title: Piperlonguminine downregulates endothelial protein C receptor shedding in vitro and in vivo.
abstract: Endothelial cell protein C receptor (EPCR) plays an important role in coagulation and inflammation. EPCR can be shed from the cell surface, and this is mediated by tumor necrosis factor-α-converting enzyme (TACE). Piperlonguminine (PL), an important component of Piper longum fruits, is known to exhibit antihyperlipidemic, antiplatelet, and antimelanogenesis activities. However, little is known about the effects of PL on EPCR shedding. Here, we investigated this issue by monitoring the effects of PL on phorbol-12-myristate 13-acetate (PMA) and on cecal ligation and puncture (CLP)-mediated EPCR shedding and underlying mechanisms. PL induced potent inhibition of PMA, and CLP induced EPCR shedding through suppression of TACE expression. And treatment with PL resulted in reduced PMA-stimulated phosphorylation of p38, extracellular regulated kinases (ERK) 1/2, and c-Jun N-terminal kinase (JNK). Given these results, PL might have potential as an anti-sEPCR shedding reagent against PMA- and CLP-mediated EPCR shedding.
authors.affiliation: Department of Anatomy and Histology, College of Oriental Medicine, Daegu Haany University, Gyeongsan, 712-715, Republic of Korea.
authors.forename: Sae-Kwang
authors.initials: SK
authors.lastname: Ku
authors.forename: Jeong Ah
authors.initials: JA
authors.lastname: Kim
authors.forename: Jong-Sup
authors.initials: JS
authors.lastname: Bae
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000072198:ADAM17 Protein; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D015703:Antigens, CD / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D004148:Dioxolanes / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000074283:Endothelial Protein C Receptor; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005638:Fruit; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D008517:Phytotherapy; D031701:Piper; D010936:Plant Extracts / Q000494:pharmacology*; D010946:Plants, Medicinal; D011956:Receptors, Cell Surface / Q000187:drug effects* / Q000378:metabolism; D018805:Sepsis / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D010881:Piperidones
chemical_list: D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000893:Anti-Inflammatory Agents; D015703:Antigens, CD; D004148:Dioxolanes; D000074283:Endothelial Protein C Receptor; D048049:Extracellular Signal-Regulated MAP Kinases; D015850:Interleukin-6; D048031:JNK Mitogen-Activated Protein Kinases; D010936:Plant Extracts; D011956:Receptors, Cell Surface; D013755:Tetradecanoylphorbol Acetate; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; C478370:PROCR protein, human; C080248:Procr protein, mouse; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse; C498077:piperlongumine; D010881:Piperidones