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ABSTRACT: The mechanisms by which the hexane extract of C. comosa increases femoral blood flow (FBF) in ovariectomised rats are not known. This study, therefore, investigated the acute effects and modes of action of a diarylhaptanoid (D3: (3R)-1,7-diphenyl-(4E,6E)-4,6-heptadien-3-ol), a phyto-oestrogen isolated from C. comosa, on FBF in ovariectomised rats. On day 7 after ovariectomy, three groups of rats were intra-arterially injected with D3 (100, 200, 400, and 800 μg/kg body weight (BW)), 17-β-oestradiol (E2) (1, 2, 4, and 8 μg/kg BW) or vehicle. Mean arterial blood pressure (mABP) and FBF were recorded using a pressure transducer and a Laser Doppler Flow meter, respectively. D3 and E2 dose dependently increased FBF without any alterations in mABP and heart rate. The EC(50) at 120 min for D3 and E2 were 195.8 μg/kg BW and 1.8 μg/kg BW, respectively. Both D3 and E2 also dose-dependently decreased femoral vascular resistance (FVR). The EC(50) of D3 was about 100-fold greater than that of E2. The effects of D3 and E2 on FBF and FVR were diminished after intravenous injection of N(G) -nitro-L-arginine methyl ester (L-NAME) (10 mg/kg BW). Pretreatment with L-NAME (10 mg/kg BW), 1 H-[1,2,4] oxadiazolo-[4,3-a] quinoxalin-1-one (ODQ) (900 μg/kg BW) or ICI 128,780 (900 μg/kg BW) for 30 minutes prevented the effects of D3 and E2 on FBF and FVR. The results suggest that a phyto-oestrogen, D3, increases FBF in ovariectomised rats via oestrogen receptor and NO-guanylyl cyclase signaling, which, in turn, relaxes the femoral vascular resistance. © 2013 The Authors Clinical and Experimental Pharmacology and Physiology © 2013 Wiley Publishing Asia Pty Ltd.
Clinical and Experimental Pharmacology and Physiology 01/2013; · 1.85 Impact Factor
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ABSTRACT: Estrogen promotes growth in many tissues by activating Wnt/β-catenin signaling. Recently, ASPP 049, a diarylheptanoid isolated from Curcuma comosa Roxb., has been identified as a phytoestrogen. This investigation determined the involvement of Wnt/β-catenin signaling in the estrogenic activity of this diarylheptanoid in transfected HEK 293T and in mouse preosteoblastic (MC3T3-E1) cells using a TOPflash luciferase assay and immunofluorescence. ASPP 049 rapidly activated T-cell-specific transcription factor/lymphoid enhancer binding factor-mediated transcription activity and induced β-catenin accumulation in the nucleus. Interestingly, the effects of ASPP 049 on the transcriptional activity and induction and accumulation of β-catenin protein in the nucleus of MC3T3-E1 cells were greater compared with estradiol. Activation of β-catenin in MC3T3-E1 cells was inhibited by ICI 182,780, suggesting that an estrogen receptor is required. In addition, ASPP 049 induced phosphorylations at serine 473 of Akt and serine 9 of GSK-3β. Moreover, ASPP 049 also induced proliferation and expressions of Wnt target genes Axin2 and Runx2 in MC3T3-E1 cells. In addition, ASPP 049 increased alkaline phosphatase expression, and activity that was abolished by DKK-1, a blocker of the Wnt/β-catenin receptor. Taken together, these results suggest that ASPP 049 from C. comosa induced osteoblastic cell proliferation and differentiation through ERα-, Akt-, and GSK-3β-dependent activation of β-catenin signaling. Our findings provide a scientific rationale for using C. comosa as a dietary supplement to prevent bone loss in postmenopausal women.
Journal of Biological Chemistry 08/2012; 287(43):36168-78. · 4.77 Impact Factor
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ABSTRACT: Topoisomerase II α enzyme plays a critical role in DNA replication process. It controls the topologic states of DNA during transcription and is essential for cell proliferation. Human DNA topoisomerase II α (hTopo II α) is a promising chemotherapeutic target for anticancer agents against a variety of cancer types. In the present study, andrographolide and its structurally modified analogues were investigated for their inhibitory activities on hTopo II α enzyme. Five out of nine andrographolide analogues potently reduced hTopo II α activity and inhibited cell proliferation in four mammalian cell lines (Hela, CHO, BCA-1 and HepG2 cells). IC(50) values for cytotoxicity of analogues 3A.1, 3A.2, 3A.3, 1B and 2C were 4 to 7 μM. Structure-activity relationship studies revealed that both core structure of andrographolide and silicon based molecule of functional group were important for the inhibition of hTopo II α activity whereas position C-19 of analogues was required for anti-proliferation. In addition, the analogue 2C at 10 μM concentration inhibited hTopo II α, and induced apoptosis with nuclear fragmentation and formation of apoptotic bodies in HepG2 cells. The analogue 2C may, therefore, have a therapeutic potential as effective anticancer agent targeting the hTopo II α functions.
Investigational New Drugs 08/2012; · 3.36 Impact Factor
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ABSTRACT: Diarylheptanoids, isolated from the rhizome of Curcuma comosa Roxb., have several biological activities including anti-oxidant and anti-inflammation. The present study investigated the effect of five diarylheptanoids isolated from C. comosa rhizome on the proliferation of murine P388 leukemic cells. Compound-092, (3S)-1-(3,4-dihydroxyphenyl)-7-phenyl-(6E)-6-hepten-3-ol, bearing a catechol moiety, was the most potent diarylheptanoid (IC(50) of 4 μM) in inhibiting P388 leukemic cell viability by causing DNA breakage and inducing apoptosis. Apoptotic cell death was characterized by the presence of chromatin condensation, formation of apoptotic bodies, DNA fragmentation, and externalization of plasma membrane phosphatidylserine. This compound increased caspase-3 activity about fivefold above the untreated control, decreased the intracellular reduced glutathione level, and impaired mitochondrial transmembrane potential. In the presence of Cu(II) ion, the compound exhibited a pro-oxidant activity causing DNA strand breakage and enhancing the anti-proliferative activity. The results provide evidence for the pro-oxidant activity of the diarylheptanoid bearing a catechol moiety in the induction of apoptosis in murine P388 leukemia.
Cell Biology and Toxicology 07/2011; 27(6):413-23. · 2.51 Impact Factor
