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关键词： 鸡传染性贫血病毒   转移因子   免疫抑制   细胞因子  

摘要： 为探索转移因子的免疫增强作用及其对鸡传染性贫血病毒（Chicken infectious anemia virus,CIAV）感染的抑制作用，试验研究了高、低两种剂量转移因子对SPF鸡CD4+和CD8+T淋巴细胞水平，鸡白细胞介素-12(IL-12)、γ-干扰素（IFN-γ）等6种细胞因子和Mx抗病毒蛋白表达的影响，以及对SPF鸡体重、器官发育指数、红细胞压积（HCT）值和血液、肝脏、胸腺中CIAV增殖的影响。结果显示：转移因子可引起CD4+和CD8+T细胞比重显著增加并上调IFN-γ、Mx蛋白表达量（P<0.01）;CIAV感染组的脾脏发育指数相对于空白对照组显著增加（P<0.05），胸腺发育指数极显著降低（P<0.01），转移因子可以缓解感染CIAV带来的脾脏肿大和胸腺萎缩；转移因子可显著抑制CIAV在血液、肝脏和胸腺中的复制（P<0.01），且高剂量组抑制作用强于低剂量组；CIAV感染组血浆HCT值极显著低于空白对照组（P<0.01），高剂量转移因子使用后缓解了CIAV感染引起的HCT值下降。研究表明，转移因子对缓解CIAV感染引起的危害具有良好的应用价值，为防控鸡传染性贫血提供新的辅助措施。

摘要： Ferroptosis is an iron-dependent form of cell death that influences cancer immunity. Therapeutic modulation of ferroptosis is considered a potential strategy to enhance the efficacy of other cancer therapies, including immunotherapies such as chimeric antigen receptor (CAR) T-cell therapy. In this study, we demonstrated that IFN kappa influenced the induction of ferroptosis. IFN kappa could enhance the sensitivity of tumor cells to ferroptosis induced by the small molecule compound erastin and the polyunsaturated fatty acid arachidonic acid. Mechanistically, IFN kappa in combination with arachidonic acid induced immunogenic tumor ferroptosis via an IFNAR/STAT1/ACSL4 axis. Moreover, CAR T cells engineered to express IFN kappa showed increased antitumor efficiency against H460 cells (antigen positive) and H322 cells (antigen-negative) both in vitro and in vivo. We conclude that IFN kappa is a potential cytokine that could be harnessed to enhance the antitumor function of CAR T cells by inducing tumor ferroptosis.

摘要： Immune checkpoint inhibitors (ICI) have revolutionized cancer therapy, but their use is limited by the development of autoimmunity in healthy tissues as a side effect of treatment. Such immune-related adverse events (IrAE) contribute to hospitalizations, cancer treatment interruption and even premature death. ICI-induced autoimmune diabetes mellitus (ICI-T1DM) is a life-threatening IrAE that presents with rapid pancreatic beta-islet cell destruction leading to hyperglycemia and life-long insulin dependence. While prior reports have focused on CD8 T cells, the role for CD4 T cells in ICI-T1DM is less understood. Here, we identify expansion CD4 T follicular helper (Tfh) cells expressing interleukin 21 (IL-21) and interferon gamma (IFNG) as a hallmark of ICI-T1DM. Furthermore, we show that both IL-21 and IFNG are critical cytokines for autoimmune attack in ICI-T1DM. Because IL-21 and IFNG both signal through JAK-STAT pathways, we reasoned that JAK inhibitors (JAKi) may protect against ICI-T1DM. Indeed, JAKi provide robust protection against ICI-T1DM in a mouse model that is associated with decreased islet-infiltrating Tfh cells. Moreover, JAKi therapy impaired Tfh cell differentiation in patients with ICI-T1DM. These studies highlight CD4 Tfh cells as underrecognized but critical mediators of ICI-T1DM that may be targeted with JAKi to prevent this grave IrAE.

关键词： cardiac fibrosis   antifibrotic   TGR5   ursodeoxycholic acid   dilated cardiomyopathy   Interleukin-11  

摘要： Introduction Cardiac fibrosis occurs in a wide range of cardiac diseases and is characterised by the transdifferentiation of cardiac fibroblasts into myofibroblasts these cells produce large quantities of extracellular matrix, resulting in myocardial scar. The profibrotic process is multi-factorial, meaning identification of effective treatments has been limited. The antifibrotic effect of the bile acid ursodeoxycholic acid (UDCA) is established in cases of liver fibrosis however its mechanism and role in cardiac fibrosis is less well *** In this study, we used cellular models of cardiac fibrosis and living myocardial slices to characterise the macroscopic and cellular responses of the myocardium to UDCA treatment. We complemented this approach by conducting RNA-seq on cardiac fibroblasts isolated from dilated cardiomyopathy patients. This allowed us to gain insights into the mechanism of action and explore whether the IL-11 and TGF beta/WWP2 profibrotic networks are influenced by UDCA. Finally, we used fibroblasts from a TGR5 KO mouse to confirm the mechanism of *** and discussion We found that UDCA reduced myofibroblast markers in rat and human fibroblasts and in living myocardial slices, indicating its antifibrotic action. Furthermore, we demonstrated that the treatment of UDCA successfully reversed the profibrotic IL-11 and TGF beta/WWP2 gene networks. We also show that TGR5 is the most highly expressed UDCA receptor in cardiac fibroblasts. Utilising cells isolated from a TGR5 knock-out mouse, we identified that the antifibrotic effect of UDCA is attenuated in the KO fibroblasts. This study combines cellular studies with RNA-seq and state-of-the-art living myocardial slices to offer new perspectives on cardiac fibrosis. Our data confirm that TGR5 agonists, such as UDCA, offer a unique pathway of action for the treatment of cardiac fibrosis. Medicines for cardiac fibrosis have been slow to clinic and have the potential to be used in the

关键词： Syphilis   pregnancy   IL-10   serological response   immunology  

摘要： Background Approximately 50% of pregnant individuals treated for syphilis do not achieve a decline in non-treponemal titers by delivery. The serological response in pregnant persons is significantly slower compared to non-pregnant individuals, with unclear pathogenesis and clinical significance. This study aimed to determine the association between the host immune response and serological outcome in pregnant individuals with syphilis. Methods Twenty-four females with early syphilis, including 14 pregnant individuals, were included. Pro-inflammatory and regulatory cytokines (IFN-gamma, TNF-alpha, IL-4, IL-1 beta, IL-10, TGF-beta) were measured before treatment and 6 months after penicillin injection. Results The median time to serological cure was 5 months for pregnant individuals and 2 months for non-pregnant females. Pregnant individuals had significantly higher serum levels of IL-10 and TGF-beta at baseline and at 6 months post-treatment compared to non-pregnant individuals (p < .05). Conclusions A robust regulatory immune response to syphilis may be associated with a slower serological response to therapy during pregnancy.

关键词： 生长分化因子15   单克隆抗体   胶质母细胞瘤   肿瘤免疫治疗   肿瘤微环境   PD-1  

摘要： 目的 验证生长分化因子15（GDF15）中和性单克隆抗体对胶质母细胞瘤（GBM）的治疗作用，证实GDF15作为GBM免疫治疗靶点的可行性。方法 利用C57小鼠原位胶质瘤模型和病毒诱导自发性胶质瘤模型，评价GDF15中和抗体的治疗效果。此外，研究GDF15中和抗体与PD-1单克隆抗体的联合应用效果，并评估其在胶质瘤治疗中的临床应用前景。结果 GDF15中和抗体在原位胶质瘤小鼠模型和自发性胶质瘤小鼠模型上都表现出明显的抑制胶质瘤进展疗效并且可以有效延长荷瘤小鼠的生存期。另外，使用GDF15中和抗体和PD-1单克隆抗体联合治疗展现出的抗肿瘤作用比GDF15抗体或PD-1单克隆抗体单一治疗都更强。结论 GDF15中和性单克隆抗体能够有效抑制胶质瘤的生长，其机制可能是通过改善肿瘤引发的免疫抑制，促进抗肿瘤免疫反应。该研究一定程度证实了GDF15作为GBM免疫治疗靶点的潜在应用价值，为GBM免疫治疗新靶点和干预策略的选择提供了方向。

关键词： anti-cancer   mexican poppy   colon cancer   medicinal plants   PI3/AKT pathway   skin cancer  

摘要： Introduction: Cancer has emerged as one of the leading causes of fatality all over the world. Phytoconstituents are being studied for their synergistic effects, which include disease prevention by altering molecular pathways and immunomodulation without side effects. The present experiment aims to explore the cancer preventive activities of Argemone mexicana Linn leaves extract in skin cancer cell lines (A431) and colon cancer cell lines (COLO 320DM)). In addition, TNF-alpha expression patterns and NF-kB signaling pathways have been examined. Methods: LC/MS study of Argemone mexicana Linn extracts in various solvents revealed anti-cancerous phytoconstituents. Network pharmacology analysis used Binding DB, STRING, DAVID, and KEGG for data mining to evaluate predicted compounds using functional annotation analysis. Cytoscape 3.2.1 created "neighbourhood approach" and networks. The MNTD of these extracts was tested on L929 fibroblasts. Skin cancer (A431) and colon cancer (COLO 320DM) cell lines were tested for IC50 inhibition. Evaluation of TNF-alpha and NF-kB expression in cell culture supernatants and homogenates reveals anti-cancerous effects. Results: LC-MS analysis of extracts predicted the presence of anticancer alkaloids Berberine, Atropine, Argemexicin, and Argemonin. In Network pharmacology analysis, enrichment was linked to the PI3-AKT pathway for both cancer types. MNTD was calculated at 1000 mu g/ml in L929. The ethanolic extract at 1000 mu g/ml significantly inhibited skin cancer cell proliferation by 67% and colon cancer cells by 75%. Ethanolic extract significantly reduced TNF-alpha expression in both cell lines (p<0.001), with the highest inhibition at 1000 mu g/ml. In TNF-alpha stimulated cell lines, 1000 mu g/ml ethanolic extract significantly reduced the regulation of the NF-kB pathway, which plays a role in cancer progression (p<0.001). Conclusion: Argemone mexicana Linn. known as 'swarnkshiri' in Ayurveda has been reported to be used by the traditi

摘要： HLA-B*27 confers a strong risk of developing spondyloarthritis (SpA), which includes axial SpA with or without peripheral arthritis, enthesitis, acute anterior uveitis and gastrointestinal inflammation. Although no definitive mechanism has been established to explain the role of this HLA class I protein in the pathogenesis of SpA, three main hypotheses have emerged. First is the idea that self-peptides displayed by HLA-B27 resemble microorganism-derived peptides, leading to the expansion of autoreactive CD8+ T cells that trigger disease. The second and third hypotheses focus on aberrant properties of HLA-B27, including its tendency to form cell-surface dimers that can activate innate killer immunoglobulin-like receptors on CD4+ T helper 17 cells, triggering the production of pathogenic cytokines. HLA-B27 also misfolds in the endoplasmic reticulum, which can activate the unfolded protein response, increasing IL-23 expression and thereby promoting the production of type 17 cytokines. HLA-B27 misfolding in mesenchymal stem cells has also been linked to enhanced bone formation by mesenchymal stem cell-derived osteoblasts, which could contribute to structural damage in axial SpA. In this Review we summarize prevailing ideas about the role of HLA-B27 in SpA, discuss the latest developments as well as the gaps in current knowledge, and provide recommendations for future research to address these unmet needs.

关键词： 代谢相关脂肪性肝病   肝脏脂质沉积   经典/非经典铁死亡途径   绞股蓝皂苷  

摘要： 目的：以经典/非经典铁死亡多途径为切入点，探讨绞股蓝皂苷（GPs）对代谢相关脂肪性肝病（MAFLD）小鼠肝脏脂质沉积的影响及机制。方法：空白组8只雄性C57BL/6小鼠，32只雄性载脂蛋白E基因敲除(ApoE-/-)小鼠随机分为模型组、GPs低剂量（GPs-L）组、GPs高剂量（GPs-H）组和辛伐他汀（SV）组。第2周开始，给予空白组小鼠维持饲料，其余四组小鼠每日喂养高脂饲料，饲养8周后，按照GPs-L、GPs-H组分别给予小鼠GPs 1.49 mg·kg-1·d-1、2.97 mg·kg-1·d-1，辛伐他汀组给予小鼠辛伐他汀2.275 mg·kg-1·d-1，空白组和模型组给予小鼠等体积生理盐水进行灌胃4周。全自动生化分析仪检测各组小鼠血清中总胆固醇（TC）、甘油三酯（TG）、低密度脂蛋白胆固醇（LDL-C）、高密度脂蛋白胆固醇（HDL-C）、丙氨酸氨基转移酶（ALT）和天冬氨酸氨基转移（AST）含量；试剂盒测定小鼠肝脏组织NEFA、TG水平；苏木素-伊红（HE）、油红O染色观察小鼠肝脏组织结构及脂质沉积变化；酶联免疫吸附测定法（ELISA）检测小鼠血清辅酶Q10（CoQ10）、谷胱甘肽（GSH）、丙二醛（MDA）、Fe2+水平及肝脏还原型辅酶II［NAD（P）H］水平；免疫组化（IHC）法观察小鼠肝脏中铁死亡抑制蛋白1（FSP1）蛋白表达，时荧光定量聚合酶链式反应（Real-time qPCR）及Wes全自动蛋白表达分析系统分析小鼠经典/非经典铁死亡途径相关基因和蛋白表达。结果：与空白组比较，模型组小鼠血清TC、TG、LDL-C、ALT、AST水平及肝脏中TG、NEFA水平明显升高，血清HDL-C水平明显降低（P<0.01）；肝组织结构改变，出现大小不等脂肪空泡和大量红色脂滴，脂质沉积明显；血清中CoQ10、GSH及肝脏NADH水平明显降低，血清中MDA、Fe2+水平明显升高（P<0.01）；胱氨酸/谷氨酸转运体（xCT/SLC7A11）、胱甘肽过氧化物酶（GPX4）、p62、核因子E2相关因子2（Nrf2）、FSP1 mRNA和蛋白表达明显下降，细胞肿瘤抗原（p53）、亚精胺/精胺N1-乙酰转移酶1（SAT1）、花生四烯酸15-脂氧合酶（ALOX15）、Kelch样环氧氯丙烷相关蛋白-1（Keap1） mRNA和蛋白表达明显上升（P<0.01）。与模型组比较，GPs-L、GPs-H组和辛伐他汀组小鼠血清中TC、TG、LDL-C、ALT、AST水平及肝脏中TG、NEFA水平下降，血清中HDL-C水平明显升高（P<0.05，P<0.01）；肝组织结构和脂质沉积状况有所改善；血清中CoQ10、GSH及肝脏NADH水平明显升高，血清中MDA、Fe2+水平明显降低（P<0.05，P<0.01）；xCT、GPX4、p62、Nrf2、FSP1 mRNA和蛋白表达明显上升，p53、SAT1、ALOX15、Keap1 mRNA和蛋白表达明显下降（P<0.05，P<0.01）。结论：绞股蓝皂苷可以通过经典/非经典铁死亡途径干预MAFLD小鼠的肝脏脂质沉积。