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Biomedical subjects

M Hosoi

Publications and source records attributed to M Hosoi.

At least 19 recordsLinked to original sources
PubMed2006

Stimulation of cAMP signalling allows isolation of clonal pancreatic precursor cells from adult mouse pancreas.

AIMS/HYPOTHESIS: Duct cells of the pancreas are thought to include latent progenitors of islet endocrine cells that can be induced to differentiate by appropriate morphogens. Here we developed a method for isolating pancreatic ductal epithelial cells from adult mice that overcomes the shortcomings of previous methods. MATERIALS AND METHODS: Pancreatic ductal cells were grown in serum-free DMEM/F12 medium in the presence of cholera toxin or 8-bromo-cyclic adenosine monophosphate, which is known to be an intracellular cAMP generator. Single cell cloning was performed by limiting dilution in serum-free medium. RESULTS: The isolated clonal cells expressed high levels of cytokeratin and Ipf1 (formerly known as Pdx-1). Adenovirus-mediated expression of ngn3 (also known as Neurog3) and Ptf1a in these cells induced expression of insulin and somatostatin, and of carboxypeptidase A, respectively. Furthermore, albumin production was induced by dexamethasone or by long-term culture in serum-containing medium. CONCLUSIONS/INTERPRETATION: Stimulation of the cAMP-dependent signalling allowed us to isolate clonal pancreatic ductal cells from adult mice. These cells are able to partially differentiate into endocrine cells, exocrine cells and hepatocyte-like cells and are therefore considered to have the characteristics of endodermal progenitor cells.

Animals↗
PubMed2006

Decrease in tetrahydrobiopterin as a possible cause of nephropathy in type II diabetic rats.

A decrease in renal synthesis of nitric oxide (NO) in the progression of diabetic nephropathy has been documented. As (6R)-5,6,7,8-tetrahydrobiopterin (BH4) is an essential cofactor of NO synthase, we investigated whether BH4 deficiency is involved in the pathogenesis of nephropathy. Ten-week-old Otsuka Long-Evans Tokushima Fatty (OLETF) rats were used as a type II diabetic model, and Long-Evans Tokushima Otsuka (LETO) rats as the healthy controls. OLETF rats were orally treated with BH4 (10 mg/kg daily) or with water from 10 to 61 weeks of age. In another experiment, OLETF rats were treated orally with a calcium channel blocker, benidipine (5 mg/kg daily), or with 0.3% carboxymethyl cellulose (nontreated) from 10 to 52 weeks of age. Proteinuria was observed periodically, and at the end of the study, BH4 level and GTP cyclohydrolase I (GTPCH) activity in the kidney were measured. Proteinuria was observed at 13 weeks of age in the OLETF rats, and deteriorated until 61 weeks of age. Supplemental BH4 reduced the proteinuria. At 52 weeks of age, GTPCH activity and the BH4 level were decreased in the plasma and kidneys of OLETF rats, whereas they were significantly higher in the benidipine group than in the nontreated group. Proteinuria was milder in the benidipine group than in the nontreated group, without a concomitant decrease in blood pressure. Histologically observed glomerulosclerosis was mild in the BH4 and benidipine groups. In type II diabetic rats, renal BH4 is considered to play a crucial role in the pathogenesis of diabetic nephropathy. Benidipine was found to preserve BH4 levels, suggesting therapeutic renoprotective effects.

Animals↗
PubMed2006

Comparison of Pycnogenol and Daflon in treating chronic venous insufficiency: a prospective, controlled study.

The aim of this study was to investigate the clinical efficacy of oral Pycnogenol (Horphag Research Ltd., UK) in patients with severe chronic venous insufficiency (CVI) in comparison to the combination of diosmin and hesperidin (Daflon, Servier, France). A group of 86 patients with severe chronic venous insufficiency (CVI), venous hypertension, ankle swelling) and previous history of venous ulcerations received either oral Pycnogenol (capsules) 150 mg or 300 mg daily for 8 weeks or Daflon, 1,000 mg/day. All patients completed the study without dropouts. At the end of the study, microcirculatory results indicated: a progressive decrease of skin flux at rest (RF); a significant decrease in capillary filtration (RAS); an improvement in the symptomatic venous score (ASLS); a reduction in edema; a significant improvement (increase) in pO(2) and a decrease in pCO(2) in the Pycnogenol group. A significant level of improvement was reached after 4 weeks of treatment in most patients (p < .05) of the Pycnogenol group while clinical improvement was significant only in 6 subjects in the Daflon group. The positive effects of treatment with Pycnogenol after 8 weeks were significantly larger in comparison with the Daflon group. In conclusion, this study confirms the fast clinical efficacy of Pycnogenol in patients with chronic venous insufficiency and venous microangiopathy and its superiority-considering the evaluated parameters-to the combination of diosmin and hesperidin.

Adult↗
PubMed2006

Diabetic ulcers: microcirculatory improvement and faster healing with pycnogenol.

Diabetic microangiopathy leads to lower limb ulcers that are very slow to heal. Pycnogenol was evaluated on diabetic ulcers in a controlled trial. Ulcer medications were used in 4 groups (30 patients): (1) systemic Pycnogenol and local application; (2) local Pycnogenol only; (3) oral Pycnogenol; and (4) medications only (control group). Ulcerated areas and symptom scores were more reduced with the combined oral and local treatment (P < .05). Oral and local treatment were less effective, but still improved compared with the controls. Combined treatment produced 89% complete healing at 6 weeks versus 84% with local treatment and 85% with oral treatment; healing in controls was 61%. The combined treatment group and oral only group had better microcirculation after the combined treatment. Combined local and systemic application of Pycnogenol may offer a new treatment of diabetic ulcers. Local treatment also speeds ulcer healing.

Diabetes Complications↗
PubMed2005

Coronary arterial calcification is associated with albuminuria in type 2 diabetic patient.

AIM: Although microalbuminuria has been suggested as an independent risk factor for ischemic heart disease, the relationship between diabetic nephropathy and macroangiopathy remains unclear. Previously, we reported that coronary artery calcification detected by electron beam computed tomography (EBCT) could indicate the degree of coronary atherosclerosis in type 2 diabetic patients. In this study, we examine the association between coronary arterial calcification and microalbuminuria and aortic calcification and microalbuminuria. METHODS: Two hundred and fifty-six patients, including 177 type 2 diabetic patients (106 patients with normoalbuminuria, 71 with microalbuminuria) and 79 non-diabetic patients were evaluated by assessing the urinary albumin excretion rate and using EBCT to determine a coronary calcification score (CCS) and an aortic calcification score (ACS). RESULTS: No differences were observed regarding age, smoking index or BMI. Diabetic patients exhibited a greater CCS than non-diabetic subjects (non-diabetes 33 +/- 75 vs. diabetes 203 +/- 467, p < 0.05). Diabetic patients with microalbuminuria exhibited the most advanced CCS (253 +/- 491, p < 0.05). In contrast, no difference was observed in ACS among three groups. Multiple regression analysis showed that CCS is significantly associated with urinary albumin excretion rate as well as age, duration of diabetes and serum creatinine (R(2) = 0.31), while ACS is strongly associated with age, smoking, serum creatinine, systolic blood pressure and low-density lipoprotein cholesterol level (R(2) = 0.29). CONCLUSION: Increased urinary albumin excretion is associated with coronary arterial calcification in diabetic patients.

Age Factors↗
PubMed2003

Aldose reductase gene polymorphism is associated with progression of diabetic nephropathy in Japanese patients with type 1 diabetes mellitus.

AIM: The objective of this study was to investigate cross-sectionally and longitudinally whether polymorphism of the (A-C)n dinucleotide repeat sequence of the aldose reductase (AR) gene may modulate risk for diabetic nephropathy or retinopathy in Japanese patients with type 1 diabetes. METHODS: We obtained DNA samples from 101 patients followed up after the onset of type 1 diabetes and analysed a (A-C)n dinucleotide repeat polymorphic marker in the AR gene by polymerase chain reaction (PCR) method. RESULTS: Ten alleles ranging from Z-10 (128 bp) to Z+8 (146 bp) in repeat number were identified. In cross-sectional studies, the prevalence of the Z+2 allele was higher than that of any other allele in patients with diabetic nephropathy (37.5% of patients in a microalbuminuria group, and 41.7% of those in a macroalbuminuria group including patients with chronic renal failure and maintenance haemodialysis treatment). Prevalence of the Z+2 allele was not increased in patients with diabetic retinopathy. In longitudinal Kaplan-Meier plots, the cumulative incidence of nephropathy was significantly associated with homozygosity for the Z+2 allele (log rank test, p = 0.031); respective prevalence of nephropathy after diabetes durations of 10 and 15 years was 42.9% and 100% in Z+2 homozygotes (n = 8), 17.6% and 27.4% in Z+2 heterozygotes (n = 44), and 6.1% and 17.4% in patients without the Z+2 allele (n = 49). However, occurrence of retinopathy was not influenced by the Z+2 allele (log rank test, p = 0.926). CONCLUSIONS: Homozygosity for the Z+2 allele was associated with accelerated early progression of diabetic nephropathy in Japanese type 1 diabetic patients.

Adult↗
PubMed2001

Effect of exercise training on serum leptin levels in type 2 diabetic patients.

To evaluate the effect of exercise training on serum leptin levels 50 sedentary subjects with type 2 diabetes were enrolled in either 6 weeks of aerobic exercise training with diet therapy (n = 23) or diet therapy alone (n = 27). The training program consisted of walking and cycle ergometer exercise for 1 hour at least 5 times per week, with the intensity of exercise maintained at 50% of maximum oxygen uptake. Serum leptin levels decreased significantly in the exercise training (TR) group (7.2 +/- 3.6 to 4.6 +/- 2.5 ng/mL, P <.05), but not in the sedentary (SED) group (6.9 +/- 3.4 to 5.6 +/- 2.9 ng/mL). Leptin levels standardized for percentage body fat (dividing serum leptin level by percentage body fat) after treatment were lower in the TR subjects compared with the SED subjects. Body weight and percentage body fat decreased in all patients; however, no significant changes were observed in either group. Fasting concentrations of plasma insulin and cortisol and the urinary excretion of 17-hydroxycorticosteroid (17-OHCS) did not differ between the groups either before or after treatment. Fasting plasma glucose and hemoglobin A(1c) (HbA(1c)) improved significantly in both groups, although no significant differences were observed between the groups either before or after treatment. Ventilatory threshold increased significantly in the exercise training subjects. This study demonstrates that exercise training in type 2 diabetic subjects reduces serum leptin levels independent of changes in body fat mass, insulin, or glucocorticoids.

17-Hydroxycorticosteroids↗
PubMed2001

Nine cases of granular cell tumors in B6C3F1 mice.

The histological characteristics of 9 cases of granular cell tumors (GCTs) observed in B6C3F1 mice were examined to determine their cellular origin. Seven of the 9 cases were found in the uterus and other 2 cases were in the subcutaneous tissue. Tumor cells had abundant granules in the cytoplasm which were stained with PAS and were resistant to diastase treatment. Ultrastructurally, the granules were identified as lysosomes. The cell surface had cytoplasmic processus showing interdigitation with adjacent cells. A character feature of the tumor cells was the presence of a desmosome-like structure on their cell surface but no basal lamina was demonstrated. Although GCTs have been considered to be derived from Schwann cells on the basis of their ultrastructural features and S-100 protein-immunopositive findings, the absence of basal lamina in the present cases may raise a controversy as to their origin.

Animals↗
PubMed2000

Peroxisome proliferator-activated receptor-gamma agonists increase vascular endothelial growth factor expression in human vascular smooth muscle cells.

Vascular endothelial growth factor (VEGF), expressed in a variety of mesenchymal cells including vascular smooth muscle cells (VSMC), is a potent mitogen for endothelial cells, and is used clinically applied for ischemic disease of peripheral vessels. To determine whether peroxisome proliferator-activated receptor gamma (PPARgamma) regulates VEGF production in VSMC, we examined VEGF secretion from VSMC treated with PPAR agonists. Troglitazone increased VEGF secretion in a time- and dose-dependent manner (261 +/- 35% with 25 mM of troglitazone for 24 h), and also increased levels of VEGF mRNA. VEGF secretion was also increased by other PPARgamma agonists, pioglitazone, LY171883, and 15d-PGJ2 (224 +/- 17.1%, 247 +/- 36.8% and 171 +/- 7.8%, respectively), but not the PPARgamma agonists bezafibrate and Wy14643 (85.2 +/- 1.5%, 94.6 +/- 3.2, respectively). Our findings suggest that thiazolidinediones might be useful for the therapeutic angiogenesis for ischemic artery disease.

Acetophenones↗
PubMed2000

Clinical efficacy of insulin-like growth factor-1 in a patient with autoantibodies to insulin receptors: a case report.

The type B insulin-resistance syndrome is characterized by the presence of anti-insulin receptor antibodies that cause severe insulin resistance. Treatments including steroids, cyclophosphamide, plasmapheresis, or insulin-like growth factor-1 (IGF-1) are chosen according to severity of insulin resistance. We describe a patient with type B insulin resistance syndrome who was treated successfully with human recombinant (hr) IGF-1, although this treatment provoked a severe allergic reaction. An elderly man with impaired glucose tolerance and unpredictable hypoglycemic episodes which were gradually worsening increased in hemoglobin (Hb)A1c concentration from 6.5 to 13.4%. His fasting and postprandial hyperglycemia were associated with severe hyperinsulinemia. The patient was diagnosed with type B insulin-resistance syndrome by the presence of anti-insulin receptor antibodies. Double-filtration plasmapheresis, plasma exchange, and immunosuppressive therapy with cyclophosphamide and cyclosporin all failed to suppress anti-insulin receptor antibodies more than transiently. When we attempted the treatment by daily administration of hrIGF-1, fasting and postprandial plasma glucose concentrations became normal and HbA1c levels decreased to 7.1% over 2 months, until on one occasion administration resulted in anaphylaxis. After the patient became stable, desensitization therapy was performed successfully, and hrIGF-1 could be administered again with the plasma glucose returning. We concluded that IGF-1 therapy was an effective treatment choice for type B insulin-resistance syndrome in cases whose plasma exchange and immunosuppressive therapy have failed.

Aged↗
PubMed2000

Hypothalamic mechanisms of pain modulatory actions of cytokines and prostaglandin E2.

A decrease and subsequent increase in nociceptive threshold in the whole body are clinical symptoms frequently observed during the course of acute systemic infection. These biphasic changes in nociceptive reactivity are brought about by central signal substances induced by peripheral inflammatory messages. Systemic administration of lipopolysaccharide (LPS) or interleukin-1 beta (IL-1 beta), an experimental model of acute infection, may mimic the biphasic changes in nociception, hyperalgesia at small doses of LPS, and IL-1 beta and analgesia at larger doses. Our behavioral and electrophysiological studies have revealed that IL-1 beta in the brain induces hyperalgesia through the actions of prostaglandin E2 (PGE2) on EP3 receptors in the preoptic area and its neighboring basal forebrain, whereas the IL-1 beta-induced analgesia is produced by the actions of PGE2 on EP1 receptors in the ventromedial hypothalamus. An intravenous injection of LPS (10-100 micrograms/kg) produced hyperalgesia only during the period before fever develops and was abolished by microinjection of NS-398 (an inhibitor of cyclooxygenase 2) into the preoptic area, but not into the other areas in the hypothalamus. The hyperalgesia induced by the cytokines PGE2 and LPS may explain the systemic hyperalgesia clinically observed in the early phase of infectious diseases, which probably warns the organisms of infection before the full development of sickness symptoms. The switching of nociception from hyperalgesia to analgesia accompanied by sickness symptoms may reflect changes in the host's strategy for fighting microbial invasion as the disease progresses.

Animals↗
PubMed1999

Distinct role of cAMP and cGMP in the cell cycle control of vascular smooth muscle cells: cGMP delays cell cycle transition through suppression of cyclin D1 and cyclin-dependent kinase 4 activation.

cAMP and cGMP are known to suppress vascular smooth muscle cell (SMC) proliferation. In this study, our aim was to delineate the molecular mechanism underlying cAMP and cGMP suppression of cell cycle transition in human SMCs. cAMP inhibits both platelet-derived growth factor-stimulated cyclin-dependent kinase (cdk) 2 and cdk4 activation through upregulation of the cdk2 inhibitor p27(Kip1) and downregulation of cyclin D1 expression, which leads to a complete arrest of the cells in phase G(1). In contrast, cGMP inhibits cyclin D1 expression, inhibits cdk4 activation, and delays platelet-derived growth factor-mediated cdk2 activation, resulting in a delay in G(1)/S transition. A transient increase in p27(Kip1) in cdk2 immunoprecipitates, without changes in total cellular p27(Kip1) levels, correlates with the delay in cdk2 activation caused by cGMP. Thus, cAMP and cGMP differentially affect cell cycle through distinct regulation of cell cycle molecules in human SMCs.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1999

Hyperalgesic response to noxious stimulation in genetically polydipsic mice.

Inbred mice, STR/N, are known to exhibit extreme polydipsia and polyuria but no abnormality in the response to exogenous vasopressin (AVP) and renal functions. Our previous studies have revealed that the brain opioid system is involved in the polydipsia of these mice. We here report that the STR/N mice show a decrease in the nociceptive threshold and a low, anti-nociceptive sensitivity to opioid receptors agonists. The paw-withdrawal latency (PWL) on a hot-plate in the STR/N mice was significantly shorter than that in their controls (BALB/c and C3H mice). This hyperalgesia was not affected by water restriction. Subcutaneous (s.c.) injections of morphine (5 mg/kg) and a kappa-opioid receptor agonist, U50,488H (16 mg/kg) had no effect on the PWL in the STR/N mice, whereas the control mice prolonged PWL after administration of the opioids. However, the STR/N mice gained the ability to show morphine analgesia after up-regulation of the opioid system by repeated administration of naltrexone (s.c., 5 mg/kg) for 3 consecutive days. The results suggest that the anti-nociceptive function of the opioid system is down-regulated in STR/N mice as is observed in chronic morphine-treated animals.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1999

Prostaglandin E(2) has antinociceptive effect through EP(1) receptor in the ventromedial hypothalamus in rats.

The effects of microinjection of prostaglandin E(2) (PGE(2)) (50 fg-50 ng/0.2 microl) into the ventromedial hypothalamus (VMH) on nociception were studied using a hot-plate test in rats. Microinjection of PGE(2) (5-500 pg and 50 ng/0.2 microl) into the VMH significantly prolonged the paw-withdrawal latency on a hot plate 5 and 10 min after injection, respectively. Maximal prolongation was obtained 5 min after the injection of PGE(2) at 5 pg. Subsequently, to determine whether the PGE(2) receptor subtype EP(1) is involved in the PGE(2)-induced antinociceptive effect in the VMH, we observed the changes in nociception after intraVMH microinjection of SC19220, an EP(1) receptor antagonist, and 17-phenyl-omega-trinor PGE(2), an EP(1) receptor agonist. Simultaneous injection of SC19220 (150 ng) with PGE(2) (500 pg) into the VMH blocked the PGE(2)-induced prolongation of the paw-withdrawal latency. Moreover, an intraVMH microinjection of 17-phenyl-omega-trinor PGE(2) (500 pg) prolonged it. These results indicate that PGE(2) in the VMH has antinociceptive effect through its actions on EP(1) receptors in rats.

Analgesics↗
PubMed1999

Remission of insulin autoimmune syndrome in a patient with Grave's disease by treatment with methimazole.

The patient, a 24-year-old man, had suffered from hunger, sweating, tachycardia and palpitation for three years. He was diagnosed as having Graves' disease (GD) and treated with methimazole (MMI) for 3 months. He noted that palpitation and perspiration seemed to particularly occur when he was hungry, and thus he was examined to determine whether these symptoms were caused by hypoglycemia. As a markedly elevated immunoreactive insulin level and the presence of insulin antibody in serum were found, he was diagnosed as having insulin autoimmune syndrome (IAS). HLA typing revealed the patient to be positive for group Bw62/Cw4/DR4, which is reportedly a specific HLA type in MMI-treated euthyoroid GD patients with IAS. In spite of the continuation of MMI treatment, the % binding of IRI decreased and the hypoglycemic episode disappeared. In contrast to the previously reported MMI induced IAS in GD cases, MMI is unlikely to have exacerbated IAS in the present case, although his HLA combination is identical to that of the previous cases.

Adult↗
PubMed1999

Association of ACE gene polymorphism with arterial stiffness in patients with type 2 diabetes.

OBJECTIVE: To assess the relationship between the insertion (I)/deletion (D) polymorphism of the ACE gene and arterial distensibility in patients with type 2 diabetes and healthy control subjects. RESEARCH DESIGN AND METHODS: Aortic and carotid arterial distensibility were evaluated by measuring aortic pulse-wave velocity (a-PWV) and carotid stiffness beta using an echo-tracking system in 137 patients with type 2 diabetes and 260 age-matched control subjects. RESULTS: a-PWV and carotid stiffness beta were significantly higher in patients with type 2 diabetes than in age-matched control subjects (P < 0.05). Both stiffness beta and a-PWV were significantly higher in the patients with the II genotype than in those with the DD genotype (P < 0.001). In the control subjects, multiple regression analysis showed that age and decreased HDL cholesterol were independently associated with increased a-PWV (R2 = 0.244, P < 0.0001) and that age, systolic and diastolic blood pressure, and BMI were independently associated with increased carotid stiffness beta (R2 = 0.454, P < 0.0001). In the patients with type 2 diabetes, age, gene dose of the I allele, and systolic and diastolic blood pressure were independently associated with increased a-PWV (R2 = 0.545, P < 0.0001), and age, gene dose of the I allele, and systolic blood pressure were associated with increases in carotid stiffness beta (R2 = 0.314, P < 0.0001). CONCLUSIONS: These results suggested that ACE polymorphism is associated with the impairment of aortic and carotid distensibility in patients with type 2 diabetes.

Acetylcholinesterase↗
PubMed1998

Pain modulatory actions of cytokines and prostaglandin E2 in the brain.

Proinflammatory cytokines such as IL-1, IL-6, and TNF alpha are known to enhance nociception at peripheral inflammatory tissues. These cytokines are also produced in the brain. We found that an intracerebroventricular injection of IL-1 beta only at nonpyrogenic doses in rats reduced the paw-withdrawal latency on a hot plate and enhanced the responses of the wide dynamic range neurons in the trigeminal nucleus caudalis to noxious stimuli. This hyperalgesia, as assessed by behavioral and neuronal responses, was blocked by pretreatment with IL-1 receptor antagonist (IL-1Ra), Na salicylate, or alpha melanocyte-stimulating hormone, indicating the involvement of IL-1 receptors and the synthesis of prostanoids. IL-6 and TNF alpha at nonpyrogenic doses also induced hyperalgesia in a prostanoid-dependent way. Furthermore, the preoptic area (POA) was most sensitive to IL-1 beta (5-50 pg/kg) in the induction of behavioral hyperalgesia. The maximal response was obtained 30 min after injection of IL-1 beta at 20 pg/kg. On the other hand, an injection of IL-1 beta (20-50 pg/kg) into the ventromedial hypothalamus (VMH) prolonged the paw-withdrawal latency maximally 10 min after injection. This analgesia, as well as the intraPOA IL-1 beta-induced hyperalgesia, was completely blocked by IL-1Ra or Na salicylate. Our previous study has revealed that i.c.v. injection of PGE2 induces hyperalgesia through EP3 receptors and analgesia through EP1 receptors by its central action. The results, taken together, suggest (1) that IL-1 beta at lower doses in the brain induces hyperalgesia through EP3 receptors in the POA and (2) that the higher doses of brain IL-1 beta produces analgesia through EP1 receptors, probably, in the VMH.

Animals↗