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T淋巴细胞激活与凋亡的信号转导及其分子机制

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中国实验血液学杂志 1998年第4期6卷 241-245页

作者：郑德先中国医学科学院中国协和医科大学血液学研究所实验血液学国家重点实验室

研究发现,人T淋巴细胞抗原受体复合物(TCR/CD3)中,TCR负责接受抗原刺激,CD3负责转导抗原刺激信号。抗TCR或抗CD3抗体的刺激不仅可以激活T淋巴细胞,也可以导致胸腺细胞、激活后的或转化的T淋巴细胞凋亡,但其分子机制和信号转导途径还不... 详细信息

研究发现,人T淋巴细胞抗原受体复合物(TCR/CD3)中,TCR负责接受抗原刺激,CD3负责转导抗原刺激信号。抗TCR或抗CD3抗体的刺激不仅可以激活T淋巴细胞,也可以导致胸腺细胞、激活后的或转化的T淋巴细胞凋亡,但其分子机制和信号转导途径还不清楚。本文着重介绍了近年来这方面的研究工作进展。首先,利用人CD3ε过量表达的转基因小鼠发现,CD3ε分子的过量表达可阻断胎鼠的胸腺细胞发育,而在小鼠出生后,促进小鼠胸腺细胞的凋亡,随着年龄增加,胸腺细胞凋亡的数目增多。进而采用基因定点突变和基因转移等分子生物学研究技术,构建了CD8胞外区与跨膜区和CD3ε胞内区的融合分子及其突变分子,转染CD8^-的T淋巴细胞后,建立了细胞凋亡模型。利用此细胞凋亡模型,发现T细胞激活和凋亡的信号转导均是通过CD3ε分子的胞内区免疫酪氨酸受体激活基序(ITAM)中的2个酪氨酸转导的,其中任何1个或2个酪氨酸突变,均可阻断细胞信号的转导;在T细胞凋亡的过程中,立早基因Nur77和细胞凋亡基因fas表达显著增加,但未发现fas配体表达增加;在T细胞激活过程中,3-磷脂酰肌醇激酶P85α亚基与CD3ε-ITAM中的2个酪氨酸特异性地结合,其中任何1个酪氨酸突变,均大大减低P85α与CD3ε-ITAM的结合能力;

关键词： T淋巴细胞细胞凋亡信号转导 T淋巴细胞抗原受体复合物

伊鲁阿克治疗间变性淋巴瘤激酶融合基因阳性局部晚期或转移性非小细胞肺癌中国专家共识(2024版)

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中华肿瘤杂志 2024年第3期46卷 189-205页

作者：中国医疗保健国际交流促进会肿瘤内科学分会中国医师协会肿瘤医师分会石远凯郝学志汪麟杨建良刘鹏韩晓红冯宇朱豪华谢同济陈馨蕊谢祖成不详国家癌症中心、国家肿瘤临床医学研究中心、中国医学科学院北京协和医学院肿瘤医院内科、抗肿瘤分子靶向药物临床研究北京市重点实验室北京100021 中国医学科学院北京协和医院临床药理中心清华大学临床医学院、清华大学附属北京清华长庚医院肿瘤内科

间变性淋巴瘤激酶(ALK)融合基因是非小细胞肺癌(NSCLC)常见的驱动基因之一。流行病学数据显示,在中国晚期NSCLC患者中ALK融合基因的阳性率为9.06%。ALK酪氨酸激酶抑制剂(TKIs)已经成为ALK融合基因阳性晚期NSCLC患者的标准治疗选择。目... 详细信息

间变性淋巴瘤激酶(ALK)融合基因是非小细胞肺癌(NSCLC)常见的驱动基因之一。流行病学数据显示,在中国晚期NSCLC患者中ALK融合基因的阳性率为9.06%。ALK酪氨酸激酶抑制剂(TKIs)已经成为ALK融合基因阳性晚期NSCLC患者的标准治疗选择。目前中国国家药品监督管理局已经批准7种ALK-TKIs上市,分别是克唑替尼、塞瑞替尼、阿来替尼、恩沙替尼、布格替尼、洛拉替尼和伊鲁阿克。伊鲁阿克是中国自主研发的新型ALK-TKI,2023年6月27日,国家药品监督管理局批准伊鲁阿克上市,用于既往接受过克唑替尼治疗后疾病进展或对克唑替尼不耐受的ALK融合基因阳性局部晚期或转移性NSCLC患者的治疗,2024年1月16日,国家药品监督管理局批准伊鲁阿克用于ALK融合基因阳性局部晚期或转移性NSCLC患者的一线治疗。为了帮助广大医师更好地了解伊鲁阿克的疗效和安全性,使伊鲁阿克得到更合理的临床应用,中国医疗保健国际交流促进会肿瘤内科学分会和中国医师协会肿瘤医师分会组织专家编写了《伊鲁阿克治疗间变性淋巴瘤激酶融合基因阳性局部晚期或转移性非小细胞肺癌中国专家共识(2024版)》。

关键词：肺肿瘤非小细胞癌间变性淋巴瘤激酶酪氨酸激酶抑制剂伊鲁阿克专家共识

Internalization and distribution of three α1-adrenoceptor subtypes in HEK293A cells before and after agonist stimulation

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Acta Pharmacologica Sinica 2007年第3期28卷 359-366页

作者： Shu-yi WANG~2 Yao SONG~2 Ming XU~2 Qi-hua HE~3 Qi-de HAN~2 You-yi ZHANG~(2,4)2 institute of Vascular Medicine,peking University Third Hospital and Key laboratory of molecular Cardiovascular sciences,Ministry of Education,beijing 100083,china 2 Center of medical Analysis,peking University,Health science Center,beijing 100083,china institute of Vascular Medicine Peking University Third Hospital and Key Laboratory of Molecular Cardiovascular Sciences Ministry of Education Beijing 100083 China Center of medical Analysis Peking University Health Science Center Beijing 100083 China

Aim:To examine the subcellular distribution of the 3 α1-adrenoceptor（α1-AR）subtypes and their internalization and trafficking upon agonist stimulation in hu-man embryonic kidney 293A ***:Confocal real-time imaging,enzymelinked immunosorbent assay（ELISA）and whole cell[3H]-prazosin binding assaywere applied to detect the distribution and localization of the 3 α1B-AR ***:α1A-AR was found both on the cell surface and in the cytoplasm;α1B-AR,however,was predominantly detected on the cell surface,while α1D-AR wasdetected mainly in the intracellular *** stimulation withphenylephrine,localization changes were detected by confocal microscopy forα1A-and α1B-AR, but the localization of α1D-AR were *** promoted a more rapid internalization of α1B-AR than α1A-AR.α1D-ARinternalization was detected only by *** cell[3H]-prazosin bindingassay showed that α1A-AR functional receptors were detected both on the cellsurface and in the cytoplasm;α1B-AR,however,were detected predominantly onthe cell surface,while α1D-AR were detected mainly in intracellular *** stimulation promoted internalization of α1A-and α***:Phenylephrine stimulation induced changes in the localization of the3α1-AR.

关键词： adrenoceptor agonist stimulation confocal image enzyme-linked immunosorbent assay [~3H]-prazosin binding assay internalization subcellular distribution subtype

Remove glycosylation of Prion Protein Provoke Apoptosis in Neural and Non-neural Cell in vitro

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Remove glycosylation of Prion Protein Provoke Apoptosis in N...

第一届全国脑与认知科学学术研讨会

作者： Lan Chen Yang Yang, Jim Han, Bao-Yun Zhang, Lin Zhao, Kai Nie,Xiao-Fan Wang, Feng Li, Chen Gao, Xiao-Ping Dong, Cai-Min Xu national laboratory of medical molecular biology, institute of basic medical science, chinese academy of medical sciences and peking union medical college, Dong Dan San Tiao 5, beijing 100005, People’s Republic of china. national institute for Viral Disease Control and Prevention, chinese Center for Disease Control and Prevention, Ying-Xin Rd 100, beijing 100052, People’s Republic of china.

The function of cellular prion protein (PrPC) and the pathogenesis of prion diseases are not yet clarified. Cell apoptosis was focused on to explore these questions. In our study, both cell apoptosis and the increase of non-glycosylation prion protein were observed in hamster brain infected with scrapie 263K strain. To elucidate the relationship between cell apoptosis and glycosylation profile of prion protein, we overexpressed wild type HuPrP and

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NLRP3 inflammasome pathway is involved in olfactory bulb pathological alteration induced by MPTP

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Acta Pharmacologica Sinica 2019年第8期40卷 991-998页

作者： Ying Chen Qiu-shuang Zhang Qian-hang Shao Shuo Wang Yu-he Yuan Nai-hong Chen Hong-bo Wang State Key laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia Medica & Neuroscience CenterChinese Academy of Medical Sciences and Peking Union Medical College Key laboratory of molecular Pharmacology and Drug Evaluation (Yantai University) Ministry of EducationYantai University

Olfactory bulb,as one of sensory organs opening to the outside,is susceptible to toxic environment and easy to *** studies in Parkinson’s disease(PD)patients and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-treated monkeys have shown that abnormal a-synuclein is accumulated in the olfactory glomeruli,suggesting that the lesions of PD are not only confined to the substantia nigra(SN)but also located in the olfactory ***,olfactory bulb might be the region of onset in PD pathogenesis and a targeted region for diagnosis and treatment of ***,the relationship between olfactory bulb and pathogenesis of PD remains *** the present study,we investigated the inflammatory pathological alterations in olfactory bulb and the underlying mechanisms in chronic MPTP *** were treated with MPTP/P, i.e.,MPTP(25 mg/kg,s.c.)plus probenecid(250 mg/kg,i.p.)every 4 days,for ten *** mice displayed typical parkinsonian *** we examined their olfactory function and the pathologic changes in olfactory *** mice showed obvious olfactory dysfunction in a buried pellet *** studies revealed that tyrosine hydroxylase(TH)protein levels were significantly decreased,whereas abnormal a-synuclein was significantly increased in the olfactory ***,the olfactory bulbs in MPTP/P-treated mice showed significantly increased levels of interleukin-1β(IL-1β),caspase-1,glial fibrillary acidic protein(GFAP),Toll receptor 4(TLR4),phosphorylation of p65,as well as activated molecules of NOD-like receptor protein 3(NLRP3)that were associated with *** results demonstrate that MPTP/P-caused olfactory bulb damage might be related to NLRP3-mediated inflammation.

关键词： Parkinson’s disease olfactory bulb α-synuclein TLR4 NF-κB NLRP3 neuroinflammation MPTP probenecid

Identification of new centrosome proteins by autoimmune patient sera

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science china(Life sciences) 2007年第2期50卷 194-202页

作者： XIA Liang1, LI Yan1, YANG Dong1, WANG LiMin1, HE Fang1, ZHOU ChunYuan1, LI YongZhe2, ZENG ChangQing1 & He DaCheng1 1 Key laboratory for Cell Proliferation and Regulation biology of Ministry of Education, beijing Normal University, beijing 100875, china 2 peking union medical Hospital, peking union medical college, beijing 100730, china 3 beijing Genomic institute, beijing 101300, china 1. Key laboratory for Cell Proliferation and Regulation biology of Ministry of Education Beijing Normal University Beijing 100875 China 2. peking union medical Hospital Peking Union Medical College Beijing 100730 China

Compared to other subcellular organelles, centrosome proteome can hardly be studied, due to the dif- ficulties in separation and purification of centrosome. Auto-antisera from 6 autoimmune patients, which recognized centrosome specifically in immunofluorescence, were used to identify the corresponding centrosomal proteins. The sera were first tested by Western blot on whole cell lysate, and all bound antibodies were then eluted from each single band in Western blot membrane to assure which antibody was responsible for the centrosome specific immunofluorescence staining. The corresponding pro- teins were obtained by immunoprecipitation and identified by mass spectrometry. Six centrosomal proteins, including 2 known centrosomal proteins and 4 proteins with unknown localization or report- edly non-centrosomal localization, were identified. These proteins apparently involve in cell cycle regulation, signal transduction pathways, molecular chaperons, and metabolism enzymes, which may reflect the expected functional diversity of centrosome.

关键词： centrosome autoimmune patient sera elution of antibody immunoflourescence immunoprecipitation mass spectrometry

Retroviral mediated human β-globin gene transfer and expression in vitro

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中国实验血液学杂志 1997年第3期5卷 286-286页

作者： Depei Liu, Chih-Chuan Liang national laboratory of medical molecular biology, institute of basic medical sciences, chinese academy of medical sciences and peking union medical college, beijing 100005

Retroviral mediated gene transfer of humanglobin gene into hematopoietic stem cells is apromising approach for thalassemia gene *** problem of the transferred globin gene was lowlevel expression of the gene with its proximal cis-acting sequence. The locus control region (LCR) ofthe human β-globin gene cluster consists of four majorDNase I hypersensitive sites (HS). When linked

关键词： globin hematopoietic proximal hypersensitive locus enhancer packaging Major transferred induction

Echinacoside attenuates 6-hydroxydopamine-induced neurotoxicity in PC12 cells

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Echinacoside attenuates 6-hydroxydopamine-induced neurotoxic...

第二届世界天然药物和传统药物药理学学术会议

作者： Yue-Hua WANG~(1,2),Shuo TIAN~2,Guo-Rong HE~2,Lian-Hua FANG~2,Xiao-Ping PU~(1*),Guan-Hua DU~(2*) (1.Department of molecular and Cellular Pharmacology,School of Pharmaceutical sciences,peking University, beijing 100191,china 2.beijing Key laboratory of Drug Target Identification and Drug Screening, institute of Materia Medica,chinese academy of medical sciences & peking union medical college, beijing 100050,china)

＜正＞AIM To investigate the effects and the underlying mechanism of Echinacoside（ECH） against 6-OHDA-induced injury in *** 6-OHDA was added to cultured PC12 cells after pretreatment for 1 h with different concentration of ECH or saline and co-incubated for another 24 *** evaluate the protective effects of ECH,the morphological change was observed by microscope,the viability of PC12 cells was assayed by MTT *** explore the mechanism of ECH against 6-OHDA neurotoxicity, the mitochondrial oxidation-reduction activity（REDOX）,mitochondrial membrane potential（△ψm）,reactive oxygen species（ROS） production,ATP level,cytochrome c release,the activity of caspase 3,and apoptosis in PC12 cells were *** 6-OHDA induced the decrease of cell viability,ROS generation increase,ATP content decrease,mitochondrial dysfunction,and mitochondria -mediated apoptosis in PC12 *** could attenuate 6-OHDA-induced neurotoxicity,inhibit the collapse of△ψm,reduce the mitochondrial *** also inhibited cyt c release and caspase 3 *** Our results indicate that ECH attenuates 6-OHDA-induced neurotoxicity through anti-oxidative and anti-apoptosis mediated by mitochondria.

关键词： echinacoside Parkinson’s disease 6-hydroxydopamine

DL0805,a Rho-kinase inhibitor,attenuates angiotensin Ⅱ-induced vascular contraction in vitro by inhibiting Ca2+ influx and ERK1/2 activation

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DL0805,a Rho-kinase inhibitor,attenuates angiotensin Ⅱ-indu...

中国药理学会第十一次全国学术会议

作者： LI Li,CHEN Bai-nian,GONG Li-li,FANG Lian-hua,DU Guan-hua (national Center for Pharmaceutical Screening,institute of Materia Medica,chinese academy of medical sciences and peking union medical college,beijing 100050,china)

AngiotensinⅡ(AngⅡ) activates Rho-kinase and initiates the contractile activity in vascular smooth *** this study,we investigated the vasorelaxing effect of DL0805,a Rho-kinase inhibitor,on AngⅡ-induced vascular contractions and its molecular mechanism of *** found that DL0805 inhibited AngⅡ-induced vascular contractions in both endothelium-intact and en-dothelium -denuded rat aortic ***,increased phosphorylation level of myosin light chain 2(MLC2) at Serl9 by AngⅡstimulation was significantly attenuated by DL0805 in both endothelium-intact and -denuded rat aortic ***,DL0805 significantly suppressed AngⅡ-induced Ca influx in *** addition,DL0805 was found to block the increase in ERK1/2 phosphorylation at Thr202/Tyr204 in response to AngⅡin both rat aortic rings and *** results demonstrate that DL0805 inhibits AngⅡ-induced rat aortic rings contraction and the mechanism involves the inhibition of AngⅡ-induced Ca influx and ERK1/2 activation.

关键词： DL0805 angiotensinⅡ rat aortic rings contraction Ca2+ influx ERK1/2 MAPK