Isatin Counteracts Diethylnitrosamine/2-Acetylaminofluorene-Induced Hepatocarcinogenesis in Male Wistar Rats by Upregulating Anti-Inflammatory, Antioxidant, and Detoxification Pathways
Hepatocellular carcinoma (HCC) represents around 85% of all known types of liver cancers and is estimated to be the fifth most common cause of cancer-related death worldwide. The current study assessed the preventive efficacy of isatin on diethylnitrosamine (DENA)/2-acetylaminofluorene (2-AAF)-induc...
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MDPI AG
2022-04-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/11/4/699 |
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| author | Nagwa G. Tawfik Wafaa R. Mohamed Hanan S. Mahmoud Mohammed A. Alqarni Ibrahim A. Naguib Alzhraa M. Fahmy Osama M. Ahmed |
| author_facet | Nagwa G. Tawfik Wafaa R. Mohamed Hanan S. Mahmoud Mohammed A. Alqarni Ibrahim A. Naguib Alzhraa M. Fahmy Osama M. Ahmed |
| author_sort | Nagwa G. Tawfik |
| collection | DOAJ |
| description | Hepatocellular carcinoma (HCC) represents around 85% of all known types of liver cancers and is estimated to be the fifth most common cause of cancer-related death worldwide. The current study assessed the preventive efficacy of isatin on diethylnitrosamine (DENA)/2-acetylaminofluorene (2-AAF)-induced hepatocarcinogenesis in male Wistar rats and investigated the underlying cellular and molecular mechanisms. HCC was initiated by intraperitoneal injection of DENA (150 mg/kg/week) for two weeks, followed by oral 2-AAF (20 mg/kg) every other day for three successive weeks. Oral isatin or vehicle (control) was administered at 25 mg/kg for 20 weeks during and following HCC induction. Isatin ameliorated the deleterious effects of DENA/2-AAF on liver function as evidenced by reduced serum levels of AST, ALT, total bilirubin, albumin, and liver tumor biomarkers (CA19.9 and AFP) compared to control DENA/2-AAF-treated rats. Histopathological evaluations demonstrated that isatin-mediated protection against hepatocarcinogenesis was accompanied by a decline in hepatic lipid peroxidation, a marker of oxidative stress, and enhanced antioxidant capacity, as evidenced by increased glutathione and superoxide dismutase expression. Isatin treatment also upregulated expression of the major stress-response transcription factor Nrf2 and the detoxifying enzymes NAD(P)H quinine oxidoreductase and glutathione-S-transferase alpha 2 and downregulated expression of the proliferation marker Ki67. Moreover, isatin significantly reduced the DENA/2-AAF-induced decrease in hepatic expression of anti-apoptotic Bcl2 and the DENA/2-AAF-induced increases in pro-inflammatory and pro-apoptotic factors (TNF-α, NF-κB p50, NF-κB p65, p53, and caspase 3). Thus, it can be concluded that isatin may protect against chemically induced hepatocarcinogenesis by enhancing cellular antioxidant, anti-inflammatory, and detoxification mechanisms, in part through upregulation of the Nrf2 signaling pathway. |
| first_indexed | 2024-03-09T11:13:55Z |
| format | Article |
| id | doaj.art-5d58d3c59fc14aa0a9460b43977f39b5 |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-09T11:13:55Z |
| publishDate | 2022-04-01 |
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| series | Antioxidants |
| spelling | doaj.art-5d58d3c59fc14aa0a9460b43977f39b52023-12-01T00:35:20ZengMDPI AGAntioxidants2076-39212022-04-0111469910.3390/antiox11040699Isatin Counteracts Diethylnitrosamine/2-Acetylaminofluorene-Induced Hepatocarcinogenesis in Male Wistar Rats by Upregulating Anti-Inflammatory, Antioxidant, and Detoxification PathwaysNagwa G. Tawfik0Wafaa R. Mohamed1Hanan S. Mahmoud2Mohammed A. Alqarni3Ibrahim A. Naguib4Alzhraa M. Fahmy5Osama M. Ahmed6Physiology Division, Zoology Department, Faculty of Science, Beni-Suef University, Beni-Suef 62521, EgyptDepartment of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, EgyptEcology Division, Zoology Department, Faculty of Science, Beni-Suef University, Beni-Suef 62521, EgyptDepartment of Pharmaceutical Chemistry, College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi ArabiaDepartment of Pharmaceutical Chemistry, College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi ArabiaTropical Medicine and Infectious Diseases Department, Faculty of Medicine, Beni-Suef University, Beni-Suef 62521, EgyptPhysiology Division, Zoology Department, Faculty of Science, Beni-Suef University, Beni-Suef 62521, EgyptHepatocellular carcinoma (HCC) represents around 85% of all known types of liver cancers and is estimated to be the fifth most common cause of cancer-related death worldwide. The current study assessed the preventive efficacy of isatin on diethylnitrosamine (DENA)/2-acetylaminofluorene (2-AAF)-induced hepatocarcinogenesis in male Wistar rats and investigated the underlying cellular and molecular mechanisms. HCC was initiated by intraperitoneal injection of DENA (150 mg/kg/week) for two weeks, followed by oral 2-AAF (20 mg/kg) every other day for three successive weeks. Oral isatin or vehicle (control) was administered at 25 mg/kg for 20 weeks during and following HCC induction. Isatin ameliorated the deleterious effects of DENA/2-AAF on liver function as evidenced by reduced serum levels of AST, ALT, total bilirubin, albumin, and liver tumor biomarkers (CA19.9 and AFP) compared to control DENA/2-AAF-treated rats. Histopathological evaluations demonstrated that isatin-mediated protection against hepatocarcinogenesis was accompanied by a decline in hepatic lipid peroxidation, a marker of oxidative stress, and enhanced antioxidant capacity, as evidenced by increased glutathione and superoxide dismutase expression. Isatin treatment also upregulated expression of the major stress-response transcription factor Nrf2 and the detoxifying enzymes NAD(P)H quinine oxidoreductase and glutathione-S-transferase alpha 2 and downregulated expression of the proliferation marker Ki67. Moreover, isatin significantly reduced the DENA/2-AAF-induced decrease in hepatic expression of anti-apoptotic Bcl2 and the DENA/2-AAF-induced increases in pro-inflammatory and pro-apoptotic factors (TNF-α, NF-κB p50, NF-κB p65, p53, and caspase 3). Thus, it can be concluded that isatin may protect against chemically induced hepatocarcinogenesis by enhancing cellular antioxidant, anti-inflammatory, and detoxification mechanisms, in part through upregulation of the Nrf2 signaling pathway.https://www.mdpi.com/2076-3921/11/4/699hepatocellular carcinomadiethylnitrosamineacetylaminofluoreneisatininflammationapoptosis |
| spellingShingle | Nagwa G. Tawfik Wafaa R. Mohamed Hanan S. Mahmoud Mohammed A. Alqarni Ibrahim A. Naguib Alzhraa M. Fahmy Osama M. Ahmed Isatin Counteracts Diethylnitrosamine/2-Acetylaminofluorene-Induced Hepatocarcinogenesis in Male Wistar Rats by Upregulating Anti-Inflammatory, Antioxidant, and Detoxification Pathways Antioxidants hepatocellular carcinoma diethylnitrosamine acetylaminofluorene isatin inflammation apoptosis |
| title | Isatin Counteracts Diethylnitrosamine/2-Acetylaminofluorene-Induced Hepatocarcinogenesis in Male Wistar Rats by Upregulating Anti-Inflammatory, Antioxidant, and Detoxification Pathways |
| title_full | Isatin Counteracts Diethylnitrosamine/2-Acetylaminofluorene-Induced Hepatocarcinogenesis in Male Wistar Rats by Upregulating Anti-Inflammatory, Antioxidant, and Detoxification Pathways |
| title_fullStr | Isatin Counteracts Diethylnitrosamine/2-Acetylaminofluorene-Induced Hepatocarcinogenesis in Male Wistar Rats by Upregulating Anti-Inflammatory, Antioxidant, and Detoxification Pathways |
| title_full_unstemmed | Isatin Counteracts Diethylnitrosamine/2-Acetylaminofluorene-Induced Hepatocarcinogenesis in Male Wistar Rats by Upregulating Anti-Inflammatory, Antioxidant, and Detoxification Pathways |
| title_short | Isatin Counteracts Diethylnitrosamine/2-Acetylaminofluorene-Induced Hepatocarcinogenesis in Male Wistar Rats by Upregulating Anti-Inflammatory, Antioxidant, and Detoxification Pathways |
| title_sort | isatin counteracts diethylnitrosamine 2 acetylaminofluorene induced hepatocarcinogenesis in male wistar rats by upregulating anti inflammatory antioxidant and detoxification pathways |
| topic | hepatocellular carcinoma diethylnitrosamine acetylaminofluorene isatin inflammation apoptosis |
| url | https://www.mdpi.com/2076-3921/11/4/699 |
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