title: Luteolin protects HUVECs from TNF-α-induced oxidative stress and inflammation via its effects on the Nox4/ROS-NF-κB and MAPK pathways.
abstract: OBJECTIVE
  Inflammation and oxidative stress are now recognized to be two important contributing factors to the development of atherosclerosis(AS). NADPH oxidase-4 (Nox4)-derived reactive oxygen species(ROS), NF-κB and MAPK play crucial roles in these processes. Luteolin, a flavone rich in many plants, can interrupt the molecular expression and inhibit the progression of inflammation and oxidative stress. The present study was designed to test whether luteolin inhibits TNF-α-induced inflammation and oxidative stress in human umbilical vein endothelial cells(HUVECs) and identify some of the mechanisms underlying these effects.
  
  
  METHODS
  HUVECs were treated with luteolin in the presence/absence of TNF-α. The mechanism of luteolin against TNF-α-induced cell injury was evaluated using Western blotting, real-time RT-PCR and flow cytometry analyses.
  
  
  RESULTS
  Luteolin suppressed the TNF-α-activated ROS generation, as well as the Nox4, p22phox, and ICAM-1 and VCAM-1 expression. Luteolin also enhanced the Bcl-2 and reduced caspase-3, -9 expression in the TNF-α-treated HUVECs. Finally, luteolin inhibited the TNF-α-induced transcriptional activity of NF-κB and p38 in addition to ERK1/2 phosphorylation. The inhibitors and siRNA of Nox4 and NF-κB not only reduced ROS generation, p38, ERK1/2 phosphorylation and the ICAM-1 and VCAM-1 expression, but also enhanced Bcl-2 expression. The inhibitor of p38 had the same effect on the expression of ICAM-1, VCAM-1 and Bcl-2, while the inhibitor of ERK1/2 increased the Bcl-2 expression rather than reducing the ICAM-1 and VCAM-1 expression.
  
  
  CONCLUSIONS
  Luteolin attenuates TNF-α-induced oxidative stress and inflammation via its effects on the Nox4/ROS-NF-κB and MAPK pathways. These results suggest that luteolin may provide a beneficial effect in treating vascular diseases associated with oxidative stress and inflammation.
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University.
authors.forename: Fan
authors.initials: F
authors.lastname: Xia
authors.forename: Changyuan
authors.initials: C
authors.lastname: Wang
authors.forename: Yue
authors.initials: Y
authors.lastname: Jin
authors.forename: Qi
authors.initials: Q
authors.lastname: Liu
authors.forename: Qiang
authors.initials: Q
authors.lastname: Meng
authors.forename: Kexin
authors.initials: K
authors.lastname: Liu
authors.forename: Huijun
authors.initials: H
authors.lastname: Sun
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects*; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D047311:Luteolin / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D047311:Luteolin