Andrographolide enhances redox status of liver cells by regulating microRNA expression

• Published in: Free radical biology & medicine Vol. 130; pp. 397 - 407
• Main Authors: Khole, Swati, Mittal, Smriti, Jagadish, Nidhi, Ghosh, Debjani, Gadgil, Vijay, Sinkar, Vilas, Ghaskadbi, Saroj
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2019
• Subjects: Antioxidants - pharmacology; Diterpenes - pharmacology; Gene Expression Regulation - drug effects; Glutathione Peroxidase - genetics; Heme Oxygenase-1 - genetics; Hep G2 Cells; Hepatocyte Nuclear Factor 4 - genetics; Hepatocytes - drug effects; Humans; Liver - drug effects; Liver/hepatocytes; MicroRNAs - genetics; NF-E2-Related Factor 2 - genetics; Oxidation-Reduction - drug effects; Oxidative stress; Oxidative Stress - drug effects; Receptor, Adenosine A2A - genetics; Signal Transduction - drug effects; Thioredoxins - genetics; Transcription/transcription factors; Tumor Suppressor Protein p53 - genetics; TXN1; Oxidative stress; TXNRD1; SP-1; HO-1; GR; GS; ChIP; AP-1; BACH1; GPx; P53; NF-κb; GCLC; Liver/hepatocytes; ARE; Nrf2; HNF4A; TXNIP; BAX; Transcription/transcription factors; GCLM
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2018.11.004

Andrographis paniculata Nees and its principal compound andrographolide are well known for exerting beneficial effects by modulating signaling pathways in different biological systems. Our earlier studies have demonstrated the ability of andrographolide as well as andrographolide enriched extracts to activate Nrf2/HO-1 pathway through adenosine A2a receptor. Present study investigated ability of andrographolide to regulate Nrf2 induced antioxidant defense systems by miRNAs using HepG2 cells. Andrographolide strongly induced Nrf2 which in turn modulated enzymes of glutathione and thioredoxin antioxidant systems. It also regulated crucial transcription factors viz. hepatocyte nuclear factor alpha (HNF4A) and tumor suppressor protein 53 (p53). Downregulation of HNF4A by andrographolide led to decrease in miRNAs regulating Heme oxygenase-1 (miR-377) and glutathione cysteine ligase (miR-433). Upregulation of p53 on the other hand led to increase in miRNAs regulating thioredoxin interacting protein (miR-17, miR-224) and glutathione peroxidase (miR-181a). Involvement of p53 and HNF4A in modulation of these miRNAs was confirmed by chromatin immunoprecipitation assay. Overall, the work reveals that andrographolide through modulation of p53 and HNF4A, regulates miRNAs leading to upregulation of HO-1, glutathione and thioredoxin systems. Andrographolide thus, can play a beneficial role in modulating antioxidant defense in oxidative stress induced diseases such as diabetes, ageing etc. [Display omitted] •Andrographolide induces robust Nrf2 expression.•It strongly upregulates HO-1, and enzymes of glutathione and thioredoxin system.•This upregulation is through modulation of miRNAs.•Transcription factors HNF4A and p53 are involved in regulating miRNAs.