@article{d74e2fc411f24dd2bd5c86d97ed7b1c7,
title = "Sulforaphane prevents and reverses allergic airways disease in mice via anti-inflammatory, antioxidant, and epigenetic mechanisms",
abstract = "Sulforaphane has been investigated in human pathologies and preclinical models of airway diseases. To provide further mechanistic insights, we explored L-sulforaphane (LSF) in the ovalbumin (OVA)-induced chronic allergic airways murine model, with key hallmarks of asthma. Histological analysis indicated that LSF prevented or reversed OVA-induced epithelial thickening, collagen deposition, goblet cell metaplasia, and inflammation. Well-known antioxidant and anti-inflammatory mechanisms contribute to the beneficial effects of LSF. Fourier transform infrared microspectroscopy revealed altered composition of macromolecules, following OVA sensitization, which were restored by LSF. RNA sequencing in human peripheral blood mononuclear cells highlighted the anti-inflammatory signature of LSF. Findings indicated that LSF may alter gene expression via an epigenetic mechanism which involves regulation of protein acetylation status. LSF resulted in histone and α-tubulin hyperacetylation in vivo, and cellular and enzymatic assays indicated decreased expression and modest histone deacetylase (HDAC) inhibition activity, in comparison with the well-known pan-HDAC inhibitor suberoylanilide hydroxamic acid (SAHA). Molecular modeling confirmed interaction of LSF and LSF metabolites with the catalytic domain of metal-dependent HDAC enzymes. More generally, this study confirmed known mechanisms and identified potential epigenetic pathways accounting for the protective effects and provide support for the potential clinical utility of LSF in allergic airways disease.",
keywords = "Airway hypersensitivity, Allergic airways disease, Anti-inflammatory, Antioxidant, Epigenetic regulatory mechanisms, Sulforaphane",
author = "Royce, {Simon G.} and Licciardi, {Paul V.} and Beh, {Raymond C.} and Bourke, {Jane E.} and Chantal Donovan and Andrew Hung and Ishant Khurana and Liang, {Julia J.} and Scott Maxwell and Nadia Mazarakis and Eleni Pitsillou and Siow, {Ya Yun} and Snibson, {Kenneth J.} and Tobin, {Mark J.} and Katherine Ververis and Jitraporn Vongsvivut and Mark Ziemann and Samuel, {Chrishan S.} and Tang, {Mimi L.K.} and Assam El-Osta and Karagiannis, {Tom C.}",
note = "Funding Information: We acknowledge the intellectual and financial support from McCord Research (Iowa, USA). The authors would like to acknowledge the use of the facilities provided by Monash University (Clayton, VIC, Australia) and the Murdoch Children{\textquoteright}s Research Institute (Parkville, VIC, Australia) for their care and husbandry of the mice. The Gomori{\textquoteright}s aldehyde-fuchsin and silver impregnation stains were performed by Ms Laura Leone at the Melbourne University Histology Platform (University of Melbourne, School of Biomedical Sciences, Parkville, VIC, Australia). The authors would like to acknowledge the use of the facilities provided by Monash Micro Imaging (MMI) at the Alfred Research Alliance (ARA, Melbourne, VIC, Australia) and, particularly, the expert assistance from Drs Stephen Cody and I{\'s}ka Carmichael. FPA-FTIR imaging measurements were undertaken at the IRM beamline at the Australian Synchrotron, part of ANSTO (Clayton, VIC, Australia). Various figures in this manuscript were created with BioRender.com. We thank the National Computing Infrastructure (NCI), and the Pawsey Supercomputing Centre in Australia (funded by the Australian Government). Further, we thank the Spartan High Performance Computing service (University of Melbourne), and the Partnership for Advanced Computing in Europe (PRACE) for awarding the access to Piz Daint, hosted at the Swiss National Supercomputing Centre (CSCS), Switzerland. We acknowledge our use of the gene set enrichment analysis, GSEA software, and Molecular Signature Database (MSigDB) (Subramanian, Tamayo, et al. (2005), PNAS 102, 15545-15550, http://www.broad.mit.edu/gsea/). Funding Information: We would like to acknowledge intellectual and financial support by McCord Research (Iowa, USA). AEO is supported by an National Health and Medical Research Council (NHMRC) Senior Research Fellowship (1154650). PVL is supported by an NHMRC Career Development Fellowship (1146198). CD is supported by an NHMRC Early Career Postdoctoral Fellowship (1120152). JJL is supported by an Australian Government Research Training Program Scholarship. Funding Information: We acknowledge the intellectual and financial support from McCord Research (Iowa, USA). The authors would like to acknowledge the use of the facilities provided by Monash University (Clayton, VIC, Australia) and the Murdoch Children{\textquoteright}s Research Institute (Parkville, VIC, Australia) for their care and husbandry of the mice. The Gomori{\textquoteright}s aldehyde-fuchsin and silver impregnation stains were performed by Ms Laura Leone at the Melbourne University Histology Platform (University of Melbourne, School of Biomedical Sciences, Parkville, VIC, Australia). The authors would like to acknowledge the use of the facilities provided by Monash Micro Imaging (MMI) at the Alfred Research Alliance (ARA, Melbourne, VIC, Australia) and, particularly, the expert assistance from Drs Stephen Cody and I{\'s}ka Carmichael. FPA-FTIR imaging measurements were undertaken at the IRM beamline at the Australian Synchrotron, part of ANSTO (Clayton, VIC, Australia). Various figures in this manuscript were created with BioRender.com. We thank the National Computing Infrastructure (NCI), and the Pawsey Supercomputing Centre in Australia (funded by the Australian Government). Further, we thank the Spartan High Performance Computing service (University of Melbourne), and the Partnership for Advanced Computing in Europe (PRACE) for awarding the access to Piz Daint, hosted at the Swiss National Supercomputing Centre (CSCS), Switzerland. We acknowledge our use of the gene set enrichment analysis, GSEA software, and Molecular Signature Database (MSigDB) (Subramanian, Tamayo, et al. (2005), PNAS 102, 15545-15550, http://www.broad.mit.edu/gsea/ ). Publisher Copyright: {\textcopyright} 2022, Crown.",
year = "2022",
month = nov,
doi = "10.1007/s00018-022-04609-3",
language = "English",
volume = "79",
journal = "Cellular and Molecular Life Sciences",
issn = "1420-682X",
publisher = "Birkhauser",
number = "11",
}
