Search Results (1,601)

Disinfection byproducts (DBPs) are ubiquitous contaminants formed during drinking water treatment and are traditionally regulated based on cytotoxic and genotoxic endpoints. However, evidence suggests that DBPs may also act as metabolic disruptors interfering with hepatic metabolic pathways. This study investigates the early metabolic disruption and steatogenic effects of four regulated DBPs, bromoform (BR), bromodichloromethane (BDCM), monochloroacetic acid (MCA), and dichloroacetic acid (DCA), using the human hepatic cell models HepG2 (derived from hepatocellular carcinoma) and HUH7 (derived from hepatoblastoma). Cells were exposed to a broad concentration range (1 pM–100 µM) to capture both sub-cytotoxic and mechanistically informative responses at low, environmentally relevant levels. Effects on lipid and sterol metabolism were assessed through the transcriptional modulation of a panel of nuclear receptors (AHR, PXR, RXR, and LXR) and the sterol regulatory enzyme HMG-CoA reductase (HMGCR) as well as intracellular lipid accumulation; cytotoxicity and oxidative stress endpoints were concurrently evaluated. All DBPs tested induced significant, dose-dependent alterations in nuclear receptor signaling and also promoted lipid accumulation in the low-concentration range and without concurrent cytotoxicity; conversely, oxidative stress responses were limited or absent, and HMGCR emerged as a sensitive target, albeit with different patterns (upregulation by BR and MCA, and downregulation by BDCM and DCA). Relevant substance-specific aspects were also observed for other transcriptional targets, e.g., PXR upregulation was particularly evident for BR and BCDM while DCA downregulated the tested receptors. DBP-induced lipid accumulation was more pronounced in HUH7. Regulated DBPs can elicit early steatogenic and metabolic effects even at concentrations below current regulatory thresholds. The findings highlight that endocrine–metabolic disruption should be considered as a relevant endpoint in DBP risk assessment. Full article

Dihydroquercetin (DHQ) is a promising object for the development of a treatment for patients with obesity and prediabetes requiring a moderate therapeutic effect. This paper reports a clinical case of DHQ application in a 30-year-old Caucasian male and proposes a molecular mechanism of its anti-obesity effect. DHQ was administrated as a dietary supplement at a dose of 100–200 mg/day during 3 months with treatment interruption for 1 month. The data collected one month before the treatment were used as a control. The molecular aspects were studied via molecular docking with β₃-adrenoceptor (ADRB3, PDB ID: 9IJE) and peroxisome proliferator-activated receptor γ (PPARG, PDB ID: 2ZNO) and molecular dynamic simulation under conditions mimicking a human cellular environment. A pronounced weight decrease up to 0.73 kg/week was observed during DHQ administration. The highest affinity to ADRB3 was observed for the non-ionized H2aH3e-conformation of 2S,3R-DHQ (–8.846 kcal/mol). Molecules with 2S-configuration demonstrate 0.332 kcal/mol higher affinity to PPARG compared to 2R-stereoisomers. The intermolecular complex with cis-DHQ demonstrated higher stability in molecular dynamics simulation. The insights gained from this study may contribute to our understanding of flavonoids not merely as antioxidants but also as active ingredients that selectively interact with receptors. If future investigations confirm these results, they may serve as a foundation for developing a new class of anti-obesity remedies that act via ADRB3. Full article

During infection in vitro with the strain 438/06 of bovine coronavirus (BCoV), a β-coronavirus similar to severe acute respiratory syndrome (SARS) CoV-2, treatment with 6-pentyl-α-pyrone (6PP), a fungal metabolite obtained from Trichoderma atroviride, was recently shown to influence viral load by reducing viral entry. Herein, the ability of 6PP to counteract the BCoV infection was further investigated both in vitro and in silico. Following the BCoV (strain 282/23) infection in bovine (MDBK) cells, the 6PP in co-treatment increased cell viability, reduced morphological signs of cell death, and significantly inhibited viral yield, by lessening the expression of the viral spike (S) protein, as well as the gene transcription of the viral nucleocapsid (NP) protein. In addition, a noticeable down-regulation in the expression of aryl hydrocarbon receptor (AhR) signaling, a strategic modulator of CoVs infection, was found. Molecular docking studies were performed to evaluate the potential interaction between 6PP and AhR involved in the BCoV infection. The docking 3D structural model showed that 6PP fits into a binding pocket positioned between the PASB and TAD domains of bovine AhR (bAhR), where the ligand is stabilized through hydrophobic interactions. In addition, the obtained computational data strongly suggest that the bAhR binding mechanism of 6PP is principally mediated by a well-conserved hydrophobic cavity playing a key role in the modulation of the receptor functions. Overall, our findings showed an antiviral action of 6PP versus BCoV infection in vitro and in silico. Full article

Background/Objectives: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a highly toxic environmental contaminant whose adverse biological effects are primarily mediated through activation of the aryl hydrocarbon receptor (AhR). Upon ligand binding, AhR undergoes conformational changes that initiate nuclear translocation and transcriptional activation of xenobiotic-responsive genes, contributing to toxicity, carcinogenesis, and dysregulated immune and metabolic responses. Understanding the molecular basis of AhR activation by TCDD is therefore critical for the rational development of targeted therapeutic strategies. Methods: In this study, molecular docking simulations were employed to characterize the interaction of TCDD and selected AhR antagonists (CH223191, BAY 2416964, GNF-351) with the ligand-binding domain of AhR, with particular emphasis on the canonical PAS-B domain. Results: Docking analyses identified the PAS-B cavity (pocket C1) as the most biologically relevant binding site for high-affinity ligands, consistent with experimental evidence. Comparative docking of known AhR antagonists revealed stable binding poses characterized by hydrophobic packing, π–π interactions, and hydrogen-bonding networks that competitively block agonist access and prevent receptor activation. These findings support a competitive antagonism mechanism as a viable approach to counteract TCDD-induced AhR signaling. Conclusions: Collectively, this in silico study provides mechanistic insight into TCDD toxicity at the molecular level and highlights AhR antagonism as a promising strategy for the development of targeted therapies against dioxin-related pathologies. Full article

To investigate SARS-CoV-2 antibody kinetics and household transmission, infected children along with their families were tested for anti-nucleocapsid antibodies at 1, 3, 6, 9 and 12 months post-SARS-CoV-2 infection during the Ancestral, Alpha, Delta, and Omicron waves. We prospectively included SARS-CoV-2 acute infected children (n = 189). After household recruitment (n = 76 households), the total study population was 228 children and 105 adults. The median age (IQR) of children and adults was 96 (115) months and 504 (96) months, respectively. Anti-nucleocapsid (anti-N) COI (cut-off index) titers peaked at three months post-infection and declined thereafter (p-value < 0.001), and 89.2% remained seropositive at 12 months. Children displayed significantly higher anti-N COI titers than adults during the Delta (p-value: 0.018) and Omicron (p-value: 0.047) periods. Household contact anti-N positivity (evidence of infection) was associated with pediatric index cases (aOR: 1.61, 95% CI: 1.11–2.35; p-value: 0.013) and elevated early anti-N COI titers (aOR: 1.24 per log₁₀ unit, 95% CI: 1.05–1.48; p-value: 0.011). Higher secondary attacks were detected in Delta (aOR: 2.12, 95% CI: 1.19–3.77; p-value: 0.011) and Omicron (aOR: 2.75, 95% CI: 1.44–5.25; p-value: 0.002) compared to Ancestral. Waning of SARS-CoV-2 anti-N titers was faster in secondary cases (aHR: 1.62, 95% CI: 1.01–2.59; p-value: 0.047, Cox model) and during Omicron infection (aHR: 1.74 vs. Ancestral, 95% CI: 1.08–2.79; p-value: 0.023). In contrast, waning was slower in SARS-CoV-2 cases with higher baseline anti-N COI titers (aHR: 0.77, 95% CI: 0.64–0.93; p-value: 0.011). These findings demonstrate variant-specific, age-dependent antibody kinetics, emphasizing that pediatric index cases were associated with higher odds of household infection. Full article

Background: The adenoid surface serves as a potential bacterial reservoir for upper respiratory tract pathologies, including Adenoid Hypertrophy (AH) and Otitis Media with Effusion (OME). While dysbiosis is implicated in the pathogenesis of these conditions, it remains unclear whether the microbiome of children with otitis media differs significantly from those with simple hypertrophy when compared against a healthy baseline. This study aimed to characterize the adenoid microbiome in children with adenoid hypertrophy with and without middle ear effusion, contrasting them with a healthy control group. Methods: We conducted a cross-sectional case–control study involving 58 pediatric participants divided into three groups: adenoid hypertrophy, adenoid hypertrophy and otitis media with effusion and healthy controls. Nasopharyngeal swabs were collected, and bacterial community composition was analyzed using 16S rRNA gene V4 sequencing. Alpha and beta diversity metrics, taxonomic composition, and differential abundance were evaluated. Results: Alpha diversity was significantly reduced in both disease groups compared to healthy controls (p < 0.001), indicating a collapse of microbial richness and evenness. Beta diversity analysis revealed a distinct separation between healthy and diseased cohorts; however, the microbial profiles of the AH and AH with OME groups were nearly identical. Taxonomic analysis demonstrated that disease was characterized by the depletion of health-associated commensals, specifically Veillonella, Actinomyces, and Gemella, and a concomitant expansion of Fusobacterium, Haemophilus, and Streptococcus. Conclusions: Adenoid hypertrophy is associated with a profound dysbiotic shift characterized by the loss of protective commensal flora and the dominance of pathobionts. The lack of significant microbial differentiation between the AH and AH with OME groups suggests that the adenoid surface acts as a centralized reservoir of dysbiosis, the composition of which is conserved regardless of the presence of middle ear effusion. These findings highlight the importance of restoring the commensal microbiome in the management of chronic adenoid disease. Full article

Background and Objectives: While non-vitamin K antagonist oral anticoagulants (NOACs) show better renal preservation than warfarin in nonvalvular atrial fibrillation (NVAF) patients, real-world evidence within Asian populations remains limited. This study compared the renal outcomes between NOACs and warfarin in Thai patients with NVAF. Materials and Methods: A retrospective cohort study was conducted among NVAF patients who received either NOACs or warfarin from two university hospitals in Thailand from January 2015 to December 2019. The primary outcome was a ≥30% decline in the estimated glomerular filtration rate (eGFR) with a doubling of the serum creatinine (SCr), while acute kidney injury (AKI) and incidence rate of stroke and systemic embolism event (SEE) were secondary outcomes. All outcomes of each NOAC versus the warfarin group were analyzed using Cox proportional hazards regression. Results: A total of 1456 patients were enrolled. During a follow-up period of 24 months, NOACs were associated with a lower risk of a ≥30% decline in the eGFR than warfarin after inverse probability of treatment weighting (IPTW) and multivariable adjustment (adjusted hazard ratio (aHR) of 0.67, 95% confidence interval [CI] 0.45–1.00, p = 0.050). No significant differences were observed between NOACs and warfarin regarding the doubling of SCr (aHR 0.64, 95% CI 0.24–1.72, p = 0.373) or AKI (aHR 0.69, 95% CI 0.41–1.17, p = 0.169), although a trend toward a lower risk was noted in the NOAC group. Similarly, a trend toward a lower risk of the incidence rate of ischemic stroke and SEE were observed in the NOAC group (aHR 0.49, 95% CI 0.22–1.10, p = 0.084). Conclusions: In real-world data, NOACs may be associated with a lower eGFR decline and lower doubling of SCr and AKI than warfarin. Additionally, NOACs may reduce the risk of ischemic stroke and SEE, supporting their potential benefit over warfarin in both renal and thromboembolic outcomes. Full article

Glioblastoma (GBM) is a universally fatal cancer for which the standard of care has remained largely unchanged for the last 20 years. Recent work has demonstrated that most therapeutic trials for GBM fail due to complex mechanisms of immunosuppression mediated by both the innate and adaptive immune systems. Various metabolic alterations in the tumor microenvironment help maintain this local and systemic immunosuppression, of which the axis of hypoxia-driven tryptophan degradation has garnered substantial attention over the last decade. This paper synthesizes a much-needed elucidation of the immunometabolic reshaping of glioma, myeloid, endothelial, and lymphoid cell lineages induced by hypoxia. The current paper critically evaluates the role of IDO1/TDO2-mediated breakdown of tryptophan and the consequent accumulation of kynurenine, a metabolite that triggers GCN2- and AHR-mediated CD8+ T-cell exhaustion and supports regulatory T-cell differentiation and expansion. Furthermore, we propose a synthesis of mechanistic evidence that establishes a role for the Trp-GCN2-ATF4-VEGFA axis in hypoxia-induced immunosuppression, supporting that pro-tumoral metabolic dysregulation is directly linked to angiogenesis. In GBM, hypoxia and tryptophan–kynurenine pathway dysregulation operate as an integrated metabolic circuit that drives widespread immunosuppression. These mechanisms can be captured by a metabolic signature shared across nearly every cell type in the GBM microenvironment. Drawing on recent spatial transcriptomic, metabolomic, and pharmacologic studies, we outline how this metabolic axis shapes disease biology and how it can be targeted to restore effective antitumor immunity. Full article

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is now widely identified as a multisystem disorder with oncogenic implications that extend beyond liver-specific outcomes. Nonetheless, the link between MASLD and gynecologic cancers remains insufficiently characterized in robust, well-powered population studies. We investigated this association by menopausal status in a large cohort of Korean women. Methods: We performed a longitudinal cohort study utilizing data from a nationwide Korean cohort of over 2 million women, with a median observation period of 12.3 years. MASLD, including its subtypes metabolic alcohol-associated liver disease (MetALD), and alcohol-related liver disease (ALD) with metabolic dysfunction were identified using the most recent diagnostic standards. Adjusted hazard ratios (aHR) for gynecologic cancers were estimated with Cox models, accounting for metabolic, reproductive, and lifestyle factors. Results: In premenopausal women, MASLD was associated with increased risks of cervical (aHR, 1.13, 95% CI, 1.01–1.26), endometrial (aHR, 1.63, 95% CI, 1.50–1.79) and ovarian cancer (aHR, 1.22, 95% CI, 1.12–1.33). In postmenopausal women, MASLD similarly conferred elevated risks across all three cancers: cervical (aHR, 1.12, 95% CI, 1.05–1.20), endometrial (aHR, 1.42, 95% CI, 1.32–1.54) and ovarian cancer (aHR, 1.14, 95% CI, 1.08–1.20). Conclusions: MASLD should be considered an independent and modifiable risk determinant for gynecologic cancers. These data underscore the necessity of including hepatic steatosis in risk assessment protocols for cancer prevention. Early recognition and directed screening among metabolically susceptible women may provide important avenues for proactive cancer risk reduction. Full article

Background: Inflammatory bowel disease (IBD) and gout are both chronic inflammatory conditions. Emerging evidence suggests a potential link between IBD and gout through shared inflammatory and metabolic pathways; however, epidemiological findings remain limited and inconsistent, and the temporal direction of this association has not been clearly established. Methods: Through the use of the South Korean National Health Insurance database, we conducted a nationwide bidirectional matched cohort study. In Study I, 10,793 patients with IBD were matched 1:4 to controls without IBD. In Study II, 25,624 patients with gout were matched 1:4 to nongout controls. Exact matching was performed on age, sex, income level, and region of residence, followed by propensity score overlap weighting. Overlap-weighted Cox proportional hazards models were employed to measure adjusted hazard ratios (aHRs) for incident gout (Study I) and incident IBD (Study II). Results: In Study I, patients with IBD experienced a greater occurrence of gout than matched controls (28.40 vs. 24.20 per 10,000 person-years). IBD was linked to a higher likelihood of gout (aHR, 1.16; 95% CI, 1.04–1.29). When stratified by subtype, Crohn’s disease (CD) revealed a significant relationship with gout (aHR, 1.25; 95% CI, 1.05–1.48), whereas ulcerative colitis (UC) did not. Notably, the association between IBD (including CD and UC) and gout was consistently significant among participants younger than 45 years. In Study II, gout was not related to an elevated likelihood of IBD (aHR, 1.04; 95% CI, 0.91–1.21) or its subtypes. Conclusions: IBD, particularly CD, was linked to a greater likelihood of gout, especially among younger adults, whereas gout was not associated with subsequent IBD, suggesting an asymmetric association between IBD and gout. Full article

Background/Objectives: Treatment delays have been shown to be associated with overall survival (OS) in head and neck squamous cell carcinomas (HNSCCs). Given the slow tumor growth kinetics of adenoid cystic carcinoma (ACC), it is unclear if delays have a similar impact in this tumor histology. Methods: We queried the National Cancer Database for patients diagnosed with non-metastatic ACC between the years 2004 and 2019 and treated with surgery followed by RT. A multivariable Cox regression model was used to examine the associations between the time from diagnosis to surgery, the duration of RT, and OS. Results: A total of 1449 patients were included for analysis. Increased time from diagnosis to surgery (HR: 1.02, 95% CI: 1.01–1.03, p < 0.001) and duration of RT (HR: 1.14, 95% CI: 1.04–1.25, p = 0.004) were associated with worse survival on UVA, while time from surgery to RT start was not (p = 0.647). Increased duration of RT (aHR: 1.13, 95% CI: 1.03–1.24, p = 0.012) remained significantly associated with OS on multivariable analysis, while time from diagnosis to surgery (aHR: 1.00, 95% CI: 0.98–1.02, p = 0.979) did not. Conclusions: Delays in treatment initiation and in the interval from surgery to radiation did not result in clinically significant differences in survival in this analysis, while prolonged duration of radiation therapy was significantly associated with worse survival. These findings are hypothesis-generating and suggest that treatment delays for ACC may have different effects on oncologic outcomes than those for HNSCC; however, prospective data is paramount to verify these results before strong conclusions can be made. Full article

Mast cells (MCs) are multifunctional innate immune cells that regulate inflammation, tissue repair, and immune responses, and they are increasingly recognized as contributors to chronic liver disease. In parallel, the aryl hydrocarbon receptor (AhR) has emerged as a key environmental sensor activated by gut-derived tryptophan metabolites such as kynurenine and microbial indoles. The current literature separately describes the role of AhR in MC signaling, as well as the contributions of MCs to liver pathology and the disrupted gut–liver axis, which drives immune dysfunction in chronic liver disease. However, these aspects have been rarely considered together. This review aims to bridge these fragmented areas, providing an integrated framework where AhR-driven MC responses are examined within the gut–liver axis along with their impacts on liver inflammation and fibrosis. We discuss how this microbial–immune dialogue shapes autoimmune and cholestatic liver diseases, including autoimmune hepatitis, primary sclerosing cholangitis, and primary biliary cholangitis. Finally, we highlight translational perspectives, from microbiota modulation to AhR-targeting approaches, as potential strategies to control MC-driven hepatic inflammation. By integrating these currently separate concepts, this review offers a novel perspective on the role of MCs as important mediators at the interface of gut-derived signals and liver pathology via AhR signaling, while highlighting innovative therapeutic avenues through the modulation of the microbiota, targeting of AhR, and regulation of MC responses. Full article

Introduction: Uremic toxins have been shown to cause adverse pulmonary effects by inducing endothelial and epithelial dysfunction, disrupting the alveolar-capillary barrier, and increasing inflammation and oxidative stress. This article reviews these effects with a specific focus on chronic kidney disease and the mechanisms by which uremic toxins affect lung tissue. Methods: A narrative review was conducted using keywords related to uremic toxins and lung injury to search the PubMed database. An advanced literature review was conducted in PubMed to identify studies explaining the mechanisms underlying lung pathophysiology in chronic kidney disease (CKD), with particular focus on CKD-induced pulmonary epithelial and endothelial dysfunction. Additionally, to highlight the pathological processes of lung congestion in CKD, studies on CKD-induced dysfunction of the alveolar-capillary barrier were retrieved. Studies published up to November 2025 were evaluated. Results: A total of 148 articles were reviewed in full text. Uremic toxins negatively impact lung tissue structure and function through multiple mechanisms, including oxidative stress, inflammation, and direct effects. Uremic toxins appear to share signaling pathways in endothelial cells, including those linked to Mitogen-activated protein kinases (MAPK), the Aryl Hydrocarbon Receptor (AhR), the receptor for advanced glycation end products (RAGE), and pro-inflammatory transcription factors such as nuclear factor κB (NF-κB). Additionally, oxidative stress acts as a pro-inflammatory signal shared by several uremic toxins. The mechanisms behind the harmful interactions between CKD and lung disease are mostly unknown, although more evidence exists for acute kidney injury (AKI). Conclusions: Chronic kidney disease, which leads to the buildup of uremic toxins, negatively affects the lungs. Overall, the accumulation of uremic toxins in CKD impairs endothelial and epithelial cells and the alveolar capillary barrier. Further research is needed to understand the specific mechanisms underlying these effects and to identify therapeutic options to protect the lungs in these patients. Full article

High-strength low-alloy (HSLA) steels in marine environments suffer from microbiologically influenced corrosion (MIC) and hydrogen-assisted degradation. This study investigates the synergistic effects of sulfate-reducing bacterial biofilms, mechanical stress, and seawater chemistry on HSLA AH36 steel using electrochemical, microstructural, and magnetic Barkhausen noise (MBN) monitoring. Under multiparametric exposure (80% yield strength tensile stress, Desulfovibrio vulgaris, 28 days), biotic samples exhibited sustained 1.88× corrosion acceleration despite 86% sulfate depletion. Magnetic Barkhausen noise RMS amplitude (MBN_RMS) peaked at day 7 (612 ± 38 mV/mm) at pit depths of only 20–50 μm, detecting subsurface hydrogen damage before macroscopic failure. Quantitative correlations (R² ≥ 0.99) between MBN_RMS and cumulative mass loss revealed distinctive linear relationships in abiotic conditions and nonlinear cubic polynomials in biotic conditions, providing a non-destructive signature diagnostic of hydrogen-assisted MIC. Directional anisotropy analysis (parallel vs. perpendicular fields) showed that hydrogen-induced damage produces isotropic magnetic signatures (anisotropy ratio: 1.27 → 1.15), enabling discrimination between hydrogen embrittlement and stress-controlled degradation. The integration of portable MBN measurements with electrochemical monitoring establishes a quantitative framework for real-time structural health assessment and predictive maintenance of HSLA steels in maritime applications. Full article

Background/Objectives: Cesarean deliveries (CD) have been associated with an increased risk for offspring long-term respiratory morbidity. We sought to evaluate whether children born via CD in different stages of labor, and partially exposed to vaginal flora, would differ in their long-term respiratory morbidity. Methods: A population-based study comparing long-term respiratory morbidity of children according to their mode of delivery and CD indication was conducted. Children born via CD for first stage non-progressive labor (CD-NPL1) and children born via CD for non-progressive labor in the second stage (CD-NPL2) were compared with children born vaginally (VD) as a reference group. Offspring hospitalizations up to 18 years involving respiratory morbidities were evaluated. Results: 313,782 deliveries were included; 97.7% were VD, 1.6% were CD for NPL1 and 0.7% were CD for NPL2. The overall respiratory-related hospitalization rates as well as the cumulative incidence of respiratory hospitalizations were significantly higher in children born via CD, with a graded association, related to fetal exposure to vaginal flora, noted between VD, CD-NPL2 and CD-NPL1 with the highest incidence. In a Cox model, controlling for multiple confounding variables, NPL1 (vs. VD) was associated with an increased risk for offspring long-term respiratory morbidity (aHR 1.15), while NPL2 did not differ in risk. Conclusions: The risk for respiratory morbidity is increased for NPL1 offspring (with lower exposure to vaginal flora) as compared with NPL2 and VD offspring, with a graded association noted between exposure to vaginal flora during labor and the risk for offspring long-term respiratory morbidity. Full article