Objective Increased transcytosis of low-density lipoprotein (LDL)across the endothelium and oxidation of LDL deposited within the subendothelial space are crucial early events in atherogenesis. C1q/TNF-related protein...Objective Increased transcytosis of low-density lipoprotein (LDL)across the endothelium and oxidation of LDL deposited within the subendothelial space are crucial early events in atherogenesis. C1q/TNF-related protein (CTRP) 5 is a novel secreted glycoprotein and its biological functions are largely undefined.展开更多
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
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
This study examined the association of a common polymorphic allele（25G） of the low-density lipoprotein receptor-related protein1（LRP1） gene with myocardial infarction（MI）.The genotypes of LRP1 25CG（rs35282763）...This study examined the association of a common polymorphic allele（25G） of the low-density lipoprotein receptor-related protein1（LRP1） gene with myocardial infarction（MI）.The genotypes of LRP1 25CG（rs35282763） were determined in 347 MI patients and 347 age-and sex-frequency-matched controls from an unrelated Chinese Han population.Factor Ⅷ（FⅧ） levels were measured in the MI patients and controls by chromogenic assay and enzyme-linked immunosor-bent assay（ELISA）.The results showed that LRP1 25CG（rs35282763） genotype distribution did not differ significantly between patients（n=206 for 25CC,n=122 for 25CG） and controls（n=191 for 25CC,n=126 for 25CG;P0.05）.The 25G allele was not associated with a reduced risk of MI（P0.05）.Further stratifications for age,sex,and other cardiovascular risk factors did not affect the negative findings.It was concluded that the presence of the G allele at the 25CG（rs35282763） polymorphism of the LRP1 is not associated with a reduced risk of MI,and genotyping for LRP1 25CG（rs35282763） polymor-phism is not useful in assessing the individual risk of MI.展开更多
Alzheimer's disease,the primary cause of dementia,is characterized by neuropathologies,such as amyloid plaques,synaptic and neuronal degeneration,and neurofibrillary tangles.Although amyloid plaques are the primar...Alzheimer's disease,the primary cause of dementia,is characterized by neuropathologies,such as amyloid plaques,synaptic and neuronal degeneration,and neurofibrillary tangles.Although amyloid plaques are the primary characteristic of Alzheimer's disease in the central nervous system and peripheral organs,targeting amyloid-beta clearance in the central nervous system has shown limited clinical efficacy in Alzheimer's disease treatment.Metabolic abnormalities are commonly observed in patients with Alzheimer's disease.The liver is the primary peripheral organ involved in amyloid-beta metabolism,playing a crucial role in the pathophysiology of Alzheimer's disease.Notably,impaired cholesterol metabolism in the liver may exacerbate the development of Alzheimer's disease.In this review,we explore the underlying causes of Alzheimer's disease and elucidate the role of the liver in amyloid-beta clearance and cholesterol metabolism.Furthermore,we propose that restoring normal cholesterol metabolism in the liver could represent a promising therapeutic strategy for addressing Alzheimer's disease.展开更多
AIM： To compare three kinds of fluorescent probes for in vitro labeling and in vivo tracking of endothelial progenitor cells（EPCs） in a mouse model of laser-induced retinal injury.METHODS： EPCs were isolated from ...AIM： To compare three kinds of fluorescent probes for in vitro labeling and in vivo tracking of endothelial progenitor cells（EPCs） in a mouse model of laser-induced retinal injury.METHODS： EPCs were isolated from human umbilical cord blood mononuclear cells and labeled with three different fluorescent probes： 5-（and-6）-carboxyfluorescein diacetate succinimidyl ester（CFSE）, 1,1′-dilinoleyl-3,3,3′,3′-tetramethylindo-carbocyanine perchlorate linked acetylated low-density lipoprotein（Di I-Ac LDL）, and green fluorescent protein（GFP）. The fluorescent intensity of EPCs was examined by confocal microscopy. Survival rate of labeled EPCs was calculated with trypan blue staining, and their adhesive capability was assessed. A mouse model of retinal injury was induced by laser, and EPCs were injected into the vitreous cavity. Frozen section and fluorescein angiography on flat-mounted retinal samples was employed to track the labeled EPCs in vivo.RESULTS： EPCs labeled with CFSE and Di I-Ac LDL exhibited an intense green and red fluorescence at the beginning; the fluorescence intensity decreased gradually to 20.23% and 49.99% respectively, after 28 d. On the contrary, the florescent intensity of GFP-labeled EPCs increased in a time-dependent manner. All labeled EPCs showed normal morphology and no significant change in survival and adhesive capability. In the mouse model, transplantation of EPCs showed a protective effect against retinal injury. EPCs labeled with CFSE and Di I-Ac LDL were successfully tracked in mice during the development of retinal injury and repair; however, GFP-labeled EPCs were not detected in the laser-injured mouse retina.CONCLUSION： The three fluorescent markers used in this study have their own set of advantages and disadvantages. CFSE and Di I-Ac LDL are suitable for short-term EPClabeling, while GFP should be used for long-term labeling. The choice of fluorescent markers should be guided by the purpose of the study.展开更多
文摘Objective Increased transcytosis of low-density lipoprotein (LDL)across the endothelium and oxidation of LDL deposited within the subendothelial space are crucial early events in atherogenesis. C1q/TNF-related protein (CTRP) 5 is a novel secreted glycoprotein and its biological functions are largely undefined.
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.
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.
基金supported by grants from the National Basic Scientific Research Program of China (973 Program, No. 2007CB935803)the National Natural Sciences Foundation of China (No. 30825018)
文摘This study examined the association of a common polymorphic allele（25G） of the low-density lipoprotein receptor-related protein1（LRP1） gene with myocardial infarction（MI）.The genotypes of LRP1 25CG（rs35282763） were determined in 347 MI patients and 347 age-and sex-frequency-matched controls from an unrelated Chinese Han population.Factor Ⅷ（FⅧ） levels were measured in the MI patients and controls by chromogenic assay and enzyme-linked immunosor-bent assay（ELISA）.The results showed that LRP1 25CG（rs35282763） genotype distribution did not differ significantly between patients（n=206 for 25CC,n=122 for 25CG） and controls（n=191 for 25CC,n=126 for 25CG;P0.05）.The 25G allele was not associated with a reduced risk of MI（P0.05）.Further stratifications for age,sex,and other cardiovascular risk factors did not affect the negative findings.It was concluded that the presence of the G allele at the 25CG（rs35282763） polymorphism of the LRP1 is not associated with a reduced risk of MI,and genotyping for LRP1 25CG（rs35282763） polymor-phism is not useful in assessing the individual risk of MI.
基金financially supported by the Science and Technology Innovation Program of Hunan Province,No.2022RC1220(to WP)China Postdoctoral Science Foundation,No.2022M711733(to ZZ)+2 种基金the National Natural Science Foundation of China,No.82160920(to ZZ)Hebei Postdoctoral Scientific Research Project,No.B2022003040(to ZZ)Hunan Flagship Department of Integrated Traditional Chinese and Western Medicine(to WP)。
文摘Alzheimer's disease,the primary cause of dementia,is characterized by neuropathologies,such as amyloid plaques,synaptic and neuronal degeneration,and neurofibrillary tangles.Although amyloid plaques are the primary characteristic of Alzheimer's disease in the central nervous system and peripheral organs,targeting amyloid-beta clearance in the central nervous system has shown limited clinical efficacy in Alzheimer's disease treatment.Metabolic abnormalities are commonly observed in patients with Alzheimer's disease.The liver is the primary peripheral organ involved in amyloid-beta metabolism,playing a crucial role in the pathophysiology of Alzheimer's disease.Notably,impaired cholesterol metabolism in the liver may exacerbate the development of Alzheimer's disease.In this review,we explore the underlying causes of Alzheimer's disease and elucidate the role of the liver in amyloid-beta clearance and cholesterol metabolism.Furthermore,we propose that restoring normal cholesterol metabolism in the liver could represent a promising therapeutic strategy for addressing Alzheimer's disease.
基金Supported by the National Natural Science Foundation of China(No.81400403)the International Science and Technology Cooperation Program of Jilin Province(No.20110733)the Technology Program of Soochow City(No.SYS201375)
文摘AIM： To compare three kinds of fluorescent probes for in vitro labeling and in vivo tracking of endothelial progenitor cells（EPCs） in a mouse model of laser-induced retinal injury.METHODS： EPCs were isolated from human umbilical cord blood mononuclear cells and labeled with three different fluorescent probes： 5-（and-6）-carboxyfluorescein diacetate succinimidyl ester（CFSE）, 1,1′-dilinoleyl-3,3,3′,3′-tetramethylindo-carbocyanine perchlorate linked acetylated low-density lipoprotein（Di I-Ac LDL）, and green fluorescent protein（GFP）. The fluorescent intensity of EPCs was examined by confocal microscopy. Survival rate of labeled EPCs was calculated with trypan blue staining, and their adhesive capability was assessed. A mouse model of retinal injury was induced by laser, and EPCs were injected into the vitreous cavity. Frozen section and fluorescein angiography on flat-mounted retinal samples was employed to track the labeled EPCs in vivo.RESULTS： EPCs labeled with CFSE and Di I-Ac LDL exhibited an intense green and red fluorescence at the beginning; the fluorescence intensity decreased gradually to 20.23% and 49.99% respectively, after 28 d. On the contrary, the florescent intensity of GFP-labeled EPCs increased in a time-dependent manner. All labeled EPCs showed normal morphology and no significant change in survival and adhesive capability. In the mouse model, transplantation of EPCs showed a protective effect against retinal injury. EPCs labeled with CFSE and Di I-Ac LDL were successfully tracked in mice during the development of retinal injury and repair; however, GFP-labeled EPCs were not detected in the laser-injured mouse retina.CONCLUSION： The three fluorescent markers used in this study have their own set of advantages and disadvantages. CFSE and Di I-Ac LDL are suitable for short-term EPClabeling, while GFP should be used for long-term labeling. The choice of fluorescent markers should be guided by the purpose of the study.
