Drug and Chemical Toxicology最新文献

Non-clinical steps for development, validation and biosafety of new medicines and products comprises studies on cells, proteins, and animals. Herein, we evaluated the toxic activity of antitumoral 2-chloro-N-arylacetamides on eukaryotic dividing cells and animal replacement models. Firstly, the cytotoxicity of chloro (compound 2), bromo (compound 3) and nitro (compound 4) acetamides was analyzed by fluorescent assays in fibroblasts. Next, toxicity was evaluated on Allium cepa meristematic cells and 48h-living Artemia salina larvae. Finally, embryos of Danio rerio (zebrafish) were exposed to the compound 2 (0.14 - 7.2 μg/mL) for 120 h exposure. All arylacetamides were cytotoxic on murine and human fibroblasts, with IC₅₀ values ranging from 1.2 μg/mL (5.6 µM = compound 4 on L-929) to 4.9 μg/mL (24 µM = compound 2 on MRC-5 cells), respectively, and inhibited root growth from 10 to 100 µg/mL, corroborated by mitotic index reduction and cell cycle arrest in interphase (p < 0.05) without clastogenic injuries. Compound 2 showed time- and concentration-dependent killing effects on zebrafish embryos. Its 24 h-acute toxicity at higher concentrations (1.93 and 7.2 μg/mL with 90% and 100% death) corroborated toxicity on aquatic A. salina organisms. After 96 h exposure at 0.52 μg/mL (2.55 µM), almost 100% of the embryos showed more than one lethal/sublethal morphological abnormality (p < 0.05). Then, all arylacetamides showed unspecific toxic effects, mainly the halogenated electrophile chloroacetamide. They present strong antimitotic action on vertebrate and vegetal cells, although such antiproliferative activity does not seem to be directly related to chromosomal damage inductions.

The purpose of this trial was to assess the effects of methylphenidate on the kidney tissues and to investigate the protective effect of adenosine triphosphate (ATP) against possible methylphenidate nephrotoxicity in rats. The rats were separated into; healthy control (HG), methylphenidate (MPHG), ATP (ATPG), and ATP+ methylphenidate (AMPG). The ATPG and AMPG groups were administered ATP 4 mg/kg bw/d, and the HG and MPHG groups received distilled water intraperitoneally. One hour from, ATP and distilled water administration, methylphenidate 10 mg/kg bw/d was applied via oral gavage to the AMPG and MPHG groups once daily for 30 d (1 × 1). Animals were euthanized after 30 d and tissues were collected. The levels of certain oxidant/antioxidant parameters, pro-inflammatory cytokines, and Blood urea nitrogen (BUN) and creatinine levels were measured. Kidneys were also examined histopathologically. ATP inhibited the increase in oxidant and decrease antioxidant levels induced by methylphenidate. The amounts of pro-inflammatory cytokines were increased in methylphenidate-treated kidney tissue compared with the HG and AMPG groups. However, ATP increased oxidative damage markers and cytokines levels close to the healthy group. Serum BUN and creatinine levels increased with methylphenidate but ATP prevented BUN and creatinine from rising in the ATPG and MPHG groups. ATP also reduced the histopathological damage increased by methylphenidate. The potential efficacy of ATP in treating kidney damage induced by methylphenidate use.

Cannabidiol (CBD) is widely marketed as a health and wellness product. However, evidence for its effectiveness and safety remains limited. This study assessed the toxicity and toxicokinetic profile of CBD in Sprague Dawley rats over 13 weeks at low (5 mg/kg/day), mid (15 mg/kg/day), and high (150 mg/kg/day) doses, followed by a 4-week recovery period. Toxicokinetic analyses revealed no marked sex differences in systemic exposure to CBD or its metabolite 6-OH-CBD; however, female rats had slightly higher exposure to metabolites 7-OH-CBD and 7-COOH-CBD. Accumulation of CBD and its metabolites was observed following repeated oral administration of CBD. No CBD-related effects on mortality, clinical observations, or ophthalmoscopy were observed during the study. Higher food consumption was observed in rats treated with the high CBD dose group; however, this did not correlate with a statistically significant increase in body weight. A slightly higher fold increase in serum alanine aminotransferase (∼1.4-fold to 1.5-fold) was observed in the CBD high group, which was determined to be reversible. Histopathological analyses showed hepatocyte hypertrophy, but this effect was not accompanied by inflammatory changes or other microscopic lesions and resolved over the recovery period. Hypertrophy of pars distalis cells in pituitary gland and cortical cell vacuolation in adrenal glands were determined to be adaptive changes and reversible during the recovery period. The no-observed effect level was considered to be lower than the lowest tested dose (5 mg/kg/day) and no-observed adverse effect level to be the highest tested dose (150 mg/kg/day).

Rotenone is a pesticide compound that selectively damages dopaminergic neurons in the substantia nigra pars compacta and produces Parkinson's like symptoms in rodents. Deposition of iron and reactive oxygen species (ROS) generation by its oxidation are contributing factors in the etiology of Parkinson's disease. Deferoxamine (DFO) is an iron chelator with high affinity produced by Streptomyces wadayamensis, S. malaysiense, like organisms. The present study provides insight to evaluate the protective effect of DFO in rotenone-induced neurotoxicity in rats. Rotenone (6 μg/2 μl/rat, unilaterally) was injected intranigral on day-1 using a digital stereotaxic apparatus. DFO (50 and 100 mg/kg, intraperitoneally) was given orally daily for 21 days starting from day 8 after the intranigral surgery. On day 28, animals were sacrificed, and the striatum was isolated for oxidative stress parameters (lipid peroxidation, nitrite and reduced glutathione, glutathione peroxidase, superoxide dismutase, catalase), neuroinflammatory cytokines (IL-1β, IL-6, and TNF-α), mitochondrial complexes-I and IV, neurotransmitters (brain catecholamines, gamma-aminobutyric acid, glutamate), and iron level estimation. Unilateral intranigral infusion of rotenone led to significant motor deficits as evidenced by impairments in locomotor activity in open field test, rotarod activity (motor coordination), grip strength, and narrow beam walk performance. DFO administration dose-dependently significantly improved against rotenone-induced behavioral abnormalities in rats, restored the altered level of neurotransmitters in the striatum, and attenuated oxidative stress and inflammatory response in the striatum. These findings indicate that DFO successfully achieved antioxidant and anti-inflammatory properties and protect dopaminergic neurons against rotenone-induced neurotoxicity.

A myriad of therapeutic candidates targeting SARS-CoV-2 have entered clinical trials; however, the ongoing challenges in SARS-CoV-2 drug discovery, such as adverse effects associated with some therapeutic candidates, necessitate continuous efforts to identify novel therapeutic targets and strategies. This study leverages integrated in silico approaches, encompassing ensemble docking, molecular dynamics (MD) simulations, dynamic unbinding (DUck), and ADMET predictions, to identify novel saquinavir-related antiviral inhibitors targeting the catalytic dyad and oxyanion-hole loop of the SARS-CoV-2 main protease (Mpro). From a library of 33 saquinavir-related analogs, ensemble docking identified three high-affinity ligands (ΔG ≤ -9.8 kcal/mol). Subsequent MD simulations revealed stable Mpro-ligand complexes and significant structural perturbations within the catalytic dyad (His41-Cys145, ΔD_dyad >1.0 Å) and the oxyanion-hole (Gly143-Ser144-Cys145, Δθ_oxy >5°). DUck simulations elucidated a stepwise dissociation mechanism, identifying key hotspot residues critical for ligand binding. Compounds CHEMBL3706523 and CHEMBL3706524 emerged as promising candidates, exhibiting robust interactions and slower dissociation rates (W_QB >6 kcal/mol). These ligands stabilized the receptor and induced conformational changes that may hinder substrate binding, suggesting a potential 'block cluster' mechanism for inhibition. Favorable ADMET profiles further support their potential as drug candidates with low mammalian toxicity. This study provides a strong foundation for experimental validation and the subsequent development of effective antiviral therapies against SARS-CoV-2.

Exposure to heavy metal mixtures HMM can elicit significant health risks due to their combined toxic effects. This study investigates the mechanisms of hippocampal toxicity associated with HMM exposure. Rats were exposed to lead (Pb) 20, aluminum (Al) 35 and manganese (Mn) 0.564 mg/kg body weight alone or in combination for 90 days. The rats exposed to Pb-Al-Mn mixture spent least time exploring the open arms and had longer latency to find the hidden platform than the control and individual metal exposure groups in the Elevated Plus Maze test. Bioaccumulation of Pb, Al and Mn in the hippocampus was measured, oxido-inflammatory, markers, caspase-3, Nrf-2, Aβ40, Aβ42, occludin, BDNF were evaluated. Al, Pb and Mn exposure individually significantly (p ≤ 0.05) decreased the hippocampal antioxidant enzymes activities, glutathione level and increased oxidative stress and neuroinflammation biomarkers. HMM significantly increased caspase-3, Nrf-2, Aβ40 and Aβ42 and significantly decreased occludin, BDNF, HO-1 when compared with the control. HMM significantly (p ≤ 0.05) exacerbated hippocampal in comparison to individual Al, Pb or Mn. HMM induced hippocampal toxicity via multiple targets, namely biometal accumulation, increase in oxidative stress, inflammation, and caspase-3 activation in rats via Nrf-2/HO-1/BDNF. All in all, this study has shown that exposure to Pb-Al-Mn tertiary mixture, even at lower doses than individual heavy metals, significantly amplified anxiety-like behavior in comparison to exposure to individual heavy metals, which were associated with the alternations in Nrf-2, HO-1, Aβ-40, Aβ-42, BDNF, occludin levels, COX-2 and Caspase-3 activities in the hippocampus.

The term serotonin syndrome (SS) is a potentially life-threatening devastating condition triggered by the excessive accumulation of serotonin, often due to an overdose or the concurrent use of multiple serotonergic drugs. Lavandula angustifolia (lavender), a known plant from the Lamiaceae family, is very rich in essential oils, minerals, and tannins. This study aimed to elucidate the detrimental effects of SS on the brain and to evaluate the neuroprotective potential of L. angustifolia essential oil. Male rats were randomly divided into the following groups: control (Group 1); L. angustifolia-treated (Group 2); ondansetron-treated high-dose (Group 3); sertraline-treated high-dose (Group 4); low-dose ondansetron + sertraline-treated (Group 5); high-dose ondansetron + sertraline-treated (Group 6); low-dose ondansetron + sertraline + L. angustifolia-treated (Group 7); and high-dose ondansetron + sertraline + L. angustifolia-treated (Group 8). Neurotransmitter levels, dopamine metabolites, and expressed cytokines were quantified. Additionally, histological assessment of the hippocampus was performed. The results revealed significant disruptions in neurotransmitter and amino acid levels within the hippocampus across the treated groups. Notably, the high-dose ondansetron + sertraline group presented pronounced increases in serotonin, 5-HIAA, and proinflammatory cytokines, resulting in neurotoxicity and pronounced alterations in the hippocampus. Conversely, treatment with L. angustifolia significantly attenuated these neurotoxic effects. The findings suggest that L. angustifolia confers neuroprotection against the deleterious effects of SS, particularly by counteracting the neurotoxic impact of combined serotonin 5-HT3 receptor antagonists and serotonin reuptake inhibitors within the hippocampus. These findings highlight the potential of L. angustifolia as a natural therapeutic agent for mitigating SS-induced neurotoxicity.

Benzophenone-2 (BP2) is considered a potential endocrine disruptor, but due to limited data availability, its specific impact on reproductive function is not fully understood. The current study investigated the in vivo toxic effect of BP2 in female mice at 50, 100, and 200 mg/kg body weight, which aimed to evaluate whether it can show an impact on reproductive estrous cycle, ovarian weight, biochemical parameters, histoarchitecture, and ovarian follicle count when administered daily for 7 and 21 days in female mice. This study tested the hypothesis that BP2 disrupts pregnancy parameters in mice. The data indicate that 7- and 21-day exposure to BP2 caused irregularities in different phases of the estrous cycle, such as significantly prolonged duration in estrus and significantly decreased duration in the diestrus phase. The effects of BP2 included elevated serum AST, ALT, cholesterol, and triglycerides. The percentage of different stages of developed, healthy follicles, and corpus luteum was significantly reduced, and atretic follicles increased in the treatment mice. Besides, BP2 altered prenatal fertility outcomes in pregnant mice. In conclusion, this study suggests that the BP2 exerts an anti-fertility effect on reproductive functions in adult female mice, highlighting the potential risks of reproductive issues caused in females exposed to BP2.

Doxorubicin (DOX), a chemotherapeutic drug used for cancer treatment, faces limitations in clinical use due to its cardiotoxicity. The study intended to investigate the effect of microRNA (miR)-27b-3p on DOX-induced cardiotoxicity. Quantitative polymerase chain reaction was conducted to identify the miR-27b-3p expression in cardiac tissues of 24 mice exposure to doxorubicin for 0-7days. To investigate the functions of miR-27b-3p, the remaining 40 mice were assigned into 4 experimental groups (n=10 per group): Control+miR-scramble, Control+miR-27b-3p, chronic heart failure (CHF) + miR-scramble, and CHF+miR-27b-3p. Specifically, C57BL/6J mice received a tail vein injection of adeno-associated viral 9 (AAV9)-miR-27b-3p/miR-scramble and/or intraperitoneal injection of 15mg/kg DOX. Echocardiography was used to measure basic cardiac function parameters. Hematoxylin-eosin and Sirius red staining were performed to assess cardiac structural changes and fibrotic areas. For cellular experiments, neonatal mouse cardiomyocytes were exposure to 5μg/ml DOX. The levels of inflammatory factors and oxidative stress indicators in cardiac tissues or cardiomyocytes were assessed by western blotting, enzyme-linked immunosorbent assay, or corresponding detection kits. The results showed that miR-27b-3p expression was downregulated in mouse cardiac tissues following DOX treatment. Overexpression of miR-27b-3p improved cardiac function and ameliorated pathological changes in mice. In addition, DOX-induced myocardial inflammation and oxidative stress were mitigated by miR-27b-3p overexpression both in vivo and in vitro. MiR-27b-3p negatively regulated the expression of four target genes (Plk2, Adora2b, Apaf1 and Nrk) in DOX-stimulated cardiomyocytes. In conclusion, miR-27b-3p ameliorates DOX-induced cardiac dysfunction and myocardial injury by inhibiting inflammation and oxidative stress.