LIM zinc finger domain containing 1(LIMS1),an evolutionarily conserved LIM domain adaptor protein,is implicated in diverse pathologies,including cancer and neurological disorders.However,its roles in cardiac diseases ...LIM zinc finger domain containing 1(LIMS1),an evolutionarily conserved LIM domain adaptor protein,is implicated in diverse pathologies,including cancer and neurological disorders.However,its roles in cardiac diseases and the underlying mechanisms remain unclear.Here,we explore the functions and mechanisms of LIMS1 in cardiac remodeling and heart failure.We identify the elevated LIMS1 expression in patients with dilated cardiomyopathy and murine cardiomyocytes,suggesting that LIMS1 dysregulation contributes to cardiac pathology.Using CRISPR/Cas9 technology,we generate a zebrafish model of lims1 loss-offunction mutant,which exhibits severe cardiac chamber remodeling,systolic dysfunction,and premature mortality,demonstrating the essential role of lims1 in maintaining cardiac integrity.Transcriptomic profiling reveals the activation of the gp130/Jak1/Stat3 signaling in the lims1-deficient hearts.Strikingly,pharmacological inhibition of Stat3 or c-Fos partially rescues cardiomyopathy phenotypes.Our findings reveal the underlying mechanism of lims1 deficiency-caused heart failure through gp130/Jak1/Stat3 hyperactivation,offering insights into cardiac remodeling and potential therapeutic strategies.展开更多
Background:Chronic kidney disease(CKD)is associated with common pathophysiological processes,such as inflammation and fibrosis,in both the heart and the kidney.However,the underlying molecular mechanisms that drive th...Background:Chronic kidney disease(CKD)is associated with common pathophysiological processes,such as inflammation and fibrosis,in both the heart and the kidney.However,the underlying molecular mechanisms that drive these processes are not yet fully understood.Therefore,this study focused on the molecular mechanism of heart and kidney injury in CKD.Methods:We generated an microRNA(miR)-26a knockout(KO)mouse model to investigate the role of miR-26a in angiotensin(Ang)-II-induced cardiac and renal injury.We performed Ang-II modeling in wild type(WT)mice and miR-26a KO mice,with six mice in each group.In addition,Ang-II-treated AC16 cells and HK2 cells were used as in vitro models of cardiac and renal injury in the context of CKD.Histological staining,immunohistochemistry,quantitative real-time polymerase chain reaction(PCR),and Western blotting were applied to study the regulation of miR-26a on Ang-II-induced cardiac and renal injury.Immunofluorescence reporter assays were used to detect downstream genes of miR-26a,and immunoprecipitation was employed to identify the interacting protein of LIM and senescent cell antigen-like domain 1(LIMS1).We also used an adeno-associated virus(AAV)to supplement LIMS1 and explored the specific regulatory mechanism of miR-26a on Ang-II-induced cardiac and renal injury.Dunnett’s multiple comparison and t-test were used to analyze the data.Results:Compared with the control mice,miR-26a expression was significantly downregulated in both the kidney and the heart after Ang-II infusion.Our study identified LIMS1 as a novel target gene of miR-26a in both heart and kidney tissues.Downregulation of miR-26a activated the LIMS1/integrin-linked kinase(ILK)signaling pathway in the heart and kidney,which represents a common molecular mechanism underlying inflammation and fibrosis in heart and kidney tissues during CKD.Furthermore,knockout of miR-26a worsened inflammation and fibrosis in the heart and kidney by inhibiting the LIMS1/ILK signaling pathway;on the contrary,supplementation with exogenous miR-26a reversed all these changes.Conclusions:Our findings suggest that miR-26a could be a promising therapeutic target for the treatment of cardiorenal injury in CKD.This is attributed to its ability to regulate the LIMS1/ILK signaling pathway,which represents a common molecular mechanism in both heart and kidney tissues.展开更多
目的 探讨LIM和SH3蛋白1(LIM and SH3 protein 1, LASP1)、激肽释放酶相关肽酶11(Kallikrein related peptidase 11, KLK11)表达水平与结直肠癌(Colorectal cancer, CRC)临床病理的关系及预后影响因素。方法 选择2017年1月至2018年10月...目的 探讨LIM和SH3蛋白1(LIM and SH3 protein 1, LASP1)、激肽释放酶相关肽酶11(Kallikrein related peptidase 11, KLK11)表达水平与结直肠癌(Colorectal cancer, CRC)临床病理的关系及预后影响因素。方法 选择2017年1月至2018年10月于本院就诊并接受手术治疗的82例CRC患者作为研究对象,术中收集癌组织和癌旁组织。免疫组织化学法检测癌旁组织和癌组织中LASP1和KLK11的阳性表达情况,分析LASP1和KLK11阳性表达与CRC临床病理的相关性。ROC曲线分析LASP1和KLK11在CRC诊断中的价值,分析LASP1和KLK11在CRC癌组织中表达的相关性。对患者进行5年随访并记录患者生存情况,确定LASP1和KLK11阳性表达与CRC患者生存的关系,Cox分析确定影响CRC患者生存的风险因素。结果 相对于癌旁组织,LASP1和KLK11在CRC癌组织中的阳性表达更高(P<0.05)。LASP1和KLK11表达与TNM分期和淋巴结转移有关(P均<0.05)。相对于Ⅰ/Ⅱ期和未发生淋巴结转移的患者,Ⅲ/Ⅳ期和发生淋巴结转移的患者中LASP1和KLK11表达为阳性的占比更高(P均<0.05)。ROC曲线分析结果显示,LASP1和KLK11能够作为CRC的有效诊断指标,且二者联合诊断价值更高。相关性分析结果显示,LASP1和KLK11在CRC癌组织中的表达呈正相关(r=0.33,P=0.003)。LASP1阳性和KLK11阳性患者的生存率显著低于LASP1阴性和KLK11阴性患者(P<0.05)。Cox多因素分析显示,分化程度、TNM分期、淋巴结转移、LASP1阳性表达、KLK11阳性表达是影响CRC患者预后的独立因素(P均<0.05)。结论 LASP1和KLK11阳性表达与CRC患者临床病理指标存在相关性,LASP1和KLK11表达或可作为CRC的有效诊断指标且与患者预后相关。展开更多
目的观察双相躁狂患者血浆中微小RNA-134(micro RNA-134)及LIM激酶-1(LIMK-1)m RNA的表达水平与双相躁狂之间的关系。方法 105例双相躁狂患者作为患者组,100例与患者组在年龄和性别上匹配的健康志愿者作为对照组,患者组常规应用情绪稳...目的观察双相躁狂患者血浆中微小RNA-134(micro RNA-134)及LIM激酶-1(LIMK-1)m RNA的表达水平与双相躁狂之间的关系。方法 105例双相躁狂患者作为患者组,100例与患者组在年龄和性别上匹配的健康志愿者作为对照组,患者组常规应用情绪稳定剂治疗1个月。患者组于入组时和治疗1个月时、对照组于入组时分别评定Bech-Rafaelsen躁狂量表(BRMS)评分表并收集血浆,采用实时荧光定量聚合酶链式反应(PCR)技术检测血浆micro RNA-134及LIMK-1 m RNA的表达水平,最后对检测结果及BRMS评分进行统计分析。结果治疗前,患者组血浆micro RNA-134及LIMK-1 m RNA表达水平分别为(1.17±0.02)、(0.37±0.02)显著低于对照组的(1.46±0.04)、(0.46±0.01),差异有统计学意义(P<0.05);治疗1个月后,患者组血浆micro RNA-134、LIMK-1 m RNA表达水平分别为(1.36±0.07)、(0.52±0.01)较治疗前显著升高,差异有统计学意义(P<0.05)。患者组治疗前及治疗后血浆micro RNA-134表达水平与BRMS评分之间均存在负相关(r=-0.48、-0.39,P<0.05)。结论血浆micro RNA-134、LIMK-1 m RNA的表达水平和双相障碍躁狂发作有关,有可能作为双相躁狂的生物标记物。展开更多
目的 :探讨LIM矿化蛋白1(LIM mineralization protein 1,LMP-1)在大鼠磨牙牙髓损伤修复中的表达。方法 :建立大鼠磨牙牙髓损伤修复动物模型,用免疫组织化学染色方法观察LMP-1在大鼠牙髓损伤修复中的表达,并用Image-Pro Plus 6.0图像分...目的 :探讨LIM矿化蛋白1(LIM mineralization protein 1,LMP-1)在大鼠磨牙牙髓损伤修复中的表达。方法 :建立大鼠磨牙牙髓损伤修复动物模型,用免疫组织化学染色方法观察LMP-1在大鼠牙髓损伤修复中的表达,并用Image-Pro Plus 6.0图像分析软件及单因素方差分析比较各组间的差异。结果 :在正常大鼠牙髓组织中LMP-1表达阴性;在大鼠牙髓损伤后1 d,LMP-1表达于成牙本质细胞及部分牙髓成纤维细胞;术后3 d,LMP-1表达于坏死牙髓下方的细胞增殖层;术后7 d,LMP-1显著表达于增殖活跃的牙髓细胞及部分成牙本质细胞中。结论:LMP-1在牙髓损伤修复过程中呈时空特异性表达,可能参与成牙本质细胞及牙髓细胞的增殖、分化及修复性牙本质的形成。展开更多
基金the National Natural Science Foundation of China(82070394,82371863,31970504,82100491,and 82000307)the Hunan Provincial Key Laboratory of Regional Hereditary Birth Defects Prevention and Control project(HPKL2023001)for their support of this research.
文摘LIM zinc finger domain containing 1(LIMS1),an evolutionarily conserved LIM domain adaptor protein,is implicated in diverse pathologies,including cancer and neurological disorders.However,its roles in cardiac diseases and the underlying mechanisms remain unclear.Here,we explore the functions and mechanisms of LIMS1 in cardiac remodeling and heart failure.We identify the elevated LIMS1 expression in patients with dilated cardiomyopathy and murine cardiomyocytes,suggesting that LIMS1 dysregulation contributes to cardiac pathology.Using CRISPR/Cas9 technology,we generate a zebrafish model of lims1 loss-offunction mutant,which exhibits severe cardiac chamber remodeling,systolic dysfunction,and premature mortality,demonstrating the essential role of lims1 in maintaining cardiac integrity.Transcriptomic profiling reveals the activation of the gp130/Jak1/Stat3 signaling in the lims1-deficient hearts.Strikingly,pharmacological inhibition of Stat3 or c-Fos partially rescues cardiomyopathy phenotypes.Our findings reveal the underlying mechanism of lims1 deficiency-caused heart failure through gp130/Jak1/Stat3 hyperactivation,offering insights into cardiac remodeling and potential therapeutic strategies.
基金supported by grants from the National Natural Science Foundation of China(Nos.82200749,82241047,82070735,82030024,81720108007 and 81270725)Natural Science Foundation of Jiangsu Province(No.BK20221282)National Key Research Programme of Ministry of Science and Technology(Nos.2018YFC130046,2018YFC1314000).
文摘Background:Chronic kidney disease(CKD)is associated with common pathophysiological processes,such as inflammation and fibrosis,in both the heart and the kidney.However,the underlying molecular mechanisms that drive these processes are not yet fully understood.Therefore,this study focused on the molecular mechanism of heart and kidney injury in CKD.Methods:We generated an microRNA(miR)-26a knockout(KO)mouse model to investigate the role of miR-26a in angiotensin(Ang)-II-induced cardiac and renal injury.We performed Ang-II modeling in wild type(WT)mice and miR-26a KO mice,with six mice in each group.In addition,Ang-II-treated AC16 cells and HK2 cells were used as in vitro models of cardiac and renal injury in the context of CKD.Histological staining,immunohistochemistry,quantitative real-time polymerase chain reaction(PCR),and Western blotting were applied to study the regulation of miR-26a on Ang-II-induced cardiac and renal injury.Immunofluorescence reporter assays were used to detect downstream genes of miR-26a,and immunoprecipitation was employed to identify the interacting protein of LIM and senescent cell antigen-like domain 1(LIMS1).We also used an adeno-associated virus(AAV)to supplement LIMS1 and explored the specific regulatory mechanism of miR-26a on Ang-II-induced cardiac and renal injury.Dunnett’s multiple comparison and t-test were used to analyze the data.Results:Compared with the control mice,miR-26a expression was significantly downregulated in both the kidney and the heart after Ang-II infusion.Our study identified LIMS1 as a novel target gene of miR-26a in both heart and kidney tissues.Downregulation of miR-26a activated the LIMS1/integrin-linked kinase(ILK)signaling pathway in the heart and kidney,which represents a common molecular mechanism underlying inflammation and fibrosis in heart and kidney tissues during CKD.Furthermore,knockout of miR-26a worsened inflammation and fibrosis in the heart and kidney by inhibiting the LIMS1/ILK signaling pathway;on the contrary,supplementation with exogenous miR-26a reversed all these changes.Conclusions:Our findings suggest that miR-26a could be a promising therapeutic target for the treatment of cardiorenal injury in CKD.This is attributed to its ability to regulate the LIMS1/ILK signaling pathway,which represents a common molecular mechanism in both heart and kidney tissues.
文摘目的观察双相躁狂患者血浆中微小RNA-134(micro RNA-134)及LIM激酶-1(LIMK-1)m RNA的表达水平与双相躁狂之间的关系。方法 105例双相躁狂患者作为患者组,100例与患者组在年龄和性别上匹配的健康志愿者作为对照组,患者组常规应用情绪稳定剂治疗1个月。患者组于入组时和治疗1个月时、对照组于入组时分别评定Bech-Rafaelsen躁狂量表(BRMS)评分表并收集血浆,采用实时荧光定量聚合酶链式反应(PCR)技术检测血浆micro RNA-134及LIMK-1 m RNA的表达水平,最后对检测结果及BRMS评分进行统计分析。结果治疗前,患者组血浆micro RNA-134及LIMK-1 m RNA表达水平分别为(1.17±0.02)、(0.37±0.02)显著低于对照组的(1.46±0.04)、(0.46±0.01),差异有统计学意义(P<0.05);治疗1个月后,患者组血浆micro RNA-134、LIMK-1 m RNA表达水平分别为(1.36±0.07)、(0.52±0.01)较治疗前显著升高,差异有统计学意义(P<0.05)。患者组治疗前及治疗后血浆micro RNA-134表达水平与BRMS评分之间均存在负相关(r=-0.48、-0.39,P<0.05)。结论血浆micro RNA-134、LIMK-1 m RNA的表达水平和双相障碍躁狂发作有关,有可能作为双相躁狂的生物标记物。
