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Neuroscience Bulletin 2020年第10期36卷 1171-1181页

作者： Xu Luo Lina Li Weilin Xu Yuan Cheng Zongyi Xie Department of Neurosurgery The Second Affiliated HospitalChongqing Medical UniversityChongqing 400010China Department of Nephrology The Third Affiliated HospitalChongqing Medical UniversityChongqing 401120China Department of Neurosurgery The Second Affiliated HospitalZhejiang University School of MedicineHangzhou 310009China

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 *** study was designed to explore the anti-apoptotic role of HLY78 in experimental *** 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 *** lrp6 small-interfering ribonucleic acid reversed the effects of *** conclusion,HLY78 attenuates neuronal apoptosis and improves neurological deficits through the lrp6/GSK3β/β-catenin signaling pathway after SAH in ***78 is a promising therapeutic agent to attenuate early brain injury after SAH.

关键词： Subarachnoid hemorrhage HLY78 lrp6 Neuronal apoptosis

ATP6AP2,a regulator of lrp6/β-catenin protein trafficking,promotes Wnt/β-catenin signaling and bone formation in a cell type dependent manner

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Bone Research 2024年第2期12卷 453-468页

作者： Lei Xiong Hao-Han Guo Jin-Xiu Pan Xiao Ren Daehoon Lee Li Chen Lin Mei Wen-Cheng Xiong Department of Neurosciences School of MedicineCase Western Reserve UniversityClevelandOH 44106USA Louis Stoke VA Medical Center ClevelandOH 44106USA

Wnt/β-catenin signaling is critical for various cellular processes in multiple cell types,including osteoblast(OB)differentiation and *** how Wnt/β-catenin signaling is regulated in OBs remain ***6AP2,an accessory subunit of V-ATPase,plays important roles in multiple cell types/organs and multiple signaling ***,little is known whether and how ATP6AP2 in OBs regulates Wnt/β-catenin signaling and bone *** we provide evidence for ATP6AP2 in the OB-lineage cells to promote OB-mediated bone formation and bone homeostasis selectively in the trabecular bone *** knocking out(CKO)ATP6AP2 in the OB-lineage cells(Atp6ap2^(Ocn-Cre))reduced trabecular,but not cortical,bone formation and bone *** and cellular biochemical studies revealed that lrp6 and N-cadherin were reduced in ATP6AP2-KO BMSCs and OBs,but not *** in vitro and in vivo studies revealed impairedβ-catenin signaling in ATP6AP2-KO BMSCs and OBs,but not osteocytes,under both basal and Wnt stimulated conditions,although lrp5 was decreased in ATP6AP2-KO osteocytes,but not *** cell biological studies uncovered that osteoblastic ATP6AP2 is not required for Wnt3a suppression ofβ-catenin phosphorylation,but necessary for lrp6/β-catenin and N-cadherin/β-catenin protein complex distribution at the cell membrane,thus preventing their *** of activeβ-catenin diminished the OB differentiation deficit in ATP6AP2-KO *** together,these results support the view for ATP6AP2 as a critical regulator of both lrp6 and N-cadherin protein trafficking and stability,and thus regulatingβ-catenin levels,demonstrating an un-recognized function of osteoblastic ATP6AP2 in promoting Wnt/lrp6/β-catenin signaling and trabecular bone formation.

关键词： lrp6 impaired organs

Garlic-derived compound S-allylmercaptocysteine inhibits hepatocarcinogenesis through targeting lrp6/Wnt pathway

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Acta Pharmaceutica Sinica B 2018年第4期8卷 575-586页

作者： Jia Xiao Feiyue Xing Yingxia Liu Yi Lv Xiaogang Wang Ming-Tat Ling Hao Gao Songying Ouyang Min Yang Jiang Zhu Yu Xia Kwok-Fai So George L.Tipoe State Key Discipline of Infectious Diseases Shenzhen Third People's Hospital Department of Immunobiology Institute of Tissue Transplantation and ImmunologyJinan University School of Biomedical Sciences The University of Hong Kong Department of Cell Biology & Institute of Biomedicine Jinan University Australian Prostate Cancer Research Centre-Queensland and Institute of Health and Biomedical Innovation Queensland University of Technology Institute of Traditional Chinese Medicine and Natural Products College of PharmacyJinan University Biomedical Research Center of South China College of Life SciencesFujian Normal University JM Medical (Shenzhen) LLC GMH Institute of Central Nervous System Regeneration Jinan University

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.

关键词： S-allylmercaptocysteine HCC Wnt lrp6 Human Nude mice

lrp6基因多态性与代谢综合征的相关性研究进展

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中国药理学通报 2016年第5期32卷 603-607页

作者：王振敏罗建权张伟中南大学湘雅医院临床药理研究所湖南长沙410008 中南大学临床药理研究所遗传药理湖南省重点实验室湖南长沙410078

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-... 详细信息

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。

关键词： Wnt信号通路 lrp6 代谢综合征 Ⅱ型糖尿病高血脂症动脉粥样硬化冠状动脉疾病

机械牵张调控lrp6磷酸化介导心脏侧群干细胞增殖

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复旦学报（医学版） 2016年第6期43卷 668-675页

作者：陈志丹龚惠叶勇张国平李洋杨春杰贾剑国邹云增复旦大学附属中山医院上海市心血管病研究所上海200032 复旦大学生物医学研究院上海200032

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... 详细信息

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。

关键词：机械牵张压力负荷心脏侧群干细胞 lrp6 增殖

lrp6调控经典Wnt信号通路作用于阿霉素诱导的心肌细胞损伤

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中山大学学报（医学版） 2019年第4期40卷 503-509页

作者：梁莉莹路静刘培庆中山大学药学院药理毒理实验室

【目的】探究lrp6和经典Wnt/β-catenin信号通路在阿霉素心肌病中的作用及其机制。【方法】采用阿霉素(Dox)刺激H9C2细胞12h,在细胞水平上建立阿霉素心肌病模型;12只SD大鼠分为两组(各6只),腹腔分别注射生理盐水和Dox,在动物水平上建立... 详细信息

【目的】探究lrp6和经典Wnt/β-catenin信号通路在阿霉素心肌病中的作用及其机制。【方法】采用阿霉素(Dox)刺激H9C2细胞12h,在细胞水平上建立阿霉素心肌病模型;12只SD大鼠分为两组(各6只),腹腔分别注射生理盐水和Dox,在动物水平上建立阿霉素心肌病;Westernblot和qPCR检测相应蛋白和mRNA表达水平变化;通过转染siRNA靶向沉默lrp6表达;采用罗丹明123、Hoechst和Mitotracker染色分别检测线粒体膜电位、细胞核固缩以及线粒体肿胀;通过流式细胞技术检测凋亡比率变化。【结果】在细胞及动物水平上,成功建立阿霉素心肌病模型;Dox引起lrp6的mRNA和蛋白水平下降;敲低lrp6加重阿霉素引起的心肌细胞凋亡和线粒体损伤;Dox和沉默lrp6均下调β-catenin,激活β-catenin可以逆转阿霉素造成的心肌损伤。【结论】Dox通过诱导lrp6表达下调,抑制了经典Wnt/β-catenin信号通路,从而引起心肌细胞凋亡和线粒体损伤。

关键词： lrp6 阿霉素心肌病 Wnt/β-catenin 凋亡线粒体

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lrp6和VEGFR2在牦牛肺的分布

畜牧兽医学报 2018年第7期49卷 1550-1557页

作者：马俊兴何俊峰崔燕张倩刘鹏刚甘肃农业大学动物医学院兰州730070

旨在探究lrp6和VEGFR2在不同年龄段牦牛肺组织中的表达和定位,以及两者对牦牛肺低氧适应性结构形成和可能的调控作用。选取新生(1~7日龄)、半岁(5~6月龄)、成年(3~6岁)和老年(7~10岁)健康牦牛肺组织样品各5头份,采用酶联免疫吸附试验、W... 详细信息

旨在探究lrp6和VEGFR2在不同年龄段牦牛肺组织中的表达和定位,以及两者对牦牛肺低氧适应性结构形成和可能的调控作用。选取新生(1~7日龄)、半岁(5~6月龄)、成年(3~6岁)和老年(7~10岁)健康牦牛肺组织样品各5头份,采用酶联免疫吸附试验、Western-blot和免疫组织化学方法对不同年龄的牦牛肺组织中lrp6和VEGFR2的表达量和准确分布位置进行研究。结果显示:lrp6和VEGFR2在初生和半岁牦牛组之间的表达量均差异不显著(P>0.05),初生、半岁与老年组牦牛的表达量均差异显著(Plrp6主要分布于肺内支气管和其分支的上皮细胞以及肺泡Ⅱ型细胞,其表达较强;少量分布在肺血管内皮细胞和管壁平滑肌细胞,表达较弱;VEGFR2主要分布于肺内支气管及其分支的上皮细胞、管壁平滑肌细胞和肺泡隔细胞以及肺泡Ⅰ型细胞中,其表达较强;在肺血管内皮细胞和平滑肌细胞内也有分布,但表达较弱。综上表明,lrp6和VEGFR2不仅在不同年龄段的牦牛肺组织中表达量具有差异性,而且它们对高原环境下牦牛肺适应低氧适应性的结构形成和维持可能的调控具有重要的意义。

关键词：牦牛肺 lrp6 VEGFR2 适应性

Canonical Wnt signaling pathway is involved in astrogliosis via activation of lrp6

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Canonical Wnt signaling pathway is involved in astrogliosis ...

lrp6、ARID1A mRNA在宫颈癌中的表达及临床意义

中国神经科学学会第十届全国学术会议

作者： Siqi LI Chunzhang YANG Zhengping ZHUANG Albert Cheung Hoi YU Neuroscience Research Institute Department of NeurobiologySchool of Basic Medical SciencesPeking University Key Laboratory for Neuroscience Ministry of Education(Peking University) Key Laboratory for Neuroscience Ministry of National Health and Family Planning Commission(Peking University) Surgical Neurology Branch National Institute of Neurological Disorders and StrokeNational Institutes of Health Laboratory of Translational Medicine Institute of Systems BiomedicinePeking University

Mechanical injury of the brain has been studied for decades utilizing in vitro model of astrocytes,regarding to their remarkable cellular responses to the *** previous finding demonstrated that astrocytic beta-catenin plays fundamental roles in traumatic signal transduction and initiating cellular ***,it is still obscure about the details in molecular mechanism by which astrocytes initiate activation process and activate beta-catenin *** present study,we investigated the extracellular ligands mat trigger Wnt signal transduction during injury-associated astrocytic *** found that injury induced a global change in gene expression profile of Wnt family in *** injury-related Wnt production caused phosphorylation and internalization of Low-density lipoprotein receptor-related protein 6（lrp6）,a co-receptor of canonical Wnt ***,lrp6 was recruited into Axin/APC/GSK3beta degradation complex after injury,suggesting lrp6 inhibits the degradation process of *** further demonstrated that the activation of lrp6 is essential for astrocytic activation,since siRNA silencing of lrp6 resulted in enhanced beta-catenin degradation and attenuated wound healing *** summary,we demonstrated that canonical Wnt signaling pathway was activated to inhibit beta-catenin degradation in astrogliosis and mediates the cellular activation of astrocytes.

关键词： astrocyte mechanical injury beta-catenin Wnt lrp6

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LRP6、ARID1A mRNA在宫颈癌中的表达及临床意义

作者：汤雅丽中南大学

学位级别：硕士

目的：通过检测低密度脂蛋白受体相关蛋白6(low density lipoprotein receptor-related protein6, lrp6) mRNA、AT丰富结合域蛋白1A(AT-rich interacting domain containing protein1A, ARID1A) mRNA在宫颈炎组织、中-重度宫颈上皮内瘤变组织(CIN Ⅱ-Ⅲ)、宫颈癌组织的表达情况,探讨lrp6、ARID1AmRNA的表达与宫颈癌临床病理参数的关系。方法：1.应用实时荧光定量PCR技术检测15例宫颈炎、15例CIN Ⅱ-Ⅲ、40例宫颈癌组织中lrp6、ARID1AmRNA的表达。2.分析lrp6、ARID1AmRNA的表达与宫颈癌临床病理参数之间的关系。3.分析lrp6、ARID1AmRNA在宫颈癌中的表达相关性。4.应用统计学SPSS17.0软件进行数据分析,检验水准α=0.05。结果：***6mRNA在宫颈炎、CIN Ⅱ-Ⅲ、宫颈癌组织中的相对表达量分别为1.6463±0.2501、2.2306±0.3213.2.8432±0.8687,在宫颈炎、CIN Ⅱ-Ⅲ、宫颈癌组织中表达逐渐升高,差异有统计学意义(P6.4405±4.0526、8.3827±3.5489、0.9682±0.9187,在宫颈炎、CIN Ⅱ-Ⅲ、宫颈癌组织中表达逐渐下降,差异有统计学意义(P6mRNA在宫颈癌中的表达与临床分期、组织分化程度、高危型HPV感染有关,差异有统计学意义(P0.05)。***1AmNA在宫颈癌中的表达与组织分化程度、组织类型有关,差异有统计学意义(P0.05)。5. Spearman相关性检验结果显示lrp6、ARID1A mRNA在宫颈癌中的表达呈负相关(r=-0.393,P=0.0126mRNA在宫颈炎、CIN Ⅱ-Ⅲ、宫颈癌组织中表达逐渐升高,且与宫颈癌的临床分期、组织分化程度、高危型HPV感染有关,提示LERP6的过度表达可能参与宫颈癌的发生发展。***1AmRNA在宫颈炎、CIN Ⅱ-Ⅲ、宫颈癌组织中表达逐渐下降,且与宫颈癌的组织分化程度、组织病理类型有关,提示ARID1A的失活可能与宫颈癌的发生有关。

关键词：宫颈癌 lrp6 ARID1A 实时荧光定量PCR

lrp6和VEGFR2在不同年龄牦牛肺脏内分布的研究

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LRP6和VEGFR2在不同年龄牦牛肺脏内分布的研究

作者：马俊兴甘肃农业大学

学位级别：硕士

为探究lrp6和VEGFR2在不同年龄牦牛肺组织中的定位和表达,探讨这两种细胞因子对牦牛肺脏低氧适应性结构形成的可能调控作用。论文选取新生(1～7日龄)、半岁(5～6月龄)、成年(3～6岁)和老年(7～10岁)健康牦牛肺组织样品作为研究对象,首... 详细信息

为探究lrp6和VEGFR2在不同年龄牦牛肺组织中的定位和表达,探讨这两种细胞因子对牦牛肺脏低氧适应性结构形成的可能调控作用。论文选取新生(1～7日龄)、半岁(5～6月龄)、成年(3～6岁)和老年(7～10岁)健康牦牛肺组织样品作为研究对象,首先采用RT-PCR技术克隆牦牛lrpP6和VEGFR2基因序列,并进行相关生物信息学分析;之后运用qRT-PCR、ELISA和Western-blot实验方法,从mRNA和蛋白两个方面探讨不同年龄牦牛肺脏中lrp6和VEGFR2的表达情况;最后采用免疫组织化学技术,对lrp6和VEGFR2在不同年龄牦牛肺脏内的准确的分布位置和表达量进行研究。结果表明:1.克隆得到牦牛lrp6基因(GenBank登录号:MF776096),其牦牛开放阅读框长度为624bp,起始密码子位于41bp处,终止密码子位于664bp处,编码207个氨基酸。同源性分析和系统进化树显示,牦牛lrp6基因与野牦牛、北美野牛和绵羊的进化水平较为相近,与人、猕猴和食蟹猴进化水平较远。克隆得到牦牛VEGFR2基因(GenBank登录号:MF590245),其牦牛开放阅读框长度为312bp,起始密码子位于96bp处,终止密码子位于407bp处,编码103个氨基酸。同源性分析和系统进化树显示,牦牛VEGFR2基因与瘤牛、家牛和野牦牛的进化水平较为相近,与小鼠、褐鼠和人进化水平较远。***6和VEGFR2基因mRNA和蛋白在牦牛肺脏的表达模式相同,表达量从新生到老年均呈增长趋势。lrp6和VEGFR2在初生和半岁牦牛组之间的表达量差异不显著(P>0.05),初生、半岁和老年组牦牛的表达量差异均显著(Plrp6和VEGFR2基因mRNA主要在老年牦牛肺脏组织中表达,其余年龄组有少量表达,这可能与牦牛生长调控机制作用有关。***6主要分布于肺内支气管和其分支的上皮细胞以及肺泡Ⅱ型细胞,其表达较强;少量分布在肺血管内皮细胞和管壁平滑肌细胞,表达较弱;VEGFR2主要分布于肺内支气管及其分支的上皮细胞、管壁平滑肌细胞和肺泡隔细胞以及肺泡Ⅰ型细胞中,其表达较强;在肺血管内皮细胞和平滑肌细胞内也有分布,但表达较弱。这两种因子可能参与了牦牛肺脏气道和肺动脉的结构的形成。

关键词：牦牛肺 lrp6 VEGFR2