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1.
Specific members of the Rho family of GTPases exert unique influences on thymocyte proliferation, differentiation and deletion. Dbs is a guanine nucleotide exchange factor which is expressed throughout thymocyte development and is able to activate the Rho family GTPases CDC42, RhoA and RhoG. Transgenic mice expressing an activated form of Dbs had increased numbers of double-negative thymocytes. The Dbs transgene promoted expansion of double-negative thymocytes in the absence of pre-TCR, but had no effect on pre-TCR-dependent differentiation of double-negative thymocytes into double-positive thymocytes. Transgenic double-positive thymocytes were proliferative in vivo, but were also susceptible to apoptosis in vivo and in vitro. The transgenic single-positive thymocytes had attenuated proliferative responses following TCR ligation, and were depleted rather than expanded during culture in the presence of anti-CD3. When expressing a positively selectable TCR, transgenic double-positive thymocytes were increased in number and activated, but the output of single-positive thymocytes was reduced. Transgenic double-positive thymocytes were acutely sensitive to deletion by TCR ligation in vivo. These results indicate that activation of Dbs has the potential to promote proliferation throughout thymocyte development, but also sensitizes double-positive and single-positive thymocytes to deletion. 相似文献
2.
The expression of Rho proteins decreases with human brain tumor progression: Potential tumor markers
Forget MA Desrosiers RR Del M Moumdjian R Shedid D Berthelet F Béliveau R 《Clinical & experimental metastasis》2002,19(1):9-15
Astrocytic tumors are the most common human brain tumors. Establishment of tumor grade is a key determinant both in the choice of a therapeutic approach and in the prognosis. The diagnosis of astrocytic tumors is currently determined following histopathological analysis. The identification of molecular markers would offer a complementary tool for characterizing tumors with respect to their clinical behavior. In this study we determined the expression levels of 3 small GTP binding proteins (RhoA, RhoB and Rac1), of their inhibitor RhoGDI and of caveolin-1 in 24 human astrocytic tumors of grades I to IV. Our results demonstrated that the expression of RhoA and RhoB decreased significantly in all brain tumors studied and was inversely related with tumor of grade II to IV malignancy. The amount of caveolin-1 immunodetected was not significantly different from normal brain samples while the Rac1 expression level was diminished in astrocytic tumors of grades III and IV. Our finding that RhoA and RhoB expression levels are correlated to tumor malignancy suggests that they may serve as novel and efficient diagnostic markers for astrocytic brain tumors of histological grade II to IV and complement currently applied histopathological analysis. 相似文献
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Esnault and colleagues (pp. 943–958) take a genomics approach to investigate the role of SRF (serum response factor) in the serum response of fibroblasts. The well-established dual role of SRF with alternative cofactors and responsiveness to two signaling pathways is illustrated at the genome-wide level, yet new insight comes from this global picture. 相似文献
6.
E. Theodorsson O. Rugarn 《Scandinavian journal of clinical and laboratory investigation》2013,73(5):411-418
Galanin is a regulatory peptide with wide distribution in the central and peripheral nervous system and with numerous biological effects. Several radioimmunoassays based on antisera raised against porcine galanin have been used to measure immunoreactivity in rat tissues. However, considerable lack of parallelism has been observed between the porcine standard and rat tissue extracts, which may decrease the reliability of the quantitative data. The purpose of the present study was therefore to raise antibodies against rat galanin and establish a competitive radioimmunoassay for rat galanin. Two antisera, RatGal4 and RatGal5, were characterized in detail. The homogeneity of the immunoreactive material from several tissues was also investigated with column chromatography. At reverse-phase high-pressure liquid chromatography more than 95% of the immunoreactive material from rat CNS eluted as a single peak in the position of synthetic rat galanin, whereas almost half of the immunoreactive material from the intestine eluted in positions different from the synthetic peptide. Extracts of rat brains as well as jejunum diluted in parallel with the standard curve for both antisera. We conclude that measurements of rat galanin based on these antisera are therefore more reliable than those based on antisera raised against porcine galanin. 相似文献
7.
《药学学报(英文版)》2020,10(2):327-343
Our recent studies demonstrated that the natural product nobiletin (NOB) served as a promising multidrug resistance (MDR) reversal agent and improved the effectiveness of cancer chemotherapy in vitro. However, low aqueous solubility and difficulty in total synthesis limited its application as a therapeutic agent. To tackle these challenges, NOB was synthesized in a high yield by a concise route of six steps and fourteen derivatives were synthesized with remarkable solubility and efficacy. All the compounds showed improved sensitivity to paclitaxel (PTX) in P-glycoprotein (P-gp) overexpressing MDR cancer cells. Among them, compound 29d exhibited water solubility 280-fold higher than NOB. A drug-resistance A549/T xenograft model showed that 29d, at a dose of 50 mg/kg co-administered with PTX (15 mg/kg), inhibited tumor growth more effective than NOB and remarkably increased PTX concentration in the tumors via P-gp inhibition. Moreover, Western blot experiments revealed that 29d inhibited expression of NRF2, phosphorylated ERK and AKT in MDR cancer cells, thus implying 29d of multiple mechanisms to reverse MDR in lung cancer. 相似文献
8.
研究Rho激酶抑制剂Y27632 对视网膜缺血再灌注损伤大鼠视网膜组织形态学的影响。方法:实验研究。将60只SD大鼠随机分为4组,每组15只:正常对照组(正常组)、急性缺血再灌注损伤组(IRI组)、0.9%氯化钠溶液对照组(生理盐水组)、Y27632治疗组(Y27632组)。再灌注损伤后24 h(10只)和168 h(5只)处死各组动物,行HE染色、ADP酶染色检查,光镜下观察大鼠视网膜组织病理学变化及视网膜厚度变化。数据采用单因素方差分析。结果:正常组大鼠视网膜结构清晰,三层细胞结构排列整齐。IRI组于再灌注24 h后视网膜厚度增加,内外丛状层组织疏松,视网膜节细胞、内外核层细胞水肿明显、排列紊乱,视网膜节细胞减少。168 h后,视网膜水肿消退、厚度变薄、呈萎缩状,神经节细胞及内外核层细胞数量减少,在视网膜前和神经纤维层可见毛细血管。再灌注
24 h后,IRI组视网膜厚度较正常组增加(P=0.005),Y27632组视网膜厚度低于生理盐水组(P=0.032)。再灌注168 h后,IRI组视网膜厚度低于正常组(P<0.001),Y27632组视网膜厚度较生理盐水组增加(P=0.025)。正常组大鼠视网膜血管自视乳头发出,向四周呈放射状均匀分布,毛细血管网结构清晰。再灌注24 h后,IRI组视网膜血管管径变细,走行较僵直,分支减少,视乳头周围及中周部视网膜可见大片无灌注区,无灌注区周围可见新生血管芽渐成网状。Y27632组可见视乳头周围及中周部视网膜局部无灌注区形成,无灌注区周围可见新生血管。后极部4PD无灌注区面积明显小于IRI组及生理盐水组。结论:Y27632玻璃体腔注射可以减轻视网膜缺血再灌注早期的视网膜水肿,减少视网膜神经节细胞的凋亡,减少视网膜新生血管生成,减轻再灌注晚期的视网膜萎缩,具有视神经保护作用。 相似文献
9.
《药学学报(英文版)》2020,10(5):799-811
Overexpression of adenosine triphosphate (ATP)-binding cassette subfamily G member 2 (ABCG2) in cancer cells is known to cause multidrug resistance (MDR), which severely limits the clinical efficacy of chemotherapy. Currently, there is no FDA-approved MDR modulator for clinical use. In this study, rociletinib (CO-1686), a mutant-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), was found to significantly improve the efficacy of ABCG2 substrate chemotherapeutic agents in the transporter-overexpressing cancer cells in vitro and in MDR tumor xenografts in nude mice, without incurring additional toxicity. Mechanistic studies revealed that in ABCG2-overexpressing cancer cells, rociletinib inhibited ABCG2-mediated drug efflux and increased intracellular accumulation of ABCG2 probe substrates. Moreover, rociletinib, inhibited the ATPase activity, and competed with [125I] iodoarylazidoprazosin (IAAP) photolabeling of ABCG2. However, ABCG2 expression at mRNA and protein levels was not altered in the ABCG2-overexpressing cells after treatment with rociletinib. In addition, rociletinib did not inhibit EGFR downstream signaling and phosphorylation of protein kinase B (AKT) and extracellular signal-regulated kinase (ERK). Our results collectively showed that rociletinib reversed ABCG2-mediated MDR by inhibiting ABCG2 efflux function, thus increasing the cellular accumulation of the transporter substrate anticancer drugs. The findings advocated the combination use of rociletinib and other chemotherapeutic drugs in cancer patients with ABCG2-overexpressing MDR tumors. 相似文献
10.
Feng Xue Terumi Takahara Yutaka Yata Qiang Xia Kazunobu Nonome Eiji Shinno Masami Kanayama Shiro Takahara Toshiro Sugiyama 《Hepatology research》2008,38(8):810-817
Aim: There is growing evidence that the Rho/Rho-associated coiled coil-forming kinase (ROCK) signaling pathway is upregulated in tumors and plays a key role in cancer invasion and metastasis. Our aim was to test the anticancer effects of Rho/ROCK inhibitor, Y-27632, including possible mechanisms in a highly-metastasizing hepatocellular carcinoma (HCC) mouse model on its secretion of matrix metalloproteinase (MMP) and tumor progression.
Methods: Following orthotopic implantation of CBO140C12 HCC tumor fragments into the liver of mice, the mice were randomly assigned to a Y-27632-treated group or control group. After treatment for 4 weeks, specimens were obtained to evaluate tumor size, metastases, and immunohistochemical findings. In vitro , we examined the effects of Y-27632 and RhoC siRNA on MMP-2 and -9 expressions, invasiveness, and apoptosis in cultured tumor cells.
Results: Both RhoA and RhoC were upregulated in HCC-bearing livers, and Y-27632 significantly inhibited not only tumor growth and intrahepatic metastasis ( P < 0.05), but also tumoral MMP-9 expression. Moreover, Y-27632 treatment resulted in large necrotic areas in tumors. In vitro , Y-27632 and RhoC siRNA reduced MMP-2 and -9 expressions, as well as the chemotactic migration of tumor cells dose-dependently, and increased apoptosis eight times.
Conclusion: Y-27632 suppresses progression and limits the intrahepatic metastasis of established HCC. This could be linked to the decreased MMP expression and induction of apoptosis in tumor cells. Rho signaling may prove to be a productive target in anticancer therapy. 相似文献
Methods: Following orthotopic implantation of CBO140C12 HCC tumor fragments into the liver of mice, the mice were randomly assigned to a Y-27632-treated group or control group. After treatment for 4 weeks, specimens were obtained to evaluate tumor size, metastases, and immunohistochemical findings. In vitro , we examined the effects of Y-27632 and RhoC siRNA on MMP-2 and -9 expressions, invasiveness, and apoptosis in cultured tumor cells.
Results: Both RhoA and RhoC were upregulated in HCC-bearing livers, and Y-27632 significantly inhibited not only tumor growth and intrahepatic metastasis ( P < 0.05), but also tumoral MMP-9 expression. Moreover, Y-27632 treatment resulted in large necrotic areas in tumors. In vitro , Y-27632 and RhoC siRNA reduced MMP-2 and -9 expressions, as well as the chemotactic migration of tumor cells dose-dependently, and increased apoptosis eight times.
Conclusion: Y-27632 suppresses progression and limits the intrahepatic metastasis of established HCC. This could be linked to the decreased MMP expression and induction of apoptosis in tumor cells. Rho signaling may prove to be a productive target in anticancer therapy. 相似文献