Kimiye Baba

Antioxidant constituents in the dayflower (Commelina communis L.) and their α-glucosidase-inhibitory activity

The dayflower, Commelina communis L., contains 1-deoxynojirimycin (DNJ) and (2R,3R,4R,5R)2,5-bis(hydroxymethyl)-3,4-dihydroxypyrrolidine (DMDP), potent α-glucosidase inhibitors. The extracts and powder of this herb are important food materials for prophylaxis against type 2 diabetes. Eleven flavonoid glycosides as antioxidants, isoquercitrin, isorhamnetin-3-O-rutinoside, isorhamnetin-3-O-β-d-glucoside, glucoluteolin, chrysoriol-7-O-β-d-glucoside, orientin, vitexin, isoorientin, isovitexin, swertisin, and flavocommelin, were identified from the aerial parts of C. communis. Their antioxidant activities were measured using in vitro assays employing the 1,1-diphenyl-2-picrylhydrazyl radical- and superoxide radical-scavenging assays. The results showed that glucoluteolin, orientin, isoorientin, and isoquercitrin are the predominant antioxidants in this herb. Moreover, isoquercitrin, isorhamnetine-3-O-rutinoside, vitexin, and swertisin inhibited the activity of α-glucosidase from rat intestine.

Isolation of an anti-angiogenic substance from Agaricus blazei Murill: its antitumor and antimetastatic actions.

We previously found that ergosterol isolated from Agaricus blazei inhibited tumor growth through the inhibition of tumor‐induced neovascularization. In the present study, we isolated further anti‐angiogenic substances (A‐1 and A‐2) from this fungus using an assay system of angiogenesis induced by Matrigel supplemented with vascular endothelial growth factor, and A‐1 was identified as sodium pyroglutamate. Next, we examined the antitumor and antimetastatic actions of A‐1 using Lewis lung carcinoma (LLC)‐bearing mice. A‐1 (30, 100 and 300 mg/kg) inhibited tumor growth and metastasis to the lung. The reduction of the numbers of splenic lymphocytes, CD4+ and CD8+ T cells in LLC‐bearing mice was inhibited by the oral administration of A‐1 (30, 100 and 300 mg/kg). Further, A‐1 increased the number of apoptotic cells of tumors and the numbers of CD8+ T and natural killer cells invading the tumors, and inhibited the increase of von Willebrand factor expression (a measure of angiogenesis) in the tumors. These results suggest that the antitumor and antimetastatic actions of A‐1 (sodium pyroglutamate) may be associated with inhibition of the reduction of immune response caused by the tumor growth and tumor‐induced neovascularization. This is the first report showing that sodium pyroglutamate isolated from A. blazei as an anti‐angiogenic substance has potent antitumor and antimetastatic actions, as well as immune‐modulatory activity, in tumor‐bearing mice.

Antitumor and antimetastatic activities of Angelica keiskei roots, part 1: Isolation of an active substance, xanthoangelol.

The roots of Angelica keiskei Koizumi have traditionally been used as a health food, with diuretic, laxative, analeptic and galactagogic effects. It has been thought that the roots and leaves of A. keiskei have preventive effects against coronary heart disease, hypertension and cancer. In the present study, we examined the antitumor and antimetastatic activities of various fractions isolated from a 50% ethanol extract of A. keiskei roots. The ethyl acetate‐soluble fraction of the 50% ethanol extract inhibited tumor growth in LLC‐bearing mice at a daily dose of 100 mg/kg prolonged survival time and inhibited metastasis to the lung after surgical removal of primary tumors. Two active substances were isolated from fractions 1 and 2: compound 1 was identified as xanthoangelol based on the data of the 1H‐ and 13C‐NMR spectra. Xanthoangelol inhibited tumor growth in LLC‐bearing mice as well as lung metastasis and prolonged survival time in carcinectomized mice at a daily dose of 50 mg per kg. Furthermore, xanthoangelol (50 or 100 mg per kg daily) inhibited liver metastasis and the growth of metastasized tumor cells in the livers of mice with intrasplenically implanted LLC. Xanthoangelol inhibited DNA synthesis in LLC cells at concentrations of 10 and 100 μM, but it had no effect on DNA synthesis in HUVECs or on the adherence of LLC cells to HUVECs. Xanthoangelol inhibited tumor‐induced neovascularization (in vivo) at doses of 10 and 20 mg per kg, and it inhibited the Matrigel‐induced formation of capillary‐like tubes by HUVECs at concentrations of 1–100 μM. Furthermore, xanthoangelol inhibited the binding of VEGF to HUVECs at concentrations of 1–100 μM. These results indicate that the antitumor and/or antimetastatic activities of xanthoangelol may be due to inhibition of DNA synthesis in LLC cells and of tumor‐induced neovascularization through inhibition of the formation of capillary‐like tubes by vascular endothelial cells and inhibition of the binding of VEGF to vascular endothelial cells.

Antitumor activities of synthetic and natural stilbenes through antiangiogenic action

We reported that the antitumor and antimetastatic actions of resveratrol might be due to the inhibition of tumor‐induced angiogenesis. To search for anticancer agents with stronger activity than resveratrol, we examined the antiangiogenic effects of 21 synthetic and/or natural stilbenes. Among these 21 stilbenes, 2,3‐, 3,4‐, and 4,4′‐dihydroxystilbene inhibited the pro‐matrix metalloproteinase (pro‐MMP)–9 production in colon 26 cells at 5–25 µM, vascular endothelial growth factor (VEGF)–induced human umbilical vein endothelial cell (HUVEC) migration at 10 and 25 µM, and VEGF‐induced angiogenesis at 5–50 µM. Resvertarol inhibited the pro‐MMP‐9 production and VEGF‐induced angiogenesis at 25 or 50 µM. Thus, the inhibition of pro‐MMP‐9 production in colon 26 cells and VEGF‐induced angiogenesis by three dihydroxystilbenes were greater than those of resveratrol. The three dihydroxystilbenes (8 mg/kg, intraperitoneal injection) inhibited the tumor‐induced neovascularization in colon 26–packed chamber‐bearing mice and the tumor growth in colon 26–bearing mice. Furthermore, the three dihydroxystilbenes inhibited VEGF‐induced VEGFR‐2 phosphorylation. On the other hand, the three dihydroxystilbenes had no effect on VEGFR‐1 and‐2 expression, and VEGF‐induced VEGFR‐1 phosphorylation in HUVECs. These findings suggest that the inhibition of tumor‐induced neovascularization by these three dihydroxystilbenes may be due to the inhibition of VEGF‐induced endothelial cell migration and VEGF‐induced angiogenesis through the inhibition of VEGF‐induced VEGFR‐2 phosphorylation in endothelial cells and pro‐MMP‐9 expression in colon 26 cells. (Cancer Sci 2008; 99: 2083–2096)

Chalcones from Angelica keiskei

Abstract Four new chalcones, xanthangelols B–E were isolated from roots of Angelica keiskei and their structures determined to be 2′,4,4′-trihydroxy-3′-[( E )-6-hydroxy-3,7-dimethyl-2,7-octadienyl]chalcone, 2′,4,4′-trihydroxy-3′-[( E )-3-methy]-6-oxo-2-hexenyl]chalcone, 2′,4-dihydroxy-4′-methoxy-3′-(2-hydroxy-3-methyl-3-butenyl)chalcone and 2′,4-dihydroxy-4′-methoxy-3′-(2-hydroperoxy-3-methyl-3-butenyl)chalcone, respectively, by means of chemical and spectral analyses.

Hypotensive and lipid regulatory actions of 4‐hydroxyderricin, a chalcone from Angelica keiskei, in stroke‐prone spontaneously hypertensive rats

1. Previously, we found that Angelica keiskei extract (ethyl acetate extract from the yellow liquid of stems) elevated serum high‐density lipoprotein (HDL) levels and reduced liver triglyceride content in stroke‐prone spontaneously hypertensive rats (SHRSP). To identify the active substance in A. keiskei extract, we examined the effect of 4‐hydroxyderricin, a characteristic chalcone isolated from the yellow liquid of stems, on blood pressure and lipid metabolism in SHRSP.

Coumarin glycosides from Edgeworthia chrysantha

Abstract Rutarensin and two new coumarins, edgeworoside B and C, were isolated from the root and stem of Edgeworthia chrysantha ( E. papyrifera ). The structures of edgeworoside B and C were determined as 3-(7-coumarinyloxy)-8-(7-hydroxycoumarin-8-yl)-7-β- d -apiofranosyloxycoumarin and 8-(7-hydroxycoumarin-8-yl)-7-α- l -rhamnopyranosyloxycoumarin.

Inhibition of gastric H+,K+-ATPase and acid secretion by cassigarol A, a polyphenol from Cassia garrettiana Craib

The effects of cassigarol A, a naturally occurring polyphenol, on gastric H+,K(+)-ATPase and gastric acid secretion were studied. Cassigarol A inhibited H+,K(+)-ATPase and K-stimulated p-nitrophenyl phosphatase from hog gastric mucosa with 50% inhibition of 1.2 x 10(-6) and 6.3 x 10(-6) M, respectively. The kinetic study showed that the inhibition of H+,K(+)-ATPase by cassigarol A was competitive with respect to ATP and non-competitive with respect to K+. Cassigarol A inhibited both H+,K(+)-ATPase-mediated proton transport and 2-deoxy-D-glucose-induced acid secretion. On the other hand, cassigarol A acetate, in which phenolic hydroxy groups are acetylated, was not effective in the inhibition of enzyme activity and acid secretion. These results indicate that cassigarol A is a potent inhibitor of gastric H+,K(+)-ATPase, that the anti-secretory activity of cassigarol A is related to the inhibition of H+,K(+)-ATPase and that an important moiety of cassigarol A in the interaction with the enzyme is the phenolic hydroxy groups.

Antitumor and antimetastatic actions of anthrone‐C‐glucoside, cassialoin isolated from Cassia garrettiana heartwood in colon 26‐bearing mice

We examined the antitumor and antimetastatic actions of 10‐hydroxy‐anthrone‐C‐glucoside cassialoin isolated from Cassia garrettiana heartwood in colon 26‐bearing mice. Cassialoin (5 and 10 mg/kg) inhibited tumor growth and metastasis to the abdomen and the expression of CD31 (angiogenesis marker) in the tumors, and it increased the numbers of the γ‐interferon (IFN‐γ)‐positive, CD8+ T and natural killer cells in the small intestine or spleen of colon 26‐bearing mice. Furthermore, cassialoin inhibited tumor‐induced angiogenesis in colon 26‐packed chamber‐bearing mice. We examined the metabolic activities in the blood, stomach and small intestine after p.o. administration of cassialoin to mice. These results suggest that cassialoin might be converted to chrysophanol through chrysophanol‐9‐anthrone and metabolized to aloe‐emodin from chrysophanol. Chrysophanol‐9‐anthrone inhibited vascular endothelial growth factor (VEGF) and matrix metallopeptidase‐9 expression in colon 26 cells at 5 and 10 µM, and it inhibited VEGF‐induced angiogenesis and migration in human umbilical vein endothelial cells (HUVEC) at 0.5–10 µM. Furthermore, chrysophanol‐9‐anthrone inhibited VEGF receptor (VEGFR)‐2 expression and VEGF‐induced VEGFR‐2 phosphorylation. Aloe‐emodin also inhibited the VEGF‐induced angiogenesis by HUVEC at 1–100 µM. Cassialoin, chrysophanol‐9‐anthrone and aloe‐emodin enhanced concanavalin A‐induced IFN‐γ production in splenocytes of colon 26‐bearing mice at a low concentration of 0.1 µM. From these results, it is suggested that the antitumor and antimetastatic actions of p.o. administered cassialoin may be partly due to cassialoin and its metabolites such as chrysophanol‐9‐anthrone and aloe‐emodin through their anti‐angiogenic activities and/or the modulation of the immune systems in the spleen and small intestine in tumor‐bearing mice. (Cancer Sci 2008; 99: 2336–2348)

Inhibition of 15-hydroxyprostaglandin dehydrogenase activity in rabbit gastric antral mucosa by panaxynol isolated from oriental medicines

Panaxynol is a polyacetylene compound with anti‐inflammatory and anti‐platelet‐aggregatory effects isolated from commonly used oriental medicines. The effects of panaxynol on the activity of prostaglandin‐synthesizing and catabolizing enzymes in the rabbit gastric antral mucosa have been examined.