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关键词： Inflammatory biomarkers   Type 2 diabetes mellitus   Coronary artery disease   Cardiovascular prognosis   TNF receptor 1  

摘要： Objectives: To examine the relationship between inflammatory biomarkers and the occurrence of cardiovascular events in patients with type 2 diabetes mellitus (DM2) and stable coronary artery disease. Methods: A total of 964 patients with stable coronary artery disease were included. Plasma levels of inflammatory markers, including tumour necrosis factor receptors 1 and 2 (TNF-R1 and TNF-R2), growth differentiation factor-15 (GDF-15), soluble suppression of tumorigenicity 2 (sST2), and high-sensitivity C-reactive protein (hsCRP) were measured. The primary endpoint was the development of acute ischaemic events (any type of acute coronary syndrome, stroke, or transient ischaemic attack). Results: There were 232 diabetic patients and 732 non-diabetic patients. Patients with coronary artery disease and DM2 (232, 24%) had higher levels of TNF-R1, TNF-R2, GDF-15, sST2 (P<.001), and hsCRP compared to patients without DM2, indicating a higher inflammatory state. After a median follow-up of 5.39 (2.81-6.92) years, patients with DM2 more frequently developed the primary endpoint (15.9% vs 10.8%;P=.035). Plasma levels of TNF-R1 were independent predictors of the primary endpoint in patients with DM2, along with male gender, triglyceride levels, and the absence of treatment with angiotensin-converting enzyme inhibitors. None of these inflammatory markers predicted the development of this event in non-diabetic patients. Conclusions: Patients with stable coronary artery disease and DM2 exhibit elevated levels of the proinflammatory markers TNF-R1, TNF-R2, GDF-15, and sST2. Moreover, TNF-R1 is an independent predictor of acute ischaemic events only in diabetic patients. (c) 2024 Sociedad Espanola de Arteriosclerosis. Published by Elsevier Espana, S.L.U. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

关键词： cartilage degeneration   interleukin-6 receptor   JAK2 signaling   osteoarthritis   senescent cells  

摘要： Osteoarthritis (OA) is an age-related degenerative joint disease, prominently influenced by the pro-inflammatory cytokine interleukin-6 (IL-6). Although elevated IL-6 levels in joint fluid are well-documented, the uneven cartilage degeneration observed in knee OA patients suggests additional underlying mechanisms. This study investigates the role of interleukin-6 receptor (IL-6R) in mediating IL-6 signaling and its contribution to OA progression. Here, significantly elevated IL-6R expression is identified in degenerated cartilage of OA patients. Further, in vivo experiments reveal that intra-articular injection of recombinant IL-6R protein or activation of gp130 (Y757F mutation) accelerates OA progression. Conversely, knockout of IL-6R or JAK2, as well as treatment with a JAK inhibitor, alleviates OA symptoms. Mechanistically, chondrocytes derived from degenerative cartilage exhibit impaired nuclear localization of SOX9, a key regulator of cartilage homeostasis. JAK inhibition stabilizes SIRT1, reduces SOX9 acetylation, and thereby facilitates SOX9 nuclear localization, promoting cartilage repair. Additionally, the JAK inhibitor-induced apoptosis in p21-positive senescent cells, and their targeted clearance successfully alleviates OA in p21-3MR mice. In conclusion, these findings reveal a novel mechanism by which inhibiting the IL-6R/JAK2 pathway can alleviate OA. Furthermore, this study proposes targeting p21-positive senescent cells as a new therapeutic strategy for OA.

关键词： CCL2   degeneration   dog   human explant   intervertebral disc  

摘要： BackgroundCell-free regenerative strategies, such as notochordal cell (NC)-derived extracellular vesicles (EVs), are an attractive alternative in developing new therapies for intervertebral disc (IVD) degeneration. NC-EVs have been reported to elicit matrix anabolic effects on nucleus pulposus cells from degenerated IVDs cultured under basal conditions. However, the degenerative process is exacerbated by pro-inflammatory cytokines contributing to the vicious degenerative cycle. Therefore, this study explores whether NC-EVs modulate interleukin (IL)-1 beta-mediated pro-inflammatory responses in the degenerating *** study utilized two IL-1 beta induced pro-catabolic culture models;a dog 3D nucleus pulposus (NP) cell pellet culture and a human patient-derived, ex vivo NP tissue culture system. Porcine NC-EVs were generated from NC-conditioned medium by differential centrifugation followed by size exclusion chromatography. Donor matched EV-depleted media were generated by overnight ultracentrifugation, whereafter the EV-depleted NCCM supernatant was subjected to size exclusion chromatography. To investigate whether observed effects were EV-associated, NC-EVs conditions were compared to EV-depleted controls in the absence and presence of IL-1 *** size and concentration of NC-EVs were quantified by nanoparticle tracking analysis, which showed minimal donor variation and confirmed depletion of EVs in the EV-depleted media. In the IL-1 beta-induced catabolic cascade, the NC-EVs did not elicit anabolic effects at the matrix level nor did they rescue the pro-catabolic phenotype within dog pellets. Modification of the CCL2 secretion seemed to be context dependent in the human explants: where EVs treatment stimulated CCL2 secretion but in the presence of IL-1 beta this effect was counteracted. Secretion of IL-6 and C-X-C motif chemokine ligand 1 was significantly decreased in NC-EV + IL-1 beta vs. control+IL-1 beta but not compared to EV-depleted human

关键词： Hepatitis B virus   Single nucleotide polymorphism   Interleukin-12   Chronic infection  

摘要： Hepatitis B virus (HBV) infection is a major cause of chronic liver diseases worldwide. Cytokines are important in immune responses, with T-helper1 (Th1) cytokines aiding in viral clearance through cell-mediated immunity. Interleukin-12 (IL-12) plays a critical role in regulating the secretion of IFN-y by Th1 cells and natural killer cells. Mutations in cytokine genes, like IL-12 composed of p35 and p40 chains, can impact protein production in HBV-infected hepatic cells. This study aims to explore how IL12A and IL12B genotypes affect the development of chronic hepatitis B. A total of 380 patients, 340 healthy controls, and 123 healthy individuals who had recovered from HBV infection were included in the study. Polymorphisms at positions -1148T/C (rs2243123) and 277G/A (rs568408) in the IL-12A gene, as well as rs6887695G/C in the IL-12B gene, were analyzed using the polymerase chain reaction-restriction fragment length polymorphism method. The frequencies of rs568408 genotypes in HBV patients were GG (70.5%), AG (27.9%), AA (1.6%), in healthy controls GG (70%), AG (26.5%), AA (3.5%), and in the cleared group GG (73.2%), AG (24.4%), AA (2.4%) with a p-value of 0.505. The frequencies of -1148TT, TC, and CC genotypes in the chronic HBV group were 71.6, 25.5, and 2.9%, in the healthy group 65, 28.8, and 6.2%, and in the cleared group 65, 28.3, and 6.5%, with a p-value of 0.129. The frequencies of rs6887695 genotypes in HBV patients, healthy controls, and the cleared group for GG were 53.9, 37.9, and 8.7%, for GC 37.9, 45.3, and 45.3%, and for CC 8.7, 8.2, and 8.1% (p = 0.256). This study is the first to investigate the role of genetic polymorphisms (rs2243123, rs2243123, and rs6887695) of IL12A and IL12B genes in the development of chronic hepatitis B in the Iranian population.

关键词： circular dichroism   fibroblasts   IL-4 peptide   iPSCs   molecular docking   myoblasts   SDF-1 peptide  

摘要： Skeletal muscle regeneration depends on satellite cells, which, in response to injury, activate, proliferate, and reconstruct damaged tissue. However, under certain conditions, such as large injuries or myopathies, this process may not be properly executed, and muscle function may be affected. Thus, pro-regenerative actions, such as the use of various factors or cells, are widely tested as a tool to improve muscle regeneration. In the current study, we designed peptides derived from the IL-4 and SDF-1 proteins, namely IL-4-X, IL-4-Y, SDF-1-X, and SDF-1-Y. We showed that these peptides can bind to appropriate receptors and can adopt proper structure in solution. Importantly, we documented, using in vitro culture, that they do not negatively affect the cells that are present and active in skeletal muscles, such as myoblasts and fibroblasts, bone marrow stromal cells, as well as induced pluripotent stem cells, which can serve as a source of myoblasts. The presence of peptides did not affect cell proliferation compared to untreated cells. In vitro culture and differentiation protocols documented that selected IL-4 and SDF-1 peptides increased cell migration and inhibited undesirable adipogenic differentiation. Thus, we proved that these peptides are safe to use in in vivo studies aimed at improving skeletal muscle regeneration.

关键词： Asthma   Bispecific antibody   IL-23   TNF-alpha   Airway hyperresponsiveness   Pulmonary inflammation  

摘要： Asthma, a chronic multi-factorial pulmonary inflammatory condition with a high morbidity rate, is characterized by airway hyperresponsiveness and persistent pulmonary inflammation. There is a need to develop more effective treatment(s) for the management of asthma. In this study, we have investigated the therapeutic potential of BiSpekDAb (an engineered bispecific antibody comprising an anti-IL-23 domain antibody and an antiTNF-alpha domain antibody fused together via flexible linkers to a half-life extension partner) in asthma. Asthma was established by sensitization and challenge of female Wistar rats with the combination of ovalbumin and lipopolysaccharide and the efficacy of BiSpekDAb was investigated by its subcutaneous administration for 11 days on each alternative day (6 doses) during the challenge phase. Significant deterioration of pulmonary functions, enhanced airway hyperresponsiveness, increase in the number of immune cells such as lymphocytes, eosinophils, neutrophils in blood circulation as well as in lungs, enhanced production of inflammatory cytokines (IL-23, TNF alpha, IL-1 beta, IL-6, IL-22), allergic IgE antibodies, oxidative stress markers, and histopathological changes (thickening of epithelial lining, infiltration of immune cells, mast cell degranulation, and overproduction of mucus) were observed in asthma animals, and administration of BiSpekDAb attenuated airway hyperresponsiveness (AHR), pulmonary inflammation and other pathological changes. BiSpekDAb significantly inhibited IL-23 and TNF-alpha levels in the lungs of asthmatic rats. Our results suggest that targeting IL-23 and TNF-alpha simultaneously opens a new therapeutic window for biologics development aimed at mitigating pulmonary inflammation such as asthma.

关键词： HLA-DQB1*06:01:01:09 novel allele   Illumina   next-generation sequencing  

摘要： The HLA-DQB1*06:01:01:09 allele differs from HLA-DQB1*06:01:01:01 by a single nucleotide substitution in intron 2.

关键词： HLA   HLA-DQA1   nanotype sequencing   novel allele   sequencing-based typing  

摘要： The novel allele HLA-DQA1*05:89 differs from HLA-DQA1*05:05:01:01 by one non-synonymous nucleotide substitution in exon 2.

摘要： Nuclear factor-kappa B (NF-kappa B)/p65, a vital signaling molecule in the NF-kappa B pathway, participates in diverse physiological functions and host-virus interactions. However, the involvement of NF-kappa B/p65 in fish virus infection remains poorly understood. In this study, we explored the role of the p65 in virus infection and its impact on IL- 18 regulation in largemouth bass ( Micropterus salmoides). Bioinformatics analysis showed that the ORF sequence of Msp65 spanned 1941 bp, encoding 646 amino acids with two conserved functional domains, including RHD and IPT domain. Msp65 mRNA was presented in various tissues, with higher levels detected in the liver and gill. After exposure to largemouth bass virus (LMBV), red grouper nervous necrosis virus, lipopolysaccharide and poly (I:C), Msp65 expression was activated in vivo. In addition, the antiviral role of Msp65 were explored. In vitro, Msp65 overexpression hindered LMBV replication and formation of viral assembly site. In vivo, we found that disruption of Msp65 by using maslinic acid (MA) notably promoted the infectivity of LMBV, indicating its antiviral capabilities in largemouth bass. Besides, the downregulation of Msp65 suppressed the expression of inflammatory and interferon signaling molecules. Conversely, Msp65 overexpression boosted the activities of IFN-I, IFN-III and ISRE promoters, suggesting the positive regulation of Msp65 on interferon immune pathway. Furthermore, to unveil the regulatory role of Msp65 on MsIL-18, a promoter investigation was conducted. The luciferase reporter assay demonstrated that Msp65 positively influenced the expression of MsIL18. Subsequent analysis suggested that the putative binding sites for MsIL-18 could potentially reside within the-228 to-203 bp of the MsIL-18 promoter. These findings illustrated that Msp65 involved in LMBV infection by modulating immune responses, presenting a novel insight into the antiviral mechanisms of p65 in bony fish.

关键词： Kimura disease   Nocardiosis   Primary immune deficiency  

摘要： A 12-year-old boy who had been diagnosed with Kimura disease was brought with a history suggestive of acute pyelonephritis. There was a family history of a first-degree relative with a diagnosis of Mendelian Susceptibility to Mycobacterial disease. Investigations revealed a left renal abscess. Aspirate culture grew Nocardia otitidiscaviarum. Targeted gene sequencing revealed a novel mutation in the IL12RB1 gene. Based on the above information a diagnosis of an underlying primary immune deficiency disorder was made. He was managed with appropriate antibiotics, showing steady improvement and eventually a complete recovery.