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Rho/ROCK pathway and neural regeneration: a potential therapeutic target for central nervous system and optic nerve damage 被引量:31
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作者 Hai-Bo Tan Yi-Sheng Zhong +1 位作者 Yu Cheng and Xi Shen 《International Journal of Ophthalmology(English edition)》 SCIE CAS 2011年第6期652-657,共6页
Rho-associated kinase (ROCK) is a serine/threonine kinase and one of the major downstream effectors of the small GTPase RhoA. The Rho/ROCK pathway is closely related to the pathogenesis of several central nervous syst... Rho-associated kinase (ROCK) is a serine/threonine kinase and one of the major downstream effectors of the small GTPase RhoA. The Rho/ROCK pathway is closely related to the pathogenesis of several central nervous system (CNS) disorders, and involved in many aspects of neuronal functions including neurite outgrowth and retraction. In the adult CNS, the damaged neuron regeneration is very difficult due to the presence of myelin-associated axon growth inhibitors such as Nogo, myelin-associated glycoprotein (MAG) and oligodendrocyte-myelin glycoprotein (Omgp), etc. The effects of these axon growth inhibitors are reversed by blocking the Rho/ROCK pathway 47 vitro, and the inhibition of Rho/ROCK pathway can promote axon regeneration and functional recovery in the injured CNS in viva In addition, the therapeutic effects of the Rho/ROCK inhibitors have also been demonstrated in some animal models and the Rho/ROCK pathway becomes an attractive target for the development of drugs for treating CNS disorders. In this review, we summarized on the effect of the Rho and the downstream factor ROCK in neural regeneration, and the potential therapeutic effect of Rho/ROCK inhibitors in the survival and axonal regeneration of retinal ganglion cell was also discussed. 展开更多
关键词 Rho/rock pathway neural regeneration potential therapeutic effect optic nerve damage
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Research progress of RhoA/ROCK pathway in diabetes-related diseases
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作者 Pei-Yun Zeng Qi Zhang +2 位作者 Zi-Bing Qian Zhi-Xiu Zhang Jing Liu 《Journal of Hainan Medical University》 2021年第5期66-70,共5页
RhoA is a small GTPase protein.Its downstream effector protein Rho kinase(ROCK)regulates a variety of cell functions,including cell growth,gene expression and cytoskeleton recombination.Studies have demonstrated that ... RhoA is a small GTPase protein.Its downstream effector protein Rho kinase(ROCK)regulates a variety of cell functions,including cell growth,gene expression and cytoskeleton recombination.Studies have demonstrated that this pathway plays an important pathophysiological role in diabetic nephropathy and other complications,hypertension,stroke,tumor,osteoarthritis,acute lung injury and other diseases.The occurrence and development of diabetes-related disease is closely related to the activation or up-regulation of RhoA/ROCK pathway.As a key target of drug development,ROCK inhibitors have been widely concerned by scholars.This article reviews the relationship between RhoA/ROCK pathway and diabetesrelated disease,and offers a new and effective strategy for the prevention and treatment of this series of diseases. 展开更多
关键词 RhoA/rock pathway Diabetes-related diseases INHIBITORS
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Rho/Rock signal transduction pathway is required for MSC tenogenic differentiation 被引量:6
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作者 Edward Maharam Miguel Yaport +5 位作者 Nathaniel L Villanueva Takintope Akinyibi Damien Laudier Zhiyong He Daniel J Leong Hui B Sun 《Bone Research》 SCIE CAS CSCD 2015年第3期173-181,共9页
Mesenchymal stem cell (MSC)-based treatments have shown promise for improving tendon healing and repair. MSCs have the potential to differentiate into multiple lineages in response to select chemical and physical st... Mesenchymal stem cell (MSC)-based treatments have shown promise for improving tendon healing and repair. MSCs have the potential to differentiate into multiple lineages in response to select chemical and physical stimuli, including into tenocytes. Cell elongation and cytoskeletal tension have been shown to be instrumental to the process of MSC differentiation. Previous studies have shown that inhibition of stress fiber formation leads MSCs to default toward an adipogenic lineage, which suggests that stress fibers are required for MSCs to sense the environmental factors that can induce differentiation into tenocytes. As the Rho/ROCK signal transduction pathway plays a critical role in both stress fiber formation and in cell sensation, we examined whether the activation of this pathway was required when inducing MSC tendon differentiation using rope-like silk scaffolds. To accomplish this, we employed a loss-of-function approach by knocking out ROCK, actin and myosin (two other components of the pathway) using the specific inhibitors Y-27632, Latrunculin A and blebbistatin, respectively. We demonstrated that independently disrupting the cytoskeleton and the Rho/ ROCK pathway abolished the expression of tendon differentiation markers and led to a loss of spindle morphology. Together, these studies suggest that the tension that is generated by MSC elongation is essential for MSC teno-differentiation and that the Rho/ROCK pathway is a critical mediator of tendon differentiation on rope-like silk scaffolds. 展开更多
关键词 MSCS FIGURE Rho/rock signal transduction pathway is required for MSC tenogenic differentiation
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Mertk Reduces Blood-Spinal Cord Barrier Permeability Through the Rhoa/Rock1/P-MLC Pathway After Spinal Cord Injury
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作者 Jiezhao Lin Yuanfang Sun +5 位作者 Bin Xia Yihan Wang Changnan Xie Jinfeng Wang Jinwei Hu Lixin Zhu 《Neuroscience Bulletin》 SCIE CAS CSCD 2024年第9期1230-1244,共15页
Disruption of the blood-spinal cord barrier(BSCB)is a critical event in the secondary injury following spinal cord injury(SCI).Mertk has been reported to play an important role in regulating inflammation and cytoskele... Disruption of the blood-spinal cord barrier(BSCB)is a critical event in the secondary injury following spinal cord injury(SCI).Mertk has been reported to play an important role in regulating inflammation and cytoskeletal dynamics.However,the specific involvement of Mertk in BSCB remains elusive.Here,we demonstrated a distinct role of Mertk in the repair of BSCB.Mertk expression is decreased in endothelial cells following SCI.Overexpression of Mertk upregulated tight junction proteins(TJs),reducing BSCB permeability and subsequently inhibiting inflammation and apoptosis.Ultimately,this led to enhanced neural regeneration and functional recovery.Further experiments revealed that the RhoA/Rock1/P-MLC pathway plays a key role in the effects of Mertk.These findings highlight the role of Mertk in promoting SCI recovery through its ability to mitigate BSCB permeability and may provide potential targets for SCI repair. 展开更多
关键词 Spinal cord injury Mertk Blood-spinal cord barrier RhoA/rock1/P-MLC pathway Apoptosis INFLAMMATION
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Effect of QingguanganⅡon Rho/ROCK associated factors in the retina of DBA/2J mice
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作者 Jian Shi Jun Peng +3 位作者 Xiao-Lei Yao Jia-Hui Sun Yin-Xin Li Qing-Hua Peng 《Journal of Hainan Medical University》 2022年第13期16-21,共6页
Objective:The effect of QingguanganⅡon the transcription of RhoA mRNA,ROCK mRNA,Caspase-3 mRNA and Bcl-2 mRNA in the retina of DBA/2J mice was observed.Methods:Forty-eight DBA/2J mice were randomly divided into six g... Objective:The effect of QingguanganⅡon the transcription of RhoA mRNA,ROCK mRNA,Caspase-3 mRNA and Bcl-2 mRNA in the retina of DBA/2J mice was observed.Methods:Forty-eight DBA/2J mice were randomly divided into six groups:model groups,Qingguangan II decoction group,low concentration,medium concentration and high concentration group of Qingguangan II effective ingredient and positive control group(Yimaikang tablet group),and eight C57BL/6 mice were used as blank group,DBA/2J mice were fed until 38 weeks before forming a glaucoma model,The transcription of RhoA mRNA,ROCK mRNA,Caspase-3 mRNA and Bcl-2 mRNA in the retinal of DBA/2J mice was detected using real-time fluorescence quantitative PCR(Quantitative Real-time PCR)after 4 weeks of intervention.Results:Four weeks after the intervention,In the transcription of the RhoA mRNA,ROCK mRNA and the Caspase-3 mRNA,Compared to the blank groups,Relative expression was increased in the other 6 groups,There are statistical differences in the model group,Yimaikang tablet group and low concentration group(P<0.05);In comparison to the model groups,The other 6 groups were lower than the model group,Among them,there are statistical differences between the effective groups of Qingguangan II decoction and high concentration group of Qingguangan II effective ingredient in RhoA mRNA transcription(P<0.05);In the transcription of the ROCK mRNA and the Caspase-3 mRNA,Statistics have differences between the model group and the effective component of the medium and high concentration group(P<0.05);In the Bcl-2 mRNA transcription,Compare them to blank groups,Relexpression expression decreased in the other 6 groups,Statistics have differences between model group,Qingguangan II decoction group and low concentration groups(P<0.05);The relative expression of Bcl-2 mRNA in high concentration group of effective component is higher than that of the model group,There are differences in statistics(P<0.05).Conclusion:The high concentration of QingguanganⅡprescription probably attenuated Caspase-3 transcription in retinal ganglion cells by inhibiting the Rho/ROCK signaling pathway and activated Bcl-2 expression by inhibiting ROCK signaling,which attenuated apoptosis in retinal ganglion cells. 展开更多
关键词 QingguanganⅡprescription DBA/2J mice Rho/rock signaling pathway Caspase-3 mRNA Bcl-2 mRNA
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Environmental enrichment combined with fasudil promotes motor function recovery and axonal regeneration after stroke 被引量:8
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作者 Yi-Tong Zhu Qun Zhang +4 位作者 Hong-Yu Xie Ke-Wei Yu Gao-Jing Xu Si-Yue Li Yi Wu 《Neural Regeneration Research》 SCIE CAS CSCD 2021年第12期2512-2520,共9页
Fasudil,a Rho-associated protein kinase(ROCK)inhibitor,has a protective effect on the central nervous system.In addition,environmental enrichment is a promising technique for inducing the recovery of motor impairments... Fasudil,a Rho-associated protein kinase(ROCK)inhibitor,has a protective effect on the central nervous system.In addition,environmental enrichment is a promising technique for inducing the recovery of motor impairments in ischemic stroke models.The present study aimed to explore whether environmental enrichment combined with fasudil can facilitate motor function recovery and induce cortical axonal regeneration after stroke.First,a mouse model of ischemic cerebral stroke was established by photochemical embolization of the left sensorimotor cortex.Fasudil solution(10 mg/kg per day)was injected intraperitoneally for 21 days after the photothrombotic stroke.An environmental enrichment intervention was performed on days 7-21 after the photothrombotic stroke.The results revealed that environmental enrichment combined with fasudil improved motor function,increased growth-associated protein 43 expression in the infarcted cerebral cortex,promoted axonal regeneration on the contralateral side,and downregulated ROCK,p-LIM domain kinase(LIMK)1,and p-cofilin expression.The combined intervention was superior to monotherapy.These findings suggest that environmental enrichment combined with fasudil treatment promotes motor recovery after stroke,at least partly by stimulating axonal regeneration.The underlying mechanism might involve ROCK/LIMK1/cofilin pathway regulation.This study was approved by the Institutional Animal Care and Use Committee of Fudan University,China(approval No.20160858A232)on February 24,2016. 展开更多
关键词 axon regeneration biotinylated dextran amines environmental enrichment FASUDIL growth-associated protein 43 ischemic stroke motor recovery Nissl bodies Rho/rock pathway
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Inhibition of neurite outgrowth using commercial myelin associated glycoprotein-Fc in neuro-2a cells 被引量:2
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作者 Fu Liu Mei-Ling Gao +2 位作者 Juan Bai Ya-Fang Wang Xia-Qing Li 《Neural Regeneration Research》 SCIE CAS CSCD 2018年第11期1893-1899,共7页
Myelin-associated glycoprotein(MAG) inhibits the growth of neurites from nerve cells. Extraction and purification of MAG require complex operations; therefore, we attempted to determine whether commercially availabl... Myelin-associated glycoprotein(MAG) inhibits the growth of neurites from nerve cells. Extraction and purification of MAG require complex operations; therefore, we attempted to determine whether commercially available MAG-Fc can replace endogenous MAG for research purposes. Immunofluorescence using specific antibodies against MAG, Nogo receptor(NgR) and paired immunoglobulin-like receptor B(PirB) was used to determine whether MAG-Fc can be endocytosed by neuro-2a cells. In addition, neurite outgrowth of neuro-2a cells treated with different doses of MAG-Fc was evaluated. Enzyme linked immunosorbent assays were used to measure RhoA activity. Western blot assays were conducted to assess Rho-associated protein kinase(ROCK) phosphorylation. Neuro-2a cells expressed NgR and PirB, and MAG-Fc could be endocytosed by binding to NgR and PirB. This activated intracellular signaling pathways to increase RhoA activity and ROCK phosphorylation, ultimately inhibiting neurite outgrowth. These findings not only verify that MAG-Fc can inhibit the growth of neural neurites by activating RhoA signaling pathways, similarly to endogenous MAG, but also clearly demonstrate that commercial MAG-Fc is suitable for experimental studies of neurite outgrowth. 展开更多
关键词 nerve regeneration myelin growth inhibitors myelin-associated glycoprotein MAG-Fc cell culture receptors for myelin-associatedglycoprotein neuro-2a cell line RhoA/rock signaling pathways neurite outgrowth neural regeneration
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Houshiheisan and its components promote axon regeneration after ischemic brain injury 被引量:14
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作者 Yue Lu Flora Hsiang +5 位作者 Jia-Hui Chang Xiao-Quan Yao Hui Zhao Hai-Yan Zou Lei Wang Qiu-Xia Zhang 《Neural Regeneration Research》 SCIE CAS CSCD 2018年第7期1195-1203,共9页
Houshiheisan,a classic prescription in traditional Chinese medicine,contains Flos Chrysanthemi,Radix Saposhnikoviae,Ramulus Cinnamomi,Rhizoma Chuanxiong,Radix et Rhizoma Asari,Radix Platycodonis,Rhizoma Atractylodis m... Houshiheisan,a classic prescription in traditional Chinese medicine,contains Flos Chrysanthemi,Radix Saposhnikoviae,Ramulus Cinnamomi,Rhizoma Chuanxiong,Radix et Rhizoma Asari,Radix Platycodonis,Rhizoma Atractylodis macrocephalae,Poria,Rhizoma Zingiberis,Radix Angelicae sinensis,Radix et Rhizoma Ginseng,Radix Scutellariae and Concha Ostreae.According to traditional Chinese medicine theory,Flos Chrysanthemi,Radix Saposhnikoviae,Ramulus Cinnamomi,Rhizoma Chuanxiong,Radix et Rhizoma Asari and Radix Platycodonis are wind-dispelling drugs;Rhizoma Atractylodis macrocephalae,Poria,Rhizoma Zingiberis,Radix Angelicae sinensis and Radix et Rhizoma Ginseng are deficiency-nourishing drugs.A large number of randomized controlled trials have shown that Houshiheisan is effective in treating stroke,but its mechanism of action is unknown.Axonal remodeling is an important mechanism in neural protection and regeneration.Therefore,this study explored the effect and mechanism of action of Houshiheisan on the repair of axons after cerebral ischemia.Rat models of focal cerebral ischemia were established by ligating the right middle cerebral artery.At 6 hours after model establishment,rats were intragastrically administered 10.5 g/kg Houshiheisan or 7.7 g/kg wind-dispelling drug or 2.59 g/kg deficiency-nourishing drug.These medicines were intragastrically administered as above every 24 hours for 7 consecutive days.Houshiheisan,and its wind-dispelling and deficiency-nourishing components reduced the neurological deficit score and ameliorated axon and neuron lesions after cerebral ischemia.Furthermore,Houshiheisan,and its wind-dispelling and deficiency-nourishing components decreased the expression of proteins that inhibit axonal remodeling:amyloid precursor protein,neurite outgrowth inhibitor protein A(Nogo-A),Rho family small GTPase A(Rho A) and Rho-associated kinase 2(Rock2),and increased the expression of growth associated protein-43,microtubule-associated protein-2,netrin-1,Ras-related C3 botulinum toxin substrate 1(Rac1) and cell division cycle 42(Cdc42).The effect of Houshiheisan was stronger than wind-dispelling drugs or deficiency-nourishing drugs alone.In conclusion,Houshiheisan,and wind-dispelling and deficiency-nourishing drugs promote the repair of axons and nerve regeneration after cerebral ischemia through Nogo-A/Rho A/Rock2 and Netrin-1/Rac1/Cdc42 signaling pathways.These effects are strongest with Houshiheisan. 展开更多
关键词 nerve regeneration Houshiheisan wind-dispelling drug deficiency-nourishing drug cerebral ischemia Nogo-A/Rho A/rock2 signaling pathway axonal recovery Netrin-1/Rac1/Cdc42 signaling pathway neuroprotection neural regeneration
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ROCK inhibitor:Focus on recent updates
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作者 Yaodong You Kun Zhu +7 位作者 Jie Wang Qi Liang Wen Li Lin Wang Baojun Guo Jing Zhou Xuanlin Feng Jianyou Shi 《Chinese Chemical Letters》 SCIE CAS CSCD 2023年第12期111-125,共15页
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
关键词 rock-I rock-I rock inhibitor rock signaling pathway Structure-activity relationship Pharmacological activity
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Moxibustion pretreatment inhibits RhoA/ROCK signaling to prevent lung inflammation in asthmatic rats 被引量:3
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作者 Hai-zhen ZHENG Qi QIU +2 位作者 Jun XIONG Jun CHEN Ling-cong GUAN 《World Journal of Acupuncture-Moxibustion》 CSCD 2022年第3期230-236,共7页
Objective:To determine whether pretreatment moxibustion prevents asthma by down-regulating the lung RhoA/ROCK pathway in rats with bronchial asthma and benignly mediating the lung inflammatory response.Methods:Twenty ... Objective:To determine whether pretreatment moxibustion prevents asthma by down-regulating the lung RhoA/ROCK pathway in rats with bronchial asthma and benignly mediating the lung inflammatory response.Methods:Twenty Sprague Dawley(SD)rats were randomly divided into normal control group(C),asthma model group(M),suspended moxibustion 40 min+asthma group(SM40),and suspended moxibustion 10 min+asthma group(SM10).Ovalbumin was used as a sensitizer.The two moxibustion groups completed moxibustion treatment lasted 40 min or 10 min respectively 30 min before modeling onset,and was repeated five times in each modeling cycle,for a total of 15 times.Samples were harvested on day 30.Results:Lung impairment was significant in the M group,whereas pretreatment with SM10 and SM40 dramatically attenuated the injury.After modeling,mRNA expression of RhoA and ROCK2 in the lung tissue was significantly higher than that in C group(both P<0.001),resulting in significant increase in protein levels of IL-17 A(P<0.001).Significant decrease in RhoA and ROCK2 mRNA expression was seen in the SM10(P<0.001,P<0.01)and SM40(both P<0.001)groups compared to that with M rats.The differential trend in the SM40 group was more evident than that in the SM10 group.Regarding IL-10 or IL-17 A protein concentration,an upregulation or down-regulation was observed in both SM10(P<0.05,P<0.01)and SM40 groups(both P<0.001)compared to that with the M group.Conclusions:Moxibustion pretreatment significantly prevented pulmonary inflammation in asthmatic rats,potentially via inhibition of the RhoA/ROCK pathway.The efficacty of moxibustion appeared to be significantly associated with the duration of intervention with moxibustion. 展开更多
关键词 MOXIBUSTION ASTHMA RhoA/rock pathway Prevention INFLAMMATION
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Effects of Bunao-Fuyuan decoction serum on proliferation and migration of vascular smooth muscle cells in atherosclerotic 被引量:7
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作者 GUO Huan-Yu LU Zhen-Ya +3 位作者 ZHAO Bo JIANG Wen-Wei XIONG Yan-Hua WANG Kai 《Chinese Journal of Natural Medicines》 SCIE CAS CSCD 2021年第1期36-45,共10页
Atherosclerosis(AS)is a chronic inflammatory disease,the main causes of which include abnormal lipid metabolism,endothelial injury,physical and chemical injury,hemodynamic injury,genetic factors and so on.These causes... Atherosclerosis(AS)is a chronic inflammatory disease,the main causes of which include abnormal lipid metabolism,endothelial injury,physical and chemical injury,hemodynamic injury,genetic factors and so on.These causes can lead to inflammatory injury of blood vessels and local dysfunction.Bunao-Fuyuan decoction(BNFY)is a traditional Chinese medicine compound that can treat cardiovascular and cerebrovascular diseases,but its effect on AS is still unknown.The aim of this study was to investigate the effect and mechanism of BNFY in proliferation and migration of vascular smooth muscle cells(VSMCs)on AS.At first,the expression ofα-SMA protein in ox-LDL-induced VSMCs,which was detected by immunofluorescence staining and western blot.CCK-8 technique and cloning technique were used to detect the cell proliferation of ox-LDL-induced VSMCs after adding BNFY.Meanwhile,the expression of proliferating protein Ki67 was detected by immunofluorescence staining.Western blot was also used to detect the expression of proliferation-related proteins CDK2,CyclinE1 and P27.Flow cytometry was used to detect the effect of BNFY on cell cycle.The effects of BNFY on proliferation and migration of cells were detected by cell scratch test and Transwell.Western blot was used to detect the expression of adhesion factors ICAM1,VCAM1,muc1,VE-cadherin and RHOA/ROCK-related proteins in cells.We found that the expression of AS markerα-SMA protein increased significantly and cells shriveled and a few floated on the medium after induction of ox-LDL on VSCMs.The proliferation rate of ox-LDL VSMCs decreased significantly after adding different doses of BNFY,and BNFY can inhibit cell cycle.Meanwhile,we also found that cell invasion and migration rate were significantly inhibited and related cell adhesion factors ICAM1,VCAM1,muc1 and VE-cadherin were inhibited too by BNFY.Finally,we found that BNFY inhibited the expression of RHOA,ROCK1,ROCK2,p-MLC proteins in the RHOA/ROCK signaling pathway.Therefore,we can summarize that BNFY may inhibit the proliferation and migration of atherosclerotic vascular smooth muscle cells by inhibiting the activity of RHOA/ROCK signaling pathway. 展开更多
关键词 ATHEROSCLEROSIS Bunao-Fuyuan decoction PROLIFERATION MIGRATION RHOA/rock signaling pathway
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