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关键词： PCSK9   HMGB1   TLR4   Monocyte subtypes   Statin   Coronary artery disease  

摘要： Despite statin use in coronary artery disease (CAD), significant risk remains, potentially due to increased proprotein convertase subtilisin/kexin-type 9 (PCSK9) production, which raises LDL-C levels and induces inflammation. The exact relationship between PCSK9, inflammatory markers like TNF alpha, TLR4, CRP, and HMGB1, and monocyte subsets is poorly understood. This study aimed to explore these relationships in non-statin and statin-taking CAD patients. This case-control study included 91 controls and 91 stable CAD patients, divided into no-statin (NS, n = 25), low-dose statin (LDS, n = 25), and high-dose statin (HDS, n = 41) groups. Serum levels of LDL-C, CRP, PCSK9, TLR4, HMGB1, and TNF alpha were measured. Monocyte subsets were classified using flow cytometry into classical monocytes (CM), intermediate monocytes (IM), and non-classical monocytes (NCM). CAD patients showed elevated PCSK9, LDL-C, and inflammatory markers compared to controls. Statin groups (LDS, HDS) had lower LDL-C and inflammatory markers but higher PCSK9 than the NS group, with the HDS group showing the lowest LDL-C and inflammatory markers but the highest PCSK9. In the NS group, PCSK9 positively correlated with inflammatory markers (HMGB1, TNF alpha, TLR4, CRP) and monocyte subsets (IM%, NCM%). In the total statin group (LDS + HDS), PCSK9 negatively correlated with HMGB1, TLR4, and NCM%, for each, respectively, and positively with CM%. Multivariable linear regression showed significant associations between PCSK9 and HMGB1, NCM%, and IM% in the NS group, and HMGB1, NCM%, and TLR4 in the total statin group. In conclusion, we recommend combining PCSK9 inhibitors with statins in high-risk CAD patients. This may enhance statin efficacy, reduce LDL-C, and inhibit the TLR4/NF-& kcy;B inflammatory pathway, decreasing atherosclerotic inflammation.

关键词： Bacterial infections   Cytokines   Infectious disease  

摘要： Gonorrhea, caused by the human-restricted pathogen Neisseria gonorrhoeae, is a commonly reported sexually transmitted infection. Since most infections in women are asymptomatic, the true number of infections is likely much higher than reported. How gonococci (GC) colonize women's cervixes without triggering symptoms remains elusive. Using a human cervical tissue explant model, we found that GC inoculation increased the local secretion of both pro- (IL-1β and TNF-α) and anti-inflammatory (IL-10) cytokines during the first 24-h. Cytokine induction required GC expression of Opa isoforms that bind the host receptors carcinoembryonic antigen-related cell adhesion molecules (CEACAMs). GC inoculation induced NF-κB activation in both cervical epithelial and subepithelial cells. However, inhibition of NF-κB activation, which reduced GC-induced IL-1β and TNF-α, did not affect GC colonization. Neutralizing IL-10 or blocking IL-10 receptors by antibodies reduced GC colonization by increasing epithelial shedding and epithelial cell-cell junction disassembly. Inhibition of the CEACAM downstream signaling molecule SHP1/2, which reduced GC colonization and increased epithelial shedding, decreased GC-induced IL-10 secretion. These results show that GC induce local secretion of IL-10, a potent anti-inflammatory cytokine, at the cervix by engaging the host CEACAMs to prevent GC-colonizing epithelial cells from shedding, providing a potential mechanism for GC asymptomatic colonization in women.

关键词： 猪圆环病毒2型   病毒样颗粒   三倍轴区域   外源表位  

摘要： 为了探索PCV2病毒样颗粒三倍轴区域展示外源抗原表位的潜力，本研究借助结构模拟和蛋白质的三维结构展示，分析了PCV2核衣壳表面氨基酸残基突变后的结构差异。通过分析不同cap基因突变质粒在大肠杆菌表达系统中所表达的突变体蛋白的可溶性和纯化难易程度，确定合适的外源表位嵌合区。将嵌合PPV抗原表位的Cap蛋白经体外组装获得重组的病毒样颗粒，将此病毒样颗粒免疫小鼠，通过抗体检测来评价其免疫原性。结果显示，PCV2核衣壳表面三倍轴区域存在两个适合用于展示外源表位的氨基酸区域（命名为Motif A和Motif B）；相同表达条件下，Motif A区域的突变蛋白均以可溶性表达为主，且能一步纯化获得目的蛋白，而Motif B区域的突变蛋白多以包涵体形式存在；Motif A区域嵌合PPV表位后，纯化的重组蛋白能在体外组装成cVLPs，并通过间接免疫荧光实验证明其保留有野生型VLPs内化PK15细胞的能力；形成的cVLPs能刺激小鼠机体产生分别针对PCV2 VLPs、B5-E1表位和PPV VP2蛋白的抗体。结果表明PCV2 Cap蛋白Loop GH区域Motif A能够将外源表位展示在病毒样颗粒外表面，并且能够被机体免疫细胞识别产生特异性抗体。

关键词： Bimekizumab   Secukinumab   CJM112   Hidradenitis suppurativa   IL-17 inhibitors  

关键词： 黄芪   银屑病   维生素D   CYP27B1   CYP24A1   IL-22  

摘要： 目的：观察黄芪对银屑病模型小鼠皮损维生素D系统关键酶（CYP27B1、CYP24A1）表达及1，25（OH）2D3、白细胞介素（interleukin， IL）-22水平的影响。方法：将造模成功小鼠，随机分为模型对照组、维生素D组、甲氨蝶呤组和黄芪中、低、高剂量组，另设正常对照组，持续干预3周。采用皮损严重程度指数（PASI）评分对小鼠皮损进行评分；苏木素-依红（hematoxylin-eosin stain， HE）染色观察小鼠皮损组织病理；酶联免疫吸附测定法（enzyme-linked immunosorbent assay， ELISA）检测小鼠血清1，25（OH）2D3、IL-22水平；Real-Time qPCR及免疫组化分别检测小鼠皮损CYP27B1、CYP24A1 mRNA及蛋白表达。结果：与正常对照组比较，模型组皮损改变明显，PASI评分显著升高（P＜0.05），银屑病特征性病理改变，血清1，25（OH）2D3水平显著降低（P＜0.05），IL-22水平显著升高（P＜0.05），皮损CYP27B1表达显著下调（P＜0.05），CYP24A1表达显著上调（P＜0.05）；与模型对照组比较，维生素D组、甲氨蝶呤组和黄芪中、高剂量组PASI评分显著降低（P＜0.05），组织病理改善，1，25（OH）2D3水平显著升高（P＜0.05），IL-22水平显著降低（P＜0.05），皮损CYP27B1表达显著上调（P＜0.05），CYP24A1表达显著下调（P＜0.05）。结论：黄芪改善银屑病小鼠IL-22水平可能与调节维生素D 系统关键酶CYP27B1、CYP24A1表达有关。

关键词： 补体系统   旁路途径   补体因子B   补体因子B小分子抑制剂  

摘要： 补体系统的旁路途径是多种疾病发病的关键因素,包括阵发性睡眠性血红蛋白尿、非典型溶血性尿毒症综合征、C3肾小球病、年龄相关性黄斑变性等。补体因子B (complement factor B, CFB)是一种胰蛋白酶样丝氨酸蛋白,以潜伏形式在人体血液中循环。其作为补体旁路途径的关键节点,是治疗补体系统介导疾病的重要靶点。随着伊普可泮(iptacopan)的成功上市,使得CFB小分子抑制剂成为目前的研究热点,国内外多家制药公司都在积极研发CFB小分子抑制剂。本文主要就近年来CFB小分子抑制剂的研究进展做了系统总结,按照结构类型和设计思路对代表化合物及其活性进行了介绍,从而为后续CFB小分子抑制剂的研究提供借鉴和思路。

关键词： Puumala virus   GWAS   fine-mapping   HLA  

摘要： Puumala virus (PUUV) infections can cause severe illnesses such as Hemorrhagic Fever with Renal Syndrome in humans. However, human genetic risk factors contributing to disease severity are still poorly understood. Our goal was to elucidate genetic factors contributing to PUUV infections and understand the biological mechanisms underlying individual vulnerability to PUUV infections. Leveraging data from the FinnGen study, we conducted a genome-wide association study on severe Hemorrhagic Fever with Renal Syndrome caused by PUUV with 2227 cases. We identified associations at the Human Leukocyte Antigen (HLA) locus and ERAP1 with severe PUUV infection. HLA molecules are canonical mediators for immune recognition and response. ERAP1 facilitates immune system recognition and activation by cleaving viral proteins into smaller peptides which are presented to the immune system via HLA class I molecules. Notably, we identified that the lead variant (rs26653, OR = 0.84, P = 2.9 x 10-8) in the ERAP1 gene was a missense variant changing amino acid arginine to proline. From the HLA region, we showed independent and significant associations with both HLA class I and II genes. Furthermore, we showed independent associations with four HLA alleles with severe PUUV infection using conditional HLA fine mapping. The strongest association was found with the HLA-C*07:01 allele (OR = 1.54, P = 4.0 x 10-24) followed by signals at HLA-B*13:02, HLA-DRB1*01:01, and HLA-DRB1*11:01 alleles (P < 5 x 10-8). Our findings suggest an association of viral peptide processing with ERAP1 and antigen presentation through HLA alleles that may contribute to the development of severe PUUV disease.

关键词： Manganese   Thyroid cancer   Prospective cohort  

摘要： Dietary Mn intake may have a beneficial effect in reducing cancer risk;however, its association with thyroid cancer (TC) risk remains inadequately understood. Additionally, Mn was associated with inflammation markers. Thus, we examined whether dietary Mn intake emerges a protective role against TC and whether this preventative effect has an interaction with IL1 receptor type 1 (IL1R1) rs3917225. The prospective study was designed at National Cancer Center in Korea between October 2007 and December 2020 including 17 754 participants. We identified TC cases by following participants until December 2020. Mn intake was collected using a semiquantitative food frequency questionnaire (SQFFQ). Genotyping was performed to determine IL1R1 rs3917225. The hazard ratios (HR) and 95 % confidence interval (CI) were calculated with a Cox proportional hazards model. We ascertained 108 incident TC cases throughout follow-up duration. Dietary Mn intake was found to be inversely associated with TC risk (HR (95% CI)=064 (044, 095)). However, IL1R1 rs3917225 seemed to modify this association;the protective effect was limited to G-allele carriers (HR = 030 (011, 086), P interaction=0028). A higher dietary Mn was suggested to be a protective factor against TC. Additionally, we drew a potential biological interaction between Mn intake and IL1R1 rs3917225 with a greater effect among individuals with a minor allele. This implies that when considering the cancer-preventive role of Mn, it is important to account for the influence of inflammatory gene participation.