rho/ROCK2的特异性抑制对中枢神经损伤修复及AD的治疗有重要的意义。为此,本文针对Rho/ROCK2通路在阿尔茨海默病发展中的作用做一综述。 展开更多
关键词 RHO Rho相关卷曲螺旋形成蛋白激酶 阿尔茨海默病 抑制剂
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RhoA/ROCK信号通路与心血管系统疾病关系的研究进展 被引量:2
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作者 张丽美 王国强 +2 位作者 陈世娇 许金鹏 宋书江 《医学研究与教育》 CAS 2021年第2期8-13,共6页
心血管疾病是中国人群死亡的主要原因,然而其发病机制尚不明确。研究发现,RhoA/ROCK信号通路与高血压、冠心病、心力衰竭、心律失常等疾病的发生和发展密切相关。ROCK抑制剂也为心血管疾病的治疗提供新的思路,现就RhoA/ROCK信号通路在... 心血管疾病是中国人群死亡的主要原因,然而其发病机制尚不明确。研究发现,RhoA/ROCK信号通路与高血压、冠心病、心力衰竭、心律失常等疾病的发生和发展密切相关。ROCK抑制剂也为心血管疾病的治疗提供新的思路,现就RhoA/ROCK信号通路在心血管疾病中研究做一综述。 展开更多
关键词 RhoA/rock信号通路 心血管疾病 RHO激酶抑制剂
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Upregulation of miR-345-5p suppresses cell growth of lung adenocarcinoma by regulating ras homolog family member A(RhoA)and Rho/Rho associated protein kinase(Rho/ROCK)pathway 被引量:1
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作者 Qiao-Yun Zhou Shu-Yu Gui +1 位作者 Peng Zhang Mei Wang 《Chinese Medical Journal》 SCIE CAS CSCD 2021年第21期2619-2628,共10页
Background:Microribose nucleic acids(miRNAs)are implicated in the progression of lung adenocarcinoma.MicroRNA-345-5p(miR-345-5p)is a recently identified anti-oncogene in some human cancers,but its functional role and ... Background:Microribose nucleic acids(miRNAs)are implicated in the progression of lung adenocarcinoma.MicroRNA-345-5p(miR-345-5p)is a recently identified anti-oncogene in some human cancers,but its functional role and possible molecular mechanism in lung adenocarcinoma remain unknown.This study aimed to identify the biological function and underlying mechanism of miR-345-5p in lung adenocarcinoma cells.Methods:In this study,lung adenocarcinoma tissues and adjacent tissues were collected in the First Affiliated Hospital of Anhui Medical University between April 2016 and February 2017.The expression of miR-345-5p and ras homolog family member A(RhoA)in lung adenocarcinoma tissues and human lung adenocarcinoma cell lines(A549,H1650,PC-9,and H441)was detected by reverse transcription quantitative polymerase chain reaction analysis.Functional assays including colony formation,flow cytometry analysis,wound healing,and transwell assays were performed to assess the proliferation,apoptosis,migration,and invasion of lung adenocarcinoma cells.In addition,RNA pulldown and luciferase reporter assays were conducted to evaluate the relationship between miR-345-5p and RhoA.Difference between the two groups was analyzed with Student’st test,while that among multiple groups was analyzed with one-way analysis of variance.Results:MiR-345-5p expression displayed lower level in lung adenocarcinoma tissues(0.241±0.095vs.1.000±0.233,t=19.247,P<0.001)and cell lines(F=56.992,P<0.001)than control tissues and cells.Functional experiments demonstrated that upregulation of miR-345-5p inhibited the malignant phenotypes of lung adenocarcinoma cells via suppressing cell proliferation,migration,invasion,and facilitating cell apoptosis.Additionally,RhoA was verified to be the downstream target of miR-345-5p.Expression of RhoA was downregulated by overexpression of miR-345-5p in PC-9(0.321±0.047vs.1.000±0.127,t=8.536,P<0.001)and H1650(0.398±0.054vs.1.000±0.156,t=4.429,P=0.011)cells.Rescue assays revealed that overexpression of RhoA rescued the suppressive effects of miR-345-5p upregulation on proliferation,migration,and invasion of lung adenocarcinoma cells.Further,miR-345-5p was found to regulate the Rho/Rho-associated protein kinase(ROCK)signaling pathway by downregulation of RhoA in lung adenocarcinoma cells.Conclusions:MiR-345-5p plays a tumor suppressor role in lung adenocarcinoma cells by downregulating RhoA to inactivate the Rho/ROCK pathway. 展开更多
关键词 MicroRNA-345-5p Lung adenocarcinoma Ras homolog family member A(RhoA) Rho/rho-associated protein kinase(rock)
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Stem cells in neuroinjury and neurodegenerative disorders: challenges and future neurotherapeutic prospects 被引量:9
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作者 Tarek H.Mouhieddine Firas H.Kobeissy +2 位作者 Muhieddine Itani Amaly Nokkari Kevin K.W.Wang 《Neural Regeneration Research》 SCIE CAS CSCD 2014年第9期901-906,共6页
The prevalence of neurodegenerative diseases and neural injury disorders is increasing worldwide. Research is now focusing on improving current neurogenesis techniques including neural stem cell therapy and other bioc... The prevalence of neurodegenerative diseases and neural injury disorders is increasing worldwide. Research is now focusing on improving current neurogenesis techniques including neural stem cell therapy and other biochemical drug-based approaches to ameliorate these disorders. Unfortunately, we are still facing many obstacles that are rendering current neurotherapies ineffective in clinical trials for reasons that are yet to be discovered. That is why we should start by fully understanding the complex mechanisms of neurogenesis and the factors that affect it, or else, all our suggested therapies would fail since they would not be targeting the essence of the neurological disorder but rather the symptoms. One possible paradigm shift is to switch from neuroprotectant therapies towards neurodegeneration/neurorestorative approaches. In addition, other and our laboratories are increasingly focusing on combining the use of pharmacological agents(such as Rho-associated kinase(ROCK) inhibitors or other growth factors(such as brain-derived neurotrophic factor(BDNF)) and stem cell treatment to enhance the survivability and/or differentiation capacity of transplanted stem cells in neurotrauma or other neurodegeneration animal models. Ongoing stem cell research is surely on the verge of a breakthrough of multiple effective therapeutic options for neurodegenerative disorders. Once, we fully comprehend the process of neurogenesis and its components, we will fully be capable of manipulating and utilizing it. In this work, we discuss the current knowledge of neuroregenerative therapies and their associated challenges. 展开更多
关键词 neural stem cells NEURODEGENERATION neuroinjury TBI rho-associated kinase(rock) inhibitor BDNF growth factors stem cell therapy
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Rho激酶抑制剂对百草枯中毒大鼠肺纤维化的干预研究 被引量:5
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作者 夏菁 方建江 +2 位作者 刘雪兰 徐丽艳 徐少博 《中国临床药理学与治疗学》 CAS CSCD 2016年第9期973-977,共5页
目的:探讨Rho激酶抑制剂对百草枯(PQ)中毒大鼠肺纤维化的影响及可能的机制。方法:将96只SPF级SD大鼠随机分为4组,每组24只,即正常对照组(Control组),Rho激酶抑制剂对照组(RI组),PQ染毒组(PQ组),Rho激酶抑制剂干预组(PQ+RI组)。在PQ灌胃... 目的:探讨Rho激酶抑制剂对百草枯(PQ)中毒大鼠肺纤维化的影响及可能的机制。方法:将96只SPF级SD大鼠随机分为4组,每组24只,即正常对照组(Control组),Rho激酶抑制剂对照组(RI组),PQ染毒组(PQ组),Rho激酶抑制剂干预组(PQ+RI组)。在PQ灌胃第7、14、28天后,每组随机取6只大鼠,麻醉后处死,留取肺组织标本。碱水解法测定肺组织羟脯氨酸(HYP)含量,蛋白印迹法(Western blotting)测定Ⅰ、Ⅲ型胶原蛋白、结缔组织生长因子(CTGF)的表达。光镜下观察肺组织的病理变化。结果:与Control组相比,RI组无显著变化(P>0.05),PQ染毒组和RI干预组(均满足P<0.05)在第7、14、28天,HYP含量显著升高(P<0.05),I,Ⅲ型胶原蛋白、CTGF的表达也显著提升(P<0.05)。与PQ组比较,RI干预组在第7、14、28天HYP含量显著降低,Ⅰ、Ⅲ型胶原蛋白、CTGF的表达也显著下降。肺组织的病理结果显示PQ染毒组在灌胃给药后第28天的肺纤维化程度最严重,与之相比RI干预组在第7、14、28天肺纤维化程度均有减轻。结论:Rho激酶抑制剂,通过调节CTGF以及Ⅰ、Ⅲ型胶原蛋白的表达并且减少蛋白质沉积,对百草枯中毒导致的肺纤维化有明显的治疗作用。 展开更多
关键词 百草枯 肺纤维化 RHO激酶抑制剂 Rho/rock信号转导通路
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Rho激酶抑制剂及CD8^+ T细胞在EAE模型的作用机制研究
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作者 林美容 高聪 +7 位作者 孙卫文 谢富华 杨洁 区腾飞 冯欣 占婷婷 李威 林哲聪 《广东医学》 CAS CSCD 北大核心 2010年第22期2881-2884,共4页
目的观察Rho激酶抑制剂法舒地尔对RhoA、Rock-Ⅱ以及CD8+ T细胞在脑和脊髓组织中表达的影响,探索法舒地尔在实验性自身免疫性脑脊骨髓炎(EAE)模型中的作用机制。方法把90只Lewis大鼠随机分为5组:A组(空白对照),B组(免疫后第13天),C组(... 目的观察Rho激酶抑制剂法舒地尔对RhoA、Rock-Ⅱ以及CD8+ T细胞在脑和脊髓组织中表达的影响,探索法舒地尔在实验性自身免疫性脑脊骨髓炎(EAE)模型中的作用机制。方法把90只Lewis大鼠随机分为5组:A组(空白对照),B组(免疫后第13天),C组(免疫后第21天),D组(免疫后第35天)及E组(法舒地尔干预组)。以豚鼠全脊髓为抗原混合福氏完全佐剂(CFA)诱导Lewis大鼠EAE模型,观察实验动物神经功能损害的情况;利用免疫组织化学染色法观察实验动物组脑、脊髓组织中RhoA、Rock-Ⅱ以及CD8+ T细胞的表达。结果成功建立Lewis大鼠EAE模型,A、B、C、D、E5组中RhoA、Rock-Ⅱ以及CD8+ T细胞在脑、脊髓组织中均有表达,在免疫后21d达高峰,在免疫后及法舒地尔干预组的脑、脊髓组织中表达较空白对照组明显增加,差异有统计学意义(P<0.05);法舒地尔干预组RhoA、Rock-Ⅱ以及CD8+ T细胞在脑、脊髓组织的表达较免疫后各个时间点有所减轻,差异有统计学意义(P<0.05);免疫后第13天组与免疫后35天组比较,差异无统计学意义(P>0.05)。结论 Rho激酶抑制剂可以抑制EAE的病情进展、减轻神经元及轴索损害,其机制可能是抑制了Rho激酶参与白细胞及巨噬细胞迁移、浸润、吞噬过程;抑制Rho信号转导通路对细胞骨架的调节作用,而起到促进轴突再生、保护神经元的作用。 展开更多
关键词 实验性自身免疫性脑脊髓炎 多发性硬化 RHOA rock-Ⅱ CD8+ T细胞 RHO激酶抑制剂
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基于吲哚类的ROCK激酶抑制剂定量构效关系的研究
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作者 肖元春 李燕 +2 位作者 杨银凤 王景辉 杨凌 《分子科学学报》 CAS CSCD 北大核心 2015年第4期295-303,共9页
基于计算生物学方法对61个ROCK激酶靶标分子建立三维定量构效关系(3DQSAR)模型.在基于配体叠合的基础上,发现CoMSIA中2个场组合(位阻场和疏水场)为最好的模型(Q2=0.509,R2ncv=0.987,SEE=0.131,F=287.999和R2pre=0.837).基于此模型基础... 基于计算生物学方法对61个ROCK激酶靶标分子建立三维定量构效关系(3DQSAR)模型.在基于配体叠合的基础上,发现CoMSIA中2个场组合(位阻场和疏水场)为最好的模型(Q2=0.509,R2ncv=0.987,SEE=0.131,F=287.999和R2pre=0.837).基于此模型基础上的三维等势线图形象地说明了在各个位置增加疏水性的大取代基或者亲水性基团有利于提高分子的生物活性.此外,分子对接模拟结果显示了氨基酸Glu170,Met172和Asp232在受体调节剂中发挥着重要作用.这些结果能够帮助深入了解ROCK激酶的作用机理,并且能够为今后的药物设计提供新的方向. 展开更多
关键词 rock激酶抑制剂 比较分子力场 比较相似性指数分析 分子对接
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治疗慢性移植物抗宿主病药物——belumosudil
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作者 刘悦 张斌 张海英 《临床药物治疗杂志》 2023年第3期18-22,共5页
belumosudil是一种Rho相关卷曲螺旋蛋白激酶(ROCK)抑制剂,由Kadmon制药公司开发,用于治疗慢性移植物抗宿主病(cGVHD)和系统性硬化症。2021年7月16日,belumosudil在美国首次获准上市,用于既往至少接受过2次系统一线治疗失败后的cGVHD成... belumosudil是一种Rho相关卷曲螺旋蛋白激酶(ROCK)抑制剂,由Kadmon制药公司开发,用于治疗慢性移植物抗宿主病(cGVHD)和系统性硬化症。2021年7月16日,belumosudil在美国首次获准上市,用于既往至少接受过2次系统一线治疗失败后的cGVHD成人患者和12岁及以上的cGVHD儿童患者。本文从药理作用及作用机制、药动学、临床疗效评价、安全性评价、用法用量等方面对belumosudil进行综述,旨在为临床合理用药提供参考。 展开更多
关键词 belumosudil 慢性移植物抗宿主病 rock2抑制剂
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