Search Results (545)

Chronic pulmonary diseases, including chronic obstructive pulmonary disease (COPD), idiopathic interstitial pneumonias (IIPs), pulmonary arterial hypertension (PAH), and pulmonary tuberculosis (PTB), are all marked by persistent immune imbalance, inflammation, and tissue injury. Despite the known anti-inflammatory and antioxidant properties of sea buckthorn, its protective mechanisms across these conditions remain poorly defined. We obtained active compounds and predicted targets from TCMSP and SwissTargetPrediction, and integrated disease genes from GeneCards and CTD with transcriptomic evidence from differential expression analysis and WGCNA. Using SVM-RFE, random forest, and LASSO, we identified hub genes and performed enrichment, immune infiltration, molecular docking, and molecular dynamics analyses. Our results showed that quercetin, kaempferol, and isorhamnetin were the core compounds linked to immune- and inflammation-related targets. The four diseases shared involvement in Toll-like receptor, NOD-like receptor, and related inflammatory pathways, along with recurrent alterations in myeloid cells. Besides, results from molecular docking and molecular dynamics simulations also suggested relatively stable interactions between key compounds and protein targets. Overall, these findings suggest that sea buckthorn may have potential pharmacological relevance across chronic lung diseases. It might do so by modulating common inflammatory signaling pathways and myeloid-related immune responses. At the same time, these findings provide a basis for further experimental validation. Full article

Medical ozone has emerged as a potential redox-modulating intervention in inflammatory and degenerative conditions, particularly in dermatological contexts characterized by chronic oxidative imbalance and impaired tissue remodeling. Unlike conventional pharmacological agents, ozone exerts its biological activity through rapid chemical reactions generating transient reactive and electrophilic species that activate endogenous adaptive signaling pathways. Controlled oxidative perturbations activate antioxidant transcriptional programs, primarily mediated by the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, while modulating inflammatory signaling networks, including nuclear factor kappa B (NF-κB) and the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome. This dual behavior reflects hormetic responses in which low-dose exposure promotes adaptive cellular signaling, whereas excessive oxidative burden leads to structural and functional damage. This review summarizes current knowledge on the molecular mechanisms underlying ozone-induced redox modulation, with emphasis on chemical reactivity, spatiotemporal signaling dynamics, thiol-based sensing, and metabolic reinforcement of antioxidant defenses. Particular attention is given to skin and subcutaneous adipose tissue, where oxidative stress, immune activation, and extracellular matrix remodeling converge. Dose dependency, safety constraints, and methodological variability are critically discussed, highlighting the narrow threshold between adaptive signaling and oxidative injury and the need for rigorous mechanistic and clinical validation. Full article

Background: Cardiometabolic syndrome is a cardiovascular disease characterized by metabolic dysregulation, with obesity triggering overactivation of the cardiac Renin–Angiotensin System (RAS). This leads to pathological cardiac changes and dysfunction. Empagliflozin (EMPA) modulates local RAS components in the kidney and liver, but its role in regulating cardiac RAS needs further study. Methods: Twenty-four male Wistar rats were separated into the following two groups: (1) control and (2) metabolic syndrome (MS) fed a high-fat diet, and after 8 weeks, half of each group was treated with EMPA (10 mg/kg) for 8 subsequent weeks. Finally, the animals underwent echocardiography, and under sodium thiopental anesthesia, blood samples were taken for FBS and lipid profile measurement. Finally, the left ventricle was isolated and used to measure the levels of proteins in the RAS pathway, including AngII (Angiotensin2), AT1R (Angiotensin2type1receptor), AT2R (Angiotensin2type2 receptor), and downstream pathway proteins pERK1/2 (Phosphorylated Extracellular Signal-Regulated Kinase1/2), NHE1 (Na+/H+ Exchanger1), NCX (Na+/Ca²+Exchanger), and NLRP3 (NOD-like-receptor-protein3) by Western blot, as well as ROS (reactive oxygen species) levels by ELISA. Results: EMPA treatment in MS significantly decreased FBS, TG, and LDL, increased HDL, and improved cardiac function. It was also associated with increased AT2R expression and attenuation of AngII, AT1R, pERK1/2–NHE1–NCX signaling, oxidative stress, and inflammatory markers (ROS and NLRP3) in rats with MS. Conclusion: Our findings suggest that EMPA treatment is associated with improvement in selected local cardiac RAS components and modulation of the pERK1/2–NHE1–NCX signaling pathway, along with reduced oxidative stress, decreased inflammation, and improved cardiac function in MS. Full article

NLRP6 is a member of the NOD-like receptor family that was initially characterized as an inflammasome-forming sensor in the intestine. However, accumulating evidence over the past decade has revealed that the functions of NLRP6 extend far beyond this canonical role. NLRP6 operates in a wide range of tissues, including the intestine, liver, lung, and immune system, where it exerts context-dependent effects that can be either protective or detrimental. In the intestine, NLRP6 is most consistently associated with host protection, contributing to antiviral defense, epithelial barrier integrity, and the maintenance of microbial and metabolic homeostasis through both inflammasome-dependent and -independent mechanisms. In contrast, in systemic infection models and in certain inflammatory settings, NLRP6 can also promote pathology by suppressing NF-κB signaling; inducing IL-18–mediated lymphocyte death, or enhancing inflammatory cell death pathways. Moreover, studies using both conventional and tissue-specific knockout models have highlighted the importance of the gut–organ axis; particularly the gut–liver axis, in shaping NLRP6-dependent disease outcomes. Here, we summarize recent advances in understanding the upstream regulation, downstream signaling, and tissue-specific functions of NLRP6. Full article

Cold seawater immersion is a critical lethal risk in maritime accidents and military operations, frequently inducing fatal myocardial dysfunction. However, the mechanisms underlying this seawater immersion hypothermia-induced cardiac injury remain poorly defined. This study aimed to elucidate the pathological progression and underlying mechanisms of myocardial injury induced by cold seawater immersion. A male SD rat model was immersed in 15 °C seawater for 2 h. Echocardiography, transmission electron microscopy, transcriptomics, and Western blot were performed to assess cardiac function, mitochondrial ultrastructure, and molecular mechanisms. Cold stress triggered progressive bradycardia (~480 to ~100 bpm) with initial Frank–Starling compensation, followed by decompensation with reduced cardiac output and impaired diastolic function. Mitochondrial ultrastructural damage preceded histological lesions and was accompanied by elevated cardiac injury markers (cTnT, CK-MB, BNP). Cardiac tissue exhibited upregulated TNF-α, IL-1β, and IL-6, while transcriptomic analysis revealed enrichment of inflammatory pathways (TNF, NF-κB) and coordinated upregulation of pattern recognition receptors including scavenger receptor, Toll-like receptor, and NOD-like receptor families. The Western blot confirmed NF-κB activation, NLRP3 inflammasome assembly, and the N-terminal fragment of gasdermin D (GSDMD-NT) accumulation, indicating pyroptotic cell death. These findings demonstrate that cold seawater stress disrupts mitochondrial homeostasis and activates the NF-κB/NLRP3/pyroptosis cascade, contributing to inflammatory cardiomyocyte death and cardiac decompensation. This mechanistic insight may inform therapeutic strategies for seawater immersion hypothermia. Full article

Endothelial dysfunction (ED) is an early event in cardiovascular and metabolic diseases, including atherosclerosis, diabetes, and hypertension. Emerging evidence highlights the interplay between chronic inflammation and oxidative stress, collectively termed OxInflammation, as a major driver of vascular injury and impaired tissue repair. Among the key mediators of this response is the Nod like receptor family pyrin domain containing 3 (NLRP3) inflammasome, a multiprotein complex that promotes the release of inflammatory cytokines, including Interleukin 1β (IL-1β) and Interleukin-18 (IL-18), and induces gasdermin D-mediated pyroptotic cell death. Activation of NLRP3 disrupts endothelial function, reduces nitric oxide availability, and accelerates vascular inflammation and injury. This review discusses current evidence on pharmacological strategies targeting NLRP3 inflammasome signaling using both natural and synthetic inhibitors. Studies have shown that inhibiting NLRP3 can reduce inflammation and oxidative stress, preserve endothelial integrity, improve vascular function, and support tissue repair. Several NLRP3-targeting compounds have advanced into early-phase clinical trials, showing encouraging safety profiles and efficacy in individuals with cardiovascular risk factors. By integrating the emerging concept of OxInflammation with endothelial dysfunction, this review critically evaluates the therapeutic and translational potential of NLRP3 inflammasome inhibition in cardiovascular and metabolic disorders. Collectively, the available evidence supports NLRP3 as a promising therapeutic target for restoring endothelial homeostasis and promoting vascular repair. However, further clinical studies are needed to establish long-term efficacy, optimal dosing strategies, and appropriate patient selection criteria. Full article

Background: Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by mucosal barrier disruption and dysregulated immune responses. While Intravenous Immunoglobulin (IVIG) is widely used for its immunomodulatory effects in various autoimmune conditions, its specific therapeutic mechanisms and molecular targets in colitis remain to be fully elucidated. Objective: To elucidate the therapeutic mechanisms of IVIG in dextran sodium sulfate (DSS)-induced colitis, with a focus on pyroptosis regulation via the NOD-like receptor (NLR) signaling pathway. Methods: Colitis was induced in mice via DSS administration. IVIG was administered intravenously during disease progression. Colon tissues underwent proteomic profiling, and key targets (GBP5, NLRP3, Pro-Caspase-1, GSDMD) were validated by Western blotting (WB), while interleukin (IL)-1β and IL-18 levels were quantified via ELISA. Results: IVIG significantly attenuated weight loss, Disease Activity Index (DAI) scores, colon shortening, and histopathological damage. Proteomics analysis identified 172 differentially expressed proteins between DSS and DSS + IVIG groups, with pronounced downregulation of GBP5 and NLR pathway components. IVIG suppressed GBP5/NLRP3/CASP1 activation, reduced GSDMD cleavage, and significantly decreased IL-1β production (while showing a decreasing trend for IL-18). Conclusions: IVIG ameliorates colitis by inhibiting the GBP5/NLRP3/CASP1-mediated pyroptosis pathway, highlighting its potential as a targeted therapy for ulcerative colitis. Full article

Inflammaging is defined as chronic low-grade inflammation associated with aging and is increasingly recognized as a dynamic and mechanistically driven biological process rather than a state adequately described by circulating biomarkers alone. Traditional inflammatory markers alone, including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and C-reactive Protein (CRP), fail to capture the complexity, tissue specificity, and causal architecture of inflammaging. Recent experimental evidence has demonstrated that diverse upstream drivers, including immunosenescence, gut microbiome dysbiosis, metabolic dysfunction, and cellular senescence, converge on a limited number of central inflammatory hubs, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, GMP–AMP synthase–stimulator of interferon genes (cGAS–STING), Janus kinase/signal transducer and activator of transcription (JAK/STAT), and p38 mitogen-activated protein kinase (p38 MAPK) signaling. These mechanistic nodes represent promising therapeutic targets, potentially modifiable biological processes, and support the emerging concept of ‘druggable inflammaging’, whereby senotherapeutics, inflammasome inhibitors, innate immune modulators, and metabolic interventions may actively modify aging-associated inflammatory biology rather than simply monitor it through biomarkers. This review highlights a paradigm shift from biomarker-based assessment toward mechanism-based intervention, where inflammaging can be characterized as a modifiable biological process and a central target for precision pharmacological strategies in aging-related diseases. Full article

Antiphospholipid syndrome (APS) is a systemic autoimmune disorder driven by antiphospholipid antibodies (aPLs), primarily characterized by recurrent thrombosis and pregnancy morbidity. Transcriptomic analyses of other immune compartments have provided insights into APS pathogenesis. However, despite the central role of platelets in APS pathophysiology, their transcriptomic features remain largely unexplored. We therefore aimed to characterize the platelet transcriptomic landscape in APS and identify key immune-thrombotic pathways. RNA sequencing and bioinformatic analyses of platelets from 43 APS patients, 20 asymptomatic aPL carriers, and 20 healthy controls revealed distinct proinflammatory transcriptional reprogramming, consistent with platelets as active thrombo-inflammatory hubs. APS platelets exhibited marked activation of innate immune (Toll-like and NOD-like receptors) and neutrophil pathways, which may contribute to disease propagation through a functional platelet–neutrophil axis. A 15-gene classifier (e.g., FCER1G, MAP4K4) discriminated APS from controls with high accuracy (Area Under the Curve 0.901–0.948). The classifier also highlighted molecular differences between APS and asymptomatic aPL carriers relevant to disease progression. Network analysis suggested that anti-β2-glycoprotein I antibodies were associated with unique coagulation–immunity modules, while arterial and venous thrombosis displayed divergent cytoskeletal-energetic and lipid-signaling signatures, respectively. Together, these findings suggest that platelets in APS acquire a distinct proinflammatory phenotype and function as key immunothrombotic interfaces, supporting disease stratification and platelet-derived diagnostic strategies. Full article

The first line of defense against infection is provided by the innate immune system, which is able to recognize molecular patterns in a variety of infectious agents through the action of different families of pattern recognition receptors (PRRs). These effectors detect the invading agent and trigger powerful inflammatory responses that help fight the infection from the very beginning. However, inflammatory reactions can be damaging for the host and must be properly controlled to prevent pathological consequences. Here we provide a comprehensive review of the important role of autophagy, a catabolic pathway that degrades cellular components for quality control and regulatory purposes, in the regulation of innate immune responses, and the underlying mechanisms involved. Inflammatory pathways discussed in this review include those triggered by Toll-like receptors (TLRs), Retinoic acid-Inducible Gene (RIG)-I-like receptors (RLRs), Nucleotide-binding Oligomerization Domain (NOD)-like receptors (NLRs), and the receptor for cyclic GMP–AMP Stimulator of Interferon Genes (STING). Finally, we also consider examples where autophagy plays context-dependent or even pro-inflammatory roles, reflecting a complex involvement that remains to be fully characterized. Full article

Chronic low-grade inflammation is a hallmark of aging and a major driver of metabolic and degenerative diseases. While systemic immune dysfunction has been widely investigated, the contribution of barrier tissues to persistent inflammatory signaling remains incompletely defined. The oral mucosa represents a uniquely exposed barrier, continuously challenged by microbial, mechanical, and metabolic stressors and characterized by a specialized immune architecture. Here, we synthesize current evidence supporting the oral barrier as an active immunometabolic interface linking local immune activation to systemic inflammatory tone. Spatially organized epithelial, neutrophil, and antigen-presenting cell (APC) compartments coordinate immune responses tightly coupled to metabolic reprogramming, including hypoxia-inducible factor-1α (HIF-1α)-dependent glycolysis and mitochondrial reactive oxygen species (mtROS) production. In parallel, the oral microbiota provides ligands and metabolites such as lipopolysaccharide (LPS), short-chain fatty acids (SCFAs), and succinate, which activate pattern-recognition receptors (PRRs), including toll-like receptors (TLRs) and the NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome, thereby sustaining nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB)-mediated inflammatory signaling. Barrier disruption and dysbiosis promote microbial translocation and persistent innate immune activation, while saliva and gingival crevicular fluid facilitate systemic dissemination of inflammatory mediators. Overall, sustained immunometabolic engagement at the oral barrier emerges as a key driver of chronic low-grade systemic inflammation and a potential therapeutic target in inflammaging. Full article

Doxorubicin (DOX) is a widely used anthracycline chemotherapeutic agent whose clinical application is limited by cardiotoxicity. In clinical settings, chemotherapy is given to tumor-bearing patients, whereas most preclinical studies of DOX-related cardiotoxicity use non-tumor-bearing animal models, potentially missing context-dependent differences. To address this, we compared DOX-induced cardiotoxicity between non-tumor-bearing and tumor-bearing mouse models. Cardiac function was assessed by echocardiography, and serum biomarkers, histopathological changes, and cardiac transcriptomic profiles were analyzed. Tumor burden exacerbated DOX-induced increases in BNP and CK-MB levels and myocardial structural damage, whereas systolic function was significantly reduced in non-tumor-bearing mice but did not further decline in tumor-bearing mice. Transcriptomic analysis revealed that DOX treatment induced 2528 and 398 differentially expressed genes (DEGs) in non-tumor-bearing and tumor-bearing mice, respectively, compared with their respective controls. A total of 206 shared DEGs were identified, most of which showed consistent directions of change under both conditions, while 16 genes exhibited opposite expression patterns. Common DEGs were mainly enriched in immune-inflammatory responses, cell adhesion, and extracellular matrix (ECM)–receptor interaction pathways. In non-tumor-bearing conditions, DOX-specific mechanisms were mainly associated with ECM remodeling, oxidative stress, metabolic dysregulation, and p53-mediated apoptosis. In contrast, tumor-bearing conditions showed predominant enrichment of immune-related pathways, including JAK-STAT, Toll-like receptor, NOD-like receptor, and chemokine signaling. These findings suggest that tumor burden may modulate the molecular mechanisms of DOX-induced cardiotoxicity, revealing context-dependent differences and offering insights for future cardioprotective strategies. Full article

The mammary gland is a heterogeneous organ that modulates ductal morphogenesis and alveolar differentiation. Obesity is a significant risk factor for several cancers, including postmenopausal breast cancer. We and others have described an association between obesity and increased breast cancer growth. However, the effects of obesity on the mammary fat pad microenvironment (MFPME) remain understudied. Here, we investigated the effect of the Western Diet (WD) on immunocompetent female mice and on their MFPME. Our data suggest that the WD increased body, liver, and perigonadal white adipose tissue (pWAT) weight, as well as myeloid cell infiltration into these tissues. Interestingly, we did not find any significant change in CD4⁺ and CD8⁺ T cells in the liver, blood, and pWAT. NanoString data demonstrates that various cellular processes, including the complement system, innate immune system, phagocytic activity, immune metabolism, and NOD-like receptor (NLR) signaling, were upregulated in the MFPME of obese mice. RNA-Seq data suggest that WD significantly modulated MFPME physiology through regulation of gene expression, cellular processes, and signaling pathways. Further investigation is necessary to determine how WD-mediated changes in MFPME modulate breast cancer biology. Full article

Ovarian granulosa cells (GCs) ensure proper follicular development and oocyte maturation through gap-junction-mediated intercellular communication. Zearalenone (ZEA), a mycotoxin with estrogen-like activity, specifically targets and impairs ovarian function. Most existing studies have focused on ZEA-induced apoptosis in GCs, but whether ZEA disrupts gap junctions in ovarian GCs remains unclear. Therefore, the aim of this study was to investigate whether and how ZEA induces gap junction injury in ovine ovarian GCs, with a particular focus on the roles of G protein-coupled receptor 30 (GPR30), oxidative stress, and the NLRP3 inflammasome. In the present study, primary ovine ovarian GCs were isolated, cultured, and treated with different concentrations of ZEA to establish a gap junction injury model, and specific inhibitors/antagonists were used to investigate the underlying mechanisms. The results showed that ZEA decreased granulosa cell viability and significantly inhibited the expression of the gap junction proteins Connexin 43 (Cx43) and Connexin 37 (Cx37) in a concentration-dependent manner. ZEA treatment also significantly upregulated the expression of the NOD-like receptor familypyrindomain containing 3 (NLRP3) inflammasome-related proteins (NLRP3, ASC, Cleaved Caspase-1, and the downstream pro-inflammatory cytokine IL-1β) in a concentration-dependent manner. Pretreatment with the NLRP3-specific inhibitor MCC950 significantly reversed ZEA-induced downregulation of Cx43 and Cx37 and effectively blocked NLRP3 inflammasome activation, indicating that NLRP3 is a key target in ZEA-induced gap junction injury. Further experiments confirmed that ZEA treatment significantly increased oxidative stress levels in granulosa cells; pretreatment with the reactive oxygen species (ROS) scavenger N-acetylcysteine (NAC) restored the ZEA-induced downregulation of Cx43 and Cx37 and suppressed NLRP3 inflammasome activation, suggesting that ROS acts as an upstream regulator of NLRP3 inflammasome activation. Moreover, ZEA treatment altered GPR30 expression levels, and pretreatment with the GPR30 antagonist G15 effectively inhibited ZEA-induced ROS production, NLRP3 inflammasome activation, and downregulation of Cx43/Cx37, indicating that ZEA exerts its effects through functional activation of GPR30. Collectively, ZEA activates the GPR30 receptor, induces ROS accumulation in granulosa cells, and subsequently triggers NLRP3 inflammasome activation, ultimately leading to downregulation of Cx43 and Cx37 and gap junction dysfunction. This study reveals a previously unrecognized molecular mechanism by which ZEA induces gap junction injury in ovarian GCs, providing potential therapeutic targets and a theoretical basis for preventing ZEA-induced ovarian dysfunction and improving animal reproductive health. Full article

Background: Metabolic-associated fatty liver disease (MAFLD) has a high prevalence of 30–40% in China and Asia, with a complex pathogenesis and no specific therapeutic drugs. Phytochemicals have become a research hotspot for MAFLD prevention, and ginsenosides, the core active components of Panax ginseng, show great potential in anti-MAFLD research. This review aims to comprehensively clarify the key mechanisms and targets of ginsenosides in preventing and treating MAFLD, to provide a theoretical basis for their application in metabolic diseases, and to promote the development of natural phytochemical resources. Method: The literature review method was adopted to sort out the regulatory effects and molecular targets of ginsenosides in multiple pathological processes of MAFLD from published studies. Results: Ginsenosides regulated MAFLD through multi-pathway and multi-target effects: antioxidant regulation occurred via Nuclear factor E2-related factor 2 (Nrf2)/Silent information regulator 1/6 (SIRT1/6) pathways, and anti-inflammatory regulation was achieved by inhibiting the Nuclear factor kappa-B (NF-κB)/NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome. Additionally, the measures adopted improved insulin resistance and lipid metabolism disorder, suppressed hepatocyte apoptosis/pyroptosis, repaired autophagy, alleviated hepatocyte senescence, and reshaped gut microbiota to restore gut–liver axis homeostasis. Conclusions: Ginsenosides have good potential for MAFLD prevention and treatment, but there is a prominent lack of human clinical evidence as most existing studies are only based on in vitro cell and in vivo animal models, and the synergistic mechanisms among different ginsenoside components remain unclear. Future research needs multi-omics analysis, formulation optimization, and large-sample clinical trials, and ginsenosides have broad application prospects in MAFLD intervention. Full article