Search Results (29,048)

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

Ionic liquids (ILs) have attracted considerable scientific interest over nearly three decades, with thousands of studies highlighting their low volatility, thermal stability, and potential for property modification through cation and anion selection. However, their behavior under environmental conditions remains less clear, particularly when water, soil constituents, and competing ions are present. This article examines whether concepts developed for neat ILs can be directly transferred to aqueous and soil systems. Particular attention is given to ion pairing, dissociation, surfactant-like behavior, sorption, toxicity, and biodegradation. Evidence from studies on herbicidal ILs, conventional precursor salts, and their mixtures indicates that, under environmentally relevant conditions, cations and anions frequently behave as largely independent chemical species. Hydrophobic cations are often responsible for sorption and microbial toxicity, whereas herbicidal anions typically retain mobility and biodegradation patterns comparable to their conventional salt forms. These observations question the environmental significance of ion pairing and suggest that the extent to which IL properties can be controlled through cation and anion selection may be more limited than commonly assumed. Greater emphasis should therefore be placed on precise terminology, appropriate experimental controls, and validation under realistic environmental conditions when interpreting the behavior and environmental relevance of ILs. Full article

Periodontitis is a chronic inflammatory disease characterised by progressive destruction of the periodontal tissues and alveolar bone. Cyclooxygenase-2 (COX-2) plays a key role in the pathogenesis of inflammatory responses via prostaglandin E₂ (PGE₂) receptors (EP1–4). Non-invasive physical plasma (NIPP) has been shown to modulate cellular activity and exert antimicrobial and anti-inflammatory effects. The aim of this in vitro study was to investigate the impact of NIPP on inflammation- and apoptosis-related molecules, including COX-2, EP2-EP4, Interleukin (IL)-6, IL-8, apoptotic protease activating factor 1 (APAF-1), Caspase (CASP)-3, and CASP-9, IL-10 and B-cell lymphoma 2 (BCL2) in human periodontal ligament cells (hPDLC) under normal and inflammatory conditions. After exposure of hPDLC to IL-1β to mimic inflammation in vitro, cells were treated with NIPP. Gene expression was analysed 24 h post-treatment by quantitative RT-PCR. Protein levels were assessed by ELISA. NIPP significantly inhibited IL-1β-induced upregulation of COX-2, EP2 and EP4 receptors, and APAF-1 mRNA expression in hPDLCs after 24 h. At the protein level, IL-1β-induced expression of COX-2, IL-6 and IL-8 was effectively attenuated by NIPP treatment. In conclusion, our data suggest that NIPP may modulate inflammatory responses in hPDLC, indicating its potential as a promising adjunctive approach for the treatment of periodontitis. Full article

The current study aims to assess the effects of coated sodium butyrate (CSB) on the weaning transition of White King pigeons. A total of 336 1-month-old White King pigeons were assigned randomly to four groups, including the Control group fed basal health sandand without CSB and test groups fed the basal health sand with 0.1%, 0.2%, and 0.4% CSB, respectively. The results showed that, compared with the Control group, the average daily feed intake (ADFI) was significantly increased in the 0.1% and 0.2% CSB groups (p < 0.05). The 0.1% CSB group exhibited a higher immune organ index (IOI) than the Control group (p < 0.05). The total protein (TP) and albumin (ALB) levels in the 0.1% CSB and 0.4% CSB groups significantly increased compared with the Control group (p < 0.05). In contrast, the 0.2% CSB group exhibited lower serum ALB, TP, and total cholesterol (TC) levels; TNF-α and IL-6 concentrations were reduced compared with the other groups (p < 0.05), and the 0.4% CSB group showed significantly increased serum TNF-α, IL-6, and D-lactic acid levels (p < 0.05). The ratio of villus height to crypt depth (VH/CD) of the jejunum (p < 0.05) was significantly increased in the 0.2% CSB group. In addition, the CD and VH/CD of the ileum were significantly increased in the 0.1% CSB group (p < 0.05). Firmicutes was the predominant phylum across all treatment groups, while Bacteroidota showed a more sensitive response to CSB supplementation. The 0.1% CSB group showed a significant enrichment of Oscillospiraceae and Muribaculaceae, fiber-fermenting, SCFA-producing taxa, Enterobacterales and Klebsiella, suggesting CSB-mediated alterations in luminal oxygen tension that favor the coexistence of facultative and obligate anaerobic taxa. Collectively, these data revealed that CSB supplementation efficiently improves growth performance and intestinal health of weaning pigeons by ameliorating the intestinal environment. Full article

Cardiovascular diseases (CVDs) remain the leading cause of mortality worldwide and are driven by the interplay between oxidative stress and chronic inflammation. Although these processes have been extensively investigated, their integration into a unified mechanistic framework and their translational relevance for biomarker-guided precision medicine remain insufficiently addressed. This narrative review integrates mechanistic, biomarker, and translational perspectives on the redox–inflammation axis in atherosclerosis and acute ischemic stroke, critically evaluating oxidative and inflammatory biomarkers while highlighting current challenges and emerging therapeutic opportunities. Reactive oxygen and nitrogen species (ROS/RNS) promote endothelial dysfunction, lipid oxidation, and activation of redox-sensitive pathways, including NF-κB, Nrf2/Keap1, JAK/STAT, and the NLRP3 inflammasome, resulting in vascular inflammation and injury. Biomarkers such as hs-CRP, IL-6, MPO, MDA, F2-isoprostanes, oxLDL, and antioxidant enzyme activity have demonstrated associations with cardiovascular risk, disease severity, and clinical outcomes, and therefore show diagnostic and prognostic potential. However, with the exception of selected inflammatory biomarkers, most oxidative stress biomarkers have not yet been sufficiently validated for routine clinical use because of biological variability, limited specificity, and insufficient analytical standardization. Disappointing outcomes of antioxidant supplementation further reflect the complexity of redox biology and the dual physiological and pathological roles of ROS. Here, we highlight that future progress in cardiovascular medicine will require a shift from non-specific antioxidant supplementation to precision redox modulation, integrating multimarker profiling, system biology, multi-omics, and artificial intelligence and machine-learning approaches to improve cardiovascular risk stratification and personalized therapy. Full article

Background and Objective: Post-Intensive Care Syndrome is a multidimensional sequela of critical illness that includes physical, cognitive, and psychological impairments after intensive care unit discharge. Systemic inflammation has been proposed as one potential mechanism contributing to selected PICS domains, but the direction, timing, and clinical relevance of this relationship remain uncertain. This study assessed whether serial concentrations of C-reactive protein, procalcitonin, and interleukin-6 were associated with PICSQ severity in ICU survivors. Materials and Methods: This prospective single-center cohort study included 267 adult ICU patients in the primary complete case analysis. CRP, PCT, and IL-6 were measured at predefined time points during hospitalization. PICS severity was assessed using the Post-Intensive Care Syndrome Questionnaire at ICU discharge and at 2 and 3 months after discharge. The primary endpoint was total PICSQ severity at 3 months. Correlation analyses, threshold-based group comparisons, and logistic and multivariable linear regression models adjusted for age, sex, reason for ICU admission, and length of hospitalization were performed. Secondary and domain-specific analyses were considered exploratory. Results: Correlation analyses did not show a consistent association between inflammatory biomarkers and total PICSQ severity at ICU discharge, 2 months, or 3 months. Weak inverse associations were observed between selected CRP, PCT, and IL-6 measurements and cognitive domain scores, indicating lower cognitive impairment scores among patients with higher biomarker values in some analyses. These findings were not consistent across time points and should be interpreted cautiously. In unadjusted threshold-based analyses at 3 months, selected associations were observed for CRP after one week, PCT on day 4, and IL-6 on days 2 and 4, mainly in the psychological domain. In fully adjusted linear regression models, none of the selected biomarker thresholds remained statistically significant at p < 0.05. In adjusted linear regression, PCT ≥ 2 ng/mL on day 4 showed a borderline association with the total PICSQ score at 3 months, with β = 0.44, 95% CI −0.07 to 0.94, p = 0.089, N = 267. IL-6 > 10 pg/mL on day 2 showed a borderline association with psychological domain severity at 3 months, with β = 0.46, 95% CI from −0.005 to 0.92, p = 0.052. In adjusted logistic regression, IL-6 > 10 pg/mL on day 2 was associated with higher odds of psychological domain score ≥ 4 at 3 months, with adjusted OR 3.61, 95% CI 1.26 to 10.37, p = 0.017, N = 266. No consistent association was observed for the physical domain. Conclusions: In this exploratory cohort, routinely available inflammatory biomarkers were not consistently associated with global PICSQ severity across all assessment time points. Selected time-dependent and domain-specific associations, particularly involving PCT and IL 6 at 3 months, may indicate a possible link between inflammatory activation and later psychological PICS burden. These findings do not establish causality or predictive performance and require external validation before CRP, PCT, or IL 6 can be used for PICS risk stratification. Full article

Orthoflaviviruses comprise genetically diverse mosquito-borne viruses responsible for a broad spectrum of human diseases. Although naturally circulating clinical isolates exhibit biological variability, the extent to which they generate distinct early epithelial innate immune responses remains incompletely understood. Here, we characterized five clinical orthoflavivirus isolates obtained in Oaxaca, Mexico, using human HaCaT keratinocytes as an in vitro model of early infection. Productive infection was assessed by immunofluorescence microscopy, immunostained focus appearance under isolate-optimized assay conditions, and infectious virus production, whereas host responses were evaluated by transcriptional profiling and quantitative whole-slide single-cell immunofluorescence. All isolates established productive infection and exhibited different viral replication profiles. Temporal transcriptional analyses revealed variable expression of antiviral (IFNβ, Mx1, OAS1, PKR, IFITM3, Viperin, and RANTES) and inflammatory (TNF-α, IL-8, and MCP-1) genes. Quantitative whole-slide analysis provided complementary evidence of variable STAT1 and NF-κB signaling activation across the analyzed isolates. Within this limited panel, viral replication was not consistently aligned with the selected transcriptional and signaling readouts, although the exploratory nature of these comparisons precludes establishing independence between these variables. Together, the virological, transcriptional, and imaging analyses revealed distinct multidimensional functional profiles across the isolate panel. Overall, these findings demonstrate functional heterogeneity among the analyzed clinical orthoflavivirus isolates and highlight integrated functional phenotyping as a useful framework for examining virus–host interactions beyond viral replication alone. Full article

Background and Aims: The glucose metabolism pattern of the liver is closely related to liver diseases. In recent years, alcoholic hepatitis, viral hepatitis, fatty liver and other diseases have become important liver diseases that impact people’s lives. IL-33 (interleukin-33), as a member of the IL-1 cytokine family, and “alarmin” play a multi-dimensional regulatory role in various physiological and pathological processes of the liver. Methods: This study, by integrating transcriptomic data analysis and in vitro and in vivo experiments, expounds on new insights into the regulation of hepatocyte fate by IL-33 through metabolic reprogramming and reveals the potential, new role of IL-33 as a regulatory factor of metabolism. Conclusions: Our research further confirmed that IL-33, in addition to serving as an alarm hormone, is also a key checkpoint for liver metabolism, capable of promoting oxidative phosphorylation in hepatocytes and antagonizing acute liver injury induced by CCl₄. Full article

Diabetic foot ulcer (DFU) affects approximately 25% of diabetic patients and represents the leading cause of non-traumatic lower extremity amputation. Neutrophil extracellular traps (NETs) contribute to chronic inflammation; however, their mechanistic role in DFU healing failure remains incompletely characterized. This study integrated bulk RNA sequencing (GSE143735, n = 9) and single-cell RNA sequencing (scRNA-seq; GSE165816, n = 11) datasets to investigate NET-related transcriptional programs. Differential expression analysis identified 96 differentially expressed genes, with significant NET pathway enrichment in non-healers (normalized enrichment score = 4.35, false discovery rate q < 0.001). Analysis of 33,654 single cells revealed elevated NET activity scores in neutrophils from non-healing wounds (p = 4.73 × 10⁻¹⁵⁹). Four neutrophil subpopulations were identified, with the NETs-high subset expanded in non-healers (43.1% versus 15.4%). Cell–cell communication analysis demonstrated enhanced S100A8/A9–RAGE and IL1B–IL1R signaling in the non-healing state. A six-gene signature (S100A8, S100A9, MPO, ELANE, NCF1, HMGB1) achieved an area under the receiver operating characteristic curve of 0.750 for healing prediction under leave-one-out cross-validation. These findings implicate NET pathway activation as a potential driver of DFU healing impairment and identify candidate prognostic biomarkers warranting prospective validation. Full article

Chronic gastritis (CG) is linked to gut–gastric axis dysbiosis. Wenweishu Capsules (WWS) are clinically used to treat CG, but their concurrent regulatory effects on this axis remain unclear. A CG rat model was established using sodium deoxycholate, ammonia, ethanol, and irregular feeding. Rats received WWS (0.38 g·kg⁻¹·d⁻¹) for 4 weeks. Gastric lesions, inflammation, and gut microbiota were evaluated via histopathology, ELISA, 16S rRNA sequencing, PICRUSt prediction, and correlation analysis. WWS improved general condition, food intake, and weight gain in CG rats, alleviated gastric mucosal damage, and reduced serum TNF-α and IL-6. These effects were associated with altered IκBα expression and NF-κB pathway modulation. WWS reversed gut microbiota dysbiosis, restored α- and β-diversity, increased Lachnospiraceae NK4A136 group abundance, and suppressed potential pathogens. Functional prediction showed that WWS upregulated beneficial pathways such as carbohydrate metabolism and downregulated infection-related pathways. Correlation analysis linked TNF-α/IL-6 negatively with the Lachnospiraceae NK4A136 group and positively with Bacteroides. WWS ameliorates CG through a multi-dimensional mechanism that may involve modulation of the NF-κB inflammatory axis, rebalancing of gut microbiota structure, and remodeling of microbial metabolic function. These findings provide preliminary evidence for a potential microbe–drug interaction strategy for CG, though causal relationships require further mechanistic validation. Full article

Satellite glial cells (SGCs) play a critical role in the development and maintenance of chronic pain through complex interactions with inflammatory mediators and the opioid pathway. This systematic review synthesizes recent advances in the molecular mechanisms underlying SGC activation and implications for chronic pain management, particularly in conditions associated with the dorsal root ganglia (DRG) and trigeminal ganglia (TG). A systematic search was conducted in four databases (PubMed, Embase, Scopus, and Web of Science) covering studies published between January 2004 and May 2026. After screening 111 records, 19 studies were included. This review highlights how pro-inflammatory cytokines such as IL-1β, IL-1α, and TNF-α, as well as neurotransmitters like ATP and glutamate, contribute to SGC activation, neuroinflammation, and pain modulation. It also explores the role of receptors like CXCR4, TLR4, and P2X7 in SGCs in enhancing analgesic effects and their contributions to opioid tolerance and hyperalgesia. The findings underscore the potential of targeting SGCs to improve pain management outcomes across various pain models, including neuropathic, cancer-related, and visceral pain. Despite promising insights, variability in study methodologies and the complexity of glial–neuronal interactions present challenges. Future research should focus on standardizing experimental protocols and developing targeted therapies to modulate SGC activity to offer hope for patients suffering from chronic pain, particularly in managing opioid tolerance. Full article

Identifying genetic contributors to idiopathic central precocious puberty (CPP) beyond established monogenic causes remains a research priority, as most cases lack a resolved genetic basis. We performed comprehensive Sanger sequencing of all 34 coding exons of NOTCH2 in 100 Korean girls with idiopathic CPP and 100 age-matched healthy female controls. Among 55 identified sequence variants, including 11 missense variants, the primary finding was a statistically significant frequency difference for the NOTCH2 heterodimerization domain C (HD-C) subdomain variant p.Ile1689Phe: this variant was absent from all 200 CPP alleles while present in 6.5% of control alleles (Fisher’s exact p = 0.0002), raising the hypothesis of a candidate protective association that requires independent replication before any causal inference can be drawn. Three additional missense variants, including p.Thr235Ser, p.Ala1361Thr, and the novel ankyrin (ANK) domain variant p.Ala1992Val, were identified exclusively in CPP patients as singletons; however, no pathogenic interpretation is warranted from these observations alone. This preliminary study reports a significant NOTCH2 variant frequency difference and raises the hypothesis that NOTCH2 coding variants may contribute to pubertal timing modulation within the Notch signaling pathway; independent replication and functional validation are required before causal conclusions can be established. 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

Background and Objectives: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous type 2 inflammatory disease characterized by frequent postoperative recurrence despite endoscopic sinus surgery (ESS). Reliable biomarkers capable of predicting recurrence remain insufficiently validated. This study evaluates the prognostic utility of circulating biomarkers for recurrence prediction in CRSwNP, in addition to the predictive performance of the blood eosinophilia. Materials and Methods: A prospective cohort of 69 patients with CRSwNP undergoing primary ESS was followed for up to 3 years. Periostin, eotaxin-3, procalcitonin and IL-33 were taken from blood before surgery and analyzed by ELISA technique. Clinical outcomes were assessed using SNOT-22 and Perioperative Sinus Endoscopy (POSE) scores. Statistical analyses included Spearman’s correlation, the Mann–Whitney U test, the Kruskal–Wallis test, Cox proportional hazards regression, multivariable binary logistic regression, ROC analysis, and longitudinal MANCOVA. Results: Blood eosinophilia remained the strongest clinical predictor of recurrence (OR = 4.55, p = 0.001). Serum periostin, eotaxin and procalcitonin significantly correlated with postoperative disease severity and recurrence, particularly with POSE scores at 1 and 3 years (p < 0.05). Patients with recurrence demonstrated significantly higher serum levels of these biomarkers compared with controlled patients (all p < 0.001). Multivariate Cox regression identified periostin (HR = 1.033, p = 0.010), eotaxin (HR = 1.554, p < 0.001) and procalcitonin (HR = 1.183, p < 0.001) as significant predictors of recurrence. Procalcitonin demonstrated the highest predictive performance in ROC analysis (AUC = 0.805). Longitudinal MANCOVA confirmed significant associations between periostin, eotaxin, procalcitonin, and persistent postoperative inflammatory burden over 3 years. Conclusions: Circulating periostin, eotaxin and procalcitonin are promising predictors of CRSwNP recurrence and appear to contribute to prognostic accuracy. Integration of serum biomarker profiling into clinical practice may improve personalized postoperative management and risk stratification in CRSwNP. Full article

Obesity is associated with metabolic dysregulation and impaired male reproductive capacity, where the gut microbiota affects male reproductive function through diverse mechanisms that warrant further elucidation. This study aims to evaluate the effects of ketogenic and vegan dietary interventions in attenuating obesity-associated testicular injury and to examine the extent to which specific gut microbiota profiles mediate their impact. Forty-nine male adult albino rats were assigned to seven groups: control group, obese group (HFD), obese group + modified microbiota, obese group + ketogenic diet, obese group + ketogenic diet + modified microbiota, obese group + vegan diet, and obese group + vegan diet + modified microbiota. Metabolic markers (glucose, insulin, leptin, and HOMA-IR), reproductive hormones (testosterone, FSH, and LH), and testicular gene expression (IL-6, eNOS, and androgen receptor) were analyzed over five months. Gut microbiota composition (qPCR) and testicular histology/immunohistochemistry were assessed. HFD-fed rats exhibited hyperglycemia, insulin resistance, hypogonadism, and testicular degeneration. Both diets improved metabolic and hormonal profiles, restored testicular architecture, and downregulated inflammatory genes. Microbiota modification additively enhanced these effects, increasing the abundance of Lactobacillus and Akkermansia while reducing inflammation. The vegan diet showed superior efficacy in improving metabolic parameters, modulating pituitary–gonadal hormones, and attenuating testicular structural and functional alterations. Our findings demonstrate that ketogenic and vegan diets alleviate obesity-induced testicular dysfunction and that microbiota modulation amplifies these benefits by regulating the gut–testicular axis. Integrating dietary and microbial interventions may provide a basis for a promising approach to managing obesity-related male infertility. Full article