Prevention of arterial thrombosis by nobiletin: In vitro and in vivo studies

Wan-Jung Lu, Kao Chang Lin, Chun Ping Liu, Chia Ying Lin, Hsh Chu Wu, Duen Suey Chou, Pitchairaj Geraldine, Shih Yi Huang, Cheng Ying Hsieh, Joen Rong Sheu

研究成果: 雜誌貢獻文章

15 引文 (Scopus)

摘要

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.
原文英語
頁(從 - 到)1-8
頁數8
期刊Journal of Nutritional Biochemistry
28
DOIs
出版狀態已發佈 - 二月 1 2016

指紋

Platelets
Thrombosis
Platelet Aggregation
Platelet Activation
Blood Platelets
Chemical activation
Agglomeration
flavone
Hydroxyl Radical
Cardiovascular Diseases
Collagen
Phorbol 12,13-Dibutyrate
Inflammation
nobiletin
In Vitro Techniques
Citrus fruits
Phospholipases
Citrus
Guanylate Cyclase
Mitogen-Activated Protein Kinases

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Molecular Biology
  • Endocrinology, Diabetes and Metabolism
  • Nutrition and Dietetics

引用此文

Prevention of arterial thrombosis by nobiletin : In vitro and in vivo studies. / Lu, Wan-Jung; Lin, Kao Chang; Liu, Chun Ping; Lin, Chia Ying; Wu, Hsh Chu; Chou, Duen Suey; Geraldine, Pitchairaj; Huang, Shih Yi; Hsieh, Cheng Ying; Sheu, Joen Rong.

於: Journal of Nutritional Biochemistry, 卷 28, 01.02.2016, p. 1-8.

研究成果: 雜誌貢獻文章

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title = "Prevention of arterial thrombosis by nobiletin: In vitro and in vivo studies",
abstract = "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.",
keywords = "Akt, Arterial thrombosis, Citrus fruits, Hydroxyl radical, Nobiletin",
author = "Wan-Jung Lu and Lin, {Kao Chang} and Liu, {Chun Ping} and Lin, {Chia Ying} and Wu, {Hsh Chu} and Chou, {Duen Suey} and Pitchairaj Geraldine and Huang, {Shih Yi} and Hsieh, {Cheng Ying} and Sheu, {Joen Rong}",
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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

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.

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KW - Hydroxyl radical

KW - Nobiletin

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