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Nigishi Hotta

Publications and source records attributed to Nigishi Hotta.

15 recordsLinked to original sources
PubMed2006

Soluble adhesion molecules and C-reactive protein in the progression of silent cerebral infarction in patients with type 2 diabetes mellitus.

The purpose of this study was to investigate the association between the progression of silent cerebral infarction (SCI) and levels of soluble adhesion molecules and high-sensitivity C-reactive protein (hs-CRP) in type 2 diabetic patients. One hundred twenty middle-aged and elderly diabetic patients without histories of vascular events were followed up for a period of 3 years. We measured levels of soluble intercellular adhesion molecule 1 (sICAM-1), vascular cell adhesion molecule 1, E-selectin, and hs-CRP and assessed brain ischemic lesions by magnetic resonance imaging at baseline and 3 years later. Silent cerebral infarction was observed in 13% of the patients at baseline, and these patients were significantly older and had significantly higher blood pressure than those without SCI. Thirty-two patients had newly diagnosed SCI after 3 years. There were no significant differences in factors such as age, blood pressure, and diabetic control between patients without SCI and those in whom it was newly diagnosed. However, only sICAM-1 levels, but not the other soluble adhesion molecules or hs-CRP, were associated with the progression of SCI, and this relationship remains after adjustment for risk factors. On the other hand, higher levels of sICAM-1 and hs-CRP at baseline were observed in 7 patients who were excluded from the present study because of the onset of symptomatic cerebral infarction during follow-up. Our present study suggests that sICAM-1 levels may be a potential marker for SCI, which may lead to future stroke and vascular dementia, and that this marker could be useful in monitoring disease progression and as a surrogate marker in treatment studies.

Aged↗
PubMed2006

Long-term clinical effects of epalrestat, an aldose reductase inhibitor, on diabetic peripheral neuropathy: the 3-year, multicenter, comparative Aldose Reductase Inhibitor-Diabetes Complications Trial.

OBJECTIVE: We sought to evaluate the long-term efficacy and safety of epalrestat, an aldose reductase inhibitor, on diabetic peripheral neuropathy. RESEARCH DESIGN AND METHODS: Subjects with diabetic neuropathy, median motor nerve conduction velocity (MNCV) >or=40 m/s, and HbA(1c) <or=9% were enrolled in this open-label, multicenter study and randomized to 150 mg/day epalrestat or a control group. After excluding the withdrawals, 289 (epalrestat group) and 305 (control group) patients were included in the analyses. The primary end point was change from baseline in median MNCV at 3 years. Secondary end points included assessment of other somatic nerve function parameters (minimum F-wave latency [MFWL] of the median motor nerve and vibration perception threshold [VPT]), cardiovascular autonomic nerve function, and subjective symptoms. RESULTS: Over the 3-year period, epalrestat prevented the deterioration of median MNCV, MFWL, and VPT seen in the control group. The between-group difference in change from baseline in median MNCV was 1.6 m/s (P < 0.001). Although a benefit with epalrestat was observed in cardiovascular autonomic nerve function variables, this did not reach statistical significance compared with the control group. Numbness of limbs, sensory abnormality, and cramping improved significantly with epalrestat versus the control group. The effects of epalrestat on median MNCV were most evident in subjects with better glycemic control and with no or mild microangiopathies. CONCLUSIONS: Long-term treatment with epalrestat is well tolerated and can effectively delay the progression of diabetic neuropathy and ameliorate the associated symptoms of the disease, particularly in subjects with good glycemic control and limited microangiopathy.

Adult↗
PubMed2004

Suppression of 3-deoxyglucosone and heparin-binding epidermal growth factor-like growth factor mRNA expression by an aldose reductase inhibitor in rat vascular smooth muscle cells.

Reactive carbonyl compounds and oxidative stress have been recently shown to up-regulate the expression of heparin-binding epidermal growth factor-like growth factor (HB-EGF), a potent mitogen for vascular smooth muscle cells (SMCs) produced by SMC themselves. Because the polyol pathway has been reported to influence the formation of carbonyl compounds and the oxidative stress in various cells, we conducted this study to investigate whether the polyol pathway affects HB-EGF expression along with the generation of carbonyl compounds and the oxidative stress in SMCs. We found that, compared with those cultured with 5.5mM glucose, SMCs cultured with 40 mM glucose showed the accelerated thymidine incorporation, elevated levels of intracellular sorbitol, 3-deoxyglucosone (3-DG), advanced glycation end products (AGEs), and thiobarbituric acid-reactive substances (TBARS) along with the enhanced expression of HB-EGF mRNA. An aldose reductase inhibitor (ARI), SNK-860, significantly inhibited all of these abnormalities, while aminoguanidine suppressed 3-DG levels and HB-EGF mRNA expression independent of sorbitol levels. The results suggest that the polyol pathway may play a substantial role in SMC hyperplasia under hyperglycemic condition in part by affecting HB-EGF mRNA expression via the production of carbonyl compounds and oxidative stress.

Aldehyde Reductase↗
PubMed2003

The role of polyol pathway in glucose-induced apoptosis of cultured retinal pericytes.

The pathogenesis of pericyte loss, an initial deficit in the early stage of diabetic retinopathy, remains unclear. Recent studies have suggested that polyol pathway hyperactivity and apoptosis may be involved in pericyte loss. The mechanisms of the glucose-induced apoptosis in retinal pericytes were investigated to evaluate the pathogenesis of diabetic retinopathy. Under the 20 mM glucose condition, intracellular calcium concentrations and caspase-3 activities were significantly increased, and reduced glutathione (GSH) contents were significantly decreased compared with those under the 5.5 mM glucose condition. These abnormalities were all significantly prevented by an aldose reductase inhibitor, SNK-860. Glucose-induced apoptosis was partially but significantly prevented by SNK-860, an inhibitor of calcium-dependent cysteine protease, calpain, or GSH supplementation, and completely normalized by a caspase-3 inhibitor. These observations suggest that glucose-induced apoptosis in retinal pericytes, as one of the pathogenic factors of diabetic retinopathy, would be mediated through an aldose reductase-sensitive pathway including calcium-calpain cascade and increased oxidative stress, and that caspase-3 would be located furthest downstream of these apoptotic signals.

Aldehyde Reductase↗
PubMed2002

P-selectin-dependent macrophage migration into the tubulointerstitium in unilateral ureteral obstruction.

BACKGROUND: Interstitial infiltration of macrophages (Mø) is one of the main causal factors for the tubulointerstitial injury. However, precise mechanisms of Mø infiltration into tubulointerstitium have not been fully explored. The purposes of this study were to assess the role of selectins in the acute infiltration of Mø in rats with unilateral ureteral obstruction (UUO) and to evaluate the role of vasa recta, that is, whether they facilitate massive influx of Mø into the interstitium by functioning as specialized vessels. METHODS: To evaluate the role of selectins in Mø infiltration into tubulointerstitium, the expression of selectins and L-selectin ligands was examined by immunohistochemistry and immunoelectron microscopy. The functional role of P-selectin in vasa recta was studied by Stamper-Woodruff assay, in vivo p-Mø migration assay and in vivo blocking experiments with the monoclonal antibody (mAb) ARP2-4. RESULTS: Selective expression of P-selectin was detected in vasa recta as early as one hour after UUO, and the expression increased thereafter for 96 hours. In contrast, endothelial expression of L-selectin ligands and E-selectin were not detectable. In the Stamper-Woodruff assay on kidney sections of rats with UUO, the adhesion of isolated rat peritoneal Mø (p-Mø) to vasa recta was significantly inhibited by the mAb ARP2-4 (P-selectin blocker; P < 0.01), but not by mAb ARE-5 (E-selectin blocker) or rLECIg (rat L-selectin chimeric protein). In the in vivo transfer experiments with fluorescein-labeled p-Mø into rats 48 hours after UUO, labeled p-Mø had accumulated around vasa recta at three minutes and had infiltrated predominantly into the outer medulla at 180 minutes. The number of labeled p-Mø was reduced when the rats were pretreated with ARP2-4 (P < 0.01). Finally, ARP2-4 (10 mg/kg), injected 15 minutes before UUO, reduced the number of infiltrated Mø (P < 0.01). CONCLUSION: The results suggest that vasa recta, which express P-selectin, contribute to massive infiltration of Mø into the interstitium by functioning as specialized post-capillary venules.

Animals↗
PubMed2002

Risk factors for IgA nephropathy: a case-control study with incident cases in Japan.

BACKGROUND/AIM: Our previous study with prevalent cases suggested that some genetic, immunological and lifestyle-related factors increased the risk of immunoglobulin A nephropathy (IgAN). To confirm this hypothesis, we conducted another case-control study. METHODS: The study included 116 incident cases and 276 sex-, age- and residence-matched controls in central Japan. Information on family and individual history and on lifestyle was collected using a self-administered questionnaire. The strength of association between IgAN and a potential risk factor was assessed by calculating an odds ratio. RESULTS: A family history of chronic glomerulonephritis, susceptibility to the common cold, episodes of tonsillitis in the preceding year, preference for salty foods and a high intake of rice and n-6 polyunsaturated fatty acids (PUFA) were associated with an increased risk of IgAN. Coffee consumption and dietary calcium intake were somewhat negatively related to the risk. A significance of alcohol drinking, use of vitamin supplements, consumption of raw eggs and intake of nutrients other than n-6 PUFA and calcium, though previously suggested, was not shown in the present study. CONCLUSION: Our findings imply that some genetic factors, immune response to infections in the upper respiratory tract and nutritional imbalance would promote the development of IgAN.

Adult↗
PubMed2002

Role of medial amygdala in controlling hemodynamics via GABA(A) receptor in anesthetized rats.

Experiments were conducted to determine whether the medial amygdala could control hemodynamics through the GABA receptor in anesthetized rats. Bicuculline (10-100pmol), a GABA(A) antagonist, injected into the anterior basomedial amygdala (medial amygdala) produced dose-related increases in blood pressure (BP) and heart rate (HR). Following microinjection of a 100pmol dose, plasma norepinephrine and epinephrine also rose significantly. In a group that had undergone bilateral adrenalectomy, the same dose of bicuculline into the same region of the amygdala caused similar increases in BP and HR to those produced in normal rats. Pretreatment with an intraperitoneal injection of hexamethonium prevented these responses. When bicuculline was given intravenously (100pmol) it failed to effect these cardiovascular changes. Bicuculline-induced hypertension and tachycardia were inhibited by microinjection of muscimol, a GABA agonist, into the anterior basomedial amygdala. The results thus demonstrate that the influence of bicuculline on BP and HR is through action on the anterior basomedial amygdala and direct sympathetic outflow to heart and vascular smooth muscle. There is tonic GABAergic inhibition of sympathetic outflow in the medial amygdala that plays a part in regulating hemodynamics in the limbic system.

Amygdala↗
PubMed2000

Complement activation products in the urine from proteinuric patients.

The presence of plasma proteins in the tubular lumen has variety of adverse effects on the tubular cells. Among various plasma proteins filtered through glomerular barrier, complement has been proven as the possible candidate inducing tubulointerstitial injury. To study the role of intratubular complement activation in proteinuric patients, complement activation products (CAP) at C3 level (iC3b and Bb) and C9 level (membrane attack complex) were measured in both plasma and urine of patients with minimal change nephrotic syndrome (MCNS), focal glomerular sclerosis, IgA nephropathy, membranous nephropathy, and diabetic nephropathy. For evaluation of the effect of metabolic acidosis on the intratubular complement activation, urinary CAP were measured before and after sodium bicarbonate administration in patients with renal insufficiency. The following results were obtained: (1) Patients with focal glomerular sclerosis and diabetic nephropathy showed the highest level of urinary CAP excretion rate (unit/creatinine), while MCNS revealed no increase. (2) Patients with membranous nephropathy showed a unique finding, i.e., isolated increase of membrane attack complex excretion. (3) There was no significant correlation between urine and plasma levels of CAP. (4) Except for MCNS patients, the urinary excretion rate of CAP significantly increased when the level of proteinuria exceeded the nephrotic range, and it was significantly correlated with the serum creatinine level. (5) Urinary CAP excretion rate significantly decreased 2 wk after sodium bicarbonate administration without affecting the level of proteinuria or plasma CAP. These results suggest that the degree of intratubular complement activation correlates with the level of proteinuria, type of glomerular disease, impairment of renal function, and metabolic acidosis.

Adolescent↗
PubMedDate not supplied

Transition metals and polyol pathway in the development of diabetic neuropathy in rats.

BACKGROUND: The transition metal-catalyzed reaction is a major source of oxygen free radicals, which play an important role in vascular dysfunction leading to ischemia in diabetic tissues. The inhibition of polyol pathway hyperactivity has been reported to ameliorate neurovascular abnormalities in diabetic rats and has been proposed to improve the oxygen free radical scavenging capacity. The present study was conducted to compare the effect of a transition metal chelating agent, trientine (TRI), on diabetic neuropathy with that of an aldose reductase inhibitor, NZ-314 (NZ). METHODS: Diabetic rats were divided into three groups: (1). untreated, (2). TRI-treated, and (3). NZ-treated. TRI (20 mg/kg) or NZ (100 mg/kg) was administered by gavage or chow containing NZ, respectively, for 8 weeks. Motor nerve conduction velocity (MNCV), coefficient of variation of the R - R interval on electrocardiogram (CVr-r), sciatic nerve blood flow (SNBF), platelet aggregation activities, and serum concentrations of malondialdehyde were measured. RESULTS: Untreated diabetic rats showed delayed MNCV, decreased CV(R-R), and reduced SNBF compared to normal rats. TRI or NZ completely prevented these deficits. Platelet hyperaggregation activities in diabetic rats were prevented by NZ, but not by TRI. Increased concentrations of malondialdehyde in diabetic rats were partially but significantly ameliorated by either TRI or NZ. CONCLUSIONS: These observations suggest that increased free radical formation through the transition metal-catalyzed reaction plays an important role in the development of diabetic neuropathy and that the preventive effect of an aldose reductase inhibitor on diabetic neuropathy may also be mediated by decreasing oxygen free radicals.

Aldehyde Reductase↗
PubMedDate not supplied

Polyol pathway and protein kinase C activity of rat Schwannoma cells.

BACKGROUND: Polyol pathway hyperactivity-induced decreases in protein kinase C (PKC) activities have been proposed as a pathogenic mechanism of diabetic neuropathy. Increased PKC activities have recently been invoked in the pathogenesis of other diabetic complications, especially retinopathy, nephropathy, and macroangiopathy. However, it remains unclear whether PKC activities in neural cells such as Schwann cells are increased, decreased, or unchanged. This study investigated the effects of high glucose and increased polyol pathway activity on neural cell growth and PKC activities. METHODS: Rat Schwannoma cells were cultured in 5.5 or 20 mM glucose in the presence or absence of an aldose reductase inhibitor, epalrestat (1 microM) for 14 days. Proliferation activities, PKC activities, and the protein expression of PKC isoforms were measured. RESULTS: Proliferation and PKC activities under the 20 mM glucose condition were significantly decreased compared to those under the 5.5 mM glucose condition and were prevented by epalrestat. Among PKC isoforms, the protein expression of PKC-alpha under the 20 mM glucose condition was significantly reduced compared to that under the 5.5 mM glucose condition. Epalrestat significantly inhibited the decreased expression of PKC-alpha protein. There were no significant changes in the protein expression of PKC-beta. CONCLUSIONS: These results suggest that PKC, especially PKC-alpha activity, is decreased in Schwann cells exposed to high glucose and that this deficit is mediated through polyol pathway hyperactivity.

Aldehyde Reductase↗
PubMedDate not supplied

A copper chelating agent suppresses carbonyl stress in diabetic rat lenses.

To clarify whether transition metals are involved in carbonyl stress in diabetic tissues, we observed the effects of a metal chelating agent, trientine (TE) hydrochloride on the levels of methylglyoxal (MG), 3-deoxyglucosone (3-DG), advanced glycation end products, 8-hydroxy-2'-deoxyguanosine (8-OHdG), and polyol pathway metabolites along with semicarbazide-sensitive amine oxidase (SSAO) enzyme activity in lenses from streptozotocin-induced diabetic rats. Lens MG and 3-DG levels were significantly higher in diabetic rats than nondiabetic controls, and TE significantly restored the increase of these compounds. Lens argpyrimidine was also increased in diabetic rats as compared with controls and was significantly reduced by TE. Lens SSAO activity and 8-OHdG were also significantly elevated in diabetic rats, and TE suppressed both of them, whereas TE showed no effect on the polyol pathway metabolites. The results indicate that transition metals play a significant role in the formation of MG and 3-DG via oxidative stress and SSAO activity.

8-Hydroxy-2'-Deoxyguanosine↗