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Identification of novel small-molecule inhibitors of SARS-CoV-2 by chemical genetics

Acta Pharmaceutica Sinica B 2024年第9期14卷 4028-4044页

作者： Chris Chun-Yiu Chan Qian Guo Jasper Fuk-Woo Chan Kaiming Tang Jian-Piao Cai Kenn Ka-Heng Chik Yixin Huang Mei Dai Bo qin Chon Phin Ong Allen Wing-Ho Chu Wan-Mui Chan Jonathan Daniel Ip Lei Wen Jessica Oi-Ling Tsang Tong-Yun Wang Yubin Xie zhenzhi qin Jianli Cao Zi-Wei Ye Hin Chu Kelvin Kai-Wang To Xing-Yi Ge Tao Ni Dong-Yan Jin Sheng Cui Kwok-Yung Yuen Shuofeng Yuan State Key Laboratory of Emerging Infectious Diseases Carol Yu Centre for InfectionDepartment of MicrobiologySchool of Clinical MedicineLi Ka Shing Faculty of Medicinethe University of Hong KongPokfulamHong Kong SAR 999077China Department of Infectious Diseases and Microbiology the University of Hong Kong-Shenzhen HospitalShenzhen 518000China Centre for Virology Vaccinology and TherapeuticsHong Kong Science and Technology ParkHong Kong SAR 999077China Academician Workstation of Hainan Province Hainan Medical University-the University of Hong Kong Joint Laboratory of Tropical Infectious DiseasesHaikou 571100China School of Biomedical Sciences Li Ka Shing Faculty of Medicinethe University of Hong KongPokfulamHong Kong SAR 999077China NHC Key Laboratory of Systems Biology of Pathogens Institute of Pathogen Biology Chinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100730China College of Biology Hunan Provincial Key Laboratory of Medical VirologyHunan UniversityChangsha 410082China

There are only eight approved small molecule antiviral drugs for treating *** them,four are nucleotide analogues(remdesivir,JT001,molnupiravir,and azvudine),while the other four are protease inhibitors(nirmatrelvir,ensitrelvir,leritrelvir,and simnotrelvir-ritonavir).Antiviral resistance,unfavourable drug‒drug interaction,and toxicity have been reported in previous *** there is a dearth of new treatment options for *** this work,a three-tier cell-based screening was employed to identify novel compounds with anti-SARS-CoV-2 *** compound,designated 172,demonstrated broad-spectrum antiviral activity against multiple human pathogenic coronaviruses and different SARS-CoV-2 variants of *** studies validated by reverse genetics showed that compound 172 inhibits the 3-chymotrypsin-like protease(3CLpro)by binding to an allosteric site and reduces 3CLpro dimerization.A drug synergistic checkerboard assay demonstrated that compound 172 can achieve drug synergy with nirmatrelvir in *** vivo studies confirmed the antiviral activity of compound 172 in both Golden Syrian Hamsters and K18 humanized ACE2 ***,this study identified an alternative druggable site on the SARS-CoV-23CLpro,proposed a potential combination therapy with nirmatrelvir to reduce the risk of antiviral resistance and shed light on the development of allosteric protease inhibitors for treating a range of coronavirus diseases.

关键词： SARS-CoV-2 High throughput screening Broad-spectrum antiviral treatment 3CLpro inhibitor Allosteric-site inhibitor Animal models Chemical genetics Reverse genetics

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Targeting papain-like protease for broad-spectrum coronavirus inhibition

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Protein & Cell 2022年第12期13卷 940-953页

作者： Shuofeng Yuan Xiaopan Gao Kaiming Tang Jian-Piao Cai Menglong Hu Peng Luo Lei Wen Zi-Wei Ye Cuiting Luo Jessica Oi-Ling Tsang Chris Chun-Yiu Chan Yaoqiang Huang Jianli Cao Ronghui Liang zhenzhi qin Bo qin Feifei Yin Hin Chu Dong-Yan Jin Ren Sun Jasper Fuk-Woo Chan Sheng Cui Kwok-Yung Yuen State Key Laboratory of Emerging Infectious Diseases Li Ka Shing Faculty of MedicineThe University of Hong KongPokfulamHong Kong SARChina Department of Microbiology Li Ka ShingFaculty of MedicineThe University of Hong KongPokfulamHong Kong SARChina NHC Key Laboratory of Systems Biology of Pathogens Institute of Pathogen BiologyChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100730China School of Biomedical Sciences Li Ka Shing Faculty of MedicineThe University of Hong KongPokfulamHong Kong SARChina Department of Molecular and Medical Pharmacology David Geffen School of MedicineUniversity of California Los AngelesLos AngelesCAUSA Key Laboratory of Tropical Translational Medicine of Ministry of Education Hainan Medical UniversityHaikou 571199China Academician Workstation of Hainan Province Hainan Medical UniversityHaikou 571199China Hainan Medical University-The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases The University of Hong KongPokfulamHong Kong Special Administrative RegionChina Guangzhou Laboratory Guangzhou 510320China Department of Clinical Microbiology and Infection Control The University of Hong Kong-Shenzhen HospitalShenzhen 518053China

The emergence of SARS-CoV-2 variants of concern and repeated outbreaks of coronavirus epidemics in the past two decades emphasize the need for next-generation pan-coronaviral *** the multi-functional papain-like protease(PLpro)domain of the viral nsp3 holds ***,none of the known coronavirus PLpro inhibitors has been shown to be in vivo ***,we screened a structurally diverse library of 50,080 compounds for potential coronavirus PLpro inhibitors and identified a noncovalent lead inhibitor F0213 that has broad-spectrum anti-coronaviral activity,including against the Sarbecoviruses(SARSCoV-1 and SARS-CoV-2),Merbecovirus(MERS-CoV),as well as the Alphacoronavirus(hCoV-229E and hCoVOC43).Importantly,F0213 confers protection in both SARS-CoV-2-infected hamsters and MERS-CoV-infected human DPP4-knockin mice.F0213 possesses a dual therapeutic functionality that suppresses coronavirus replication via blocking viral polyprotein cleavage,as well as promoting antiviral immunity by antagonizing the PLpro deubiquitinase *** the significant difference of substrate recognition,mode of inhibition studies suggest that F0213 is a competitive inhibitor against SARS2-PLpro via binding with the 157K amino acid residue,whereas an allosteric inhibitor of MERSPLpro interacting with its 271E *** proof-ofconcept findings demonstrated that PLpro is a valid target for the development of broad-spectrum anticoronavirus *** orally administered F0213 may serve as a promising lead compound for combating the ongoing COVID-19 pandemic and future coronavirus outbreaks.

关键词： protease inhibitor coronavirus Nsp3 antiviral

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面向可持续发展的文化旅游景区规划设计--荆州古城环城旅游景区保护利用规划探析

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规划师 2011年第1期27卷 72-79页

作者：何芳江东秦振芝秦军范琪荆州市城市规划设计研究院风景园林规划设计室荆州市城市规划设计研究院城市规划设计室荆州市城市规划设计研究院

荆州古城环城旅游景区串联着古城历史街区、文保单位、主题商住及绿化水系等特色地段。规划从用地、文化、生态和交通四个方面研究荆州古城的可持续发展性,合理安排古城旅游、居住及市政设施,形成"一环、五线、十区"的"一环串珠"式的功... 详细信息

荆州古城环城旅游景区串联着古城历史街区、文保单位、主题商住及绿化水系等特色地段。规划从用地、文化、生态和交通四个方面研究荆州古城的可持续发展性,合理安排古城旅游、居住及市政设施,形成"一环、五线、十区"的"一环串珠"式的功能区划与总体结构形态。通过整合荆州历史脉络肌理,发展古城旅游服务事业,将荆州古城环城旅游景区建设成为集环城旅游、绿化休闲、古城保护等系统于一体的城市景观精品地带及环城绿色生态圈。

关键词：可持续发展文化旅游荆州古城

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NOD2 protect LPS/D-Gal induced acute hepatic injury via suppressing MAPK signaling pathway and inhibiting apoptosis

NOD2 protect LPS/D-Gal induced acute hepatic injury via supp...

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第十三届全国免疫学学术大会

作者： xiaomin ma Yumin Qiu Lihui Zhu Yueke Lin Dapeng Ma Caiyu Sun zhenzhi qin Xuecheng Shen Lihui Han Department of Immunology Shandong University School of Basic Medical Sciences

Objective: Acute hepatic injury caused by inflammatory liver disease is associated with high *** oligomerization domain 2(NOD2), a member of innate immune sensor, is known to play an important role in the inflammatory ***, whether NOD2 plays a role in acute hepatic injury remained ***: In this study, we constructed LPS/D-GalN induced acute liver injury mice model in NOD2 null mice and investigate the role of NOD2 in liver *** curve and HE staining were used to define the function of NOD2 in acute hepatic injury *** index was detected to reflect the degree of liver *** cytometry was performed to detect the variation of immune ***-PCR was used to detect the levels of cytokine and *** staining was used to detect apoptosis of *** blot was performed to detect the altered signaling ***: NOD2mice showed higher death rate and more severe liver injury compared with wide type *** amount of infiltrated macrophages and neutrophils were significantly increased in the liver of *** inflammatory cytokines, including TNFα, IL1β, IL-6, IL8 and chemokines including CXCL2, CXCL5 were also dramatically increased in the liver tissue of *** investigation showed NOD2mice have much lower hepatic apoptosis and suppressed MAPK signaling pathway compared with the wild type mice, which indicated that NOD2 played a protective role in acute liver injury by suppressing MAPK pathway and inducing ***: NOD2 protected the LPS/D-GalN induced acute hepatic injury via inhibiting apoptosis by suppressing MAPK signaling pathway.

关键词： NOD2 hepatic injury apoptosis MAPK

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Arginine methyltransferase PRMT5 negatively regulates cGAS-mediated antiviral immune response

Arginine methyltransferase PRMT5 negatively regulates cGAS-m...

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第十四届全国免疫学学术大会

作者： Dapeng Ma Min Yang Qiushi Wang Caiyu Sun Hongbiao Shi Weiqiang Jing Yuxuan Bi Xuecheng Shen Xiaomin Ma zhenzhi qin Yueke Lin Lihui Zhu Yunxue Zhao Yeping Cheng Lihui Han Shandong Provincial Key Laboratory of Infection and Immunology Department of Immunology School of Basic Medical Sciences Cheeloo College of Medicine Shandong University Shandong University Department of Geriatric Gastroenterology Qilu Hospital Shandong University Department of Urology Qilu Hospital Cheeloo College of Medicine Shandong University Department of Gastroenterology Shandong Provincial Hospital Affiliated to Shandong University

Cyclic GMP-AMP synthase(cGAS) functions as an essential DNA sensor, which senses the cytoplasmic double-stranded DNA and activates the antiviral response. However, the posttranslational modification of cGAS remains to be fully understood and whether it has arginine methylation modification remains unknown. Here, we identified protein arginine methyltransferase 5(PRMT5) as a direct binding partner of cGAS, and it catalyzed the arginine symmetrical dimethylation of cGAS at the Arg124 residue. Further investigation demonstrated that methylation of cGAS by PRMT5 attenuated cGAS-mediated antiviral immune response by blocking the DNA binding ability of cGAS. Oral administration of PRMT5 inhibitors significantly protected mice from HSV-1 infection and prolonged the survival time of these infected mice. Therefore, our findings revealed an essential regulatory effect of PRMT5 on cGAS-mediated antiviral immune response and provided a promising potential antiviral strategy by modulating PRMT5.

关键词： cGAS PRMT5 arginine methylation antiviral immunity

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乳酸调控巨噬细胞功能促进登革病毒2型感染

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中华微生物学和免疫学杂志 2024年第5期44卷 396-405页

作者：胡欢覃燕春黄贞植周璐吴家红商正玲贵州医科大学基础医学院免疫学教研室安顺550025 贵州医科大学基础医学院寄生虫教研室安顺550025

目的探究外源性乳酸对Raw264.7细胞、小鼠骨髓来源巨噬细胞(mouse bone marrow-derived macrophages,BMDMs)及THP-1细胞中登革病毒2型(dengue virus type 2,DENV-2)复制的影响及乳酸与细胞活化之间的关系。方法培养和诱导BALB/c小鼠骨... 详细信息

目的探究外源性乳酸对Raw264.7细胞、小鼠骨髓来源巨噬细胞(mouse bone marrow-derived macrophages,BMDMs)及THP-1细胞中登革病毒2型(dengue virus type 2,DENV-2)复制的影响及乳酸与细胞活化之间的关系。方法培养和诱导BALB/c小鼠骨髓中的BMDMs,流式细胞术检测F4/80+CD11b+细胞纯度。qRT-PCR检测不同时间点DENV-2感染BMDMs中葡萄糖转运体1(glucose transporter type 1,GLUT1)、己糖激酶2(hexokinase 2,HK2)、乳酸转运体4(monocarboxylate transporters 4,MCT4)的mRNA表达水平,比色法检测细胞上清液中乳酸含量。使用CCK-8法评估不同浓度乳酸对Raw264.7细胞、BMDMs及THP-1细胞活力的影响,qRT-PCR检测不同浓度乳酸对不同MOI DENV-2感染细胞中病毒E基因、CD163、TGF-β、CD86、视黄酸诱导基因Ⅰ(retinoic acid-inducible geneⅠ,RIG-Ⅰ)、IFN-β、干扰素刺激基因15(interferon-stimulated gene 15,ISG15)及ISG56的mRNA表达水平,流式细胞术检测CD86和CD206蛋白的表达。结果BMDMs纯度为(87.53±1.66)%。DENV-2(MOI=3)感染BMDMs后,GLUT1 mRNA转录水平在12 h一过性增高,在24 h降低(P0.05)。结论本研究发现外源性乳酸能促进DENV-2在人源及鼠源巨噬细胞中的感染,该现象与细胞M2型极化有关。

关键词：乳酸巨噬细胞登革病毒病毒复制 M2型极化干扰素信号通路

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野黄芩苷通过CCN1介导抑制核转录因子-κB信号通路改善脂多糖诱导的肾损伤

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中华危重病急救医学 2022年第4期34卷 400-406页

作者：刘雪秦振志管陈徐翎钰代杰杨成宇周斌栾弘赵龙张伟罗从娟徐岩青岛大学附属医院肾内科山东青岛266003 临沂市中心医院肾内科山东临沂276400 青岛大学山东青岛266003

目的探讨野黄芩苷(Scu)对脓毒症相关性急性肾损伤(SA-AKI)的保护作用及其机制。方法①体内实验:将36只雄性C57BL/6小鼠按随机数字表法分为生理盐水(NS)对照组、脂多糖(LPS)致SA-AKI模型组(LPS组)、20 mg/kg Scu对照组(Scu 20对照组)及5... 详细信息

目的探讨野黄芩苷(Scu)对脓毒症相关性急性肾损伤(SA-AKI)的保护作用及其机制。方法①体内实验:将36只雄性C57BL/6小鼠按随机数字表法分为生理盐水(NS)对照组、脂多糖(LPS)致SA-AKI模型组(LPS组)、20 mg/kg Scu对照组(Scu 20对照组)及5、10、20 mg/kg Scu预处理组,每组6只。腹腔注射10 mg/kg LPS制备SA-AKI小鼠模型;NS对照组给予等量NS;Scu预处理组于注射LPS前腹腔注射不同剂量Scu,每日1次、持续1周;Scu 20对照组仅给予20 mg/kg Scu,持续1周。各组于LPS处理24 h后处死小鼠取肾脏,观察肾组织损伤情况;采用蛋白质免疫印迹试验(Western blotting)检测核转录因子-κB(NF-κB)信号通路相关分子、凋亡相关蛋白及富含半胱氨酸蛋白61-结缔组织生长因子-肾母细胞瘤过表达基因1(CCN1)的蛋白表达。②体外实验:体外培养人肾小管上皮细胞株HK-2,待细胞融合至80%时用于实验。在未经LPS处理和经过100 g/L的LPS处理后的细胞中,分别转染pcDNA3.1-CCN1过表达CCN1或小干扰RNA(siRNA)抑制CCN1表达,观察CCN1是否参与了NF-κB信号通路激活和细胞凋亡;同时在转染和未转染CCN1 siRNA的HK-2细胞中加入100 g/L的LPS及20μmol/L的Scu,观察Scu对LPS诱导HK-2细胞损伤保护作用的机制。结果①体内实验结果:LPS诱导SA-AKI小鼠肾功能显著下降,肾小管严重受损;Scu可呈剂量依赖性缓解肾功能及组织学损伤。Western blotting条带分析进一步证实,Scu预处理可呈剂量依赖性降低AKI小鼠肾组织中NF-κB信号通路相关分子及CCN1的蛋白表达,并对细胞凋亡具有显著的缓解作用,说明CCN1参与了NF-κB信号通路激活和细胞凋亡。②体外实验结果:在未经LPS处理的HK-2细胞中,过表达CCN1对凋亡相关蛋白及NF-κB信号通路促炎因子表达无显著影响。而在经过LPS处理的HK-2细胞中,过表达CCN1可显著抑制促炎因子白细胞介素-1β(IL-1β)、肿瘤坏死因子-α(TNF-α)和单核细胞趋化蛋白-1(MCP-1)的mRNA表达,与单纯LPS刺激细胞比较差异有统计学意义〔IL-1βmRNA(2^(-ΔΔCT)):3.20±0.57比4.88±0.69,TNF-αmRNA(2^(-ΔΔCT)):2.99±0.44比5.00±0.81,MCP-1 mRNA(2^(-ΔΔCT)):2.81±0.50比5.41±0.75,均P<0.05〕,并使凋亡相关蛋白显著下调;当用siRNA抑制CCN1表达时,促炎因子的mRNA表达则较单纯LPS刺激细胞上调〔IL-1βmRNA(2^(-ΔΔCT)):6.01±1.13比4.88±0.69,TNF-αmRNA(2^(-ΔΔCT)):5.15±0.86比5.00±0.81,均P<0.05〕,同时凋亡相关蛋白显著上调。在LPS诱导的细胞模型中,经过Scu处理后HK-2细胞中促炎因子的mRNA表达显著下调,与单纯LPS刺激细胞比较差异有统计学意义〔IL-1βmRNA(2^(-ΔΔCT)):2.55±0.50比6.15±1.04,TNF-αmRNA(2^(-ΔΔCT)):2.58±0.40比3.95±0.52,MCP-1 mRNA(2^(-ΔΔCT)):2.64±0.44比6.21±0.96,均P<0.05〕,而且凋亡相关蛋白显著下调;当用siRNA抑制CCN1表达时,则削弱了Scu对细胞的保护作用,表现为细胞中促炎因子的mRNA表达较未抑制CCN1表达的细胞显著上调〔IL-1βmRNA(2^(-ΔΔCT)):5.34±0.76比2.55±0.50,TNF-αmRNA(2^(-ΔΔCT)):3.66±0.54比2.58±0.40,MCP-1 mRNA(2^(-ΔΔCT)):5.15±0.79比2.64±0.44,均P<0.05〕,且凋亡相关蛋白表达亦显著上调。结论Scu能保护SA-AKI小鼠的肾功能,该保护作用与NF-κB信号通路和CCN1有关;Scu可能通过CCN1调节NF-κB信号通路以减轻LPS诱导的肾损伤。

关键词：野黄芩苷脓毒症相关性急性肾损伤 CCN1 核转录因子-κB

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白纹伊蚊唾液蛋白rAlb-34k2-1诱导的特异性细胞免疫应答对BMDM细胞中DENV-2复制的影响

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中国热带医学 2024年第8期24卷 907-913页

作者：覃燕春李莹胡欢周璐黄贞植吴家红商正玲贵州医科大学基础医学院免疫学教研室贵州贵阳561113 贵州医科大学基础医学院寄生虫学教研室贵州贵阳561113

目的体外探究白纹伊蚊唾液蛋白rAlb-34k2-1诱导的小鼠脾淋巴细胞特异性免疫应答对2型登革病毒(dengue virus type 2,DENV-2)感染小鼠骨髓来源巨噬细胞(bone marrow-derived macrophages,BMDM)的影响。方法采用CCK-8法分析rAlb-34k2-1蛋白对免疫/未免疫小鼠脾细胞的特异性增殖反应;制备荷载蚊唾液蛋白rAlb-34k2-1、rAalb_CTL1蛋白(蚊唾液C型凝集素蛋白)的抗原提呈细胞(antigen presenting cell,APC),与免疫/未免疫小鼠脾淋巴细胞进行混合淋巴细胞培养,取细胞培养上清处理DENV-2感染的BMDM细胞,实时荧光定量逆转录PCR(real-time quantitative reverse transcription PCR,qRT-PCR)检测DENV-2的核酸变化,分析rAlb-34k2-1蛋白诱导的特异性T淋巴细胞应答对BMDM内DENV-2复制的影响。将免疫/未免疫小鼠脾淋巴细胞与rAlb-34k2-1蛋白预处理的感染BMDM进行共培养,通过qRT-PCR检测培养48、72 h后DENV-2 E基因的表达,分析免疫/未免疫小鼠淋巴细胞对预处理的BMDM中DENV-2复制的影响。结果小鼠脾细胞体外特异性增殖实验显示,与未免疫组比较,rAlb-34k2-1蛋白能导致免疫小鼠脾细胞特异性增殖,刺激指数(stimulation index,SI)>2,P<0.0001;荷载rAalb_CTL1蛋白的混合淋巴细胞培养上清未影响BMDM细胞中DENV-2的复制,荷载rAlb-34k2-1蛋白的混合淋巴细胞培养上清可抑制BMDM中DENV-2复制(2^(-ΔΔCT) <0.5,P<0.05);与免疫/未免疫小鼠脾淋巴细胞混合培养后,rAlb-34k2-1预处理的BMDM中DENV-2复制无差异。结论rAlb-34k2-1蛋白诱导的小鼠T淋巴细胞应答上清可抑制BMDM细胞中DENV-2的复制,为探究蚊唾液蛋白诱导免疫效应在蚊媒病毒致病中的作用提供前期实验基础。

关键词： rAlb-34k2-1蛋白 2型登革病毒细胞免疫应答

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Bi-level Coordinated Planning of Active Distribution Network Considering Demand Response Resources and Severely Restricted Scenarios

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Journal of Modern Power Systems and Clean Energy 2021年第5期9卷 1088-1100页

作者： Huang Yixin Lin zhenzhi Liu Xinyi Yang Li Dan Yangqing Zhu Yanwei Ding Yi Wang qin College of Electrical Engineering Zhejiang UniversityHangzhouChina State Grid Zhejiang Economic Research Institute HangzhouChina State Grid Ningbo Power Supply Company HangzhouChina Electric Power Research Institute Palo AltoUSA

Due to the uncertainty and fluctuation of distributed generation(DG)and load,the operation of active distribution network(ADN)is affected by multi-dimension factors which are described by massive operation *** and accurate screening of severely restricted scenarios(SRSs)has become a new challenge in ADN *** this paper,a novel bi-level coordinated planning model which combines the short-time-scale operation problem with the long-time-scale planning problem is *** the upper level,the demand response(DR)resource,an effective non-component planning resource characterized by low capacity price,high energy price,and short contract term,is co-optimized with the configuration of lines and energy storage systems(ESSs)to achieve the economic trade-off between the investment cost and the operation cost under *** the lower level,with the planning scheme obtained from the upper level,massive operation problems are optimized to minimize the daily operation cost;and the SRSs are provided to the upper level through a shadow-price-based scenario screening method,which simulates the planning information(i.e.,the restricted degrees of operation scenarios)feedback process from ADN operators to ADN *** studies on a 62-node distribution system in Jianshan New District,Zhejiang Province,China,illustrate the effectiveness of the proposed bi-level coordinated planning model considering DR resources and SRSs.

关键词： Active distribution network demand response resource bi-level coordinated planning severely restricted scenario screening shadow price

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虾青素通过CCN1调节肾间质纤维化的潜在分子作用机制

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中华肾病研究电子杂志 2022年第6期11卷 318-326页

作者：尹丽丽管陈赵龙蒋伟秦振志李宸羽徐岩 266003　青岛大学附属医院肾内科；261041　潍坊市人民医院血液净化中心 266003　青岛大学附属医院肾内科 999077　香港大学李嘉诚医学院 266003　青岛大学附属医院肾内科；80336　慕尼黑大学附属医院

目的探讨虾青素(AST)对肾间质纤维化的潜在分子作用机制,为临床防治肾脏纤维化提供数据。方法动物实验采用单侧输尿管结扎(UUO)法建立肾间质纤维化模型。60只雄性C57BL/6小鼠随机分为6组(10只/组):假手术组、假手术+AST(200 mg/kg)组、... 详细信息

目的探讨虾青素(AST)对肾间质纤维化的潜在分子作用机制,为临床防治肾脏纤维化提供数据。方法动物实验采用单侧输尿管结扎(UUO)法建立肾间质纤维化模型。60只雄性C57BL/6小鼠随机分为6组(10只/组):假手术组、假手术+AST(200 mg/kg)组、UUO模型组、UUO+AST(50 mg/kg)组、UUO+AST(100 mg/kg)组、UUO+AST(200 mg/kg)组。细胞实验采用TGF-β1诱导HK-2细胞株上皮间充质转化(EMT)模型。质粒转染实验将HK-2细胞分为7组:对照组、空白组、CCN1过表达组、CCN1敲低组、TGF-β1诱导组、TGF-β1+CCN1过表达组、TGF-β1+CCN1敲低组。AST处理实验将HK-2细胞分为5组:对照组、TGF-β1诱导组、TGF-β1+AST组、TGF-β1+CCN1敲低组、TGF-β1+CCN1敲低+AST组。实时定量荧光PCR法检测肾组织肾损伤生物标志物中性粒细胞明胶酶相关脂质运载蛋白(NGAL)、肾损伤分子-1(KIM-1)、血清胱抑素-C(Cys-C)和白介素-18(IL-18)。Western印迹检测肾组织和细胞的纤维化标志物Ⅰ型胶原蛋白(Col-Ⅰ)、纤连蛋白(FN)、α-平滑肌肌动蛋白(α-SMA)、波形蛋白和E-钙粘蛋白(E-cad),以及TGF-β1/Smad和Notch信号通路分子:pSmad3、Notch1、Notch3、Jagged-1的表达。结果与假手术组相比,UUO组小鼠肾损伤生物标志物NGAL、KIM-1、Cys-C和IL-18的水平显著升高;肾脏纤维化标志物蛋白表达水平显著升高,E-cad表达水平显著下降;pSmad3、Notch1、Notch3、Jagged-1的蛋白表达水平显著增加,Smad7表达显著减少。AST处理使肾损伤生物标志物(NGAL、KIM-1、Cys-C和IL-18)、纤维化标志物蛋白表达水平显著下降,E-cad蛋白表达显著上升且呈剂量依赖性。细胞实验结果显示:CCN1过表达可以抑制TGF-β1/Smad和Notch信号通路的激活,而敲低CCN1不仅增强了TGF-β1/Smad和Notch信号通路的激活,还减弱了AST在TGF-β1诱导的EMT模型中的保护作用。结论AST可能通过CCN1调节TGF-β1/Smad和Notch信号通路,从而可能具有减轻肾间质纤维化、保护肾脏的作用。

关键词：虾青素 CCN1 肾间质纤维化 Notch信号通路

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