Ameliorative effect of betanin on experimental cisplatin‐induced liver injury; the novel impact of miRNA‐34a on the SIRT1/PGC‐1α signaling pathway

• Published in: Journal of biochemical and molecular toxicology Vol. 35; no. 6; pp. 1 - 14
• Main Authors: El Shaffei, Ismail, Abdel‐Latif, Ghada A., Farag, Doaa B., Schaalan, Mona, Salama, Rania M.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.06.2021
• Subjects: AMP; Anticancer properties; Antioxidants; Antitumor agents; BAX protein; betanin; Chemotherapy; Cisplatin; Deregulation; DNA damage; Food dyes; Heme; Hepatotoxicity; Inflammation; Injury prevention; Kinases; Liver; liver injury; MicroRNAs; miRNA; miRNA‐34a; Molecular docking; Oxidative stress; Oxygenase; Protein kinase; Ribonucleic acid; RNA; Signal transduction; Signaling; SIRT1 protein; SIRT1/PGC‐1α; liver injury; SIRT1/PGC-1α; cisplatin; miRNA-34a; betanin
• ISSN: 1095-6670; 1099-0461
• DOI: 10.1002/jbt.22753

The anticancer agent, cisplatin (CIS), is associated with hepatotoxic effects related to activation of oxidative stress and inflammation pathways. CIS‐induced oxidative DNA damage reduces sirtuin 1 (SIRT1) activity, which in turn, modulates the activity of peroxisome proliferator‐activated receptor‐gamma coactivator 1‐alpha (PGC‐1α). Moreover, microRNA‐34a (miRNA‐34a) was shown to hinder both SIRT1 and nuclear factor erythroid 2‐related factor 2 (Nrf2) activity. Thus, targeting such a pathway can alleviate CIS‐induced hepatotoxicity. Betanin (BET) is a natural red glycoside food dye obtained from beets, which is reported to exhibit antioxidant function. However, its role in CIS‐induced liver injury and the molecular mechanism has not been fully elucidated. Thus, the aim of this study was to investigate the ameliorative effect of BET on CIS‐induced acute hepatotoxicity through the SIRT1/PGC‐1α signaling pathway and illustrate the impact of miRNA‐34a. Seventy‐two rats were divided into six equal groups: (1) Control, (2) BET, (3) CIS, (4) CIS/BET, (5) CIS/EX527, and (6) CIS/BET/EX527. CIS‐induced liver injury was evidenced by deregulated BAX and BCL2 levels, decreased levels of AMP‐activated protein kinase and PGC‐1α expression, and decreased SIRT1 activity. Consequently, reduced levels of Nrf2 and the expression of associated heme oxygenase‐1 and glutamate‐cysteine ligase modifier subunit were observed. Intriguingly, BET succeeded in reducing the CIS‐induced liver injury through reducing miRNA‐34a expression and enhancing the SIRT1/PGC‐1α pathway. These findings coincide with the molecular docking results and the histopathological picture. In conclusion, the current research provided novel findings of the BET ameliorative effect on CIS‐induced liver injury through modulating miRNA‐34a expression and the SIRT1/PGC‐1α signaling cascade. Cisplatin (CIS) is associated with hepatotoxicity, which appears to be related to oxidative stress, apoptosis, reduced sirtuin 1 (SIRT1) and peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha (PGC‐1α) activity, and reduced AMP activated protein kinase (AMPK) levels. Betanin effectively reduced CIS‐induced hepatotoxicity via reducing miRNA34a expression and enhancing SIRT1/PGC‐1α pathway, which led to enhanced nuclear factor erythroid related factor 2 (Nrf2) and its downstream antioxidants; glutathione cysteine ligase modifier (GCLM) and hemeoxigenase‐1 (HO‐1). This was reflected in rebalanced BAX/BCL2 ratio and alleviated CIS‐induced liver injury.