Ryuichi Higuchi

Role of macrophages in inflammatory lymphangiogenesis: Enhanced production of vascular endothelial growth factor C and D through NF-κB activation ☆

The close association of inflammation, angiogenesis and cancer progression is now highlighted, and in this study we especially focused on a close association of inflammation and lymphangiogenesis. We found that proinflammatory cytokine, interleukin-1beta (IL-1beta), could induce lymphangiogenesis in mouse cornea through enhanced production of potent lymphangiogenic factors, VEGF-A, VEGF-C and VEGF-D. IL-1beta-induced lymphangiogenesis, but not angiogenesis, was inhibited by administration of a selective anti-VEGF receptor-3 (VEGFR-3) neutralizing antibody. And in mouse cornea we observed recruitment of monocyte/macrophages and neutrophils by IL-1beta implanted cornea. Depletion of macrophages by a bisphosphonate encapsulated in liposomes inhibited this IL-1beta-induced lymphangiogenesis and also up-regulation of VEGF-A, VEGF-C, and VEGF-D. Furthermore, IL-1beta-induced lymphangiogenesis and angiogenesis were suppressed by NF-kappaB inhibition with marked suppression of VEGF-A, VEGF-C, and VEGF-D expression.

Structure of desacylsaponins obtained from the bark of Quillaja saponaria

Abstract A triterpenoid saponin mixture (so-called quillajasaponin) obtained from the bark of Quillaja saponaria was treated with weak alkali and two major desacylsaponins were isolated. On the basis of chemical and spectral evidence, they were determined as 3-O-β- D -galactopyranosyl-(1 → 2)-[β- D -xylopyranosyl-(1 → 3)]-β- D -glucuronopyranosyl quillaic acid 28-O-β- D -apiofuranosyl-(1 → 3)-β- D -xylopyranosyl-(1 → 4)-α- L -rhamnopyranosyl-(1 → 2)-β- D -fucopyranoside and 28-O-β- D -apiofuranosyl-(1 → 3)-β- D -xylopyranosyl-(1 → 4)-[β- D -glucopyranosyl-(1 → 3)]-α- L -rhamnopyranosyl-(1 → 2)-β- D -fucopyranoside. Diazomethane degradation providing selectively the 28-O-glycoside from the 3,28-O-bisglycoside was a useful method for the structure elucidation.

An acylated triterpenoid saponin from Quillaja saponaria

Abstract A new major component in the acylated triterpenoid saponin mixture (called quillajasaponin) obtained from the bark of Quillaja saponaria was isolated in a pure state. It was characterized on the basis of chemical and spectral data as 3- O -β- d -galactopyranosyl-(1 → 2)-[β- d -xylopyranosyl-(1 → 3)]-β- d -glucuronopyranosyl quillaic acid 28- O -β- d -apiofuranosyl- (1 → 3)-β- d -xylopyranosyl- (1 → 4)-[β- d -glucopyranosyl- (1 → 3)]-α- l -rhamnopyranosyl-(1 → 2)-3-[5- O -[5- O -α- l -rhamnopyranosyl-(1 → 2)-α- l -arabinofuranosyl-3,5-dihydroxy-6-methyl-octanoyl]-3,5-dihydroxy-6-methyl-octanoyl]-β- d -fucopyranoside. The diazomethane cleavage method providing selectively 28- O - glycoside from 3,28- O -bisglycoside was effective for the structure elucidation. Negative fast atom bombardment mass spectrometry was useful in providing information on the molecular weight and the structure of the complex acylated oligoglycoside.

Sedative activity of two flavonol glycosides isolated from the flowers of Albizzia julibrissin durazz

The flowers of Albizzia julibrissin are used as a sedative in oriental traditional medicine. The phytochemical study of this plant allowed the isolation of two flavonol glycosides, quercitrin (1) and isoquercitrin (2). The sedative activity of these compounds was evaluated, and both compounds 1 and 2 increased pentobarbital-induced sleeping time in dose-dependent manner in mice. These results support the use of the flowers of this plant as a sedative agent.

Costunolide, a sesquiterpene lactone from Saussurea lappa, inhibits the VEGFR KDR/Flk-1 signaling pathway

Costunolide (CT), a sesquiterpene lactone constituent isolated from Saussurea lappa (Compositae), exerted an antiangiogenic effect. CT selectively inhibited the endothelial cell proliferation induced by vascular endothelial growth factor (VEGF). Further, CT was also found to inhibit the VEGF-induced chemotaxis of human umbilical vein endothelial cells (HUVECs) in a dose-dependent manner. From these results, we hypothesized that CT might inhibit angiogenesis by blocking the angiogenic factor signaling pathway. VEGF interacts with its cognate receptors, KDR/Flk-1 and Flt-1, and exerts its angiogenic effect. CT inhibited the autophosphorylation of KDR/Flk-1 without affecting that of Flt-1. Moreover, administration of CT reduced VEGF-induced neovascularization in a mouse corneal micropocket assay. These results suggest that CT may prove useful for the development of a novel angiogenesis inhibitor.

Field desorption mass spectrometry of natural products—II1: Physiologically active pennogenin—and hederagenin-glycosides

Abstract Field desorption mass spectra of underivatized saponios, naturel oligoglycosides of physiological activity, showed intense ions formed by attachment of alkali cations to the neutral molecule and to structurally highly significant subunits. This cationization was generated by small amounts of alkali salts which were present in samples after isolation from biological material. When the mass spectre were produced by laser-supported desorption and were recorded at high resolution on vapor-deposited AgBr plates unambiguous determination of the molecular weghts (in the mass range from 700 to 1400) was performed. Moreover, ions formed by direct bond cleavages in the oligosaccharide moiety of the natural saponins clearly gave information about the sequence of the sugar units in the molecule and their individual chemical structures. The formation of these fragments in FD-MS is discussed in relation to the well established mechanism of glycosidic bond cleavage by acidic solvolysis. In principle this comparison showed the usefulness of this approach for the interpretation of FD mass spectra of substances containing heteroatom linkages e.g., glycosides, esters, amides, imines, mercaptans, etc.

Structures of compounds derived from the acyl moieties of quillajasaponin

Abstract Three compounds, an acid and two glycosidic acids, derived from the acyl moieties of quillajasaponin were obtained from the alkaline hydrolysate of the saponin mixture. On the basis of chemical and spectral evidence, they were identified as 3,5-dihydroxy-6-methyl-octanoic acid, 3,5-dihydroxy-6-methyl-octanoic acid 5- O -α- L -arabinofuranoside and 5- O -α- L -rhamnopyranosyl-(1 → 2)-α- L -arabinofuranoside. The first compound was, in fact, isolated and characterized as its lactone form. FDMS was useful in providing information on the M , of the unique acid and glycosidic acids.

Dorisenones, cytotoxic spongian diterpenoids, from the nudibranch Chromodoris obsoleta

Abstract Seven new cytotoxic spongian diterpenoids, dorisenones A ( 1 ), B ( 2 ), C ( 3 ), D ( 4 ), 7α-hydroxyspongian-16-one ( 5 ), 15α, 16α-diacetoxy-11, 12β-epoxyspongian ( 6 ) and 7α-acetoxydendrillol-3 ( 7 ) were isolated from a Japanese marine mollusk Chromodoris obsoleta (Chromodorididae), together with four known spongian diterpenoids. Their structures have been elucidated by spectroscopic evidence and single crystal X-ray analysis.

Isolation and structures of aplykurodins a and b, two new isoprenoids from the marine mollusk aplysia kurodai

Abstract Two new isoprenoids, aplykurodins A and B, were isolated from the marine mollusk, Aplysia kurodai (Aplysiidae), and their structures were determined by chemical, spectral and X-ray crystallographic analyses.

Triterpenoid saponins from the stem bark of Symplocos spicata

Abstract From the stem bark of Symplocos spicata a mixture of triterpenoid saponins was obtained. It behaved as a pure compound in TLC and HPLC, but heterogeneity was suspected on the basis of chemical and NMR spectral data. It was separated to give two analogous glycosides, which were identified as 3,28- O -bis-β- d -glucopyranosides of 19α-hydroxyarjunolic and 19α-hydroxyasiatic acids.