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关键词： Autoimmune disorders   AlphaFold protein modeling   fusion protein   IL-1 receptor antagonist   glycosylation,eukaryotic protein expression  

摘要： Introduction The extended IL-1 activity is implicated in autoimmune disorders, such as rheumatoid arthritis, diabetes mellitus, and Parkinson's disease, as well as delayed wound healing. Additionally, it can result in cytokine storms during pathogenic *** The regulation was carried out by Interleukin-1 receptor antagonist (IL-1RA), a key anti-inflammatory molecule. IL-1RA serves as a decoy protein that competes with Interleukin-1 receptors (IL-1RI and IL-1RII) for binding, effectively counteracting the activity of Interleukin-1 (IL-1). The deficiency was substantiated by commercially available recombinant IL-1RA called Anakinra. The main problem with the existing drug is that it has less pharmacokinetics and reduced binding affinity to its receptor, which requires frequent administration of the drug. To overcome these drawbacks, we have designed a new fusion protein by adding an Fc fragment of Human IgGI fused with IL-1RA using a linker in between, and the design aimed to transport the protein into the N-glycosylation pathway. These characteristic features increase the pharmacokinetics, solubility, and binding efficiency of the protein. As the protein was designed to be expressed in a eukaryotic system, to understand the possibility of the proposed hypothesis, we used machine learning-based AlphaFold2 to model the protein structure and molecular simulation studies to understand the functional integrity of the designed *** The in silico results showed that the modeled fusion protein structure has very good binding to its receptor with the support of 21 H bonds and 7 salt bridges and maintained the binding stability over the MD *** These findings support fusion protein's potential as a promising and stable therapeutic candidate.

关键词： abdominal trauma   traumatic bowel rupture   IL-17A   cytokines   prognosis  

摘要： Objective - This study aimed to investigate the serum levels of interleukin (IL)-17A in patients with traumatic bowel rupture and its clinical significance, particularly its correlation with inflammatory cytokines, preoperative severity, and postoperative prognosis. Methods - A total of 104 patients with traumatic bowel rupture admitted to Ruian People's Hospital between February 2021 and June 2024 were included in this prospective observational study. All patients underwent standard surgical treatment for traumatic bowel rupture at our hospital. Serum levels of IL-17A, IL-6, tumor necrosis factor-alpha, and C-reactive protein were measured at various time points using enzyme-linked immunosorbent assay. Clinical data and demographics were collected. Patients were followed up for 3 months post-discharge. Results - The study found significantly higher levels of IL-17A and IL-6 in patients with an injury severity score (ISS) of >= 16 compared to those with an ISS of <16 (p < 0.05). Serum IL-17A levels were particularly elevated in patients with poor prognosis (p < 0.05). Of particular importance, receiver operating characteristic curve analysis demonstrated that serum IL-17A levels at 72 h post-surgery had predictive value for poor prognosis, with an area under the curve of 0.773, a cutoff value of 41.75 pg/mL, a sensitivity of 62.2%, and a specificity of 83.6%. Logistic regression analysis identified elevated IL-17 levels at 72 h post-surgery as a significant risk factor for poor prognosis (odds ratio = 1.273, 95% confidence interval: 1.115-1.453, p < 0.001). Conclusion - In summary, our study highlights the significant potential of serum IL-17A as a biomarker for predicting poor prognosis in patients with traumatic bowel rupture post-surgery, suggesting its utility in clinical assessment and potential as a therapeutic target.

关键词： CS   corticosteroids   EoE   eosinophilic esophagitis   ICD   International Classification of Diseases   ICS   inhaled corticosteroids   IL   interleukin   OCS   oral corticosteroids   SCS   systemic corticosteroids   SD   standard deviation   SES   Socio-Economic Status   STC   swallowed topical corticosteroid   US   United States  

关键词： CircSEC24A   miR-515-5p   NAMPT   IL-1 beta   Osteoarthritis  

摘要： Osteoarthritis (OA) is a chronic joint disease characterized by articular cartilage degeneration and damage. Increasing circular RNAs (circRNAs) have been identified to participate in the pathogenesis of OA. Hsa_circ_0128006 (also known as circSEC24) was reported as an upregulated circRNA in OA tissues, but its biological role and underlying mechanism in OA are still to be discussed. circSEC24A and NAMPT expression levels were upregulated, and miR-515-5p was reduced in OA cartilage tissues and IL-1 beta-treated CHON-001 cells. The absence of circSEC24A overturned IL-1 beta-induced suppression of cell viability and promotion of oxidative stress, apoptosis, extracellular matrix (ECM) degradation, and inflammation in CHON-001 cells. Mechanistically, circSEC24A acted as a molecular sponge for miR-515-5p to affect NAMPT expression. CircSEC24A knockdown could attenuate IL-1 beta-triggered CHON-001 cell injury partly via the miR-515-5p/NAMPT axis, providing new insight into the underlying application of circSEC24A in OA treatment.

关键词： Antigen presentation   HLA   MHCII   Parkinson’s disease   T cells   alpha-synuclein   microglia  

摘要： Major histocompatibility complex class II (MHCII) molecules are antigen presentation proteins and increased in post-mortem Parkinson's disease (PD) brain. Attempts to decrease MHCII expression have led to neuroprotection in PD mouse models. Our group reported that a SNP at in the MHCII gene Human leukocyte Antigen (HLA) DRA is associated with increased MHCII transcripts and surface protein and increased risk for late-onset idiopathic PD. We therefore hypothesized that decreased MHCII may mitigate dopaminergic degeneration. During an ongoing α-synuclein lesion, mice with MHCII reduction in systemic and brain innate immune cells (LysMCre+I-Ab or CRE+) displayed brain T cell repertoire shifts and greater preservation of the dopaminergic phenotype in nigrostriatal terminals. Next, we investigated a human cohort to characterize the immunophenotype of subjects with and without the high-risk genotype at the SNP. We confirmed that the high-risk genotype is associated with peripheral changes in MHCII inducibility, frequency of CD4+ T cells, and differentially accessible chromatin regions within the MHCII locus. Although our mouse studies indicate that myeloid MHCII reduction coinciding with an intact adaptive immune system is insufficient to fully protect dopamine neurons from α-synuclein-induced degeneration, our data are consistent with the overwhelming evidence implicating antigen presentation in PD pathophysiology.

摘要： Melanoma is an aggressive cancer in dogs involving skin and mucosa similar to humans. Anchored immunotherapeutics offer a novel approach to increase intratumoral retention of therapeutic payloads while decreasing systemic exposure, and this strategy can be critically evaluated through a comparative oncology approach. JEN-101 is an anchored canine IL-12 tethered to aluminum hydroxide administered by local injection. A phase I study was conducted to determine the tolerability, activity, and immune responses of JEN-101 in dogs with advanced melanoma. A 3 + 3 dose-escalation design was used to evaluate intratumoral injection of JEN-101 at 1, 3, 10, or 20 mu g/kg every 3 weeks for four cycles. A second course was allowable in the absence of disease progression or toxicity. Peripheral blood, serum, and tumor biopsies were collected at baseline and at prespecified timepoints for pharmacokinetic and immune analyses, which included serum cytokine assay, IHC, and gene expression assessment. JEN-101 was well tolerated with adverse events being fever, lethargy, and isolated elevated liver enzymes. Five dogs experienced grade 3 events, and no grade 4 events were observed. Pharmacokinetic analysis showed a trend toward dose-related maximum serum concentration within 8 hours of injection. Responding dogs demonstrated increased systemic IFN-gamma and IL-10 AUC levels and local recruitment of CD3+ T cells. Increased proinflammatory and antigen-processing gene expression was identified in responding lesions. JEN-101 was well tolerated with evidence of biological and therapeutic activities. Anchored IL-12 immunotherapy merits further investigation in dogs with melanoma, and our approach represents an immunocompetent model to inform human clinical trials.

关键词： Zerumbone   anti-inflammatory effect   antioxidant enzyme   signal transduction   periodontal ligament cells  

摘要： ObjectivesPeriodontal disease is a chronic inflammatory disease caused by periodontopathogenic bacteria, and its progression leads to periodontal tissue destruction and tooth loss. Zerumbone is a bioactive substance found in ginger (Zingiber zerumbet) and is known to have bioactive effects such as anticancer effects, but there have been no attempts to use it for periodontitis treatment. In addition, there have been no reports examining its effects on periodontal tissue component cells. In this experiment, we aimed to determine whether zerumbone affects the production of inflammatory mediators induced by tumor necrosis factor (TNF)-alpha in human periodontal ligament cells (HPDLCs), including its effects on signaling *** were stimulated by TNF-alpha (10 ng/ml) with or without zerumbone (6.25, 12.5, or 25 mu M). Cytokine production in supernatant was determined using ELISA. Activation of signal transduction pathways and intracellular protein expression were investigated using the western blot *** significantly suppressed TNF-alpha-induced production of CC chemokine ligand 2 (CCL2), CCL20, CXC chemokine ligand 10 (CXCL10), and interleukin-6 (IL-6) in HPDLCs. In addition, zerumbone decreased intercellular adhesion molecule-1 (ICAM-1) and cyclooxygenase-2 (COX-2) expression in TNF-alpha-stimulated HPDLCs. Furthermore, zerumbone suppressed activation of nuclear factor (NF)-kappa B and signal transducer and activator of transcription 3 (STAT3) pathways in TNF-alpha-treated HPDLCs. Finally, zerumbone enhanced the production of heme oxygenase-1 (HO-1), an antioxidant enzyme, in *** results suggest that zerumbone suppressed the production of several inflammatory mediators by inhibiting the NF-kappa B and STAT3 pathways in HPDLCs.

关键词： Extracellular matrix   fibrosis   matrix metalloproteinases   pro-inflammatory cytokines   tissue remodeling  

摘要： Purpose To evaluate matrix metalloprotease-1 (MMP-1), matrix metalloprotease-3 (MMP-3), tumor necrosis factor alpha (TNF-alpha), and interleukin-6 (IL-6) levels in the eyelid skin and fibroadipose tissue in patients with inactive moderate-to-severe Graves' orbitopathy (GO). Methods This prospective study included 23 patients with inactive moderate-to-severe GO who underwent upper blepharoplasty and medial fat excision, and 22 age- and sex-matched healthy subjects. MMP-1, MMP-3, TNF-alpha, and IL-6 levels in the skin and fibroadipose tissue obtained during surgery were measured using the ELISA method. Results The mean MMP-1 level in the eyelid skin (p = .003) and the mean MMP-3 level in the fibroadipose tissue (p = .04) were significantly lower in the GO group compared to the healthy control group. There were no differences in other mediators in both tissues between the two groups (p > .05). Conclusions The lower levels of proteolytic enzymes such as MMP-1 and MMP-3 in the eyelid skin and orbital fibroadipose tissue of patients with chronic inactive GO may play a role in the increase of collagen and glycosaminoglycans in orbital soft tissues.

关键词： SLE   Anifrolumab   Deucravacitinib   Daxdilimab   Litifilimab  

摘要： Introduction: Patients with Systemic Lupus Erythematosus (SLE) experience varied manifestations and unpredictable flares, complicating treatment and drug development. Despite these challenges, anifrolumab, voclosporin, and belimumab were approved by FDA. These treatments complement, but don't replace, traditional therapies like NSAIDs, corticosteroids, antimalarials, and immunosuppressives. Therefore, there remains an unmet need for more effective medications targeting excessive proinflammatory cytokines in SLE patients. Areas covered: This review summarizes the clinical trial outcomes of four upcoming medications targeting cytokine activity: Litifilimab showed a 7-point reduction in CLASI-A in its phase II trial. Daxdilimab was unsuccessful in its phase II trial. Anifrolumab reduced SLE activity in both phase II and III trials. Deucravacitinib decreased disease activity by multiple measures in its phase II trial. Expert opinion: High levels of IFN-I (type 1 interferon) are present in most SLE patients, making this pathway an attractive target for drug development. Litifilimab downregulates IFN-I by targeting BDCA2, while dexadilimab targets ILT7 to recruit effector cells, reducing IFN-I production by killing PDCs. Anifrolumab binds to the IFN-I receptor, blocking the activity of all IFN-Is, and deucravacitinib reduces IFN-I by inhibiting TYK2, thereby interfering with downstream signaling. Therapies that target IFN-I represents a promising class of medications for SLE patients.