The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Koji Nakanishi - One of the best experts on this subject based on the ideXlab platform.
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Identification of Ginkgolide targets in brain by photoaffinity-labeling
Chemical Biology & Drug Design, 2016Co-Authors: Akira Kawamura, Doina M. Mihai, Francesca Bartolini, Milica Tesic Mark, Ilyas Washington, Gregg G. Gundersen, Koji NakanishiAbstract:Ginkgolides are terpene trilactones in Ginkgo biloba, a popular medicinal herb for memory disorders. Although Ginkgolides are known for various neurobiological effects, their macromolecular target in brain is unknown. In this work, we employed benzophenone derivatives of Ginkgolides to identify their binding target in brain. Photolabeling of bovine hippocampus homogenates identified a series of α-tubulin isotypes. Selective photolabeling of α-tubulin over β-tubulin, which is equally abundant in brain, suggested that Ginkgolides might modulate microtubule biology differently than typical microtubule-binding agents, such as taxol. In fact, Ginkgolide A did not affect microtubule polymerization or cell proliferation; instead, it inhibited detyrosination of α-tubulin and reorientation of microtubule-organizing centers. Taken together, the current findings indicate that Ginkgolides constitute a new class of microtubule-binding agents with distinct effects on α-tubulin biology.
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blood brain barrier permeability of Ginkgolide comparison of the behavior of pet probes 7α 18f fluoro and 10 o p 11c methylbenzyl Ginkgolide b in monkey and rat brains
Bioorganic & Medicinal Chemistry, 2016Co-Authors: Hisashi Doi, Hideo Shindou, Satoshi Ishii, Kengo Sato, Kengo Sumi, Hiroko Koyama, Takamitsu Hosoya, Yasuyoshi Watanabe, Hideo Tsukada, Koji NakanishiAbstract:Abstract The blood–brain barrier permeability of Ginkgolide B was examined using positron emission tomography (PET) probes of a 18 F-incorporated Ginkgolide B ([ 18 F]- 2 ) and a 11 C-incorporated methylbenzyl-substituted Ginkgolide B ([ 11 C]- 3 ). PET studies in monkeys showed low uptake of [ 18 F]- 2 into the brain, but small amounts of [ 11 C]- 3 were accumulated in the parenchyma. Furthermore, when cyclosporine A was preadministered to rats, the accumulation of [ 18 F]- 2 in the rat brain did not significantly change, however, the accumulation of [ 11 C]- 3 was five times higher than that in the control rat. These results provide effective approaches for investigating the drug potential of Ginkgolides.
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protection against β amyloid induced abnormal synaptic function and cell death by Ginkgolide j
Neurobiology of Aging, 2009Co-Authors: Ottavio V Vitolo, Koji Nakanishi, Stanislav Jaracz, Sergei V Dzyuba, Hideki Ishii, Bing Gong, Zixuan Cao, Ottavio Arancio, Roger Lefort, Michael L ShelanskiAbstract:A new Ginkgo biloba extract P8A (TTL), 70% enriched with terpene trilactones, prevents A beta(1-42) induced inhibition of long-term potentiation in the CA1 region of mouse hippocampal slices. This neuroprotective effect is attributed in large part to Ginkgolide J that completely replicates the effect of the extract. Ginkgolide J is also capable of inhibiting cell death of rodent hippocampal neurons caused by A beta(1-42). This beneficial and multi-faceted mode of action of the Ginkgolide makes it a new and promising lead in designing therapies against Alzheimer's disease.
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probing the pharmacophore of Ginkgolides as glycine receptor antagonists
Journal of Medicinal Chemistry, 2007Co-Authors: Anders A Jensen, Koji Nakanishi, Stine B Vogensen, Nasreen Begum, Kolja M Knapp, Klaus Gundertofte, Sergei V Dzyuba, Hideki Ishii, Uffe Kristiansen, Kristian StromgaardAbstract:Ginkgolides are antagonists of the inhibitory ligand-gated ion channels for the neurotransmitters glycine and gamma-aminobutyric acid (GABA). In this study the Ginkgolide structure was modified in order to investigate the minimum structural requirements for glycine receptor antagonism. The five native Ginkgolides and a series of 29 Ginkgolide derivatives were characterized at the three glycine receptor subtypes alpha1, alpha1beta, and alpha2, which revealed that only minor changes in the Ginkgolide skeleton were allowed for maintaining glycine receptor antagonism. A pharmacophore model was generated and applied in a virtual screening of a compound database (300000 compounds), resulting in the identification of 31 hits. Twenty-seven of these hits were screened for biological activity, but none displayed antagonist activity at the glycine receptors. This strongly suggests the importance of other pharmacophore components in the binding of Ginkgolides to glycine receptors, and we propose that the structural rigidity of the Ginkgolide molecule may be crucial for its glycine receptor activity.
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a concise synthesis of Ginkgolide m a minor component of a terpene trilactone fraction from ginkgo biloba roots
Journal of Natural Products, 2006Co-Authors: Sergei Bolshakov, Sergei V Dzyuba, John Decatur, Koji NakanishiAbstract:Ginkgolide M (GM), which is found only in the roots of the Ginkgo biloba tree and is an inhibitor of ligand-operated ion channels in the central nervous system, has been prepared in three steps from 10-benzylGinkgolide C, an intermediate generated during the isolation and separation of Ginkgolides from Ginkgo biloba leaf extract. The described synthetic sequence can be applied to access GM derivatives for biological studies.
Cynthia L Darlington - One of the best experts on this subject based on the ideXlab platform.
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Ginkgolide b accelerates vestibular compensation of spontaneous ocular nystagmus in guinea pig following unilateral labyrinthectomy
Experimental Neurology, 1995Co-Authors: Karyn Maclennan, Paul F. Smith, Cynthia L DarlingtonAbstract:Abstract The aim of this study was to investigate the effects of Ginkgolide B on the behavioral recovery process (vestibular compensation) which occurs following surgical removal of the vestibular receptor cells in one labyrinth (unilateral labyrinthectomy, UL). Guinea pigs received a single ip injection of Ginkgolide B at the time of the UL (25, 50, or 100 mg/kg) and the effects on the compensation of the UL symptoms, spontaneous ocular nystagmus (SN), yaw head tilt (YHT), and roll head tilt (RHT), were evaluated. The effects of a single vehicle injection or a similar injection of Ginkgolide A were used for comparison. Twenty-five mg/kg Ginkgolide B significantly increased the rate of SN compensation compared to the vehicle control group (P
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Ginkgolide b accelerates vestibular compensation of spontaneous ocular nystagmus in guinea pig following unilateral labyrinthectomy
Experimental Neurology, 1995Co-Authors: Karyn Maclennan, Paul F. Smith, Cynthia L DarlingtonAbstract:The aim of this study was to investigate the effects of Ginkgolide B on the behavioral recovery process (vestibular compensation) which occurs following surgical removal of the vestibular receptor cells in one labyrinth (unilateral labyrinthectomy, UL). Guinea pigs received a single ip injection of Ginkgolide B at the time of the UL (25, 50, or 100 mg/kg) and the effects on the compensation of the UL symptoms, spontaneous ocular nystagmus (SN), yaw head tilt (YHT), and roll head tilt (RHT), were evaluated. The effects of a single vehicle injection or a similar injection of Ginkgolide A were used for comparison. Twenty-five mg/kg Ginkgolide B significantly increased the rate of SN compensation compared to the vehicle control group (P < 0.02). However, 50 mg/kg Ginkgolide B had no significant effect on either SN frequency or the rate of SN compensation. Ginkgolide B (100 mg/kg) significantly altered the rate of SN compensation (P < 0.02); however, SN frequency values were higher at most measurement times. YHT and RHT were not significantly affected by Ginkgolide B at any of the doses used. Twenty-five mg/kg Ginkgolide A had no significant effect on any of the UL symptoms. These results suggest that, at the optimal dose of 25 mg/kg, a single ip injection of Ginkgolide B at the time of the UL can produce an acceleration of SN compensation.
Beidong Chen - One of the best experts on this subject based on the ideXlab platform.
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Ginkgolide b inhibits jam a cx43 and ve cadherin expression and reduces monocyte transmigration in oxidized ldl stimulated human umbilical vein endothelial cells
Oxidative Medicine and Cellular Longevity, 2015Co-Authors: Yanyang Zhao, Beidong Chen, Wei Wu, Ruomei QiAbstract:Aim. To investigate the effect of Ginkgolide B on junction proteins and the reduction of monocyte migration in oxidized low-density lipoprotein- (ox-LDL-) treated endothelial cells. Methods. Human umbilical vein endothelial cells (HUVECs) were used in the present study. Immunofluorescence and Western blot were performed to determine the expression of junctional adhesion molecule-A (JAM-A), connexin 43 (Cx43), and vascular endothelial cadherin (VE-cadherin). Monocyte migration was detected by the Transwell assay. Results. ox-LDL stimulation increased JAM-A expression by 35%, Cx43 expression by 24%, and VE-cadherin expression by 37% in HUVECs. Ginkgolide B (0.2, 0.4, and 0.6 mg/mL) dose-dependently abolished the expression of these junction proteins. The monocyte transmigration experiments showed that the level of monocyte migration was sixfold higher in the ox-LDL-treated group than in the control group. Ginkgolide B (0.6 mg/mL) nearly completely abolished monocyte migration. Both Ginkgolide B and LY294002 suppressed Akt phosphorylation and the expression of these junction proteins in ox-LDL-treated endothelial cells. These results suggest that the Ginkgolide B-induced inhibition of junction protein expression is associated with blockade of the PI3K/Akt pathway. Conclusion. Ginkgolide B suppressed junction protein expression and reduced monocyte transmigration that was induced by ox-LDL. Ginkgolide B may improve vascular permeability in atherosclerosis.
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Ginkgolide b reduces lox 1 expression by inhibiting akt phosphorylation and increasing sirt1 expression in oxidized ldl stimulated human umbilical vein endothelial cells
PLOS ONE, 2013Co-Authors: Xueqing Liu, Yanyang Zhao, Beidong ChenAbstract:Oxidized low-density lipoprotein (ox-LDL) is an important risk factor in the development of atherosclerosis. LOX-1, a lectin-like receptor for ox-LDL, is present primarily on endothelial cells and upregulated by ox-LDL, tumor necrosis factor a, shear stress, and cytokines in atherosclerosis. Recent studies demonstrated that Ginkgolide B, a platelet-activating factor receptor antagonist, has antiinflammatory and antioxidant effects on endothelial and nerve cells. The present study investigated the effects of Ginkgolide B on LOX-1 expression and the possible mechanism of action. Our results showed that Ginkgolide B inhibited LOX-1 and intercellular cell adhesion molecule-1 (ICAM-1) expression in ox-LDL-stimulated endothelial cells through a mechanism associated with the attenuation of Akt activation. Similar data were obtained by silencing Akt and LY294002. We also evaluated Sirt1 and nuclear factor erythroid 2-related factor 2 (Nrf2) expression. These molecules play a protective role in endothelial cell injury. The results showed that Ginkgolide B increased Sirt1 expression in ox-LDL-treated cells. The inhibitory effects of Ginkgolide B on LOX-1 and ICAM-1 expression were reduced in Sirt1 siRNA-transfected cells. Nrf2 expression was increased in ox-LDL-treated cells, and Ginkgolide B downregulated Nrf2 expression. These results suggest that Ginkgolide B reduces Nrf2 expression by inhibiting LOX-1 expression, consequently reducing oxidative stress injury in ox-LDL-stimulated cells. Altogether, these results indicate that the protective effect of Ginkgolide B on endothelial cells may be attributable to a decrease in LOX-1 expression and an increase in Sirt1 expression in ox-LDL-stimulated endothelial cells, the mechanism of which is linked to the inhibition of Akt activation. Ginkgolide B may be a multiple-target drug that exerts protective effects in ox-LDL-treated human umbilical vein endothelial cells.
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Ginkgolide b reduces inflammatory protein expression in oxidized low density lipoprotein stimulated human vascular endothelial cells
Journal of Cardiovascular Pharmacology, 2011Co-Authors: Shan Zhang, Beidong Chen, Li BaoAbstract:Ginkgolide B is a herbal constituent extracted from leaves of the ginkgo biloba tree. Previous studies have shown that Ginkgolide B is a specific platelet activating factor (PAF) receptor antagonist, and it suppresses PAF-mediated platelet activation via competitive binding. In this study, the effect of Ginkgolide B on nicotinamide adenine dinucleotide phosphate oxidase and other inflammatory proteins in ox-LDL (low-density lipoprotein)-stimulated human vascular endothelial cells was investigated. Another PAF receptor antagonist CV3988 was employed to compare with Ginkgolide B in this study. Our results show that the enhancement of Nox4 expression and reactive oxygen species generation was attenuated by Ginkgolide B in cells treated with ox-LDL but not with CV3988. Increases in monocyte chemoattractant protein-1 and intercellular adhesion molecule 1 expression induced by ox-LDL, however, were inhibited by both Ginkgolide B and CV3988. The translocation of NF-kappaB p65 (NF-κB) into the nucleus was inhibited by both Ginkgolide B and CV3988. In conclusion, both Ginkgolide B and CV3988 can inhibit the expression of inflammatory proteins by blocking NF-κB translocation. It seems that Ginkgolide B possesses some pharmacological action on intracellular oxidative stress in association with the downregulation of Nox4 expression.
Karyn Maclennan - One of the best experts on this subject based on the ideXlab platform.
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Ginkgolide b accelerates vestibular compensation of spontaneous ocular nystagmus in guinea pig following unilateral labyrinthectomy
Experimental Neurology, 1995Co-Authors: Karyn Maclennan, Paul F. Smith, Cynthia L DarlingtonAbstract:Abstract The aim of this study was to investigate the effects of Ginkgolide B on the behavioral recovery process (vestibular compensation) which occurs following surgical removal of the vestibular receptor cells in one labyrinth (unilateral labyrinthectomy, UL). Guinea pigs received a single ip injection of Ginkgolide B at the time of the UL (25, 50, or 100 mg/kg) and the effects on the compensation of the UL symptoms, spontaneous ocular nystagmus (SN), yaw head tilt (YHT), and roll head tilt (RHT), were evaluated. The effects of a single vehicle injection or a similar injection of Ginkgolide A were used for comparison. Twenty-five mg/kg Ginkgolide B significantly increased the rate of SN compensation compared to the vehicle control group (P
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Ginkgolide b accelerates vestibular compensation of spontaneous ocular nystagmus in guinea pig following unilateral labyrinthectomy
Experimental Neurology, 1995Co-Authors: Karyn Maclennan, Paul F. Smith, Cynthia L DarlingtonAbstract:The aim of this study was to investigate the effects of Ginkgolide B on the behavioral recovery process (vestibular compensation) which occurs following surgical removal of the vestibular receptor cells in one labyrinth (unilateral labyrinthectomy, UL). Guinea pigs received a single ip injection of Ginkgolide B at the time of the UL (25, 50, or 100 mg/kg) and the effects on the compensation of the UL symptoms, spontaneous ocular nystagmus (SN), yaw head tilt (YHT), and roll head tilt (RHT), were evaluated. The effects of a single vehicle injection or a similar injection of Ginkgolide A were used for comparison. Twenty-five mg/kg Ginkgolide B significantly increased the rate of SN compensation compared to the vehicle control group (P < 0.02). However, 50 mg/kg Ginkgolide B had no significant effect on either SN frequency or the rate of SN compensation. Ginkgolide B (100 mg/kg) significantly altered the rate of SN compensation (P < 0.02); however, SN frequency values were higher at most measurement times. YHT and RHT were not significantly affected by Ginkgolide B at any of the doses used. Twenty-five mg/kg Ginkgolide A had no significant effect on any of the UL symptoms. These results suggest that, at the optimal dose of 25 mg/kg, a single ip injection of Ginkgolide B at the time of the UL can produce an acceleration of SN compensation.
Yanyang Zhao - One of the best experts on this subject based on the ideXlab platform.
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Ginkgolide b inhibits jam a cx43 and ve cadherin expression and reduces monocyte transmigration in oxidized ldl stimulated human umbilical vein endothelial cells
Oxidative Medicine and Cellular Longevity, 2015Co-Authors: Yanyang Zhao, Beidong Chen, Wei Wu, Ruomei QiAbstract:Aim. To investigate the effect of Ginkgolide B on junction proteins and the reduction of monocyte migration in oxidized low-density lipoprotein- (ox-LDL-) treated endothelial cells. Methods. Human umbilical vein endothelial cells (HUVECs) were used in the present study. Immunofluorescence and Western blot were performed to determine the expression of junctional adhesion molecule-A (JAM-A), connexin 43 (Cx43), and vascular endothelial cadherin (VE-cadherin). Monocyte migration was detected by the Transwell assay. Results. ox-LDL stimulation increased JAM-A expression by 35%, Cx43 expression by 24%, and VE-cadherin expression by 37% in HUVECs. Ginkgolide B (0.2, 0.4, and 0.6 mg/mL) dose-dependently abolished the expression of these junction proteins. The monocyte transmigration experiments showed that the level of monocyte migration was sixfold higher in the ox-LDL-treated group than in the control group. Ginkgolide B (0.6 mg/mL) nearly completely abolished monocyte migration. Both Ginkgolide B and LY294002 suppressed Akt phosphorylation and the expression of these junction proteins in ox-LDL-treated endothelial cells. These results suggest that the Ginkgolide B-induced inhibition of junction protein expression is associated with blockade of the PI3K/Akt pathway. Conclusion. Ginkgolide B suppressed junction protein expression and reduced monocyte transmigration that was induced by ox-LDL. Ginkgolide B may improve vascular permeability in atherosclerosis.
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Ginkgolide b reduces lox 1 expression by inhibiting akt phosphorylation and increasing sirt1 expression in oxidized ldl stimulated human umbilical vein endothelial cells
PLOS ONE, 2013Co-Authors: Xueqing Liu, Yanyang Zhao, Beidong ChenAbstract:Oxidized low-density lipoprotein (ox-LDL) is an important risk factor in the development of atherosclerosis. LOX-1, a lectin-like receptor for ox-LDL, is present primarily on endothelial cells and upregulated by ox-LDL, tumor necrosis factor a, shear stress, and cytokines in atherosclerosis. Recent studies demonstrated that Ginkgolide B, a platelet-activating factor receptor antagonist, has antiinflammatory and antioxidant effects on endothelial and nerve cells. The present study investigated the effects of Ginkgolide B on LOX-1 expression and the possible mechanism of action. Our results showed that Ginkgolide B inhibited LOX-1 and intercellular cell adhesion molecule-1 (ICAM-1) expression in ox-LDL-stimulated endothelial cells through a mechanism associated with the attenuation of Akt activation. Similar data were obtained by silencing Akt and LY294002. We also evaluated Sirt1 and nuclear factor erythroid 2-related factor 2 (Nrf2) expression. These molecules play a protective role in endothelial cell injury. The results showed that Ginkgolide B increased Sirt1 expression in ox-LDL-treated cells. The inhibitory effects of Ginkgolide B on LOX-1 and ICAM-1 expression were reduced in Sirt1 siRNA-transfected cells. Nrf2 expression was increased in ox-LDL-treated cells, and Ginkgolide B downregulated Nrf2 expression. These results suggest that Ginkgolide B reduces Nrf2 expression by inhibiting LOX-1 expression, consequently reducing oxidative stress injury in ox-LDL-stimulated cells. Altogether, these results indicate that the protective effect of Ginkgolide B on endothelial cells may be attributable to a decrease in LOX-1 expression and an increase in Sirt1 expression in ox-LDL-stimulated endothelial cells, the mechanism of which is linked to the inhibition of Akt activation. Ginkgolide B may be a multiple-target drug that exerts protective effects in ox-LDL-treated human umbilical vein endothelial cells.