TY - JOUR
T1 - Prevention of arterial thrombosis by nobiletin
T2 - In vitro and in vivo studies
AU - Lu, Wan-Jung
AU - Lin, Kao Chang
AU - Liu, Chun Ping
AU - Lin, Chia Ying
AU - Wu, Hsh Chu
AU - Chou, Duen Suey
AU - Geraldine, Pitchairaj
AU - Huang, Shih Yi
AU - Hsieh, Cheng Ying
AU - Sheu, Joen Rong
N1 - Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2016/2/1
Y1 - 2016/2/1
N2 - Nobiletin, a bioactive polymethoxylated flavone isolated from citrus fruits, has been proven to prevent cancer and inflammation. Dietary flavonoids have been shown to reduce the risk of cardiovascular diseases (CVDs), and platelet activation plays a crucial role in CVDs. This study investigated the effect of nobiletin on platelet activation in vitro and in vivo. Nobiletin (10-30 μM) inhibited collagen- and arachidonic acid-induced platelet aggregation in washed human platelets, but it did not inhibit platelet aggregation induced by other agonists such as thrombin and 9,11-dideoxy-11α,9α-epoxymethanoprostaglandin. Nobiletin inhibited the phosphorylation of phospholipase PLCγ2, protein kinase PKC, Akt and mitogen-activated protein kinase MAPKs in collagen-activated human platelets and markedly reduced intracellular calcium mobilization and hydroxyl radical (OH·) formation. Nobiletin did not affect either phorbol-12,13-dibutyrate-stimulated PKC activation or platelet aggregation. In addition, neither SQ22536, an adenylate cyclase inhibitor nor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, a guanylate cyclase inhibitor, significantly reversed the nobiletin-mediated inhibition of platelet aggregation. Moreover, nobiletin substantially prolonged the closure time in whole blood according to platelet function analysis and increased the occlusion time of thrombotic platelet plug formation in mice. In conclusion, this study demonstrates for the first time that, in addition to being a potential agent for preventing tumor growth and inflammation, nobiletin exhibits potent antiplatelet activity, which initially inhibits the PLCγ2/PKC cascade and hydroxyl radical formation, subsequently suppresses the activation of Akt and MAPKs and ultimately inhibits platelet activation. Our study suggests that nobiletin represents a potential therapeutic agent for preventing or treating thromboembolic disorders.
AB - Nobiletin, a bioactive polymethoxylated flavone isolated from citrus fruits, has been proven to prevent cancer and inflammation. Dietary flavonoids have been shown to reduce the risk of cardiovascular diseases (CVDs), and platelet activation plays a crucial role in CVDs. This study investigated the effect of nobiletin on platelet activation in vitro and in vivo. Nobiletin (10-30 μM) inhibited collagen- and arachidonic acid-induced platelet aggregation in washed human platelets, but it did not inhibit platelet aggregation induced by other agonists such as thrombin and 9,11-dideoxy-11α,9α-epoxymethanoprostaglandin. Nobiletin inhibited the phosphorylation of phospholipase PLCγ2, protein kinase PKC, Akt and mitogen-activated protein kinase MAPKs in collagen-activated human platelets and markedly reduced intracellular calcium mobilization and hydroxyl radical (OH·) formation. Nobiletin did not affect either phorbol-12,13-dibutyrate-stimulated PKC activation or platelet aggregation. In addition, neither SQ22536, an adenylate cyclase inhibitor nor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, a guanylate cyclase inhibitor, significantly reversed the nobiletin-mediated inhibition of platelet aggregation. Moreover, nobiletin substantially prolonged the closure time in whole blood according to platelet function analysis and increased the occlusion time of thrombotic platelet plug formation in mice. In conclusion, this study demonstrates for the first time that, in addition to being a potential agent for preventing tumor growth and inflammation, nobiletin exhibits potent antiplatelet activity, which initially inhibits the PLCγ2/PKC cascade and hydroxyl radical formation, subsequently suppresses the activation of Akt and MAPKs and ultimately inhibits platelet activation. Our study suggests that nobiletin represents a potential therapeutic agent for preventing or treating thromboembolic disorders.
KW - Akt
KW - Arterial thrombosis
KW - Citrus fruits
KW - Hydroxyl radical
KW - Nobiletin
UR - http://www.scopus.com/inward/record.url?scp=84952765703&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84952765703&partnerID=8YFLogxK
U2 - 10.1016/j.jnutbio.2015.09.024
DO - 10.1016/j.jnutbio.2015.09.024
M3 - Article
C2 - 26878777
AN - SCOPUS:84952765703
SN - 0955-2863
VL - 28
SP - 1
EP - 8
JO - Journal of Nutritional Biochemistry
JF - Journal of Nutritional Biochemistry
ER -