Low-density lipoprotein receptor-related protein 1(LRP1,also known as CD91),a multifunctional endocytic and cell signaling receptor,is widely expressed on the surface of multiple cell types such as hepatocytes,fibrobl...Low-density lipoprotein receptor-related protein 1(LRP1,also known as CD91),a multifunctional endocytic and cell signaling receptor,is widely expressed on the surface of multiple cell types such as hepatocytes,fibroblasts,neurons,astrocytes,macrophages,smooth muscle cells,and malignant cells.Emerging in vitro and in vivo evidence demonstrates that LRP1 is critically involved in many processes that drive tumorigenesis and tumor progression.For example,LRP1 not only promotes tumor cell migration and invasion by regulating matrix metalloproteinase(MMP)-2and MMP-9 expression and functions but also inhibits cell apoptosis by regulating the insulin receptor,the serine/threonine protein kinase signaling pathway,and the expression of Caspase-3.LRPI-mediated phosphorylation of the extracellular signal-regulated kinase pathway and c-jun N-terminal kinase are also involved in tumor cell proliferation and invasion.In addition,LRP1 has been shown to be down-regulated by microRNA-205 and methylation of LRP1CpG islands.Furthermore,a novel fusion gene,LRP1-SNRNP25,promotes osteosarcoma cell invasion and migration.Only by understanding the mechanisms of these effects can we develop novel diagnostic and therapeutic strategies for cancers mediated by LRP1.展开更多
Monocyte chemoattractant protein-1(MCP-1), a potent chemoattractant, is thought to play an important role in migration of monocytes into atherosclerotic lesions. The present study was designed to investigate the capac...Monocyte chemoattractant protein-1(MCP-1), a potent chemoattractant, is thought to play an important role in migration of monocytes into atherosclerotic lesions. The present study was designed to investigate the capacity of human peripheral blood monocytes to express MCP-1 and effects of native very low density lipoprotein (VLDL) and oxidized VLDL(OX-VLDL) on the expression. The total RNA was extracted from cultured monocytes, which were exposed to VLDL and OX-VLDL, and the media conditioned by monocytes were collected. MCP-1 mRNA expression was examined by Northern blot analysis. MCP-1 protein in conditioned media was determined by using sandwich ELISA. The results showed that monocytes can express MCP-1 after a 24 h incubation at 37℃，and the expression was markedly increased by a exposure to OX-VLDL, whereas the expression was slightly increased when exposed to VLDL. It suggests that the capacity of monocytes to produce MCP-1 that recruits and activates circulating monocytes may be of considerable importance in atherogenesis, and oxidation of VLDL enhances its potential to promote atherogenesis.展开更多
As the leading cause of worldwide hospital-acquired infection,Clostridioides difficile(C.difficile)infection has caused heavy economic and hospitalized burden,while its pathogenesis is not fully understood.Toxin B(Tcd...As the leading cause of worldwide hospital-acquired infection,Clostridioides difficile(C.difficile)infection has caused heavy economic and hospitalized burden,while its pathogenesis is not fully understood.Toxin B(Tcd B)is one of the major virulent factors of C.difficile.Recently,CSPG4 and FZD2 were reported to be the receptors that mediate Tcd B cellular entry.However,genetic ablation of genes encoding these receptors failed to completely block Tcd B entry,implicating the existence of alternative receptor(s)for this toxin.Here,by employing the CRISPR-Cas9 screen in CSPG4-deficient He La cells,we identified LDL receptor-related protein-1(LRP1)as a novel receptor for Tcd B.Knockout of LRP1 in both CSPG4-deficient He La cells and colonic epithelium Caco2 cells conferred cells with increased Tcd B resistance,while LRP1 overexpression sensitized cells to Tcd B at a low concentration.Co-immunoprecipitation assay showed that LRP1 interacts with full-length Tcd B.Moreover,CROPs domain,which is dispensable for Tcd B’s interaction with CSPG4 and FZD2,is sufficient for binding to LRP1.As such,our study provided evidence for a novel mechanism of Tcd B entry and suggested potential therapeutic targets for treating C.difficile infection.展开更多
目的探讨早发型子痫前期(early onset pre-eclampsia,EOSP)患者血清内皮细胞特异性分子-1(endothelial cell specific molecule-1,ESM1)及低密度脂蛋白受体相关蛋白-1(low-density lipoprotein receptor-related protein-1,LRP1)水平及...目的探讨早发型子痫前期(early onset pre-eclampsia,EOSP)患者血清内皮细胞特异性分子-1(endothelial cell specific molecule-1,ESM1)及低密度脂蛋白受体相关蛋白-1(low-density lipoprotein receptor-related protein-1,LRP1)水平及与病情严重程度的相关性。方法选取2019年2月~2021年2月盐城市妇幼保健院218例早发型子痫前期患者为研究对象(病例组),根据病情分为轻度组(n=117)和重度组(n=101),以同期健康体检的80例健康孕妇为对照组。比较各组血清ESM1和LRP1水平。采用多因素Logistic回归分析早发型子痫前期病情严重程度的影响因素。绘制受试者工作曲线分析血清ESM1和LRP1对早发型重度子痫前期的诊断价值。结果病例组血清ESM1(323.05±45.17 mmol/L),LRP1(12.25±0.97μg/ml)水平高于对照组(195.20±31.67 mmol/L,6.41±0.84μg/ml),差异具有统计学意义(t=23.291,47.677,均P<0.05)。重度组患者血清ESM1(672.44±83.61 pg/ml),血清LRP1(14.52±1.05μg/ml)、舒张压(113.17±12.24mmHg)、收缩压(165.19±16.63mmHg)、24h尿蛋白量(2.63±0.45g/24h)、血肌酐(74.47±20.82μmol/L)、血尿素氮(4.32±0.78mmol/L)、血尿酸(339.65±50.13μmol/L)高于轻度组(551.74±72.20 pg/ml,9.63±0.89μg/ml,92.41±9.29mmHg,147.25±14.66mmHg,1.42±0.33g/24h,69.64±15.07μmol/L,3.95±0.91mmol/L,303.82±41.71μmol/L),新生儿体质量低于轻度组(2.73±0.62 kg vs 3.20±0.62 kg),差异具有统计学意义(t=1.980~37.978,均P<0.05)。病例组患者血清ESM1及LRP1水平与舒张压、收缩压、24h尿蛋白定量、血肌酐、血尿素氮及血尿酸呈正相关(r=0.413~0.515,均P<0.05),与胎儿体质量呈负相关(r=-0.563,-0.604,均P<0.05)。高血清ESM1水平(OR=1.217,95%CI:1.036~1.429)和高血清LRP1水平(OR=1.486,95%CI:1.056~2.090)是影响早发型重度子痫前期发生的独立危险因素。血清ESM1联合LRP1诊断早发型重度子痫前期的曲线下面积(area under the curve,AUC)0.884(0.853~0.916)大于ESM1(AUC=0.749,95%CI:0.705~0.792)和LRP1(AUC=0.760,95%CI:0.712~0.807)单独诊断(Z=6.752,4.297,均P<0.05)。结论早发型子痫前期患者血清ESM1和LRP1水平升高,二者均与早发型子痫前期疾病严重程度有关,联合检测能提高早发型重度子痫前期的诊断效能。展开更多
低密度脂蛋白受体相关蛋白1(low density lipoprotein receptor related protein 1,LRP1),也被称为CD91或α2巨球蛋白受体,是一种普遍表达于细胞表面的大分子量内吞性受体,属于低密度脂蛋白受体家族的成员之一。LRP1主要参与细胞的两个...低密度脂蛋白受体相关蛋白1(low density lipoprotein receptor related protein 1,LRP1),也被称为CD91或α2巨球蛋白受体,是一种普遍表达于细胞表面的大分子量内吞性受体,属于低密度脂蛋白受体家族的成员之一。LRP1主要参与细胞的两个生理过程:内吞作用和信号通路的调控。许多结构和功能不同的蛋白质都可以作为其配体而被内吞至细胞内;LRP1还可作为信号受体与胞质内蛋白质结合而调控信号通路。因此,LRP1在细胞的病理生理过程中发挥重要作用。在心血管疾病中,LRP1可通过其独特的功能参与疾病的发生发展,并可能成为心血管疾病治疗的新靶点。展开更多
基金the National Natural Science Foundation of China(81372872 to J.Yang,81402215 to X.Du,and 81320108022 to K.Chen)funds from the University Cancer Foundation via the Sister Institution Network Fund at the Tianjin Medical University Cancer Institute and Hospital,Fudan University Shanghai Cancer Center,and University of Texas MD Anderson Cancer Centersupported by the program for Innovative Research Team in University in China(IRT1076 to K.Chen)
文摘Low-density lipoprotein receptor-related protein 1(LRP1,also known as CD91),a multifunctional endocytic and cell signaling receptor,is widely expressed on the surface of multiple cell types such as hepatocytes,fibroblasts,neurons,astrocytes,macrophages,smooth muscle cells,and malignant cells.Emerging in vitro and in vivo evidence demonstrates that LRP1 is critically involved in many processes that drive tumorigenesis and tumor progression.For example,LRP1 not only promotes tumor cell migration and invasion by regulating matrix metalloproteinase(MMP)-2and MMP-9 expression and functions but also inhibits cell apoptosis by regulating the insulin receptor,the serine/threonine protein kinase signaling pathway,and the expression of Caspase-3.LRPI-mediated phosphorylation of the extracellular signal-regulated kinase pathway and c-jun N-terminal kinase are also involved in tumor cell proliferation and invasion.In addition,LRP1 has been shown to be down-regulated by microRNA-205 and methylation of LRP1CpG islands.Furthermore,a novel fusion gene,LRP1-SNRNP25,promotes osteosarcoma cell invasion and migration.Only by understanding the mechanisms of these effects can we develop novel diagnostic and therapeutic strategies for cancers mediated by LRP1.
文摘Monocyte chemoattractant protein-1(MCP-1), a potent chemoattractant, is thought to play an important role in migration of monocytes into atherosclerotic lesions. The present study was designed to investigate the capacity of human peripheral blood monocytes to express MCP-1 and effects of native very low density lipoprotein (VLDL) and oxidized VLDL(OX-VLDL) on the expression. The total RNA was extracted from cultured monocytes, which were exposed to VLDL and OX-VLDL, and the media conditioned by monocytes were collected. MCP-1 mRNA expression was examined by Northern blot analysis. MCP-1 protein in conditioned media was determined by using sandwich ELISA. The results showed that monocytes can express MCP-1 after a 24 h incubation at 37℃，and the expression was markedly increased by a exposure to OX-VLDL, whereas the expression was slightly increased when exposed to VLDL. It suggests that the capacity of monocytes to produce MCP-1 that recruits and activates circulating monocytes may be of considerable importance in atherogenesis, and oxidation of VLDL enhances its potential to promote atherogenesis.
基金supported by the National Natural Science Foundation of China(NSFC31430025)the Beijing Advanced Innovation Center for Genomics at Peking Universitythe Peking-Tsinghua Center for Life Sciences。
文摘As the leading cause of worldwide hospital-acquired infection,Clostridioides difficile(C.difficile)infection has caused heavy economic and hospitalized burden,while its pathogenesis is not fully understood.Toxin B(Tcd B)is one of the major virulent factors of C.difficile.Recently,CSPG4 and FZD2 were reported to be the receptors that mediate Tcd B cellular entry.However,genetic ablation of genes encoding these receptors failed to completely block Tcd B entry,implicating the existence of alternative receptor(s)for this toxin.Here,by employing the CRISPR-Cas9 screen in CSPG4-deficient He La cells,we identified LDL receptor-related protein-1(LRP1)as a novel receptor for Tcd B.Knockout of LRP1 in both CSPG4-deficient He La cells and colonic epithelium Caco2 cells conferred cells with increased Tcd B resistance,while LRP1 overexpression sensitized cells to Tcd B at a low concentration.Co-immunoprecipitation assay showed that LRP1 interacts with full-length Tcd B.Moreover,CROPs domain,which is dispensable for Tcd B’s interaction with CSPG4 and FZD2,is sufficient for binding to LRP1.As such,our study provided evidence for a novel mechanism of Tcd B entry and suggested potential therapeutic targets for treating C.difficile infection.
文摘目的探讨早发型子痫前期(early onset pre-eclampsia,EOSP)患者血清内皮细胞特异性分子-1(endothelial cell specific molecule-1,ESM1)及低密度脂蛋白受体相关蛋白-1(low-density lipoprotein receptor-related protein-1,LRP1)水平及与病情严重程度的相关性。方法选取2019年2月~2021年2月盐城市妇幼保健院218例早发型子痫前期患者为研究对象(病例组),根据病情分为轻度组(n=117)和重度组(n=101),以同期健康体检的80例健康孕妇为对照组。比较各组血清ESM1和LRP1水平。采用多因素Logistic回归分析早发型子痫前期病情严重程度的影响因素。绘制受试者工作曲线分析血清ESM1和LRP1对早发型重度子痫前期的诊断价值。结果病例组血清ESM1(323.05±45.17 mmol/L),LRP1(12.25±0.97μg/ml)水平高于对照组(195.20±31.67 mmol/L,6.41±0.84μg/ml),差异具有统计学意义(t=23.291,47.677,均P<0.05)。重度组患者血清ESM1(672.44±83.61 pg/ml),血清LRP1(14.52±1.05μg/ml)、舒张压(113.17±12.24mmHg)、收缩压(165.19±16.63mmHg)、24h尿蛋白量(2.63±0.45g/24h)、血肌酐(74.47±20.82μmol/L)、血尿素氮(4.32±0.78mmol/L)、血尿酸(339.65±50.13μmol/L)高于轻度组(551.74±72.20 pg/ml,9.63±0.89μg/ml,92.41±9.29mmHg,147.25±14.66mmHg,1.42±0.33g/24h,69.64±15.07μmol/L,3.95±0.91mmol/L,303.82±41.71μmol/L),新生儿体质量低于轻度组(2.73±0.62 kg vs 3.20±0.62 kg),差异具有统计学意义(t=1.980~37.978,均P<0.05)。病例组患者血清ESM1及LRP1水平与舒张压、收缩压、24h尿蛋白定量、血肌酐、血尿素氮及血尿酸呈正相关(r=0.413~0.515,均P<0.05),与胎儿体质量呈负相关(r=-0.563,-0.604,均P<0.05)。高血清ESM1水平(OR=1.217,95%CI:1.036~1.429)和高血清LRP1水平(OR=1.486,95%CI:1.056~2.090)是影响早发型重度子痫前期发生的独立危险因素。血清ESM1联合LRP1诊断早发型重度子痫前期的曲线下面积(area under the curve,AUC)0.884(0.853~0.916)大于ESM1(AUC=0.749,95%CI:0.705~0.792)和LRP1(AUC=0.760,95%CI:0.712~0.807)单独诊断(Z=6.752,4.297,均P<0.05)。结论早发型子痫前期患者血清ESM1和LRP1水平升高,二者均与早发型子痫前期疾病严重程度有关,联合检测能提高早发型重度子痫前期的诊断效能。
文摘低密度脂蛋白受体相关蛋白1(low density lipoprotein receptor related protein 1,LRP1),也被称为CD91或α2巨球蛋白受体,是一种普遍表达于细胞表面的大分子量内吞性受体,属于低密度脂蛋白受体家族的成员之一。LRP1主要参与细胞的两个生理过程:内吞作用和信号通路的调控。许多结构和功能不同的蛋白质都可以作为其配体而被内吞至细胞内;LRP1还可作为信号受体与胞质内蛋白质结合而调控信号通路。因此,LRP1在细胞的病理生理过程中发挥重要作用。在心血管疾病中,LRP1可通过其独特的功能参与疾病的发生发展,并可能成为心血管疾病治疗的新靶点。
