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关键词： Metrnl   autoimmune disease   biomarker   multi-omics   bone metabolism  

摘要： Background Ankylosing spondylitis (AS) is an autoimmune disease characterized by bone destruction and abnormal remodeling. Metrnl, a secreted protein involved in inflammation and immune regulation, has recently been linked to bone growth. This study aimed to evaluate serum Metrnl levels in AS patients and explore its bone regulatory mechanisms using cell models and multi-omics *** A total of 275 participants aged 16-60 years were included to measure serum Metrnl levels using Enzyme-Linked-Immunosorbent Assay (ELISA). Correlation and receiver operating characteristic (ROC) curve analyses assessed the diagnostic and predictive value of Metrnl. Mouse pre-osteoblastic MC3T3-E1 cells were treated with recombinant Metrnl (0/10/50 ng/mL) during 28-day osteogenic differentiation. RT-qPCR and alkaline phosphatase (ALP)/Alizarin Red S (ARS) staining was used to evaluate direct osteogenic differentiation effects. Transcriptomic and proteomic studies were conducted to further explore bone metabolism mechanisms. Finally, multi-omics integration analyses identified key pathways and *** Elevated serum Metrnl levels correlated directly with disease activity markers (CRP, ESR, IL-6) in AS-Active patients, but not in AS-Stable patients. ROC analysis validated Metrnl as a potential auxiliary diagnostic biomarker for high disease activity. In vitro, Metrnl suppressed ALP/OCN expression without altering overall osteogenic differentiation. Transcriptomic and proteomic analyses revealed Metrnl's regulatory effects on osteogenic genes and proteins, emphasizing its role in bone and cartilage development. Bioinformatics highlighted Metrnl's inhibition of endochondral ossification, delaying cartilage development and promoting osteoclast differentiation. Multi-omics integration identified Aspn and Sp7 as key targets in bone remodeling and resorption *** Metrnl may serve as an additional diagnostic biomarker for AS and as an indicator for monitoring AS d

关键词： butyrate   colorectal cancer   colorectal homeostasis   EP4 receptors   IBD   interleukin-4   prostaglandin E-2  

摘要： In this article, onset mechanisms of colorectal cancer and intestinal bowel diseases (IBD) are postulated to involve the aberrant expression/hyper-activation of E-type prostanoid 4 (EP4) receptors. Although prostaglandin E-2 and EP4 receptors are important factors for maintaining colorectal homeostasis, their mediated signaling is also considered to be involved in the etiology of severe intestinal diseases. To prevent uncontrollable activations of EP4 receptors, two safety factors are proposed: butyrate as an external safety factor and interleukin (IL)-4 as an internal safety factor. Thus, for maintaining vulnerable colorectal homeostasis, the levels of EP4 receptors, butyrate, and IL-4 are proposed as an important triad for protecting against development/onset risks of, at least, EP4 receptor-mediated cancer and IBD.

关键词： Asthma   Benralizumab   Mepolizumab   Omalizumab   Transcriptomics  

关键词： gestational diabetes mellitus   HLA-DQA1/DQB1   risk   variant   gene-gene interaction  

摘要： Background: Gestational diabetes mellitus (GDM) is an endocrine disorder that occurs easily in women during pregnancy. HLA-DQA1/DQB1 genes play a crucial role in the regulation of the human immune and endocrine systems, potentially influencing the pathogenesis of GDM. Objective: To explore the associations between single nucleotide polymorphisms (SNPs) in HLA-DQA1/DQB1 genes and the risk of GDM. Methods: Seven functional SNPs of HLA-DQA1/DQB1 genes were selected and genotyped in 523 GDM patients and 638 normal pregnant women. The odds ratio (OR) and its corresponding 95% confidence interval (CI) were utilized to assess the association between candidate SNPs and the risk of GDM. And then, false positive report probability (FPRP), multifactor dimensionality reduction (MDR) and haplotype analysis were employed to validate the statistically significant associations between studied SNPs and GDM risk. Results: Compared to those with 0-1 risk genotypes, individuals with 2-7 unfavorable genotypes presented an increased risk of GDM (adjusted OR = 1.54, 95% CI=1.04-2.28, P=0.033). A dose- accumulation effect was detected between the number of unfavorable genotypes and GDM risk (P-trend=0.024). Furthermore, stratified analysis revealed that the increased GDM risk was more likely to occur in individuals with higher blood pressure and TG, and lower HDL-c levels (P<0.05). Multifactor dimensionality reduction (MDR) analysis revealed that rs9274666 was the best single locus model, whereas the 7-loci model was the best multifactor interaction model for predicting GDM risk (chi(2)=134.28, P<0.0001). Finally, haplotype analysis revealed that the ACGAGTA and ACGGATA haplotypes were significantly associated with the increased GDM risk. HLA-DQA1/DQB1 SNPs can significantly alter individuals' genetic susceptibility to GDM. Conclusions: The genetic variations in the HLA-DQA1 and HLA-DQB1 genes may collectively contribute to the susceptibility to gestational diabetes mellitus. These finding

关键词： experimental cerebral malaria   macrophages   malaria   microglia   nitric oxide   IL-1 beta   iNOS   TNF  

摘要： Microglia play a fundamental role in maintaining central nervous system homeostasis by monitoring brain tissue for physical, structural, and biochemical alterations. Its involvement in the pathogenesis of various neurological disorders is well documented. However, the role of microglia in cerebral malaria, a disease associated with high mortality and long-term neurological sequelae, remains poorly understood. In this study, we utilized the classical model of experimental cerebral malaria (Plasmodium berghei ANKA-infected C57BL/6 mice) to investigate the dynamics and response of resident brain cell populations, particularly microglia, and the influx of other leukocytes during the development of experimental cerebral malaria. By employing flow cytometry and established markers for different leukocyte populations, we were able to discern and document an increase in the number of Ly6C+ T cells (CD45hiCD11b-CD3+ cells), inflammatory monocytes (CD45hiCD11b+TMEM119-CD206- cells), resident macrophages (CD45hiCD11b+TMEM119-CD206+ cells), and microglia (CD45lowCD11b+ TMEM119+CD206- cells) following infection. Moreover, our ex vivo analysis demonstrated an increment in the overall number of inflammatory monocytes, resident macrophages and microglia expressing inducible nitric oxide synthase (iNOS), in addition to those producing interleukin-1 beta or TNF. These findings highlight the pronounced reactivity of microglia in experimental cerebral malaria and provide valuable information on cell dynamics and immune responses in the brain.

关键词： allogeneic hematopoietic stem cell transplant   GvHD   reduced- dose post-transplant cyclophosphamide   toxicity  

摘要： Objective This retrospective, single-center study aims to compare the efficacy and safety of a reduced dose of post-transplantation cyclophosphamide (PTCy) (60 mg/kg total dose) versus the standard dose (100 mg/kg total dose), both combined with tacrolimus, in adult patients undergoing allogeneic hematopoietic stem cell transplantation from HLA-matched related or unrelated donors. Methods We report clinical outcomes of 59 consecutive patients who received standard doses of PTCy and 48 with the new reduced dose. Results Neutrophil and platelet recovery occurred later in the standard-dose group (p < 0.01). The incidence of febrile neutropenia was higher in the standard-dose group (p < 0.01). No significant differences were found in the incidence of acute cardiac events, early bacteremia, CMV reactivation within the first 100 days post-HSCT, or the development of hemorrhagic cystitis. There were no significant differences in the incidence of grade II-IV and III-IV acute GvHD, moderate-to-severe chronic GvHD, or in 20-month overall survival and progression-free survival (p > 0.05). Non-relapse mortality at 100 days and at 1 year was comparable between groups, as was 1-year GVHD-free/relapse-free and immunosuppression-free survival (p > 0.05). Conclusions Reduced doses of CyPT combined with a single immunosuppressive agent are emerging as a safe and effective alternative for adult patients undergoing allo-HSCT from HLA-matched donors. Our findings support that this approach preserves key clinical outcomes while potentially reducing acute hematological and infectious toxicity.

关键词： Ligand binding assay   ELISA   singlicate vs. duplicate analysis   mouse model   NHP model  

摘要： BackgroundThe use of duplicate analysis in biomarker assays is a standard practice. While it does not inherently increase variability or contribute to assay failure, it can reveal the high variability associated with manual pipetting, thereby highlighting potential issues within the *** design and methodsThis study evaluated the reliability of singlicate analysis compared to duplicate analysis for interferon-gamma (IFN-gamma) assays using ELISA in mouse and non-human primate (NHP) serum samples. Assay performance was assessed across 50 plates, with results analyzed for minimum required dilution (MRD), standard curve linearity, surrogate sample accuracy, recovery, precision, and variability between analysts, including both an experienced and a novice *** were minimal differences in relative accuracy, and precision between singlicate and duplicate analysis, with CVs less than 5% for both methods. Singlicate and duplicate-generated standard curves were strongly correlated (NHP R2 = 0.9995, mouse R2 = 1.0000). Analyst variability had less impact on singlicate analysis, with lower inter-analyst CVs (1.0-6.5%) compared to duplicate analysis (5.0-7.5%).ConclusionsThese findings underscore the robustness of singlicate analysis. A workflow for singlicate assay validation is proposed, demonstrating its potential to streamline biomarker assay development while ensuring regulatory compliance. This study supports the adoption of singlicate analysis as a viable alternative to conventional duplicate methods for biomarker assays.

关键词： Dickkopf-related protein 1   miR-103a-3p   mitogen-activated protein kinase kinase kinase 7   rheumatoid arthritis   tumor necrosis factor alpha  

摘要： Tumor necrosis factor alpha (TNF-alpha) plays important roles in inflammation and bone destruction in rheumatoid arthritis (RA), but the detailed mechanism is still not fully elucidated. Here, we found that the levels of microRNA (miR)-103a-3p were decreased markedly in the inflamed synovial tissues of patients with RA compared with osteoarthritis (OA) or healthy control subjects. Further studies uncovered that miR-103a-3p was significantly downregulated by TNF-alpha/IL-1 beta in RA fibroblast-like synoviocytes (FLSs) through an NF-kappa B-dependent manner via the de novo produced transcription factor Yin Yang 1 (YY1). In addition, downregulation of miR-103a-3p in FLSs promoted NF-kappa B signaling pathway activation, inflammatory cytokines secretion, and bone marrow-derived monocytes (BMMs) cells differentiation into osteoclasts, whereas ectopic expression of miR-103a-3p had the opposite effects. Notably, miR-103a-3p was downregulated thousands of times in the sera of RA patients and CIA mice, while the blockade of TNF-alpha with infliximab greatly recovered its levels in RA patients in sustained remission. Consistently, rescue of miR-103a-3p expression by an agomiR potently ameliorated inflammatory responses and bone erosion in CIA mice. Mechanistically, mitogen-activated protein kinase kinase kinase 7 (MAP3K7) and Dickkopf-related protein 1 (DKK1) were identified as the direct targets of miR-103a-3p, by which it exerts the effects on synovial inflammation and cartilage bone destruction. Taken together, miR-103a-3p mediates TNF-triggered synovial inflammation and joint bone destruction via targeting MAP3K7 and DKK1;it thus serves as a candidate target for RA treatment.