胸腺素β4的研究与开发进展

1966年Goldstein等首先从小牛胸腺中提取出促淋巴细胞生成因子，命名为“胸腺素（thymosin）”。1975年Hooper等又进一步提纯到胸腺素组分5，并证明其是30种以上9～50肽的混合物。从此关于胸腺素的研究得以快速发展。胸腺素根据等电点不同可分为α、β、γ三类，其中等电点位于5．0～7．0的为β族胸腺素（β-thymosins，Tβ）。     

In vivo 4-androstene-3,17-dione and 4-androstene-3β,17β-diol supplementation in young men

To determine if known androgenic hormone precursors for testosterone in the androgen pathway would be readily transformed to testosterone, eight male subjects [mean age 23.8 (SEM 3) years, bodymass 83.1 (SEM 8.7) kg, height 175.6 (SEM 8.5) cm] underwent a randomized, double-blind, cross-over, placebo-controlled oral treatment with 200 mg of 4-androstene-3,17-dione (Δ4), 4-androstene-3β,17β-diol (Δ4Diol), and placebo (PL). The periods of study were separated by 7 days of washout. Blood was drawn at baseline and subsequently every 30 min for 90 min after treatment. Analysis revealed mean area-under-the-curve (AUC) serum Δ4 concentrations to be higher during Δ4 treatment [2177 (SEM 100) nmol · l⁻¹] than Δ4Diol [900 (SEM 96) nmol · l⁻¹] or PL [484 (SEM 82) nmol · l⁻¹; P < 0.0001]. The Δ4 treatment also revealed a significant effect on total testosterone with a mean AUC [1632.5 (SEM 121) nmol · l⁻¹] that was greater than PL [1418.5 (SEM 131) nmol · l⁻¹; P < 0.05] but not significantly different from those observed after Δ4Diol treatment [1602.9 (SEM 119) nmol · l⁻¹; P = 0.77]. Free testosterone concentrations followed a similar pattern where mean AUC for the Δ4 treatment [6114.0 (SEM 600) pmol · l⁻¹] was greater than after PL [4974.6 (SEM 565) pmol · l⁻¹; P < 0.06] but not significantly different from those observed after Δ4Diol [5632.0 (SEM 389) pmol · l⁻¹; P = 0.48]. The appearance and apparent conversion to total and free testosterone over 90 min was stronger for the Δ4 treatment (r = 0.91, P < 0.045) than for Δ4Diol treatment (r = 0.69, NS) and negatively correlated for PL (r = −0.90, P < 0.02). These results would suggest that Δ4, and perhaps Δ4Diol, taken by month are capable of producing in vivo increases in testosterone concentrations in apparently healthy young men as has already been observed in women after treatment with Δ4. Accepted: 26 August 1999     

APC-β-catenin-Tcf-4信号转导通路与卵巢癌

APC -β- catenin -Tcf -4信号转导通路异常与卵巢癌的发生发展密切相关。该通路异常主要表现为β- cate nin蛋白在胞浆及胞核内异常积聚、β- catenin编码基因 (CTNNB1)突变、APC基因的突变以及下游靶基因cyclinD1的激活等。对该通路的特点及异常的研究 0将有助于卵巢癌的靶向治疗。     

胸腺素β4促进创伤愈合机制的研究进展

胸腺素β4是由43个氨基酸组成的高度保守的水溶性多肽,存在于除红细胞外的所有真核细胞中.它可以和G-actin结合,抑制F-actin的形成,从而影响细胞骨架,被认为是细胞中主要的肌动蛋白调节因子.细胞外的胸腺素β4有多种生物学功能,包括促进血管生成、加速内皮细胞迁移、调节炎症反应和神经系统发育等.它有可能成为促进角膜、皮肤和心脏创伤愈合的新的治疗药物.     

重症β-海洋性贫血4例遗传特征分析

目的 对畲族居民4例重症β-海洋性贫血患者临床表现，血液学改变，分子生物学及遗传学诸方面进行较系统的分析研究。方法 对浙西南地区畲族居民3465例进行β-海洋性贫血患病状况调查研究，其中4例重症进行全面体格检查，遗传病家谱调查及基因分析所得资料。结果 4例重症者皆有发育迟缓，身材偏小，特殊面容，肝脾肿大。头颅特征性改变，周围血红细胞大小不等，异型、靶型或呈有核红细胞。血红蛋白电泳HbA2，HbF明显增高，遗传病家谱调查后表明：4例重症三代家谱示：先证者世代均为畲族，男女均可发病，代代遗传。分子生物学检测：4例重症均为-28(A-G)／-28(A—G)点突变，为纯合子。结论 畲族居民β-海洋性贫血符合常染色体显性遗传，基因突变类型为转录点突变，应避免族内婚配。     

胃癌及其淋巴转移灶β1,β4亚单位整合素表达的临床意义

胃癌及其淋巴转移灶β１、β４亚单位整合素表达的临床意义许洪卫何金王元和陈泳莲一、材料与方法１．标本采集与处理：２９例手术切除新鲜标本取自１９９４年６月至１９９５年５月间住入我院普通外科的胃癌患者，每例包括原发灶、距癌边缘５ｃｍ以上的邻近正常胃粘膜和可...     

Rotavirus-neutralizing antibodies inhibit virus binding to integrins α2β1 and α4β1

Summary Rotavirus outer capsid proteins VP5^*, VP8^* and VP7 elicit neutralizing, protective antibodies. The α2β1 integrin is a cellular receptor for rotavirus that is bound by VP5^*. Some rotaviruses also recognize the α4β1 integrin. In this study, the effects of antibodies to rotavirus on virus binding to recombinant α2β1 and α4β1 expressed on K562 cells were determined. All neutralizing monoclonal antibodies to VP5^* tested (YO-2C2, 2G4, 1A10) and two to VP7 (RV-3:2, RV-4:2) inhibited rotavirus binding to α2β1. Rotavirus binding to α4β1 was reduced by 2G4 and neutralizing antibody F45:2, directed to VP7. However, a neutralizing antibody to VP8^* (RV-5:2) and one to VP7 (RV-3:1) did not affect rotavirus binding to these integrins. Virus-cell binding was unaffected by non-neutralizing antibody RVA to the rotavirus inner capsid protein VP6. The attachment of human rotavirus strain Wa to these integrins was inhibited by infection sera with neutralizing activity collected from two children hospitalised with severe rotavirus gastroenteritis. A negative reference serum did not affect rotavirus-cell attachment. As the binding of rotaviruses to α2β1 and α4β1 is inhibited by neutralizing antibodies to VP5^* and VP7, and serum from children with rotavirus disease, rotavirus recognition of these integrins may be important for host infection.     

小鼠毛囊再生与胸腺素β4的促进效应

背景:近年来研究表明,胸腺素β4与毛囊的生长发育和毛发的生长周期有着密切关系,但其作用机制尚不清楚。目的:探讨胸腺素β4通过Wnt信号通路作用于毛囊干细胞对毛囊再生的促进作用。方法:将实验小鼠随机分为低剂量胸腺素β4组、高剂量胸腺素β4组和对照组,使用松香/石蜡混合制剂建立脱毛模型。低剂量胸腺素β4组和高剂量胸腺素β4组给药浓度分别为0.3μg/50μL和3μg/50μL,对照组给予等量PBS,每隔12 h给药1次,均匀涂抹于小鼠脱毛背部。应用大体照相、苏木精-伊红染色、免疫组化及原位杂交技术,观察毛发生长情况,检测不同时间点和不同给药浓度下小鼠毛囊根部细胞β-catenin、LEF-1 mRNA的表达水平。结果与结论:低剂量胸腺素β4组毛发再生速度高于高剂量胸腺素β4组和对照组。苏木精-伊红染色显示在脱毛初期,各组小鼠真皮和皮下脂肪层有一定炎性细胞浸润,9 d时,低剂量胸腺素β4组生长期毛囊数量明显多于高剂量胸腺素β4组和对照组。免疫组织化学和原位杂交结果分别显示β-catenin和LEF-1 mRNA主要表达于毛囊隆突部和外根鞘处细胞的胞浆中,经积分吸光度分析发现低剂量胸腺素β4组阳性细胞数量和染色强度高于高剂量胸腺素β4组和对照组(P0.05),高剂量胸腺素β4组与对照组间差异无显著性意义。结果显示低剂量的胸腺素β4可以增加部分毛囊外根鞘处细胞内β-catenin和LEF-1 mRNA的表达。胸腺素β4可以促进毛囊再生的机制可能与影响Wnt信号通路有关。     

T cell-associated α4β7 but not α4β1 integrin is required for the induction and perpetuation of chronic colitis

Anti-adhesion therapies that target α₄ integrins (e.g., natalizumab) are thought to work by blocking T-cell recruitment to the intestinal tissues in patients with Crohn's disease (CD); however, little direct evidence is available to confirm this contention. We wished to evaluate the importance of T cell-associated α₄ integrins in a chronic colitis model in mice and to determine the effect of natalizumab treatment on intestinal tissue T-cell accumulation in human CD. Adoptive transfer of T cells lacking α4 (α₄^−/−) but not β₁ integrin into immunodeficient mice produced significantly attenuated disease. This was correlated with reduced numbers of colon CD4 T cells compared with the control mice; however, tissue distribution of T helper type 1 (Th1) and T helper type 17 (Th17) cells and regulatory T cells (Tregs) was not affected by the lack of α₄. Furthermore, α4^−/− T cells demonstrated defective homing to the chronically inflamed small intestines and colons. Finally, patients treated with natalizumab showed significant reduction in mucosal CD4 T cells and no skewing in the foxp3⁺ Treg or T-bet⁺Th1 fractions thereof. These results demonstrate a direct role for T cell-associated α₄β₇ but not α₄β₁ integrins during initiation and perpetuation of chronic colitis. Moreover, our data demonstrated that natalizumab treatment reduced mucosal CD4 T-cell accumulation in CD patients.     

βA_4在帕金森病大脑皮层中表达的研究

<正> 帕金森病是一种病因不十分清楚的锥体外系退行变性疾病,主要病变为中脑黑质纹状体多巴胺能神经元及通路变性,临床特征为静止性震颤、肌强直和运动迟缓,病程中常伴有痴呆.     

TLR4与β2GPI/抗β2GPI复合物在动脉粥样硬化中的作用研究

<正>动脉粥样硬化(Atherosclerosis,AS)所引起的血栓形成及心血管疾病是目前全世界导致人类死亡的主要原因,对人类的生存和生活质量是一种巨大的威胁和破坏。弗雷明汉研究提出了一系列动脉粥样硬化的危险因素,例如高胆固醇血症、高血压、吸烟、肥胖和家族史等,但这些危险因素已不足以解释该病的发生发展,有关AS的自身免疫因素越来越受到关注。自身免疫性疾病如抗磷脂综合征(An-     

Targeting Integrin α4β7 in Steroid-Refractory Intestinal Graft-versus-Host Disease

Steroid refractory acute graft-versus-host-disease of the gut is a serious complication associated with high mortality after allogeneic stem cell transplantation. Treatment options are limited and not predictably effective. We describe the treatment of steroid-refractory acute graft-versus-host-disease with vedolizumab, an antibody directed against integrin α4β7, in 6 patients. All patients responded, and 4 of 6 patients are alive with a median follow-up of 10 months.     

大鼠气道上皮整合素β4表达随年龄的变化

正整合素β4(integrin β4)是一种介导细胞和其外环境之间连接的跨膜受体,与层黏连蛋白结合可介导上皮细胞与基底膜黏附,是维持气道屏障完整性的重要分子。但是,衰老对其的影响尚不清楚。本研究检测了不同年龄段的大鼠气道上皮整合素β4表达,研究衰老对整合素β4表达的影响。1材料与方法1.1材料:清洁级SD大鼠42只,随机分为6组,分别为     

MAdCAM costimulation through Integrin-α4β7 promotes HIV replication

Human gut-associated lymphoid tissues (GALT) play a key role in the acute phase of HIV infection. The propensity of HIV to replicate in these tissues, however, is not fully understood. Access and migration of naive and memory CD4⁺ T cells to these sites is mediated by interactions between integrin α₄β₇, expressed on CD4⁺ T cells, and MAdCAM, expressed on high endothelial venules. We report here that MAdCAM delivers a potent costimulatory signal to naive and memory CD4⁺ T cells following ligation with α₄β₇. Such costimulation promotes high levels of HIV replication. An anti-α₄β₇ mAb that prevents mucosal transmission of SIV blocks MAdCAM signaling through α₄β₇ and MAdCAM-dependent viral replication. MAdCAM costimulation of memory CD4⁺ T cells is sufficient to drive cellular proliferation and the upregulation of CCR5, while naive CD4⁺ T cells require both MAdCAM and retinoic acid to achieve the same response. The pairing of MAdCAM and retinoic acid is unique to the GALT, leading us to propose that HIV replication in these sites is facilitated by MAdCAM–α₄β₇ interactions. Moreover, complete inhibition of MAdCAM signaling by an anti-α₄β₇ mAb, an analog of the clinically approved therapeutic vedolizumab, highlights the potential of such agents to control acute HIV infection.     

β4整合素在前列腺各组织中的表达及意义

目的　探讨 β4 整合素在前列腺各组织中的表达及意义。方法　将 10 0例诊断明确的前列腺标本分为五组 ,即正常组 (NP)、良性前列腺增生组 (BPH)、高级别上皮内瘤组 (HPIN)、偶发癌组 (PIC)及前列腺癌组 (PC) ,每组 2 0例。应用免疫组化SP法检测 β4 整合素在以上五组标本中的表达情况。结果　β4 整合素在NP、BPH、HPIN、PIC及PC组织中的表达是逐渐降低的 ,BPH组表达明显强于HPIN组 ,其差异有显著意义 (P <0 .0 5 ) ,HPIN组和PIC组的表达无显著差别 (P >0 .0 5 )。结论　β4 整合素与前列腺癌发生、发展密切相关。     

α3β2与α3β4烟碱型乙酰胆碱受体α和β亚基不同配比的药理活性研究

目的:比较α和β亚基不同配比形成α3β2和α3β4烟碱型乙酰胆碱受体(nAChR)敏感性的差异。方法:体外转录获得α和β亚基的cRNA,采用显微注射将3种不同配比(α∶β分别为1∶10、1∶1和10∶1)的cRNA注入非洲爪蟾卵母细胞,利用双电极电压钳检测受体表达情况。利用激动剂乙酰胆碱(ACh)和拮抗剂α-芋螺毒素Reg IIA(α-CTx Reg IIA)检测在3种配比条件下形成受体药理活性的差异。结果:对于α3β2 nAChR亚型,在3种配比情况下,ACh的半数有效浓度(EC50)分别为91.2μmol/L、104.4μmol/L和130.6μmol/L,α-CTx Reg IIA的半数抑制浓度(IC50)分别为40.2 nmol/L、36.4 nmol/L和42.3 nmol/L。对于α3β4 nAChR亚型,在3种配比情况下,ACh的EC50分别为44.0μmol/L、110.0μmol/L和230.0μmol/L,α-CTx Reg IIA的IC50分别为226.8 nmol/L、71.5 nmol/L和49.4 nmol/L。结论:α3和β4亚基比例的改变会导致α3β4 nAChR结构和药理活性的改变。α3和β2亚基比例的改变对α3β2 nAChR结构和活性没有影响。     

Macrophage motility requires distinct α5β1/FAK and α4β1/paxillin signaling events

Macrophages function as key inflammatory mediators at sites of infection and tissue damage. Integrin and growth factor receptors facilitate recruitment of monocytes/macrophages to sites of inflammation in response to numerous extracellular stimuli. We have shown recently that FAK plays a role in regulating macrophage chemotaxis and invasion. As FAK is an established downstream mediator of integrin signaling, we sought to define the molecular circuitry involving FAK and the predominant β1 integrin heterodimers expressed in these cells-α4β1 and α5β1. We show that α4β1 and α5β1 integrins are required for efficient haptotactic and chemotactic invasion and that stimulation of these integrin receptors leads to the adoption of distinct morphologies associated with motility. FAK is required downstream of α5β1 for haptotaxis toward FN and chemotaxis toward M-CSF-1 and downstream of α4β1 for the adoption of a polarized phenotype. The scaffolding molecule paxillin functions independently of FAK to promote chemotaxis downstream of α4β1. These studies expand our understanding of β1 integrin signaling networks that regulate motility and invasion in macrophages and thus, provide important new insights into mechanisms by which macrophages perform their diverse functions.     

βA_4在皮克氏病脑组织中表达的研究

<正> 皮克氏病(Pick’s病)是一种以痴呆为主要表现的神经变性疾病,发病年龄多在50～60岁之间.病理改变为额叶和颞叶萎缩,镜下改变为神经元缺失、胶质细胞增生及出现皮克细胞和皮克小体.临床表现上同AD难以鉴别.病理主要靠发现皮克细胞和皮克小体,但如果没有发现上述特征,即使在病理上也是难以鉴别的.βA_4是由42个氨基酸组成的蛋白质,一直被     

4-苯基丁酸抗内质网应激诱导胰岛β细胞凋亡

目的 探讨4-苯基丁酸（4-PBA）对2型糖尿病（T2DM）大鼠胰岛β细胞内质网应激（ERS）诱导的细胞凋亡的保护作用。方法 高脂饮食喂养加小剂量链脲佐菌素（STZ）腹腔注射建立SD大鼠T2DM模型,造模成功后取其中10只给予4-PBA灌胃20d。放射免疫法检测各组大鼠游离脂肪酸（FFA）、血糖及胰岛素的变化。醛品红染色观察胰岛形态改变,RT-PCR检测内质网相关蛋白（Caspase-3、GRP78、CHOP）的mRNA表达变化。结果 高脂对照组（EM> n/EM>＝10）和T2DM组（ EM>n/EM>＝8）大鼠血清FFA比正常对照组（EM>n/EM>＝10）显著增加,4-PBA治疗后显著下降（ EM>n/EM>＝8）。4-PBA治疗升高了T2DM造成的