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1.
目的探讨RhoA基因对唾液腺腺样囊性癌(salivary adenoidcysticcarcinoma,SACC)细胞的迁移和侵袭能力的影响。方法将液氮冻存的20例SACC及正常癌旁组织研磨匀浆,分别提取总RNA和总蛋白检测RhoA的表达情况。同时构建RhoA?siRNA转染2个细胞株SACC?LM和SACC?83细胞进行细胞学实验,实验分为实验组(转染RhoA?siRNA基因),阴性对照组(转染siRNA?NC基因)和空白对照组。通过qRT?PCR检测各组细胞RhoA的mRNA表达并确定转染效率;Western blot分析各组细胞RhoA及上皮-间充质转换(epithelial?mesenchymal transition,EMT)标志分子(E?cadherin、N?cadherin、Vimentin)的蛋白表达;Transwell实验及划痕实验分析各组细胞侵袭和迁移能力的变化。结果与正常癌旁组织相比,RhoA mRNA和蛋白相对表达量在SACC组织中增高(P<0.01);实验组与对照组相比,RhoA mRNA的相对表达量和蛋白的相对表达量降低,E?cadherin蛋白的相对表达量增加,N?cadherin、Vimentin蛋白的相对表达量降低(P<0.01);实验组细胞侵袭和迁移能力降低(P<0.01)。结论RhoA在SACC组织中表达增高;体外沉默RhoA基因可有效抑制SACC?LM和SACC?83细胞迁移和侵袭能力,其可能通过作用EMT影响SACC细胞迁移和侵袭能力。  相似文献   
2.
[目的] 明确自发性高血压大鼠(SHR)脑损害与RhoA、ROCK-1的相关性,探讨针刺干预SHR脑保护的Rho通路机制。[方法] 将SHR随机分为模型对照组、太冲穴组,WKY大鼠设为正常对照组。太冲穴组针刺干预4周,其余两组在干预期内给予相同程度、相同时长的抓取。观测各组大鼠收缩压、舒张压、平均动脉压的改变;苏木精-伊红(HE)染色观察脑组织形态学改变;蛋白免疫印迹(Western blot)法测定各组大鼠脑组织中RhoA、ROCK-1的表达水平。[结果] 在干预周期内,正常对照组收缩压、舒张压、平均压均处于正常血压范围内。与正常对照组比较,模型对照组收缩压、舒张压、平均压均较高,且有随着周龄增加而增高的趋势。与模型对照组相比,太冲穴组可有效降低收缩压,有降低舒张压、平均压的趋势。模型对照组较正常对照组脑组织细胞排列紊乱,细胞坏死及间质水肿程度加重,RhoA、ROCK-1表达升高;太冲穴组与模型对照组比较,脑细胞排列规则,细胞坏死及间质水肿消失,RhoA、ROCK-1表达下降。[结论] 针刺太冲穴能有效降低SHR血压,改善脑损害,其机制可能与抑制RhoA/ROCK-1信号通路表达相关。  相似文献   
3.
RhoA has been identified as having a gain-of-function mutation in approximately 20% of diffuse gastric cancer patients. However, the carcinogenic role of RhoA mutations in gastric cancer (GC) is unclear. In the present study, we report that RhoA directly interacts with c-Met and can be phosphorylated by c-Met at Y42 before subsequent K48-linked polyubiquitination and proteasome-mediated protein degradation. Y42C-mutated RhoA exhibits higher protein levels and promotes the proliferation and motility of GC cells. Interestingly, a c-Met inhibitor significantly repressed the growth of GC cells transfected with WT RhoA but not RhoA mutated at Y42 in vivo and in vitro. Analyses of human GC tissues showed that the combined levels of p-c-Met and p-RhoA are a better predictor for prognosis than either factor alone. Taken together, our findings unravel the mechanism by which the RhoA Y42 mutant is linked to poor prognosis in GC. Moreover, this study helps to identify a strategy for patient stratification and optimization of targeted c-Met therapy. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.  相似文献   
4.
杨建  王敏  高莹  王舒 《天津中医药》2020,37(3):313-317
[目的]明确自发性高血压大鼠(SHR)脑损害与RhoA、ROCK-1的相关性,探讨针刺干预SHR脑保护的Rho通路机制。[方法]将SHR随机分为模型对照组、太冲穴组,WKY大鼠设为正常对照组。太冲穴组针刺干预4周,其余两组在干预期内给予相同程度、相同时长的抓取。观测各组大鼠收缩压、舒张压、平均动脉压的改变;苏木精-伊红(HE)染色观察脑组织形态学改变;蛋白免疫印迹(Western blot)法测定各组大鼠脑组织中RhoA、ROCK-1的表达水平。[结果]在干预周期内,正常对照组收缩压、舒张压、平均压均处于正常血压范围内。与正常对照组比较,模型对照组收缩压、舒张压、平均压均较高,且有随着周龄增加而增高的趋势。与模型对照组相比,太冲穴组可有效降低收缩压,有降低舒张压、平均压的趋势。模型对照组较正常对照组脑组织细胞排列紊乱,细胞坏死及间质水肿程度加重,RhoA、ROCK-1表达升高;太冲穴组与模型对照组比较,脑细胞排列规则,细胞坏死及间质水肿消失,RhoA、ROCK-1表达下降。[结论]针刺太冲穴能有效降低SHR血压,改善脑损害,其机制可能与抑制RhoA/ROCK-1信号通路表达相关。  相似文献   
5.
目的:探讨油酸型急性肺损伤模型中IL‐8与RhoA的相关性。方法建立大鼠油酸急性肺损伤模型,检测各组大鼠肺湿/干重比及肺泡灌洗液(BALF)中中性粒细胞比例,比较肺组织病理学改变;采用聚合酶链反应检测肺组织匀浆RhoA表达,酶联免疫吸附法(ELISA )测定大鼠IL‐8的变化。结果肺W/D损伤组在2、6、12、24 h均较正常组明显升高,并且损伤组2 h比值最高;损伤组各时间点BALF中中性粒细胞计数比例明显高于正常组,24 h中性粒细胞细胞比例达峰值;损伤组个时间点血浆及BALF中IL‐8较正常组明显升高,两者具有相关性;损伤组各时间点RhoA的表达明显高于正常组。结论油酸型急性肺损伤大鼠中存在RhoA的高表达,RhoA表达增加可致IL‐8的表达增加,进而引起炎症细胞浸润。  相似文献   
6.
Multiple myeloma (MM) is a B lymphocyte malignancy that remains incurable despite extensive research efforts. This is due, in part, to frequent disease recurrences associated with the persistence of myeloma cancer stem cells (mCSCs). Bone marrow mesenchymal stromal cells (BMSCs) play critical roles in supporting mCSCs through genetic or biochemical alterations. Previously, we identified mechanical distinctions between BMSCs isolated from MM patients (mBMSCs) and those present in the BM of healthy individuals (nBMSCs). These properties of mBMSC contributed to their ability to preferentially support mCSCs. To further illustrate mechanisms underlying the differences between mBMSCs and nBMSCs, here we report that (i) mBMSCs express an abnormal, constitutively high level of phosphorylated Myosin II, which leads to stiffer membrane mechanics, (ii) mBMSCs are more sensitive to SDF‐1α‐induced activation of MYL2 through the G(i./o)‐PI3K‐RhoA‐ROCK‐Myosin II signaling pathway, affecting Young's modulus in BMSCs and (iii) activated Myosin II confers increased cell contractile potential, leading to enhanced collagen matrix remodeling and promoting the cell–cell interaction between mCSCs and mBMSCs. Together, our findings suggest that interfering with SDF‐1α signaling may serve as a new therapeutic approach for eliminating mCSCs by disrupting their interaction with mBMSCs.  相似文献   
7.
Breast cancer is the most prevalent malignant disease in women worldwide. In patients with breast cancer, metastasis to distant sites directly determines the survival outcome. However, the molecular mechanism underlying metastasis in breast cancer remains to be defined. In this report, we found that Friend leukemia virus integration 1 (FLI1) proto-oncogene was differentially expressed between the aggressive MDA-MB231 and the non-aggressive MCF-7 breast cancer cells. Congruently, immunohistochemical staining of clinical samples revealed that FLI1 was overexpressed in breast cancers as compared with the adjacent tissues. The abundance of FLI1 protein was strongly correlated with the advanced stage, poor differentiation, and lymph node metastasis in breast cancer patients. Knockdown of FLI1 with small interfering RNAs significantly attenuated the potential of migration and invasion in highly metastatic human breast cancer cells. FLI1 oncoprotein activated the Rho GTPase pathway that is known to play a role in tumor metastasis. This study for the first time identifies FLI1 as a clinically and functionally important target gene of metastasis, providing a rationale for developing FLI1 inhibitors in the treatment of breast cancer.  相似文献   
8.
9.
Microglial polarization to the anti-inflammatory M2 phenotype is essential in resolving neuroinflammation, making it a promising therapeutic strategy for stroke intervention. The actin cytoskeleton is known to be important for the physiological functions of microglia, including migration and phagocytosis. Profilin 1 (PFN1), an actin-binding protein, is involved in the dynamic transformation and reorganization of actin. However, the role of PFN1 in microglial polarization and ischemia/reperfusion injury is unclear. The role of PFN1 on microglial polarization was examined in vitro in BV2 microglial cells subjected to oxygen-glucose deprivation/reoxygenation (OGDR) and in vivo in male mice after transient middle cerebral artery occlusion (MCAO). Knockdown of PFN1 inhibited M1 microglial polarization and promoted M2 microglia polarization 48 hr after OGDR stimulation in BV2 cells and 7 days after MCAO-induced injury in male mice. RhoA/ROCK pathway was involved in the regulation of PFN1 during microglial polarization. Knockdown of PFN1 also significantly attenuated brain infarcts and edema, improved cerebral blood flow and neurological deficits in MCAO-injured mice. Inhibition of PFN1 effectively protected the brain against ischemia/reperfusion injuries by promoting M2 microglial polarization in vitro and in vivo.  相似文献   
10.
Pyrin is a cytosolic pattern-recognition receptor that normally functions as a guard to trigger capase-1 inflammasome assembly in response to bacterial toxins and effectors that inactivate RhoA. The MEFV gene encoding human pyrin is preferentially expressed in phagocytes. Key domains in pyrin include a pyrin domain (PYD), a linker region, and a B30.2 domain. Binding of ASC to pyrin by a PYD-PYD interaction triggers inflammasome assembly. Pyrin is held in an inactive conformation by negative regulation mechanisms to avoid premature inflammasome assembly. One mechanism of negative regulation involves phosphorylation of the linker by PRK kinase which in turn is positively regulated by active RhoA. The B30.2 domain also negatively regulates pyrin. Gain of function mutations in MEFV responsible for the autoinflammatory disease Familial Mediterranean Fever (FMF) map to exon 10 encoding the B30.2 domain. Insights into pyrin regulation have come from studies of several Yersinia effectors, which are injected into phagocytes and interact with the RhoA-PRK-pyrin axis during infection. Two effectors, YopE and YopT, inactivate RhoA to disrupt phagocytic signaling. To counteract an effector-triggered immune response, a third effector, YopM, binds to and inhibits pyrin by hijacking PRK and RSK and directing linker phosphorylation. Inhibition of pyrin by YopM is required for virulence of Yersinia pestis, the agent of plague. Recent results from infection studies with human phagocytes and mice producing pyrin B30.2 FMF variants show that gain of function MEFV mutations bypass inhibition by YopM. Population genetic data suggest that MEFV mutations were selected for in individuals of Mediterranean decent during historic plague pandemics. This review discusses current concepts of pyrin regulation and its interaction with Yersinia effectors.  相似文献   
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