慢性乙型肝炎患者的干扰素-α/β受体

干扰素(IFN)是担负防御病毒感染的细胞分裂素类,其中的 IFN-α或 IFN-β,具有最强的直接的抗病毒作用。与病毒感染有关的患者体内 IFN-α/β受体的病理变化研究,尚未见报道。作者对乙型肝炎病毒携带者(AsC)的末梢血液中单核细胞(PBMC)内 IFN-     

对冠心病人合用α-β阻滞剂的血液动力学优于单用β阻滞剂

作者对12例冠心病患者,男性,年龄25—64岁。6例用β阻滞剂心得安,另6例用α-β阻滞剂柳氨苄心定进行急性血液动力学随机比较。心得安组用心得安后发现静息时患者系统血压无改变,但在运功中下降,心输出量和心率减少,且无论静息时或运动中肺动脉压和SVR均明显增加.柳氨苄心定组用柳氨苄心定后,患者静息时和运动中系     

αvβ3 and αvβ5 integrin antagonists inhibit angiogenesis in vitro

Although angiogenesis is believed to require cell-extracellular matrix interactions which are mediated in part via integrins alphav beta 3 and alphav beta 5, a formal demonstration that alphav beta 3 and alphav beta 5 are involved in endothelial-cell invasion and capillary-like tube formation is still required. This has arisen from the cellular complexities which occur in vivo and the difficulty in finding appropriate in vitro model systems. Here we have used a three-dimensional assay which employs bovine aortic and microvascular endothelial cells, to show that alphav beta 3 and alphav beta 5 regulate angiogenesis in vitro. We cloned and characterized 350-450 bp regions of the bovine homologues of alphav, beta 3 and beta 5, covering much of the beta -propeller and A-domain regions, and show that they are >95% identical to their human orthologues. We used cyclic peptides EMD 121974, 85189 and 66203, which selectively inhibit alphav beta 3 and alphav beta 5, but not gpIIbIIIa or alpha5 beta 1, to probe in vitro angiogenesis induced by angiogenic cytokines in three-dimensional fibrin or collagen gels. We found that these peptides are potent inhibitors of endothelial cell invasion and differentiation induced by vascular endothelial growth factor-A or fibroblast growth factor-2 but do not affect the unstimulated cells in 3D culture. Inhibition was greatest when cells were grown on fibrin, but also occurred on collagen I which is not a recognized ligand for alphav beta 3. These findings demonstrate the requirement for endothelial cell alphav beta 3 and alphav beta 5 integrins during angiogenesis in vitro, and are in accord with the proposed therapeutic application of alphav beta 3 and alphav beta 5 antagonists.     

老年人血管α-、β-肾上腺素能受体平衡无改变

有些学者认为,β-肾上腺素能受体介导功能随增龄而降低,降低程度比α-受体要大。老年人的这种失衡可因不能拮抗外周血管α-受体兴奋而使血管阻力增加。本研究旨在对此假设作出评价。方法健康老、青年人各12名(男6女6),平均年龄分别为69岁(61～77)、29岁(23～34),无吸烟及长期用药史,实验前二周起停用各种药物。受试者平卧位,连续监测心电图,自动记录血压,测定静止时各例基准值后,输注肾上腺素4分钟,初始速度每分钟1ng/kg,于输注前及第4分钟采血测几茶酚胺含量,记录脉搏、血压,测定小腿血流量。随后给药速度以每分钟2、4,8、16、32、64、128ng/kg递增,平均动脉压=1/3脉压+舒张压,用静脉闭合体积描记法记录小腿血量最大变化     

肿瘤坏死因子-α和白介素-1β与克隆病复发

经内科治疗而缓解的克隆病病人中,30％～60％将在1年内复发。研究者调查了缓解期克隆病病人结肠固有层单核细胞产生肿瘤坏死因子-α(TNF-α)、白介素-1β(IL-1β)与疾病复发之间的关系。     

α-与β-肾上腺素能受体在心脏调节中的作用

Ahlquist在1948年提出α-与β-肾上腺素能受体是儿茶酚胺拟交感神经作用传递器的概念,认为除心脏外,大多数器官都存在α-与β-二种受体,唯心脏仅有β-受体,其功能是传递正性的变力性、变时性、变传导性、变阈性效应.然而,目前知道心脏调节中不但有β-受体,而且还有α-受体在起作用.α-受体位于心脏神经节后纤维突触前,其功能是在交感神经兴奋后,通过反馈机制控制去甲肾上腺素的释放量.突触间隙内去     

慢性丙型肝炎病毒感染病人干扰素-α和干扰素-β治疗的差异

本研究的目的旨在比较慢性丙型肝炎病毒(ＨＣＶ)感染病人对人淋巴母细胞性干扰素(ＩＦＮ α)和人纤维母细胞性干扰素 (ＩＦＮ β)治疗的病毒学、生化学和免疫反应。病人和方法　研究对象为 1 2 0例慢性ＨＣＶ感染病人 ,其中男 72例 ,女 48例 ,年龄 2 0～ 70岁。病人随机分为 3组 :Ａ组 (6 0例 )应用ＩＦＮ α治疗 ,6ＭＵ ,每日 1次 ,共 1个月 ,随后 5个月改为每周 3次 ;Ｂ组 (4 0例 )应用ＩＦＮ β治疗 ,6ＭＵ ,每日 1次 ,共 2个月 ;Ｃ组 (2 0例 )应用ＩＦＮ β治疗 ,3ＭＵ ,每日 2次 (6ＭＵ/ｄ) ,共 2个月。各组病人临床、生物学和组织学数…     

急性弓形虫病产生干扰素-α/β和-γ的关系

体内和体外的研究证实,活化的巨噬细胞是杀死刚地弓形虫或抑制其增殖的主要细胞,而干扰素-γ(IFN-γ)则是自然宿主在弓形虫感染应答期活化巨噬细胞的主要因素。然而,小鼠和人的急性弓形虫病期的IFN-γ水平下降伴随着免疫抑制。此外,刚地弓形虫还能引起感染小鼠中干扰素-α/β(IFN-α/β)的产生。本文研究了小鼠急性弓形虫病期间血清和脾细胞IFN-α/β和IFN-γ产生的动力学及IFN异常与免疫抑制的关系。 8～10周龄、无病原微生物的雌性NMR1小鼠,每组10只,感染组经后足垫皮下接种含5×10~3活的刚地弓形虫Rh株速殖子的生理     

慢性乙型肝炎患者干扰素-α治疗应答与干扰素-α/β受体启动子-408基因多态性的相关性

目的:探讨干扰素(IFN)-α/β受体启动子-408位点的单核苷酸多态性(SNP)与IFN疗效的关系。方法:应用聚合酶链反应(PCR)并基因测序法检测210例慢性乙型肝炎(CHB)患者(轻度38例、中度102例、重度70例)的IFN-α/β受体基因启动子-408位点的SNP。对210例中既往未用过IFN治疗的80例CHB患者给予聚乙二醇化干扰素α-2a or 2b(Peg-IFN-α-2a/2b)治疗48周。比较SNP与Peg-IFN疗效的关系。结果:80例患者中,IFN治疗持久应答(SR)33例(41.3%),非持久应答(NSR)47例(58.7%)。IFN-α/β受体启动子-408位点CT基因型患者干扰素治疗SR为65%(13/20),显著高于CC基因型患者干扰素治疗SR 29.5%(13/44),两者比较差异有显著性意义(χ2=7.166,P=0.007)。干扰素治疗SR组IFN-α/β-408位点等位基因C、T的频率与NSR组的频率比较差异无显著性意义(P>0.05)。结论:IFN-α/β受体启动子-408为CT杂合基因型的CHB患者可能对Pec-IFN治疗效果较好。     

慢性肝病的转移生长因子β_1和α与α-干扰素疗法的效果

肝硬化是致病机理不明的一种肝脏弥漫性纤维化和再生结节形成的过程。在动物实验中,转移生长因子(TGF)β_1可诱导肝细胞产生细胞外基质蛋白,故被认为与肝脏纤维化的发病有关。TGFα是一种肝细胞的有丝分裂原,参与肝脏的再生过程。     

Dimerization of LTβR by LTα1β2 is necessary and sufficient for signal transduction

Homotrimeric TNF superfamily ligands signal by inducing trimers of their cognate receptors. As a biologically active heterotrimer, Lymphotoxin(LT)α₁β₂ is unique in the TNF superfamily. How the three unique potential receptor-binding interfaces in LTα₁β₂ trigger signaling via LTβ Receptor (LTβR) resulting in lymphoid organogenesis and propagation of inflammatory signals is poorly understood. Here we show that LTα₁β₂ possesses two binding sites for LTβR with distinct affinities and that dimerization of LTβR by LTα₁β₂ is necessary and sufficient for signal transduction. The crystal structure of a complex formed by LTα₁β₂, LTβR, and the fab fragment of an antibody that blocks LTβR activation reveals the lower affinity receptor-binding site. Mutations targeting each potential receptor-binding site in an engineered single-chain variant of LTα₁β₂ reveal the high-affinity site. NF-κB reporter assays further validate that disruption of receptor interactions at either site is sufficient to prevent signaling via LTβR.The TNF receptor and ligand superfamilies (TNFRSF and TNFSF, respectively) play critical roles in mammalian biology and mediate proinflammatory immune responses. Lymphotoxin (LT)-α and LTβ are two related TNFSF members produced predominately by activated cells of the innate and adaptive immune response. LTα exists as a secreted homotrimeric molecule (LTα₃) that signals via TNFR1 and TNFR2, or as a heterotrimer with LTβ on the cell surface (major form LTα₁β₂, minor form LTα₂β₁) and signals through the LTβ receptor (LTβR) (1). As a heterotrimer rather than a homotrimer, LTα₁β₂ is unique in the TNFSF.The role of LT in the immune response has been well characterized as critical for the development and orchestration of robust immune responses (2). Signaling through LTβR, expressed on nonhematopoeitic cells and follicular dendritic cells, directs normal development of lymph nodes and appropriate germinal center architecture via the elaboration of various cytokines and chemokines, as revealed in LTα-, LTβ-, or LTβR-deficient mice (3, 4). During chronic immune responses, cellular effectors can infiltrate target tissue and organize anatomically into de novo lymphoid structures, instigated and maintained by LT-mediated pathways (5).Surface LTα₁β₂ is detected on subsets of activated T and B cells and NK cells (6–9). Dysregulation of these immune cell types underlies the pathogenesis of autoimmune diseases. In mouse models of rheumatoid arthritis (RA), experimental autoimmune encephalomyelitis (EAE), and delayed-type hypersensitivity (DTH), treatment with a depleting antibody specific to murine LTα resulted in amelioration of disease in all circumstances. In these studies, the Fc-dependent efficacy achieved with anti-LTα resulted from depletion of pathogenic LT-expressing Th1 and Th17 cells. Moreover, blockade of LTβR signaling using a decoy receptor fusion protein, LTβR-Ig, was sufficient to drive efficacy in a number of autoimmune models when delivered preventatively (10). Motivated by the concerted effects of LTα and LTβ in driving major inflammatory pathways and pathologies, we previously generated a humanized anti-LTα mAb (MLTA3698A, hereafter referred to as anti-LTα), and demonstrated increased survival in a xenogeneic human T-cell–dependent mouse model of graft-versus-host disease (GVHD) (11).TNFRSF members are typically activated by TNFSF-induced trimerization or higher order oligomerization, resulting in initiation of intracellular signaling processes including the canonical and noncanonical NF-κB pathways (2, 3). Ligand–receptor interactions induce higher order assemblies formed between adaptor motifs in the cytoplasmic regions of the receptors such as death domains or TRAF-binding motifs and downstream signaling components such as Fas-associated protein with death domain (FADD), TNFR1-associated protein with death domain (TRADD), and TNFR-associated factor (TRAF). In particular, LTβR signals via TRAF3 and the structure of a peptide derived from the intracellular region of LTβR bound to the TRAF3 C-terminal domain revealed a 3:3 trimeric complex (12, 13).Most TNFSF ligands are compact homotrimers formed by protomers possessing a conserved beta-strand jellyroll fold. Each protomer is formed by an inner and outer β-sheet consisting of strands A’AHCF and B’BGDE, respectively (14). In contrast, multidomain TNFRSFs have an elongated shape and are composed of pseudorepeats of ∼40 residue cysteine-rich domains (CRDs). The extracellular domain (ECD) of LTβR comprises four CRDs and is expected to have similar overall architecture to other multidomain TNFRSF members such as TNFR1. Crystal structures of several ligand–receptor complexes in this superfamily (15–23) revealed that receptors bind in a symmetrical manner at the monomer–monomer interfaces of the ligands, with CRD2 and CRD3 mediating most receptor–ligand interactions (Fig. S1A).Unlike most TNFSF ligands, biochemical studies surprisingly indicated that the LIGHT [TNFSF member homologous to LT, inducible expression, competes with herpes simplex virus (HSV) glycoprotein D for HSV entry mediator (HVEM), a receptor expressed on T lymphocytes; TNFSF14] homotrimer and the LTα₁β₂ heterotrimer are only capable of binding two copies of their cognate receptor, LTβR. However, difficulty in making recombinant, soluble LTα₁β₂ precluded further characterization (1). Nonetheless, the inherent asymmetry of the LTα₁β₂ heterotrimer suggests three distinct possible receptor-binding sites in LTα₁β₂ as opposed to three equivalent sites in a homotrimer (Fig. S1 B and C). Herein we draw on structural, biochemical, and cellular data to show that dimeric clustering of LTβR by the LTα₁β₂ heterotrimer triggers signal transduction and that disrupting one receptor-binding site on LTα₁β₂ is sufficient to block signaling through LTβR.     

β-七叶皂甙钠对脑出血患者急性期TNF-α和IL-1β的影响

目的探讨β-七叶皂甙钠对脑出血患者急性期肿瘤坏死因子-α（TNF-α）和白细胞介素-1β（IL-1β）的影响。方法将67例脑出血住院患者随机分为实验组（35例）和对照组（32例）,对照组入院后按常规治疗;实验组入院后即开始应用β-七叶皂甙钠（每天0.5 mg/kg）,其余治疗同对照组。所有病例均在发病初和发病后第3天抽血应用ELISA法查TNF-α和IL-1β,并选取同期健康体检者46例作为健康对照组。结果治疗前三组间TNF-α和IL-1β的含量比较无显著性差异（P〉0.05）;发病后第3天实验组较健康组和治疗前轻度升高（P〈0.05）,但较对照组明显下降（P〈0.01）;对照组较健康组和治疗前明显升高（P〈0.01）。结论β-七叶皂甙钠能抑制TNF-α和IL-1β的表达和释放,从而抑制炎症反应,减轻脑水肿和继发的缺血损伤。     

原发性高血压患者血清肿瘤坏死因子-α和-β水平测定及临床意义

目的:探讨原发性高血压(EH)患者血清肿瘤坏死因子(TNF)水平变化与EH发生的关系。方法:ELISA法检测260例河南汉族EH患者和394名对照者的血清TNF-α及TNF-β水平。结果:与对照者比较,EH患者血清TNF-α及TNF-β水平均显著增高[(7.648±2.115)pg/ml︰(5.417±1.903)pg/ml,(6.036±1.227)pg/ml︰(4.925±1.737)pg/ml,均P<0.01]。EH患者血清TNF水平随收缩压和舒张压的升高而升高,呈正相关(均P<0.01)。结论:EH患者的血清TNF水平增高可能与EH的发生相关。     

Gene expression polymorphisms of interleukins-1β, -4, -6, -8, -10, and tumor necrosis factors-α, -β: regression analysis of their effect upon oral squamous cell carcinoma

Purpose  Functional DNA polymorphisms affecting gene expression and serum or saliva levels of interleukins IL-1β,-4,-6,-8,-10 and tumor necrosis factors TNF-α,-β have been associated with increased risk for the development of oral squamous cell carcinoma (OSCC). The present retrospective case–control study examines possible interactions between seven cytokine genotype polymorphisms and their combinatory effect in predicting the occurrence of OSCC in Caucasians. Methods  Three hundred and thirty Greeks and Germans were studied, consisting of 162 OSCC cases and 168 healthy controls of comparable age, gender, and ethnicity. A series of multivariate logistic regression models, adjusted for age and gender, was constructed in order to assess the contribution of homozygous or heterozygous variant genotypes of polymorphisms IL-1β (+3953C/T), IL-4 (-590C/T), IL-6 (-174G/C), IL-8 (-251A/T), IL-10 (-1082A/G), TNF-α (-308G/A) and TNF-β (+252G/A) upon overall, early and advanced stages of OSCC development. Results  The contribution of TNF-α and IL-6 was consistent and robust in almost all models constructed. Furthermore, when the mode of inheritance of each variant allele was taken into account in a “biological” multivariate logistic regression model, four polymorphisms emerged as primary predictors for overall stages of OSCC: TNF-α (OR = 15.27; 95% CI = 7.30–31.96), IL-6 (OR = 8.33; 95% CI = 3.95–17.58), IL-8 (OR = 3.54; 95% CI = 1.69–7.43) and IL-10 (OR = 2.65; 95% CI = 1.28–5.46). Finally, IL-1β, IL-4 and TNF-β polymorphisms were not primary predictors of OSCC development in all constructed models. Conclusions  This study revealed the highly significant contributions of two out of seven studied cytokines (IL-6 and TNF-α) in the occurrence of OSCC. Based on these findings and previous reports, possible stoichiometrical interactions of cytokines leading to OSCC development are discussed. Eleftherios Vairaktaris and Christos Yapijakis have contributed equally in this work.     

高容量通气对兔肺组织肿瘤坏死因子-α、白介素-1β、转化生长因子-β1表达的作用

目的:探讨高容量机械通气对大白兔肺组织TNF-α、IL-1β、TGF-β1的作用.方法:将30只3月龄雄性大白兔随机分成3组:对照组、常规潮气量组及大潮气量组,每组各10只.对照组插管后不机械通气,另2组插管后机械通气.常规潮气量组VT8 mL/kg,大潮气量组VT 25 mL/kg,其它参数相同,通气时间24 h.观察实验前后动脉血pH值、PaO2及PaCO2的变化、ELISA法测定肺组织TNF-α、IL-1β,SABC法测定TGF-β1、测定肺组织湿/干重(W/D)值、观察肺组织病理学变化.结果:与对照组比较,大潮气量组通气24 h后动脉血pH、PaO2和PaCO2变化显著(均P＜0.05),肺组织W/D、TNF-α、IL-1β、TGF-β1升高(均P＜0.01),肺组织水肿,常规潮气量组相应指标无显著变化(P＞0.05).结论:大潮气量机械通气易发生呼吸机相关性肺损伤(VILI),表现为动脉氧分压、肺组织W/D、肺组织病理变化,同时肺组织TNF-α、IL-1β、TGF-β1升高,表明VILI与TNF-α、IL-1β、TGF-β1炎性细胞因子有关.     

病毒性心肌炎肿瘤坏死因子-α白介素-2及白介素-1β的检测及其意义

目的探讨病毒性心肌炎患者血清肿瘤坏死因子-α(TNF-α)、白介素-2(IL-2)、白介素-1β(IL-1β)的变化及临床意义。方法采用酶联免疫吸附试验(ELISA)法测定2004年中山大学第三附属医院及第一附属医院心脏内科45例病毒性心肌炎患者血清TNF-α、IL-2、IL-1β,并与正常对照组35名进行比较。结果病毒性心肌炎患者急性期TNF-α、IL-2、IL-1β明显高于恢复期及正常对照组(P<0.01);病情越重,血清TNF-α、IL-2、IL-1β越高;并与磷酸肌酸激酶同工酶(CK-MB),乳酸脱氢酶同工酶(LDH1)呈明显的正相关;恢复期血清TNF-α、IL-2、IL-1β与正常对照组比较差异无显著性意义(P>0.05)。结论病毒性心肌炎患者存在细胞免疫功能紊乱,TNF-α、IL-2、IL-1β增高可能与其发生、发展有关,并可作为病情判断及疗效的观察指标。     

慢性丙型肝炎时白介素-1β和肿瘤坏死因子-α的肝内表达

丙型肝炎病毒 (ＨＣＶ)感染绝大多数形成慢性化 ,病毒的持续存在可能与宿主选择性免疫缺陷有关。已有资料显示慢性丙型肝炎患者外周血单个核细胞中单核因子含量减少。本文旨在通过肝内白介素 1 β(ＩＬ 1 β)和肿瘤坏死因子 α(ＴＮＦ α)的检测 ,以探讨ＨＣＶ感染慢性化的机制。方法　肝组织标本取自慢性丙型肝炎患者(2 9例 )、原发性胆汁性肝硬化患者 (1 2例 ) ,正常对照者 (1 9例 )。丙型肝炎患者平均病毒负荷量为 1 0 7× 1 0 5拷贝 /ｍＬ ,ＨＣＶ基因型为 1ａ(9例)、1ｂ(1 1例 )、2ａ(2例 )、3ａ(1例 )、混合型 (3例 ) ,乙型肝炎病毒…     

整合素-α2和整合素-β3基因多态性与急性心肌梗死的相关性研究

目的探讨整合素-α2(ITGA2)基因C807T和整合素-β3(ITGB3)基因T176C多态性与急性心肌梗死(AMI)的关系及其脂蛋白水平对血脂的影响。方法选择AMI患者180例为AMI组,同期选择健康体检者200例为对照组,应用聚合酶链反应-限制性片段长度多态性方法检测两组ITGA2和ITGB3的基因型,同时测定血脂、脂蛋白水平。结果 AMI组患者TC、TG、LDL-C水平明显高于对照组(P0.05),2组的ITGB3基因T176C多态性分布差异无统计学意义(P0.05),而ITGA2基因C807T多态性分布差异有统计学意义(P0.05),等位基因频率的相对风险分析发现,T等位基因携带者患AMI的风险是C等位基因的1.608倍(OR=1.608,95% CI:1.194～2.165),携带T等位基因的AMI患者TC水平显著高于未携带T等位基因者(P0.05)。结论 ITGA2基因C807T多态性与AMI的发病具有相关性,其中T等位基因可能是AMI的遗传易感基因;ITGA2基因C807T多态性可能通过影响血脂水平而影响AMI的发生。