Toxicology and applied pharmacology最新文献

While exercise is well-established as a protective strategy against non-alcoholic fatty liver disease, its role in acute liver injury (ALI) remains poorly understood. Nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of antioxidant response element (ARE)-dependent gene expression, plays an important role in the pathogenesis of liver diseases, where oxidative stress contributes significantly to both chronic progression and acute injury. This study investigated whether exercise confers protection against ALI via the Nrf2 signaling pathway and elucidated the underlying molecular mechanisms. We found that acute treadmill exercise time- and intensity-dependently activated hepatic Nrf2 signaling in mouse, conferring significant protection against ALI induced by alcohol, acetaminophen, or carbon tetrachloride. Conversely, exercise failed to protect against and even exacerbated ALI in Nrf2-deficient mice. Furthermore, using antioxidant Trolox and AMPKα2-knockout mice, we demonstrated that exercise activated hepatic Nrf2 primarily via ROS and AMPK signaling. Additionally, we identified exercise-induced elevation of epinephrine as a novel mechanism for activating hepatic Nrf2. In conclusion, our study demonstrates that exercise protects against ALI by activating the hepatic Nrf2/ARE signaling axis and delineates the associated molecular mechanisms, providing a scientific rationale for exercise-based therapeutic interventions.

Urinary neutrophil gelatinase-associated lipocalin (uNGAL) is a sensitive marker of tubular stress and injury that may detect early renal involvement before overt changes in conventional kidney function tests. This case-control study evaluated uNGAL as an early biomarker of subclinical kidney injury among adults with substance use disorder (SUD). Adults with SUD and no known kidney disease (n = 31) were compared with age-matched controls (n = 31). uNGAL was measured by ELISA together with serum creatinine and estimated glomerular filtration rate (eGFR; Cockcroft-Gault). uNGAL was markedly higher in participants with SUD than in controls (1913.1 ± 770.9 vs 71.5 ± 26.5 ng/mL; p < 0.001). Serum creatinine was higher, and eGFR was lower in the SUD group, although both remained within generally non-severe ranges. uNGAL demonstrated excellent discrimination between groups (AUC = 1.00; cutoff = 611.5 ng/mL; sensitivity and specificity = 100% in this sample). These findings suggest that uNGAL may reflect early or subclinical renal tubular injury in adults with SUD even when conventional renal markers show only limited changes. Larger prospective studies are needed to validate these findings and clarify prognostic utility.

This study aims to delineate the specific mechanism through which TGF-β mediates NaF-induced cardiotoxicity, with a focus on its regulatory role in the Wnt/β-catenin signaling pathway. We assessed NaF-induced cytotoxicity in AC16 cardiomyocytes by CCK-8, crystal violet staining, and EdU assays; determined cell cycle progression and apoptosis by flow cytometry; and systematically evaluated ROS levels, mitochondrial function, oxidative stress, inflammation, and expression using fluorescent probes, enzymatic assays, RT-qPCR, and Western Blot. The in vivo cardiotoxic mechanism of NaF was further verified in a rat model. NaF triggers cardiotoxicity in AC16 cardiomyocytes by inhibiting the Wnt/β-catenin pathway and activating TGF-β signaling, leading to suppressed proliferation, cell cycle arrest, and apoptosis. These changes further intensify oxidative stress, mitochondrial dysfunction, and inflammation. In rats, NaF exposure caused abnormal ECG patterns and cardiac tissue damage, linked to upregulated TGF-β signaling and downregulated Wnt/β-catenin activity. Corresponding molecular changes included decreased expression of antioxidant factors (NQO1, HO-1), increased levels of inflammatory mediators (IL-6, IL-8), and P16, MMP3, P53, P21. Together, these findings clarify key mechanisms of fluoride-induced cardiotoxicity and offer a theoretical basis for managing fluorosis-related cardiac injury. NaF inhibits AC16 cardiomyocyte proliferation and induces apoptosis, cell cycle arrest, oxidative stress, mitochondrial damage, and inflammatory responses. These effects are mediated through upregulation of the TGF-β signaling pathway and concurrent inhibition of the Wnt/β-catenin pathway.

Dihydroxynaphthalenes (DHNs) are widely detected in combustion-derived pollution. However, their isomer-specific developmental toxicity remains poorly understood. In this study, we systematically compared the developmental toxicity of three DHN isomers-1,5-dihydroxynaphthalene (1,5-DHN), 2,3-dihydroxynaphthalene (2,3-DHN), and 2,7-dihydroxynaphthalene (2,7-DHN)-using zebrafish embryos as a vertebrate model. Exposure to DHNs induced distinct, isomer-dependent developmental abnormalities, with 2,3-DHN exerting the most severe effects. Prominent phenotypes included cranial hemorrhage, disrupted cerebrovascular architecture, abnormal erythrocyte distribution, impaired hematopoietic stem cell development, and selective suppression of immune cell populations. In addition, DHN exposure resulted in pronounced neurodevelopmental and craniofacial defects, particularly in the 2,3-DHN treated group. Biochemical analyses revealed significant accumulation of reactive oxygen species (ROS), elevated lipid peroxidation, and disruption of antioxidant enzyme activities, indicating oxidative stress as an important toxicological response. Consistent with these findings, transcriptional analysis demonstrated isomer-specific alterations in genes associated with vascular development, apoptosis, and neurodevelopment, whereas proliferation-related gene expression remained largely unaffected. These results demonstrate that DHN exposure induces multisystem developmental toxicity in zebrafish in a strongly isomer-dependent manner, following the toxicity ranking of 2,3-DHN > 1,5-DHN > 2,7-DHN. Subtle differences in hydroxyl substitution position translate into pronounced differences in redox reactivity and biological outcomes, highlighting oxidative stress as a key contributing mechanism associated with DHN-induced developmental toxicity. These findings demonstrate that environmental transformation of polycyclic aromatic hydrocarbons does not necessarily attenuate toxicity, but may generate derivatives with distinct and potentially enhanced toxicological profiles. Collectively, this study underscores the necessity of incorporating oxygenated PAHs and isomer-specific effects into environmental toxicology and ecological risk assessment.

Melanocyte proliferation gene 1 (MYG1) has been implicated in cellular metabolic regulation; however, its role in cardiomyocyte metabolic reprogramming during acute myocardial infarction (AMI) remains unclear. In this study, a rat AMI model was established, and MYG1 knockdown was achieved by lentiviral injection to investigate its effects on myocardial injury and metabolism. Myocardial infarct size, apoptosis, and the expression of metabolic- and autophagy-related proteins were assessed using TTC staining, Western blotting, immunohistochemistry, and TUNEL assays. In parallel, an oxygen-glucose deprivation (OGD) model was generated in H9C2 cells, in which MYG1 was overexpressed alone or in combination with the glycolysis inhibitor 2-deoxy-d-glucose (2-DG), the AMPK activator AICAR, or the mTOR inhibitor rapamycin. MYG1 expression was significantly upregulated in myocardial tissues following AMI. MYG1 knockdown attenuated cardiomyocyte apoptosis, enhanced the expression of mitophagy-related proteins PINK1 and Parkin, reduced the levels of key glycolytic enzymes hexokinase 2 and enolase 1, and promoted mitochondrial oxidative phosphorylation. In vitro, MYG1 overexpression facilitated glycolysis and aggravated OGD-induced cellular injury, whereas inhibition of glycolysis by 2-DG effectively reversed these effects. Furthermore, modulation of the AMPK/mTOR pathway influenced MYG1-associated metabolic alterations, as evidenced by changes in cellular metabolic flux and improved mitochondrial autophagy and ultrastructural integrity. These findings suggest that MYG1 participates in cardiomyocyte metabolic reprogramming during AMI, potentially through regulation of the AMPK/mTOR pathway, and may represent a candidate target for therapeutic intervention.

Sepsis-associated liver injury is one of the signs of multiple organ damage brought on by sepsis. Acute liver injury (ALI) is a potentially fatal acute inflammatory disease that causes necrotic cell death and immediate hepatocyte destruction. This study aimed to investigate the protective effect of ezetimibe (EZE) against lipopolysaccharide (LPS)-induced acute liver injury. Five days prior to a single intraperitoneal injection of LPS (3 mg/kg), male Swiss albino mice weighing 18-25 g were pre-treated orally with EZE at two different dosages (5 and 10 mg/kg), while animals of the control group received only the vehicles. Serum was used to test liver function, while mouse tissue homogenates were used to measure oxidative stress and inflammatory mediators. EZE improved histological changes and dramatically reduced serum liver transaminases. Reduced levels of malondialdehyde (MDA) and increased levels of reduced glutathione (GSH) in hepatic tissues are further indications of its antioxidant action. Moreover, EZE pretreatment significantly reduced the hepatic expression of toll-like receptor 4 (TLR4), nuclear factor kappa B (NF-κB)p65, interleukin (IL)-1β and tumor necrosis factor (TNFα). Additionally, myeloid differentiation primary-response protein 88 (MYD88), TNF Receptor Associated Factor 6 (TRAF-6) and IL-6 were markedly reduced in the liver by EZE. Collectively, EZE may be a promising candidate in sepsis-related liver injury following further clinical studies.

Objective: This study aimed to investigate whether ophiopogonin B (OP-B), suppresses the progression of triple-negative breast cancer (TNBC) by modulating protein tyrosine phosphatase 1B (PTP1B) activity and the downstream PI3K/Akt signaling pathway.

Methods: The anti-TNBC effects of OP-B on MDA-MB-231 and BT549 cells were evaluated using CCK-8, colony formation, wound healing, and Transwell assays. Cell apoptosis was assessed by TUNEL staining. PTP1B gain- and loss-of-function models were established via lentiviral transduction. Protein expression of PTP1B, PI3K, p-PI3K, Akt, and p-Akt was examined by Western blot. The in vivo antitumor activity of OP-B was investigated in a TNBC xenograft model, with subsequent IHC, TUNEL, and Western blot analyses of tumor tissues.

Results: OP-B inhibited the proliferation, migration, and invasion of TNBC cells in a concentration-dependent manner and induced apoptosis. Western blot analysis revealed that OP-B treatment down-regulated the expression of PTP1B protein and suppressed the activity of the PI3K/Akt pathway. Genetic rescue experiments confirmed the critical role of PTP1B: knocking down PTP1B both mimicked and potentiated the antitumor effects of OP-B and its inhibition of the PI3K/Akt pathway, whereas overexpressing PTP1B antagonized these effects. In the MDA-MB-231 cell xenograft mouse model, OP-B treatment significantly inhibited tumor growth, reduced the percentage of Ki67-positive cells in tumor tissues, increased apoptosis, and recapitulated the suppression of the PTP1B/PI3K/Akt signaling axis.

Conclusion: Collectively, these findings indicate that ophiopogonin B exerts anti-tumor effects against triple-negative breast cancer both in vitro and in vivo through modulating PTP1B and suppressing the downstream PI3K/Akt signaling pathway.