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关键词： IL-1 beta   Rheumatoid arthritis   Epilepsy  

摘要： Aims: Numerous clinical studies have revealed a positive correlation between rheumatoid arthritis (RA) and an elevated risk of epilepsy. This study aimed to investigate the seizure susceptibility in the collagen-induced arthritis (CIA) mice model. Main methods: The classic CIA model was used to mimic RA pathogenesis in mice. The pentylenetetrazole (PTZ)induced seizure model and audiogenic seizure model were used to evaluate seizure susceptibility. Neuroinflammation was assessed through ELISA, Western blot, and immunofluorescence staining. Additionally, electrophysiological techniques were applied to investigate the excitation/inhibition (E/I) balance. Key findings: CIA modeling raised the level of IL-1(3, induced E/I imbalance in the dentate gyrus (DG) region, and enhanced seizure susceptibility to PTZ in C57BL/6 mice. However, knockout (KO) of IL-1(3 attenuated peripheral inflammatory symptoms and blocked the increase in seizure susceptibility in CIA-modeled mice. Additionally, conditional IL-1R1 KO in CaMKII alpha-positive neurons did not affect the peripheral inflammatory symptoms but rescued both the increased seizure susceptibility and E/I imbalance in CIA-modeled mice. Furthermore, increased susceptibility to audiogenic seizure susceptibility was also observed in CIA-modeled BDA/1 mice, accompanied by the elevated IL-1(3 levels and neuronal IL-1R1-related Akt phosphorylation in the hippocampus. Significance: Increased seizure susceptibility in the CIA mouse model depends on IL-1(3 and neuronal IL-1R1. These data indicated that IL-1(3 and neuronal IL-1R1 may be the key targets for its intervention.

关键词： alcohol   bone loss   microbiota   segmental gut   precision medicine   prostaglandin D2   Th17 cells  

摘要： Introduction Alcohol-induced damage to bone microstructure leads to alcoholic osteoporosis (AOP). While prior studies have demonstrated alcohol's negative impact on bone density, the mechanisms by which alcohol induces osteoporosis through immune pathways, gut microbiota dysbiosis, and metabolic alterations remain insufficiently characterized. Given that alcohol is primarily absorbed in the upper gastrointestinal tract, in this research, we aimed to elucidate the role of spatial distribution disorders in gut microbiota and metabolites in the pathogenesis of alcohol-induced osteoporosis. We further sought to evaluate the potential of microbiota supplementation and targeted immunosuppressants as therapeutic strategies for related bone *** An osteoporosis model using mice was established using alcohol drinking bottles, and bone loss was validated using micro-computed tomography. Segmented intestinal samples and fecal samples were analyzed using 16S rRNA sequencing and metabolomics. Mechanistic studies were conducted by supplementing R. intestinalis, prostaglandin D2 (PGD2), and its specific immune inhibitor, ramatroban. Analytical methods included tartrate-resistant acid phosphatase staining, flow cytometry, and enzyme-linked immunosorbent *** Alcohol disrupted the spatial complexity of intestinal segments and fecal microbiota in mice, causing metabolic dysregulation and ultimately leading to elevated PGD2 levels. This, in turn, triggered Th17/Treg immune imbalance and osteoclast activation, resulting in bone loss. Supplementation with the probiotic R. intestinalis or inhibition of PGD2 significantly improved bone density and alleviate *** This study demonstrates that alcohol-induced elevation of PGD2 is a key pathogenic factor in AOP. PGD2 accelerates bone loss by promoting osteoclast formation through the activation of Th17 cells. Furthermore, this study highlights the importance of investigating the spatial distribution of

关键词： hidradenitis suppurativa   medical dermatology   clinical research   biologic therapy   COVID-19   vaccines   SARS-CoV-2  

摘要： Background and Objectives: Tumour necrosis factor-alpha (TNF-alpha) inhibitors such as adalimumab and infliximab are commonly used in moderate-to-severe hidradenitis suppurativa (HS). While the impact of TNF-alpha inhibitors on outcomes after an active infection in patients with HS has been explored, their effect on the SARS-CoV-2 vaccine response remains unknown. We investigated the impact of TNF-alpha inhibitor therapy on the immunogenic response to the SARS-CoV-2 vaccine in patients with ***: This is a single-centre retrospective chart review of 120 patients with recorded levels of anti-SARS-CoV-2 spike antibody. This cohort was characterized descriptively by demographics, antibody levels, vaccine brand, number of doses, and days elapsed from vaccination. These variables were then compared by usage of anti-TNF therapy. Secondary analyses included comparison by biologic type, time on biologic, and biologic ***: We found no significant difference in seroconversion following SARS-CoV-2 vaccination while on anti-TNF therapy in HS patients;a finding that holds in comparisons between anti-TNF therapy type, time exposed to biologic, and anti-TNF ***: Patients with HS on anti-TNF therapy receiving the SARS-CoV-2 mRNA vaccine seroconvert similarly as those without anti-TNF therapy, indicating this population should receive the vaccine and expect a similar degree of protection against COVID-19 compared to HS patients who do not receive anti-TNF therapy.

关键词： apoptosis   DNA damage   DNase   trans-kingdom effector   Type VI secretion systems (T6SSs)   Yersinia pseudotuberculosis  

摘要： The Type VI secretion system (T6SS) is a key virulence mechanism utilized by many Gram-negative bacteria to mediate the microbial competition and host pathogenesis. Despite the identification of diverse T6SS effectors targeting eukaryotic or prokaryotic cells, the trans-kingdom T6SS effectors that simultaneously target both eukaryotic and prokaryotic cells remain rarely reported. In this study, it is demonstrated that Yersinia pseudotuberculosis (Yptb) T6SS secretes a DNase effector, TkeA, which induces apoptosis in host cells. The translocation of TkeA into host cells causes nuclear DNA damage. This, in turn, activates the DNA-sensing cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway. The activation of the cGAS-STING pathway by TkeA subsequently triggers apoptosis in host cells via extrinsic pathways, with tumor necrosis factor (TNF) signaling playing a critical role. Additionally, TkeA enhances bacterial competition by targeting rival bacteria, thereby promoting host colonization. These findings reveal that the transkingdom T6SS effector TkeA executes a "one weapon, two battlefields" strategy, acting as a trans-kingdom effector that enhances interbacterial competition while inducing apoptosis in host cells through the activation of the cGAS-STING-TNF axis. This highlights a previously unrecognized dimension of bacterial virulence strategies and expands the understanding of host-pathogen interactions involving T6SS effectors.

关键词： CO2/N-2 selective separation   PVDF   MMMs   ZIF-L   IL  

摘要： This study aimed to develop an effective CO2/N-2 selective separation membrane for the capture of CO2 from air or flue gas. Polyvinylidene fluoride (PVDF) was chosen as the organic substrate for the preparation of mixed-matrix membranes (MMMs). To enhance the CO2 mass transfer rate, an ionic liquid (IL) with high CO2 solubility was introduced through direct material blending, while a leaf-like zeolitic imidazolate framework (ZIF-L) was functionalized with silane coupling agents as the inorganic filler. Subsequently, the prepared PVDF-IL@ZIF MMMs were tested for the CO2 separation performance and mechanical properties. The results revealed that IL loading could significantly enhance the separation performance of MMMs for CO2/N-2 separation, and the AZL-incorporated IL loading MMM (PPAZL) exhibited the optimal gas separation performance, with 24.5% CO2/N-2 selectivity at 2 bar transmembrane pressure. Notably, AZL also demonstrated superior interfacial compatibility with PVDF compared to both ZIF-8 and pristine ZIF-L, which facilitated the maximization of IL loading in the MMM, achieving more than 10% higher IL capacity than ZIF-8-filled counterparts while stabilizing IL immobilization within the membrane matrix.

关键词： Glucocorticoids-induced osteonecrosis of the femoral head   Calcified cartilage zone remodeling   IL-1 beta   Cartilage degeneration   Biomechanics  

摘要： Glucocorticoids-induced osteonecrosis of the femoral head (GONFH) is characterized by progressive cartilage degeneration, yet the role of calcified cartilage zone (CCZ) remodeling in this process remains poorly understood. This study investigated how the inflammatory microenvironment within necrotic subchondral bone drove CCZ remodeling and subsequent cartilage degeneration. Using osteochondral tissues from GONFH patients and interleukin-1 beta (IL-1 beta)-treated hypertrophic chondrocytes induced by ATDC5 cells, we combined histology, immunohistochemistry, scanning electron microscopy, energy dispersive spectrometer, transmission electron microscopy, nanoindentation testing, enzyme linked immunosorbent assay and fluorescent tracking to evaluate morphological, biomechanical, and molecular changes. Our findings revealed that CCZ of GONFH exhibited significant thinning, matrix decomposition, demineralization, diminished mechanical strength, and increased porosity. Spatial analysis demonstrated a strong correlation between CCZ remodeling and site-specific cartilage degeneration. Notably, IL-1 beta was overexpressed in necrotic subchondral bone and the site deep zones of cartilage. It potently enhanced catabolic activity in hypertrophic chondrocytes, promoting matrix metalloproteinase expression while impairing mineralization capacity. This study uncovers a novel pathological cascade in GONFH: necrotic subchondral bone-derived IL-1 beta drives CCZ remodeling via biomechanical and biological pathways, leading to cartilage degeneration independent of femoral head collapse. Our findings highlight IL-1 beta as a critical therapeutic target, providing a rationale for subchondral bone-targeted anti-inflammatory strategies to mitigate GONFH *** AbstractNecrotic subchondral bone expresses inflammatory cytokines, especially IL-1 beta, and triggers pathological remodeling of the calcified cartilage zone (CCZ). This remodeling manifests as reduced thickness, matr

关键词： periodontitis   host-pathogen interactions   Porphyromonas gingivalis   prostaglandin   inflammation  

摘要： The interaction between pathogenic microorganisms and stromal cells, in particular fibroblasts, significantly contributes to the pathogenesis of many bacterially driven diseases. In periodontitis, oral pathogens penetrate the epithelial barrier and aggravate ongoing gingival inflammation by promoting the production of inflammatory mediators, such as prostaglandin E2 (PGE2). This study aimed to investigate the functional consequences of the interplay between oral pathogens and a pro-inflammatory environment in the activation of the PGE2 pathway in primary human gingival fibroblasts (GFs). GF infection with Fusobacterium nucleatum, Porphyromonas gingivalis, or Filifactor alocis in the presence of tumor necrosis factor (TNF) led to synergistic induction of cyclooxygenase-2 (COX-2), a key enzyme in the PGE2 synthesis pathway, as well as secretion of PGE2. A similar synergy in COX-2 upregulation was observed upon GF infection with oral pathogens in the presence of IL-1 alpha, IL-1 beta, and interferon-alpha (IFN-alpha). This effect required toll-like receptor-2 (TLR2) and the p38 MAP kinase activation and was specific for fibroblasts as infection of macrophages or keratinocytes with oral pathogens in the proinflammatory environment did not cause synergistic COX-2 induction. Finally, we demonstrated that conditioned media from GFs infected with F. nucleatum under inflammatory conditions amplified the expression of the neutrophil chemokine IL8 in macrophages and confirmed that this effect was mediated by synergistic induction of PGE2 in GFs. Collectively, we identify a new mechanism of stromal-immune cross-talk that is driven by synergistic PGE2 induction by oral pathogens and inflammatory cytokines in GFs and may contribute to excessive macrophage activation and neutrophil infiltration in periodontitis. IMPORTANCE Periodontitis is a highly prevalent, dysbiosis-driven chronic inflammatory disease that not only leads to tooth loss but also is associated with severe systemic

关键词： Oncolytic Virus   Neoantigen Vaccines   Peptide-MHC Complexes   Tumor Immunotherapy  

摘要： Neoantigen vaccine is a promising breakthrough in tumor immunotherapy. However, the application of this highly personalized strategy in the treatment of solid tumors is hindered by several obstacles, including very costly and time-consuming preparation steps, uncertainty in prediction algorithms and tumor heterogeneity. Universalization of neoantigen vaccine is an ideal yet currently unattainable solution to such limitations. To overcome these limitations, we engineered oncolytic viruses co-expressing neoantigens and neoantigen-binding major histocompatibility complex (MHC) molecules to force ectopic delivery of peptide-MHC ligands to T cell receptors (TCRs), enabling specific targeting by neoantigen vaccine-primed host immunity. When integrated with neoantigen vaccination, the engineered viruses exhibited potent cytolytic activity in a variety of tumor models irrespective of the neoantigen expression profiles, eliciting robust systemic antitumor immunity to reject tumor rechallenge and inhibit abscopal tumor growth with a favorable safety profile. Thus, this study provides a powerful approach to enhance the universality and efficacy of neoantigen vaccines, meeting the urgent need for universal neoantigen vaccines in the clinic to facilitate the further development of tumor immunotherapy.

关键词： AhR/IL-22   黄芪甲苷   溃疡性结肠炎   肠道屏障  

摘要： 目的：研究黄芪甲苷 （Astragaloside IV，AS-IV）对溃疡性结肠炎（Ulcerative colitis，UC）小鼠肠道屏障功能的影响，并探讨其潜在机制。方法：使用3%葡聚糖硫酸钠（Dextran sulfate sodium，DSS）构建小鼠UC模型，建模成功后分为空白对照组、模型空白对照组、黄芪甲苷低、中、高剂量组（10 mg/kg、20 mg/kg、40 mg/kg），各组灌胃相应药物，每日1次，连续给药10d。Western blotting检测AhR/IL-22通路的蛋白表达水平；荧光原位杂交技术检测结肠组织切片DAPI染色情况；流式细胞术检测细胞凋亡水平；qRT-PCR检测AHR、CYP1A1、IL-22等mRNA表达水平。结果：AS-IV可能通过促进AhR/IL-22通路改善结肠炎小鼠的肠道炎症状态，降低了肠道通透性，并促进了结肠紧密连接结构的修复。AhR拮抗剂CH223191可部分阻断AS-IV的治疗效果，而AhR激动剂FICZ可改善结肠炎小鼠的症状和肠道屏障功能。进一步的体外机制研究发现，AS-IV处理显著提高了MNK-3细胞中AhR下游靶蛋白CYP1A1的表达水平（p<0.01），并通过促进AhR核转位显著增强IL-22的分泌（p<0.01）。重要的是，在AhR基因沉默的MNK-3细胞（shAhR-MNK3）中，AS-IV对CYP1A1表达和IL-22分泌的促进作用被显著抑制（p<0.05），表明AS-IV通过AhR依赖性机制调控IL-22的产生。结论 AS-IV通过ILC3中的AhR/IL-22通路改善肠上皮屏障，改善结肠炎，从而为UC提供潜在的治疗方法。