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Yoshiya Tanaka Tsutomu Takeuchi Hisanori Umehara Toshihiro Nanki Nobuyuki Yasuda Fumitoshi Tago 《Modern rheumatology / the Japan Rheumatism Association》2018,28(1):58-65
Objective: Fractalkine (CX3CL1/FKN) is a chemokine that regulates chemotaxis and adhesion of CX3C chemokine receptor 1 (CX3CR1)-expressing inflammatory cells. We conducted the first phase 1/2, open-label, multiple ascending dose study of E6011, a humanized anti-FKN monoclonal antibody, in Japanese rheumatoid arthritis (RA) patients (clinicaltrial.gov identifier: NCT02196558).Methods: Active RA patients with an inadequate response or intolerance to methotrexate or tumor necrosis factor (TNF) inhibitor received E6011 at week 0, 1, 2, and thereafter every 2 weeks for 12 weeks.Results: Twelve, 15, and 10 subjects were enrolled in the 100, 200, and 400?mg cohorts, respectively. No severe adverse events (AEs) or deaths occurred, and no major differences were observed in the incidence or severity of AEs across the cohorts. Serum E6011 concentrations increased dose dependently. American College of Rheumatology (ACR) 20, 50, and 70 responses at week 12 were 75.0%, 33.3%, and 8.3% in the 100?mg cohort; 66.7%, 20.0%, and 13.3% in the 200?mg cohort; and 60.0%, 30.0%, and 20.0% in the 400?mg cohort, respectively.Conclusions: E6011 appeared to be safe and well tolerated in RA patients during this 12-week treatment period, suggesting that E6011 has an effective clinical response in active RA patients. 相似文献
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Atherosclerosis is currently considered an inflammatory disease. Much attention has been focused on the potential role of inflammatory mediators as prognostic/diagnostic markers or therapeutic targets of atherosclerotic cardiovascular disease. CX3CL1 (or fractalkine) is a structurally and functionally unique chemokine with a well documented role in atherosclerosis. In its membrane bound form it promotes the firm adhesion of rolling leucocytes onto the vessel wall, while in its soluble form it serves as a potent chemoattractant for CX3CR1-expressing cells. Additionally, CX3CL1 exerts cytotoxic effects on the endothelium as well as anti-apoptotic and proliferative effects on vascular cells, affecting the context and stability of the atherosclerotic plaque. Studies on animal models have shown that the blockade of the CX3CL1/CX3CR1 pathway ameliorates the severity of atherosclerosis, while genetic epidemiology has confirmed that a genetically-defined less active CX3CL1/CX3CR1 pathway is associated with a reduced risk of atherosclerotic disease in humans. Although several studies support an important pathogenic role of CX3CL1/CX3CR1 in atherogenesis and plaque destabilization, this does not necessarily suggest that this pathway is a suitable therapeutic target or that CX3CL1 can serve as a prognostic/diagnostic biomarker. Further studies on the CX3CL1/CX3CR1 chemokine pathway are clearly warranted to justify the clinical relevance of its role in atherosclerosis. 相似文献
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目的:利用大鼠模型观察慢性间歇低氧(chronic intermittenthypoxia,CIH)对肝的损伤以及对肝趋化因子fractalkine表达的影响,并探讨其可能的机制。方法:利用间歇低氧大鼠模型模拟阻塞性睡眠呼吸暂停低通气综合征(obstructive sleep apnea-hypopnea syndrome,OSAHS)的CIH的病理生理过程。30只雄性Spraque—Dawley大鼠随机分为5%慢性间歇低氧组、s%慢性间歇低氧复氧组和正常对照组,每组10只。5%慢性间歇低氧组给予间歇性低氧处理3周,低氧频率均为20次/h,每次循环180s,8h/d;s%慢性间歇低氧复氧组给予间歇性低氧处理3周,低氧频率均为20次/h,每次循环180s,8h/d,3周后继续正常气体环境饲养3周。处死大鼠后采用HE染色法观察各组大鼠肝组织病理改变,免疫组织化学法比较各组大鼠肝fractalkine的表达水平。结果:1)与正常对照组相比,5%慢性间歇低氧组和5%慢性间歇低氧复氧组大鼠肝脂肪变程度及炎症反应均增加(均P〈0.01);s%慢性间歇低氧复氧组大鼠肝损伤较5%慢性间歇低氧组显著减轻(P〈0.01)。2)与正常对照组相比,5%慢性间歇低氧组和5%慢性间歇低氧复氧组大鼠肝组织fractalkine表达均显著增强(均P〈O.01);5%慢性间歇低氧复氧组较5%慢性间歇低氧组显著减弱(P〈0.01)。结论:CIH可诱导大鼠肝组织损伤及大鼠肝组织趋化因子fractalkine表达增加。 相似文献
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目的 探讨急性冠脉综合征(acute coronary syndrome, ACS)早期单核细胞亚群及其趋化因子即单核细胞趋化蛋白-1 (monocyte chemoattractant protein, MCP-1)和不规则趋化因子(fractalkine, FKN)的表达特点,并分析其相关性。方法 选取我院2016年9月至12月以胸痛症状入院拟行冠脉造影术(coronary angiography, CAG)的患者。手术当天术前抽取静脉血,采用流式细胞术检测外周血单核细胞(monocyte, Mon) 3个亚型的含量及其比例,依据分化抗原-14 (cluster differentiation-14, CD-14)和CD16表达分为3个亚型即CD14+CD16-Mon (Mon1)、CD14+CD16+Mon (Mon2)和CD14-CD16+Mon (Mon3);手术当天术前及术后一天抽取静脉血,ELISA检测Mon1的趋化因子MCP-1和Mon3的趋化因子FKN水平,比较不同组MCP-1-Mon1和FKN-Mon3水平变化,并分析其相关性。结果共入选70例患者,结合其临床症状、心肌标志物、心电图、CAG检查结果进行诊断分组:急性心肌梗死(acute myocardium infarction, AMI)组患者30例、不稳定性心绞痛(unstable angina pectoris, UAP)组患者25例、CAG完全正常者(对照组) 15例。流式细胞术结果显示AMI组Mon1所占比例高于UAP组和正常对照组(P<0.05),Mon3在各组间尚无差异。AMI组患者外周血Mon3/Mon1比值低于对照组(P<0.05)。AMI组和UAP组患者FKN、MCP-1和红细胞分布宽度均高于对照组,并且FKN和Mon3具有强相关性(P<0.05;R=0.650 2)。结论 单核细胞亚群(Mon1和Mon3)在ACS早期水平增高,并伴有其负责招募的趋化因子(MCP-1和FKN)增加,且FKN和Mon3具有强相关性,提示MCP-1 Mon1和FKN-Mon3两条通路可能参与患者ACS早期病理生理过程。 相似文献
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Liran Franco Frances M.K. Williams Svetlana Trofimov Gabriela Surdulescu Timothy Spector Gregory Livshits 《Metabolism: clinical and experimental》2013
Objective
Plasma fractalkine (FRACT) is involved in the development of numerous inflammatory conditions including atherosclerosis. It is associated with type 2 diabetes mellitus and adipose inflammation. However, whether FRACT is associated with major risk factors for cardiovascular disease, in particular obesity, metabolic syndrome and blood lipids, is virtually unknown.Methods
The study included a large community-based sample of 3306 middle-aged women drawn from the general UK population. Blood samples were analyzed for circulating levels of FRACT, leptin, insulin, glucose, LDL-C, HDL-C, Apo-A, ApoB and IL-6. Obesity was assessed by fat body mass (FBM) using dual-energy x-ray absorptiometry and by body mass index (BMI).Results
We found no association between FRACT and body composition, in particular adiposity. Obese and non obese subjects with metabolic syndrome tended to have higher levels of FRACT compared with non-obese subjects without metabolic syndrome but this did not reach statistical significance. Most importantly we report significant correlations between FRACT and circulating IL-6, Apo-B, LDL-C and insulin. The associations with IL-6 and Apo-B were particularly significant (P-value < 0.001), and survived correction for multiple testing and adjustment for age and other covariates.Conclusion
Higher FRACT levels correlated with elevated levels of IL-6, Apo-B, LDL-C and insulin, all known risk factors for several clinical related diseases suggesting a potential role of FRACT in inflammation and tissue injury. Variations of FRACT levels are not influenced by body composition and are not correlated with leptin indicating that fat mass alone is not responsible for elevation of FRACT seen in obese individuals. 相似文献9.
Yun Wang Hong Chen Yonglun Fu Ai Ai Songguo Xue Qifeng Lyu Yanping Kuang 《International journal of clinical and experimental pathology》2013,6(12):2824-2834
MiR-195, which exhibits a proliferation-inhibiting role in different tumors, has been reported to be down-regulated in the ectopic endometrium. The aim of this study was to determine the impact of miR-195 on the biological characteristic of the endometrial stromal cells (ESCs). MiR-195 has been presumed to target the 3’-untranslated regions (3’-UTR) of Fractalkine (FKN), which also plays important roles in endometriosis. Fluorescence reporter assays showed that miR-195 effectively binds to the 3’-UTR of FKN. The normal ESCs showed a significant higher miR-195 expression than that of eutopic and ectopic ESCs associated with endometriosis, while the FKN expression showed opposite results. MiR-195 mimics inhibited proliferation and growth and induced apoptosis of eutopic ESCs, and these effects were abolished by FKN-siRNA. miR-195 could decrease the expression of survivin, matrix metalloproteinase-9 (MMP9) and up-regulate the expression of CD82, tissue inhibitor of metalloproteinase 1 (TIMP1) and TIMP2 of eutopic ESCs by targeting FKN. Our study has demonstrated for the first time that miR-195 plays important roles in regulating the functions of ESCs through targeting FKN. The information may be useful for developing a new therapeutic strategy for endometriosis. 相似文献
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M Nakano T Fujii M Hashimoto N Yukawa H Yoshifuji K Ohmura A Nakaizumi T Mimori 《Clinical and experimental immunology》2012,170(1):94-100
Type I interferon (IFN) medications cause various adverse reactions, including vascular diseases. Although an association between chemokines and vascular diseases has also been reported, the relationship between type I IFN and chemokines in vascular endothelial cells (VEC) remains unclear. To provide clues to pathogenesis of the diseases, we analysed the effects of type I IFN on chemokine production in human VEC. Type I IFN induced higher CX3CL1 (fractalkine) mRNA expression and protein secretion in pulmonary arterial VEC than in umbilical vein VEC. Type I IFN also induced CCL5 [regulated upon activation normal T cell expressed and secreted (RANTES)] production in VEC, especially in lung micro-VEC. IFN-β induced much higher chemokine production than IFN-α, and Janus protein tyrosine kinase (JAK) inhibitor I prevented type I IFN-induced chemokine secretion. Type I IFN-induced chemokines may be involved in the pathophysiology of pulmonary vascular diseases, and the JAK inhibitor may serve as a therapeutic option for these diseases. 相似文献