Article ; Online: Upregulation of Nrf2 signaling and suppression of ferroptosis and NF-κB pathway by leonurine attenuate iron overload-induced hepatotoxicity.
Chemico-biological interactions
2022 Volume 356, Page(s) 109875
Abstract: Hepatotoxicity is a major health concern that associates the iron overload diseases including hemochromatosis, sickle cell anemia, and thalassemia. Induction of ferroptosis, oxidative stress, and inflammation substantially mediates the iron-evoked ... ...
| Abstract | Hepatotoxicity is a major health concern that associates the iron overload diseases including hemochromatosis, sickle cell anemia, and thalassemia. Induction of ferroptosis, oxidative stress, and inflammation substantially mediates the iron-evoked hepatotoxicity. The current work investigated the potential protective effect of the natural alkaloid leonurine against the iron-induced hepatotoxicity and elucidated the underlining molecular mechanisms. Male Wistar rats were treated with iron only (30 mg/kg every other day over a ten-day period via intraperitoneal injection) or with iron and leonurine (leonurine: 100 mg/kg/day per oral via gastric gavage for 10 days) to establish the iron-overload model. Liver and blood specimens were then collected and subjected to molecular, biochemical, and histopathological investigations. The results revealed the ability of leonurine to suppress the iron-induced ferroptosis as reflected by modulation of the ferroptotic biomarkers glutathione peroxidase 4, cyclooxygenase-2, liver iron content, lipid hydroperoxides, and the leakage of the liver intracellular enzymes. Leonurine alleviated the iron-induced oxidative damage and inflammatory response in the liver tissues as indicated by decreased levels of DNA oxidation, lipid peroxidation, and the pro-inflammatory cytokines. In the same context, it improved the antioxidant potential of the liver tissues and ameliorated the iorn-induced histopathological abnormalities. Mechanistically, leonurine enhanced nuclear translocation of the antioxidant transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and increased protein levels of its downstream targets NAD(P)H-quinone oxidoreductase 1 and heme oxygenase-1. Additionally, it suppressed the nuclear translocation of the inflammatory transcription factor nuclear factor kappa B (NF-κB) and downregulated its downstream pro-inflammatory cytokines tumor necrosis factor-alpha and interleukin-1 beta. The study highlights the hepatoprotective activity of leonurine against the iron-evoked hepatotoxicity that is potentially mediated through modulation of Nrf2 and NF-κB signaling. |
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| MeSH term(s) | Animals ; Chemical and Drug Induced Liver Injury/drug therapy ; Ferroptosis ; Gallic Acid/analogs & derivatives ; Iron Overload/complications ; Iron Overload/drug therapy ; Male ; NF-E2-Related Factor 2/metabolism ; NF-kappa B/metabolism ; Oxidative Stress ; Rats ; Rats, Wistar ; Up-Regulation |
| Chemical Substances | NF-E2-Related Factor 2 ; NF-kappa B ; leonurine (09Q5W34QDA) ; Gallic Acid (632XD903SP) |
| Language | English |
| Publishing date | 2022-03-03 |
| Publishing country | Ireland |
| Document type | Journal Article |
| ZDB-ID | 218799-1 |
| ISSN | 1872-7786 ; 0009-2797 |
| ISSN (online) | 1872-7786 |
| ISSN | 0009-2797 |
| DOI | 10.1016/j.cbi.2022.109875 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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