Studies on the role of dietary diacylglycerols in human nutrition.
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Adipose Tissue↗
Biomedical subjects
T Nagao
Publications and source records attributed to T Nagao.
Bradykinin mediates the acute effect of an angiotensin-converting enzyme inhibitor on cerebral autoregulation in rats.
BACKGROUND AND PURPOSE: In patients with stroke and long-standing hypertension, the autoregulation curve of cerebral blood flow (CBF) shifts toward higher blood pressure levels. Angiotensin-converting enzyme (ACE) inhibitors reduce blood pressure and shift the autoregulation curve back to normal in hypertensive patients. ACE inhibitors have 2 major pharmacological properties: they inhibit both the production of angiotensin II and the breakdown of kinins. Hence, we investigated whether the effect of an ACE inhibitor on the lower limit of CBF autoregulation is mediated by the potentiation of bradykinin-mediated vasodilatation. METHODS: In 28 male Sprague-Dawley rats, CBF was measured by laser-Doppler flowmetry during stepwise controlled hypotension. The lower limit of CBF autoregulation was defined as the mean arterial pressure at which CBF decreased by 20% of the baseline value. The rats were treated with an ACE inhibitor, captopril, in the captopril group; a bradykinin BK2-receptor antagonist, Hoe140, in the Hoe140 group; and both agents in the captopril+Hoe140 group. Other rats served as a control group. The lower limits of CBF autoregulation were compared among the 4 groups. RESULTS: In the captopril group, the lower limit of CBF autoregulation was 43+/-8 mm Hg (mean+/-SD), which was significantly lower than that in the control group (57+/-14 mm Hg). Inhibition of bradykinin abolished the effect of captopril on the lower limit of CBF autoregulation. Hoe140 alone had no significant effect on the lower limit of CBF autoregulation. CONCLUSIONS: These results suggest that the shift of the lower limit of CBF autoregulation by captopril is mediated, at least in part, by bradykinin.
Angiotensin-Converting Enzyme Inhibitors↗
Polymorphism of the lipoprotein lipase gene and risk of atherothrombotic cerebral infarction in the Japanese.
BACKGROUND AND PURPOSE: Lipid and lipoprotein abnormalities have been implicated in the pathogenesis of ischemic cerebrovascular disease and atherosclerosis. Lipoprotein lipase (LPL) plays an important role in plasma lipoprotein metabolism. Several studies have recently reported the presence of a relationship between Ser447Stop mutation of LPL and coronary artery disease. Other polymorphisms (HindIII and PvuII) of the LPL gene have already been shown to correlate significantly with dyslipidemia. We investigated whether these polymorphisms are associated with increased risk of ischemic cerebrovascular disease (CVD). METHODS: We recruited 177 CVD patients (atherothrombotic infarction, n=71; cardioembolic infarction, n=30; lacunar infarction, n=76) and 177 healthy control subjects. Subjects were genotyped for the Ser447Stop mutation and for HindIII/PvuII restriction fragment length polymorphisms of the LPL gene, and the findings were investigated for associations with the clinical subtypes of CVD and with lipid levels. RESULTS: The Ser447Stop mutation correlated significantly with CVD (0.107 versus 0.158; P=0.035). For the CG+GG versus CC genotype, the odds ratio between control subjects and CVD patients with atherothrombotic infarction was 0.42 (95% CI, 0.18 to 0.99) (P=0.046). Serum HDL cholesterol and triglyceride levels did not correlate significantly with the Ser447Stop genotype. HindIII polymorphism correlated significantly with CVD (0.234 versus 0.169; P=0.031), but the frequency of PvuII polymorphism was not significantly different between groups. CONCLUSIONS: Our results suggest that the Ser447Stop mutation of the LPL gene is a novel genetic marker for low risk of atherothrombotic cerebral infarction.
Cerebral Infarction↗
Antiproliferative constituents in the plants 7. Leaves of Clerodendron bungei and leaves and bark of C. trichotomum.
The constituents of the leaves of Clerodendron bungei STEUD. (Verbenaceae) and leaves and bark of C. trichotomum THUNB. were investigated guided by the antiproliferative activity against three tumor cell lines (MK-1: human gastric adenocarcinoma, HeLa: human uterus carcinoma, and B16F10: murine melanoma). Two phenylethanoid glycoside caffeic acid esters, acteoside and isoacteoside, were isolated as the constituents which selectively inhibit the growth of B16F10 cells. The antiproliferative activities against B16F10 cells of acteoside (GI50: 8 microM), isoacteoside (8 microM) and their methanolysis products, methyl caffeate (26 microM), 3,4-dihydroxyphenethyl alcohol (8 microM), 3,4-dihydroxyphenethyl glucoside (10 microM), desrhamnosyl acteoside (6 microM), and desrhamnosyl isoacteoside (6 microm) suggested that the 3,4-dihydroxyphenethyl alcohol group might be more responsible for the activities of acteoside and isoacteoside than the caffeoyl group. The activities of chlorogenic acid, 3,4-dihydroxyphenylacetic acid, 3-(3,4-dihydroxyphenyl) alanine, 3,4-dihydroxy-phenethylamine hydrochloride, ferulic acid, sinapic acid, and five dihydroxybenzoic acids were also determined and compared with those of the above compounds.
Animals↗
Involvement of prostaglandin E2 in clearance of aggregated protein via protein kinase A in glomeruli.
Recently we immunohistochemically demonstrated that prostaglandin E2 (PGE2) promoted the clearance of aggregated bovine serum albumin (a-BSA) deposited in glomeruli. Herein, we investigated the role of PGE2 and its signal transduction in the disposal of macromolecules in glomeruli. EP2 and EP4 receptor mRNA was detected in glomeruli by RT-PCR analysis. A-BSA was injected twice into mice. Glomeruli were then isolated and incubated. A-BSA gradually disappeared from isolated glomeruli. PGE2 increased the intracellular cyclic AMP and decreased a-BSA level in glomeruli. Additionally, 8-bromocyclic AMP evoked a loss of a-BSA in isolated glomeruli. The effect of 8-bromo-cyclic AMP on the clearance of a-BSA was abolished by KT 5720 in glomeruli. PGE2 and 8-bromo-cyclic AMP also prompted disposal of a-BSA in cultured mesangial cells. These findings indicate that PGE2 positively regulates the removal of macromolecules via cyclic AMP and protein kinase A in glomeruli, and they provide insight into how to prevent the development of glomerulonephritis and glomerulosclerosis.
8-Bromo Cyclic Adenosine Monophosphate↗
Diltiazem ameliorates contractile dysfunction without shortening of action potential duration in ischemic heart of anesthetized dogs.
The purpose of the following experiment was to determine whether amelioration of myocardial contractile dysfunction by diltiazem is mediated by shortening of monophasic action potential duration (MAPD) during myocardial ischemia in anesthetized dogs. Diltiazem improved regional contraction during reperfusion after 10-min occlusion. The shortening of MAPD and increase in [K+]e were blunted by treatment with diltiazem. These results suggest that shortening of action potential duration during myocardial ischemia is unlikely to be a reason for the amelioration of contractile dysfunction.
Action Potentials↗
Altered diurnal variation of blood pressure in elderly subjects with decreased activity of daily living and impaired cognitive function.
Activity of daily living (ADL) and cognitive are indices of physical and psychological activity in elderly subjects. The present study was performed to clarify the relationship among ADL, cognitive function, and ambulatory blood pressure (ABP) in the elderly. Study subjects were 77 females and 22 males (aged 60 to 101 years) with various levels of ADL and cognition, who were in nursing homes or geriatric hospitals. ABP was recorded every 30 min for 24 h by a noninvasive device. Mini-mental state examination (MMSE) and Barthel index measurement were used to evaluate cognitive function and ADL, respectively. Both the MMSE and Barthel index values showed a significant positive correlation with daytime ABP but not with nighttime ABP. The dip in nighttime BP correlated negatively with age, and positively with MMSE and Barthel index. In the multiple regression analysis, age and Barthel index values remained significant determinants of the dip in nighttime BP. Presence of stroke and MMSE became significant when the Barthel index values were removed from the analyses. When subjects were classified by tertiles of MMSE or Barthel index, subjects in the lowest MMSE group and those in the lowest Barthel index group had both lower daytime ABP and smaller nighttime BP dip than those of the other groups. A low BP level during the daytime was associated with altered diurnal variation of BP in elderly subjects with greater age, impaired cognitive function, and/or decreased ADL. ADL had a greater influence on diurnal BP variation than did cognitive function.
Activities of Daily Living↗
Infrastructure of pharmaceutical research and development in Japan.
OBJECTIVE: To examine the roles of different types of hospitals in implementation of multicenter Phase II/III trials in Japan, specifically focusing on two dichotomies: public versus private, and academic versus nonacademic. Possible explanation was sought as to why a hospital of one category was more likely to participate in specific types of trials in the Japanese medical environment. METHODS: A database containing attributes of published clinical trials (n = 217) was established from four journals featuring reports of clinical trial results. The preferences of public and academic hospitals for specific types of trials were estimated by applying a linear regression model. The trial compositions of these institutions were also estimated, taking the actual prevalence of trials in 1995 into consideration. RESULTS: Public sector hospitals, which were established for particular policy purposes in the national healthcare system, were more likely to accept trials in some fields (e.g., cardiovascular diseases, anesthesiology, antineoplastics, pediatrics) and of some kinds (e.g., Phase II rather than Phase III trials, trials supervised by the principal investigator in the public sector). Academic hospitals also showed preferences for some types of trials (e.g., cardiovascular diseases, dermatology; Phase II rather than Phase III trials). The analysis focusing on public hospitals suggested that policy purposes were achieved at least in some fields such as antineoplastics and anesthesiology. CONCLUSIONS: Japanese clinical trials were unevenly distributed between public and private sectors, and also between academic and nonacademic sectors. These data provide fundamental information about the clinical research environment for future pharmaceutical research and development strategies and policies.
Academic Medical Centers↗
Sarcoidosis with granulomatous interstitial nephritis: report of three cases.
Three cases of sarcoidosis with granulomatous interstitial nephritis are reported. Patients were all male and over 50 years of age. They simultaneously had evidence of multiorgan involvement of sarcoidosis including lung and skin and/or eye. In addition, distinct features were found in each case: a granulomatous infiltration mimicking unilateral renal tumor (case 1); renal insufficiency solely due to granulomatous interstitial nephritis (case 2); and renal insufficiency with calcemic nephropathy and granulomatous interstitial nephritis (case 3). Prednisolone therapy resulted in disappearance of the pseudotumor in case 1 and partial improvement of renal function in cases 2 and 3. In cases 2 and 3, however, plasma creatinine did not return to normal values and a second renal biopsy in case 2 demonstrated residual interstitial fibrosis and few granulomas, suggesting that steroid therapy did not achieve complete reversal of changes.
Aged↗
Trauma sites and clinical features associated with acute hyperextension spinal cord injury without bone damage--relationship between trauma site and severity.
To elucidate whether a relationship exists between the site of trauma and severity of acute hyperextension spinal cord injury without bone damage, we examined the clinical features of 25 male and 10 female patients aged 13 to 88 years. None of the patients had vertebral damage such as fracture and dislocation. The site of impact was classified as the buccal, forehead, or mandibular region. The neurological findings were assessed according to Frankel's classification at admission and at follow up after 3 months or more to assess outcome. Eleven patients suffered trauma in the buccal region, one patient in Frankel's grade B, three in grade C, and seven in grade D at admission. All 11 of these patients showed an improvement of one grade or more to an outcome of C in one patient, D in one, and E in nine. Trauma occurred at the forehead region in 18 patients, four in grade B, 10 in grade C, and four in grade D. Improvement was seen at follow up by one grade or more to C in one patient, D in 10, and E in seven. Trauma occurred at the mandibular region in six patients, four in grade B and two in grade C. Four of these patients showed improvement of one grade or more to grade B in one, grade C in four, and grade E in one. Overall, seven patients had poor outcomes, five of whom suffered trauma to the mandibular region, indicating that impact to the mandibular region tends to have an unfavorable clinical outcome. Our findings indicate that the site of trauma greatly influences the severity of hyperextension spinal cord injury.
Adolescent↗
Neurosarcoidosis without systemic sarcoidosis--case report.
A 20-year-old male presented with symptoms of isolated neurosarcoidosis including epilepsy. Magnetic resonance imaging disclosed multiple enhanced right temporal and frontal lesions. Cerebrospinal fluid examination identified mild lymphocytic pleocytosis, and histological examination of a stereotactic brain biopsy specimen demonstrated noncaseating granulomas, so fungal or other inflammatory or granulomatous diseases were excluded. The diagnosis was cerebral sarcoidosis, despite the absence of systemic manifestations. Corticosteroid therapy improved his neurological state and radiological findings. Neurosarcoidosis is a well-recognized occurrence in systemic sarcoidosis, but diagnosis may be difficult in the absence of extracerebral manifestations.
Adult↗
Analysis of the p53 gene in parotid gland cancers: a relatively high frequency of mutations in low-grade mucoepidermoid carcinomas.
Mutations and overexpression of the p53 gene and protein were analyzed in 40 cases with various types of parotid gland cancers. Mutations were found in 12 cases (30%), and low-grade mucoepidermoid carcinomas (43%) and highly malignant carcinomas including adenocarcinoma, salivary duct carcinoma, and undifferentiated carcinoma (56%) showed a relatively high frequency of mutations. Overexpression of the protein was observed in 11 cases (28%) and 4 of the 11 cases also had p53 mutations. These results suggest that mutations of the p53 gene have significance in certain types of parotid cancers irrespective of the aggressiveness of a tumor type.
Carcinoma, Mucoepidermoid↗
Novel macrolactins as antibiotic lactones from a marine bacterium.
Seven new macrolactins (named G~M) and known macrolactins A and F were isolated from a culture broth of Bacillus sp. PP19-H3. The strain had been isolated from the macroalga, Schizymenia dubyi. Macrolactin A, which was 24-membered lactone, had previously been reported to show antibacterial, cytotoxic and antiviral activities. The new macrolactins include 22-membered ring or dicyclic lactone in addition to geometric isomers of known macrolactins A and F. The antibacterial activities of all the macrolactins examined in this study were relatively weak.
Anti-Bacterial Agents↗
[Problems associated with the National Health Insurance coverage for nursing].
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Aged↗
Serine residue in the IIIS5-S6 linker of the L-type Ca2+ channel alpha 1C subunit is the critical determinant of the action of dihydropyridine Ca2+ channel agonists.
The dihydropyridine (DHP)-binding site has been identified within L-type Ca(2+) channel alpha(1C) subunit. However, the molecular mechanism underlying modulation of Ca(2+) channel gating by DHPs has not been clarified. To search for novel determinants of high affinity DHP binding, we introduced point mutations in the rat brain Ca(2+) channel alpha(1C) subunit (rbCII or Ca(v)1.2c) based on the comparison of amino acid sequences between rbCII and the ascidian L-type Ca(2+) channel alpha(1) subunit, which is insensitive to DHPs. The alpha(1C) mutants (S1115A, S1146A, and A1420S) and rbCII were transiently expressed in BHK6 cells with beta(1a) and alpha(2)/delta subunits. The mutation did not affect the electrophysiological properties of the Ca(2+) channel, or the voltage- and concentration-dependent block of Ca(2+) channel currents produced by diltiazem and verapamil. However, the S1115A channel was significantly less sensitive to DHP antagonists. Interestingly, in the S1115A channel, DHP agonists failed to enhance whole-cell Ca(2+) channel currents and the prolongation of mean open time, as well as the increment of NP(o). Responsiveness to the non-DHP agonist FPL-64176 was also markedly reduced in the S1115A channel. When S1115 was replaced by other amino acids (S1115D, S1115T, or S1115V), only S1115T was slightly sensitive to S-(-)-Bay K 8644. These results indicate that the hydroxyl group of Ser(1115) in IIIS5-S6 linker of the L-type Ca(2+) channel alpha(1C) subunit plays a critical role in DHP binding and in the action of DHP Ca(2+) channel agonists.
Amino Acid Sequence↗
G alpha(i) and G alpha(o) are target proteins of reactive oxygen species.
Reactive oxygen species (ROS) have been identified as central mediators in certain signalling events. In the heart, ROS have important functions in ischaemia/reperfusion-induced cardiac injury and in cytokine-stimulated hypertrophy. Extracellular signal-regulated kinase (ERK) is one of the ROS-responsive serine/threonine kinases. Previous studies showed that tyrosine kinases and small G proteins are involved in the activation of ERK by ROS; however, the initial target protein of ROS that leads to ERK activation remains unknown. Here we show that inhibition of the betagamma-subunit of G protein (G betagamma) attenuates hydrogen peroxide (H2O2)-induced ERK activation in rat neonatal cardiomyocytes. The G betagamma-responsive ERK activation induced by H2O2 is independent of ligands binding to Gi-coupled receptors, but requires phosphatidylinositol-3-kinase and Src activation. In in vitro studies, however, treatment with H2O2 increases [35S]GTP-gammaS binding to cardiac membranes and directly activates purified heterotrimeric Gi and Go but not Gs. Analysis using heterotrimeric Go and its individual subunits indicates that H2O2 modifies G alpha(o) but not G betagamma, which leads to subunit dissociation. We conclude that G alpha(i) and G alpha(o) are critical targets of oxidative stress for activation of ERK.
Animals↗
Stimulation of hepatocyte growth factor production in human fibroblasts by the protein phosphatase inhibitor okadaic acid.
In this study, we examined whether the production of hepatocyte growth factor (HGF) in fibroblasts is regulated by protein phosphatase(s). Inhibitors of the enzymes okadaic acid and calyculin A were used for this purpose. Both inhibitors markedly stimulated HGF production in human skin fibroblasts in a dose-dependent manner. The effects of okadaic acid and calyculin A were maximal at 25-37.5 and 1.25 nM, respectively. Highly active HGF production in MRC-5 human embryonic lung fibroblasts was also promoted by both inhibitors. The effect of okadaic acid was accompanied by an up-regulation of HGF gene expression. The stimulating effect of okadaic acid on HGF production was synergistic with that of phorbol 12-myristate 13-acetate (PMA) and epidermal growth factor (EGF), whereas it was additive to the effect of cholera toxin. The protein kinase C (PKC) inhibitor GF 109203X inhibited the effect of PMA, but not of okadaic acid and EGF. The effect of okadaic acid as well as EGF was not inhibited, but rather enhanced in human skin fibroblasts pretreated for 24 hr with a high dose of PMA to deplete PKC, as compared with its effect in untreated cells. PD 98059, an inhibitor of mitogen-activated protein (MAP) kinase kinase, suppressed the effects of okadaic acid and EGF, but not those of cholera toxin and 8-bromo-adenosine 3',5'-cyclic monophosphate (cAMP). These results suggest that HGF production in human skin fibroblasts is down-regulated by protein phosphatase(s) and that HGF production stimulated by okadaic acid is, at least in part, dependent on the activation of the MAP kinase cascade.
Cells, Cultured↗
Involvement of BK(Ca) channels in the relaxation of detrusor muscle via beta-adrenoceptors.
Detrusor muscle relaxes upon activation of beta-adrenoceptors on smooth muscle cells. However, the mechanism of relaxation following the stimulation of beta-adrenoceptors remains unclear. In order to clarify the mechanism, we investigated the involvement of ion channels in bladder relaxation. In guinea-pig isolated bladder strips precontracted by high-K(+), isoproterenol caused concentration-dependent relaxation. The relaxation caused by isoproterenol (1 microM) was larger in 30 mM K(+) than in 120 mM K(+) (54.2+/-8.0% and 18.2+/-4.1% of papaverine-induced relaxation, respectively, n=4). Iberiotoxin (100 nM) inhibited the isoproterenol-induced relaxation (vehicle 69.5+/-8.0% vs. iberiotoxin 24.9+/-6.2%, respectively, n=5). Whole-cell patch-clamp recording revealed that isoproterenol as well as forskolin increased the iberiotoxin-sensitive K(+) currents, and this increase was abolished by protein kinase inhibitor. These results suggest that the isoproterenol-induced relaxation of guinea-pig bladder smooth muscle is mainly mediated by facilitation of BK(Ca) channels subsequent to the activation of the cAMP/protein kinase A pathway.
Animals↗