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Results for “Systemic inflammation”

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PubMed2026

Inherited Predisposition to Increased Systemic Inflammation Predicts a Broad Class of Disease Phenotypes.

Chronic, low-grade systemic inflammation is a polygenic trait captured with the INFLA-score, a composite of C-reactive protein, platelet count, leukocyte count, and granulocyte-to-lymphocyte ratio. We derived a polygenic risk score from the INFLA-score (iPRS) in a multi-ancestry population from the UK Biobank (n=421,368), then evaluated and used it in a phenome-wide association study among participants in the All of Us Research Program (AoU). The multi-ancestry iPRS was tested for association with the INFLA-score in AoU (N=4,833 with biomarker data) via linear regression, adjusting for age, sex, and genetically-determined principal components (PCs) and with 2,821 phecodeX-defined phenotypes in AoU (N=265,068) via logistic regression, adjusting for sex, age, EHR length, race, ethnicity and PCs. The iPRS predicted the INFLA-score (R-squared=0.026, beta=0.980, p<2x10-16) and was associated with 47 phenotypes (Bonferroni-corrected p<0.05). The strongest associations were with blood-related phenotypes: elevated white blood cell count (OR=1.19, p=3.85x10-66), thrombocytopenia (OR=0.86, p=5.70x10-44), platelet defects (OR=0.86, p=2.47x10-43), neutropenia (OR= 0.86, p=5.52x10-18), myeloproliferative disorder (OR= 1.2, p=2.77x10-15). Others included celiac disease (OR=0.713, p=2.98x10-46), ankylosing spondylitis (OR=1.4, p=1.33 x 10-17), hypertension (OR=1.04, p=4.56x10-15), rheumatoid arthritis (OR=1.09, p=1.02x10-13), hematuria (OR=1.05, p=1.96x10-10). Removing major-histocompatibility-complex SNPs abolished associations with known autoimmune diseases, while all other associations remained. We replicated 17 (42.5%) of 40 significant phenotypes available in the Vanderbilt University Medical Center's BioVU. Our findings demonstrate that systemic inflammation can be predicted using the iPRS across multiple ancestries, and the iPRS is associated with numerous clinical endpoints. This multi-ancestry iPRS may have future utility in stratifying risk for inflammation-driven conditions across diverse populations.

Journal Article↗

PubMed2025

Association of Lung Quantitative CT Scan Textures With Systemic Inflammation and Mortality in COPD.

BACKGROUND: COPD is characterized by persistent inflammation that is responsible for remodeling the bronchovascular bundles (BVBs), which may lead to poor quality of life. Quantitative CT (QCT) scan textures of the lung can capture local disease patterns of inflammation and related respiratory morbidity. RESEARCH QUESTION: Are BVB textures, obtained from the adaptive multiple feature method, associated with systemic inflammation, morbidity, and mortality in COPD? STUDY DESIGN AND METHODS: We analyzed data from the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS; n = 2,981) and the Genetic Epidemiology of COPD (COPDGene) study (n = 10,305). The predictors included 2 QCT scan biomarkers, the BVB and CT density gradient (CTDG) textures, age, sex, BMI, race, smoking status, pack-years of smoking, CT scan-detected emphysema, and square root of the wall area of a hypothetical airway with a 10-mm lumen perimeter (Pi10). Outcomes included plasma biomarker concentrations from Meso Scale Discovery proteomics assays and CBC counts, both as markers of inflammation, along with FEV1, FEV1 to FVC ratio, St. George's Respiratory Questionnaire score, 6-minute walk distance, and modified Medical Research Council dyspnea scale score. Associations of these QCT scan textures with FEV1 decline and all-cause mortality also were investigated. RESULTS: Increased BVB texture was associated significantly with elevated neutrophil and monocyte counts and the neutrophil to lymphocyte ratio, independent of clinical covariates, CT scan-detected emphysema, and Pi10. Elevated CTDG was associated with increased neutrophil count, NLR, and tumor necrosis factor α. Increased CTDG and BVB textures also were associated with a lower FEV1 and 6-minute walk distance. CTDG at baseline was also associated with decline in FEV1 at the 5-year follow-up in the COPDGene study. We observed a significant association of both BVB texture (SPIROMICS: hazard ratio [HR], 1.084 [95% CI, 1.035-1.135; P < .001]; COPDGene: HR, 1.106 [95% CI, 1.080-1.131; P < .001]) and CTDG texture (SPIROMICS: HR, 1.033 [95% CI, 1.003-1.064; P = .03]; COPDGene: HR, 1.079 [95% CI, 1.061-1.096; P < .001]) with all-cause mortality independent of CT scan-detected emphysema and Pi10. INTERPRETATION: QCT scan textures may provide imaging evidence of the spatial heterogeneity of lung inflammation and overall disease burden in COPD. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; Nos.: NCT01969344 (SPIROMICS) and NCT00608764 (COPDGene); URL: www. CLINICALTRIALS: gov.

Humans↗

PubMed2026

Childhood Economic Mobility and Systemic Inflammation Among Men Who Experienced Low Income in Toddlerhood: The Moderating Role of Trait Hostility.

OBJECTIVE: Childhood economic upward mobility (ie, increases in family income across childhood) may attenuate links between childhood poverty and systemic inflammation in adulthood, the extent of which may vary depending on inter-individual differences in personality characteristics, including hostility. METHODS: Men who experienced low income in toddlerhood (N=171) were followed prospectively into adulthood. Annual family income was collected 12 times when men were 1.5 to 17 years old. Men completed the Cook-Medley Hostility Scale and had their fasting blood drawn to measure circulating levels of C-reactive protein (CRP) at age 32. Multiple linear regression analyses examined main and moderation effects of childhood economic upward mobility and adult hostility on CRP levels adjusting for income at 1.5 years, race, parent educational attainment, and adult income, education, waist circumference, and smoking status. RESULTS: Main effects were nonsignificant, but an interaction effect emerged. Counter to expectations, childhood economic upward mobility related to greater adult CRP as trait hostility decreased ( β =-0.203, P =.018). Simple slope analyses further revealed that childhood economic upward mobility was positively associated with CRP among men lower in hostility ( β =0.23, SE=0.09, P =.020) but was unrelated to CRP among men higher in hostility. Results of post hoc sensitivity analyses are also discussed. CONCLUSIONS: Counterintuitive findings suggest that for men who experience poverty in toddlerhood, the association between childhood economic upward mobility and adult CRP may be nuanced and even in the positive direction for men low in hostility, which aligns with work on unintended health consequences of upward mobility.

Humans↗

PubMed2026

Effects of exercise on muscle strength and characteristics in rheumatic diseases and sarcopenia: Protocol for the Care for Muscle (C4M) Study.

OBJECTIVE: Muscle weakness is prevalent in rheumatoid arthritis (RA), osteoarthritis (OA) and sarcopenia (SARC). Endurance exercises may improve mitochondrial function and oxidative capacity, while strength exercises are thought to stimulate myofibrillar protein synthesis. This study aims to compare the effects of strength and endurance exercise and explore the association between muscle characteristics and exercise outcomes in patients with RA, OA and SARC. We hypothesize that responses to endurance and strength exercises in patients with muscle weakness are influenced by intramuscular pathology including muscle morphology, mitochondrial function, and systemic inflammation, based on their disease pathology, potentially requiring personalized training schedules. METHODS: This two-arm, parallel-group exploratory trial will enroll 69 patients (23 RA, 23 OA, 23 SARC), randomized to endurance (n = 35) or muscle strength exercises (n = 34), using minimization to balance disease type and gender. The 8-week intervention includes two supervised sessions per week using a controlled cable pulley device (Reforter™) and fitness equipment, plus one weekly home-based session. The primary outcome is isokinetic muscle strength (peak torque), measured with the Biodex system®. Secondary outcomes include muscle morphology, mitochondrial function, systemic inflammation and muscle endurance (by Biodex and 6 Minute Walk test). Muscle morphology will be assessed via 3D ultrasound imaging of the vastus lateralis. Mitochondrial function will be analyzed using high-resolution respirometry on muscle biopsies. Systemic inflammation will be measured using multiplex assays or ELISA on serum samples. DISCUSSION: This study will explore differential responses to muscle endurance and muscle strength exercises in patients with RA, OA, and SARC, offering novel insights into the molecular mechanisms of muscle weakness. The findings may help identify potential mechanisms underlying variability in exercise response and provide effect size estimates to guide future confirmatory studies and more targeted exercise interventions. TRIAL REGISTRATION: ClinicalTrials.gov NCT06480643 (date of registration28-06-24).

Humans↗

PubMed2026

Association of time-averaged systemic immune-inflammation indices with in-hospital mortality after intracerebral hemorrhage: a retrospective study.

BACKGROUND: Systemic inflammation plays a central role in secondary brain injury following intracerebral hemorrhage (ICH). Although inflammatory indices such as the neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), and systemic inflammation response index (SIRI) are linked to poor outcomes, their associations with mortality are commonly assumed to be linear, potentially overlooking nonlinear patterns where mortality risk rises steeply at higher levels. METHODS: We conducted a retrospective study using the MIMIC-IV database, including 440 patients with non-traumatic ICH who were alive and remained in the ICU for at least 72 h after admission. Mean NLR, SII, and SIRI were calculated from measurements obtained during this period. Multivariable logistic regression and restricted cubic spline (RCS) analyses were applied to assess their independent and nonlinear associations with in-hospital mortality. Model discrimination and calibration were internally validated using 1,000 bootstrap resamples. RESULTS: The in-hospital mortality rate was 26.1%. After multivariable adjustment, NLR and SIRI remained independently associated with mortality. Patients in the highest SIRI quartile had the highest risk of death (aOR = 5.12; 95% CI: 2.57-12.24; p < 0.001). RCS analysis revealed a significant nonlinear association between SIRI and mortality (p-nonlinearity < 0.05), showing a steep risk increase at higher SIRI levels. Adding SIRI to the base model provided a modest improvement in discrimination (AUC 0.762 to 0.785, p = 0.045) and significantly improved risk reclassification (cNRI = 0.4778, p < 0.001; IDI = 0.0240, p = 0.0151). CONCLUSIONS: Among patients with ICH who met the 72-hour eligibility criterion, higher 72-hour average SIRI was independently associated with in-hospital mortality. As a time-averaged measure, SIRI should be interpreted as a dynamic marker integrating the initial inflammatory state and the early clinical course rather than as a purely baseline prognostic factor. Although adding SIRI to the base model modestly improved discrimination and risk reclassification, it should be considered a candidate prognostic marker requiring external validation before clinical application.

Humans↗

PubMed2026

Matrine Alleviates Sepsis-Induced Acute Lung Injury by Reinforcing NQO1/SLC7A11/GPX4-Associated Anti-Ferroptotic Defenses and Attenuating NF-κB-Driven Inflammation.

BACKGROUND: Sepsis triggers dysregulated systemic inflammation and multiple-organ dysfunction, with the lungs being particularly susceptible to injury. Sepsis-induced acute respiratory distress syndrome (ARDS) is mainly driven by TLR4/NF-κB-mediated hyperinflammation and alveolar macrophage activation. Matrine, a bioactive alkaloid derived from Sophora flavescens, has been reported to modulate redox homeostasis and ferroptosis-associated lipid peroxidation. However, the target-specific mechanisms underlying its effects on ferroptosis and inflammatory signaling in sepsis-induced acute lung injury (SALI) remain incompletely understood. PURPOSE: This study aimed to evaluate the therapeutic effects of matrine in a cecal ligation and puncture (CLP)-induced SALI model and to determine whether its protective effects involve reinforcement of NQO1/SLC7A11/GPX4-associated anti-ferroptotic defenses and suppression of NF-κB-driven inflammation. METHODS: We analyzed the single-cell RNA-sequencing (scRNA-seq) dataset GSE273924 to characterize CD45-enriched pulmonary immune-cell subsets in sham mice and mice with intratracheal Escherichia coli-induced pneumonia. Network pharmacology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to predict Kushen (KS)-related targets and pathways associated with SALI. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) of GSE245013 were used to identify candidate targets. Matrine-NQO1 binding and intracellular target engagement were evaluated using molecular docking, molecular dynamics simulations, surface plasmon resonance (SPR), and the cellular thermal shift assay (CETSA). The therapeutic effects of matrine were assessed in mice with CLP-induced SALI and in lipopolysaccharide (LPS)-stimulated MH-S cells. Lung histopathology, inflammatory cytokine production, target protein expression, ferroptosis-associated indicators, and NF-κB activation were evaluated using molecular, biochemical, and histological assays. The functional contribution of NQO1 was further examined using the NQO1 inhibitor ES936. RESULTS: scRNA-seq analysis of GSE273924 revealed substantial remodeling of the CD45-enriched pulmonary immune-cell landscape in mice with intratracheal E. coli-induced pneumonia, including macrophage transcriptional programs associated with ferroptosis and inflammatory signaling. Integrated network pharmacology and bioinformatics analyses prioritized NQO1 as a candidate target of matrine and identified NF-κB signaling as a potentially relevant pathway. Molecular docking, molecular dynamics simulations, SPR, and CETSA supported matrine-NQO1 binding and intracellular target engagement. Functionally, matrine improved survival, attenuated lung injury, reinforced NQO1/SLC7A11/GPX4-associated anti-ferroptotic defenses, and suppressed NF-κB activation in CLP mice. Similar protective effects were observed in LPS-stimulated MH-S cells. ES936 partially attenuated the matrine-mediated improvements in cell viability, redox homeostasis, ferroptosis-associated indicators, and NF-κB p65 phosphorylation, supporting a functional contribution of NQO1 to the protective effects of matrine. CONCLUSION: Matrine alleviates SALI by reinforcing NQO1/SLC7A11/GPX4-associated anti-ferroptotic defenses and attenuating NF-κB-driven inflammation.

Animals↗

PubMed2026

The IL-1 system in inflammation and cancer.

Inflammation is a pathogenetic driver of several pathological conditions, including cancer. The tumor microenvironment, which includes cellular, molecular, and structural components, is an essential component of cancer, involved in tumor promoting or controlling processes. In particular, inflammatory players contribute to the establishment of a tumor-promoting microenvironment, which affects all stages of tumor development, from initiation to metastasis, as well as response to therapy. The IL-1 system includes two large sets of structurally related ligands and receptors, with agonist or regulatory activity, playing non-redundant roles in inflammation and immunity. Each of them has specific functions in tissue homeostasis, inflammation, innate and adaptive immune responses, and potentially contributes to processes related to carcinogenesis and metastasis, or immune-mediated control of cancer cells. Depending on the context and cellular target, IL-1 family members may play dual roles in cancer, driving both pro- or anti-tumor processes. IL-1α and IL-1β can directly promote cancer cell proliferation, survival, and plasticity, in addition to contribute to the establishment of a pro-inflammatory environment that promotes tissue remodeling, cellular stress responses, and genomic instability. On the other hand, IL-1 is a lymphoproliferative and activating molecule in innate and adaptive responses, thus contributing to anti-tumor immune mediated responses. In addition, members of the IL-1 system act as regulators of mechanisms involved in cancer, including emergency hematopoiesis, trained immunity, and metabolism. Here, we will provide an overview of the IL-1 system in cancer and discuss the functional complexity of IL-1 family cytokines, which orchestrate both protective and pro-tumorigenic responses, by directly acting on cancer cells and by driving environmental stimuli which indirectly act on cancer cells.

Humans↗

PubMed2026

Plasma proteomic profiling of septic shock and acute pancreatitis identifies shared signatures and disease-specific pathways.

Septic shock represents the most severe form of infection-driven systemic inflammation, whereas acute pancreatitis induces a sterile inflammatory response. Although clinically similar, their molecular profiles may reveal distinct mechanisms underlying infectious and non-infectious inflammation. We performed plasma proteomic profiling using LC-MS/MS in patients with septic shock (n = 13), acute pancreatitis (n = 8), and healthy controls (n = 8). Among 663 quantified proteins, 231 were differentially expressed in septic shock versus controls, 83 in pancreatitis versus controls, and 29 in septic shock versus pancreatitis. Septic shock was characterized by higher plasma concentrations of MARCKS, HSP90AA1, PSAP, CD163, and GANAB, whereas pancreatitis showed higher levels of CPA1, APOC4, APOC3, BPGM, and APOC2. Cluster analysis demonstrated separation between groups, with overlapping proteomic patterns in sepsis and pancreatitis. Gene Ontology and KEGG analyses revealed shared inflammatory signatures, including upregulation of acute-phase responses and downregulation of coagulation pathways. However, septic shock exhibited more extensive proteomic alterations, with distinct activation of PI3K-Akt signaling and suppression of lipid metabolism. In conclusion, septic shock and pancreatitis share common inflammatory pathways, while proteomic differences highlight divergent regulation of coagulation, lipid metabolism, and anti-inflammatory signaling, offering potential biomarkers to distinguish infectious from sterile systemic inflammation.

Shock, Septic↗

PubMed2025

Dapagliflozin reduces epicardial adipose tissue in patients with heart failure and type 2 diabetes.

BACKGROUND: Epicardial adipose tissue (EAT) has a contributory role in the progression of heart failure. We tested whether dapagliflozin reduces EAT in adults with type 2 diabetes (T2D) and heart failure and explored links with systemic inflammation and cardiac structure. METHODS: This analysis is based on pooled data from two phase 2, single-centre, double-blind, placebo-controlled randomised trials (REFORM and DAPA-LVH) conducted in Scotland. Exactly 122 participants with T2D and stage B or C heart failure were randomised to dapagliflozin 10 mg once daily or placebo for 12 months. Cardiac magnetic resonance imaging (CMR) was used to assess EAT. At baseline and follow-up, the inflammatory markers TNF, IL-1, IL-6, IL-10, and CRP were measured. RESULTS: At baseline, obesity was common (75% with BMI ≥30 kg/m2) and heart-failure phenotypes were balanced (HFpEF 51%, HFrEF 49%). After 12 months, dapagliflozin significantly reduced EAT independently of changes in BMI (-1.16 ± 0.18 vs. +0.36 ± 0.19 cm2, p < 0.001), BMI (-1.17 ± 0.16 vs. -0.18 ± 0.17 kg/m2, p < 0.001), and left ventricular mass (-3.53 ± 1.77 vs. +1.57 ± 1.83 g, p = 0.048) compared with placebo. CONCLUSION: Dapagliflozin shrinks EAT and LV mass independently of BMI in T2D patients with stage B/C heart failure, supporting EAT as a modifiable target of SGLT2 inhibition. The absence of parallel changes in systemic inflammation suggests primarily local mechanisms.

Humans↗

PubMed2026

Prognostic modeling of overall survival in metastatic pancreatic cancer: an inflammation-based tool validated in PANTHEIA-SEOM cohort.

PURPOSE: To develop and internally validate the PANTHEIA-SIRI prognostic model, which integrates log-transformed systemic inflammation response index (SIRI) with clinical predictors, to estimate overall survival (OS) in metastatic pancreatic ductal adenocarcinoma (mPDAC) treated with first-line chemotherapy. METHODS: We used data from the multicenter PANTHEIA-SEOM registry. OS was defined from chemotherapy start. The model was fitted as a Weibull accelerated failure time model in the survival-analysis population with multiple imputation. Predictors were log-transformed baseline SIRI, modeled with restricted cubic splines, ECOG, tumor burden, chemotherapy regimen, and anorexia-cachexia syndrome. Internal validation used a separate, non-overlapping cohort from the same registry; the centers contributing to each cohort are listed in a supplementary annex. TRIPOD was followed. Discrimination was assessed with Harrell´s C-index and calibration with IPCW Brier scores and IPA. RESULTS: The derivation cohort comprised 672 patients with SIRI data (593 analyzed for survival) across 22 Spanish hospitals (2015-2025); 80.1% had died after a median OS of 9.9 months. The imputation-pooled derivation C-index was 0.654 (95% CI, 0.627-0.681); optimism-corrected, 0.629. Internal validation used 62 separate patients from the same registry; 96.8% had died after a median OS of 9.2 months. The validation C-index was 0.603 (95% CI, 0.518-0.687). Calibration was adequate at 6 and 12 months. CONCLUSIONS: The PANTHEIA-SIRI model provides individualized OS estimates in mPDAC with routine clinical predictors. Its open-access calculator ( https://pantheia-siri.shinyapps.io/calc/ ) may support prognostic communication, treatment-intensity selection, and supportive-care planning. Routine clinical implementation will require further validation in larger, fully independent cohorts.

Cachexia↗

PubMed2026

Proteomic profiling identifies systemic drivers of blood-brain barrier injury in sickle cell disease.

Sickle cell disease (SCD) causes brain injury and cognitive disability. Systemic inflammation and endothelial injury are central to SCD pathophysiology, yet the relationship between systemic drivers of blood-brain barrier (BBB) disruption and brain injury remains understudied. This cross-sectional study assessed whole-brain and regional BBB permeability (Ktrans) using dynamic contrast-enhanced magnetic resonance imaging for 37 adults with SCD in steady state and 37 adults without SCD. Cerebral oxygen extraction fraction (OEF) and white matter mean diffusivity (MD) measured tissue hypoxia and microstructural injury, respectively. The SCD cohort showed elevated Ktrans compared with controls (3.6 × 10-4·min-1 vs 2.58 × 10-4·min-1; 95% confidence interval [CI] median difference, 0.36 × 10-4·min-1 to 1.30 × 10-4·min-1; P< .001), indicating BBB disruption. In SCD, white matter Ktrans was associated with MD (β, 6.25 [95% CI, 1.72-10.77]; P = .008), independent of OEF (β, 0.22 [95% CI, 0.09-0.35]), and silent cerebral infarcts (β, 0.01 [95% CI, 0.00-0.02]). The interaction (P = .037) between Ktrans and OEF on MD suggested a combined, deleterious effect of BBB disruption and hypoxia on microstructural injury. High-throughput plasma proteomics followed by differential expression analysis, and weighted gene correlation network analysis in a subset of 61 participants revealed that 79 proteins associated with BBB permeability belonged to iron homeostasis, response to hypoxia, immune dysregulation, extracellular matrix degradation, lipoprotein homeostasis, and arginine-proline metabolism pathways. All pathways were independently associated with microstructural injury. BBB permeability was a mediator of brain injury for all pathways except extracellular matrix degradation. Targeting specific systemic pathways to protect the BBB may represent a therapeutic approach to preserve brain health in SCD.

Humans↗

PubMed2026

Intestinal blood vessel-associated macrophages and gut-vascular barrier dysfunction in cirrhosis.

BACKGROUND: Bacterial translocation in cirrhosis can trigger infection and hepatic decompensation, leading to systemic inflammation, organ failure and increased mortality. These infections often originate from the gastrointestinal tract after bacteria breach the intestinal barrier and disseminate to systemic sites. OBJECTIVE: In this study, we explore the mechanisms underlying intestinal barrier dysfunction in cirrhosis using an experimental cirrhosis model and patient-derived intestinal biopsies. DESIGN: We developed a murine model of cirrhosis through chronic administration of carbon tetrachloride for up to 20 weeks. We investigated both the intestinal epithelial and vascular compartments and performed single-cell transcriptomic profiling of myeloid cells isolated from cirrhotic mice and from individuals with compensated and decompensated cirrhosis. RESULTS: Our findings indicate that bacterial translocation in cirrhosis is the result of failure at multiple checkpoints, including aberrant epithelial cell death, vascular barrier damage and dysfunction of gut-vascular macrophages. In a preclinical model of cirrhosis, macrophages exhibited increased levels of monocyte-attracting chemokines, reduced bacterial clearance and impaired interactions with blood vessels. Importantly, depleting vascular-lining macrophages resulted in bacterial translocation to systemic sites, even in the absence of experimental liver disease. Transcriptional profiling of macrophages from duodenal biopsies of patients with cirrhosis indicated similar dysregulation of pathways supporting blood vessels and elevated expression of chemokines. CONCLUSIONS: This study emphasises the critical role of intestinal macrophages in preventing the dissemination of luminal bacteria and highlights the multifaceted breakdown of the intestinal barrier in cirrhosis and the importance of the gut-vascular barrier.

Animals↗

PubMed2026

From glycosylation to inflammation: insights from NMR-Derived GlycA and GlycB.

Post-translational modifications (PTMs) play a crucial role in increasing proteomic diversity. N-linked glycosylation acts as a key regulatory layer that influences protein stability, trafficking, circulation, and immune responses. Unlike conventional inflammatory biomarkers that measure individual proteins, nuclear magnetic resonance (NMR) spectroscopy identifies the combined signals GlycA and GlycB from glycoproteins, offering an overall view of systemic glycoprotein changes. These signals represent the N-glycosylation patterns of several abundant acute-phase proteins (APPs), giving detailed molecular insights. This review offers a detailed assessment of GlycA and GlycB as mechanistically grounded indicators of liver glycoprotein remodeling and systemic inflammation. GlycA mainly indicates the levels and structural complexity of N-acetylglucosamine (GlcNAc) and N-acetylgalactosamine (GalNAc) residues linked to acute-phase glycoproteins and glycan branching. In contrast, GlycB reflects changes in terminal sialylation, which influences glycoprotein half-life, immune recognition via lectins, and inflammatory signaling. Collectively, these biomarkers combine measurements of hepatic APP production with variations in glycan structure, offering mechanistically anchored reporters of hepatic glycoprotein remodeling. We explore the enzymatic pathways responsible for N-glycan branching, fucosylation, and sialylation, as well as the roles of major APP scaffolds in the GlycA and GlycB resonances. We also highlight the emerging clinical significance of these signals across infectious, autoimmune, cardiovascular, metabolic, neurodegenerative, and cancer-related diseases. Rather than serving simply as markers of inflammation, GlycA and GlycB provide mechanistically interpretable readouts of cytokine-driven hepatic glycoprotein remodeling and systemic immune activation, supporting their application in disease risk stratification, longitudinal monitoring, therapeutic response assessment, and precision medicine.

GlycA↗

PubMed2026

Integrative Multidimensional Profiling of Individuals Recovered from Mild COVID-19 Reveals Immune-Metabolic-Oxidative Network Interactions.

The COVID-19 pandemic underscored the need to better characterize immune and molecular responses following SARS-CoV-2 infection and vaccination. Beyond antibody and cellular immunity, COVID-19 involves oxidative stress and DNA damage, affecting repair mechanisms and metabolic adaptation linked to immune resilience. Here, we present a multidimensional analysis of 20 individuals who recovered from mild COVID-19, integrating clinical features with humoral and cellular immune responses, T cell and myeloid phenotypes, oxidative stress, DNA damage, and metabolomic and lipidomic profiles. Although most individual parameters fell within physiological ranges, network modeling revealed structured associations spanning multiple biological domains. A central finding was a coherent cluster organized around vaccine dose number, linking anti-Spike antibody titers, oxidative stress, bioenergetic signatures, and granulocyte activation. Higher vaccination was associated with stronger humoral responses, lower oxidative stress, and a more balanced myeloid-metabolic profile, suggesting a potential protective role extending beyond antibody induction. Additional associations linked symptom patterns to T cell differentiation states, anti-nucleocapsid responses to systemic inflammation, and anaerobic signatures to DNA damage markers, revealing interconnections between immunometabolism, clinical expression, and genomic stress. Despite the small sample size, these findings offer a preliminary systems-level perspective on mild COVID-19 recovery and illustrate the value of integrative exploratory frameworks in infectious disease research, laying the groundwork for validation in larger longitudinal cohorts.

Humans↗

PubMed2026

Anti-inflammatory and phosphorylation effects of CFTR modulator triple therapy in cystic fibrosis.

CFTR modulators like elexacaftor-tezacaftor-ivacaftor (ETI) improve morbidity in cystic fibrosis (CF), but their systemic effects on young children are not yet clear. We hypothesize that ETI has anti-inflammatory effects and reverse disease-associated molecular signatures in children with CF. This exploratory pilot study evaluates the cellular mechanisms of ETI on peripheral immune cells in children (<12 years) with CF using a multi-omics approach. Seventeen children with CF (median age 8.7 years, 26% female) and 12 controls (median age 9.6 years, 42% female) were included for blood RNA-sequencing, proteomics and phosphoproteomics. Baseline pathway enrichment analysis revealed systemic inflammation, transmembrane transporter deficiencies, reduced protein kinase, and GTPase activity. Three months post-ETI, anti-inflammatory effects, epigenetic modulation, and increased protein kinase activity were observed, indicating partial reversal of cellular abnormalities. ETI modified systemic inflammatory, epigenetic, and phosphorylation pathways in young children with CF, offering insights into CF pathology and potential biomarkers for treatment monitoring.

cystic fibrosis↗

PubMed2025

Parabacteroides goldsteinii mitigates parkinsonism in LRRK2 mutant mice by reducing neuroinflammation through Gut-Brain axis.

INTRODUCTION: Alterations in the gut microbiota accompanied by intestinal inflammation are early features of Parkinson's disease (PD). Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene represent a common genetic risk factor for PD and inflammatory bowel disease. Parabacteroides goldsteinii has been reported to alleviate intestinal and systemic inflammation. However, whether modulation of the gut microenvironment at early disease stage can attenuate PD progression remains unclear. OBJECTIVE: To investigate the impact of P. goldsteinii colonization prior to the onset of motor dysfunction on PD progression. METHODS: We established a germ-free PD mouse model carrying the LRRK2 G2019S mutation and administered P. goldsteinii orally at the pre-symptomatic stage to evaluate its effects on motor performance and PD-related neuropathology. Spatial and bulk RNA transcriptomic analyses of brain tissue, together with cytokine profiling, were conducted to assess central changes. To investigate gut immunomodulatory mechanisms, we performed intestinal bulk and single-cell RNA sequencing, spectral flow cytometry as well as cellular bioenergetic analyses. RESULTS: Germ-free conditions partially alleviated PD-like phenotypes in LRRK2 G2019S mice. Colonization with P. goldsteinii at 5-months of age, prior to motor symptom onset, further improved locomotor performance, reduced neuronal α-synuclein aggregations, and mitigated microglial activation and dopaminergic neurodegeneration. Neuroprotection was mediated through enhanced noncanonical neuronal IL-12 receptor-dependent neurotrophic support without activating the canonical STAT4 phosphorylation pathway, along with suppression of microglial activation and downregulation of LRRK2 kinase activity. At the intestinal level, P. goldsteinii suppressed TLR4-driven inflammation, expanded anti-inflammatory intraepithelial CD4+CD8αα+ T cells, promoted dendritic cell and macrophage differentiation, upregulated epithelial tight-junction genes, and improved mitochondrial bioenergetics in intestinal cells. CONCLUSION: P. goldsteinii colonization attenuates the progression of LRRK2-associated parkinsonism by restoring intestinal homeostasis and reducing neuroinflammation. These findings underscore the therapeutic potential of modulating the gut-immune-brain axis during the prodromal stage of PD.

Animals↗

PubMed2026

Repair and regeneration across the lifespan: an ontogenetic perspective.

The capacity for tissue repair and regeneration undergoes a profound and progressive decline across the human lifespan, representing a fundamental driver of aging and chronic disease. This review establishes a comprehensive ontogenetic framework by mapping the continuous biological transition from the flawless, scarless regenerative plasticity of embryonic development to the irreversible fibrotic scarring and organ failure characteristic of senescence. We synthesize the hierarchical collapse of reparative networks across multiple biological scales. Importantly, this ontogenetic decline should not be interpreted as a purely degenerative trajectory but rather as a dynamic systems-level reprogramming in which evolutionary trade-offs prioritize tumor suppression, immune surveillance, and reproductive fitness over long-term regenerative fidelity. Recognizing this adaptive reallocation of biological resources reframes aging not simply as failure but as a predictable recalibration of repair hierarchies. At the molecular and cellular levels, the accumulation of genomic instability, unresolvable DNA damage, and mitochondrial dysfunction gradually overwhelms intracellular quality-control mechanisms. Concurrently, epigenetic drift and chronic, low-grade systemic inflammation ("inflammaging") dismantle the stem cell niche, driving adult stem cell exhaustion and shifting wound healing away from functional tissue replacement toward maladaptive fibrosis. Furthermore, we examine divergent, organ-specific repair trajectories. By contrasting the severe regenerative restrictions of the adult central nervous system and myocardium with the persistent, yet exhaustible, resilience of the liver, we elucidate the unique intrinsic and microenvironmental barriers that impede structural and functional recovery. Finally, we evaluate the clinical paradigm shift from passive management of age-related degeneration to active restoration of tissue integrity. By integrating systemic geroscience-which addresses the global hallmarks of aging-with targeted bioengineering and in vivo epigenetic modulation, contemporary regenerative medicine seeks to recreate permissive, youthful microenvironments. Ultimately, mastering these ontogenetic principles holds unprecedented potential to reactivate endogenous repair pathways, mitigate multi-organ collapse, and significantly extend human functional healthspan.

DNA repair↗

PubMed2026

Causal Relationships Between Oral Microbiota and Inflammatory Skin Diseases.

INTRODUCTION AND AIMS: The oral microbiome has been increasingly linked to systemic inflammation and immune dysregulation, but whether specific oral bacteria causally contribute to inflammatory skin diseases remains unclear due to confounding and reverse causation. This study aimed to assess the causal effects of 43 oral microbiota taxa on the risk of five inflammatory skin diseases using a Mendelian randomization (MR) approach. METHODS: We performed a two-sample MR analysis using genetic instruments for oral microbiota derived from publicly available genome-wide association studies and outcome data from the FinnGen consortium. Causal effects of oral taxa on systemic lupus erythematosus, vitiligo, pemphigus, localized scleroderma, and dermatitis herpetiformis were estimated. The inverse-variance weighted method served as the primary analysis, complemented by sensitivity analyses to evaluate horizontal pleiotropy, heterogeneity, and reverse causality. RESULTS: MR analyses identified several putative causal associations between oral microbiota and inflammatory skin diseases. Genus Granulicatella and an unknown Streptococcus species (ASV0009) showed causal effects on systemic lupus erythematosus. Family Lachnospiraceae_[XIV] and an unknown Rothia species (ASV0016) were associated with vitiligo. Five oral microbiota taxa demonstrated causal associations with pemphigus. Actinomyces species micronuciformis was linked to localized scleroderma. Order Fusobacteriales and an unknown Neisseria species (ASV0004) were associated with dermatitis herpetiformis. No significant heterogeneity or horizontal pleiotropy was detected in sensitivity analyses. CONCLUSION: This MR study provides genetic evidence supporting a causal role of specific oral bacteria in the development of several inflammatory skin diseases, highlighting the oral microbiome as a potential contributor to cutaneous autoimmunity and inflammation. CLINICAL RELEVANCE: Our findings highlight the putative role of the oral microbiome as a plausible candidate for mechanistic and clinical investigations into the prevention or adjunctive management of selected inflammatory skin diseases. However, oral hygiene improvement, targeted antimicrobials, and other microbiota-directed interventions were not directly tested in this MR study and remain hypothetical strategies requiring validation in experimental and clinical studies.

Humans↗