Drug and Chemical Toxicology最新文献

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.

This study investigates the molecular mechanisms underlying anthracyclines (ANT)-induced cardiotoxicity, with a specific focus on ferroptosis regulated by the long non-coding RNA (lncRNA) H19/heme oxygenase-1 (Hmox1) signaling axis. A retrospective analysis was performed on 50 breast cancer patients who developed ANT-associated cardiac dysfunction. Clinical assessments included measurements of left ventricular ejection fraction (LVEF) and serum markers, such as cardiac troponin I (cTnI), creatine kinase-MB (CK-MB), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and serum iron levels. Serum analysis revealed a marked downregulation of lncRNA H19 and upregulation of Hmox1, both significantly correlated with impaired cardiac function and disrupted iron homeostasis. To further elucidate the mechanism, an Epirubicin (EPI)-induced injury model in HL-1 cardiomyocytes was established. EPI exposure led to suppression of lncRNA H19, upregulation of Hmox1, and induction of apoptosis and ferroptotic cell death. RNA-seq analysis identified potential downstream targets linking lncRNA H19 to iron metabolism via Hmox1 modulation. Functional assays demonstrated that overexpression of lncRNA H19 mitigated EPI-induced ferroptosis, while enforced expression of Hmox1 reversed these protective effects. Collectively, these findings identify the lncRNA H19/Hmox1 axis as a critical regulator of ferroptosis in ANT-induced cardiotoxicity and suggest it as a potential therapeutic target for mitigating cardiac injury in breast cancer patients undergoing anthracycline chemotherapy.

Copper and Zinc Oxide Nanoparticles are widely used in pharmacy, cosmetics, agriculture and engineering fields according to their chemical and biological properties; their toxic effects on living systems up to the environment and humans are seen in physiological processes. The study included 60 male mice divided into 10 groups; 100 μl water as placebo in the control group, copper oxide (CuO-NP) and zinc oxide (ZnO-NP) nanoparticles and CuO-NP+ZnO-NP groups were administered oral gavage at different doses (1, 5 and 25 mg/kg/day) for 14 days to investigate the toxic effects on the tissues of male mice. Antioxidant enzyme activities glutathione-S-transferase (GST), catalase (CAT), superoxide dismutase (SOD) and oxidative damage parameters glutathione (GSH) and thiobarbituric acid reactive substance (TBARS) were measured in the tissues by spectrophotometric methods. Stress protein 70 (HSP70) and DNA oxidation (8-OHdG) levels were measured using ELISA methods. The exposure to CuO-NPs + ZnO-NPs, CuO-NPs, and ZnO-NPs resulted in changes in biochemical parameters in the liver and kidney tissues, with varying effects observed across the groups compared to the control. The most significant changes were observed in the CuO-NPs + ZnO-NPs group, including decreases in SOD, CAT activities, GSH levels and increases in GST activity, HSP70 and 8-OHdG levels. As the oxidative damage and biomolecular parameters stress protein and DNA oxidation were induced, which are consistent with the parameters of toxic effects in both examined tissues, the co-exposure to CuO-NPs and ZnO-NPs appears to suppress the antioxidant system, suggesting that these biomarkers may serve as potential indicators of tissue toxicity caused by nanoparticles.

Obesity is a chronic and multifactorial disease, in which activation of endoplasmic reticulum (ER) stress and resulting cell death have been widely implicated leading to the emergence of neurological diseases. Misfolded or unfolded proteins accumulation triggers ER stress, which modulates mitochondrial-associated death signals. Bisphenol A (BPA), an endocrine-disrupting chemical, is known to exert multiple deleterious effects on the brain. However, the influence of pre-established obesity in females on BPA-induced neurotoxicity remains poorly characterized. This study examines whether obesity aggravates the BPA toxicity in the cerebral cortex region of the brain. Rats were divided into five groups: control, HFD (high-fat diet), HFD + BPA, BPA, and thapsigargin (positive control). Obesity was induced by feeding 60% HFD (12 weeks), followed by chronic exposure to BPA (10 ppm in drinking water) for another 12 weeks. Thapsigargin (10 µg; 5 µg on either side) was given intracerebroventricularly 72 h before sacrifice. Transmission electron microscopy (TEM) revealed the deformed morphology of the ER and mitochondria. Expression levels of ER stress-associated proteins (BiP and CHOP) and genes (ATF4 and GADD34) were significantly higher (p < 0.05) in HFD + BPA rats compared to BPA alone. p-eif2α was significantly upregulated (p < 0.05) in all the treated rats as compared to the control. BPA-exposed obese rats had also shown a significantly increased ratio of apoptotic proteins Bax and Bcl2. Our findings suggest that the exacerbation of BPA toxicity through obesity can be attributed to the involvement of ER stress and the mitochondrial death signals it mediates.

Acetaminophen (APAP) is a well-known analgesic, and antipyretic drug and its overdose or chronic consumption can lead to kidney damage. Oleuropein (OLE) exhibits various pharmacological properties. This study aimed to determine the possible therapeutic benefits of OLE in improving APAP-induced kidney injury. In this experimental study, 36 male Wistar rats were assigned to six groups (n = 6). The rats initially received a single dose of APAP (500 mg/kg) and then 1 hour later were treated with a single dose of OLE at 50, 100, and 200 mg/kg depending on their groups. 24 hours after treatment with OLE, various indicators including kidney biochemical tests, histopathological changes, oxidative stress markers, and anti-apoptotic and anti-inflammatory parameters were investigated in the renal tissue. OLE (100 mg/kg) significantly decreased serum creatinine, caspase-3, kidney tissue damage score (P < 0.05), malondialdehyde (MDA) (P < 0.01), and increased superoxide dismutase (SOD) and total antioxidant capacity (TAC) (P < 0.05) in the APAP + OLE 100 mg/kg group versus APAP group. Additionally, OLE (200 mg/kg) significantly reduced blood urea nitrogen (BUN), NF-κB, p53, Bax (p < 0.05), serum creatinine, TNF-α, caspase-3, kidney tissue damage score (p < 0.01), MDA, and Bax: Bcl-2 ratio (p < 0.001) in the APAP + OLE 200 mg/kg group versus APAP group. Also, OLE (200 mg/kg) significantly enhanced glutathione peroxidase (GPx), SOD, Bcl-2 (p < 0.05), and TAC (p < 0.01) in the APAP + OLE 200 mg/kg group contrasted to APAP group. However, OLE at 50 mg/kg didn't alter measured parameters. These findings demonstrate that OLE (200 mg/kg) could attenuate acetaminophen-induced kidney injury through its anti-oxidant, anti-inflammatory, and anti-apoptosis properties.

Nephrotoxicity is a sign in which endogenous or exogenous toxicants have damaged the kidney-specific detoxification and excretion processes. Vancomycin (VAN) exposure mostly causes kidney damage and a loss of body homeostasis regulation. This study aimed to investigate the protective effects of piribedil and thymol and its basic mechanisms against nephrotoxicity caused by VAN. Randomly, the animals were categorized into six groups (n = 8). For 7 d, Group I only received vehicles, Group II received piribedil (5 mg/kg/once daily, i.p.), Group III received thymol (25 mg/kg/once daily, i.p), Group IV was administered a single daily dose of VAN (200 mg/kg, i.p.), VAN+ piribedil was administered to Group V, and VAN + thymol was administered to Group VI. The findings showed that piribedil or thymol improved renal function parameters by an increase in serum albumin level in parallel to a decrease in serum creatinine and blood urea nitrogen (BUN) levels in addition to decreased levels of KIM-1 and serum cystatin C. Furthermore, enhanced oxidative stress biomarkers as GSH, myeloperoxidase (MPO), and malondialdehyde (MDA) as well as tumor necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1β), indicators of inflammatory mediators, were markedly reduced compared to VAN group. Moreover, piribedil or thymol markedly improved the histopathological aberrations provoked by VAN, increased the Nrf-2 and HO-1 renal protein expressions and reduced VAN-induced elevation of Keap-1 protein expression. In addition, NF-kB, Bax, and caspase 3 expression levels were considerably declined after piribedil or thymol co-treatment. These findings revealed that co-administration of piribedil or thymol with VAN may be a sensible therapeutic approach for reducing renal intoxication caused by VAN.