Abstract
The transcription factor NF-E2 Related Factor-2 (NRF2) is an important drug target. Activation of NRF2 has chemopreventive effects in cancer and exerts beneficial effects in a number of diseases, including neurodegenerative diseases, inflammatory diseases, hepatosteatosis, obesity and insulin resistance. Hence, there have been great efforts to discover and characterize novel NRF2 activators. One reported NRF2 activator is the labdane diterpenoid andrographolide. In this study, we identified the mechanism through which andrographolide activates NRF2. We showed that andrographolide inhibits the function of KEAP1, a protein that together with CUL3 and RBX1 forms an E3 ubiquitin ligase that polyubiquitinates NRF2. Andrographolide partially inhibits the interaction of KEAP1 with CUL3 in a manner dependent on Cys151 in KEAP1. This suggests that andrographolide forms Michael acceptor dependent adducts with Cys151 in KEAP1 in vivo, leading to inhibition of NRF2 ubiquitination and consequently accumulation of the transcription factor. Interestingly, we also showed that at higher concentrations andrographolide increases NRF2 protein expression in a Cys151 independent, but likely KEAP1 dependent manner, possibly through modification of other Cys residues in KEAP1. In this study we also screened secondary metabolites produced by endophytes isolated from non-flowering plants for NRF2-inducing properties. One of the extracts, ORX 41, increased both NRF2 protein expression and transcriptional activity markedly. These results suggest that endophytes isolated from non-flowering or other plants may be a good source of novel NRF2 inducing compounds.
Highlights
Plant extracts are known to have anti-inflammatory properties and are widely used in traditional medicine
MLN4924 inhibits the function of all Cullin RING E3 ubiquitin ligases (CRLs), including the Cullin 3 (CUL3)/RBX1/KEAP1 ligase, leading to a marked NF-E2 Related Factor-2 (NRF2) stabilization (Fig 1B)
We found that andrographolide increased NRF2 protein levels in a time dependent manner (Fig 1C, long exposure)
Summary
Plant extracts are known to have anti-inflammatory properties and are widely used in traditional medicine. NRF2 transcription factor regulation by andrographolide and plant endophytes medicinal plant Andrographis paniculata. This herb has long been used as traditional medicine in Asian countries for the treatment of the common cold, sore throat, upper respiratory tract infections, fever, diarrhea and inflammation [1]. Andrographolide has been reported to exhibit anti-cancer and anti-inflammatory properties both in vitro and in vivo [2] and may have neuroprotective potential in the treatment of stroke [3]. Andrographolide has been shown to decrease inflammation through the inhibition of NF-κB activation [4]. 2004 have shown that andrographolide covalently reacts with cysteine 62 of the p50 subunit of NFκB, accounting for the inhibitory effect on NF-κB transcriptional activity
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