Search Results (882)

Pain remains one of the most burdensome symptoms in rheumatoid arthritis (RA), often persisting despite inflammatory remission and profoundly impairing quality of life. This review aimed to evaluate the clinical efficacy and mechanistic pathways by which Janus kinase (JAK) inhibitors alleviate RA-related pain. Evidence from randomized clinical trials demonstrates that JAK inhibitors have demonstrated rapid and significant pain relief, often exceeding that of methotrexate or biologic DMARDs. Improvements in patient-reported pain scores seem to typically emerge within 1–2 weeks and are sustained over time. Beyond anti-inflammatory effects, JAK inhibitors modulate central sensitization and nociceptive signaling by attenuating IL-6 and GM-CSF activity, reducing astrocyte and microglial activation, and downregulating nociceptor excitability in dorsal root ganglia and spinal pathways. Preclinical models further suggest that JAK inhibition interrupts neuroimmune feedback loops critical to chronic pain maintenance. Comparative and network meta-analyses consistently position JAK inhibitors among the most effective agents for pain control in RA. However, individual variability in response, partly due to differential JAK-STAT activation and cytokine receptor uncoupling, underscores the need for biomarker-guided treatment approaches. JAK inhibitors represent a mechanistically distinct and clinically impactful class of therapies that target both inflammatory and non-inflammatory pain in RA. Their integration into personalized pain management strategies offers a promising path to address one of RA’s most persistent unmet needs. Full article

Background: Osteoarthritis (OA) is a major global health issue, increasing with aging and obesity. Current therapies mainly address symptoms without modifying disease progression. Platelet-rich growth factor (PRGF) therapy has potential regenerative effects through high cytokines and growth factors, but the outcomes of these therapies remain heterogeneous. This study explores the relationship between patient nutritional status, PRGF characteristics, and clinical outcomes in knee OA treatment. Methods: Baseline anthropometric, metabolic, and nutritional assessments of 41 patients with knee OA who underwent PRGF treatment were conducted. Blood samples were analyzed for metabolic and inflammatory markers. PRGF composition was assessed by protein content and extracellular vesicle (EV) markers. KOOS and VAS pain scores were collected at 2, 6, and 12 months. Responders improved KOOS by ≥10 points. An elastic-net regularized logistic model allowed the identification of the predictors of treatment response. Results: KOOS and VAS scores improved significantly at all follow-ups. At 2 months, the PRGF of responder patients showed higher PRGF G-CSF levels; at 12 months, increased CD49e and HLA-ABC expression. Higher BMI correlated with increased IL-6, IL-1ra, and resistin in PRGF samples. Hypercholesterolemic patients displayed altered EV profiles, with elevated levels of CD8 but reduced CD49e, HLA-ABC, CD42a, and CD31. Multivariate analysis identified BMI, biceps fold, fat percentage, red blood cell, platelet, and neutrophil counts as predictors of early response. Conclusions: Metabolic and immunological factors influence PRGF composition and clinical efficacy in knee OA. Baseline body composition and hematological parameters as key predictors of response, highlighting the potential of personalized PRGF therapy. Full article

Background/Objectives: Gestational diabetes mellitus (GDM) is characterized by a systemic inflammatory response and the expression of inflammatory factors in visceral adipose tissue (VAT). However, the association between these two inflammatory processes has not been fully elucidated. Therefore, this study aimed to (1) investigate whether whole blood counts, the neutrophil–lymphocyte ratio (NLR), the monocyte–lymphocyte ratio (MLR), serum adiponectin levels, and the mRNA expression of inflammatory genes (TLR2, TLR4, pro-inflammatory cytokines: IL-1β, IL-6, and TNF-α, anti-inflammatory cytokines: IL-1RA, IL-10, and adiponectin) in VAT are altered in women with GDM in comparison to pregnant women with normal glucose tolerance (NGT), and (2) determine the correlations between systemic and local VAT inflammation in all, GDM, and NGT women. Methods: Study of 50 GDM and 50 women with NGT with a cross-sectional design. Standard biochemical and hematological tests were conducted and relative mRNA expression in VAT was measured by RT-qPCR. Results: Women with GDM showed higher neutrophil, monocyte, NLR, MLR, and VAT TNF-α/IL-10 mRNA expression ratios while lymphocyte and eosinophil counts, serum adiponectin, and mRNA local VAT inflammatory markers such as TLR2, TLR4, IL-1β, IL-6, IL-1RA, and IL-10 were lower in women with GDM relative to women with NGT. Additionally, the circulating monocyte count were associated with TLR2 and TLR-4 VAT mRNA expression levels and eosinophils count were associated with IL-1β, IL-6, IL-10, and IL-1RA VAT expression levels in women with GDM. Conclusions: GDM is characterized by systemic inflammation, and some circulating immune cells, such as monocytes and eosinophils, are associated with the expression of inflammatory markers in VAT. Full article

Background/Objectives: Osteoarthritis (OA) is a progressive joint disease characterized by inflammation, cartilage degradation, and subchondral bone changes, for which effective disease-modifying therapies are lacking. Messenger RNA (mRNA)-based therapeutics offer a versatile approach to modulate joint pathology, but their application to OA remains limited. Methods: We evaluated intra-articular delivery of therapeutic mRNAs using polyplex nanomicelles, a non-inflammatory and minimally invasive carrier system, in a rat model of inflammation-driven OA induced by monosodium iodoacetate (MIA). Results: IL-1 receptor antagonist (IL-1Ra) mRNA reduced synovial inflammation and alleviated pain and swelling. RUNX1 mRNA, a transcription factor critical for chondrogenesis, supported chondrocyte viability, type II collagen expression, and cartilage structure. Under conditions of pronounced inflammation, however, the protective effects of RUNX1 mRNA alone were modest. Notably, combined administration of IL-1Ra and RUNX1 mRNAs produced synergistic therapeutic benefits, with enhanced chondroprotection and preservation of subchondral bone integrity. Conclusions: These findings suggest that while RUNX1 is essential for maintaining cartilage homeostasis, effective control of joint inflammation is required for its therapeutic activity. Dual mRNA therapy delivered by polyplex nanomicelles therefore represents a promising strategy to address the multifactorial pathology of OA. Full article

Metastatic spread remains the primary cause of mortality in melanoma. Our aim was to investigate the role of dermal endothelial cells in modulating melanoma cell invasiveness and cytokine/chemokine pattern. Primary melanoma cell lines were co-cultured with human dermal endothelial cells and assessed using Matrigel invasion assays. Invasive and non-invasive subpopulations were separated for gene expression analyses, and candidate molecules were further evaluated in patient tissue and plasma samples. Co-culture of melanoma and dermal endothelial cells revealed altered expression of several cytokine receptor genes (CCR5, CXCR7, IL1RAPL2, IL4R, IL6ST, IL18R1, IL22RA2, TNFRSF10A, TNFRSF11B, and TNFRSF21). Analysis of clinical melanoma samples showed significant downregulation of IL1RAPL2 and TNFRSF10A in cutaneous metastases, whereas IL6ST expression correlated with Breslow thickness of the primary tumor rather than metastatic site. Proteome profiling of dermal endothelial cells revealed alterations in Midkine, GROα, MIP-3α, IL-8, and SDF-1 following co-culture with melanoma cells. Plasma measurements in melanoma patients confirmed elevated Midkine levels in skin metastases and decreased MIP-3α in metastatic disease. These results highlight potential cytokine and chemokine-mediated pathways involved in melanoma dermal invasion and cutaneous metastasis. While some findings did not reach statistical significance, concordant trends between in vitro and patient-derived data suggest their relevance and warrant further investigation in larger cohorts. Full article

Background/Objectives: Silicosis caused by dust from engineered stone (ES) exposure is an emerging occupational lung disease that severely impacts respiratory health. This study aimed to analyze the association between cytokine profiles and disease severity and progression in patients with engineered stone silicosis (ESS) to assess their potential as biomarkers of progression and their usefulness to stratify risk. Methods: A longitudinal study was conducted with a seven-year follow-up (2017-2024) on 72 workers with simple silicosis (SS) or progressive massive fibrosis (PMF), all with a history of cutting, polishing, and finishing ES countertops. Data on lung function and levels of 27 cytokines were collected at four control points. Machine learning (ML) models were built to classify the disease stage and predict its progression. Results: 39% of patients with SS progressed to PMF. Significant differences in the expression of some cytokines were observed between ESS stages, suggesting a role in the evolution of the inflammatory process. Specifically, higher levels of IL-1RA, IL-8, IL-9, and IFN-$\gamma$ were found at checkpoint 1 in patients with PMF compared to SS. The longitudinal analysis revealed a significant relationship between IL-1RA and MCP-1$\alpha$ and disease duration with MCP-1$\alpha$ also being associated with time and disease grade. Machine learning (ML) models were built using the cytokines selected through a sequential backward feature selection. The Support Vector Machine model achieved an accuracy of 83% in classifying disease stage (SS, PMF), and of 77% in predicting the disease progression. Conclusions: The findings suggest that cytokines can be used as dynamic biomarkers to reflect underlying inflammatory processes and monitor disease evolution. The performance of ML algorithms to predict diagnostic status based on cytokine profiles highlights their clinical value in supporting early diagnosis, monitoring disease progression, and guiding clinical decisions. Full article

Rheumatoid arthritis synovial fibroblasts (RASFs) play a pivotal role in joint destruction in RA. Myostatin (MSTN), a myokine, is highly expressed in the RA synovium; however, its role in the function of RASFs is unclear. We hypothesized that MSTN amplifies inflammatory cytokines/chemokines, promotes RASF invasion, and facilitates CD4⁺ Th cell transmigration. Immortalized MH7A cells (RASFs) and healthy synovial fibroblasts (HSFs) were treated with MSTN (0, 10, 20 ng/mL) for 0, 24, and 48 h. Cytokines (IL-8, IL-17, TNF-α, IL-6, IL-23, IFN-γ, IFN-β) and chemokines (CCL2, CCL20, CXCL13, CXCL1) were quantified by ELISA, RT-qPCR, and Western blotting. To evaluate MSTN regulation, cells were treated with pro-inflammatory mediators (TNF-α, IL-17, IFN-γ, IFN-β, CCL2, CXCL1). MSTN’s effects on Thy-1(CD90)⁺ RASF/HSF proliferation, RASF invasion, and CD4⁺ T-cell transmigration were assessed. Compared with HSFs, RASFs exhibited greater proliferative activity. MSTN significantly upregulated cytokines/chemokines, with CXCL1 showing the strongest induction in RASFs. IFN-γ and IL-17 robustly increased MSTN expression, indicating a feed-forward loop. MSTN did not alter Thy-1(CD90)⁺ fibroblast proliferation but significantly enhanced RASF invasion and CD4⁺ T-cell transmigration. Neutralizing CXCL1 or IL-17 reduced transmigration, with stronger inhibition via CXCL1. These findings offer new insights into the role of MSTN in RA pathogenesis and highlight its potential as a therapeutic target. Full article

Ischemic stroke is a leading cause of mortality and disability in adults. The inflammatory cascade is driven by various inflammatory molecules, such as interleukin-1β (IL-1β), and counteracted by its antagonist, interleukin-1 receptor antagonist (IL-1Ra). Eicosanoids are inflammatory derivatives of free fatty acids. Arachidonic acid (AA) derivatives exhibit pro-inflammatory activity, while eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) derivatives, known as specialized pro-resolving mediators, have anti-inflammatory properties. This study aimed to analyze potential associations between eicosanoids and key inflammatory molecules, including IL-1β and its antagonist IL-1Ra. In this prospective study, we investigated inflammatory molecules in 73 ischemic stroke patients. We analyzed interactions between IL-1β, IL-1Ra, and eicosanoids as follows: resolvin E1, prostaglandin E2, resolvin D1, lipoxin A4 (5S, 6R, 15R), protectin DX, maresin 1, leukotriene B4, 18RS-HEPE, 13S-HODE, 9S-HODE, 15S-HETE, 17 HDHA, 12S-HETE, 5-oxo-ETE, and 5-HETE. In 73 ischemic stroke patients, mean IL-1β was 1.31 ± 1.54 pg/mL and IL-1Ra 810.8 ± 691.0 pg/mL. Spearman correlations showed positive associations between IL-1β and protectin DX (ρ = 0.56, p < 0.001), and 17 HDHA (ρ = 0.26, p < 0.05) and 5-oxo-ETE (ρ = 0.27, p < 0.05). IL-1Ra correlated negatively with protectin DX (ρ = −0.58, p < 0.001) and 17 HDHA (ρ = −0.29, p < 0.05), and positively with leukotriene B4 (ρ = 0.34, p < 0.005). After multivariable adjustment, associations with IL-1β lost statistical significance, whereas the inverse relationships between IL-1Ra and protectin DX/17 HDHA remained significant (p < 0.005). Despite the known anti-inflammatory roles of protectin DX and 17 HDHA, and the pro-inflammatory role of leukotriene B4, their activity in the early subacute phase of ischemic stroke appears to be influenced by complex interplays, possibly mediated by IL-1β and IL-1Ra. The activity of protectin DX, 17 HDHA, and leukotriene B4 is correlated with IL-1β and IL-1Ra levels in the early subacute phase of stroke. Full article

Background: Lipoprotein(a) [Lp(a)]-induced inflammation contributes to coronary artery spasm (CAS) by the contraction of vascular smooth muscle cells. However, the interaction between Lp(a) and soluble CD36 (sCD36)/interleukin (IL)-6/RAS Homolog Family Member A (RhoA)-GTP signaling pathway has not been evaluated. Methods: We investigated the relevance of Lp(a)/CD36 signaling in CAS patient monocyte-derived macrophages (PMDMs) and a human coronary artery smooth muscle cell (HCASMC) line using expression profile correlation analyses, molecular docking, RNA sequencing, flow cytometry, immunoblotting, and quantitative reverse transcription polymerase chain reaction. Results: Plasma Lp(a) and sCD36 levels in 41 CAS patients were significantly higher (p = 0.001) and positively correlated (r² = 0.3145, p < 0.001), a trend not observed in 36 non-CAS controls. RNA sequencing indicated a significant co-overexpression of CD36 and RhoA in Lp(a)-treated CAS PMDMs and HCASMCs, of which the mRNA and protein expression of CD36 and RhoA were significantly enhanced (p < 0.001) dose-dependently. Lp(a) rather than LDL preferentially induced CD80+ PMDM (M1) polarization. In HCASMCs, the CD36 knockdown using either short hairpin RNA or natural biflavonoid amentoflavone suppressed Lp(a)-upregulated protein expression of CD36, RhoA-GTP, IL-6, tumor necrosis factor (TNF)-α, nuclear factor (NF)-κB, and CD80; however, overexpressed CD36 increased their levels. Lp(a) decreased and amentoflavone increased the epigenetic expression of CD36 inhibitors, miR-335-5p, and miR-448, respectively. Reciprocally, an miRNA inhibitor or mimic could magnify or diminish Lp(a)-induced CD36, TNF-α, NF-κB and IL-6 expressions in HCASMCs, respectively. Conclusions: Elevated Lp(a) levels upregulate the CD36-dependent TNF-α/NF-κB/IL-6/RhoA-GTP signaling pathway in CAS PMDMs and HCASMCs, indicating that Lp(a)/CD36 inflammatory signaling, HCASMC activation, and macrophage M1 polarization mediate CAS development. Full article

Background: Obesity is closely linked to metabolic dysfunction and systemic low-grade inflammation. Glucagon-like peptide-1 receptor agonists (GLP-1RA) are increasingly utilized for obesity treatment due to their significant metabolic benefits, including weight loss and improved glycemic control. The aim of the study was to evaluate the effect of submaximal doses of long-lasting GLP-1RA semaglutide on selected biomarkers of obesity-related inflammation, adipocytokines levels and metabolism in a real-world population of obese patients. Methods: We performed a prospective, observational study involving 32 adult patients (11 men, 21 women; mean age 49 ± 12 years; BMI 40.5 ± 7.3 kg/m²) treated with submaximal doses of semaglutide over 12 weeks, together with hypocaloric diet and increased physical activity based. We analyzed selected biomarkers including insulin, leptin, ferritin, resistin, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) and plasminogen activator inhibitor-1 (PAI-1) before and after three months of treatment. Results: We observed significant reductions in weight, BMI, waist circumference, insulin and leptin levels (all p < 0.001). On the other hand, no significant changes were recorded in ferritin (p = 0.806), IL-6 (p = 0.607), TNF-α (p = 0.633), resistin (p = 0.250) or PAI-1 (p = 0.134) levels. Correlation analyses revealed the correlation between IL-6 and adiposity indices (BMI, waist circumference) both before and after treatment. Ferritin and PAI-1 levels positively correlated with waist circumference, while resistin showed a negative correlation with central obesity. Conclusions: Submaximal-dose GLP-1 RA therapy was associated with significant improvements in metabolic parameters and adipokine regulation, but did not affect systemic inflammatory markers within 12 weeks. Future studies with larger cohorts and longer follow-ups are needed to clarify the associations. Full article

Tumor drug resistance exhibits substantial heterogeneity across cancer types, reflecting distinct molecular mechanisms in each malignancy. To characterize this complexity, we developed a pan-cancer transfer learning framework that integrates bulk RNA-seq data with a residual variational autoencoder (Res VAE) backbone. Five models were trained on the Genomics of Drug Sensitivity in Cancer (GDSC) dataset, which includes drug response profiles for 72 chemotherapeutic agents. Among them, three models are specially designed by incorporating variational autoencoders and large pretrained models (LLMs): the LLM large VAE (VAE_LL), the LLM small VAE (VAE_LS), and the LLM distillation VAE (VAE_LD). Random Forest (RF) and eXtreme Gradient Boosting (XGB) were included as ensemble learning baselines. After internal cross-validation, the top four models (VAE_LL, VAE_LD, XGB, and RF) were applied to five representative TCGA cohorts comprising 1,836 patients. For each cancer type, resistance to nine clinically relevant first-line drugs was modeled, resulting in 180 drug–cancer prediction tasks. Among all models, VAE_LD achieved the best overall performance, with a mean AUC of 0.81 and an F1 score of 0.92 on the GDSC benchmark, and maintained strong predictive power in the clinical validation phase. Interpretation analyses identified tumor-specific resistance biomarkers with clinical significance. In lung adenocarcinoma, elevated expression of TFF1 was repeatedly associated with resistance to Gefitinib and correlated with poor patient prognosis, indicating its potential as a therapeutic target. In glioblastoma, OPALIN, LTF, IL2RA, and SLC17A7 were implicated in Temozolomide resistance through pathways related to epithelial differentiation and angiogenesis. In conclusion, the VAE_LD model offers a high-performing and interpretable approach for predicting drug resistance across multiple tumor types. It supports the identification of clinically actionable biomarkers and provides a robust framework for precision oncology applications. Full article

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by a multistep pathogenesis, from the preclinical phase of autoantibody emergence to the clinical onset of synovitis and joint destruction. Cytokines play central roles throughout this progression by orchestrating immune cell activation, tissue inflammation, and bone erosion. In the preclinical phase, several cytokines, including IL-12, IL-6, IL-21 and TGF-β, promote Tfh and Tph cell differentiation, helping autoreactive B cells to produce ACPA. During the clinical phase, TNF-α, IL-6, and IL-1β drive synovitis by activating macrophages and fibroblast-like synoviocytes, while also promoting RANKL (Receptor Activator of Nuclear factor κB Ligand) expression and osteoclast differentiation. This review highlights the pathogenic role of cytokines in RA and discusses their relevance as biomarkers and therapeutic targets. A better understanding of cytokine networks may offer new opportunities for early intervention and disease prevention in RA. Full article

Background: Preterm birth (PTB) remains the leading cause of neonatal morbidity and mortality worldwide, with approximately two-thirds of cases occurring spontaneously (SPTB), but the etiology is still poorly understood. Chronic inflammatory diseases, such as periodontitis (PD), have been considered SPTB risk factors. However, we hypothesized that SPTB may instead represent a clinical manifestation of a broader genetic predisposition to dysregulated inflammation. Using PD as a model of chronic inflammation, we examined shared genetic susceptibility. Methods: In a case–control study (N = 126 Portuguese postpartum women), we screened 56 SNPs in 36 inflammation-related genes. Four functionally plausible variants (IL1RN rs4251961, TLR1 rs5743618, IL6 rs2069827, and IL6R rs4845617) were selected for detailed regression, adjusting for gestational age, floss usage, and an SPTBxPD interaction term. Results: IL1RN rs4251961 was recessively associated with SPTB risk, consistent with reduced IL-1RA expression linked to this variant. IL6R rs4845617 showed a modest protective effect. TLR1 rs5743618 exhibited the strongest association with the composite “inflammation” phenotype under multiple models, with CC homozygotes showing four-fold increased odds, independent of SPTB/PD co-occurrence. Conclusions: This study provides original evidence that shared genetic variants in inflammatory pathways—particularly TLR1 rs5743618—may underlie susceptibility to SPTB and PD. Our findings suggest a paradigm shift, viewing SPTB as a possible outcome of systemic inflammatory dysregulation rather than merely a consequence of comorbid inflammatory conditions. Future studies should validate this marker in larger cohorts. Full article

Background/Objectives: Chronic exercise training reduces markers of systemic inflammation; however, less is known about how to optimize this adaptation using nutrition. Dairy products, especially fermented ones, like Greek yogurt (GY), contain anti-inflammatory constituents. This secondary analysis aimed to examine the influence of post-exercise GY consumption vs. an isoenergetic carbohydrate pudding (CP; control) on markers of systemic inflammation during an exercise training intervention. Methods: Thirty healthy young males completed 12 weeks of resistance and plyometric exercise training and were randomized to consume GY (n = 15) or CP (n = 15). Rested/fasted blood samples were acquired at baseline, and weeks 1 and 12, and inflammatory biomarkers (tumor necrosis factor-alpha [TNF-α], interleukin [IL]-6, IL-1 receptor antagonist [IL-1ra], IL-1Beta [IL-1β], IL-10, and C-reactive protein [CRP]) were measured. Linear mixed models were run on the absolute concentrations, and linear regressions were performed on the absolute change (baseline to week 12), allowing us to account for important covariates. Results: In both groups, CRP (pro) and IL-1ra (anti) increased at week 1 vs. baseline and week 12, while IL-1β (pro) decreased at week 12 vs. baseline (main time effects). We observed significant interactions for IL-6, TNF-α, and the TNF-α/IL-10 ratio, indicating that at week 12, IL-6 (pro) was lower in GY, whereas TNF-α and TNF-α/IL-10 (both pro-inflammatory) were higher in CP vs. week 1 and baseline, respectively. Additionally, within our linear regression models, higher baseline concentrations of IL-1ra (anti), IL-10 (anti) and CRP (pro) predicted greater change over the intervention. Conclusions: These results indicate that our intervention benefited circulating inflammatory markers, and GY supplementation may enhance these effects. Full article

Rheumatoid arthritis (RA) is a systemic autoimmune disease that, beyond joint destruction, contributes to neuropsychiatric symptoms such as depression, anxiety, and cognitive impairment. These symptoms are often underrecognized despite their major impact on quality of life. Accumulating evidence suggests that pro-inflammatory cytokines, particularly tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), play a key role in this neuroimmune interface. This narrative review examined 16 clinical studies evaluating the effects of biologic therapies targeting TNF-α and IL-6 on mental health outcomes in RA. The total study population comprised 9939 patients, including 2467 treated with TNF-α inhibitors and 7472 with IL-6 or IL-6 receptor inhibitors. TNF-α inhibitors were associated with improved depressive symptoms and emotional well-being. IL-6 inhibitors demonstrated similar psychiatric benefits, particularly in patients with elevated IL-6 levels. The findings highlight that biological therapies in RA may influence not only physical symptoms but also mental health, likely through modulation of neuroimmune pathways including blood–brain barrier permeability, microglial activation, and HPA axis regulation. Future research is needed to clarify these effects in populations stratified by psychiatric comorbidity and inflammatory biomarkers. Clinical implications: Incorporating psychiatric symptom screening and considering neuroinflammatory profiles may help guide the selection of biologic therapy in RA, particularly in patients with comorbid depression or fatigue. Full article