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关键词： Biomarkers   Quality of life   biological DMARD   omics  

关键词： Cytokines and Chemokines   Interdisciplinary research   Fatigue  

摘要： Background: Despite anti-inflammatory drugs effectively reducing joint inflammation, patients with established rheumatoid arthritis (RA) can still experience functional decline due to muscle fatigue [1–3]. Muscle fatigue is defined as the inability to maintain a given force over a specified period and affects up to 60% of RA patients, posing a significant socio-economic burden. Although clinicians often attribute muscle weakness in RA to reduced muscle size, intramuscular impairments also contribute to fatigue. One potential mechanism involves dysfunctional mitochondrial respiration, which is key to muscle energy production (ATP) and hence sustaining force. Elevated systemic inflammatory cytokines in RA, such as tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and interferon gamma (IFN-γ), may affect mitochondrial function in skeletal muscle. It however remains unclear if and how this occurs in RA. The primary aim of this study was to investigate how TNF-α, IL-6, and IFN-γ, at concentrations relevant in established RA, impact muscle mitochondrial respiration, muscle size, and muscle mitochondrial gene expression in vitro. Objectives: Investigate the in-vitro effect of TNF-α, IL-6, and IFN-γ concentrations, that are present in established-RA serum concentrations on (i) myofiber size; (ii) muscle mitochondrial respiration and (iii) mitochondrial gene expression in-vitro. Methods: Human primary muscle cells (myoblasts) obtained from the München Tissue Culture Collection were cultured and differentiated into myotubes as previously described [4], and subsequently exposed for 72 hours to 0, 10, 20, 40, or 160 pg/mL of TNF-α, IL-6, or IFN-γ. These concentration ranges were measured with a multiplex bead-based immune-assay (BD Cytometric Bead Array) based on RA patient blood samples from the Amsterdam UMC biobank (Figure 1A–C) and prior literature [5] comparing established RA patients and healthy controls. Mitochondrial respiration was then assessed by Seahorse re

关键词： Cytokines and Chemokines   Adaptive immunity   Fibroblasts  

关键词： flavivirus   tick-borne encephalitis virus   NS1 protein   endothelial hyperpermeability   TNF-alpha signaling pathway   TEER  

摘要： Orthoflavivirus encephalitidis (tick-borne encephalitis virus, TBEV) is of high concern due to its ability to cause severe neurological manifestations. Despite the fact that the role of NS1 proteins from various mosquito-borne flaviviruses in pathogenesis and their ability to affect human endothelial permeability have been investigated, TBEV NS1 has thus far been insufficiently studied. In this study, human endothelial permeability was assessed using TEER and transwell permeability assays. Signaling pathways were determined by RNAseq. The ability of the NS1 protein of TBEV to affect human endothelial permeability was investigated for the first time. It was shown that recombinant TBEV NS1 produced in eucaryotic cells directly affected human lung microvascular endothelial cells (HLMVECs) in vitro but not human umbilical vein endothelial cells (HUVECs). It was indicated that TBEV NS1 induced endothelial hyperpermeability of HLMVECs through activating TNF-alpha and other inflammatory signaling pathways.

关键词： autoimmunity   anti-PD1-antibody   cutaneous side effects   skin   gene expression   bullous pemphigoid   immune-related bullous pemphigoid   immune-related adverse events   immune checkpoint inhibitor  

摘要： Background/Objectives: Cutaneous side effects are the most common immune-related adverse events (irAEs) caused by immune checkpoint inhibitors (ICIs) and affect 70-90% of patients. Besides diverse types of exanthema, rare skin toxicity includes bullous dermatoses in 0.3% of cases. Systemic steroids are the first-line treatment for immune-related bullous pemphigoid (irBP);however, some cases are corticosteroid-resistant. IrBP is one of the irAEs most frequently chronic and associated with long-term steroid use. However, steroids may interfere with tumor response. Therefore, alternative treatment strategies for irBP are desperately needed. Dupilumab, a monoclonal antibody blocking the receptor binding of interleukin-4 (IL-4) and interleukin-13 (IL-13), has been successfully used to treat spontaneous forms of bullous pemphigoid (BP). In this study, we analyzed the gene expression profiles of BP and irBP. Patients and Methods: A retrospective multicenter study evaluated the gene expression profiles of irBP and BP in comparison to healthy controls. Gene expression analyses of skin biopsies were performed using NanoString technology from patients with BP (n = 17), irBP (n = 19), and healthy skin (n = 24) after the patients had consented to participate in this study, and differentially expressed genes (DEGs) were determined using Rosalind software. Results: Compared to healthy skin, BP showed 167 DEGs, and irBP revealed 99 DEGs. Some of the DEGs from irBP and BP vs. healthy skin overlapped. Specifically, IL-4- and IL-13-associated genes were upregulated in both irBP and BP compared to healthy skin. Interestingly, expression profiles of BP vs. irBP also showed 13 DEGs. Conclusions: These findings suggest a possibility for therapeutic efficacy of IL-4 and IL-13 inhibitors in the treatment of irBP.

关键词： Periodontitis   Interleukin-17   Fenugreek   Phytochemicals   Molecular docking   In silico  

摘要： Periodontitis is a chronic inflammatory disease of the oral cavity, which is characterized by the excessive immune response to microbial stimuli and poses significant systemic health risks. The pro-inflammatory cytokine Interleukin-17 (IL-17) plays a pivotal role in the progression of periodontitis, by promoting immune cell recruitment and activating tissue-destructive molecules. This study explores the potential of fenugreek-derived phytochemicals-specifically isovitexin, rhaponticin, galactomannan, and quercetin-as inhibitors of IL-17 and its receptor, IL-17R, to mitigate inflammatory pathways in periodontitis. Using an in silico approach, molecular docking, molecular dynamics (MD) simulations, and binding affinity analysis were employed to assess the interaction of these compounds with the IL-17-IL-17R complex. Results indicate that isovitexin (IVI) and rhaponticin (RHA) exhibit strong binding affinities, with stable protein-ligand interactions throughout the simulations, supporting their potential as therapeutic agents. The study's findings contribute to the growing evidence of the anti-inflammatory benefits of fenugreek phytochemicals, suggesting that they may be utilized to develop novel therapeutic strategies for managing chronic inflammatory conditions such as periodontitis.

关键词： Autoubiquitination   Dimerization   IBD   MARCH2   MARCH8  

摘要： BackgroundRegulation of the nuclear factor-kappa B (NF-kB) signaling pathway is a major host homeostatic mechanism for controlling hyper-inflammation or chronic inflammation. Despite extensive research, the regulatory factors of NF-kB signaling required to preserve homeostasis and control inflammatory disorders are not fully understood. Moreover, the role of MARCH2 in chronic inflammation models and the regulation of MARCH2 activation remain to be *** monitored disease severity and mortality in MARCH2-/- or MARCH2+/+ mice induced experimental colitis. Susceptibility to DSS-induced experimental colitis was determined by various methods, including Swiss roll assay and fluorescein isothiocyanate (FITC)-dextran treatment, respectively. RNA-sequencing was conducted to recognize the inflammatory response-related genes in the distal colon of colitis-induced mice. Enzyme-linked immunosorbent assay (ELISA) was used to measure the cytokines and chemokines with in vitro and in vivo samples. Affinity purification and LC-MS/MS analysis were used to identify the MARCH2 interacting proteins and posttranslational modifications. The underlying mechanism was elucidated using immunoblotting, co-immunoprecipitation, ubiquitination assay, and confocal ***, we report that MARCH2-/- mice were more susceptible to experimental inflammatory bowel disease (IBD) due to the massive production of cytokines. Stimulation by inflammatory cytokines such as TNF induces dimerization of MARCH2 at a later stage and dimerized MARCH2 undergoes K63-linked autoubiquitination at lysine 127 and 238, which promotes NEMO recognition, ubiquitination and proteasomal degradation. We also show an interaction between MARCH2 and MARCH8 in resting cells that inhibits MARCH2 activation. Taken together, these findings provide new insights into the molecular mechanism of MARCH2 and suggest a crucial role of MARCH2 in the modulation of inflammation and cellular ***

关键词： SARS-CoV-2   inflammatory response   genetic polymorphisms   disease severity   Brazilian population  

摘要： Background/Objectives: Genetic variants in cytokine genes such as IL1B, IL6, and TNF may influence inflammatory responses to SARS-CoV-2 and affect disease severity. This study investigates the role of these variants in relation to COVID-19 outcomes, including hospitalization, ICU admission, and mortality. Methods: A total of 500 unvaccinated individuals from southern Brazil diagnosed with COVID-19 via RT-PCR were analyzed. DNA was extracted from nasopharyngeal swabs and genotyped for functional variants selected based on evidence of regulatory function and prior associations with inflammatory outcomes-IL1B (rs4848306, rs1143623, rs16944, rs1143627), IL6 (rs1800795, rs2069832, rs2069840, rs2069845), and TNF (rs1799964, rs1800630, rs1799724, rs1800629, rs361525). Multivariate logistic regression analysis, adjusted for sex and age, was employed to assess the association between these genetic variants and severe clinical outcomes. Results: The results indicated that the IL1B rs16944-AG (OR: 1.98 [95% CI: 1.22-3.23], p = 0.006) and TNF rs1799964-CT (OR: 1.97 [95% CI: 1.22-3.22], p = 0.006) genotypes were associated with the need for hospitalization, while TNF rs1800630-AA (OR: 2.37 [95% CI: 1.08-5.33], p = 0.034) was associated with ICU admission. Additionally, the CC genotype of TNF rs1799964 was associated with a higher risk of mortality (OR: 3.73 [95% CI: 1.21-14.37], p = 0.034). Conclusions: Genetic variants-specifically IL1B rs16944 and rs1143627, and TNF rs1799964 and rs1800630-were associated with COVID-19 severity and should be further investigated in larger studies to evaluate their potential as predictive markers of severe outcomes in COVID-19.