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关键词： Syringic acid   Rheumatoid arthritis   CFA   Pro-inflammatory mediators   TNF- alpha   Molecular docking   IL-4, IL-10  

摘要： Syringic acid with reported anti-inflammatory attribute was investigated in the present study to assess its anti-arthritic potential at doses of 25 mg/kg, 50 mg/kg and 100 mg/kg using adjuvant-induced arthritic rats. The rat's paw size (mm), arthritic index and behavioral parameters were observed at baseline and subsequently at seven days' interval until the completion of the study, following complete Freund's adjuvant (CFA) induction. The animals were anesthetized on 28th day and blood samples were obtained for the determination of numerous biochemical, hematological, pro-inflammatory, anti-inflammatory and oxidative biomarkers. Afterwards, the weight of lymphoid organs and radiographic, as well as histopathological examinations of the inflamed paw, were conducted. Furthermore, molecular docking was done to find out the interaction between syringic acid and Interleukins-1 beta, tumor necrosis factor-alpha, Interleukins-6 (IL-6), Interleukins-4 (IL-4) and Cyclooxygenase-2 (Cox-2). Results revealed that chronic syringic acid administration significantly reduced the paw size, arthritic index, and showed improvement in behavioral parameters with retrieval of altered hematological and biochemical parameters. Treatment with syringic acid also exhibited substantial recovery from oxidative stress markers and lymphoid organ weight was retrieved. Upon quantitative real-time polymerase chain reaction (qRT-PCR) examination, syringic acid significantly reduced the mRNA expression of tumor necrosis factor-alpha and all the other inflammatory cytokines while enhancing the mRNA expression of anti-inflammatory cytokines. Decreased serum concentration of PGE2 was noted with syringic acid as determined by enzyme-linked immunosorbent assay (ELISA). Histopathological analysis and radiographs further confirmed the findings. Molecular docking studies showed good interaction between syringic acid and IL-1 beta, tumor necrosis factor-alpha, IL-6, IL-4 and COX-2 when compared against standa

关键词： therapeutic drug monitoring   anti-TNF   point-of-care testing   loss of response  

摘要： Background and Aims: Point-of-care tests (POCT) enable immediate measurement of anti-TNF blood concentrations. This study examined the association between loss of response (LOR) to infliximab (IFX) or adalimumab (ADL) and serum concentrations measured with POCT and enzyme-linked immunosorbent assay (ELISA) in inflammatory bowel disease (IBD) patients. Methods: Patients with IBD with stored IFX or ADL serum samples were recruited. POCT was conducted, agreement with ELISA was evaluated using Bland-Altman plots. The primary endpoint was LOR defined as change in therapy, IBD-related surgery, new actively draining fistula, and/or endoscopic deterioration. ROC curves and quartile analysis assessed the association between concentrations and LOR. Results: A total of 176 patients were included (92 IFX/84 ADL, 154 Crohn's disease, and 22 ulcerative colitis). Median follow-up time was 20 months (interquartile range 9-38). LOR occurred in 37/84 (44%) ADL users and 55/92 (60%) IFX users. Median serum concentrations were significantly lower in LOR patients compared with sustained response, measured by both techniques for ADL (POCT: 6.45 vs 13.48 mu g/mL, P <.001;ELISA: 4.80 vs 8.80 g/mL, P <.001) and IFX (POCT: 2.39 vs 6.50 g/mL, P <.001;ELISA: 1.70 vs 4.40 g/mL, P <.001). Quartile analysis revealed that higher serum concentrations were associated with maintained response. ROC curve analysis demonstrated good or excellent discrimination for POCT and ELISA in association with LOR (AUC IFX: POCT = 0.82, ELISA = 0.76;AUC ADL: POCT = 0.82, ELISA = 0.81;all P <.0001). An overestimation of serum concentrations with POCT was observed. Conclusions: Serum ADL and IFX POCT concentrations are comparable to ELISA and associated with LOR, indicating its clinical utility. This study assessed the association between loss of response (LOR) and infliximab or adalimumab serum concentrations measured by point-of-care testing and ELISA in inflammatory bowel disease patients. POCT correla

关键词： non-thermal plasma   endothelial cell inflammation   reactive oxygen species   NF-kappa B  

摘要： Non-thermal plasma (NTP) has emerged as a promising therapeutic tool due to its anti-inflammatory properties;however, its molecular effects on vascular endothelial inflammation remain unclear. This study investigated the effects of NTP on tumor necrosis factor-alpha (TNF-alpha)-induced inflammation in human umbilical vein endothelial cells (HUVECs). NTP treatment significantly reduced intracellular reactive oxygen species (ROS) levels and downregulated the expression of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), which are key markers of endothelial activation. In addition, NTP suppressed mRNA expression of pro-inflammatory cytokines, including TNF-alpha, interleukin-1 beta (IL-1 beta), and interleukin-6 (IL-6). Mechanistically, NTP inhibited the nuclear translocation of phosphorylated NF-kappa B p65, indicating attenuation of NF-kappa B signaling. These results demonstrate that NTP modulates inflammatory responses in endothelial cells by attenuating ROS generation and suppressing NF-kappa B-mediated signaling. Our findings suggest that NTP may serve as a potential therapeutic strategy for treating vascular inflammation and related pathologies.

关键词： fibrosis   immunology and pathology   lymphocytes   peritoneal dialysis  

关键词： interleukin-27   neonatal sepsis   STAT-3   lysosome   bacteria   inflammation   blood   spleen  

摘要： Interleukin (IL)-27 is a heterodimeric immunoregulatory cytokine expressed at elevated levels early in life that compromises bacterial clearance and promotes severe outcomes during neonatal sepsis. In turn, IL-27R alpha-deficient neonatal mice exhibit better control of bacteria, reduced systemic inflammation, and improved outcomes. IL-27 primarily activates and signals through either Signal transducer and activator of transcription (STAT )-1 or STAT-3 in macrophages. Targeted deletion of STAT-3 in macrophages has been reported to improve responsiveness to Lipopolysaccharide (LPS) and promote Th1 activity. As such, in the present study, we investigated the role of STAT-3 signaling in IL-27-mediated suppression of bacterial clearance and lysosomal activity in neonatal macrophages during in vitro infection and sepsis. Bone marrow- derived macrophages from myeloid-specific STAT-3 deletion in neonatal mice (LysMcre STAT-3fl/fl) showed improved control of intracellular bacteria and lysosomal acidification. Consistent with these findings, E. coli-infected neonatal LysMcreSTAT-3fl/fl mice demon strated improved bacterial clearance, but conversely, increased inflammatory response and mortality compared with neonatal mice with intact STAT-3 signaling. Pharmacologi cal inhibition of STAT-3 in WT neonatal mice using S32-201 resulted in the inability to clear bacteria in either the blood or spleen relative to control mice. This study revealed that STAT-3 is necessary for IL-27 suppression of macrophage-mediated bacterial killing, but neither myeloid-specific nor global STAT-3 inhibition during neonatal sepsis achieves the same outcome as loss of IL-27 signaling. This suggests that STAT-3 is not a promising therapeutic target to mitigate IL-27 activity in early life infection.

关键词： Intervertebral disc   Cartilaginous endplate 3D culture   Agarose   Dynamic compression   Catabolism   Mechanobiology   Pro-inflammatory cytokines   Hydrogel  

摘要： Intervertebral disc (IVD) degeneration is the leading cause of low back pain in young adults, and the cartilaginous endplate (CEP) is likely to play a key role in early IVD degeneration. To elucidate the effects of pro-inflammatory cytokines on the mechanobiology of the CEP, human CEP cells were seeded into 2% agarose, dynamically compressed up to 7%, and stimulated with tumor necrosis factor (TNF). It was hypothesized that dynamic compression would be sufficient to induce anabolism, while stimulation with TNF would induce catabolism. TNF was sufficient to induce a catabolic, time-dependent response in human CEP cells through downregulation of anabolic gene expression and increased secretion of pro-inflammatory proteins associated with herniated discs, bacteria inhibition, and pain. However, 7% strain or scaffold material, agarose, may not lead to full activation of integrins and downregulation of pro-inflammatory pathways, demonstrated in part through the unchanged gene expression of integrin subunits alpha 5 and beta 1.

摘要： Background Immune-mediated hearing loss (IMHL) patients (comprised of autoimmune inner ear disease (AIED) and sudden sensorineural hearing loss (SSNHL)) may be at higher risk for hearing loss following Coronavirus disease (COVID-19) infection and/or vaccination. Methods We compared inflammatory cytokine expression in response to SARS-CoV2 spike protein between two groups of patients with IMHL: IMHL patients that temporally demonstrated worsening SNHL following COVID vaccination or infection as compared to IMHL patients with worsening SNHL unrelated to COVID exposure: (IMHL-COVID ( +)) (n = 11) (IMHL-COVID (-)) (n = 10). In these two groups, we treated isolated PBMCs with increasing amounts of SARS-CoV-2 spike protein and compared responses to stimulation with positive and negative controls. Results Peripheral Blood Mononuclear Cells (PBMC) from IMHL-COVID ( +) patients had increased expression and release of both IL-1 beta and IL-6 in response to spike protein as compared to IMHL-COVID (-) patients. However, when the IMHL-COVID ( +) group was broken down into AIED patients compared to SSNHL, it became apparent that the greatest responses were from the AIED patients (p < 0.005 for IL-6 mRNA expression and p < 0.003 for IL-6 release when compared between any two similar groups using Wilcoxon Rank-Sum Test). When we broke down the COVID ( +) group to infection versus vaccination, the immune responses in the infection group (N = 3 AIED, 1 SSNHL) were stronger. Conclusions COVID-19 exposure with reported changes in hearing sensitivity in IMHL patients resulted in pro-inflammatory responses in response to spike protein. The inflammatory responses were greatest in AIED patients, and greater following infection rather than vaccination. Therefore, based on these studies, we would recommend AIED patients take additional precautions to avoid COVID exposure. Furthermore, we do recommend COVID vaccination during periods of hearing stability, as the immune responses are even more

关键词： Asthma   Relapse   Single-cell transcriptomics   ILC2   Il1rl1  

摘要： BackgroundAsthma is a chronic inflammatory airway disease characterized by recurrent episodes that significantly impair disease control and reduce patients' quality of life. Despite its clinical importance, the mechanisms underlying asthma relapse remain poorly understood, and effective strategies to prevent exacerbations are still *** acute allergic asthma relapse mouse model was established using ovalbumin sensitization and challenge. Single-cell transcriptomics was employed to investigate the cellular and molecular mechanisms driving asthma relapse. Flow cytometry and gene knockout experiments were conducted to validate the *** successfully established an acute allergic asthma relapse mouse model. Single-cell transcriptomic analysis revealed that T cells and type 2 innate lymphoid cells (ILC2s) are pivotal during asthma relapse, serving as the primary cellular sources of type 2 inflammatory cytokines. Further subcluster analysis identified T-cell subcluster 4 and ILC2 subcluster 0 as the predominant contributors to type 2 cytokine production. Complex intercellular communication networks were observed, with macrophages, natural killer (NK) cells, and dendritic cells functioning as central signaling hubs. Pseudo-time trajectory analysis highlighted the critical role of ILC2s and the Il1rl1 signaling pathway in asthma relapse. These findings were corroborated by flow cytometry. Il1rl1-deficient mice displayed similar pulmonary inflammation to wild-type mice during the initial asthma episode;however, asthma relapse was significantly attenuated. Mechanistically, Il1rl1 deficiency resulted in a substantial reduction in both the number and functional capacity of *** recurrence of acute allergic asthma is driven, at least in part, by ILC2s through Il1rl1 signaling. Genetic ablation of Il1rl1 significantly suppresses asthma relapse, suggesting that targeting Il1rl1 may represent a novel therapeutic strategy for preventing asthm

关键词： Abdominal metastases   Engineering bacteria   Poloxamer 407   Tumor immunotherapy   Tumor microenvironment  

摘要： BackgroundTumor immunotherapy is one of the most promising strategies in cancer treatment. Specifically, intraperitoneal immunotherapy has emerged as a novel approach for dealing with abdominal metastases. Previously, we developed a genetically engineered strain of Mycobacterium smegmatis (Ms-IL15) that expresses the cytokine interleukin-15 (IL15), demonstrating significant anti-tumor effects after intratumoral injection. However, intratumoral infusion might not be feasible in the case of diffuse abdominal metastases, making intraperitoneal injection a preferred *** this study, we developed a bacterial delivery system by incorporating Ms-IL15 into Poloxamer 407, an injectable thermosensitive hydrogel, for intraperitoneal administration. A murine model of peritoneal metastasis was established, and tumor-bearing mice were administered P407/Ms-IL15 once weekly for two consecutive weeks. The anti-tumor efficacy and alterations in the tumor immune microenvironment were systematically *** injection of this system exhibited a remarkable tumor-suppressive effect, significantly prolonging the survival of treated mice. Flow cytometric analysis of the tumor immune microenvironment revealed enhanced maturation and activation of dendritic cells (DC), an increased proportion of effector memory T cells and Granzyme B, and suppressed macrophage polarization towards the M2 *** findings indicate that a hydrogel-based bacterial delivery system is a safe and effective approach for the treatment of abdominal metastases.

关键词： Celiac disease   Gluten   Genetic factors   Environmental factors   HLA   Non HLA genes  

摘要： IntroductionCeliac disease is an autoimmune disorder characterized by enteropathy and systemic manifestations, triggered by the ingestion of gluten. The incidence of this disease is on the rise. This paper presents an overview of the epidemiology, diagnostic criteria, and pathological aspects of celiac disease. Furthermore, we provide a summary of the key genes associated with this *** this systematic review, a comprehensive search from the years 2000 to 2024 was conducted across major databases such as PubMed, Scopus, and Google Scholar to identify studies related to celiac disease, utilizing relevant keywords. Studies that did not pertain to celiac disease were systematically excluded from *** to a review of 63 studies, celiac disease is an immune mediated disorder that is triggered by the consumption of gluten in genetically predisposed individuals;however intestinal microbiota and genetic influences, significantly contribute to the disease's development. The genetic foundation of celiac disease is robust. Strong associations between this disease and HLA DQ2, DQ8, and over 100 non-HLA genes have been *** disease is rooted in genetic factors. Understanding these genetic underpinnings enhances our comprehension of the disease mechanisms, thereby facilitating the development of novel treatment strategies and preventive interventions.