Inhibition of 12/15-Lipoxygenase Protects Against β-Cell Oxidative Stress and Glycemic Deterioration in Mouse Models of Type 1 Diabetes
| Autor: | Ryan M. Anderson, Gaurav Chopra, Chanelle Benjamin, Jonathan Fine, Jerry L. Nadler, Raghavendra G. Mirmira, Abass M. Conteh, Sarah A. Tersey, David J. Maloney, Marimar Hernandez-Perez, Jennifer B. Nelson, Kara S. Benninger, Amelia K. Linnemann |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Blood Glucose medicine.medical_specialty Programmed cell death endocrine system diseases Endocrinology Diabetes and Metabolism Thiophenes Biology Naphthalenes medicine.disease_cause Arachidonate 12-Lipoxygenase Proinflammatory cytokine 03 medical and health sciences Mice Mice Inbred NOD Diabetes mellitus Internal medicine Insulin-Secreting Cells Internal Medicine medicine Animals Arachidonate 15-Lipoxygenase Humans Computer Simulation Lipoxygenase Inhibitors Cells Cultured chemistry.chemical_classification Reactive oxygen species geography Type 1 diabetes geography.geographical_feature_category Molecular Structure Isoxazoles medicine.disease Islet Pharmacology and Therapeutics 3. Good health Oxidative Stress 030104 developmental biology Endocrinology Diabetes Mellitus Type 1 chemistry Hydroxyquinolines Female Insulitis Oxidative stress Software Protein Binding |
| Zdroj: | Diabetes |
| ISSN: | 1939-327X 0012-1797 |
| Popis: | Islet β-cell dysfunction and aggressive macrophage activity are early features in the pathogenesis of type 1 diabetes (T1D). 12/15-Lipoxygenase (12/15-LOX) is induced in β-cells and macrophages during T1D and produces proinflammatory lipids and lipid peroxides that exacerbate β-cell dysfunction and macrophage activity. Inhibition of 12/15-LOX provides a potential therapeutic approach to prevent glycemic deterioration in T1D. Two inhibitors recently identified by our groups through screening efforts, ML127 and ML351, have been shown to selectively target 12/15-LOX with high potency. Only ML351 exhibited no apparent toxicity across a range of concentrations in mouse islets, and molecular modeling has suggested reduced promiscuity of ML351 compared with ML127. In mouse islets, incubation with ML351 improved glucose-stimulated insulin secretion in the presence of proinflammatory cytokines and triggered gene expression pathways responsive to oxidative stress and cell death. Consistent with a role for 12/15-LOX in promoting oxidative stress, its chemical inhibition reduced production of reactive oxygen species in both mouse and human islets in vitro. In a streptozotocin-induced model of T1D in mice, ML351 prevented the development of diabetes, with coincident enhancement of nuclear Nrf2 in islet cells, reduced β-cell oxidative stress, and preservation of β-cell mass. In the nonobese diabetic mouse model of T1D, administration of ML351 during the prediabetic phase prevented dysglycemia, reduced β-cell oxidative stress, and increased the proportion of anti-inflammatory macrophages in insulitis. The data provide the first evidence to date that small molecules that target 12/15-LOX can prevent progression of β-cell dysfunction and glycemic deterioration in models of T1D. |
| Databáze: | OpenAIRE |
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