Structural analysis of the inhibitory effects of polyphenols, (+)-hopeaphenol and (-)-isohopeaphenol, on human SIRT1.

Human sirtuin 1 (hSIRT1) is a NAD+ -dependent deacetylase that regulates several cellular processes. Unlike resveratrol, natural polymeric phenolic compounds isolated from Vitaceae are mostly hSIRT1 inhibitors. The resveratrol tetramer, (+)-hopeaphenol ((+)-HP), and its geometric isomer, (-)-isohopeaphenol ((-)-iHP), were tested for inhibitory effects on purified hSIRT1 using a fluorescent derivative of peptide substrate p53-AMC (Fluor de Lys) and a cofactor NAD+ . The Lineweaver-Burk plots indicated that both (+)-HP and (-)-iHP were competitive inhibitors against NAD+ . Computer-assisted modeling of the binding of these molecules with hSIRT1 protein provided the most feasible conformation of the enzyme-inhibitor complex. © 2018 BioFactors, 45(2):253-258, 2019.

Alkylbenzoquinone involved in development of cellular slime molds.

The structure of the prespore-cell-promoting factor from Dictyostelium discoideum was determined to be 2-hydroxy-5-methyl-6-pentylbenzoquinone. The synthetic compound has prespore-cell-promoting activity similar to the natural one, with half-maximal induction at a concentration as low as 40 pM. It was also found that the factor induces aggregation in an aggregation-deficient mutant of a related species, Polysphodilium violaceum. Both these activities are sensitive to positional isomerism with the 6-methyl-5-pentyl isomer showing no detectable activity.

A new pentacyclic triterpenoid from the leaves of Lantana montevidensis (Spreng.) Briq.

A new pentacyclic triterpenoid, 3ß,25-epoxy-3α,22ß,23α-trihydroxy-olean-12-en-28-oic acid (1), together with seven known compounds, including five triterpenoids, ß-amyrin (2), lantadene B (3), lantanilic acid (4), lantanolic acid (5) and ursolic acid (6) in addition to ß-sitosterol (7) and benzoic acid (8) has been isolated from the leaves of Lantana montevidensis. Their chemical structures were elucidated by spectroscopic analysis and by comparison with the literature data and/or authentic samples. Compound 1 showed moderate to weak antibacterial activity against Staphylococcus aureus and Escherichia coli.

Suppressive effect of the hot-water extract of Ficus pseudopalma Blanco leaves on the postprandial increase in blood glucose level in mice.

The use of medicinal plants with anti-diabetic properties continues because of the high cost of diabetes mellitus treatment. In the Bicol region of the Philippines, one local source is the leaves of Ficus pseudopalma Blanco (Philippine fig), which is utilized as an ingredient of their cuisine, and the decoction of its leaves is believed to have a blood-glucose lowering effect. The aim of this study was to evaluate the blood-glucose lowering effect of F. pseudoplama using sugar/carbohydrate-loaded and normoglycemic mice. The results showed that the hot-water extract of the leaves significantly suppressed the increase of blood glucose levels after glucose, maltose and starch loading. On the other hand, the extract did not show any hypoglycemic activity in either fasted or non-fasted mice as compared to the positive control drugs. These results suggest that F. pseudopalma is potentially useful for the management of blood glucose levels in the postprandial condition, as believed in the Bicol region of the Philippines.

Cyclic dipeptides exhibit potency for scavenging radicals.

Twenty kinds of cyclic dipeptides containing l-leucine were synthesized, and their antioxidant activity against ·OH and O(2)(·-) was investigated. Compounds possessing polar amino acid residues, such as Asp, Cys, Glu, Lys, Pro, Ser, and Trp, exhibited higher antioxidant activity against ·OH than vitamin E. However, only cyclo(l-Cys-l-Leu) scavenged O(2)(·-).

Benzenepolycarboxylic acids with potential anti-hemorrhagic properties and structure-activity relationships.

Previously, we reported the structural requirements of the cinnamic acid relatives for inhibition of snake venom hemorrhagic action. In the present study, we examined the effect of benzenepolycarboxylic acids and substituted benzoic acids against Protobothropsflavoviridis venom-induced hemorrhage. Pyromellitic acid (1,2,4,5-benzenetetracarboxylic acid) was found to be a potent inhibitor of hemorrhage, with an IC(50) value of 0.035 µM. In addition, most of the antihemorrhagic activity of compounds tested in this experiment showed good correlation to acidity.

Protective effects of cyclo(L-Leu-L-Tyr) against postischemic myocardial dysfunction in guinea-pig hearts.

The protective effects of cyclic dipeptides in alcoholic beverages were investigated in the perfused guinea-pig hearts subjected to ischemia and reperfusion. Subsequently, in order to determine the importance of cyclic dipeptide structure, the effects of cyclo(L-Leu-L-Tyr) (cLY) were compared with those of the newly synthesized non-cyclic dipeptides, L-Leu-L-Tyr (LY) and L-Tyr-L-Leu (YL). After reperfusion, pressure recovery (%) in the left ventricle reached a peak of over 90% in the presence of cLY (10(-6) M and 10(-5) M) (control: 22.9%). The recovery by LY and YL was significantly lower than that by cLY, and ATP levels simultaneously monitored using (31)P-NMR were already lower during the ischemic end period than those observed with cLY treatment. In perfused mitochondrial preparations, cLY significantly inhibited mitochondrial Ca(2+) ([Ca(2+)](m)) elevation in a similar way to that of the mitochondrial permeability transition pore (MPTP) inhibitor cyclosporin A. In vitro electron paramagnetic resonance (EPR) revealed that the active oxygen radicals quenching activity of cLY was greater than those of non-cyclic dipeptides. cLY inhibited caspase-3-induced apoptosis. The cyclic dipeptide structure inhibits opening of the MPTP by preventing [Ca(2+)](m) overload-induced apoptosis related to mitochondrial active oxygen radical accumulation in ischemia-reperfusion hearts.

Contribution of cinnamic acid analogues in rosmarinic acid to inhibition of snake venom induced hemorrhage.

In our previous paper, we reported that rosmarinic acid (1) of Argusia argentea could neutralize snake venom induced hemorrhagic action. Rosmarinic acid (1) consists of two phenylpropanoids: caffeic acid (2) and 3-(3,4-dihydroxyphenyl)lactic acid (3). In this study, we investigated the structural requirements necessary for inhibition of snake venom activity through the use of compounds, which are structurally related to rosmarinic acid (1). By examining anti-hemorrhagic activity of cinnamic acid analogs against Protobothrops flavoviridis (Habu) venom, it was revealed that the presence of the E-enoic acid moiety (-CH=CH-COOH) was critical. Furthermore, among the compound tested, it was concluded that rosmarinic acid (1) (IC(50) 0.15 µM) was the most potent inhibitor against the venom.

Rosmarinic acid in Argusia argentea inhibits snake venom-induced hemorrhage.

A methanolic extract of Argusia (or Messerschmidia or Tournefortia) argentea (Boraginaceae) significantly inhibited hemorrhage induced by crude venom of Trimeresurus flavoviridis. The extract was then separated according to antivenom activity by using silica gel column chromatography and HPLC equipped with an octadecylsilanized silica gel (ODS) column to afford rosmarinic acid (RA) (1) as an active principle. RA (1) significantly inhibited the hemorrhagic effect of crude venoms of T. flavoviridis, Crotalus atrox, Gloydius blomhoffii, Bitis arietans as well as snake venom metalloproteinases, HT-b (C. atrox), bilitoxin 2 (Agkistrodon bilineatus), HF (B. arietans), and Ac1-proteinase (Deinagkistrodon acutus). This is the first report of the antihemorrhage activity of RA (1), and RA (1) greatly contributes to the antihemorrhagic efficiency of A. argentea against crude snake venoms and hemorrhagic toxins.

Biological and pathological studies of rosmarinic acid as an inhibitor of hemorrhagic Trimeresurus flavoviridis (habu) venom.

In our previous report, rosmarinic acid (RA) was revealed to be an antidote active compound in Argusia argentea (family: Boraginaceae). The plant is locally used in Okinawa in Japan as an antidote for poisoning from snake venom, Trimeresurus flavoviridis (habu). This article presents mechanistic evidence of RA's neutralization of the hemorrhagic effects of snake venom. Anti-hemorrhagic activity was assayed by using several kinds of snake venom. Inhibition against fibrinogen hydrolytic and collagen hydrolytic activities of T. flavoviridis venom were examined by SDS-PAGE. A histopathological study was done by microscopy after administration of venom in the presence or absence of RA. RA was found to markedly neutralize venom-induced hemorrhage, fibrinogenolysis, cytotoxicity and digestion of type IV collagen activity. Moreover, RA inhibited both hemorrhage and neutrophil infiltrations caused by T. flavoviridis venom in pathology sections. These results demonstrate that RA inhibited most of the hemorrhage effects of venom. These findings indicate that rosmarinic acid can be expected to provide therapeutic benefits in neutralization of snake venom accompanied by heat stability.

Differentiation inducing factors in Dictyostelium discoideum: a novel low molecular factor functions at an early stage(s) of differentiation.

There are reports that secreted factor(s) are involved in prespore cell differentiation in Dictyostelium discoideum, but the structures and functions of the various factors have not been elucidated. Previously, we described two prespore cell-inducing factors in conditioned medium; one was a glycoprotein named prespore cell-inducing factor (psi factor, or PSI-1), and the other, a heat stable dialyzable factor(s). In the present paper, we purified and characterized the most potent prespore cell-inducing activity in dialysates. The factor began to be secreted after the onset of starvation and stopped being secreted once the cells had aggregated, which was earlier than the onset of the psi factor gene expression. In addition, unlike psi factor, its secretion did not appear to depend on activation of protein kinase A. Interestingly, the purified factor not only induced prespore cell specific genes such as pspA and cotC but also a prestalk-cell specific gene, ecmB in vitro. The purified factor is tentatively designated polyketide-like factor (PLF), because it seems to be a novel polyketide with 208 Da. Half maximal induction of prespore cell was obtained with 26 nmol/L of PLF. We propose that PLF plays a key role in the acquisition of differentiation commitment, before the psi factor induces specifically prespore cell differentiation.

Opposite effects of two resveratrol (trans-3,5,4'-trihydroxystilbene) tetramers, vitisin A and hopeaphenol, on apoptosis of myocytes isolated from adult rat heart.

It has been reported that resveratrol (trans-3,5,4'-trihydroxystilbene) from Vitis plants has various cardioprotective effects. Vitis plants also include various resveratrol tetramers. The aim of our study is to clarify the pharmacological properties of resveratrol tetramers. We isolated two resveratrol tetramers as major products of Vitis plants. One is vitisin A, a complex of two resveratrol dimers, (+)-epsilon-viniferin and ampelopsin B, and the other is hopeaphenol, composed of 2 mol ampelopsin B. Vitisin A (30-300 nM) unexpectedly dose-dependently facilitated swelling and depolarization of mitochondria and cytochrome c release from mitochondria, which are indices of cardiomyocyte apoptosis. Furthermore, vitisin A induced apoptosis in the primary culture of adult rat ventricular myocytes. On the other hand, hopeaphenol (1-10 microM) dose-dependently inhibited Ca(2+) (30 microM)-induced mitochondrial depolarization and cytochrome c release from mitochondria but had not affected mitochondrial swelling. Moreover, hopeaphenol inhibited vitisin A-induced apoptosis. In structural and functional studies, we further confirmed that vitisin B, one of the resveratrol tetramers having (+)-epsilon-viniferin unit, induces mitochondrial swelling and cytochrome c release from mitochondria like vitisin A and that vitisifuran A, one of the resveratrol tetramers having the ampelopsin B unit, inhibits Ca(2+)-induced cytochrome c release from mitochondria like hopeaphenol. These results show that resveratrol tetramers have at least two opposite effects on cardiomyocytes; the one having the (+)-epsilon-viniferin unit induces cardiomyocyte apoptosis, and the other having ampelopsin B but not (+)-epsilon-viniferin unit inhibits it.

Three new pentasaccharide resin glycosides from the roots of sweet potato (Ipomoea batatas).

Three new pentasaccharide resin glycosides, batatosides III-V (1-3), were isolated from the roots of Sweet potato (Ipomoea batatas). Saponification of the crude resin glycoside mixture yielded substituents and simonic acid B. The structures of the isolated compounds (1-3) were established through spectroscopic analyses, including high field NMR spectroscopy and HR-ESI-MS, and chemical correlation. The major characteristics of 3 are the presence of three different substituents, especially the substituent of cinnamic acid was seldom. The monosaccharides of 1-3 were proved by GC-MS and the absolute configuration of aglycone was further established as S by Mosher's method with R-methyloxyphenylacetic acid (MPA) and S-MPA.

Diterpenes from Coleus forskohlii (WILLD.) BRIQ. (Labiatae).

Three new minor labdane diterpene glycosides, forskoditerpenoside C, D, and E (1-3), and a novel labdane diterpene forskoditerpene A (4) were isolated from the ethanol extract of the whole plant of Coleus forskohlii. Their structures and relative stereochemistry were elucidated on the basis of extensive spectroscopic analyses including 1D-, 2D-NMR, and HR-ESI-MS experiments. Compounds 1-3 showed an unusual 8,13-epoxy-labd-14-en-11-one glycoside pattern. They showed relaxative effects on isolated guinea pig tracheal spirals in vitro. Compound 4 with a cyclopropyl, confirmed by a single-crystal X-ray diffraction determination, is the first known labdane derivative with a spiro element.

Two minor diterpene glycosides and an eudesman sesquiterpene from Coleus forskohlii.

Two new labdane diterpene glycosides, forskoditerpenosides A, B (1, 2) and a new eudesmane sesquiterpene, 4beta,7beta,11-enantioeudesmantriol (3), were isolated from the ethanol extract of the whole plant of Coleus forskohlii. Their structures and stereochemistry were elucidated by extensive spectroscopic analysis and chemical methods. The structure of compound 3 was confirmed by X-ray diffraction. This is the first report about the occurrence of glycosides derived from the kind of labdane diterpene, 8,13-epoxy-labd-14-en-11-one, in the nature. Compounds 1 and 2 showed relaxative effects on isolated guinea pig tracheal spirals in vitro.

Antioxidant constituents in distillation residue of Awamori spirits.

Constituents in a distillation residue of Awamori (millet spirits) and their antioxidant activity are investigated in this study. The supernatant of the distillation residue obtained by centrifugation was partitioned with n-hexane, chloroform, ethyl acetate, and n-butanol against water to afford the corresponding solubles. Among them, n-hexane and chloroform solubles showed higher antioxidant potency than l-ascorbic acid by the bleomycin-Fe method. In chloroform solubles, seven cyclic dipeptides were identified along with ethyl 2-pyrrolidione-5-carboxylate, tyrosol, and ethyl p-hydoroxyphenyllactate. Antioxidant activity of ethyl p-hydoroxyphenyllactate was 4.2 times that of l-ascorbic acid, whereas cyclic dipeptides showed activity 0.89-1.29 times as strong as that of l-ascorbic acid. On the other hand, scavenging effect of cyclic dipeptides against O(2)(-.) and OH(.) by using electron spin resonance was also investigated. In the results, cyclo(l-Ile-l-Pro) showed significantly strong inhibitory effect against OH(.) (95.4% at 2.5 x 10-3 M) and cyclo(l-Phe-l-Pro), cyclo(l-Pro-l-Val), and cyclo(l-Leu-l-Pro) inhibited OH(.) 64.9, 54.1, and 51.0%, respectively, whereas alpha-tocopherol showed 37.7% inhibition, though only a few cyclic dipeptides weakly inhibited O(2)(-.).

Two new monodesmosidic triterpene saponins from Gypsophila oldhamiana.

Two new monodesmosidic triterpene saponins were isolated from the roots of Gypsophila oldhamiana (Caryophyllaceae). Their structures were elucidated on the basis of spectral data to be quillaic acid, alpha-L-arabinopyranosyl-(1-->4)-alpha-L-arabinopyranosyl-(1-->3)-beta-D-xylopyranosyl-(1-->4)-alpha-L-rhamnopyranosyl-(1-->2)-beta-D-fucopyranosyl ester (1), and vaccaric acid, beta-D-glucopyranosyl-(1-->3)-[beta-D-xylopyranosyl-(1-->4)]-alpha-L-rhamnopyranosyl-(1-->2)-beta-D-fucopyranosyl ester (2). Compound 1 showed a significant enhancement of granulocyte phagocytosis in vitro.

Constituents of leaves of Phellodendron japonicum MAXIM. and their antioxidant activity.

Three new flavonoid derivatives, 6'''-O-acetyl amurensin (1), 6'''-O-acetyl phellamurin (3) and (2R)-phellodensin-F (5), together with thirty known compounds have been isolated from the leaves of Phellodendron japonicum MAXIM. Their structures were established by means of spectroscopic analysis, including extensive 2D NMR and Mass spectra. The known compounds were identified by comparison with published physical and spectral data. The isolated compounds were screened for their in vitro antioxidant activity through DPPH (1,1-diphenyl-2-picrylhydrazyl) radical scavenging assay. Compounds quercetin and phellodenin-A demonstrated significant radical scavenging activity.

Biotransformation of ferulic acid into two new dihydrotrimers by Momordica charantia peroxidase.

As a result of a continuing investigation of the biotransformation of ferulic acid with H2O2/Momordica charantia peroxidase at pH 5.0 in the presence of acetone, triFA1 (1) and triFA2 (2), two new FA dehydrotrimers, have been isolated. The structures were elucidated from the spectroscopic data including 2D-NMR such as HSQC, HMBC and NOESY data. TriFA1 (1) is a unique FA dehydrotrimer possessing a 3a,9b-dihydro-1H-furo[3,4-c][1]benzopyran-3(4H)-one ring system. The possible mechanism for the formation of triFA1 was also discussed.

Novel flavonol glycoside, 7-O-methyl mearnsitrin, from Sageretia theezans and its antioxidant effect.

A novel flavonol glycoside, 7-O-methylmearnsitrin (7,4'-O-dimethylmyricetin 3-O-alpha-L-rhamnopyranoside), and myricetrin, kaempferol 3-O-alpha-L-rhamnopyranoside, europetin 3-O-alpha-L-rhamnoside, and 7-O-methyl quercetin 3-O-alpha-L-rhamnopyranoside were isolated from the leaves of Sageretia theezans, and their chemical structures were identified by spectroscopic analyses including two-dimensional NMR (HSQC, HMBC). Whereas myricetrin, europetin 3-O-alpha-L-rhamnoside, and 7-O-methylquercetin 3-O-alpha-L-rhamnopyranoside showed stronger activities than ascorbic acid and alpha-tocopherol, 7-O-methylmearnsitrin showed very weak antioxidant activities by ESR and LDL oxidation inhibition tests.