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Biomedical subjects

N Hotta

Publications and source records attributed to N Hotta.

At least 19 recordsLinked to original sources
PubMed2001

Midkine is involved in neutrophil infiltration into the tubulointerstitium in ischemic renal injury.

Midkine (MK) is a multifunctional heparin-binding protein and promotes migration of neutrophils, macrophages, and neurons. In the normal mouse kidney, MK is expressed in the proximal tubules. After renal ischemic reperfusion injury, its expression in proximal tubules was increased. Immediate increase of MK expression was found when renal proximal tubular epithelial cells in culture were exposed to 5 mM H(2)O(2). Histologically defined tubulointerstitial damage was less severe in MK-deficient (Mdk(-/-)) than in wild-type (Mdk(+/+)) mice at 2 and 7 days after ischemic reperfusion injury. Within 2 days after ischemic injury, inflammatory leukocytes, of which neutrophils were the major population, were recruited to the tubulointerstitium. The numbers of infiltrating neutrophils and also macrophages were lower in Mdk(-/-) than in Mdk(+/+) mice. Induction of macrophage inflammatory protein-2 and macrophage chemotactic protein-1, chemokines for neutrophils and macrophages, respectively, were also suppressed in Mdk(-/-) mice. Furthermore, renal tubular epithelial cells in culture expressed macrophage inflammatory protein-2 in response to exogenous MK administration. These results suggested that MK enhances migration of inflammatory cells upon ischemic injury of the kidney directly and also through induction of chemokines, and contributes to the augmentation of ischemic tissue damage.

Animals↗
PubMed2001

Role of PKC and TGF-beta receptor in glucose-induced proliferation of smooth muscle cells.

The role of protein kinase C (PKC) and transforming growth factor (TGF)-beta in the proliferation of vascular smooth muscle cells (SMCs) under a high glucose condition was investigated. [3H]-thymidine incorporation under 20 mM glucose was significantly accelerated compared with that under 5.5 mM glucose, and this increase was inhibited by an anti-TGF-beta antibody or a PKC-beta specific inhibitor, LY333531. The amount of active and total TGF-beta1 in the conditioned media did not differ between 5.5 and 20 mM glucose. However, the expression of TGF-beta receptor type II under 20 mM glucose was significantly increased, but that of the TGF-beta receptor type I was not. This increased expression of the TGF-beta receptor type II was prevented by LY333531. These observations suggest that the increased expression of the TGF-beta receptor type II via PKC-beta plays an important role in the accelerated proliferation of SMCs under a high glucose condition, leading to the development of diabetic macroangiopathy.

Activin Receptors, Type I↗
PubMed2001

Glucose-induced hyperproliferation of cultured rat aortic smooth muscle cells through polyol pathway hyperactivity.

AIMS/HYPOTHESIS: The protein kinase C (PKC), platelet-derived growth factor (PDGF) and polyol pathway play important parts in the hyperproliferation of smooth muscle cells, a characteristic feature of diabetic macroangiopathy. The precise mechanism, however, remains unclear. This study investigated the relation between polyol pathway, protein kinase C and platelet-derived growth factor in the development of diabetic macroangiopathy. METHODS: Smooth muscle cells were cultured with 5.5 or 20 mmol/l glucose with or without an aldose reductase inhibitor, epalrestat, or a PKC-beta specific inhibitor, LY333531. Protein kinase C activities, the expression of PKC-beta II isoform and PDGF-beta receptor protein, free cytosolic NAD+:NADH ratio, the contents of reduced glutathione, and proliferation activities were measured. RESULTS: Smooth muscle cells cultured with 20 mmol/l glucose showed statistically significant increases in protein kinase C activities, the expression of PKC-beta II isoform and PDGF-beta receptor protein, and proliferation activities, compared with smooth muscle cells cultured with 5.5 mmol/l glucose. Although epalrestat and LY333531 inhibited protein kinase C activation induced by glucose to the same degree, the effects of epalrestat on proliferation activities and expression of the PDGF-beta receptor were more prominent than those of LY333531. Epalrestat improved the glucose-induced decrease in free cytosolic NAD+:NADH ratio and reduced glutathione content, but LY333531 did not. The increased expression of membranous PKC-beta II isoform was normalized by epalrestat. CONCLUSION/INTERPRETATION: These observations suggest that polyol pathway hyperactivity contributes to the development of diabetic macroangiopathy through protein kinase C, PDGF-beta receptor, and oxidative stress, and that an aldose reductase inhibitor has a therapeutic value for this complication.

Aldehyde Reductase↗
PubMed2001

Magnetic resonance imaging findings in schizophrenia and atypical psychoses.

The differences among MRI findings were studied in schizophrenic psychoses. The schizophrenics and atypical psychotics had significant reductions in bilateral hippocampal volumes compared to controls, but the two patient groups did not differ from each other. As for ventricle volume, the schizophrenics showed significantly larger temporal horns and third ventricle than normal controls, whereas atypical psychotics did not. Moreover, the left temporal horn in the schizophrenics was significantly larger than that seen in the atypical psychotics. By cluster analysis, schizophrenics and atypical psychotics were found to have a tendency to be distributed in different groups. These results might be considered to support the classification of schizophrenic psychoses into schizophrenia and atypical psychoses.

Adult↗
PubMed2001

Physiological and morphometric analyses of neuropathy in sucrose-fed OLETF rats.

To investigate the characteristic features of diabetic neuropathy in type 2 diabetes mellitus, Otsuka Long-Evans Tokushima fatty (OLETF) rats, an animal model of human type 2 diabetes mellitus, and non-diabetic Long-Evans Tokushima Otsuka (LETO) rats were fed with or without sucrose and/or an aldose reductase inhibitor, [5-(3-thienyl) tetrazol-1-yl] acetic acid (TAT), for 24 weeks, and physiological, biochemical and morphological assessments were performed. Sucrose administration caused remarkable hyperglycemia in OLETF rats but not in LETO rats. Sucrose-fed OLETF rats demonstrated delayed nerve conduction velocity, decreased coefficient of variation of R-R interval, reduced sciatic nerve blood flow, increased platelet aggregation activity, a lower concentration of erythrocyte 2,3-diphosphoglycerate, and decreased Na+/K+-ATPase activity in sciatic nerves, compared with the non-sucrose-fed OLETF and LETO rats. TAT prevented all these deficits except hyperglycemia. Sorbitol and fructose accumulation and myo-inositol depletion in tail nerves of sucrose-fed OLETF rats were ameliorated by TAT. Myelinated fiber size and density in sural nerves of sucrose-fed OLETF rats were decreased and increased, respectively, compared with non-sucrose-fed OLETF and LETO rats. These morphological abnormalities were normalized by TAT. These observations suggest that the sucrose-fed OLETF rat developed diabetic neuropathy not only electrophysiologically but also histologically, and that an aldose reductase inhibitor, TAT, possesses therapeutic value for the treatment of diabetic neuropathy.

2,3-Diphosphoglycerate↗
PubMed2001

The role of C5a in the development of thrombotic glomerulonephritis in rats.

Thrombus formation is the important pathologic finding observed in glomerulonephritis induced by antiglomerular basement membrane (GBM) antibodies. Although strong deposition of C3 and membrane attack complex (MAC) is observed in this disease, the role of complement has not been fully elucidated. The aim of this work was to investigate the role of complement, especially an anaphylatoxin C5a, in a rat model of thrombotic glomerulonephritis. Rats were first pretreated with subclinical dose of lipopolysaccharide (LPS). Thrombotic glomerulonephritis was then induced by intravenous injection with rabbit antirat GBM (RbAGBM) (Group I). For the evaluation of the role of complement, the soluble complement receptor type 1 (sCR1) (Group II) or the C5a receptor antagonist peptide (C5aR-AP) (Group III) was intravenously administered 30 min before RbAGBM injection. For exploring the role of neutrophils, rats were pretreated with cyclophosphamide before induction of disease (Group IV). All rats were sacrificed at 6 h, and histological examination was performed. Rats in Group I developed severe glomerular thrombosis. Leucocyte accumulation and strong binding of C3 and MAC were observed in the glomeruli. In rats treated with sCR1 (Group II) and C5aR-AP (Group III), both leucocyte accumulation and thrombus formation in the glomeruli were significantly inhibited. C3 and MAC were negative in the glomeruli in Group II rats, while they were strongly observed in Group III. In neutrophil depleted rats (Group IV), there was also deposition of C3 and MAC in the glomeruli but thrombus formation was not observed. These findings indicated that glomerular thrombosis is dependent on the leucocytes, and mediated in part by the anaphylatoxin C5a but not MAC in the present model.

Animals↗
PubMed2001

Effects of a new synthetic selectin blocker in an acute rat thrombotic glomerulonephritis.

In an attempt to explore a novel therapeutic approach, a new synthetic sulfatide derivative (SKK60037) was evaluated in an acute rat model of P-selectin and leukocyte-dependent thrombotic glomerulonephritis (TG). In vitro, SKK60037 inhibits the function of P- and L-selectin more effectively than sialyl Lewis X (sLe(x)), a well-established selectin blocker. TG was induced by the intravenous administration of nephrotoxic globulin (NTG) to rats pretreated with a subclinical dose of lipopolysaccharide. In this model, platelet accumulation was remarkable within 10 minutes after induction of disease, followed by the infiltration of leukocytes, mainly neutrophils and macrophages. Thrombus formation and fibrinogen deposition in the glomeruli were observed within 1 hour, and they proceeded until 6 hours. P-selectin was highly expressed in glomeruli, whereas E-selectin and L-selectin ligands were not detected. We tested the effects of SKK60037 in this model in comparison with sLe(x) and antirat P-selectin monoclonal antibody (ARP2-4). SKK60037 blocked platelet accumulation in glomerular capillaries at 10 minutes after NTG injection. At 6 hours, leukocyte infiltration and thrombosis were significantly suppressed. Protective effects of SKK60037 were similar to those of ARP2-4, whereas sLe(x) showed minimum effect. The superior effects and more favorable characteristics of SKK60037 to sLe(x) suggest the potential of SKK60037 for clinical application.

Animals↗
PubMed2001

Lipid peroxidation may predict restenosis after coronary balloon angioplasty.

The present study assessed whether lipid peroxidation in plasma might predict restenosis after coronary balloon angioplasty. A total of 87 patients, who had undergone successful coronary balloon angioplasty using standard techniques, were enrolled. Fasting blood samples before the intervention were measured for plasma levels of thiobarbituric acid reactive substances (TBARS, an indicator of lipid peroxidation). Angiography was carried out before and 15 min after angioplasty, and at follow-up (4 months after angioplasty), and evaluated using a quantitative approach. There were 23 patients with restenosis (group R) and 64 patients without restenosis (group N) after coronary balloon angioplasty. The plasma TBARS level (mean+/-SEM) of 4.3+/-0.1 micromol/L in group R was significantly higher than that of 3.2+/-0.1 micromol/L in group N (p<0.01). There were no significant differences in other parameters, including plasma lipid levels, between the 2 groups. The plasma level of TBARS positively correlated with lumen loss of the coronary artery at the time of follow-up angiography (r=0.57, p<0.01). Our results suggest that oxidative stress contributes to restenosis and indicate that an elevated plasma level of TBARS may be a reliable predictor of restenosis.

Aged↗
PubMed2001

Physiological responses to water-walking in middle aged women.

The purpose of the present study was to examine the physiological responses to water-walking using the Flowmill, which has a treadmill at the base of a water-flume, in two groups of women. In the first group, the women were known to regularly swim and exercise in water (group A), while in the second, they did not routinely participate in water-exercise (group B). In both groups, twelve healthy female volunteers in their fifties participated in the study. All of the subjects walked in water using the Flowmill for the first time. Subjects completed four consecutive bouts of 4-minute duration at progressively increasing speeds (20, 30, 40, and 50 m.min-1), with 1-minute rests between each bout. In addition, water-velocity was adjusted to the walking speed of each bout. The water-depth of the Flowmill was the level of the xiphoid process. The water and room temperatures were 30.3 +/- 0.1 degrees C and 24.9 +/- 0.4 degrees C, respectively. In both groups, the relationship between walking speed and oxygen uptake (VO2) as well as that between walking speed and heart rate (HR) changed exponentially as the walking speed increased, and the relationship between HR and VO2 was linear. The relationship between HR and VO2 was similar in both groups, and there was no significant difference between the predicted maximal oxygen uptake (VO2max) of the two groups. VO2 and HR of group B during water-walking, however, were significantly higher than those of group A at all walking speeds. The results of this study clearly showed that experience in moving through the water strongly affects physiological responses to water-exercise, even when fitness levels are equivalent.

Anthropology, Cultural↗
PubMed2001

Thermoregulatory responses to low-intensity prolonged swimming in water at various temperatures and treadmill walking on land.

The purpose of the present study was to examine the effect of water temperature on the human body during low-intensity prolonged swimming. Six male college swimmers participated in this study. The experiments consisted of breast stroke swimming for 120 minutes in 23 degrees C, 28 degrees C and 33 degrees C water at a constant speed of 0.4 m.sec-1 in a swimming flume. The same subjects walked on a treadmill at a rate of approximately 50% of maximal oxygen uptake (VO2max) at the same relative intensity as the three swimming trials. Rectal temperature (Tre) in 33 degrees C water was unchanged during swimming for 120 minutes. Tre during treadmill walking increased significantly compared to the three different swimming trials. Tre, mean skin temperature (Tsk) and mean body temperature (Tb) in 23 degrees C and 28 degrees C water decreased significantly more than in both the 33 degrees C water and walking on land. VO2 during swimming in 23 degrees C water increased more than during swimming in the 28 degrees C and 33 degrees C trials; however, there were no significant differences in VO2 between the 23 degrees C swimming trial and treadmill walking. Heart rate (HR) during treadmill walking on land increased significantly compared with HR during the three swimming trials. Plasma adrenaline concentration at the end of the treadmill walking was higher than that at the end of each of the three swimming trials. Noradrenaline concentrations at the end of swimming in the 23 degrees C water and treadmill walking were higher than those during the other two swimming trials. Blood lactate concentration during swimming in 23 degrees C water was higher than that during the other two swimming trials and walking on land. These results suggest that the balance of heat loss and heat production is maintained in the warm water temperature. Therefore, a relatively warm water temperature may be desirable when prolonged swimming or other water exercise is performed at low intensity.

Adolescent↗
PubMed2001

Clinical efficacy of fidarestat, a novel aldose reductase inhibitor, for diabetic peripheral neuropathy: a 52-week multicenter placebo-controlled double-blind parallel group study.

OBJECTIVE: The purpose of this study was to evaluate the efficacy of fidarestat, a novel aldose reductase (AR) inhibitor, in a double-blind placebo controlled study in patients with type 1 and type 2 diabetes and associated peripheral neuropathy. RESEARCH DESIGN AND METHODS: A total of 279 patients with diabetic neuropathy were treated with placebo or fidarestat at a daily dose of 1 mg for 52 weeks. The efficacy evaluation was based on change in electrophysiological measurements of median and tibial motor nerve conduction velocity, F-wave minimum latency, F-wave conduction velocity (FCV), and median sensory nerve conduction velocity (forearm and distal), as well as an assessment of subjective symptoms. RESULTS: Over the course of the study, five of the eight electrophysiological measures assessed showed significant improvement from baseline in the fidarestat-treated group, whereas no measure showed significant deterioration. In contrast, in the placebo group, no electrophysiological measure was improved, and one measure significantly deteriorated (i.e., median nerve FCV). At the study conclusion, the fidarestat-treated group was significantly improved compared with the placebo group in two electrophysiological measures (i.e., median nerve FCV and minimal latency). Subjective symptoms (including numbness, spontaneous pain, sensation of rigidity, paresthesia in the sole upon walking, heaviness in the foot, and hypesthesia) benefited from fidarestat treatment, and all were significantly improved in the treated versus placebo group at the study conclusion. At the dose used, fidarestat was well tolerated, with an adverse event profile that did not significantly differ from that seen in the placebo group. CONCLUSIONS: The effects of fidarestat-treatment on nerve conduction and the subjective symptoms of diabetic neuropathy provide evidence that this treatment alters the progression of diabetic neuropathy.

Aldehyde Reductase↗
PubMed2001

Aldose reductase inhibition ameliorates pupillary light reflex and F-wave latency in patients with mild diabetic neuropathy.

OBJECTIVE: The present study was conducted to investigate the effect of an aldose reductase inhibitor, epalrestat, on autonomic and somatic neuropathy at an early stage in type 2 diabetic patients by assessing the pupillary light reflex and minimum latency of the F-wave. RESEARCH DESIGN AND METHODS: A total of 30 diabetic patients with subclinical or mild diabetic neuropathy were randomly allocated to a control group (n = 15) and epalrestat (150 mg/day) group (n = 15). After 24 weeks, the pupillary light reflex test, cardiovascular autonomic function tests, and nerve conduction study were performed. RESULTS: The beneficial effect of epalrestat on the pupillary light reflex was observed in the minimum diameter after light stimuli (P = 0.044), constriction ratio (P = 0.014), and maximum velocity of constriction (P = 0.008). Among cardiovascular autonomic nerve functions, the ratio of the longest expiratory R-R interval to the shortest inspiratory R-R interval during deep breathing was significantly improved by epalrestat (P = 0.037). Minimum latencies of F-wave of median and tibial motor nerves were significantly shortened by epalrestat (P = 0.002 and P = 0.001, respectively); however, no significant effects were observed in motor or sensory nerve conduction velocity. CONCLUSIONS: These observations suggest that epalrestat may have therapeutic value at the early stage of diabetic neuropathy and that the pupillary light reflex and minimum latency of F-wave may be useful indicators of diabetic neuropathy.

Aldehyde Reductase↗
PubMed2001

[Clinical study on the cases in which INH or RFP was discontinued during treatment for pulmonary tuberculosis].

Short course regimens; 2HRZ (E)(S)/4HR (E), 6HRS (E)/3-6HR and 6-9HR have been accepted as a standard chemotherapy (SC) for initial treatment of pulmonary tuberculosis in Japan. We studied the frequency of the treatment completion, the causes of the treatment failure and the outcome of the patients in whom INH or RFP was discontinued within 6 months after starting SC. The subjects included 597 newly diagnosed culture positive pulmonary tuberculosis patients admitted to 16 national hospital in 1996. Results were as follows. 1. In 47 (7.9%) of the 597 patients, either INH (19; 3.2%) or RFP (33; 5.5%) was discontinued. These 47 cases were defined as a SC incompleted group and the other 550 as a SC completed group. 2. The patients in the SC incompleted group were seen more frequently in the ages of 20s (11.9%), 50s (10.9%), 60s (11.7%) or 70s (11.4%). 21 (13.6%) of 154 female patients and 26 (5.9%) of 443 male patients were in the SC incompleted group. 3. The causes of cessation of INH or RFP were drug side effects (33; 5.5%), drug resistance (10; 1.7%) and complications or underlying diseases (8; 1.3%). 4. Fever or eruption (19; 3.2%) and drug induced hepatitis (12; 2.0%) were frequently seen as drug related side effects causing the cessation of INH or RFP. 5. The rate of culture negative conversion of TB bacilli at 6 months after the start of the treatment was 98.9% in the SC completed and 88.9% in the SC incompleted group respectively. In the SC incompleted group, there were three cases continuously positive and two other patients who relapsed and became culture positive again. In these five patients, INH or RFP was discontinued because of drug resistance.

Adolescent↗
PubMed2001

[Clinical difference between thiazolidinediones and biguanides].

Hyperglycemia in patients with type 2 diabetes mellitus is caused by peripheral insulin resistance, which results in decreased insulin-mediated glucose disposal and increased endogenous glucose production, and inadequate insulin secretion. Recently, either biguanides or thiazolidinediones among oral hypoglycemic agents is widely used to patients with type 2 diabetes mellitus for reversal of insulin resistance. As clinical difference between biguanides and thiazolidinediones in reducing blood glucose, the former primarily lowers endogenous glucose production presumably at the level of liver, whereas the latter increases insulin-mediated peripheral glucose disposal, which occurs predominantly in skeletal muscle. Therefore, combination therapy with these two drugs results in further improvement in glucose control. Combination therapy including these two drugs is attractive prospects in future treatment for patients with type 2 diabetes.

Biguanides↗
PubMed2000

Constitutive activation of MAP kinase kinase (MEK1) is critical and sufficient for the activation of MMP-2.

We investigated the role of MEK1 signaling in MMP-2 activation by use of constitutive active/dominant negative forms of MEK1 and MEK1-specific inhibitor. We found that cell transformation with active forms of MEK1 dramatically increased secretion and proteolytic activation of MMP-2 and subsequently stimulated invasiveness of cells. Contrary, expression of dominant negative form of MEK1 in v-src-transformed cells or in Con A-activated cells resulted in the suppression of the augmented secretion and proteolytic activation of MMP-2. In addition, treatment of v-src-transformed cells with PD98059, a MEK1-specific inhibitor, strongly suppressed the secretion and activation of MMP-2, whereas treatment with wortmannin, a PI3 kinase inhibitor, showed no clear effect on MMP-2 secretion. Taken together, these results strongly suggest that MEK-MAP kinase signaling, but not PI3 kinase signaling, plays a critical role in the activation of MMP-2 secretion and, subsequently, in the invasiveness of v-src-transformed cells.

Animals↗
PubMed2000

Aldose reductase inhibition prevents glucose-induced apoptosis in cultured bovine retinal microvascular pericytes.

The pathogenesis of pericyte loss, an initial deficit in the early stage of diabetic retinopathy, remains unclear. Polyol pathway hyperactivity has been implicated in the pathogenesis of diabetic retinopathy, and recent studies have suggested that apoptosis may be involved in pericyte loss. The present study was conducted to investigate whether high glucose induces apoptosis in cultured bovine retinal pericytes. The effect of an aldose reductase inhibitor, SNK-860, was also examined. After a 5 day incubation with various concentrations of glucose (5.5-40 m M) in the presence or absence of SNK-860, the cell viability and the percentages of dead cells were measured, and staining with the TUNEL method and Hoechst 33342, and DNA electrophoresis were performed. High glucose reduced the viability and increased the percentages of dead cells. TUNEL-positive cells were observed in pericytes under high glucose, but not in those under 5.5 m M glucose. In the staining of nuclei with Hoechst 33342, the percentage of apoptotic cells in total cells counted under high glucose was higher than that under 5.5 m M glucose. DNA electrophoresis of pericytes cultured with high glucose demonstrated a 'ladder pattern'. Hyperosmolarity also induced apoptosis in pericytes, but less than that by high glucose. SNK-860 inhibited the glucose-induced apoptosis in pericytes. These observations suggest that the pericyte loss in diabetic retinopathy involves an apoptotic process, and that the polyol pathway hyperactivity plays an important role in inducing apoptosis in pericytes by high glucose.

Aldehyde Reductase↗