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关键词： IL-6   Pulmonary fibrosis   Fibroblast-to-Myofibroblast transition   STAT3   PD-L1  

摘要： Pulmonary fibrosis is a fatal lung disease. Owing to its unknown pathogenesis, treatment options are limited. Interleukin (IL)-6, a multifunctional cytokine, is overexpressed in pulmonary fibrosis and may contribute to its development through multiple pathways, mainly the signal transduction and transcriptional activator 3 (STAT3) signaling pathway. Moreover, programmed cell death ligand 1 (PD-L1), an immune checkpoint molecule, is crucial in immune regulation and also shows abnormal expression in pulmonary fibrosis, potentially involved in fibrogenesis. PD-L1 may be regulated by IL-6 in pulmonary disorders. Given the pivotal role of IL-6 and PD-L1 in the pathogenesis of pulmonary fibrosis, this study aimed to explore the effect and mechanism of blocking IL-6 on PD-L1 expression and pulmonary fibrosis. We established the pulmonary fibrosis model by instilling bleomycin (BLM) intratracheally into mice and stimulating human fetal lung fibroblasts 1 (HFL1s) with transforming growth factor-beta 1 (TGF-(31). Upon inhibition of IL-6 signaling or reduction of PD-L1 expression, we analyzed the tissue morphology, protein expression and function. We observed elevated expression of IL-6 and PD-L1 in pulmonary fibrosis models. Blocking IL-6 relieved BLM-induced lung tissue destruction, diminished collagen production and deposition and inhibited the expression of alpha smooth muscle actin (alpha-SMA), Vimentin, and Collagen I. Blocking IL-6 could reverse fibroblast-to-myofibroblast transformation induced by TGF-(31 in HFL1s via inhibiting the STAT3 signaling pathway. Interestingly, targeting IL-6/STAT3 signaling could also downregulate PD-L1 expression. Inhibiting PD-L1 could mitigate pulmonary fibrosis. Our findings provide new molecular targets for exploring the pathogenesis and treatment of pulmonary fibrosis.

关键词： checkpoint blockades   immunotherapy   response prediction   MHC-I pathway   tumor mutational burden   TMB  

摘要： Immune checkpoint inhibitors produce durable antitumor effects in various cancers, but not all patients respond. High tumor mutational burden (TMB) is a known predictor of clinical benefit. In this study, we focused on the MHC-I-dependent neoantigen presentation pathway to enhance predictive capabilities beyond TMB. Using pan-cancer immunogenomic analyses of somatic mutation data from The Cancer Genome Atlas (TCGA) and The International Cancer Genome Consortium (ICGC), we analyzed 33 cancer types. Objective response rates (ORRs) to PD-1/PD-L1 inhibitors were evaluated in relation to immune characteristics, including TMB, neoantigen load, MHC-I gene expression, and CD8+ T cell fraction. Spearman's rank correlation was used to assess these relationships. TMB s howed the strongest correlation with ORR (r=0.783, P=2.17x10-5). However, integrating TMB, HLA-A expression, and CD8+ T cell fraction significantly improved predictive accuracy (r=0.865, P=1.80x10-6). Validation in external cohorts confirmed these findings, revealing notable differences in MHC-I pathway activity between responders and non-responders to immunotherapy. Our results demonstrate that the MHC-I antigen presentation pathway is strongly associated with response to PD-1/PD-L1 inhibitors. Importantly, combining antigen expression, processing, presentation, and recognition features provides superior predictive power compared to TMB alone. This integrated approach could improve treatment outcome predictions and advance personalized immunotherapy strategies.

关键词： Atherosclerosis   C1q/TNF-related protein-1   Mendelian randomization   Coronary artery disease   Ischemic stroke   Multivariate  

摘要： Aims: To investigate the causal relationship between C1q/TNF-related protein-1 (CTRP1) and atherosclerosis across various vascular sites, informed by studies connecting CTRP1 to coronary artery disease. Methods: Summary statistics of CTRP1 from the available genome-wide association studies and atherosclerosis in classic vascular sites (including cerebral, coronary, and other arteries) from the FinnGen biobank were extracted for a primary MR analysis, and the analysis was replicated using Ischemic Stroke cohort (large artery atherosclerosis) for validation. The inverse variance-weighted method was used for primary assessment. Sensitivity analysis was performed by Cochrane's Q test and leave-one-out analysis. Potential pleiotropic effects were assessed by MR-Egger intercept and MR-PRESSO global test. Additionally, multivariable MR (MVMR) analysis was performed to investigate the independent effect of CTRP1 on atherosclerosis after removing confounding factors. Results: Reliable causal evidence was found for CTRP1 involvement in three atherosclerosis endpoints: causal effects of CTRP1 on cerebral atherosclerosis (OR =1.31, CI:1.04-1.66;FDR_P=0.0222)], coronary atherosclerosis (OR=1.13, CI: 1.08-1.19;FDR_P=2.86e-07), and atherosclerosis at other sites (OR=1.06, CI:1.02-1.11;FDR_P=0.0125). The validation cohort further confirmed its causal effect on large-artery atherosclerosis (OR=1.10, CI:1.03-1.18;FDR_P=0.0115). The reverse MR analysis did not support the causal effect of atherosclerosis on CTRP1. Moreover, the MVMR analysis, adjusting for confounders (CTRP3, CTRP5, and CTRP9A), highlighted a significant independent causal effect of CTRP1 remaining on atherosclerosis. Conclusion: CTRP1 may represent a promising target for preventing and treating systemic atherosclerosis.

关键词： Gynecology   Interleukin 10   Neopterin   Nutritional risk index   Oncology  

摘要： Introduction: We aimed to investigate the relationship between preoperative nutritional status with postoperative interleukin-10 (IL-10) and neopterin in gynecologic oncology cases. Materials and methods: This prospective study included cases hospitalized in our clinic. Preoperative cases were divided into two groups as low and high risk according to Nutritional risk score (NSR-2002). Demographic and clinical characteristics and questionnaires including the NSR-2002 form were recorded. IL-10 and neopterin levels were analyzed 1 week postoperatively. Results: Forty-five low-risk and 43 high-risk cases were evaluated. The mean ages of the cases were 56.7 +/- 7.8 and 57.2 +/- 14.3 years, respectively, and no significant difference was found between them (P = 0.854). There was a statistically significant difference between the two groups in terms of upper arm circumference (P = 0.043), triceps skinfold thickness (P = 0.010), shorter wound healing time (P = 0.009), neopterin (P = 0.037), IL-10 (P = 0.043), preoperative ferritin (P = 0.001), hemoglobulin (P = 0.026), albumin (P = 0.047), postoperative ferritin (P = 0.015), hemoglobulin (P = 0.044), and albumin (P = 0.042) levels in favor of the low-risk group. Among the significant factors, only wound healing time had positive correlation (P = 0.006, r = +0.290). Conclusions: Nutritional status is closely related to case recovery in the postoperative period. Postoperative changes to high interleukin-10 and neopterin levels in cases with low nutritional index show the importance of nutrition in the postoperative period. (c) 2025 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

关键词： Lymphocyte-specific protein-1 (LSP1)   Experimental Sjogren's syndrome (ESS   Th17 cells   Primary Sjogren's syndrome (pSS  

摘要： Lymphocyte-specific protein-1 (LSP1) is known to negatively regulate T cell migration in autoimmune diseases. However, its role in the development of T cell-dependent Sjogren's syndrome remains unknown. In this study, we found that LSP1 expression was decreased in T cells in salivary glands (SGs) of mice with experimental Sjogren's syndrome, accompanied by enhanced infiltration of leukocytes into SGs. Moreover, Lsp1- /- mice had higher frequency of IL-17A-expressing T cells in cervical lymph nodes as well as increased severity in SGs than WT mice. Concurrently, LSP1 expression was reduced in human T cells of primary Sjogren's syndrome (pSS) patient. Particularly, pSS patients showed an increased Th17 cells, which inversely correlated with LSP1 expression. Taken together, these findings suggest that LSP1 deficiency promote Th17 cell development and exacerbation of pSS. LSP1 might be a potential therapeutic target to regulate Th17 response and to treat autoimmune diseases like pSS.

关键词： Ferulic acid ethyl ester   Inflammatory adipocytes   Atrial arrhythmias   Secretome   Electrical remodeling  

摘要： Inflammatory epicardial adipose tissue impacts cardiomyocytes, creating an arrhythmogenic substrate. This study examines the effects of tumor necrosis factor-alpha (TNF-alpha)-stimulated adipocytes on atrial cardiomyocytes and the protective role of ferulic acid ethyl ester (FAEE). TNF-alpha-stimulated 3T3-L1-derived adipocytes were utilized and analyzed. Conditioned media from TNF-alpha-stimulated and TNF alpha/FAEE-cotreated adipocytes were examined. Biochemical and electrophysiological studies were performed on HL-1 myocytes exposed to these media. TNF-alpha stimulation increased the levels of the proinflammatory proteins monocyte chemoattractant protein-1 (MCP-1) and interleukin-6 (IL-6) in the adipocytes and conditioned media. The ratio of phosphorylated-NF-kappa B (pNF-kappa B) to NF-kappa B was higher in TNF-alpha-stimulated adipocytes than in the control group. While the levels of IL-6, MCP-1, and pNF-kappa B induced by TNF alpha stimulation in the adipocytes remained unchanged with FAEE cotreatment, FAEE increased the protein levels of adiponectin in the adipocytes and the conditioned medium. FAEE also upregulated the protein levels of heme-oxygenase 1 (HO-1) and nuclear translocation of nuclear factor-erythroid 2-related factor-2 (Nrf2). The elevated adiponectin levels observed in FAEE-cotreated adipocytes were abolished following treatment with SnPP, a HO-1 inhibitor. The elevated levels of Ca2 + /calmodulin-dependent protein kinase II and connexin 43, and the enhanced reverse mode Na+ -Ca2+ exchanger current observed in HL-1 myocytes cultured in TNF-alpha-conditioned medium were abolished when these cardiomyocytes were cultured in TNF alpha/FAEE-conditioned medium. FAEE modulates the electrical remodeling of HL-1 cardiomyocytes induced by the secretome of TNF-alpha-stimulated adipocytes, possibly through Nrf2/HO-1 signaling and adiponectin expression. These findings demonstrate FAEE's cardioprotective mechanisms and therapeutic potential. (c) 2025 The Au

关键词： Baicalein   EAM   Macrophages   Chemotactic   Th1 cells   TNF-alpha   CCR2  

摘要： Myocarditis refers to localized or diffuse inflammatory lesions of the myocardium. Experimental autoimmune myocarditis (EAM) in mice is commonly utilized as an animal model for studying the pathogenesis of myocarditis. Baicalein (BAI), the main active component extracted from Scutellaria baicalensis root, has been proven to possess diverse effects such as anti-inflammatory, anti-tumor, and antioxidant activities. However, further investigation is warranted to elucidate the mechanism of action underlying BAI's efficacy in EAM. The aim of this study is to the potential of BAI in combination with TNF-alpha to downregulate the TNF-alpha/TNFR1-AP-1 signaling pathway. Furthermore, we will explore whether BAI exhibits an inhibitory effect on the CCL2/CCR2-ROCK1 signaling pathway. In this study, we employed the EAM animal model to investigate the inhibitory effect of BAI on macrophage and Th1 cell chemotaxis towards cardiac tissue in EAM mice. Techniques such as HE staining, immunofluorescence, and other methods were utilized for assessment. Additionally, computer-simulated molecular docking, Streptavidin pull-down, and co-immunoprecipitation experiments were conducted to explore the potential binding of BAI with TNF-alpha and CCR2. Furthermore, real-time quantitative polymerase chain reaction (qPCR), western blotting, and flow cytometry were employed to elucidate the impact of BAI on the TNF-alpha/TNFR1-CCL2/CCR2 signaling pathway. BAI suppressed the expression of chemokine CCL2 in EAM mouse myocardial tissue and attenuated the infiltration of macrophages and Th1 cells. In vitro, BAI exhibited binding affinity to TNF-alpha, leading to downregulation of the TNF-alpha/TNFR1-AP-1 signaling pathway and subsequent inhibition of CCL2 secretion by macrophages and vascular endothelial cells. Additionally, BAI demonstrated binding capability to CCR2, resulting in downregulation of the CCL2/CCR2-ROCK1 pathway and consequent inhibition of chemotactic migration of macrophages and Th1

关键词： Terahertz waves   Metasurface   Immunosensing   Single-stranded DNA aptamer   TNF-alpha  

摘要： In this study, we present a terahertz metasurface biosensor modified with single-stranded DNA aptamers for the specific detection of tumor necrosis factor-alpha (TNF-alpha). We employed micro-nano fabrication techniques to construct the biosensor, which was subsequently characterized using terahertz frequency-domain spectroscopy. The system demonstrated a theoretical sensitivity reaching 124.71 GHz/RIU. To achieve specific detection of TNF-alpha, the sensor surface was functionalized with a nucleic acid aptamer. The experimental results show that the frequency shift of the resonance peak is linearly correlated with the concentration of tumor necrosis factor-alpha. The method achieves a detection limit of 0.1 ng/ml and a sensitivity of 13.9 GHz/lg(ng/ml). Most notably, the sensor exhibits greater sensitivity to TNF-alpha compared to ovalbumin and whey protein, confirming its highly specific detection capabilities. This study presents a novel approach for the real-time, efficient, and label-free detection of TNF-alpha, offering significant implications for the diagnosis of cancer and other associated diseases.

关键词： Nervous necrosis virus   Oral immunization   IFN-gamma   DNA vaccine   Immune effect  

摘要： Viral nervous necrosis (VNN), caused by nervous necrosis virus (NNV), poses a major threat to global aquaculture, causing severe mortality and economic losses in high-value species like grouper. Oral vaccination offers a practical approach for large-scale prevention but faces challenges including gastrointestinal antigen degradation and inadequate mucosal immunity. To overcome these, we developed an oral DNA vaccine by encapsulating a plasmid encoding the NNV capsid protein (CP) and IFN-gamma within PLGA microparticles (CPIF@PLGA). Synthesized via double emulsion-solvent evaporation, these spherical microparticles (ca. 8 mu m in diameter) exhibited high encapsulation efficiency (84.3 %). In vivo immunization of grouper demonstrated that CPIF@PLGA significantly increased survival to 82.2 % post-NNV challenge versus controls, reduced viral loads in brain and eyes, and enhanced systemic and mucosal immunity. This was evidenced by elevated serum IgM, IgT, lysozyme, SOD, and complement activity, alongside upregulated expression of immune-related genes (IL-1 beta, TNF-alpha, CD4, CD8 alpha, MHCI alpha, IgM) in spleen and hindgut. Our findings establish PLGA microparticles as an effective oral delivery platform and IFN-gamma as a potent adjuvant, eliciting robust and durable protection. This study provides a promising strategy for developing effective and scalable oral vaccines against NNV in aquaculture.

关键词： IL-33   Ror2   Wnt/beta-catenin   Organoid   Intrauterine adhesion   Endometrial injury  

摘要： Background: Intrauterine adhesions (IUA) are a major cause of secondary infertility, yet existing treatments have limited efficacy. This study explores the potential of targeting Ror2, a key mediator in the IL-33/Wnt/(3-catenin signaling pathway for IUA treatment. Methods: First, we established an IL-33-induced intrauterine adhesion (IUA) mouse endometrial organoid (EMOs) model. Using parallel reaction monitoring (PRM) technology, we identified Ror2 as the target protein linking IL-33 to the Wnt/(3-catenin signaling pathway in mouse uterine tissue. Subsequently, we constructed lentiviral vectors for Ror2 knockdown (Lv-shRor2) and overexpression (Lv-Ror2) to evaluate the role of Ror2 in endometrial fibrosis and stem cell proliferation. Finally, we assessed murine fertility via in situ injection of Ror2-overexpressing adenoviral particles (Ad-Ror2) into the uterine cavity. Results: The results showed that IL-33 at 100 ng/ml for 24 h had the strongest effect on the model. Lv-shRor2 promoted endometrial fibrosis by activating the Wnt/(3-catenin pathway, while Lv-Ror2 inhibited this pathway, enhancing endometrial stem cell proliferation and improving fertility in IUA mice. Conclusions: These findings suggest that Ror2 could be a promising target for regulating the Wnt/(3-catenin pathway in IUA treatment.