Computational repositioning of dimethyl fumarate for treating alcoholic liver disease View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2020-08-18

AUTHORS

Ye Zhang, Shuang Zhao, Ying Fu, Lu Yan, Yilu Feng, Yaqi Chen, Yijia Wu, Yalan Deng, Guiying Zhang, Zhuchu Chen, Yongheng Chen, Ting Liu

ABSTRACT

Alcoholic liver disease (ALD) is a chronic alcohol-induced disorder of the liver for which there are few effective therapies for severe forms of ALD and for those who do not achieve alcohol abstinence. In this study, we used a systematic drug-repositioning bioinformatics approach querying a large compendium of gene-expression profiles to identify candidate U.S. Food and Drug Administration (FDA)–approved drugs to treat ALD. One of the top compounds predicted to be therapeutic for ALD by our approach was dimethyl fumarate (DMF), an nuclear factor erythroid 2-related factor 2 (NRF2) inducer. We experimentally validated DMF in liver cells and in vivo. Our work demonstrates that DMF is able to significantly upregulate the NRF2 protein level, increase NRF2 phosphorylation, and promote NRF2 nuclear localization in liver cells. DMF also reduced the reactive oxygen species (ROS) level, lipid peroxidation, and ferroptosis. Furthermore, DMF treatment could prevent ethanol-induced liver injury in ALD mice. Our results provide evidence that DMF might serve as a therapeutic option for ALD in humans, and support the use of computational repositioning to discover therapeutic options for ALD. More... »

PAGES

641

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41419-020-02890-3

DOI

http://dx.doi.org/10.1038/s41419-020-02890-3

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1130162619

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/32811823


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31 schema:description Alcoholic liver disease (ALD) is a chronic alcohol-induced disorder of the liver for which there are few effective therapies for severe forms of ALD and for those who do not achieve alcohol abstinence. In this study, we used a systematic drug-repositioning bioinformatics approach querying a large compendium of gene-expression profiles to identify candidate U.S. Food and Drug Administration (FDA)–approved drugs to treat ALD. One of the top compounds predicted to be therapeutic for ALD by our approach was dimethyl fumarate (DMF), an nuclear factor erythroid 2-related factor 2 (NRF2) inducer. We experimentally validated DMF in liver cells and in vivo. Our work demonstrates that DMF is able to significantly upregulate the NRF2 protein level, increase NRF2 phosphorylation, and promote NRF2 nuclear localization in liver cells. DMF also reduced the reactive oxygen species (ROS) level, lipid peroxidation, and ferroptosis. Furthermore, DMF treatment could prevent ethanol-induced liver injury in ALD mice. Our results provide evidence that DMF might serve as a therapeutic option for ALD in humans, and support the use of computational repositioning to discover therapeutic options for ALD.
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38 DMF treatment
39 Drug Administration
40 Nrf2 nuclear localization
41 Nrf2 phosphorylation
42 Nrf2 protein levels
43 U.S. Food
44 abstinence
45 administration
46 alcohol abstinence
47 alcohol-induced disorders
48 alcoholic liver disease
49 approach
50 bioinformatics approach
51 cells
52 compendium
53 compounds
54 computational repositioning
55 dimethyl fumarate
56 disease
57 disorders
58 drugs
59 effective therapy
60 ethanol-induced liver injury
61 evidence
62 factors
63 ferroptosis
64 food
65 form
66 fumarate
67 gene expression profiles
68 humans
69 inducer
70 injury
71 large compendium
72 levels
73 lipid peroxidation
74 liver
75 liver cells
76 liver disease
77 liver injury
78 localization
79 mice
80 nuclear factor
81 nuclear localization
82 options
83 oxygen species levels
84 peroxidation
85 phosphorylation
86 profile
87 protein levels
88 reactive oxygen species levels
89 repositioning
90 results
91 severe form
92 species level
93 study
94 therapeutic options
95 therapy
96 top compounds
97 treatment
98 use
99 vivo
100 work
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