Drug and Chemical Toxicology最新文献

Diphenyl ether (DE) is a chemical compound being used in a number of industries such as soap, detergents, perfumes, adhesive, dyes, herbicides and as a flame retardant in plastics, rubbers and textiles, etc. DE is the final debromination product of polybrominated diphenyl ethers (PBDEs) under anaerobic conditions. The present investigation evaluated the genotoxic, biochemical, histopathological, ultrastructural (SEM) and biomolecular (ATR-FTIR) changes in the zebrafish larvae after DE exposure. After the determination of 96 h LC₅₀ value zebrafish embryos were exposed to sublethal concentrations (¼ LC₅₀ and ½ LC₅₀) of DE. Significantly increased DNA damage in terms of tail length (TL), tail intensity (TI), olive tail moment (OTM) and tail moment (TM) was observed after the DE exposure to zebrafish larvae. Also, increased lipid peroxidation (MDA) and decreased FRAP activity were reported after DE exposure. The catalase (CAT), Glutathione-S-transferase (GST), and Acetylcholinesterase (AChE) activity were reported to be significantly increased and a decreased superoxide dismutase (SOD) activity was observed in DE-exposed groups. After DE exposure, Decreased cell viability and increased apoptosis were reported in zebrafish larvae. The histological and ultrastructural (SEM) analysis revealed the alterations in the zebrafish larvae exposed to DE. The ATR-FTIR study revealed the changes in the biomolecules such as DNA and protein after the DE exposure. The present study will help to understand the destructive aspects of DE in the early life stages of aquatic organisms and could be utilized to assess environmental risk.

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 evaluates the antioxidant effects of aqueous leaf extract of Pistacia lentiscus (ALEPL) and its potential to counteract oxaliplatin (OXA)-induced mitochondrial oxidative stress in rat livers, a common side effect of chemotherapy in cancer treatment. Bioactive compounds were identified using High-Performance Liquid Chromatography coupled with Tandem Mass Spectrometry (HPLC-MS and MS), with Fourier-Transform Infrared Spectroscopy (FTIR) and Atomic Absorption Spectrophotometry (AAS) for chemical and mineral analysis. ALEPL showed notable antioxidant activity, with IC50 values of 4.30 ± 0.27 μg/mL for DPPH (2,2-Diphenyl-1-picrylhydrazyl) scavenging, 13.64 ± 0.51 μg/mL for reducing power, 32.62 ± 5.32 μg/mL for hydroxyl radical scavenging, and 205.08 ± 25.77 μg/mL for superoxide anion radical scavenging. In ex vivo experiments, mitochondria isolated from Wistar rat livers were treated with OXA and ALEPL in a dose-dependent manner. ALEPL pretreatment effectively restored mitochondrial antioxidant enzyme activities, increased glutathione (GSH) levels, and reduced lipid peroxidation (MDA) caused by OXA. These findings suggest that ALEPL has the potential to act as a natural antioxidant to support cancer treatment by mitigating chemotherapy-induced oxidative stress. Future studies could explore its application as an adjuvant in clinical settings to enhance the efficacy of chemotherapy while reducing its side effects.

This work reports the in vivo investigation of telluride cadmium quantum dots (CdTe QDs) conjugated to plant lectins from Schinus terebinthifolia (SteLL) and Punica granatum (PgTeL) for acute toxicity and genotoxicity in healthy mice and 24-h biodistribution in sarcoma 180-bearing animals. Acute toxicity data indicated their safety, despite some histopathological alterations. Comet assay revealed that the QDs-PgTeL group presented a higher damage index and frequency of damage than the negative control. The micronucleus test did not reveal a genotoxic effect. The 24-h biodistribution study showed a major uptake of cadmium by the liver, spleen, and kidneys. A greater accumulation of cadmium was found in tumors of the QDs-SteLL group. In conclusion, the biodistribution study showed no influence of the studied lectins in the absorption of QDs by different organs and that the conjugation of SteLL resulted in increased targeting of QDs to sarcoma 180 cells, suggesting a potential theranostic application in cancer.

Tolypocladium sinense is a new asexual strain isolated from natural Cordyceps sinensis. The mycelium produced by its fermentation culture has similar chemical components and pharmacological effects to C. sinensis. T. sinense soft capsule is primarily prepared from T. sinense mycelium, which is mainly used for the treatment of body damage induced by low-dose ionizing radiation. However, its potential toxicity remains unclear. This study was designed to assess the toxicological characteristics of T. sinense soft capsules through acute and 28-day repeated dose toxicity studies. In the acute toxicity study, no toxic symptoms or mortality were observed in rats following a single oral administration of 10 000 mg/kg of T. sinense soft capsules. The maximum tolerated dose for a single oral dose of T. sinense soft capsules in rats was over 10 000 mg/kg. During the repeated dose toxicity test, oral administration of 90, 360, and 1440 mg/kg/day of T. sinense soft capsules for 28 consecutive days did not lead to significant toxic effects in rats. The no observed adverse effect level in rats surpassed 1440 mg/kg/day. These results provide preliminary evidence that T. sinense soft capsules are relatively safe.

Methotrexate (MTX) is a generally applied chemotherapeutic medicine in most cancers treatment. Morin hydrate, a robust antioxidant, is a secondary metabolite observed in numerous plants, along with figs, white mulberries, and others. The hypothesis of this study is that morin hydrate can effectively reduce MTX-induced kidney injury in rats by increasing antioxidant enzyme activity and inhibiting apoptotic processes. This study, 35 male Wistar albino rats were used, and five different experimental groups, each consisting of 7 rats were established. Group 1 served as the control group while Group 2 received morin exclusively via oral administration (at a dose of 100 mg/kg). Group 3, however, was administered MTX exclusively (at a dose of 20 mg/kg). Group 4 received a combination of MTX (20 mg/kg) and morin (50 mg/kg), and Group 5 received a combination of MTX (20 mg/kg) and morin (100 mg/kg). The MTX group showed a significant increase in kidney biomarkers, including serum urea, creatinine, and the lipid peroxidation biomarker MDA, compared to the control group, along with a notable decrease in antioxidant enzyme activity (SOD, CAT, GPx) and GSH levels. Furthermore, MTX notably decreased the expression of procas-3, Bcl-2, procas-9, and procas-8 while concurrently increasing the expression of apoptotic genes such as CYT-C and Bax. Co-administration of morin hydrate with MTX at doses of 50 and 100 mg/kg effectively managed oxidative damage levels and apoptotic markers, demonstrating antioxidant and anti-apoptotic properties. Notably, the 100 mg/kg dose provided more robust protection than the 50 mg/kg dose, indicating a dose-dependent efficacy. This investigation thus supports the conclusion that morin hydrate, at both dosage levels, effectively mitigates MTX-induced renal damage.

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).

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.

This study investigates the drug-like properties of target molecules containing thiophene sulfonamide groups (7a-7s) using computational molecular docking techniques. The binding interactions of these derivatives were assessed using protein 2NSD (Enoyl acyl carrier protein reductase InhA, complexed with N-(4-methylbenzoyl)-4-benzylpiperidine, PDB DOI: 10.2210/pdb2NSD/pdb) as the receptor. Molecular docking results revealed notable docking scores for all compounds, ranging from -6 to -12 kcal/mol. Compounds 7e, 7i, and 7f, in particular, demonstrated impressive glide scores (>11 kcal/mol) and were selected for further analysis through molecular dynamics simulations, which provided deeper insights into their dynamic behavior and stability. The drug-like properties of these molecules were evaluated based on Lipinski's Rule of Five and ADME (Absorption, Distribution, Metabolism, and Excretion) criteria and compared with known drugs. Additionally, we synthesized these target molecules (7a-7s) using Suzuki-Miyaura coupling with a nickel catalyst replacing palladium. The chemical structures of the synthesized compounds were confirmed through elemental analysis, LC-MS,¹H-NMR, and ¹³C-NMR spectroscopy.

Maternal exposure to zearalenone (ZEA), a mycotoxin, can impact fetal liver development. This study investigated the protective effects of carvacrol (CRV) against ZEA-induced fetal liver damage. Thirty-two pregnant rats were allocated to four groups (eight rats/group); control, CRV (75 mg/kg), ZEA (5 mg/kg), and co-treated group (ZEA + CRV). The animals were given their doses during the gestation period. Maternal exposure to ZEA revealed a significant increase in the malondialdehyde (MDA) level in the fetal liver. In contrast, glutathione S-transferase (GST), superoxide dismutase (SOD), and catalase (CAT) activities, besides glutathione (GSH) levels, were decreased in ZEA-intoxicated rats. Additionally, ZEA increased the expression of pro-apoptotic genes (P53, Bax, and caspase-9), elevated the immunoreactivity of caspase-3, decreased anti-apoptotic Bcl-2, and induced severe fatty degeneration, congestion, and necrosis in the fetal liver. The comet assays revealed significant DNA damage, as evidenced by reduced head DNA content and increased tail DNA content and tail moment in the ZEA-exposed rats. Surprisingly, co-treatment with CRV significantly mitigated fetal hepatic lipid peroxidation, antioxidant disturbance, apoptosis, and DNA damage after maternal exposure to ZEA. These findings highlight the potential of CRV as a promising approach to mitigate ZEA-associated developmental hepatotoxicity.