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Yan Wang - One of the best experts on this subject based on the ideXlab platform.
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Doxorubicin cardiomyopathy is ameliorated by Acacetin via Sirt1-mediated activation of AMPK/Nrf2 signal molecules.
Journal of Cellular and Molecular Medicine, 2020Co-Authors: Yukai Cui, Yixiang Hong, Yan WangAbstract:Doxorubicin cardiotoxicity is frequently reported in patients undergoing chemotherapy. The present study investigates whether cardiomyopathy induced by doxorubicin can be improved by the natural flavone Acacetin in a mouse model and uncovers the potential molecular mechanism using cultured rat cardiomyoblasts. It was found that the cardiac dysfunction and myocardial fibrosis induced by doxorubicin were significantly improved by Acacetin in mice with impaired Nrf2/HO-1 and Sirt1/pAMPK molecules, which is reversed by Acacetin treatment. Doxorubicin decreased cell viability and increased ROS production in rat cardiomyoblasts; these effects are significantly countered by Acacetin (0.3-3 μM) in a concentration-dependent manner via activating Sirt1/pAMPK signals and enhancing antioxidation (Nrf2/HO-1 and SOD1/SOD2) and anti-apoptosis. These protective effects were abolished in cells with silencing Sirt1. The results demonstrate for the first time that doxorubicin cardiotoxicity is antagonized by Acacetin via Sirt1-mediated activation of AMPK/Nrf2 signal molecules, indicating that Acacetin may be a drug candidate used clinically for protecting against doxorubicin cardiomyopathy.
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doxorubicin cardiomyopathy is ameliorated by Acacetin via sirt1 mediated activation of ampk nrf2 signal molecules
Journal of Cellular and Molecular Medicine, 2020Co-Authors: Yukai Cui, Yixiang Hong, Yan WangAbstract:Doxorubicin cardiotoxicity is frequently reported in patients undergoing chemotherapy. The present study investigates whether cardiomyopathy induced by doxorubicin can be improved by the natural flavone Acacetin in a mouse model and uncovers the potential molecular mechanism using cultured rat cardiomyoblasts. It was found that the cardiac dysfunction and myocardial fibrosis induced by doxorubicin were significantly improved by Acacetin in mice with impaired Nrf2/HO-1 and Sirt1/pAMPK molecules, which is reversed by Acacetin treatment. Doxorubicin decreased cell viability and increased ROS production in rat cardiomyoblasts; these effects are significantly countered by Acacetin (0.3-3 μM) in a concentration-dependent manner via activating Sirt1/pAMPK signals and enhancing antioxidation (Nrf2/HO-1 and SOD1/SOD2) and anti-apoptosis. These protective effects were abolished in cells with silencing Sirt1. The results demonstrate for the first time that doxorubicin cardiotoxicity is antagonized by Acacetin via Sirt1-mediated activation of AMPK/Nrf2 signal molecules, indicating that Acacetin may be a drug candidate used clinically for protecting against doxorubicin cardiomyopathy.
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Atherosclerosis is attenuated by Acacetin via Sirt1-mediated activation of AMPK/Sirt3 signals in diabetic ApoE-/- mice
2020Co-Authors: Wei-min Han, Xu-chang Chen, Yan WangAbstract:Abstract BackgroundThe strategy of decreasing atherosclerotic cardiovascular disorder is imperative to reduce premature death and improve quality of life in patients with diabetes mellitus. The present study was designed to investigate whether the natural flavone Acacetin could improve diabetes- accelerated atherosclerotic lesions.MethodsDiabetic model was established in 7-week-old ApoE−/− mice by intraperitoneal injection of STZ (daily 50 mg/kg) for 5 days. Animals of control, control with Acacetin treatment, STZ-diabetes, STZ-diabetes with Acacetin treatment received Acacetin prodrug subcutaneously (20 mg/kg, b.i.d.) or equivolume saline for 12 weeks, and the elasticity of carotid artery and the ability of vascular wall movement were determined with ultrasound and magnetic resonance imaging. Human umbilical vein endothelial cells (HUVECs) were cultured with medium containing 5.5 mM or 33 mM glucose and treated with Acacetin or vehicle. Changes of related aortic lesions and signaling molecules were determined by biochemical and molecular approaches in animals and cultured HUVECs.ResultsIt was found that Acacetin significantly suppressed atherosclerotic lesions and neointima hyperplasia, improved the elasticity of carotid artery and the ability of vascular wall movement without reducing blood glucose level and reversed the impaired signaling molecules (i.e. SOD, Bcl2, PGC-1α, pAMPK, Sirt3 and Sirt1) in artery tissues in diabetic mice. In cultured HUVECs, high glucose-induced cell viability reduction, ROS over-production, decrease of anti-oxidation, increase of apoptosis, and impairment of mitochondrial function were countered by Acacetin (0.3-3 µM) in a concentration-dependent manner. Moreover, Acacetin relies on Sirt1 activation by increasing NAMPT and NAD+ followed by Sirt3, pAMPK and PGC-1α activation. Silencing Sirt1 abolished Acacetin-induced activation of Sirt3, pAMPK, and PGC-1α.ConclusionsThese results indicate that Sirt1-mediated activation of pAMPK/Sirt3 signals is involved in protective effects of Acacetin against atherosclerosis in diabetes by preserving mitochondrial function via reducing mitochondrial apoptosis and ROS production and enhancing its biogenesis, which suggests that Acacetin may be a drug candidate for reducing atherosclerotic cardiovascular disorder in patients with diabetes.
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The Natural Flavone Acacetin Confers Cardiomyocyte Protection Against Hypoxia/Reoxygenation Injury via AMPK-Mediated Activation of Nrf2 Signaling Pathway.
Frontiers in Pharmacology, 2018Co-Authors: Yukai Cui, Yixiang Hong, Ling-jun Jie, Yan WangAbstract:The present study investigates the potential signal pathway of Acacetin in cardioprotection against ischemia/reperfusion injury using an in vitro hypoxia/reoxygenation model in primary cultured neonatal rat cardiomyocytes and H9C2 cardiomyoblasts. It was found that Acacetin (0.3-3 μM) significantly decreased the apoptosis and reactive oxygen species production induced by hypoxia/reoxygenation injury in cardiomyocytes and H9C2 cardiomyoblasts via reducing the pro-apoptotic proteins Bax and cleaved-caspase-3 and increasing the anti-apoptotic protein Bcl-2. In addition, Acacetin not only suppressed the release of pro-inflammatory cytokines TLR-4 and IL-6 induced by hypoxia/reoxygenation injury, but also increased the secretion of anti-inflammatory cytokine IL-10. Moreover, Acacetin increased Nrf2 and HO-1 in a concentration-dependent manner, and rescued SOD1 and SOD2 reduction induced by hypoxia/reoxygenation insult. These beneficial effects of Acacetin disappeared in cells with silenced Nrf2, suggesting that Nrf2 activation participates in the cardioprotective effect of Acacetin against hypoxia/reoxygenation insult. However, Acacetin-induced Nrf2 activation was not observed in cells with silenced AMPK and in ventricular tissues of rat hearts treated with the AMPK inhibitor Compound C and subjected to ischemia/reperfusion injury. Our results demonstrate for the first time that AMPK-mediated Nrf2 activation is involved in the cardiomyocytes protection of Acacetin against hypoxia/reoxygenation injury by activating a series of intracellular signals involved in anti-oxidation, anti-inflammation, and anti-apoptosis.
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the natural flavone Acacetin confers cardiomyocyte protection against hypoxia reoxygenation injury via ampk mediated activation of nrf2 signaling pathway
Frontiers in Pharmacology, 2018Co-Authors: Yukai Cui, Yixiang Hong, Ling-jun Jie, Yan WangAbstract:The present study investigates the potential signal pathway of Acacetin in cardioprotection against ischemia/reperfusion injury using an in vitro hypoxia/reoxygenation model in primary cultured neonatal rat cardiomyocytes and H9C2 cardiomyoblasts. It was found that Acacetin (0.3-3 μM) significantly decreased the apoptosis and reactive oxygen species production induced by hypoxia/reoxygenation injury in cardiomyocytes and H9C2 cardiomyoblasts via reducing the pro-apoptotic proteins Bax and cleaved-caspase-3 and increasing the anti-apoptotic protein Bcl-2. In addition, Acacetin not only suppressed the release of pro-inflammatory cytokines TLR-4 and IL-6 induced by hypoxia/reoxygenation injury, but also increased the secretion of anti-inflammatory cytokine IL-10. Moreover, Acacetin increased Nrf2 and HO-1 in a concentration-dependent manner, and rescued SOD1 and SOD2 reduction induced by hypoxia/reoxygenation insult. These beneficial effects of Acacetin disappeared in cells with silenced Nrf2, suggesting that Nrf2 activation participates in the cardioprotective effect of Acacetin against hypoxia/reoxygenation insult. However, Acacetin-induced Nrf2 activation was not observed in cells with silenced AMPK and in ventricular tissues of rat hearts treated with the AMPK inhibitor Compound C and subjected to ischemia/reperfusion injury. Our results demonstrate for the first time that AMPK-mediated Nrf2 activation is involved in the cardiomyocytes protection of Acacetin against hypoxia/reoxygenation injury by activating a series of intracellular signals involved in anti-oxidation, anti-inflammation, and anti-apoptosis.
Hui Liu - One of the best experts on this subject based on the ideXlab platform.
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The Natural Flavone Acacetin Blocks Small Conductance Ca2+-Activated K+ Channels Stably Expressed in HEK 293 Cells.
Frontiers in Pharmacology, 2017Co-Authors: Kui-hao Chen, Hui Liu, Man-wen Jin, Guo-sheng Xiao, Hai-ying Sun, Yan WangAbstract:The natural flavone Acacetin inhibits several voltage-gated potassium currents in atrial myocytes, and has anti-atrial fibrillation effect in experimental atrial fibrillation models. The present study investigates whether Acacetin inhibits the Ca2+-activated potassium (KCa) currents, including small conductance (SKCa1, SKCa2, and SKCa3), intermediate conductance (IKCa), and large-conductance (BKCa) channels stably expressed in HEK 293 cells. The effects of Acacetin on these KCa channels were determined with a whole-cell patch voltage-clamp technique. It was found that Acacetin inhibited the three subtype SKCa channel currents in concentration-dependent manner with IC50 of 12.4 μM for SKCa1, 10.8 μM for SKCa2 and 11.6 μM for SKCa3. Site-directed mutagenesis of SKCa3 channels generated the mutants H490N, S512T, H521N, and A537V. Acacetin inhibited the mutants with IC50 of 118.5 μM for H490N, 275.2 μM for S512T, 15.3 μM for H521N, and 10.6 μM for A537V, suggesting that Acacetin interacts with the P-loop helix of SKCa3 channel. However, Acacetin at 3-10 μM did not decrease, but induced a slight increase of BKCa (+70 mV) by 8% at 30 μM. These results demonstrate the novel information that Acacetin remarkably inhibits SKCa channels, but not IKCa or BKCa channels, which suggests that blockade of SKCa by Acacetin likely contributes to its anti-atrial fibrillation property previously observed in experimental atrial fibrillation.
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The Natural Flavone Acacetin Blocks Small Conductance Ca2+-Activated K+ Channels Stably Expressed in HEK 293 Cells
Frontiers Media S.A., 2017Co-Authors: Hui Liu, Man-wen Jin, Guo-sheng Xiao, Hai-ying Sun, Kui-hao Chen, Yan WangAbstract:The natural flavone Acacetin inhibits several voltage-gated potassium currents in atrial myocytes, and has anti-atrial fibrillation (AF) effect in experimental AF models. The present study investigates whether Acacetin inhibits the Ca2+-activated potassium (KCa) currents, including small conductance (SKCa1, SKCa2, and SKCa3), intermediate conductance (IKCa), and large-conductance (BKCa) channels stably expressed in HEK 293 cells. The effects of Acacetin on these KCa channels were determined with a whole-cell patch voltage-clamp technique. The results showed that Acacetin inhibited the three subtype SKCa channel currents in concentration-dependent manner with IC50 of 12.4 μM for SKCa1, 10.8 μM for SKCa2, and 11.6 μM for SKCa3. Site-directed mutagenesis of SKCa3 channels generated the mutants H490N, S512T, H521N, and A537V. Acacetin inhibited the mutants with IC50 of 118.5 μM for H490N, 275.2 μM for S512T, 15.3 μM for H521N, and 10.6 μM for A537V, suggesting that Acacetin interacts with the P-loop helix of SKCa3 channel. However, Acacetin at 3–10 μM did not decrease, but induced a slight increase of BKCa (+70 mV) by 8% at 30 μM. These results demonstrate the novel information that Acacetin remarkably inhibits SKCa channels, but not IKCa or BKCa channels, which suggests that blockade of SKCa by Acacetin likely contributes to its anti-AF property previously observed in experimental AF
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Water-soluble Acacetin prodrug confers significant cardioprotection against ischemia/reperfusion injury.
Scientific Reports, 2016Co-Authors: Hui Liu, Lei Yang, Guo-sheng Xiao, Hai-ying Sun, Kui-hao Chen, Feng Lin, Yan WangAbstract:The morbidity and mortality of patients with ischemic cardiomyopathy resulted from ischemia/reperfusion injury are very high. The present study investigates whether our previously synthesized water-soluble phosphate prodrug of Acacetin was cardioprotective against ischemia/reperfusion injury in an in vivo rat model. We found that intravenous administration of Acacetin prodrug (10 mg/kg) decreased the ventricular arrhythmia score and duration, reduced ventricular fibrillation and infarct size, and improved the impaired heart function induced by myocardial ischemia/reperfusion injury in anesthetized rats. The cardioprotective effects were further confirmed with the parent compound Acacetin in an ex vivo rat regional ischemia/reperfusion heart model. Molecular mechanism analysis revealed that Acacetin prevented the ischemia/reperfusion-induced reduction of the anti-oxidative proteins SOD-2 and thioredoxin, suppressed the release of inflammation cytokines TLR4, IL-6 and TNFα, and decreased myocyte apoptosis induced by ischemia/reperfusion. Our results demonstrate the novel evidence that Acacetin prodrug confer significant in vivo cardioprotective effect against ischemia/reperfusion injury by preventing the reduction of endogenous anti-oxidants and the release of inflammatory cytokines, thereby inhibiting cardiomyocytes apoptosis, which suggests that the water-soluble Acacetin prodrug is likely useful in the future as a new drug candidate for treating patients with acute coronary syndrome.
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water soluble Acacetin prodrug confers significant cardioprotection against ischemia reperfusion injury
Scientific Reports, 2016Co-Authors: Hui Liu, Lei Yang, Guo-sheng Xiao, Hai-ying Sun, Kui-hao Chen, Feng Lin, Yan WangAbstract:The morbidity and mortality of patients with ischemic cardiomyopathy resulted from ischemia/reperfusion injury are very high. The present study investigates whether our previously synthesized water-soluble phosphate prodrug of Acacetin was cardioprotective against ischemia/reperfusion injury in an in vivo rat model. We found that intravenous administration of Acacetin prodrug (10 mg/kg) decreased the ventricular arrhythmia score and duration, reduced ventricular fibrillation and infarct size, and improved the impaired heart function induced by myocardial ischemia/reperfusion injury in anesthetized rats. The cardioprotective effects were further confirmed with the parent compound Acacetin in an ex vivo rat regional ischemia/reperfusion heart model. Molecular mechanism analysis revealed that Acacetin prevented the ischemia/reperfusion-induced reduction of the anti-oxidative proteins SOD-2 and thioredoxin, suppressed the release of inflammation cytokines TLR4, IL-6 and TNFα, and decreased myocyte apoptosis induced by ischemia/reperfusion. Our results demonstrate the novel evidence that Acacetin prodrug confer significant in vivo cardioprotective effect against ischemia/reperfusion injury by preventing the reduction of endogenous anti-oxidants and the release of inflammatory cytokines, thereby inhibiting cardiomyocytes apoptosis, which suggests that the water-soluble Acacetin prodrug is likely useful in the future as a new drug candidate for treating patients with acute coronary syndrome.
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Synthesis of a highly water-soluble Acacetin prodrug for treating experimental atrial fibrillation in beagle dogs.
Scientific Reports, 2016Co-Authors: Hui Liu, Ya-jing Wang, Lei Yang, Mei Zhou, Man-wen Jin, Guo-sheng Xiao, Yan Wang, Hai-ying SunAbstract:We previously reported that duodenal administration of the natural flavone Acacetin can effectively prevent the induction of experimental atrial fibrillation (AF) in canines; however, it may not be used intravenously to terminate AF due to its poor water-solubility. The present study was to design a water-soluble prodrug of Acacetin and investigate its anti-AF effect in beagle dogs. Acacetin prodrug was synthesized by a three-step procedure. Aqueous solubility, bioconversion and anti-AF efficacy of Acacetin prodrug were determined with different methodologies. Our results demonstrated that the synthesized phosphate sodium salt of Acacetin prodrug had a remarkable increase of aqueous solubility in H2O and clinically acceptable solution (5% glucose or 0.9% NaCl). The Acacetin prodrug was effectively converted into Acacetin in ex vivo rat plasma and liver microsome, and in vivo beagle dogs. Intravenous infusion of Acacetin prodrug (3, 6 and 12 mg/kg) terminated experimental AF without increasing ECG QTc interval in beagle dogs. The intravenous LD50 of Acacetin prodrug was 721 mg/kg in mice. Our preclinical study indicates that the synthesized Acacetin prodrug is highly water-soluble and safe; it effectively terminates experimental AF in beagle dogs and therefore may be a promising drug candidate for clinical trial to treat patients with acute AF.
Jian Jin - One of the best experts on this subject based on the ideXlab platform.
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determination of Acacetin in rat plasma by uplc ms ms and its application to a pharmacokinetic study
Journal of Chromatography B, 2015Co-Authors: Lihua Fan, Deyuan Chen, Ning Zhang, Yiyan Wang, Yuanyuan Shan, Jian JinAbstract:A rapid, sensitive and selective ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was developed and validated for the determination and pharmacokinetic investigation of Acacetin in rat plasma. Sample preparation was accomplished through a simple one-step deproteinization procedure with 0.2 mL of acetonitrile to a 0.1 mL plasma sample. Plasma samples were separated by UPLC on an Acquity UPLC BEH C18 column using a mobile phase consisting of acetonitrile-0.1% formic acid in water with gradient elution. The total run time was 2.0 min and the elution of Acacetin was at 0.83 min. The detection was performed on a triple quadrupole tandem mass spectrometer equipped with positive-ion electrospray ionization (ESI) by multiple reaction monitoring (MRM) of the transitions at m/z 285.3→242.2 for Acacetin and m/z 237.2→194.3 for carbamazepine (internal standard). The calibration curve was linear over the range of 1-1600 ng/mL with a lower limit of quantitation (LLOQ) of 1.0 ng/mL. Mean recovery of Acacetin in plasma was in the range of 78.4-85.2%. Intra-day and inter-day precision were both <10.5%. This method was successfully applied in pharmacokinetic study after intravenous administration of 5.0mg/kg Acacetin in rats.
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Determination of Acacetin in rat plasma by UPLC-MS/MS and its application to a pharmacokinetic study
Journal of Chromatography B, 2015Co-Authors: Lihua Fan, Deyuan Chen, Ning Zhang, Yiyan Wang, Yuanyuan Shan, Jian JinAbstract:A rapid, sensitive and selective ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was developed and validated for the determination and pharmacokinetic investigation of Acacetin in rat plasma. Sample preparation was accomplished through a simple one-step deproteinization procedure with 0.2 mL of acetonitrile to a 0.1 mL plasma sample. Plasma samples were separated by UPLC on an Acquity UPLC BEH C18 column using a mobile phase consisting of acetonitrile-0.1% formic acid in water with gradient elution. The total run time was 2.0 min and the elution of Acacetin was at 0.83 min. The detection was performed on a triple quadrupole tandem mass spectrometer equipped with positive-ion electrospray ionization (ESI) by multiple reaction monitoring (MRM) of the transitions at m/z 285.3→242.2 for Acacetin and m/z 237.2→194.3 for carbamazepine (internal standard). The calibration curve was linear over the range of 1-1600 ng/mL with a lower limit of quantitation (LLOQ) of 1.0 ng/mL. Mean recovery of Acacetin in plasma was in the range of 78.4-85.2%. Intra-day and inter-day precision were both
Lei Yang - One of the best experts on this subject based on the ideXlab platform.
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water soluble Acacetin prodrug confers significant cardioprotection against ischemia reperfusion injury
Scientific Reports, 2016Co-Authors: Hui Liu, Lei Yang, Guo-sheng Xiao, Hai-ying Sun, Kui-hao Chen, Feng Lin, Yan WangAbstract:The morbidity and mortality of patients with ischemic cardiomyopathy resulted from ischemia/reperfusion injury are very high. The present study investigates whether our previously synthesized water-soluble phosphate prodrug of Acacetin was cardioprotective against ischemia/reperfusion injury in an in vivo rat model. We found that intravenous administration of Acacetin prodrug (10 mg/kg) decreased the ventricular arrhythmia score and duration, reduced ventricular fibrillation and infarct size, and improved the impaired heart function induced by myocardial ischemia/reperfusion injury in anesthetized rats. The cardioprotective effects were further confirmed with the parent compound Acacetin in an ex vivo rat regional ischemia/reperfusion heart model. Molecular mechanism analysis revealed that Acacetin prevented the ischemia/reperfusion-induced reduction of the anti-oxidative proteins SOD-2 and thioredoxin, suppressed the release of inflammation cytokines TLR4, IL-6 and TNFα, and decreased myocyte apoptosis induced by ischemia/reperfusion. Our results demonstrate the novel evidence that Acacetin prodrug confer significant in vivo cardioprotective effect against ischemia/reperfusion injury by preventing the reduction of endogenous anti-oxidants and the release of inflammatory cytokines, thereby inhibiting cardiomyocytes apoptosis, which suggests that the water-soluble Acacetin prodrug is likely useful in the future as a new drug candidate for treating patients with acute coronary syndrome.
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Water-soluble Acacetin prodrug confers significant cardioprotection against ischemia/reperfusion injury.
Scientific Reports, 2016Co-Authors: Hui Liu, Lei Yang, Guo-sheng Xiao, Hai-ying Sun, Kui-hao Chen, Feng Lin, Yan WangAbstract:The morbidity and mortality of patients with ischemic cardiomyopathy resulted from ischemia/reperfusion injury are very high. The present study investigates whether our previously synthesized water-soluble phosphate prodrug of Acacetin was cardioprotective against ischemia/reperfusion injury in an in vivo rat model. We found that intravenous administration of Acacetin prodrug (10 mg/kg) decreased the ventricular arrhythmia score and duration, reduced ventricular fibrillation and infarct size, and improved the impaired heart function induced by myocardial ischemia/reperfusion injury in anesthetized rats. The cardioprotective effects were further confirmed with the parent compound Acacetin in an ex vivo rat regional ischemia/reperfusion heart model. Molecular mechanism analysis revealed that Acacetin prevented the ischemia/reperfusion-induced reduction of the anti-oxidative proteins SOD-2 and thioredoxin, suppressed the release of inflammation cytokines TLR4, IL-6 and TNFα, and decreased myocyte apoptosis induced by ischemia/reperfusion. Our results demonstrate the novel evidence that Acacetin prodrug confer significant in vivo cardioprotective effect against ischemia/reperfusion injury by preventing the reduction of endogenous anti-oxidants and the release of inflammatory cytokines, thereby inhibiting cardiomyocytes apoptosis, which suggests that the water-soluble Acacetin prodrug is likely useful in the future as a new drug candidate for treating patients with acute coronary syndrome.
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Synthesis of a highly water-soluble Acacetin prodrug for treating experimental atrial fibrillation in beagle dogs.
Scientific Reports, 2016Co-Authors: Hui Liu, Ya-jing Wang, Lei Yang, Mei Zhou, Man-wen Jin, Guo-sheng Xiao, Yan Wang, Hai-ying SunAbstract:We previously reported that duodenal administration of the natural flavone Acacetin can effectively prevent the induction of experimental atrial fibrillation (AF) in canines; however, it may not be used intravenously to terminate AF due to its poor water-solubility. The present study was to design a water-soluble prodrug of Acacetin and investigate its anti-AF effect in beagle dogs. Acacetin prodrug was synthesized by a three-step procedure. Aqueous solubility, bioconversion and anti-AF efficacy of Acacetin prodrug were determined with different methodologies. Our results demonstrated that the synthesized phosphate sodium salt of Acacetin prodrug had a remarkable increase of aqueous solubility in H2O and clinically acceptable solution (5% glucose or 0.9% NaCl). The Acacetin prodrug was effectively converted into Acacetin in ex vivo rat plasma and liver microsome, and in vivo beagle dogs. Intravenous infusion of Acacetin prodrug (3, 6 and 12 mg/kg) terminated experimental AF without increasing ECG QTc interval in beagle dogs. The intravenous LD50 of Acacetin prodrug was 721 mg/kg in mice. Our preclinical study indicates that the synthesized Acacetin prodrug is highly water-soluble and safe; it effectively terminates experimental AF in beagle dogs and therefore may be a promising drug candidate for clinical trial to treat patients with acute AF.
Bing-hua Jiang - One of the best experts on this subject based on the ideXlab platform.
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Acacetin inhibits vegf expression tumor angiogenesis and growth through akt hif 1α pathway
Biochemical and Biophysical Research Communications, 2011Co-Authors: Ling-zhi Liu, Yi Jing, Lisa L. Jiang, Xiu-e. Jiang, Yue Jiang, Yongyut Rojanasakul, Bing-hua JiangAbstract:Acacetin (5,7-dihydroxy-4′-methoxyflavone) is a flavone compound, some of which have anti-cancerous effects. Vascular endothelial growth factor (VEGF) plays an important role in angiogenesis and tumor growth. In this study, we found that Acacetin decreased the steady level of VEGF mRNA level and inhibited VEGF transcriptional activation. To further determine the potential mechanism of Acacetin in inhibiting VEGF expression, we showed that Acacetin inhibited HIF-1α expression and AKT activation. Over-expression of HIF-1α or AKT restored Acacetin-decreasing VEGF transcriptional activation, indicating that AKT and HIF-1 are the essential downstream targets of Acacetin for inhibiting VEGF expression in the cells. Moreover, Acacetin significantly inhibited ovarian cancer cell-induced angiogenesis and tumor growth in vivo through inhibiting HIF-1α and VEGF expression. Acacetin did not change HIF-1α mRNA level, but inhibited HIF-1α protein level through increasing its degradation and decreasing its stability. These results indicate that Acacetin may be a useful natural compound for ovarian cancer prevention and treatment.
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Acacetin inhibits VEGF expression, tumor angiogenesis and growth through AKT/HIF-1α pathway.
Biochemical and Biophysical Research Communications, 2011Co-Authors: Ling-zhi Liu, Yi Jing, Lisa L. Jiang, Xiu-e. Jiang, Yue Jiang, Yongyut Rojanasakul, Bing-hua JiangAbstract:Acacetin (5,7-dihydroxy-4′-methoxyflavone) is a flavone compound, some of which have anti-cancerous effects. Vascular endothelial growth factor (VEGF) plays an important role in angiogenesis and tumor growth. In this study, we found that Acacetin decreased the steady level of VEGF mRNA level and inhibited VEGF transcriptional activation. To further determine the potential mechanism of Acacetin in inhibiting VEGF expression, we showed that Acacetin inhibited HIF-1α expression and AKT activation. Over-expression of HIF-1α or AKT restored Acacetin-decreasing VEGF transcriptional activation, indicating that AKT and HIF-1 are the essential downstream targets of Acacetin for inhibiting VEGF expression in the cells. Moreover, Acacetin significantly inhibited ovarian cancer cell-induced angiogenesis and tumor growth in vivo through inhibiting HIF-1α and VEGF expression. Acacetin did not change HIF-1α mRNA level, but inhibited HIF-1α protein level through increasing its degradation and decreasing its stability. These results indicate that Acacetin may be a useful natural compound for ovarian cancer prevention and treatment.
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Abstract A51: Acacetin in inhibiting tumor growth and angiogenesis
Chemoprevention and Biological Therapies, 2010Co-Authors: Bing-hua Jiang, Ling-zhi Liu, Yi Jing, Lisa Jiang, Xiu-e. JiangAbstract:Background: Acacetin (5,7-dihydroxy-4′-methoxyflavone) is a member of the flavonoid compound familys, some of which have anti-cancerous effects. Angiogenesis is a key process during carcinogenesis and tumor growth; however, but the effect and the mechanisms of Acacetin on angiogenesis and tumor growth remain to be elucidated. Methods: In order to determine the effect of Acacetin on the expression of vascular endothelial growth factor (VEGF) and HIF-1α expression, we tested VEGF expression by reporter assay and HIF-1α expression by Western blotting and RT-PCR assay. To test whether overexpression of active form of AKT increases HIF-1 expression, transient transfection was performed. Tumor angiogenesis and tumor formation in vivo were examined by chicken chorioallantoic membrane (CAM). Results: Acacetin decreased the steady level of VEGF mRNA under the normoxia and hypoxia conditions while inhibiting, and inhibited VEGF transcriptional activation. To further determine the potential mechanism of Acacetin in inhibiting VEGF expression, we showed demonstrated that Acacetin inhibited HIF-1α expression and AKT activation. Overexpression of HIF-1α or AKT abolished Acacetin-decreasing VEGF transcriptional activation, indicating that AKT and HIF-1 are the essential downstream targets of Acacetin for inhibiting VEGF expression in the cells. Moreover, Acacetin significantly inhibited ovarian cancer cells-induced angiogenesis and tumor growth in vivo through inhibiting HIF-1α and VEGF expression. Acacetin inhibited HIF-1α protein expression through increasing its degradation and decreasing its stability, but did not alter HIF-1α mRNA levels. Conclusion: These results indicate that Acacetin inhibits tumor agnigenensis and growth by blocking the AKT/HIF-1/VEGF pathway. It may be a useful natural compound for cancer prevention and treatment. Citation Information: Cancer Prev Res 2010;3(12 Suppl):A51.
