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- Title
Tanshinone IIA Regulates Keap1/Nrf2 Signal Pathway by Activating Sestrin2 to Restrain Pulmonary Fibrosis.
- Authors
Li, Hongxia; Wu, Mingyu; Guo, Congying; Zhai, Rao; Chen, Jun
- Abstract
Tanshinone IIA (Tan-IIA) is a major component extracted from the traditional herbal medicine Danshen, which has shown antipulmonary fibrosis by suppress reactive oxygen species-mediated activation of myofibroblast. However, the exact mechanism of Tan-IIA against pulmonary fibrosis (PF) remains unclear. This work aimed to explore the underlying mechanism of the protective effects of Tan-IIA on PF. By using high-throughput RNA-Seq analysis, we have compared the genome-wide gene expression profiles and pathway enrichment of Tan-IIA-treated NIH-3T3 cells with or without transforming growth factor beta 1 (TGF- β 1) induction. In normal NIH-3T3 cells, Tan-IIA treatment up-regulated 181 differential expression genes (DEGs) and down-regulated 137 DEGs. In TGF- β 1-induced NIH-3T3 cells, Tan-IIA treatment up-regulated 709 DEGs and down-regulated 1075 DEGs, and these DEGs were enriched in extracellular matrix organization, collagen fibril organization, cell adhesion, ECM–receptor interaction, PI3K-Akt signaling pathway and P53 signaling pathway. Moreover, there were 207 co-expressed DEGs between Tan-IIA treatment vs. the Control and TGF- β 1 plus Tan-IIA treatment vs. TGF- β 1 alone treatment, some of which were related to anti-oxidative stress. In both normal and TGF- β 1-induced NIH-3T3 cells, protein–protein interaction network analysis indicated that Tan-IIA can regulate the expression of several common anti-oxidant genes including Heme oxygenase 1 (Ho-1, also known as Homx1), Sestrin2 (Sesn2), GCL modifier subunit (Gclm), GCL catalytic subunit (Gclc) and Sequestosome-1 (Sqstm1). Quantitative Real-time polymerase chain reaction analysis confirmed some DEGs specifically expressing on Tan-IIA treated cells, which provided new candidates for further functional studies of Tan-IIA. In both in vitro and in vivo PF models, the protein expression of Sesn2 was significantly enhanced by Tan-IIA treatment. Overexpression and knockdown experiments showed that Sesn2 is required for Tan-IIA against TGF- β 1-induced myofibroblast activation by reinforcing nuclear factor-erythroid 2-related factor 2 (Nrf2)-mediated anti-oxidant response via downregulation of kelch-like ECH-associated protein 1 (Keap1). These results suggest Tan-IIA inhibits myofibroblast activation by activating Sesn2-Nrf2 signaling pathway, and provide a new insight into the essential role of Sesn2 in PF.
- Subjects
CHINA; RNA analysis; HYDROCARBON metabolism; PROTEIN metabolism; IN vitro studies; EXPERIMENTAL design; MUSCLE cells; HERBAL medicine; GOATS; SEQUENCE analysis; CELL culture; IMMUNOGLOBULINS; GROWTH factors; NUCLEAR factor E2 related factor; ANIMAL experimentation; NONSTEROIDAL anti-inflammatory agents; WESTERN immunoblotting; CELLULAR signal transduction; OXIDATIVE stress; CANCER; MEDICAL protocols; COMPARATIVE studies; TRANSFERASES; GENE expression profiling; CELLS; GENOMES; DESCRIPTIVE statistics; PULMONARY fibrosis; POLYMERASE chain reaction; DATA analysis software; CARRIER proteins; CHINESE medicine; MICE; RADIOIMMUNOASSAY; EVALUATION
- Publication
American Journal of Chinese Medicine, 2022, Vol 50, Issue 8, p2125
- ISSN
0192-415X
- Publication type
Article
- DOI
10.1142/S0192415X22500914