Drug and Chemical Toxicology最新文献

Prangos uechtritzii Boiss & Hausskn stands out for its rich bioactive constituents including prantschimgin (PRA), imperatorin (IMP), suberosin (SUB), adicardin (ADI), and oxypeucedanin hydrate (OPH) in the Apiaceae family. Although these molecules contribute to several biological activities, their mitochondrial toxicity were not illuminated in depth with the appropriate in vitro and in silico models. Cell viability studies investigated the cytotoxic activities of molecules in HepG2 cells by replacing glucose with galactose due to Warburg effects. Mitochondrial toxicity (mitotoxicity) parameters such as cellular adenosine triphosphate (ATP) and mitochondrial membrane potential (MMP) levels were assessed with cytotoxic concentrations of selected molecules. Molecular docking and dynamics studies were also conducted against mitochondrial electron transport chain (ETC) complexes (I-V) with selected compounds. In vitro results showed that PRA, SUB, and IMP reduced cell viability more in galactose media compared to high glucose media in a dose-dependent manner. PRA, IMP, and SUB decreased ATP levels and MMP, especially in the galactose medium. The in silico study revealed that PRA, IMP, and SUB might bind to complexes I-V at different levels. The docking study demonstrated that PRA had the highest binding potential with the complexes, higher than the standard ligands in some cases. The molecular dynamics (MD) simulation study showed that PRA formed stable complexes with complexes II, III, and IV. In addition, PRA was anticipated to remain inside the binding site of complex II most stably during the 230 ns simulation period. Our study suggests that PRA, IMP, and SUB exhibit mitotoxicity.

Methotrexate (MTX), a widely used chemotherapeutic agent, often induces hepatotoxicity, limiting its clinical utility. Cannabidiol (CBD), derived from hemp, possesses antioxidant, anti-inflammatory, and antiapoptotic properties. This study aims to investigate CBD's protective effects against MTX-induced liver injury and elucidate the underlying mechanisms. Thirty-two female Wistar Albino rats were divided into four groups: control, MTX (20 mg/kg intraperitoneally [i.p.] once), MTX+CBD (20 mg/kg i.p. once + 5 mg/kg i.p. for seven days), and CBD (5 mg/kg, i.p. for seven days). Biochemical analyses of serum and liver tissues were performed to assess oxidative stress markers (total oxidant status, total antioxidant status, oxidative stress index), liver function tests (AST, ALT), and antioxidant enzyme activities (glutathione peroxidase, superoxide dismutase). Histopathological and immunohistochemical examinations were conducted to evaluate liver tissue damage and TNF-α expression. Genetic analyses were performed to measure the expression levels of SIRT-1, p53, Bcl-2, and Bax genes using RT-qPCR. MTX administration increased oxidative stress markers, liver enzymes, TNF-α, p53, and Bax levels while decreasing antioxidant defenses and SIRT-1 expression. CBD administration reversed these alterations effectively. CBD mitigated MTX-induced hepatotoxicity by reducing oxidative stress, inflammation, and apoptosis. It activates antioxidant defenses via SIRT-1 upregulation, suppresses inflammation by reducing TNF-α, and prevents apoptosis by modulating p53, Bcl-2, and Bax gene expressions. These findings suggest CBD could be a promising therapeutic agent for chemotherapy-induced liver damage. Further research is warranted to explore additional pathways and broader molecular mechanisms.

This study aimed to investigate the neuroprotective role of probiotics and 1,25-dyhydroxyvitamin D₃ (calcitriol) against neurotoxicity on rotenone-induced human neuroblastoma cell line SH-SY5Y. Rotenone was administered to induce neurotoxic effects in SH-SY5Y cells. Calcitriol and probiotics were administered at different concentrations as pre- and post-treatment. The thiazolyl blue tetrazolium bromide (MTT) assay was performed to measure cell viability. Intracellular protein levels of antioxidant enzymes (protein tyrosine kinase (PTK), superoxide dismutase (SOD), glutathione peroxidase (GSH), glutathione reductase (GSR), and catalase (CAT)) were determined by the enzyme-linked immunosorbent assay (ELISA). Rotenone (150 nM) reduced (p < 0.001) cell viability compared to control cells. Single and combined pretreatments with probiotics (0.01 mg/ml, 0.05 mg/ml, and 0.1 mg/ml) and calcitriol (1.25 µM, 2.5 µM, and 5 µM) increased (p < 0.05) cell viability compared to rotenone group. In the pre- and post-treatment design, all treatment groups increased the SOD and GSH levels and decreased the GSR levels compared to rotenone. None of the pretreatments reversed the PTK levels (except probiotics: 0.01 mg/ml). Calcitriol (2.5 µM) increased the CAT levels in pretreatment design, and probiotics (0.05 mg/ml and 0.1 mg/ml) increased CAT levels in post-treatment design compared to rotenone group. Calcitriol and probiotics protect against rotenone-induced neurotoxicity in SH-SY5Y cells by decreasing reactive oxygen species (ROS) and increasing antioxidant enzyme parameters. These neuroprotective effects of calcitriol and probiotics against rotenone-induced dopaminergic neurotoxicity provide an experimental basis for their potential clinical use in the treatment of Parkinson's disease (PD).

Nanoliposomes are drug delivery systems that improve bioavailability by encapsulating therapeutic agents. The main objective of this study was to investigate the effects of nanoliposomal (NL) formulation on enhancing the bioavailability of essential oil. The essential oil of Satureja hortensis (SHO) was encapsulated in nanoliposomes (SHNLs). Physicochemical characterizations of NL formulations (size, charge, polydispersity index [PDI]) were evaluated by dynamic light scattering technique. The nanoliposome encapsulation efficiency (EE) was calculated as 89.90%. The prepared bionanosystems demonstrated significant antibacterial activities against Escherichia coli ATCC 10536, Pseudomonas aeruginosa ATCC 15442, and Staphylococcus aureus ATCC as determined by the agar diffusion method and microdilution tests. Minimum inhibitory concentration (MIC) values for SHNLs were found to be 5.187 µg/µL for E. coli and 2.59 µg/µL for both P. aeruginosa and S. aureus. Importantly, despite the lower substance content, both SHNLs and SHO exhibited comparable antibacterial activity against all tested strains. Furthermore, in order to determine the toxicity profile and possible effects on DNA damage or repair both the genotoxic and antigenotoxic effects of SHNLs were assessed using the cytokinesis-blocked micronucleus (CBMN) method in human lymphocyte cultures. The experimental data collectively indicate that the NL formulation of the S. hortensis essential oil enhances antibacterial activities and provides genoprotective effects against DNA damage. This highlights the significance of liposomal formulations of antioxidants in augmenting their biological activity. The results indicate that SHNLs can be a safe antibacterial agent for the pharmaceutical industry.

Pharmaceutical waste from point and non-point sources enters, persists, or disseminates in the environment and is known as environmentally persistent pharmaceutical pollutants. Understanding the impacts of pharmaceutical pollutants on the environment and health is essential. This study investigates the behavioral impacts of pharmaceutical pollutants on aquatic organisms and delineates the possible nexus of oxidative stress. The male zebrafish were exposed to four major representative pharmaceutical pollutants, viz., acetaminophen, carbamazepine, metformin, and trimethoprim at environmentally relevant concentrations individually as well as in a mixture for seven days. Substantial alterations in social interaction, aggressive nature, novel tank exploration, and light and dark zone preferences were recorded and the degree varied to different pharmaceutical pollutants. The activity of oxidative stress markers, superoxide dismutase, glutathione-S-transferase, and catalase, was found to be suppressed to 66-20%, 42-25%, and 59-20% respectively with the elevated malondialdehyde generation (180-260%) compared to control. The activity level of acetylcholine esterase was found to be increased to 200-500% across all treatment groups. Despite the synergistic impacts of pharmaceutical pollutants on the whole system that could not be ascertained, this comprehensive study highlights their toxicity nature to induce neurobehavioral toxicity in zebrafish through oxidative stress mechanisms and altered cholinergic systems.

In our study, the antioxidant and anti-inflammatory effects of different lichen applications were investigated in rats using an experimental ethanol toxicity model. 48 rats were used in the study and they were divided into 6 groups with 8 rats in each group. These groups were: control, ethanol (2 g/kg), ethanol + Usnea longissima Ach. (200 mg/kg), ethanol + Usnea longissima Ach. (400 mg/kg), ethanol + Xanthoparmelia somloensis (Gyelnik) Hale (100 mg/kg) and ethanol + Xanthoparmelia somloensis (Gyelnik) Hale (200 mg/kg). The experimental work continued for 21 days. Lichen extracts and ethanol were administered by gavage to rats divided into groups. According to the experimental protocol, the experimental animals were sacrificed and their liver tissues were isolated. Biochemical parameters in serum, histological examinations, oxidative stress and inflammation parameters both at biochemical and molecular level in liver tissues were performed. Oxidative stress and inflammatory response were increased in the liver tissue of rats treated with ethanol for 21 days, and liver functions were impaired. It was found that U. longissima and X. somloensis extracts showed good antioxidant activity and conferred protective effects against ethanol-induced oxidative stress and inflammation. This could be attributed to the presence of secondary metabolites in the extract, which act as natural antioxidants and could be responsible for increasing the defence mechanisms against free radical production induced by ethanol administration.

Neuropathic pain is the crucial dose-limiting side effect of paclitaxel in chemotherapy patients that negatively impacts the quality of life and survival. Currently, no effective treatment option is available. Aprepitant, a well-established chemotherapy antiemetic performing neurokinin-1 receptor antagonism, shows analgesic effects in some pain models. We studied aprepitant analgesic effects on the paclitaxel-induced neuropathic pain model in rats besides inflammatory markers assessment. Rats intraperitoneally received paclitaxel, reaching the cumulative paclitaxel dose of 8 mg/kg. Aprepitant was orally administered every alternate day between days 2 and 14, with a prescribed dosage of 10 or 20 mg/kg. The evaluation of mechanical allodynia and cold hyperalgesia involved the measurement of paw withdrawal threshold and acetone test score on days 0, 7, and 14. On day 14, paw licking latency was measured using a hot plate test before scarification and tissue collection for interleukin 1β, tumor necrosis factor α, and nuclear factor kappa B (NF-kB) evaluation. Paclitaxel induced neuropathy as indicated by a lowered hind paw withdrawal threshold in the Von Frey test, a higher score in the acetone test, and shortened hot plate latency. Aprepitant effectively alleviated cold and thermal hyperalgesia as well as mechanical allodynia. Moreover, aprepitant administration significantly reversed paclitaxel-mediated elevation of proinflammatory cytokines levels in dorsal root ganglia. In addition, aprepitant application suppressed the protein expression of NF-kB in the dorsal root ganglia of paclitaxel-treated rats, as revealed by western blot analysis. Aprepitant treatment ameliorates neuropathy induced by paclitaxel, which is associated with decreasing proinflammatory cytokines and NF-kB expression.

Plants are a rich source of antioxidants that are produced naturally. Therefore, this study was aimed to evaluate the effect of the plant Ricinodendron heudelotii (Baill.) in the attenuation of paracetamol (PCM) hepatotoxicity in Wistar rats. Twenty-four male albino Wistar rats weighing between 200 and 250 g were divided into four groups, with six rats each. Group 1 served as the control group, receiving just distilled water. Groups 2 and 3 received orally 250 mg/kg bwt/day PCM and 300 mg/kg bwt/day methanol extract of Ricinodendron heudelotii (Baill.) leaves for two weeks, respectively. For group 4, the Ricinodendron heudelotii (Baill.) leaf extract was pre-administered for 1 week before receiving 300 mg/kg bwt/day Ricinodendron heudelotii (Baill.) leaves extract and 250 mg/kg bwt/day PCM for 2 weeks. As a marker of liver damage, serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured. Liver tissue reduced glutathione (GSH) concentration, superoxide dismutase (SOD), glutathione-S-transferase (GST), and catalase activities were utilized to determine antioxidant state, while malondialdehyde (MDA) concentration was employed as a lipid peroxidation indicator. When compared to the control group, the activities of serum AST, ALT, SOD, and MDA levels were considerably (p < 0.05) higher in the PCM group, although GSH level and GST and catalase activities were significantly lower. In comparison to the PCM group, co-administration of PCM with Ricinodendron heudelotii (Baill.) extract decreased serum AST and ALT activities. This study shows that the leaf extracts of Ricinodendron heudelotii (Baill.) protects Wistar rats' livers from PCM-induced oxidative stress by increasing antioxidant enzymes.

It is well-known that the hepatotoxicity of drugs can significantly influence their clinical use. Despite their effective therapeutic efficacy, many drugs are severely limited in clinical applications due to significant hepatotoxicity. In response, researchers have created several machine learning-based hepatotoxicity prediction models for use in drug discovery and development. Researchers aim to predict the potential hepatotoxicity of drugs to enhance their utility. However, current hepatotoxicity prediction models often suffer from being unverified, and they fail to capture the detailed toxicological structures of predicted hepatotoxic compounds. Using the 56 chemical constituents of Gardenia jasminoides as examples, we validated the trained hepatotoxicity prediction model through literature reviews, principal component analysis (PCA), and structural comparison methods. Ultimately, we successfully developed a model with strong predictive performance and conducted visual validation. Interestingly, we discovered that the predicted hepatotoxic chemical constituents of Gardenia possess both toxic and therapeutic effects, which are likely dose-dependent. This discovery greatly contributes to our understanding of the dual nature of drug-induced hepatotoxicity.

Acrylamide (ACR) can have adverse environmental effects because of its multiple applications. Relevant scientific literatures of the existence of ACR residues in foods following processing steps have raised concern in the biochemistry, chemistry and safety of this vinyl substance. The interest has focused on the hepatotoxicity of ACR in animals and humans and on the ACR content mitigation and its detoxification. Borax (BX), as a naturally occurring antioxidant featured boron compound, was selected in this investigation to assess its possible neuro-protective potential against ACR-induced neurotoxicity. Nrf2 axis signaling pathways and detoxification response to oxidative stress after exposure to ACR in brains of rainbow trout, and the effect of BX application on reducing ACR-induced neurotoxicity were investigated. Rainbow trout were acutely exposed to ACR (12.5 mg/L) alone or simultaneously treated with BX (0.75 mg/L) during 96h. The exposed fish were sampled at 48th and 96th and oxidative stress response endpoints, 8-OHdG, Nrf2, TNF-α, caspase-3, in addition to IL-6 activities and the levels of AChE and BDNF in brain tissues of rainbow trout (Oncorhynchus mykiss) were evaluated. Samples showed decreases in the levels of ACR-mediated biomarkers used to assess neural toxicity (SOD, CAT, GPx, AChE, BDNF, GSH), increased levels of MDA, MPO, DNA damage and apoptosis. ACR disrupted the Nrf2 pathway, and induced neurotoxicity. Inhibited activities' expressions under simultaneous administration experiments, revealed the protective effects of BX against ACR-induced toxicity damage. The obtained data allow the outline of early multi-parameter signaling pathways in rainbow trout.