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关键词： IL-41/Metrnl   Acute lung injury   AMPK/SIRT1 pathway   Apoptosis   Inflammation  

摘要： Introduction: Interleukin-41 (IL-41), also known as Metrnl, is a multifunctional adipokine recognized for its neurotrophic and anti-inflammatory properties that play a significant role in diseases such as sepsis and chronic obstructive pulmonary disease. Despite its crucial biological functions, the mechanisms by which IL-41 mitigates lipopolysaccharide (LPS)-induced acute lung injury (ALI) are not well understood. This study aimed to elucidate the protective effects of IL-41 against LPS-induced inflammation and apoptosis in a murine model and in vitro using bronchial epithelial cells (Beas-2b). Methods: We administered recombinant IL-41 to mice subjected to LPS-induced ALI and observed changes in lung histopathology, inflammation, and apoptosis. Concurrently, Beas-2b cells were transfected with IL-41 constructs, and the role of the AMPK/SIRT1 pathway was investigated using specific inhibitors and agonists. Results: Our results demonstrated that LPS-induced ALI is characterized by increased inflammatory cell chemotaxis in lung lavage fluid, enhanced phosphorylation of NF kappa B p65, and elevated Bax protein expression, coupled with a decrease in IL-41 protein levels. Treatment with recombinant IL-41 effectively mitigated these pathological changes by upregulating AMPK phosphorylation and SIRT1 expression and inhibiting I kappa B/NF kappa B p65 phosphorylation. In cellular assays, overexpression of IL-41 reversed LPS-induced oxidative stress, apoptosis, and the secretion of inflammatory cytokines, whereas suppression of IL-41 or inhibition of AMPK reversed these protective effects. Conclusions: In conclusion, IL-41 exerts significant protective effects against ALI by activating the AMPK/SIRT1 signaling pathway and reducing excessive inflammation and apoptosis. These findings suggest that IL-41 holds promise as a therapeutic target for ALI, potentially allowing for personalized treatments based on serum IL-41 levels.

关键词： Caspase-1 and IL-10   FAI   HOMA-IR   PCOS  

摘要： Introduction:Polycystic Ovary Syndrome (PCOS) is a major health concern for women worldwide, particularly those of childbearing age. PCOS is a common endocrine disorder that has widely known reproductive, metabolic, cardiovascular adverse effects that lead to significant morbidity. There is continued research into the nature of this disorder and still many gaps to fill in the understanding of the exact ways in which PCOS *** and Methods:This study aims to investigate this uncharted horizon of PCOS by analysing the association between serum Caspase-1, IL-10, and biochemical indices relative to insulin resistance (HOMA-IR), hyperandrogenism (FAI), dyslipidemia, and oxidative stress in our female population. It expands on the significance of inflammation and insulin resistance, together with dyslipidemia, in the advancement and signs and symptoms of PCOS. Given the dearth of research that has explored the relationship between Caspase-1 and IL-10 in Indian women with established PCOS, this research preserves a central position. Its goal to improve the knowledge of the disease's inflammatory and metabolic mechanisms and promote biomarkers and therapeutic targets discovery. The preface to this work in emphasizing the desire to contribute to medical science in its capacity to treat disease patients, in arguing that interdisciplinary collaboration between biochemistry, endocrinology, and gynaecology to improve to patient *** Outcome:Our goal is to reveal possible approaches to reduce the impact of PCOS to improve the outcomes of its diagnostic, treatment and preventive methodologies for millions of afflicted women.

关键词： HLA class II   HLA typing   HLA-DQB1*04:108   next-generation sequencing   peptide-binding domain  

摘要： HLA-DQB1*04:108, the first HLA-DQB1*04 allele with Glutamine at residue 52 in the peptide-binding domain.

关键词： biological drugs   clinical remission   drug persistence   inflammatory bowel disease   patient reported outcome  

摘要： BackgroundReal-word comparisons between first-line biologicals in inflammatory bowel disease (IBD) are *** aim of this study is to compare drug persistence and patient reported outcome-2 (PRO-2) remission rates of first-line biological classes [anti-tumor necrosis factor (TNF) agents vs anti-integrin vedolizumab vs IL-12/23 inhibitor ustekinumab] in real life *** level data of 946 adults (588 Crohn's disease and 358 ulcerative colitis) were retrieved from UR-CARE IBD platform. Adjusted drug survival curves using a pooled logistic model and PRO-2 remission rates for each class of biologicals were calculated and *** Crohn's disease, no differences in drug survival were observed for anti-TNF agents vs vedolizumab vs ustekinumab as estimated survival with 95% confidence intervals were 0.81 (0.77-0.84) vs 0.89 (0.82-0.96) vs 0.88 (0.79-0.97) at year 1 and 0.52 (0.46-0.58) vs 0.58 (0.37-0.78) vs 0.58 (0.39-0.77) at year 4. In ulcerative colitis, however, anti-TNF agents had shorter drug survival than vedolizumab with estimated drug survival with 95% confidence intervals 0.60 (0.52-0.67) vs 0.76 (0.67-0.84) at year 1 and 0.37 (0.30-0.44) vs 0.50 (0.36-0.64) at year 4. No differences in PRO-2 remission rates were observed between drug classes in Crohn's disease (P = 0.95), but more patients enjoyed PRO-2 remission in ulcerative colitis treated with anti-TNF agents compared to vedolizumab (94.8 vs 78.9%, P = 0.002).ConclusionOur real-world data suggest similar drug persistence and efficacy of first-line treatments with anti-TNF agents, vedolizumab and ustekinumab in Crohn's disease. In ulcerative colitis, however, drug persistence was higher for vedolizumab compared to anti-TNF agents, but on the cost of lower PRO-2 remission rates.

关键词： autoimmunity   B cell   extrafollicular   germinal center   IL-12   infection  

摘要： Upon activation, B cells undergo either the germinal center (GC) or extrafollicular (EF) response. While GC are known to generate high-affinity memory B cells and long-lived plasma cells, the role of the EF response is less well understood. Initially, it was thought to be limited to that of a source of fast but lower-quality antibodies until the GC can form. However, recent evidence strongly supports the EF response as an important component of the humoral response to infection. EF responses are now also recognized as a source of pathogenic B cells in autoimmune diseases. The EF response itself is dynamic and regulated by pathways that are only recently being uncovered. We have identified that the cytokine IL-12 acts as a molecular switch, enhancing the EF response and suppressing GC through multiple mechanisms. These include direct effects on both B cells themselves and the coordinated differentiation of helper CD4 T cells. Here, we explore this pathway in relation to other recent advancements in our understanding of the EF response's role and highlight areas for future research. A better understanding of how the EF response forms and is regulated is essential for advancing treatments for many disease states.

关键词： NGS   Read length   Sample number   Flow cell  

摘要： Two NGS-based assays, HLA typing (HLA-A, B, C, DRB1/3/4/5, DQA1/B1, DPA1/B1) and chimerism testing (202 single nucleotide polymorphisms) were combined and sequenced together, using the MiSeq V2 reagent kit. The HLA typing library pool (sample number: X, 1.42 nM) and the chimerism library pool (sample number: Y, 1.33 nM) were combined at the volume ratio X:2Y (X + 2Y <= 100). Chimerism MiSeq sample sheets (dual index) were edited to support 150 bp read length and uploaded to the BaseSpace Sequence Hub. After NGS, chimerism FASTQ files were downloaded and analyzed. An HLA typing MiSeq sample sheet was then uploaded to requeue indices for FASTQ file generation. Both the combined and the separate NGS achieved sufficient read numbers, sequence quality, chimerism assay sensitivity of 0.1 %, and comparable test results on clinical samples (HLA typing, N = 44;chimerism genotyping, N = 24, % recipient chimerism, N = 95). Potential benefits and considerations in combining NGS-based tests are discussed.

关键词： HLA-DQB1*04:01:09   nanopore sequencing   new allele  

摘要： HLA-DQB1*04:01:09 has one nucleotide substitution compared to HLA-DQB1*04:01:01:03 at position 759 in exon 4.

摘要： Background:Anti-interleukin (IL)-4Rα monoclonal antibodies (mAb) improve lung function and decrease the number of exacerbations in patients with COPD type (T)2 inflammation. However, the involvement of early innate immune responses underlying these treatment effects is not well known. We sought to understand the effect and mechanisms of IL-4Rα mAb treatment on bronchial epithelial cells (BECs) from COPD patients under T2 inflammatory conditions with and without rhinoviral infection. Methods:Primary BECs from healthy and COPD patients were grown at an air-liquid interface and stimulated with IL-4 or IL-13 cytokines in the presence of IL-4Rα mAb. Cells were infected with human rhinovirus 1B and collected 24 h after infection. Antiviral mediators (, interferons (IFNs) and pattern recognition receptors (PRRs)), as well as chemokine and alarmin expression, were measured by reverse transcriptase quantitative PCR and ELISA. Results:Treatment with IL-4Rα mAb (100 nM) inhibited the eotaxin-3 (CCL26) gene after IL-4/IL-13 induction (p<0.05) in COPD BECs. However, no significant changes in rhinovirus-induced IFN-β, PRRs or thymic stromal lymphopoietin gene responses were observed with IL-4/IL-13 stimulation and IL-4Rα mAb treatment. A significant increase in mucin 5AC gene expression was observed with both IL-4 and IL-13 stimulation, but it was not reduced with IL-4Rα treatment in BECs. Conclusions:Inhibition of IL-4Rα reduced CCL26 levels without affecting antiviral immune responses in BECs from COPD patients. Inhibition of IL-4Rα reduced IL-4/IL-13 signalling without broadly suppressing the immune system, which might suggest that inhibition of the IL-4Rα pathways may prevent COPD exacerbations through reduction of eosinophil chemotaxis.

关键词： apoptosis   DEHP   NF-kB   oxidative stress   TNF-alpha  

摘要： Di (2-ethylhexyl) phthalate (DEHP) is a plasticiser used in plastic products;and it dissolves easily and leaks into the environment. Due to its lipophilic nature, DEHP accumulates in organisms and can bioaccumulate through food chains. The natural flavonoid, like morin hydrate, possesses various pharmacological properties, including anti-inflammatory, antioxidant, and free radical scavenging. The purpose of this study was to investigate the effect of morin hydrate (MH) on kidney function of DEHP-treated mice. To investigate the underlying processes of the proposed objective, DEHP (500 mg/kg) and DEHP, along with MH at doses of 10 and 100 mg/kg, were administered to Swiss albino mice for 14 days. Our results showed that MH treatment improved kidney function by decreasing creatinine and urea levels in DEHP-intoxicated mice. Furthermore, the MH also alleviates DEHP-induced kidney fibrosis and kidney histoarchitecture. DEHP-mediated oxidative stress and stimulated apoptosis in the kidney were also mitigated by MH treatment. The elevated expression of NF-kB/TNF-alpha by the DEHP treatment was also down-regulated by the MH treatment. In addition, the abundance of HSP70 increased in the kidneys after DEHP treatment, and MH treatment also decreased the abundance of HSP70 in the kidneys. In conclusion, DEHP treatment caused kidney toxicity in mice, and MH mitigates the kidney functions via modulating NF-kB/TNF-alpha/oxidative stress/apoptosis pathway. Our findings provide the new findings that MH protects the kidneys from DEHP intoxication, highlighting the potential of MH as a protective treatment for DEHP toxicity and offering hope for future research and treatments.