Untargeted Proteomics and Systems-Based Mechanistic Investigation of Artesunate in Human Bronchial Epithelial Cells.

Article Details

Citation

Ravindra KC, Ho WE, Cheng C, Godoy LC, Wishnok JS, Ong CN, Wong WS, Wogan GN, Tannenbaum SR

Untargeted Proteomics and Systems-Based Mechanistic Investigation of Artesunate in Human Bronchial Epithelial Cells.

Chem Res Toxicol. 2015 Oct 19;28(10):1903-13. doi: 10.1021/acs.chemrestox.5b00105. Epub 2015 Sep 21.

PubMed ID
26340163 [ View in PubMed
]
Abstract

The antimalarial drug artesunate is a semisynthetic derivative of artemisinin, the principal active component of a medicinal plant Artemisia annua. It is hypothesized to attenuate allergic asthma via inhibition of multiple signaling pathways. We used a comprehensive approach to elucidate the mechanism of action of artesunate by designing a novel biotinylated dihydroartemisinin (BDHA) to identify cellular protein targets of this anti-inflammatory drug. By adopting an untargeted proteomics approach, we demonstrated that artesunate may exert its protective anti-inflammatory effects via direct interaction with multiple proteins, most importantly with a number of mitochondrial enzymes related to glucose and energy metabolism, along with mRNA and gene expression, ribosomal regulation, stress responses, and structural proteins. In addition, the modulatory effects of artesunate on various cellular transcription factors were investigated using a transcription factor array, which revealed that artesunate can simultaneously modulate multiple nuclear transcription factors related to several major pro- and anti-inflammatory signaling cascades in human bronchial epithelial cells. Artesunate significantly enhanced nuclear levels of nuclear factor erythroid-2-related factor 2 (Nrf2), a key promoter of antioxidant mechanisms, which is inhibited by the Kelch-like ECH-associated protein 1 (Keap1). Our results demonstrate that, like other electrophilic Nrf2 regulators, artesunate activates this system via direct molecular interaction/modification of Keap1, freeing Nrf2 for transcriptional activity. Altogether, the molecular interactions and modulation of nuclear transcription factors provide invaluable insights into the broad pharmacological actions of artesunate in inflammatory lung diseases and related inflammatory disorders.

DrugBank Data that Cites this Article

Drugs
Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
Artenimol40S ribosomal protein S13ProteinHumans
Unknown
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Artenimol40S ribosomal protein S17ProteinHumans
Unknown
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Details
Artenimol40S ribosomal protein S18ProteinHumans
Unknown
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Details
Artenimol40S ribosomal protein S19ProteinHumans
Unknown
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Details
Artenimol40S ribosomal protein S28ProteinHumans
Unknown
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Details
Artenimol40S ribosomal protein S5ProteinHumans
Unknown
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Details
Artenimol40S ribosomal protein S6ProteinHumans
Unknown
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Details
Artenimol40S ribosomal protein S8ProteinHumans
Unknown
Ligand
Details
Artenimol40S ribosomal protein S9ProteinHumans
Unknown
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Details
Artenimol60S ribosomal protein L10ProteinHumans
Unknown
Ligand
Details
Artenimol60S ribosomal protein L14ProteinHumans
Unknown
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Details
Artenimol60S ribosomal protein L18ProteinHumans
Unknown
Ligand
Details
Artenimol60S ribosomal protein L23aProteinHumans
Unknown
Ligand
Details
Artenimol60S ribosomal protein L35ProteinHumans
Unknown
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Details
Artenimol60S ribosomal protein L4ProteinHumans
Unknown
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Details
ArtenimolActin, cytoplasmic 2ProteinHumans
Unknown
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Details
ArtenimolAlpha-aminoadipic semialdehyde dehydrogenaseProteinHumans
Unknown
Ligand
Details
ArtenimolAlpha-enolaseProteinHumans
Unknown
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Details
ArtenimolAlpha-ketoglutarate-dependent dioxygenase FTOProteinHumans
Unknown
Ligand
Details
ArtenimolAnnexin A2ProteinHumans
Unknown
Ligand
Details
ArtenimolATP synthase subunit alpha, mitochondrialProteinHumans
Unknown
Ligand
Details
ArtenimolATP synthase subunit g, mitochondrialProteinHumans
Unknown
Ligand
Details
ArtenimolATP synthase subunit O, mitochondrialProteinHumans
Unknown
Ligand
Details
ArtenimolCalpastatinProteinHumans
Unknown
Ligand
Details
ArtenimolChloride intracellular channel protein 1ProteinHumans
Unknown
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Details
ArtenimolCofilin-1ProteinHumans
Unknown
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Details
ArtenimolCysteine and glycine-rich protein 1ProteinHumans
Unknown
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Details
ArtenimolCytochrome cProteinHumans
Unknown
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Details
ArtenimolDesmoplakinProteinHumans
Unknown
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Details
ArtenimolDihydropyrimidinase-related protein 2ProteinHumans
Unknown
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Details
ArtenimolElongation factor 1-alpha 1ProteinHumans
Unknown
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Details
ArtenimolFar upstream element-binding protein 2ProteinHumans
Unknown
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Details
ArtenimolFilamin-AProteinHumans
Unknown
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Details
ArtenimolFructose-bisphosphate aldolase AProteinHumans
Unknown
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Details
ArtenimolGalectin-1ProteinHumans
Unknown
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Details
ArtenimolGlucose-6-phosphate 1-dehydrogenaseProteinHumans
Unknown
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Details
ArtenimolGlucose-6-phosphate isomeraseProteinHumans
Unknown
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Details
ArtenimolGlyceraldehyde-3-phosphate dehydrogenaseProteinHumans
Unknown
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Details
ArtenimolGlyceraldehyde-3-phosphate dehydrogenase, testis-specificProteinHumans
Unknown
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Details
ArtenimolHeat shock cognate 71 kDa proteinProteinHumans
Unknown
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Details
ArtenimolHeat shock protein beta-1ProteinHumans
Unknown
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Details
ArtenimolHeterochromatin protein 1-binding protein 3ProteinHumans
Unknown
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Details
ArtenimolHeterogeneous nuclear ribonucleoprotein D0ProteinHumans
Unknown
Ligand
Details
ArtenimolHeterogeneous nuclear ribonucleoprotein KProteinHumans
Unknown
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Details
ArtenimolHeterogeneous nuclear ribonucleoproteins A2/B1ProteinHumans
Unknown
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Details
ArtenimolL-lactate dehydrogenase A chainProteinHumans
Unknown
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Details
ArtenimolL-lactate dehydrogenase B chainProteinHumans
Unknown
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Details
ArtenimolMalate dehydrogenase, cytoplasmicProteinHumans
Unknown
Ligand
Details
ArtenimolMicrotubule-associated protein 4ProteinHumans
Unknown
Ligand
Details
ArtenimolMyosin-9ProteinHumans
Unknown
Ligand
Details
ArtenimolNucleophosminProteinHumans
Unknown
Ligand
Details
ArtenimolPeptidyl-prolyl cis-trans isomerase AProteinHumans
Unknown
Ligand
Details
ArtenimolPeroxiredoxin-1ProteinHumans
Unknown
Ligand
Details
ArtenimolPhosphoglycerate kinase 1ProteinHumans
Unknown
Ligand
Details
ArtenimolPhosphoglycerate mutase 1ProteinHumans
Unknown
Ligand
Details
ArtenimolProbable ATP-dependent RNA helicase DDX5ProteinHumans
Unknown
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Details
ArtenimolProfilin-1ProteinHumans
Unknown
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Details
ArtenimolProtein disulfide-isomeraseProteinHumans
Unknown
Ligand
Details
ArtenimolPuromycin-sensitive aminopeptidaseProteinHumans
Unknown
Ligand
Details
ArtenimolPyruvate kinase PKMProteinHumans
Unknown
Ligand
Details
ArtenimolRas GTPase-activating-like protein IQGAP1ProteinHumans
Unknown
Ligand
Details
ArtenimolSerine hydroxymethyltransferase, mitochondrialProteinHumans
Unknown
Ligand
Details
ArtenimolSerine/arginine-rich splicing factor 4ProteinHumans
Unknown
Ligand
Details
ArtenimolSignal recognition particle 14 kDa proteinProteinHumans
Unknown
Ligand
Details
ArtenimolSmall nuclear ribonucleoprotein Sm D2ProteinHumans
Unknown
Ligand
Details
ArtenimolSpliceosome RNA helicase DDX39BProteinHumans
Unknown
Ligand
Details
ArtenimolSplicing factor 1ProteinHumans
Unknown
Ligand
Details
ArtenimolSplicing factor, proline- and glutamine-richProteinHumans
Unknown
Ligand
Details
ArtenimolT-complex protein 1 subunit gammaProteinHumans
Unknown
Ligand
Details
ArtenimolTransgelinProteinHumans
Unknown
Ligand
Details
ArtenimolTransgelin-2ProteinHumans
Unknown
Ligand
Details
ArtenimolTriosephosphate isomeraseProteinHumans
Unknown
Ligand
Details
ArtenimolTropomyosin alpha-1 chainProteinHumans
Unknown
Ligand
Details
ArtenimolTubulin alpha-1A chainProteinHumans
Unknown
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Details
ArtenimolTubulin beta chainProteinHumans
Unknown
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Details
ArtenimolTubulin beta-4A chainProteinHumans
Unknown
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Details
ArtenimolTubulin beta-6 chainProteinHumans
Unknown
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Details
ArtenimolVimentinProteinHumans
Unknown
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ArtenimolZyxinProteinHumans
Unknown
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Details