Objective. To determine the effects of losartan and captopril treatment on ventricular remodeling and function after myocardial infarction in rats. Methods. Thirty-two rats with MI induced by coronary ligation after s...Objective. To determine the effects of losartan and captopril treatment on ventricular remodeling and function after myocardial infarction in rats. Methods. Thirty-two rats with MI induced by coronary ligation after seven days were divided into four groups randomly and treated with captopril(2 g. liter-1, group A), losartan(10 mg. kg-1. d-1, group B), losartan(30 mg. kg-1. d-1,group C) and placebo (no drug, group D) for six weeks, respectively. Shamoperated rats(group E)served as controls. Echocardiography was performed at 1 and 7 weeks after MI, re- spectively. Results. Compared with the results before treatment,both LV end-diastolic internal diameter and volume decreased significantly and the thickened Posterior wall was reversed in group A, B and C; the peak early filling velocity decreased whereas the peak velocity was increased in these three groups. There are no significant difference among the three treated groups. However,LV end-diastolic internal diameter and the E/A were still increased,whereas the thickness of anterior wall and the peak velocity of LV outflow were decreased in group A,B,and C after treatment comparing with group E. Conclusion. Both angiotensin converting enzyme inhibitor and angiotensin II receptor antagonist can prevent the ventricular remodeling and improve the ventricular function.展开更多
目的:探讨中药验方天龙喘咳灵水煎剂干预支气管哮喘气道重塑的可能机制。方法:实验设3组,盐水对照组,哮喘模型组,天龙咳喘灵治疗组。小鼠经常规OVA致敏后连续18天给予1.5%的OVA雾化吸入激发。治疗组小鼠每次激发后给予雾化天龙咳喘灵水...目的:探讨中药验方天龙喘咳灵水煎剂干预支气管哮喘气道重塑的可能机制。方法:实验设3组,盐水对照组,哮喘模型组,天龙咳喘灵治疗组。小鼠经常规OVA致敏后连续18天给予1.5%的OVA雾化吸入激发。治疗组小鼠每次激发后给予雾化天龙咳喘灵水煎剂。末次激发后72h,利用气道插管检测各组小鼠气道反应性;肺泡灌洗,观察肺泡灌洗液(BALF)中细胞总数和细胞分类;分离小鼠右肺制备组织切片进行病理分析;分离小鼠左肺提取总蛋白,检测肺部α-SMA表达水平和丝裂原活化蛋白激酶(mitogen activatedprotein,MAPK)信号通路,信号传导及转录活化因子-3(signal transducers and activators of transcription-3,Stat3)的活化情况。结果:与盐水对照组相比,OVA-哮喘组小鼠气道反应性显著升高(P<0.01),相应BALF中细胞总数和嗜酸性粒细胞比例也明显增加(P<0.01);天龙咳喘灵治疗组小鼠气道反应性明显低于哮喘组小鼠(P<0.01),但BALF中细胞总数和嗜酸性粒细胞比例亦较正常对照组增加(P<0.01)。肺组织病理切片显示哮喘组上皮下基底膜层明显增厚,α-SMA表达水平增高,而天龙咳喘灵治疗组气道上皮下未见明显改变,α-SMA表达水平与盐水对照组无显著差别。在哮喘小鼠肺部,MAPKs信号通路当中的胞外信号调节激酶(extracellular signal-reg-ulated kinase,ERK)通路和Stat3通路明显激活,而天龙咳喘灵能有效抑制该信号途径的活化。结论:天龙喘咳灵水煎剂能有效防治慢性哮喘小鼠模型的气道重塑,其机制可能是通过抑制ERKs通路和Stat3通路的活化实现的。展开更多
Dynamic and heterogeneous interaction between tumor cells and the surrounding microenvironment fuels the occurrence,progression,invasion,and metastasis of solid tumors.In this process,the tumormicroenvironment(TME)fra...Dynamic and heterogeneous interaction between tumor cells and the surrounding microenvironment fuels the occurrence,progression,invasion,and metastasis of solid tumors.In this process,the tumormicroenvironment(TME)fractures cellular and matrix architecture normality through biochemical and mechanical means,abetting tumorigenesis and treatment resistance.Tumor cells sense and respond to the strength,direction,and duration of mechanical cues in the TME by various mechanotransduction pathways.However,far less understood is the comprehensive perspective of the functions and mechanisms of mechanotransduction.Due to the great therapeutic difficulties brought by the mechanical changes in the TME,emerging studies have focused on targeting the adverse mechanical factors in the TME to attenuate disease rather than conventionally targeting tumor cells themselves,which has been proven to be a potential therapeutic approach.In this review,we discussed the origins and roles ofmechanical factors in the TME,cell sensing,mechano-biological coupling and signal transduction,in vitro construction of the tumormechanicalmicroenvironment,applications and clinical significance in the TME.展开更多
Multiple myeloma(MM) is still an incurable hematologic malignancy, which is eagerly to the discovery of novel therapeutic targets and methods. N-acetyltransferase 10(NAT10) is the first reported regulator of mRNA acet...Multiple myeloma(MM) is still an incurable hematologic malignancy, which is eagerly to the discovery of novel therapeutic targets and methods. N-acetyltransferase 10(NAT10) is the first reported regulator of mRNA acetylation that is activated in many cancers. However, the function of NAT10 in MM remains unclear. We found significant upregulation of NAT10 in MM patients compared to normal plasma cells, which was also highly correlated with MM poor outcome. Further enforced NAT10 expression promoted MM growth in vitro and in vivo, while knockdown of NAT10 reversed those effects. The correlation analysis of acetylated RNA immunoprecipitation sequencing(ac RIP-seq) and ribosome profiling sequencing(Ribo-seq) combined with RIP-PCR tests identified centrosomal protein 170(CEP170) as an important downstream target of NAT10. Interfering CEP170 expression in NAT10-OE cells attenuated the acceleration of cellular growth caused by elevated NAT10. Moreover,CEP170 overexpression promoted cellular proliferation and chromosomal instability(CIN) in MM.Intriguingly, remodelin, a selective NAT10 inhibitor, suppressed MM cellular growth, induced cellular apoptosis in vitro and prolonged the survival of 5TMM3VT mice in vivo. Collectively, our data indicate that NAT10 acetylates CEP170 mRNA to enhance CEP170 translation efficiency, which suggests that NAT10 may serve as a promising therapeutic target in MM.展开更多
基金This study was supported by National Natural Science Foundation of China (39470313)
文摘Objective. To determine the effects of losartan and captopril treatment on ventricular remodeling and function after myocardial infarction in rats. Methods. Thirty-two rats with MI induced by coronary ligation after seven days were divided into four groups randomly and treated with captopril(2 g. liter-1, group A), losartan(10 mg. kg-1. d-1, group B), losartan(30 mg. kg-1. d-1,group C) and placebo (no drug, group D) for six weeks, respectively. Shamoperated rats(group E)served as controls. Echocardiography was performed at 1 and 7 weeks after MI, re- spectively. Results. Compared with the results before treatment,both LV end-diastolic internal diameter and volume decreased significantly and the thickened Posterior wall was reversed in group A, B and C; the peak early filling velocity decreased whereas the peak velocity was increased in these three groups. There are no significant difference among the three treated groups. However,LV end-diastolic internal diameter and the E/A were still increased,whereas the thickness of anterior wall and the peak velocity of LV outflow were decreased in group A,B,and C after treatment comparing with group E. Conclusion. Both angiotensin converting enzyme inhibitor and angiotensin II receptor antagonist can prevent the ventricular remodeling and improve the ventricular function.
文摘目的:探讨中药验方天龙喘咳灵水煎剂干预支气管哮喘气道重塑的可能机制。方法:实验设3组,盐水对照组,哮喘模型组,天龙咳喘灵治疗组。小鼠经常规OVA致敏后连续18天给予1.5%的OVA雾化吸入激发。治疗组小鼠每次激发后给予雾化天龙咳喘灵水煎剂。末次激发后72h,利用气道插管检测各组小鼠气道反应性;肺泡灌洗,观察肺泡灌洗液(BALF)中细胞总数和细胞分类;分离小鼠右肺制备组织切片进行病理分析;分离小鼠左肺提取总蛋白,检测肺部α-SMA表达水平和丝裂原活化蛋白激酶(mitogen activatedprotein,MAPK)信号通路,信号传导及转录活化因子-3(signal transducers and activators of transcription-3,Stat3)的活化情况。结果:与盐水对照组相比,OVA-哮喘组小鼠气道反应性显著升高(P<0.01),相应BALF中细胞总数和嗜酸性粒细胞比例也明显增加(P<0.01);天龙咳喘灵治疗组小鼠气道反应性明显低于哮喘组小鼠(P<0.01),但BALF中细胞总数和嗜酸性粒细胞比例亦较正常对照组增加(P<0.01)。肺组织病理切片显示哮喘组上皮下基底膜层明显增厚,α-SMA表达水平增高,而天龙咳喘灵治疗组气道上皮下未见明显改变,α-SMA表达水平与盐水对照组无显著差别。在哮喘小鼠肺部,MAPKs信号通路当中的胞外信号调节激酶(extracellular signal-reg-ulated kinase,ERK)通路和Stat3通路明显激活,而天龙咳喘灵能有效抑制该信号途径的活化。结论:天龙喘咳灵水煎剂能有效防治慢性哮喘小鼠模型的气道重塑,其机制可能是通过抑制ERKs通路和Stat3通路的活化实现的。
基金National Natural Science Foundation of China,Grant/Award Numbers:U19A2006,12132004,11972111,31900940,32071304,32171309,32171395Sichuan Science and Technology Program,Grant/Award Number:21YJ0130Joint Funds of Center for Engineering Medicine,Grant/Award Numbers:ZYGX2021YGLH017,ZYGX2021YGLH010,ZYGX2021YGLH023。
文摘Dynamic and heterogeneous interaction between tumor cells and the surrounding microenvironment fuels the occurrence,progression,invasion,and metastasis of solid tumors.In this process,the tumormicroenvironment(TME)fractures cellular and matrix architecture normality through biochemical and mechanical means,abetting tumorigenesis and treatment resistance.Tumor cells sense and respond to the strength,direction,and duration of mechanical cues in the TME by various mechanotransduction pathways.However,far less understood is the comprehensive perspective of the functions and mechanisms of mechanotransduction.Due to the great therapeutic difficulties brought by the mechanical changes in the TME,emerging studies have focused on targeting the adverse mechanical factors in the TME to attenuate disease rather than conventionally targeting tumor cells themselves,which has been proven to be a potential therapeutic approach.In this review,we discussed the origins and roles ofmechanical factors in the TME,cell sensing,mechano-biological coupling and signal transduction,in vitro construction of the tumormechanicalmicroenvironment,applications and clinical significance in the TME.
基金supported by National Key R&D Program of China (2020YFA0509400) (to Ye Yang)National Natural Science Foundation of China 81970196 (to Chunyan Gu) and 82073885 (to Ye Yang)+4 种基金Natural Science Foundation of Jiangsu Province (China) BK20200097 (to Chunyan Gu)National Natural Science Foundation of China 82073888 (to Hongbo Wang)the Science and Technology Support Program for Youth Innovation in Universities of Shandong (China) (2019KJM009) (to Hongbo Wang)Bohai rim Advanced Research Institute for Drug Discovery (China) (LX211011) (to Hongbo Wang)Jiangsu Postgraduate Research and Practice Innovation Program (China) KYCX21_1769 (to Rongfang Wei)。
文摘Multiple myeloma(MM) is still an incurable hematologic malignancy, which is eagerly to the discovery of novel therapeutic targets and methods. N-acetyltransferase 10(NAT10) is the first reported regulator of mRNA acetylation that is activated in many cancers. However, the function of NAT10 in MM remains unclear. We found significant upregulation of NAT10 in MM patients compared to normal plasma cells, which was also highly correlated with MM poor outcome. Further enforced NAT10 expression promoted MM growth in vitro and in vivo, while knockdown of NAT10 reversed those effects. The correlation analysis of acetylated RNA immunoprecipitation sequencing(ac RIP-seq) and ribosome profiling sequencing(Ribo-seq) combined with RIP-PCR tests identified centrosomal protein 170(CEP170) as an important downstream target of NAT10. Interfering CEP170 expression in NAT10-OE cells attenuated the acceleration of cellular growth caused by elevated NAT10. Moreover,CEP170 overexpression promoted cellular proliferation and chromosomal instability(CIN) in MM.Intriguingly, remodelin, a selective NAT10 inhibitor, suppressed MM cellular growth, induced cellular apoptosis in vitro and prolonged the survival of 5TMM3VT mice in vivo. Collectively, our data indicate that NAT10 acetylates CEP170 mRNA to enhance CEP170 translation efficiency, which suggests that NAT10 may serve as a promising therapeutic target in MM.
