Acer Nikoense Research Articles

New TNF-α releasing inhibitors as cancer preventive agents from traditional herbal medicine and combination cancer prevention study with EGCG and sulindac or tamoxifen

Herbal medicines are now attracting attention as potential sources of cancer preventive agents. Using inhibition of tumor necrosis factor-α (TNF-α) release assay, we studied Acer nikoense, Megusurino-ki in Japanese. Inhibitory potential was found in the leaf extract, and the main active principles were identified as geraniin and corilagin. The IC 50 values for TNF-α release inhibition were 43 μM for geraniin and 76 μM for corilagin, whereas that for (−)-epigallocatechin gallate (EGCG), the green tea polyphenol, as control was 26 μM. Furthermore, treatment with geraniin inhibited okadaic acid tumor promotion in a two-stage carcinogenesis experiment on mouse skin. Geraniin and corilagin are present in another well-known Japanese traditional herb, Geranium thunbergii, Genno-shoko in Japanese. Considering seasonal variations of the agents and sites of cultivation of herbs, this paper reviews the significance of geraniin as a new cancer preventive agent. In addition, based on accumulated results of green tea as a cancer preventive, we review two important results with EGCG: the synergistic effects of EGCG with sulindac or tamoxifen on cancer preventive activity in PC-9 cells, and cancer prevention of intestinal tumor development in multiple intestinal neoplasia (Min) mice by cotreatment using EGCG with sulindac. We report here new findings on additional gene expression resulting from cotreatment with EGCG and sulindac in PC-9 cells compared with gene expression by EGCG alone or sulindac alone. Overall, our results indicate that, with the continuing spread of cancer chemoprevention as a fundamental medical strategy, both clinicians and researchers should take a closer look at herbal medicine.

Medicinal foodstuffs. XXXI. Structures of new aromatic constituents and inhibitors of degranulation in RBL-2H3 cells from a Japanese folk medicine, the stem bark of Acer nikoense.

Four new aromatic constituents, rhododendroketoside, (-)-sakuraresinoside, acernikol, and nikoenoside, were isolated from a Japanese folk medicine, the stem bark of Acer nikoense MAXIM. The structures of the new constituents were determined on the basis of chemical and physicochemical evidence. The principle cyclic diarylheptanoids were found to show inhibitory effects on the release of beta-hexosaminidase in RBL-2H3 cells.

Structures of New Cyclic Diarylheptanoids and Inhibitors of Nitric Oxide Production from Japanese Folk Medicine Acer nikoense

Three new cyclic diarylheptanoids, acerosides B1 and B2 and aceroketoside, were isolated together with 20 known compounds from a Japanese folk medicine, the stem bark of Acer nikoense. The absolute stereostructures of the new compounds were determined on the basis of chemical and physicochemical evidence. In addition, the principal diarylheptanoid constituents were found to exhibit inhibitory activity on nitric oxide production in lipopolysaccharide-activated macrophages.

New TNF-alpha releasing inhibitors, geraniin and corilagin, in leaves of Acer nikoense, Megusurino-ki.

The success of green tea as a cancer preventive is based on evidence that green tea contains tannins and antioxidants, does not show toxicity in humans and has long traditional use in Asia. In the light of this, herbal medicines are now also attracting attention as potential sources of cancer preventive agents. Using the inhibition of TNF-alpha release assay, we studied Acer nikoense (Megusurino-ki in Japanese), one of the herbal medicines. The inhibitory activity of TNF-alpha release was found in the leaf extract rather than the bark extract, and the main active constituents were identified as geraniin and corilagin, which are present in another Japanese traditional herb, Geranium thunbergii (Genno-shoko). The IC50 values of TNF-alpha release inhibition were 43 microM for geraniin and 76 microM for corilagin, whereas that for (-)-epigallocatechin gallate (EGCG) was 26 microM. Treatment with geraniin prior to application of okadaic acid, a tumor promoter on mouse skin initiated with 7,12-dimethylbenz(a)anthracene, reduced the percentage of tumor-bearing mice from 80.0 to 40.0% and the average numbers of tumor per mouse from 3.8 to 1.1 in week 20. Thus, geraniin has slightly weaker inhibitory activity than EGCG. Since geraniin and corilagin have been well investigated as representative tannins, we discuss here the new possibility of classical herbal medicine in the development of preventive agents for cancer and other life-style related diseases.

Antifungal activity of plant extracts against Arthrinium sacchari and Chaetomium funicola

Various plant extracts were examined for antifungal activity with the objective of improving the commercial sterility of aseptically filled tea beverage products in PET bottles. When the hot water extract and the methanol extract of 29 samples were measured for their antifungal activity against Arthrinium sacchari M001 and Chaetomium funicola M002 strains, five samples, Acer nikoense, Glycyrrhiza glabra, Lagerstroemia speciosa, Psidium guajava and Thea sinensis, showed high activity. Of these, the extracts from A. nikoense, G. glabra and T. sinensis were fractionated by extraction with CHCl 3, and the CHCl 3-soluble fractions from G. glabra showed antifungal activity with minimum inhibitory concentrations (MICs) between 62.5 and 125 μg/ml against the above-mentioned two fungi. When the EtOAc-soluble fraction of A. nikoense was used, the MIC against A. sacchari M001 was 62.5 μg/ml. However, none of the fractions from A. nikoense or T. sinensis showed high activity against C. funicola M002 and their MICs were greater than 500 μg/ml. A licorice preparation made from the commercially available oil-based extract of G. glabra showed a low MIC of 25 μg/ml against five tested strains of filamentous fungi, but not against Aspergillus fumigatus M008, in a blended tea. Consequently, the possibility of adding a licorice preparation made from the oil-based extract of G. glabra to tea beverages (aseptically filled into PET bottles) was suggested.

Antifungal Activity of Plant Extracts against Arthrinium sacchari and Chaetomium funicola.

Various plant extracts were examined for antifungal activity with the objective of improving the commercial sterility of aseptically filled tea beverage products in PET bottles. When the hot water extract and the methanol extract of 29 samples were measured for their antifungal activity against Arthrinium sacchari M001 and Chaetomium funicola M002 strains, five samples, Acer nikoense, Glycyrrhiza glabra, Lagerstroemia speciosa, Psidium guajava and Thea sinensis, showed high activity. Of these, the extracts from A. nikoense, G. glabra and T. sinensis were fractionated by extraction with CHCl3, and the CHCl3-soluble fractions from G. glabra showed antifungal activity with minimum inhibitory concentrations (MICs) between 62.5 and 125 μg/ml against the above-mentioned two fungi. When the EtOAc-soluble fraction of A. nikoense was used, the MIC against A. sacchari M001 was 62.5 μg/ml. However, none of the fractions from A. nikoense or T. sinensis showed high activity against C. funicola M002 and their MICs were greater than 500 μg/ml. A licorice preparation made from the commercially available oil-based extract of G. glabra showed a low MIC of 25 μg/ml against five tested strains of filamentous fungi, but not against Aspergillus fumigatus M008, in a blended tea. Consequently, the possibility of adding a licorice preparation made from the oil-based extract of G. glabra to tea beverages (aseptically filled into PET bottles) was suggested.

Hot water extract of bark of Nikko maple (Acer nikoense) induces apoptosis in leukemia cells.

In screening for antitumor constituents in traditional crude drugs, we used three cultured cell lines: mouse leukemia P388 cells, doxorubicin-resistant P388 cells and leczyme (catalytic lectin)-resistant P388 cells. The hot water extract (HWE) of the bark of Nikko maple (Acer nikoense) showed concentration-dependent inhibitory effects on the growth of these three cell lines. DNA fragmentation and morphological changes, accompanied by condensed and fragmented nuclei, were observed in the leukemia cell lines cultured with HWE of the bark of Nikko maple. Treatment with this HWE increased the expression of sialylated glycoconjugates on the apoptotic cells. These results suggest that HWE induces cell death via apoptosis in vitro.

(+)-rhododendrol and epi-rhododendrin suppress the NO production by activated macrophages in vivo.

In this study, we investigated the effect of (+)-rhododendrol (1) and epi-rhododendrin (2) isolated from Acer nikoense Maxim. (Aceraceae) on nitric oxide (NO) production in mouse peritoneal macrophages elicited by bacillus Calmette-Guérin and in vitro stimulated by lipopolysaccharide. The NO production was not affected by an oral administration of methanol extract at a dose of 100 mg/kg/day. However, the AcOEt soluble fraction significantly reduced the NO production. (+)-Rhododendrol (1) isolated as an active substance from the AcOEt fraction suppressed the NO production. epi-Rhododendrin (2), the glucoside of (+)-rhododendrol (1) isolated from the n-BuOH fraction, also suppressed the NO production. As NO is one of the critical mediators in inflammation, these results suggest that (+)-rhododendrol (1) and epi-rhododendrin (2) contribute in part to the anti-inflammatory effect of A. nikoense.

Synthesis of Acerogenin C and (+)-Acerogenin A, Two Macrocyclic Diarylheptanoid Constituents ofAcer nikoense

The macrocyclic ketone acerogenin C (3) and the corresponding alcohol (+)-accerogenin A (1), diarylheptanoid constituents of the maple Acer nikoense were synthesized. The key steps were the selective reduction of the double bond of an α,β-unsaturated ketone (10) and macrocyclization of an iodophenol (13) by a modified Ullmann diarylether synthesis.

Rhododendrol biosynthesis and metabolism in Acer nikoense callus

Cell suspensions derived from Acer nikoense callus, not containing (S)-rhododendrol, converted 4-(p-hydroxyphenyl)-2- butanone into (R)-, (S)-rhododendrol and their glycosides. (R)- and (S)-rhododendrol formed was only detected in the culture medium and their glycosides only in the cells. The former compound disappeared within a short time and the latter one also tended to decrease during prolonged culture. Quantitative analysis of rhododendrol glycosides in the callus showed that most of them were (S)-rhododendrol 2-O-β-D-glucopyranoside and its content was much lower than that of the original plants. © Rapid Science Ltd. 1998

Studies on the Constituents of Aceraceae Plants. XIII. Diarylheptanoids and Other Phenolics from Acer nikoense.

From a mixture of the bark and twigs of Acer nikoense MAXIM. (Aceraceae), nine compounds (1-9) were newly isolated. Compound 1 was identical with acerogenin E, and compounds 8 and 9 were β-orcinol derivatives. Acerogenin K (2), a new diarylheptanoid of the cyclic diphenyl type, yielded acerogenin E on oxidation. Acerogenins F (3) through L (7) are new diarylheptanoids of the cyclic biphenyl ether type, whose skeletons and substituents of the diphenyl ether moieties are the same as those of acerogenin A. Their structures were elucidated on the basis of chemical and spectroscopic evidence.

Bioconversion of rhododendrol by Acer nikoense

Callus derived from Acer nikoense tissue contained the same compounds as the parent plants, but (+)-rhododendrol, which has hepatoprotective activity, was not detected in the methanol extract of the callus. Cells in suspension culture converted ( RS)-rhododendrol into ( RS)-rhododendrol 2-O-β- d-glucopyranoside and ( R)-rhododendrol 2-O- β- d-xylopyranosyl-(1 → 6)-β- d-glucopyranoside . This is the first time that the latter compound has been isolated from a natural source.

Stereospecific synthesis and absolute configuration of (+)-rhododendrol

The stereospecific synthesis of (+)-rhododendrol, a constituent of Rhododendron maximum and Acer nikoense, by enzymatic reduction of4-(4′-hydroxyphenyl)-2-butanone has shown that the absolute configuration of the molecule is S.

Studies on the Constituents of Aceraceae Plants. XI. Two Types of Cyclic Diarylheptanoid from Acer nikoense.

Studies on the Constituents of Aceraceae Plants. XI. Two Types of Cyclic Diarylheptanoid from Acer nikoense.

Constituents of Acer nikoense and Myrica rubra. On diarylheptanoids

The diarylheptanoid constituents of the titled plants and their close plants were reviewed. Many new diarylheptanoids and their glycosides named acerogenin and aceroside were isolated from the stem bark of Acer nikoense, A. griseum and A. triflorum. Myricanone, myricanol and its five new glycosides were isolated from the stem bark of Myrica rubra, and myricanone and galeon, from the stem of M. gale var. tomentosa. The structures of these compounds were determined on the basis of chemical and spectral evidence, and chemotaxonomy of the above plants was briefly discussed. In addition biosynthesis of acerogenin A, revision of the structure for isomyricanone derived from myricanone, and some biological activities of A. nikoense and M. rubra were described.

Protective effects of the fractions extracted from the callus of Acer nikoense Maxim. on alpha-naphthylisothiocyanate induced liver injury

It has been reported that the methanol extract from the bark of Acer nikoense MAXIM. (AN) and the fractions separated from this extract showed the protection for liver injuries induced by carbontetrachloride (CCl4) in rat. On the other hand, the evidence manifested that the fractions of the callus of young branches from AN were recognized to have protective effects on the CCl4-induced liver injuries in rat. In this study, the protective activities of the fractions extracted from the callus of AN were investigated on the alpha-naphthylisothiocyanate (ANIT)-induced liver injuries in rat. The protectively active principles on the ANIT-induced liver injuries were found in the ether soluble fraction. The components of the protective effect were purified by repeated silica gel chromatographies. One of the protective substances in this fraction was identified to be beta-sitosterol. The protective fractions on the ANIT-induced liver injuries showed the protective effects on ANIT-induced cholestasis, but did not show cholagogic effects.

ラット四塩化炭素肝障害に対するメグスリノキカルスの防護効果

The decoctions extracted from the bark and leaf of Acer nikoense Maxim. (AN) have been used as a folk medicine for eye-wash and hepatic disease. As previously reported, the methanol extract from the bark of AN and the fractions of the methanol extract have protective effects for liver injury induced by carbon tetrachloride (CCl4) in rats. In this study, protective effects of the fractions extracted from the callus of AN were investigated on CCl4-induced liver injury in rat. The active principles for the protection of CCl4-induced liver injury were recognized in a fraction (EF 3-3) obtained by using silica gel chromatography (solvent: CHCl3-MeOH-H2O). The components were further fractionated by silica gel chromatography followed by gel filtration (solvent: CHCl3-MeOH). In addition, the mechanism of the protective action against liver injury induced by CCl4 was also examined. The fractions with protective effects in vivo showed the inhibitory effects on CCl4-dependent lipid peroxidation in microsomal fraction in vitro.

Studies on chemical protectors against radiation. XXVI. Protective effect of various extracts on crude drugs on skin injury induced by X-irradiation

The protective potency against skin injury on mice induced by X-irradiation was studied by use of 72 extracts of crude drugs. The protective potency was determined according to the degrees on skin injury after irradiation of 1100R, 30 k Vp soft X-ray. As a result of these study, 16 kinds of crude drugs such as Rosae Fructus, Aloe arborescens (Herba), Citri Leiocarpae Exocarpium, Schizonepetae Spica, Evodiae Fructus, Bupleuri Radix, Corni Fructus, Perillae Herba, Anemarrhenae Rhizoma, Menthae Herba, Trapae Fructus, Angelicae Dahuricae Radix, Sinomeni Caulis et Rhizoma, Ephedrae Herba, Acer nikoense (Cortex), Forsythiae Fructus, revealed protective potencies on skin injury.

Biosynthesis of acerogenin A, a diarylheptanoid from acer nikoense

The biosynthesis of acerogenin A was studied by feeding various 14C-labelled compounds to the young shoots of Acer nikoense. Phenylalanine and cinnamic acid were the best precursors. C-2 of both acetate and malonic acid were efficiently incorporated into acerogenin A, but C-1 of acetate and the methyl carbon of methionine were incorporated very poorly. These results show that acerogenin A is probably biosynthesized via (−)-centrolobol derived from two p-coumarate residues and one malonate.

Studies on the constituents of aceraceae plants. VI. Revised stereochemistry of (-)-centrolobol, and new glycosides from Acer nikoense.

Two diarylheptanoid glycosides, named aceroside VII (8), C25H34O8, mp 144-145°C, [α]15D -28.4°, and aceroside VIII (9), C30H42O12, [α]15D -64.8° were isolated from the stem bark of Acernikoense MAXIM. (Aceraceae). On acid hydrolysis 8 yielded (-)-centrolobol (10) and glucose, while 9, on partial hydrolysis, gave 8 and apiose. Acerosides VII (8) and VIII (9) were determined to be the 3-O-β-D-glucopyranoside and the 3-O-β-D-apiofuranosyl-(1→6)-β-D-glucopyranoside of (-)-centrolobol (10), respectively, on the basis of carbon-13 nuclear magnetic resonance (13C-NMR) spectral analyses and additional chemical data.The absolute configuration S for (-)-centrolobol (10) has been claimed, but the authors propose its revision to R(-) on the basis of Brewster's empirical rule on the correlation between absolute configuration and optical rotation. The stereochemistries of some compounds related to 10 such as acerogenin A (1) and (-)-centrolobin should also be revised. At the same time, partial revision of the 13C-NMR signal assignments for acerosides III (3) and VI (4) is also necessary.