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关键词： Cellular crosstalk   Chronic kidney diseases   Local interstitial acidosis   Local inflammation   IL-6 effects   p38-signaling  

摘要： Background Local interstitial acidosis in chronic kidney disease (CKD) induces inflammatory responses and dedifferentiation of proximal tubule cells (PTCs), disrupting cellular crosstalk through cytokine and COX-2 metabolite secretion. This promotes a switch to an inflammatory fibroblast phenotype, further exacerbating inflammation and PTC dedifferentiation. p38-signaling and downstream transcription factors, including P-CREB and c-fos, contribute to these responses. This study investigates the impact of acidosis on inflammatory responses in PTCs and fibroblasts, focusing on cellular crosstalk and the role of p38-signaling. Methods HK-2 (human PTCs) and CCD-1092Sk (human fibroblasts) were exposed to acidic or control media in mono- and coculture for 30 min, 3 h, or 48 h. Protein expression of IL-6, phosphorylated (P-) and total CREB, P- and total SRF, c-fos, and P- and total p38 was analyzed by western blot. IL-6 secretion was measured using ELISA. The impact of p38 and IL-6 receptor activity was assessed by pharmacological intervention. Results In coculture, acidosis initially caused a transient decrease in IL-6 secretion but significantly increased IL-6 levels after 48 h. Acidosis induced intracellular IL-6 expression in HK-2 cells within 3 h independent of culture conditions, with sustained IL-6 protein increase after 48 h only in coculture. Acidosis also enhanced P-CREB and c-fos expression in coculture during the first 3 h. Regardless of culture conditions, acidosis increased IL-6, c-fos, and P-SRF expression in CCDSK cells after 48 h. P-CREB and COX-2 expression were elevated in CCDSK in coculture. Acidosis-mediated effects on IL-6, P-CREB, and P-SRF expression were p38-dependent in both cell lines. Finally, we assessed the pH-dependency of IL-6 action and found that IL-6 addition increased COX-2 expression via the IL-6 receptor in acidic but not control media. Thus, acidosis enhances IL-6 secretion and potentiates its receptor-mediated biological effects. Con

摘要： We report the initial case of EBV-positive classic Hodgkin lymphoma (cHL) after guselkumab therapy for psoriasis. High-plex spatial proteomic analysis showed a Th2-polarized immunosuppressive tumor microenvironment, indicating immune reprogramming from IL-23 inhibition might have triggered the onset of EBV-positive cHL.

摘要： Allergic asthma is driven by type 2 immune cells including type 2 innate lymphoid cells (ILC2s). ILC2s respond to the tissue alarmins IL-33 and IL-25, however these signals do not uniquely promote type 2 inflammation, and the factors that maintain ILC2s ability to produce type 2 cytokines are not known. Here, we show that allergen-driven tissue alarmins IL-33 and IL-25 rapidly induce IL-9, which directly upregulates the transcriptional repressor Blimp-1 through an autocrine/paracrine mechanism. Blimp-1 promotes type 2 responses by directly repressing type 1 inflammation including the cytokines IFNγ and TNF. Deletion of Blimp-1 in ILC2s increases type 1 cytokines and concomitantly reduces type 2 cytokines, ameliorating mucus production and airway inflammation in response to allergens. Thus, Blimp-1 maintains the type 2 transcriptional identity of ILC2s in response to inflammation, driving type 2 immunity and allergic asthma.

关键词： Helicobacter pylori   chronic gastritis   prevalence   gastrointestinal pathologies   histopathology  

摘要： Background/Objectives: Helicobacter pylori (H. pylori) is a significant global health issue causing chronic gastritis, peptic ulcers, and gastric malignancies. Unfortunately, many, particularly in the Middle East, continue to exhibit alarming rates of prevalence. This study aimed to elucidate local epidemiological patterns of H. pylori and examine its histopathological impact on the gastric mucosa. Methods: This retrospective-cross-sectional study included 805 symptomatic adults (329 males, 476 females) who underwent endoscopic evaluation at King Salman Hospital, Ha'il, Saudi Arabia. Biopsies from the antrum and body were processed using routine formalin fixation and paraffin embedding. Staining with hematoxylin-eosin (H&E) and Giemsa permitted assessment of chronic gastritis and detection of H. pylori. Data were evaluated by IBM SPSS (version 23, IBM Corp., Armonk, NY) for associations among infection, histopathology, and patient characteristics. Results: A total of 727 (90.3%) were H. pylori-positive with marginally higher rates in females (91.2%) than males (89.0%). Infection spanned all age groups, reaching 100% in males aged 60-80 years. Overall chronic GI complications were identified in 726 (99.9%), with chronic gastritis being the most profound histopathologically (19.3%). Lymphoid aggregates in 93.0% biopsies reflected a pronounced immune response. Advanced lesions, including metaplasia (0.8%), atrophy (0.3%), and lymphoma (0.1%), were uncommon, though indicative of potential malignant progression. Despite both sexes exhibiting universal symptoms of gastritis, dyspepsia, and heartburn, there were no statistically significant gender-based differences (p > 0.05);specifically, post-H. pylori signs such as vomiting, nausea, weight loss, bleeding or hematemesis occurred equally in all. Histopathology consistently revealed chronic active gastritis with glandular distortion, lymphoplasmacytic infiltration, and occasional mucosal erosions. Giemsa staining further c

关键词： Osteoarthritis   chondrocytes   Long-stranded noncoding RNA   SNHG7   PCBP1  

摘要： Purpose We probed the roles of SNHG7, miR-146b, PCBP1, and IL-beta in the development of osteoarthritis (OA). Materials and methods OA models were established using anterior cruciate ligaments, and chondrocytes were obtained from mouse cartilage tissue. Cells were treated with 10 ng/ml Il-1 beta. RT-qPCR was used to detect the expression of SNHG7, miR-146b, PCBP1, and IL-beta in tissues and cells. Safranin-O/Fast Green staining was performed to analyze the cartilage damage in each group of mice. Results SNHG7 and PCBP1 expressions were down-regulated, and miR-146b expression was up-regulated in OA tissue and IL-1 beta-treated chondrocytes compared to normal cartilage tissue and chondrocytes. Forced SNHG7 expression improved cartilage structure, enhanced proliferative viability of chondrocytes, and inhibited apoptosis and IL-1 beta release in IL-1 beta-treated chondrocytes in OA mice. In contrast, miR-146b upregulation decreased proliferative viability and promoted apoptosis and IL-1 beta release in chondrocytes. Rescue assays showed that miR-146b attenuated the protective effects of SNHG7 on apoptosis and inflammation in IL-1 beta-treated chondrocytes, and activation of PCBP1 expression significantly inhibited the cytotoxic effects of miR-146b. Mechanistically, SNHG7 acted as a competitive endogenous RNA by targeting miR-146b to promote the expression of PCBP1. Conclusions This study confirms that SNHG7 inhibits IL-1 beta-mediated inflammatory responses in chondrocytes via the miR-146b/PCBP1 axis, thereby suppressing IL-1 beta-induced OA.

关键词： 急性主动脉夹层   中性粒细胞/淋巴细胞比值   多中心  

摘要： 目的　探讨中性粒细胞/淋巴细胞比值（NLR）在多中心医院急性主动脉夹层（AAD）患者院内死亡风险预测中的作用。方法　本研究为多中心回顾性队列研究。收集2010年8月—2021年12月来自三省五家教学医院（华中科技大学同济医学院附属同济医院、河南省人民医院、郑州大学华中阜外医院、新乡医学院第三附属医院以及重庆医科大学附属第二医院）住院治疗的2642例AAD患者。基于NLR分布的四分位点将患者分为Q1（n=660）、Q2（n=661）、Q3（n=661）、Q4（n=660）四组，并对各组的临床资料及生化指标进行比较；采用偏相关分析方法评估NLR与心血管指标之间的关系；利用限制性立方样条、Kaplan-Meier法及Cox回归模型对NLR水平与AAD患者院内死亡风险的相关性进行评估。结果　所有患者的中位年龄为54（46，63）岁，其中男性2096例，女性546例。与Q1—Q3组比较，Q4组患者吸烟史和糖尿病病史的发生率较低，且更有可能患DeBakey Ⅰ型AAD（P<0.05），Q4组患者的谷草转氨酶、高密度脂蛋白胆固醇、肌酐及D-二聚体水平较高，而三酰甘油及CRP水平较低（P<0.01）。偏相关分析结果显示，血浆NLR水平与D-二聚体（r=0.43，P<0.01）和肌酐（r=0.16，P<0.01）呈正相关。Cox模型中的限制性立方样条函数揭示了血浆NLR水平与AAD患者临床结局之间存在明显的非线性关系（P<0.01）。Kaplan-Meier曲线分析显示，与Q1—Q3组比较，Q4组患者的院内死亡发生率最高（P<0.0001）。多因素Cox回归分析表明，与Q1组相比，Q4组NLR的风险比（HR）为1.77（95%CI 1.33～2.37，P<0.001），是主要终点事件的独立危险因素。结论　较高的血浆NLR水平与AAD患者心血管事件的发生相关，即使校正了多中心就诊医院等潜在混杂因素后仍相关。

关键词： cholesterolized liposome   combination therapy   IL-1 beta   immunotherapy   inflammasome   oxidized mitochondrial DNA   radiotherapy   TLR7 agonist  

摘要： BackgroundRadiotherapy (RT) is a key treatment modality in cancer therapy, utilizing high-energy radiation to directly kill tumor cells. Recent research has increasingly highlighted RT's potential to indirectly enhance antitumor immunity. However, this immune activation alone often fails to generate sustained systemic antitumor responses. In this study, we aimed to investigate the antitumor effects of combining cholesterolized toll-like receptor 7 (TLR7) agonist liposomes, specifically 1V209-Cho-Lip, with *** tumor models were used to assess the impact of combining 1V209-Cho-Lip with RT on tumor progression and modification of the tumor microenvironment. In vitro, primary mouse bone marrow-derived dendritic cells (BMDCs) were utilized to investigate changes in function and the activated pathways through RNA sequencing. Additionally, we explored the role of oxidized mitochondrial DNA (ox-mtDNA) released from irradiated tumor cells as a damage-associated molecular pattern in modulating immune responses. The involvement of interleukin-1 beta (IL-1 beta) and the inflammasome pathway in the antitumor efficacy of the combined treatment was evaluated using Il-1 beta-/- and cysteinyl aspartate specific proteinase 1 knockout (Casp1-/-) mouse *** combination of 1V209-Cho-Lip and RT significantly inhibited tumor growth and induced antitumor immunity in tumor models. This combination therapy enhanced maturation, antigen presentation and IL-1 beta secretion of dendritic cells (DCs) in vitro. Ox-mtDNA released from irradiated tumor cells synergized with 1V209-Cho-Lip to activate the inflammasome pathway in DCs. The antitumor effect of the combined therapy was significantly reduced in Il-1 beta-/- and Casp1-/- *** study suggests that the combination of 1V209-Cho-Lip with RT might be a promising antitumor strategy and further studies are warranted to explore the clinical relevance of this combination therapy.

关键词： 免疫球蛋白A肾病   微小核糖核酸   发病机制   生物标志物   中医药  

摘要： 免疫球蛋白A（Immunoglobulin A，IgA）肾病（IgA Nephropathy，IgAN）是世界范围内最常见的原发性肾小球疾病，部分患者可能进展为终末期肾病，目前“多重打击学说”仍为IgAN发病机制的主要研究领域，半乳糖缺乏的的IgA1（Galactose-deficient IgA1，Gd-IgA1）在循环中的合成升高，作为一种自身抗原诱导抗Gd-IgA1特异性抗体的产生，随后循环中的Gd-IgA1和抗Gd-IgA1的特异性抗体形成致病性免疫复合物并在系膜区沉积，导致系膜细胞的增殖、肾小球炎症和肾损伤，而Gd-IgA1则被认为是IgAN发病的关键环节。目前IgAN的诊断仍依靠肾活检，除了蛋白尿水平、肾小球滤过率之外，尚缺乏已验证的用于IgAN预后评估的尿液或血清标记物，亟需探寻具有预后评估与诊断价值的血清或尿液生物标志物。微小核糖核酸（microRNA，miRNA）作为一种小型非编码RNA，具有调控基因表达的作用，与IgAN的发生、进展具有密切联系。在发病机制方面，部分miRNA通过靶向1β1，3-半乳糖基转移酶（Core 1 β1，3-galactosyltransferase，C1GALT）和Cosmc等关键基因调节IgA1的糖基化过程，进而影响Gd-IgA1的生成。在IgAN进展及肾纤维化进程中，部分血浆及尿外泌体的miRNA表达水平与lgAN疾病预后相关风险因素也具有一定的相关性，能够通过调控转化生长因子（Transforming Growth Factor，TGF）-1/SMAD3信号通路等机制参与肾纤维化进程，为评估疾病进展及肾纤维化进程提供了重要参考价值。诊断方面，血浆及尿外泌体miRNA因其微创及便捷性，作为IgAN诊断的生物标记物具有重要意义。黄芪、绞股蓝等中药及中药复方通过上调或下调特定miRNA的表达，能够发挥抗肾纤维化作用，改善lgAN患者的肾功能。文章就miRNAs在IgAN发生、进展、诊断及中医药治疗中的研究现状进行综述。

摘要： OBJECTIVE:To assess the association of single nucleotide polymorphisms (SNPs) of interleukin-23 receptor (IL-23R) gene with susceptibility to psoriasis. METHODS:Two hundred and ten psoriasis patients admitted to Xinxiang Central Hospital from January 2019 to December 2024 were selected as the study group, and 210 healthy individuals undergoing physical examination during the same period were selected as the control group. 3 mL of peripheral venous blood sample was collected from each individual from the two groups, and PCR-Restriction fragment length polymorphism (PCR-RFLP) assay was used to determine the polymorphisms of the IL-23R gene at rs2201841, rs1004819, rs10889677, rs1343151 and rs1495965 loci. Genotypic and allelic distribution of each SNP locus was calculated to assess the association between SNPs of the IL-23R gene with the onset of psoriasis, and the difference in serum IL-23 levels among patients with different genotypes at each locus was compared. This study was approved by the Medical Ethics Committee of Xinxiang Central Hospital (Ethic No. 2024-749). RESULTS:The results showed that the frequency of CC genotype at rs1004819 locus of the study group was significantly higher than that of the control group (26.19% vs. 18.10%, P < 0.05), and the frequency of C allele was also significantly higher than that of the control group (54.05% vs. 42.62%, P < 0.05). There was no significant difference in allelic and genotypic frequencies between the two groups at rs2201841, rs10889677, rs1343151, and rs1495965 loci (P > 0.05). The dominant and recessive inheritance patterns at the rs1004819 locus are associated with susceptibility to psoriasis (P < 0.05), while the different inheritance patterns at rs2201841, rs10889677, rs1343151, and rs1495965 loci are not associated with psoriasis (P > 0.05). The serum IL-23 levels of patients with CC genotype at the rs1004819 locus were higher than those with the CT and TT genotypes (P < 0.05). No significant difference was d