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关键词： COVID-19   Exhaustion   Insulin resistance   Senescent   T cells  

摘要： Insulin resistance is one of the metabolic complications of COVID-19. Our previous study showed a 22% median increase in homeostasis model assessment-estimated insulin resistance (HOMA-IR) in obese individuals at 12 months post-infection compared to acute infection. This study aimed to investigate the association between various subsets of IFN-γ-expressing SARS-CoV-2-specific CD4 and CD8 T cells and insulin resistance in convalescent COVID-19 patients over a one-year post-infection follow-up period. A nested case control study of 47 COVID-19 patients was followed for 12 months post-infection and categorized into three groups based on obesity and changes in HOMA-IR at one year: non-obese without increased HOMA-IR (NO), obese without increased HOMA-IR (O), and obese with increased HOMA-IR (O-IR). Increased HOMA-IR was defined as a HOMA-IR ratio (12-month to 1-month convalescence phase) > 1.21. To study antigen-specific responses, peripheral blood mononuclear cells (PBMC)s were isolated and incubated with SARS-CoV-2 peptide antigens for 24 h. Intracellular IFN-γ expression, as well as exhaustion and senescence markers, in various CD4 and CD8 T cell subsets were measured by flow cytometry. The abundance of IFN-γ-expressing SARS-CoV-2-specific CD4 T cells was lower in the O-IR group compared to individuals without increased HOMA-IR during the 9th to 12th months of follow-up (p < 0.05). Conversely, the O-IR group exhibited a mild but significantly higher IFN-γ-expressing CD8 T cells from the 3rd to the 9th month of the convalescence phase (p < 0.05). A reduced proportion of functional (PD-1CD57) SARS-CoV-2-specific T cells was observed in O-IR group. Furthermore, the reduced proportion of functional SARS-CoV-2-specific CD4⁺ T cells observed within 12 months of convalescence were have significant weak negative correlation with HOMA-IR ratio as well as HOMA-IR value. Our study demonstrates that obese individuals with increased HOMA-IR exhibited a reduced proportion of IFN-γ

关键词： 乙型肝炎病毒感染   免疫状态   壳多糖酶3样蛋白1   白细胞介素33   临床结局  

摘要： 目的：分析血清壳多糖酶3样蛋白1（CHI3L1）和白细胞介素33（IL-33）水平在慢性乙型肝炎病毒（HBV）感染者免疫状态评估中的临床价值。方法：纳入2022年1月至2023年6月遵义市第一人民医院收治的156例慢性HBV感染者为研究对象，根据不同免疫状态分为A组（免疫耐受期，n=51）、B组（免疫活动期，n=48）、C组（免疫控制期，n=32）、D组（再活动期，n=25），另选同期50名体检正常健康志愿者为对照组（n=50）。检测所有对象血清CHI3L1、IL-33水平。采用Spearman相关系数分析血清CHI3L1、IL-33水平与慢性HBV感染者免疫状态的相关性。对慢性HBV感染者进行抗病毒治疗后随访12个月，根据疾病进展情况分为预后良好组（n=102）和预后不良组（n=54），比较不同临床结局慢性HBV感染者血清CHI3L1、IL-33水平；绘制受试者工作特征（ROC）曲线分析CHI3L1、IL-33对慢性HBV感染者预后不良的预测价值。结果：不同免疫状态慢性HBV感染者CHI3L1、IL-33水平比较，D组＞B组＞C组＞A组，且四组血清CHI3L1、IL-33水平均高于对照组，差异有统计学意义（P<0.05）；Spearman相关系数分析显示，血清CHI3L1、IL-33水平与慢性HBV感染者免疫状态均呈正相关（P<0.05）。预后良好组血清CHI3L1、IL-33水平均低于预后不良组，差异有统计学意义（P<0.05）。ROC曲线分析显示，CHI3L1、IL-33水平及联合检测的曲线下面积（AUC）分别为0.792、0.785、0.861，联合检测优于单一检测（P<0.05）。结论：血清CHI3L1、IL-33水平与慢性HBV感染者免疫状态相关，二者对辅助评估慢性HBV感染者预后情况有一定价值。

关键词： PRRSV   14-3-3 gamma   IL-8 mRNA   IL-8 protein   N protein   viral replication  

摘要： Porcine reproductive and respiratory syndrome virus (PRRSV) has posed a significant threat to the global swine industry for over 3 decades, resulting in substantial economic losses. In this study, we identified the cellular protein 14-3-3 gamma as an antiviral factor that suppresses PRRSV replication by downregulating the mRNA levels of interleukin-8 (IL-8). Intriguingly, while IL-8 mRNA levels were positively correlated with PRRSV genome replication, the IL-8 protein itself exhibited a potent inhibitory effect on viral replication. Mechanistic studies revealed that 14-3-3 gamma enhances IL-8 transcription. In contrast, the viral nucleocapsid (N) protein upregulates IL-8 transcription. A critical nuclear localization signal (NLS) domain (amino acid residues 11-13) within the N protein, particularly the lysine residues at positions 10 and 12, was identified as essential for this regulatory function. The nuclear distribution of the N protein was found to be indispensable for its activity. Furthermore, we demonstrated that 14-3-3 gamma and IL-8 competitively bind to the N protein, modulating its nuclear distribution. This study elucidates the intricate regulation of IL-8 at both transcriptional and protein levels in modulating PRRSV replication. It uncovers a novel function of IL-8 in viral pathogenesis and highlights its potential as a promising candidate for the development of anti-PRRSV *** reproductive and respiratory syndrome virus (PRRSV) has severely impacted swine production worldwide for decades. This study reveals that the cellular protein 14-3-3 gamma suppresses PRRSV replication by downregulating interleukin-8 mRNA, while IL-8 protein itself inhibits viral replication. Mechanistically, 14-3-3 gamma upregulates IL-8 transcription, whereas the viral nucleocapsid (N) protein enhances IL-8 transcription, which is dependent on its nuclear localization signal (amino acid residues 11-13, particularly K10/K12). Nuclear distribution of the

关键词： IL-2   IL-10   IFNγ   EGFR   cytokine   cytokine release syndrome   vascular leak syndrome   immunotherapy   targeted therapy   T cell exhaustion  

摘要： Wild-type interleukin (IL)-2 induces anti-tumor immunity and toxicity, predominated by vascular leak syndrome (VLS) leading to edema, hypotension, organ toxicity, and regulatory T cell (Treg) expansion. Efforts to uncouple IL-2 toxicity from its potency have failed in the clinic. We hypothesize that IL-2 toxicity is driven by cytokine release syndrome (CRS) followed by VLS and that coupling IL-2 with IL-10 will ameliorate toxicity. Our data, generated using human primary cells , mouse models, and non-human primates, suggest that coupling of these cytokines prevents toxicity while retaining cytotoxic T cell activation and limiting Treg expansion. In syngeneic murine tumor models, DK2 10 epidermal growth factor receptor (EGFR), an IL-2/IL-10 fusion molecule targeted to EGFR via an anti-EGFR single-chain variable fragment (scFV), potently activates T cells and natural killer (NK) cells and elicits interferon (IFN)γ-dependent anti-tumor function without peripheral inflammatory toxicity or Treg accumulation. Therefore, combining IL-2 with IL-10 uncouples toxicity from immune activation, leading to a balanced and pleiotropic anti-tumor immune response.

摘要： Das familiäre Mittelmeerfieber (FMF) ist die häufigste monogene autoinflammatorische Erkrankung in Deutschland. Die genetische Testung auf Mediterranean FeVer (MEFV)-Varianten ist diagnostisch zentral, ihr Einfluss auf Therapieentscheidungen ist bislang weitestgehend unklar. Untersuchung des Zusammenhangs zwischen MEFV-Variante und Krankheitsverlauf sowie der Notwendigkeit einer Therapieeskalation mit Interleukin-1-Inhibitoren. Es wurden 59 pädiatrische FMF-Patienten mit mindestens einer MEFV-Variante erfasst, genetisch über INFEVERS klassifiziert und in 4 Kohorten eingeteilt, basierend auf der Pathogenität der vorliegenden Varianten. Kohorte 1 mit 2 pathogenen bzw. wahrscheinlich pathogenen Varianten zeigte trotz genetischer Last die längste Zeit bis zur Diagnose und niedrige Symptomhäufigkeit; 31 % erhielten Anakinra, 15 % Canakinumab. Kohorte 2 umfasste Patienten mit einer pathogenen oder wahrscheinlich pathogenen Variante kombiniert mit einer Variante unklarer oder benigner Signifikanz und wies das früheste Erkrankungsalter auf; kein Patient erhielt ein Biologikum. In Kohorte 3 mit einer sicher pathogenen Variante erhielten 2 Patienten (7 %) Anakinra und im Verlauf Canakinumab. Kohorte 4 mit ausschließlich Varianten unklarer oder benigner Signifikanz zeigte milde Verläufe unter Colchicin. Pathogene MEFV-Varianten – insbesondere in homozygoter oder compound-heterozygoter Form – waren mit früherem Symptombeginn, längerer Diagnosedauer und höherem Therapiebedarf assoziiert. Frühzeitige genetische Diagnostik könnte eine gezielte Therapieeskalation unterstützen.

关键词： Holstein–Friesian cows   antioxidant enzymes   inflammation   metabolic regulation   periparturient health   selenitetriglycerides   selenium supplementation   transition period  

摘要： The transition period in dairy cows, spanning late pregnancy and early lactation, is associated with substantial metabolic and immunological challenges, leading to increased oxidative stress and inflammation. Selenium (Se), particularly in organic forms, supports antioxidant defenses, immune function, and metabolic regulation. This study investigated the effects of supplementing periparturient Holstein-Friesian cows with orally administered selenitetriglycerides (0.5 mg Se/kg body weight/day starting 12 days before the expected calving date and continuing until parturition) on antioxidant enzyme activity and on the hepatic expression of key inflammatory and metabolic genes. Serum selenium concentrations and erythrocyte glutathione peroxidase (GSH-Px) activity were assessed before and after parturition, and hepatic gene expression levels of tumor necrosis factor alpha (), peroxisome proliferator-activated receptor alpha () and delta () were assessed 24 h and 7 days postpartum. Supplemented cows showed significantly elevated serum Se levels and increased GSH-Px activity, reflecting improved antioxidant capacity. Moreover, hepatic expression of and was significantly reduced postpartum in the supplemented group, whereas expression remained stable. These findings indicate that selenitetriglycerides effectively enhance antioxidant defenses, moderate inflammation, and stabilize metabolic pathways during the periparturient phase, potentially reducing postpartum metabolic disorders and improving dairy-cow health.

关键词： Apoptosis   Gasdermin E   Granulosa cells   IL2RG   Polycystic ovary syndrome  

摘要： Polycystic ovary syndrome (PCOS) is a common endocrine disorder with significant impacts on women’s reproductive health. Interleukin (IL)-2 receptor subunit gamma (IL2RG), a common receptor for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21, has been shown to interrupt estrous cycle, yet its role in PCOS remains unclear. The evaluated expression levels of IL2RG in human granulosa cells (GCs) and IL2RG-dependent cytokines (IL-2, IL-4, IL-15) in follicular fluid were demonstrated in 18 PCOS patients and 22 control subjects. The positive correlation between IL2RG and PCOS was analysed through GEO databases. In vivo, we found that in the PCOS model (6 mg/100 g body-weight of dehydroepiandrosterone subcutaneous injection for 21 days), the ovarian index, testosterone, glucose, and LH/FSH levels were elevated, and the estrous cycle was disrupted. Knocking down IL2RG (KO) restored the above levels. However, in the dehydroepiandrosterone-treated group, these levels did not recover even after IL2RG was knocked-down. The decreased expression of Gasdermin E (GSDME) but increased caspase-3 level in IL2RG KO rats compared with WT were found. In vitro, knockdown of IL2RG by siRNA inhibited caspase-3-mediated GSDME cleavage in testosterone-induced KGN cells. Furthermore, the caspase-3 inhibitor Z-DEVD-FMK and the caspase-1 inhibitor Belnacasan alleviated pyroptosis in testosterone-induced KGN cells by lactate dehydrogenase test, fluorescence assay, and flow cytometry. IL2RG is expressed higher in PCOS patients, exerting an inhibitory effect on caspase-3-mediated GSDME cleavage upon knockdown. However, the knockout of IL2RG led to the conversion of GSDME-mediated pyroptosis into apoptosis. This study explores the function of IL2RG and provides insights for therapeutic targets in PCOS.

关键词： Inflammation   Osteoarthritis   Pain perception   Statistical modeling   Synovial microenvironment  

摘要： This study delineates distinct late-stage osteoarthritis (OA) profiles, characterized by NF-κB, TNF-α, and TGF-β-mediated synovial inflammation and pain, in a cohort of 31 patients undergoing joint arthroplasty. Histopathological analysis demonstrated synoviocyte hyperplasia, increased stromal cellularity, inflammatory infiltrates, and enhanced vascularization, findings that correlated with higher synovitis scores and exacerbated movement-associated nociception. Increased expression of NF-κB and TNF-α in the synovial membrane confirmed their association with stronger inflammation and pain perception. Bayesian networks revealed relationships among NF-κB, TNF-α, and pain scores, suggesting that NFκB is a primary driver of pain in low-grade synovitis, while TNF-α becomes more influential in high-grade synovitis. Cluster analysis identified four distinct patient subgroups: (1) males with severe radiographic OA, elevated NF-κB in both the synovium and fluid, and the absence of synovitis; (2) predominantly females with metabolic comorbidities, a variable degree of synovitis, and elevated TNF-α in synovial fluid; (3) patients with low pain scores and no histopathologically confirmed synovial inflammation; and (4) patients with high-grade synovitis, pronounced tissue alterations, increased NF-κB, TNF-α, and TGF-β expression in the synovial membrane, but without metabolic comorbidities. The findings clarify the influence of synovitis in late-stage OA and suggest that the identified profiles may assist in earlier disease stratification and the development of tailored treatments in the future.

关键词： 急性肝衰竭   解毒化瘀颗粒   白细胞介素6/Janus激酶2/信号传导和转录激活因子3   免疫炎症  

摘要： 目的 急性肝衰竭(Acute Liver Failure，ALF)是一种短期内死亡率很高的急危重症疾病。解毒化瘀颗粒(JDHY)已被临床证实是治疗ALF的有效方剂，用于治疗ALF已有20余年历史，但其疗效机制尚未被完全阐明。本文旨在探讨JDHY调控白细胞介素6（Interleukin-6，IL-6）/蛋白酪氨酸激酶（Janus Kinase 2，JAK2）/信号传导和转录激活因子3（Signal Transducer And Activator Of Transcription 3，STAT3）信号通路对D-氨基半乳糖( D-Galactosamine，D-GALN)和脂多糖( Lipopolysaccharides，LPS)诱导的ALF大鼠的作用机制及JDHY的干预效应。方法 用随机数字表法将雄性SD大鼠30只分为正常对照组（Control）、模型组（D-GALN/LPS）、D-GALN/LPS+JDHY组（JDHY），每组10只。D-GALN/LPS组和JDHY组按照D-GALN 600mg/kg 和LPS 20μg/kg腹腔注射构建ALF大鼠模型，JDHY组在造模前按0.22g/ml浓度中药液灌胃，每天1次，连续3天，Control组和D-GALN/LPS组则给予等量生理盐水灌胃，造模24小时后处死老鼠收集相关样本，观察肝脏大小、外观变化；检测血清谷丙转氨酶（Alanine aminotransferase，ALT）、谷草转氨酶（Aspartate aminotransferase，AST）、总胆红素（Total bilirubin，TBIL）、凝血酶原时间（Prothrombin time，PT）；HE染色观察肝组织病理学变化，酶联免疫吸附法（Enzyme-linked immunosorbent assay，ELISA）检测血清IL-6、白细胞介素-1β(Interleukin-1β，IL-1β)、核转录因子-κB（Nuclear factor kappa-B，NF-κB）、肿瘤坏死因子（Tumor necrosis factor-alpha，TNF-α）水平；蛋白质印迹（Western Blot，WB）检测肝组织JAk2、STAT3、P-JAk2、P-STAT3和该信号通路下游蛋白B细胞淋巴瘤-2(BCL-2)、BCL-2相关X蛋白(BAX)的表达；免疫组织化学法(Immunohistochemistry，IHC) 检测JAK2、STAT3、BCL-2、BAX蛋白表达；聚合酶链式反应（Quantitative real time polymerase chain reaction，q-PCR）检测JAK2、STAT3、BAX、BCL-2的mRNA表达。结果 经JDHY提前干预后，ALF大鼠的肝功能、凝血功能得到改善、肝组织炎症浸润范围缩小，死亡率降低，血清IL-6、IL-1β、NF-κB、TNF-α炎症细胞因子水平明显降低，肝组织JAK2、P-JAK2、STAT3、P-STAT3、BCL-2、BAX蛋白表达均下调，JAK2、P-JAK2、STAT3、P-STAT3 mRNA水平下降。结论 JDHY能有效改善ALF肝损伤，降低死亡率，其机制可能与下调IL-6/JAK2/STAT3信号通路表达有关。