The novel NADPH oxidase 4 selective inhibitor GLX7013114 counteracts human islet cell death in vitro.
It has been proposed that pancreatic beta-cell dysfunction in type 2 diabetes is promoted by oxidative stress caused by NADPH oxidase (Nox) over-activity. The aim of the present study was to evaluate the efficacy of novel Nox inhibitors as protective agents against cytokine- or high glucose + palmit...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2018-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC6161897?pdf=render |
| _version_ | 1819106941079650304 |
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| author | Xuan Wang Andris Elksnis Per Wikström Erik Walum Nils Welsh Per-Ola Carlsson |
| author_facet | Xuan Wang Andris Elksnis Per Wikström Erik Walum Nils Welsh Per-Ola Carlsson |
| author_sort | Xuan Wang |
| collection | DOAJ |
| description | It has been proposed that pancreatic beta-cell dysfunction in type 2 diabetes is promoted by oxidative stress caused by NADPH oxidase (Nox) over-activity. The aim of the present study was to evaluate the efficacy of novel Nox inhibitors as protective agents against cytokine- or high glucose + palmitate-induced human beta-cell death. The Nox2 protein was present mainly in the cytoplasm and was induced by cytokines. Nox4 protein immunoreactivity, with some nuclear accumulation, was observed in human islet cells, and was not affected by islet culture in the presence of cytokines or high glucose + palmitate. Nox inhibitors with partial or no isoform selectivity (DPI, dapsone, GLX351322, and GLX481372) all reduced ROS production of human islet cells exposed to high glucose + palmitate. This was paralleled by improved viability and reduced caspase 3 activation. The Nox1 selective inhibitor ML171 failed to reduce human islet cell death in response to both cytokines and high glucose + palmitate. The selective Nox2 inhibitor Phox-I2 also failed to protect against cytokines, but protected partially against high glucose + palmitate-induced cellular death. The highly selective Nox4 inhibitor GLX7013114 protected islet cells against both cytokines and high glucose + palmitate. However, as no osmotic control for high glucose was used, we cannot exclude the possibility that the high glucose effect was due to osmosis. It is concluded that Nox4 may participate in stress-induced islet cell death in human islets in vitro. We propose that Nox4 mediates pro-apoptotic effects in intact islets under stressful conditions and that selective Nox4-inhibition may be a therapeutic strategy in type 2 diabetes. |
| first_indexed | 2024-12-22T02:46:08Z |
| format | Article |
| id | doaj.art-bdcce17215334561ab80bd872523ecd5 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-22T02:46:08Z |
| publishDate | 2018-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-bdcce17215334561ab80bd872523ecd52022-12-21T18:41:32ZengPublic Library of Science (PLoS)PLoS ONE1932-62032018-01-01139e020427110.1371/journal.pone.0204271The novel NADPH oxidase 4 selective inhibitor GLX7013114 counteracts human islet cell death in vitro.Xuan WangAndris ElksnisPer WikströmErik WalumNils WelshPer-Ola CarlssonIt has been proposed that pancreatic beta-cell dysfunction in type 2 diabetes is promoted by oxidative stress caused by NADPH oxidase (Nox) over-activity. The aim of the present study was to evaluate the efficacy of novel Nox inhibitors as protective agents against cytokine- or high glucose + palmitate-induced human beta-cell death. The Nox2 protein was present mainly in the cytoplasm and was induced by cytokines. Nox4 protein immunoreactivity, with some nuclear accumulation, was observed in human islet cells, and was not affected by islet culture in the presence of cytokines or high glucose + palmitate. Nox inhibitors with partial or no isoform selectivity (DPI, dapsone, GLX351322, and GLX481372) all reduced ROS production of human islet cells exposed to high glucose + palmitate. This was paralleled by improved viability and reduced caspase 3 activation. The Nox1 selective inhibitor ML171 failed to reduce human islet cell death in response to both cytokines and high glucose + palmitate. The selective Nox2 inhibitor Phox-I2 also failed to protect against cytokines, but protected partially against high glucose + palmitate-induced cellular death. The highly selective Nox4 inhibitor GLX7013114 protected islet cells against both cytokines and high glucose + palmitate. However, as no osmotic control for high glucose was used, we cannot exclude the possibility that the high glucose effect was due to osmosis. It is concluded that Nox4 may participate in stress-induced islet cell death in human islets in vitro. We propose that Nox4 mediates pro-apoptotic effects in intact islets under stressful conditions and that selective Nox4-inhibition may be a therapeutic strategy in type 2 diabetes.http://europepmc.org/articles/PMC6161897?pdf=render |
| spellingShingle | Xuan Wang Andris Elksnis Per Wikström Erik Walum Nils Welsh Per-Ola Carlsson The novel NADPH oxidase 4 selective inhibitor GLX7013114 counteracts human islet cell death in vitro. PLoS ONE |
| title | The novel NADPH oxidase 4 selective inhibitor GLX7013114 counteracts human islet cell death in vitro. |
| title_full | The novel NADPH oxidase 4 selective inhibitor GLX7013114 counteracts human islet cell death in vitro. |
| title_fullStr | The novel NADPH oxidase 4 selective inhibitor GLX7013114 counteracts human islet cell death in vitro. |
| title_full_unstemmed | The novel NADPH oxidase 4 selective inhibitor GLX7013114 counteracts human islet cell death in vitro. |
| title_short | The novel NADPH oxidase 4 selective inhibitor GLX7013114 counteracts human islet cell death in vitro. |
| title_sort | novel nadph oxidase 4 selective inhibitor glx7013114 counteracts human islet cell death in vitro |
| url | http://europepmc.org/articles/PMC6161897?pdf=render |
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