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Free Radic Biol Med. 2019 Sep 16. pii: S0891-5849(19)30996-7. doi: 10.1016/j.freeradbiomed.2019.09.013. [Epub ahead of print]

Seaweed natural products modify the host inflammatory response via Nrf2 signaling and alter colon microbiota composition and gene expression.

Author information

1
Department of Medicinal Chemistry, University of Florida, 1345 Center Drive, Gainesville, FL, 32610, USA; Center for Natural Products, Drug Discovery, and Development (CNPD3), University of Florida, 1345 Center Drive, Gainesville, FL, 32610, USA; Institute of Molecular and Cellular Biology (IMCB), A*STAR, Proteos, 138673, Singapore.
2
Department of Medicinal Chemistry, University of Florida, 1345 Center Drive, Gainesville, FL, 32610, USA; Center for Natural Products, Drug Discovery, and Development (CNPD3), University of Florida, 1345 Center Drive, Gainesville, FL, 32610, USA.
3
Division of Gastroenterology, Department of Medicine, University of Florida, Gainesville, FL, 32610, USA.
4
Proteomics and Mass Spectrometry, Interdisciplinary Center for Biotechnology Research, University of Florida, Gainesville, FL, 32610, USA.
5
Proteomics and Mass Spectrometry, Interdisciplinary Center for Biotechnology Research, University of Florida, Gainesville, FL, 32610, USA; Department of Biology, Genetics Institute, Plant Molecular and Cellular Biology Program, University of Florida, Gainesville, FL, 32610, USA.
6
Institute of Molecular and Cellular Biology (IMCB), A*STAR, Proteos, 138673, Singapore; Lee Kong Chian School of Medicine, Nanyang Technological University, 59 Nanyang Drive, 636921, Singapore.
7
Smithsonian Marine Station, 701 Seaway Drive, Fort Pierce, Florida, 34949, USA.
8
Department of Medicinal Chemistry, University of Florida, 1345 Center Drive, Gainesville, FL, 32610, USA; Center for Natural Products, Drug Discovery, and Development (CNPD3), University of Florida, 1345 Center Drive, Gainesville, FL, 32610, USA; Institute of Molecular and Cellular Biology (IMCB), A*STAR, Proteos, 138673, Singapore; Lee Kong Chian School of Medicine, Nanyang Technological University, 59 Nanyang Drive, 636921, Singapore. Electronic address: luesch@cop.ufl.edu.

Abstract

Seaweeds are an important component of human diets, especially in Asia and the Pacific islands, and have shown chemopreventive as well as anti-inflammatory properties. However, structural characterization and mechanistic insight of seaweed components responsible for their biological activities are lacking. We isolated cymopol and related natural products from the marine green alga Cymopolia barbata and demonstrated their function as activators of transcription factor Nrf2-mediated antioxidant response to increase the cellular antioxidant status. We probed the reactivity of the bioactivation product of cymopol, cymopol quinone, which was able to modify various cysteine residues of Nrf2's cytoplasmic repressor protein Keap1. The observed adducts are reflective of the polypharmacology at the level of natural product, due to multiple electrophilic centers, and at the amino acid level of the cysteine-rich target protein Keap1. The non-polar C. barbata extract and its major active component cymopol, reduced inflammatory gene transcription in vitro in macrophages and mouse embryonic fibroblasts in an Nrf2-dependent manner. Cymopol-containing extracts attenuated neutrophil migration in a zebrafish tail wound model. RNA-seq analysis of colonic tissues of mice exposed to non-polar extract or cymopol showed an antioxidant and anti-inflammatory response, with more pronounced effects exhibited by the extract. Cymopolia extract reduced DSS-induced colitis as measured by fecal lipocalin concentration. RNA-seq showed that mucosal-associated bacterial composition and transcriptional profile in large intestines were beneficially altered to varying degrees in mice treated with either the extract or cymopol. We conclude that seaweed-derived compounds, especially cymopol, alter Nrf2-mediated host and microbial gene expression, thereby providing polypharmacological effects.

KEYWORDS:

Anti-inflammatory agents; Cancer prevention; Microbiome; Natural products; Nrf2; Seaweed; Zebrafish

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