CXCL13及其受体CXCR5在喉鳞状细胞癌中的表达及临床意义

目的观察趋化因子CXCL13及受体CXCR5在喉鳞状细胞癌组织及癌旁组织中的表达情况,并探讨其临床意义。方法采用免疫组织化学法检测喉鳞状细胞癌和癌旁正常黏膜石蜡包埋组织中CXCL13及CXCR5蛋白的表达,并结合临床病理参数分析二者的临床意义。结果 (1)喉鳞癌组织中CXCL13及CXCR5阳性表达与癌旁正常黏膜组织相比差异有统计学意义(P<0.01),CXCL13及CXCR5在喉鳞癌中的表达强度明显高于癌旁组织;(2)研究CXCL13和CXCR5表达与喉鳞癌组织各临床病理参数的相关性发现:CXCL13及CXCR5蛋白表达强度与性别、年龄无明显相关性,而与TNM分期、淋巴结转移情况及临床分期呈显著相关性(P<0.05);CXCL13及CXCR5的表达强度在声门型喉癌与声门上型喉癌中差异具有统计学意义(P<0.05);CXCL13的表达可能与分化程度相关(P=0.05);(3)在喉鳞癌组织中,CXCL13与CXCR5的表达具有显著相关性。结论 CXCL13及CXCR5在喉鳞癌组织中的阳性表达显著高于癌旁组织,说明CXCL13及其受体蛋白CXCR5表达水平可以作为评估喉癌发病及可能发生侵袭转移的指标,并提示CXCL13及CXCR5可能为喉癌患者的不良预后因子。     

CXCR4趋化因子拮抗剂Plerixafor

CXCR4又叫融合素，是基质细胞衍生因子-1（SDF-1，最新的称谓为CXCL12）的一种特异性α-趋化因子受体，作为与G蛋白偶联而介导信号传导途径的7-跨膜受体，它可通过增加细胞内钙离子浓度来传递信号，并显示强效淋巴细胞趋化活性，在红细胞生成、神经元和心血管生长、肿瘤扩散和发展以及免疫系统的组织结构形成等方面也发挥作用。此外，SDF-1α与CXCR4受体还参与干细胞动员。     

CXCL12及CXCR7在鼻内翻性乳头状瘤中的表达及意义

目的:探讨趋化因子CXCL12及趋化因子受体CXCR7在鼻内翻性乳头状瘤(NIP)中的表达情况,及其在该病的发生、发展中的意义。方法:采用免疫组织化学染色方法检验44例鼻内翻性乳头状瘤(NIP),32例慢性肥厚性鼻炎(CHR)及15例鼻鳞状细胞癌(NSCC)组织中趋化因子CXCL12及趋化因子受体CXCR7的表达情况。结果:(1)CXCL12在CHR、NIP、NSCC中表达阳性率分别为6.25%,54.54%,86.67%,呈递增型;(2)CXCR7在CHR、NIP、NSCC中表达阳性率分别为9.38%,52.28%,93.3%,呈递增型;(3)spearman秩相关分析显示两者在鼻内翻性乳头状瘤中的表达呈正相关(rs=0.762,P<0.05)。结论:CXCL12和CXCR7均参与NIP的发生、发展过程,并且二者在NIP的发生、发展过程中起协同作用。     

儿童自身免疫性甲状腺炎患者血清趋化因子CXCL10及其受体CXCR3的变化及其临床意义

目的 探讨血清趋化因子CXCL10及其受体CXCR3在儿童自身免疫性甲状腺炎（HT）患者中的水平变化及其临床意义.方法 采用ELISA检测42例儿童自身免疫性甲状腺炎患者血清CXCL10和CXCR3水平,并以42例健康体检儿童作为对照.结果 HT组患者血清CXCL10和CXCR3水平明显高于对照组（t=15.509、23.751,均P＜0.05）,且血清CXCL10和CXCR3水平在儿童HT发病初期及未缓解期高于缓解期（t=17.188、20.048、16.427、20.369,均P＜0.05）；血清CXCL10与CXCR3表达呈高度正相关（r=0.772,P＜0.01）.结论 CXCL10和CXCR3在儿童自身免疫性甲状腺炎的过度表达可能与其发生和发展有关,在儿童HT病程中存在着动态变化,可以作为预测儿章HT的疾病活动性的指标之一.     

雌激素对大鼠趋化因子受体CXCR2表达的影响：动脉粥样硬化的指征

目的：研究17β-雌二醇对体内单核细胞趋化因子受体CXCR2表达的影响．方法：流式细胞仪测定单核细胞趋化因子受体CXCR2的蛋白表达、逆转录PCR测定其mRNA水平．结果：在卵巢完整和切除卵巢的大鼠中,喂养富含胆固醇饮食6周增加单核细胞趋化因子受体CXCR2 mRNA和蛋白水平．在切除卵巢的大鼠,注射17β-雌二醇(5和20μg．kg^-1．d^-1)显著减少了胆固醇诱导的CXCR2 mRNA及蛋白表达的增加．正常饮食的大鼠,切除卵巢增加了趋化因子受体CXCR2 mRNA和蛋白水平的表达,但是注射17β-雌二醇可以防止它表达的增加．结论：生理性浓度的雌激素调节基础及胆固醇诱导的趋化因子受体CXCR2表达．     

二磷酸盐对骨癌痛模型小鼠趋化因子CXCL1及受体CXCR2表达影响的研究

目的分析趋化因子CXCL1及受体CXCR2在小鼠骨癌痛模型中的作用,并探讨二磷酸盐对小鼠骨癌痛模型的干预机制。方法 60只小鼠随机分为3组:对照组、模型组和治疗组。股骨远端骨髓腔注射NCTC2742细胞复制小鼠股骨痛模型,治疗组给予二磷酸盐治疗,对照组和模型组给予等量生理盐水。Real-time PCR分析各组中趋化因子CXCL1和CXCR2mRNA的表达,Western blot检测CXCL1、CXCR2蛋白及肿瘤坏死因子TNF-α以及细胞凋亡蛋白Bax/Bcl2以及Caspase-3的表达。结果模型组小鼠的机械缩爪阈值较对照组有显著的增高(P<0.05,P<0.01),而药物治疗组对模型组小鼠的升高的阈值有显著的改善作用(P<0.01);与对照组比较,骨癌痛模型小鼠趋化因子CXCL1及受体CXCR2表达明显增强(P<0.01),二磷酸盐可以显著抑制CXCL1及CXCR2的表达(P<0.01);与对照组比较,骨癌痛模型小鼠肿瘤坏死因子TNF-α、促细胞凋亡蛋白Bax及Caspase-3的表达明显增高,凋亡蛋白Bcl2的表达明显降低(P<0.01),而二磷酸盐可以显著改善上述指标表达(P<0.01)。结论二磷酸盐通过下调骨癌痛模型小鼠趋化因子CXCL1及受体CXCR2表达、促进细胞凋亡发挥治疗骨癌痛模型小鼠的作用。     

CXCL12/CXCR4在肾癌中的研究进展

肾癌是泌尿系统常见的恶性肿瘤之一,早期症状不明显,发现时往往已发生了转移。近年来发现趋化因子CXCL12及其受体CXCR4在肾癌转移中发挥着重要的作用,对CXCR4检测有利于判断肾癌转移及患者的预后。CXCR4靶向治疗已在动物模型及临床前试验中取得了成功,有望成为治疗肾癌新的突破口。     

乳腺癌肿瘤细胞中趋化因子CXCL12及其受体CXCR4的研究进展

CXCL12因子及其受体CXCR4作为趋化因子家族中与肿瘤关系最为密切的一对。特别在乳腺癌方面,无论是对原位肿瘤还是转移性肿瘤都进行了一系列深入的研究,本文就这一方面的研究进行了总结和展望。     

趋化因子受体CXCR7在妇科肿瘤中的研究进展

趋化因子是一类对不同细胞具有趋化吸引作用的蛋白质,它必须与趋化因子受体相结合而发挥生物学作用,从而调控肿瘤细胞的生长和扩散.CXCR7作为趋化因子CXCL12的又一新发现的受体,它在调节细胞黏附和增殖、激活丝裂原激活的蛋白激酶（MAPK）和AKT信号通路、调节CXCR4的生物学活性及升高相关基质金属蛋白酶（MMPS）浓度方面发挥着越来越重要的作用.通过探讨CXCR7在妇科肿瘤的作用机制,提出检测CXCR7将成为妇科肿瘤预防、早期诊断和治疗、判断预后的新指标和方向.     

CXCL12-CXCR4轴与乳腺癌转移研究进展

"归巢"理论认为乳腺癌的转移是一个主动、有序、有器官选择性的过程,其中特异性趋化因子受体4(CXCR4)和趋化因子配体12(CXCL12)所构成的生物学轴在乳腺癌器官特异性转移中发挥重要作用,本文就该轴与乳腺癌转移的临床试验和动物实验研究及其发挥作用机理的研究进展作一综述.     

SDF-1α/CXCL12 enhances GABA and glutamate synaptic activity at serotonin neurons in the rat dorsal raphe nucleus

The serotonin (5-hydroxytryptamine; 5-HT) system has a well-characterized role in depression. Recent reports describe comorbidities of mood-immune disorders, suggesting an immunological component may contribute to the pathogenesis of depression as well. Chemokines, immune proteins which mediate leukocyte trafficking, and their receptors are widely distributed in the brain, mediate neuronal patterning, and modulate various neuropathologies. The purpose of this study was to investigate the neuroanatomical relationship and functional impact of the chemokine stromal cell-derived factor-1α/CXCL12 and its receptor, CXCR4, on the serotonin dorsal raphe nucleus (DRN) system in the rat using anatomical and electrophysiological techniques. Immunohistochemical analysis indicates that over 70% of 5-HT neurons colocalize with CXCL12 and CXCR4. At a subcellular level, CXCL12 localizes throughout the cytoplasm whereas CXCR4 concentrates to the outer membrane and processes of 5-HT neurons. CXCL12 and CXCR4 also colocalize on individual DRN cells. Furthermore, electrophysiological studies demonstrate CXCL12 depolarization of 5-HT neurons indirectly via glutamate synaptic inputs. CXCL12 also enhances the frequency of spontaneous inhibitory and excitatory postsynaptic currents (sIPSC and sEPSC). CXCL12 concentration-dependently increases evoked IPSC amplitude and decreases evoked IPSC paired-pulse ratio selectively in 5-HT neurons, effects blocked by the CXCR4 antagonist AMD3100. These data indicate presynaptic enhancement of GABA and glutamate release at 5-HT DRN neurons by CXCL12. Immunohistochemical analysis further shows CXCR4 localization to DRN GABA neurons, providing an anatomical basis for CXCL12 effects on GABA release. Thus, CXCL12 indirectly modulates 5-HT neurotransmission via GABA and glutamate synaptic afferents. Future therapies targeting CXCL12 and other chemokines may treat serotonin related mood disorders, particularly depression experienced by immune-compromised individuals.     

The N-terminal region of CXCL11 as structural template for CXCR3 molecular recognition: synthesis, conformational analysis, and binding studies

The chemokines and their receptors play a key role in immune and inflammatory responses by promoting recruitment and activation of different subpopulations of leukocytes. The membrane receptor CXCR3 binds three chemokines, CXCL9, CXCL10, and CXCL11, and its involvement is recognized in many inflammatory diseases and cancers. Therefore, the inhibition of CXCR3 pathway through interactions with three ligands was indicated as putative therapeutic target for the treatment of these diseases, and some inhibitory compounds have already been described in the literature. Recently, we studied the interaction between CXCR3 and its three natural ligands and showed that three CXCR3 ligands bound the receptor mainly by their N-terminal regions using aromatic and electrostatic interactions, and, in particular, CXCL11 had the highest affinity for CXCR3. In light of these results, we focused our attention on what structural region(s) of CXCL11 interacted with CXCR3 and what were the structural features. Therefore, we have synthesized three peptides, corresponding to the N-terminal region of CXCL11, but with different aromatic amino acids, analyzed their conformations by circular dichroism, NMR, and molecular dynamics simulations, simulated their complexes with CXCR3 by docking methods, and validated these data by in vitro studies. The results showed that two peptides were able to bind CXCR3 and to mimic the molecular recognition of CXCL11 and demonstrated that N-terminal region of CXCL11 can be used as template and starting point to obtain new molecules by de novo design approaches.     

CXCR3-binding chemokines: novel multifunctional therapeutic targets

The goal to attenuate inflammation without inducing generalized immunosuppression has focused the attention on chemokines, a family of chemotactic peptides that regulate the leukocyte traffick into tissues. However, the development of drugs that block ckemokine activity may be hampered by the observation that some chemokines display pleiotropic biologic functions. For example, the chemokines CXCL9/Mig, CXCL10/IP-10, and CXCL11/I-TAC exhibit the ability to recruit different leukocytes subsets, the capacity to induce the proliferation of vascular pericytes as well as powerful anti-tumor effects, which are mediated by a common receptor, named CXCR3. Because of their pleiotropic biologic effects, these chemokines have been proposed as possible therapeutic targets in cancer, allograft rejection, glomerulonephritis, diabetes, multiple sclerosis, and autoimmune disorders of the thyroid. The chemokine CXCL4/PF4 shares several activities with CXCL9, CXCL10, and CXCL11, including angiostatic effects, although its specific receptor has remained unknown for a long time. Recently, we provided evidence that the different functions of CXCL9, CXCL10, and CXCL11 on distinct cell types can be at least partly explained by the interaction of these chemokines with two distinct receptors. Indeed, in addition to the classic form of CXCR3 receptor, which we have renamed as CXCR3-A, a novel CXCR3 receptor variant (CXCR3-B) was identified, that not only mediates the angiostatic activity of CXCR3 ligands, but also acts as functional receptor for CXCL4. In this review, we focus on the accumulating evidence demonstrating the pivotal role of CXCR3-binding chemokines in several human diseases. Studies based on CXCR3 targeting have shown its importance in different pathologic conditions and orally active small molecules capable of inhibiting this receptor are now being developed in order to be tested for their activity in humans.     

The role of chemokines in adjusting the balance between CD4 + effector T cell subsets and FOXp3-negative regulatory T cells

Chemokines are small (~ 8–14 kDa) structurally-related chemotactic cytokines that regulate cell trafficking through interactions with specific seven-trans membrane, G protein-coupled receptors (GPCRs). One of the important features of G protein-coupled receptors (GPCRs) is their ability to transmit diverse signaling cascades upon binding different ligands. The current review focuses on the interplay between three ligands: CXCL9, CXCL10 and CXCL11 binding the same receptor (CXCR3) on CD4 + T cells, yet direct different signaling cascades to shape T cell mediated immunity. The review brings about a new concept regarding the biological activities of chemokines in shaping CD4 + T cell immunity, and also a new approach for applying chemokine based therapy of autoimmune diseases.     

Transdermal delivery of therapeutic agents using dendrimers (US20140018435A1): a patent evaluation

A method of treating CXCL13-mediated inflammatory diseases by the co-administration of a CXCL13 antagonist and a TNF-α antagonist is claimed. Their use is claimed to provide methods of treating asthma, chronic obstructive pulmonary disorder (COPD), pulmonary fibrosis and systemic lupus erythematosus. The reported activity of such combinations in animal models provides evidence for the CXCR5 chemokine receptor as a potential drug target in such diseases.     

CXCL12-CXCR4 axis in angiogenesis, metastasis and stem cell mobilization

Chemokines are key players in the attraction and activation of leukocytes and are thus implicated in the recruitment of immune cells at sites of infection and/or inflammation. They exert their action by binding to seven-transmembrane G protein-coupled receptors. The chemokine stromal cell-derived factor-1 (SDF-1)/CXCL12 represents the single natural ligand for the chemokine receptor CXCR4. CXCL12 possesses angiogenic properties and is involved in the outgrowth and metastasis of CXCR4-expressing tumors and in certain inflammatory autoimmune disorders, such as rheumatoid arthritis. CXCR4 expression on tumor cells is upregulated by hypoxia and angiogenic factors, such as vascular endothelial growth factor (VEGF). CXCR4 also acts as a co-receptor for entry of human immunodeficiency virus (HIV) in CD4(+) T cells. Finally, CXCL12/CXCR4 interactions were shown to play an important role in the migration of hematopoietic stem cells and their progenitors from, and their retention within, the bone marrow, a site characterized by high CXCL12 expression. As such, CXCR4 inhibitors may be utilized to inhibit HIV-1 infection, tumor growth and metastasis and to mobilize hematopoietic stem cells from the bone marrow in the circulation, where they can be collected for autologous stem cell transplantation. Here, we discuss the different aspects of CXCL12/CXCR4 biology as well as the development and anti-cancer/stem cell mobilizing activity of CXCR4 antagonists.     

A CXCL8 receptor antagonist based on the structure of N-acetyl-proline-glycine-proline

A role for the collagen-derived tripeptide, N-acetyl proline-glycine-proline (NAc-PGP), in neutrophil recruitment in chronic airway inflammatory diseases, including COPD and cystic fibrosis, has recently been delineated. Due to structural similarity to an important motif for interleukin-8 (CXCL8) binding to its receptor, NAc-PGP binds to CXCR1/2 receptors, leading to neutrophil activation and chemotaxis. In an effort to develop novel CXCL8 antagonists, we describe the synthesis of four chiral isomers of NAc-PGP (NAc-l-Pro-Gly-l-Pro (ll-NAc-PGP), NAc-l-Pro-Gly-d-Pro (lD-NAc-PGP), NAc-d-Pro-Gly-l-Pro (dl-NAc-PGP), and NAc-d-Pro-Gly-d-Pro (dd-NAc-PGP)), characterize them by circular dichroism and NMR spectroscopy, compare their structures to the equivalent region of CXCL8, and test them as potential antagonists of ll-NAc-PGP and CXCL8. We find that ll-NAc-PGP superimposes onto the CXCR1/2 contacting E²⁹S³⁰G³¹P³² region of CXCL8 (0.59A rmsd for heavy atoms). In contrast, dd-NAc-PGP has an opposing orientation of key functional groups as compared to the G³¹P³² region of CXCL8. As a consequence, dd-NAc-PGP binds CXCR1/2, as demonstrated by competition with radiolabeled CXCL8 binding in a radioreceptor assay, yet acts as a receptor antagonist as evidenced by inhibition of CXCL8 and ll-NAc-PGP mediated neutrophil chemotaxis. The ability of dd-NAc-PGP to prevent the activation of CXC receptors indicates that dd-NAc-PGP may serve as a lead compound for the development of CXCR1/2 inhibitors. In addition, this study further proves that using a different technical approach, namely preincubation of NAc-PGP instead of simultaneous addition of NAc-PGP with radiolabeled CXCL8, the direct binding of NAc-PGP to the CXCL8 receptor is evident.     

Targeting of a common receptor shared by CXCL8 and N-Ac-PGP as a therapeutic strategy to alleviate chronic neutrophilic lung diseases

Persistent neutrophilia is implicated in the pathology of several chronic lung diseases and consequently targeting the signals that drive the recruitment of these cells offers a plausible therapeutic strategy. The tripeptide Pro-Gly-Pro (PGP) is a neutrophil chemoattractant derived from extracellular matrix collagen and implicated in diseases such as COPD and cystic fibrosis. It was anticipated that PGP exerts its chemoatactic activity by mimicking key sequences found within classical neutrophil chemokines, such as CXCL8, and binding their receptors, CXCR1/2. Recently, however, the role of CXCR1/2 as the receptors for PGP has been questioned. In this issue of European Journal of Pharmacology, three studies address this controversy and demonstrate CXCR1/2 to be a common receptor for CXCL8 and PGP. Accordingly, these studies demonstrate the therapeutic potential of targeting this shared receptor to simultaneously alleviate neutrophilic inflammation driven by multiple neutrophil chemoattractants.     

Design of noncompetitive interleukin-8 inhibitors acting on CXCR1 and CXCR2

Chemokines CXCL8 and CXCL1 play a key role in the recruitment of neutrophils at the site of inflammation. CXCL8 binds two membrane receptors, CXCR1 and CXCR2, whereas CXCL1 is a selective agonist for CXCR2. In the past decade, the physiopathological role of CXCL8 and CXCL1 has been investigated. A novel class of small molecular weight allosteric CXCR1 inhibitors was identified, and reparixin, the first drug candidate, is currently under clinical investigation in the prevention of ischemia/reperfusion injury in organ transplantation. Reparixin binding mode to CXCR1 has been studied and used for a computer-assisted design program of dual allosteric CXCR1 and CXCR2 inhibitors. In this paper, the results of modeling-driven SAR studies for the identification of potent dual inhibitors are discussed, and three new compounds (56, 67, and 79) sharing a common triflate moiety have been selected as potential leads with optimized pharmacokinetic characteristics.     

CXCR2--the receptor to hit?

Emigration of leukocytes from the microcirculation into inflammatory tissues is one of the hallmarks of our immune system. However, excessive leukocyte recruitment can disturb the integrity of the organism and aggravate acute and chronic inflammatory diseases. Chemokines are chemoattractant peptides that are used as messengers to direct leukocytes to sites of inflammation. They mediate their effects through G-protein-coupled chemokine receptors on the surface of leukocytes and other, nonhematopoietic cells, where they induce a variety of cell responses including cell activation and transmigration. CXC chemokine receptor 2 (CXCR2) has been implicated in numerous inflammatory disorders. In many models of acute and chronic inflammatory diseases, blockade of CXCR2 substantially reduces leukocyte recruitment, tissue damage and mortality. The physiological importance of CXCR2 has led to the development of selective CXCR2 inhibitors that are now being tested in clinical trials. This review will summarize current knowledge about CXCR2 in inflammatory diseases and discuss its potential as a pharmaceutical target.