Search Results (1,533)

Chronic heart failure (CHF) is characterized by heightened cardiac sympathetic activity and neuroinflammation within the stellate ganglia (SG), contributing to cardiac arrhythmogenesis. However, the upstream mediators of this neuroimmune interaction remain incompletely defined. This study investigated whether systemic neutralization of granulocyte–macrophage colony-stimulating factor (GM-CSF, an inflammatory cytokine) attenuates SG inflammation and cardiac sympathetic overactivation in a rat model of coronary artery ligation-induced CHF. Male Sprague–Dawley rats underwent myocardial infarction or sham surgery and were treated with a GM-CSF neutralizing antibody or vehicle. Cardiac sympathetic nerve activity (CSNA), heart rate variability (HRV), cytokine expression, and the electrophysiological properties of cardiac sympathetic post-ganglionic (CSP) neurons were assessed. CHF increased the levels of GM-CSF, ionized calcium-binding adaptor molecule 1 (IBA1, an activated macrophage marker) and pro-inflammatory markers (TNF-α, pro IL-1β) in the SG, enhanced neuronal Ca²⁺ currents, cell excitability, and CSNA, and impaired HRV. The GM-CSF neutralizing antibody significantly attenuated SG inflammation, partially normalized Ca²⁺ currents and neuronal firing, decreased CSNA, and improved cardiac autonomic balance. These findings identify GM-CSF as a key regulator of SG neuroinflammation and sympathetic dysregulation in CHF. Targeting this GM-CSF protein may represent a novel therapeutic strategy to mitigate autonomic imbalance and arrhythmic risk. Full article

Heterochromatin Protein 1γ, encoded by the Cbx3 gene, is a crucial epigenetic regulator that plays an essential role in mammalian meiotic progression. However, the functional divergence and conservation of this protein in teleosts—organisms possessing duplicated Cbx3 paralogs due to whole-genome duplication—remain to be elucidated. Building on previous research, we focused on cbx3a in Nile tilapia (Oreochromis niloticus), a significant aquaculture species and an excellent model for teleost reproductive studies, emphasizing its role in spermatogenesis. Expression analysis revealed that Cbx3a is localized to primordial germ cells and is sustained in spermatogonia, spermatocytes, and spermatids during spermatogenesis. CRISPR/Cas9-mediated knockout of cbx3a demonstrated that Cbx3a deficiency induces germ cell apoptosis, meiotic arrest, and sperm defects, including shortened tails and impaired motility, resulting in profound defects in sperm quantity and quality, strongly implying compromised male fertility. Transcriptomic analysis further identified dysregulated molecular pathways, including cytokine signaling and neuroactive ligand–receptor interactions. This provides novel mechanistic insights into HP1γ-mediated epigenetic regulation of meiosis. Notably, cbx3a mutants exhibited phenotypic bifurcation: a subset showed meiotic defects accompanied by sporadic germ cell apoptosis, whereas others underwent full meiotic arrest with pervasive germ cell apoptosis in adult gonads. Collectively, these findings clarify the essential and conserved role of Cbx3a/HP1γ in Nile tilapia spermatogenesis, thereby advancing the field of vertebrate reproductive epigenetics and providing a valuable theoretical basis for potential applications in reproductive management, such as improving sperm quality. Full article

Background: Dysregulated immune cells contribute to Schistosoma japonicum-induced liver injury. However, the underlying mechanisms remain poorly understood. This study aimed to identify feature genes and immune infiltration patterns linked to chronic schistosomiasis-associated liver injury. Methods: Differential gene expression analysis was conducted using dataset GSE61376 from the Gene Expression Omnibus (GEO) database. Functional enrichment of differentially expressed genes (DEGs) was performed via Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Weighted Gene Co-expression Network Analysis (WGCNA) was applied to construct further characterization of molecular networks. LASSO regression and random forest algorithms were combined to screen hub genes, whose diagnostic efficacy was assessed by ROC analysis. CIBERSORT estimated immune cell infiltration, and GSEA explored pathways associated with hub genes. Results: A total of 412 DEGs were identified between chronic schistosomiasis and control groups. The green module from WGCNA exhibited significant correlation with chronic schistosomiasis (r = −0.85, p < 0.05). ANKMY2 and FCER1A were identified as hub genes with AUC values of 0.875 (95% CI, 0.500–1.000) and 0.792 (95% CI, 0.458–1.000). GSEA revealed associations with cytokine–receptor interaction and other signaling pathways. A total of 11 differentially distributed immune cell subsets were observed, and hub genes were correlated with multiple immune cell populations. Conclusions: ANKMY2 and FCER1A participate in liver injury of chronic schistosomiasis by regulating the hepatic immunopathological microenvironment. These two genes may serve as promising targets for immunotherapy against S. japonicum-induced liver injury. Full article

The intestinal barrier is a key interface maintaining host–microbial segregation and systemic homeostasis. A broad range of viruses, including enteric, respiratory, and systemic pathogens, can disrupt this barrier through effects on epithelial integrity, vesicular transport, immune responses, and microbial ecology. Whether these diverse insults converge on shared regulatory nodes or act through distinct virus-specific pathways that ultimately result in barrier failure remains unclear. Building on this premise, this review systematically delineates the molecular and cellular mechanisms underlying virus-induced disruption of the intestinal barrier. Viral infection disrupts epithelial integrity through multiple converging processes, including disassembly of tight junction architecture, activation of programmed cell death pathways, degradation of the mucus layer, impaired regeneration driven by intestinal stem cells, and dysregulation of transcellular transport. These processes are interconnected and collectively drive epithelial dysfunction and barrier breakdown. Beyond epithelial damage, we further highlight the pivotal contribution of host immune responses to barrier breakdown. Viral infection induces dysregulated cytokine production and aberrant immune activation, which amplify epithelial damage and further increase barrier permeability. In parallel, increasing evidence supports a bidirectional interaction between viral infection and gut microbiota dysbiosis, in which each process reinforces the other to accelerate barrier disruption and disease progression. We also discuss emerging therapeutic strategies aimed at restoring intestinal homeostasis, including antiviral therapies, host-targeted interventions, and microbiota modulation. Despite recent progress, key questions remain, particularly regarding mechanisms of failed barrier repair after viral clearance and the multilayered regulatory networks linking viruses, immunity, and the microbiota. Together, this review provides a framework for understanding virus-induced intestinal barrier dysfunction and identifies potential therapeutic nodes for intervention. Full article

Immune checkpoint inhibitor-related pneumonitis (CIP) is an uncommon but clinically relevant toxicity in renal cell carcinoma (RCC), where immune checkpoint inhibitors are frequently used either as dual immunotherapy or in combination with VEGF-targeted tyrosine kinase inhibitors. In RCC, CIP poses specific diagnostic challenges because respiratory symptoms and computed tomography findings may overlap with pulmonary metastases, infections, thromboembolic events, heart failure, and TKI-related lung toxicity. This review summarizes the incidence of CIP across pivotal RCC trials and real-world cohorts, compares its epidemiology with non-small cell lung cancer, and discusses clinical presentation, radiological patterns, differential diagnosis, and current management strategies. Particular attention is given to RCC-specific mechanisms, including immune-mediated alveolar injury, T cell activation, cytokine dysregulation, macrophage activation, GSDME-mediated pyroptosis, and the potential contribution of VEGF pathway inhibition to pulmonary inflammation. We also review risk factors, steroid-refractory disease, second-line immunosuppression, and the unresolved issue of ICI rechallenge after pneumonitis. A better understanding of these mechanisms and clinical features may improve early recognition, guide multidisciplinary management, and support safer use of immunotherapy-based combinations in patients with RCC. Full article

Coronavirus disease 2019 (COVID-19) and influenza share key pathogenic mechanisms, including viral invasion, dysregulated innate immune activation, and the development of severe systemic complications. A central mediator of disease progression in both infections is the hyperactivation of the NLRP3 inflammasome, which drives excessive production of pro-inflammatory cytokines, immunothrombosis, multiorgan injury, and increased mortality. Colchicine possesses a unique pharmacokinetic property of preferential accumulation within myeloid cells, where sufficiently high intracellular concentrations inhibit NLRP3 inflammasome activation. This mechanism provides a biological rationale for preventing the cytokine storm and its downstream consequences when colchicine is administered early during infection. Available pharmacokinetic, toxicological, and clinical evidence suggests that loading doses of colchicine up to approximately 0.05 mg/kg body weight can be administered safely in appropriately selected patients, provided that clinically significant drug–drug interactions and hepatic or renal impairment are carefully excluded. The widely accepted belief that total doses of 7–7.5 mg are inherently lethal appears to reflect historical cases complicated by drug interactions and/or hepatic or renal impairment, rather than toxicity attributable to colchicine dose alone. These observations support reconsideration of current guideline recommendations regarding colchicine dosing. In particular, cumulative doses below 0.1 mg/kg appear to be consistently safe, whereas doses between 0.1 and 0.2 mg/kg are associated with only a low risk of toxicity and rarely with severe intoxication. Reassessment of colchicine dosing strategies may therefore be warranted to optimize NLRP3 inflammasome inhibition and improve outcomes in patients with COVID-19 and influenza. Full article

During HIV infection, the immune system initiates an immune response to control the viremia. In this in vitro study, we investigated the immunomodulatory and anti-HIV potential of a traditional medicine formulation, Product Nkabinde (PN). A freeze-dried extract of PN was used to determine cytotoxicity in MT4 cells. Non-cytotoxic doses were used to evaluate the immunomodulatory and anti-HIV effects of PN using neutralization, prophylactic and treatment approaches. Post-treatment, cytokine quantification and p24 detection were performed. In the neutralization strategy, PN restored IL-1α (p = 0.0389) and IL-10 (p = 0.0443) to levels of uninfected cells. It also reduced HIV-induced elevations in IL-8 (p = 0.035), IP-10 (p = 0.0886), and MCP-1 (p = 0.0733) compared to HIV-infected cells. In the prophylactic approach, HIV infection upregulated IL-1α (p = 0.676), which was suppressed by PN. In the treatment strategy, PN reversed the elevated levels of IL-1α (p = 0.049). IL-10 was fully restored by PN to levels of uninfected cells. In all strategies, PN induced a significant and dose-dependent decrease in HIV replication. These findings demonstrate that PN exerts potent immunomodulatory effects all strategies used by reversing HIV-induced cytokine dysregulation, thereby inducing significant anti-HIV effects. Full article

Both SARS-CoV-2 infection and COVID-19 vaccination have been associated with renal complications. In the context of SARS-CoV-2 infection, kidney injury is primarily attributed to a complex interplay of systemic immune dysregulation and vascular damage. Severe infection triggers a cytokine-mediated inflammatory response characterized by elevated levels of pro-inflammatory mediators, resulting in systemic hemodynamic instability, increased capillary permeability, and renal hypoperfusion, ultimately leading to acute tubular injury. In addition, virus-induced endothelial activation promotes a prothrombotic state, microvascular injury, and further impairment of renal perfusion. Collectively, these processes converge to produce acute kidney injury (AKI) and, in severe or prolonged cases, may contribute to chronic tubulointerstitial damage and progressive renal dysfunction. In contrast, renal manifestations following COVID-19 vaccination are relatively uncommon and are thought to arise primarily from immune-mediated dysregulation rather than direct cytopathic effects. Reported cases include minimal change disease, IgA nephropathy, focal segmental glomerulosclerosis (FSGS), acute interstitial nephritis and other glomerulopathies, which present as either new-onset disease or relapses. These lesions are thought to result from transient immune activation following vaccination, including T-cell stimulation and altered humoral responses, which may trigger or unmask an underlying susceptibility to renal injury. Careful post-vaccination monitoring in high-risk populations may be warranted, and further molecular and population-level studies are needed to elucidate the underlying mechanisms and refine risk assessment. Full article

Osteoarthritis (OA) is a significant clinical problem that places a substantial burden on both patients and the healthcare system. Characterized by progressive cartilage degeneration, synovial inflammation, and subchondral bone remodeling, OA is a rapidly growing and increasingly studied disease affecting millions around the world. Growing evidence has expanded on the traditional view of OA as a mechanical “wear-and-tear” disease, highlighting that disease progression is driven not only by mechanical stress but also by chronic dysregulation of the osteoimmune environment. Activation of innate and adaptive immune pathways, macrophage M1 polarization, and dysregulated cytokine signaling all contribute to progressive joint degeneration. While current therapeutics often focus on managing symptoms or restoring joint mechanics, interventions often overlook the role of osteoimmunology in disease progression. This review summarizes the biological and bioengineering strategies emerging to address OA. These platforms include bioceramics, metal-based scaffolds, hydrogels, nanoparticles, and microsphere systems. Furthermore, small molecules, cell-based therapies, and gene-modified systems have also been shown to modulate the inflammatory microenvironment, enhance regulatory immune responses, and restore cartilage homeostasis. Together, these approaches represent the evolving research landscape, shifting away from just symptom alleviation and towards targeted disease-modifying therapies, including osteoimmunomodulation. However, significant barriers to clinical translation remain, such as limited large animal studies and species immune system differences, which need to be addressed for the development of clinically applicable interventions. Full article

Microplastics (MPs) can adsorb and transport heavy metals, but their influence on cadmium (Cd)-induced hepatotoxicity in mammals remains unclear. Forty-eight male Kunming mice were assigned to control, Cd, MP, and Cd + MP groups and exposed by oral gavage for 42 days. Growth performance, liver injury, oxidative stress, and inflammation were assessed, and transcriptomic and metabolomic analyses were integrated with qPCR, mitochondrial DNA (mtDNA) copy number, and ATP measurements. Compared with Cd alone, combined exposure resulted in greater reductions in body weight gain, the liver index, and antioxidant enzyme activities, together with more severe hepatic lesions and higher levels of liver injury markers and inflammatory cytokines. Co-exposure also induced broader transcriptional and metabolic disturbances than Cd alone. Integrated omics analyses converged on the dysregulation of AMPK–FOXO signaling and related energy metabolic processes. qPCR confirmed more pronounced alterations in pathway-related genes after co-exposure, while reductions in mtDNA copy number and ATP content indicated aggravated mitochondrial dysfunction and impaired energy metabolism. Collectively, these results demonstrate that MPs exacerbate Cd-induced liver injury and suggest that disruption of AMPK–FOXO-associated energy metabolism is a key molecular feature underlying the enhanced hepatotoxicity observed under combined exposure. Full article

Background: Autoimmune hepatitis (AIH) represents a clinically challenging immune-mediated liver disease, owing to its complex pathogenesis and limited targeted therapeutic options. Growing evidence highlights the key role of lymphocyte-mediated hepatic inflammation, dysregulated cytokine milieu, and oxidative stress in AIH progression. Oridonin (ORI), a bioactive diterpenoid with well-established antioxidant, anti-inflammatory, and immunoregulatory effects, remains unexplored in AIH. The present work aims to survey the potential impacts of ORI in Concanavalin A (Con A)-prompted AIH in mice, with particular emphasis on TLR7/PKM2/NLRP3 inflammatory signaling and macrophage polarization. Methods: Male BALB/c mice (n = 30) were allocated into five groups: CTR group, ORI-CTR group, Con A group, ORI (5 mg/kg) + Con A group, and ORI (10 mg/kg) + Con A group. ORI was administered i.p. for 4 days before a single Con A injection (15 mg/kg i.v.). Serum liver enzymes, hepatic pathological changes, oxidative milieu, and varied immunological factors were assessed. Results: ORI markedly attenuated Con A-induced hepatic injury, as evidenced by the reduced liver transaminases, preserved hepatic architecture, and restored oxidative milieu. Moreover, ORI suppressed T-cell activation, modulated M1/M2 polarization, and reduced pro-inflammatory cytokines. These effects were accompanied by the suppression of TLR7/PKM2/NLRP3 inflammatory signaling. Conclusions: ORI exhibits hepatoprotective effects against Con A-induced AIH and these effects are associated with the modulation of inflammatory and immunometabolic responses as well as downregulating TLR7/PKM2/NLRP3 signaling. Full article

Behçet’s disease (BD) is a chronic, multisystem vasculitis characterized by dysregulated immune responses and prominent Th1/Th17 polarization; however, the upstream epigenetic regulatory mechanisms driving this inflammatory imbalance remain incompletely understood. Here, we investigated the coordinated expression and diagnostic relevance of key long non-coding RNAs (lncRNAs; NEAT1 and MEG3) and microRNAs (miR-124 and miR-146a), and their association with IL-17/IL-6-mediated inflammation in BD. In a case–control study, serum levels of the selected non-coding RNAs were quantified by quantitative real-time PCR, while cytokine concentrations were measured using ELISA, complemented by bioinformatic interaction analysis and integrated statistical and machine learning approaches. Patients with BD exhibited marked downregulation of NEAT1, MEG3, miR-124, and miR-146a (p < 0.0001), accompanied by significantly elevated IL-17 and IL-6 levels. Individually, biomarkers demonstrated strong discriminatory capacity (AUC 0.83–0.92), while combined panels further improved classification performance. Multivariate modeling identified these non-coding RNAs as independent predictors of BD, and machine learning analysis identified miR-146a and IL-17 as the most influential contributors to disease classification. Notably, selected biomarkers showed associations with specific clinical manifestations, supporting their potential clinical relevance. Bioinformatic analyses identified putative interactions between NEAT1 and miR-124/miR-146a, while MEG3 demonstrated independent diagnostic value without evidence of direct interaction with the investigated miRNAs. Collectively, these findings provide a hypothesis-generating framework for future mechanistic investigations and support the potential diagnostic value of the investigated biomarker panel, although validation in larger multicenter cohorts and disease-control populations is warranted. Full article

6PPD and its ozonation product 6PPD-quinone (6PPD-Q) are ubiquitous tire-derived pollutants linked to environmental and potential human health risks. This study systematically investigated their mechanisms in lipid-metabolism-related diseases (atherosclerosis, type 2 diabetes, and nonalcoholic fatty liver disease) through network toxicology, transcriptomic validation, molecular docking, and experimental models. Targets of 6PPD and 6PPD-Q were predicted using multiple databases and intersected with disease-associated genes. Protein–protein interaction networks, hub gene screening, GO/KEGG enrichment, and GEO transcriptomic datasets identified key shared core targets, including PTGS2, MMP9, CXCL8 (for 6PPD), MAPK14, and PTGS2 (for 6PPD-Q). Molecular docking suggested potential strong binding affinities. Integrative analysis highlighted convergence on oxidative stress, inflammation, lipid dysregulation, and MAPK signaling. In vivo, 40-day exposure to 6PPD and 6PPD-Q in C57BL/6 mice induced hepatic steatosis, elevated serum TC, LDL-C, and HDL-C, upregulated inflammatory cytokines (TNF-α, IL1B, IL6, and IFNG), and core targets. In vitro, both compounds caused dose-dependent cytotoxicity, ROS accumulation, glutathione redox imbalance, and pro-inflammatory activation. These findings suggest that 6PPD and 6PPD-Q may contribute to lipid-metabolism-related toxic responses through shared and distinct processes involving oxidative stress, inflammatory activation, and lipid dysregulation. These results provide preliminary mechanistic insights into their metabolic toxicity and support further experimental evaluation for environmental health risk assessment. Full article

Oral lichen planus (OLP) is a chronic inflammatory oral disease associated with immune dysregulation and malignant transformation risk. Vitamin D and probiotics may modulate immune and microbial pathways involved in OLP. In this study, we evaluated their effects on clinical outcomes and multi-omics profiles in 25 adult OLP patients (median age: 68 years). Vitamin D-deficient patients received 2000 IU/day vitamin D3, and all participants received a probiotic blend (Limosilactobacillus reuteri LRE11, Lacticaseibacillus rhamnosus LR04, and Lacticaseibacillus casei LC04) for 16 weeks. Clinical assessments and analyses of saliva, serum, oral swabs, and stool samples were performed before and after treatment. Clinical outcomes improved significantly, with reductions in lesion number (p < 0.001), lesion size (p = 0.004), and bleeding lesions (p = 0.014); 76% of patients were classified as in remission. Vitamin D levels increased significantly among deficient patients receiving correction (p < 0.01). Salivary and fecal metabolomics showed significant remodeling of amino acid and carbohydrate pathways, including decreases in branched-chain amino acids in saliva and modulation of nicotinamide- and amino acid-related metabolites in feces. Microbiome α-diversity remained stable, whereas β-diversity shifted significantly across oral and fecal sites, with enrichment of Lacticaseibacillus and other context-dependent commensals. Multi-omics integration identified three latent factors linking salivary cytokines, microbial taxa, metabolites, and systemic lipid profiles, suggesting coordinated mucosal–metabolic–immune remodeling across the oral–gut axis. Full article

Aging is a major risk factor for impaired bone-defect healing, and dysregulation of the immune microenvironment, especially macrophage dysfunction, is closely linked to this process. Interleukin-34 (IL-34) plays a crucial role in macrophage biology; however, its role in aging-related bone-defect healing remains elusive. Herein, young and aged male C57BL/6 mice were utilized to establish a tibial bone defect model. Microcomputed tomography, histological staining, flow cytometry, RNA sequencing and in vitro cell experiments were conducted to explore the role and mechanism of action of IL-34 in aging-impaired bone healing. Aging markedly decreased bone mass, inhibited osteogenic differentiation and impaired bone defect healing in mice. Moreover, aging reduces macrophage numbers at bone defects and suppresses M2 polarization, with the drop likely driven by recruitment, survival or proliferation defects rather than impaired recruitment exclusively. IL-34 was a key differentially expressed gene that was downregulated in aged mice, which was further confirmed at the protein level. Furthermore, aging decreased IL-34 secretion by macrophages and impaired macrophage proliferation and M2 polarisation. Thus, aging impairs tibial bone-defect healing by downregulating IL-34 expression, decreasing macrophage infiltration, and inhibiting M2 polarisation. Furthermore, IL-34 acts as a pro-reparative cytokine that promotes bone healing by regulating macrophage function, suggesting its role as a potential therapeutic target for enhancing age-related bone repair. Full article