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

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

doi:10.1007/s10787-024-01458-3

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

Inflammopharmacology. 2024 Apr 3. doi: 10.1007/s10787-024-01458-3. Online ahead of print.

Authors

Affiliations

¹ Cellular Engineering and Isotope Diagnostics Lab, Department of Physiology, Jagiellonian University Medical College, 31-531, Krakow, Poland.
² Department of Pharmacology, Jagiellonian University Medical College, Krakow, Poland.
³ Proteomics Laboratory, Centre for the Development of Therapies for Civilization and Age-Related Diseases, Jagiellonian University Medical College, Krakow, Poland.
⁴ Department of Physiology, Jagiellonian University Medical College, Krakow, Poland.
⁵ Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, T2N 1N4, Canada.
⁶ Department of Physiology, Jagiellonian University Medical College, Krakow, Poland. katarzyna.magierowska@uj.edu.pl.

PMID: 38570398
DOI: 10.1007/s10787-024-01458-3

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.

Keywords: ATB-340; Acetylsalicylic acid; Gastric ulcer healing; Hydrogen sulphide; Peptic ulcer disease; Proteomics.

Abstract

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