CD4+CD45RA+CXCR4+ lymphocytes are inversely associated with progression in stages I–III melanoma patients

The chemokine receptor CXCR4 was described as an independent predictor of poor prognosis in primary human melanoma. To investigate on a possible role of CXCR4 expression on peripheral blood lymphocytes (PBL) subsets, 195 patients with melanoma were evaluated for correlations between PBL subsets CXCR4 expressing and clinicopathological and prognostic features. One hundred ninety-five patients with stages I–III melanoma were enrolled in this study. Lymphocytes subsets were assayed by the direct fluorescence method for whole blood and staining with fluorochrome-conjugated monoclonal antibodies. Correlations between PBL subsets, baseline patient, and tumor features were studied by contingency tables and the χ² test. The Kaplan–Meier product limit method was applied to plot disease-free- and overall-survival curves. Univariate analysis was performed with the log-rank test. Cox proportional-hazards regression was used to analyze the effect of multiple risk factors on disease-free survival (DFS). Melanoma patients characterized by CD4⁺CD45RA⁺CXCR4⁺ higher than 25% of PBL showed a longer DFS. Conversely, CD4⁺CD45RA⁺CXCR4⁺ <25% increased the risk of relapse. The 5-year DFS rate was 76% for patients with CD4⁺CD45RA⁺CXCR4⁺ lymphocytes <25% of PBL, and 94% for patients with CD4⁺CD45RA⁺CXCR4⁺ >25% (p = 0.030 at log-rank test). Univariate and multivariate analysis for DFS confirmed the prognostic value of the CD4⁺CD45RA⁺CXCR4⁺ lymphocytes. Although further studies are needed to better define the involved subpopulation, the detection of cellular subset CD4⁺CD45RA⁺CXCR4⁺ is an easy and feasible evaluation of melanoma patients in concomitance with the established melanoma prognostic markers.     

趋化因子受体CXCR1、CXCR2与肿瘤研究进展

趋化因子受体是由7个跨膜区组成的G蛋白偶联受体,多个系统的肿瘤细胞均表达趋化因子受体,其在肿瘤的发生、发展和转移等各个阶段都发挥重要作用.近年来有不少研究发现趋化因子受体中的CXCR1和CXCR2与肿瘤关系密切,认为其可能成为肿瘤治疗的一个潜在新靶点.本文就CXCR1和CXCR2这两种趋化因子受体与肿瘤的关系做一综述.     

Peritoneal cavity is dominated by IFNγ-secreting CXCR3+ Th1 cells

The chemokine receptor CXCR3, which was shown to take part in many inflammatory processes, is considered as a Th1 specific marker. Here, we show in a mouse model that CXCR3 expressing CD4(+) cells preferentially migrate to the peritoneal cavity under steady-state conditions. The peritoneal cavity milieu leads to an up-regulated expression of CXCR3. However, blocking of known ligands of this chemokine receptor did not alter the preferential migration. The peritoneal cavity environment also results in an increased percentage of memory cells producing cytokines. Up-regulation of IFNγ production occurs mostly in CXCR3(+) cells considered as Th1, whereas the up-regulation of IL-4 affects mostly in CXCR3(-) cells which are considered as Th2. We conclude that the peritoneal cavity does not change the Th-lineage of the cells, but that domination of this anatomic niche by Th1 cells rather results from preferential migration to this compartment.     

中性粒细胞CXCR1、CXCR2活化及其信号传导

中性粒细胞属非特异性免疫细胞,其表面可表达CXCR1和CXCR2.IL-8是其共同配体,它们彼此结合激活后续级联信号传导,产生一系列生物学效应,在介导炎症反应、促进血管新生、维持中性粒细胞稳态等起重要作用.Reparixin是非竞争变构的CXCR1和CXCR2阻滞剂,可抑制中性粒细胞过度趋化、迁移介导的炎症反应.     

Zn2+与Cr6+对水车前毒害的协同效应

比较研究了水体中单一Cr6 及外施Zn2 后对水车前抗氧化酶系统(SOD、POD、CAT)和叶绿素含量的影响,以探讨金属元素联合作用机理。结果表明:单一Cr6 处理下,1 mg·L-1处理浓度可产生一定的积极刺激作用, 表现为提高了SOD、POD和CAT活性和增加了叶绿素含量。与单一Cr6 处理相比,施加不同浓度的Zn2 后都不同程度地削弱了保护酶活性,叶绿素含量下降的幅度也更明显。这表明Zn2 的加入,削弱了水车前保护酶系统的保护作用,使水车前对Cr6 胁迫的耐性减弱,协同作用的趋势显著。     

膀胱癌组织中CXCR4 和CXCR7 的表达及临床意义

目的:探讨膀胱癌组织中趋化因子受体4(CXCR4)和趋化因子受体7(CXCR7)的表达及临床意义。方法:收集2012年1月至2014年1月我院收集的膀胱癌组织标本96例,肿瘤旁正常组织标本42例,采用免疫组化方法检测组织标本中CXCR4和CXCR7的表达情况。结果:96例癌组织中检出CXCR4阳性59例,阳性率为61.46%,检出CXCR7阳性表达71例,阳性率为73.96%;42例癌旁组织中检出CXCR4阳性11例,阳性率26.19%,检出CXCR7阳性8例,阳性率为19.05%,癌组织与癌旁组织中CXCR4和CXCR7的表达具有统计学差异(均P0.05);相关性分析显示在膀胱癌组织中,CXCR4和CXCR7的表达呈正相关性(r=0.497,P=0.001);CXCR4和CXCR7在浸润性高(T2-T3)的膀胱癌和分化程度低(G2-G3)的膀胱癌表达强度较高,且差异具有统计学意义(均P0.05)。结论:CXCR4和CXCR7协同参与了膀胱癌的发生发展,并且与肿瘤的分化程度和浸润程度密切相关,有望成为诊断和治疗的重要靶点,在临床应用上具有重要意义。     

CXCR1和CXCR2在系统性红斑狼疮中的表达及意义

目的:检测白介素-8受体CXCR1和CXCR2在系统性红斑狼疮(SLE)患者外周血CD14+单核细胞上的表达,探讨其与SLE疾病活动的相关性和可能涉及的SLE炎症发病机制.方法:36例活动期SLE患者和34例健康志愿者,采用流式细胞术(FCM)检测CXCR1、CXCR2在SLE患者和健康志愿者外周血CD14+单核细胞上的MFI表达.结果:CXCR2在SLE组外周血CD14+单核细胞上MFI表达(195.75±52.76)与对照组(298.82±51.86)相比明显降低(P＜0.01);CXCR2在SLE患者外周血CD14+单核细胞上MFI表达下降与C3存在着正相关关系(rs=0.421,P=0.022),与dsDNA、SLEDAI存在着负相关关系(分别为rs=-0.390,P=0.032;rs=-0.463,P=0.011).结论:SLE患者外周血CD14+单核细胞CXCR2的表达异常,提示CXCR2可能参与了SLE的发病过程.检测SLE患者外周血CD14+单核细胞的CXCR2表达水平,可能是评价SLE疾病活动性有价值的潜在的生物学标志之一.     

Transforming growth factor-β promotes the function of HIV-specific CXCR5+CD8 T cells

HIV replication can be inhibited by CXCR5⁺CD8 T cells (follicular cytotoxic T cell [TFC]) which transfer into B-cell follicles where latent HIV infection persists. However, how cytokines affect TFC remain unclear. Understanding which cytokines show the ability to affect TFC could be a key strategy toward curing HIV. Similar mechanisms could be used for the growth and transfer of TFCs and follicular helper T (TFH) cells; as a result, we hypothesized that cytokines IL-6, IL-21, and transforming growth factor-β (TGF-β), which are necessary for the differentiation of TFH cells, could also dictate the development of TFCs. In this work, lymph node mononuclear cells and peripheral blood mononuclear cells from HIV-infected individuals were cocultured with IL-6, IL-21, and TGF-β. We then carried out T-cell receptor (TCR) repertoire analysis to compare the differences between CXCR5^– and CXCR5⁺CD8 T cells. Our results showed that the percentage and function of TFC can be enhanced by stimulation with TGF-β. Besides, TGF-β stimulation enhanced the diversity of TCR and complementarity-determining region 3 sequences. HIV DNA showed a negative correlation with TFC. The use of TGF-β to promote the expression of CXCR5⁺CD8 T cells could become a new treatment approach for curing HIV.     

CXCL8及其受体CXCR1、CXCR2在慢性乙肝中的表达及意义

为探讨CXC趋化因子8(CXCL8)及其受体CXC趋化因子受体1(CXCR1)、CXC趋化因子受体2(CXCR2)在慢性乙型肝炎中的表达及意义,本研究选取了我院治疗的慢性乙型肝炎患者64例(观察组),同时选取健康志愿者60例作为对照组,两组均采用SABC免疫细胞化学染色法检测CXCL8、CXCR1和CXCR2在各组外周血中性粒细胞(PMNs)内的表达量,采用RT-PCR检测PMNs中CXCL8、CXCR1和CXCR2mRNA表达。实验发现,观察组外周血PMNs中CXCL8、CXCR1表达明显强于对照组(p0.05);观察组和对照组外周血PMNs中CXCR2表达强度差异比较无统计学意义(p0.05);观察组外周血PMNs中CXCL8mRNA、CXCR1 mRNA和CXCR2 mRNA相对表达量分别为(1.16±0.15)、(0.87±0.24)和(1.01±0.22),明显高于对照组(p0.05);观察组中HBV-DNA阳性者外周血PMNs中CXCL8 mRNA和CXCR1 mRNA相对表达量分别为(1.27±0.10)和(1.02±0.13),明显高于HBV-DNA阴性者(p0.05);HBV-DNA阳性者和HBV-DNA阴性者CXCR2 mRNA相对表达量比较差异无统计学意义(p0.05);CXCL8 mRNA和CXCR1 mRNA相对表达量与ALT呈正相关(r=0.673和0.681,p0.05),CXCR2 mRNA相对表达量与ALT无相关性(p0.05)。慢性乙肝患者PMNs内CXCL8、CXCR1、CXCR2的mRNA水平升高,其中CXCL8、CXCR1的mRNA与血清ALT呈正相关,同时与HBV DNA载量有一定的相关性。     

CXCL12/CXCR4/CXCR7轴在子宫内膜异位症中的研究进展

子宫内膜异位症(endometriosis, EMT)是常见的妇科疾病,发病率高,且有年轻化的趋势。因其治疗困难且复发率高,严重影响了女性的生活质量和生育能力。研究发现趋化因子CXCL12与其受体CXCR4和CXCR7在恶性肿瘤中起重要作用。虽然EMT为良性疾病,但有恶性肿瘤的生物学特征,近来发现CXCL12/CXCR4/CXCR7轴可以影响子宫内膜异位症的定植、侵袭和转移。本文就当前国内外研究CXCL12/CXCR4/CXCR7轴在EMT发生发展过程中的作用进行了综述,旨在为EMT的治疗找到新靶点。     

HIV共受体CXCR4研究进展

ＣＸＣＲ是ＨＩＶ－１侵染宿细胞的主要共受体之一,研究结果表明ＣＸＣＲ４在细胞表面的表达受多种因素的影响;对ＣＸＣＲ４结构的研究通常是通过嵌合体受体,ＣＸＣＲ４部分区域删除和点突变等方式来进行;ＣＸＣＲ４结构功能的研究对新的抗病毒药物的设计、阻止Ｔ－向性ＨＩＶ－１的进一步侵染、延缓、ＡＩＤＳ的发生有着重要的意义。     

Mo6+-Cys配合物的合成及表征

研究了Mo6+-Cys配合物的合成方法,探讨了合成工艺的主要影响因素,确定了最佳反应时间,温度,pH值及原料配比,采用X射线衍射光谱对配合物进行分析鉴定,结果表明元素钼能与半胱氨酸形成配合物。     

Hypoxic preconditioning advances CXCR4 and CXCR7 expression by activating HIF-1α in MSCs

Recent evidence indicated that sublethal hypoxic preconditioning (HP) of bone marrow-derived mesenchymal stem cells (MSCs) before transplantation could ameliorate their capacity to survive and engraft in the target tissue through yet undefined mechanisms. In this study, we demonstrated that HP (3% oxygen) induced the high expression of both chemokine stromal-derived factor-1 (SDF-1) receptors, CXCR4 and CXCR7, in MSCs. HP also improved in vitro migration, adhesion and survival of MSCs. Although SDF-1-induced migration of HP-MSCs was only abolished by an anti-CXCR4 antibody, both CXCR4 and CXCR7 were responsible for elevated adhesion of HP-MSCs. Moreover, CXCR7 but not CXCR4 was essential for the resistance to oxidative stress of HP-MSC. In addition, HP also evoked an increase in expression of hypoxia-inducible factor-1 (HIF-1α) and phosphorylation of Akt. The chemical inducers of HIF-1α, desferrioxamine (DFX) and cobalt chloride (CoCl₂), induced upregulation of CXCR4 and CXCR7 expression in MSCs under normoxic conditions. Contrarily, blockade of HIF-1α by siRNA and inhibition of Akt by either wortmannin or LY294002 abrogated upregulation of HP-induced CXCR4 and CXCR7 in MSCs. Collectively, these findings provide evidence for a crucial role of PI3K/Akt-HIF-1α-CXCR4/CXCR7 pathway on enhanced migration, adhesion and survival of HP-MSCs in vitro.     

Cr6+胁迫对莱茵衣藻光合作用的影响

以莱茵衣藻(Chlamydomonas reinhardtii)为研究材料,采用氧电极和快速叶绿素a荧光诱导动力学方法研究了不同浓度和时间Cr6+处理对其光合作用的影响.结果表明:当Cr6+浓度大于40 μmol/L时,莱茵衣藻细胞数逐渐下降,而藻细胞变大;表观光合速率成为负值,呼吸作用随Cr6+处理浓度的增加先上升后下降至对照水平;莱茵衣藻有活性放氧复合体比例随Cr6+处理浓度的增加逐渐降低,80 μmol/L Cr6+处理3 d时已下降至13.72%;光合驱动力(DFABS)随Cr6+浓度增加逐步下降,并以DFφPo在DFABS的下降中的贡献最大.研究发现,重金属Cr6+胁迫显著影响莱茵衣藻的光合作用,而对呼吸作用则影响较小;Cr6+主要通过损伤供体侧的放氧复合体以及阻断QA至QB的电子传递而抑制光系统Ⅱ的功能;莱茵衣藻光系统Ⅱ对Cr6+处理比较敏感且存在着多个作用位点,并首先影响反应中心光能捕获效率,其次影响反应中心的活性,最后影响QA-之后的电子传递.     

Cr6+、Cr3+胁迫对黑藻生理生化影响的比较研究

以沉水植物黑藻 (Hydrillaverticillata(L .f.)Royle)为实验材料 ,通过模拟水体Cr6+ 、Cr3 + 污染环境 ,比较研究了两种价态铬对黑藻叶的毒害影响。结果表明 :随着Cr6+ 、Cr3 + 浓度的加大 ,超氧阴离子 (O 2)产生速率、丙二醛 (MDA)、可溶性蛋白含量皆呈先升后降趋势。Cr6+ 、Cr3 + 浓度过高时 ,三种抗氧化酶 (SOD、POD、CAT)活性比例失衡 ,且Cr6+ 处理组的O 2 产生速率、MDA含量高于Cr3 + 处理组 ,叶绿素、可溶性蛋白含量、叶绿素a/b值低于Cr3 + 处理组 ,显示出Cr6+ 的毒性远大于Cr3 + 。     

Th1-Like ICOS+ Foxp3+ Treg Cells Preferentially Express CXCR3 and Home to β-Islets during Pre-Diabetes in BDC2.5 NOD Mice

Type 1 diabetes (T1D) occurs through a breakdown of self-tolerance resulting in the autoimmune destruction of the insulin producing β-islets of the pancreas. A numerical and functional waning of CD4⁺Foxp3⁺ regulatory T (T_reg) cells, prompted by a pancreatic IL-2 deficiency, accompanies Th1 autoimmunity and T1D progression in non-obese diabetic (NOD) mice. Recently, we identified a dominant subset of intra-islet T_reg cells that expresses the ICOS costimulatory receptor and promotes self-tolerance delaying the onset of T1D. ICOS co-stimulation potently enhances IL-2 induced survival and proliferation, and suppressive activity of T_reg cells in situ. Here, we propose an ICOS-dependent mechanism of T_reg cell homing to the β-islets during pre-diabetes in the NOD model via upregulation of the CXCR3 chemokine receptor. The islet-specific ICOS⁺ T_reg cell subset preferentially expresses CXCR3 in the pancreatic lymph nodes (pLN) in response to T_eff cell-mediated pancreatic inflammation, an expression correlating with the onset and magnitude of IFN-γ production by T_eff cells in pancreatic sites. We also reveal that intra-pancreatic APC populations and insulin-producing β, but not α nor δ, islet cells secrete the CXCR3 chemokines, CXCL9, 10 and 11, and selectively promote ICOS⁺CXCR3⁺ T_reg cell chemotaxis in vitro. Strikingly, islet-derived T_reg cells also produce these chemokines suggesting an auto-regulation of homing by this subset. Unlike ICOS^- cells, ICOS⁺ T_reg cells adopt a Th1-like T_reg phenotype while maintaining their suppressive capacity, characterized by expression of T-bet and CXCR3 and production of IFN-γ in the draining pLNs. Finally, in vivo neutralization of IFN-γ blocked T_reg cell CXCR3 upregulation evincing its role in regulating expression of this chemokine receptor by T_reg cells. Thus, CXCR3-mediated trafficking of T_reg cells could represent a mechanism of homeostatic immunoregulation during diabetogeneesis.     

脊椎动物趋化因子受体CXCR基因分化研究

为了探讨脊椎动物CXCR(CXC chemokine receptor)在基因组上进化和分化的规律,采用生物信息学软件绘制了脊椎动物7个CXCR的基因结构图,分析了它们的系统进化关系,研究这些受体在不同物种基因同源性.结果表明,脊椎动物CXCR 7个成员在进化上发生了不同程度地分化.人、鼠、蜥蜴CXCR1和CXCR2在同一条染色体上,蛋白相似率很高,在进化树上混杂聚集在一起,形成CXCR1/2;而硬骨鱼类CXCR1和CXCR2发生了分化,形成了单独的CXCR1和CXCR2.鱼类CXCR3分化为3个基因,其中CXCR3b1、CXCR3b2与其他脊椎动物CXCR3同源性较高,聚集在一起,而CXCR3a分化较大.脊椎动物CXCR5和CXCR6基因较保守,基因同源性高.CXCR4和CXCR7在哺乳类、鸟类、爬行类和两栖类均仅一个基因,但在硬骨鱼类中它们各自分化为2个基因.CXCR4和CXCR7位于同一条染色体上.鱼类CXCR4a和CXCR7a与其他脊椎动物CXCR4和CXCR7基因同源性较高.而CXCR4b和CXCR7b这两个基因无论是从基因结构还是基因同源性上都发生了一定程度的分化.     

CXCR4在骨肉瘤组织中的表达

研究趋化因子受体4(Chemokine receptor 4,CXCR4)的表达水平与骨肉瘤肺转移的关系并探讨CXCR4在骨肉瘤组织中表达的意义.采用免疫组织化学方法测定5例肺转移和11例无肺转移患者的骨肉瘤组织中CXCR4的表达水平.发现16例骨肉瘤组织中均有CXCR4蛋白的表达,但其表达水平存在差异,与肺转移的骨肉瘤组织(80.52±9.93)相比,11例非肺转移的骨肉瘤组织中CXCR4的表达水平(65.56±12.75)显著较低(P=0.037＜0.05).实验结果表明CXCR4的上调表达见于肺转移率较高的骨肉瘤组织,提示CXCR4可能参与了骨肉瘤的肺转移.     

SDF-1／CXCR4的研究进展

基质细胞衍生因子-1(stromal cell—derived factorl,SDF-1)是α趋化因子家族的—个新成员,其受体CX—CR4广泛地表达在许多组织和器官上。SDF—1／CXCR4与造血干／祖细胞的动员和归巢密切相关,并且是白血病细胞迁移、播散的重要因子。近来研究发现,SDF—1／CXCR4参与调节造血干／祖细胞的增殖及其白血病细胞抗凋亡过程;能够通过免疫调节发挥抗感染、抗肿瘤作用。因此,对SDF—1／CXCR4的深入研究将有助于阐述造血机制和肿瘤细胞生长机制,为临床移植和抗肿瘤治疗提供新的途径。