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关键词： bile acid homeostasis   cholestasis   gut-liver axis   FXR   inflammatory cytokine  

摘要： Background: Intestinal inflammation is a common factor in similar to 70% of patients diagnosed with primary sclerosing cholangitis. The TNF Delta ARE+/- mouse overexpresses TNF alpha and spontaneously develops ileitis after weaning. The aim of this study was to examine the influence of ileitis and TNF alpha overexpression on hepatic injury, fibrosis, inflammation, and bile acid homeostasis. Methods: Using serum, hepatic, and ileal tissue isolated from 24- to 26-week-old C57BL/6 and TNF Delta ARE+/- mice, hepatic injury and fibrosis, inflammation, ductal proliferation, and regulation of bile acid synthesis were assessed by immunohistochemical and quantitative PCR methods. Results: Compared to age-matched C57BL/6mice, TNF Delta ARE+/- mice exhibited increased serum AST, ALT, and serum bile acids, which corresponded to increased hepatic picrosirius red staining, and an increase in hepatic mRNA expression of Tgfb, Timp1, Col1a1, and MMP9 supporting induction of fibrosis. Examining inflammation, immunohistochemical staining revealed a significant periportal increase in MPO+ neutrophils, CD3+ lymphocytes, and a panlobular increase in F4/80+ macrophages. Importantly, periportal inflammation corresponded to significantly increased proinflammatory chemokines as well as hepatic cytokeratin 7 staining supporting increased ductular proliferation. In the liver, increased mRNA expression of bile acid transporters was associated with suppression of classical but not alternative bile acid synthesis. In the ileum, increased inflammation correlated with suppression of Nr1h4 and increased Fgf15 and Nr0b2 mRNA expression. Conclusions: Increased TNF alpha expression is sufficient to promote both intestinal and hepatobiliary inflammation and fibrotic injury and contributes to hepatic dysregulation of FXR signaling and bile acid homeostasis. Overall, these results suggest that the TNF Delta ARE+/- mouse may be a useful model for studying chronic hepatic inflammation.

关键词： Intracerebral hemorrhage   Neuronal apoptosis   Sphingosine-1-phosphate receptor 3   TNF-alpha   Caspase-3  

摘要： Background: Intracerebral hemorrhage (ICH) has a high incidence and mortality rate among cerebrovascular diseases, and effective treatments are lacking. Sphingosine-1-phosphate receptor 3 (S1PR3) is associated with secondary immune inflammatory injury following ICH. However, its relationship with neuronal apoptosis and the specific underlying mechanism are not clear. Methods: We observed the effect of S1PR3 on neuronal apoptosis by assessing neurobehavioral scores, performing Western blot (WB) analysis, and performing TUNEL staining in a mouse model of ICH. Moreover, WBs and flow cytometry were used to study the specific mechanism and signaling pathways in HT22 cells in vitro. Results: The expression of S1PR3, CCL2, TNF-alpha, and cleaved-caspase-3 (c-caspase-3) and neuronal apoptosis were significantly increased after ICH, accompanied by neurobehavioral deterioration. These effects were significantly improved by treatment with CAY10444, a specific S1PR3 antagonist. After S1P stimulation of HT22 cells, the expression of S1PR3, CCL2, TNF-alpha and c-caspase-3 increased, and neuronal apoptosis increased by activating caspase-3 through the downstream PI3K/AKT apoptosis signaling pathway. After CAY10444 treatment, the expression of CCL2, TNF-alpha and c-caspase-3 was significantly reduced, and the PI3K/AKT apoptotic signaling pathway was regulated to reduce neuronal apoptosis. Conclusion: An increase in S1P/S1PR3 after ICH may induce neuronal apoptosis by increasing TNF-alpha expression and activating the PI3K/AKT signaling pathway and the expression of caspase-3 effector proteins. CAY10444 can reduce neuronal apoptosis, improve symptoms and play a neuroprotective role by antagonizing S1PR3. S1PR3 may be a promising therapeutic target.

关键词： Uveitis   Children   Pediatric rheumatology   Anti-TNF   Anti-IL6   Anti-CTLA4   Jak-inhibitors   Adalimumab   Infliximab   Tocilizumab   Golimumab   Abatacept   Rituximab   Eye   Treatment   Therapy  

摘要： Objective: Since adalimumab approval in childhood chronic non-infectious uveitis (cNIU), the prognosis has been dramatically changed, but the 25 % failed to achieve inactivity. There is not accordance if it is better to switch to another anti-TNF or to swap to another category of biologic. Thus, we aim to summarize evidence regarding the best treatment of cNIU refractory to the first anti-TNF. Methods: A systematic literature review and meta-analysis, according to PRISMA Guidelines, was performed(Jan2000-Aug2023). Studies investigating the efficacy of treatment in cNIU refractory to the first anti-TNF were considered for inclusion. The primary outcome was the improvement of intraocular inflammation according to SUN. A combined estimation of the proportion of children responding to switch or swap and for each drug was performed. Results: 23 articles were eligible, reporting 150 children of whom 109 switched anti-TNF (45 adalimumab, 49 infliximab, 9 golimumab) and 41 swapped to another biologics (31 abatacept, 8 tocilizumab and 1 rituximab). The proportion of responding children was 46 %(95 % CI 23-70) for switch and 38 %(95 % CI 8-73) for swap (chi(2)0.02, p = 0.86). Instead analysing for each drug, the proportion of responding children was the 24 %(95 % CI 2-55) for adalimumab, 43 %(95 % CI 2-80) for abatacept, 79 %(95 % CI 61-93) for infliximab, 56 %(95 % CI 14-95) for golimumab and 96 %(95 % CI 58-100) for tocilizumab. We evaluated a superiority of tocilizumab and infliximab compared to the other drugs(chi(2) 27.5 p < 0.0001). Conclusion: Although non-conclusive, this meta-analysis suggests that, after the first anti-TNF failure, tocilizumab and infliximab are the best available treatment for the management of cNIU.

关键词： DSA   histocompatibility typing   HLA   kidney transplantation   next generation sequencing  

摘要： HLA-compatibility remains an important triage test for deceased donor kidney allocation. Low-intermediate resolution donor HLA-typing is typically available at allocation, but its accuracy in assigning pre-transplant donor-specific anti-HLA antibody (DSA) and HLA mismatches compared to 2-field high-resolution typing is poorly characterised. Consecutive deceased donor/recipient pairs from a single centre between 2016 and 2020 were included. Majority of donor typing at HLA-ABDRB1 loci were performed at low-intermediate resolution, with 2-field high-resolution NGS typing across extended loci performed by NGS-technique post-transplantation. We compared the two typing methods for (1) accuracy of pre-transplant DSA assignment;(2) misassignment of HLA-antigen/allele mismatches and performance of each model for acute rejection and (3) proportion of recipients who developed de novo DSA (dnDSA) when matched at antigen but mismatched at allele level. Of 179 deceased donor/recipient pairs, 157 donors had low-intermediate resolution typing and 22 with high-resolution ONT typing. Sixty-two recipients (35%) had potential pre-transplant DSAs, with incorrect assignment of allele-specific Class I and II actual DSAs in 31% and 53% of cases, respectively. NGS typing identified 59 (33%) additional HLA-DRB1 allele mismatches. ONT typing accurately assigned pre-transplant DSAs and allele mismatches in all cases. Seven (4%) recipients with antigen/allele level discordance developed dnDSAs, majority HLA-DQ antibodies. Two-field high-resolution donor HLA typing may provide a more accurate transplant immunological risk assessment and identify those at risk of developing dnDSA to matched HLA antigen.

关键词： Dermatophytosis   T. rubrum   TNF-alpha   IL-10   Immune response  

摘要： Dermatophytosis is a very common superficial mycosis, but there are few studies about the human immune response to dermatophytes. We aim to analyze the in situ expression of TNF-alpha and IL-10 in human dermatophytosis. Expression of TNF-alpha and IL-10 were evaluated in skin samples from 10 patients with dermatophytosis and 12 healthy subjects using an immunohistochemistry assay. TNF-alpha and IL-10 were significantly elevated in lesions from patients with dermatophytosis compared to healthy controls. These data illustrate the balance of pro- and anti-inflammatory cytokines suggesting Trichophyton rubrum infection could control the local immune response.

关键词： rheumatoid arthritis   collagen-induced arthritis   IL-37a   cytokines   Th17 cells   Treg cells  

摘要： Cytokines play a complex and pivotal role in modulating synovitis in rheumatoid arthritis. Interleukin (IL)-37 is known for its extensive anti-inflammatory properties that set it apart from the majority of other IL-1 family members. However, IL-37a, a member of the IL-37 family, lacks research into rheumatoid arthritis. This research aims to explore the role of IL-37a in regulating T-cell homeostasis in rheumatoid arthritis using the Collagen-Induced Arthritis(CIA) model. IL-37atg mice, a genetically altered strain carrying the human IL-37a gene, were used to test the influence of this cytokine on the progression of arthritis. The results show that IL-37atg mice demonstrated a notable reduction in both the incidence and severity of arthritis relative to WT mice. The protective effect was accompanied by lower levels of cytokines in plasma and synovial tissues (such as IL-17A and IL1 beta) that drive the inflammatory response. The ratio of Th17/Treg decreased in the lymph nodes of IL-37atg mice. However, the knockout of IL1R8 in IL37atg mice eliminated the effects of IL-37a. Additionally, transcriptomic analysis revealed that Th17 cell differentiation is a key pathway through which IL-37a exerts its protective effects, and experiments confirmed that IL-37a suppresses Th17-polarizing in vitro.

关键词： TMEM2   TLR3   CXCL10   IFN-beta   ISG56   Hyaluronan  

摘要： Background Bronchial epithelial cells are at the front line of viral infections. Toll-like receptor 3 (TLR3) cascade causes the expression of interferon (IFN)-beta and IFN-stimulated genes (ISGs), which in turn induce an antiviral response. Members of the transmembrane protein (TMEM) family are expressed in various cell types. Although the prognostic value of TMEM2 in various cancers has been reported, its association with infectious diseases remains unknown. In this study, we investigated the effects of TMEM2 on antiviral immunity in BEAS-2B bronchial epithelial cells. Methods and results TMEM2 protein was found in the cytoplasm of normal human bronchial epithelial cells and differed between organs using immunohistochemistry. Cultured BEAS-2B cells were transfected with TMEM2 siRNA, followed by administration of TLR3 ligand polyinosinic-polycytidylic acid (poly IC) or recombinant human (r(h)) IFN-beta. The expression of TMEM2, IFN-beta, ISG56, C-X-C motif chemokine ligand 10 (CXCL10) and hyaluronan were evaluated appropriately by western blotting, quantitative reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. TMEM2 expression was not altered by poly IC stimulation. Knockdown of TMEM2 increased poly IC-induced expression of IFN-beta, CXCL10, and ISG56, while IFN-beta-induced expression of ISG56 and CXCL10 were not changed by TMEM2 knockdown. The hyaluronan concentration in the medium was decreased by either TMEM2 knockdown or poly IC, but additive or synergistic effects were not observed. Conclusions TMEM2 knockdown enhanced TLR3-mediated IFN-beta, CXCL10, and ISG56 expression in BEAS-2B cells. This implies that TMEM2 suppresses antiviral immune responses and prevents tissue injury in bronchial epithelial cells.

关键词： Neutrophil gelatinase-associated lipocalin   Treatment response   Inflammation   Schizophrenia   Interferon-gamma   Clinical outcomes  

摘要： Background: Early prediction of treatment efficacy can assist psychiatrists in optimizing personalized treatment strategies for drug-na & iuml;ve schizophrenia patients. This study aimed to explore the predictive value of plasma concentrations of Interferon-gamma (IFN-gamma) and Neutrophil gelatinase-associated lipocalin (NGAL) in early treatment responses. Methods: We conducted a longitudinal study involving 125 drug-na & iuml;ve schizophrenia patients and 75 healthy controls. Plasma samples were collected and analyzed at baseline and after 8 weeks of treatment. Based on treatment outcomes, patients were classified as Responders (R, n = 84) or Non-responders (NR, n = 41). Results: At baseline, schizophrenia patients showed significantly lower IFN-gamma and NGAL concentrations compared to healthy controls. NGAL levels were notably lower in the NR group compared to the R group. After treatment, both IFN-gamma and NGAL concentrations increased in all patients, with a marked rise in IFN-gamma levels. NGAL concentration negatively correlated with the positive factor at baseline, adjusting for confounders such as age, BMI, smoking, and duration of untreated illness. Logistic regression analysis identified lower baseline NGAL concentrations as a predictor of poor early treatment response. Conclusion: Pre-treatment plasma NGAL concentrations may serve as a potential biomarker for predicting early treatment response in drug-na & iuml;ve Chinese Han schizophrenia patients. These findings highlight NGAL as a possible target for future therapeutic development in schizophrenia.

关键词： TIDM   Pro-inflammatory cytokines   IL-6   TNF   miRNA-34   miRNA-14   Pathogenesis  

摘要： Background: Type I diabetes mellitus (T1DM) is one of the most common chronic autoimmune diseases worldwide. miRNAs are a class of small non-coding RNA molecules that have been linked to immune system functions, beta-cell metabolism, proliferation, and death, all of which contribute to pathogenesis of TIDM. Dysregulated miRNAs have been identified in Egyptian TIDM patients. Aim: Several miRNAs were profiled in Egyptian TIDM patients to determine whether they can be used as molecular biomarkers for T1DM. The relationship between the investigated miRNAs and pro-inflammatory cytokines (TNF-alpha and IL-6) has also been evaluated in the development of TIDM, in addition to the creation of a proposed model for TIDM prediction. Patients & methods: Case-control study included 177 Egyptian patients with confirmed type I diabetes mellitus and 177 healthy individuals. MiRNA-34 and miRNA-146 were detected in serum samples using real-time PCR, whereas TNF-alpha and IL-6 levels were assessed using ELIZA. Results: Patients with TIDM showed a significant decrease in the expression of miRNA-146, with a cut-off value <= 3.3, 48 % specificity, and 92.1 % sensitivity, whereas miRNA-34 had the highest sensitivity (95.5 %) and specificity (97.2 %) for differentiating diabetic patients from controls. Furthermore, other diagnostic proinflammatory markers showed lower sensitivity and specificity. Conclusion: Serum levels of miRNA-34a, miRNA-146, IL-6, and TNF-alpha provide new insights into T1DM pathogenesis and could be used for screening and diagnosis purposes. They can be also a potential therapeutic target, as well as allowing for more strategies to improve T1DM disease outcomes.

关键词： CD47-SLAMF7   glioma   mesenchymal stem cells  

摘要： High expression of cellular self-activated immunosuppressive molecules and extensive infiltration of suppressive immune cells in the tumor microenvironment are the main factors contributing to glioma's resistance to immunotherapy. Nonetheless, technology to modify the expression of glioma cellular self-molecules through gene editing requires further development. This project advances cell therapy strategies to reverse the immunosuppressive microenvironment of glioma (TIME). Bone marrow-derived mesenchymal stem cells (MSCs) are engineered to express bioactive proteins and demonstrate tumor-homing characteristics upon activation by TGF-beta. These MSCs are designed to secrete the anti-tumor immune cytokine IL-12 and the nCD47-SLAMF7 fusion protein, which regulates T-cell activity and macrophage phagocytosis. The engineered MSCs are then injected in situ into the glioma site, circumventing the blood-brain barrier to deliver high local concentrations of bioactive proteins. This approach aims to enhance the M1 polarization of infiltrating macrophages, stimulate macrophage-mediated tumor cell phagocytosis, activate antigen-presenting cells, and promote effector CD8+ T cell infiltration, effectively controlling glioma. Additionally, the engineered MSCs may serve as a universal treatment for other tumors that express TGF-beta at high levels. This study proposes a novel treatment strategy for the clinical management of glioma patients. High expression of cellular self-activated immunosuppressive molecules and extensive infiltration of suppressive immune cells in the tumor microenvironment are the main factors leading to the resistance of glioma to immunotherapy. This study constructed engineering MSCs expressing IL-12 and nCD47-SLAMF7 (anti-CD47 nanobody combined with the extracellular domain of SLAMF7). Intracranial injection of these two kinds of engineered MSCs could promote M1 polarization of infiltrating macrophages, phagocytosis of tumor cells by macrophages and antige