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Hui-Jun Wu,
Wei Wu,
Hai-Ying Sun,
Guo-Wei Qin, Hong-Bing Wang,
Panwen Wang,
Hari Krishna Yalamanchili,
Junwen Wang,
Hung-Fat Tse,
Chu-Pak Lau,
Paul M. Vanhoutte,
Gui-Rong Li
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ABSTRACT: We have demonstrated that the natural flavone acacetin selectively inhibits ultra-rapid delayed rectifier potassium current (IKur) in human atria. However, molecular determinants of this ion channel blocker are unknown. The present study was designed to investigate the molecular determinants underlying the ability of acacetin to block hKv1.5 channels (coding IKur) in human atrial myocytes using the whole-cell patch voltage-clamp technique to record membrane current in HEK 293 cells stably expressing the hKv1.5 gene or transiently expressing mutant hKv1.5 genes generated by site-directed mutagenesis. It was found that acacetin blocked hKv1.5 channels by binding to both closed and open channels. The blockade of hKv1.5 channels by acacetin was use- and frequency-dependent, and the IC50 of acacetin for inhibiting hKv1.5 was 3.5, 3.1, 2.9, 2.1, and 1.7 μM, respectively, at 0.2, 0.5, 1, 3, and 4 Hz. The mutagenesis study showed that the hKv1.5 mutants V505A, I508A, and V512A in the S6-segment remarkably reduced the channel blocking properties by acacetin (IC50, 29.5 μM for V505A, 19.1 μM for I508A, and 6.9 μM for V512A). These results demonstrate the novel information that acacetin mainly blocks open hKv1.5 channels by binding to their S6 domain. The use- and rate-dependent blocking of hKv1.5 by acacetin is beneficial for anti-atrial fibrillation.Highlights► We investigate the molecular determinants of acacetin in blocking hKv1.5 channels. ► Acacetin blocks hKv1.5 channels in a use- and frequency-dependent manner. ► The natural flavone acacetin inhibits hKv1.5 channels by binding to the S6-domain.
Journal of Molecular and Cellular Cardiology 08/2011; 51(6):966-973. · 5.17 Impact Factor
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ABSTRACT: Six tigliane-type diterpenoids (1-6) were isolated from the roots of Euphorbia fischeriana. Their structures were elucidated by various spectral analyses. Among them, compounds 1 and 3 were new, and compounds 2, 4, and 5 were naturally obtained for the first time. All compounds were tested against two human cancer cell lines, MDA-MB-231 and HepG2, and one human immortalized cell line, and only compound 6 showed cytotoxicity for MDA-MB-231 cells with an IC(50) value of 6.694 μM.
Journal of Asian natural products research 12/2010; 12(12):1038-43. · 0.61 Impact Factor
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ABSTRACT: One new guaiane-type sesquiterpene (1) was isolated from Saussurea laniceps. The structure of the new compound was elucidated by spectroscopic data analysis. The immunomodulatory activity of compound 1 was evaluated. It was found that compound 1 showed significant inhibition for proliferation of murine T cells in vitro.
Fitoterapia 10/2010; 81(7):937-9. · 1.85 Impact Factor
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ABSTRACT: Four new "cage-like" monoterpene glucosides (1-4) were isolated from Paeonia lactiflora. The structures of these compounds were established by spectroscopic methods, mainly 1D and 2D NMR, and mass spectrometric analysis. Compound 4 exhibited moderate cell-protective activity against hydrogen peroxide-induced PC12 cell damage.
Journal of Natural Products 05/2009; 72(7):1321-4. · 3.13 Impact Factor
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ABSTRACT: Nuclear factor-kappaB (NF-kappaB) is critically important for tumor cell survival, growth, angiogenesis, and metastasis. One of the key events in the NF-kappaB signaling is the activation of inhibitor of NF-kappaB kinase (IKK) in response to stimuli of various cytokines. We have identified 17-acetoxyjolkinolide B (17-AJB) from a traditional Chinese medicinal herb Euphorbia fischeriana Steud as a novel small-molecule inhibitor of IKK. 17-AJB effectively inhibited tumor necrosis factor-alpha-induced NF-kappaB activation and induced apoptosis of tumor cells. 17-AJB had no effect on binding of tumor necrosis factor-alpha to its receptor or on binding of NF-kappaB to DNA. It inhibited NF-kappaB nuclear translocation. Detailed analysis revealed that the direct target of 17-AJB was IKK. 17-AJB kept IKK in its phosphorylated form irreversibly. This irreversible modification of IKK inactivated its kinase activity, leading to its failure to activate NF-kappaB. The effect of 17-AJB on IKK was specific. It had no effect on other kinases such as p38, p44/42, and JNK. In addition, 17-AJB induced apoptosis in tumor cells. The effects of 17-AJB on apoptosis correlated with inhibition of expression of the NF-kappaB-regulated genes. Taken together, our data suggest that 17-AJB is a novel type NF-kappaB pathway inhibitor. Its unique interaction mechanism with IKK may render it a strong apoptosis inducer of tumor cells and a novel type anticancer drug candidate.
Molecular Cancer Therapeutics 07/2008; 7(6):1523-32. · 5.23 Impact Factor
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Gui-Rong Li, Hong-Bing Wang,
Guo-Wei Qin,
Man-Wen Jin,
Qiang Tang,
Hai-Ying Sun,
Xin-Ling Du,
Xiu-Ling Deng,
Xiao-Hua Zhang,
Jing-Bo Chen,
Lei Chen,
Xiao-Hui Xu,
Lik-Cheung Cheng,
Shui-Wah Chiu,
Hung-Fat Tse,
Paul M Vanhoutte,
Chu-Pak Lau
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ABSTRACT: The development of atrium-selective antiarrhythmic agents is a current strategy for inhibiting atrial fibrillation (AF). The present study investigated whether the natural flavone acacetin from the traditional Chinese medicine Xuelianhua would be an atrium-selective anti-AF agent.
The effects of acacetin on human atrial ultrarapid delayed rectifier K(+) current (I(Kur)) and other cardiac ionic currents were studied with a whole-cell patch technique. Acacetin suppressed I(Kur) and the transient outward K(+) current (IC(50) 3.2 and 9.2 mumol/L, respectively) and prolonged action potential duration in human atrial myocytes. The compound blocked the acetylcholine-activated K(+) current; however, it had no effect on the Na(+) current, L-type Ca(2+) current, or inward-rectifier K(+) current in guinea pig cardiac myocytes. Although acacetin caused a weak reduction in the hERG and hKCNQ1/hKCNE1 channels stably expressed in HEK 293 cells, it did not prolong the corrected QT interval in rabbit hearts. In anesthetized dogs, acacetin (5 mg/kg) prolonged the atrial effective refractory period in both the right and left atria 1 to 4 hours after intraduodenal administration without prolongation of the corrected QT interval, whereas sotalol at 5 mg/kg prolonged both the atrial effective refractory period and the corrected QT interval. Acacetin prevented AF induction at doses of 2.5 mg/kg (50%), 5 mg/kg (85.7%), and 10 mg/kg (85.7%). Sotalol 5 mg/kg also prevented AF induction (60%).
The present study demonstrates that the natural compound acacetin is an atrium-selective agent that prolongs the atrial effective refractory period without prolonging the corrected QT interval and effectively prevents AF in anesthetized dogs after intraduodenal administration. These results indicate that oral acacetin is a promising atrium-selective agent for the treatment of AF.
Circulation 06/2008; 117(19):2449-57. · 14.74 Impact Factor
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ABSTRACT: Two new morphinane alkaloid dimers, 2,2'-disinomenine (1) and 7',8'-dihydro-1,1'-disinomenine (2), and known 1, 1'-disinomenine (3), were isolated from ethanol extracts of stems of Sinomenium acutum. Their structures were elucidated on the basis of spectroscopic methods. The absolute configuration of alkaloids 1-3 was determined by direct comparison of their CD spectra with the known alkaloid sinomenine. The isolated alkaloids were tested for cytotoxicity against A549, P388, and HeLa cell lines, and 1 and 3 showed weak inhibition against A549 and Hela cells.
Journal of Natural Products 02/2008; 71(1):127-9. · 3.13 Impact Factor
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ABSTRACT: One new guaiane-type sesquiterpene glucoside (1) and one new phenolic glucoside (2) were isolated from the whole herb of Saussurea involucrata. Their structures were established by spectroscopic methods, mainly 1D and 2D NMR, and mass spectral analysis.
Journal of Asian Natural Products Research 09/2007; 9(6-8):603-7. · 0.94 Impact Factor
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ABSTRACT: From the dried roots of Euphorbia fischeriana, seven new diterpenoids, 3alpha,17-dihydroxy-ent-pimara-8(14),15-diene (1), 7beta,11beta,12beta-trihydroxy-ent-abieta-8(14),13(15)-dien-16,12-olide (2), 17-acetoxyjolkinolide B (3), 13beta-hydroxy-ent-abiet-8(14)-en-7-one (4), 12-deoxyphorbaldehyde-13-acetate (5) 12-deoxyphorbaldehyde-13-hexadecacetate (6), and 12-deoxyphorbol-13-(9Z)-octadecanoate-20-acetate (7), and two known compounds, 12-deoxyphorbol-13-decanoate (8) and prostratin (9), were isolated. The structures of the new compounds were elucidated on the basis of spectroscopic analysis. The structure of compound 1 was confirmed by single-crystal X-ray crystallography. Compounds 3 and 8 exhibited potent cytotoxic activity to Ramos B cells with IC50 values of 0.023 and 0.0051 microg/mL, respectively.
Journal of Natural Products 07/2006; 69(6):967-70. · 3.13 Impact Factor
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ABSTRACT: Two new guaiane-type sesquiterpenoids (1 and 2) and one new eudesmane-type sesquiterpenoid (3) were isolated from Saussurea laniceps. The structures of these compounds were established by spectroscopic methods, and the absolute stereochemistry of compounds 1 and 2 was determined by Mosher's method. The immunomodulatory activities of compounds 1-3 were evaluated. Of these, compound 3 showed significant inhibition of the proliferation of murine T and B cells in vitro.
Journal of Natural Products 06/2005; 68(5):762-5. · 3.13 Impact Factor
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ABSTRACT: Six new dihydrochalcones, 3-hydroxyasebotin (5), asebogenin 2'-O-beta-D-ribohexo-3-ulopyranoside (6), 2' '-acetylasebotin (7), 3',4,5'-trihydroxy-4'-methoxydihydrochalcone 3',5'-di-O-beta-D-glucopyranoside (8), and pierotins A (9) and B (10), along with four known dihydrochalcones, phloretin (1), phlorizin (2), asebogenin (3), and asebotin (4), were isolated from the leaves of Pieris japonica. Their structures were elucidated on the basis of spectroscopic analysis including HMQC, HMBC, NOESY, and X-ray crystal diffraction. Compounds 1, 3-5, and 7-10 inhibited the proliferation of murine B cells and compounds 5 and 10 inhibited the proliferation of murine T cells in vitro significantly.
Journal of Natural Products 04/2005; 68(3):392-6. · 3.13 Impact Factor
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ABSTRACT: A new minor 1,5-seco-5-oxo-grayanotoxin named grayanotoxin XXI (1), together with three known grayanotoxins, grayanotoxins I, IV and VIII, has been isolated from the leaves of Rhododendron decorum (Ericaceae). The structure of the new compound (1) was determined on the basis of spectroscopic data.
Journal of Asian Natural Products Research 03/2005; 7(1):87-90. · 0.94 Impact Factor
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Article:
Note
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ABSTRACT: A new minor 1,5-seco-5-oxo-grayanotoxin named grayanotoxin XXI ( 1 ), together with three known grayanotoxins, grayanotoxins I, IV and VIII, has been isolated from the leaves of Rhododendron decorum (Ericaceae). The structure of the new compound ( 1 ) was determined on the basis of spectroscopic data.
Journal of Asian Natural Products Research 01/2005; 7(1):87-90. · 0.94 Impact Factor
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ABSTRACT: Two new limonoids, munronolide (1) and munronolide 21-O-beta-D-glucopyranoside (2), were isolated from the whole plant of Munronia henryi (Meliaceae). Their structures have been elucidated on the basis of spectroscopic and chemical methods. The D-glucose moiety attached to C-21 position of limonoid is firstly reported.
Natural Product Research 11/2004; 18(5):415-9. · 1.01 Impact Factor
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ABSTRACT: Three flavone glucosides, pleiosides A-C, were isolated from the leaves of Pleioblastus amarus, along with two known flavones: tricin and tricetin 3,5-dimethoxy-7-O-beta-d-glucopyranoside. Their structures were elucidated by extensive spectral studies. Pleiosides A-C were found to inhibit the proliferation of murine T and significantly stimulate the proliferation of murine B lymphocytes in vitro.
Phytochemistry 05/2004; 65(7):969-74. · 3.35 Impact Factor
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ABSTRACT: A novel polyisoprenyl benzophenone derivative named eugeniaphenone (1) was isolated from the stem bark of Garcinia eugeniaefolia Wall. Its structure was elucidated by spectroscopic methods, including 1D and 2D NMR techniques, and confirmed by single-crystal X-ray diffraction analysis. It is the first example in which an isoprenyl unit formed a cyclobutane-containing side chain in the polyisoprenyl benzophenone derivatives.
Journal of Asian Natural Products Research 10(5-6):509-13. · 0.94 Impact Factor
