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关键词： Pseudorabies virus   Resveratrol   Osteopontin   Antiviral activity   Immune response  

摘要： Pseudorabies virus (PRV) can infect most mammals and has caused significant economic losses in global pig production. The emergence of new mutants significantly reduces the protective effect of vaccination, indicating an urgent need for the development of specific therapeutic agents against PRV infection. In this study, we analyzed the changes in the cellular proteome after PRV infection in resveratrol-treated PK-15 cells using TMT quantitative proteomics combined with LC-MS/MS. The results identified the differential proteins osteopontin (iOPN) and interleukin-1 receptor accessory protein (IL-1RAP), which have significant biological implications. The regulation of OPN-IL-1 beta signaling by PRV infection was further studied through the OPN-ERK/JNK-IL-1 beta signaling axis. The transcriptional levels of OPN, C-JUN, IL-1RAP, and IL-1 beta, along with the protein levels of ERK, JNK, C-Jun, and their phosphorylated forms at 8, 12, and 16 h post-infection, were determined. The results showed that PRV infection inhibited the activation of this signaling axis, which was upregulated by resveratrol treatment. Down-regulation of OPN by siRNA increased PRV proliferation and inhibited the activation of the signaling axis, which was antagonized by resveratrol treatment. In PRV-infected mice, resveratrol treatment produced the same changes observed in vitro. The present study demonstrated that resveratrol can promote innate immune responses by regulating the OPN-ERK/JNK-IL-1 beta signaling axis, thereby activating host antiviral defenses against PRV infection. Significance: Resveratrol targets the OPN-ERK/JNK-IL-1 beta axis to enhance innate immunity, offering a novel antiviral strategy against PRV infection. This study identifies OPN as a key regulator of host defense, linking ERK/JNK signaling to IL-1 beta-mediated antiviral responses. In vivo validation demonstrates resveratrol's therapeutic potential, reducing PRV replication and mortality in mice via immune pathway activati

关键词： Esophageal cancer treatment   HDAC6 inhibitor   MHC class II complex  

摘要： OBJECTIVE:This study aimed to investigate the therapeutic potential of the novel HDAC6 inhibitor 9r in esophageal cancer (EC). Specifically, it focused on evaluating 9r's ability to inhibit tumor growth, migration, and apoptosis while enhancing antitumor immunity through the modulation of MHC class II signaling pathways. METHODS:The study employed in vitro experiments using TE-1 and MEC25 esophageal cancer cells to assess anti-tumor effects of compound 9r. RNA sequencing and bioinformatics analysis were utilized to explore the molecular mechanisms underlying its action, particularly its impact on MHC class II pathways. In vivo experiments were conducted using a murine MEC25 cell xenograft model to evaluate tumor growth inhibition and immune activation. Techniques such as flow cytometry, RT-qPCR, Western blotting, and immunohistochemistry were used for functional validation. RESULTS:Compound 9r significantly suppressed TE-1 cell proliferation, migration, and induced apoptosis in vitro. RNA-seq analysis revealed that 9r upregulated MHC class II-related genes (e.g., HLA-DRA, CD74), which were further enhanced by IFN-γ co-stimulation. In vivo studies demonstrated that 9r inhibited tumor growth in MEC25 xenografts while increasing CD4 and CD8 T cell infiltration in both tumor tissue and spleen. Immunohistochemistry confirmed reduced Ki-67 expression and increased acetylation of α-tubulin, indicating HDAC6 inhibition. The compound exhibited minimal toxicity in treated mice. CONCLUSION:The HDAC6 inhibitor 9r effectively suppresses esophageal cancer progression through dual mechanisms: direct tumor inhibition and enhancement of antitumor immune responses via MHC class II pathway activation. These findings establish 9r as a promising candidate for esophageal cancer treatment and provide a foundation for further clinical development.

关键词： Biomarker interaction   Peripheral biomarkers   Therapeutic drug monitoring   Treatment-resistant depression  

关键词： IL-6 trans-signalling   Microglia   Neuroinflammation   TDP-43 protein aggregates   sgp130Fc  

摘要： Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by chronic inflammation in both the central nervous system (CNS) and peripheral tissues. Interleukin-6 (IL-6) has been implicated in ALS pathology; however, IL-6 exhibits both anti-inflammatory and pro-inflammatory functions. Notably, IL-6 trans-signalling possesses pro-inflammatory properties and is emerging as a key contributor to neuroinflammation during neurodegeneration. In this study, we aimed to characterize the expression of the IL-6 trans-signalling pathway in ALS mouse models and investigate its role in ALS protein aggregate-mediated inflammation in microglia and peripheral immune cells. Our results revealed that the protein expression level of a key IL-6 trans-signalling component, soluble IL-6 receptor (sIL-6R), was significantly increased in the spinal cord and tibialis anterior (TA) muscles of both SOD1 and rNLS8 TDP-43 transgenic mice. Additionally, using mouse primary microglia, human monocyte-derived microglia-like cells (MDMi), and blood peripheral immune cells, we demonstrated that recombinant TDP-43 protein elicits robust pro-inflammatory cytokine responses, including IL-6, TNF-α, IL-23, and MCP-1. These responses were attenuated when treated with a specific IL-6 trans-signalling inhibitor, sgp130Fc. Our findings suggest that the TDP-43-induced inflammatory response is, in part, IL-6 trans-signalling-dependent and highlight the role of IL-6 trans-signalling as a potential driver of chronic inflammation contributing to ALS pathology. These results support IL-6 trans-signalling as a promising therapeutic target for mitigating inflammation and slowing disease progression. Future research should explore the broader implications of modulating IL-6 trans-signalling in ALS.

关键词： Ankylosing Spondylitis (AS)   Immunosenescence   Signal Transduction Pathways   Therapeutic Strategies  

摘要： BACKGROUND:This study aims to explore the common mechanisms between aging and the pathogenesis of ankylosing spondylitis (AS) and to identify potential therapeutic targets. METHODS:A total of 87 patients with AS and matched controls were analyzed via multidimensional flow cytometry to examine the peripheral blood immune signature. Single-cell RNA sequencing was employed to characterize T-cell subsets. The infiltration of Ly49h + cells (the murine homolog of NKG2C) was observed in a collagen-induced arthritis mouse model, and functional experiments were conducted to validate the cytotoxicity of NKG2C + CD8 + T cells. The mechanisms were further confirmed via the use of HLA-B27 transgenic mice and RNA-sequencing. RESULTS:The peripheral blood immune signature of AS patients exhibited dysregulation similar to that observed during aging. NKG2C + CD8 + T cells activated the PI3K‒Akt signaling pathway and increased phagocytosis in AS patients. HLA-B27 stimulation significantly increased the cytotoxicity of this subset, an effect that could be reversed by NKG2C blockade. In HLA-B27 transgenic mice, Ly49h + T cells exhibited significantly enhanced degranulation ability. RNA sequencing validated the activation of the PI3K‒Akt pathway in NKG2C + CD8 + T cells by HLA-B27. CONCLUSIONS:HLA-B27 drives the cytotoxicity of aging-related NKG2C + CD8 + T cells via activation of the PI3K‒Akt signaling pathway. Targeting NKG2C inhibition may represent a novel therapeutic strategy for AS. This study elucidates the association between immune aging and the pathogenesis of AS, providing theoretical evidence for clinical intervention.

关键词： CP: Cancer   CP: Immunology   IL-33   ST2 receptor   Treg   cSCC   cancer   immune-surveillance   inflammation   skin   type 2 immunity  

摘要： Interleukin (IL)-33 is constitutively expressed in many epithelial tissues at steady state and signals through the receptor, ST2. IL-33 is released upon tissue injury and functions as an endogenous danger signal to alert the immune system to tissue damage. Here we investigate the physiological role of the IL-33/ST2 axis in skin homeostasis and cancer development. We show that the expression of IL-33 differentiates malignant from normal and benign human tissues and that in mouse models of cutaneous squamous cell carcinoma the IL-33/ST2 axis protects against carcinogenesis. Tissue regulatory T cells (Tregs) are the predominant cells expressing ST2 in the skin and localize around the hair follicle and IL-33 epithelial cells (ECs). Adoptive transfer experiments demonstrate that skin Tregs regulate EC differentiation, minimizing mutational load and restraining cancer development after exposure to an environmental carcinogen. Our findings indicate an important role for EC-Treg cross-talk as an early checkpoint for containing tissue damage and carcinogenesis.

关键词： IL-33   cell death   endophthalmitis   inflammation   proteomic profiler   retina  

摘要： Bacterial and fungal pathogens are major causes of infectious endophthalmitis following eye surgery or trauma, often leading to vision impairment or blindness. The distinct clinical outcomes observed in bacterial and fungal endophthalmitis suggest differences in host immune responses. To investigate these differences, we utilized cytokine arrays and murine models of bacterial () and fungal () endophthalmitis. Our analysis revealed that cytokine responses peaked in bacterial infections at 12-24 h, whereas fungal infections exhibited a delayed peak at 48 h. Several inflammatory mediators, including MMP9, MMP3, CD14, LIX, LCN2, retinol-binding protein 4, ICAM1, and VCAM1, were differentially elevated. Notably, interleukin-33 (IL-33) levels peaked early in bacterial infections but continued to rise throughout all time points in fungal endophthalmitis. Analysis of patient vitreous samples further confirmed higher levels of IL-33 in bacterial (=40) and fungal (=20) endophthalmitis cases. Functional studies in IL-33-deficient mice revealed an increased fungal burden and elevated TNF-α and IL-6 levels, but bacterial endophthalmitis severity remains largely unaffected. Additionally, bone marrow-derived macrophages from IL-33 mice exhibited increased cell death in response to fungal and bacterial infection. Our findings reveal divergent innate immune responses between bacterial and fungal endophthalmitis and emphasize the immunomodulatory function of IL-33 in ocular infections.

摘要： BACKGROUND:Spondyloarthritis (SpA) is a chronic inflammatory disorder with axial and peripheral manifestations. A strong association between HLA-B27 and SpA has been known for more than 50 years. Remarkably, HLA-B27 and human β2-microglubulin transgenic rats (B27 rat) develop manifestations recapitulating SpA, referred to as rat SpA. Antigen-presenting cells such as dendritic cells (DC) and CD4 T cells are mandatory to develop rat SpA. Serum levels of granulocyte macrophage-colony stimulating factor (GM-CSF), a key growth factor for DC generation and functions, are significantly increased during SpA. Conventional (c)DCs can be divided in two subsets implicated either in immune tolerance (cDC1) or in adaptive immune responses induction (cDC2). In this study, we aimed to determine the influence of GM-CSF on cDC subsets functions linked to T cell activation and differentiation, in the B27 rat model. METHODS:cDC subsets were isolated from spleens of B27 and nontransgenic (NTG) rats, primed with GM-CSF and tested for their ability to support CD4h T cell differentiation. RNA sequencing was performed on GM-CSF-primed cDC subsets. RESULTS:GM-CSF-primed cDC2 from B27 rat were strong inducers of TNF-producing proinflammatory CD4 T cells. In contrast, whereas control cDC1 required GM-CSF to support T cell proliferation, HLA-B27 cDC1 primed with GM-CSF failed to do so. RNA sequencing analysis demonstrated that HLA-B27 expression promoted endoplasmic reticulum stress and unfolded protein response in both cDC subsets. In addition, HLA-B27 expression promoted inflammatory cytokine synthesis by cDC2 and a signature interfering with regulation of cell adhesion and activation in cDC1. CONCLUSION:Altogether, our study reveals a dual role of GM-CSF during SpA. In one hand, GM-CSF promotes proinflammatory functions of cDC2. On the other hand, GM-CSF is required for cDC1 to induce T cell proliferation, and those functions are blunted by HLA-B27 expression.

关键词： Chronic Obstructive Pulmonary Disease   Emphysema   IL-33   Modified Fangji Huangqi decoction   Neutrophils  

摘要： ETHNOPHARMACOLOGICAL RELEVANCE:Chronic Obstructive Pulmonary Disease (COPD) is a progressive respiratory disorder with complex pathogenesis and multiple contributing factors. Modified Fangji Huangqi decoction (MFJHQ), a traditional Chinese medicine formula, has demonstrated clinical efficacy in COPD treatment. However, the pharmacological roles and underlying mechanisms of MFJHQ in treating COPD remain unclear. AIM OF STUDY:To investigate the therapeutic effects and molecular mechanisms of MFJHQ in the treatment of COPD. METHODS:COPD models were established in vitro using alveolar organoid (AOs) and 16 Human Bronchial Epithelial (16HBE) cells separately, induced by porcine pancreatic elastase (PPE) and in vivo in PPE-induced COPD mice. MFJHQ was administered via gavage for three weeks. RNA-sequencing and network pharmacology were employed to elucidate potential mechanisms of action. RESULTS:In vitro, MFJHQ enhanced epithelial barrier integrity by reducing permeability and upregulating zonula occludens-1 (ZO-1) expression. In vivo, MFJHQ effectively improved pulmonary function, alleviated emphysema and airway obstruction, and protected lung tissue structure from damage. Mechanistically, RNA-sequencing and network pharmacology predicted, and subsequent experiments confirmed, that MFJHQ inhibited PPE-induced IL-33 and its downstream NF-κB signaling and CXCL5 expression thereby reducing neutrophil recruitment in lung tissues. CONCLUSION:MFJHQ ameliorates COPD progression by inhibiting neutrophil infiltration through suppression of IL-33 and CXCL5 providing a new multi-targeted therapeutic strategy for COPD.

关键词： CD8+ T lymphocytes   IL-33   listeriosis   mitophagy   perinatal infection  

摘要： Listeriosis is a foodborne disease caused by (Lm) that usually leads to serious adverse outcomes in pregnant women. Interleukin (IL)-33/serum stimulation (ST)2 axis has an important impact on infectious diseases, but its role in listeriosis is rarely studied. Here, the immunomodulatory effects of IL-33/ST2 axis during perinatal Lm infection were investigated. In our study, the perinatal Lm infection model was constructed by injecting Lm into the tail vein of C57BL/6J mice. IL-33/ST2 axis was blocked by intraperitoneal injection of anti-IL-33Rα/ST2 antibody. , mouse cytotoxic T lymphocyte cell line (CTLL)-2 cells were activated by using CD3/CD28 antibodies. Perinatal Lm infection caused massive necrosis of liver tissue. Blocking IL-33/ST2 axis in pregnant mice inhibited the infiltration of CD8 T lymphocytes into the site of infection and further aggravated liver damage. We also found that IL-33 promotes mitochondrial autophagy in activated CTLL-2 cells . Mitochondrial autophagy was beneficial to the clearance of damaged mitochondria and reduced the production of reactive oxygen species. IL-33/ST2 axis affects the immune function of CD8 T lymphocytes by regulating mitophagy, which plays a very important role in the occurrence and development of perinatal Lm infection. Immunomodulation targeting IL-33/ST2 axis may be an effective way to adjuvant treatment of perinatal Lm infection.