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关键词： 大黄游离蒽醌   重症急性胰腺炎   细胞因子风暴   糖原代谢  

摘要： 早期识别和及时干预细胞因子风暴（CS）对于急性胰腺炎患者非常重要，可以有效改善患者的预后。大黄游离蒽醌（FTRAs）具有抗炎及免疫调节作用，能改善急性炎症反应，为探究FTRAs对糖原代谢途径及下游尿苷二磷酸葡萄糖/嘌呤能受体14-信号转导与转录激活因子1（UDPG/P2Y14-STAT1）通路对重症急性胰腺炎（SAP）大鼠CS的影响，首先通过胰胆管逆行注射牛黄胆酸钠（NaTc）建造SAP大鼠模型，于手术后0 h、12 h、24 h给予FTRAs（22.5、45和90 mg/kg）、大黄（900 mg/kg，阳性对照）或等量的生理盐水，进行胰腺损伤后CS严重程度与UDPG的相关性分析，后采用分子对接技术检测FTRAs的有效成分与糖原代谢通路基因间的关联度，再通过提取SAP大鼠腹腔巨噬细胞进行UDPG/P2Y14-STAT1通路机制研究，最后给予糖原磷酸化酶抑制剂（GPI，5 mg/kg）进行机制验证。结果表明：（1）FTRAs缓解SAP大鼠的胰腺损伤，降低血清淀粉酶（AMS）、脂肪酶（LPS）活性（P < 0.01）；FTRAs能降低SAP大鼠血清中促炎因子和UDPG水平（P < 0.05）；UDPG与AMS、LPS、白细胞介素（IL）-1β、肿瘤坏死因子-α（TNF-α）、IL-6、干扰素（IFN）-γ的Pearson相关性分析结果呈良好正相关性（P < 0.001）。（2）FTRAs主要活性成分与肝糖原磷酸化酶（PYGL）和糖原合成酶1（GYS1）具有较强对接活性，与UDP-葡萄糖焦磷酸化酶2（UGP2）和P2Y14具有一般对接活性，与STAT1对接活性较差。（3）FTRAs及GPI抑制大鼠腹腔巨噬细胞PYGL、UGP2、GYS1、P2Y14、STAT1蛋白表达（P < 0.05）。本研究表明SAP大鼠病程早期存在糖原代谢及P2Y14-STAT1炎症通路过度激活的现象，该通路的异常激活与CS密切相关，通过FTRAs干预后，能明显抑制SAP大鼠糖原代谢途径及后续的P2Y14-STAT1炎症通路，减轻大鼠的CS严重程度。（图8表1参54）

关键词： TGF-beta   IL-1 beta   intracellular calcium levels   voltage-operated calcium channels   L-type calcium channels   bone marrow mesenchymal stem cells   chondrocytes   chondrogenesis  

摘要： Background: Transforming growth factor-beta (TGF-beta) and interleukin 1 beta (IL-1 beta) are key regulators of the chondrogenic differentiation, physiology and pathology of cartilage tissue, with TGF-beta promoting chondrogenesis and matrix formation, while IL-1 beta exerts catabolic effects, inhibiting chondrogenesis and contributing to cartilage degradation. Both cytokines alter the intracellular calcium ion (iCa2+) levels;however, the exact pathways are not known. Objectives: This study aimed to evaluate the impact of TGF-beta 3 and IL-1 beta on calcium homeostasis in human bone marrow-derived mesenchymal stem cells (hBM-MSCs) and chondrocytes during chondrogenesis. Results: TGF-beta 3 increased iCa2+ levels in both hBM-MSCs and chondrocytes. Furthermore, TGF-beta 3 increased the functional activity of L-type voltage-operated calcium channels (L-VOCCs) in hBM-MSCs but not in chondrocytes. TGF-beta 3 and IL-1 beta reduced L-VOCCs subunit CaV1.2 (CACNA1C) gene expression in chondrocytes. In hBM-MSCs, TGF-beta 3 and IL-1 beta increased SERCA pump (ATP2A2) gene expression, while in chondrocytes, this effect was observed only with TGF-beta 3. Conclusions: TGF-beta 3 increases iCa2+ both in osteoarthritic chondrocytes and hBM-MSCs during chondrogenesis. In hBM-MSCs, TGF-beta 3-mediated elevation in iCa2+ is related to the increased functional activity of L-VOCCs. IL-1 beta does not change iCa2+ in osteoarthritic chondrocytes and hBM-MSCs;however, it initiates the mechanisms leading to further downregulation of iCa2+ in both types of cells. The differential and cell-specific roles of TGF-beta 3 and IL-1 beta in the calcium homeostasis of osteoarthritic chondrocytes and hBM-MSCs during chondrogenesis may provide a new insight into future strategies for cartilage repair and osteoarthritis treatment.

摘要： Photosensitivity is observed in numerous autoimmune diseases and drives poor quality of life and disease flares. Elevated epidermal type I interferon (IFN) production primes for photosensitivity and enhanced inflammation, but the substrates that sustain and amplify this cycle remain undefined. We show that IFN-induced Z-DNA binding protein 1 (ZBP1) stabilizes ultraviolet (UV) B-induced cytosolic Z-DNA derived from oxidized mitochondrial DNA. ZBP1 is up-regulated in the epidermis of adult and pediatric patients with autoimmune photosensitivity. In patient-derived samples, lupus keratinocytes accumulate extensive cytosolic Z-DNA after UVB exposure, and transfection of keratinocytes with Z-DNA results in stronger IFN production through cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) activation compared with the more conventional B-DNA. ZBP1 knockdown abrogates UVB-induced IFN responses, whereas overexpression results in a lupus-like phenotype with spontaneous Z-DNA accumulation and IFN production. Our results highlight Z-DNA and ZBP1 as critical mediators for UVB-induced inflammation and uncover how type I IFNs prime for cutaneous inflammation in photosensitivity.

关键词： Cohort study   TNF-alpha   Cancer   Leukemia   Lymphoma  

摘要： This retrospective cohort study included all user of tumor necrosis factor-alpha inhibitors (TNFi), including etanercept, infliximab, adalimumab, and golimumab, among Korean patients with psoriasis and rheumatoid arthritis (N of user = 7,645) and the non-user who was diagnosed with same diseases, never used TNFi, and was served as the reference. Cumulative usage of TNFi was calculated between the newly diagnosed date and index date (2-year from the diagnosed date). Adjusted hazard ratio (aHR [95% confidence intervals (CIs)]) for colorectal, liver, lung, kidney, breast, and thyroid cancer were not significantly increased or decreased: 0.92 [0.61-1.38], 0.90 [0.53-1.53], 1.00 [0.73-1.37], 1.20 [0.62-2.34], 0.91 [0.62-1.34], and 0.91 [0.66-1.26], respectively. The increased risk of lymphoma in the infliximab user (2.49 [1.33-4.66];p < 0.01) was statistically significant. Similarly, the risk of leukemia increased significantly in the etanercept (3.87 [1.71-8.76];p < 0.01) and adalimumab (3.36 [1.65, 6.84];p < 0.001) user. Accumulated prescriptions of TNFi for two years did not increase the incidence of cancer, except lymphoma and leukemia. Since the use of TNFi increases the risk of leukemia and lymphoma, a decision for frequent prescription of TNF-alpha inhibitors should be more careful.

关键词： 克罗恩病   疗效   影响因素   安全性   乌司奴单克隆抗体  

摘要： 目的　分析乌司奴单克隆抗体(UST)治疗中重度克罗恩病(CD)的疗效和安全性以及影响临床结局的相关因素。方法　回顾性收集2020年11月－2023年5月于浙江中医药大学附属第一医院和杭州市中医院使用UST治疗的中重度CD患者，根据既往是否使用生物制剂治疗分为一线治疗组(未使用生物制剂治疗，n=68)与二线治疗组(使用生物制剂治疗，n=66)。比较两组患者的基线特征(包括年龄、性别、吸烟状况、病程、确诊年龄、病变部位、疾病行为、肛周疾病、肠道手术史和CD相关药物使用情况等)；于基线、第14周、第52周记录患者罗恩病活动指数(CDAI)，评估第14、52周的临床疗效；于基线和第52周行内镜检查，评估第52周的内镜疗效、药物持续治疗率、治疗期间药物安全性；采用单因素和多因素logistic回归分析探讨第52周临床缓解和治疗失应答的影响因素。结果　共纳入134例CD患者，UST治疗第14周的临床应答率和临床缓解率分别为75.4(101/134)和33.6%(45/134)；一线治疗与二线治疗的临床疗效比较差异无统计学意义(临床应答率：77.9% vs. 72.7%，P=0.484；临床缓解率：38.2% vs. 28.8%，P=0.247)。UST治疗第52周的临床应答率和临床缓解率分别为79.9%(107/134)和56.0%(75/134)，内镜应答率和内镜缓解率分别为70.9%(95/134)和38.8%(52/134)；一线治疗与二线治疗的临床疗效(临床应答率：80.9% vs.78.8%，P=0.763；临床缓解率：60.3% vs. 51.5%，P=0.306)和内镜疗效(内镜应答率：76.5% vs. 65.2%，P=0.149；内镜缓解率：42.6% vs. 34.8%，P=0.354)比较差异无统计学意义。UST治疗第52周的药物持续治疗率为85.8%(115/134)，药物不良反应发生率为4.5%(6/134)。二线治疗组采取剂量优化治疗者的比例明显高于一线治疗组(45.5% vs. 22.1%，P=0.004)。多因素logistic回归分析显示，第14周临床应答是第52周临床缓解的独立影响因素，肛周疾病和肠道手术史是治疗失应答的独立影响因素(P<0.05)。结论　UST可有效改善CD患者的临床疗效及内镜表现，具有较好的药物安全性。第14周临床应答与第52周临床缓解存在相关性，且有肛周疾病和肠道手术史的患者易出现治疗失应答。

关键词： Myoblasts   Inflammation   Skeletal muscles   Analysis of variance   MTT assay   Cytokine therapy   Cytokines   Enzyme-linked immunoassays  

摘要： Muscle inflammation is one of the hallmarks of Duchenne muscular dystrophy (DMD). Dystrophin-deficient skeletal muscle cells produce higher levels of pro-inflammatory cytokines such as interleukin 1 beta (IL-1 beta) in response to toll-like receptor stimulation compared to normal muscle skeletal cells. IL- 1 beta induces the human skeletal muscle secretion of the myokine Interleukin-6 (IL-6). Here, we evaluated the effect of a human IgG1 kappa monoclonal antibody (canakinumab (Ilaris (R))) that specifically blocks the IL-1 beta effect on IL-6 secretion by human skeletal muscle cells. Canakinumab is an excellent candidate for therapeutic repositioning to treat DMD because it is an FDA-approved drug to treat periodic fever syndromes and systemic juvenile idiopathic arthritis. Unlike previous generations of IL-1 inhibitors, canakinumab is highly specific for the IL-1 beta ligand, has a longer half-life, and does not interfere with other IL-1-activated inflammatory pathways. Following cell culture optimization and viability assays to assess toxicity, skeletal muscle cells were stimulated with IL-1 beta (10 ng/mL) for 48 hours in the presence of nine concentrations of canakinumab ranging from 0.001 nM to 1000 nM, and IL-6 production was measured with an enzyme-linked immunosorbent assay. Pre-incubation of myoblasts with canakinumab before IL-1 beta-stimulation, significantly reduced IL-6 production at concentrations of 1, 10, 100, 250, and 1000 nM relative to controls, yielding an IC50 of 0.264 nM. On the other hand, co-incubation of canakinumab with IL-1 beta before addition to myoblasts resulted in a significant inhibition with the IC50 reducing to 0.126 nM, less than half of the previous method. Canakinumab also did not affect myotube viability at 10 nM and was also able to significantly reduce the production of IL-6, when the cells were stimulated with IL-1 beta (10 ng/ml). Taken together, our results show that canakinumab is a potent inhibitor of IL-1 beta signaling

关键词： 脓毒症   白细胞介素-5   急性肾损伤   细胞焦亡   NLRP3炎症小体  

摘要： 目的：探究白细胞介素-5(IL-5)对脓毒症所致小鼠急性肾损伤的影响及机制。方法：盲肠结扎穿孔法（CLP）构建小鼠脓毒症急性肾损伤模型，40只小鼠随机分为假手术（Sham）组、脓毒症模型（CLP）组、IL-5干预（CLP+IL-5）组、假手术+IL-5(Sham+IL-5)组。造模后24 h取材，ELISA检测各组小鼠血清中肿瘤坏死因子-α(TNF-α)、IL-6、IL-1β、肌酐（Scr）、尿素氮（BUN）的含量；HE染色观察肾脏病理学改变；TUNEL染色检测肾组织细胞凋亡情况；Western Blot检测肾脏组织中NLRP3、caspase-1蛋白表达。结果：IL-5减轻了脓毒症小鼠肾脏病理损伤程度，降低脓毒症小鼠血清中TNF-α、IL-6、IL-1β、Scr、BUN的浓度及肾组织NLRP3、caspase-1蛋白表达水平（P<0.05），抑制细胞凋亡与炎症反应，改善脓毒症相关急性肾损伤。结论：IL-5能够抑制全身炎症反应，从而减轻脓毒症所致的急性肾损伤，其作用机制可能与IL-5抑制NLRP3炎症小体的激活以及caspase-1介导的经典细胞焦亡途径的活化相关。

关键词： Myeloid-Derived Suppressor Cells   Immune Checkpoint Inhibitor   Immunosuppression   JAK-STAT   Lung Cancer  

摘要： Background Some patients with non-small-cell lung cancer (NSCLC) benefit from immune checkpoint inhibitors (ICIs) despite programmed death-ligand 1 (PD-L1) expression. To address the mechanism of ICI resistance in PD-L1-positive NSCLC, we investigated the role of tumor-cell-intrinsic function of PD-L1 in interleukin (IL)-6-mediated *** Cohorts of NSCLC patients treated with ICI and public datasets were analyzed. PD-L1-overexpressing and PD-L1-knockdown NSCLC cells were submitted to RNA-seq, in vitro analyses, chromatin immunoprecipitation-qPCR, CUT&Tag, and biochemical assays. Human myeloid-derived suppressor cells (MDSCs) sorted from peripheral blood mononuclear cells were co-cultured with NSCLC cells and then assessed for their immunosuppressive activity on T-cells. Mouse Lewis lung carcinoma (LLC) cells with PD-L1 overexpression or knockdown were subcutaneously injected into wild-type or PD-1-knockout C57BL/6 mice in the presence of IL-6 and/or PD-1 *** In the ICI cohort with RNA-seq data, the IL-6/Jak/Stat3 pathway was enriched, and IL-6 expression was higher in patients with PD-L1-high NSCLCs who did not respond to ICIs. In another cohort, a higher baseline serum IL-6 level was associated with poor clinical outcomes after ICI therapy. IL-6 expression and the IL-6/Jak/Stat3 pathway were enhanced in PD-L1-high NSCLCs in the ICI cohorts and The Cancer Genome Atlas analysis. IL-6 expression correlated positively with tumor-infiltrating MDSCs in NSCLCs. In NSCLC cells, PD-L1 activated Jak2/Stat3 signaling by binding to and inhibiting protein tyrosine phosphatase 1B. PD-L1 also bound to p-Stat3 in the nucleus, thus promoting the activity of p-Stat3 in the transcription of several cytokines (IL-6, TGF-beta, TNF-alpha, IL-1 beta) and chemokines. PD-L1-overexpressing NSCLC cells enhanced the migration and immunosuppressive activity of human MDSCs in vitro, mediated by IL-6 and CXCL1. In both wild-type and PD-1-knockout mice, PD-L1-over