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By phytochemical investigation of the leaves of Premna japonica, four monoacyl 6-O-α-L-rhamnopyranosylcatalpols were isolated. The structures of these compounds were established to be 6-O-α-L-(2″-O-trans-p-coumaroyl) rhamnopyranosylcatalpol (saccatoside), 6-O-α-L-(4″-O-trans- and cis-p-coumaroyl) rhamnopyranosylcatapols, 6-O-α-L-(2″-O-caffeoyl) rhamnopyranosylcatapol, and 6-O-α-L-(3″-O-caffeoyl) rhamnopyranosylcatapol

A new ent-spirosecokaurene diterpenoid, named isolongirabdiol, was isolated from the aerial parts of Rabdosia longituba together with the known compounds oridonin, lasiokaurin, and nodosin. The structure of the new compound was elucidated on the basis of spectroscopic and chemical evidence

Inorganic constituents of the leaves of several kinds of plants growing on different soil types were investigated using energy-dispersive X-ray fluorescence spectrometry. The results can be summarized as follows: (1) Each plant exhibited a characteristic metals profile, even if they were grown on similar soil types. (2) As we would expect, the metals profile of the plant leaves depends on the inorganic constitution of the soil on which it is grown. However, the degree of the influence of the soil types on the metals profile of the plant differs according to the kind of inorganic element: Ca and Cu are almost independent of the soil types, but the Ti and Fe content is dependent upon the soil types. (3) Sr content of plant leaves is closely related to the ratio of Sr to Ca of the soil on which the plants are grown. (4) This information should be helpful in identifying the producing district or original plant of a crude drug by its metals profile.

Three new diterpenoids, rabdoternins A (1), B (2) and C (3) have been isolated from the bried leaves of Rabdosia ternifolia (D. DON) HARA. Their structures have been elucidated on the basis of spectroscopic and chemical evidence.

The structures of isodonal and rabdolasional were re-examined by means of two-dimensional nuclear magnetic resonance spectroscopy (2D-NMR) and were revised to 1 and 2 from the previously reported structures, 3 and 4. The structures of the chemically correlated diterpenoids, isodonoic acid and trichodonin were also revised to 7 and 8, respectively.

The ethyl acetate-soluble fraction from a MeOH extract of the roots of Ferula varia gave six new sesquiterpene lactones (1-6) and five known sesquiterpenes (7-11). Their structures were established on the basis of spectroscopic evidence. The cytotoxic activities of 1-11 were evaluated against selected human cancer cell lines. Compound 4 showed significant selective cytotoxicity against multidrug-resistant cancer cells (KB-C2). The cytotoxicities of compounds 1, 3, 5, 8, and 11 against KB-C2 cells were enhanced in the presence of nontoxic concentrations of colchicine.

The tyrosinase inhibitory activity of the extracts of 53 parts of 36 plant species cultivated for edible and medicinal use in Okinawa was investigated. The extract of Nandina domestica showed potent activity among these. The inhibitor in the extract was purified by assay-guided fractionation to give a simple phenol glucoside. Although it was a known compound (4-beta-D-glucopyranosyloxybenzoic acid), its inhibitory activity toward tyrosinase is revealed for the first time in this work.

From a 1-BuOH-soluble fraction of the MeOH extract of leaves of Euodia meliaefolia, collected in Okinawa, seven megastigmane glucosides, named euodionosides A-G, were isolated together with three known megastgmane glucosides, and two aliphatic and three phenolic compounds. Their structures were elucidated through a combination of spectroscopic analyses and application of the modified Mosher's method.

A new phenolic glucoside was isolated from the aerial parts of Origanum tyttanthum, an Uzbek medicinal plant, together with 12 known compounds. The structure of the new compound was elucidated as 4-O-beta-D-glucopyranosylbenzyl-3'-hydroxyl-4'-methoxybenzoate (1) based on the spectral and chemical evidence.

A new acyclic monoterpene glucosyl ester 1 was isolated from the leaves of Lantana lilacia together with the known compound, acteoside. The structure of the new compound was elucidated by spectroscopic and chemical analyses.

From the leaves of Glochidion obovatum, a new neoligan glucoside, (7S,8R)-dihydrodehydrodiconiferyl alcohol-9′-O-β-glucoside, named as glochidioboside, was isolated along with the known compounds, blumeol C glucoside, benzyl alcohol glucoside, bergenin, dendranthemoside B and icariside B1. The structure of the new compound was elucidated by spectroscopic methods.

Four new megastigmane glucosides, named macarangiosides A-D (2-5), together with mallophenol B, lauroside E, methyl brevifolin carboxylate, and hyperin and isoquercitrin as a mixture were isolated from the leaves of Macaranga tanarius (L.) MULL.-ARG. (Euphorbiaceae). Their structures were elucidated by spectroscopic and chemical analyses. Macarangioside A-C (2-4) and mallophenol B were galloylated on glucose moiety and possessed the potent 2,2-diphenyl-picrylhydrazyl (DPPH) radical-scavenging activity.

The chemical investigation of leaves of Bridelia glauca f. balansae afforded six megastigmane glucosides, named bridelionosides A-F, along with seven known megastigmane glucosides. Their structures were determined by a combination of spectroscopic analyses and by application of the modified Mosher's method.

From the aerial parts of Stachys byzantina, two new megastigmane glucosides, byzantionosides A and B, were isolated, together with the known glycosides, icariside B-2, blumeol C glucoside, (6R, 9R)- and (6R, 9S)-3-oxo-alpha-ionol glucosides and verbascoside. The structures of the new compounds have been elucidated by spectroscopic means. Copyright (C) 1997 Elsevier Science Ltd.

Chemical investigation of leaves of Staphylea bumalda DC., collected in the suburbs of Hiroshima City, afforded 11 new megastigmane glucosides, named staphylionosides A-K (3-13), along with two known megastigmane glucosides (1, 2). The relative structures were elucidated from spectroscopic evidence, and the absolute structures of the aglycones were determined by means of the combination of beta-D-glucosylation-induced shift-trends and the modified Mosher's method.

Chemical investigation of leaves of Staphylea bumalda DC., collected in the suburbs of Hiroshima City, afforded 11 new megastigmane glucosides, named staphylionosides A-K (3-13), along with two known megastigmane glucosides (1, 2). The relative structures were elucidated from spectroscopic evidence, and the absolute structures of the aglycones were determined by means of the combination of beta-D-glucosylation-induced shift-trends and the modified Mosher's method.

5, 8, 11, 13-Abietatetraen-3-one (3) and its 12-methoxy derivative (7) were oxidized to the corresponding 3, 7-diones, which were rearranged respectively into 2-isopropyl-6-methyl-5-(4-methyl-3-oxopentyl)naphthalene (6) and its 12-methoxy derivative (10) by sodium borohydride reduction and subsequent dehydration with boron trifluoride etherate. Compound 10 was further converted into 3-oxosapriparaquinone (1) via 5-(3-acetoxy-4-methylpentyl)-2-isopropyl-6-methyl-3, 4-naphthoquinone (14).

Two new polyprenylated benzophenones, a new polyprenylated phloroglucinol, and six new xanthone derivatives were isolated from the aerial parts of the Uzbekistan medicinal plant Hypericum scabrum. Their structures were elucidated on the basis of spectroscopic evidence. The isolated compounds showed moderate cytotoxicity for human tumor cells.

From the leaves of Breynia officinalis, collected on Okinawa Island, six terpenic glucosides and six phenolic glycosides were isolated. Two of the terpenic glucosides were found to be known, and they were identified as turpinionoside B and betulalbuside A. The structures of the remaining terpenic glucosides were elucidated to be megastigmane glucosides, named breyniaionosides A-D, using spectroscopic analyses. The absolute structure of breyniaionoside D was determined using the modifed Mosher's method. The absolute structure of the known compound betulalbuside A was determined for the first time in this study. Six phenolic glycosides were found to be arbutin and its derivatives. Two known compounds were found to be robustaside A and eximine. New compounds were named isorobustaside A, and breyniosides A and B, and their structures were elucidated from spectroscopic evidence.

The dimeric butenolides glochidiolide and isoglochidiolide, a new glucoside of a nitrogen-containing C(8) dimer, acuminaminoside, and glucosides of C(8) compounds, designated glochidacuminosides A-D, were isolated from the leaves of Glochidion acuminatum. The structures of glochidionolactone and acuminaminoside were determined by X-ray analyses, and those of the remaining C(8) glucosides by NMR spectroscopic analyses, chemical conversion, and a modified Mosher's method.

A new flavonol with a tetrasaccharide unit named alangiflavoside [4] was isolated from the water-soluble fraction of a methanol extract of Alangium premnifolium leaves, along with three known flavonol glycosides. Structure determination was made based on spectroscopic and chemical evidence

From the leaves of Rhamnella inaequilatera, three flavone C,O-bisglycosides, rhamnellaflavosides A, B and C, were isolated and their structures were elucidated based on their spectral data and chemical evidence.

The cytotoxic activity of ethanol extracts from 53 parts of 36 species of medicinal and edible plants cultivated in Okinawa was measured by using K562 human leukemia cells by a flow cytometric method. Two extracts from Rhodea japonica and Hypericum chinense were cytotoxic at a concentration of 10 microg/ml. The main cytotoxic constituent of Rhodea japonica was isolated and identified to be rhodexin A, which has been isolated as a cardetonic agent of the plant. The IC(50) value for rhodexin A against the growth of K562 cells was 19 nM, this activity being much stronger than that of ouabain (IC(50), 60 nM).

From Glochidion zeylanicum, two megastigmane glucosides, 3- and 9-O-β- d -glucopyranosides of (3S,5R,6R,7E,9S)-megastigman-7-ene-3,5,6,9-tetrol (1 and 2, respectively), were isolated. Their structures were different from those of kiwiionoside (3) and actinidioionoside (4), isolated from Actinidia chinensis and Actinidia polygama, respectively, in the stereochemistry at the 9-positions. Alangionosides E (5) and O (6), isolated from the leaves of Alangium premnifolium, are also megastigmane glucosides, and the latter is closely related to 1 and actinidioionoside (4). However, the absolute configurations of the 9-position remained to be determined. They were analyzed to be R by means of a modified Mosher's method. Alangionoside E (5) is identical with corchoionoside A in all aspects. The name of corchoionoside A must be retained thereafter.

Five megastigmane glucosides were isolated from the leaves of Glochidion zeylanicum. One of them was a known compound, blumenol C O-beta-D-glucopyranoside (1), and the structures of the four new compounds, glochidionionosides A-D (2-5), were mainly elucidated by spectroscopic methods, including a modified Mosher's method. The absolute configurations of the six-membered ring of glochidionionoside D (5) were deduced by beta-D-glucopyranosylation-induced shift trends in the (13)C-NMR spectra and confirmed by X-ray analysis as its p-bromobenzoate (5b), and the axis chirality of C-7 was determined to be R.

Uzbekistan is one of the Turcic republics in Central Asia where a desert continental climate mainly prevails in territories. Nevertheless, this expedition was carried out in the northeast and east higher lands, where flora is richer. The interviews were performed in seven villages of Toshkent and in neighboring provinces of Samarqand, Djizzax and at Urgut Bazaar of Samarqand. Altogether 177 folk remedies were recorded in the surveyed area. Among these folk remedies, 162 remedies were obtained from 79 different kinds of plant species that belong to 31 different families, whereas, 15 animal originated remedies that belong to 8 different animals are listed, which includes their vernacular and scientific names, indications and recipes for preparations.

From the aerial parts of Rabdosia shikokiana var. occidentalis, two new 8,9-seco-ent-kaurenoid diterpenes, rabdoshikoccins A and B, were isolated together with the known compounds, shikoccin, shikoccidin and leukamenin E. The structures of the new compounds were elucidated based on the spectroscopic and chemical evidence.

A new iridoid glucoside dimer (1) and a non-glycosidic iridoid (2) was isolated together with the known compounds, asperuloside (3), paederoside (4), daphylloside (5), citroside A (6) and benzyl 6-O-alpha-L-rhamnopyranosyl-beta-D-glucopyranoside (7), from the leaves of Lasianthus wallichii. The structures of the new compounds were elucidated by spectroscopic and chemical evidence.

A solution of carnosic acid quinone, which is a radical chain-termination product having no antioxidant activity in the antioxidant reaction of carnosic acid, recovers potent antioxidant activity upon standing. The HPLC analysis of an aged solution of carnosic acid quinone revealed that several antioxidants are produced in the solution. From the time-course and quantitative analyses of the formation of the products and their structural analysis, an antioxidant mechanism from carnosic acid quinone is proposed that includes a redox reaction of carnosic acid quinone in addition to the isomerization to lactone derivatives. In the first stage of antioxidation, carnosic acid, the reduction product from carnosic acid quinone, contributes to the potent antioxidant activity of the solution. This proposed mechanism can explain one of the reasons for the strong antioxidant activity of the extract of the popular herbs sage and rosemary.

An unusual new sesquiterpene derivative, kuhistaferone (1), was isolated from the fruits of the Uzbekistan medicinal plant Ferula kuhistanica. The structure of 1 was established on the basis of spectroscopic evidence. Compound 1 showed moderate cytotoxicity against the human colon tumor cell line HCT116.

BACKGROUND Hepatitis B virus (HBV) is closely linked to hepatocellular carcinoma (HCC). The objective of the current study was to identify the factors involved in the prognosis of patients with HBV-associated HCC using multivariate analysis. METHODS The current study included 74 patients with HBV-associated HCC who were admitted to Nagasaki University Hospital, Nagasaki, Japan, between 1983–1998. Of these, 13 patients underwent surgical tumor resection; 43 patients received nonsurgical treatment with transcatheter arterial embolization, percutaneous ethanol injection, or both; and 18 patients were followed without any active treatment. The significance of the patient's age; gender; history of blood transfusion; alcohol use; serum levels of alanine aminotransferase, α-fetoprotein, and HBV-DNA; number and size of liver tumors; clinical stage; and histologic diagnosis of HCC as prognostic factors was evaluated using univariate and multivariate analyses. RESULTS The 3-year, 5-year, and 10-year postdiagnosis cumulative survival rates were 36%, 21%, and 17%, respectively. Multivariate analysis identified the level of serum HBV-DNA and tumor size at diagnosis as independent and significant prognostic factors (P = 0.0022 and P = 0.0106, respectively). In addition, a low level of viremia was found to be associated with longer survival (P = 0.0057) even in patients who were negative for the hepatitis B e antigen. CONCLUSIONS The results of the current study suggest that viral load is a useful prognostic marker for HBV-related HCC and that HCC patients with a less favorable course appear either to clear the virus poorly or to have a greater level of virus production. Cancer 2002;94:2663–8. © 2002 American Cancer Society. DOI 10.1002/cncr.10557

From leaves of Turpenia ternata (Staphylaceae), one megastigmane and seven of its glucosides (1-8) were isolated. Megastigmane and two of the glucosides were found to be known compounds, namely, 3S,5R,6R,9S-tetrahydroxymegastigmane (1), corchoionoside C (2), and icariside B4 (3). The structures of compounds 4-8 (turpinionosides A-E, respectively) were elucidated by means of spectroscopic analyses, and then their absolute structures were determined by the modified Mosher's method to be (3S,5R,6S,9S)-3,6,9-trihydroxymegastigman-7-ene 3-O- and 9-O-beta-D-glucopyranosides (4, 5, respectively), (1S,3S,5R,6S,9R)-3,9,12-trihydroxymegastigmane 3-O-beta-D-glucopyranoside (6), (3S,4R,9R)-3,4,6-trihydroxymegastigman-5-ene 3-O-beta-D-glucopyranoside (7), and (2S,9R)-2,9-dihydroxymegastigman-5-en-4-one 2-O-beta-D-glucopyranoside (8).

In chronic hepatitis B virus (HBV) infection, the quiescent immunotolerant phase evolves into the immunoactive phase. The aim of the present study was to clarify the virological alterations relevant to progression. Serial serum samples obtained from a patient with HBV during long-term follow-up were analysed by sequencing of the full-length HBV-DNA using polymerase chain reaction (PCR). In addition, PCR products of HBV genome from each serum sample were transfected into HuH-7 human hepatoma cells for the functional analysis of the transfected viral genomes. Based on the HBV-DNA sequence analysis, the patient had the genotype C virus, and the mutant HBV with common core promoter mutations (T(1762)A(1764)) and deletion of the pre-S region responsible for large surface protein transcription emerged before the onset of hepatitis. When the vigorous host immune response developed (indicated by the flare-up of hepatitis), the mutant HBV containing common core promoter mutations and another pre-S deletion causing lack of the surface protein promoter became predominant. The HBV-DNA sequences, other than pre-S and core promoter regions were identical to the wild-type sequence throughout the study. Transfection of PCR products containing the mutant HBV sequences resulted in increased amounts of intracellular replicative intermediates but the decreased secretion of HBsAg and HBeAg into culture media, suggesting accumulation of nonenveloped viral core particles within the cells. These results indicate that pre-S deletion and core promoter mutations may participate cooperatively in progression of the disease.

The seeds of Punica granatum, known as hap roman in the Arabian Peninsula, are commonly eaten as a dessert. As part of an ongoing project to find nonnutritional natural products which have health benefits, or that can be exploited to protect crops, the chloroform-soluble extract of the fermented seeds of P. granatum was found to be rich in 1-O-trans,cis,trans-9,11,13-octadecatrienoyl glycerol (1). The seed oil is not lethal to brine shrimp larvae. 1-O-isopentyl-3-O-octadec-2-enoyl glycerol (2) and the known cis-9-octadecenoic, octadecanoic, and eicosanoic acids were also detected in small amounts in the seed oil by LC and MS. The structure of 1 was determined from NMR and MS spectral data.

From the leaves of Chloranthus glaber Makino, a new sesquiterpenoid, chloranthalactone F was isolated together with the known compounds, chloranthalactones A, B and E, atractylenolide II and (−)-4β,7α-dihydroxyaromadendrane. The structure of the new compound was elucidated by spectroscopic methods.

The acetate (11), propanoate (12), butanoate (13), 2-methylpropanoate (14), hexanoate (15), decanoate (16), and hexadecanoate (17) of (±)-2-(p-tolyl)-1-propanol (2) were predominantly hydrolyzed with lipase to give (S)-(-)-2-(p-tolyl)-1-propanol (2). However, the 2, 2-dimethylpropanoate (18), benzoate (19), and phenylacetate (20) of (±)-2 were recovered intact even when the reaction was carried out for 100h. From the viewpoints of enentioselectivity and reaction rate, the racemic ester 11 was found to be the most suitable substrate for the optical resolution of (±)-2.

From the dried aerial parts of Rabdosia longituba (MIQ). HARA, two new diterpenes, named rabdokaurin C (1) and rabdokaurin D (8), were isolated together with the known compounds ordonin, lasiokaurin, effusanin B, rabdophyllin G, and rabdokaurin B. The structures of the two new compounds were determined on the basis of spectroscopic and chemical evidence.

By means of single crystal X-ray analysis of dendranthemoside A pentaacetate, the absolute configuration of the asymmetric center at the 9-position was determined to be R. The configurations of three other positions, which had been determined to be 3S, 5R and 6S by application of β-D-glucosylation induced shift trends, were verified.

To determine the antioxidant mechanism of food phenolics against the oxidation of food components, the reaction of carnosic acid, an antioxidative constituent of the popular herbs sage and rosemary, was investigated in the presence of ethyl linoleate and the radical oxidation initiator 2,2‘-azobis(2,4-dimethylvaleronitrile). During this process, carnosic acid was oxidized to an o-quinone and a hydroxy p-quinone, the chemical structures of which were confirmed by physical and chemical techniques. From a quantitative time course analysis of the production of these quinones, an antioxidant mechanism of carnosic acid is proposed, consisting of the oxidative coupling reaction with the peroxyl radical at the 12- or 14-position of carnosic acid and subsequent degradation reactions. Keywords: Carnosic aid; antioxidant mechanism; radical termination; sage; Labiatae; o-quinone

Ethyl acetate extracts of the air-dried fruits of Ferula kuhistanica afforded three daucane esters: kuhistanicaol H, I and J, together with nine other known compounds. Their structures were established on the basis of spectroscopic evidence. Isolated compounds in this paper and previously reported compounds from the roots and stems of F. kuhistanica were tested for antibacterial activity. Some of them were selectively toxic against Gram-positive bacteria, including methicillin-sensitive and methicillin-resistant Staphylococcus aureus (MSSA and MRSA).

Geranylgeraniol (GGOH), an intermediate of mevalonate metabolism, is known to induce apoptosis in various lines of cancer cells. The present study was undertaken to clarify the signaling pathways of apoptosis induced by GGOH in human hepatoma cells. HuH-7 human hepatoma cells were incubated in the absence or presence of GGOH. Activation of caspase-8 /-9 /-3 in HuH-7 cells was found after 8 h treatment with GGOH, at which time DNA fragmentation and loss of mitochondrial transmembrane potential (Deltaphim) occurred. HuH-7 cells do not express Bcl-2; however, down-regulation of Bcl-xL expression preceded activation of the caspase cascade in GGOH-treated HuH-7 cells, while Bax expression was not changed by GGOH treatment. Addition of caspase inhibitors restored the decreased cell viability of HuH-7 cells by GGOH, including Deltaphim, to the baseline level, which indicated that caspase triggers mitochondria-dependent apoptotic pathways in GGOH-treated HuH-7 cells. Similarly, GGOH-mediated apoptosis of HuH-7 cells was clearly prevented by coadministration of ursodeoxycholic acid (UDCA), which led to restoration of the level of Bcl-xL expression. Activation of caspase-8 /-9 /-3, as well as Deltaphim, by GGOH treatment was suppressed by addition of UDCA. Our results indicate that activation of the caspase cascade initiating from caspase-8, which could be accelerated by down-regulation of Bcl-xL expression, plays a key role in an apoptotic process induced by GGOH in human hepatoma cells.

Four kinds of galloyl flavonol glycosides were found in the leaf extract of Pemphis acidula, a plant growing on the subtropical seashore. Their chemical structures were elucidated to be quercetin or kaempferol 6"-O-galloyl-beta-D-glycosides by using spectroscopic and chemical analyses. One of the flavonols, kaempferol-3-O-(6-O-galloyl-beta-D-galactopyranoside), was newly isolated from natural sources and its structure was completely determined in this investigation. The antioxidant-related activities of the galloyl flavonoids were examined by the DPPH antiradical activity, inhibition of methyl linoleate oxidation, and inhibition of oxidative cell death. These results were compared with those of the corresponding non-galloylated flavonol glycosides and their aglycones. The galloyl flavonoids showed more efficient activity than that of the corresponding flavonol glycosides, but not more than that of the corresponding aglycones in the three assays applied.

Eleven new sesquiterpenes (1--11) and two thymol derivatives (12, 13), along with 12 known sesquiterpenes and monoterpenes, were isolated from the bark of Inula macrophylla. Their structures were determined on the basis of spectral evidence (especially by HREIMS and 2D NMR) as well as chemical transformations. The structure of macrophyllic acid A (1) was confirmed by X-ray analysis, and the absolute configuration of 1 was determined on the basis of the appropriate chemical conversions and the application of a modified Mosher's method.

The methanol extract of the dried roots of Rheum maximowiczii afforded four phenylbutanoid and two stilbene derivatives. Their structures were established on the basis of chemical and spectroscopic studies.

In this study, we aimed to determine the growth inhibition and the induction of apoptotic cell death brought about by the herb Anemarrhena asphodeloides Bunge in gastric cancer cell lines, and to clarify the mechanism of this apoptosis. Water-soluble ingredients of A. asphodeloides, and the gastric cancer cell lines, MKN45 and KATO-III, were used in vitro. Growth inhibition, induction of cell death, morphological features, the presence of DNA ladders, increases in caspase-3-like activity, the effects of a caspase-3 inhibitor on apoptotic cell death, and the release of cytochrome c by A. asphodeloides were analyzed. A. asphodeloides inhibited the growth and decreased the viability of the gastric cancer cell lines. The viability of normal skin fibroblasts in the presence of low concentrations of A. asphodeloides was higher than that of gastric cancer cells. Apoptotic bodies and DNA ladders were observed to be induced in MKN45 and KATO-III by A. asphodeloides. The caspase 3 inhibitor, Ac-DEVD-CHO, inhibited the apoptotic cell death of gastric cancer cells induced by A. asphodeloides. The caspase 3-like activity in MKN45 and KATO-III cells increased after the addition of A. asphodeloides. Cytochrome c was released from mitochondria into the cytosol 8 h after the addition of A. asphodeloides, and reached a peak at 16 h. The peak of cytochrome c release was earlier than that of caspase 3-like activity. We concluded that A. asphodeloides inhibited the growth of the gastric cancer cell lines MKN45 and KATO-III and induced apoptosis. The apoptosis of MKN45 and KATO-III cells induced by A. asphodeloides was associated with the release of cytochrome c from the mitochondria, followed by an increase in caspase 3-like activity.

Geranylgeranylacetone (GGA), an isoprenoid compound, is used clinically as an anti-ulcer drug. Since some isoprenoids including retinoids have anti-tumor and anti-viral activities in a variety of cell types, we investigated whether GGA could induce anti-viral proteins in human hepatoma cells. The HuH-7 and HepG2 cells were treated with GGA, and expression of anti-viral proteins such as 2'5'-oligoadenylate synthetase (2'5'-OAS) and double-stranded RNA-dependent protein kinase (PKR) in these cells was analyzed. GGA stimulated 2'5'-OAS and PKR gene expression at the transcriptional level through the formation of interferon-stimulated gene factor 3 (ISGF3), which regulates both gene transcription. By Western blotting, GGA induced expression of signal transducers and activators of transcription 1, 2 (STAT1, STAT2) and p48 proteins, components of ISGF3, together with the phosphorylation of STAT1. These results suggest that GGA acts as a potent inducer of anti-viral gene expression by stimulating the ISGF3 formation in human hepatoma cells.