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Journal of Clinical and Translational Hepatology 2024年第10期12卷 892-895页

作者： Ruoqi Zhou Yuwei Wang Xinxin Liu xia Yu dajing xia Yihua Wu Yu Shi State Key Laboratory for Diagnosis and Treatment of Infectious Diseases National Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina Department of Toxicology of School of Public Health and Department of Gynecologic Oncology of Women’s Hospital Zhejiang University School of MedicineHangzhouZhejiangChina

Metabolic dysfunction-associated steatotic liver disease(MASLD)is a growing cause of chronic liver diseases worldwide,with a global prevalence of 38%.1 Patients with MASLD are at risk of developing liver-related complications,such as cirrhosis,hepatocellular carcinoma,and extra-hepatic adverse events.1 In recent years,endocrine-disrupting chemicals(EDCs)have been linked to the development and progression of MASLD.

关键词： Metabolic liver diseases

Ticagrelor inhibits the NLRP3 inflammasome to protect against inflammatory disease independent of the P2Y_(12 ) signaling pathway

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Cellular & Molecular Immunology 2021年第5期18卷 1278-1289页

作者： Bo Huang Yufeng Qian Shujun Xie xianhua Ye Hanwen Chen Zhifeng Chen Lihuan Zhang Jinming Xu Hu Hu Shenglin Ma Paul Héroux Di Wang Han-Ming Shen Yihua Wu dajing xia Department of Toxicology of School of Public Health and Department of Gynecologic Oncology of Women’s HospitalZhejiang University School of MedicineHangzhouChina Department of Cardiology Affiliated Hangzhou First People’s HospitalZhejiang University School of MedicineHangzhouChina Translational Medicine Research Center and Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang ProvinceAffiliated Hangzhou First People’s HospitalZhejiang University School of MedicineHangzhouChina Department of Thoracic Surgery The First Affiliated HospitalZhejiang University School of MedicineHangzhouChina Department of Pathology and Pathophysiology Zhejiang University School of MedicineHangzhouChina Department of Oncology Affiliated Hangzhou First People’s HospitalZhejiang University School of MedicineHangzhouChina Department of Epidemiology Biostatistics and Occupational HealthMcGill UniversityMontrealQCCanada Institute of Immunology Zhejiang University School of MedicineHangzhouChina Department of Physiology Yong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore

Ticagrelor is the first reversibly binding oralP2Y_(12) receptor antagonist to inhibit platelet activation and has been approved by the Food and Drug Administration for the treatment of coronary artery disease. At present, the other pharmacological functions of ticagrelor remain poorly understood. The NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome plays a critical role in the innate immune system, but its excessive activation also contributes to the pathogenesis of complex diseases. In this study, we systematically examined the effects of ticagrelor on the NLRP3 inflammasome and found that ticagrelor inhibits NLRP3 inflammasome activation in macrophages independent of its classic inhibitory effect on theP2Y_(12) signaling pathway. Further mechanistic studies demonstrate that ticagrelor attenuates the oligomerization of apoptosis-associated speck-like protein containing a CARD (ASC) by blocking chloride efflux, an effect achieved through the degradation of chloride intracellular channel proteins (CLICs) and blockade of the translocation of CLICs to the plasma membrane. Moreover, experiments on lipopolysaccharide-induced sepsis and alum-induced peritonitis in mice confirmed that ticagrelor mitigates the severity of systemic inflammation independent ofP2Y_(12) receptor antagonism. Importantly, oral administration of ticagrelor rapidly and strongly inhibited NLRP3 inflammasome activation in peripheral blood mononuclear cells from patients with acute coronary syndrome. Overall, our study reveals a novel pharmacological function of ticagrelor in addition to its classic antiplatelet properties, which suggests that ticagrelor may serve as a potential therapeutic agent for use in NLRP3-associated diseases.

关键词： Ticagrelor NLRP3 inflammasome P2Y_(12) Chloride efflux ASC

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1106例血培养与血浆降钙素原结果分析

中华急诊医学杂志 2016年第10期25卷 1304-1306页

作者：郑辉夏大静浙江大学医学院公共卫生系浙江大学医学院感染与免疫研究中心杭州310058

血流感染包括菌血症和败血症，是由于致病菌进入血液后生长繁殖并释放毒素和代谢产物，引起急性重症感染性疾病，其发病率和致死率都较高，危害极大。血培养一直以来是血流感染诊断的金标准，但培养耗时较长，至少需要24～48h，由于采... 详细信息

血流感染包括菌血症和败血症，是由于致病菌进入血液后生长繁殖并释放毒素和代谢产物，引起急性重症感染性疾病，其发病率和致死率都较高，危害极大。血培养一直以来是血流感染诊断的金标准，但培养耗时较长，至少需要24～48h，由于采样误差的关系，即使一次培养结果阴性也不能排除感染的可能，因此需要一种快速简便的检测方法帮助临床评估患者是否发生血流感染。降钙素原（procalcitonin，PCT）是降钙素的前体，在健康人的外周血中含量很低，当细菌感染时，血浆中的PCT会明显升高。

关键词：血浆降钙素原血培养重症感染性疾病血流感染代谢产物生长繁殖感染诊断采样误差

Reduced glycodeoxycholic acid levels are associated with negative clinical outcomes of gestational diabetes mellitus

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2021年第3期22卷 223-232页

作者： Bo ZHU Zhixin MA Yuning ZHU Lei FANG Hong ZHANG Hongwei KONG dajing xia Department of Laboratorial Medicine Women’s HospitalSchool of MedicineZhejiang UniversityHangzhou310006China Clinical Prenatal Diagnosis Center Women’s HospitalSchool of MedicineZhejiang UniversityHangzhou310006China Key Laboratory of Separation Science for Analytical Chemistry Dalian Institute of Chemical PhysicsChinese Academy of SciencesDalian116023China Hangzhou HealthBank Medical Laboratory Hangzhou310051China Department of Toxicology School of Public HealthZhejiang UniversityHangzhou310006China Department of Gynecologic Oncology Women’s HospitalSchool of MedicineZhejiang UniversityHangzhou310006China

Gestational diabetes mellitus(GDM) is characterized by glycemia and insulin *** acids(BAs) have emerged as vital signaling molecules in glucose metabolic *** change in GDM is still unclear,which exerts great significance to illustrate the change of BAs in *** patients and normal pregnant women were enrolled during the oral glucose tolerance test(OGTT) screening *** serums were sampled for the measurement of *** metabolism profiles were analyzed in both pregnant women with GDM and those with normal glucose tolerance(NGT).Delivery characteristics,delivery gestational age,and infant birthweight were extracted from medical *** patients presented distinctive features compared with NGT patients,including higher body mass index(BMI),elevated serum glucose concentration,raised insulin(both fasting and OGTT),and increased hemoglobin A1 c(HbA1c) *** homeostasis model assessment of insulin resistance(HOMA-IR) and decreased β-cell compensation(i.e.,oral disposition index(DIo)) were also prevalent in this *** BAs(TBAs) remained stable,but glycodeoxycholic acid(GDCA) and taurodeoxycholic acid(TDCA) levels declined significantly in *** was inversely correlated with HOMA-IR and positively correlated with *** obvious differences in clinical outcome between the GDM and NGT groups were ***,GDM patients with high HOMA-IR and low DIo tended to have a higher cesarean delivery rate and younger delivery gestational *** conclusion,GDCA provides a valuable biomarker to evaluate HOMA-IR and DIo, and decreased GDCA levels predict poorer clinical outcomes for GDM.

关键词： Gestational diabetes mellitus(GDM) Bile acid Insulin resistance β-Cell compensation

USH2A mutation and specific driver mutation subtypes are associated with clinical efficacy of immune checkpoint inhibitors in lung cancer

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2023年第2期24卷 143-156页

作者： DEXIN YANG YUQIN FENG HAOHUA LU KELIE CHEN JINMING XU PEIWEI LI TIANRU WANG dajing xia YIHUA WU Department of Toxicology of School of Public Health and Department of Gynecologic Oncology of Women's HospitalSchool of MedicineZhejiang UniversityHangzhou 310058China Graduate School of Biomedical Sciences University of Texas MD Anderson Cancer Center and UTHealthHoustonDepartment of Biochemistry and Molecular BiologyMcGovern Medical SchoolUniversity of Texas Health Science CenterHoustonTX 77030USA Department of Thoracic Surgery the First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhou 310003China Department of Gastroenterology the Second Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhou 310009China Epidemiology Stream Dalla Lana School of Public HealthUniversity of TorontoTorontoM5S 2E8Canada Research Unit of Intelligence Classification of Tumor Pathology and Precision Therapy Chinese Academy of Medical Sciences 2019RU042Hangzhou 310058China

This study aimed to identify subtypes of genomic variants associated with the efficacy of immune checkpoint inhibitors(ICIs)by conducting systematic literature search in electronic databases up to May 31,*** main outcomes including overall survival(OS),progression-free survival(PFS),objective response rate(ORR),and durable clinical benefit(DCB)were correlated with tumor genomic features.A total of 1546 lung cancer patients with available genomic variation data were included from 14 *** Kirsten rat sarcoma viral oncogene homolog G12C(KRAS^(G12C))mutation combined with tumor protein P53(TP53)mutation revealed the promising efficacy of ICI therapy in these ***,patients with epidermal growth factor receptor(EGFR)classical activating mutations(including EGFRL858Rand EGFRΔ19)exhibited worse outcomes to ICIs in OS(adjusted hazard ratio(HR),1.40;95%confidence interval(CI),1.01-1.95;P=0.0411)and PFS(adjusted HR,1.98;95%CI,1.49-2.63;P<0.0001),while classical activating mutations with EGFR^(T790)Mshowed no difference compared to classical activating mutations without EGFR^(T790)Min OS(adjusted HR,0.96;95%CI,0.48-1.94;P=0.9157)or PFS(adjusted HR,0.72;95%CI,0.39-1.35;P=0.3050).Of note,for patients harboring the Usher syndrome type-2A(USH2A)missense mutation,correspondingly better outcomes were observed in OS(adjusted HR,0.52;95%CI,0.32-0.82;P=0.0077),PFS(adjusted HR,0.51;95%CI,0.38-0.69;P<0.0001),DCB(adjusted odds ratio(OR),4.74;95%CI,2.75-8.17;P<0.0001),and ORR(adjusted OR,3.45;95%CI,1.88-6.33;P<0.0001).Our findings indicated that,USH2A missense mutations and the KRAS^(G12C)mutation combined with TP53 mutation were associated with better efficacy and survival outcomes,but EGFR classical mutations irrespective of combination with EGFR^(T790)Mshowed the opposite role in the ICI therapy among lung cancer *** findings might guide the selection of precise targets for effective immunotherapy in the clinic.

关键词： Immune checkpoint inhibitor(ICI) Lung cancer Usher syndrome type-2A(USH2A)missense mutation Kirsten rat sarcoma viral oncogene homolog G12C(KRAS^(G12C))mutation combined with tumor protein P53(TP53)mutation Epidermal growth factor receptor(EGFR)mutation

Impact of antitumor regimens on the outcomes of cancer patients with COVID-19:a pooled analysis

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2021年第10期22卷 876-884页

作者： Haohua LU Yu SHI Kelie CHEN Zhi CHEN Haihong ZHU Yuequn NIU dajing xia Yihua WU Department of Toxicology of School of Public Health and Department of Gynecologic Oncology of Women’s Hospital School of MedicineZhejiang UniversityHangzhou 310058China The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases the First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhou 310003China Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases Hangzhou 310003China National Clinical Research Center for Infectious Diseases Hangzhou 310003China

Since the outbreak of coronavirus disease 2019(COVID-19),which is caused by the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)discovered in December 2019,the disease has emerged as a global pandemic(Shi et al.,2020;World Health Organization,2020).Several studies have shown a higher incidence of COVID-19,as well as related poor outcomes in patients with malignancies as compared with those without them(Liang et al.,2020;Tian et al.,2020).

关键词： patients regimen

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锌与自噬

浙江大学学报（医学版） 2016年第3期45卷 308-314页

作者：刘巧云沈汉明夏大静浙江大学公共卫生学院毒理系浙江杭州310058 新加坡国立大学杨潞龄医学院生理系 117597

细胞自噬主要指对胞质内受损的细胞器或生物大分子进行降解和回收利用的过程。自噬过程依赖于溶酶体，并由一系列复杂的信号分子进行调控。锌元素通过锌转运蛋白和锌指蛋白等多种酶或蛋白发挥催化和结构作用，在自噬的发生发展过程中发... 详细信息

细胞自噬主要指对胞质内受损的细胞器或生物大分子进行降解和回收利用的过程。自噬过程依赖于溶酶体，并由一系列复杂的信号分子进行调控。锌元素通过锌转运蛋白和锌指蛋白等多种酶或蛋白发挥催化和结构作用，在自噬的发生发展过程中发挥了重要作用。自噬调节紊乱同样也会导致胞内锌离子代谢稳态的重大改变。许多研究结果还提示锌对细胞的保护作用很可能是通过自噬来实现的。本文总结了当前国内外自噬研究进展，重点介绍锌在细胞自噬过程中发挥的作用和细胞自噬在锌代谢中的作用以及自噬介导的锌对细胞的保护作用等，揭示锌与自噬之间相互调控的发生机制，阐明自噬与疾病之间的关系，以期为治疗和预防多种人类重大疾病提供相关思路。

关键词：锌自噬肿瘤综述

三尖杉酯碱通过下调Mcl-1蛋白诱导NB4细胞凋亡

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浙江大学学报（医学版） 2013年第4期42卷 431-436页

作者：邬春晓沈红强夏大静浙江大学医学院附属妇产科医院检验科浙江杭州310006 浙江大学医学院附属儿童医院实验检验中心浙江杭州310003 浙江大学医学院免疫学研究所浙江杭州310058

目的:考察三尖杉酯碱(HT)对人急性早幼粒白血病(APL)细胞株NB4细胞的生长抑制作用和凋亡诱导作用,并探讨其杀伤白血病细胞的作用机制。方法:采用台盼兰染色法,细胞计数,考察HT对NB4细胞的生长抑制作用和细胞毒性作用;采用AO-EB荧光染色... 详细信息

目的:考察三尖杉酯碱(HT)对人急性早幼粒白血病(APL)细胞株NB4细胞的生长抑制作用和凋亡诱导作用,并探讨其杀伤白血病细胞的作用机制。方法:采用台盼兰染色法,细胞计数,考察HT对NB4细胞的生长抑制作用和细胞毒性作用;采用AO-EB荧光染色法和细胞形态学观察,考察HT对NB4细胞的凋亡诱导作用;采用PI染色的流式细胞术,考察HT对NB4细胞的凋亡诱导作用;采用Western Blotting技术,考察HT对NB4细胞凋亡相关蛋白的影响;采用siRNA干扰技术,沉默目的蛋白证明推论;提取APL患者血液样本,验证HT的凋亡诱导作用及作用机制。结果:HT能够呈剂量依赖和时间依赖地抑制NB4细胞生长并杀伤NB4细胞,HT处理72h后GI50为(32.0±2.5)nmol/L;HT能够呈现剂量依赖和时间依赖的诱导NB4细胞凋亡,HT处理6h后其诱导凋亡百分率为66%;HT诱导NB4细胞凋亡,引起PARP蛋白裂解,并不下调Bcl-2,不影响Bax和Bak的表达,但显著下调Mcl-1蛋白水平;siRNA沉默Mcl-1的蛋白表达可以显著提高HT对NB4细胞的凋亡诱导作用;HT诱导APL患者白血病样本细胞凋亡,并下调Mcl-1蛋白。结论:HT通过抑制细胞生长和诱导细胞凋亡杀伤NB4细胞,HT可能通过下调Mcl-1蛋白发挥诱导NB4细胞凋亡的抗白血病作用。

关键词：三尖杉酯碱/药理学白血病,早幼粒细胞,急性/药物疗法细胞凋亡/药物作用 NB4细胞 Mcl-1

Myricetin inhibits NLRP3 inflammasome activation by reducing ROS-dependent ubiquitination of ASC and promoting NLRP3 ubiquitination

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Myricetin inhibits NLRP3 inflammasome activation by reducing...

Activated NKT Cells Facilitated Functional Switch of Myeloid-derived Suppressor Cells at Inflammation Sites in Fulminant Hepatitis Mice

浙江省免疫学会第六次会员代表大会暨第十一次学术大会

作者： Hanwen Chen Hui Lin Shujun Xie Bo Huang Kelie Chen Yuequn Niu Jing Leng dajing xia Yihua Wu Department of Toxicology School of Public Health Zhejiang University

Myricetin is a plant-derived flavonoid with diverse pharmacological ***3(NLR Family,Pyrin Domain-Containing 3 Protein)inflammasome is a cytosolic multi-protein complex that plays a critical role in innate immune system and is involved in the pathogenesis of multiple inflammatory *** this study,we found that myricetin was able to inhibit NLRP3 inflammasome assembly by promoting ROS-independent ubiquitination NLRP3 and reducing ROSdependent ubiquitination of ASC(apoptosis-associated speck-like protein containing a CARD),disrupting the interaction between ASC and NLRP3 and thereby inhibiting ASC *** models of LPS-induced sepsis and alum-induced peritonitis further confirmed this effect in *** results suggest the potential therapeutic value of myricetin by targeting NLRP3-driven inflammatory diseases.

关键词： Myricetin inflammasome NLRP3 ASC

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Activated NKT Cells Facilitated Functional Switch of Myeloid...