Direct targeting of S100A9 with Icariin counteracted acetaminophen‑induced hepatotoxicity.
In: International immunopharmacology, Jg. 136 (2024-07-30), S. 112296
Online
academicJournal
Zugriff:
Acetaminophen (APAP) is a widely used antipyretic and analgesic medication, but its overdose can induce acute liver failure with lack of effective therapies. Icariin is a bioactive compound derived from the herb Epimedium that displays hepatoprotective activities. Here, we explored the protective effects and mechanism of icariin on APAP-induced hepatotoxicity. Icariin (25/50 mg/kg) or N-Acetylcysteine (NAC, 300 mg/kg) were orally administered in wild-type C57BL/6 mice for 7 consecutive days before the APAP administration. Icariin attenuated APAP-induced acute liver injury in mice, as measured by alleviated serum enzymes activities and hepatic apoptosis. In vitro, icariin pretreatment significantly inhibited hepatocellular damage and apoptosis by reducing the BAX/Bcl-2 ratio as well as the expression of cleaved-caspase 3 and cleaved-PARP depended on the p53 pathway. Moreover, icariin attenuated APAP-mediated inflammatory response and oxidative stress via the Nrf2 and NF-κB pathways. Importantly, icariin reduced the expression of S100A9, icariin interacts with S100A9 as a direct cellular target, which was supported by molecular dynamics simulation and surface plasmon resonance assay (equilibrium dissociation constant, K D = 1.14 μM). In addition, the genetic deletion and inhibition of S100A9 not only alleviated APAP-induced injury but also reduced the icariin's protective activity in APAP-mediated liver injury. These data indicated that icariin targeted S100A9 to alleviate APAP-induced liver damage via the following signaling pathways NF-κB, p53, and Nrf2.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Titel: |
Direct targeting of S100A9 with Icariin counteracted acetaminophen‑induced hepatotoxicity.
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Autor/in / Beteiligte Person: | Shen, P ; Xue, M ; Hu, Z ; Han, L ; Deng, X |
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Zeitschrift: | International immunopharmacology, Jg. 136 (2024-07-30), S. 112296 |
Veröffentlichung: | Amsterdam ; New York : Elsevier Science, c2001-, 2024 |
Medientyp: | academicJournal |
ISSN: | 1878-1705 (electronic) |
DOI: | 10.1016/j.intimp.2024.112296 |
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