Acer Nikoense Research Articles

A natural diphenolic glucoside, sonnerphenolic C: Chemical synthesis, structural revision, redox transformation, and identification as an antioxidant

To investigate the redox o-hydroxylation of epirhododendrin (1) with tyrosinase and vitamin C, the possible product, sonnerphenolic C (2), and its epimer, tripodantoside (3), were synthesized for the first time via key steps including glycosylation and epimeric separation. The NMR data of synthetic compounds 2 and 3 were completely consistent with those of natural products 2 and 3, respectively. However, the specific rotation value of synthesized 2 (−15.5, c 1.8 in MeOH) was different from that of the previously reported data (+33.4, c 1.8 in MeOH) of natural product 2. L-Glucoside 5, the enantiomer of 2, was successively prepared through a similar synthetic route using l-glucose as the sugar material. The specific rotation value of 5 was recorded as +18.5 (c 1.8 in MeOH), indicating that the structure of natural product 2 should be revised to that of 5. Additionally, 1 and its epimer rhododendrin (4), were concisely synthesized using the same steps for 2 and 3. The initially proposed redox transformation of 1 to 2 was confirmed by the analysis of the reaction mixture with 1, tyrosinase, and vitamin C. Furthermore, 2 was newly identified in Acer nikoense extract as a natural antioxidant by HPLC and 2,2-diphenyl-1-picrylhydrazyl radical scavenging experiments.

Complete chloroplast genome sequence of Acer nikoense (Sapindaceae)

Acer nikoense (Sapindaceae: Acer) is a deciduous tree, belonging to the Ser. Grisea of Sect. Trifoliata. Its complete genome sequence was obtained using genome Illumina pair-end sequencing data. It had a typical quadripartite structure with 155,952 bp in length, consisting of a large single-copy region (85,720 bp) and a small single-copy region (18,072 bp), as well as a pair of inverted repeats (26,080 bp). The total GC content was 37.9%. A total of 113 unique genes were annotated, including 30 tRNAs, 4 rRNAs, and 79 protein-coding genes. The phylogenetic analysis indicated that A. nikoense and A. triflorum were the most closely related.

Vasorelaxant effects of diarylheptanoids, acerogenin A and (−)‐centrolobol from the bark of Acer nikoense

ABSTRACTAimThe bark of Acer nikoense (Aceraceae) is used in Japanese folk medicine as a remedy for hepatic disorders and eye diseases. The aim of this study was to investigate the vasorelaxant effects of A. nikoense extracts and further clarify the active constituents and mechanisms of action.MethodsDried A. nikoense bark was extracted with methanol. The extract was further extracted with diethyl ether, ethyl acetate, and 1‐butanol, successively. The major constituents of the extracts were isolated using chromatography. Vasorelaxant effects of the extracts and isolated constituents were assessed using isolated rat aorta. The aorta was placed in a well‐oxygenated bath of modified Krebs–Henseleit solution and the mechanical tension measured isometrically.ResultsThe extracts had a vasorelaxant effect on aorta precontracted with 3 × 10−7 mol/L norepinephrine (NE). Isolated major constituents of A. nikoense bark, diarylheptanoids, such as acerogenin A (compound 1), B (compound 2), (−)‐centrolobol (compound 3), aceroside I (compound 5), B1 (compound 6), VII (compound 7) III (compound 8), and phenolic compound, (+)‐rhododendrol (compound 4) were examined. Compounds 1 and 3 had vasorelaxant effects on rat aorta with or without endothelium in the NE‐induced preparation. Furthermore, compounds 1 and 3 inhibited contraction induced by a high concentration (60 mmol/L) of K+ and also had a moderate inhibitory effect on NE‐induced vasoconstriction in the presence of nicardipine.ConclusionThe inhibition of NE‐induced vasoconstriction by compounds 1 and 3 may be attributed to factors such as endothelial independency by blocking of Ca2+ influx via voltage‐dependent Ca2+ channels and receptor‐operated Ca2+ channels.

Chemical synthesis, redox transformation, and identification of sonnerphenolic C, an antioxidant in Acer nikoense

Sonnerphenolic C (3), which was predicted in a redox product of epirhododendrin (1) isolated from Acer nikoense, was synthesized for the first time via the epimeric separation of benzylidene acetal intermediates as a key step. From a similar synthetic route, 1 was obtained concisely. As a result of their antioxidative evaluation, only 3 revealed potent activity. The redox transformation of 1 into 3 was achieved in the presence of tyrosinase and vitamin C. Moreover, 3 was identified in the decoction of A. nikoense by HPLC analysis with the effective use of synthesized 3. Thus, a novel naturally occurring antioxidant 3 was developed through the sequential flow including redox prediction, chemical synthesis, evaluation of the activity, and identification as the natural product.

Acerogenin C from Acer nikoense exhibits a neuroprotective effect in mouse hippocampal HT22 cell lines through the upregulation of Nrf-2/HO-1 signaling pathways

Oxidative stress contributes to neuronal death in the brain, and neuronal death can cause aging or neurodegenerative disease. Heme oxygenase1 (HO-1) serves a vital role in the regulation of biological reactions, including oxidative stress associated with reactive oxygen species. In the present study, acerogeninC isolated from the Aceraceae plant Acernikoense, which is used as a Japanese folk medicine for hepatic disorders and eye diseases. However, there have been no studies on the mechanisms underlying the antineurodegenerative biological activities of acerogeninC. In the present study, acerogeninC demonstrated neuroprotective action against glutamate‑induced cell death in hippocampal HT22 cells through the upregulation of HO‑1 expression. These effects were also associated with nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and the activation of phosphoinositide 3‑kinase/protein kinase B. Taken together of the efficacy researches, this study determines that the Nrf2/HO‑1 pathways denotes a biological mark and that acerogenin C might contribute to prevention of neurodegenerative disorders.

Rhododenol and raspberry ketone impair the normal proliferation of melanocytes through reactive oxygen species-dependent activation of GADD45

Rhododenol or rhododendrol (RD, 4-(4-hydroxyphenyl)-2-butanol) occurs naturally in many plants along with raspberry ketone (RK, 4-(4-hydroxyphenyl)-2-butanone), a ketone derivative, which include Nikko maple tree (Acer nikoense) and white birch (Betula platyphylla). De-pigmenting activity of RD was discovered and it was used as a brightening ingredient for the skin whitening cosmetics. Recently, cosmetics containing RD were withdrawn from the market because a number of consumers developed leukoderma, inflammation and erythema on their face, neck and hands. Here, we explored the mechanism underlying the toxicity of RD and RK against melanocytes using B16F10 murine melanoma cells and human primary epidermal melanocytes. Treatment with RD or RK resulted in the decreased cell viability in a dose-dependent manner which appeared from cell growth arrest. Consistently, ROS generation was significantly increased by RD or RK as determined by DCF-enhanced fluorescence. An antioxidant enzyme, glutathione peroxidase was depleted as well. In line with ROS generation, oxidative damages and the arrest of normal cell proliferation, GADD genes (Growth Arrest and DNA Damage) that include GADD45 and GADD153, were significantly up-regulated. Prevention of ROS generation with an anti-oxidant, N-acetylcysteine (NAC) significantly rescued RD and RK-suppressed melanocyte proliferation. Consistently, up-regulation of GADD45 and GADD153 was significantly attenuated by NAC, suggesting that increased ROS and the resultant growth arrest of melanocytes may contribute to RD and RK-induced leukoderma.

Acylated Triterpene Saponins from the Stem Bark of Acer nikoense (Aceraceae).

Three new acylated triterpene saponins, acernikoenosides A-C (1-3), were isolated from the stem bark of Acer nikoense, together with a known sterol glucoside. Their structures were elucidated on the basis of extensive spectroscopic analyses. This study provided the first example of triterpene saponins isolated from this plant. The anti-genotoxic activity of 1, 3 and 4 against ultraviolet irradiation was evaluated by comet assay.

Acerogenin A from Acer nikoense Maxim Prevents Oxidative Stress-Induced Neuronal Cell Death through Nrf2-Mediated Heme Oxygenase-1 Expression in Mouse Hippocampal HT22 Cell Line.

Oxidative cell damage contributes to neuronal degeneration in many central nervous system (CNS) diseases such as Parkinson’s disease, Alzheimer’s disease, and ischemia. Inducible heme oxygenase (HO)-1 acts against oxidants that are thought to play a key role in the pathogenesis of neuronal diseases. The stem bark of Acer nikoense Maxim (Aceraceae) is indigenous to Japan; it has been used in folk medicine as a treatment of hepatic disorders and eye diseases. Acerogenin A, a natural compound isolated from Japanese folk medicine A. nikoense, showed neuroprotective effects and reactive oxygen species (ROS) reduction on glutamate-induced neurotoxicity by inducing the expression of HO-1 in mouse hippocampal HT22 cells. Furthermore, acerogenin A caused the nuclear accumulation of nuclear factor-E2-related factor 2 (Nrf2) and the activation of the PI3K/AKT signaling pathways. In this study, we demonstrated that acerogenin A effectively prevents glutamate-induced oxidative damage, and HO-1 induction via PI3K/Akt and Nrf2 pathways appears to play a key role in the protection of HT22 cells. Therefore, this study implies that the Nrf2/HO-1 pathway represents a biological target and that acerogenin A might be a candidate for the prevention of neurodegeneration.

Total synthesis of acerogenins E, G and K, and centrolobol

The first total synthesis of the diarylheptanoid acerogenins E and K, isolated from Acer nikoense MAXIM., is described. Formation of the 13-membered m,m-cyclophane skeleton was successfully achieved on the basis of a domino process involving a Miyaura arylborylation–intramolecular Suzuki reaction. The cyclization precursor was prepared via a Wittig reaction and Claisen–Schmidt condensation, which proceeded in moderate yields. The total synthesis of acerogenin G and centrolobol was also achieved from a common synthetic intermediate.

Melanogenesis‐Inhibitory and Cytotoxic Activities of Diarylheptanoids from Acer nikoense Bark and Their Derivatives

Nine cyclic diarylheptanoids, 1-9, including two new compounds, i.e., 9-oxoacerogenin A (8) and 9-O-β-D-glucopyranosylacerogenin K (9), along with three acyclic diarylheptanoids, 10-12, and four phenolic compounds, 13-16, were isolated from a MeOH extract of the bark of Acer nikoense (Aceraceae). Acid hydrolysis of 9 yielded acerogenin K (17) and D-glucose. Two of the cyclic diarylheptanoids, acerogenin A (1) and (R)-acerogenin B (5), were converted to their ether and ester derivatives, 18-24 and 27-33, respectively, and to the dehydrated derivatives, 25, 26, 34, and 35. Upon evaluation of compounds 1-16 and 18-35 for their inhibitory activities against melanogenesis in B16 melanoma cells, induced with α-melanocyte-stimulating hormone (α-MSH), eight natural glycosides, i.e., six diarylheptanoid glycosides, 2-4, 6, 9, and 12, and two phenolic glycosides, 15 and 16, exhibited inhibitory activities with 24-61% reduction of melanin content at 100 μM concentration with no or almost no toxicity to the cells (88-106% of cell viability at 100 μM). In addition, when compounds 1-16 and 18-35 were evaluated for cytotoxic activity against human cancer cell lines, two natural acyclic diarylheptanoids, 10 and 11, ten ether and ester derivatives, 18-22 and 27-31, and two dehydrated derivatives, 34 and 35, exhibited potent cytotoxicities against HL60 human leukemia cell line (IC(50) 8.1-19.3 μM), and five compounds, 10, 11, 20, 29, and 30, against CRL1579 human melanoma cell line (IC(50) 10.1-18.4 μM).

Cyclic diarylheptanoids as inhibitors of NO production from Acer nikoense

We prepared a series of acerogenins A and B derivatives as inhibitors of nitric oxide (NO) production in vitro. Our results suggested that an ester group at a hydroxyl at C-2 improved inhibitory effects without cytotoxicity. A benzoyl ester derivative of acerogenin C showed the most potent inhibitory activity of NO production from lipopolysaccharide-activated macrophages.

Osteogenic activity of diphenyl ether-type cyclic diarylheptanoids derived from Acer nikoense

Osteogenic activity of six diarylheptanoids, acerogenin A (1), (R)-acerogenin B (2), aceroside I (3), aceroside B(1) (4), aceroside III (5) and (-)-centrolobol (6) and two phenolic compounds; (+)-rhododendrol (7) and (+)-cathechin (8), isolated from the stem bark of Acer nikoense (Nikko maple) was evaluated using alkaline phosphatase (ALP) activity as a marker for early osteoblast differentiation. We found that the diphenyl ether-type cyclic diarylheptanoids 1-5 promoted ALP activity in mouse preosteoblastic MC3T3-E1 cells without affecting cell proliferation, but linear-type diarylheptanoid 6 and phenolic compounds 7 and 8 did not. Diphenyl ether-type cyclic diarylheptanoids 1-4 also increased protein production of osteocalcin, a late stage maker for osteoblast differentiation, and induced osteoblastic mineralization. Structure-activity relationships of these compounds demonstrated that the stimulative efficacy of aglycones was higher than that of its glycosides. Taken together, diphenyl ether-type cyclic diarylheptanoids promote early- and late-stage osteoblastogenesis, which may open the possibility for the development of novel osteogenic agents.

Acerogenin A, a natural compound isolated from Acer nikoense Maxim, stimulates osteoblast differentiation through bone morphogenetic protein action

We investigated the effects of acerogenin A, a natural compound isolated from Acer nikoense Maxim, on osteoblast differentiation by using osteoblastic cells. Acerogenin A stimulated the cell proliferation of MC3T3-E1 osteoblastic cells and RD-C6 osteoblastic cells (Runx2-deficient cell line). It also increased alkaline phosphatase activity in MC3T3-E1 and RD-C6 cells and calvarial osteoblastic cells isolated from the calvariae of newborn mice. Acerogenin A also increased the expression of mRNAs related to osteoblast differentiation, including Osteocalcin, Osterix and Runx2 in MC3T3-E1 cells and primary osteoblasts: it also stimulated Osteocalcin and Osterix mRNA expression in RD-C6 cells. The acerogenin A treatment for 3days increased Bmp-2, Bmp-4, and Bmp-7 mRNA expression levels in MC3T3-E1 cells. Adding noggin, a BMP specific-antagonist, inhibited the acerogenin A-induced increase in the Osteocalcin, Osterix and Runx2 mRNA expression levels. These results indicated that acerogenin A stimulates osteoblast differentiation through BMP action, which is mediated by Runx2-dependent and Runx2-independent pathways.

ChemInform Abstract: Cyclic Diarylheptanoids as Na+‐Glucose Cotransporter (SGLT) Inhibitors from Acer nikoense.

AbstractIsolation, structure determination and structure—activity relationships of two new diarylheptanoids, acerogenins A (Ia) and B (Ib), are described.

Cyclic diarylheptanoids as Na +-glucose cotransporter (SGLT) inhibitors from Acer nikoense

Two cyclic diarylheptanoids, acerogenins A ( 1) and B ( 2) have been isolated from the bark of Acer nikoense as inhibitors of Na +-glucose cotransporter (SGLT). Acerogenins A ( 1) and B ( 2) inhibited both isoforms, SGLT1 and SGLT2. Structure–activity relationship of acerogenin derivatives on inhibitory activity of SGLT as well as conformational analysis of 1 and 2 on the basis of J-resolved HMBC spectra and X-ray analysis were discussed.

Vasorelaxant Effects of Acer nikoense Extract and Isolated Coumarinolignans on Rat Aortic Rings

The organic extract of the heartwood of Acer nikoense Maxim. (Aceraceae) showed vasorelaxant activity on rat aorta with or without endothelium. Coumarin [scopoletin (1)] and coumarinolignans [cleomiscosin A (2) and aquillochin (3)] were isolated as major constituents from the organic extract of the heartwood of A. nikoense. Compounds 1-3 exhibited moderate vasorelaxant effects on rat aorta, while 2 and 3 showed vasorelaxant effects in the norepinephrine-stimulated and also in high K+-depolarized preparations.

Search for bioactive constituents from several medicinal foods: hepatoprotective, antidiabetic, and antiallergic activities

In the course of our characterization studies on bioactive constituents from medicinal herbs, several medicinal foods and their constituents were found to show the following biological activities: (1) hepatoprotective sesquiterpenes from Zedoariae Rhizoma (2) α-glucosidase and aldose reductase inhibitors form Salacia spices and the flowers of Chrysanthemum indicum, and (3) anti-allergic and antiinflammatory diaryloheptanoids from the barks of Myrica rubra and Acer nikoense.

Acerogenin M, a Cyclic Diarylheptanoid, and Other Phenolic Compounds from Acer nikoense and Their Antiinflammatory and Antitumor‐Promoting Effects.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Acerogenin M, a Cyclic Diarylheptanoid, and Other Phenolic Compounds from Acer nikoense and Their Anti-inflammatory and Anti-tumor-Promoting Effects

A new cyclic diarylheptanoid, acerogenin M (1), has been isolated along with nine known diarylheptanoids, 2-10, and two known phenolic compounds, 11 and 12, from a MeOH extract of the stem bark of Acer nikoense MAXIM. (Aceraceae). The structure of 1 was determined on the basis of a spectroscopic method. Upon evaluation of the inhibitory effects on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation (1 microg/ear) in mice of nine of the compounds (2-6, 8, 10-12), six (2, 4-6, 8, 10) showed a marked anti-inflammatory effect with a 50% inhibitory dose (ID(50)) of 0.26-0.81 mg per ear. In addition, upon an evaluation against the Epstein-Barr virus early antigen (EBV-EA) activation induced by TPA for all of the compounds, all exhibited moderate inhibitory effects against EBV-EA induction (IC(50) values of 356-534 mol ratio/32 pmol TPA).

Melanogenesis Inhibitory and Free Radical Scavenging Activities of Diarylheptanoids and Other Phenolic Compounds from the Bark of Acer nikoense

Melanogenesis inhibitory and free radical scavenging activities of nine cyclic (1-9) and one acyclic diarylheptanoids (10), and two phenolic compounds, (+)-rhododendrol (11) and (+)-catechin (12), isolated from the ethyl acetate-soluble fraction of the MeOH extract of the bark of Acer nikoense MAXIM. (Aceraceae) were examined. Upon evaluation of compounds 1-12 on the melanogenesis in the B16 melanoma cells, two compounds, 2 and 8, exhibited marked inhibitory activity with 55.6% and 46.8% reduction, respectively, of melanin content at 25 microg/ml without inhibition of cell proliferation. In addition, upon an evaluation of eleven compounds, 1-7 and 9-12 against the scavenging activities of free radicals (against the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical), compound 12 (IC(50) 9.0 microgM) followed by compounds 1, 3, 4, and 6 (IC(50) 40.2-44.0 microgM) showed potent scavenging activities.