Background Acute decompensated heart failure (ADHF) is characterized by a systemic inflammatory response with elevated circulating cytokines that correlate with adverse outcomes. Glatiramer acetate (GA), an established immunomodulatory agent, exerts broad effects on innate and adaptive immunity and has demonstrated cardioprotective properties in preclinical models. We hypothesized that GA could reduce the cytokine surge associated with ADHF. Methods We conducted a small, investigator-initiated, hypothesis-generating randomized clinical trial to evaluate the effects of GA on inflammatory cytokines in patients with ADHF and reduced ejection fraction. Patients were randomized 1:1 to standard care or an add-on treatment with GA. Circulating cytokines were measured using multiplex ELISA assays at baseline, day 2, and day 14. Secondary outcomes included changes in NT-proBNP and troponin. Results Fourteen patients were enrolled. GA therapy was associated with a broad attenuation of the cytokine response, with a significant reduction in IL-6 levels compared with standard care (adjusted p = 0.01). Analysis of normalized data demonstrated a marked blunting of the cytokine surge in the GA group at days 2 and 14 (pooled log2 fold-change −5.2 vs. +7.3, p < 0.0001). GA treatment was also associated with a reduction in NT-proBNP levels at both time points, whereas troponin levels were unchanged. No treatment-related adverse events were observed. Conclusions In this proof-of-concept study, GA was associated with attenuation of the inflammatory cytokine surge and reduction in NT-proBNP levels in ADHF. These findings support further evaluation of GA in larger trials.
The liver plays a central role in metabolic and immunological homeostasis through integrated signaling networks coordinating inflammation, mitochondrial markers, oxidative stress, nitric oxide bioavailability, and autophagy. Interleukin-10 (IL-10) is a key anti-inflammatory cytokine involved in tissue homeostasis, whereas physical exercise is a non-pharmacological strategy capable of improving mitochondrial markers and attenuating inflammation. However, whether IL-10 is required for hepatic autophagy–mitochondrial–inflammatory adaptations induced by strength training remains unclear. Here, we investigated the effects of IL-10 deficiency on hepatic mitochondrial markers, autophagic flux, inflammatory signaling, nitric oxide metabolism, and liver morphology, as well as the effects of strength training. Wild-type (WT) and IL-10 knockout (IL-10 KO) mice were allocated to sedentary or strength-trained groups for 8 weeks. Liver samples were analyzed by RT-qPCR, western blotting, electron paramagnetic resonance, chemiluminescence-based detection of nitric oxide metabolites, and histological assessment. Global IL-10 deficiency was associated with reduced liver autophagic flux and total STAT3 protein levels, together with increased hepatic inflammation and hepatic lipid volume fraction. Strength training improved physical performance in both genotypes and potentiated mitochondrial adaptations in IL-10 KO mice, including upregulation of respiratory chain complexes and bioenergetic gene expression. In IL-10 KO mice, strength training attenuated hepatic inflammation and modulated nitric oxide metabolism but did not restore autophagic flux or reduce hepatic lipid volume fraction. Exploratory bioinformatic analyses identified associations between IL-10 expression, selected autophagy-related genes, and chronic liver disease stage. Together, these findings suggest that strength training induces beneficial, but incomplete, hepatic adaptations in IL-10-deficient mice and highlight an association between IL-10 deficiency and alterations in hepatic autophagy, mitochondrial markers, and inflammatory status.
Background Early structural lung remodeling may develop during pulmonary tuberculosis (TB) treatment, but its relationship with circulating mediators of fibrotic signaling remains poorly characterized. We investigated circulating transforming growth factor-beta (TGF-β) and SMAD3 in relation to early radiological fibrotic changes and pulmonary function. Methods In this prospective cohort study, 38 adults with newly diagnosed pulmonary TB completed two months of standard intensive-phase treatment. Serum TGF-β and SMAD3 were measured by ELISA, while radiological fibrosis severity and pulmonary function were assessed after the intensive phase. Between-group differences and associations with fibrosis severity were evaluated using appropriate parametric and non-parametric analyses. Results Early radiological fibrotic changes were identified in 31/38 participants (81.6%). FVC and FEV1 were numerically lower with greater fibrosis severity, although overall between-group differences were not significant (p = 0.145 and p = 0.213, respectively). Fibrosis severity was inversely correlated with FVC (ρ = −0.388, p = 0.016) and FEV1 (ρ = −0.341, p = 0.036). Circulating TGF-β did not differ significantly across fibrosis categories (p = 0.179). In contrast, SMAD3 differed across categories (p = 0.035) and correlated with fibrosis severity (ρ = 0.483, p = 0.002); after Holm adjustment, only the no-fibrosis versus severe-fibrosis comparison remained significant (p = 0.025). Conclusions Circulating SMAD3, but not TGF-β, was associated with early radiological fibrosis severity during TB treatment. These findings support further longitudinal investigation of molecular changes accompanying post-TB pulmonary remodeling without establishing pathway activation or clinical biomarker utility.
Cross-platform comparisons of serum cytokine immunoassays have often focused on rank correlation, but the extent of absolute agreement and systematic bias between platforms remains insufficiently characterized. Few independent head-to-head evaluations have compared multiple immunoassay platforms on the same clinical samples using overlapping cytokines. Here, serum samples from 48 adult participants were analyzed in parallel for seven cytokines (IL-6, IL-7, IL-8, IL-10, IL-15, TNF-α, IFN-γ), four chemokines (CCL2, CCL3, CCL4, CXCL10), and one growth factor (VEGF-A) using three multiplex platforms: OLINK proximity extension assay-based, LUMINEX bead-based, and V-PLEX electrochemiluminescence-based immunoassays. LLOQs, absolute concentrations, rank correlations, ICCs, and Bland-Altman biases were compared between platforms. Absolute serum cytokine concentrations differed by up to two orders of magnitude. Correlations between OLINK and V-PLEX were generally strong, whereas correlations involving LUMINEX were often weak or non-significant. ICCs were poor (<0.5) for most analytes and platform pairs, with IL-8 as a notable exception. Bland-Altman analyses on log-transformed concentrations revealed large, analyte-specific multiplicative biases and wide ratio-scale limits of agreement, indicating poor absolute agreement. These findings show that OLINK, LUMINEX, and V-PLEX measurements are not interchangeable at the level of absolute concentrations and underscore key analytical limitations that currently hinder the broad adoption of cytokine immunoassays, particularly multiplex panels, as regulator-approved tests.
Background Cell-count–derived inflammatory indices, including the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII), are widely used to assess COVID-19 severity, but hepatic dysfunction and thrombocytopenia may alter their prognostic meaning. We tested whether FIB-4-defined hepatic risk modifies the interpretation of cell-count inflammation and whether this discordance has a cytokine or chemokine correlate. Methods We applied an a priori 2 × 2 framework to 575 hospitalized adults with COVID-19 undergoing CT pulmonary angiography, classified by cardiometabolic burden and FIB-4-defined hepatic risk. Associations with oxygen requirement, ICU admission, in-hospital death, composite ICU/death and prolonged hospitalization were analyzed. A separate non-overlapping cytokine cohort of 90 patients was used for cytokine/chemokine profiling. Results Hepatic-risk phenotypes had higher adjusted odds of adverse outcomes but paradoxically lower NLR, PLR, SII and derived NLR. Significant index × hepatic-risk interactions showed that NLR, SII and dNLR retained their expected risk gradients in non-hepatic-risk patients but were attenuated or absent in hepatic-risk patients. In the cytokine cohort, the cellular pattern was reproduced, CXCL10/IP-10 and IL-8/CXCL8 were selectively elevated, and hepatic-risk patients were enriched in the NLR-low/CXCL10-high quadrant. Cell-normalized CXCL10 metrics and a CXCL10–NLR discordance score supported disproportionate chemokine enrichment relative to suppressed peripheral cell-count readouts. Conclusion FIB-4-defined hepatic-risk COVID-19 identifies a CXCL10/IP-10-enriched, peripherally cell-count-suppressed inflammatory phenotype. Conventional NLR-, PLR-, SII- and dNLR-based risk interpretation may underestimate clinical risk when hepatic risk is present.
