Toshiro Matsui

Antihypertensive effect of valyl-tyrosine, a short chain peptide derived from sardine muscle hydrolyzate, on mild hypertensive subjects.

The present study was conducted to determine whether Valyl-Tyrosine (VY) has an antihypertensive effect on high-normal blood pressure and mild essential hypertension, as well as spontaneous hypertensive rats (SHR). A randomised double-blind placebo-controlled study was carried out on 29 volunteers. A 100-ml drink containing 3 mg of VY and a 100-ml placebo drink were prepared. The subjects were grouped as VY(16M/1F, 45.5 ± 3.2 years, 146.4 ± 2.3/90.5 ± 1.8 mm Hg) and the placebo (P) (11 M/1F, 48.8 ± 3.0 years, 145.5 ± 2.4/92.3 ± 1.8 mm Hg). At 3 weeks of the control (C) period, a VY- or P-drink was administered twice a day for 4 weeks in the experimental (E) period and during the 4-week recovery period, neither drink was given to either group. Blood pressure (BP) was measured every week in the morning in the sitting position. Blood specimens were taken on the last day of the C and E periods. In the VY-group, reduction in systolic (S) and diastolic (D) BP was 9.7 and 5.3 mm Hg (P < 0.001) at 1 week, and 9.3 and 5.2 mm hg (P < 0.001) at 4 weeks, following the start of the e period, respectively. neither sbp nor dbp changed in the p-group. bp in the vy-group increased gradually by the end of the recovery period. plasma angiotensin (ang) i and vy concentrations significantly increased while ang ii and aldosterone significantly decreased after vy administration in the vy-group. vy appeared to have a significant antihypertensive effect on mild hypertensive subjects via ang i-converting enzyme inhibition, as well as shr, but no adverse effects could be detected at all.

Gastrointestinal enzyme production of bioactive peptides from royal jelly protein and their antihypertensive ability in SHR

In order to clarify the potential physiological function of royal jelly (RJ), we report here the gastrointestinal enzyme production of antihypertensive peptides from RJ. Intact RJ and its protein fraction did not retard the action of angiotensin I-converting enzyme (ACE) activity at all. However, development of ACE inhibition power of RJ was newly observed by pepsin hydrolysis (IC(50)=0.358 mg protein/mL), and the subsequent trypsin and chymotrypsin hydrolyses (IC(50)=0.099 mg protein/mL). Single oral administration of this gastrointestinal RJ hydrolysate (1 g/kg dose) in 10-week spontaneously hypertensive rat resulted in a significant reduction of systolic blood pressure of 22.7 plus minus 3.6 mmHg at 2 hr (P<0.05 vs. 0 hr by one-way ANOVA, n=7). Then, the RJ hydrolysate was fractionated with gel permeation chromatography to obtain the di- and tri-peptides (DTP) fraction. As a result of isolation from the DTP fraction by reversed phase-high performance liquid chromatography, eleven ACE inhibitory peptides were isolated from the DTP-RJ hydrolysate. Some of the ACE inhibitors were derived from the RJ-glycoprotein; eight peptides with the IC(50) value of <10 &mgr;M were identified from natural resources for the first time. Consequently, RJ protein was thought to be a good resource of ACE inhibitory peptides produced by the gastrointestinal enzyme hydrolyses.

Preparation and characterization of novel bioactive peptides responsible for angiotensin I-converting enzyme inhibition from wheat germ

Reported is the preparation of wheat germ (WG) hydrolyzate with potent angiotensin I‐converting enzyme (ACE) inhibitory activity, and the characterization of peptides responsible for ACE inhibition. Successful hydrolyzate with the most potent ACE inhibitory activity was obtained by 0.5 wt.%–8 h Bacillus licheniformis alkaline protease hydrolysis after 3.0 wt.%–3 h α‐amylase treatment of defatted WG (IC50; 0.37 mg protein ml−1). The activity of WG hydrolyzate was markedly increased by ODS and subsequent AG50W purifications (IC50; 0.018 mg protein ml−1). As a result of isolations by high performance liquid chromatographies, 16 peptides with the IC50 value of less than 20 μm, composed of 2–7 amino acid residues were identified from the WG hydrolyzate. Judging from the high content (260 mg in 100 g of AG50W fraction) and powerful ACE inhibitory activity (IC50; 0.48 μm), Ile‐Val‐Tyr was identified as a main contributor to the ACE inhibition of the hydrolyzate. Copyright

The 10trans,12cis isomer of conjugated linoleic acid suppresses the development of hypertension in Otsuka Long-Evans Tokushima fatty rats.

Conjugated linoleic acid (CLA) is a mixture of positional and geometric isomers of linoleic acid found in beef, lamb, and dairy products. CLA has attracted considerable attention over the past several decades because of its potentially beneficial biological effects, including protective effects against several cancers, atherosclerosis, and obesity. Here we provide the first evidence that the 10trans,12cis-CLA isomer is able to suppress increases in blood pressure during the onset of obesity in OLETF rats. After 3 weeks of feeding with 10t,12c-CLA, systolic blood pressure was significantly lowered compared with rats fed linoleic acid or 9c,11t-CLA. Abdominal adipose tissue weight was also significantly lowered in rats fed 10t,12c-CLA, but not in those which were fed 9c,11t-CLA. In addition, we found that the relative mRNA expressions of angiotensinogen and leptin were suppressed by 10t,12c-CLA in adipose tissue. We speculate that the antihypertensive effect of 10t,12c-CLA can be attributed to the lowered secretion of hypertensive adipocytokines from abdominal adipose tissues.

Val-Tyr As A Natural Antihypertensive Dipeptide Can Be Absorbed Into The Human Circulatory Blood System

1. Intact absorption of the bioactive dipeptide Val‐Tyr (VY), with in vivo antihypertensive ability in normotensive human subjects, was investigated.

The PepT1-transportable soy tripeptide VPY reduces intestinal inflammation.

BACKGROUND Inflammatory bowel disease (IBD) is a chronic inflammation of the gastrointestinal tract. The peptide transporter PepT1 is responsible for the intestinal uptake of dietary peptides, and its expression in the gastrointestinal tract is up-regulated during intestinal inflammation, indicating that PepT1 may be a promising target for IBD therapeutics. METHODS The transport of soy-derived di- and tripeptides across Caco-2 intestinal epithelial cells was examined, and the anti-inflammatory effects of the transported peptide VPY were evaluated in vitro in Caco-2 and THP-1 macrophages, and in vivo in a mouse model of DSS-induced colitis. RESULTS VPY inhibited the secretion of IL-8 and TNF-α, respectively, from Caco-2 and THP-1 cells. VPY transport and anti-inflammatory activity in Caco-2 cells was reduced in the presence of Gly-Sar, indicating this activity was mediated by PepT1. In mice, VPY treatment reduced DSS-induced colitis symptoms and weight loss, improved colon histology, reduced MPO activity, and decreased gene expression of the pro-inflammatory cytokines TNF-α, IL-6, IL-1β, IFN-γ and IL-17 in the colon. CONCLUSIONS AND GENERAL SIGNIFICANCE VPY is a novel PepT1 substrate that can inhibit the production of pro-inflammatory mediators in vitro in intestinal epithelial and immune cells, and reduce the severity of colitis in mice by down-regulating the expression of pro-inflammatory cytokines in the colon, suggesting that VPY may be promising for the treatment of IBD.

Caffeoylsophorose, a New Natural α-Glucosidase Inhibitor, from Red Vinegar by Fermented Purple-Fleshed Sweet Potato

The suppressive effect on the postprandial blood glucose rise through α-glucosidase (AGH) inhibition was investigated in this study in order to clarify an antihyperglycemic function of 6-O-caffeoylsophorose (CS) from diacylated anthocyanin. The administration of CS (100 mg/kg) following maltose (2 g/kg) to Sprague-Dawley rats resulted in the maximal blood glucose level after 30 min being significantly decreased by 11.1% compared to the control. A reduction in the serum insulin secretion was also observed in parallel to the decrease in blood glucose level. No blood glucose change was apparent when sucrose or glucose was ingested, suggesting that the antihyperglycemic effect of CS was achieved by maltase inhibition, rather than by sucrase or glucose transport inhibition. An AGH inhibitory assay demonstrated that the non-competitive maltase inhibition of CS was partly due to acylation by phenolic acid with sugar, the presence of hydroxyl groups in the aromatic ring, and the presence of an unsaturated alkyl chain in the acylated moiety.

Identification of ACE-inhibitory peptides in salt-free soy sauce that are transportable across caco-2 cell monolayers

In present study, we aimed to identify angiotensin I-converting enzyme (ACE)-inhibitory peptides from a salt-free soy sauce (SFS), a newly developed antihypertensive seasoning obtained by Aspergillus oryzae fermentation of soybean in the absence of salt, which can be transported through caco-2 cell monolayers. Through an Ussing transport investigation of SFS across caco-2 cell monolayers, three di-peptides, Ala-Phe, Phe-Ile and Ile-Phe, were successfully identified from the SFS as transportable inhibitory peptides. Ala-Phe and Ile-Phe, but not Phe-Ile, exhibited ACE-inhibitory activity with IC(50) values of 165.3 microM and 65.8 microM, respectively. Kinetic studies revealed that Ile-Phe (Km: 3.1 mM, P(app): 2.4 x 10(-6) cm/s) exhibited greater affinity toward the transport compared with Ala-Phe (K(m): 48.1 mM, P(app): 1.4 x 10(-6) cm/s) and Phe-Ile (K(m): 12.7 mM, P(app): 1.4 x 10(-6) cm/s).

Luteolin, a Flavone, Does Not Suppress Postprandial Glucose Absorption Through an Inhibition of α-Glucosidase Action

In order to clarify the postprandial glucose suppression via α-glucosidase (AGH) inhibitory action by natural compounds, flavonoids were examined in this study. Among the flavonoids (luteolin, kaempferol, chrysin, and galangin), luteolin showed the potent maltase inhibitory activity with the IC50 of 2.3 mM, while less inhibitions were observed against sucrase. In addition, the effects of maltase inhibition by flavonoids were observed in the descending order of potency of luteolin>kaempferol>chrysin>galangin. Apparently, the AGH inhibition power greatly increased with the replacement of hydroxyl groups at 3′ and 4′-position of the B-ring. However, the inhibitory power of luteolin was poorer than a therapeutic drug (acarbose: IC50; 430 nM). As a result of a single oral administration of maltose or sucrose (2 g/kg) in SD rats, no significant change in blood glucose level with the doses of 100 and 200 mg/kg of luteolin was observed. These findings strongly suggested that luteolin given at less than 200 mg/kg did not possess the ability to suppress the glucose production from carbohydrates through the inhibition of AGH action in the gut.

Antiproliferative action of an angiotensin I-converting enzyme inhibitory peptide, Val-Tyr, via an L-type Ca2+ channel inhibition in cultured vascular smooth muscle cells.

Recent antihypertensive studies have demonstrated that small peptides with angiotensin I-converting enzyme (ACE) inhibitory activity had an ability to lower or to modulate a pressor blood pressure response in mild hypertensive subjects. However, the underlying mechanisms still remain unclear. Based on our previous finding that a small peptide, Val-Tyr (VY), was accumulated in the rat aorta and kidney as well as in the circulating blood system, we here investigated whether antihypertensive small peptides exert an antiproliferative effect on serum- or mitogen-induced human vascular smooth muscle cells (VSMCs). Treatment with some ACE inhibitory small peptides (VY, Ile-Trp [IW], and Ile-Val-Tyr [IVY]) had diverse effects on serum-stimulated VSMC proliferation that were independent of their ACE inhibitory activity, though only VY exerted a potent antiproliferative action. VY also showed a greater inhibition of WST-8 incorporation in response to angiotensin (Ang) II-stimulation than the other two small peptides. The attenuation of Ang II-stimulated WST-8 incorporation by VY was not affected by Ang II receptor antagonists (losartan and saralasin ([Sar1, Ile8]-Ang II)), indicating that the antiproliferative action of VY may not be due to the peptides antagonistic effect against Ang II receptors. Treatment with VY had a significant inhibitory effect on the WST-8 incorporation induced by the stimulation of a voltage-gated L-type Ca2+ channel agonist, Bay K 8644. Even in the presence of a K+ channel blocker (paxillin) the inhibition was apparent, suggesting that VY inhibited the proliferation of VSMCs by serving as a natural L-type Ca2+ channel blocker, but not as a K+ channel agonist.