Abstract Benzoic acid (BA) is widely used in pharmaceutical, cosmetic, and dermatological formulations, yet its pharmacokinetic and toxicological profile has not been examined within a unified predictive and experimental framework. This study aimed to characterize BA using an integrated in silico and in vitro framework with dermatological implications, combining absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction, toxicity modeling, phenotype-driven molecular docking, and HEK293 cell assays. The BA structure was retrieved from PubChem and analyzed using pkCSM and ProTox-III for ADMET prediction. Molecular docking was performed with AutoDock Vina against eight phenotype-driven target proteins representing inflammation, oxidative stress, survival, and migration pathways. In vitro validation used HEK293 cells exposed to BA at 0, 15, 250, and 1,000 μM, with cell viability, wound-healing capacity, clonogenic capacity, lipid peroxidation (malondialdehyde), catalase activity, and total oxidant/antioxidant status assessed. BA showed favorable absorption and low predicted metabolic interaction liability, with platform-dependent discrepancies between pkCSM and ProTox-III regarding hepatotoxicity and blood–brain barrier penetration. Docking yielded moderate binding affinities (−5.175 to −6.388 kcal/mol), strongest against sphingosine-1-phosphate receptor 3, catalase, and cyclooxygenase-2. In HEK293 cells, BA produced dose-dependent reductions in viability (IC50 ≈ 242 μM), migration, and colony formation, alongside dose-dependent oxidative imbalance. Overall, BA displays a favorable pharmacokinetic profile but a mixed toxicological pattern. The predictive discrepancies and dose-dependent in vitro effects indicate caution in dermatological applications of BA and support further experimental studies on its cutaneous safety.
Abstract This study evaluated the preventive effects of quercetin (QR) and N-acetylcysteine (NAC), alone or combined, in a rat model of acute acetaminophen (APAP)-induced hepatotoxicity. Twenty-five male rats were allocated to five groups (n = 5): control, APAP, NAC + APAP, QR + APAP, and NAC + QR + APAP. NAC (150 mg/kg) and/or QR (50 mg/kg) were administered orally for 7 days before a single oral APAP dose (2 g/kg). Serum liver-function indices, lipid profile, circulating TNF-α and IL-6, hepatic oxidative-status indices, hepatic COX-2, TGF-β1, Nrf2, and HO-1 mRNA abundance, histopathology, and IL-1β immunohistochemistry were assessed. APAP increased ALT, AST, triglycerides, total cholesterol, TNF-α, IL-6, and hepatic MDA, while decreasing total protein, albumin, HDL-C, GSH, CAT, SOD, and GPx. It also increased COX-2 and TGF-β1 transcripts and decreased Nrf2 and HO-1 transcripts. Pretreatment with NAC or QR partially attenuated these changes, whereas their combination generally produced values closer to control. The combined regimen also reduced histological injury and IL-1β immunoreactivity relative to APAP. These findings support a preventive association between combined NAC/QR exposure and improved redox and inflammatory indices. Because protein abundance, Nrf2 nuclear translocation, treatment after injury, and treatment-only controls were not evaluated, the data do not establish pathway activation, pharmacological synergy, or therapeutic efficacy after established overdose.
Abstract Benzo(a)pyrene (BaP), a widespread environmental pollutant, has been implicated in osteoarthritis (OA) development, yet underlying mechanisms remain unclear. This study aimed to elucidate the molecular mechanisms of BaP-induced OA through integrative network toxicology and experimental validation. Overlapping genes between BaP exposure and OA were identified from multiple databases (CTD, SwissTargetPrediction, NCBI, Malacards, and OMIM). Protein–protein interaction networks and enrichment analyses were performed to identify core targets and pathways. Microarray data (GSE117527) of BaP-treated human primary T lymphocytes were analyzed for differentially expressed genes. Experimental validation was conducted using human primary T lymphocytes and CHON-001 chondrocytes through Western blotting, qPCR, ELISA, and conditioned media co-culture experiments. We identified 915 overlapping genes between BaP and OA, with 17 core targets including TP53, TNF, and AKT. Transcriptomic analysis revealed the PI3K/AKT signaling pathway as a critical regulatory hub. BaP exposure significantly activated PI3K/AKT phosphorylation and upregulated TNF-α and IL-6 expression and secretion in T lymphocytes. Notably, conditioned media from BaP-stimulated T lymphocytes significantly exacerbated CHON-001 apoptosis and reduced viability compared to direct BaP exposure, demonstrating potent indirect toxicity mediated by immune cells. BaP exposure is associated with OA pathogenesis through a co-occurring network involving PI3K/AKT pathway activation and immune-mediated inflammatory responses. The discovery of T lymphocyte-mediated indirect toxicity provides novel insights into environmental pollutant-related osteoarthritis.
Abstract Arsenic contamination of drinking water, food, and environmental components remains a major global health concern because chronic exposure to inorganic arsenic is associated with multisystem toxicity and carcinogenesis. Arsenic-induced toxicity includes a complex interaction of pathways including oxidative and thiol stress, mitochondrial dysfunction, inflammatory signaling, DNA damage, epigenetic dysregulation and altered apoptotic responses. This study critically reviews the potential benefits of plant-derived phytochemicals and medicinal-plant formulations to mitigate arsenic toxicity, focusing on their molecular processes, empirical information, and translational significance. Polyphenols, flavonoids, organosulfur compounds, carotenoids and other bioactive constituents have demonstrated protective effects mainly in cellular and animal models through the modulation of antioxidant defense, glutathione homeostasis, NRF2/ARE and NF-κB/MAPK signaling, mitochondrial function, inflammation and apoptosis. Some bioactive compounds and phytochemical–chelator combinations have been proven to interact directly with arsenic, modify arsenic disposition, or improve elimination; however, this observation does not apply to all phytochemicals. Limited human evidence provides preliminary translational support, although clinical efficacy remains insufficiently established. Complementary efforts to reduce arsenic exposure through agricultural management, molecular breeding and plant-based environmental remediation are also examined. Major translational challenges are low or variable bioavailability, lack of dosage standardization, insufficient pharmacokinetic data, possible herb-drug interactions, and a lack of controlled clinical studies. This review highlights the phytochemicals represent a promising complementary approach to mitigate arsenic-induced cellular and tissue damage. However, additional mechanistic validation, standardized formulations, safety assessment, and well-designed human studies are needed before their clinical application.
Abstract This study aimed to elucidate the toxic mechanism by which bisphenol A (BPA) exacerbates acne pathogenesis from an ecotoxicological perspective. We identified 55 potential toxic targets of BPA and conducted network analysis, which revealed five core hub genes: MMP9, INS, ESR1, BCL2, and CXCL8. Validation with clinical samples demonstrated that MMP9 and CXCL8 were significantly upregulated in acne lesions. Conversely, ESR1 was downregulated, indicating their potential as diagnostic biomarkers. In contrast, BCL2 and INS did not show significant expression alterations. Acne pathogenesis was found to be critically driven by CXCL8 and MMP9, two genes that ranked at the vanguard of hub genes as delineated through machine learning analysis. Molecular docking and molecular dynamics (MD) simulations suggested a potentially stable interaction between BPA and these core target proteins. In vitro experiments demonstrated that BPA increased lipid droplet formation while upregulating CXCL8 and MMP9 expression in sebaceous gland cells. Further bioinformatic analysis revealed that these hub genes critically modulate the infiltration of neutrophils, macrophages, and T cells. This modulation disrupts skin immune homeostasis and drives the inflammatory progression of acne. Our findings demonstrate that environmental exposure to BPA increases acne susceptibility by targeting key regulatory genes and disturbing the local immune microenvironment. This work provides a mechanistic framework for evaluating the cutaneous ecotoxicity of BPA. Additionally, the established computational strategy offers a rapid, cost-effective, and ethically feasible approach for assessing the hazards of environmental pollutants. This supports environmental safety control and public health initiatives aimed at preventing pollutant-associated skin diseases.
