BACKGROUND NLRP3-mediated pyroptosis is recognized as an essential modulator of renal disease pathology.Long noncoding RNAs(lncRNAs)are active participators of diabetic nephropathy(DN).X inactive specific transcript(X...BACKGROUND NLRP3-mediated pyroptosis is recognized as an essential modulator of renal disease pathology.Long noncoding RNAs(lncRNAs)are active participators of diabetic nephropathy(DN).X inactive specific transcript(XIST)expression has been reported to be elevated in the serum of DN patients.AIM To evaluate the mechanism of lncRNA XIST in renal tubular epithelial cell(RTEC)pyroptosis in DN.METHODS A DN rat model was established through streptozotocin injection,and XIST was knocked down by tail vein injection of the lentivirus LV sh-XIST.Renal metabolic and biochemical indices were detected,and pathological changes in the renal tissue were assessed.The expression of indicators related to inflammation and pyroptosis was also detected.High glucose(HG)was used to treat HK2 cells,and cell viability and lactate dehydrogenase(LDH)activity were detected after silencing XIST.The subcellular localization and downstream mechanism of XIST were investigated.Finally,a rescue experiment was carried out to verify that XIST regulates NLR family pyrin domain containing 3(NLRP3)/caspase-1-mediated RTEC pyroptosis through the microRNA-15-5p(miR-15b-5p)/Toll-like receptor 4(TLR4)axis.RESULTS XIST was highly expressed in the DN models.XIST silencing improved renal metabolism and biochemical indices and mitigated renal injury.The expression of inflammation and pyroptosis indicators was significantly increased in DN rats and HG-treated HK2 cells;cell viability was decreased and LDH activity was increased after HGtreatment. Silencing XIST inhibited RTEC pyroptosis by inhibiting NLRP3/caspase-1. Mechanistically,XIST sponged miR-15b-5p to regulate TLR4. Silencing XIST inhibited TLR4 by promotingmiR-15b-5p. miR-15b-5p inhibition or TLR4 overexpression averted the inhibitory effect ofsilencing XIST on HG-induced RTEC pyroptosis.CONCLUSIONSilencing XIST inhibits TLR4 by upregulating miR-15b-5p and ultimately inhibits renal injury inDN by inhibiting NLRP3/caspase-1-mediated RTEC pyroptosis.展开更多
目的检测肾癌组织Yes相关蛋白1(Yes-associated protein 1,YAP1),PDZ结合域的转录共刺激因子(transcriptional coactivator with PDZ-binding motif,TAZ)蛋白表达,并探讨其与临床病理特征及患者远期生存的关系。方法前瞻性选取安徽医科...目的检测肾癌组织Yes相关蛋白1(Yes-associated protein 1,YAP1),PDZ结合域的转录共刺激因子(transcriptional coactivator with PDZ-binding motif,TAZ)蛋白表达,并探讨其与临床病理特征及患者远期生存的关系。方法前瞻性选取安徽医科大学第二附属医院2016年1月~2018年10月收治的132例肾癌患者。根据三年内是否死亡将其分为死亡组(n=20)和生存组(n=108)。采用免疫组织化学二步法检测YAP1,TAZ蛋白表达,用COX回归分析探讨患者死亡的危险因素。结果手术组切缘正常组织YAP1,TAZ蛋白阳性表达率分别为22.41%和17.24%,癌组织YAP1,TAZ蛋白阳性表达率分别为53.45%和48.28%,对应癌组织高于切缘正常组织(χ^(2)=11.864,12.680,P=0.001,0.000)。穿刺活检癌组织YAP1和TAZ蛋白阳性表达率分别为77.14%和62.86%。临床分期、有副肿瘤综合征、有远处转移、伴下腔静脉癌栓、组织学分级与癌组织YAP1蛋白阳性表达率均呈正相关(χ^(2)=8.664~21.321,P=0.000~0.003),与TAZ蛋白阳性表达率也呈正相关(χ^(2)=6.518~25.529,P=0.000~0.001);癌组织YAP1,TAZ蛋白阳性表达与肾癌三年内生存率均呈正相关(χ^(2)=10.273,12.657;P=0.001,0.000);临床分期Ⅲ~Ⅳ期[风险比(hazard ratio,HR)=3.550,P=0.016]、有副肿瘤综合征(HR=4.267,P=0.012)、组织学Ⅲ~Ⅳ级(HR=5.382,P=0.001)、癌组织TAZ蛋白阳性表达(HR=5.760,P=0.007)、伴下腔静脉癌栓(HR=6.508,P=0.005)、有远处转移(HR=7.330,P=0.003)、癌组织YAP1蛋白阳性表达(HR=7.877,P=0.001)均是肾癌三年内死亡的危险因素。结论肾癌组织YAP1和TAZ蛋白阳性表达率高,且与临床分期、组织学分级、副肿瘤综合征、远处转移和下腔静脉癌栓有关,上述病理特征与癌组织YAP1和TAZ蛋白阳性表达均是患者远期生存的影响因素。展开更多
目的:旨在评估肿瘤浸润性程序性死亡受体-1(programmed cell death protein-1,PD-1)阳性淋巴细胞及调节性T细胞(regu-latory T cell,Treg)对转移性肾癌(metastatic renal cell carcinoma,mRCC)预后的预测价值。探讨PD-1和Treg在mRCC中...目的:旨在评估肿瘤浸润性程序性死亡受体-1(programmed cell death protein-1,PD-1)阳性淋巴细胞及调节性T细胞(regu-latory T cell,Treg)对转移性肾癌(metastatic renal cell carcinoma,mRCC)预后的预测价值。探讨PD-1和Treg在mRCC中的表达及其与患者临床病理参数、预后的相关性。方法:收集2007年6月至2017年6月269例复旦大学附属中山医院mRCC患者的临床病理资料,应用免疫组织化学法检测mRCC患者组织中PD-1和Treg的表达,分析其与各项临床指标及预后的关系。结果:mRCC患者组织中PD-1表达的阳性率为31.60%(85/269),表达水平与肿瘤Fuhrman分级呈正相关,与预后呈负相关;Treg表达的阳性率为36.80%(99/269),表达水平亦与肿瘤Fuhrman分级呈正相关,与预后呈负相关。单因素分析显示,PD-1阳性和高Treg浸润数量与总生存(overall survival,OS)率及无进展生存(progression free survival,PFS)率呈负相关。PD-1阳性和高Treg浸润数量为OS和PFS的独立预后指标,二者联合可起到较好的预测效果。结论:PD-1阳性或高Treg浸润数量可作为mRCC的预后指标,二者联合预测效果更佳。mRCC患者组织中PD-1阳性淋巴细胞或Treg浸润数量的评估可为临床预后判断提供依据。展开更多
基金Supported by Natural Science Foundation of Shenzhen University General Hospital (SUGH2020QD011)
文摘BACKGROUND NLRP3-mediated pyroptosis is recognized as an essential modulator of renal disease pathology.Long noncoding RNAs(lncRNAs)are active participators of diabetic nephropathy(DN).X inactive specific transcript(XIST)expression has been reported to be elevated in the serum of DN patients.AIM To evaluate the mechanism of lncRNA XIST in renal tubular epithelial cell(RTEC)pyroptosis in DN.METHODS A DN rat model was established through streptozotocin injection,and XIST was knocked down by tail vein injection of the lentivirus LV sh-XIST.Renal metabolic and biochemical indices were detected,and pathological changes in the renal tissue were assessed.The expression of indicators related to inflammation and pyroptosis was also detected.High glucose(HG)was used to treat HK2 cells,and cell viability and lactate dehydrogenase(LDH)activity were detected after silencing XIST.The subcellular localization and downstream mechanism of XIST were investigated.Finally,a rescue experiment was carried out to verify that XIST regulates NLR family pyrin domain containing 3(NLRP3)/caspase-1-mediated RTEC pyroptosis through the microRNA-15-5p(miR-15b-5p)/Toll-like receptor 4(TLR4)axis.RESULTS XIST was highly expressed in the DN models.XIST silencing improved renal metabolism and biochemical indices and mitigated renal injury.The expression of inflammation and pyroptosis indicators was significantly increased in DN rats and HG-treated HK2 cells;cell viability was decreased and LDH activity was increased after HGtreatment. Silencing XIST inhibited RTEC pyroptosis by inhibiting NLRP3/caspase-1. Mechanistically,XIST sponged miR-15b-5p to regulate TLR4. Silencing XIST inhibited TLR4 by promotingmiR-15b-5p. miR-15b-5p inhibition or TLR4 overexpression averted the inhibitory effect ofsilencing XIST on HG-induced RTEC pyroptosis.CONCLUSIONSilencing XIST inhibits TLR4 by upregulating miR-15b-5p and ultimately inhibits renal injury inDN by inhibiting NLRP3/caspase-1-mediated RTEC pyroptosis.
文摘目的检测肾癌组织Yes相关蛋白1(Yes-associated protein 1,YAP1),PDZ结合域的转录共刺激因子(transcriptional coactivator with PDZ-binding motif,TAZ)蛋白表达,并探讨其与临床病理特征及患者远期生存的关系。方法前瞻性选取安徽医科大学第二附属医院2016年1月~2018年10月收治的132例肾癌患者。根据三年内是否死亡将其分为死亡组(n=20)和生存组(n=108)。采用免疫组织化学二步法检测YAP1,TAZ蛋白表达,用COX回归分析探讨患者死亡的危险因素。结果手术组切缘正常组织YAP1,TAZ蛋白阳性表达率分别为22.41%和17.24%,癌组织YAP1,TAZ蛋白阳性表达率分别为53.45%和48.28%,对应癌组织高于切缘正常组织(χ^(2)=11.864,12.680,P=0.001,0.000)。穿刺活检癌组织YAP1和TAZ蛋白阳性表达率分别为77.14%和62.86%。临床分期、有副肿瘤综合征、有远处转移、伴下腔静脉癌栓、组织学分级与癌组织YAP1蛋白阳性表达率均呈正相关(χ^(2)=8.664~21.321,P=0.000~0.003),与TAZ蛋白阳性表达率也呈正相关(χ^(2)=6.518~25.529,P=0.000~0.001);癌组织YAP1,TAZ蛋白阳性表达与肾癌三年内生存率均呈正相关(χ^(2)=10.273,12.657;P=0.001,0.000);临床分期Ⅲ~Ⅳ期[风险比(hazard ratio,HR)=3.550,P=0.016]、有副肿瘤综合征(HR=4.267,P=0.012)、组织学Ⅲ~Ⅳ级(HR=5.382,P=0.001)、癌组织TAZ蛋白阳性表达(HR=5.760,P=0.007)、伴下腔静脉癌栓(HR=6.508,P=0.005)、有远处转移(HR=7.330,P=0.003)、癌组织YAP1蛋白阳性表达(HR=7.877,P=0.001)均是肾癌三年内死亡的危险因素。结论肾癌组织YAP1和TAZ蛋白阳性表达率高,且与临床分期、组织学分级、副肿瘤综合征、远处转移和下腔静脉癌栓有关,上述病理特征与癌组织YAP1和TAZ蛋白阳性表达均是患者远期生存的影响因素。
