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关键词： systemic lupus erythematosus   interleukin-10   interleukin-6  

摘要： Interleukin-10 (IL-10) presents a dual role in systemic lupus erythematosus (SLE), illustrating pro-inflammatory and anti-inflammatory effects. This study addressed the possible associations between serum IL-10 levels and demographic characteristics, laboratory parameters, organ manifestations, disease activity, and treatment response in SLE patients. A total of 88 SLE patients from the Rheumatology Clinic of the Clinical Rehabilitation Hospital, Iasi, were enrolled. Disease activity was assessed using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Serum cytokine levels were measured using an enzyme-linked immunosorbent assay (ELISA). Serum IL-10 levels were significantly higher in males compared to females (47.62 pg/mL vs. 13.24 pg/mL, p = 0.011) but not significantly associated with age or disease duration. However, IL-10 showed positive correlations with inflammatory markers and autoantibodies, including C-reactive protein (p = 0.002), IL-6 (p = 0.01), ANA (p = 0.014), and anti-SSB antibodies (p = 0.005). Our findings indicate that IL-10 may be involved in inflammatory and immune processes in SLE, as evidenced by its significant correlations with specific autoantibodies and inflammatory markers in our study. However, IL-10 did not correlate with disease activity, organ involvement, or treatment response. These results underline the participation of IL-10 in SLE and emphasize the need for further research to clarify its potential as a biomarker or therapeutic target.

关键词： porcine IL-3   IL-7   IL-15   fusion expression   immunity   mice  

摘要： China's livestock industry grapples with challenges posed by infectious diseases and the misuse of antibiotics, resulting in a heightened risk of drug-resistant pathogens. This study explored the immunomodulatory effects of co-expressing porcine interleukin 3, 7, and 15 in Yarrowia lipolytica, denoted as Po1h-IL-3/7/15. A 42-day experiment involving mouse immunization and pathogen challenge was conducted, during which in vivo assessments of antibodies, immune-related cells, and gene expression were detected following oral administration of Po1h-IL-3/7/15. Immunological alterations in mice were analyzed using flow cytometry, qRT-PCR, ELISA, and HE staining. Notably, the serum IgG and intestinal sIgA levels in the Po1h-IL-3/7/15 group were substantially elevated compared to the control groups (p < 0.01), so were the contents of IL-7, IL-15, IFN-gamma, IL-22, IL-23, and TNF-alpha. Furthermore, there was a marked increase in na & iuml;ve T cells and central memory T cells, accompanied by a significant decrease in regulatory T cells in peripheral blood. Post-challenge with Staphylococcus aureus or Salmonella typhimurium, the expression levels of BD2, IL-1 beta, IL-8, Jak1, RegIII, S100A8, STAT1, and TNF-alpha genes in the intestines of the Po1h-IL-3/7/15 group were markedly higher than those in the control groups (p < 0.01). Following the challenges, the survival rate of the Po1h-IL-3/7/15 group was 100%, a significant increase compared to the 20% and 40% survival rates observed in the control groups (p < 0.05). These results confirm that IL-3/7/15 significantly boosts innate immunity, humoral and cell-mediated immune responses, and intestinal mucosal immunity in mice, enhancing resistance to bacterial infections and exhibiting potent protective effects.

关键词： IL1RAP   恶性肿瘤   信号通路   IL-1   IL1RAP   Malignant Tumors   Signaling Pathway   IL-1  

摘要： 白介素1受体辅助蛋白(IL1RAP)是白介素1 (IL-1)家族的共受体，通过与白介素1受体(IL-1R)结合形成多聚复合物并激活下游信号通路发挥生物学效应。IL1RAP介导的信号通路在各类恶性肿瘤中表现出促增殖和促侵袭、迁移的特性，包括血液系统肿瘤、消化道肿瘤、乳腺癌、宫颈癌等。本综述旨在阐明IL1RAP介导的信号通路的生物学效应，以及IL1RAP在各类恶性肿瘤中作用机制的研究进展。

关键词： Psoriasis   Th17/IL-17A axis   PLEK   Hub genes  

摘要： Psoriasis is a common chronic skin disorder with a polygenic background. It is widely acknowledged that Th17/IL-17A axis plays a key role in the pathogenesis of psoriasis. However, numerous regulatory genes upstream of the pathway remain undiscovered, creating a knowledge gap in our understanding of the genetic aspects of the Th17/IL-17A axis. In this study, we employed machine learning algorithms to identify three target genes associated with psoriasis: CCR7, IL2RG, and PLEK. The validation of these genes was carried out in specimens from psoriatic patients. In vivo, investigations assessed the relationship between these three genes and IL-17A-related inflammation and their connection to psoriatic phenotypes. To further confirm the significance of the newly discovered gene, PLEK, we performed experiments involving the blockade of its expression. Our bioinformatics analysis revealed three novel genes closely linked to psoriasis: CCR7, IL2RG, and PLEK. These genes exhibited upregulated expression in psoriasis, consistently aligning with the Th17/IL-17A axis. Inhibition of PLEK expression reduced Th17/IL-17A-related inflammation and alleviated psoriatic phenotypes. CCR7, IL2RG, and PLEK show potential as three novel biomarkers for psoriasis, with PLEK being reported for the first time in this context. These genes contribute to pathogenesis by associating with the Th17/IL-17A signaling pathway.

关键词： 新孢子虫   虫草素   牛   巨噬细胞   细胞因子   干扰素  

摘要： 牛新孢子虫病的防治目前缺乏确切有效的疫苗和特效药物,因此,开发安全、经济且高效的新孢子虫防治药物是该病防治研究的重点。虫草素(cordycepin)是一种从冬虫夏草中提取的核苷类化合物,本研究旨在研究虫草素抗新孢子虫感染的作用。采用CCK-8法确定虫草素对牛巨噬细胞的安全剂量;通过实时荧光定量PCR分析和免疫荧光法分析虫草素对牛巨噬细胞荷虫数的影响;利用实时荧光定量分析虫草素对新孢子虫诱导牛巨噬细胞分泌细胞因子、干扰素和防御介素的影响。结果显示,与空白对照组相比,虫草素在2.8125～180μmol/L浓度范围内对牛巨噬细胞没有毒性作用;与新孢子虫感染组相比,虫草素在5.625、11.25和22.5μmol/L浓度下均显著减少了牛巨噬细胞的荷虫数,并降低了胞内的荧光虫体数量。此外,新孢子虫感染降低了炎性细胞因子TNF-α、IL-1β和IL-6的水平,而虫草素则显著诱导促炎细胞因子的表达;同时,新孢子虫显著诱导IFN-α、IFN-β和IFN-γ的表达水平升高,而虫草素降低了干扰素的表达,但仍维持了一定程度的表达水平。综上所述,虫草素具有抗新孢子虫感染的作用,展示出治疗牛新孢子虫病的潜在药用价值。

关键词： immunotherapy resistance   immune-checkpoint blockade   single-cell RNA sequencing   hepatocellular carcinoma   HCC   myeloid-derived suppressor cells   interleukin-8  

摘要： Durable responses to immune checkpoint blockade (ICB) in hepatocellular carcinoma (HCC) are limited to a minority of patients, yet reliable biomarkers are still lacking. Inflammatory cytokines such as interleukin-8 (IL-8) are associated with HCC progression, and IL-8 is known as the chemoattractant for immunosuppressive myeloid cells. Therefore, we aim to elucidate the ICB resistance mechanisms mediated by the activation of the IL-8/CXCR2 pathway. Single-cell RNA sequencing (scRNA-seq) was performed in advanced HCC patients with baseline and on-treatment biopsy after pembrolizumab in a phase 2 clinical trial cohort. Our data revealed that IL-8 and its receptor, CXCR2, mainly derived from immunosuppressive myeloid-derived suppressor cells (MDSCs). In particular, the high circulating IL-8 level was strongly associated with poor ICB response. This myeloid IL-8/CXCR2 pathway was further elucidated in our ICB-resistant orthotopic mouse model using AZD5069, a clinically available CXCR2 antagonist. Suppression of the IL-8/CXCR2 pathway significantly abrogated MDSC trafficking and immunosuppressive activity, which sensitized the anti-PD-L1 blockade to reduce tumor growth and prolong survival. The association between myeloid IL-8 and ICB therapeutic outcomes also extended to multiple cancer types. Collectively, our study not only suggests a potential noninvasive biomarker for patient stratification and monitoring of ICB response but it also provides a proof of concept for combinational immunotherapy to benefit patients who are nonresponsive to ICB monotherapy.

关键词： heart transplantation   IL-10   myocardial ischemia-reperfusion injury   spliceosome   Y4 RNA fragment  

摘要： Myocardial ischemia-reperfusion injury (MIRI) inevitably occurs during heart transplantation, highlighting the imperative for effective therapeutic interventions. A Y4 RNA fragment (YF1) was applied to treat a syngeneic mouse model of heart transplantation, with the heart subjected to cold ischemia-reperfusion (CIR). Cardiomyocytes and macrophages were treated with YF1, and a cellular cold hypoxia-reoxygenation (CHR) model was established. We found that YF1 alleviated CIRinduced inflammatory macrophage infiltration and cardiomyocytes injury in the graft heart. YF1 had no direct effects on cardiomyocytes in vitro, while YF1 inhibited macrophage polarization to the pro-inflammatory phenotype with increased expression of anti-inflammatory factors. Moreover, YF1 attenuated CHRinduced cardiomyocyte injury by regulating the interleukin-10 (IL-10) expression in macrophages. Mechanistically, YF1 increased the mRNA expression ratio of IL-10/pre-IL-10 by binding to SNRNP200, a spliceosome-specific protein for pre-mRNA splicing, with reduced SNRNP200 ubiquitination. It was reversed by Brr2-IN-3, a specific SNRNP200 inhibitor. Collectively, we hold that YF1 might alleviate MIRI in heart transplantation via binding to SNRNP200 and regulating its ubiquitination to enhance IL-10 pre-mRNA splicing. These findings further clarify the effects and mechanism of YF1 on MIRI and suggest a potential cardioprotective therapy in heart transplantation.

摘要： IL-12 is a potent NK cell-stimulating cytokine, but the presence of immunosuppressive myeloid cells such as myeloid-derived suppressor cells (MDSC) can inhibit IL-12-induced NK-cell cytotoxicity. Thus, we hypothesized that trabectedin, a myeloid cell-depleting agent, would improve the efficacy of IL-12 in triple-negative breast cancer (TNBC). In vitro treatment of healthy donor NK cells with trabectedin increased expression of the activation marker CD69 and mRNA expression of T-box transcription factor (Tbx21), the cytotoxic ligands TNF-related apoptosis-inducing ligand (TNFSF10), Fas ligand (FASLG), and the dendritic cell (DC)-recruiting chemokine lymphotactin (XCL1). The combination of IL-12 and trabectedin increased NK-cell cytotoxicity and activation and production of IFN-gamma, TNF-alpha, and granzyme B in the presence of human TNBC cells. Treatment of 4T1 and EMT6 tumor-bearing mice with IL-12 and trabectedin led to a significant reduction in tumor burden compared with single-agent controls and the highest levels of plasma IFN-gamma, intratumoral CD8+ T cells, and conventional type 1 DC. MDSC and M2-like macrophages were significantly decreased with combination therapy. NK-cell depletion abrogated the effects of combination therapy, as did the elimination of CD8+ T cells. NK-cell depletion led to lower levels of the NK cell-derived chemokine CCL5 and the DC-derived chemokine CXCL10, higher tumor burden, and decreased intratumoral CD8+ T cells. IL-12 and trabectedin also significantly enhanced the response of TNBC to anti-PD-L1 therapy. These data suggest that MDSC depletion augments the ability of IL-12-activated NK cells to drive the infiltration of DC and CD8+ T cells into TNBC for an antitumor effect.

摘要： Pediatric high-grade gliomas (pHGG) and pediatric diffuse midline gliomas (pDMG) are devastating diseases without durable and curative options. Although targeted immunotherapy has shown promise, the field lacks immunocompetent animal models to study these processes in detail. To achieve this, we developed a fully immunocompetent, genetically engineered mouse model (GEMM) for pDMG and pHGG that incorporates the glioma-associated antigen, interleukin 13 receptor alpha 2 (IL13RA2). Utilizing the RCAS-Tva delivery system in Nestin-Tva mice, we induced gliomagenesis by overexpressing PDGFB and deleting p53 (p53(fl/fl)) or both p53 and PTEN (p53(fl/fl) PTENfl/fl), with or without IL13RA2 in neonatal mice. De novo tumors developed in models with and without IL13RA2, showing no statistical difference in onset (n = 33, 38 days, p = 0.62). The p53(fl/fl) PTENfl/fl tumors displayed more aggressive characteristics (n = 12, 31 days). Tumors exhibited features typical of high-grade glioma, including infiltration, pseudopalisading necrosis, and microvascular proliferation. They also showed a high Ki-67 index, variable IL13RA2 expression, a high frequency of CD11b + macrophages, and a low proportion of CD3 + T cells. The model proved effective for evaluating IL13RA2-targeted immunotherapies, with a significant response to CAR T-cell treatment that extended survival (46 days vs. 28 days control;p < 0.0001) and achieved 25% long-term survival in mice. This model facilitates the preclinical assessment of IL13RA2-directed therapies and holds potential for clinical application.

关键词： 脑出血   血肿清除术   并发症  

摘要： 目的 观察神经内镜下血肿清除术与小骨窗血肿清除术在基底节脑出血治疗中的效果及对肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)水平的影响。方法 选取2021年5月—2023年12月在邹平市人民医院接受治疗的200例基底节脑出血患者为研究对象,根据不同治疗方法分为传统操作组、内镜可视化操作组,各100例。传统操作组施以小骨窗血肿清除术治疗,内镜可视化操作组施以神经内镜下血肿清除术治疗。观察两组神经功能受损评分、意识状态评分及TNF-α水平的变化,比较两组手术相关指标及血肿清除率、临床疗效、并发症发生情况。结果 内镜可视化操作组手术时长、术中出血量、住院时长、血肿清除率均优于传统操作组,差异均有统计学意义(P均<0.05)。术后,两组神经功能受损评估量表、意识状态评估量表评分与TNF-α水平均优于术前,且内镜可视化操作组术后1个月的神经功能受损评估量表评分低于传统操作组,意识状态评估量表评分高于传统操作组,术后1周的TNF-α水平低于传统操作组,差异均有统计学意义(P均<0.05)。内镜可视化操作组治疗有效率为94.00%(94/100),高于传统操作组的84.00%(84/100),差异有统计学意义(χ^(2)=5.107,P<0.05)。内镜可视化操作组术后并发症发生率为4.00%(4/100),低于传统操作组的12.00%(12/100),差异有统计学意义(χ^(2)=4.348,P<0.05)。结论 较小骨窗血肿清除术相比,神经内镜下血肿清除术治疗基底节脑出血的临床效果更加突出,可明显降低患者的TNF-α水平,手术安全性较高,患者预后效果良好。