title: Isolation of Phorbol Esters from Euphorbia grandicornis and Evaluation of Protein Kinase C- and Human Platelet-Activating Effects of Euphorbiaceae Diterpenes.
abstract: Human platelets contain conventional (α and β) and novel isoforms of PKC (δ and θ), and PKC activation can result in platelet aggregation and secretion reaction that are important for thrombus formation. Several tumor-promoting Euphorbiaceae diterpenes are known to act as direct activators of PKC, but many types of such diterpenes have not been studied as platelet stimulators. In the present study, two new and five known phorbol esters were isolated from Euphorbia grandicornis. Two of the isolated phorbol esters together with compounds representing ingenane, jatrophane, and myrsinane structural types were studied on PKC activation and platelet stimulation. The investigated phorbol esters and ingenane esters induced blood platelet aggregation and ATP secretion. PKC activation was demonstrated by inducing membrane translocation of PKCs, phosphorylation of PKC substrates, and activation of PKC signaling pathways. The PKC-activating effect of the compounds correlated well with their efficacy to cause platelet stimulation. Moreover, by using an isoform-specific PKC inhibitor, it was found that besides conventional PKCs novel PKCs also play a positive role in platelet activation caused by phorbol/ingenane esters, especially in regulating platelet aggregation. The present results suggest that platelets afford a useful model for studying PKC activators of natural origin or their chemical derivatives.
authors.affiliation: Graduate Institute of Natural Products and ‡Research Center for Natural Products and Drug Development, Kaohsiung Medical University , Kaohsiung 807, Taiwan.|Department of Pharmacognosy and ⊥Interdisciplinary Centre for Natural Products, University of Szeged , Eötvös u. 6, H-6720 Szeged, Hungary.
authors.forename: Ju-Ying
authors.initials: JY
authors.lastname: Tsai
authors.affiliation: Graduate Institute of Natural Products and ‡Research Center for Natural Products and Drug Development, Kaohsiung Medical University , Kaohsiung 807, Taiwan.|Department of Pharmacognosy and ⊥Interdisciplinary Centre for Natural Products, University of Szeged , Eötvös u. 6, H-6720 Szeged, Hungary.
authors.forename: Dóra
authors.initials: D
authors.lastname: Rédei
authors.affiliation: Graduate Institute of Natural Products and ‡Research Center for Natural Products and Drug Development, Kaohsiung Medical University , Kaohsiung 807, Taiwan.|Department of Pharmacognosy and ⊥Interdisciplinary Centre for Natural Products, University of Szeged , Eötvös u. 6, H-6720 Szeged, Hungary.
authors.forename: Peter
authors.initials: P
authors.lastname: Forgo
authors.affiliation: Graduate Institute of Natural Products and ‡Research Center for Natural Products and Drug Development, Kaohsiung Medical University , Kaohsiung 807, Taiwan.|Department of Pharmacognosy and ⊥Interdisciplinary Centre for Natural Products, University of Szeged , Eötvös u. 6, H-6720 Szeged, Hungary.
authors.forename: Yu
authors.initials: Y
authors.lastname: Li
authors.affiliation: Graduate Institute of Natural Products and ‡Research Center for Natural Products and Drug Development, Kaohsiung Medical University , Kaohsiung 807, Taiwan.|Department of Pharmacognosy and ⊥Interdisciplinary Centre for Natural Products, University of Szeged , Eötvös u. 6, H-6720 Szeged, Hungary.
authors.forename: Andrea
authors.initials: A
authors.lastname: Vasas
authors.affiliation: Graduate Institute of Natural Products and ‡Research Center for Natural Products and Drug Development, Kaohsiung Medical University , Kaohsiung 807, Taiwan.|Department of Pharmacognosy and ⊥Interdisciplinary Centre for Natural Products, University of Szeged , Eötvös u. 6, H-6720 Szeged, Hungary.
authors.forename: Judit
authors.initials: J
authors.lastname: Hohmann
authors.affiliation: Graduate Institute of Natural Products and ‡Research Center for Natural Products and Drug Development, Kaohsiung Medical University , Kaohsiung 807, Taiwan.|Department of Pharmacognosy and ⊥Interdisciplinary Centre for Natural Products, University of Szeged , Eötvös u. 6, H-6720 Szeged, Hungary.
authors.forename: Chin-Chung
authors.initials: CC
authors.lastname: Wu
mesh_terms: D001792:Blood Platelets / Q000187:drug effects*; D004224:Diterpenes / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D028481:Euphorbia / Q000737:chemistry*; D006801:Humans; D006814:Hungary; D015394:Molecular Structure; D010766:Phosphorylation; D035261:Plant Components, Aerial / Q000737:chemistry; D010974:Platelet Aggregation / Q000187:drug effects; D020033:Protein Isoforms; D011493:Protein Kinase C / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D004224:Diterpenes; D020033:Protein Isoforms; C530110:ingenane; C530345:jatrophane; D011493:Protein Kinase C