Human & Experimental Toxicology最新文献

Peripheral neurotoxicity injury caused by local anesthetics is a common complication of clinical anesthesia. The study of its mechanism is helpful to prevent and treat the neurotoxic injury of local anesthetics. Previous studies on peripheral neurotoxicity injury caused by local anesthetics have mainly focused on in vitro cell experiments. Due to the lack of an animal model of peripheral neurotoxicity damage caused by local anesthetics, there are few in vivo experimental studies regarding this topic. Herein, 1% ropivacaine hydrochloride was injected into the sciatic nerve by direct incision and exposure of the sciatic nerve to create a local anesthetic neurotoxic injury model. The results showed that 1% ropivacaine hydrochloride could reduce the lower limb motor score and mechanical paw withdrawal threshold in mice 48 hours after injection. Pathological sections showed that 48 hours after treatment with 1% ropivacaine hydrochloride, the sciatic nerve showed increased axonal edema and degeneration, edema between nerve fiber bundles, increased degeneration of axon and myelin sheath vacuoles, edema of nerve bundle membrane and local degeneration and necrosis, and a large number of inflammatory cells around the nerve adventitia were soaked. The above results show that under open vision, 1% ropivacaine hydrochloride can cause injury to the sciatic nerve after 48 h of treatment, which can simulate the neurotoxic damage of local anesthetics. This animal model provides a research tool for studying the mechanism of neurotoxic injury caused by local anesthetics.

Objective: The treatment of tuberculosis with isoniazid and rifampin is associated with hepatocellular damage. Therefore, the study was designed to evaluate the hepatoprotective potential of diosmin against hepatotoxic effect of isoniazid and rifampin in Wistar rats.

Methods: Hepatotoxicity was induced by administering isoniazid and rifampin (100 mg/kg), whereas diosmin was given as treatment control. Markers of liver function (ALT, AST, ALP and bilirubin), inflammatory cytokines (TNFα, IL-6 and IL-1β), apoptosis (caspase-3), oxidative stress parameters (LPO, GSH, CAT and SOD) and histological changes in liver were assessed in normal, hepatotoxic control and treatment groups.

Results: The administration of isoniazid and rifampin significantly increased markers of liver dysfunction (ALT, AST, ALP and bilirubin), cytokines (TNFα, IL-6 and IL-1β) and apoptosis (caspase-3). However, daily dosing of diosmin significantly reduced these markers of liver dysfunction, inflammatory cytokines and apoptosis to near normal levels. Additionally, markers of hepatocellular oxidative stress parameters were significantly altered as evident from increased LPO level and decreased endogenous antioxidants such as GSH, SOD and CAT in isoniazid-and rifampin-treated hepatotoxic group. It was observed that diosmin treatment reduced high levels of LPO and demonstrated significant improvement in antioxidant levels. Histological studies of liver also supported our biochemical findings, which are also manifested as diosmin treatment exhibited protection against hepatocellular degeneration and inflammation.

Conclusion: Results of the present study demonstrate hepatoprotective potential of diosmin against isoniazid-and rifampin-treated hepatotoxicity. Thus, we conclude that diosmin may be used along with anti-tubercular drugs (isoniazid and rifampin) in tuberculosis patients to overcome their hepatotoxic adverse effect.

Background: Cyclophosphamide (CP) is a commonly used chemotherapeutic and immunosuppressive alkylating agent. However, cardiac adverse effects of CP interfere with its clinical benefit. Cardio-oncology research is currently an important issue and finding effective cardiopreserving agents is a critical need. For the first time, we aimed to detect if dapagliflozin (DAP) could ameliorate CP-induced cardiac injury and investigated the role of hypoxia inducible factor α (HIF1α)/vascular endothelial growth factor (VEGF)/endothelial nitric oxide synthase (eNOS) pathway.

Methods: Forty male Wistar albino rats were included in the current model. Studied groups are: control group; CP-induced cardiotoxicity group; CP group treated with DAP; CP group treated with DAP and administered a nitric oxide synthase inhibitor; nitro-ω-L-arginine (L-NNA) before DAP to explore the role of eNOS.

Results: Our data revealed that CP could induce cardiac damage as manifested by significant increases in cardiac enzymes, blood pressure, malondialdehyde (MDA), tumor necrosis factor alpha (TNFα), HIF1α, sodium glucose co-transporter 2 (SGLT2) and cleaved caspase-3 levels with toxic histopathological changes. However, there are significant decreases in reduced glutathione (GSH), total antioxidant capacity (TAC), VEGF, and eNOS. On the opposite side, co-administration of DAP showed marked improvement of CP-induced cardiac damage that may be due to its ability to inhibit SGLT2, antioxidant, anti-inflammatory and anti-apoptotic properties. Results showed decreasing the cardioprotective effect of DAP on administration of L-NNA, reflecting the critical effect of eNOS in mediating such protection.

Conclusion: DAP could reduce CP cardiotoxicity based upon its ability to modulate SGLT2 and HIF1α/VEGF/eNOS signaling pathway.

Aim: To investigate the protective effect of α-lipoic acid on sodium arsenite (NaAsO₂) induced INS-1 cells injury and its mechanism.

Methods: The cell viability was measured by CCK-8 assay. The autophagosomes was observed under transmission electron microscopy. The autophagosomes in cells transfected with green fluorescent protein microtubule-associated protein light chain 3 (GFP-LC3) plasmids were observed under a laser scanning con-focal microscope. The expression of LC3-II, P62, PI3K, and mTOR proteins in INS-1 cells treated with a combination of chloroquine (CQ, autophagy inhibitor) and NaAsO₂ were detected by Western blot assay. The expression of LC3-II, P62, PI3K, and mTOR proteins were detected in INS-1 cells treated with a combination of rapamycin (autophagy inducer, mTOR inhibitor) and α-LA.

Results: The cytotoxicity induced by NaAsO₂ was reversed by α-LA, and the viability of NaAsO₂-treated INS-1 cells increased. α-LA pretreatment decreased the autophagosome accumulation induced by NaAsO_2. α-LA also reduced the fluorescence spot aggregation of GFP-LC3 in INS-1 cells exposed to NaAsO₂ as observed under a laser scanning con-focal microscope. α-LA inhibited NaAsO₂ induced autophagy by up-regulating PI3K and mTOR and down-regulating LC3-II and P62. CQ inhibited NaAsO₂ induced autophagy by up-regulating PI3K, mTOR, P62 and down-regulating LC3-II. α-LA inhibited rapamycin-induced autophagy by up-regulating PI3K, mTOR and P62 and down-regulating LC3-II. The results showed that NaAsO₂ could induce autophagy activation in INS-1 cells. The α-LA may inhibit autophagy activation by regulating the PI3K/mTOR pathway.

Conclusion: The data indicated that α-LA might inhibit the NaAsO₂-induced autophagic death of INS-1 cells by regulating the PI3K/mTOR pathway.

Background: Studies have shown oxidative stress and apoptosis are the main pathogenic mechanisms of renal ischemia/reperfusion (IR) injury (IRI). Genistein, a polyphenolic non-steroidal compound, has been extensively explored in oxidative stress, inflammation and apoptosis. Our research aims to reveal the potential role of genistein on renal IRI and its potential molecular mechanism both in vivo and in vitro.

Methods: In vivo experiments, mice were pretreated with or without genistein. Renal pathological changes and function, cell proliferation, oxidative stress and apoptosis were measured. In vitro experiments, overexpression of ADORA2A and knockout of ADORA2A cells were constructed. Cells proliferation, oxidative stress and apoptosis were analyzed.

Results: Our results in vivo showed that the renal damage induced by IR was ameliorated by genistein pretreatment. Moreover, ADORA2A was activated by genistein, along with inhibition of oxidative stress and apoptosis. The results in vitro showed that genistein pretreatment and ADORA2A overexpression reversed the increase of apoptosis and oxidative stress in NRK-52E cells induced by H/R, while the knockdown of ADORA2A partially weakened this reversal from genistein treatment.

Conclusions: Our results demonstrated that genistein have a protective effect against renal IRI by inhibiting oxidative stress and apoptosis via activating ADORA2A, presenting its potential use for the treatment of renal IRI.

Background: Epilepsy is a common disorder affecting approximately 50 million people worldwide. Oxidative stress is known to play an important role in the pathophysiology of diseases, including epilepsy. In this study, we investigated the effects of sennoside B on PTZ-induced seizures in rats.

Method: The rats were grouped into Group Electroencephalography and Group Behavioral. Both Groups were divided into eight subgroups, and these subgroups were compared in terms of the time of first myoclonic jerk, Racine's Convulsion Scale, malondialdehyde levels, and brain superoxide dismutase activity. The experimental seizure model was performed with pentylenetetrazol.

Results: The spike percentage was significantly lower in groups that received sennoside B, and this beneficial effect was shown to be associated with the dose of sennoside B received. The RCS score was lower and the FJM onset time was higher in the sennoside B-administered groups. Additionally, brain MDA and brain aquaporin-3 levels were lower and brain SOD activity was higher in the sennoside-administered groups.

Conclusions: The present study shows the beneficial effects of sennoside B on PTZ-induced convulsion in rats. It is considered that sennoside B which is a natural and safe product would be a good candidate for strengthening the management of epilepsy without serious side effects.

Objective: We aimed to explore the mechanisms underlying paraquat (PQ)-induced damage using cell lines (NCTC1469, TC-1, TCMK-1) and bioinformatic analysis of the GSE153959 dataset. Assessment of changes in the expression of ferroptosis-related genes in cellular damage due to paraquat poisoning and the important value of these genes in the pathogenesis.

Methods: Data were retrieved from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) related to ferroptosis were identified by Venn plots and analyzed for enrichment. Proteins encoded by these DEGs were studied for interactions. qRT-PCR and western blotting analyses of cultured cells were used to determine the expression of ferroptosis-related DEGs and their corresponding protein levels.

Results: We identified 25 DEGs primarily involved in epidermal growth factor receptor signaling, apoptotic signaling pathways, endoplasmic reticulum (ER) stress, and ferroptosis. From these, we uncovered eight ferroptosis-related DEGs, four of which were involved in ER response and regulators of ferroptosis-Chac1 (ChaC glutathione specific gamma-glutamylcyclotransferase 1), Atf3 (activating transcription factor 3), Tfrc (transferrin receptor), and Slc7a11 (solute carrier family 7 member 11). Significant changes in mRNA and protein levels of CHAC1, ATF3, TFRC, and SLC7A11 were confirmed in PQ-exposed cells.

Conclusion: ER stress and ferroptosis are critical for PQ-induced cell damage. CHAC1, ATF3, TFRC, and SLC7A11 are essential molecules implicated in PQ-induced ferroptosis that may serve as therapeutic targets for the amelioration of PQ poisoning.

Background: Salidroside (SAL) is an anti-inflammatory, antioxidant, anticancer, neuroprotective, and renal protective active ingredient extracted from the Chinese herb. Rhodiola Rosea. However, the role of SAL in kidney injury has not yet been elucidated. The study investigates SAL's protective effect and mechanism in lipopolysaccharide (LPS)-induced kidney injury.

Methods: Male C57BL/6 wild-type mice (6-8 weeks old) were intraperitoneally injected with 10 mg/kg LPS for 24 h and SAL (50 mg/kg) 2 h before the LPS injection. Biochemical and TUNNEL staining assay analyses were carried out to assess kidney injury. The Elisa assay analyzed the mRNA expression of NGAL and KIM-1. RT-qPCR and Western blotting measured the mRNA and protein expression of HO-1, NQO1, Beclin1, P62, SIRT1, Nrf2, and PNCA, respectively.

Results: Our study found that mice co-treated with SAL had significantly reduced blood urea nitrogen (BUN), serum creatinine (Scr), neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM-1) levels in serum of LPS-induced mice. SAL cotreatment potentially decreased the apoptosis rate of kidney tissue and podocytes induced by LPS. SAL significantly reduced the content of malondialdehyde (MDA) and increased superoxide dismutase (SOD) in LPS-treated mice. Autophagy-related proteins Beclin-1 increased but decreased P62 protein expression by cotreatment of SAL in LPS-injected mice. SAL enhanced the Sirtuin 1 (SIRT1) and nuclear factor erythroid 2-related factor 2 (Nrf2) protein expression in LPS-induced kidney tissues.

Conclusion: Our results speculate that SAL protects against LPS-induced kidney injury through activation of the SIRT1/Nrf2 pathway.

Dasatinib is an effective treatment for chronic myeloid leukemia. However, cases of idiosyncratic hepatotoxicity were reported. This study was conducted to investigate the chemopreventive effects of hydroxychloroquine against dasatinib-induced hepatotoxicity. Balb/c mice were randomly assigned into four groups; vehicle control (5% DMSO, i.p., n = 6), dasatinib (50 mg/kg; i.p., n = 6), hydroxychloroquine (10 mg/kg, i.p., n = 6), and hydroxychloroquine + dasatinib (10 mg/kg + 50 mg/kg; i.p., n = 6). Treatments were given once every 2 days for 14 days. Serum and histopathological assessments of liver architecture and fibrosis were performed using H&E, Masson's trichrome, and reticulin staining. The infiltration of lymphocytes was assessed using immunohistochemistry. The gene expression of antioxidant enzymes (CAT, SOD-2, GPX-1) was assessed using real-time quantitative PCR. Dasatinib showed a significant increase in liver injury biomarkers (AST and ALT) with higher lymphocytes infiltration (as indicated by CD3⁺, CD4⁺, CD8⁺, and CD20⁺ immunohistochemistry). Hepatic tissue of Dasatinib group exhibited significant downregulation in the gene expression of antioxidant enzymes (CAT, SOD-2, and GPX-1) compared to the control group. However, the combination of hydroxychloroquine with dasatinib showed a slight increase in AST and ALT. Also, hydroxychloroquine + dasatinib treated mice showed a significant reduction in lymphocytes infiltration as compared to dasatinib. The results showed that dasatinib induces an immune response leading to an increase in lymphocytes infiltration which promotes hepatocyte destruction and persistent liver injury. The results also suggest that hydroxychloroquine ameliorates dasatinib-induced hepatotoxicity via reduction in hepatic infiltration of T and B immune cells.