Human & Experimental Toxicology最新文献

Regulation of endoplasmic reticulum stress (ER) stress-induced apoptosis and nerve regeneration is a hopeful way for acute spinal cord injury (SCI). Sitagliptin (Sita) is one of dipeptidyl peptidase-4 (DPP-4) inhibitor, which is beneficial neurons damaged diseases. However, its protective mechanisms of avoiding nerve injury remain unclear. In this study, we further investigated the mechanism of the anti-apoptotic and neuroprotective effects of Sita in promoting locomotor recovery from SCI. In vivo results showed that Sita treatment reduced neural apoptosis caused by SCI. Moreover, Sita effectively attenuated the ER tress and associated apoptosis in rats with SCI. A striking feature was the occurrence of nerve fiber regeneration at the lesion site, which eventually led to significant locomotion recovery. In vitro results showed that the PC12 cell injury model induced by Thapsigargin (TG) also showed similar neuroprotective effects. Overall, sitagliptin showed potent neuroprotective effects by targeting the ER stress-induced apoptosis both in vivo and vitro, thus facilitating the regeneration of the injured spinal cord.

Background: The local renin-angiotensin system has been discovered in the eyes; thus, this study evaluates the Azilsartan effect in the retina and optic nerve toxicity induced by Cisplatin in vivo.

Methodology: Forty-eight male rats were randomly assigned into six groups of 8 animals. Group 1 was healthy control that received 0.5 mL/day of 0.5% carboxymethyl cellulose (CMC) orally (PO). Group 2 received a single dose of the 7.0 mg/kg CIS intraperitoneally with 0.5 mL/day of 0.5% CMC-PO. Groups 3 and 4 received 3.5 and 7.0 mg/kg/day of AZIL-PO, respectively. Groups 5 and 6 received 3.5 and 7.0 mg/kg/day of AZIL-PO, respectively together with a single dose of 7.0 mg/kg of CIS-IP. The ocular tissue and serum estimated the TNF-α, NF-kβ, and Casp-3. A complete blood count was also measured, and the eye was sent for histological examination.

Results: The administration of the 3.5 mg/kg AZIL significantly (p < 0.05) reduced the ocular tissue and serum TNF-α, NF-kB, and Casp-3 levels, when given to CIS treated group, while the 7.0 mg/kg AZIL does not. Additionally, azilsartan shows no negative impact on the CBC in rats. Finally, the eye histological examination showed a significant (p < 0.05) drop in the signs of inflammation and cellular degeneration, particularly after administration of the 3.5 mg/kg AZIL to the CIS-treated group.

Conclusion: A low dose of AZIL exerts an anti-inflammation and an anti-apoptotic effect through significant suppression of the pro-inflammatory mediators and an apoptotic biomarker by blocking the local angiotensin II type.

Doxorubicin (Dox) was reported to cause mitochondrial dysfunction and oxidative stress in cardiomyocytes, leading to cardiomyocyte apoptosis and ultimately heart failure. Serum and glucocorticoid inducible kinase 1 (SGK1) participates in the progression of various cardiovascular diseases. Thus, we aimed to explore the role and regulatory mechanism of SGK1 in Dox-induced cardiomyocyte injury. The expression of SGK1 was evaluated in blood samples of heart failure children, and in myocardial tissues and blood samples of Dox-induced rats. Subsequently, we treated cardiomyocytes with Dox in vitro. A gain-of-function assay was performed to assess the effects of SGK1 on mitochondrial dysfunction and oxidative stress in Dox-induced cardiomyocytes. Furthermore, the modulation of SGK1 on Neural precursor cell-expressed developmentally down-regulated 4 type 2 (NEDD4-2) expression and the subsequent Hippo pathway was validated. In our study, we found that SGK1 was downregulated in blood samples of heart failure children, as well as myocardial tissues and blood samples of Dox-induced rats. SGK1 overexpression alleviated the decreases of mitochondrial complex activity, mitochondrial membrane potential, adenosine triphosphate (ATP) content and ATP synthetase activity stimulated by Dox. Besides, SGK1 overexpression reversed the promoting effects of Dox on oxidative stress and apoptosis. Mechanistically, SGK1 overexpression inhibited the expression of NEDD4-2 and blocked the subsequent activation of Hippo pathway. NEDD4-2 overexpression or activation of Hippo reversed the protective effects of SGK1 overexpression on Dox-induced cardiomyocyte injury. In conclusion, our results revealed that SGK1 modulated mitochondrial dysfunction and oxidative stress in Dox-induced cardiomyocytes by regulating Hippo pathway via NEDD4-2.

The present study aimed to clarify the expressions and roles of clock genes involved in drug metabolism in patients taking benzodiazepines (BZDs), as well as the drug metabolism regulators controlled by clock genes for each BZD type. The relationships between the expressions of the clock genes BMAL1, PER2, and DBP and the drug-metabolizing enzymes CYP3A4 and CYP2C19 were investigated using livers from BZD-detected autopsy cases. In addition, the effect of BZD exposure on various genes was examined in HepG2 human hepatocellular carcinoma cells. The expressions of DBP, CYP3A4, and CYP2C19 in the liver were lower in the diazepam-detected group than in the non-detected group. Furthermore, BMAL1 expression correlated with CYP2C19 expression. Cell culture experiments showed that the expressions of DBP and CYP3A4 decreased, whereas those of BMAL1 and CYP2C19 increased after diazepam and midazolam exposure. The results of the analyses of autopsy samples and cultured cells suggested that DBP regulates CYP3A4 when exposed to BZD. Understanding the relationship between these clock genes and CYPs may help achieve individualized drug therapy.

To explore the potential function of tricin in diabetic retinopathy (DR) and investigate whether Sestrin2 is closely involved in DR. A single intraperitoneal injection of streptozotocin-induced diabetes model in Sprague-Dawley rats and a high glucose-induced retinal epithelial cell model in ARPE-19 cells were established. The retinas were removed and examined by hematoxylin-eosin (HE) staining and dihydroethidium (DHE) staining. The proliferation ability and reactive oxygen species (ROS) level of ARPE-19 cells were detected by 5-ethynyl-2'-deoxyuridine (EdU) and flow cytometry. Then, the content of superoxide dismutase (SOD), malonaldehyde (MDA), and glutathione peroxidase (GSH-Px) in serum or cell supernatant was tested using enzyme linked immunosorbent assay (ELISA). In addition, the expression of Sestrin2, nuclear factor erythroid-2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), platelet endothelial cell adhesion molecule-1 (CD31), and vascular endothelial growth factor receptor 2 (VEGFR2) in retina tissue or ARPE-19 cells were validated through western blot and immunofluorescence assays. With the increase of MDA and ROS concentration, Sestrin2 expression was downregulated significantly, and Nrf2 and HO-1 expression was also reduced in retina tissue or ARPE-19 cells of model group, whereas CD31 and VEGFR2 expression was upregulated. However, tricin ameliorated the oxidative stress and angiogenesis and rectified the abnormal expression of Sestrin2/Nrf2 in diabetic retinopathy. Further mechanistic studies showed that silence Sestrin2 reduced the protective effect of tricin on ARPE-19 cells, as well as abolished its regulating effect on the Nrf2 pathway. These results suggested that tricin inhibits oxidative stress and angiogenesis in retinal epithelial cells of DR rats via reinforcing Sestrin2/Nrf2 signaling.

Background: The role and underlying mechanism of liver macrophages and their derived miR-155-5p in hepatic lymphangiogenesis in liver fibrosis remain unclear. Here, we investigated the mechanism by which macrophages and miR-155-5p were involved in lymphangiogenesis during liver fibrosis and cirrhosis.

Methods: In vivo, hepatic lymphatic vessel expansion was evaluated; the liver macrophage subsets, proportion of peripherally-derived macrophages and expressions of CCL25, MCP-1, VAP-1 and MAdCAM-1 were documented; and miR-155-5p in the peripheral blood and liver was detected. In vitro, macrophages with miR-155-5p overexpression and inhibition were used to clarify the effect of miR-155-5p on regulation of macrophage polarization and the possible signalling pathway.

Results: Hepatic lymphangiogenesis was observed in mice with liver fibrosis and cirrhosis challenged with carbon tetrachloride (CCl4). In the liver, the number of M1 macrophages was associated with lymphangiogenesis and the degree of fibrosis. The liver recruitment of peripherally-derived macrophages occurred during liver fibrosis. The levels of miR-155-5p in the liver and peripheral blood gradually increased with aggravation of liver fibrosis. In vitro, SOCS1, a target of miR-155-5p, regulated macrophage polarization into the M1 phenotype through the JAK1/STAT1 pathway.

Conclusion: MiR-155-5p-SOCS1/JAK1/STAT1 pathway participates in hepatic lymphangiogenesis in mice with liver fibrosis and cirrhosis induced by CCl4 by regulating the polarization of macrophages into the M1 phenotype.

The widespread use of acetaminophen (APAP) in children as an over-the-counter treatment can cause acute liver failure through accidental overdose or ingestion. Therefore, the current research sought to investigate the function of hemin in mitigating the acute hepatotoxic effect of APAP in rat offspring. Thirty-two rats were assigned into four groups: control, hemin, APAP, and hemin/APAP groups. Liver enzymes were measured in serum along with oxidative stress indicators, tumor necrosis factor-α (TNF-α), interleukin-1beta (IL-1β), total nitrites (NOx), and caspase 3 in liver. Immunoblotting of heme oxygenase-1 (HO-1), interleukin-6 (IL-6), Janus kinase 2 (Jak2), and signal transducer and activator of transcription 3 (STAT3) was carried out. The Bax/Bcl2 mRNA expression ratio was determined. A histological study and an immunohistochemical study of phosphorylated STAT3 were also done. Hemin reduced liver enzymes, MDA, TNF-α, NOx, caspase 3, IL-1β, p-STAT3 expression, p-Jak2 expression, IL-6 expression, and Bax/Bcl2 mRNA expression ratio. In contrast, hemin increased GSH, TAC, and the expression of HO-1, improving the histopathological picture of liver tissue. Thus, hemin could ameliorate APAP-induced hepatic toxicity in rat offspring through anti-oxidant, anti-apoptotic, and anti-inflammatory actions with a possible role for the IL-6/HO-1/Jak2/STAT3 pathway.

Background: Cisplatin (DDP) resistance in ovarian cancer (OC) patients usually leads to treatment failure and increased mortality. Anlotinib has been shown to improve progression-free survival and overall survival in patients with platinum-resistant ovarian cancer, but the mechanism is unclear. This study aims to explore the mechanism by which anlotinib ameliorates platinum resistance in OC cells.

Methods: Cell viability was detected by the 3-4,5-dimethylthiazol-2,5-diphenyltetrazolium bromide (MTT) method, and the apoptosis rate and changes in the cell cycle distribution were evaluated by flow cytometry. Bioinformatics analysis was used to predict the potential gene target of anlotinib in DDP-resistance SKOV3 cells, and its expression was verifies it by RT-qPCR, western blotting and immunofluorescence staining. Finally, ovarian cancer cells overexpressing AURKA were constructed, and the predicted results were verified by animal experiments.

Results: Anlotinib effectively induced apoptosis and G2/M arrest in OC cells and decreased the proportion of EdU-positive cells. AURKA was identified as a possible key target of anlotinib for inhibiting tumorigenic behaviors in SKOV3/DDP cells. Through combined immunofluorescence and western blot analyses, it was demonstrated that anlotinib could effectively inhibit the protein expression of AURKA and upregulate the expression of p53/p21, CDK1, and Bax protein. After overexpression of AURKA in OC cells, the induction of apoptosis and G2/M arrest by anlotinib were significantly inhibited. Anlotinib also effectively inhibited the growth of tumors in nude mice injected with OC cells.

Conclusions: This study demonstrated that anlotinib can induce apoptosis and G2/M arrest in cisplatin-resistant ovarian cancer cells through the AURKA/p53 pathway.