The anti-ulcer effects of bifidobacteria, lactobacilli and streptococci were examined using the acetic acid-induced gastric ulcer and ethanol-induced erosion models in rats. Bifidobacterium breve YIT4014 and 4043, and Bifidobacterium bifidum YIT4007 were administered orally, and anti-ulcer effects were confirmed for not only these organisms but also their polysaccharide fractions (PSFs). The major component of these anti-ulcer polysaccharides was rhamnose. In particular, polysaccharides in which the rhamnose content exceeded 60% were more effective in healing gastric ulcers. After administration of the PSF from B. bifidum YIT4007, the levels of epidermal growth factor and basic fibroblast growth factor increased in gastric tissues. Similar results were observed for the culture supernatant of gastric epithelial cells cultured with PSF. Furthermore, the production of 6-ketoprostaglandin F1 alpha by macrophages was also enhanced by PSF. These results indicated that these bacteria and their polysaccharides induced host repair and protective systems in the gastric ulcer model.
Antihypertensivecompounds werepurified froman extract of autologousLactohacillus casei cell lysates. Themosteffective compounds werepolysaccharide-glycopeptidecomplexes,foundin the cell wall. Theaverage molecular weight wasestimated as 180,000from gel filtration using Sephacryl S-300. The polysaccharide moiety of the complexes consisted of glucose, rhamnose, and galactose, whereasthe glycopeptide moiety consisted of iY-acetylglucosamine, iV-acetylmuramicacid, asparagine, glutamine,alanine, andlysine. Thevarieties of the components of these moietieswereconstant and independent of complexmolecular size. Whenthese complexeswereorally administered to spontaneously hypertensive rats (SHR) and renal hypertensive rats (RHR) at doses of 1 mg/kg-body weight, systolic blood pressure (SBP) decreased by 10-20 mmHg6 to 12 hr after administration without any change in heart rate. Appreciable hypotensive activity was lost by treating the complexes with hydrofluoric acid, which hydrolytically cleaves the phosphodiester bond between the polysaccharide and glycopeptide moiety.Several kinds of natural materials such as mannans1} from yeast and plants, arginic acids2) from seaweeds, pectinic acids3) from beets, and brewer's yeast4) have been reportedto have blood-pressure-lowering activity against SHR.5) However, hundreds of mg/kgbody weight or more of these materials and daily oral administration for several weeks were required to decrease the SBP of SHR. Wealso investigated some pharmacological activities6'^of Lactobacillus casei and have recently discovered blood-pressure-lowering activity in extracts of autologous cell lysates of Lactobacillus casei (LEx).8) In our previous study, we found that 10 mg ofLEx significantly decreased the SBP per oral and that the polysaccharide fraction had the most effective blood-pressurelowering activity. In this paper, the purification and the further characterization of the polysaccharide fraction are described. Isolation ofSG-1. LEx (270g) was dissolved in 5,000ml of distilled water. After adjustment of the pH to 8.0 by 25%ammoniumhydroxide, the solution was centrifuged at 14,000xg for lOmin. The supernatant was filterd through a membranefilter with a pore size of 0.45/mi. Perchloric acid was added to the filtrate to a final concentration of 5% and the precipitate removed by centrifugation at 14,000 x g for 10 min. The precipitate was dissolved in 10mMammoniumformate buffer at pH 8.5, and perchloric acid was added to a final concentration of 5%and centrifuged once more. These supernatants were mixed and dialyzed against 5mM ammonium formate buffer (pH 8.0) in a molecularporous membrane tube (Spectra/pore 1, MWCO6,000-8,000) for 1 day at 4°C. The nondialyzable fraction was then filtered through a membrane filter with a pore size of 0.2/mi. After 500ml of Q-Sepharose FF was added to the filtrate to remove proteins and nucleic acids, the nonadsorbed fraction was concentrated to 500ml by a rotary evaporator. This solution was dialyzed with 100mMacetate buffer (pH 5.4)
Since the pioneering results of the Framingham study disclosed in 1971, 1) hypercholesterolemia has been recognized as a major risk factor for the development of coronary heart disease (CHD).2,3) Agents controlling total plasma cholesterol levels are expected to serve as an effective therapeutic method for atherosclerosis, 4) since lowering plasma cholesterol levels has been proven to reduce mortality from myocardial infarction.5) Acyl-CoA: cholesterol O-acyltransferase (ACAT, EC 2.3.1.26) 6,7) is an intracellular enzyme responsible for catalyzing the esterification of free cholesterol with fatty acyl-CoA to produce cholesteryl esters. This enzyme plays important roles in the absorption of dietary cholesterol from the small intestine, the secretion of very lowdensity lipoprotein (VLDL) from the liver, and the accumulation of cholesteryl esters in atherosclerotic lesions. Inhibition of ACAT should reduce the absorption of cholesterol, lower plasma cholesterol levels, [8][9][10][11][12] and should arrest the progression and promote the regression of atherosclerotic plaque. 13,14) Therefore, ACAT inhibitors are a prime objective in the development of new therapeutic agents for hypercholesterolemia and atherosclerosis. 15) On this basis, metabolites were screened from about three thousand fungi and numerous plant components that produce an ACAT inhibitor. Of these, it was found that 1-(4-hydroxy-3-methoxyphenyl)-7-phenylhept-1-en-3-one (1, Yakuchinone B), which is a component of the seeds of Alpinia oxyphylla MIQUEL (Zingiberaceae), 16) has ACAT inhibitory activity. In order to obtain ACAT inhibitors that exhibit a high level of hypocholesterolemic activity in vivo, the structure-activity relationships of three structural moieties of Yakuchinone B (1) as the lead compound ( Fig. 1) were examined. The compounds prepared were tested for the ability to inhibit the microsomal ACAT from rat liver and to suppress the elevation of plasma cholesterol levels in rats given a high cholesterol diet.The present paper will describe the structure-activity relationships and biological activities of these novel ACAT inhibitors.Chemistry Diarylheptanoids (1-7) were synthesized by condensation of 1-phenyl-5-hexanone with corresponding benzaldehydes according to the previously described method. 17)As shown in Chart 1, phenylalkylamides (11, 13-15) or anilides (12, 17, 18) were prepared by alkylation of 8, followed by amidation with appropriate phenylalkylamine or aniline by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) in CHCl 3 .Phenylpiperamides (16, 19-46) can be synthesized from 8 via intermediates 9a, b or 10a, b (Chart 1). In the case of the modification of region C in the molecule (Fig. 1), phenylpiperamides (16, 30-41) were prepared by alkylation of 8 with corresponding halide, followed by amidation with appropriate phenylpiperazine. With modification of region A in the molecule (Fig. 1), phenylpiperamides (19-29, 42-46) were prepared by amidation of 8 with corresponding phenylpiperazine, followed by alkyla...
A pure complex of staphylokinase and plasmin was prepared by affinity chromatography with lysine-Sepharose, which enabled the simple analysis of the mechanism of plasminogen activation by staphylokinase. We used a truncated staphylokinase (SAK), which lacks the 10 amino acid residues at the NH2 terminal of native staphylokinase. The purity of this complex was confirmed by the native PAGE profile. Image analysis of the SDS-PAGE profile revealed that the molar ratio of plasmin and SAK in the complex was about 1:1. Using this SAK-plasmin complex, the kinetic parameters for the activation of Glu- or Lys-plasminogen were determined. The kinetic constant, kcat/Km, obtained when Lys-plasminogen was used as a substrate was approximately 10 times higher than that obtained when Glu-plasminogen was used. This plasminogen activation property of the SAK-plasmin complex was comparable to that of other plasminogen activators, such as streptokinase, urokinase, and tissue-type plasminogen activator (t-PA). This SAK-plasmin complex will simplify the elucidation of plasminogen activation by SAK. Through kinetic studies, the fibrin specificity and participation of plasminogen activator inhibitor will be clarified.
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