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关键词： Subarachnoid hemorrhage   IL-33   ST2   AKT   Microglia  

摘要： Background and purpose: ST2, a member of the interleukin-1 (IL-1) receptor family, along with its ligand IL-33, plays critical roles in immune regulation and inflammatory responses. This study investigates the roles of endogenous IL-33/ST2 signaling in subarachnoid hemorrhage (SAH) and elucidates the underlying mechanisms. Methods: Dynamic changes in endogenous IL-33 levels were examined following SAH induction in vivo. Rats underwent the endovascular perforation model of SAH and were randomly assigned to receive either recombinant IL-33 (rIL-33) or a vehicle, administered intranasally 1 h post-SAH. ST2 siRNA or an AKT selective inhibitor was administered intraperitoneally (i.p.) 48 h prior to SAH induction to explore the potential mechanisms of IL33-mediated neuroprotection. Results: Endogenous IL-33 and ST2 levels were elevated in in vitro models of SAH. Exogenous IL-33 significantly alleviated neuronal apoptosis, reduced brain edema, and enhanced short-term neurofunction in a dosedependent manner following SAH in rats. Conclusion: Exogenous rIL-33 alleviates SAH-induced neurological deficits by promoting M2-like polarization of microglia post-SAH. These findings suggest a potential role of the microglial ST2/AKT axis in IL-33-related neuroprotection, which warrants further investigation.

关键词： Anti-TNF alpha   A1AT   drug reprofiling   neuroprotection   stroke  

摘要： Neuroprotection after ischemic stroke has been focused on targeting one pathway of the ischemic cascade. In this study, we have hypothesized that combination therapy with alpha-1 antitrypsin (A1AT) and a blocker of tumor necrosis factor (TNF alpha) could be beneficial in the acute phases after ischemia. Following a detailed safety assessment of the co-administration of both drugs, we tested their neuroprotective effect in a transient mouse model of proximal middle cerebral artery occlusion (MCAo) by evaluating infarct extension and functional outcomes. Anti-TNF alpha (20 mg/kg) and A1AT were administered at different doses (ranging from 60 mg/kg to 700 mg/kg), as a single therapy during occlusion or at different time-points following reperfusion. Results showed that the administration of A1AT (60 mg/kg) in combination with anti-TNF alpha (20 mg/kg) was safe and effective when given during occlusion by reducing infarct volume at 24 h by 27% compared with the vehicle group (p = 0.0001). In conclusion, the synergy of the anti-apoptotic and anti-inflammatory properties of both drugs can reduce infarct volume in a stroke mouse model when given in the hyperacute phase. This approach shows promise as an early intervention strategy for stroke patients and underscores the potential of drug repurposing to develop new stroke treatments.

关键词： TNF-alpha   Anti-TNF-alpha therapy   Sepsis   Treatment failure  

摘要： Sepsis, a condition of significant clinical concern, is characterized by life-threatening organ dysfunction that arises from an infection and is exacerbated by a dysregulated host response. Targeting immune modulation, particularly against tumor necrosis factor-alpha (TNF-alpha), has emerged as a promising anti-inflammatory therapeutic strategy. However, approaches such as blood purification to eliminate inflammatory mediators or the use of anti-TNF-alpha therapies have shown limited efficacy in clinical practice. This literature review aims to elucidate the pathogenesis of sepsis and dissect the factors contributing to unfavorable outcomes in TNF-alpha-targeted treatments. Our analysis highlights several potential reasons for therapeutic failure. Complete blockade of TNF-alpha may adversely affect both TNFR1 and TNFR2 signaling, thereby reducing the efficacy of TNF-alpha inhibitors. Additionally, the complex heterogeneity of sepsis, including the etiology of infection, patient-specific factors (e. g., immune responsiveness, body mass index, and obesity), the development of anti-drug antibodies, and treatment duration, significantly influences therapeutic outcomes. Based on these insights, we emphasize the need for precision medicine in sepsis management. This includes stratifying patients into subgroups, using TNFR2 agonists or TNFR1-specific antagonists, refining drug design, implementing multi-target combination therapies, and considering the patient's physiological state at the time of treatment. Collectively, these strategies could enhance the efficacy of sepsis management. This review underscores the multifaceted nature of sepsis treatment and highlights the imperative for personalized, multimodal therapeutic approaches to improve clinical outcomes.

关键词： Paneth cells   sepsis   TNF   treatment  

摘要： In a recent Cell Host & Microbe paper, Wallaeys et al. demonstrate that TNF signaling critically regulates Paneth cell dysfunction and bacterial sepsis pathogenesis, and highlights a critical localized mechanism in the gut, making a substantial contribution to our understanding of TNF's role in gut-derived sepsis pathogenesis.

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： 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： 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： 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： infliximab   subcutaneous   CT-P13   inflammatory bowel disease   immunogenicity   ADA   anti-drug antibodies   CD   Crohn’s disease   CI   confidence interval   CRP   c-reactive protein   EOW   every other week   FC   fecal calprotectin   HR   hazard ratio   IBD   inflammatory bowel disease   IFX   infliximab   IQR   interquartile range   IV   intravenous   NOS   Newcastle-Ottawa Scale   OR   odds ratio   RoB2   Cochrane risk-of-bias tool   SC   subcutaneous   TNF   tumour necrosis factor   W   week  

摘要： Background and aims Intravenous (IV) infliximab (IFX) combined with an immunomodulator (combination therapy) outperforms IV IFX monotherapy in terms of clinical, endoscopic and immunogenicity outcomes in inflammatory bowel disease (IBD) patients. With the advent of subcutaneous (SC) IFX, which is associated with higher serum drug concentrations, it is essential to assess whether SC IFX monotherapy provides similar pharmacokinetic and clinical benefits as combination therapy. Methods We conducted a systematic review and meta-analysis (until August 2024), of studies on IBD patients treated with SC IFX. The primary outcome was anti-drug antibodies (ADA) formation within 12 months (M) after starting SC IFX or after switching from IV to SC IFX. Secondary outcomes included treatment persistence, clinical efficacy and biochemical parameters. Results Twenty-four studies (n=3172), were included. Among patients transitioning from IV IFX induction to SC IFX, immunogenicity was more prevalent with monotherapy than combination treatment (median 68% vs. 48%, OR 3.29, 95% CI 1.71-6.31, P<0.001). Clinical response rates at 12M were comparable, with a trend favouring combination therapy (OR 0.73, 95% CI 0.50-1.06, P=0.10). In patients switching from IV maintenance to SC IFX, relapse rates were low (median 12% at 6M, 11% at W50), with stable biochemical markers. Treatment persistence was high (93% at 6M, 92% at 12M). Among patients with quiescent disease at the time of switching, one-year relapse rates were 9–11%, with baseline immunogenicity predicting treatment failure. Conclusion SC IFX monotherapy is associated with higher immunogenicity rates compared to combination therapy, particularly in new IFX starters. Although clinical response was comparable, a trend favouring combination therapy warrants further investigation.