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摘要： Background and aims: Cardiovascular disease (CVD) is one of the leading causes of morbidity and mortality worldwide, yet the underlying molecular mechanisms remain less understood. Chronic low-grade inflammation is a complex immune response contributing to the pathophysiology of cardiovascular disease. This response is signaled in part by interleukin-6 (IL-6), a pleiotropic, pro-inflammatory cytokine. Phenotypic variance in circulating IL-6 level may be explained in part by DNA methylation which is increasingly being associated with cardiovascular effects. Methods: In this study we evaluated methylated DNA (CpG sites) associated with blood IL-6 levels across similar to 4,400 ancestrally diverse individuals (81 % self-reported White;9 % Black or African American, 8 % Hispanic or Latino/a, and 2 % Chinese American). Results: We identified 178 CpG sites associated with IL-6 (p<0.05/similar to 395,000). Among the sites, cg04437762 is located within the transcription unit of IL6R, a current therapeutic target for inflammatory disease, and cg26692003 and cg00464927 were significant for IL6 and IL6ST trans-CpG-gene transcripts. Functional gene expression downstream of methylation identified cellular response to IL-6 and B-cell regulation and activation pathways. Four genes were linked with both a genetic component of cardiovascular disease and an IL-6 associated CpG site. Three CpG sites identified through Mendelian randomization analyses supported inference of a causal effect on IL-6 levels, including the LYN gene that regulates immune cell signaling and has been previously associated with atherosclerosis. Conclusions: Overall, we identified several novel IL-6-CpG sites and downstream pathways affected by methylation. Follow-up functional studies including the regulation of IL-6 would complement current knowledge of CVD pathophysiology and potential therapeutic targets.

关键词： TNF-alpha   OX40L   OX40   hidradenitis suppurativa   Nanobody   xenograft graft-versus-host disease   T cell-dependent antibody response   delayed-type hypersensitivity skin reaction  

摘要： Background: Chronic inflammatory conditions are among the leading causes of disability and mortality. Although therapies have been significantly improved with the introduction of target-specific biologics, many chronic inflammatory conditions can be only moderately controlled by inhibition of individual cytokines. Objective: We sought to compare individual versus simultaneous blockade of TNF-a and OX40L in controlling inflammation. Methods: Analysis was conducted of the murine xenograft graft-versus-host disease model, a novel cynomolgus monkey model of simultaneous T cell-dependent antibody response (TDAR) and delayed-type hypersensitivity (DTH) skin reaction, and samples of patients with hidradenitis suppurativa (HS). Results: Compared with individual inhibition, combined targeting of TNF-a and OX40L using mAbs more potently suppressed TDAR and DTH in cynomolgus monkey. We therefore created SAR442970, a bispecific pentavalent Nanobody containing 2 domains each binding to OX40L and TNF-a and 1 domain binding serum albumin to extend half-life. In xenograft graft-versus-host disease, disease control by SAR442970 was superior compared with treatment with monospecific anti-TNF-a or anti-OX40L Nanobodies. In cynomolgus monkey, SAR442970 potently suppressed TDAR and DTH. The transcriptional signature of inflamed monkey skin showed similarities to that of lesional skin of patients with atopic dermatitis and, even more so, HS and was inhibited by SAR442970 treatment. Increased numbers of cells expressing OX40 were observed in HS lesions, and bioinformatics analyses of single-cell and bulk RNA sequencing data identified cells expressing OX40 as T cells with a highly mobile phenotype. Conclusion: OX40-OX40L interaction is a key pathogenetic feature in HS, and patients with HS might benefit from combined TNF-a/OX40L blockade by SAR442970, which is currently investigated in a clinical phase 2 trial. (J Allergy Clin Immunol Global 2025;4:100483.)

关键词： IL-39   Inflammation   Autoimmune disease   Dysbiosis   Periodontitis   Autoantibody  

摘要： IL-39, a cytokine from the IL-12 family that appears to be produced primarily by B cells, consists of the IL-23p19 and Ebi3 subunits, which signal through IL-23R/gp130 to activate STAT1/STAT3. Some studies suggest elevated IL-39 levels in certain autoimmune conditions, such as relapsing-remitting multiple sclerosis (RRMS), ankylosing spondylitis (AS), and autoimmune thyroid disease (ATD), possibly indicating a link between IL-39 and autoimmunity mediated by B cells. Preliminary evidence indicates that IL-39 might stimulate NETosis in neutrophils and promote BAFF (B-cell activating factor) secretion, which theoretically, in turn, may activate IL-39 production, T-cell-independent IgA isotype switching and somatic hypermutation. Some reports have revealed correlations between IL-39 and disease-specific autoantibodies, including RF and ACPAs in rheumatoid arthritis (RA), anti-dsDNA in systemic lupus erythematosus (SLE), and anti-AQP4 antibodies in neuromyelitis optica spectrum disorder (NMOSD), although these associations require further confirmation. Theoretically, through NETosis, IL39 could potentially expose intracellular antigens and facilitate their citrullination via peptidyl arginine deiminase (PAD), which might contribute to autoimmunity initiation. Some data suggest that in P. gingivalis-associated dysbiosis, IL-36 gamma may increase IL-39 secretion by epithelial cells. As dysbiosis and inflammatory bowel disease (IBD) increase gut permeability and LPS exposure-a possible stimulus for IL-39 production-the relationships among IL-39, gut dysbiosis, and autoimmunity appear to warrant further investigation. While some studies have reported conflicting results regarding the immunological activity of IL-39 in humans, these theoretical considerations suggest the need for more rigorous, standardized research, as current investigations remain limited by small sample sizes and heavy reliance on animal models or in vitro studies rather than comprehensive human studies ex

关键词： Extracellular matrix   Growth factor   IFN gamma   TGF-beta   Liver fibrosis  

摘要： Background & Aims: The extracellular matrix protein 1 (ECM1) is essential for liver homeostasis by keeping latent transforming growth factor-beta quiescent. Upon hepatocyte damage, ECM1 is significantly downregulated, facilitating fibrosis and chronic liver disease (CLD) progression. We investigated the mechanism of ECM1 regulation in hepatocytes under pathophysiological conditions. Methods: We used promoter analysis to predict Ecm1 transcriptional regulators and assessed the expression of Ecm1-related genes by single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq. Functional assays were performed with AML12 cells, mouse and human primary hepatocytes, and liver tissue from mice and patients. Results: In healthy hepatocytes, epidermal growth factor (EGF)/EGF receptor (EGFR) signalling sustains ECM1 expression through phosphorylating signal transducer and activator of transcription 1 (STAT1) at serine727 (S727), thus enhancing its binding to the ECM1 promoter and boosting gene transcription. This process is disrupted during liver inflammation by interferon gamma (IFN gamma), which downregulates EGFR and inhibits EGF/EGFR/STAT1-mediated ECM1 promoter binding. Mechanistically, IFN gamma-induced STAT1 phosphorylation at tyrosine701 (Y701) impairs the binding of p-STAT1 S727 to the ECM1 promoter. Additionally, IFN gamma induces nuclear factor erythroid 2-related factor 2 (NRF2) nuclear translocation, which repressively binds to the promoter of ECM1, further reducing its expression. These findings are confirmed in several CLD mouse models (n = 2-6). Moreover, AAV8-ECM1 attenuates liver fibrosis and injury in Western diet-fed mice (n = 8-10), counteracting the effects of EGF signalling inhibition and IFN gamma/NRF2 activation. In CLD patients (n = 22), ECM1 levels correlate positively with EGFR expression (p <0.0001) and negatively with IFN gamma/NRF2 activation (p <0.0001). Conclusions: EGF/STAT1 signalling promotes whereas IFN gamma/NRF2 inhibits ECM1 expression in hepa

关键词： Small HERC family   Crucian carp HERC7   RNA binding activity   Negative regulation   mRNA decay   Protein degradation  

摘要： Crucian carp (Carassius auratus) HERC7 is a recently identified, fish-specific member of small HERC family that plays a pivotal role in negatively regulating the interferon (IFN) antiviral response by targeting three RLR signaling factors, STING, MAVS and IRF7. Mechanistically, crucian carp HERC7 facilitates proteasomedependent protein degradation to downregulate STING- and MAVS-mediated IFN response. Although HERC7's role in degrading IRF7 protein is known, its potential regulation of IRF7 mRNA has not been clarified. In this study, we further characterized crucian carp HERC7 as an unorthodox RNA binding protein (RBP) that was unique to IRF7 coding RNA, exactly to its N-terminal coding region. These features endowed crucian carp HERC7 to facilitate IRF7 mRNA decay, thereby downregulating IRF7-mediated IFN response. Despite lacking canonical RNA-binding domains (RBDs), the N-terminal RLD domain of crucian carp HERC7 protein exhibited a binding potential to IRF7 mRNA in vitro. However, either the full length or the E3 ligase activity was required for crucian carp HERC7 to bind IRF7 mRNA in living cells. Functional comparisons between wild-type crucian carp HERC7 and its E3 ligase mutant (C958A) further revealed that, crucian carp HERC7 inhibited IRF7-mediated IFN response primarily by targeting IRF7 mRNA decay, which required its E3 ligase activity and RNA binding activity, while C958A did so by targeting IRF7 protein degradation independently of both activities. Taken together, our results suggest that crucian carp HERC7 has acquired RNA-binding activity and E3 ligase activity to fine-tune fish IFN response through two distinct mechanisms.

关键词： Zinc   BPA   Zinc transporter   Inflammation   Reproduction  

摘要： Bisphenol A (BPA) is an endocrine-disrupting chemical that is toxic to reproduction. Zinc (Zn) plays an important role in male reproductive health. Zn deficiency (ZD) can co-exist with BPA. In order to investigate the specific mechanism of reproductive damage caused by BPA exposure in ZD male mice, a mouse model of ZD, BPA exposure, and their combined exposure was established in this study. Forty 4-week-old SPF male ICR mice with an average body weight of 31.7 +/- 4.2 g were divided into four groups including normal Zn diet group 30 mg/(kg center dot d), BPA exposure group 150 mg/(kg center dot d), zinc deficiency diet group 7.5 mg/(kg center dot d), and BPA + ZD combined exposure group (BPA 150 mg/(kg center dot d) + ZD 7.5 mg/(kg center dot d)). The mice were kept for 8 weeks. The results showed that the testicular tissue structure was disturbed, and semen quality, serum Zn, testicular tissue Zn, and testicular tissue free Zn ions were decreased in the BPA-exposed and ZD groups. The expression of zinc transporters (ZIP7, ZIP8, ZIP13, and ZIP14) in testicular tissue was changed. The expressions of pro-inflammatory cytokines including TNF-alpha and IL-1 beta as well as inflammatory pathway-related proteins (IKB-alpha, p-IKB-alpha, NF-kappa B, p-NF-kappa B, Caspase8, and Caspase3) were increased, while the expressions of anti-inflammatory cytokines (TGF-beta and IL-10) were decreased. The changes in the above indexes in the BPA + ZD group were more obvious. Both BPA exposure and ZD can induce testicular tissue inflammation through the TNF-alpha/NF-kappa B/Caspase8 signaling pathway, and BPA further aggravates zinc deficiency-induced testicular tissue inflammation and apoptosis damage.

关键词： Optical coherence tomography angiography   SARS-CoV-2   Ophthalmology   Inflammation   Hypoxia   Peripapillary vessel density  

摘要： BackgroundThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been associated with endothelial dysfunction, which may also compromise the microcirculation within ocular tissues. This prospective study evaluated associations between radial peripapillary capillary (RPC) vessel density (VD) and systemic treatment, age, hypoxia, D-dimer, and interleukin-6 (IL-6) levels in patients recovering from coronavirus disease 2019 (COVID-19) related ***-three individuals who were admitted to the hospital due to COVID-19 bilateral pneumonia underwent ophthalmic examination two months post-discharge. RPC VD was measured using optical coherence tomography angiography. Associations with age, arterial hypertension, and systemic treatment (dexamethasone, remdesivir, and oxygen therapy), oxygen saturation, D-dimer, and IL-6 levels were evaluated. The control group comprised 43 control participants with no history of COVID-19 who attended routine ophthalmic *** ophthalmic abnormalities were detected. RPC VD did not differ significantly with hypertension or systemic treatment with dexamethasone and remdesivir. However, patients receiving oxygen therapy had higher RPC VD. A borderline inverse correlation was observed between inferior RPC VD and age. There were no correlations between RPC VD and oxygen saturation. Significant inverse correlations were found between nasal RPC and mean RPC with D-dimer levels and between inferior RPC VD and IL-6 levels. No significant differences in RPC parameters were observed when comparing the COVID-19 group with *** or systemic treatment had no significant effect on RCP VD. However, VD in specific RPC areas correlated inversely with D-dimer and IL-6 levels, highlighting the need for monitoring peripapillary microvasculature for potential long-term ocular effects of COVID-19.

关键词： Hesperidin   ifosfamide   Apoptosis   Renal toxicity   Antioxidant  

摘要： This study explored the protective effects of hesperidin (HES) against ifosfamide (IFA)-induced nephrotoxicity in rats using biochemical, histopathological, and immunohistochemical techniques. The rats were administered IFA at a dose of 500 mg/kg body weight, followed by oral HES treatment at doses of 200 and 300 mg/kg body weight. The results demonstrated that HES significantly reduced IFA-induced increases in urea and creatinine levels, indicating improved kidney function. HES was shown to mitigate IFA-induced lipid peroxidation, likely due to its antioxidant properties, and to enhance the activities of key antioxidant enzymes, including catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx), as well as elevate glutathione (GSH) levels. Biochemical and immunohistochemical analyses further revealed that HES exhibited anti-inflammatory, antiapoptotic and anti-endoplasmic reticulum stress effects, suppressing the elevated levels of nuclear factor kappa-B (NF-kappa B), interleukin-1n (IL-1n), tumor necrosis factor-alpha (TNF-alpha), Caspase-3, 6, 9, Bax, Apaf1, p53, serine/threonine-protein kinase/endoribonuclease inositol-requiring enzyme 1 alpha (IRE1 alpha), glucose-regulated protein 78 (GRP78), activating transcription factor 6 (ATF-6), and protein kinase R-like ER kinase (PERK), CHOP and alleviating level of Bcl-2 in IFA-exposed kidney tissue. Additionally, the immunohistochemical staining results for TIM-1 in rat kidney tissues showed minimal expression in the control and HES groups. However, the IFA-treated group exhibited a significant increase in TIM-1 expression. Co-administration of IFA with HES at 200 or 300 mg/kg resulted in a significant reduction in TIM-1 expression. In conclusion, these results demonstrate that HES efficiently alleviated kidney toxicity induced by IFA.

关键词： IL‐33/ST2L axis   carbon monoxide   diabetic cardiomyopathy   pyroptosis  

摘要： OBJECTIVES:This study aimed to investigate whether carbon monoxide (CO) can alleviate cardiomyocyte pyroptosis by downregulating the IL-33/ST2L axis in diabetic cardiomyopathy (DCM). METHODS:The diabetic mouse model was established and treated with CO-releasing molecule-2 (CORM-2) or invalid CORM-2 (iCORM-2). For in vitro studies, cardiomyocytes were treated with high glucose (HG). RESULTS:The HG-treated cardiomyocytes exhibited increased IL-33, ST2L, and pyroptosis-related protein expression compared with that in the control group (p < 0.05). Treatment with recombinant IL-33 further increased the expression of HG-induced pyroptosis-related proteins (p < 0.05). Compared with control mice, DCM mice showed reduced cardiac function and elevated expression of IL-33, ST2L, and pyroptosis-related proteins (p < 0.01). Intervention with CORM-2 ameliorated cardiac injury, and decreased the expression of IL-33, ST2L, and pyroptosis-related proteins in vivo and in vitro (p < 0.05). However, iCORM-2 had no effect both in vivo and in vitro. CONCLUSIONS:In conclusion, CO may inhibit cardiomyocyte pyroptosis by downregulating the IL-33/ST2L axis in DCM mice.

关键词： DvL   CAM assay   Immunohistochemistry   Pro-inflammatory  

摘要： Due to their interesting biological activities, a mannose-binding lectin isolated from Dioclea violacea seeds, known as DvL have attracted considerable attention. In this study, we performed macroscopic, histologic, and immunohistochemical analysis on chicken embryo chorioallantoic membranes (CAM) to investigate the effects of DvL on the angiogenic process. Data showed a potential angiogenic effect of DvL at the highest concentrations tested (50 and 100 mu g/mL). This effect was confirmed through increased neovascularization, inflammatory cells, and fibroblasts in histological analysis of the CAM. In addition, the immunohistochemistry of CAM showed that DvL induced secretion of TNF-alpha and VEGF, important cytokines involved in angiogenesis. Therefore, increased neovascularization may result from a pro-inflammatory response through VEGF and TNF-alpha secretion. In contrast, the DvL effects on the angiogenic process and the TNF-alpha and VEGF secretion were significantly reduced by co-incubation with mannose. Thus, protein-carbohydrate interactions between DvL and cell membrane glycans are likely the main events involved in this effect. Therefore, our results demonstrated that DvL is a potent angiogenic agent, suggesting its potential application as a prototype molecule for developing new drugs with healing properties.