Toxicology Research最新文献

The exposure to non-pharmaceutical chemicals has been increasingly associated with liver injury, yet the underlying molecular mechanisms remain unclear. This study investigates the impact of three such chemicals-sunset yellow (SUN), tartrazine (TART), and triclosan (TRI)-on human HepaRG cells to elucidate potential toxicological targets and pathways. We conducted differential expression analysis on HepaRG cells exposed to SUN, TART, and TRI, identifying differentially expressed genes (DEGs). Intersection analyses were performed to uncover common targets, followed by heatmap visualization and enrichment analyses using GO and KEGG pathways. Protein-protein interaction (PPI) and immune cell infiltration analyses further elaborated the effects, complemented by molecular docking studies to assess chemical binding affinities. Our findings identified 47 upregulated and 123 downregulated DEGs as common targets across all chemical exposures. Enrichment analysis revealed significant alterations in biological processes related to liver metabolism and development. Four core toxic targets (KNG1, PLG, SERPINE1, SERPINF2) were identified with significant connectivity in PPI analysis, confirmed by altered gene expression. Immune cell infiltration analysis indicated modulation of various immune cell populations. The molecular docking study highlighted strong binding of TART and SUN to PLG, suggesting a potential mechanism of liver injury. This study provides insights into the molecular mechanisms of liver injury induced by non-pharmaceutical chemical exposure, identifying key toxicological targets and pathways. The results suggest that chemicals like SUN and TART can significantly alter liver function through specific gene expression changes and immune modulation, offering potential biomarkers and therapeutic targets for mitigating such toxic effects.

Cadmium (Cd), a well-known environmental pollutant, widely exists in water, soils, sediments, and air, and produces various system dysfunctions including those affecting the nervous system. L-carnitine (L-CAR) is an antioxidant that plays neuroprotective roles by improving enzyme functions. The purpose of our study was to evaluate whether L-CAR could efficiently protest against neurotoxicity induced by Cd. Rats were exposed to different concentrations of Cd (0, 25, 50, 100 mg/l) for 4 weeks. We used the open-field test (OFT) and forced-swimming test (FST) to observe the rats'spontaneous locomotor activity and exploration behavior; brain histopathological section to observe the damage of cortical neurons in the brain; Oxidative stress indicators reactive oxygen species (ROS), malondialdehyde (MDA) and superoxide dismutase (SOD) were determined at terminal time-points. The protective effects of L-CAR(1.5 g/l) were evaluated in parallel. Here, we corroborated that that L-CAR is a potential pharmacological agent that protests against the neurotoxicity of Cd. The results of brain histopathological sections show that with the increase of cadmium dosage in drinking water, but the damage to cortical neurons becomes more severe;the Cd(100 mg/l) + L-CAR(1.5 g/l) group, the neuronal cell membrane was intact, the cell outline was clear. The Cd-induced oxidative stress in the cerebral cortex was proven by elevation of ROS, MDA levels, and reduction of SOD activity. However, those effects on oxidative stress were attenuated if L-CAR(1.5 g/l) was simultaneously administrated. The results suggested that L-CAR is a potential pharmacological agent that protects the neurotoxicity of Cd.

This study investigated Puerarin's protective effects and mechanisms against high glucose (HG)-induced damage in human lens epithelial cells (HLECs), which are relevant to diabetic complications. Using an HG-exposed HLEC model, varying doses of Puerarin (10 μM, 20 μM, 50 μM) were tested. While non-toxic to normal HLECs, both 20 μM and 50 μM Puerarin significantly and dose-dependently restored cell viability reduced by HG (P < 0.05). Puerarin effectively reversed HG-induced apoptosis and mitigated oxidative stress by increasing levels of antioxidant enzymes (SOD, GSH-Px) and decreasing malondialdehyde (MDA) concentrations. Mechanistically, Puerarin significantly upregulated the expression of the transcription factor Nrf2, with the strongest effect observed at 50 μM. Crucially, when Nrf2 expression was knocked down using shRNA Nrf2 transfection in HG-treated HLECs, the protective effects of high-dose Puerarin were completely abolished. This loss of protection resulted in significantly increased cell death and oxidative stress markers compared to control cells transfected with shRNA Ctrl and treated with Puerarin. The findings demonstrate that Puerarin, particularly at doses of 20 μM and 50 μM, protects HLECs from HG-induced damage in a dose-dependent manner. This protection involves preserving cell viability, reducing apoptosis, and enhancing cellular antioxidant defenses. The Nrf2 signaling pathway is identified as a key mechanism mediating Puerarin's beneficial effects. These results suggest that Puerarin has potential as a therapeutic agent for preventing diabetic complications affecting the lens epithelium.

Methotrexate (MTX) is a drug used to treat autoimmune diseases and certain cancers. However, its untreatable hepatotoxic effect severely limits its clinical use. Therefore, further studies are required to combat MTX-induced liver injury. Nitrate, abundant in green vegetables, possesses anti-inflammatory, antioxidant, and immunoregulatory effects. Our study investigated the preventive effects of nitrate on MTX-induced liver injury. Liver injury in mice was induced by administering a single dose of MTX (20 mg/kg body weight) intraperitoneally (i.p.). Pre-treatment of mice with 2 mM nitrate in drinking water 5 days prior effectively mitigated the MTX-elevated serum aminotransferase activities, attenuated hepatic pathological injury, reduced hepatic apoptosis and restored the proliferative capacity of hepatocytes. RNA sequencing analysis indicated that the molecular mechanism may involve the activation of the Wnt/β-catenin pathway. The AML 12 cell line was employed for in vitro validation. In this study, the hepatoprotective effect of nitrate against drug-induced liver injury (DILI) was identified for the first time, providing a new approach to preventing DILI in clinical practice.

Acute pediatric poisoning is a severe global public health issue that represents a leading cause of morbidity and mortality in pediatrics. The study discussed the accuracy rate of the new PMS to be applied to pediatric acutely poisoned patients after modification to be called the pediatric new poisoning mortality score (pediatric new-PMS) and compared it to the poisoning severity score (PSS). The study was conducted on acutely pediatric intoxicated patients admitted to a pediatric intensive care unit (PICU) during the period from January 2021 to January 2024 (181 cases). 48.6% of cases were males, and 51.4% were females; the median age was 5 years. Regarding the fate of cases, 65.2% recovered completely, 16.57% recovered with a complicated course, and 18.23% died. The pediatric new-PMS above 50 points had an accuracy rate of 85.3% with good discrimination for mortality, sensitivity of 78.8%, specificity of 77.7%, positive predictive value of 44%, and negative predictive value of 94%. The PSS above 2 had an accuracy rate of 84.5% with good discrimination for mortality, sensitivity of 97%, specificity of 71.6%, positive predictive value of 43.2%, and negative predictive value of 99%. The study concluded that the PSS and pediatric new PMS can be used efficiently to predict mortality in acute pediatric intoxicated patients. The pediatric new-PMS score is easy to calculate even before admission to PICU, as it depends on objective markers that can be obtained even in the prehospital stage, such as vital signs, mental state, demographics, and poisoning-related variables.

Central precocious puberty (CPP) refers to gonadotropin-dependent sexual precocity that results from the early activation of the hypothalamic-pituitary-gonadal (HPG) axis. Zearalenone (ZEA), a non-steroidal mycotoxin, is one of the important triggering factors for the development of CPP; however, its regulatory mechanism remains unclear. In this study, the correlation between urinary zearalenone (ZEA) levels and the blood expression of MKRN3 (makorin RING-finger protein-3) in patients with central precocious puberty (CPP) was investigated. Subsequently, the regulatory mechanism of ZEA on MKRN3, as well as its association with gonadotropin-releasing hormone (GnRH) production, cell proliferation, and the expression and localization of the G protein-coupled estrogen receptor (GPER) were explored in the hypothalamic cell line GT1-7. Analysis of clinical samples revealed that urinary ZEA levels were negatively correlated with blood MKRN3 expression in CPP patients. The in vitro experiments revealed that ZEA treatment up-regulated cell proliferation as well as the expressions of GnRH and GPER and re-location of GPER in GT1-7 cells by triggering MKRN3 auto-ubiquitination and down-regulation. However, such effects were attenuated by GPER overexpression. In conclusion, this study reveals a novel mechanism by which ZEA influences CPP using clinical samples and an in vitro model. The findings suggest that MKRN3 may serve as a potential therapeutic target and a diagnostic biomarker for CPP.

Mycoplasma genitalium is increasingly recognized for its role in severe health conditions, including sexually transmitted infections, ovarian and prostate cancer. The adhesion protein plays a crucial role in the pathogen's ability to attach to and invade host cells, making it a key target for vaccine development. The need to develop a vaccine against M. genitalium stems from its rising antibiotic resistance, limited treatments and effectiveness. This study focuses on the design and computational evaluation of adhesion protein-based epitope vaccine. Through an immunoinformatic approach, multiple novel cytotoxic T lymphocyte (CTL), helper T lymphocyte (HTL), and linear B-cell epitopes were identified from the adhesion protein, demonstrating strong antigenic, non-allergenic, and immunogenic properties. The vaccine construct's 3D structure was validated using Ramachandran plot analysis, ProSA, and ERRAT servers, confirming its stability and suitability. Molecular docking studies revealed a high binding affinity of the vaccine with the TLR-2 receptor, further supported by 100 ns molecular dynamics (MD) simulations that confirmed the structural stability and robust interaction of the vaccine with immune receptors. In silico immune simulations using the C-ImmSim server demonstrated the vaccine's potential to elicit strong humoral and cell-mediated immune responses. Codon optimization for expression in E. coli using the pET-29a(+) vector predicted efficient production of the vaccine. The comprehensive computational analysis, underscores the potential of this epitope-based vaccine as a promising candidate against M. genitalium infections. However, the study emphasizes the necessity of in vitro and in vivo experiments to validate the vaccine's efficacy and safety before advancing to clinical trials.

This study aims to evaluate the long-term dose-dependent effects of sodium nitrate on serum ALT, AST, and ALP in healthy female and male rats. A total of 120 rats (60 females and 60 males) were divided into 6 subgroups (n = 10). In each sex, a control group received regular tap water, while five treatment groups received sodium nitrate in tap water (50, 100, 150, 250, and 500 mg/L). Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and nitric oxide (NO) metabolites (NOx) were measured at baseline (month 0) and after 6 mo. Hormetic zones for sodium nitrate in female rats were 10-230 mg/L for ALT, 20-180 mg/L for AST, and 8-270 mg/L for ALP. In males, the zones were 5-190 mg/L for ALT, 7-180 mg/L for AST, and 7-265 mg/L for ALP. Serum NOx levels were negatively correlated with ALT (r = -0.498) and AST (r = -0.320) at moderate doses (100-150 mg/dL) but positively correlated with ALT (r = 0.500) and AST (r = 0.300) at higher doses (250-500 mg/dL (all P < 0.05). Sodium nitrate exhibited a J-shaped dose-response relationship with liver function tests (LFTs) in both female and male rats. Protective effects were observed at moderate doses (100 mg/L for ALT and AST; 150 mg/L for ALP), while low doses (<10 mg/L) were ineffective, and high doses (>200 mg/L for ALT/AST; >250 mg/L for ALP) were toxic. These findings highlight the dual potential of sodium nitrate as both beneficial and harmful, depending on the dosage in healthy state.

Calcium homeostasis plays a pivotal role in neuronal function, and its dysregulation is closely associated with oxidative stress-induced neurotoxicity. This study investigated the protective effects of a methanol alkaloid extract (MAE), rich in allocryptopine, tetrahydropalmatine, and tetrahydroberberine N-oxide, on H₂O₂-induced calcium dysregulation in fPC12 cells. Flow cytometry analysis revealed that MAE pretreatment significantly attenuated intracellular Ca²⁺ accumulation caused by oxidative stress. In line with this, MAE markedly downregulated the mRNA and protein expression levels of CACNA1C (Cav1.2 subunit) and CACNA1D (Cav1.3 subunit), two L-type voltage-gated calcium channels responsible for calcium influx. Furthermore, MAE suppressed the expression of key calcium regulatory proteins, including CALM1, CaMK2A, PMCA (ATP2B1), SERCA (ATP2A1), RyR1, and IP3R (ITPR1), as confirmed by ELISA and Western Blot analysis. Protein-protein interaction (PPI) network analysis demonstrated a highly interconnected and functionally enriched network among these targets, indicating coordinated regulation of calcium signaling pathways. Molecular docking studies supported these findings by showing strong binding affinities of MAE's isoquinoline alkaloids, particularly tetrahydropalmatine, to SERCA (ATP2A1) and IP3R (ITPR1). These interactions suggest a direct modulatory effect on calcium-handling proteins. Overall, this study provides experimental and in silico evidence that MAE exerts multifaceted neuroprotective effects by restoring calcium homeostasis and modulating oxidative stress responses, highlighting its therapeutic potential in calcium-related neurodegenerative conditions.

Zebrafish (Danio rerio) has emerged as a valuable model organism in toxicology and drug discovery research. This article provides an overview of the significant contributions of zebrafish to advancing our understanding of toxicology and drug development. Zebrafish offers several advantages, including high fecundity, transparent embryos, and genetic tractability, making it an ideal system for studying drug toxicity and efficacy. The review article highlights key areas where zebrafish has made substantial contributions, such as assessing chemical toxicity, understanding drug metabolism and pharmacokinetics, and identifying novel therapeutic compounds. Furthermore, zebrafish-based assays and screening platforms have been developed to evaluate drug candidates and identify potential toxic effects and researchers have used zebrafish-based tests to study the therapeutic properties of natural compounds. The unique capabilities of zebrafish with its physiological and genetic similarities to humans, have propelled it to the forefront of toxicology and drug discovery, expanding the frontiers of research in these fields.