• 【C3外切酶对体内外周轴突再生没有影响。】 复制标题 收藏 收藏
    DOI:10.1111/jns5.12004 复制DOI
    作者列表:Auer M,Allodi I,Barham M,Udina E,Neiss WF,Navarro X,Klimaschewski L
    BACKGROUND & AIMS: :Peripheral nerve injury triggers the activation of the small GTPase RhoA in spinal motor and peripheral sensory neurons. C3 transferase, an exoenzyme produced by Clostridium botulinum that inactivates RhoA by ADP-ribosylation, has been successfully applied in central nervous system (CNS) lesion models to facilitate regeneration functionally and morphologically. Until now it has not been demonstrated if C3bot exerts positive effects on peripheral axon regeneration as well. In organotypic spinal cord preparations, C3bot reduced axonal growth of motoneurons, while no effect on sensory axon outgrowth from dorsal root ganglia (DRG) explants was observed. Enzymatically inactive C3E174Q was ineffective in both culture models. Spinal cord slices exhibited a significant increase in microglia/macrophages after treatment with C3bot suggesting an inflammatory component in the inhibition of axon growth. C3bot or C3E174Q were then applied into conduits implanted after transection of the sciatic nerve in rats. Functional evaluation by electrophysiology, nociception, and walking track tests did not show any significant difference between groups with active or mutant C3E174Q . Transmission electron microscopy of the regenerated nerves revealed no significant differences in the number of myelinated and unmyelinated axons 6 weeks after surgery. Compared to the CNS, the functional significance of RhoA may be limited during nerve regeneration in a growth-promoting environment.
    背景与目标: :周围神经损伤触发脊髓运动和周围感觉神经元中小GTPase RhoA的激活。 C3转移酶是由肉毒梭菌产生的一种外切酶,可通过ADP-核糖基化使RhoA失活,已成功应用于中枢神经系统(CNS)病变模型中,以促进功能和形态上的再生。到目前为止,尚未证明C3bot是否也对外周轴突再生产生积极作用。在器官型脊髓制剂中,C3bot减少了运动神经元的轴突生长,而未观察到背根神经节(DRG)外植体对感觉轴突生长的影响。在两种培养模型中,无酶活性的C3E174Q均无效。用C3bot处理后,脊髓切片显示出小胶质细胞/巨噬细胞的显着增加,表明炎性成分可抑制轴突的生长。然后将C3bot或C3E174Q应用于大鼠坐骨神经横切后植入的导管中。通过电生理学,伤害感受和步行试验的功能评估未显示具有活性或突变C3E174Q的组之间的任何显着差异。再生神经的透射电子显微镜显示,术后6周有髓和无髓轴突的数量没有显着差异。与CNS相比,RhoA的功能意义可能在促进生长的环境中的神经再生过程中受到限制。
  • 【希瓦氏菌表达系统中四血红素细胞色素c3的成熟过程。】 复制标题 收藏 收藏
    DOI:10.1093/jb/mvm015 复制DOI
    作者列表:Takayama Y,Shen Y,Akutsu H
    BACKGROUND & AIMS: :The process of maturation of multiheme proteins is not yet well known, while that of monoheme ones has been relatively well investigated. Two kinds of partly unfolded tetraheme cytochrome c3 were obtained on overexpression in Shewanella oneidensis TSP-C. These proteins were characterized by circular dichroism and nuclear magnetic resonance spectroscopy. It turned out that the tetraheme architecture, and the fifth and sixth ligand coordination are almost mature, while some parts of the polypeptide are unfolded. The unfolded residues are mainly located in the helix-rich region including heme attachment and axial ligand sites. This suggests that the formation of the heme architecture, coordination of axial ligands and helix formation should be coupled with each other. While the former two can take place automatically, the helix formation would need help by a chaperone-like function in the cytochrome c maturation (Ccm) machinery. It must be working in sulphate-reducing bacteria. The Ccm machinery in S. oneidensis is likely insufficient to help the maturation of proteins with cyclic heme architectures. This is the first report providing an insight into the process of maturation of tetraheme cytochrome c3.
    背景与目标: :多血红素蛋白的成熟过程尚未广为人知,而单血红素蛋白的成熟过程已得到了比较充分的研究。过度表达在沙瓦氏假单胞菌TSP-C中获得了两种部分未折叠的四血红素细胞色素c3。这些蛋白质通过圆二色性和核磁共振光谱法表征。事实证明,在多肽的某些部分未折叠的情况下,四血红素的结构以及第五和第六配体的配位几乎已经成熟。未折叠的残基主要位于富含血红素的区域,包括血红素附着和轴向配体位点。这表明血红素结构的形成,轴向配体的配位和螺旋的形成应相互耦合。虽然前两个可以自动发生,但是螺旋的形成将需要细胞色素成熟(Ccm)机制中的类似伴侣分子的功能来帮助。它必须在减少硫酸盐的细菌中起作用。拟南芥中的Ccm机制可能不足以帮助具有环状血红素结构的蛋白质成熟。这是第一份报告,深入介绍了四血红素细胞色素c3的成熟过程。
  • 【人补体成分C3的多肽片段在大肠杆菌中的表达:对C3的α链具有特异性的cDNA克隆的遗传和免疫学表征。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Ma D,Sessler MJ,Meyer TF,Schrod L,Hänsch GM,Burger R
    BACKGROUND & AIMS: :The third component of complement C3 and its fragments have a central role in a variety of host defense mechanisms. The identification of functionally relevant C3 domains is important because of the marked functional versatility of the C3 molecule. Several human C3 cDNA clones from a human liver cDNA library were isolated and characterized. A bacterial expression vector system was used to express cDNA clones that were identified by an immunological screening procedure. The C3 cDNA clones produced in E. coli the hybrid proteins consisting of cro-beta-galactosidase and polypeptide segments of human C3, as revealed by Western blotting with antisera to human C3. The C3 moiety of the hybrid proteins had a m.w. of up to 46.000. Polyclonal antibodies against the C3 segments expressed by one of the C3 cDNA clones (ReC3-1) have been raised in mice and rabbit, and in addition, a monoclonal antibody was produced. The antisera and the monoclonal antibody reacted in Western blotting analysis selectively with the alpha-chain, but not the beta-chain of human C3. Restriction mapping of the different cDNA clones was performed, and revealed that the different clones were partially overlapping. The ReC3-1 cDNA clone included a 0.7 kb noncoding region at the 3' terminal end of the C3 cDNA. One of the restriction sites (Hind III) identified in the ReC3-1 cDNA clone was not present in the recently published sequence of human C3 cDNA. This difference in nucleotide sequence provides direct evidence for C3 polymorphism at the DNA level. The combination of immunologic procedures with recombinant DNA methodology should facilitate additional analysis of the structure-function relationship of the C3 molecule.
    背景与目标: 补体C3的第三部分及其片段在多种宿主防御机制中起着核心作用。由于C3分子具有明显的功能多样性,因此对功能相关的C3域的鉴定非常重要。从人肝脏cDNA文库中分离出几个人C3 cDNA克隆并进行了表征。使用细菌表达载体系统表达通过免疫筛选程序鉴定的cDNA克隆。 C3 cDNA克隆在大肠杆菌中产生了杂种蛋白质,该杂种蛋白质由cro-β-半乳糖苷酶和人C3的多肽片段组成,这是通过对人C3的抗血清进行Western印迹证实的。杂合蛋白的C3部分具有m.w。高达46.000。已经在小鼠和兔子中产生了针对由C3 cDNA克隆之一(ReC3-1)表达的C3节段的多克隆抗体,并且还产生了单克隆抗体。抗血清和单克隆抗体在Western印迹分析中与人C3的α链(而非β链)选择性反应。进行了不同cDNA克隆的限制性作图,并揭示了不同克隆部分重叠。 ReC3-1 cDNA克隆在C3 cDNA的3'末端包含一个0.7 kb的非编码区。 ReC3-1 cDNA克隆中鉴定出的一个限制性酶切位点(Hind III)在最近发布的人C3 cDNA序列中不存在。核苷酸序列的这种差异为DNA水平的C3多态性提供了直接证据。免疫程序与重组DNA方法的结合应有助于对C3分子的结构-功能关系进行额外的分析。
  • 【基于倾向评分匹配的血清C3 / C4比值与免疫球蛋白A肾病预后的关系。】 复制标题 收藏 收藏
    DOI:10.1097/CM9.0000000000000674 复制DOI
    作者列表:Zhang Y,Duan SW,Chen P,Yin Z,Wang Y,Cai GY,Chen XM
    BACKGROUND & AIMS: BACKGROUND:Aberrant activation of the complement system plays an important role in the pathogenesis and development of immunoglobulin A nephropathy (IgAN). The relationship between serum complement and the clinical-histopathological features and outcomes of IgAN is controversial. This retrospective study aimed to examine the relationship between the complement 3/4 (C3/C4) ratio and the clinicopathologic changes and prognosis of patients with IgAN. METHODS:A total of 397 patients with primary IgAN from January 2007 to December 2012 at the Chinese People's Liberation Army General Hospital were included in this study. The correlation test and Chi-square test or one-way analysis of variance test were performed to evaluate the relationship between the C3/C4 ratio and other clinical-pathological factors. Propensity score matching and a multivariate Cox regression model were used to calculate the risk factors of renal outcome. RESULTS:The median follow-up period was 75 months. During the follow-up period, 62 patients (15.6%) developed into the end-stage renal disease (ESRD). The C3/C4 ratio at baseline was associated with the level of serum creatinine (SCr), 24 h urinary protein excretion (24 h Upre), global glomerular sclerosis, and tubulointerstitial lesion. The level of SCr and 24 h Upre and the degree of chronic kidney injury were statistically different among groups defined by different C3/C4 ratio levels. The survival rates of patients among groups with different C3/C4 ratio levels were different. After propensity score matching, eighty-eight pairs of patients were successfully matched, and the C3/C4 ratio was an influencing factor for the patients' outcome (hazard ratio 0.587, 95% confidence interval 0.329-0.880). Patients with a C3/C4 ratio <3.6 had a poorer outcome compared with the others (P = 0.002). CONCLUSIONS:IgAN patients with decreased C3/C4 ratio displayed significantly more severe clinical symptoms and chronic renal injury than patients with higher ratios. A low C3/C4 ratio could be a risk factor for patients developing to ESRD.
    背景与目标: 背景:补体系统的异常激活在免疫球蛋白A肾病(IgAN)的发病和发展中起着重要作用。血清补体与IgAN的临床组织病理学特征和预后之间的关系尚存争议。这项回顾性研究旨在探讨IgAN患者补体3/4(C3 / C4)比率与临床病理变化和预后之间的关系。
    方法:纳入2007年1月至2012年12月在中国人民解放军总医院的397例原发性IgAN患者。进行相关检验和卡方检验或方差检验的单向分析,以评估C3 / C4比率与其他临床病理因素之间的关系。倾向得分匹配和多元Cox回归模型用于计算肾脏预后的危险因素。
    结果:中位随访期为75个月。在随访期间,有62名患者(15.6%)患上了晚期肾病(ESRD)。基线时的C3 / C4比值与血清肌酐(SCr),24 h尿蛋白排泄(24 h Upre),总体肾小球硬化和肾小管间质病变的水平有关。在不同的C3 / C4比水平所定义的组之间,SCr和24 h Upre的水平以及慢性肾脏损伤的程度在统计学上是不同的。不同C3 / C4比率水平的组之间患者的存活率是不同的。倾向得分匹配后,成功匹配了88对患者,C3 / C4比是影响患者预后的因素(危险比0.587,95%置信区间0.329-0.880)。 C3 / C4比<3.6的患者的预后较其他患者差(P = 0.002)。
    结论:C3 / C4比值降低的IgAN患者比高比值的患者表现出更严重的临床症状和慢性肾损伤。 C3 / C4比率低可能是发展为ESRD患者的危险因素。
  • 【9-Cis-视黄酸通过类视黄醇X受体α和复制因子C3诱导类视黄醇敏感的乳腺癌和海胆胚胎细胞的生长抑制。】 复制标题 收藏 收藏
    DOI:10.1210/me.2012-1104 复制DOI
    作者列表:Maeng S,Kim GJ,Choi EJ,Yang HO,Lee DS,Sohn YC
    BACKGROUND & AIMS: :There is widespread interest in defining factors and mechanisms that suppress the proliferation of cancer cells. Retinoic acid (RA) is a potent suppressor of mammary cancer and developmental embryonic cell proliferation. However, the molecular mechanisms by which 9-cis-RA signaling induces growth inhibition in RA-sensitive breast cancer and embryonic cells are not apparent. Here, we provide evidence that the inhibitory effect of 9-cis-RA on cell proliferation depends on 9-cis-RA-dependent interaction of retinoid X receptor α (RXRα) with replication factor C3 (RFC3), which is a subunit of the RFC heteropentamer that opens and closes the circular proliferating cell nuclear antigen (PCNA) clamp on DNA. An RFC3 ortholog in a sea urchin cDNA library was isolated by using the ligand-binding domain of RXRα as bait in a yeast two-hybrid screening. The interaction of RFC3 with RXRα depends on 9-cis-RA and bexarotene, but not on all-trans-RA or an RA receptor (RAR)-selective ligand. Truncation and mutagenesis experiments demonstrated that the C-terminal LXXLL motifs in both human and sea urchin RFC3 are critical for the interaction with RXRα. The transient interaction between 9-cis-RA-activated RXRα and RFC3 resulted in reconfiguration of the PCNA-RFC complex. Furthermore, we found that knockdown of RXRα or overexpression of RFC3 impairs the ability of 9-cis-RA to inhibit proliferation of MCF-7 breast cancer cells and sea urchin embryogenesis. Our results indicate that 9-cis-RA-activated RXRα suppresses the growth of RA-sensitive breast cancer and embryonic cells through RFC3.
    背景与目标: :人们对确定抑制癌细胞增殖的因素和机制有着广泛的兴趣。维甲酸(RA)是一种有效的乳癌抑制因子,可抑制发育性胚胎细胞的增殖。但是,尚不清楚9-顺式-RA信号传导在RA敏感的乳腺癌和胚胎细胞中诱导生长抑制的分子机制。在这里,我们提供证据表明9-顺式-RA对细胞增殖的抑制作用取决于类视色素X受体α(RXRα)与复制因子C3(RFC3)的9-顺式-RA依赖性相互作用,而后者是该蛋白的一个亚基。 RFC异戊二烯,可打开和关闭DNA上的环状增殖细胞核抗原(PCNA)钳。通过使用RXRα的配体结合域作为诱饵,在酵母双杂交筛选中分离出海胆cDNA文库中的RFC3直系同源物。 RFC3与RXRα的相互作用取决于9-顺式-RA和贝沙罗汀,但不取决于全反式-RA或RA受体(RAR)选择性配体。截短和诱变实验表明,人和海胆RFC3中的C末端LXXLL基序对于与RXRα的相互作用至关重要。 9-顺式-RA激活的RXRα和RFC3之间的瞬时相互作用导致PCNA-RFC复合体的重新配置。此外,我们发现敲低RXRα或RFC3的过度表达会削弱9-顺式-RA抑制MCF-7乳腺癌细胞增殖和海胆胚胎发生的能力。我们的结果表明9-顺式-RA激活的RXRα通过RFC3抑制了RA敏感的乳腺癌和胚胎细胞的生长。
  • 【含有P3的C3'-内折叠的吡咯烷对RNA结合具有良好的几何结构:新型的乙醇锁定PNA(乙醇-PNA)。】 复制标题 收藏 收藏
    DOI:10.1016/j.bmc.2013.05.015 复制DOI
    作者列表:Banerjee A,Kumar VA
    BACKGROUND & AIMS: :A novel peptide nucleic acid (PNA) analogue is designed with a constraint in the aminoethyl segment of the aegPNA backbone so that the dihedral angle β is restricted within 60-80°, compatible to form PNA:RNA duplexes. The designed monomer is further functionalized with positively charged amino-/guanidino-groups. The appropriately protected monomers were synthesized and incorporated into aegPNA oligomers at predetermined positions and their binding abilities with cDNA and RNA were investigated. A single incorporation of the modified PNA monomer into a 12-mer PNA sequence resulted in stronger binding with complementary RNA over cDNA. No significant changes in the CD signatures of the derived duplexes of modified PNA with complementary RNA were observed.
    背景与目标: :设计了一种新的肽核酸(PNA)类似物,其在aegPNA主链的氨乙基片段中具有限制,使得二面角β被限制在60-80°内,从而形成PNA:RNA双链体。设计的单体被带正电荷的氨基/胍基进一步官能化。合成适当保护的单体,并在预定位置将其掺入aegPNA低聚物中,并研究其与cDNA和RNA的结合能力。将修饰的PNA单体单次掺入12聚体PNA序列中会导致与互补RNA的结合力强于cDNA。没有观察到修饰的PNA与互补RNA的衍生双链体的CD标记的显着变化。
  • 【黏附依赖性从人血粒细胞和单核细胞释放肝细胞生长因子和白介素-1受体拮抗剂:血浆IgG,补体C3和β2整联蛋白参与的证据。】 复制标题 收藏 收藏
    DOI:10.1007/s00011-004-1253-5 复制DOI
    作者列表:Takeda Y,Shiobara N,Saniabadi AR,Adachi M,Hiraishi K
    BACKGROUND & AIMS: OBJECTIVE:Evolving evidence of anti-inflammatory effects is observed in patients with rheumatoid arthritis or ulcerative colitis following periodic adsorptive granulocyte and monocyte (GM) apheresis with a column containing cellulose acetate (CA) beads as apheresis carriers. This study was undertaken to obtain insights into mechanisms of anti-inflammatory actions of adsorptive GM apheresis with CA beads. METHODS:In a series of in-vitro experiments, we investigated the effects of plasma proteins and the leucocytes beta2 integrin (CD18) on granulocyte adsorption to CA beads. RESULTS:Granulocyte adsorption to CA beads required plasma IgG, the complement C3 and was inhibited by an antibody to leucocytes CD18. Further, hepatocyte growth factor (HGF) and interleukin-1 receptor antagonist (IL-1ra) which have strong anti-inflammatory actions were released by granulocytes that adhered to CA beads. CONCLUSIONS:Plasma IgG, C3 derived complement activation fragments and leucocytes CD18 are involved in granulocyte adhesion to CA beads and hence the release of HGF and IL-1ra.
    背景与目标: 目的:观察到类风湿性关节炎或溃疡性结肠炎患者在定期吸收性粒细胞和单核细胞(GM)血液采血后,使用醋酸纤维素(CA)珠作为血液采血载体的色谱柱,具有抗炎作用的不断发展的证据。进行这项研究是为了获得对带有CA珠粒的吸附性GM血液单采的抗炎作用机制的见解。
    方法:在一系列体外实验中,我们研究了血浆蛋白和白细胞β2整合素(CD18)对粒细胞吸附CA珠的影响。
    结果:粒细胞吸附到CA珠上需要血浆IgG,补体C3,并被白细胞CD18抗体抑制。此外,附着于CA珠的粒细胞释放出具有强抗炎作用的肝细胞生长因子(HGF)和白介素-1受体拮抗剂(IL-1ra)。
    结论:血浆IgG,C3衍生的补体激活片段和白细胞CD18参与粒细胞与CA珠的粘附,并因此释放HGF和IL-1ra。
  • 【原发性肾小球肾炎合并C3沉积:这是一个与溶血性尿毒症综合征共有常见遗传危险因素的新实体。】 复制标题 收藏 收藏
    DOI:10.1136/jmg.2006.045328 复制DOI
    作者列表:Servais A,Frémeaux-Bacchi V,Lequintrec M,Salomon R,Blouin J,Knebelmann B,Grünfeld JP,Lesavre P,Noël LH,Fakhouri F
    BACKGROUND & AIMS: INTRODUCTION:Abnormal control of the complement alternative pathway (CAP) (factor H, factor I and membrane cofactor protein (MCP) deficiencies) is a well established risk factor for the occurrence of haemolytic uraemic syndrome (HUS). In some instances, HUS may be associated with an unusual glomerulonephritis with isolated C3 deposits (glomerulonephritis C3). We determined whether HUS and glomerulonephritis C3 share common genetic susceptibility factors. METHODS:We identified 19 patients with glomerulonephritis C3. We measured levels of circulating complement components, performed assays for the detection of C3 nephritic factor (C3NeF) and screened factor H, factor I and MCP coding genes for the presence of mutations. RESULTS:Patients were divided in two groups based on renal pathology findings: group I (n = 13) had typical features of type I membranoproliferative glomerulonephritis (glomerulonephritis C3 with membranoproliferative glomerulonephritis (MPGN)) and group II (n = 6) was characterised by mesangial and epimembranous C3 deposits in the absence of mesangial proliferation (glomerulonephritis C3 without MPGN). Mutations in complement regulatory genes were detected in 4/6 patients with glomerulonephritis C3 without MPGN (heterozygous mutations in factor H gene (two patients) with low factor H antigenic level in one case, heterozygous mutations in factor I gene (two patients)) and in only 2/13 patients with glomerulonephritis C3 with MPGN (heterozygous mutations in factor H gene (one patient) and double heterozygous mutation in CD 46 gene (one patient)). In contrast, C3NeF was present in 5/13 patients with glomerulonephritis C3 with MPGN and in 2/6 patients with glomerulonephritis C3 without MPGN, one of whom had a factor H mutation. CONCLUSION:HUS and glomerulonephritis C3 without MPGN share common genetic risk factors. Constitutional or acquired dysregulation of the CAP is probably associated with a wide spectrum of diseases, ranging from HUS to glomerulonephritis C3 with MPGN.
    背景与目标: 简介:补体旁路途径(CAP)(H因子,I因子和膜辅因子蛋白(MCP)缺陷)的异常控制是溶血性尿毒症综合征(HUS)发生的公认危险因素。在某些情况下,HUS可能与不寻常的肾小球肾炎相关,伴有孤立的C3沉积物(C3肾小球肾炎)。我们确定了HUS和C3肾小球肾炎是否具有共同的遗传易感性因素。
    方法:我们确定了19例C3型肾小球肾炎患者。我们测量了循环补体成分的水平,进行了检测C3肾病因子(C3NeF)的检测,并筛选了H因子,I因子和MCP编码基因是否存在突变。
    结果:根据肾脏病理结果将患者分为两组:第一组(n = 13)具有典型的I型膜肺增生性肾小球肾炎(C3肾小球性肾炎和膜肺增生性肾小球肾炎(MPGN)),第二组(n = 6)的特征是肾小球膜和膜上C3沉积,而没有肾小球膜增生(无MPGN的肾小球性肾炎C3)。在没有MPGN的4/6例C3肾小球性肾炎患者中检测到补体调节基因突变(H因子基因杂合突变(两名患者),H因子抗原水平低(一例),I因子基因杂合突变(两例)和仅2/13例MPGN肾小球性肾炎C3患者(H因子杂合突变(一名患者)和CD 46基因双杂合突变(一名患者))。相比之下,C3NeF存在于5/13患有MPGN的C3肾小球性肾炎和2/6没有MPGN的C3肾小球性肾炎的患者中,其中一名患有H因子突变。
    结论:HUS和无MPGN的C3肾小球肾炎具有共同的遗传危险因素。 CAP的体质性或获得性失调可能与多种疾病有关,从HUS到MPGN的肾小球性肾炎C3。
  • 【在哺乳动物细胞细菌入侵过程中,来自金黄色葡萄球菌的C3-Like ADP-核糖基转移酶的定位。】 复制标题 收藏 收藏
    DOI:10.1128/IAI.02013-05 复制DOI
    作者列表:Molinari G,Rohde M,Wilde C,Just I,Aktories K,Chhatwal GS
    BACKGROUND & AIMS: :The C3stau2 exoenzyme from Staphylococcus aureus is a C3-like ADP-ribosyltransferase which possesses no specific receptor-binding domain or translocation unit required for entry in target cells where its substrate is located. Here we show that C3stau2 can reach its target after invasion of staphylococci in eukaryotic cells without needing translocation.
    背景与目标: :来自金黄色葡萄球菌的C3stau2外切酶是一种C3样的ADP-核糖基转移酶,它不具有进入其底物所在的靶细胞所需的特异性受体结合域或易位单元。在这里,我们显示C3stau2可以在葡萄球菌入侵真核细胞后达到其目标,而无需转运。
  • 【心脏同种异体移植物中补体C3的双相表达和细胞因子调节。】 复制标题 收藏 收藏
    DOI:10.1016/j.trim.2010.10.004 复制DOI
    作者列表:Wu W,Wang HD,He P,Zhang YJ,Yang K,Hua X
    BACKGROUND & AIMS: :Locally synthesized complement may play a more important role in regulating antigen-specific immune response than circulating complement; however, complement production in transplanted heart remains obscure. In the current study, we investigated local production of the complement C3 in mouse cardiac allografts and examined the relationship between C3 production and cytokine expression. The cardiac grafts of allogeneic (C57BL/6-BALB/c mice) and syngeneic mouse models were subjected to histopathological and immunohistochemical analyses for C3 expression on days 0-6 after operation. mRNA and protein expression of C3, IL-2, IFN-γ in transplanted heart and primary culture cardiomyocytes were analyzed. Our results demonstrated that C3 mRNA exhibited biphasic patterns in transplanted heart. The first expression phase correlated with ischemical reperfusion injury over 2 days post-transplant. The second peak of C3 deposition was found only in allografts on day 5, concurrent with the secretion of IL-2 and IFN-γ accompanied by severe diffuse leukocyte infiltration. Furthermore, in vitro studies showed that IL-2 and IFN-γ enhanced C3 mRNA and protein production in cardiocytes. Together, these observations suggest that both ischemical reperfusion injury and the subsequent acute rejection result in elevated cardiocyte secretion of C3, and the second phase of expression appears to be regulated by cytokines secreted by the infiltrating cells.
    背景与目标: :局部合成的补体可能比循环补体在调节抗原特异性免疫应答中起更重要的作用;但是,移植心脏中补体的产生仍然不清楚。在当前的研究中,我们调查了小鼠心脏同种异体移植物中补体C3的局部产生,并研究了C3产生与细胞因子表达之间的关系。在手术后0-6天,对同种异体(C57BL / 6-BALB / c小鼠)和同系小鼠模型的心脏移植物进行C3表达的组织病理学和免疫组化分析。分析了移植心脏和原代培养心肌细胞中C3,IL-2,IFN-γ的mRNA和蛋白表达。我们的结果表明,C3 mRNA在移植心脏中表现出双相模式。第一个表达阶段与移植后2天内的缺血性再灌注损伤相关。 C3沉积的第二个高峰仅在第5天的同种异体移植中发现,并伴有IL-2和IFN-γ的分泌,并伴有严重的弥漫性白细胞浸润。此外,体外研究表明,IL-2和IFN-γ增强了心肌细胞中C3 mRNA和蛋白质的产生。总之,这些观察结果表明,缺血再灌注损伤和随后的急性排斥反应均导致C3的心肌细胞分泌增加,并且表达的第二阶段似乎受浸润细胞分泌的细胞因子的调节。
  • 【ras相关的C3肉毒毒素底物1和p21激活的激酶1的表达增加对N0M0上尿路尿路上皮癌和无癌手术切缘患者的影响。】 复制标题 收藏 收藏
    DOI:10.1093/jjco/hyz155 复制DOI
    作者列表:Kuroda K,Asano T,Horiguchi A,Ito K
    BACKGROUND & AIMS: BACKGROUND:As a member of the Rho small guanosine triphosphatase family, ras-related C3 botulinum toxin substrate 1 (RAC1) interacts with various specific effectors, and p21-activated kinase 1 (PAK1), which has a role in both carcinogenesis and cellular invasion, binds to RAC1, after which activated PAK1 regulates cellular functions. There have been few reports about the simultaneous analysis of RAC1 and its downstream effector PAK1 in upper urinary tract urothelial carcinoma (UTUC). We assessed the expressions of both RAC1 and PAK1 and evaluated their association with clinicopathological parameters. METHODS:Immunohistochemical studies of RAC1 or PAK1 were performed with specimens from 104 patients with N0M0 UTUC and cancer-free surgical margins. Correlation of the positive expression of RAC1 or PAK1 or both with clinicopathological parameters was evaluated. RESULTS:A hazard model showed that the presence of mixed histologic features and moderate or strong positive expression of both RAC1 and PAK1 were independent factors for shortened disease-specific survival time (Ps = 0.041 and 0.016, respectively), and another hazard model revealed that only moderate or strong positive expression of both RAC1 and PAK1 was an independent factor for shortened recurrence-free survival time in the multivariate analysis (P = 0.036). Neither moderate or strong positive expression of RAC1 alone nor moderate or strong positive expression of PAK1 alone was an independent factor for a worse rate of disease-specific or recurrence-free survival in multivariate analysis. CONCLUSIONS:Patients with N0M0 UTUC, cancer-free surgical margins and moderate or strong positive expression of both RAC1 and PAK1 should be carefully monitored after surgery.
    背景与目标: 背景:作为Rho小鸟苷三磷酸酶家族的成员,与ras相关的C3肉毒毒素底物1(RAC1)与各种特定的效应子以及p21激活的激酶1(PAK1)相互作用,后者在致癌作用和细胞侵袭中均起作用,与RAC1绑定,之后激活的PAK1调节细胞功能。尚无关于同时分析RAC1及其下游效应物PAK1在上尿路尿路上皮癌(UTUC)中的报道。我们评估了RAC1和PAK1的表达,并评估了它们与临床病理参数的关联。
    方法:采用104例N0M0 UTUC和无癌手术切缘患者的标本对RAC1或PAK1进行免疫组织化学研究。评估了RAC1或PAK1或两者的阳性表达与临床病理参数的相关性。
    结果:一个危害模型表明,RAC1和PAK1的混合组织学特征以及中度或强阳性表达的存在是缩短疾病特异性生存时间的独立因素(分别为Ps = 0.041和0.016),另一个危害模型表明在多变量分析中,只有RAC1和PAK1的中度或强阳性表达是缩短无复发生存时间的独立因素(P = 0.036)。在多变量分析中,单独的RAC1的中度或强阳性表达或单独的PAK1的中度或强阳性表达都不是导致疾病特异性或无复发生存率降低的独立因素。
    结论:手术后应仔细监测N0M0 UTUC,无癌手术切缘以及RAC1和PAK1的中度或强阳性表达的患者。
  • 【C3缺陷型小鼠移植物抗宿主疾病的减少与供体Th1 / Th17分化的减少有关。】 复制标题 收藏 收藏
    DOI:10.1016/j.bbmt.2012.05.014 复制DOI
    作者列表:Ma Q,Li D,Nurieva R,Patenia R,Bassett R,Cao W,Alekseev AM,He H,Molldrem JJ,Kroll MH,Champlin RE,Sale GE,Afshar-Kharghan V
    BACKGROUND & AIMS: :Graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation is mediated by the activation of recipient dendritic cells and subsequent proliferation of donor T cells. The complement system was recently shown to modulate adaptive immunity through an interaction of the complement system and lymphocytes. Complement proteins participate in the activation of dendritic cells, antigen presentation to T cells, and proliferation of T cells. Our studies with a murine model of bone marrow transplantation demonstrate that complement system regulates alloimmune responses in GVHD. Mice deficient in the central component of the complement system (C3(-/-)) had significantly lower GVHD-related mortality and morbidity compared with wild-type recipient mice. The numbers of donor-derived T cells, including IFN-γ(+), IL-17(+), and IL-17(+)IFN-γ(+) subsets, were decreased in secondary lymphoid organs of C3(-/-) recipients. Furthermore, the number of recipient CD8α(+)CD11c(+) cells in lymphoid organs was reduced. We conclude that C3 regulates Th1/17 differentiation in bone marrow transplantation, and define a novel function of the complement system in GVHD.
    背景与目标: :同种异体造血干细胞移植后的移植物抗宿主病(GVHD)是由受体树突状细胞的激活和供体T细胞的随后增殖介导的。最近显示补体系统通过补体系统和淋巴细胞的相互作用来调节适应性免疫。补体蛋白参与树突状细胞的活化,向T细胞的抗原呈递以及T细胞的增殖。我们对小鼠骨髓移植模型的研究表明补体系统调节GVHD中的同种免疫反应。与野生型受体小鼠相比,补体系统中央成分(C3(-/-))缺乏的小鼠的GVHD相关死亡率和发病率显着降低。在C3(-/-)受者的次级淋巴器官中,包括IFN-γ(),IL-17()和IL-17()IFN-γ()亚群的供体来源T细胞数量减少。此外,减少了淋巴器官中的受体CD8α()CD11c()细胞的数量。我们得出结论,C3调节骨髓移植中的Th1 / 17分化,并定义GVHD中补体系统的新功能。
  • 【操纵介体:在健康,疾病和治疗中调节替代补体途径C3转化酶。】 复制标题 收藏 收藏
    DOI:10.1016/j.imbio.2012.07.016 复制DOI
    作者列表:Ricklin D
    BACKGROUND & AIMS: :The complement network is increasingly recognized as an important triage system that is able to differentiate between healthy host cells, microbial intruders, cellular debris and immune complexes, and tailor its actions accordingly. At the center of this triage mechanism is the alternative pathway C3 convertase (C3bBb), a potent enzymatic protein complex capable of rapidly converting the inert yet abundant component C3 into powerful effector fragments (C3a and C3b), thereby amplifying the initial response on unprotected surfaces and inducing a variety of effector functions. A fascinating molecular mechanism of convertase assembly and intrinsic regulation, as well as the interplay with a panel of cell surface-bound and soluble inhibitors are essential for directing complement attack to intruders and protecting healthy host cells. While efficiently keeping immune surveillance and homeostasis on track, the reliance on an intricate cascade of interaction and conversion steps also renders the C3 convertase vulnerable to derail. On the one hand, tissue damage, accumulation of debris, or polymorphisms in complement genes may unfavorably shift the balance between activation and regulation, thereby contributing to a variety of clinical conditions. On the other hand, pathogens developed powerful evasion strategies to avoid complement attack by targeting the convertase. Finally, we increasingly challenge our bodies with foreign materials such as biomaterial implants or drug delivery vehicles that may induce adverse effects that are at least partially caused by complement activation and amplification via the alternative pathway. The involvement of the C3 convertase in a range of pathological conditions put this complex into the spotlight of complement-targeted drug discovery efforts. Fortunately, the physiological regulation and microbial evasion approaches provide a rich source of inspiration for the development of powerful treatment options. This review provides insight into the current knowledge about the molecular mechanisms that drive C3 convertase activity, reveals common and divergent strategies of convertase inhibition employed by host and pathogens, and how this inhibitory arsenal can be tapped for developing therapeutic options to treat complement-related diseases.
    背景与目标: 补体网络日益被认为是一种重要的分类系统,能够区分健康的宿主细胞,微生物入侵者,细胞碎片和免疫复合物,并据此调整其作用。这种分类机制的中心是替代途径C3转化酶(C3bBb),这是一种有效的酶蛋白复合物,能够将惰性而丰富的组分C3快速转化为强大的效应子片段(C3a和C3b),从而放大未保护表面上的初始反应并诱导各种效应子功能。令人着迷的转化酶组装和内在调节的分子机制,以及与一系列细胞表面结合和可溶性抑制剂的相互作用,对于将补体攻击引向入侵者和保护健康的宿主细胞至关重要。在有效地保持免疫监控和体内稳态的同时,对复杂的相互作用和转化步骤的依赖也使C3转化酶容易脱轨。一方面,补体基因中的组织损伤,碎片堆积或多态性可能不利地改变了激活与调节之间的平衡,从而导致了多种临床状况。另一方面,病原体发展了强大的逃避策略,通过靶向转化酶来避免补体攻击。最后,我们越来越多地用异物(例如生物材料植入物或药物输送媒介)挑战人体,这些异物可能会引起不良反应,这些不良反应至少部分是由补体激活和通过替代途径扩增引起的。 C3转化酶在一系列病理条件下的参与使这种复合物成为补体靶向药物发现努力的焦点。幸运的是,生理调节和微生物逃逸方法为开发强大的治疗选择提供了丰富的灵感来源。这篇综述提供了有关驱动C3转化酶活性的分子机制的当前知识的洞察力,揭示了宿主和病原体采用的抑制转化酶的常见和不同策略,以及如何利用这种抑制性阿森纳来开发治疗补体相关疾病的治疗方案。
  • 【C3-杂芳酰基大麻素作为CB2大麻素受体的光标记配体。】 复制标题 收藏 收藏
    DOI:10.1016/j.bmcl.2012.06.013 复制DOI
    作者列表:Dixon DD,Tius MA,Thakur GA,Zhou H,Bowman AL,Shukla VG,Peng Y,Makriyannis A
    BACKGROUND & AIMS: :A series of tricyclic cannabinoids incorporating a heteroaroyl group at C3 were prepared as probes to explore the binding site(s) of the CB1 and CB2 receptors. This relatively unexplored structural motif is shown to be CB2 selective with K(i) values at low nanomolar concentrations when the heteroaromatic group is 3-benzothiophenyl (41) or 3-indolyl (50). When photoactivated, the lead compound 41 was shown to successfully label the CB2 receptor through covalent attachment at the active site while 50 failed to label. The benzothiophenone moiety may be a photoactivatable moiety suitable for selective labeling.
    背景与目标: :准备了一系列在C3处掺有杂芳基的三环大麻素作为探针,以探索CB1和CB2受体的结合位点。当杂芳族基团是3-苯并噻吩基(41)或3-吲哚基(50)时,该相对未开发的结构基序在低纳摩尔浓度下具有K(i)值,具有CB2选择性。光活化后,铅化合物41已显示出通过活性位点上的共价连接成功标记了CB2受体,而50个未标记。苯并噻吩酮部分可以是适合于选择性标记的可光活化部分。
  • 【重度,病态和极度肥胖患者的C3水平:其与胰岛素抵抗和不同心血管危险因素的关系。】 复制标题 收藏 收藏
    DOI:10.1038/sj.ijo.0803543 复制DOI
    作者列表:Hernández-Mijares A,Jarabo-Bueno MM,López-Ruiz A,Solá-Izquierdo E,Morillas-Ariño C,Martínez-Triguero ML
    BACKGROUND & AIMS: OBJECTIVE:Increased C3 has been related to body mass index (BMI) and insulin resistance, although there are not sufficient studies in subjects with morbid obesity. The purpose of this study was to evaluate the levels of C3 as a function of the BMI in subjects of both sexes, with severe, morbid and extreme obesity, and their possible relationship to insulin resistance or associated diseases such as diabetes, hypertension and dyslipidemia. SUBJECTS:The study included a total of 316 patients (110 men and 206 women) with severe obesity (17.1%), morbid obesity (54.4%) and extreme obesity (28.4%), with an average BMI of 46.70+/-7.37 kg/m2. MEASUREMENTS:The glucose and insulin levels were determined baseline, and 2 h after a 75 g of oral glucose load. The homeostasis model of assessment for insulin resistance (HOMA-IR) was calculated. A lipid profile (total cholesterol, triglycerides, high-density lipoprotein cholesterol, apolipoprotein AI and apolipoprotein B100) was obtained and C3 levels determined by nephelometry. RESULTS:When distributing the patients by quartiles of BMI, we found a progressive increase in the levels of C3, and no significant differences in the rest of analytical variables studied were found; the mean values of C3 were 127.78+/-29.7 mg/dl.A significant correlation was found between C3 and the BMI (r=0.263, P<0.001), baseline insulin (r=0.237, P=0.001) and HOMA-IR (r=0.237, P=0.001). High blood pressure was found in 111 patients, type 2 diabetes in 74 patients and dyslipidemia in 139 cases. When distributing the levels of C3 according to the number of associated risk factors (hypertension, diabetes and dyslipidemia), we found significant differences between these patients and those who presented no associated diseases (P<0.01). CONCLUSION:A relationship between C3 and the progressive increase of BMI in subjects with severe, morbid or extreme obesity was established. This increase in C3 was closely related to insulin levels and the values for HOMA-IR. Furthermore, we also found an increase in C3 as more diseases related to insulin resistance, such as diabetes, hypertension and dyslipidemia, were associated with the obesity.
    背景与目标: 目的:尽管对于病态肥胖的受试者尚无足够的研究,但C3升高与体重指数(BMI)和胰岛素抵抗有关。这项研究的目的是评估患有严重,病态和极端肥胖的男女受试者中C3水平与BMI的关系,以及它们与胰岛素抵抗或相关疾病如糖尿病,高血压和血脂异常的可能关系。
    研究对象:该研究共纳入316例重度肥胖(17.1%),病态肥胖(54.4%)和极度肥胖(28.4%)的患者(110例男性和206例女性),平均BMI为46.70 /-7.37 kg /平方米
    测量:血糖和胰岛素水平是在基线时以及口服75 g葡萄糖后2小时确定的。计算了胰岛素抵抗评估的稳态模型(HOMA-IR)。获得脂质概况(总胆固醇,甘油三酸酯,高密度脂蛋白胆固醇,载脂蛋白AI和载脂蛋白B100),并通过浊度法测定C3水平。
    结果:当按BMI的四分位数分配患者时,我们发现C3的水平逐渐升高,其余研究分析变量均无显着差异。 C3的平均值为127.78 /-29.7 mg / dl.C3与BMI(r = 0.263,P <0.001),基线胰岛素(r = 0.237,P = 0.001)和HOMA-IR之间存在显着相关性r = 0.237,P = 0.001)。高血压患者111例,2型糖尿病74例,血脂异常139例。当根据相关危险因素(高血压,糖尿病和血脂异常)的数量分配C3水平时,我们发现这些患者与没有相关疾病的患者之间存在显着差异(P <0.01)。
    结论:在重度,病态或极度肥胖的受试者中,C3与BMI的进行性增加之间存在关系。 C3的增加与胰岛素水平和HOMA-IR值密切相关。此外,我们还发现C3升高,因为与胰岛素抵抗相关的更多疾病(例如糖尿病,高血压和血脂异常)与肥胖有关。

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