Hydrogen Sulfide-Releasing Indomethacin-Derivative (ATB-344) Prevents the Development of Oxidative Gastric Mucosal Injuries
Hydrogen sulfide (H<sub>2</sub>S) emerged recently as an anti-oxidative signaling molecule that contributes to gastrointestinal (GI) mucosal defense and repair. Indomethacin belongs to the class of non-steroidal anti-inflammatory drugs (NSAIDs) and is used as an effective intervention in...
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MDPI AG
2023-08-01
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| Series: | Antioxidants |
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| author | Urszula Głowacka Marcin Magierowski Zbigniew Śliwowski Jakub Cieszkowski Małgorzata Szetela Dagmara Wójcik-Grzybek Anna Chmura Tomasz Brzozowski John L. Wallace Katarzyna Magierowska |
| author_facet | Urszula Głowacka Marcin Magierowski Zbigniew Śliwowski Jakub Cieszkowski Małgorzata Szetela Dagmara Wójcik-Grzybek Anna Chmura Tomasz Brzozowski John L. Wallace Katarzyna Magierowska |
| author_sort | Urszula Głowacka |
| collection | DOAJ |
| description | Hydrogen sulfide (H<sub>2</sub>S) emerged recently as an anti-oxidative signaling molecule that contributes to gastrointestinal (GI) mucosal defense and repair. Indomethacin belongs to the class of non-steroidal anti-inflammatory drugs (NSAIDs) and is used as an effective intervention in the treatment of gout- or osteoarthritis-related inflammation. However, its clinical use is strongly limited since indomethacin inhibits gastric mucosal prostaglandin (PG) biosynthesis, predisposing to or even inducing ulcerogenesis. The H<sub>2</sub>S moiety was shown to decrease the GI toxicity of some NSAIDs. However, the GI safety and anti-oxidative effect of a novel H<sub>2</sub>S-releasing indomethacin derivative (ATB-344) remain unexplored. Thus, we aimed here to compare the impact of ATB-344 and classic indomethacin on gastric mucosal integrity and their ability to counteract the development of oxidative gastric mucosal injuries. Wistar rats were pretreated intragastrically (i.g.) with vehicle, ATB-344 (7–28 mg/kg i.g.), or indomethacin (5–20 mg/kg i.g.). Next, animals were exposed to microsurgical gastric ischemia-reperfusion (I/R). Gastric damage was assessed micro- and macroscopically. The volatile H<sub>2</sub>S level was assessed in the gastric mucosa using the modified methylene blue method. Serum and gastric mucosal PGE<sub>2</sub> and 8-hydroxyguanozine (8-OHG) concentrations were evaluated by ELISA. Molecular alterations for gastric mucosal barrier-specific targets such as cyclooxygenase-1 (COX)-1, COX-2, heme oxygenase-1 (HMOX)-1, HMOX-2, superoxide dismutase-1 (SOD)-1, SOD-2, hypoxia inducible factor (HIF)-1α, xanthine oxidase (XDH), suppressor of cytokine signaling 3 (SOCS3), CCAAT enhancer binding protein (C/EBP), annexin A1 (ANXA1), interleukin 1 beta (IL-1β), interleukin 1 receptor type I (IL-1R1), interleukin 1 receptor type II (IL-1R2), inducible nitric oxide synthase (iNOS), tumor necrosis factor receptor 2 (TNFR2), or H<sub>2</sub>S-producing enzymes, cystathionine γ-lyase (CTH), cystathionine β-synthase (CBS), or 3-mercaptopyruvate sulfur transferase (MPST), were assessed at the mRNA level by real-time PCR. ATB-344 (7 mg/kg i.g.) reduced the area of gastric I/R injuries in contrast to an equimolar dose of indomethacin. ATB-344 increased gastric H<sub>2</sub>S production, did not affect gastric mucosal PGE<sub>2</sub> content, prevented RNA oxidation, and maintained or enhanced the expression of oxidation-sensitive HMOX-1 and SOD-2 in line with decreased IL-1β and XDH. We conclude that due to the H<sub>2</sub>S-releasing ability, i.g., treatment with ATB-344 not only exerts dose-dependent GI safety but even enhances gastric mucosal barrier capacity to counteract acute oxidative injury development when applied at a low dose of 7 mg/kg, in contrast to classic indomethacin. ATB-344 (7 mg/kg) inhibited COX activity on a systemic level but did not affect cytoprotective PGE<sub>2</sub> content in the gastric mucosa and, as a result, evoked gastroprotection against oxidative damage. |
| first_indexed | 2024-03-11T00:10:16Z |
| format | Article |
| id | doaj.art-27f459ed419641cfb9d6422c3eead0f4 |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-11T00:10:16Z |
| publishDate | 2023-08-01 |
| publisher | MDPI AG |
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| spelling | doaj.art-27f459ed419641cfb9d6422c3eead0f42023-11-19T00:01:34ZengMDPI AGAntioxidants2076-39212023-08-01128154510.3390/antiox12081545Hydrogen Sulfide-Releasing Indomethacin-Derivative (ATB-344) Prevents the Development of Oxidative Gastric Mucosal InjuriesUrszula Głowacka0Marcin Magierowski1Zbigniew Śliwowski2Jakub Cieszkowski3Małgorzata Szetela4Dagmara Wójcik-Grzybek5Anna Chmura6Tomasz Brzozowski7John L. Wallace8Katarzyna Magierowska9Department of Physiology, Jagiellonian University Medical College, 16 Grzegórzecka Street, 31-531 Kraków, PolandDepartment of Physiology, Jagiellonian University Medical College, 16 Grzegórzecka Street, 31-531 Kraków, PolandDepartment of Physiology, Jagiellonian University Medical College, 16 Grzegórzecka Street, 31-531 Kraków, PolandDepartment of Physiology, Jagiellonian University Medical College, 16 Grzegórzecka Street, 31-531 Kraków, PolandDepartment of Physiology, Jagiellonian University Medical College, 16 Grzegórzecka Street, 31-531 Kraków, PolandDepartment of Physiology, Jagiellonian University Medical College, 16 Grzegórzecka Street, 31-531 Kraków, PolandDepartment of Physiology, Jagiellonian University Medical College, 16 Grzegórzecka Street, 31-531 Kraków, PolandDepartment of Physiology, Jagiellonian University Medical College, 16 Grzegórzecka Street, 31-531 Kraków, PolandDepartment of Physiology and Pharmacology, University of Calgary, Calgary, AB T2N 1N4, CanadaDepartment of Physiology, Jagiellonian University Medical College, 16 Grzegórzecka Street, 31-531 Kraków, PolandHydrogen sulfide (H<sub>2</sub>S) emerged recently as an anti-oxidative signaling molecule that contributes to gastrointestinal (GI) mucosal defense and repair. Indomethacin belongs to the class of non-steroidal anti-inflammatory drugs (NSAIDs) and is used as an effective intervention in the treatment of gout- or osteoarthritis-related inflammation. However, its clinical use is strongly limited since indomethacin inhibits gastric mucosal prostaglandin (PG) biosynthesis, predisposing to or even inducing ulcerogenesis. The H<sub>2</sub>S moiety was shown to decrease the GI toxicity of some NSAIDs. However, the GI safety and anti-oxidative effect of a novel H<sub>2</sub>S-releasing indomethacin derivative (ATB-344) remain unexplored. Thus, we aimed here to compare the impact of ATB-344 and classic indomethacin on gastric mucosal integrity and their ability to counteract the development of oxidative gastric mucosal injuries. Wistar rats were pretreated intragastrically (i.g.) with vehicle, ATB-344 (7–28 mg/kg i.g.), or indomethacin (5–20 mg/kg i.g.). Next, animals were exposed to microsurgical gastric ischemia-reperfusion (I/R). Gastric damage was assessed micro- and macroscopically. The volatile H<sub>2</sub>S level was assessed in the gastric mucosa using the modified methylene blue method. Serum and gastric mucosal PGE<sub>2</sub> and 8-hydroxyguanozine (8-OHG) concentrations were evaluated by ELISA. Molecular alterations for gastric mucosal barrier-specific targets such as cyclooxygenase-1 (COX)-1, COX-2, heme oxygenase-1 (HMOX)-1, HMOX-2, superoxide dismutase-1 (SOD)-1, SOD-2, hypoxia inducible factor (HIF)-1α, xanthine oxidase (XDH), suppressor of cytokine signaling 3 (SOCS3), CCAAT enhancer binding protein (C/EBP), annexin A1 (ANXA1), interleukin 1 beta (IL-1β), interleukin 1 receptor type I (IL-1R1), interleukin 1 receptor type II (IL-1R2), inducible nitric oxide synthase (iNOS), tumor necrosis factor receptor 2 (TNFR2), or H<sub>2</sub>S-producing enzymes, cystathionine γ-lyase (CTH), cystathionine β-synthase (CBS), or 3-mercaptopyruvate sulfur transferase (MPST), were assessed at the mRNA level by real-time PCR. ATB-344 (7 mg/kg i.g.) reduced the area of gastric I/R injuries in contrast to an equimolar dose of indomethacin. ATB-344 increased gastric H<sub>2</sub>S production, did not affect gastric mucosal PGE<sub>2</sub> content, prevented RNA oxidation, and maintained or enhanced the expression of oxidation-sensitive HMOX-1 and SOD-2 in line with decreased IL-1β and XDH. We conclude that due to the H<sub>2</sub>S-releasing ability, i.g., treatment with ATB-344 not only exerts dose-dependent GI safety but even enhances gastric mucosal barrier capacity to counteract acute oxidative injury development when applied at a low dose of 7 mg/kg, in contrast to classic indomethacin. ATB-344 (7 mg/kg) inhibited COX activity on a systemic level but did not affect cytoprotective PGE<sub>2</sub> content in the gastric mucosa and, as a result, evoked gastroprotection against oxidative damage.https://www.mdpi.com/2076-3921/12/8/1545hydrogen sulfidenon-steroidal anti-inflammatory drugsindomethacinATB-344gastric oxidative injury |
| spellingShingle | Urszula Głowacka Marcin Magierowski Zbigniew Śliwowski Jakub Cieszkowski Małgorzata Szetela Dagmara Wójcik-Grzybek Anna Chmura Tomasz Brzozowski John L. Wallace Katarzyna Magierowska Hydrogen Sulfide-Releasing Indomethacin-Derivative (ATB-344) Prevents the Development of Oxidative Gastric Mucosal Injuries Antioxidants hydrogen sulfide non-steroidal anti-inflammatory drugs indomethacin ATB-344 gastric oxidative injury |
| title | Hydrogen Sulfide-Releasing Indomethacin-Derivative (ATB-344) Prevents the Development of Oxidative Gastric Mucosal Injuries |
| title_full | Hydrogen Sulfide-Releasing Indomethacin-Derivative (ATB-344) Prevents the Development of Oxidative Gastric Mucosal Injuries |
| title_fullStr | Hydrogen Sulfide-Releasing Indomethacin-Derivative (ATB-344) Prevents the Development of Oxidative Gastric Mucosal Injuries |
| title_full_unstemmed | Hydrogen Sulfide-Releasing Indomethacin-Derivative (ATB-344) Prevents the Development of Oxidative Gastric Mucosal Injuries |
| title_short | Hydrogen Sulfide-Releasing Indomethacin-Derivative (ATB-344) Prevents the Development of Oxidative Gastric Mucosal Injuries |
| title_sort | hydrogen sulfide releasing indomethacin derivative atb 344 prevents the development of oxidative gastric mucosal injuries |
| topic | hydrogen sulfide non-steroidal anti-inflammatory drugs indomethacin ATB-344 gastric oxidative injury |
| url | https://www.mdpi.com/2076-3921/12/8/1545 |
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