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关键词： AMPK   chondrocyte   osteoarthritis   PACAP   senescence   SIRT3  

摘要： Osteoarthritis (OA) is a degenerative joint disease closely associated with aging, in which chondrocyte senescence plays a critical role in cartilage degradation. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide known for its anti-inflammatory and cytoprotective effects;however, its role in chondrocyte senescence remains poorly understood. This study investigated the protective effects of PACAP38 on tumour necrosis factor-alpha (TNF-alpha)- induced chondrocyte senescence and the underlying mechanisms. Intracellular reactive oxygen species (ROS) levels were measured using 2 ',7 '-dichlorodihydrofluorescein diacetate (DCFH-DA) staining, oxidative DNA damage was assessed by 8-hydroxy-2 '-deoxyguanosine (8-OHdG) enzyme-linked immunosorbent assay (ELISA), and senescence markers were evaluated by senescence-associated beta-galactosidase (SA-beta-Gal) staining, telomerase activity assay, and telomere length analysis. Gene and protein expression were examined via real-time polymerase chain reaction (PCR) and Western blotting. We found that PACAP type I receptor (PAC1R), the receptor for PACAP, was expressed in both murine and human chondrocytes and was downregulated by TNF-alpha stimulation. PACAP38 treatment significantly reduced ROS and 8-OHdG levels, restored telomerase activity and telomere length, and decreased SA-beta-Gal activity. Mechanistically, PACAP38 upregulated sirtuin 3 (SIRT3), a mitochondrial deacetylase that regulates oxidative stress and metabolism, while suppressing acetylated p53 (ac-p53) and plasminogen activator inhibitor-1 (PAI-1) expression. Furthermore, PACAP38 reversed TNF-alpha-induced dephosphorylation of AMP-activated protein kinase alpha (AMPK-alpha) and its downstream target acetyl-CoA carboxylase (ACC). Importantly, inhibition of AMPK by compound C abolished these protective effects, confirming the essential role of the AMPK-SIRT3 signalling pathway. In conclusion, our findings demonstrate that PACAP38 mitigates TN

关键词： Interleukin-1β   NLRP1   inflammasome   Staphylococcus aureus   keratinocytes   staphopain A   microbial proteases  

摘要： Interleukin-1β (IL-1β) is a pivotal mediator of innate immunity, essential for orchestrating the acute inflammatory response. While the canonical activation of IL-1β involves cleavage of its inactive precursor (pro-IL-1β) by the inflammatory cysteine protease caspase-1, certain bacterial proteases, such as those secreted by group A Streptococcus and Pseudomonas aeruginosa , can also activate pro-IL-1β. In this study, we demonstrate that infection of human N/TERT-1 immortalized keratinocytes by Staphylococcus aureus induces IL-1β processing independently of the classical inflammasome pathways. Biochemical analysis reveals that a secreted factor from S. aureus cleaves pro-IL-1β at a site proximal to the canonical caspase-1 cleavage site, rendering the cytokine bioactive. Specifically, we identify the secreted cysteine protease staphopain A as responsible for this cleavage. Our findings highlight a novel mechanism of inflammasome-independent IL-1β activation through microbial proteases, expanding the understanding of pathogen-host interactions in immune responses, specifically in the skin.

关键词： Hepatocellular carcinoma   CTLA-4   SPP-1   Combination therapy   Immunotherapy  

摘要： Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide, and secreted phosphoprotein 1 (SPP-1) is linked to tumor progression and immune evasion. This study investigates whether anti-SPP-1 therapy can enhance the anti-tumor effects of anti-CTLA-4 immunotherapy in HCC and elucidates the underlying molecular mechanisms. Data from The Cancer Genome Atlas (TCGA) comprising 374 HCC patients were analyzed to examine SPP-1 expression and its correlation with clinical prognosis using the Kaplan-Meier survival curve and multivariate Cox regression models. Multiple bioinformatics platforms including TIMER and TISIDB were employed to assess SPP-1's role in the tumor immune microenvironment. In vivo validation was performed in H22 hepatocellular carcinoma syngeneic mouse models treated with anti-SPP-1 and anti-CTLA-4 antibodies, where tumor growth and immune cell infiltration were evaluated using flow cytometry, immunohistochemistry, and molecular interaction studies. In the 374 HCC patient cohort, high SPP-1 expression was significantly associated with advanced TNM staging, pathological grading, and vascular invasion. Lower SPP-1 expression significantly correlated with improved overall survival, disease-specific survival, and progression-free intervals, confirming SPP-1 as an independent prognostic factor in multivariate analysis. Immune infiltration analysis revealed that SPP-1 was positively correlated with immune cells and checkpoint molecules including CTLA-4. In a syngeneic tumor model, combination therapy with anti-SPP-1 and anti-CTLA-4 significantly inhibited tumor growth, increased CD8+ T cell infiltration, and promoted M1 macrophage polarization. Mechanistically, combination therapy significantly reduced IL-6 expression and suppressed STAT3 signaling, while interferon-gamma levels were elevated in the combination therapy group. Co-immunoprecipitation experiments confirmed SPP-1/IL-6 protein interaction. SPP-1 serves as both a potential prognostic mar

关键词： colorectal cancer   immune checkpoint blockade   intratumoral bacteria   probiotics   patient-derived autologous organoids and TILs coculture   immunotherapy   Clostridium butyricum   cytotoxic CD8   T cells  

摘要： Most colorectal cancer (CRC) patients do not respond to immune checkpoint blockade (ICB) therapy. Here, we identify Clostridium butyricum as a probiotic that boosts anti-PD-1 efficacy in CRC. In orthotopic allografts of microsatellite instability-high (MSI-H) and microsatellite stable (MSS) CRC, C. butyricum potentiates tumor suppressive effect of anti-PD-1, which is verified in AOM/DSS-induced CRC and germ-free mice. Single-cell RNA-seq reveals that C. butyricum activates cytotoxic CD8 + T lymphocytes (CTLs) and impairs tumor-associated macrophages (TAMs), especially in conjunction with anti-PD-1. Mechanistically, C. butyricum surface protein secD binds to CRC cell receptor glucose-regulated protein 78 (GRP78), which inactivates GRP78 and PI3K-AKT-NF-κB pathway, leading to reduced secretion of interleukin (IL)-6, an immunosuppressive cytokine that blunts CTLs and induces TAMs. Translational impact of C. butyricum in boosting anti-PD-1 efficacy is validated in huCD34 + humanized mice and autologous patient-derived CRC organoids-CTLs co-culture system. To summarize, C. butyricum is a promising adjuvant to augment ICB therapy.

关键词： germinal center B cell   plasma cell differentiation   PTEN   signaling  

摘要： The germinal center (GC) reaction is essential for generating high-quality humoral memory. Positively selected GC B cells must decide whether to remain in the GC for further affinity maturation or differentiate into memory or plasma cells (PCs). Previously, we identified IL-21R and CD40 signaling as critical promoters of GC B cell effector differentiation. However, the mechanisms regulating the strength of these signals remain unclear. PTEN, a negative regulator of PI3K signaling, is markedly upregulated in GC B cells. To explore the role of PTEN in GC B cell fate decisions, we used a tamoxifen-driven Cre system to delete PTEN in B cells after GC reaction was fully established. We found that PTEN deletion in ongoing GC B cells led to significantly increased differentiation into PCs, while having limited effects on class switching or memory precursor differentiation. These results were further confirmed using a GC B cell transfer system, where wild-type and PTEN-deficient GC B cells were transferred into the same recipient mice. Mechanistically, PTEN deletion or inhibition in established GC B cells resulted in more sustained IL-21R signaling and enhanced CD40 signaling-both known to promote PC differentiation. Interestingly, Peyer's patch GC B cells exhibited higher PTEN levels than de novo GC B cells generated through immunization. Notably, PTEN deficiency selectively expanded GC B cells in Peyer's patches but had no impact on those induced by immunization. These findings reveal previously unrecognized roles for PTEN in regulating GC B cell signaling and limiting their differentiation into PCs.

关键词： Interleukin-18 (IL-18)   atopic dermatitis (AD)   chronic inflammatory skin disease   type 2 immune response   IL-1 family   (N-)GSDMD   (N-terminal) Gasdermin D   AD   Atopic dermatitis   AIM2   Absent in melanoma 2   Akt   Protein kinase B   AP-1   Activator protein 1   DCs   Dendritic cells   ERK   Extracellular signal-regulated kinase   FLG   Filaggrin   GWAS   Genome-wide association study   IFN-γ   Interferon-γ   IgE   Immunoglobulin E   IL   Interleukin   IL-18BP   IL-18 binding protein   IL18R1   IL-18 receptor 1   IL18RAP   IL-18 receptor accessory protein   ILC(2)   Innate lymphoid cell (type 2)   IRAK   Interleukin-1 receptor-associated kinase   JAK   Janus kinase   JNK   c-Jun N-terminal kinase   LOR   Loricrin   LPS   Lipopolysaccharide   MAPK   Mitogen-activated protein kinase   MAS   Macrophage activation syndrome   MyD88   Myeloid differentiation primary response D88   NF-κB   Nuclear factor kappa B   NK cell   Natural killer cell   NLRC   NOD-like receptor family CARD domain-containing protein   NLRP   NLR containing a pyrin domain   NMF   Natural moisturizing factor   PAPA   Pyogenic arthritis, pyoderma gangrenosum, and acne   PD-L1   Programmed cell death ligand 1   PI3K   Phosphoinositide 3-kinase   PRR   Pattern recognition receptor   pTh   Pathogenic T helper cell   scRNA-seq   single-cell RNA-sequencing   SEB   Staphylococcus aureus enterotoxin B   SIGIRR   Single immunoglobulin IL-1-related receptor   SpA   Staphylococcus aureus protein A   SpeB   Streptococcal pyrogenic exotoxin B   STAT   Signal transducer and activator of transcription   TEWL   Transepidermal water loss   TIR   Toll-interleukin-1 receptor   TLR   Toll-like receptor   TNF-α   Tumor necrosis factor α   TRAF6   Tumor necrosis factor receptor associated factor 6   TRAM   TRIF-related adaptor molecule   TSLP   Thymic stromal lymphopoietin  

摘要： Atopic dermatitis (AD) is a common chronic inflammatory skin disease characterized by pruritus, barrier dysfunction and immune cell infiltration. Despite significant progress in our understanding of AD pathophysiology, the molecular mechanisms driving the disease remain only partially elucidated. Recently, the cytokine IL-18, a member of the IL-1 family, has drawn attention for its involvement in diverse immune responses and potential impact on disease severity. In this review, we examine the role of IL-18 in AD, with a focus on genetic associations, biomarker potential, and cellular sources. Elevated IL-18 levels in both the skin and serum of AD patients are positively correlated with disease severity, type 2 immune response and impaired barrier function. Mouse models of AD reinforce the importance of IL-18, where neutralization or genetic knockout alleviates AD-like features. We further explore how IL-18 drives type 2 immune responses in the skin and the cellular mechanisms involved. Collectively, current literature supports a crucial role for IL-18 in AD pathophysiology, indicating that targeting IL-18 may be a promising therapeutic strategy for managing the disease.

关键词： Grass carp (Ctenopharyngodon idella)   Natural grass feeding mode   IFN-gamma 2   Muscle cell  

摘要： Grass carp (Ctenopharyngodon idella), as the highest-yielding freshwater species in China, has become a focus of muscle quality research. Previous studies have shown that natural grass feeding (GF) mode can improve the muscle quality of grass carp compared with artificial feeding (AF) mode, but its mechanism has not been revealed. In this study, we identified that interferon-gamma 2 (IFN-gamma 2) can be induced in the muscle tissues under GF mode. Therefore, recombinant IFN-gamma 2 protein was obtained to study its effect on grass carp muscle cells (GCMCs). We found that IFN-gamma 2 can facilitate the proliferation of GCMCs, and promote the myotube enlargement of GCMCs. Meanwhile, mRNA level investigations indicated that IFN-gamma 2 can regulate the expression of genes related to cell physiological processes. By transcriptome analysis, we screened a series of genes related to cell proliferation, differentiation, and migration. Using STAT1 inhibitor fludarabine in vitro, we confirmed that IFN-gamma 2 regulates the physiological development of GCMCs through JAK/STAT1. Finally, by knocking down IFN-gamma 2 in grass carp individuals, we verified that IFN-gamma 2 has an effective regulatory effect in vivo. This study provides novel target for improving the muscle quality of grass carp and provides inspiration for the development of aquaculture feeding *** grass feeding mode induces IFN-gamma 2 expression in grass carp ***-gamma 2 promotes the proliferation of grass carp muscle cells via JAK/***-gamma 2 regulates the expression of genes related to muscle proliferation in vivo.

关键词： Endoplasmic reticulum stress   fibroblast-like synoviocytes   IL-21/IL-21R pathway   rheumatoid arthritis   USP18/GSDMD axis  

摘要： IntroductionThe persistent presence of fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA) contributes significantly to joint damage, yet the anti-apoptotic mechanisms involved are not well understood. This study investigates how the interleukin-21 (IL-21)/IL-21 receptor (IL-21R) pathway affects RA-FLS survival during endoplasmic reticulum stress (ERS).MethodsClinical data, in vitro, and in vivo experiments were comprehensively *** patients with moderate-high disease activity and anti-CCP antibodies have high serum IL-21 levels. IL-21 enhances HFLS-RA cell survival and prevents apoptosis under ERS by upregulating IL-21R. It activates autophagy, shown by increased LC3II/I;ratio and p62 degradation, and inhibits ERS-mediated apoptosis by downregulating GRP78 and CHOP. Overexpressing IL-21R boosts autophagy and suppresses ERS. Transcriptome analysis identified USP18 as a key downstream effector of IL-21R. Silencing USP18 increased GSDMD expression and negated IL-21R's protective effects. In vivo, silencing IL-21R reduced joint inflammation and cartilage degradation in RA mouse models, reversing excessive autophagy and ERS marker expression in synovial *** study elucidates, for the first time, the mechanism by which IL-21/IL-21R synergistically modulates the survival of RA-FLS through the "autophagy-ERS balance" and the USP18/GSDMD axis.

关键词： 冠心病合并高血压   西药   血清因子   血压  

摘要： 本研究针对冠心病并发高血压个体,基于先前研究,明确中西医结合治疗的疗效,着重总结该治疗方式对机体血清炎症因子、血管内皮功能的作用。方法 纳入80例样本,均符合本研究纳入标准,均分为两组(n=40),分别予以单一西药治疗与中西医结合治疗,对比治疗后各组间相关指标,以达成研究目的。结果 治疗后,组间观察指标对比,相较于对照组,观察组血压改善幅度更大,症状发作时间更短且频次更少,组间治疗后的炎症因子水平均有降低,且观察组降幅更大,比较而言,观察组整体治疗有效率较对照组更高,数值对比有差异性,P<0.05。结论 针对冠心病并发高血压,结合中西医治疗方式的临床治疗效果更加理想,能够稳定降压的同时改善患者的炎症、血管内皮功能,以此减少症状的发作,减轻病情,治疗效果理想,值得推广应用。