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关键词： Airway inflammation response   Allergic asthma   Ferroptosis   GPX4   IL-33   Inflammation   Therapeutic Targets  

摘要： In the context of asthma pathophysiology, especially during exacerbations and airway inflammation, interleukin-33 (IL-33) holds a pivotal role. This study delves into elucidating the impact of IL-33 on ferroptosis during asthma exacerbations. Through comprehensive transcriptomic and proteomic analyses, IL-33 and GPX4 emerged as crucial regulators in this intricate process. In vitro experiments showcased the remarkable anti-inflammatory and ferroptosis-mitigating effects of an IL-33 antibody in IL-13-induced BEAS-2B cells. Subsequent in vivo validation in mice underscored the ability of the IL-33 antibody to diminish inflammatory responses, enhance GPX4 expression, and ameliorate asthma symptoms. These compelling findings suggest that the IL-33 antibody holds promise in suppressing ferroptosis, alleviating inflammation, and modulating GPX4 expression, thereby proposing novel therapeutic strategies for managing asthma exacerbations by targeting the IL-33 and ferroptosis pathways.

关键词： IL-5   IL-9   allergic asthma   polymorphism   sensitivity  

摘要： BackgroundThe purpose of this research is to examine whether or not there is a connection between polymorphisms in the IL-5 and IL-9 genes and the prevalence of allergic asthma in Iraqi *** investigate the variants in the genes rs2069812T/C (IL-5) and rs1859430 C/T (IL-9) and their association with the likelihood of developing allergic *** hundred forty, one hundred twenty without asthma and one hundred twentywith the condition, made up the healthy subjects. We determined the levels of IL-5 and IL-9 using the enzyme-linked immunosorbent assay (ELISA) after separating sera from peripheral blood. Additionally, the allele-specific PCR method was used to identify the polymorphism distribution of rs2069812 (IL-5) and rs1859430 (IL-9).ResultsStudy participants with allergic asthma had significantly higher levels of interleukin (IL)-9 and interleukin (IL)-5 than those in the healthy subjects: 2 and 2.39 ± 0.18 pg/ml, compared to 1.004 ± 0.04 pg/ml and 2.21 ± 0.16 pg/ml, respectively, with a significance level of P < 0.05. In terms of age, gender, and place of residence, there was no statistically significant difference between the ill group and the healthy control group. The patients' group had 66 cases of the heterozygous genotype TG compared to 58 cases in the control group. Thus, the TG genotype was associated with an increased risk of allergic asthma illness (etiologic fraction: 0.2963) and an odds ratio of 2.4074 (95% CI: 1.2462-4.6505). The patients' group also had a higher frequency of the homozygous genotype GG (65 cases vs. 54 cases in the control group). The odds ratio for allergic asthma illness was 1.0578 (95% CI: 0.6386-1.7522), and the etiologic fraction was 0.0299, indicating that genotype GG was a risk *** findings provide more evidence that interleukin-5 and interleukin-9 play critical roles in allergic asthma, particularly in eosinophilic inflammation. Consequently, it is important to target them in order

关键词： 加味散偏汤   偏头痛   网络药理学   白细胞介素-17/核转录因子-κB信号通路   作用机制  

摘要： 目的：基于网络药理学和动物实验探讨加味散偏汤干预白细胞介素-17 (IL-17) /核转录因子(NF)-κB（NF-κB）信号通路对大鼠偏头痛神经源性炎症反应的作用机制。方法：通过网络药理学获得加味散偏汤调控偏头痛的潜在靶点及信号通路，并将核心成分和核心靶点进行分子对接。动物实验通过腹腔注射硝酸甘油（NTG）构建大鼠偏头痛模型，随机分组后灌胃给药，连续观察大鼠造模后1 h内每30 min时间段挠头次数；酶联免疫吸附测定（ELISA）检测大鼠三叉神经脊束核尾核（TNC）组织IL-17、白细胞介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）、一氧化氮（NO）和降钙素基因相关肽（CGRP）等含量；实时荧光定量聚合酶链式反应（real-time PCR）检测大鼠TNC区IL-17和IL-6 mRNA表达；免疫组织化学（IHC）检测大鼠TNC组织CGRP表达；Western blot法检测大鼠TNC组织IL-17、NF-κB p65、pNF-κB p65蛋白表达。结果：网络药理学显示，共得到加味散偏汤治疗偏头痛的化合物47个，“成分-疾病”交集靶点147个，主要活性成分为槲皮素、山柰酚、β-谷甾醇、木犀草素、豆甾醇等，核心靶点主要有TNF、IL6、IL1B、IL17等，涉及生物过程主要包括对异生物刺激、凋亡、转录调节的反应；细胞组分主要涉及大分子复合物、细胞外区、膜筏等；分子功能主要涉及酶结合力、蛋白结合、细胞因子活性等。KEGG通路预测主要有糖尿病并发症晚期糖基化终末产物受体（AGE-RAGE）信号通路、IL-17信号通路、肿瘤坏死因子（TNF）信号通路等。以上靶点和化合物分子对接结合活性均小于-2.0 kJ/mol。动物实验显示，与正常对照组比较，模型对照组大鼠在0～30 min及30～60 min时间段挠头次数均显著升高( P<0. 01)，TNC区组织中IL-17、IL-6、TNF-α、NO和CGRP含量显著升高（P<0.01）；TNC区组织的IL-17和IL-6 mRNA表达显著上调（P<0.01），CGRP、IL-17、pNF-κB p65蛋白表达明显上调（P<0.05或P<0.01）；与模型对照组比较，受试药物组大鼠以上时间段挠头次数明显降低（P<0. 05），TNC区组织中CGRP、IL-6、TNF-α和NO含量明显降低（P<0.05或P<0.01），加味散偏汤12.96 g/kg组TNC区组织中IL-17含量明显降低（P<0.05）；除加味散偏汤3.24 g/kg组外，其余各给药组大鼠TNC区组织IL-17和IL-6 mRNA表达明显下调（P<0.05或P<0.01）；各给药组大鼠TNC区组织CGRP、pNF-κB p65蛋白表达均明显下调（P<0.05或P<0.01），加味散偏汤12.96 g/kg组TNC区组织中IL-17蛋白表达显著下调（P<0.01）。结论：加味散偏汤能通过多成分、多靶点及多途径发挥治疗偏头痛的作用。同时，加味散偏汤可能通过干预IL-17/NF-κB信号通路，减轻神经源性炎症反应，发挥治疗偏头痛的作用。

关键词： berberine   hormesis   mitochondrial membrane potential   p53 mediated apoptosis pathways   pancreatic β-cells  

摘要： Damage to pancreatic β-cells serves as a critical pathological basis in the progression of diabetes. Berberine (BBR), an isoquinoline alkaloid, potentially protects pancreatic β-cells, exerting hypoglycemic effects. However, the dose-response relationship and the specific protective mechanism are still unclear. Hormesis is a self-protective response triggered by mild stimuli and has been reported to determine the extent to which phytochemicals can combat diabetes. In this study, we found that BBR exhibited a typical hormetic effect in IL-1β-induced damage to pancreatic β-cells, where low doses of BBR protect cells while high doses aggravate the damage. A model-based approach was used to describe dose-response relationships, as well as to detect and estimate hormetic effects. In addition, the regulatory effect of BBR in preventing apoptosis in pancreatic β-cells was confirmed, and an appropriate dose of BBR stabilized the mitochondrial membrane potential and prevented DNA damage. Moreover, the results showed that the hormetic effect of BBR was closely related to p53 and apoptosis pathways. To further investigate the role of the p53-mediated apoptosis pathways, our study interfered with the p53 pathway, resulting in the attenuation of the hormetic effect of BBR. These results introduce the concept of hormesis to study the biphasic effects of berberine on damaged pancreatic β-cells, while also exploring the relationship between the hormetic mechanism of BBR and the p53-mediated apoptosis pathway. These findings provide clues to explore the potential application of BBR in treating diabetes.

摘要： BACKGROUND:Sporotrichosis is a subcutaneous mycosis caused by members of the genus Sporothrix, among which Sporothrix globosa (S. globosa) is the predominant etiological agent in Asia. T cell immunity plays crucial roles in fungal infections, yet the local T cell immune profile in sporotrichosis lesions remains unclear. IL-18, a pleiotropic cytokine capable of modulating T cell responses, is also poorly understood in host defense against S. globosa. METHODOLOGY/PRINCIPAL FINDINGS:qPCR, western blot, and IHC/mIHC were employed to profile IL-18, IL-18 BP, caspase-1 and IL-18R axis, along with Th1,Th2, and Th17 cells and their specific cytokines in sporotrichosis lesions versus healthy skin. Cellular sources of IL-18 in the lesions were identified via mIHC, and IL-18 production from keratinocyte/PBMCs exposed to S. globosa in vitro was tested by qPCR and western blot. Flow cytometry was performed to evaluate the role of IL-18 in Th2 polarization in the PBMCs-S. globosa coculture system. Lesional skin exhibited hyperactivated IL-18 signaling, marked by upregulated IL-18, caspase-1, and IL-18R, alongside decreased IL-18 BP. IL-18 was primarily released by dermal dendritic cells and Langerhans cells, rather than keratinocytes. A mixed Th1/Th2/Th17 microenvironment with Th2 predominance correlated strongly with prolonged disease duration. Strikingly, IL-18 synergistically interacted with Th1-derived IL-2 to establish a self-reinforcing Th2 loop, as evidenced by the strong correlation between lesional IL-4 and IL-18 levels (r = 0.70) and the concomitant upregulation of IL-18/IL-2 during S. globosa-induced Th2 expansion in PBMCs-an effect reversed by IL-18/IL-2 neutralizing antibodies. Critically, this Th2 skewing was mechanistically dependent on NF-κB signaling, as demonstrated through pharmacological pathway inhibition. CONCLUSIONS/SIGNIFICANCE:This study unveils the dual role of IL-18 in human sporotrichosis caused by S. globosa-amplifying both Th1 and Th2 responses but u

关键词： 铜绿假单胞菌   中性粒细胞胞外诱捕网   树突状细胞   免疫调节   细胞因子  

摘要： 目的：探讨铜绿假单胞菌（PAO1）诱导的中性粒细胞胞外诱捕网（NETs）对树突状细胞（DCs）的调控作用。方法：体外分离人外周血中性粒细胞，分别以佛波酯（PMA）和PAO1菌株（感染复数MOI=1、10、100）诱导NETs形成，通过免疫荧光染色观察NETs形态，并利用Picogreen荧光定量法测定NET-DNA浓度。将PAO1诱导的NETs与DCs共培养，采用流式细胞术检测DCs表面共刺激分子（CD40、CD86、CD80）的表达水平，RT-qPCR和ELISA检测白介素-1β(IL-1β)、白介素-12(IL-12)、肿瘤坏死因子-α(TNF-α)的转录及分泌水平。结果：PAO1诱导的NETs呈现核膨大及丝状连接结构，MOI=100组的NET-DNA浓度较MOI=1组显著增加（P<0.01），且NET-DNA释放量在1～3 h先升后降，4 h达峰值。PAO1诱导的NETs显著上调DCs表面共刺激分子CD40、CD86和CD80的表达（P<0.001），并促进IL-1β、IL-12和TNF-α的分泌（P<0.01）。结论：PAO1诱导的NETs能促进DCs的成熟及活化，并分泌促炎因子IL-1β、IL-12及TNF-α，这种促炎作用可能具有双重效应。

关键词： psoriasis   immunology  

关键词： Inflammation   Interleukin-35   Interleukin-37   Parkinson's disease  

摘要： Background:Parkinson's disease (PD) is increasingly recognized as a condition driven by both central and peripheral inflammatory responses, largely mediated by cytokine activity. Objective:To assess IL-35 (P35 and Ebi3 subunits) and IL-37 gene expression, along with the serum levels of IL-35 protein in patients with PD compared to healthy controls. Methods:Cytokine gene expression was measured using the qRT-PCR technique, while IL-35 serum levels were measured using the ELISA method. The data obtained were analyzed using a Bayesian regression model in the R software. Results:The results revealed that the expression of P35 gene, of the two subunits of IL-35, did not differ significantly between the two groups. However, Ebi3 and IL-37 transcript levels were significantly lower in patients compared to healthy individuals (p<0.001). In contrast, IL-35 serum level in patients showed a significant increase compared to the control group (p=0.016). Notably, IL-37 expression showed a negative correlation with age (p=0.004). . We also observed positive and significant correlations between the gene expression of P35 and Ebi3 (p= 0.02, r= 0.4), P35 and IL-37 (p= 0.008, r= 0.45), and Ebi3 and IL-37 (p= 0.016, r= 0.41). Conclusion:In conclusion, our study revealed a higher serum protein level of IL-35 in PD patients compared to the healthy control group. Meanwhile, gene expression levels of IL-37 and Ebi-3 were significantly reduced. These alterations in the expression of these cytokines are suggested to be partly responsible for the immune system dysregulation in this disease.