The mitochondria-targeted sulfide delivery molecule attenuates drugs-induced gastropathy. Involvement of heme oxygenase pathway
dc.contributor.author | Magierowska, K | |
dc.contributor.author | Wójcik-Grzybek, D | |
dc.contributor.author | Korbut, E | |
dc.contributor.author | Bakalarz, D | |
dc.contributor.author | Ginter, G | |
dc.contributor.author | Danielak, A | |
dc.contributor.author | Kwiecień, S | |
dc.contributor.author | Chmura, A | |
dc.contributor.author | Torregrossa, R | |
dc.contributor.author | Whiteman, M | |
dc.contributor.author | Magierowski, M | |
dc.date.accessioned | 2023-11-13T11:38:00Z | |
dc.date.issued | 2023-08-12 | |
dc.date.updated | 2023-11-13T10:38:22Z | |
dc.description.abstract | Hydrogen sulfide (H2S) signaling and H2S-prodrugs maintain redox balance in gastrointestinal (GI) tract. Predominant effect of any H2S-donor is mitochondrial. Non-targeted H2S-moieties were shown to decrease the non-steroidal anti-inflammatory drugs (NSAIDs)-induced gastrotoxicity but in high doses. However, direct, controlled delivery of H2S to gastric mucosal mitochondria as a molecular target improving NSAIDs-pharmacology remains overlooked. Thus, we treated Wistar rats, i.g. with vehicle, mitochondria-targeted H2S-releasing AP39 (0.004-0.5 mg/kg), AP219 (0.02 mg/kg) as structural control without H2S-releasing ability, or AP39 + SnPP (10 mg/kg) as a heme oxygenase (HMOX) inhibitor. Next, animals were administered i.g. with acetylsalicylic acid (ASA, 125 mg/kg) as NSAIDs representative or comparatively with 75% ethanol to induce translational hemorrhagic or necrotic gastric lesions, that were assessed micro-/macroscopically. Activity of mitochondrial complex IV/V, and DNA oxidation were assessed biochemically. Gastric mucosal/serum content of IL-1β, IL-10, TNF-α, TGF-β1/2, ARG1, GST-α, or phosphorylation of mTOR, NF-κB, ERK, Akt, JNK, STAT3/5 were evaluated by microbeads-fluorescent xMAP®-assay; gastric mucosal mRNA level of HMOX-1/2, COX-1/2, SOD-1/2 by real-time PCR. AP39 (but not AP219) dose-dependently (0.02 and 0.1 mg/kg) diminished NSAID- (and ethanol)-induced gastric lesions and DNA oxidation, restoring mitochondrial complexes activity, ARG1, GST-α protein levels and increasing HMOX-1 and SOD-2 expression. AP39 decreased proteins levels or phosphorylation of gastric mucosal inflammation/oxidation-sensitive markers and restored mTOR phosphorylation. Pharmacological inhibition of HMOX-1 attenuated AP39-gastroprotection. We showed that mitochondria-targeted H2S released from very low i.g. doses of AP39 improved gastric mucosal capacity to cope with NSAIDs-induced mitochondrial dysfunction and redox imbalance, mechanistically requiring the activity of HMOX-1. | en_GB |
dc.description.sponsorship | Jagiellonian University Medical College (Poland) | en_GB |
dc.format.extent | 102847- | |
dc.format.medium | Print-Electronic | |
dc.identifier.citation | Vol. 66, article 102847 | en_GB |
dc.identifier.doi | https://doi.org/10.1016/j.redox.2023.102847 | |
dc.identifier.grantnumber | N41/DBS/000877 | en_GB |
dc.identifier.grantnumber | N41/DBS/000578 | en_GB |
dc.identifier.grantnumber | N41/DBS/001140 | en_GB |
dc.identifier.grantnumber | N41/DBS/000106 | en_GB |
dc.identifier.grantnumber | N41/DBS/000784 | en_GB |
dc.identifier.uri | http://hdl.handle.net/10871/134506 | |
dc.identifier | ORCID: 0000-0002-6583-6779 (Whiteman, Matthew) | |
dc.language.iso | en | en_GB |
dc.publisher | Elsevier | en_GB |
dc.relation.url | https://www.ncbi.nlm.nih.gov/pubmed/37597422 | en_GB |
dc.rights | © 2023 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) | en_GB |
dc.subject | Gastric mucosa | en_GB |
dc.subject | Heme oxygenase | en_GB |
dc.subject | Hydrogen sulfide | en_GB |
dc.subject | Mitochondria | en_GB |
dc.subject | Non-steroidal anti-inflammatory drugs | en_GB |
dc.title | The mitochondria-targeted sulfide delivery molecule attenuates drugs-induced gastropathy. Involvement of heme oxygenase pathway | en_GB |
dc.type | Article | en_GB |
dc.date.available | 2023-11-13T11:38:00Z | |
dc.identifier.issn | 2213-2317 | |
exeter.article-number | 102847 | |
exeter.place-of-publication | Netherlands | |
dc.description | This is the final version. Available on open access from Elsevier via the DOI in this record | en_GB |
dc.description | Data availability: Data will be made available on request. | en_GB |
dc.identifier.eissn | 2213-2317 | |
dc.identifier.journal | Redox Biology | en_GB |
dc.relation.ispartof | Redox Biol, 66 | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | en_GB |
dcterms.dateAccepted | 2023-08-11 | |
dc.rights.license | CC BY | |
rioxxterms.version | VoR | en_GB |
rioxxterms.licenseref.startdate | 2023-08-12 | |
rioxxterms.type | Journal Article/Review | en_GB |
refterms.dateFCD | 2023-11-13T11:32:52Z | |
refterms.versionFCD | VoR | |
refterms.dateFOA | 2023-11-13T11:38:06Z | |
refterms.panel | A | en_GB |
Files in this item
This item appears in the following Collection(s)
Except where otherwise noted, this item's licence is described as © 2023 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)