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Biomedical subjects

N Hirose

Publications and source records attributed to N Hirose.

At least 19 recordsLinked to original sources
PubMed2005

Interactions among mu- and delta-opioid receptors, especially putative delta1- and delta2-opioid receptors, promote dopamine release in the nucleus accumbens.

The effect of interactions among mu- and delta-opioid receptors, especially the putative delta(1)- and delta(2)-opioid receptors, in the nucleus accumbens on accumbal dopamine release was investigated in awake rats by in vivo brain microdialysis. In agreement with previous studies, perfusion of the nucleus accumbens with the mu-, delta(1)- and delta(2)-opioid receptor agonists [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO), [D-Pen(2,5)]-enkephalin (DPDPE) and [D-Ser(2)]Leu-enkephalin-Thr(6), respectively, significantly enhanced the extracellular amount of accumbal dopamine in a dose-related manner (5.0 nmol and 50.0 nmol). However, the highest concentration tested (50.0 nmol) of DAMGO induced a biphasic effect, i.e. a rapid onset increase lasting for 75 min followed by a slower onset gradual and prolonged increase. The mu-opioid receptor antagonist D-Phe-Cys-Tyr-d-Trp-Orn-Thr-Phe-Thr-NH(2) (0.15 nmol) primarily reduced the DAMGO-induced second component. The delta(1)-opioid receptor antagonist (E)-7-benzylidenenaltrexone (0.15 nmol) significantly reduced the first component and abolished the second component induced by DAMGO, while the delta(2)-opioid receptor antagonist naltriben (1.5 nmol) significantly reduced only the first component. The DPDPE (50.0 nmol)-induced dopamine increase was almost completely abolished by (E)-7-benzylidenenaltrexone, but only partially reduced by D-Phe-Cys-Tyr-d-Trp-Orn-Thr-Phe-Thr-NH(2) and naltriben. The [D-Ser(2)]Leu-enkephalin-Thr(6) (50.0 nmol)-induced dopamine increase was almost completely abolished by naltriben, but not at all by D-Phe-Cys-Tyr-d-Trp-Orn-Thr-Phe-Thr-NH(2) and (E)-7-benzylidenenaltrexone. The non-selective opioid receptor antagonist naloxone (0.75 and 1.5 nmol) dose-dependently reduced the effects of DAMGO, DPDPE and [D-Ser(2)]Leu-enkephalin-Thr(6) but only to about 10-25% of the control values. Moreover, perfusion with the sodium channel blocker tetrodotoxin (0.1 nmol) reduced the DAMGO-induced dopamine increase by 75%, while it almost completely abolished the increase induced by DPDPE or [D-Ser(2)]Leu-enkephalin-Thr(6). The results show that stimulation of mu-opioid receptors or, to a lesser degree, delta(1)-opioid receptors results in a large naloxone-sensitive increase and a small naloxone-insensitive increase of extracellular dopamine. It is suggested that the naloxone-insensitive component is also tetrodotoxin-insensitive. Furthermore, it is hypothesized that stimulation of mu-opioid receptors activates delta(1)-receptors, which in turn activate delta(2)-opioid receptors, thereby giving rise to a rapid onset increase of extracellular dopamine. In addition, it is hypothesized that stimulation of another group of mu-opioid receptors activates a second group of delta(1)-opioid receptors that is not coupled to delta(2)-opioid receptors and mediates a slow onset increase of extracellular dopamine. Finally, it is suggested that stimulation of delta(1)- or delta(2)-opioid receptors inhibits mu-opioid receptors involved in the slow onset increase in extracellular dopamine, whereas stimulation of delta(1)-, but not delta(2)-, opioid receptors is suggested to activate mu-opioid receptors involved in the rapid increase in extracellular dopamine.

Analgesics, Opioid↗
PubMed2005

Protective effect of a radical scavenger, MCI-186 on islet cell damages induced by oxidative stress.

Oxidative stress generated during islet isolation and transplantation causes islet cell damage. These oxidative injuries are mediated by reactive oxygen species (ROS) and reactive nitrogen species (RNS). MCI-186 is an antioxidant used for clinical treatment of cerebral infarction in Japan. We examined a possible protective effect of MCI-186 on islet cells against oxidative stress. Islets isolated from Sprague-Dawley rats by collagenase P digestion were purified by density gradient centrifugation with Ficoll. Islets were treated with hydrogen peroxide (H(2)O(2); 5 to 250 micromol) in the presence or absence of MCI-186. Cell death was measured by an LDH release assay. Maximum islet cell death was observed at 250 micromol of H(2)O(2). MCI-186 inhibited islet cell death in a dose-dependent manner with significant reduction above 30 micromol. From the results observed we suggest that the antioxidant effects of MCI-186 may prove beneficial to improve the preservation of islet cells.

Animals↗
PubMed2001

Synthesis of 9-(2,3-dideoxy-2-fluoro-beta-D-threo-pentofuranosyl)adenine (FddA) via a purine 3'-deoxynucleoside.

A synthesis of 9-(2,3-dideoxy-2-fluoro-beta-D-threo-pentofuranosyl)adenine (1, FddA) via a 6-chloro-9-(3-deoxy-beta-D-erythro-pentofuranosyl)-9H-purine (9), which was readily obtained from inosine (5), is described. Fluorination at the C2'-beta position of the purine 3'-deoxynucleoside with diethylaminosulfur trifluoride was improved by the introduction of a 6-chloro group and proceeded in moderate yield. Purine 3'-deoxynucleoside derivatives were also subjected to nucleophilic reactions with triethylamine trihydrofluoride and gave the desired fluorinated nucleoside in good yield. The safety and yield of the fluorination process were greatly improved by the use of triethylamine trihydrofluoride. The influence of the sugar ring conformation and 6-chloro group on the rate of the nucleophilic reaction against elimination are also discussed.

Anti-HIV Agents↗
PubMed2001

Histopathological modifications of early atherosclerotic lesions by risk factors--findings in PDAY subjects.

To investigate whether histopathological modifications on early atherosclerotic lesions differ according to risk factors, we compared the histological findings of arteries obtained from a multicenter study in the USA (Pathobiological Determinants of Atherosclerosis in Youth, PDAY) with the antemortem risk factors. The materials comprised aortas and left anterior descending (LAD) coronary arteries of 140 male subjects. Measurements of intimal thickness, classification of intimal lesions, and density of foam cells and intimal fibrosis at the determined sites of LAD and aorta were evaluated. In both arteries, intimal thickness of hypertensives was greater than the normotensives with no definite proliferation of foam cells. In aortas, hypercholesterolemia was associated with an increase in foam cells, but not with an increase in intimal thickness. HDL-C value correlated inversely with number of foam cells in both the arteries, and the degree of intimal thickness in LADs, where early appearance of advanced lesion such as preatheroma and atheroma, was also indicated in the low HDL-C group. Smokers had less number of foam cells in both the arteries and more intensive intimal fibrosis in LAD than non-smokers. Our study suggests that there are several ways to advanced atherosclerotic lesions by risk factors.

Adolescent↗
PubMed2001

Lipoprotein metabolism in Japanese centenarians: effects of apolipoprotein E polymorphism and nutritional status.

OBJECTIVES: To assess the complex interaction of apolipoprotein (apo) E polymorphisms and environmental factors on lipoprotein profile in centenarians. DESIGN: Cross-sectional analysis. SETTING: Tokyo metropolitan area. PARTICIPANTS: Seventy-five centenarians and 73 healthy older volunteers (mean age 63.1 +/- 10.0) living in the Tokyo metropolitan area. MEASUREMENTS: Plasma lipids and lipoproteins, cholesteryl ester transfer protein mass, apo E phenotype, body mass index, nutritional indices (serum albumin, prealbumin, transferrin), dietary intake, inflammation markers (C-reactive protein (CRP), interleukin-6 (IL-6)), activities of daily living, and cognitive function. RESULTS: In comparison with older people, the centenarians had low concentrations of total and low-density lipoprotein cholesterol (LDL-C) and a relative predominance of high-density lipoprotein 2 cholesterol. No environmental factor, except the number of apo E epsilon2 alleles, was a significant determinant of LDL-C and apo B, suggesting that the low apo B-containing lipoprotein in centenarians may be attributable to a genetic cause. Centenarians had elevated levels of lipoprotein (a) and decreased high-density lipoprotein cholesterol (HDL-C), which seem to be an unfavorable lipoprotein profile. Lower levels of HDL-C in the centenarians were associated with decreased serum albumin, elevated CRP and IL-6 levels, and cognitive impairment, suggesting that HDL-C could be a sensitive marker for frailty and comorbidity in the oldest old. CONCLUSIONS: Low levels of apo B-containing lipoproteins attributable to a genetic cause may be advantageous for longevity. Lipoprotein profiles in centenarians were consistently related to the subjects' nutritional status, inflammation markers, and apo E polymorphisms. The results provide evidence for the importance of maintaining nutritional status in the very old.

Activities of Daily Living↗
PubMed2001

Metabolic activation of 1alpha-hydroxyvitamin D3 in human liver microsomes.

1. 1Alpha-hydroxyvitamin D3 (1alpha-OH-D3) is a synthetic prodrug of the active form of vitamin D3, and requires the hydroxylation at the C-25 position before eliciting its biological activity. 2. 25-Hydroxylation activities for 1alpha-OH-D3 were present in both microsomal and mitochondrial fractions of human liver. 3. To determine the P450 enzyme(s) involved in microsomal 25-hydroxylation, 14 P450s (CYP1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9-Arg, 2C9-Cys, 2C19, 2D6-Val, 2D6-Met, 2E1, 3A4, 4A11) were tested for their 25-hydroxylation activity of 1alpha-OH-D3. None catalysed the 25-hydroxylation reaction. 4. 1Alpha-OH-D3 in a high concentration (2.5 ng ml(-1)) showed small but significant inhibition of the catalytic activities of CYP2C8, 2C9-Cys, 2C19, 2D6-Val and 2E1 for their typical substrates. However, 1alpha-OH-D3 in a clinically used low concentration will not significantly affect drug metabolism catalysed by the 14 P450s tested. 5. In summary, the 25-hydroxylation activity of 1alpha-OH-D3 that localizes in the microsomal fraction appears to be attributable to a cytochrome P450 other than the microsomal forms tested in this study.

Biotransformation↗
PubMed2001

Serum insulin-like growth factor-1 in centenarians: implications of IGF-1 as a rapid turnover protein.

BACKGROUND: It is well documented that serum insulin-like growth factor 1 (IGF-1) levels as well as growth hormone secretion decline with advancing age. Low levels of IGF-1 are shown to be associated with low activity of growth hormone, low lean mass, and high body fat mass; however, in the elderly, the relationship has not been confirmed. METHODS: We studied serum IGF-1 levels in 49 centenarians, who are at the ultimate stage of physiological senescence, and investigated the possible relationship between IGF-1 and body mass index, lipid parameters, nutritional indices, physical and cognitive function, and frequency of hip fracture. As nutritional indices, serum levels of albumin, prealbumin, transferrin, and retinol binding protein were measured. Cognitive function of the centenarians was assessed by clinical dementia rating. RESULTS: In the centenarians, the mean levels of IGF-1 were relatively low, indicating that there is an age-associated decline in IGF-1 even in the extremely old age. We demonstrated a strong association of IGF-1 with prealbumin and retinol binding protein (r2 = .192, .195, respectively); however, there was no association with albumin, transferrin, or body mass index. Interestingly, centenarians with lower IGF-1 levels had a higher prevalence of definitive dementia. CONCLUSIONS: These data suggest that serum IGF-1 levels in the centenarians appeared to reflect their short-term nutritional status as a rapid turnover protein. It is also suggested that low levels of serum IGF-1 may be involved in the progression of dementia in the oldest old.

Aged↗
PubMed2001

Carotid plaque and intima-media thickness assessed by b-mode ultrasonography in subjects ranging from young adults to centenarians.

UNLABELLED: BACKGROUND AND PURPOSE-To investigate relationships among plaque formation, increasing intima-media thickness, and age, we examined ultrasonographically carotid arteries of subjects who had no major atherosclerotic risk factors and who ranged in age from young adults to centenarians. METHODS: We studied 319 healthy subjects (154 men, 165 women; age range, 21 to 105 years) with no history of hypertension, diabetes mellitus, or atherosclerotic disease. Mean intima-media wall thickness (IMT) of common carotid arteries at plaque-free sites and prevalence of plaques were evaluated by B-mode ultrasound. RESULTS: Mean common carotid IMT increased in a linear manner with age for all decades of life, including centenarians [IMT=(0.009xAge)+0.116] (r=0.83). In centenarians (n=30), intima-media complexes were diffusely thickened (mean IMT, 1.01 mm). Plaque prevalence increased up to the tenth decade of life (83.3%, n=30) but decreased in centenarians (60.0%). IMT and plaque prevalence were closely associated in the seventh and eighth decades of life but not at older ages. CONCLUSIONS: The present study indicates that increased IMT is a physiological effect of aging that corresponds to diffuse intimal thickening, especially in very elderly persons, and that IMT is distinct from pathological plaque formation.

Adult↗
PubMed2001

Radiographic observation of a case of gastrointestinal stromal tumor in stomach.

A case of gastrointestinal stromal tumor (GIST) in stomach was presented. Serial barium meal x-ray examinations revealed an enlarging elevated lesion on the fornix of the stomach. Tumor volume doubling time was found to be 299 days. Microscopic and immunohistochemical studies of the resected tumor disclosed GIST, uncommitted type, low grade malignant/potentially malignant. A radiographic feature of this rare type of gastric submucosal tumor was demonstrated in this report.

Female↗
PubMed2001

[Suggestions from a centenarian study--aging and inflammation].

With the numbers of elderly increasing rapidly, it is important for both individuals and society that the oldest old maintains autonomy. To know how to attain successful aging, we investigate the status of centenarians. The characteristics of centenarians in Tokyo is 1) low level of nutritional parameters, 2) low level of cholesterol and HDL-cholesterol, 3) low level of red blood cells and hemoglobin, 4) high level of CRP, 5) high level of homocysteine, 6) high level of von Willbrand factor. The incidence of dementia is 59.3%. Are these characteristics due to aging itself or other factors? We examined the effect of nutritional status, inflammation and level of homocysteine on the characteristics. The level of albumin is associated with serum level of lipid, RBC, ADL and cognitive function. The level of CRP is related to the level of albumin, suggesting that inflammation is related to nutritional status. The level of homocysteine is associated with the level of von Willbrand factor, suggesting that homocysteine is related to endothelial injury. From these data, we propose the hypothesis that proinflammatory status is associated with aging, resulting in a part of characteristics of centenarians. Homocysteine is partly responsible for endothelial injury. Intervention to suppress proinflammatory status and homocysteine level may promote QOL in the oldest old.

Aged↗
PubMed2001

Association of mild hyperhomocysteinemia with aortic calcification in hypercholesterolemic patients.

Homocysteine is considered to be an independent risk factor for atherosclerosis. Experimental animal models of hyperhomocysteinemia show aortic calcification, suggesting that this disorder is associated with aortic calcification in humans. A total of 28 patients with hyperlipidemia were enrolled into this study. The degree of aortic calcification at the level of the bifurcation and 1 cm proximal to the bifurcation was assessed by computed tomography of the aorta and the association between calcification of the aorta and the plasma level of homocysteine was then analyzed. The mean plasma homocysteine level in 28 patients was 8.7 microM. They were divided into 2 groups, high homocysteine level group (HHL; homocysteine level >8.7 microM) and low homocysteine level group (LHL; homocysteine level < = 8.7 microM). The degree of aortic calcification at the level of the bifurcation differed significantly between the two groups (19.1% vs. 10.5%; p < 0.01). We found that mild hyperhomocysteinemia was associated with aortic calcification, which suggests that interventions to reduce the plasma level of homocysteine may also reduce the severity of aortic calcification.

Aged↗
PubMed2000

Differential involvement of Src family kinases in Fc gamma receptor-mediated phagocytosis.

The tyrosine phosphorylation cascade originated from Fc gamma receptors (Fc gamma Rs) is essential for macrophage functions including phagocytosis. Although the initial step is ascribed to Src family tyrosine kinases, the role of individual kinases in phagocytosis signaling is still to be determined. In reconstitution experiments, we first showed that expression in the RAW 264.7 cell line of C-terminal Src kinase (Csk) inhibited and that of a membrane-anchored, gain-of-function Csk abolished the Fc gamma R-mediated signaling that leads to phagocytosis in a kinase-dependent manner. We next tested reconstruction of the signaling in the membrane-anchored, gain-of-function Csk-expressing cells by introducing Src family kinases the C-terminal negative regulatory sequence of which was replaced with a c-myc epitope. Those constructs derived from Lyn and Hck (a-Lyn and a-Hck) that associated with detergent-resistant membranes successfully reconstructed Fc gamma R-mediated Syk activation, filamentous actin rearrangement, and phagocytosis. In contrast, c-Src-derived construct (a-Src), that was excluded from detergent-resistant membranes, could not restore the series of phagocytosis signaling. Tyrosine phosphorylation of Vav and c-Cbl was restored in common by a-Lyn, a-Hck, and a-Src, but Fc gamma RIIB tyrosine phosphorylation, which is implicated in negative signaling, was reconstituted solely by a-Lyn and a-Hck. These findings suggest that Src family kinases are differentially involved in Fc gamma R-signaling and that selective kinases including Lyn and Hck are able to fully transduce phagocytotic signaling.

Actins↗
PubMed2000

A classification of circadian blood pressure profiles using a cumulative chi-square technique.

Non-invasive ambulatory blood pressure monitoring has been used to assess circadian rhythms in blood pressure in a qualitative fashion. However, there are no established methods for assessing circadian changes in blood pressure in a quantitative fashion. In this study, we developed a quantitative method to evaluate the circadian rhythm based on profile analysis and a cumulative chi-square technique. This method was used to analyse the circadian blood pressure variations in 100 normotensive volunteers and 127 hypertensive patients. Three blood pressure profiles were identified for the normotensive group, while four were identified for the hypertensive group. Furthermore, there was a relationship between the discriminate blood pressure profiles and the severity of hypertension. We conclude that profile analysis of 24-h ambulatory blood pressure monitoring may be used to stratify patients with regard to the risk of complications of hypertension.

Adult↗
PubMed2000

The effects of pantethine on fatty liver and fat distribution.

Although the prognosis of fatty liver depends on its causes, we feel from our clinical experience that fatty liver with hypertriglyceridemia has a good prognosis and responds well to treatment. In this study, 600 mg/day of pantethine was administered to 16 outpatients with fatty liver and hypertriglyceridemia for six months or longer to examine whether the drug improved fatty liver using abdominal plain computed tomography (CT). Nine of the 16-pantethine patients were no longer diagnosed as having fatty liver after the study period. An chi2 test indicated the significant disappearance of fatty liver. At the same time, the visceral fat calculated from the CT image passing the umbilical region was also significantly reduced. On the contrary, the subcutaneous fat area tended to increase, so the ratio of the visceral-to-subcutaneous fat area was reduced significantly. This indicates triglycerides may be pooled in the body as hepato-visceral fat and subcutaneous fat, and that pantethine may transfer fat from the liver and viscera to the subcutaneous tissue. This suggests that visceral fat deposition and fatty liver occurring with hypertriglyceridemia may have a common basis, probably excessive matrixes, and that pantethine may simultaneously improve the two conditions.

Abdomen↗
PubMed1999

Repression of nitrogenase by ethanol in nitrogen-deprived cultures of Rhodovulum sulfidophilum.

Light-dependent H2 evolution did not occur in nitrogen-deprived cultures of Rhodovulum sulfidophilum in the presence of ethanol. When ethanol was added to cells which had been grown with ammonia, derepression of the nitrogen fixation genes (nifHD) was inhibited at an ethanol concentration of 1 mM. On the other hand, when cells had nitrogenase-catalyzed proton-reducing activity prior to ethanol addition, reduction of the nifHD transcript level did not occur after the addition. In cells grown with ammonia, concomitant addition of an auxiliary oxidant such as dimethylsulfoxide or sodium bicarbonate resulted in derepression of nitrogenase activity in the presence of ethanol. These results suggest that the electron-accepting process is necessary for derepression of nif genes in cultures which use ethanol as the electron donor.

Ammonia↗