ArticleBiochemical pharmacology2015
Phagocyte-like NADPH oxidase (Nox2) promotes activation of p38MAPK in pancreatic β-cells under glucotoxic conditions: Evidence for a requisite role of Ras-related C3 botulinum toxin substrate 1 (Rac1).
Article in Biochemical pharmacology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 41 citations in OpenAlex.
- Organelle-specific crosstalk between calcium and redox signaling in pancreatic β-cells in physiology and type 2 diabetes.Frontiers in network physiology · 2026Review
- Role of ferroptosis in mitochondrial damage in diabetic retinopathy.Free radical biology & medicine · 2024Article
- Regulatory roles of CARD9-BCL10-Rac1 (CBR) signalome in islet β-cell function in health and metabolic stress: Is there room for MALT1?Biochemical pharmacology · 2023Review
- Hyperglycemic Conditions Promote Rac1-Mediated Serine536 Phosphorylation of p65 Subunit of NFκB (RelA) in Pancreatic Beta Cells.Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology · 2022Article
- Autotaxin signaling facilitates β cell dedifferentiation and dysfunction induced by Sirtuin 3 deficiency.Molecular metabolism · 2022Article
- CARD9 Mediates Pancreatic Islet Beta-Cell Dysfunction Under the Duress of Hyperglycemic Stress.Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology · 2022Article
- Underappreciated roles for Rho GDP dissociation inhibitors (RhoGDIs) in cell function: Lessons learned from the pancreatic islet β-cell.Biochemical pharmacology · 2022Review
- Maintaining Effective Beta Cell Function in the Face of Metabolic Syndrome-Associated Glucolipotoxicity-Nutraceutical Options.Healthcare (Basel, Switzerland) · 2021Review
- CARD9 mediates glucose-stimulated insulin secretion in pancreatic beta cells.Biochemical pharmacology · 2021Article
- Targeting Small GTPases and Their Prenylation in Diabetes Mellitus.Journal of medicinal chemistry · 2021Review
- Review
- RhoG-Rac1 Signaling Pathway Mediates Metabolic Dysfunction of the Pancreatic Beta-Cells Under Chronic Hyperglycemic Conditions.Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology · 2021Article
- Paradoxical regulation of glucose-induced Rac1 activation and insulin secretion by RhoGDIβ in pancreatic β-cells.Small GTPases · 2021Article
- Protein Kinases Signaling in Pancreatic Beta-cells Death and Type 2 Diabetes.Advances in experimental medicine and biology · 2021Article
- Melatonin Ameliorates Inflammation and Oxidative Stress by Suppressing the p38MAPK Signaling Pathway in LPS-Induced Sheep Orchitis.Antioxidants (Basel, Switzerland) · 2020Article
- P-Rex1 Mediates Glucose-Stimulated Rac1 Activation and Insulin Secretion in Pancreatic β-Cells.Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology · 2020Article
- Oxidative Stress in Cytokine-Induced Dysfunction of the Pancreatic Beta Cell: Known Knowns and Known Unknowns.Metabolites · 2020Review
- GPCRs, G Proteins, and Their Impact on β-cell Function.Comprehensive Physiology · 2020Review
- Gene Expression Profiling of Type 2 Diabetes Mellitus by Bioinformatics Analysis.Computational and mathematical methods in medicine · 2020Article
- Quantitative proteomics reveals novel interaction partners of Rac1 in pancreatic β-cells: Evidence for increased interaction with Rac1 under hyperglycemic conditions.Molecular and cellular endocrinology · 2019Article
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Authors and funding
6 authors at 4 institutions in 3 countries.
Funding
Abstract
It is well established that glucotoxicity (caused by high glucose concentrations; HG) underlies pathogenesis of islet dysfunction in diabetes. We have recently demonstrated that Nox2 plays a requisite role in the generation of reactive oxygen species (ROS) under HG conditions, resulting in mitochondrial dysregulation and loss of islet β-cell function. Herein, we investigated roles of Nox2 in the regulation of downstream stress kinase (p38MAPK) activation under HG conditions (20mM; 24h) in normal rodent islets and INS-1 832/13 cells. We observed that gp91-ds-tat, a specific inhibitor of Nox2, but not its inactive analog, significantly attenuated HG-induced Nox2 activation, ROS generation and p38MAPK activation, thus suggesting that Nox2 activation couples with p38MAPK activation. Since Rac1, is an integral member of the Nox2 holoenzyme, we also assessed the effects of Rac1 inhibitors (EHT 1864, NSC23766 and Ehop-016) on HG-induced p38MAPK activation in isolated β-cells. We report a significant inhibition of p38MAPK phosphorylation by Rac1 inhibitors, implying a regulatory role for Rac1 in promoting the Nox2-p38MAPK signaling axis in the β-cell under the duress of HG. 2-Bromopalmitate, a known inhibitor of protein (Rac1) palmitoylation, significantly reduced HG-induced p38MAPK phosphorylation. However, GGTI-2147, a specific inhibitor of geranylgeranylation of Rac1, failed to exert any significant effects on HG-induced p38MAPK activation. In conclusion, we present the first evidence that the Rac1-Nox2 signaling module plays novel regulatory roles in HG-induced p38MAPK activation and loss in glucose-stimulated insulin secretion (GSIS) culminating in metabolic dysfunction and the onset of diabetes.
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