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Biomedical subjects

Y Kiso

Publications and source records attributed to Y Kiso.

At least 37 records · Page 2Linked to original sources
PubMed2001

Less damaging effect of whisky in rat stomachs in comparison with pure ethanol. Role of ellagic acid, the nonalcoholic component.

BACKGROUND/AIM: Ellagic acid (EA), one of the polyphenols that are abundantly contained in whisky as a nonalcoholic component, has antioxidant and anti-inflammatory activities. In the present study, we compared the action of whisky and pure ethanol on the rat gastric mucosa, and examined the role of EA in the less-damaging effect of whisky in the stomach. METHODS: Under urethane anesthesia, a rat stomach was mounted in an ex vivo chamber, perfused with saline, and the transmucosal potential difference (PD) was measured before and after exposure to whisky (Yamazaki, Suntory) and ethanol (43%). In a separate study, the animals were given whisky or ethanol (1 ml, 43%) p.o. under unanesthetized conditions, killed 1 h later, and the gastric mucosa was examined for hemorrhagic lesions. RESULTS: Both whisky and ethanol caused a PD reduction, resulting in damage in the stomach, but these responses were less marked in the case of whisky. Although the reduced PD recovered gradually after removal of ethanol, this process was significantly expedited by co-application of EA (80 microg/ml), the recovery rate being much the same as that observed after exposure to whisky. The less-damaging effect of whisky was confirmed in unanesthetized rats after p.o. administration of these agents. In addition, EA (1-30 mg/kg), administered p.o. together with absolute ethanol (99.9%), reduced the severity of gastric lesions induced by ethanol, in a dose-dependent manner, and the effect at 30 mg/kg was equivalent to that obtained by the whisky component containing several low- and high-molecular-weight polyphenols. EA had a scavenging action against both oxygen and hydroxyl radicals in vitro, the effect being equivalent to that of catechol or alpha-tocopherol. CONCLUSION: These results suggest that whisky is less irritating to the gastric mucosa, as compared with pure ethanol, and this property of whisky may be explained by EA, one of polyphenols contained in whisky, and its radical scavenging action.

Alcoholic Beverages↗
PubMed2001

Antihypertensive effects of chicken extract against deoxycorticosterone acetate-salt-induced hypertension in rats.

We investigated the antihypertensive effect of Brand's Essence of Chicken (BEC), a popular chicken extract used as a traditional remedy, using deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Animals were unilaterally nephrectomized, and then separated into a sham-operated group (sham group) and a DOCA-salt-treated group. The latter was further separated into a normal diet group and a BEC (freeze-dried powder, 0.1 w/w%)-containing diet group. Systolic blood pressure of the normal diet group progressively increased in comparison with that of the sham group. The DOCA-salt-induced hypertension was markedly suppressed by feeding a BEC-containing diet. Systolic blood pressure after 5 weeks was 128+/-2 mmHg in sham group, 181+/-4 mmHg in the DOCA-salt-treated normal diet group and 139+/-5 mmHg in the DOCA-salt-treated BEC diet group, respectively. The treatment with DOCA and salt for 5 weeks significantly increased the weights of heart and left ventricle, but these increases were significantly suppressed in the BEC group. When the degree of vascular hypertrophy of the aorta was histochemically evaluated, DOCA-salt-induced increases in wall thickness and wall area of the vessels were significantly decreased by the BEC-feeding. Histopathological renal damage of fibrinoid-like necrosis in glomeruli, thickening of small arteries and tubular dilatation were observed in the DOCA-salt-treated normal diet group, but this damage was efficiently reduced by the BEC-feeding. In addition, BEC-feeding decreased urinary excretion of protein, which was elevated by the treatment with DOCA and salt. Thus, BEC seems to be useful as a prophylactic treatment in the development of hypertension and related tissue injuries.

Animals↗
PubMed2001

Effects of chicken essence tablets on resting metabolic rate.

Resting energy expenditure (REE) values after consuming chicken essence tablets were significantly higher than those observed after consuming skim milk protein tablets (control trial). The increased thermogenic effects continued at least for a period of one hour and gradually decreased towards the baseline. The REE values during control treatment did not show such an augmented response.

Administration, Oral↗
PubMed2001

A study of reproductive performance in pregnant, IL-2 receptor beta-chain overexpressed transgenic mice.

Relationships between female reproductive performance and uterine natural killer (uNK) cells were investigated in pregnant IL-2 receptor beta-chain overexpressed transgenic (Tg2Rbeta) mice. At 8 days of pregnancy, all fetuses were alive, suggesting that implantation normally occurred in these mice. However, 47% of fetuses were dead at 10 days of pregnancy and at 12 days all fetuses were resorbing, indicating that fetal loss progressed with the advance of pregnancy. The placenta of Tg2Rbeta mice gradually decreased in weight with the advance of pregnancy. At 10 days the placental labyrinth, decidua basalis, and metrial gland in Tg2Rbeta mice were poorly developed, and more uNK cells were found in Tg2Rbeta mice than in the control mice. We propose that Tg2RPbeta mice are the first and interesting model that uNK cells can cause abortion, to clarify the involvement of uNK cell function in female reproductive performance.

Animals↗
PubMed2000

Gene disruption analysis of DppA isolated as a periplasmic molecular chaperone-like protein for folding of dimethyl sulfoxide reductase in Rhodobacter sphaeroides f. sp. denitrificans.

The effect of inactivation of DppA, a dipeptide transport protein identified as a periplasmic molecular chaperone-like protein, on the formation of active dimethyl sulfoxide reductase (DMSOR) was examined in Rhodobacter sphaeroides f. sp. denitrificans. All of the dppA-disrupted mutants produced a normal level of native form of DMSOR and grew by DMSO respiration, indicating that the loss of DppA protein alone had no effect on the formation of active DMSOR. The periplasmic fraction of the dppA-disrupted mutant also had the activity to prevent aggregation of acid-unfolded DMSOR. Two proteins, DctP and BztA, were further identified as the proteins with the activity. Their activities, however, were much lower than that of DppA. These results suggest that several substrate binding proteins might be implicated in the folding of unfolded DMSOR in the periplasm.

Bacterial Proteins↗
PubMed2000

'Double-Drugs'--a new class of prodrug form of an HIV protease inhibitor conjugated with a reverse transcriptase inhibitor by a spontaneously cleavable linker.

We designed and synthesized a new series of prodrug-type anti-HIV agents consisting of a peptidomimetic HIV protease inhibitor conjugated with a nucleoside reverse transcriptase inhibitor in an effort to enhance the antiviral activity. For the conjugation, a series of linkers that conjoin the two different classes of inhibitors have been investigated. Conjugates using a succinyl amino acid linker were shown to release the parent components via the spontaneous imide formation at a faster rate compared to conjugates using a glutaryl amino acid linker, as expected from the energetically favorable cyclization to the five-membered ring. Herein, we report a new 'double-drug' 4b (KNI-1039) with a glutarylglycine linker, which exhibited extremely potent anti-HIV activity compared with that of the individual components.

Anti-HIV Agents↗
PubMed2000

Sesamin and alpha-tocopherol synergistically suppress lipid-peroxide in rats fed a high docosahexaenoic acid diet.

Docosahexaenoic acid (DHA) is an essential nutrient for human health, but has extremely high oxidative susceptibility. We examined the suppressing effect of sesamin, a sesame seed lignan, on lipidperoxides in rats fed a low alpha-tocopherol and high DHA containing diet. Groups of rats were fed four experimental diets: low alpha-tocopherol (10 mg/kg diet) control diet, low alpha-tocopherol + 0.2% sesamin diet, low alpha-tocopherol + 0.5% DHA diet and low alpha-tocopherol + 0.5% DHA + 0.2% sesamin diet. TBARS concentrations in plasma and liver were significantly increased by DHA, but were completely suppressed by sesamin. Alpha-tocopherol concentrations in plasma and liver decreased by addition of DHA, but with sesamin recovered to the control level. The addition of DHA into the diets caused remarkable increases of DHA concentrations in plasma and liver lipids. Sesamin caused a significant increase of DHA concentrations in the triacylglycerol of plasma.

Animals↗
PubMed2000

Fiber-in-tube solid-phase microextraction: a fibrous rigid-rod heterocyclic polymer as the extraction medium.

A novel "fiber-in-tube" configuration has been applied to the extraction tube of solid phase microextraction (SPME), and the direct coupling of the extraction process to liquid chromatography (LC) has been accomplished for the analysis of n-butylphthalate in wastewater. By using this fiber-in-tube SPME/LC system the preconcentration factor for the phthalate was about 160 with 20 min extraction and no interference peak was observed in the chromatogram. The results also showed the potential applications of this fiber-in-tube SPME/LC for the analysis of sub-ppb level (i.e., lower than 1 ng/mL) of various organic analytes in aqueous sample matrix without a large solvent consumption during the preconcentration process.

Journal Article↗
PubMed2000

The metabolism and distribution of docosapentaenoic acid (n-6) in rats and rat hepatocytes.

In this study, a new marine oil that contains 45% docosahexaenoic acid (DHA, 22:6n-3) and 13% docosapentaenoic acid (DPA, 22:5n-6) was administered to rats. The metabolism and distribution of DPA in rats was investigated. In experiment 1, the effects of DHA and n-6 fatty acids (linoleic acid, LA; arachidonic acid, AA; and DPA) on AA contents were investigated in vivo. LA group: LA 25%, DHA 30%; LA-DPA group: LA 15%, DPA 10%, DHA 35%; LA-AA-DPA group: LA 10%, AA 5%, DPA 10%, DHA 35% were administered to rats for 4 wk. In the liver, the AA content in the LA-DPA and LA-AA-DPA groups was significantly higher than in the LA group. The decreased AA contents in the LA group might be caused by DHA administration. Although DHA also was administered in the LA-DPA and LA-AA-DPA groups, the AA contents in these two groups did not decrease. These results suggested that DPA retroconverted to AA, blunting the decrease in AA content caused by DHA administration. To conduct a detailed investigation on DPA metabolism and its relation with AA and DHA, rat hepatocytes were cultured with purified DPA and DHA for 24 h. We discovered the retroconversion of DPA to AA occurred only when AA content was decreased by a high DHA administration; it did not occur when AA content was maintained at a normal level.

Animals↗
PubMed2000

Synthesis of di- and tripeptide analogues containing alpha-ketoamide as a new core structure for inhibition of HIV-1 protease.

Di- and tripeptide analogues containing alpha-ketoamide as a new core structure and incorporating allophenylnorstatine (Apns) as a transition state mimic, were designed and synthesized in the hope of obtaining a novel structural type of HIV-1 protease inhibitors. The immediate precursor, Apns-Thz-NHBu(t) was prepared by coupling of Boc-Apns with N-tert x butyl Thz-4-carboxamide hydrochloride. Removal of Boc group followed by coupling with the respective alpha-ketoacid residue (P2) gave the desired dipeptides (8-12) in almost quantitative yields. The alpha-keto tripeptides (18-21) were obtained by oxidation of the hydroxyl group of Apns (PI) in the appropriate tripeptide, iQOA-Val-Apns-(un)substituted Thz(Oxa)-NHBu(t) with DMSO/DCC. Preliminary evaluation of the activity of the synthesized derivatives was determined as percentage of enzyme inhibition at 5 microM and 50 nM levels of the di- and tripeptides respectively. The alpha-ketoamides displayed a significant enhanced potency relative to their parent isosteres as inhibitors of HIV-1 protease and are shown to be a promising new core structure for the development of enzyme inhibitors. A quantitative approach was attempted, using an LFE model, correlating the effect of structural modification and HIV-1 protease inhibition activity of the prepared dipeptides. The result indicates the contribution of the torsion angle by 84% to the activity of the inhibitors.

Amides↗
PubMed2000

Development of novel lipophilic derivatives of DADLE (leucine enkephalin analogue): intestinal permeability characateristics of DADLE derivatives in rats.

PURPOSE: The objective of this study is to examine the intestinal permeability of novel lipophilic derivatives of DADLE (Tyr-D-Ala-Gly-Phe-D-Leu), an enkephalin analogue, using isolated rat intestinal membranes. METHODS: The novel lipophilic derivatives of DADLE were synthesized by chemical modification with various fatty acids at the C terminus. The pharmacological activities of these DADLE derivatives were assessed by a hot plate test. The intestinal permeability of these derivatives was estimated by the in vitro Ussing chamber method. RESULTS: We obtained four different DADLE derivatives including acetyl-DADLE (DADLE-C2), butyryl-DADLE (DADLE-C4), caproyl-DADLE (DADLE-C6), and caprylyl-DADLE (DADLE-C8). All the derivatives of DADLE had at least 75% of the activity of native DADLE, suggesting that chemical modification of DADLE at the C terminus did not markedly affect its pharmacological activity. These DADLE derivatives were more stable than native DADLE in jejunal and colonic homogenates. A "bell-shaped" profile was observed between the apparent permeability coefficients (Papp) of DADLE derivatives and lipophilicity. In particular, DADLE-C4 had the greatest permeability characteristics across the intestinal membrane of the acyl derivatives studied in this experiment. The permeability of DADLE-C4 across the jejunal membrane was further improved in the presence of puromycin, amastatin, and sodium glycocholate (NaGC), all at a concentration of 0.5 mM. CONCLUSIONS: We suggest that the combination of chemical modification with butyric acid and the application of a protease inhibitor are effective for improving the absorption of DADLE across the intestinal membrane.

Animals↗
PubMed2000

Ultrastructural studies of implantation sites from mice deficient in uterine natural killer cells.

Implantation sites from three strains of immunodeficient mice [tgepsilon26, IL-2Rbeta nullxp56(lck)null and IL-2Rgamma null, now known as common cytokine chain gamma (gamma(c)) null], which lack uterine natural killer (uNK) cells, are histologically abnormal. The related anomalies (found from day 10 of gestation) include the absence of aggregation of lymphocytes in the mesometrial triangle, acellularity of the mesometrial decidua, decidual arteries with relatively thick walls and reduced lumen diameters, unusual prominence of the endothelium in the major decidual vessels, and an overall reduction in placental size. In this study we have characterized implantation sites in a new mouse strain (gammac(-)/RAG2(-)) that is deficient in all lymphoid lineages. We have compared implantation sites in tgepsilon26 to gammac(-)/RAG2(-)at the ultrastructural level in order to determine the earliest-time point at which implantation sites differed from those in immunocompetent mice, and the cell types affected. Implantation sites from both the uNK cell-deficient mice resemble those from random-bred, immunocompetent mice on days 6 and 7 of gestation. On day 8 of gestation, decidual cells on the mesometrial sides of implantation sites in both tgepsilon26 and gammac(-)/RAG2(-)revealed pleotrophic morphology and degeneration. In some vessels, endothelial cells were distorted or displaced from their supporting cells. Progressive changes, suggestive of loss of function of both the mesometrial decidua and endothelial cells, were seen to day 14 of gestation, the latest time-point analysed. In contrast to tgepsilon26 mice, homozygously-mated gammac(-)/RAG2(-)had normal litter sizes, with birthweights and weaning weights similar to congenic C57Bl/6J controls, and no significant perinatal loss. In both strains, the newly-documented endothelial cell lesions predict detrimental alterations to vasomotor function of the uterine vasculature. These studies add strength to the hypothesis that uNK cells may have specialized physiological, rather than classically immune, functions in the pregnant mammalian uterus.

Animals↗
PubMed2000

Thermodynamic dissection of the binding energetics of KNI-272, a potent HIV-1 protease inhibitor.

KNI-272 is a powerful HIV-1 protease inhibitor with a reported inhibition constant in the picomolar range. In this paper, a complete experimental dissection of the thermodynamic forces that define the binding affinity of this inhibitor to the wild-type and drug-resistant mutant V82F/184V is presented. Unlike other protease inhibitors, KNI-272 binds to the protease with a favorable binding enthalpy. The origin of the favorable binding enthalpy has been traced to the coupling of the binding reaction to the burial of six water molecules. These bound water molecules, previously identified by NMR studies, optimize the atomic packing at the inhibitor/protein interface enhancing van der Waals and other favorable interactions. These interactions offset the unfavorable enthalpy usually associated with the binding of hydrophobic molecules. The association constant to the drug resistant mutant is 100-500 times weaker. The decrease in binding affinity corresponds to an increase in the Gibbs energy of binding of 3-3.5 kcal/mol, which originates from less favorable enthalpy (1.7 kcal/mol more positive) and entropy changes. Calorimetric binding experiments performed as a function of pH and utilizing buffers with different ionization enthalpies have permitted the dissection of proton linkage effects. According to these experiments, the binding of the inhibitor is linked to the protonation/deprotonation of two groups. In the uncomplexed form these groups have pKs of 6.0 and 4.8, and become 6.6 and 2.9 in the complex. These groups have been identified as one of the aspartates in the catalytic aspartyl dyad in the protease and the isoquinoline nitrogen in the inhibitor molecule. The binding affinity is maximal between pH 5 and pH 6. At those pH values the affinity is close to 6 x 10(10) M(-1) (Kd = 16 pM). Global analysis of the data yield a buffer- and pH-independent binding enthalpy of -6.3 kcal/mol. Under conditions in which the exchange of protons is zero, the Gibbs energy of binding is -14.7 kcal/mol from which a binding entropy of 28 cal/K mol is obtained. Thus, the binding of KNI-272 is both enthalpically and entropically favorable. The structure-based thermodynamic analysis indicates that the allophenylnorstatine nucleus of KNI-272 provides an important scaffold for the design of inhibitors that are less susceptible to resistant mutations.

Calorimetry, Differential Scanning↗
PubMed2000

Role of hypothermia induced by tumor necrosis factor on apoptosis and function of inflammatory neutrophils in mice.

Changes in body temperature and cell infiltration, mediated by cytokines including tumor necrosis factor-alpha (TNF-alpha), occur during inflammation, but a role of body temperature on inflammatory responses remains obscure. Intraperitoneal injection of 10% casein to mice resulted in transient hypothermia followed by neutrophil accumulation in peritoneal cavities. Peritoneal TNF-alpha was rapidly raised, and pretreatment of mice with an anti-TNF-alpha antibody promoted temperature restoration and partially inhibited neutrophil accumulation. To investigate direct effects of body temperature on neutrophils, peritoneal or peripheral blood neutrophils were cultured at 35 degrees C or 37 degrees C with or without recombinant murine TNF-alpha (100 ng/ml) or a protein synthesis inhibitor cycloheximide (1 microg/ml). Significant inhibition of spontaneous and TNF-alpha-induced apoptosis was obtained at 35 degrees C compared with 37 degrees C, an effect that was not altered by the addition of cycloheximide. Moreover, phagocytic ability of peritoneal neutrophils was significantly enhanced by incubating them at the lower temperature. These results indicate that mild hypothermia induced by endogenous TNF-alpha has enhancing roles on neutrophil survival and function during peritoneal inflammation.

Animals↗
PubMed2000

Neurotrophic action of interleukin 3 and granulocyte-macrophage colony-stimulating factor on murine sympathetic neurons.

We investigated neurotrophic effects of interleukin 3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) on cultured sympathetic neurons obtained from mouse superior cervical ganglia. After 1 day of culture with physiological concentrations of mouse recombinant IL-3 and GM-CSF, the numbers of process-bearing neurons were increased. Maximum responses were elicited by 10 U/ml IL-3 and 1 U/ml GM-CSF, which were equivalent to the action of a submaximal dose (5 ng/ml) of nerve growth factor (NGF). The effects of IL-3 and GM-CSF were completely blocked by their corresponding antibodies, but not by anti-NGF, indicting their action is specific and completely independent of NGF. IL-3 and, to a lesser extent, GM-CSF were also able to protect NGF-differentiated neurons from apoptotic cell death caused by NGF withdrawal. The mitogen-activated protein (MAP) kinase signal transduction pathway is known to be involved in action of IL-3 and GM-CSF on hemopoietic cells, and thus we examined the participation of this pathway in the neurotrophic activities of IL-3 and GM-CSF. IL-3 and GM-CSF stimulation of the differentiated neurons was found to result in a rapid elevation of MAP kinase activity, and PD98059, an inhibitor of MAP kinase kinase activity, blocked both the neuritogenic and neuroprotective effects of IL-3 and GM-CSF. Immunocytochemical studies showed that IL-3 and GM-CSF receptors were present on the differentiated neurons. Thus, IL-3 and GM-CSF appear to be able to stimulate sympathetic nerve growth, via specific cytokine receptors on neurons, which lead to activation of the MAP kinase pathway that then mediates the observed neurotrophic effects.

Animals↗
PubMed2000

Structure-activity relationship of orally potent tripeptide-based HIV protease inhibitors containing hydroxymethylcarbonyl isostere.

We designed and synthesized a new class of peptidomimetic human immunodeficiency virus protease inhibitors containing a unique unnatural amino acid, allophenylnorstatine [Apns; (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid], with a hydroxymethylcarbonyl isostere as the active moiety. From a structure-activity relationship study of HIV-1 protease inhibition, enzyme selectivity for other aspartyl proteases, the antiviral activity and pharmacokinetics in rats, 24c (KNI-227) and 24d (KNI-272, our first clinical candidate) were found to be selective and orally potent HIV protease inhibitors. Moreover, an improvement of the pharmacokinetic features of KNI-272 provided two long-lasting and highly bioavailable compounds (24g: JE-2178, 24h: JE-2179).

Animals↗