趋化因子CXCL13及其受体CXCR5在肿瘤中的作用

趋化因子是一类趋化粒细胞、单核细胞和巨噬细胞等炎症细胞定向迁移的细胞因子,它的功能由相应受体介导,两者不仅在炎症反应和过敏反应中发挥重要作用,亦参与肿瘤的生长、转移。研究显示,趋化因子可调节白细胞的肿瘤浸润、肿瘤相关的血管生成、激活宿主对肿瘤的特异性免疫应答、通过自分泌或旁分泌方式刺激肿瘤细胞增殖和控制肿瘤细胞运动等,其中趋化因子CXCL13及其受体CXCR5在多种肿瘤中异常表达且与肿瘤进展密切相关,探究其作用机制可为肿瘤免疫治疗提供新策略。     

CXCL13通过CXCR5激活星形胶质细胞中JNK参与痛觉过敏

目的:探讨CXCL13及其受体CXCR5参与痛觉过敏的机制.方法:细胞培养和免疫荧光染色检测脊髓背角神经元中CXCL13的表达;通过转染CXCL13和CXCR5过表达质粒研究CXCL13和CXCR5的相互作用;Western Blot方法检测CXCL13重组因子刺激原代星形胶质细胞后JNK磷酸化水平变化和鞘内注射CXC...     

趋化因子CXCL12及其受体CXCR4在神经系统疾病中的研究进展

大脑曾被认为是免疫豁免器官,正常情况下免疫系统的细胞和分子不能进入大脑,因此不会影响其功能.但越来越多的研究发现,神经系统和免疫系统存在一些共同的分子将这两个独立的系统联系起来,趋化因子及其受体尤其是CXCL12/CXCR4就是其中的代表.近年来的研究表明许多伴有中枢免疫功能异常的中枢神经系统疾病都伴有CXCL12/C...     

子宫内膜癌组织中趋化因子CXCL12及其受体CXCR4表达水平研究

目的 观察子宫内膜癌组织中趋化因子CXCL12及其受体CXCR4表达水平,探讨其与子宫内膜癌患者临床病理特征相关性。方法 收集2012年1月～2014年12月间入院接受手术的子宫内膜癌患者52例病理标本,年龄55.6±19.2岁,以正常子宫内膜26例为对照组,年龄52.3±16.5岁。采用免疫组化技术检测趋化因子CXCL12及其受体CXCR4在子宫内膜癌组织中的表达情况,并分析它们与FIGO分期、细胞分化程度、淋巴结转移和病理类型等临床病理特征的关系。结果 CXCL12和CXCR4在子宫内膜癌组织中阳性表达率分别为76.92%和69.23%,而在正常子宫内膜组织中则分别为34.62%和30.77%,差异具有统计学意义(χ²=11.826,P＜0.01)。CXCR4的表达与子宫内膜癌细胞分化程度存在差异,有统计学意义(均P＜0.05),且与分化高低呈正相关(r=0.386,P＜0.05)。在子宫内膜癌组织中,除CXCR4表达与细胞分化程度呈正相关外,CXCL12和CXCR4表达与临床分期、淋巴结转移和病理类型无相关性(P＞0.05)。结论 CXCL12和CXCR4在子宫内膜癌组织中表达明显升高,这可能在子宫内膜癌发生发展过程中发挥重要生物学作用。     

趋化因子CXCL12及其受体CXCR4在原发性十二指肠腺癌组织中的表达及意义

目的观察趋化因子CXCL12及其特异性受体CXCR4在原发性十二指肠腺癌组织中的表达,探讨两者在该病的发生、浸润和转移中的作用。方法应用免疫组织化学方法检测78例原发性十二指肠腺癌组织、癌旁组织以及正常十二指肠黏膜组织中CXCL12和CXCR4的表达情况,分析两者表达与患者临床病理参数和术后生存率之间的关系。结果 CXCL12和CXCR4在肿瘤组织、癌旁组织以及正常十二指肠黏膜组织中均有表达,肿瘤组织中的阳性表达率明显高于癌旁组织,癌旁组织又明显高于正常十二指肠黏膜组织(P均<0.05)。两者在肿瘤组织中的表达水平与肿瘤细胞分化程度、区域淋巴结转移情况、远处转移情况和TNM分期均有关(P均<0.05)。CXCL12和CXCR4阳性表达的患者其3年和5年生存率均明显低于阴性表达者(P均<0.05)。单因素分析还提示肿瘤细胞分化程度低、肿瘤浸润肠壁较深、区域淋巴结转移、远处转移和TNM分期较晚也为原发性十二指肠腺癌患者术后预后不良的因素,Cox多因素分析则认为其中CXCL12或CXCR4阳性、肿瘤细胞分化程度低、区域淋巴结转移和TNM分期较晚为独立影响因素。结论原发性十二指肠腺癌组织中CXCL12和CXCR4的过表达与其生物学行为及预后密切相关,检测两者表达对预测该病的转移及预后判断有一定的价值。     

CXCL12-CXCR4/CXCR7趋化因子轴在肿瘤中的研究进展

近年来,多种研究表明CXCR4与CXCR7在肿瘤的发生发展过程中发挥着重要作用,CXCL12-CXCR4/CXCR7趋化因子轴与肿瘤生长和转移的关系引起人们的关注。本文对CXCL12-CXCR4/CXCR7在肿瘤中的表达、促进肿瘤增殖、侵袭转移及与肿瘤干细胞相关性等方面作一综述,提示CXCL12-CXCR4/CXCR7轴可成为抗肿瘤药物治疗的新靶点。     

系统性红斑狼疮患者外周血滤泡辅助性T细胞与CXCR5及其配体CXCL13基因表达水平的研究

目的检测滤泡辅助性T细胞(Tfh)的CXCR5、CXCL13在系统性红斑狼疮(SLE)患者外周血中的表达,探讨其与SLE的发生及病情活动性的关系。方法 90例SLE患者和60例健康对照者,采用流式细胞术检测外周血单个核细胞(PBMC)中CXCR5+PD-1+/CD4+T细胞(Tfh)比例,酶联免疫吸附试验(ELISA)法检测血清中CXCR5、CXCL13浓度,实时荧光定量RT-PCR检测PBMC中CXCR5 mRNA、CXCL13 mRNA的表达。结果活动组SLE患者外周血Tfh比例(11.01%±1.31%)、血清中CXCR5、CXCL13浓度[分别为(368.21±171.56)pg/ml、(387.59±213.54)pg/ml]和CXCR5 mRNA、CXCL13 mRNA(分别为2.15±0.63、1.71±0.37)的表达均高于健康对照组[分别为1.78%±0.11%,(210.6±100.17)pg/ml,(149.45±104.52)pg/ml,0.53±0.22,0.46±0.13;均P<0.05];SLE患者外周血Tfh比例与CXCR5 mRNA的表达水平呈正相关(r=0.68,P<0.01),与SLEDAI亦呈正相关(r=0.67,P<0.01),其中CXCR5 mRNA的表达水平与SLEDAI呈高度正相关(r=0.82,P<0.01)。SLE患者外周血Tfh比例与CXCL13 mRNA的表达水平呈正相关(r=0.73,P<0.01),与SLEDAI亦呈正相关(r=0.87,P<0.01)。结论 SLE患者外周血中Tfh细胞比例、CXCR5、CXCL13明显升高,可能在其发病过程中起了一定的作用。     

趋化因子CXCL16及受体CXCR6在神经病理性疼痛小鼠背根神经节中的表达变化

目的:检测神经病理性疼痛小鼠背根神经节(dorsal root ganglion,DRG)中CXC型趋化因子配体16(C-X-C Motif Chemokine Ligand 16,CXCL16)及其受体CXCR6的表达情况,探讨CXCL16在疼痛的发生发展过程中所发挥的作用。方法:采用ICR小鼠进行坐骨神经分支选择性损伤(spared nerve injury,SNI),诱导神经病理性疼痛,取术侧不同时间点L4~6节段DRG,通过实时定量PCR、Western Blot和免疫荧光的方法,检测SNI后CXCL16和CXCR6的m RNA和蛋白表达变化;鞘内注射CXCL16重组多肽,观察对疼痛行为的影响。结果:(1)SNI 3 d后可见小鼠DRG中Cxcl16 m RNA的表达显著增加(P<0.001),可持续至14 d(P<0.001),SNI后7 d CXCL16蛋白表达也显著增加(P<0.05),免疫荧光结果表明CXCL16主要分布在DRG中小型神经元中;(2)CXCR6的m RNA和蛋白在SNI 7 d显著增加(P<0.05);(3)鞘内注射CXCL16多肽引起小鼠机械性触诱发痛。结论:外周神经损伤诱导CXCL16和CXCR6在DRG表达增加,CXCL16能够导致痛觉过敏,提示它可能在神经病理性疼痛中发挥作用。     

SFRP5、TRPV1、NT-pro-BNP在2型糖尿病周围神经病变中的表达及相关性分析

目的 分析SFRP5、TRPV1、NT-pro-BNP在2型糖尿病周围神经病变中的表达及相关性.方法 将我院2018年1月至2019年12月间收治的99例单纯糖尿病患者作为糖尿病组,97例糖尿病周围神经病变作为神经病变组研究对象,同期选择51例健康者作为对照组;采用酶联免疫吸附法检测血清中SFRP5、TRPV1、NT-...     

狼疮肾炎患者外周血中趋化因子受体CXCR4及其配体SDF—1α的表达研究

目的探讨趋化因子受体CXCR4及其配体基质细胞衍生因子-1（SDF-1）在狼疮肾炎（LN）外周血中的表达水平及意义。方法用流式细胞术分别检测健康对照组、LN患者组、非肾损害系统性红斑狼疮（SLE）患者组的外周血中CD3＋CD4＋T淋巴细胞、CD5＋CD8＋T淋巴细胞表面CxCR4的表达,采用双抗体夹心ABC—ELISA法检测以上各组血清SDF-1α浓度水平。结果健康对照组外周血中CD3＋CD4＋T淋巴细胞、CD3＋CD8＋T淋巴细胞表面CXCR4表达及SDF-1α表达水平均明显低于狼疮肾炎组和非肾损害SLE组,而非肾损害SLE患者组外周血中CD3＋CD4＋T淋巴细胞、CD5＋CD8＋T淋巴细胞表面CXCR4表达及SDF-1α表达水平也均明显低于LN组。结论SLE患者发病与CXCR4／SDF-1α高表达有关,LN患者发病与CXCR4／SDF—1α高表达有密切关系,提示CXCRd／SDF-1α可能在LN的发病中起重要作用。     

Chemokine contribution to neuropathic pain: Respective induction of CXCL1 and CXCR2 in spinal cord astrocytes and neurons

Recent studies have indicated an important role of chemokines such as CCL2 in the development of chronic pain. However, the distinct roles of different chemokines in the development and maintenance of neuropathic pain and in their interactions with neurons have not been clearly elucidated. We found that spinal nerve ligation (SNL) not only induced persistent neuropathic pain symptoms, including mechanical allodynia and heat hyperalgesia, but also produced sustained CXCL1 upregulation in the spinal cord. Double staining of immunofluorescence and in situ hybridization revealed that CXCL1 was primarily induced in spinal astrocytes. In cultured astrocytes, tumor necrosis factor-α induced robust CXCL1 expression via the activation of the c-jun N-terminal kinase. Intrathecal administration of CXCL1 neutralizing antibody transiently reduced SNL-induced pain hypersensitivity, suggesting an essential role of CXCL1 in neuropathic pain sensitization. In particular, intraspinal delivery of CXCL1 shRNA lentiviral vectors, either before or after SNL, persistently attenuated SNL-induced pain hypersensitivity. Spinal application of CXCL1 not only elicited pain hypersensitivity but also induced rapid neuronal activation, as indicated by the expression of phosphorylated extracellular signal-regulated kinase and cAMP response element binding protein, and c-Fos in spinal cord neurons. Interestingly, CXCR2, the primary receptor of CXCL1, was upregulated in dorsal horn neurons after SNL, and the CXCR2 antagonist SB225002 completely blocked the CXCL1-induced heat hyperalgesia. SB225002 also attenuated SNL-induced pain hypersensitivity. Collectively, our results have demonstrated a novel form of chemokine-mediated glial-neuronal interaction in the spinal cord that can drive neuropathic pain. Inhibition of the CXCL1-CXCR2 signaling may offer a new therapy for neuropathic pain management.     

糖尿病性周围神经病理性疼痛中circ-SCN9A的作用与临床价值

目的:研究钠电压门控通道α亚单位9(sodium voltage-gated channel alpha subunit 9,SCN9A)基因来源的环状RNA(circular RNA,circRNA)与糖尿病性周围神经病理性疼痛(diabetic peripheral neuro-pathic pain,DPNP)的...     

趋化因子配体5及其受体趋化因子受体2在急性白血病髓外浸润中的表达和意义

目的观察趋化因子配体5(CXCL5)及其受体趋化因子受体2(CXCR2)在急性白血病(AL)髓外浸润(EI)中的表达,并探讨其临床意义。方法 60例初治成人AL患者,急性髓系白血病(AML)41例,急性淋巴系白血病(ALL)19例,骨穿取骨髓,ELISA法测定骨髓液中CXCL5含量,流式细胞术检测骨髓细胞CXCR2的相对荧光强度,统计分析其表达水平。结果 AL组、对照组的骨髓液CXCL5浓度[M(Q)]分别为3 173.93(1 392.22)pg/m L、349.88(178.67)pg/m L,差异有统计学意义(U=0.000,P0.05),CXCR2相对荧光强度分别为71.03(32.94)、19.68(8.90),差异有统计学意义(U=0.000,P0.05);伴有EI与无EI的骨髓CXCL5表达水平分别为3 687.81(885.05)pg/m L、2 305.32(781.85)pg/m L,差异有统计学意义(U=29,P0.05),骨髓细胞CXCR2相对荧光强度分别为80.72(21.11)、50.37(14.38),差异有统计学意义(U=16,P0.05);但AML组与ALL组的患者骨髓CXCL5/CXCR2表达差异无统计学意义(P0.05)。有效的化疗可以使AL患者获得完全缓解,使骨髓CXCL5、CXCR2表达水平明显下调;但在表达水平与完全缓解率方面,AML组与ALL组差异无统计学意义(P0.05)。AL患者骨髓液CXCL5浓度和骨髓细胞CXCR2的表达呈正相关(r=0.809,P=0.000);同时,骨髓CXCL5、CXCR2的表达与骨髓幼稚细胞百分比、外周血白细胞计数均呈正相关(P均0.05);与年龄、外周血小板计数均无明显相关性(P均0.05)。结论 AL患者的骨髓CXCL5、CXCR2表达均上调,在伴有EI的患者尤为明显,CXCL5、CXCR2轴的高表达可用于预测急性白血病的EI。     

A randomized,double-blind,placebo-controlled trial evaluating the efficacy and safety of ABT-594 in patients with diabetic peripheral neuropathic pain

ABT-594 is a neuronal nicotinic acetylcholine receptor (NNR) agonist that exhibits potent analgesic activity in preclinical models of acute, chronic, and neuropathic pain. The purpose of this phase 2, randomized, multicenter, double-blind, placebo-controlled study was to evaluate the safety and analgesic efficacy of ABT-594 in patients with diabetic peripheral neuropathic pain (DPNP). A total of 266 DPNP patients were randomized 1:1:1:1 to receive placebo, ABT-594 150 μg BID, ABT-594 225 μg BID, or ABT-594 300 μg BID. Patients were titrated to a fixed-dose of ABT-594 over 7 days and remained at this dose for another 6 weeks. Compared to placebo, all three ABT-594 treatment groups showed significantly greater decreases on the average diary-based 0–10 Pain Rating Scale (PRS) score from baseline to final evaluation, the primary efficacy measure (placebo, −1.1; 150 μg BID, −1.9; 225 μg BID, −1.9; 300 μg BID, −2.0). The proportion of patients achieving at least a 50% improvement in the average diary-based PRS was greater in all three ABT-594 treatment groups. However, adverse event (AE) dropout rates were significantly higher in all three ABT-594 treatment groups (28% for 150 μg BID, 46% for 225 μg BID, and 66% for 300 μg BID) than for the placebo group (9%). Consistent with the expected side-effect profile of NNR agonists, the most frequently reported AEs were nausea, dizziness, vomiting, abnormal dreams, and asthenia. This study establishes proof of concept for NNR agonists as a new class of compounds for treating neuropathic pain.     

Chronic diabetic peripheral neuropathic pain: psychometric properties of pain and physical function outcome measures

Background: Diabetic peripheral neuropathy (DPN) not only produces severe pain, tingling, and numbness sensation in the involved limbs, but also limits physical function due to loss of sensation. There are no recommended methods for clinical situations to measure these signs and symptoms. Studies with high methodological quality use the modified Brief Pain Inventory for Diabetic Peripheral Neuropathic pain (mBPI-DPN) scale and the short form Screening of Activity Limitations and Safety Awareness (sSALSA) scale for measuring these symptoms in DPN population. In order to capture a real change in the variables of interest, the psychometric properties of that measure should be within acceptable limits. As these two measures were not assessed for all of the psychometric properties, there was a need for further evaluation.

Methods: Data were collected (n?=?38 patients) in a longitudinal cohort study. Test–retest reliability (0–4 weeks) and Responsiveness- Minimal Clinically Important Difference (MCID) (0–12 weeks) were calculated between two sessions. Convergent validity was assessed (between mBPI-DPN pain interference and sSALSA scale).

Results: Both measures demonstrated acceptable test–retest reliability (mBPI-DPN scale: ICC = 0.61, SEM = 12.92; the sSALSA scale: ICC = 0.81, SEM = 4.88) and convergent validity (Spearman’s correlation coefficient r?=?0.62). The computational methods used in different methodologies to calculate MCID for the mBPI-DPN and the sSALSA scale were varied, hence the magnitude of derived MCID scores also varied.

Conclusions: Our study have provided evidence to add to the scientific basis surrounding the use of mBPI-DPN and sSALSA scales in DPN population, but standardization of these measures in a larger population is required     

趋化因子SDF-1与受体CXCR4的研究进展

趋化因子SDF-1(stromal cell-derived factor-1)与其受体CXCR4( CXC chemokine receptor 4 )分别属于CXC类趋化因子和CXCR类G蛋白偶联受体超家族.功能研究表明,SDF-1/CXCR4轴在机体的免疫、炎症、胚胎发育、器官发生、肿瘤、HIV病、WHIM综合征...     

Association between serum Sestrin2 level and diabetic peripheral neuropathy in type 2 diabetic patients

BACKGROUNDDiabetic peripheral neuropathy (DPN) is a chronic and serious microvascular complication of diabetes linked to redox imbalance. Sestrin2, a novel inducible stress protein, participates in glucose metabolic regulation and redox homeostasis. However, the association between serum Sestrin2 and DPN is unknown.AIMTo explore the association between serum Sestrin2 and DPN in patients with type 2 diabetes mellitus (T2DM).METHODSA total of 96 T2DM patients and 39 healthy volunteers, matched by age and sex, participated in this cross-sectional study. Clinical features and metabolic indices were identified. Serum Sestrin2 was measured by ELISA. The association between Sestrin2 and DPN was studied. Correlation and logistic regression analyses were used to evaluate the associations of different metabolic indices with Sestrin2 and DPN.RESULTSThe 96 patients with T2DM were divided into DPN (n = 47) and patients without DPN (n = 49). Serum Sestrin2 was significantly lower in healthy volunteers than in all T2DM patients combined [9.10 (5.41-13.53) ng/mL vs 12.75 (7.44-23.80) ng/mL, P < 0.01]. T2DM patients without DPN also had significantly higher levels of Sestrin2 than healthy volunteers [14.58 (7.93-26.62) ng/mL vs 9.10 (5.41-13.53) ng/mL, P < 0.01]. However, T2DM patients with DPN had lower circulating Sestrin2 levels compared to T2DM patients without DPN [9.86 (6.72-21.71) ng/mL vs 14.58 (7.93-26.62) ng/mL, respectively, P < 0.01]. Bivariate correlation analysis revealed that serum Sestrin2 was positively correlated with body mass index (r = 0.672, P = 0.000), hemoglobin A1c (HbA1c) (r = 0.292, P = 0.000), serum creatinine (r = 0.206, P = 0.016), triglycerides (r = 0.731, P = 0.000), and fasting glucose (r = 0.202, P = 0.040), and negatively associated with estimated glomerular filtration rate (r = -0.230, P = 0.007). After adjustment for sex, age, HbA1c, and diabetes duration, multiple regression analysis revealed that Sestrin2 was independently correlated with body mass index and triglyceride levels (P = 0.000). Logistic regression analyses indicated that Sestrin2, diabetes duration, and high-density lipoprotein were strongly associated with DPN (odds ratio = 0.855, 1.411, and 0.041, respectively).CONCLUSIONOur results show Sestrin2 is decreased in T2DM patients with DNP. As lower Sestrin2 is independently associated with DPN, Sestrin2 may contribute to progression of DPN in T2DM patients.     

趋化因子SDF-1及其受体对卵巢癌细胞增殖及迁移的影响

目的:探讨趋化因子受体CXCR4在人卵巢癌细胞中的表达及SDF-1/CXCR4系统与卵巢癌细胞恶性表现的关系.方法:采用RT-PCR检测卵巢癌细胞系SW626中CXCR4的表达,MTT法检测SW626细胞增殖能力的变化,通过体外微孔隔离室板(Transwell)检测SDF-1对SW626细胞迁移及CXCR4的封闭对其迁移的影响.结果:CXCR4 mRNA在SW626细胞呈阳性表达,抗CXCR4单克隆抗体(20 μg/mL)对SW626细胞增殖有明显的抑制作用(P＜0.05),SDF-1可促进SW626细胞的迁移,CXCR4的封闭能抑制SDF-1对SW626迁移的这种促进作用(P＜0.05).结论:SDF-1及其受体CXCR4的相互作用可能在卵巢癌细胞增殖和迁移中发挥着重要作用,干扰SDF-1/CXCR4的相互作用可能成为治疗卵巢癌的一个有意义的靶点和策略.     

原发免疫性血小板减少症患者脾脏趋化因子受体CXCR3和CCR5的表达

目的 探讨趋化因子受体CXCR3和CCR5在原发免疫性血小板减少症(ITP)患者脾脏中的表达及其临床意义.方法 以10例ITP患者(ITP组)为研究对象,并以8例创伤性脾破裂患者脾切除标本作为正常对照.应用免疫组化法检测脾脏组织CXCR3、CCR5阳性表达率,用Western blot 法检测脾脏组织中CXCR3和CCR5的蛋白表达水平,逆转录聚合酶链反应检测CXCR3和CCR5mRNA表达水平.结果 免疫组化结果显示ITP患者脾脏组织CXCR3、CCR5阳性表达率(90％、100％)均高于对照组(75％、87.5％),差异均有统计学意义(P＜0.05);ITP患者脾脏组织CXCR3蛋白、mRNA表达量分别为对照组的3.0倍、3.5倍;CCR5蛋白、mRNA表达量分别为对照组的1.2倍、1.7倍,差异均有统计学意义(P＜0.05).结论 CXCR3及CCR5的高表达可能在ITP患者脾脏免疫紊乱中起着一定的作用.