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关键词： Schlemm's canal endothelial cells (SC cells)   interleukin 6 (IL-6)   soluble interleukin 6 receptor (sIL-6R)   transforming growth factor β (TGF-β)  

摘要： Intraocular pressure (IOP) is regulated through the balance of production and drainage of aqueous humor. The main route of aqueous-humor outflow comprises the trabecular meshwork (TM) and Schlemm's canal (SC). We reported that IL-6 trans-signaling can inhibit TGF-β signaling in TM cells and may affect regulation of IOP. However, the function of IL-6 trans-signaling in SC cells remains unclear. Therefore, we investigated the role of IL-6 trans-signaling in monkey SC cells. Simultaneous treatment with IL-6 and soluble IL-6 receptor (sIL-6R) significantly decreased the trans-endothelial electrical resistance (TER) of SC cells and reduced aqueous-humor outflow resistance. Moreover, activation of IL-6 trans-signaling significantly reduced expression of fibronectin, ZO-1 and claudin-5, and increased that of several matrix metalloproteinases. We also investigated the effect of IL-6 trans-signaling on TGF-β2-induced changes in SC cells. Simultaneous treatment with IL-6 and sIL-6R significantly suppressed the TGF-β2-induced increase in the TER of SC cells but did not affect the activity of the TGF-β2 signaling pathway. By contrast, the TGF-β2-induced increases in the expression of fibronectin and collagen type I were significantly decreased upon simultaneous treatment with IL-6 and sIL-6R. The results show that IL-6 trans-signaling suppressed TGF-β2-induced increase in outflow resistance.

关键词： HUVECs   IKKα   IL-1β   NFκB   Signalling   TAK-1  

摘要： In this study we examined the activation of the non-canonical NFκB signalling pathway in endothelial cells. In HUVECs, LIGHT stimulated a delayed induction of serine 866/870 p100 phosphorylation linked to p52 NFκB formation. Surprisingly, the canonical ligand, IL-1β, stimulated a rapid phosphorylation or p100 which was not associated with p52 formation. Inhibition of IKKα activity, using DN-IKKα adenovirus, IKKα siRNA or a novel first-in-class selective IKKα inhibitor, SU1261, revealed IL-1β induced p100 phosphorylation to be dependent on IKKα. In contrast, IKKβ inhibition was found to be without effect. The NIK inhibitor, CW15337, did not affect IL-1β induced p100 phosphorylation however, both p100 and pIKKα/β phosphorylation was substantially reduced by inhibition of the upstream kinase TAK-1, suggesting phosphorylation of p100 is mediated by IKKα from within the canonical NEMO/IKKβ /IKKα complex. IL-1β also stimulated a rapid increase in nuclear translocation of p52, which was not affected by NIK inhibition, suggesting a source of p52 independent of p100 processing. Inhibition of TAK-1 abolished p52 and p65 nuclear translocation in response to IL-1β. SiRNA deletion or inhibition with dominant-negative virus of IKKα activity partially reduced p52 translocation, however pharmacological inhibition of IKKα was without effect. Inhibition of IKKβ abolished both p52 and p65 translocation. Taken together these results show that IL-1β stimulates a novel IKKα -dependent axis within the non-canonical NFκB pathway in endothelial cells which is NIK-independent and regulated by TAK-1. However, this pathway is not primarily responsible for the early nuclear translocation of p52, which is dependent on IKKβ. Elucidation of both these new pathways may be significant for NFκB biology within the endothelium.

关键词： 卵形鲳鲹   IRF3   原核表达   多克隆抗体  

摘要： 干扰素调节因子（Interferon Regulatory Factor,IRF）3可调节干扰素（Interferon,IFN）表达，在抗病免疫反应中起重要作用。为了获得卵形鲳鲹IRF3（Tro IRF3）的体外重组蛋白及其多克隆抗体，本研究利用pET32a（+）/Escherichia coli BL21（DE3）表达系统对Tro IRF3进行诱导表达，在0.1 mmol·L-1的IPTG和20℃的条件下诱导24 h，获得可溶性的重组蛋白r Tro IRF3，其分子量大小为51 kDa；经镍离子柱亲和层析纯化，得到电泳纯的r Tro IRF3；将r Tro IRF3免疫小鼠以制备多克隆抗体，并通过Western Blotting和ELISA检测多克隆抗体的效价，结果显示，所制备的多克隆抗体的效价高达1∶25 600，能与重组蛋白特异性结合，可用于后续探究Tro IRF3参与机体抗病原侵染的机制研究。

关键词： Type 2 diabetes mellitus   Diabetic kidney disease   IL-2 receptor  

摘要： ObjectivesThe aim of this study was to determine the association of serum soluble IL-2 receptor alpha (sIL-2RA) with T2DM-related characteristics and complications. MethodsSerum sIL-2RA levels were determined in 156 T2DM patients, and the association with T2DM-related characteristics and complications was evaluated. ResultsSerum sIL-2RA levels were significantly increased in T2DM patients with diabetic kidney disease (DKD) (median, IQR, 1434.9, 958.1-1896.0, pg/ml), in comparison with those without DKD (median, IQR, 851.2, 660.2-1089.9, pg/ml)(P < 0.001). The ROC analysis revealed good performance of sIL-2RA for identifying DKD, with the areas under the curve of 0.789 (95%CI of 0.711-0.867, P < 0.001). The correlation analyses showed significantly positive correlations of serum sIL-2RA with urea (r = 0.458, P < 0.001), creatinine (r = 0.508, P < 0.001) and uACR (r = 0.469, P < 0.001), and negative correlation with eGFR (r=-0.561, P < 0.001). The multivariate analyses showed that serum sIL-2RA was independently associated with the increased risks of DKD (OR, 95%CI, 6.539, 1.401-30.529, P = 0.017) and DR (OR, 95%CI, 3.606, 1.073-12.114, P = 0.038). Additionally, serum sIL-2RA was significantly associated with inflammatory indicators in DKD patients, and with metablic indicators in non-DKD patients (all P < 0.05). ConclusionSerum sIL-2RA may be closely associated with inflammation, glucose and lipid metabolisms, DKD and DR risks in T2DM. Furthermore, it may be a potential biomarker for T2DM-related micro-vascular complications.

关键词： 甘草次酸   失血性休克   急性肺损伤   炎症因子  

摘要： 目的 探讨18β-甘草次酸（18β-glycyrrhetinic acid，18β-gly）对失血性休克大鼠肺组织损伤及炎症因子TNF-α、IL-1β的影响。方法 实验用SD雌性大鼠随机分为5组：假手术组、模型组、18β-Gly/低剂量组、18β-Gly/中剂量组、18β-Gly/高剂量组，通过18β-甘草次酸预处理，采用股动脉放血制作失血性休克大鼠模型，检测大鼠失血性休克后肺组织湿/干比、肺组织病理形态变化、血液及肺泡灌洗液中炎症因子TNF-α、IL-1β的表达情况。结果 与模型组相比，18β-Gly/高剂量组肺湿/干比（4.409±0.062）降低比较明显（P＜0.05）；血液及肺泡灌洗液中18β-Gly/中剂量组和18β-Gly/高剂量组，TNF-α和IL-1β的表达均明显减少（P＜0.05）。HE显示，与模型组相比，18β-Gly/中剂量组和18β-Gly/高剂量组病理损伤明显减轻。结论 18β-Gly能减轻失血性休克大鼠肺水肿和肺组织病理损伤，降低血液及肺泡灌洗液中炎症因子TNF-α、IL-1β的表达。

关键词： 类风湿关节炎   胶原诱导关节炎   多形核-髓源性抑制细胞   B细胞活化因子   干扰素   JAK1抑制剂  

摘要： 目的：通过研究多形核-髓源性抑制细胞（polymorphonuclear myeloid- derived suppressor cells，PMN-MDSCs）高表达B细胞活化因子（B-cell activating factor， BAFF）的具体机制，为治疗类风湿关节炎（Rheumatoid Arthritis，RA）提供新的思路及理论依据。方法：通过ELISA检测胶原诱导性关节炎(collagen induced arthritis，CIA)小鼠血清中IFN-β、IFN-γ和TGF-β1细胞因子水平；采用流式细胞术、RT-qPCR检测IFN-γ对PMN-MDSCs的BAFF调控以及JAK-STAT通路相关基因表达的影响；通过流式细胞术、RT-qPCR、H&E和TRAP染色检测JAK1抑制剂对PMN-MDSCs表达BAFF的影响以及对CIA小鼠的治疗作用。结果：CIA小鼠血清中IFN-γ水平显著升高，IFN-γ在体外上调PMN-MDSCs BAFF表达；IFN-γ通过调控JAK-STAT通路和BAFF上游IFIT1、IFIT2、IRF1、IRF2、ISG15、RSAD2 基因促进PMN-MDSCs表达BAFF；Filgotinib（JAK1抑制剂）可逆转IFN-γ对PMN-MDSCs BAFF表达的影响，同时抑制BAFF上游IFIT1、IFIT2、IRF1、IRF2、ISG15、RSAD2基因；Filgotinib治疗可缓解CIA小鼠关节炎症，抑制各组织中PMN-MDSCs表达BAFF；Filgotinib治疗对CIA小鼠Th1、Th17和ThGM无显著影响。结论：IFN-γ通过JAK-STAT信号通路上调PMN-MDSCs BAFF表达，从而参与RA的发病。

关键词： Autoimmune diseases   Autoimmunity   Cytokines   T cells   Therapeutics  

摘要： Deficits in IL-2 signaling can precipitate autoimmunity by altering the function and survival of FoxP3+ regulatory T cells (Tregs) while high concentrations of IL-2 fuel inflammatory responses. Recently, we showed that the non-beta IL-2 SYNTHORIN molecule SAR444336 (SAR'336) can bypass the induction of autoimmune and inflammatory responses by increasing its reliance on IL-2 receptor alpha chain subunit (CD25) to provide a bona fide IL-2 signal selectively to Tregs, making it an attractive approach for the control of autoimmunity. In this report, we further demonstrate that SAR'336 can support non-beta IL-2 signaling in murine Tregs and limit NK and CD8+ T cells' proliferation and function. Using a murine model of spontaneous type 1 diabetes, we showed that the administration of SAR'336 slows the development of disease in mice by decreasing the degree of insulitis through the expansion of antigen-specific Tregs over Th1 cells in pancreatic islets. Specifically, SAR'336 promoted the differentiation of IL-33-responsive (ST2+), IL-10-producing GATA3+ Tregs over other Treg subsets in the pancreas, demonstrating the ability of this molecule to further orchestrate Treg adaptation. These results offer insight into the capacity of SAR'336 to generate highly specialized, tissue-localized Tregs that promote restoration of homeostasis during ongoing autoimmune disease.

关键词： ST段抬高型心肌梗死   经皮冠状动脉介入治疗   中性粒细胞/淋巴细胞比值   单核细胞/高密度脂蛋白胆固醇比值   造影剂肾病   预测  

摘要： 背景 既往研究发现中性粒细胞、单核细胞计数增多和高密度脂蛋白胆固醇减少与ST段抬高型心肌梗死（STEMI）相关，然而中性粒细胞/淋巴细胞比值（NLR）、单核细胞/高密度脂蛋白胆固醇比值（MHR）与急诊经皮冠状动脉介入治疗（PCI）术后发生造影剂肾病（CIN）的相关性研究较少。目的 探究NLR、MHR及两者联合对STEMI患者急诊PCI术后CIN的预测价值。方法 选取2019—2022年在扬州大学附属苏北人民医院接受急诊PCI的437例STEMI患者为研究对象，根据入组患者术后是否发生CIN，分成CIN组（65例）和非CIN组（372例）。收集患者一般资料及实验室检查指标，计算NLR和MHR的数值，并比较2组患者临床资料。运用单因素及多因素Logistic回归分析筛选出STEMI患者PCI术后发生CIN的独立危险因素。绘制NLR、MHR及两者联合预测STEMI患者PCI术后发生CIN的受试者工作特征（ROC）曲线，并计算ROC曲线下面积（AUC）评估NLR、MHR及两者联合对CIN发生的预测效能。结果 CIN组患者2型糖尿病史、利尿剂使用、白细胞计数、中性粒细胞计数、单核细胞计数、空腹血糖、NLR、MHR水平高于非CIN组，血红蛋白、淋巴细胞计数和肌酐水平低于非CIN组（P<0.05）。多因素Logistic回归分析结果显示，2型糖尿病史（OR=1.997,95%CI=1.063～3.751,P=0.032）、单核细胞计数（OR=2.372,95%CI=1.060～5.310,P=0.036）、NLR(OR=1.311,95%CI=1.171～1.468,P<0.001)、MHR(OR=7.075,95%CI=1.893～26.439,P=0.004)水平升高为STEMI患者急诊PCI术后CIN的独立危险因素。ROC曲线结果显示，NLR、MHR及两者联合预测STEMI患者急诊PCI术后CIN的AUC分别为0.733(95%CI=0.669～0.796,P<0.001)、0.706(95%CI=0.633～0.779,P<0.001)、0.796(95%CI=0.740～0.852,P<0.001)；灵敏度分别为66.2%、60.0%、69.2%；特异度分别为71.8%、75.3%、73.1%。结论 2型糖尿病史、单核细胞计数、NLR、MHR水平升高为STEMI患者急诊PCI术后发生CIN的独立危险因素；NLR、MHR及两者联合均可作为有效识别STEMI患者急诊PCI术后发生CIN的早期生物标志物。

关键词： Hyperuricemia   Metabolomics analysis   Tinospora crispa (L.) Hook.f. & Thomson   Urate transporters   Xanthine oxidase  

摘要： ETHNOPHARMACOLOGICAL RELEVANCE:Tinospora crispa (L.) Hook.f. & Thomson (T. crispa), is widely distributed in Xishuangbanna, Yunnan Province, China. According to the "Selected Medicinal Plants of Yunnan", T. crispa is recognized for its versatile medicinal properties, including promoting diuresis, reducing swelling, relieving pain, relaxing tendons, and promoting blood circulation, suggesting that their extracts can be used to exhibit a range of beneficial activities such as immune regulation, blood sugar reduction, and anti-inflammatory effects. In the Dai ethnic areas of China, T. crispa is commonly employed in the herbal prescription of treatment of hyperuricemia and gouty arthritis. However, further study is needed to enucleate the potential pharmacological mechanism of T. crispa. AIM OF THE STUDY:This study aimed to investigate the effects and mechanisms of T. crispa vines extract (TC) in alleviating hyperuricemia. MATERIALS AND METHODS:A hyperuricemia mouse model was established through intraperitoneal injection of potassium oxonate to evaluate the hypouricemic effects of TC. To explore the underlying mechanisms of TC, network pharmacology analysis was employed. Additionally, a series of experimental approaches-including serum biomarker assays, ELISA, reverse transcription-quantitative PCR (RT-qPCR), histopathological staining, metabolomics analysis and western blotting-were performed to assess the capability of TC in modulating uric acid levels. RESULTS:TC treatment markedly lowered serum biomarkers by inhibiting xanthine oxidase (XOD) activity and modulating the expression of urate transporters, while also alleviating renal injury in hyperuricemic mice. Through bioinformatics and network pharmacology analyses, the NOD-like receptor signaling pathway was identified as a critical mechanism underlying the therapeutic impact of TC. Metabolomics analysis uncovered 14 differential metabolites and seven metabolic pathways linked to the anti-hyperuricemic action of T