Mitochondria-targeted hydrogen sulfide donors versus acute oxidative gastric mucosal injury

Magierowska, Katarzyna; Korbut, Edyta; Wójcik, Dagmara; Bakalarz, Dominik; Śliwowski, Zbigniew; Cieszkowski, Jakub; Szetela, Małgorzata; Torregrossa, Roberta; Whiteman, Matthew; Magierowski, Marcin

doi:10.1016/j.jconrel.2022.05.051

Cited by 22 publications

(20 citation statements)

References 81 publications

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“…Additionally, the gasotransmitters NO and H 2 S have been found to modify Keap1 through nitrosylation and sulfhydration, respectively. Recent advancements in the study of NO and H 2 S have led to the development of various donors and targeted prodrugs, such as NO donor S-nitroso-N-acetylenemethamine (SNAP) ( Um et al, 2011 ), H 2 S donor S-1-propyl cysteine (CySSPe) ( Tocmo and Parkin, 2019 ), and mitochondrial-targeted H 2 S prodrugs AP39 and RT01 ( Magierowska et al, 2022 ), further expanding our understanding of their biological effects. The aforementioned studies offer valuable insights for the development of pharmaceuticals that stimulate the Nrf2 pathway.…”

Section: Discussionmentioning

confidence: 99%

Post-translational modifications of Keap1: the state of the art

Song,

Qu,

Mao

et al. 2024

Front. Cell Dev. Biol.

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The Keap1-Nrf2 signaling pathway plays a crucial role in cellular defense against oxidative stress-induced damage. Its activation entails the expression and transcriptional regulation of several proteins involved in detoxification and antioxidation processes within the organism. Keap1, serving as a pivotal transcriptional regulator within this pathway, exerts control over the activity of Nrf2. Various post-translational modifications (PTMs) of Keap1, such as alkylation, glycosylation, glutathiylation, S-sulfhydration, and other modifications, impact the binding affinity between Keap1 and Nrf2. Consequently, this leads to the accumulation of Nrf2 and its translocation to the nucleus, and subsequent activation of downstream antioxidant genes. Given the association between the Keap1-Nrf2 signaling pathway and various diseases such as cancer, neurodegenerative disorders, and diabetes, comprehending the post-translational modification of Keap1 not only deepens our understanding of Nrf2 signaling regulation but also contributes to the identification of novel drug targets and biomarkers. Consequently, this knowledge holds immense importance in the prevention and treatment of diseases induced by oxidative stress.

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Section: Discussionmentioning

confidence: 99%

Post-translational modifications of Keap1: the state of the art

Song,

Qu,

Mao

et al. 2024

Front. Cell Dev. Biol.

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“…iNOS were known to be the key mediator in in ammation and tumor microenvironment [30,31]. In addition, iNOS was con rmed to be the downstream protein of TLR9/NF-κB pathway [32].…”

Section: Discussionmentioning

confidence: 99%

SPLUNC1 regulates LPS-induced progression of nasopharyngeal carcinoma and proliferation of myeloid-derived suppressor cells

et al. 2022

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Background: Nasopharyngeal carcinoma (NPC) is one of the aggressive malignant tumors with high mortality, and the proliferation of myeloid-derived suppressor cells (MDSCs) could promote the metastasis of NPC through inhibiting the function of T cells. Meanwhile, SPLUNC1 was known to inhibit the malignant behavior of NPC cells, while the detailed function of SPLUNC1 in LPS-modi ed immune microenvironment of NPC remains unclear.Methods: To assess the impact of SPLUNC1 in immune microenvironment during the progression of NPC, NPC cells were exposed to LPS and then co-cultured with MDSCs for 48 h. RT-qPCR and western blot were performed to evaluate the mRNA and protein levels, respectively. The levels of cytokines were tested by ELISA. Meanwhile, the expression of CD33 + was tested by ow cytometry.Results: The expressions of CXCL-2 and CXCR-2 in NPC cells were higher, compared with those in NP69 cells. In contrast, SPLUNC1 level in NPC cells was much lower than that in NP69 cells. SPLUNC1 level was negatively correlated with CXCL-2 and CXCR-2. Overexpression of SPLUNC1 reversed LPS-induced in ammatory responses and proliferation in NPC cells. In addition, SPLUNC1 upregulation could reverse LPS-induced proliferation of MDSCs in tumor microenvironment. Meanwhile, SPLUNC1 overexpression could regulate CXCL-2/CXCR-2 axis.Conclusion: SPLUNC1 regulates LPS-induced progression of nasopharyngeal carcinoma and proliferation of MDSCs. Thus, our study might provide a theoretical basis for discovering new strategies against NPC.

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“…The content of 8-OHG in gastric mucosa as an RNA oxidative damage marker was assessed using an ELISA kit (589320, Cayman Chemical, Ann Arbor, MI, USA) and normalized to total RNA level, according to the manufacturer's protocol and as described in detail elsewhere [18]. Total RNA was isolated from gastric mucosa using a commercially available kit with spin columns (GeneMATRIX Universal RNA Purification Kit, EURx, Gdansk, Poland) according to manufacturer protocol.…”

Section: Evaluation Of 8-hydroxyguanozine (8-ohg) Concentration In Ga...mentioning

confidence: 99%

Hydrogen Sulfide-Releasing Indomethacin-Derivative (ATB-344) Prevents the Development of Oxidative Gastric Mucosal Injuries

et al. 2023

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Hydrogen sulfide (H2S) 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 H2S moiety was shown to decrease the GI toxicity of some NSAIDs. However, the GI safety and anti-oxidative effect of a novel H2S-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 H2S level was assessed in the gastric mucosa using the modified methylene blue method. Serum and gastric mucosal PGE2 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 H2S-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 H2S production, did not affect gastric mucosal PGE2 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 H2S-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 PGE2 content in the gastric mucosa and, as a result, evoked gastroprotection against oxidative damage.

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Mitochondria-targeted hydrogen sulfide donors versus acute oxidative gastric mucosal injury

Cited by 22 publications

References 81 publications

Post-translational modifications of Keap1: the state of the art

Post-translational modifications of Keap1: the state of the art

SPLUNC1 regulates LPS-induced progression of nasopharyngeal carcinoma and proliferation of myeloid-derived suppressor cells

Hydrogen Sulfide-Releasing Indomethacin-Derivative (ATB-344) Prevents the Development of Oxidative Gastric Mucosal Injuries

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