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03.04.2024 | Original Article

Physiological healing of chronic gastric ulcer is not impaired by the hydrogen sulphide (H₂S)-releasing derivative of acetylsalicylic acid (ATB-340): functional and proteomic approaches

verfasst von: Edyta Korbut, Maciej Suski, Zbigniew Śliwowski, Dominik Bakalarz, Urszula Głowacka, Dagmara Wójcik-Grzybek, Grzegorz Ginter, Kinga Krukowska, Tomasz Brzozowski, Marcin Magierowski, John L. Wallace, Katarzyna Magierowska

Erschienen in: Inflammopharmacology

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Abstract

Gastric ulcers affect approx. 10% of population. Non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid (ASA) predispose to or impair the physiologically complex healing of pre-existing ulcers. Since H₂S is an endogenous cytoprotective molecule, we hypothesized that new H₂S-releasing ASA-derivative (ATB-340) could overcome pathological impact of NSAIDs on GI regeneration.

Clinically translational gastric ulcers were induced in Wistar rats using state-of-the-art microsurgical model employing serosal application of acetic acid. This was followed by 9 days long i.g. daily treatment with vehicle, ATB-340 (6–24 mg/kg) or equimolar ASA doses (4–14 mg/kg). Ulcer area was assessed macro- and microscopically. Prostaglandin (PG)E2 levels, indicating pharmacological activity of NSAIDs and 8-hydroxyguanozine content, reflecting nucleic acids oxidation in serum/gastric mucosa, were determined by ELISA. Qualitative and/or quantitative pathway-specific alterations at the ulcer margin were evaluated using real-time PCR and mass spectrometry-based proteomics.

ASA, unlike ATB-340, dose-dependently delayed/impaired gastric tissue recovery, deregulating 310 proteins at the ulcer margin, including Ras signalling, wound healing or apoptosis regulators. ATB-340 maintained NSAIDs-specific cyclooxygenase-inhibiting capacity on systemic and GI level but in time-dependent manner. High dose of ATB-340 (24 mg/kg daily), but not ASA, decreased nucleic acids oxidation and upregulated anti-oxidative/anti-inflammatory heme oxygenase-1, 24-dehydrocholesterol reductase or suppressor of cytokine signalling (SOCS3) at the ulcer margin.

Thus, ASA impairs the physiological healing of pre-existing gastric ulcers, inducing the extensive molecularly functional and proteomic alterations at the wound margin. H₂S-releasing ATB-340 maintains the target activity of NSAIDs with limited impact on gastric PGE2 signalling and physiological GI regeneration, enhancing anti-inflammatory and anti-oxidative response, and providing the pharmacological advantage.

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Titel: Physiological healing of chronic gastric ulcer is not impaired by the hydrogen sulphide (H2S)-releasing derivative of acetylsalicylic acid (ATB-340): functional and proteomic approaches
verfasst von: Edyta Korbut
Maciej Suski
Zbigniew Śliwowski
Dominik Bakalarz
Urszula Głowacka
Dagmara Wójcik-Grzybek
Grzegorz Ginter
Kinga Krukowska
Tomasz Brzozowski
Marcin Magierowski
John L. Wallace
Katarzyna Magierowska
Publikationsdatum: 03.04.2024
Verlag: Springer International Publishing
Erschienen in: Inflammopharmacology
Print ISSN: 0925-4692
Elektronische ISSN: 1568-5608
DOI: https://doi.org/10.1007/s10787-024-01458-3

Die Highlights vom Kongress des American College of Cardiology 2024

Springer Medizin

Physiological healing of chronic gastric ulcer is not impaired by the hydrogen sulphide (H₂S)-releasing derivative of acetylsalicylic acid (ATB-340): functional and proteomic approaches

Abstract

Die Highlights vom Kongress des American College of Cardiology 2024

Springer Medizin

Abstract

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