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clusterin as a serum biomarker candidate contributes to the lung fibroblasts activation in chronic obstructive pulmonary disease

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Chinese Medical Journal 2022年第9期135卷 1076-1086页

作者： Qiang Zhang Yuanyi Yue Rui Zheng Department of Pulmonary and Critical Care Medicine Shengjing Hospital of China Medical UniversityShenyangLiaoning 110014China Department of Gastroenterology Medicine Shengjing Hospital of China Medical UniversityShenyangLiaoning 110014China

Background:Fibrosis in the peripheral airways contributes to airflow limitation in patients with chronic obstructive pulmonary disease(COPD).However,the key proteins involved in its development are still poorly understood.Thus,we aimed to identify the differentially expressed proteins(DEPs)between smoker patients with and without COPD and elucidate the molecular mechanisms involved by investigating the effects of the identified biomarker candidate on lung fibroblasts.Methods:The potential DEPs were identified by isobaric tags for relative and absolute quantitation(iTRAQ)-based proteomic analysis.The messenger RNA and protein levels of clusterin(CLU)in COPD patients and 12%cigarette smoke extract(CSE)-treated human bronchial epithelial cells were determined at the indicated time points.Furthermore,anin vitro COPD model was established via the administration of 8%CSE to normal human lung fibroblasts(NHLFs)at indicated time points.The effects of CSE treatment andCLU silencing on proliferation and activation of lung fibroblasts were analyzed.Results:A total of 144 DEPs were identified between COPD patients and normal smokers.The iTRAQ-based proteomics and bioinformatics analyses identified CLU as a serum biomarker candidate.We also discovered that CLU levels were significantly increased(P<0.0001)in Global Initiative for Obstructive Lung Disease II,III,and IV patients and correlated(P<0.0001)with forced expiratory volume in 1 s(R=-0.7705),residual volume(RV)(R=0.6281),RV/total lung capacity(R=0.5454),and computerized tomography emphysema(R=0.7878).Similarly,CLU levels were significantly increased in CSE-treated cells at indicated time points(P<0.0001).The CSE treatment significantly inhibited the proliferation,promoted the inflammatory response,differentiation of NHLFs,and collagen matrix deposition,and induced the apoptosis of NHLFs;however,these effects were partially reversed byCLU silencing.Conclusion:Our findings suggest that CLU may play significant roles during airway fibrosis in COPD by regulating lung fibrobl

关键词： Chronic obstructive pulmonary disease clusterin Cigarette smoke extract Airway fibrosis Lung fibroblasts

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clusterin transduces Alzheimer-risk signals to amyloidogenesis

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Signal Transduction and Targeted Therapy 2022年第10期7卷 3658-3661页

作者： Xi Liu Rongbo Che Wenping Liang Yun Zhang Liyong Wu Chao Han Hong Lu Weihong Song Yili Wu Zhe Wang The National Clinical Research Center for Geriatric Disease Department of NeurologyAdvanced Innovation Center for Human Brain ProtectionXuanwu HospitalCapital Medical UniversityBeijingPR China Department of Neurology The First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanPR China Department of Psychiatry Shandong Collaborative Innovation Center for DiagnosisTreatment&Behavioral Interventions of Mental DisordersInstitute of Mental HealthJining Medical UniversityJiningShandongPR China Oujiang Laboratory(Zhejiang Lab for Regenerative Medicine Vision and Brain Health)Institute of AgingKey Laboratory of Alzheimer’s Disease of Zhejiang ProvinceZhejiang Provincial Clinical Research Center for Mental DisordersSchool of Mental Health and The Affiliated Wenzhou Kangning HospitalWenzhou Medical UniversityWenzhouZhejiangPR China

Dear Editor,Deposition of amyloid-β(Aβ)to form neuritic plaque(NP)is the hallmark of Alzheimer’s Disease(AD).Major non-genetic risk factors such as ageing,stroke,diabetes and other conditions facilitate AD pathogenesis via unclear mechanisms.Furthermore,the mechanism underlying NP formation is unclear.Increasing Aβcauses NP in familial AD patients and in transgenic AD mice robustly expressing Aβ,but the NP formation requires long-term Aβaccumulation.

关键词： Alzheimer Aβ clusterin

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clusterin mRNA expression in apoptotic and activated rat thymocytes

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Cell Research 2003年第1期13卷 49-58页

作者： JUNG-HYUNPARK JEE-SUNPARK SUNG-KYUJU KWAN-BOKLEE KWAN-HEEYOU MYUNG-HEEKANG Yoo-KYOUNGPARK SHIN-YOUNGNA Experimental MD 20892 Department of Food and Nutrition 220 Gung-dong for Virology and Immunobiology Institute Immunology Branch Germany Versbacher Str. 7 Bethesda Daejeon 306-791 Daejeon 305-764 Hannam University 97078 Wuerzburg Chungnam National University College of Natural Science of Biology NIH Korea USA University of Wuerzburg Yuseong-gu National Cancer Institute

clusterin is a 75-80 kDa heterodimeric glycoprotein, that is produced in most tissues but which exact biological role is still not clear. Particularly, its role in protection or promotion of apoptosis is heavily disputed, since data supporting both views have been reported in several independent studies. To clarify this issue, and also to determine whether clusterin expression itself might be affected by apoptosis, in the present study, rat thymocytes were treated with dexamethasone, -a synthetic glucocorticoid that elicits apoptosis in thymocytes-, and clusterin mRNA expression was analyzed by semi-quantitative RT-PCR before and after induction of apoptosis. Interestingly, neither the treatment with dexamethasone in vitro nor triggering of apoptosis in vivo up- regulated clusterin expression, opposing the view that clusterin is involved in apoptotic processes. On the other hand, a new clusterin mRNA isoform was detected and isolated, whose expression was restricted to freshly isolated thymocytes. This

关键词： clusterin sgp-2 thymocytes apoptosis mRNA isoforms.

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clusterin in Alzheimer's disease: a player in the biological behavior of amyloid-beta

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Neuroscience Bulletin 2014年第1期30卷 162-168页

作者： Xiang Li Yifei Ma Xu Wei Yanpeng Li Huijuan Wu Jianhua Zhuang Zhongxin Zhao Department of Neurology Changzheng Hospital Second Military Medical University

Alzheimer＇s disease （AD） remains a major killer, and although its pathogenesis varies, one dominant feature is an increase in the expression, formation, and sedimentation of senile plaques of amyloid-beta （Aβ） peptides in the brain. The chaperone protein clusterin has, since its first discovery at the end of the 20^th century, been labeled as a cytoprotector. However, epigenetic studies showing that clusterin is associated with the severity and risk of AD, especially in the hippocampus, triggered studies to clarify its role in the pathogenesis of AD. It is true that clusterin can inhibit the aggregation of Aβ and therefore prevent further formation of senile plaques in the AD brain, yet it induces the formation of soluble forms of Aβ which are toxic to neurons. Another problematic finding is that clusterin is involved in a pathway through which Aβ has neurodegenerative effects intracellularly. Although the role of clusterin in the pathogenesis of AD is still not clear, this review specifically discusses the interactions between clusterin and Aβ, to open up the possibility of a potential therapeutic approach for treating AD.

关键词： clusterin Alzheimer＇s disease amyloid-beta peptides cytotoxicity cytoprotection

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Induction of clusterin Expression by Neuronal Cell Death in Zebrafish

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Journal of Genetics and Genomics 2014年第11期41卷 583-589页

作者： Yun-Mi Jeong Tae-Eun Jin Jung-Hwa Choi Mi-Sun Lee Hyun-Taek Kim Kyu-Seok Hwang Doo-Sang Park Hyun-Woo Oh Joong-Kook Choi Vladimir Korzh Melitta Schachner Kwan-Hee You Cheol-Hee Kim Department of Biology Chungnam National University Korea Research Institute of Bioscience and Biotechnology Department of Biochemistry College of MedicineChungbuk National University Institute of Molecular and Cell Biology Agency for ScienceTechnology and Research Keck Center for Collaborative Neuroscience and Department of Cell Biology and Neuroscience Rutgers University Center for Neuroscience Shantou University Medical College

clusterin, a protein associated with multiple functions, is expressed in a wide variety of mammalian tissues. Although clusterin is known to be involved in neurodegenerative diseases, ageing, and tumorigenesis, a detailed analysis of the consequences of gain- or loss-of- function approaches has yet to be performed to understand the underlying mechanisms of clusterin functions. Since clusterin levels change in neurological diseases, it is likely that clusterin contributes to cell death and degeneration in general. Zebrafish was investigated as a model system to study human diseases. During development, zebrafish clusterin was expressed in the notochord and nervous system. Embryonic overexpression of clusterin by mRNA microinjection did not affect axis formation, whereas its knock-down by anti-sense morpholino treatment resulted in neuronal cell death. To analyze the function of clusterin in neurodegeneration, a transgenic zebrafish was investigated, in which nitroreductase expression is regulated under the control of a neuron-specifc huC promoter which is active between the stages of early neuronal precursors and mature neurons. Nitroreductase turns metronidazole into a cytotoxic agent that induces cell death within 12 h. After metronidazole treatment, transgenic zebrafish showed neuron-specific cell death. Interestingly, we also observed a dramatic induction of clusterin expression in the brain and spinal cord in these fish, suggesting a direct or indirect role of clusterin in neuronal cell death and thus, more generally, in neurodegeneration.

关键词： clusterin Neuronal cell death Neurodegeneration Zebrafish

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clusterin: a multifaceted protein in the brain

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Neural Regeneration Research 2021年第7期16卷 1438-1439页

作者： Hee-Jung Moon Sarah K.Herring Liqin Zhao Department of Pharmacology and Toxicology School of PharmacyUniversity of KansasLawrenceKSUSA Neuroscience Graduate Program University of KansasLawrenceKSUSA Current address:Citoxlab A Charles River Company StilwellKSUSA

Late-onset Alzheimer 's disease(LOAD), the most common cause of dementia, currently affects 5.6 million Americans ages 65 and older.LOAD is a neurodegenerative disorder characterized by progressive loss in synaptic function, notable bioenergetic decline, increased neuronal death and brain atrophy, and significant cognitive impairment.Because the etiology of LOAD remains unknown, a treatment for LOAD has not yet been formulated, a fact that is clearly demonstrated by the more than 200 failed clinical trials.

关键词： clusterin Alzheimer atrophy

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Metformin targets clusterin to control lipogenesis and inhibit the growth of bladder cancer cells through SREBP-lc/FASN axis

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Signal Transduction and Targeted Therapy 2021年第4期6卷 1092-1094页

作者： Jun Deng Mei Peng Sichun Zhou Di Xiao Xin Hu Simeng Xu Jingtao Wu Xiaoping Yang Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province Department of Pharmacy School of MedicineHunan Normal UniversityChangsha 410013China Key Laboratory of Molecular Pharmacology and Drug Evaluation(Yantai University) Ministry of EducationYantai UniversityYantai 264005China Department of Pharmacy Xiangyo HospitalCentral South UniversityChangsha 410008China

Dear Editor,Metformin,a widely prescribed drug for treating typeⅡdiabetes,has shown an important anti-cancer property.1 However,new launched clinical trials did not achieve such desirable results.2 One explanation could be that metformin’s anti-cancer mechan-isms and precise therapeutic targets remain unclear.To identify potential therapeutic targets of metformin in bladder cancer,we screened differential proteins with metformin treatment in T24 cells by high-throughput protein chip.

关键词： bladder cancer clusterin

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clusterin对小鼠慢性肝纤维化发生发展的作用研究

Clusterin对小鼠慢性肝纤维化发生发展的作用研究

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作者：苏静中国人民解放军海军军医大学

学位级别：硕士

中国是肝病人数大国,由于目前肝病治疗策略的选择局限,以及肝纤维化有可能继续发展为肝硬化甚至是肝癌,严重危害着人民群众生命健康。这就催促着科研工作者们尽快深刻认识到肝纤维化发生发展的全面性和涉及有关通路因子的具体性。本课... 详细信息

中国是肝病人数大国,由于目前肝病治疗策略的选择局限,以及肝纤维化有可能继续发展为肝硬化甚至是肝癌,严重危害着人民群众生命健康。这就催促着科研工作者们尽快深刻认识到肝纤维化发生发展的全面性和涉及有关通路因子的具体性。本课题立足于目前已知的肝纤维化发生过程和机制,着眼于新兴改善肝纤维化的方式,发现clusterin(CLU)蛋白在肝纤维化中具有一定作用,通过两方面,CLU蛋白的表达特征及定位分析和clusterin基因敲除小鼠在药物诱导下的肝纤维化的发生情况,初步对CLU在肝脏中的具体表达类型、位点及其作用进行描述。慢性肝损伤是由于接触到化学毒性药物,酒精滥用,病毒感染,自身免疫性疾病等因素,引起肝脏炎症激活反应和氧化应激,引起肝脏肌成纤维细胞的大量激活,形成细胞外基质沉积,并多数伴有炎症细胞浸润,使肝脏形成纤维瘢痕结构,影响肝脏的生理功能,即经历了纤维生成阶段,若损伤持续存在,则会由肝纤维化慢慢进展到肝硬化,甚至肝癌。关于肝病的治疗首要任务是去除病因,但目前只有使用抗病毒药物治疗病毒感染肝病取得了较好的临床效果,其他都未有有效的临床治疗方式。这主要是因为对肝纤维化微环境及相关蛋白或因子的认识不够深刻,研究清楚在肝纤维化环境下特定分子与细胞之间的作用及涉及通路的分析将会对慢性肝损伤治疗提供重要意义。clusterin(CLU)是一种分泌型糖蛋白,由α链和β链形成异二聚体;又称载脂蛋白J,在人体体液和组织中均广泛存在,多种生物学功能被报道,调节蛋白稳态,促进细胞存活等。CLU还参与肺损伤修复,脂质代谢,肾纤维化,阿尔兹海默症的淀粉样蛋白溶解等。我们前期实验结果中可以看到,CLU在正常肝组织中低表达,而在四氯化碳(CCL4)诱导的肝损伤组织中高表达,且集中在纤维化损伤区域,这就越发揭示了 CLU与慢性损伤及纤维化的功能相关性。目前认为的肝纤维化过程中会涉及到,肝细胞变性坏死释放因子,激活炎症细胞释放促炎因子,促进肝星状细胞和其他成纤维细胞活化产生细胞外基质,形成肝纤维化。由此可知主要通过调控3个阶段,减少肝细胞死亡,炎症因子释放,成纤维细胞活化对于抑制纤维化,改善肝结构具有重要作用。那么CLU蛋白是否会影响肝纤维化的发展呢,以哪种蛋白形式,是通过改变对肝细胞的作用,还是调控肌成纤维细胞的方式?因此,为了进一步明确CLU与慢性肝损伤之间的关系,我们进行了以下实验研究:(1)首先明确在小鼠CLU的表达位置,在正常肝脏中表达在个别散点分布的肝实质细胞,中央静脉区的个别肝细胞和汇管区的个别周围肝细胞以及胆管细胞胞质。通过增加慢性肝损伤模型,胆汁淤积性肝纤维化,高脂饮食诱导的非酒精性脂肪肝病,以及CCL4诱导的肝纤维化,检测CLU在受损肝组织中的表达,结果表明CLU在肝纤维化模型中表达量最高,其他脂肪肝模型中CLU低表达,且表达位置与纤维化损伤区域具有相关性,揭示了 CLU与肝纤维化密切相关。并通过染色发现CLU大量表达在损伤区域,通过与肝细胞胆管细胞和星状细胞的共定位检测,表明了 CLU蛋白在肝损伤增加后从胆管细胞大量增加,并高表达于损伤区域周围的肝细胞中,不表达于肝星状细胞,揭示了CLU在肝损伤后呈现反馈性升高,表明其在肝纤维化中的重要作用。(2)正常小鼠与clusterin基因敲除小鼠表型特征比较及鉴定分析,通过在基因组水平和蛋白组水平以及免疫组化染色确定小鼠模型建立成功,并比较其表型差异,结果说明clusterin基因敲除对小鼠正常生长没有影响。(3)建立clusterin基因敲除小鼠的肝纤维化模型,与其同样条件处理的野生型小鼠相比,通过胶原染色和Western Blot分析,敲除小鼠在2周时就显示出明显的胶原沉积现象,比起野生型小鼠纤维化发生更迅速,在同时期纤维化标志更严重。说明了 CLU在小鼠肝脏损伤保护中具有重要作用。结论:在肝纤维化发生发展过程中,CLU呈现出反馈性高表达,大量表达在胆管细胞和肝损伤区域的肝细胞。通过clusterin基因敲除小鼠的肝纤维化模型建立,小鼠在发生肝纤维化时更加迅速和严重,说明CLU对肝纤维化发展有抑制作用。

关键词： clusterin 肝纤维化肝慢性损伤肝细胞

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丹黄消炎液对糖尿病溃疡大鼠创面TGF-β1、Twist1、clusterin表达及EMT过程的影响

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时珍国医国药 2022年第1期33卷 55-59页

作者：卢庆威王军卢增珍刘鹏牛文晶许彪杨皓天津中医药大学第一附属医院国家中医针灸临床医学研究中心天津300000

目的探究丹黄消炎液对糖尿病性溃疡愈合过程中上皮-间质转化(epithelial-mesenchymal transition,EMT)过程的影响及可能的调控机制。方法复制糖尿病性溃疡大鼠模型。随机分成空白组(普通创面组)、模型组(糖尿病性创面组)、对照组(碘伏组... 详细信息

目的探究丹黄消炎液对糖尿病性溃疡愈合过程中上皮-间质转化(epithelial-mesenchymal transition,EMT)过程的影响及可能的调控机制。方法复制糖尿病性溃疡大鼠模型。随机分成空白组(普通创面组)、模型组(糖尿病性创面组)、对照组(碘伏组)、实验组(丹黄消炎液组),观察各组创面愈合情况并计算愈合率;采用及蛋白免疫印迹法Western Blot)和实时荧光定量聚合酶链式反应法(RT-qPCR)检测干预第7天、14天时各组创面组织内转化生长因子-β1(TGF-β1)、人Twist相关蛋白1(Twist1)、聚集蛋白(clusterin)、E-钙黏蛋白(E-cadherin)、纤连蛋白(Fibronectin)的蛋白和mRNA表达情况。结果干预第7天,空白组和实验组的创面愈合率显著高于对模型和组照组(Pclusterin蛋白和mRNA表达显著升高,以上差异均具有统计学意义(Pclusterin蛋白和mRNA表达显著升高,空白组和实验组TGF-β1蛋白和mRNA表达显著升高,差异具有统计学意义(Pclusterin实现的。

关键词：糖尿病足溃疡丹黄消炎液上皮-间质转化 Twist1 clusterin TGF-β1

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clusterin表达与膀胱癌预后的关系

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癌症 2005年第6期24卷 743-747页

作者：罗俊航谢丹陈炜戴宇平李晓飞陶瑜郑克立中山大学附属第一医院泌尿外科广东广州510080 中山大学中山医学院病理教研室广东广州510080

背景与目的:目前临床上用于判断膀胱癌预后的分子标记很少。新近研究表明,clusterin蛋白表达上调与多种肿瘤发生、发展及预后有关,但其与膀胱癌预后的关系尚不清楚。本研究旨在通过建立膀胱癌组织芯片,分析clusterin蛋白表达与膀胱癌临... 详细信息

背景与目的:目前临床上用于判断膀胱癌预后的分子标记很少。新近研究表明,clusterin蛋白表达上调与多种肿瘤发生、发展及预后有关,但其与膀胱癌预后的关系尚不清楚。本研究旨在通过建立膀胱癌组织芯片,分析clusterin蛋白表达与膀胱癌临床病理学参数和预后的关系。方法:制作81例膀胱癌组织芯片,用免疫组织化学方法检测组织芯片中clusterin的表达;结合临床病理学资料,分析它们之间的相关性。结果:在组织芯片中,69例膀胱癌clusterin的表达得以成功检测,其中32例(46.4%)表现为clusterin蛋白过度表达。在这69例膀胱癌中,clusterin蛋白在低分化(G3级)膀胱癌中的过度表达率(75.0%)明显地高于分化较好的G1或G2级膀胱癌(34.7%,P=0.002);而且多数(65.4%)浸润性膀胱癌(T2～T4期)出现clusterin蛋白过度表达,明显高于表浅性(Ta、T1期)膀胱癌(34.9%,P=0.014)。另外,膀胱癌中clusterin蛋白的表达与肿瘤的预后显著性相关(log鄄rank=5.88,P=0.015),clusterin蛋白过度表达肿瘤患者的无复发生存时间(37.3个月)明显低于正常表达者(48.8个月)。结论:膀胱癌中clusterin蛋白的过度表达,可作为临床评估膀胱癌预后的分子标记之一。

关键词：膀胱肿瘤组织芯片 clusterin 预后

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