Search PubMed⌕ Search

Biomedical subjects

Akihiko Hirata

Publications and source records attributed to Akihiko Hirata.

At least 19 recordsLinked to original sources
PubMed2006

Role of angiotensin II type-1 and type-2 receptors on vascular smooth muscle cell growth and glucose metabolism in diabetic rats.

This study investigates the mechanisms whereby angiotensin II (Ang II) signaling contributes to cell growth and glucose metabolism in cultured vascular smooth muscle cells (VSMCs) from male Wistar fatty rats (WF) and their littermates (Wistar lean rats, WL). The levels of the medial outgrowth rate of VSMCs and Ang II type-1 receptors (AT1R) in aortae from WF were more enhanced than those in aortae from WL, but the level of Ang II type-2 receptors (AT2R) was not different. A mixture of insulin and Ang II additively increased the values of [(3)H]-thymidine incorporation in WF and WL, which was inhibited by olmesartan, an AT1 receptor blockade (ARB), but not by PD123,319, an AT2 receptor blockade. Similarly, insulin and Ang II phosphorylated extracellular-regulated protein kinase 1/2, retinoblastoma tumor suppressor protein, and cyclic AMP response element binding protein, and these levels were higher in WF than in WL. In contrast, the phosphorylation was suppressed by olmesartan but not PD123,319. Insulin-stimulated Akt phosphorylation and 2-deoxy-d-glucose uptake in WF were significantly reduced by Ang II, and the reduction was ameliorated by olmesartan but not PD123,319. Differently from the result of Akt, the phosphorylation of the insulin-stimulated insulin receptor beta-subunit was not affected by Ang II, olmesartan, or PD123,319. However, the phosphorylation of insulin-stimulated insulin-related substrate (IRS)-1 was suppressed by Ang II, and the suppression was ameliorated by olmesartan, but not PD123,319, in both WF and WL. In contrast, the phosphorylation of IRS-1 on Ser(307) was elevated by the Ang II, and the elevation was suppressed by olmesartan, but not by PD123,319, in both WF and WL. These findings demonstrated that Ang II signaling contributes to cell proliferation and inhibition of the insulin signaling pathways through AT1R, but not trough AT2R, in both non-diabetic and diabetic VSMCs.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2006

Direct imaging of local atomic ordering in a Pd-Ni-P bulk metallic glass using Cs-corrected transmission electron microscopy.

In amorphous alloys, crystalline atomic clusters as small as 1-2 nm are frequently observed as local lattice fringe images by high-resolution electron microscopy (HREM). These clusters can be understood as local structures of amorphous alloys corresponding to "medium-range-order (MRO)". The MRO structure can be observed only under suitable defocusing conditions of the objective lens in HREM. A clear imaging of the MRO structure is difficult in conventional TEMs, mainly due to the delocalization of the image, caused mainly by the spherical aberration of the objective lens and eventually by the chosen defocus. In the present study, we have examined MRO in a Pd-based bulk metallic glass (Pd(40)Ni(40)P(20)) using a high-resolution TEM (acceleration voltage 200 kV) fitted with a spherical aberration constant corrector (Cs corrector) for aberration correction. We found that when Cs was close to zero and defocus values were near the Gaussian focus, MRO regions with an FCC-Pd structure could be clearly observed with a low image disturbance. Under these conditions, the phase-contrast transfer function was understood to act as an ideal filter function, which distinctly selects specific lattice periods of the FCC-Pd clusters. The obtained atomic images of the glass structure including the FCC-Pd clusters are in good agreement with those expected from image simulation according to our amorphous structure model. In this study, we have demonstrated that the Cs-corrected HREM is a powerful tool to directly image locally ordered structures in metallic glasses.

Journal Article↗
PubMed2006

Dual blockade of angiotensin II with enalapril and losartan reduces proteinuria in hypertensive patients with type 2 diabetes.

In this study we evaluated the effect of a dual blockade with enalapril and losartan on the reduction of overt macroproteinuria and its potential mechanism(s) in hypertensive patients with type 2 diabetes. Twenty-six hypertensive patients with type 2 diabetes at the baseline were administered 5 mg of enalapril once daily for 12 weeks. At the beginning of the study, the subjects were assigned to receive an add-on of 50 mg of losartan once daily or 5 mg of enalapril once daily for another 12 weeks. Blood samples were collected at the baseline, at the beginning, and at the end of the study for the measurement of laboratory parameters, and these data, including blood pressure, were compared between the two groups. Treatment with 5 mg of enalapril significantly decreased the systolic blood pressure level in both groups, and the addition of losartan and/or enalapril further decreased the levels. There was no difference in blood pressure between the two groups. However, the addition of losartan, but not enalapril, significantly decreased the urinary protein excretion level, plasma aldosterone, and hypersensitive-C-reactive protein at the end of the study. The results established that the dual blockade of angiotensin II with enalapril and losartan has a greater clinical benefit for high-risk patients with hypertension and advanced diabetic nephropathy.

Aged↗
PubMed2006

Oral delivery of diclofenac sodium using a novel solid-in-oil suspension.

The present work reports on a new pharmaceutical formulation for oral delivery of diclofenac sodium (DFNa), a non-steroidal anti-inflammatory drug (NSAID). Although DFNa itself is water-soluble at neutral pH, it was readily suspended in soybean oil via complex formation with an edible lipophilic surfactant and a matrix protein. The resulting solid-in-oil (S/O) suspension containing stably encapsulated DFNa in an oil phase markedly reduced the risks for gastrointestinal ulcers upon oral administration even at the LD(50) level in rats (ca. 50 mg/kg DFNa). In addition, plasma concentration of DFNa upon administration of an S/O suspension was comparable with that of the aqueous counterpart at the same DFNa dose. These results indicate the potential use of S/O suspensions as novel oil-based pharmaceutical formulations for oral delivery of water-soluble drugs without causing severe mucitis.

Administration, Oral↗
PubMed2005

Association of decrease in serum dehydroepiandrosterone sulfate levels with the progression to type 2 diabetes in men of a Japanese population: the Funagata Study.

Association of serum dehydroepiandrosterone sulfate (DHEAS) levels with insulin resistance and impairment of insulin secretion have been reported. We here examined the association of serum DHEAS levels with type 2 diabetes mellitus (DM) and the progression to DM. The serum DHEAS levels at baseline (from 1995 to 1997) were evaluated in 1709 individuals (998 women and 711 men) from a cohort population (n = 3706) of the Funagata Study. Glucose tolerance was evaluated at baseline as well as at 5-year follow-up examinations (n = 970, follow-up rate, 56.8%) according to the 1985 World Health Organization criteria. The statistical significance of the difference between any 2 groups was determined by the Student t test. Multiple logistic regression analysis determined the association of the traits with the progression to DM at the 5-year follow-up examinations. P < .05 was accepted as statistically significant. The serum DHEAS levels were significantly lower in DM than in normal glucose tolerance. However, this difference was not significant when adjusted for age. In men, the decrease in serum DHEAS levels by the 5-year follow-up examinations was significantly larger in the subjects who became diabetic than in the subjects who remained normal glucose tolerance, even when adjusted for age ( P = .0003). Multiple logistic regression analysis revealed a significant association of the decrease in serum DHEAS levels with the progression to DM, with an odds ratio (per 0.1 log ng/mL) of 1.410 (95% confidence interval [CI], 1.020-1.948, P = .038), independently from age, height, and 2-hour plasma glucose in men. A decrease in serum DHEAS levels seems to be associated with the progression to DM in Japanese men.

Aged↗
PubMed2005

Characterization of plasma brain natriuretic peptide level in patients with type 2 diabetes.

This study investigates whether the plasma brain natriuretic peptide (BNP) level is increased by the clinical traits of diabetes, including its complications, and whether these levels are affected by the presence of other combined diseases such as hypertension, hyperlipidemia, and coronary heart disease (CHD) in patients with diabetes. In 223 patients with Type 2 diabetes, the mean value of plasma BNP reached 32.3+/-4.1 pg/mL. The levels significantly increased with age, hypertension, and CHD but not with the duration of diabetes, HbA1c level, or hyperlipidemia. With regard to the type of therapy, the BNP levels were significantly lower in the combinations of both sulfonylurea and metformin and sulfonylurea and pioglitazone than those in insulin alone. In addition, the BNP levels in the group with diabetic complications, including retinopathy and nephropathy, and macroalbuminuria were significantly elevated in comparison with those without these complications and macroalbuminuria. Interestingly, however, no difference was observed between these groups after removal of the values in patients with CHD. These results have clarified that the plasma BNP levels in diabetic patients could increase only by the progression of macrovascular diseases, such as CHD, but not by the current diabetic control or diabetic microvascular complications.

Age Factors↗
PubMed2005

[Local ablation therapy for hepatocellular carcinoma (HCC) on the liver surface: radio-frequency ablation aimed at tumor marginal pre-ablation under endoscopic surgery].

RFA for the hepatocellular carcinoma localized on the surface of the liver tends to have some complications such as bleeding, an ejection of tumor and a heat injury to other internal organs even if percutaneous RFA seemed to be done easily. Therefore, we should first choose the RFA treatment under endoscopic (either laparoscope or thoracoscope) surgery for the hepatocellular carcinoma localized on the surface of the liver. Moreover, a direct central puncture should be avoided from the viewpoint of securing a margin, prevention of bleeding and rise in the intratumorale pressure. Now, we selected the unique operation method of RFA: First, the tumor is confirmed under the endoscope, and the tumor range is marked with the endoscopic echo. Second, several times of RFA applied to the tumor surroundings are done, and the margin is secured with avoiding a direct central puncture. If tumor diameter is over 2.5 cm, central ablation of the tumor is considered to be necessary, we can directly puncture the center of the tumor without bleeding since the tumor already has the congelation by surrounding heat effect. We have done RFA by this way for 29 patients with HCC since April 1st, 2004. The complications such as a heat injury to the neighboring organ could be well prevented. An enough margin of ablation about 1 cm around the tumor was confirmed by the postoperative CT image. There was no local recurrence during the average observation period of 290 days, and a severe post operative complication has not occurred. The average of hospitalized period after the operation was about 10 days. Therefore, pre-surrounding ablation preceding central puncture under the endosope for hepatocellular carcinoma on the liver surface is a feasible technique.

Aged↗
PubMed2004

Altered PDGF-BB-induced p38 MAP kinase activation in diabetic vascular smooth muscle cells: roles of protein kinase C-delta.

OBJECTIVE: We investigated the regulation of p38 mitogen-activated protein kinase (MAPK) by platelet-derived growth factor (PDGF)-BB and its biological effects in cultured normal and diabetic rat vascular smooth muscle cells (VSMCs). METHODS AND RESULTS: VSMC growth from diabetic rats was faster than that from normal rats. The expression of the PDGF beta-receptor in diabetic VSMCs was significantly elevated compared with that in normal cells, and PDGF-BB-induced p38 phosphorylation in diabetic cells was more enhanced via MAPK kinase (MKK) 3/6. The level of PKC activity in diabetic cells increased more than that in normal cells with or without PDGF-BB. Although protein kinase C (PKC)-betaII and PKC-delta were activated by diabetes, PDGF-BB could further enhance the level of PKC-delta alone. PDGF-BB-induced cell migration was more elevated in diabetic VSMCs, and the increase was significantly inhibited by SB-203580, rottlerin, and antisense oligodeoxynucleotides for PKC-delta. PDGF-BB-induced p38 phosphorylation also regulated cell growth, cyclooxygenase-2 levels, and arachidonic acid release, but not apoptosis. These levels were more elevated in diabetic cells, which were inhibited by SB-203580. CONCLUSIONS: Our study established that PDGF-BB phosphorylated p38 via PKC-delta and the subsequent MKK 3/6, leading to cell growth regulation and the progression of a chronic inflammatory process in diabetic VSMCs.

Animals↗
PubMed2004

Progression of diabetic nephropathy enhances the plasma osteopontin level in type 2 diabetic patients.

Osteopontin (OPN) is thought to play multiple roles in the progression of atherosclerotic plaque including diabetic vascular complications. However, it still remains unclear whether the level of OPN in vivo is indeed clinically associated with the progression of diabetic complications. This study evaluated whether the levels of OPN in plasma and urine are correlated with the progression of diabetic complications, such as retinopathy, neuropathy, and nephropathy in patients with type 2 diabetes. In 229 patients with type 2 diabetes, OPN level in plasma and urine was evaluated by both the severity of diabetic complications, such as retinopathy, neuropathy, and nephropathy, and the clinical characteristics and the substantial laboratory findings. Plasma OPN level increased significantly with aging and the progression of diabetic nephropathy, especially at the stage of renal failure (p<0.05). However, the level was not related to the progression of retinopathy or neuropathy, or to laboratory findings, such as HbA1c or serum lipids. In contrast, urinary OPN level was not associated with diabetic complications in any of the subjects. There was no correlation between the plasma and urinary values of OPN. The results established that the plasma OPN was elevated in proportion to the progression of diabetic nephropathy, indicating that the plasma concentration may be a potential diagnostic predictor of diabetic end-stage renal disease.

Aged↗
PubMed2004

[Comparison between guideline for diagnosis procedure combination by Japanese Society of Laboratory Medicine in 2003 and clinical pass of Yamagata University Hospital].

UNLABELLED: In order to standardize and improve the quality of medical treatment, a guideline for diagnosis procedure combination was proposed by the Japanese Society of Laboratory Medicine (JSLM) in 2003. We investigated whether the guideline agreed with the clinical pass of Yamagata University Hospital. A total of 17 patients admitted to Yamagata University Hospital for acute myocardial infarction or type 2 diabetes mellitus were investigated. There were ten patients with acute myocardial infarction and seven patients with diabetes. We compared laboratory examinations used in the guideline and those used in our clinical pass for acute myocardial infarction and observed that they were much the same. Also laboratory examinations used for type 2 diabetes and its complications in our clinical pass were much the same as those in the JSLM guideline. CONCLUSION: The guideline proposed by JSLM in 2003 agrees well with our clinical pass. However, collaboration with other related expert associations is required in making the final draft and future amendments.

Critical Pathways↗
PubMed2003

The D allele of the angiotensin-converting enzyme insertion/ deletion (I/D) polymorphism is a risk factor for type 2 diabetes in a population-based Japanese sample.

The association of the ACE gene I/D polymorphism with type 2 diabetes (DM) was examined in a population-based Japanese sample. A total of 902 individuals (490 females and 412 males, age 58.8 +/- 12.2 yr) from a cohort population (n = 3,706) of the Funagata diabetes study were divided into three groups according to genotype: D/D (n = 104), I/D (n = 436) and I/I (n = 362). Chi-square test and ANOVA were used for association studies and to assess the differences in the traits' values, respectively. More individuals with the genotypes D/D and I/D were diabetic (8.7% and 4.1%, respectively) than those with the genotype I/I (2.8%, p = 0.008 and p = 0.032, respectively). The genotype D/D was a risk factor for DM (relative risk (RR) 3.13, 95% CI 1.31-7.51), and also for DM and IGT (RR 1.78, 95% CI 14-2.76). Multiple logistic regression analysis also showed that the genotypes with the D allele were risk factors for DM and IGT even when adjusting for age, sex, hypertension and serum total cholesterol levels (odds ratio 1.49, 95% CI 1.01-2.21). The D allele of the ACE gene I/D polymorphism is a risk factor for DM.

Aged↗
PubMed2003

Increased urinary levels of pentosidine, pyrraline and acrolein adduct in type 2 diabetes.

This study investigates whether urinary levels of pentosidine, pyrraline and acrolein adduct are increased in type 2 diabetes (DM), and whether these levels are correlated with glycemic control and clinical traits. Urinary levels of pentosidine, pyrraline and acrolein adduct in DM patients (n = 100) recruited from the outpatient clinic of our university hospital were compared with those of age- and sex-matched non-diabetic subjects (n = 50). The correlation of these urinary levels with the glycemic control and the clinical traits were examined. Furthermore, the influence of smoking habit on the levels of acrolein adduct was examined. Urinary levels of pentosidine, pyrraline and acrolein adduct were all significantly (p<0.001) higher in the DM group than in the non-DM group (pentosidine (log(pmol/mgCr)), 1.579 +/- 0.147 vs 1.427 +/- 0.142; pyrraline (log(nmol/mgCr)), 0.888 +/- 0.402 vs 0.581 +/- 0.336; acrolein adduct (log(nmol/mgCr)), 2.316 +/- 0.221 vs 2.051 +/- 0.201). Glycemic control parameters, such as fasting plasma glucose (FPG) and HbA1c, were significantly correlated with these urinary levels. Age was correlated with the urinary levels of pentosidine but not with those of pyrraline and acrolein adduct. The urinary albumin excretion rate did not correlate with any of these urinary levels. The levels of acrolein adduct were higher in the subjects with smoking habit than in those without the habit in the DM group as well as in the non-DM group (DM, 2.391 +/- 0.230 and 2.212 +/- 0.190, p=0.0004; Non-DM, 2.120 +/- 0.171 and 1.993 +/- 0.206, p=0.0503). The urinary levels of pentosidine, pyrraline and acrolein adduct were increased in DM and were significantly correlated with glycemic control levels. In addition, smoking habit seems to increase the urinary levels of acrolein adduct.

Acrolein↗
PubMed2003

Decreased serum levels of adiponectin are a risk factor for the progression to type 2 diabetes in the Japanese Population: the Funagata study.

OBJECTIVE: To examine whether decreased serum levels of adiponectin are an independent risk factor for the progression to type 2 diabetes in a Japanese population. RESEARCH DESIGN AND METHODS: The serum levels of adiponectin and tumor necrosis factor-alpha (TNF-alpha) at baseline (from 1995 to 1997) were evaluated in 1,792 individuals (1,023 women and 769 men, aged 58.5 +/- 12.5 years) from a cohort population (n = 3,706) of the Funagata study. Glucose tolerance was evaluated at baseline and also at 5-year follow-up examinations (n = 978, follow-up rate, 54.6%) according to the 1985 World Health Organization criteria. The correlation of clinical traits with serum levels of adiponectin was examined. The association of the traits with the progression to type 2 diabetes at the 5-year follow-up was also examined. RESULTS: Among the traits examined, the correlation with aging was highest (r = 0.312, P < 0.001). Eighteen subjects with normal glucose tolerance (NGT) developed diabetes, and 709 remained NGT at the 5-year follow-up examinations. The subjects who became diabetic had decreased serum levels of adiponectin (7.29 +/- 2.35 vs. 9.13 +/- 2.35 10 x log microg/ml, P = 0.009). Multiple logistic regression analysis with age, sex, waist-to-hip ratio, and 2-h plasma glucose as the variables revealed that serum adiponectin level (odds ratio [per 0.1 log microg/ml] 0.766, P = 0.029) was an independent risk factor for the progression to type 2 diabetes. The subjects whose serum levels of adiponectin were in the lowest tertile were 9.320 times (95% CI 1.046-83.1) more likely to develop diabetes than those in the highest tertile (P = 0.046). CONCLUSIONS: Decreased serum adiponectin level is an independent risk factor for progression to type 2 diabetes.

Adiponectin↗
PubMed2003

Mechanism of an inhibitory effect of nipradilol on rat vascular smooth muscle cell growth.

The aim of this study was to clarify the mechanism of an inhibitory effect of nipradilol on cultured rat vascular smooth muscle cell (VSMC) growth. After being starved, cultured VSMCs were stimulated by 5% fetal bovine serum with various concentrations of nipradilol. Nipradilol dose-dependently decreased the values of [(3)H]-thymidine incorporation, cell numbers and total cellular protein content, and the levels of phosphorylated extracellular signal-regulated protein kinase 1/2 and p38. It also suppressed the level of proliferative cell nuclear antigen in a dose-dependent manner. In contrast, nipradilol did not change the level of the phosphorylated value of c-jun NH(2)-terminal protein kinase or cytoplasmic histone-associated DNA fragments in VSMCs. These results indicate that nipradilol suppresses cell growth without apoptosis in rat VSMCs, suggesting that it could be effective for preventing the progression of restenosis after angioplasty.

Adrenergic beta-Antagonists↗
PubMed2003

Clinical utility and approach to estimate postprandial hypertriglycemia by a newly designed oral fat-loading test.

The objective of this study was to estimate postprandial hypertriglycemia by a newly designed oral fat-loading test. Twenty-three healthy normolipidemic volunteers were orally administered a test meal consisting of a mixture of Telmeal 2.0 and 20 g of salt-free butter after fasting for 12 h. To measure the levels of total cholesterol (T-Cho), triglycerides (TG), high-density lipoprotein-cholesterol (HDL-C), remnant-like particle-cholesterol (RLP-C), lipoprotein (a) [Lp (a)], free fatty acid, apolipoproteins (Apos), plasma glucose (PG), immunoreactive insulin (IRI), and high-sensitivity C-reactive protein (hs-CRP), venous blood samples were collected before the meal and at each hour until 9 h after fat-loading. The levels of both TG and RLP-C were drastically elevated at 2 h after fat-loading and these levels remained high until 4 h (p < 0.01). A significant correlation between TG and RLP-C was also observed at 2, 3 and 4 h, and the values of the correlation coefficients (r) were 0.837, 0.838, and 0.908, respectively. In contrast, the levels of T-Cho, HDL-C, Lp (a), Apos, PG, and hs-CRP did not change. Furthermore, there were no gastrointestinal symptoms during or after the study. These results strongly suggested that this newly designed fat-loading test was very useful for evaluating postprandial hypertriglycemia, including remnant concentrations.

Adult↗
PubMed2002

First total synthesis of artepillin C established by o,o'-diprenylation of p-halophenols in water.

We have demonstrated that prenylation of p-halophenols was dependent on the solvent effect and succeeded in o,o'-diprenylation of p-halophenols in water. Following the Mizoroki-Heck coupling of the diprenyl-p-iodophenol 3c with methyl acrylate and then hydrolysis, we first synthesized artepillin C [3-(4-hydroxy-3,5-di(3-methyl-2-butenyl)phenyl)-2(E)-propenoic acid] (1), which is a biologically active constituent of propolis. These reactions may be applicable to the synthesis of various useful natural products such as 2,4,6-trisubstituted phenol derivatives.

Brazil↗
PubMed2002

TX-1123: an antitumor 2-hydroxyarylidene-4-cyclopentene-1,3-dione as a protein tyrosine kinase inhibitor having low mitochondrial toxicity.

A series of 2-hydroxyarylidene-4-cyclopentene-1,3-diones were designed, synthesized, and evaluated with respect to protein tyrosine kinase (PTK) inhibition, mitochondrial toxicity, and antitumor activity. Our results show that the cyclopentenedione-derived TX-1123 is a more potent antitumor tyrphostin and also shows lower mitochondrial toxicity than the malononitrile-derived AG17, a potent antitumor tyrphostin. The O-methylation product of TX-1123 (TX-1925) retained its tyrphostin-like properties, including mitochondrial toxicity and antitumor activities. However, the methylation product of AG17 (TX-1927) retained its tyrphostin-like antitumor activities, but lost its mitochondrial toxicity. Our comprehensive evaluation of these agents with respect to protein tyrosine kinase inhibition, mitochondrial inhibition, antitumor activity, and hepatotoxicity demonstrates that PTK inhibitors TX-1123 and TX-1925 are more promising candidates for antitumor agents than tyrphostin AG17.

Antineoplastic Agents↗