Drug and Chemical Toxicology最新文献

1,3-Dichloro-2-propanol (1,3-DCP) is a moderately volatile organic compound with industrial applications in food and water processing, but it exhibits high reactivity with lipid-rich tissues. This study examines the effect of 1,3-DCP on reproductive fertility parameters in male Wistar rats. Male animals weighing 250 ± 50 grams were assigned randomly to five groups (A-E). Group A received distilled water (control), while groups B-E received oral doses of 5, 10, 15, and 20 mg/kg BW 1,3-DCP for 28 days. Then, analysis was conducted to evaluate the experimental animals' hormonal profiles, spermatogenic activity, testicular function markers, and enzymatic antioxidant status. Oral administration of the chemical caused a significant decrease in body weight, testicular weight, and testes/body weight ratio as well as cholesterol levels in serum and testicular homogenate. While the compound decreased testosterone, luteinizing and follicle-stimulating hormone concentrations, it also lowered alkaline phosphatase, acid phosphatase, and gamma-glutamyl transferase concentrations in testicular tissue samples. Increased malondialdehyde levels, accompanied by a corresponding reduction in glutathione, catalase, and superoxide dismutase in the testicular homogenate, suggest that 1,3-DCP administration resulted in reactive oxygen species-mediated oxidative stress, leading to a consequent decrease in sperm count and abnormalities in spermatozoa morphology. The findings of this study revealed that 1,3-DCP has antifertility effects in male Wistar rats.

Coagulation dysfunction, a common hematologic disorder with unclear pathogenesis, is influenced by environmental factors. Sodium dehydroacetate (SDA), a widely used preservative with high environmental mobility and persistence, has become an emerging organic contaminant and is increasingly recognized for its potential to disrupt immune homeostasis and induce coagulation abnormalities, yet its specific mechanisms remain poorly understood. In this study, we employed an integrated computational approach-combining network toxicology, machine learning (LASSO and XGBoost), bioinformatics, molecular docking, and molecular dynamics simulations-to systematically investigate SDA-induced coagulation dysfunction. We identified 191 potential targets, with significant enrichment in cancer-related pathways, atherosclerosis, and proteoglycans in cancer. Met proto-oncogene (Met) emerged as a core target through machine learning. Analysis of a colorectal cancer dataset (GSE52060) revealed elevated Met expression in patients with coagulation dysfunction, and receiver operating characteristic analysis indicated its strong diagnostic value (area under the curve = 0.856). Molecular docking showed stable binding between SDA and Met (-5.5 kcal/mol), further supported by molecular dynamics simulations demonstrating favorable hydrogen bonding and complex stability. This study provides a theoretical foundation for understanding SDA's role in coagulation dysfunction and supports future preventive and therapeutic strategy development.

Acute kidney injury (AKI) involves a sudden loss of renal function and is associated with high mortality. MicroRNA (miR)-489-3p may serve as a critical molecule in AKI according to previous studies. The study aimed to explore the functional roles of miR-489-3p in AKI and underlying mechanisms. An in vitro model of sepsis-induced cell injury was established by treating human proximal tubular epithelial cells (HK-2) with lipopolysaccharide (LPS). Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was performed to examine expression levels of kidney injury molecule-1 (KIM-1), miR-489-3p, and downstream mRNAs. After silencing miR-489-3p, receptor-interacting protein kinase 4 (RIPK4), or β-catenin signaling, HK-2 cell viability was measured using cell counting kit-8 assays. Apoptosis was assessed by TdT-mediated dUTP nick-end labeling (TUNEL) assay and flow cytometry analysis. Western blot analysis was performed to examine protein levels of apoptotic markers, RIPK4, and β-catenin. Luciferase reporter assays were conducted to explore the interaction between miR-489-3p and RIPK4. Immunofluorescence staining was performed to evaluate the distribution of β-catenin in LPS-stimulated HK-2 cells. MiR-489-3p was significantly upregulated in LPS-treated HK-2 cells. Its inhibition attenuated the pro-apoptotic effects induced by LPS, increased cell viability, and reduced KIM-1 level. MiR-489-3p directly targeted 3' untranslated region of RIPK4 and suppressed its expression. Knockdown of RIPK4 rescued the suppressive effect of miR-489-3p inhibition on cell apoptosis. Moreover, miR-489-3p was found to inactivate the β-catenin signaling by reducing RIPK4 expression. IWR-1 treatment similarly rescued the suppressive effect of miR-489-3p inhibition on cell apoptosis. In conclusion, miR-489-3p promotes LPS-induced HK-2 cell damage by targeting RIPK4 and inactivating β-catenin signaling.

Cisplatin is a potent chemotherapeutic agent widely used in cancer treatment, known for its efficacy but limited by significant cardiotoxic side effects. Oridonin, a bioactive diterpenoid derived from Rabdosia rubescens, has demonstrated potential to mitigate these adverse effects, though this protective capability against cisplatin-induced cardiotoxicity has not been extensively explored. In this study, mice were administered oridonin orally at doses of 25 or 50 mg/kg/day for seven days. Additionally, they received cisplatin injections at a dosage of 5 mg/kg on days 3 and 6, intraperitoneally. On the eighth day, after anesthesia with sodium pentobarbital (50 mg/kg, i.p.), blood and heart samples were collected for biochemical and molecular analysis. Oridonin significantly mitigated CP-induced cardiac damage, as evidenced by reduced levels of cardiac troponin I (cTnI), creatine kinase (CK), and lactate dehydrogenase (LDH). It also decreased oxidative stress markers such as malondialdehyde (MDA), while enhancing the activity of antioxidants like superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH). Additionally, oridonin reduced levels of pro-inflammatory cytokines, tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6), and modulated apoptosis-related proteins by increasing Bcl-2 and decreasing Bax and caspase-3. The protective effects of oridonin were further linked to modulation of the p62/Keap1/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, as evidenced by increased protein levels of p62 and Nrf2, and decreased protein Keap1. Oridonin confers significant protection against the cardiac side effects of cisplatin chemotherapy, highlighting its potential as a supplementary therapy in oncological treatments.

Many people often assume the safety of herbs and use them in the form of polyherbal blends to treat various health conditions. The present study aimed to evaluate the acute and subacute oral toxicity profile of a polyherbal blend in Wistar rats. The polyherbal blend was prepared to contain Terminalia chebula Retz., Terminalia bellirica (Gaertn.) Roxb., Phyllanthus emblica L., Curcuma longa L., Tribulus terrestris L., Pterocarpus marsupium Roxb., Tinospora cordifolia (Willd.) Miers, and Cinnamomum verum J. Presl. An acute oral toxicity study of a prepared polyherbal blend was conducted as per OECD guideline 423 and the subacute toxicity study was performed as per OECD 407 guidelines. There was no mortality and signs of toxicity at 2000 mg/kg single oral administration of polyherbal blend, indicating that the oral median lethal dose (LD₅₀) is greater than 2000 mg/kg. The results of the subacute toxicity study indicated no significant changes in body weight, food and water consumption, hematological and biochemical parameters in rats treated with polyherbal blend at 250, 500 and 1000 mg/kg for 28 days when compared to their respective controls. Organ weights and histopathology showed no significant alterations in treated or satellite groups as compared to controls. It is concluded that the polyherbal blend is safe at a single dose of 2000 mg/kg and 28 days repeated dose of 1000 mg/kg by oral route in rats.

Pharmaceutical drugs have detrimental effects on aquatic organisms and change the ecological implications of the aquatic ecosystem. The present study was designed to examine the acute exposure (seven days) effect of phenytoin on the physiological parameters (condition index, filtration rate (FR), and clearance rate (CR)), metabolic capacity (electron transport system activity), energy reserves content (glycogen and protein concentrations), and oxidative biomarkers (antioxidant and biotransformation enzymes activities, lipid peroxidation levels) in the freshwater mussels Lamellidens marginalis. After experimentation, decrease in gill FR (60-25 mL gDW^-1 h^-1), nitric oxide generation (0.13-0.121%), CR (0.14-0.043 mL mg^-1 DW h^-1) variations in energy reserves and antioxidant oxidative biomarkers were observed. Additionally, histological analysis shows damage to gills ciliated epithelium, damaged interlamellar junction and water tubes in the increased concentration groups. The results of the study indicated modifications to L. marginalis physiological and biochemical parameters as well as critical oxidative defenses against extrinsic hazardous threat. Phenytoin might damage L. marginalis at its cellular level by limiting their ability to thrive, grow, as well as adapt to undesirable circumstances.

The bio-accumulative nature of polychlorinated naphthalenes (PCNs) due to their slow biodegradation raise concerns regarding adverse effects on aquatic organisms and potential human health risks through trophic transfer. The persistent and traditional toxicity assessment of PCNs in aquatic species is constrained by experimental complexity, resource demands, and ethical considerations. Consequently, in silico approaches, particularly QSAR modeling in accordance with OECD guidelines, have emerged as robust alternatives to address data gaps and support hazard evaluation. In the present investigation, a Monte Carlo-based QSAR methodology employing CORAL software was utilized to assess the toxicity of PCNs in aquatic environments. An integrated dataset comprising 225 compounds with toxicity endpoints for green algae, Daphnia magna, and fish was assembled. Molecular structures were encoded using the Simplified Molecular Input Line Entry System (SMILES). Statistical evaluation confirmed the predictive robustness of the models, with Split 4 yielding superior external validation performance (r² = 0.9490, Q² = 0.9453, IIC = 0.9157, CII = 0.9633, CCC = 0.9661, r²_m = 0.8549, MAE = 0.192, S = 0.224, F = 1023). These findings substantiate the reliability of the developed QSAR model, underscoring its applicability in environmental toxicology, potential to design safer drug candidate and early-stage hazard assessment.

The thyroid gland is a central endocrine organ regulating growth, metabolism, and energy balance, and is increasingly vulnerable to interference by diverse xenobiotic compounds from pharmaceuticals, environmental pollutants, diet, and consumer products. This review introduces a thyroid '3H' framework - hormonogenesis, homeostasis, and human health - to integrate current understanding of how thyroid endocrine-disrupting chemicals (Thy-EDCs) perturb thyroid physiology and the hypothalamic-pituitary-thyroid axis. A systematic literature search was conducted using PubMed, Scopus, and Web of Science, supplemented by reference screening to ensure comprehensive coverage of mechanistic and toxicological evidence. The synthesis indicates that various exogenous compounds - including tyrosine kinase inhibitors, immune checkpoint inhibitors, heavy metals, industrial endocrine disruptors, and certain dietary phytochemicals - affect thyroid function through multiple molecular initiating events. These include inhibition of thyroperoxidase, disruption of iodine uptake and organification, altered deiodinase activity, modulation of thyroid hormone receptor signaling, and immune-mediated effects on thyroid tissue. Such perturbations lead to abnormalities in hormone synthesis, metabolism, and systemic hormone homeostasis. Emerging structure-activity relationship (SAR) and computational modeling approaches provide further insight into how specific chemical features determine thyroid-disruptive potential, supporting the advancement of predictive toxicology and risk assessment. The novelty of this review lies in its integrated 3H perspective, linking physiological, molecular, immunological, and toxicological dimensions of thyroid disruption. This conceptual framework supports improved diagnosis of thyroid dysfunction, promotes safer chemical and drug design, and informs regulatory strategies aimed at protecting endocrine health.

Lambda-cyhalothrin (LCT), a type II pyrethroid, is known to cause several side effects, including hepatorenal toxicity, despite its widespread use. This study investigates the protective effect of carvacrol (CVR) against LCT-induced oxidative stress, inflammation, and apoptotic pathway in the liver and kidney. Forty-eight male Sprague-Dawley rats were randomly assigned to eight groups; the first two groups served as controls (negative and CVR). The third, fourth, and fifth groups received LCT at doses of 2, 4, and 8 mg/kg/day via gavage. The sixth, seventh, and eighth groups received a dose of CVR (50 mg/kg/day) during LCT exposure for 90 days. Co-treatment with CVR reduced the elevated levels of hepatic biomarkers (alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and γ-glutamyl transferase (GGT)), kidney markers (urea and creatinine), and various histopathological changes caused by LCT exposure. Additionally, CVR mitigated LCT-induced oxidative stress by lowering malondialdehyde (MDA) levels, increasing cellular antioxidant (glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GR)), and upregulating the transcription of the Trx1 and Prx1 genes. Moreover, CVR decreased the pro-inflammatory cytokine (tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6)) levels, along with the activation of apoptotic markers (p53, Bax, and caspase-3), and lowered Bcl2 levels. Furthermore, the in silico study confirmed that LCT interacts directly with the active cysteine residues of Trx1, Prx1, and Bcl2 proteins at high binding energies. In conclusion, sub-chronic exposure to LCT can induce hepatorenal apoptosis by inhibiting the Trx1/Prx1/Bcl2 pathway, an effect that is reversed by CVR's antioxidant properties.

Paracetamol, commonly referred to as acetaminophen, is a widely used pain reliever and fever reducer. It is effective in treating mild to moderate pain and fever. The drug's mechanism of action involves inhibition of prostaglandin synthesis in the central nervous system, which reduces pain and fever. Paracetamol is generally well-tolerated at therapeutic doses, with minimal gastrointestinal side effects compared to nonsteroidal anti-inflammatory drugs (NSAIDs). However, paracetamol toxicity is a significant concern, particularly in cases of overdose. The primary site of toxicity is the liver, where excessive doses lead to the accumulation of a toxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI). This metabolite depletes glutathione and causes oxidative stress, resulting in hepatocellular damage and potentially acute liver failure. Renal impairment and pancreatitis are also associated with paracetamol toxicity, though less commonly. Risk factors for toxicity include chronic alcohol use, fasting, and concurrent use of enzyme-inducing drugs.