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Riyako Terazawa,
Nozomi Akimoto,
Taku Kato,
Tomohiro Itoh,
Yasunori Fujita,
Nanako Hamada,
Takashi Deguchi, Munekazu Iinuma,
Mami Noda,
Yoshinori Nozawa,
Masafumi Ito
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ABSTRACT: Neuroinflammation and oxidative stress are involved in the pathogenesis of neurodegenerative diseases such as Alzheimer's diseases and Parkinson's disease. Naturally derived kavalactones isolated from Piper methysticum (Piperaceae) have been shown to exhibit neuroprotective effects. We have previously reported that a chemically synthesized kavalactone derivative, 2',6'-dichloro-5-methoxymethyl-5,6-dehydrokawain (compound 1) protects against oxidative stress-induced neuronal cell death through activation of Nrf2 signaling. In the present study, we examined the effect of compound 1 on neuroinflammation. In BV2 microglial cells, compound 1 strongly inhibited LPS-stimulated iNOS induction and NO production, but did not affect LPS-stimulated induction of COX2. At 6h after LPS challenge, when iNOS induction was not clearly seen, treatment with LPS or compound 1 alone increased expression of heme oxygenase 1 (HO-1) whose transcription is regulated by Nrf2. When treated with both, compound 1 enhanced LPS-stimulated HO-1 induction, which was more evident at 24h after LPS treatment. Furthermore, LPS-stimulated activation of Nrf2 signaling and nuclear translocation of Nrf2 was potentiated by compound 1. The mechanism by which compound 1 activated Nrf2 signaling was supposed to be a covalent modification of the sulfhydryl groups of Keap1 by an α,β-unsaturated carbonyl group present in the compound 1. Treatment with hemin, a HO-1 inducer, and with [Ru(CO)3Cl2]2, a CO donor, decreased LPS-stimulated iNOS induction and NO production. In contrast, siRNA-mediated knockdown of HO-1 expression reduced the inhibitory effect of compound 1 on LPS-stimulated iNOS induction and NO production. The compound 1 inhibited LPS-stimulated ERK phosphorylation after LPS treatment. Finally, compound 1 suppressed LPS/IFN-γ-stimulated NO production in primary microglial cells. These results suggest that compound 1 is capable of inhibiting LPS-stimulated iNOS induction and NO production via activation of Nrf2 signaling and HO-1 induction in microglial cells. Taken together, compound 1 has a potential to reduce neuroinflammation as well as oxidative stress in neurodegenerative diseases through activation of Nrf2 signaling.
Pharmacological Research 02/2013; · 4.44 Impact Factor
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ABSTRACT: The acetone-soluble parts of Garcinia subelliptica leaves were analyzed and six new biflavonoids were isolated, i.e., garciniaflavones A-F (1-6), as well as the five known biflavonoids amentoflavone (7), podocarpusflavone A (8), (+)-morelloflavone (9), (+)-morelloflavone-7″-O-β-glucopyranoside (10), and (+)-4‴-O-methylmorelloflavone (11) and the three triterpenoids oleanan-3-one, β-amyrin, and cycloartenol. The structures of the isolates were established based on spectroscopic analyses, including a detailed NMR spectroscopic investigation. The new biflavonoids are rare mono-isoprenylated derivatives that have a flavone-(3'-8″)-flavone core (1-4: amentoflavone type) and a flavanone-(3-8″)-flavone core (5, 6: morelloflavone type). The absolute configurations of the morelloflavone-type biflavonoids (5, 6) were confirmed by circular dichroism to be 2R,3S. The biflavonoids with an isoprenyloxy group (1) and a 2-hydroxy-3-methyl-3-butenyl group (2), and the morelloflavone-type biflavonoids with a C5 unit are the first examples in nature. We found that 7, one of the major biflavonoids, strongly inhibited hypoxia-inducible factor-1 in human embryonic kidney 293 cells under hypoxic conditions.
Chemical & pharmaceutical bulletin 01/2013; 61(5):551-8. · 1.70 Impact Factor
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Satoshi Endo,
Toshiyuki Matsunaga,
Airi Fujimoto,
Sho Kumada,
Yuki Arai,
Yoko Miura,
Hiroshige Mikamo,
Ossama El-Kabbani,
Shigeru Yamano, Munekazu Iinuma,
Akira Hara
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ABSTRACT: Mammalian morphine 6-dehydrogenase (M6DH) converts morphine into a reactive electrophile, morphinone. M6DH belongs to the aldo-keto reductase (AKR) superfamily, but its endogenous substrates and entire amino acid sequence remain unknown. A recent rabbit genomic sequencing predicts three genes for novel AKRs (1C26, 1C27 and 1C28) that share >87% amino acid sequence identity and are similar to the partial sequence of rabbit liver M6DH. We isolated cDNAs for the three AKRs, and compared the properties of their recombinant enzymes. Like M6DH, only AKR1C26 that shares the highest sequence identity with hepatic M6DH oxidized morphine. The three AKRs showed NAD(+)-dependent dehydrogenase activity towards other non-steroidal alicyclic alcohols and 3α/17β-hydroxy-C(18)/C(19)/C(21)-steroids, and their mRNAs were ubiquitously expressed in rabbit tissues. The kinetic constants for the substrates suggest that at least AKR1C26 and AKR1C28 act as NAD(+)-dependent 3α/17β-hydroxysteroid dehydrogenases. AKR1C27 differed from AKR1C28 in its high K(m) values for the substrates and low sensitivity towards competitive inhibitors (ikarisoside A, hinokitiol, hexestrol and zearalenone), despite their 95% sequence identity. The site-directed mutagenesis of Tyr118 and Phe310 in AKR1C27 to the corresponding residues (Phe and Ile, respectively), in AKR1C28 produced an enzyme that was similar to AKR1C28, suggesting their key roles in ligand binding.
Archives of Biochemistry and Biophysics 12/2012; · 2.93 Impact Factor
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ABSTRACT: Investigation of the chemical constituents of Rhizoma Cyperi (Cyperus rotundus Linneus)resulted in the isolation of novel enantiomeric andmeso-stilbene trimers [i.e., (+)- and (−)-(E)-cyperusphenol A (1, 2 respectively) and (E)-mesocyperusphenol A (3)], a trimer bearing a novelhexacyclic ring system [cyperusphenol B (5)], aswell as knownstilbenoids (cyperusphenols C (4)and D (6), scirpusins A (7) and B (8), and piceid (9)) and luteolin. HPLC was used for the opticalresolution of 1 and 2 as well as for the identification of cooccurrence of enantiomers of 7. Thestructures of the isolates were established by spectroscopic analyses, including a detailed NMRspectroscopic investigation. The isolates were evaluated in terms of their antiproliferative activityemploying the Jurkat cell line (human T-cell leukemia cells), while the IC50 potencies of aracemate of 1 and 2, 3, 5, and 6 were estimated as 27.4, 40.5, 26.4, and 26.3 μM, respectively. Thesuppression of cell growth by 6 was due to the induction of apoptosis,whichwas characterized bynuclear changes and PARP-1 cleavage determined bywestern blotting.We also evaluated the freeradical scavenging activity of the isolates.
Fitoterapia 12/2012; 83(8):1420-9. · 1.85 Impact Factor
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ABSTRACT: Two novel zierane-type sesquiterpenes, named melicodenones A and B (1 and 2, resp.), and three new guaiane-type sesquiterpenes, named melicodenones C-E (3-5), were isolated from the root of Melicope denhamii (Seem.) T. G. Hartley together with zierone (6). Their structures were established by extensive NMR-spectroscopic analyses. Compounds 1-6 were tested for cytotoxicity using human colon cancer DLD-1 cells, and melicodenone A (1) was found to exhibit moderate activity.
Chemistry & Biodiversity 10/2012; 9(10):2195-202. · 1.80 Impact Factor
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ABSTRACT: Four new sesquiterpenes, chlorajapolides F-I (1-4), along with nine known terpenoids (5-13) were isolated from the aerial part of Chloranthus japonicus. Their structures were elucidated on the basis of spectroscopic analysis, and a lindenane sesquiterpene, named 9-hydroxy-heterogorgiolide, previously isolated from the C. japonicus, was revised as its 8-epimer (1a). Moreover, methanol extract (ME), EtOAc fraction (EF), water fraction (WF), and all isolates (1a, 1-13) were evaluated for their cytotoxicities using two human cancer cell lines.
Fitoterapia 09/2012; · 1.85 Impact Factor
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ABSTRACT: The anti-degranulating activity of flavonoids present in Citrus fruits was comprehensively evaluated. Among these, hesperetin and naringenin, respectively aglycones of hesperidin and narirutin, showed significant activity. The targets of hesperetin and naringenin were found: hesperetin inhibited phosphorylation of Syk and Akt, while naringenin suppressed the expression of Lyn and inhibited the phosphorylation of Akt. These results suggest that hesperetin and naringenin inhibit degranulation by suppression of pathway signals and reduce the symptoms of allergy by inhibiting phosphorylation of Akt, which leads to the suppression of cytokines. In addition, hesperetin showed inhibitory activity against the degranulation induced by calcium ionophores, indicating that hesperetin exerts its inhibitory activity by stabilizing the membrane structure.
Journal of Natural Medicines 08/2012; · 1.39 Impact Factor
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ABSTRACT: New glycosides of seven acetophenone derivatives (1-7) and two phenylpropanoids (8, 9), named juniperosides III-XI, have been isolated from the MeOH extract of the leaves and stems of Juniperus occidentalis Hook. (Cupressaceae), together with eleven other known compounds. The structures of these compounds have been successfully elucidated using a variety of spectroscopic techniques.
Journal of Natural Medicines 07/2012; · 1.39 Impact Factor
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ABSTRACT: BACKGROUND. The suppression of androgen signaling is a therapeutic target for the treatment of prostate cancer. Resveratrol (3,4',5-trihydroxystilbene) is known to inhibit the function of the androgen receptor (AR). In the present study, we investigated the anti-androgenic activities of resveratrol analogs in order to identify a potent anti-androgen compound. METHODS. Resveratrol analogs were isolated from plants or were semi-synthesized from resveratrol. AR transcriptional activity was measured in prostate cancer LNCaP cells using a luciferase assay with the MMTV-luc reporter plasmid. RESULTS. Among the resveratrol analogs tested, 4'-O-methylresveratrol (3,5-dihydroxy-4'-methoxystilbene) was the most effective inhibitor of AR transcriptional activity. Introduction of a methoxy group to the C-4' of resveratrol and its analogs increased their anti-androgenic activity compared to the unmodified counterparts. Conversely, modification of the 3- and/or 5-hydroxyl groups reduced the anti-androgenic activity. 4'-O-methylresveratrol was more effective than resveratrol in inhibiting Akt phosphorylation, which is related to androgen receptor signaling, in LNCaP cells. CONCLUSIONS. The hydroxyl groups in resveratrol play a key role in their anti-androgenic effect by modulating AR transcriptional activity.
Journal of Andrology 06/2012; · 2.97 Impact Factor
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ABSTRACT: A novel lindenane sesquiterpene with an unprecedented 18-membered triester ring, named chlorafortulide (1), along with one known lindenane sesquiterpene (2) and nine known lindenane sesquiterpene dimers (3-11), was isolated from the whole plant of Chloranthus fortunei. Their structures and relative configurations were elucidated on the basis of spectroscopic analysis. All the isolates were evaluated for their inhibitory effects on lipopolysaccharide-induced nitric oxide production in RAW264.7 cells. Henriol D (4), shizukaols E (8), G (9), M (10), and O (11) showed significant anti-inflammatory activities with IC(50) values of 1.90, 3.68, 1.95, 7.01, and 1.95 μM, respectively.
Journal of Asian natural products research 05/2012; 14(7):708-12. · 0.61 Impact Factor
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ABSTRACT: Annatto (Bixa orellana) seeds have been used as a colorant in butter and in a variety of other foods. In this study, we investigated the amelioration of retinal damage by an acetone extract of annatto (A-ext.), bixin (a main component of annatto), and four bixin derivatives (Bx-1, Bx-2, Bx-3, and Bx-4) that we have synthesized.
We used cultured retinal ganglion cells (RGC-5) to examine in vitro effects of A-ext. on stress pathways, focusing on intracellular oxidation induced by reactive oxygen species, expression of endoplasmic reticulum (ER) stress-related proteins, caspase-3 activation, and cell membrane damage. In vivo retinal damage in mice following intravitreous injection of tunicamycin was evaluated by counting the cell numbers in the ganglion cell layer (GCL) and measuring the thickness of outer nuclear layer (ONL). A-ext., bixin, and Bx-1 treatment inhibited both tunicamycin- and H₂O₂-induced cell death. Bixin derivatives also inhibited tunicamycin-induced cell death. Treatment with A-ext., bixin, and Bx-1 reduced tunicamycin-induced caspase-3 activity and inhibited the inversion of phosphatidylserine, an early apoptotic event without antioxidant effect or reduction of ER stress itself. A-ext., bixin, and Bx-1 significantly inhibited the tunicamycin-induced loss of cells from the GCL, and these materials also suppressed the tunicamycin-induced thinning of ONL.
A-ext., its main component bixin, and bixin derivatives may therefore be useful for preventive and therapeutic treatment of retinal-related diseases.
Molecular Nutrition & Food Research 05/2012; 56(5):713-24. · 4.30 Impact Factor
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ABSTRACT: ABCA1, a member of the ATP-binding cassette transporter family, regulates high-density lipoprotein (HDL) metabolism and cholesterol transport. Its expression is upregulated mainly by the activation of the liver X receptor (LXR). Since ABCA1 plays a pivotal role in cholesterol and HDL metabolism, identification of a compound capable of increasing its expression may be beneficial for the prevention and therapy of atherosclerosis. Firefly luciferase reporter assays were developed for human ABCA1 promoters and LXR enhancers, and an in-house phytochemical library was screened. It was found that a citrus flavonoid, hesperetin (1), increased ABCA1 promoter and LXR enhancer activities in THP-1 macrophages. It was also found that this flavonoid promoted PPAR-enhancing activity. In accordance with these findings, 1 increased mRNA and protein expression of ABCA1 and consequently upregulated ApoA-I-mediated cholesterol efflux. These results provide evidence that 1 promotes ApoA-I-mediated cholesterol efflux from macrophages by increasing ABCA1 expression through the activation of LXRα and PPARγ.
Journal of Natural Products 03/2012; 75(4):563-6. · 3.13 Impact Factor
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ABSTRACT: Seven new terpenoids, including two sesquiterpene dimers (1, 2), two norditerpenoids (3, 4), and three sesquiterpenes (5-7), along with six known sesquiterpene dimers and four known sesquiterpenes were isolated from the whole plant of Chloranthus serratus. Their structures and relative configurations were elucidated on the basis of spectroscopic data analysis. The absolute configuration of 1 was determined by the CD exciton chirality method. These isolates were evaluated for their inhibitory effects on lipopolysaccharide-induced nitric oxide production in RAW264.7 cells. Compound 2 and two known compounds, shizukaols B and D, showed significant anti-inflammatory activities, with IC(50) values of 0.22, 0.15, and 7.22 μM, respectively.
Journal of Natural Products 02/2012; 75(4):694-8. · 3.13 Impact Factor
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ABSTRACT: Mangiferin (3) and genkwanin 5-O-β-primeveroside (5) are the two major bioactive polyphenols with laxative property present in the extracts of agarwood (Aquilaria sinensis) leaves (AL). Here we developed an HPLC method to determine these bioactive components and four other major polyphenols in AL extracts and evaluated the pharmacological equivalence of organic and water extracts. Using mobile phase gradient conditions combined with UV detection at 330 nm, all six compounds were separated and we determined the relative extraction ratios of the six compounds present in A. sinensis extracts that were prepared under different conditions and compared the contents of the two laxative polyphenols present in the 60% ethanol extracts of A. sinensis and A. crassna. The polyphenols present in water extracts of 13 commercially cultivated A. crassna plants have also been analyzed. The laxative properties of 60% ethanol and four water extracts of A. crassna were evaluated by the frequency and weight of stools in loperamide-induced constipation model mice. The pharmacological equivalence of 60% ethanol extract and hot water (95°C) extract was identified in mice.
Journal of Nutritional Science and Vitaminology 01/2012; 58(2):136-42. · 1.20 Impact Factor
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ABSTRACT: Accumulating evidence suggests a crucial role for the unfolded protein response (UPR) in Parkinson's disease (PD). In this study, we investigated the relevance of the UPR in a mouse model of chronic MPTP/probenecid (MPTP/P) injection, which causes severe and persistent degeneration of dopaminergic neurons. Enhanced activation of the UPR branches, including ATF6α and PERK/eIF2α/ATF4, was observed after MPTP/P injections into mice. Deletion of the ATF6α gene accelerated neuronal degeneration and ubiquitin accumulation relatively early in the MPTP/P injection course. Surprisingly, astroglial activation was strongly suppressed, and production of the brain-derived neurotrophic factor (BDNF) and anti-oxidative genes, such as heme oxygenase-1 (HO-1) and xCT, in astrocytes were reduced in ATF6α -/- mice after MPTP/P injections. Decreased BDNF expression in ATF6α -/- mice was associated with decreased expression of GRP78, an ATF6α-dependent molecular chaperone in the ER. Decreased HO-1 and xCT levels were associated with decreased expression of the ATF4-dependent pro-apoptotic gene CHOP. Consistent with these results, administration of the UPR-activating reagent tangeretin (5,6,7,8,4'-pentamethoxyflavone; IN19) into mice enhanced the expression of UPR-target genes in both dopaminergic neurons and astrocytes, and promoted neuronal survival after MPTP/P injections. These results suggest that the UPR is activated in a mouse model of chronic MPTP/P injection, and contributes to the survival of nigrostriatal dopaminergic neurons, in part, through activated astrocytes.
PLoS ONE 01/2012; 7(10):e47950. · 4.09 Impact Factor
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ABSTRACT: A human member of the aldo-keto reductase (AKR) superfamily, AKR1B10, was recently identified as both diagnostic marker and therapeutic target in the treatment of several types of cancer. In this study, we have examined AKR1B10 inhibition by five xanthone derivatives, components of pericarps of mangosteen, of which α- and γ-mangostins show potential anti-cancer properties. Among the five xanthones, γ-mangostin was found to be the most potent competitive inhibitor (inhibition constant, 5.6 nM), but its 7-methoxy derivative, α-mangostin, was the second potent inhibitor (inhibition constant, 80 nM). Molecular docking of the two mangostins in AKR1B10 and site-directed mutagenesis of the putative binding residues revealed that Phe123, Trp220, Val301 and Gln303 are important for the tight binding of γ-mangostin, and suggested that the 7-methoxy group of α-mangostin impairs the inhibitory potency by altering the orientation of the inhibitor molecule in the substrate-binding site of the enzyme.
Biological & Pharmaceutical Bulletin 01/2012; 35(11):2075-80. · 1.66 Impact Factor
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ABSTRACT: The development of molecularly targeted drugs has greatly advanced cancer therapy, despite these drugs being associated with some serious problems. Recently, increasing attention has been paid to the anticancer effects of natural products. α-Mangostin, a xanthone isolated from the pericarp of mangosteen fruit, has been shown to induce apoptosis in various cancer cell lines and to exhibit antitumor activity in a mouse mammary cancer model. In this study, we investigated the influence of α-mangostin on apoptosis and cell cycle in the human breast cancer cell line MDA-MB231 (carrying a p53 mutation, and HER2, ER, and PgR negative) in order to elucidate its anticancer mechanisms. In α-mangostin-treated cells, induction of mitochondria-mediated apoptosis was observed. On cell-cycle analysis, G1-phase arrest, increased p21(cip1) expression and decreases in cyclins, cdc(s), CDKs and PCNA were observed. In conclusion, α-mangostin may be useful as a therapeutic agent for breast cancer carrying a p53 mutation and having HER2- and hormone receptor-negative subtypes.
Journal of Biomedicine and Biotechnology 01/2012; 2012:672428. · 2.44 Impact Factor
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Journal of Biomedicine and Biotechnology 01/2012; 2012:147120. · 2.44 Impact Factor
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ABSTRACT: A human member of the aldo-keto reductase (AKR) superfamily, AKR1B10, was recently suggested as a therapeutic target in the treatment of several types of cancer. Due to its high sequence identity with human aldose reductase (AKR1B1), selective inhibition of AKR1B10 compared with AKR1B1 is required for the development of anticancer agents. In this study, we have examined AKR1B10 inhibition by seven pentacyclic triterpenes (1-7) that show potential anticancer properties. Among them, oleanolic acid (1) was found to be the most potent competitive inhibitor (inhibition constant, 72 nM) with the highest AKR1B10/AKR1B1 selectivity ratio of 1370. Molecular docking of 1 with AKR1B10 and AKR1B1 and site-directed mutagenesis studies suggested that the nonconserved residues Val301 and Gln303 in AKR1B10 are important for determining its inhibitory potency and selectivity. Oleanolic acid (1) also inhibited the cellular metabolism by AKR1B10 (IC(50), 4 μM) and decreased mitomycin C tolerance of colon cancer HT29 cells. Thus, the selective and potent inhibition of AKR1B10 by 1 may be related to a possible cancer inhibitory role.
Journal of Natural Products 05/2011; 74(5):1201-6. · 3.13 Impact Factor
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ABSTRACT: Three new stilbene derivatives, albiraminols A (1) (resveratrol hexamer), B (2) (resveratrol dimer), and vatalbinoside F (3) (mono-glucoside of resveratrol dimer), along with malibatol were isolated from acetone soluble portions of the stem of Vatica albiramis. The structures of the isolates were established on the basis of spectroscopic analyses, including a detailed NMR spectroscopic investigation. The biosynthetic aspects of the isolates are discussed in this paper. Compound 1 is composed of tetrameric resveratrol (vaticanol B (1A)) and dimeric resveratrol (1B) and is the first instance of the resveratrol derivative bearing a 5,6,11,12-tetrahydro-5,11-epoxydibenzo[a,e][8]annulene ring system. Compound 2 possesses a novel 4,5-dihydro-13-oxabenzo[3,4]azuleno[7,8,1-jkl]phenanthrene skeleton in the framework.
Chemical & pharmaceutical bulletin 01/2011; 59(4):452-7. · 1.70 Impact Factor
