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关键词： HLA-B genes   Tumor necrosis factor inhibitors   Tuberculosis  

摘要： In this study, we aimed to evaluate HLA-B subtypes in cases developing TB while using anti-TNF agents and to compare with the HLA-B subtypes of three different groups including community-acquired TB cases, anti-TNF patients without TB and healthy controls. The study consisted of four groups. Group 1: 35 community-acquired TB patients, group 2;47 anti-TNF-TB patients, group 3;61 anti-TNF (non TB) patients and group 4;40 healthy controls. HLA-B subgroups were studied genetically from blood samples taken from the patients. Approval was received from the ethics committee. HLA-B typing was performed by using the LIFECODES HLA-B eRES SSO Typing SSO typing kit (Immucor, Stamford, CT, USA). Among HLA-B subtypes, significant differences between the four groups were found only for HLA-B5, HLA-B8, HLA-B27 and HLA-B38. Although frequency of HLA-B8 was highest in patients developing TB during anti-TNF treatment, significance was lost after Bonferoni correction. HLA-B27 was significantly higher in both anti-TNF groups, with and without TB, due to presence of patients with ankylosing spondylitis in those groups. To our knowledge, this is the first study analyzing HLA-B subtypes in anti-TNF patients developing TB. Although in literature HLA-B8 positivity was suggested to associate with or to confer a risk for community-acquired TB, we could not confirm this association in anti-TNF patients developing TB. However, further studies with larger number of patients from different ethnic groups are clearly needed to get the final word in this topic.

关键词： Alcohol-derived acetaldehyde   Alveolar macrophages   EcoHIV   Lung injury   People living with HIV  

摘要： Approximately 50% of people living with HIV (PWH) in the United States misuse alcohol, and they are at increased risk of chronic lung inflammation despite antiretroviral therapy. Acetaldehyde, a metabolite of alcohol, circulates systemically and directly impacts alveolar macrophages (AMs), the primary reservoir of HIV in the lungs. Acetaldehyde promotes AM HIV replication and triggers interleukin (IL)-1β release. We explored the mechanisms by which alcohol-derived acetaldehyde drives HIV replication and IL-1β release in AMs. Further, we tested if the transcription factor peroxisome proliferator-activated receptor (PPAR)γ agonist, pioglitazone, attenuates AM HIV replication and IL-1β release. Primary mouse AMs (mAMs), MH-S cells (an AM cell line), and THP-1 (human monocyte cell line)-derived macrophages were treated with alcohol-derived acetaldehyde (acetaldehyde generating system, AGS), HIV 1, and EcoHIV, a chimeric HIV that infects murine cells. HIV expression was confirmed by HIV gag RNA (qRT-PCR) and p24 release (ELISA). IL-1β was measured by qRT-PCR and ELISA. Extracellular hydrogen peroxide (HO) release was quantified by Amplex Red assay. Further, immunoblot analysis of ERK1/2, PPARγ, and nuclear factor (NF)-ĸB/p65 (p65) was used to identify how acetaldehyde potentiates HIV replication and IL-1β activation in AMs. AGS increased HO, leading to ERK1/2 phosphorylation, which deactivated PPARγ. AGS drove nuclear p65 translocation in HIV-infected cells, which enhanced HIV replication and IL-1β release. Treatment with pioglitazone decreased nuclear p65, attenuating AGS-induced HIV replication and IL-1β activation in AMs. We identified mechanisms underlying acetaldehyde-induced inflammatory activation and potentiation of HIV replication in AMs, which could be therapeutically targeted with pioglitazone to decrease HIV-related respiratory comorbidities among PWH who misuse alcohol.

关键词： TGF-beta   mast cells   secretion   CCL-2   TNF  

摘要： TGF-beta is a pleiotropic cytokine with both stimulatory and inhibitory effects on immune cells, depending on the microenvironmental context. It targets mast cells (MCs) in different physio-pathological conditions, such as inflammation and cancer. Besides acting as a potent chemoattractant for MCs, TGF-beta regulates many other aspects of MCs' physiology, including the secretion of many regulatory molecules. MCs secrete a variety of mediators, either pre-formed or newly synthesized, upon appropriate stimulation. CCL-2 chemokine and TNF cytokine act as potent chemoattractants for several immune cells and participate in the initiation of inflammatory responses by recruiting them to injured tissues. TGF-beta regulates CCL-2 and TNF secretion in different cell types and under distinct cellular contexts. Here, we report that the treatment with TGF-beta alone induces the secretion of both pre-formed and newly synthesized CCL-2 in the rat RBL-2H3 mast cells but not in mouse bone marrow-derived mast cells (BMMCs). TGF-beta-induced CCL-2 secretion depends on rapid rearrangements of the actin cytoskeleton and, remarkably, on the early secretion of soluble TNF that triggers an autocrine TNF signaling. In conclusion, we found cooperation between TGF-beta and TNF signaling pathways to promote the secretion of CCL-2 chemokine by MCs in a cell-context specific manner.

关键词： Astragalus membranaceus   flavonol glycosides   anti-skin-aging   antioxidant   anti-inflammation  

摘要： The present study investigates the anti-skin-aging properties and bioactive compounds of the aerial parts of Astragalus membranaceus, which are typically discarded as agricultural waste. Liquid chromatography-mass spectrometry analysis identified flavonoid glycosides as the major constituents of the aerial parts of A. membranaceus extract. Two principal flavonoids, astraflavonoid A (1) and astraside C (2), were isolated using repetitive chromatography. Compounds 1 and 2 demonstrated antioxidative properties, reducing reactive oxygen species and matrix metalloproteinase-1 levels in human dermal fibroblasts upon stimulation with TNF-alpha. Specifically, astraside C (2) inhibited the expression of pro-inflammatory cytokines interleukin-6 and interleukin-8, whereas astraflavonoid A (1) did not affect their expression. Additionally, the expression of inflammatory mediators such as nuclear factor kappa B and cyclooxygenase-2 (COX-2) was increased by 1, whereas it was suppressed by 2. Furthermore, in silico molecular docking experiments confirmed that compound 2 effectively binds to COX-2. These findings suggest that the aerial parts of A. membranaceus contain bioactive flavonol glycosides with promising anti-skin-aging properties, offering valuable use as agricultural byproducts.

关键词： RDW   Gal-3   NLR   冠心病   心房颤动   检测价值  

摘要： 目的:探讨红细胞分布宽度(RDW)、半乳糖凝集素-3(Gal-3)、中性粒细胞/淋巴细胞比值(NLR)与冠心病并发房颤的关联性及其联合检测价值.方法:选取 2019 年 5 月至 2021 年 9 月于本院就诊的 185 例冠心病患者作为研究对象.依据冠状动脉旁路移植术后是否出现房颤,将其分为房颤组(n=73,冠心病并发房颤)和非房颤组(n=112,冠心病未并发房颤).比较两组患者RDW、Gal-3、NLR水平及其与房颤类型、心房纤维化程度的关系,分析RDW、Gal-3、NLR与冠心病并发房颤的相关性及其联合检测价值.结果:房颤组患者的RDW、Gal-3、中性粒细胞以及NLR水平均高于非房颤组,差异均有统计学意义(P＜0.05);房颤组患者中,阵发性房颤亚型患者的RDW、Gal-3、中性粒细胞以及NLR水平低于持续性/长程持续性/永久性房颤,差异均有统计学意义(P＜0.05);高纤维化房颤患者的RDW、Gal-3、中性粒细胞以及NLR水平均高于低纤维化房颤患者,差异均有统计学意义(P＜0.05);RDW、Gal-3、NLR水平与持续性/长程持续性/永久性房颤、心房高纤维化呈正相关(P＜0.05);RDW、Gal-3、NLR联合检测冠心病患者并发房颤的曲线下面积、敏感度、特异度分别为 0.849、0.83、0.76,均高于各指标单独检测.结论:RDW、Gal-3、NLR与房颤类型、心房纤维化程度有关,在患者早期诊断中具有较高应用价值.

关键词： HS   IL-17   biologics   hidradenitis suppurativa   inflammation   treatment.  

关键词： Autoimmunity   Tolerance   Autoimmunity   Tolerance  

摘要： Recent studies have highlighted the role of the thymus in maintaining immune tolerance to type 1 interferons (T1 IFNs). Individuals with thymic abnormalities, such as autoimmune regulator (AIRE) gene mutations, frequently develop neutralizing autoantibodies to interferon-alpha (IFN alpha). Unlike mice, Aire-deficient rats develop robust autoantibodies to IFN alpha. Using this rat model, we show that Aire regulates the thymic expression of interferon-stimulated genes (ISGs), which occurs before developing anti-IFN alpha autoantibodies. In the periphery, we observed a widespread downregulation of ISGs across immune cells and reduced activation of natural killer (NK) cells. Furthermore, the presence of anti-IFN alpha autoantibodies correlated with reduced peripheral tissue inflammation, suggesting their role in dampening T1 IFN signaling and minimizing tissue infiltration. Our findings reveal that Aire-mediated regulation of thymic T1 IFN signaling is linked to the production of protective anti-IFN alpha autoantibodies, which inversely correlate with autoimmune pathology in peripheral tissues.

摘要： Questa rassegna analizza l’impatto dell’obesità sulla fertilità maschile, evidenziando come l’eccesso di tessuto adiposo alteri l’asse ormonale e la spermatogenesi, riducendo la qualità seminale. Di contro, la perdita di peso, in particolare ottenuta mediante modifiche dietetiche mirate e diete ipocaloriche, può migliorare i parametri seminali. Risultato in parte sovrapponibile, ma in parte da confermare, si ottiene considerando gli effetti della chirurgia bariatrica e dei farmaci utilizzati per ottenere il calo ponderale sulla fertilità maschile. La gestione del peso emerge, pertanto, come un elemento fondamentale nel trattamento dell’infertilità maschile.

关键词： asthma   bronchial epithelial cells   IL-4   IL-13   IL-4R alpha mAb   CCL26   IFNs   alarmins  

摘要： Introduction Severe asthma is a heterogeneous condition characterized by distinct phenotypes and endotypes based on clinical or biological characteristics. Interleukin (IL) 4 and IL-13 are central cytokines in the type 2 (T2) immune response, crucial for T2 inflammation. Biologic therapies targeting the IL-4/IL-13 pathway, such as anti-IL-4R alpha monoclonal antibodies (mAbs), have shown improvements in lung function and reductions in exacerbation rates for severe asthma. However, the precise role of early innate immune responses in mediating these therapeutic benefits remains unclear. This study investigates the acute and chronic effects of T2 cytokines on healthy and asthmatic bronchial epithelial cells (BECs), addressing the mechanisms underlying IL-4R alpha mAb therapy in acute T2-driven inflammatory conditions and rhinoviral infection in asthma *** Human BECs from healthy and asthma donors were cultured at the air-liquid interface (ALI) and stimulated with IL-4 and IL-13, acutely or chronically, with or without IL-4R alpha mAb, followed by rhinovirus (RV) infection. Cells were harvested 24 h post-infection. Expression levels of chemokines, alarmins, and antiviral mediators were quantified using RT-qPCR and multiplex *** CCL26 expression increased in response to IL-4 or IL-13 in healthy and asthmatic BECs, and this effect was significantly more pronounced in asthmatic BECs. IL-4R alpha mAb treatment effectively inhibited CCL26 production in BECs from asthma patients. IL-4 and RV infection induced a significant increase in thymic stromal lymphopoietin (TSLP) levels in BECs from asthma compared with healthy, which was normalized by IL-4R alpha mAb. No significant effects of T2 cytokines on alarmins were observed in healthy BECs. Chronic exposure to T2 cytokines following RV infection significantly decreased TSLP and IFN lambda 1 but increased IFN beta, specifically in asthmatic *** Our study on T2 cytokines' effects on BECs reveals

摘要： Abatacept reduces the risk of acute graft versus host disease (GVHD) in matched unrelated donor hematopoietic stem cell transplant (HSCT) for Sickle Cell Disease (SCD). We conducted a retrospective review of patients who underwent matched sibling donor (MSD) HSCT for SCD with and without adding abatacept to standard acute GVHD prophylaxis. Twenty-one patients, median age 7 years (range 2.0-14.8) received MSD HSCT with addition of 4 doses of abatacept to standard calcineurin inhibitor based acute GVHD prophylaxis while six patients, median age 9.8 years (range 1.9-14.4) underwent MSD HSCT with standard prophylaxis. One patient (4.5%) in the abatacept group developed grade II acute skin GVHD, while 3 patients (50%) in standard group developed grade II-III acute skin and gut GVHD (p = 0.022). Grade III-IV GVHD was 0% in abatacept group compared to 33% in standard group (p = 0.043). Disease-free survival was 83% in standard group at a median follow up of 11 years (IQR:9.5-13.25 years), and 100% in the abatacept group at a median follow up of 5 years (IQR:3-8 years). Our data show that addition of abatacept to calcineurin inhibitor based acute GVHD prophylaxis reduces the risk of severe acute GVHD in patients with SCD undergoing MSD HSCT without impacting disease-free survival.