Marine Natural Product Honaucin A Attenuates Inflammation by Activating the Nrf2-ARE Pathway

Abstract

The cyanobacterial marine natural product honaucin A inhibits mammalian innate inflammation in vitro and in vivo. To decipher its mechanism of action, RNA sequencing was used to evaluate differences in gene expression of cultured macrophages following honaucin A treatment. This analysis led to the hypothesis that honaucin A exerts its anti-inflammatory activity through activation of the cytoprotective nuclear erythroid 2-related factor 2 (Nrf2)-antioxidant response element/electrophile response element (ARE/EpRE) signaling pathway. Activation of this pathway by honaucin A in cultured human MCF7 cells was confirmed using an Nrf2 luciferase reporter assay. In vitro alkylation experiments with the natural product and N-acetyl-l-cysteine suggest that honaucin A activates this pathway through covalent interaction with the sulfhydryl residues of the cytosolic repressor protein Keap1. Honaucin A presents a potential therapeutic lead for diseases with an inflammatory component modulated by Nrf2-ARE.

Hepatoprotective, antioxidant and, anti-inflammatory potentials of gallic acid in carbon tetrachloride-induced hepatic damage in Wistar rats

“…Previous studies have also shown that green tea polyphenols such as (‐)‐epigallocatechin‐3‐gallate (EGCG) and (‐)‐epicatechin‐3‐gallate (ECG) are known NRF2 activators showing potent induction of ARE‐mediated luciferase activity [ 48 ]. EGCG potentiates cellular defense capacity against chemical carcinogens, UV, and oxidative stress via NRF2‐mediated induction of genes coding for antioxidants, modulators of inflammation, cell growth, apoptosis, cell adhesion, etc.…”

Potential Applications of NRF2 Modulators in Cancer Therapy

“…Only recently have investigators begun to focus on the pathways activated by this compound. Honaucin A forms a covalent bond with the sulfhydryl groups on KEAP1, resulting in the activation of NRF2 [85]. Many food-based NRF2 activators have been shown to work in multiple organs such as liver [86], lung [87], kidney [88], brain [89] and gastrointestinal tract [90].…”

The Role of Natural Products in Targeting Cardiovascular Diseases via Nrf2 Pathway: Novel Molecular Mechanisms and Therapeutic Approaches

“…The study showed that rutin can target the Cys 151 of Keap1, and form an adduct with Keap1 which results in Nrf2 activation and upregulation of glutamate cysteine ligase, a glutathione biosynthesis rate-limiting enzyme which plays an important role in the endogenous antioxidant system ( Sthijns et al, 2017 ). Honaucin A, an anti-inflammatory compound isolated from marine filamentous cyanobacterium Leptolyngbya crossbyana has been reported to induce alkylation of Keap1 cysteine thiols and thereby activating Nrf2/ARE pathway ( Mascuch et al, 2018 ). Similarly, treatment with withaferin A, a steroidal lactone significantly increased expression of HO-1 in HUVECs and EA.hy926 endothelial cells by enhancing nuclear translocation of Nrf2.…”