Hsa_circ_0005915 promotes N,N-dimethylformamide-induced oxidative stress in HL-7702 cells through NRF2/ARE axis
| Autor: | Honghao Peng, Yongmei Xiao, Ziqi Liu, Mengxing Cui, Daochuan Li, Qianmei He, Yuqing Wang, Wen Chen, Shen Chen, Ye Liu, Qing Wang, Liping Chen, Yangchun Zhang |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Oxygenase NF-E2-Related Factor 2 Toxicology medicine.disease_cause 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation In vivo Circular RNA medicine NAD(P)H Dehydrogenase (Quinone) Humans chemistry.chemical_classification Membrane Potential Mitochondrial Reactive oxygen species Chemistry Gene Expression Profiling Dimethylformamide RNA Circular Molecular biology Up-Regulation MicroRNAs Oxidative Stress 030104 developmental biology medicine.anatomical_structure Gene Expression Regulation Hepatocyte Hepatocytes NAD+ kinase Chemical and Drug Induced Liver Injury Reactive Oxygen Species 030217 neurology & neurosurgery Oxidative stress Heme Oxygenase-1 Signal Transduction |
| Zdroj: | Toxicology. 458 |
| ISSN: | 1879-3185 |
| Popis: | N,N-dimethylformamide (DMF) is an organic compound widely used in industrial production processes as a solvent with a low evaporation rate. Excessive exposure to DMF may lead to liver damage. Oxidative stress has been reported as one of the main causes of DMF-induced hepatotoxicity. Several doses of DMF (0, 1, 5, and 10 mM) were used to treat HL-7702 cells for a relatively long period to simulate the actual exposure pattern in occupational settings, and oxidative stress was induced. Previous studies illustrated that circular RNA (circRNA) plays a vital role in sustaining hepatocyte physiological function. To explore whether aberrant circRNA expression is involved in DMF-induced excessive ROS generation and hepatotoxicity, high-throughput transcriptional sequencing was performed to identify the altered circRNA expression profiles in HL-7702 liver cells after treatment with 0, 75, or 150 mM DMF for 48 h. We found that levels of induced oxidative stress were similar to those in the long-term exposure model. Among the altered circRNAs, one circRNA (hsa_circ_0005915) was significantly upregulated after DMF exposure, and it affected DMF-mediated oxidative stress in HL-7702 cells. Further experiments revealed that hsa_circ_0005915 downregulated the expression of nuclear factor erythoid-2-related factor 2 (NRF2) at the post-transcriptional level via promoting the ubiquitination and degradation of NRF2, which led to the increase of ROS accumulation. Further investigation demonstrated that the expression levels of NRF2-regulated antioxidative genes-heme oxygenase 1 (HO1) and NAD(P)H quinone dehydrogenase 1 (NQO1)-indeed declined after the overexpression of hsa_circ_0005915. In vivo study also indicated that DMF exposure can upregulate the expression of mmu_circ_0007941 (homologous circRNA of hsa_circ_0005915) and downregulated Nrf2 and Ho1 proteins. In summary, our results revealed that hsa_circ_0005915 plays an important role in promoting DMF-induced oxidative stress by inhibiting the transcriptional activity of the NRF2/ARE axis, which provides a potential molecular mechanism of DMF-mediated hepatotoxicity. |
| Databáze: | OpenAIRE |
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