Liver fibrosis is a significant public health issue that necessitates an ongoing urge for efficient novel treatments. Our newly synthesized fused azine derivative compounds (1a, 1b, 2a, and 2b) were used in this study based on our promising results achieved by our team in previous studies on tacrine derivatives. This study investigated these compounds' hepatoprotective effect on mice with paracetamol (APAP) induced liver fibrosis and clarified their possible mechanisms. The administration of these compounds successfully reduced APAP-induced hepatic fibrosis through decreasing serum liver enzymes, as well as the hepatic pathological deterioration. Moreover, they increased hepatic antioxidants and countered oxidative stress caused by APAP. Furthermore, by lowering inflammatory cytokine levels and raising anti-inflammatory marker levels, these compounds effectively ameliorated the inflammatory response. Additionally, they decreased APAP induced levels of apoptosis-signal-regulating kinase-1 (ASK-1) and c-Jun-N-terminal kinase (JNK1). Additionally, they reduced caspase-3 and BCL2-associated X-protein (Bax) levels and promoted Nrf2 signaling pathway activation. Notably, the in-silico computer-assisted simulation docking results were consistent with the experimental measurements.

Calcific aortic valve disease (CAVD) involves fibro-calcific remodeling, in which osteogenic differentiation of valvular interstitial cells (VICs) is a key process. Although inflammation is implicated, uncertainties persist regarding how defined pro-inflammatory pathways are transcriptionally coupled to the VIC osteogenic program at the cell-intrinsic level. We implemented an interleukin-17 (IL-17) pathway-guided transcriptomic strategy in a pure human VIC osteogenic differentiation model. RNA sequencing identified osteogenesis-associated differentially expressed genes and IL-17-related inflammatory signatures. Functional enrichment and multilayer network analyses were applied to prioritize candidate regulatory nodes, followed by in vitro validation. An IL-17-associated transcriptional program was activated during VIC osteogenic differentiation and was enriched for stress-activated and MAPK-related inflammatory pathways. Network-based analyses consistently identified the AP-1 transcription factor JUN as a central regulatory node within this IL-17-linked signature. Experimentally, JUN expression increased during VIC osteogenic differentiation, and JUN silencing attenuated calcification. IL-17 A rapidly increased the p-c-JUN/JUN ratio, and prolonged treatment upregulated JUN and IL-17RA in a concentration-dependent manner. Exogenous IL-17 A stimulation enhanced calcification-related phenotypes in VICs, which were partially reversed by JUN knockdown. In a chronic kidney disease-induced mouse CAVD model, JNK inhibition with SP600125 reduced valve calcification and leaflet thickness. IL-17-associated inflammatory signaling is engaged during VIC osteogenic differentiation and may promote calcification, partially through a JUN-dependent mechanism. These findings provide insight into how inflammatory programs interface with osteogenic transcription and offer a framework for dissecting inflammation-driven calcification in CAVD.

Endometritis is a prevalent inflammatory disorder that impairs female fertility, yet effective therapeutic strategies remain limited. Although the fibroblast growth factor (FGF) family has been increasingly implicated in inflammatory diseases, its role in endometritis remains largely unexplored. Here, systematic profiling of the FGF family identified FGF21 as the most significantly upregulated member in inflamed uterine tissues. Mechanistically, FGF21 is predominantly derived from macrophages and is positively associated with inflammatory activation. Functional studies showed that genetic deletion of FGF21 markedly exacerbates uterine inflammation, whereas exogenous administration of recombinant human FGF21 (rhFGF21) alleviates tissue injury and suppresses inflammatory responses in lipopolysaccharide-induced endometritis. At the cellular level, FGF21 attenuates macrophage-mediated inflammation and promotes proliferation while inhibiting cell death in endometrial stromal cells. Importantly, these protective effects are recapitulated in a clinically relevant methicillin-resistant Staphylococcus aureus-induced model, where rhFGF21 exhibits robust dose-dependent therapeutic efficacy. Mechanistically, FGF21 exerts its effects through activation of fibroblast growth factor receptor 1 (FGFR1), and pharmacological inhibition of FGFR1 abolishes its anti-inflammatory and pro-repair functions. Collectively, our findings identify macrophage-derived FGF21 as a critical regulator of endometrial inflammation and tissue repair, and highlight the rhFGF21 as a potential therapeutic drug for endometritis.

Chronic Pseudomonas aeruginosa (P. aeruginosa) infection impairs wound healing, yet the underlying inflammatory mechanisms remain poorly understood. This study investigates how the NLRP3 inflammasome orchestrates macrophage differentiation and inflammatory resolution during infection-associated wound healing. A murine P. aeruginosa wound infection model was established. Macrophage polarization dynamics were assessed by flow cytometry (CD11b/F4/80/Arg1/iNOS/CD206/CD86) and histology. Wound healing outcomes were compared between wild-type and NLRP3-/- mice via closure kinetics, ECM analysis (Masson's trichrome/picrosirius red), and transcriptomic profiling. Mechanistic studies employed CRISPR-edited and pharmacologically modulated (MCC950/nigericin) THP-1/U937 cells, along with ChIP-qPCR, luciferase assays, and genetic rescue experiments. P. aeruginosa-infected wounds exhibited delayed healing, reduced ECM deposition, increased cellular senescence, and impaired fibroblast activation, with M1-dominant macrophage polarization and elevated NLRP3, ASC, caspase-1, IL-6, and IL-18. NLRP3-/- mice showed further delayed healing, decreased collagen I/III, reduced macrophage recruitment, and suppressed M1-to-M2 transition. Transcriptomics revealed downregulated Tlr4, Cd74, Egr2, and IL-6/JAK/STAT3 pathways. NLRP3 knockout impaired monocyte-to-macrophage differentiation (reduced CD14[+] cells and adhesion), while NLRP3 overexpression enhanced it. EGR2 expression correlated with NLRP3 levels; EGR2 knockdown suppressed CSF-1/CSF1R and macrophage differentiation, whereas EGR2 overexpression rescued defects caused by NLRP3 knockout. Mechanistically, IL-6 promoted EGR2 nuclear translocation, and EGR2 directly bound the CSF-1 promoter to regulate its expression. The NLRP3 inflammasome drives macrophage differentiation and M1 polarization via the IL-6/EGR2/CSF-1 axis in infection-associated wound healing. Targeting this axis may represent a therapeutic strategy to modulate inflammatory responses and improve healing in infected wounds.

Neuroinflammation and macrophage polarization play important roles in secondary injury and functional recovery after spinal cord injury (SCI). GP130, the common signal-transducing receptor subunit of the IL-6 cytokine family, is closely associated with JAK/STAT3-mediated inflammatory signaling. However, its role in macrophage polarization after SCI remains unclear. This study investigated whether GP130 inhibition regulates macrophage polarization and improves functional recovery after SCI. A rat model of T10 spinal cord compression injury was established using a standardized microvascular clip compression method. The GP130 inhibitor SC144 was administered after SCI. Functional recovery was evaluated using BBB scoring and inclined plane tests. Histopathological, ultrastructural, immunofluorescence, flow cytometry, qRT-PCR, western blotting, ELISA, and single-cell RNA sequencing analyses were performed to evaluate tissue injury, inflammatory signaling, and macrophage polarization. Primary bone marrow-derived macrophages were further used to assess the direct effects of GP130 knockdown or pharmacological inhibition on macrophage phenotype in vitro. SCI induced severe locomotor impairment, tissue disruption, ultrastructural damage, and activation of GP130-related inflammatory signaling. SC144 treatment improved functional recovery, reduced inflammatory cytokine expression, and attenuated downstream STAT3 activation. Single-cell RNA sequencing revealed a prominent monocyte/macrophage-related myeloid-cell response after SCI and transcriptional heterogeneity within the myeloid compartment. Immunofluorescence and flow cytometry showed that GP130 inhibition reduced M1-like marker expression and promoted M2-like marker expression in vivo. In primary macrophages, GP130-siRNA and SC144 similarly suppressed M1-like pro-inflammatory marker expression and enhanced M2-like reparative marker expression. GP130 inhibition modulates macrophage polarization and promotes functional recovery after T10 spinal cord compression injury. These findings suggest that GP130-related inflammatory signaling may be a potential therapeutic target for regulating macrophage-mediated neuroinflammation after SCI.

This study investigates the specific role of interleukin-18 (IL-18) in lupus nephritis (LN) progression and its molecular mechanisms to provide a theoretical basis for the pathological intervention of LN. IL-18 levels were measured from systemic lupus erythematosus (SLE) patients with or without LN. MRL/lpr mice received intraperitoneal injection of IL-18 or its inhibitor to assess renal injury, inflammation, and Wnt/β-catenin pathway activity. In-vivo intervention experiments using Caspase-1 inhibitor (Ac-YVAD-CMK), Wnt pathway agonists (BML-284), and inhibitors (IWR-1-endo) were performed. In-vitro studies were conducted in human renal tubular epithelial cell line HK-2 to investigate the molecular mechanisms. IL-18 was markedly elevated in SLE patients, and further increased in urine and renal tissue of LN. In MRL/lpr mice, exogenous IL-18 significantly exacerbated renal injury, evidenced by increased urinary protein, serum creatinine, anti-dsDNA antibodies, tubulointerstitial inflammation, and increased activity index. This was accompanied by up-regulation of IFN-γ, IL-1β, IL-6, down-regulation of IL-10, and activation of the Wnt/β-catenin pathway (increased β-catenin, p-GSK-3β, and CK1α). Conversely, IL-18 blockade or Wnt inhibition attenuated these pathological changes. Notably, the protective effects of IL-18 inhibition were reversed by simultaneous Wnt activation. In-vitro, IL-18 promoted HK-2 cell proliferation and inflammatory secretion by activating Wnt/β-catenin signaling, effects which were blocked by a Caspase-1 inhibitor or a Wnt pathway inhibitor. IL-18 activated the Wnt/β-catenin signaling pathway in renal tubular epithelial cells and disrupted the balance of pro- and anti-inflammatory cytokine networks, thereby exacerbating tubulointerstitial inflammation and promoting renal injury in LN mice. These findings highlight the therapeutic potential of targeting the IL-18 signaling pathway in LN. Trial registration: Not applicable.

Oxidative stress-mediated melanocyte injury and subsequent inflammation constitute essential pathogenic mechanisms underlying vitiligo. The secretion of diverse cytokines plays a crucial role in modifying the inflammatory environment characteristics of skin lesions. Interleukin 32 (IL32) is a multifunctional cytokine recognized for its potent pro-inflammatory effects. Here, we observed significantly enhanced IL32 expression in vitiligo skin lesions. The present study investigates the role of IL32 in oxidative stress-driven melanocyte inflammation and its contribution to vitiligo progression by establishing knockdown and overexpression models in PIG cell lines. Our findings demonstrate that oxidative stress triggers IL32 production in melanocytes, and increased IL32 exacerbates oxidative stress-mediated cellular injury. IL32 suppression activates the Nrf2 pathway and mitigates the oxidative stress response. Furthermore, transcriptomic analysis revealed that IL32 may promote the secretion of multiple inflammatory cytokines and chemokines in melanocytes in vitro, especially CXCL9, thereby facilitating the recruitment of CD8[+] T cells. Notably, IL32 accelerates depigmentation in the mouse model of vitiligo. These results highlight the therapeutic promise of targeting IL32 to attenuate inflammation and oxidative damage in melanocytes associated with vitiligo.

Crohn's disease (CD) is a long-lasting, recurring inflammatory bowel disease (IBD) marked by segmental, transmural inflammation that may affect any part of the gastrointestinal tract. Growing evidence suggests that CD does not originate from a single pathogenic mechanism, but instead results from the convergence of various biological disturbances that collectively disrupt intestinal homeostasis. Genetic alterations that weaken microbial detection, autophagy, and epithelial protection appear to establish initial vulnerabilities, enabling microbes to trigger exaggerated immune responses. This vulnerability is further exacerbated by environmental factors that intensify host microbial imbalance. The ensuing microenvironment fosters a significant production of effector molecules, which exacerbate the existing inflammation and activate stromal cells, which in turn drive tissue remodeling and structural complications such as ulceration, strictures, and fistulas. In this article, we synthesize the knowledge on the molecular and cellular mechanisms involved in CD pathogenesis, emphasizing the dynamic interplay between immune and stromal components that contributes to a disease-permissive environment. We also examine key inflammatory pathways and signaling networks involved in disease progression and discuss how these mechanistic insights inform existing and emerging therapeutic strategies.

Sepsis-related myocardial injury (SRMI) is a major contributor to mortality in septic patients, driven by uncontrolled inflammation and macrophage dysregulation. Bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) possess immunomodulatory properties, but their cardioprotective mechanisms remain unclear. Here, we investigated whether BMSC-Exos deliver microRNA-143-3p (miR-143-3p) to reprogram macrophages and attenuate SRMI. Exosomes were isolated from murine bone marrow mesenchymal stem cells and characterized by electron microscopy, nanoparticle tracking analysis, and immunoblotting. In lipopolysaccharide-stimulated macrophages, BMSC-Exos promoted a shift from pro-inflammatory M1 to reparative M2 polarization, and reduced pro-inflammatory cytokine secretion. In a mouse model of endotoxemia, BMSC-Exo administration improved seven-day survival, preserved cardiac function, decreased circulating myocardial injury markers, and increased the proportion of cardiac M2 macrophages. MicroRNA sequencing identified miR-143-3p as highly enriched in BMSC-Exos but downregulated in circulating exosomes from septic mice. Delivery of miR-143-3p mimics recapitulated the protective effects of BMSC-Exos, while inhibition of miR-143-3p exacerbated injury. Mechanistically, miR-143-3p directly targeted Toll-like receptor 4 (TLR4) and suppressed the downstream myeloid differentiation primary response 88/nuclear factor-κB (MyD88/NF-κB) signaling pathway. Furthermore, TLR4 knockdown phenocopied the anti-inflammatory and M2-polarizing effects of miR-143-3p. These findings indicate that BMSC-Exos attenuate SRMI by transferring miR-143-3p to macrophages, where it inhibits TLR4/MyD88/NF-κB signaling and promotes M2 polarization, highlighting a potential therapeutic strategy for septic cardiac injury.

Synovial fibroblasts (SFs) transform into an aggressive phenotype in rheumatoid arthritis (RA), playing a significant role in sustaining synovitis and bone erosion. Baricitinib, a JAK inhibitor, has been validated as an effective treatment for RA. However, its direct inhibitory effects on RASFs remain poorly understood. The inflammatory response and aggressive behaviors (proliferation, apoptosis, migration, and invasion) of RASFs were assessed following treatment with varying concentrations of baricitinib. RNA sequencing was performed to identify differentially expressed genes and elucidate the impact of baricitinib on RASFs. The relationship between the JAK-STAT3 signaling pathway and downstream molecules (EGR1, BCL-2, MMP-2, MMP-9) was analyzed via western blotting. Collagen-induced arthritis (CIA) mice were treated with baricitinib via oral gavage or by intra-articular injection of shEGR1 to evaluate therapeutic efficacy. Baricitinib inhibited the production of inflammatory mediators in primary RASFs and reduced the progression of synovial inflammation and hyperplasia in RA patients as assessed by ultrasound. In vitro, baricitinib promoted apoptosis and inhibited the proliferation, migration, and invasion of RASFs, effects associated with decreased expression of the transcriptional regulator EGR1. In vivo, baricitinib effectively reduced arthritis scores, paw swelling, and the expression of inflammatory cytokines in the joint tissues of CIA mice. Similar therapeutic effects were observed upon inhibition of EGR1. Baricitinib inhibits the aggressive phenotype of RASFs through the JAK-STAT3-EGR1 axis, thereby contributing to the alleviation of the inflammatory response and joint destruction in RA.