Toxicology Research最新文献

Background: Sevoflurane (Sev), a widely used volatile anesthetic, can cause neurotoxicity, and impair learning and memory.

Objective: This study investigates the role and mechanisms of circHIPK3 in Sev-exposed neurotoxicity and learning and memory impairment.

Methods: SD rats and hippocampal neuronal cells were exposed to Sev. RT-qPCR analysis of circHIPK3 and miR-338-3p levels. MWM test was performed to examine the behavioral changes in rats. The levels of circHIPK3 and miR-338-3p levels were investigated using RT-qPCR. ELISA assay to analyze the expression of pro-inflammatory factors. CCK-8, flow cytometry, and commercial ROS assay kits were analyzed to detect cell viability, apoptosis, and ROS production. DLR and RIP assays validate circHIPK3 binding to miR-338-3p.

Results: Sev increased circHIPK3 expression in rat hippocampal tissue as well as in neuronal cells but decreased miR-338-3p levels compared to controls. circHIPK3 binding to miR-338-3p. Furthermore, silencing of circHIPK3 rats attenuated Sev-induced decline in learning and memory functions . silencing circHIPK3 also reduced Sev-induced secretion of inflammatory factors in rat and neuronal cells. Reducing circHIPK3 partially reversed the Sev-induced decrease in cell viability, increased apoptosis, and overproduction of ROS. However, the inhibitory effect of circHIPK3 on Sev neurotoxicity was restored upon downregulation of miR-338-3p.

Conclusion: Collectively, silencing circHIPK3 alleviates Sev exposure-induced learning and memory deficits and neurotoxicity by enhancing miR-338-3p expression.

In the present study, we investigated the protective effect of magnolin (MAG) against oxidative stress induced by cyclophosphamide (CP) and its role in the Nrf2/HO-1 signaling pathway. Rats were administered MAG (1 mg/kg, i.p.) for 14 days and CP (75 mg/kg, i.p.) on the 14th day. CP administration increased tissue damage, as evidenced by elevated levels of transaminases (aspartate and alanine), alkaline phosphatase, and renal parameters (blood urea nitrogen and creatinine). Additionally, 8-hydroxy-2'-deoxyguanosine and malondialdehyde levels were increased, whereas glutathione levels, along with catalase and superoxide dismutase activities, decreased in CP-treated rats. CP also down-regulated the expression of Bcl-2, HO-1, Nrf2, and NQO-1, while up-regulating Bax, Cas-3, TNF-α, Cox-2, iNOS, IL-6, IL-1β, and NFκB in liver and kidney tissues. In addition, CP treatment caused histopathological changes in heart, lung, liver, kidney, brain, and testis tissues. Treatment with MAG improved biochemical and oxidative stress parameters and prevented histopathological changes in CP-treated rats. Moreover, MAG suppressed the expression of inflammatory cytokines and apoptosis markers. In conclusion, MAG effectively prevented CP-induced toxicity by reducing oxidative stress, inflammation, and apoptosis, with its protective efficacy associated with the up-regulation of Nrf2/HO-1 signaling.

In recent years, the increase in environmental pollutants has been one of the most important factors threatening human and environmental health. Arsenic, a naturally occurring element found in soil, water, and air, easily enters the human body and leads to many metabolic disorders. In this study, we focused on the possible protective effects of N-acetylcysteine (NAC) against sodium arsenite (As)-induced toxic effects on embryonic fibroblast cells. The effects of As and NAC treatment on cells were evaluated, including cytotoxicity, oxidative stress, and apoptosis. Embryonic fibroblast cells were exposed to As (ranging from 0.01 μM to 10 μM) and NAC (at a concentration of 2 mM) for 24 h. The assessment of cytotoxicity markers, such as cell viability and lactate dehydrogenase (LDH), showed that As significantly reduced cell viability and increased LDH levels. Furthermore, we observed that As increased the amount of reactive oxygen species (ROS) in the cell, decreased the activity of antioxidant enzymes, and triggered apoptosis in cells. Additionally, our research revealed that the administration of NAC mitigates the detrimental effects of As. The results showed that As exerted hazardous effects on embryonic fibroblast cells through the induction of oxidative stress and apoptosis. In this context, our study provides evidence that NAC may have a protective effect against the toxicity of As in embryonic fibroblast cells.

Introduction: Bisphenols are widely used in the production of polycarbonate plastics and resin coatings. Bisphenol A (BPA) is suggested to cause a wide range of unwanted effects and "low dose toxicity". With the search for alternative substances to BPA, the use of other bisphenol derivatives namely bisphenol F (BPF) and bisphenol S (BPS) has increased.

Methods: In the current study, we aimed to evaluate the in silico predicted inhibitory concentration 50s (pIC50s) of bisphenol derivatives on immune and apoptotic markers and DNA damage on HepG2 cells. Moreover, apoptotic, genotoxic and immunotoxic effects of BPA, BPF and BPS were determined comparatively. Effects of bisphenols on apoptosis were evaluated by detecting different caspase activities. The genotoxic effects of bisphenols were evaluated by measuring the levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 8-oxoguanine glycosylase (OGG1). To determine the immunotoxic effect of bisphenol derivatives, the levels of interleukin 4 (IL-4) and interleukin 10 (IL-10), transforming growth factor beta (TGF-β) and tumor necrosis factor-alpha (TNF-α), which are known to be expressed by HepG2 cells, were measured. Results: In silico data indicate that all of the bisphenols may cause alterations in immune and apoptotic markers as well as DNA damage at low doses. İn vitro data revealed that all bisphenol derivatives could affect immune markers at inhibitory concentration 30s (IC₃₀s). In addition, BPF and BPS may also have apoptotic immunotoxic effects.

Conclusion: Both in silico and in vivo research are needed further to examine the toxic effects of alternative bisphenol derivatives.

Background: Synthetic food dyes are being exponentially used in food products and scarce studies regarding their toxicities and safety raise concern. Erythrosine is one of the synthetic food dyes being used in jams, fig, pineapple marmalades, dairy products, soft drinks, pickles, relishes, smoked fish, cheese, ketchup, maraschino cherries and a variety of other foods.

Methodology: In this study the cyto-genotoxic effect of erythrosine was evaluated, using root meristematic cells of Allium cepa for the cellular and molecular alternations at concentrations 0.1, 0.25, 0.5 and 1 mg/mL.

Results: The results revealed a significant decrease of 57.81% in the mitotic index after 96 h at the 0.1 mg/mL concentration. In biochemical analysis, the malondialdehyde content increased significantly (5.47-fold), while proline content, catalase activity and superoxide dismutase activity decreased gradually in a concentration-dependent manner showing a maximum decrease of 78.11%, 64.68% and 61.73% respectively at the highest concentration after 96 h duration. The comet assay revealed increased DNA damage with increasing concentration and attenuated total reflectance- Fourier transform infrared spectroscopy (ATR-FTIR) analysis showed significant alterations in biomolecules as indicated by multivariate analysis, i.e. Principal Component Analysis (PCA). Furthermore, molecular docking demonstrated a strong binding energy (G_best = -11.46 kcal/mol) and an inhibition constant (Ki) of 3.96 nM between erythrosine and the DNA minor groove.

Conclusion: The present study's findings revealed the cytotoxic and genotoxic potential of erythrosine on A. cepa root cells. Further, the study also proposed the usefulness of A. cepa as a model system for studying the toxicity of food additives.

Background: Copper oxide (Cu₂O) nanoparticles (CO NPs) are in extensive use during our everyday life as antimicrobial agent, lubricant, in manufacturing electrodes of lithium ion batteries as well as for photo catalytic degradation of organic pollutants. Due to extensive and diverse use Cu₂O NPs, they are likely to accumulate in the environment and to affect the live forms. Present investigation was aimed to report the biocompatibility of CO NPs in Wistar rats in sex specific manner. CO NPs, having average diameter of 14.06 nm, were synthesized by co-precipitation method and scanning electron microscopy and X ray diffraction were used for their characterization.

Methods: For 14 consecutive days, Wistar rats (6 weeks old) of both sexes were intraperitoneally injected with 10 mg/mL saline/Kg body weight of CO NPs, while the control groups intraperitoneally received saline solution for same duration. Behavioral tests (open field and novel object recognition), complete blood count, selected biomarkers of oxidative stress and Copper concentration in brain and liver were determined in all subjects.

Results: High mortality rates [male 40% and female 60%] were observed in rats exposed to CO NPs. A sever decrease in body weight was also observed in both male and female rats exposed to CO NPs. Female rats treated with CO NPs spent significantly more time with novel object as compared to control [P = 0.05] during second trial of novel object test. CO NPs treated female rats had higher mean corpuscular hemoglobin [P < 0.001] levels and Copper concentration in liver [P = 0.04] than control. Male rats exposed to CO NPs had significantly higher mean corpuscular volume [P = 0.02] and superoxide dismutase [SOD] [P = 0.04] in lungs than their control group. All other studied parameters non significantly varied upon comparison between CO NPs treated and untreated rats of both sex.

Conclusion: In conclusion, we are reporting that intraperitoneal injections of CO NPs for 14 days can disturb complete blood count and biomarkers of oxidative stress in lungs of Wistar rats.

Background: Aucklandiae Radix (CAR) and its roasted processed products (PAR) are extensively used in various Chinese patent medicines due to their diverse pharmacological activities. However, numerous side effects of CAR have been reported and the hepatotoxicity and the corresponding mechanisms have not been thoroughly investigated. Our study aims to explore the underlying mechanism of the hepatotoxic impacts of CAR.

Methods: In this study, metabolomic analysis was performed using liver tissue from the mice administered with different dosages of CAR/PAR extracts to examine the hepatotoxic impacts of CAR and elucidate the underlying mechanism. Network pharmacology was employed to predict the potential molecular targets and associated signaling pathways based on the distinctive compounds between CAR and PAR. A composition-target-GO-Bio process-metabolic pathway network was constructed by integrating the hepatotoxicity-related metabolic pathways. Finally, the target proteins related with the hepatotoxic effect of CAR were identified and validated in vivo.

Results: The metabolomics analysis revealed that 33 related metabolic pathways were significantly altered in the high-dose CAR group, four of which were associated with the hepatotoxicity and could be alleviated by PAR. The network identified NQO1 as the primary target of the hepatotoxic effect induced by CAR exposure, which was subsequently verified by Western Blotting. Further evidence in vivo demonstrated that Nrf2 and HO-1, closely related to NQO1, were also the main targets through which CAR induced the liver injury, and that oxidative stress should be the primary mechanism for the CAR-induced hepatotoxicity.

Conclusions: This preliminary study on the hepatic toxic injury of CAR provides a theoretical basis for the rational and safe use of CAR rationally and safely in clinical settings.

Drug-induced kidney injury (DIKI) is a frequently reported adverse event, associated with acute kidney injury, chronic kidney disease, and end-stage renal failure. Prospective cohort studies on acute injuries suggest a frequency of around 14%-26% in adult populations and a significant concern in pediatrics with a frequency of 16% being attributed to a drug. In drug discovery and development, renal injury accounts for 8 and 9% of preclinical and clinical failures, respectively, impacting multiple therapeutic areas. Currently, the standard biomarkers for identifying DIKI are serum creatinine and blood urea nitrogen. However, both markers lack the sensitivity and specificity to detect nephrotoxicity prior to a significant loss of renal function. Consequently, there is a pressing need for the development of alternative methods to reliably predict drug-induced kidney injury (DIKI) in early drug discovery. In this article, we discuss various aspects of DIKI and how it is assessed in preclinical models and in the clinical setting, including the challenges posed by translating animal data to humans. We then examine the urinary biomarkers accepted by both the US Food and Drug Administration (FDA) and the European Medicines Agency for monitoring DIKI in preclinical studies and on a case-by-case basis in clinical trials. We also review new approach methodologies (NAMs) and how they may assist in developing novel biomarkers for DIKI that can be used earlier in drug discovery and development.

Natural products based on their significant anti-cancer potencies have been used in cancer treatment. A natural blend of triterpenoid saponins derived from the horse chestnut (Aesculus hippocastanum L.), has been investigated in various diseases based on its main active ingredient escin. Herein, we examined the potential antiproliferative, proapoptotic, and cytotoxic activities of escin on human skin melanoma (CHL-1) cells. Cytotoxicity of escin was determined by MTT assay. Morphological changes were detected by confocal microscopy and ultrastructural changes by transmission electron microscopy studies. Phosphatidylserine translocation assay, Bcl-2 activation assessment, and oxidative stress analysis were used to determine the cell death mode of the cells. The results showed that escin reduced cell viability in a dose-dependent manner within 24 h of exposure and was highly cytotoxic at lower concentrations (IC₅₀ value 6 μg/mL). Escin inactivated Bcl-2 signaling and triggered apoptosis by increasing the reactive oxygen species and by causing morphological and ultrastructural changes that implicate to the proapoptotic activity. Escin has been found to exert high potential for an anti-cancer drug following further in vitro and in vivo investigations.

Background: Cardiotoxicity is a major toxic effect induced by several types of drugs. An electrocardiogram is done routinely in cardiovascular drug exposures. Cardiac troponin I (cTnI) is the usual biomarker for diagnosing myocardial injury. B-type natriuretic peptide (BNP) is a well-established predictor of disease state in suspected heart failure.

Aim: The study aimed to assess BNP's role as an early predictor of mortality compared with cTnI and ECG changes in acutely poisoned patients with cardiotoxicities.

Methodology: This study enrolled 70 patients with acute cardiotoxicity by drugs and toxins known to cause cardiac injury admitted to Tanta University Poison Control Center (TUPCC). Collected data included socio-demographic data, toxicological history, vital signs, ECG changes, Poison Severity Score (PSS), BNP, and cTnI serum levels.

Result: Patients were classified as survivors and non-survivors. Significantly more delay time was recorded in non-survivors. Moreover, vital signs were significantly abnormal in non-survivors. There was no statistical significance regarding the initial ECG abnormalities between survivors and non-survivors. BNP and cTnI levels were significantly higher among non-survivors. For mortality prediction, BNP had good predictive power (AUC = 0.841) with 100% sensitivity and 79.7% specificity while cTnI had an acceptable predictive power (AUC = 0.786), with 83.3% sensitivity and 78.1% specificity with insignificant difference between both biomarkers.

Conclusion: BNP and cTnI levels can predict mortality in acute cardiotoxicity compared to ECG which has no statistically significant prediction. BNP has a higher discriminatory power than cTnI for the prediction of mortality.