cytochrome-c-t and chicoric-acid

Endothelial dysfunction is a driving force during the development and progression of cardiovascular complications in diabetes. Targeting endothelial injury may be an attractive avenue for the management of diabetic vascular disorders. Chicoric acid is reported to confer antioxidant and anti-inflammatory properties in various diseases including diabetes. However, the role and mechanism of chicoric acid in hyperglycemia-induced endothelial damage are not well understood.. In the present study, human umbilical vein endothelial cells (HUVECs) were incubated with high glucose/high fat (HG + HF) to induce endothelial cell injury.. We found that exposure of HUVECs to HG + HF medium promoted the release of cytochrome c (cytc) from mitochondrion into the cytoplasm, stimulated the cleavage of caspase-3 and poly ADP-ribose-polymerase (PARP), then inducing cell apoptosis, the effects that were prevented by administration of chicoric acid. Besides, we found that chicoric acid diminished HG + HF-induced phosphorylation and degradation of IκBα, and subsequent p65 NFκB nuclear translocation, thereby contributing to its anti-inflammatory effects in HUVECs. We also confirmed that chicoric acid mitigated oxidative/nitrative stresses under HG + HF conditions. Studies aimed at exploring the underlying mechanisms found that chicoric acid activated the AMP-activated protein kinase (AMPK) signaling pathway to attenuate HG + HF-triggered injury in HUVECs as AMPK inhibitor Compound C or silencing of AMPKα1 abolished the beneficial effects of chicoric acid in HUVECs.. Collectively, chicoric acid is likely protected against diabetes-induced endothelial dysfunction by activation of the AMPK signaling pathway. Chicoric acid could be a novel candidate for the treatment of the diabetes-associated vascular endothelial injury.

Topics: AMP-Activated Protein Kinases; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Caffeic Acids; Cell Survival; Cytochromes c; Cytoplasm; Endothelium, Vascular; Glucose; Human Umbilical Vein Endothelial Cells; Humans; Hyperglycemia; Inflammation; L-Lactate Dehydrogenase; Mitochondria; Nitrosative Stress; Oxidative Stress; Poly(ADP-ribose) Polymerases; RNA, Small Interfering; Succinates

Chicoric acid has been reported to possess various bioactivities. However, the antiobesity effects of chicoric acid remain poorly understood. In this study, we investigated the effects of chicoric acid on 3T3-L1 preadipocytes and its molecular mechanisms of apoptosis. Chicoric acid inhibited cell viability and induced apoptosis in 3T3-L1 preadipocytes which was characterized by chromatin condensation and poly ADP-ribose-polymerase (PARP) cleavage. Mitochondrial membrane potential (MMP) loss, Bax/Bcl-2 dysregulation, cytochrome c release, and caspase-3 activation were observed, indicating mitochondria-dependent apoptosis induced by chicoric acid. Furthermore, PI3K/Akt and MAPK (p38 MAPK, JNK, and ERK1/2) signaling pathways were involved in chicoric acid-induced apoptosis. The employment of protein kinase inhibitors LY294002, SB203580, SP600125, and U0126 revealed that PI3K/Akt signaling pathway interplayed with MAPK signaling pathways. Moreover, chicoric acid induced reactive oxygen species (ROS) generation. Pretreatment with the antioxidant N-acetylcysteine (NAC) significantly blocked cell death and changes of Akt and MAPK signalings induced by chicoric acid. In addition, chicoric acid down regulated HO-1 and COX-2 via the PI3K/Akt pathway.

Topics: 3T3-L1 Cells; Acetylcysteine; Adipocytes; Animals; Apoptosis; bcl-2-Associated X Protein; Caffeic Acids; Caspase 3; Cell Survival; Cyclooxygenase 2; Cytochromes c; Down-Regulation; Heme Oxygenase-1; MAP Kinase Signaling System; Membrane Potential, Mitochondrial; Membrane Proteins; Mice; Phosphatidylinositol 3-Kinases; Poly(ADP-ribose) Polymerases; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Succinates