代谢综合征作为多种疾病的发病基础,发病机制复杂。近年研究发现,Wnt/β-catenin信号通路在代谢综合征的发生发展中起到重要的调控作用。低密度脂蛋白受体相关蛋白6(low-density lipoprotein receptor related protein,LRP6)作为Wnt/β-...代谢综合征作为多种疾病的发病基础,发病机制复杂。近年研究发现,Wnt/β-catenin信号通路在代谢综合征的发生发展中起到重要的调控作用。低密度脂蛋白受体相关蛋白6(low-density lipoprotein receptor related protein,LRP6)作为Wnt/β-catenin信号通路的重要协同受体,已有研究表明其与代谢综合征之间存在相关性。该文将对该基因多态性及其调节机制进行深入探讨,为代谢综合征的研究治疗提供新的思路和方向。展开更多
目的研究机械牵张对心脏侧群干细胞(cardiac side population cell,CSP)增殖的作用及机制。方法通过流式细胞仪分选并培养大鼠乳鼠CSP,牵张后观察细胞的增殖。并通过胸主动脉缩窄(transverse aorta constriction,TAC)建立压力负荷小鼠模...目的研究机械牵张对心脏侧群干细胞(cardiac side population cell,CSP)增殖的作用及机制。方法通过流式细胞仪分选并培养大鼠乳鼠CSP,牵张后观察细胞的增殖。并通过胸主动脉缩窄(transverse aorta constriction,TAC)建立压力负荷小鼠模型,流式细胞仪分选后观察CSP的比例。进一步通过荧光染色以及Western blot检测CSP的LRP6磷酸化水平。结果成功分离及培养CSP,机械牵张可促进CSP增殖。体内实验表明,压力负荷可明显促进CSP比例的升高。免疫荧光及Western blot实验表明,机械牵张可明显促进CSP的LPR6磷酸化。CSP过表达LRP6可明显增强机械牵张介导的促增殖效应。结论机械牵张可促进LRP6磷酸化,从而促进CSP增殖,有利于机体对病理性刺激产生适应性反应以维持心功能。展开更多
Lipoprotein receptor-related protein 6 （LRP6） plays a critical role in skeletal development and homeostasis in adults. However, the role of LRP6 in mesenchymal stem cells （MSCs）, skeletal stem cells that give rise...Lipoprotein receptor-related protein 6 （LRP6） plays a critical role in skeletal development and homeostasis in adults. However, the role of LRP6 in mesenchymal stem cells （MSCs）, skeletal stem cells that give rise to osteoblastic lineage, is unknown. In this study, we generated mice lacking LRP6 expression specifically in nestin＋ MSCs by crossing nestin-Cre mice with LRP6 flox mice and investigated the functional changes of bone marrow MSCs and skeletal alterations. Mice with LRP6 deletion in nestin＋ cells demonstrated reductions in body weight and body length at I and 3 months of age. Bone architecture measured by microCT （uCT） showed a significant reduction in bone mass in both trabecular and cortical bone of homozygous and heterozygous LRP6 mutant mice. A dramatic reduction in the numbers of osteoblasts but much less significant reduction in the numbers of osteoclasts was observed in the mutant mice. Osterix＋ osteoprogenitors and osteocalcin＋ osteoblasts significantly reduced at the secondary spongiosa area, but only moderately decreased at the primary spongiosa area in mutant mice. Bone marrow MSCs from the mutant mice showed decreased colony forming, cell viability and cell proliferation. Thus, LRP6 in bone marrow MSCs is essential for their survival and proliferation, and therefore, is a key positive regulator for bone formation during skeletal growth and remodeling.展开更多
Bone fracture non-unions, the failure of a fracture to heal, occur in 10%-20% of fractures and are a costly and debilitating clinical problem. The Wnt/fl-catenin pathway is critical in bone development and fracture he...Bone fracture non-unions, the failure of a fracture to heal, occur in 10%-20% of fractures and are a costly and debilitating clinical problem. The Wnt/fl-catenin pathway is critical in bone development and fracture healing. Polymorphisms of linking low-density lipoprotein receptor-related protein 6 （LRP6）, a Wnt-binding receptor, have been associated with decreased bone mineral density and fragility fractures, although this remains controversial. Mice with a homozygous deletion of Lrp6 have severe skeletal abnormalities and are not viable, whereas mice with a heterozygous deletion have a combinatory effect with Lrp5 to decrease bone mineral density. As fracture healing closely models embryonic skeletal development, we investigated the process of fracture healing in mice heterozygous for Lrp6 （Lrp6~/-） and hypothesized that the heterozygous deletion of Lrp6 would impair fracture healing. Mid-diaphyseal femur fractures were induced in Lrp6~^- mice and wild-type controls （Lrp6~/~）. Fractures were analyzed using micro-computed tomography （~CT） scans, biomechanical testing, and histological analysis. Lrp6~/- mice had significantly decreased stiffness and strength at 28 days post fracture （PF） and significantly decreased BV/TV, total density, immature bone density, and mature area within the callus on day-14 and -21 PF; they had significantly increased empty callus area at days 14 and 21 PF. Our results demonstrate that the heterozygous deletion of Lrp6 impairs fracture healing, which suggests that Lrp6 has a role in fracture healing.展开更多
Whether and how garlic-derived S-allylmercaptocysteine(SAMC) inhibits hepatocellular carcinoma(HCC) is largely unknown. In the current study, the role of low-density lipoprotein receptor(LDLR)-related protein 6(LRP6) ...Whether and how garlic-derived S-allylmercaptocysteine(SAMC) inhibits hepatocellular carcinoma(HCC) is largely unknown. In the current study, the role of low-density lipoprotein receptor(LDLR)-related protein 6(LRP6) in HCC progression and the anti-HCC mechanism of SAMC was examined in clinical sample, cell model and xenograft/orthotopic mouse models. We demonstrated that SAMC inhibited cell proliferation and tumorigenesis, while induced apoptosis of human HCC cells without influencing normal hepatocytes. SAMC directly interacted with Wnt-pathway co-receptor LRP6 on the cell membrane. LRP6 was frequently over-expressed in the tumor tissue of human HCC patients(66.7% of 48 patients) and its overexpression only correlated with the over-expression of β-catenin, but not with age, gender, tumor size, stage and metastasis. Deficiency or over-expression of LRP6 in hepatoma cells could partly mimic or counteract the anti-tumor properties of SAMC, respectively. In vivo administration of SAMC significantly suppressed the growth of Huh-7 xenograft/orthotopic HCC tumor without causing undesirable side effects. In addition, stable down-regulation of LRP6 in Huh-7 facilitated the anti-HCC effects of SAMC. In conclusion, LRP6 can be a potential therapeutic target of HCC. SAMC is a promising specific anti-tumor agent for treating HCC subtypes with Wnt activation at the hepatoma cell surface.展开更多
Neuronal apoptosis is one of the essential mechanisms of early brain injury after subarachnoid hemorrhage(SAH).Recently,HLY78 has been shown to inhibit apoptosis in tumor cells and embryonic cells c aused by carbon io...Neuronal apoptosis is one of the essential mechanisms of early brain injury after subarachnoid hemorrhage(SAH).Recently,HLY78 has been shown to inhibit apoptosis in tumor cells and embryonic cells c aused by carbon ion radiation through activation of the Wnt/β-catenin pathway.This study was designed to explore the anti-apoptotic role of HLY78 in experimental SAH.The results demonstrated that HLY78 attenuated neuronal apoptosis and the neurological deficits after SAH through the activation of low-density lipoprotein receptor-related protein 6(LRP6),which subsequently increased the level of phosphorylated glycogen synthesis kinase 3 beta(p-GSK3β)(Ser9),β-catenin,and Bcl-2,accompanied by a decrease of p-β-catenin,Bax,and cleaved caspase 3.An LRP6 small-interfering ribonucleic acid reversed the effects of HLY78.In conclusion,HLY78 attenuates neuronal apoptosis and improves neurological deficits through the LRP6/GSK3β/β-catenin signaling pathway after SAH in rats.HLY78 is a promising therapeutic agent to attenuate early brain injury after SAH.展开更多
文摘代谢综合征作为多种疾病的发病基础,发病机制复杂。近年研究发现,Wnt/β-catenin信号通路在代谢综合征的发生发展中起到重要的调控作用。低密度脂蛋白受体相关蛋白6(low-density lipoprotein receptor related protein,LRP6)作为Wnt/β-catenin信号通路的重要协同受体,已有研究表明其与代谢综合征之间存在相关性。该文将对该基因多态性及其调节机制进行深入探讨,为代谢综合征的研究治疗提供新的思路和方向。
文摘目的研究机械牵张对心脏侧群干细胞(cardiac side population cell,CSP)增殖的作用及机制。方法通过流式细胞仪分选并培养大鼠乳鼠CSP,牵张后观察细胞的增殖。并通过胸主动脉缩窄(transverse aorta constriction,TAC)建立压力负荷小鼠模型,流式细胞仪分选后观察CSP的比例。进一步通过荧光染色以及Western blot检测CSP的LRP6磷酸化水平。结果成功分离及培养CSP,机械牵张可促进CSP增殖。体内实验表明,压力负荷可明显促进CSP比例的升高。免疫荧光及Western blot实验表明,机械牵张可明显促进CSP的LPR6磷酸化。CSP过表达LRP6可明显增强机械牵张介导的促增殖效应。结论机械牵张可促进LRP6磷酸化,从而促进CSP增殖,有利于机体对病理性刺激产生适应性反应以维持心功能。
基金supported by National Institutes of Health Grant DK083350 to M. W
文摘Lipoprotein receptor-related protein 6 （LRP6） plays a critical role in skeletal development and homeostasis in adults. However, the role of LRP6 in mesenchymal stem cells （MSCs）, skeletal stem cells that give rise to osteoblastic lineage, is unknown. In this study, we generated mice lacking LRP6 expression specifically in nestin＋ MSCs by crossing nestin-Cre mice with LRP6 flox mice and investigated the functional changes of bone marrow MSCs and skeletal alterations. Mice with LRP6 deletion in nestin＋ cells demonstrated reductions in body weight and body length at I and 3 months of age. Bone architecture measured by microCT （uCT） showed a significant reduction in bone mass in both trabecular and cortical bone of homozygous and heterozygous LRP6 mutant mice. A dramatic reduction in the numbers of osteoblasts but much less significant reduction in the numbers of osteoclasts was observed in the mutant mice. Osterix＋ osteoprogenitors and osteocalcin＋ osteoblasts significantly reduced at the secondary spongiosa area, but only moderately decreased at the primary spongiosa area in mutant mice. Bone marrow MSCs from the mutant mice showed decreased colony forming, cell viability and cell proliferation. Thus, LRP6 in bone marrow MSCs is essential for their survival and proliferation, and therefore, is a key positive regulator for bone formation during skeletal growth and remodeling.
基金Grand Rapids Area Pre-College Engineering Programsupported by NIH grant AR053293
文摘Bone fracture non-unions, the failure of a fracture to heal, occur in 10%-20% of fractures and are a costly and debilitating clinical problem. The Wnt/fl-catenin pathway is critical in bone development and fracture healing. Polymorphisms of linking low-density lipoprotein receptor-related protein 6 （LRP6）, a Wnt-binding receptor, have been associated with decreased bone mineral density and fragility fractures, although this remains controversial. Mice with a homozygous deletion of Lrp6 have severe skeletal abnormalities and are not viable, whereas mice with a heterozygous deletion have a combinatory effect with Lrp5 to decrease bone mineral density. As fracture healing closely models embryonic skeletal development, we investigated the process of fracture healing in mice heterozygous for Lrp6 （Lrp6~/-） and hypothesized that the heterozygous deletion of Lrp6 would impair fracture healing. Mid-diaphyseal femur fractures were induced in Lrp6~^- mice and wild-type controls （Lrp6~/~）. Fractures were analyzed using micro-computed tomography （~CT） scans, biomechanical testing, and histological analysis. Lrp6~/- mice had significantly decreased stiffness and strength at 28 days post fracture （PF） and significantly decreased BV/TV, total density, immature bone density, and mature area within the callus on day-14 and -21 PF; they had significantly increased empty callus area at days 14 and 21 PF. Our results demonstrate that the heterozygous deletion of Lrp6 impairs fracture healing, which suggests that Lrp6 has a role in fracture healing.
基金supported by Foundation of Pearl River Science and Technology New Star (grant number 201506010087)Basic Research Fund of Shenzhen City (JCYJ20150402111430633) to Jia Xiao+7 种基金Health Medical Research Fund (HMRF,No. 12133881)General Research Fund and Small Project FundingUniversity Research Committee,The University of Hong Kong. to George L.TipoeNational Natural Science Foundation of China (No. 81570552)National Program on Key Basic Research Project of China (973 Program,2014CB542205)Funds of Leading Talents of Guangdong (2013)Programme of Introducing Talents of Discipline to Universities (B14036) to Kwok-Fai SoNational Health and Medical Research Council (1031221 & 1031228) to Ming-Tat Ling
文摘Whether and how garlic-derived S-allylmercaptocysteine(SAMC) inhibits hepatocellular carcinoma(HCC) is largely unknown. In the current study, the role of low-density lipoprotein receptor(LDLR)-related protein 6(LRP6) in HCC progression and the anti-HCC mechanism of SAMC was examined in clinical sample, cell model and xenograft/orthotopic mouse models. We demonstrated that SAMC inhibited cell proliferation and tumorigenesis, while induced apoptosis of human HCC cells without influencing normal hepatocytes. SAMC directly interacted with Wnt-pathway co-receptor LRP6 on the cell membrane. LRP6 was frequently over-expressed in the tumor tissue of human HCC patients(66.7% of 48 patients) and its overexpression only correlated with the over-expression of β-catenin, but not with age, gender, tumor size, stage and metastasis. Deficiency or over-expression of LRP6 in hepatoma cells could partly mimic or counteract the anti-tumor properties of SAMC, respectively. In vivo administration of SAMC significantly suppressed the growth of Huh-7 xenograft/orthotopic HCC tumor without causing undesirable side effects. In addition, stable down-regulation of LRP6 in Huh-7 facilitated the anti-HCC effects of SAMC. In conclusion, LRP6 can be a potential therapeutic target of HCC. SAMC is a promising specific anti-tumor agent for treating HCC subtypes with Wnt activation at the hepatoma cell surface.
基金This work was supported by the National Natural Science Foundation of China(81771961 and 81401505)the Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University(201959).
文摘Neuronal apoptosis is one of the essential mechanisms of early brain injury after subarachnoid hemorrhage(SAH).Recently,HLY78 has been shown to inhibit apoptosis in tumor cells and embryonic cells c aused by carbon ion radiation through activation of the Wnt/β-catenin pathway.This study was designed to explore the anti-apoptotic role of HLY78 in experimental SAH.The results demonstrated that HLY78 attenuated neuronal apoptosis and the neurological deficits after SAH through the activation of low-density lipoprotein receptor-related protein 6(LRP6),which subsequently increased the level of phosphorylated glycogen synthesis kinase 3 beta(p-GSK3β)(Ser9),β-catenin,and Bcl-2,accompanied by a decrease of p-β-catenin,Bax,and cleaved caspase 3.An LRP6 small-interfering ribonucleic acid reversed the effects of HLY78.In conclusion,HLY78 attenuates neuronal apoptosis and improves neurological deficits through the LRP6/GSK3β/β-catenin signaling pathway after SAH in rats.HLY78 is a promising therapeutic agent to attenuate early brain injury after SAH.
