3-nitrotyrosine and glabridin

In females, hyperglycemia abolishes estrogen-vascular protection, leading to inflammation and oxidative stress that are related to diabetes-associated cardiovascular complications. Such knowledge led us to examine the potential of glabridin, as a replacement of estrogen anti-inflammatory activity under high-glucose conditions.. In macrophage-like cells, chronic glucose stress (28 and 44 mM) upregulated inducible nitric oxide synthase (iNOS) mRNA expression by 42 and 189%, respectively. Pretreatment with glabridin, under chronic glucose stress, downregulated the LPS-induced nitric oxide secretion and nitrotyrosine formation, by 39 and 21%, respectively. Pretreatment with estradiol did not prevent the LPS-induced nitrotyrosine formation. Furthermore, glabridin, brought about a decrease in the LPS-induced iNOS mRNA expression by 48%, as compared to cells pretreated with estradiol. Glabridin decreased protein levels of liver iNOS by 69% in adult mouse offspring which developed hyperglycemia after early fetal exposure to a saturated fatty acid-enriched maternal diet. Glabridin also decreased liver nitrotyrosine levels in offspring of regular diet-fed mothers after further receiving high-fat diet.. Such results indicate that glabridin retains anti-inflammatory abilities to regulate the synthesis and activity of iNOS under high-glucose levels, implying that a glabridin supplement may serve as an anti-inflammatory agent in diabetes-related vascular dysfunction.

Topics: Animals; Anti-Inflammatory Agents; Blood Glucose; Diet, High-Fat; Disease Models, Animal; Down-Regulation; Female; Glycyrrhiza; Hyperglycemia; Inflammation; Isoflavones; Lipopolysaccharides; Liver; Macrophages; Mice; Mice, Inbred C57BL; Nitric Oxide; Nitric Oxide Synthase Type II; Oxidative Stress; Phenols; Plant Roots; RNA, Messenger; Stress, Physiological; Tumor Necrosis Factor-alpha; Tyrosine; Up-Regulation

Mitochondrial dysfunction, particularly respiratory chain disruption, is often responsible for aging-related bone diseases. In this study, the protective effects of glabridin, an isoflavan isolated from licorice root, against pharmacological inhibition of the respiratory chain were studied using osteoblastic MC3T3-E1 cells treated with antimycin A, which inhibits complex III of the electron transport system. Glabridin restored mitochondrial membrane potential dissipation, ATP loss, inactivation of complex IV, intracellular calcium elevation, and cytochrome c release that was induced by antimycin A treatment. This compound also prevented cell death. These results imply that glabridin protects osteoblasts from antimycin A-induced cell death via improved mitochondrial function. Glabridin scavenged ROS and mitochondrial superoxide anions generated by antimycin A. In addition, glabridin prevented antimycin A-induced nitrotyrosine increase and thioredoxin reductase inactivation, suggesting that glabridin may be useful for protecting mitochondria against a burst of oxidative stress. Since phosphoinositide 3-kinase (PI3K) and cAMP-response element-binding protein (CREB) signaling is known to be pro-survival, we determined whether PI3K and CREB activation is associated with the cytoprotective effects of glabridin in the MC3T3-E1 cells. Glabridin restored antimycin A-induced inactivation of PI3K and CREB, suggesting that PI3K and CREB-dependent pathways may be involved in glabridin-induced cytoprotective responses. Our study demonstrates that glabridin reduces mitochondrial dysfunction induced during aging, and could significantly prevent osteoblast damage in osteoporotic patients.

Topics: Animals; Antimycin A; Calcium; Cell Line; CREB-Binding Protein; Cytochromes c; Isoflavones; Mice; Osteoblasts; Oxidative Stress; Phenols; Phosphatidylinositol 3-Kinases; Phosphorylation; Reactive Oxygen Species; Thioredoxin-Disulfide Reductase; Tyrosine