N-Phenyl Cinnamamide Derivatives Protect Hepatocytes against Oxidative Stress by Inducing Cellular Glutathione Synthesis via Nuclear Factor (Erythroid-Derived 2)-Like 2 Activation.
Sou Hyun KimMinwoo KimDoyoung KwonJae Sung PyoJoo Hyun KimJae-Hwan KwakYoung-Suk JungPublished in: Molecules (Basel, Switzerland) (2021)
Substituted N-phenyl cinnamamide derivatives were designed and synthesized to confirm activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway by the electronic effect on beta-position of Michael acceptor according to introducing the R1 and R2 group. Compounds were screened using the Nrf2/antioxidant response element (ARE)-driven luciferase reporter assay. Compound 1g showed desirable luciferase activity in HepG2 cells without cell toxicity. mRNA and protein expression of Nrf2/ARE target genes such as NAD(P)H quinone oxidoreductase 1, hemeoxygenase-1, and glutamate-cysteine ligase catalytic subunit (GCLC) were upregulated by compound 1g in a concentration-dependent manner. Treatment with 1g resulted in increased endogenous antioxidant glutathione, showing strong correlation with enhanced GCLC expression for synthesis of glutathione. In addition, tert-butyl hydroperoxide (t-BHP)-generated reactive oxygen species were significantly removed by 1g, and the results of a cell survival assay in a t-BHP-induced oxidative cell injury model showed a cytoprotective effect of 1g in a concentration dependent manner. In conclusion, the novel compound 1g can be utilized as an Nrf2/ARE activator in antioxidative therapy.
Keyphrases
- oxidative stress
- nuclear factor
- diabetic rats
- toll like receptor
- dna damage
- reactive oxygen species
- induced apoptosis
- ischemia reperfusion injury
- single cell
- cell therapy
- high throughput
- poor prognosis
- crispr cas
- inflammatory response
- gene expression
- heat shock
- stem cells
- anti inflammatory
- molecular docking
- combination therapy
- signaling pathway
- bone marrow
- living cells
- replacement therapy
- heat shock protein
- mesenchymal stem cells
- energy transfer
- heat stress