Human & Experimental Toxicology最新文献

Background: Ifosfamide (IFO) is a widely used antineoplastic drug with broad-spectrum efficacy against various types of cancer. However, different toxicities associated with IFO has limited its use. This study was to establish the prophylactic effects of betanin, chrysin and ellagic acid against IFO-induced neurotoxicity in rats.

Methods: Animals were randomly divided into eight groups, control, IFO, IFO + betanin, IFO + chrysin, IFO + ellagic acid, betanin, chrysin and ellagic acid groups. Betanin (50 mg/kg, i.p.), chrysin (25 mg/kg, i.p.) and ellagic acid (25 mg/kg, i.p.) were administered to rats once daily for two consecutive days. IFO (500 mg/kg, i.p.) was administered on third day.

Results: Results demonstrated that only ellagic acid markedly decreased the activity of acetylcholinesterase (AChE) and butrylcholinesterase (BChE) compared with IFO alone, while chrysin was only effective on BChE activity. Also, ellagic acid ameliorated IFO-induced lipid peroxidation and glutathione (GSH) depletion, while chrysin only decreased GSH depletion. Histopathological alteration in the IFO-induced brain tissues were decreased especially after administration of ellagic acid. Intraperitoneal pretreatment with betanin, followed by IFO resulted in death of all treated animals. In addition, all mitochondrial toxicity parameters induced by IFO in the rat brain tissue were ameliorated by ellagic acid, chrysin and even betanin.

Conclusion: Taken together, our results demonstrated that especially ellagic acid and to some extent chrysin show a typical neuroprotective effect on IFO-induced acute neurotoxicity through mitochondrial protection and antioxidant properties. Also, the results of our studies showed that pretreatment with betanin followed by IFO was lethal.

Background: Colorectal carcinoma (CRC) ranks the third most frequent malignancy worldwide. Makorin RING zinc finger-2 (MKRN2) has been identified as a tumor suppressor in CRC, and the bioinformatics prediction indicated that some non-coding RNAs (ncRNAs) that directly or indirectly regulate MKRN2 might play critical roles in CRC progression. This study aimed to analyze the regulatory effect of LINC00294 on CRC progression, and to explore the underlying mechanisms by assessing miR-620 and MKRN2. The potential prognostic value of the ncRNAs and MKRN2 was also investigated.

Methods: The expression of LINC00294, MKRN2, miR-620 was examined by qRT-PCR. Cell counting kit-8 assay was used to assess the proliferation of CRC cells. Transwell assay was used to evaluate the migration, invasion of CRC cells. Kaplan-Meier method and log-rank test were used to perform comparative analysis of overall survival in CRC patients.

Results: Lower expression of LINC00294 was observed in both CRC tissues and cell lines. In CRC cells, LINC00294 overexpression inhibited cell proliferation, migration and invasion, but these effects were directly reversed by the overexpression of miR-620, which was demonstrated as a target of LINC00294. Additionally, MKRN2 was found to be a target gene of miR-620, and might mediate the regulatory function of LINC00294 in CRC progression. In CRC patients, low LINC00294, MKRN2 and high miR-620 expression was associated poor overall survival of CRC.

Conclusions: LINC00294/miR-620/MKRN2 axis had the potential to provide prognostic biomarkers for CRC patients, and negatively regulated the malignant progression of CRC cells, including proliferation, migration and invasion.

Purpose: In order to seek effective drugs for treating cisplatin-induced acute renal injury and explore the corresponding potential mechanism.

Methods: Mouse kidney injury model was established by intraperitoneal injection of 20 mg/kg cisplatin. The temporal expression of TRPM2 and the regulation of Ginkgolide A on its expression were analyzed by western blot. In order to perform the mechanical analysis, we used TRPM2-KO knockout mice. In this study, we evaluated the repair effect of GA on acute kidney injury through renal function factors, inflammatory factors and calcium and potassium content. Pathological injury and cell apoptosis were detected by H&E and TUNEL, respectively.

Result: Ginkgolide A inhibited inflammatory reaction and excessive oxidative stress, reduced renal function parameters, and improved pathological injury. Meanwhile, we also found that the repair effect of Ginkgolide A on renal injury is related to TRPM2, and Ginkgolide A downregulated TRPM2 expression and inactivated TWEAK/Fn14 pathway in cisplatin-induced renal injury model. We also found that inhibition of TWEAK/Fn14 pathway was more effective in TRPM2-KO mice than TRPM2-WT mice.

Conclusion: Ginkgolide A was the effective therapeutic drug for cisplatin-induced renal injury through acting on TRPM2, and TWEAK/Fn14 pathway was the downstream pathway of Ginkgolide A in acute renal injury, and Ginkgolide A inhibited TWEAK/Fn14 pathway in cisplatin-induced renal injury model.

Breast cancer is highly prevalent and considered the main challenge to public health among females in Egypt as in other countries. MicroRNA-21 (miR-21) and MEG-2 are noncoding RNA attributed to their aberrant expression in several diseases, including breast cancer. This study aimed to assess the reliability of serum expression levels of miR-21 and MEG-2 in discriminating stages of breast cancer and scrutinize their correlations with the targeted transforming growth factor-beta (TGF-β) expression. One hundred and 30 participants whose ages ranged from 28 to 62 years were included in this study, divided into one hundred breast cancer patients and 30 healthy participants. miR-21 and TGF-β expression levels showed upregulation in patients with BC and elevated miR-21/TGF-β levels consistent with the BC stage. In addition, LncRNA (MEG-2) showed down-regulation in patients with BC. MEG-2 expression levels revealed a gradual decrease consistent with the BC stage. In addition, a negative relationship between the MEG-2 and the miR-21 and TGF-β differential expression was also noticed. This study suggested that miR-21 and MEG-2 can be used as prospective diagnostic biomarkers and emphasized the crucible role of TGF-β as therapeutic targets for BC.

Objective: The ability of glutathione S-transferase zeta 1 (GSTZ1) to modulate homeostasis of cellular redox and induce ferroptosis was explored in bladder cancer cells, and the involvement of the high mobility group protein 1/glutathione peroxidase 4 (HMGB1/GPX4) in these effects was studied.

Methods: BIU-87 cells stably overexpressing GSTZ1 were transfected with appropriate plasmids to deplete HMGB1 or overexpress GPX4, then treated with deferoxamine and ferrostatin-1. Antiproliferative effects were assessed by quantifying levels of ferroptosis markers, such as iron, glutathione (GSH), malondialdehyde (MDA), reactive oxygen species (ROS), GPX4, transferrin, and ferritin.

Results: GSTZ1 was significantly downregulated in bladder cancer cells. GSTZ1 overexpression downregulated GPX4 and GSH, while greatly increasing levels of iron, MDA, ROS, and transferrin. GSTZ1 overexpression also decreased proliferation of BIU-87 cells and activated HMGB1/GPX4 signaling. The effects of GSTZ1 on ferroptosis and proliferation were antagonized by HMGB1 knockdown or GPX4 overexpression.

Conclusion: GSTZ1 induces ferroptotic cell death and alters cellular redox homeostasis in bladder cancer cells, and these effects involve activation of the HMGB1/GPX4 axis.

Dysregulation of long intergenic non-protein coding RNA 00,641 (LINC00641) is associated with the malignancy progression of multiple cancers, including thyroid carcinoma. The current study aimed to determine the role of LINC00641 in papillary thyroid carcinoma (PTC) and the underlying mechanism. We found that LINC00641 was downregulated in PTC tissues and cells(p < 0.05), and overexpression of LINC00641 inhibited PTC cell proliferation and invasion, and induced apoptosis(p < 0.05), while silencing LINC00641 promoted the proliferation and invasion in PTC cells, and inhibited cell apoptosis(p < 0.05). Furthermore, we found that Glioma-associated oncogene homolog 1 (GLI1) expression was negatively correlated with LINC00641 expression in PTC tissues (r² = 0.7649, p < 0.0001), and silencing GLI1 inhibited PTC cell proliferation and invasion, and induced apoptosis(p < 0.05). Meanwhile, RNA immunoprecipitation (RIP) and RNA pull-down assays confirmed that insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) bound to LINC00641 as an RNA binding protein, and overexpression of LINC00641 destabilized GLI1 mRNA by competitively binding to IGF2BP1. Rescue experiments revealed that overexpression of GLI1 restored the inhibitory effect of LINC00641 overexpression on activation of the AKT pathway, as well as PTC cell proliferation and invasion, and counteracted the induction of cell apoptosis by LINC00641 overexpression. Finally, in vivo experimental results showed that overexpression of LINC00641 markedly suppressed tumor growth and reduced expression of GLI1 and p-AKT in xenograft tumor mice(p < 0.05). In summary, this study highlighted that LINC00641 plays a critical role in the malignant biological progression of PTC by regulating the LINC00641/IGF2BP1/GLI1/AKT signaling pathway, which may serve as a potential therapeutic target for PTC.

This systematic review, conducted according to the PRISMA guidelines, focuses on genotoxicity of oxidative hair dye precursors. The search for original papers published from 2000 to 2021 was performed in Medline, Web of Science, Cochrane registry, Scientific Committee on Consumer Safety of the European Commission and German MAK Commission opinions. Nine publications on genotoxicity of p-phenylenediamine (PPD) and toluene-2,5-diamine (p-toluylenediamine; PTD) were included, reporting results of 17 assays covering main genotoxicity endpoints. PPD and PTD were positive in bacterial mutation in vitro assay, and PPD tested positive also for somatic cell mutations in the Rodent Pig-a assay in vivo. Clastogenicity of PPD and PTD was revealed by in vitro chromosomal aberration assay. The alkaline comet assay in vitro showed DNA damage after PPD exposure, which was not confirmed in vivo, where PTD exhibited positive results. PPD induced micronucleus formation in vitro, and increased micronucleus frequencies in mice erythrocytes following high dose oral exposure in vivo. Based on the results of a limited number of data from the classical genotoxicity assay battery, this systematic review indicates genotoxic potential of hair dye precursors PPD and PTD, which may present an important health concern for consumers and in particular for professional hairdressers.

Vancomycin (VCM)-induced nephrotoxicity impedes its treatment applications. Thus, it is important to clarify the relevant mechanism. This study investigated phosphoprotein changes attributable to the VCM nephrotoxicity mechanisms. Biochemical, pathological and phosphoproteomic analyses based on C57BL/6 mice were performed to explore the mechanisms.VCM-treated mice showed increased levels of blood urea nitrogen and creatinine, and signs of acute tubular necrotic lesions. Phosphoproteomic profiling identified 3025 differentially phosphorylated phosphopeptides between the model and control group. Gene Ontology enrichment analysis demonstrated that Molecular Function "oxidoreductase activity" and Cellular Component "peroxisome" were markedly enriched. KEGG pathway analysis identified an enrichment in peroxisome pathway and PPAR (peroxisome proliferator-activated receptor) signaling pathways. Parallel reaction monitoring analysis revealed a significant downregulation of CAT, SOD-1, AGPS, DHRS4, and EHHADH at phosphorylation level by VCM. Notably, the phosphorylation of ACO, AMACR, and SCPX was downregulated by VCM, which are the fatty acid β-oxidation-related proteins involved in PPAR signaling pathways. The phosphorylated PEX5 involved in peroxisome biogenesis was upregulated by VCM. Collectively, these findings indicated that VCM-induced nephrotoxicity is closely associated with peroxisome pathway and PPAR signaling pathways. The current study provides important insight into the mechanisms of VCM nephrotoxicity and will aid in the development of preventive and therapeutic strategies against this nephropathy.

Ischemia-reperfusion (I/R) is a common clinical process, and the lung is one of the most sensitive organs of I/R injury, which often leads to acute lung injury (ALI). Tanshinone IIA (Tan IIA) has anti-inflammatory, antioxidant, and anti-apoptotic activities. However, the effects of Tan IIA on lung I/R injury remain uncertain. Twenty-five C57BL/6 mice were randomly divided into five groups: control (Ctrl), I/R, I/R + Tan IIA, I/R + LY294002 and I/R + Tan IIA + LY294002 group. Tan IIA (30 μg/kg) was injected intraperitoneally 1 h before injury in the I/R + Tan IIA and I/R + Tan IIA + LY294002 groups. These data showed that Tan IIA significantly improved I/R-induced histological changes and scores of lung injury, decreased lung W/D ratio, MPO and MDA contents, reduced infiltration of inflammatory cells, and decreased the expression of IL-1β, IL-6 and TNF-α. Meanwhile, Tan IIA significantly increased the expression of Gpx4 and SLC7A11, and decreased the expression of Ptgs2 and MDA. Moreover, Tan IIA significantly reversed the low expression of Bcl2, and the high expression of Bax, Bim, Bad and cleave-caspase 3. Furthermore, Tan IIA caused a significant increase in the phosphorylation levels of PI3K, Akt and mTOR in the lungs. However, these beneficial effects of Tan IIA on I/R-induced lung inflammation, ferroptosis and apoptosis were offset by LY294002. Our data suggest that Tan IIA significantly ameliorates I/R-induced ALI, which is mediated through activation of PI3K/Akt/mTOR pathway.