NSC23766, a Known Inhibitor of Tiam1-Rac1 Signaling Module, Prevents the Onset of Type 1 Diabetes in the NOD Mouse Model
Background/Aims: Type 1 diabetes (T1D) is characterized by absolute insulin deficiency due to destruction of pancreatic β-cells by cytokines (e.g., interleukin-1β; IL-1β) released by invading immune cells. The mechanisms by which these cytokines induce β-cell dysfunction remain poorly understood. Re...
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| Format: | Article |
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Cell Physiol Biochem Press GmbH & Co KG
2016-07-01
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| Series: | Cellular Physiology and Biochemistry |
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| Online Access: | http://prod.karger.com/Article/FullText/445666 |
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| author | Rajakrishnan Veluthakal Vaibhav Sidarala Anjaneyulu Kowluru |
| author_facet | Rajakrishnan Veluthakal Vaibhav Sidarala Anjaneyulu Kowluru |
| author_sort | Rajakrishnan Veluthakal |
| collection | DOAJ |
| description | Background/Aims: Type 1 diabetes (T1D) is characterized by absolute insulin deficiency due to destruction of pancreatic β-cells by cytokines (e.g., interleukin-1β; IL-1β) released by invading immune cells. The mechanisms by which these cytokines induce β-cell dysfunction remain poorly understood. Recent evidence suggests that excessive generation of reactive oxygen species (ROS) by the phagocyte-like NADPH oxidase2 (Nox2), along with significantly low levels of antioxidants in β-cells, drive them toward oxidative damage. Rac1, a small G-protein, is one of the members of Nox2 holoenzyme. We recently reported that NSC23766, a known inhibitor of Rac1, significantly attenuated cytokine-induced Nox2 activation and ROS generation in pancreatic islet β-cells in vitro. Herein, we determined the effects of NSC23766 (2.5 mg/kg/day, i.p/daily) on the development of diabetes in the NOD mouse, a model for T1D. Methods: Two groups of experimental animals (Balb/c and NOD mice) received NSC23766, while the two control groups received equal volume of saline. Body weights and blood glucose were measured every week for 34 weeks. Rac1 activation in pancreatic islets was measured by GLISA activation assay. Rac1 and CHOP expression was determined by Western Blotting. Results: Our findings indicate that administration of NSC23766 significantly prevented the development of spontaneous diabetes in the NOD mice. Furthermore, NSC23766 markedly suppressed Rac1 expression and activity and the endoplasmic reticulum stress (CHOP expression) in NOD islets. Conclusions: Our findings provide the first evidence implicating the role of Tiam1-Rac1-Nox2 signaling pathway in the onset of spontaneous diabetes in the NOD mouse model. |
| first_indexed | 2024-12-11T18:01:48Z |
| format | Article |
| id | doaj.art-18e85557a3884287afa8263f930723b1 |
| institution | Directory Open Access Journal |
| issn | 1015-8987 1421-9778 |
| language | English |
| last_indexed | 2024-12-11T18:01:48Z |
| publishDate | 2016-07-01 |
| publisher | Cell Physiol Biochem Press GmbH & Co KG |
| record_format | Article |
| series | Cellular Physiology and Biochemistry |
| spelling | doaj.art-18e85557a3884287afa8263f930723b12022-12-22T00:55:52ZengCell Physiol Biochem Press GmbH & Co KGCellular Physiology and Biochemistry1015-89871421-97782016-07-0139276076710.1159/000445666445666NSC23766, a Known Inhibitor of Tiam1-Rac1 Signaling Module, Prevents the Onset of Type 1 Diabetes in the NOD Mouse ModelRajakrishnan VeluthakalVaibhav SidaralaAnjaneyulu KowluruBackground/Aims: Type 1 diabetes (T1D) is characterized by absolute insulin deficiency due to destruction of pancreatic β-cells by cytokines (e.g., interleukin-1β; IL-1β) released by invading immune cells. The mechanisms by which these cytokines induce β-cell dysfunction remain poorly understood. Recent evidence suggests that excessive generation of reactive oxygen species (ROS) by the phagocyte-like NADPH oxidase2 (Nox2), along with significantly low levels of antioxidants in β-cells, drive them toward oxidative damage. Rac1, a small G-protein, is one of the members of Nox2 holoenzyme. We recently reported that NSC23766, a known inhibitor of Rac1, significantly attenuated cytokine-induced Nox2 activation and ROS generation in pancreatic islet β-cells in vitro. Herein, we determined the effects of NSC23766 (2.5 mg/kg/day, i.p/daily) on the development of diabetes in the NOD mouse, a model for T1D. Methods: Two groups of experimental animals (Balb/c and NOD mice) received NSC23766, while the two control groups received equal volume of saline. Body weights and blood glucose were measured every week for 34 weeks. Rac1 activation in pancreatic islets was measured by GLISA activation assay. Rac1 and CHOP expression was determined by Western Blotting. Results: Our findings indicate that administration of NSC23766 significantly prevented the development of spontaneous diabetes in the NOD mice. Furthermore, NSC23766 markedly suppressed Rac1 expression and activity and the endoplasmic reticulum stress (CHOP expression) in NOD islets. Conclusions: Our findings provide the first evidence implicating the role of Tiam1-Rac1-Nox2 signaling pathway in the onset of spontaneous diabetes in the NOD mouse model.http://prod.karger.com/Article/FullText/445666Nox2Rac1NOD micePancreatic isletER stressDiabetes |
| spellingShingle | Rajakrishnan Veluthakal Vaibhav Sidarala Anjaneyulu Kowluru NSC23766, a Known Inhibitor of Tiam1-Rac1 Signaling Module, Prevents the Onset of Type 1 Diabetes in the NOD Mouse Model Cellular Physiology and Biochemistry Nox2 Rac1 NOD mice Pancreatic islet ER stress Diabetes |
| title | NSC23766, a Known Inhibitor of Tiam1-Rac1 Signaling Module, Prevents the Onset of Type 1 Diabetes in the NOD Mouse Model |
| title_full | NSC23766, a Known Inhibitor of Tiam1-Rac1 Signaling Module, Prevents the Onset of Type 1 Diabetes in the NOD Mouse Model |
| title_fullStr | NSC23766, a Known Inhibitor of Tiam1-Rac1 Signaling Module, Prevents the Onset of Type 1 Diabetes in the NOD Mouse Model |
| title_full_unstemmed | NSC23766, a Known Inhibitor of Tiam1-Rac1 Signaling Module, Prevents the Onset of Type 1 Diabetes in the NOD Mouse Model |
| title_short | NSC23766, a Known Inhibitor of Tiam1-Rac1 Signaling Module, Prevents the Onset of Type 1 Diabetes in the NOD Mouse Model |
| title_sort | nsc23766 a known inhibitor of tiam1 rac1 signaling module prevents the onset of type 1 diabetes in the nod mouse model |
| topic | Nox2 Rac1 NOD mice Pancreatic islet ER stress Diabetes |
| url | http://prod.karger.com/Article/FullText/445666 |
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