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Biomedical subjects

T Yamauchi

Publications and source records attributed to T Yamauchi.

At least 91 records · Page 5Linked to original sources
PubMed2000

Discovery of novel and potent retinoic acid receptor alpha agonists: syntheses and evaluation of benzofuranyl-pyrrole and benzothiophenyl-pyrrole derivatives.

In the course of our studies on retinoic acid receptor (RAR) agonists, we have designed and synthesized a series of benzofuran and benzothiophene derivatives. Some of these compounds (1a,b,e,f,j) markedly inhibited LPS-induced B-lymphocyte proliferation and exerted RARalpha selectivity. One of them, 4-[5-(4,7-dimethylbenzofuran-2-yl)pyrrol-2-yl]benzoic acid (1b), when orally administered significantly inhibited mouse antibody production and delayed type hypersensitivity (DTH) responses from a dose of 0.1 mg/kg.

Administration, Oral↗
PubMed2000

Novel retinoic acid receptor alpha agonists: syntheses and evaluation of pyrazole derivatives.

We have designed and synthesized a series of pyrazole derivatives as candidate retinoic acid receptor (RAR) agonists. One of them, 4-[5-(1, 5-diisopropyl-1H-3-pyrazolyl)-1H-2-pyrrolyl]benzoic acid (11b), which possesses a 2,5-disubstituted pyrrole moiety, showed selective transactivation activity for the RAR alpha receptor, and had highly potent cell-differentiating activity on HL-60 cells.

Binding, Competitive↗
PubMed2000

Transthyretin binds amyloid beta peptides, Abeta1-42 and Abeta1-40 to form complex in the autopsied human kidney - possible role of transthyretin for abeta sequestration.

The deposition of amyloid beta protein (Abeta), a proteolytic cleavage product of amyloid precursor protein (APP), is an invariable pathological feature of the Alzheimer's disease brain, while APP gene is widely expressed in all neuronal and non-neuronal tissues with the highest levels of expression in the brain, and kidney. To understand the role transthyretin (TTR) plays in the sequestration mechanism of Abeta in the kidney, we have investigated interactions of TTR with Abeta1-40 and Abeta1-42 molecules by an immunoprecipitation method, in vitro binding studies, and overlay assay. These in vivo and in vitro biochemical experiments showed that TTR bound Abeta1-42 preferentially, and Abeta1-40 only to a limited extent, to form TTR-monomer and -dimer-Abeta complexes in the normal human kidney. We provide new evidence supporting the hypothesis that TTR, an Abeta binding protein, plays an important role in the sequestration of Abeta and prevents amyloid formation in the kidney.

Amyloid beta-Peptides↗
PubMed2000

Regulation of endothelial constitutive nitric oxide synthase gene expression in endothelial cells and in vivo : a specific vascular action of insulin.

BACKGROUND: The vasodilatory effect of insulin can be acute or increase with time from 1 to 7 hours, suggesting that insulin may enhance the expression of endothelial nitric oxide synthase (eNOS) in endothelial cells. The objective of the present study was to characterize the extent and signaling pathways by which insulin regulates the expression of eNOS in endothelial cells and vascular tissues. METHODS AND RESULTS: Physiological concentrations of insulin (10(-10) to 10(-7) mmol/L) increased the levels of eNOS mRNA, protein, and activity by 2-fold after 2 to 8 hours of incubation in cultured bovine aortic endothelial cells. Insulin enhanced eNOS gene expression in microvessels isolated from Zucker lean rats but not from insulin-resistant Zucker fatty rats. Inhibitors of phosphatidylinositol-3 kinase (PI-3 kinase) decreased the effect of insulin on eNOS gene expression, but a general protein kinase C (PKC) inhibitor, GF109203X or PKCbeta isoform inhibitor, LY333531 enhanced eNOS expression. In contrast, PKC activators inhibited both the activation by insulin of PI-3 kinase and eNOS mRNA levels. Overexpression of PKCbeta isoform in endothelial cells inhibited the stimulation by insulin of eNOS expression and PI-3 kinase activities in parallel. CONCLUSIONS: Insulin can regulate the expression of eNOS gene, mediated by the activation of PI-3 kinase, in endothelial cells and microvessels. Thus, insulin may chronically modulate vascular tone. The activation of PKC in the vascular tissues as in insulin resistance and diabetes may inhibit PI-3 kinase activity and eNOS expression and may lead to endothelial dysfunctions in these pathological states.

Animals↗
PubMed2000

Genetic polymorphisms of human melatonin 1b receptor gene in circadian rhythm sleep disorders and controls.

Recent studies suggest that melatonin 1b (Mel1b) receptor, as well as melatonin 1a (Mel1a) receptor, is involved in the modulation of circadian rhythms in mammals. Mutational analysis was performed in the entire coding region of the human Mel1b receptor gene using genomic DNA from sleep disorder subjects. We have identified two missense mutations, G24E and L66F. However, neither is likely to be associated with sleep disorders in our study population. One of the subjects with non-24-h sleep-wake syndrome carries missense mutations in both the Mel1a and Mel1b receptor genes.

Adult↗
PubMed2000

Syntheses and structure-activity relationships of 5,6,7, 8-tetrahydro-5,5,8,8-tetramethyl-2-quinoxaline derivatives with retinoic acid receptor alpha agonistic activity.

In the course of our studies on retinoic acid receptor (RAR) agonists, we have designed and synthesized a series of quinoxaline derivatives. One of them, 4-[5-(5,6,7,8-tetrahydro-5,5,8, 8-tetramethyl-2-quinoxalinyl)-1H-2-pyrrolyl]benzoic acid (3a), which possesses a 2,5-disubstituted pyrrole moiety, showed selectivity for the RARalpha receptor and exerted highly potent cell-differentiating activity on HL-60 cells.

Benzoates↗
PubMed2000

Differential glomerular response to continuous infusion of vasopressin in spontaneously hypertensive rats and Wistar-Kyoto rats.

To determine the difference of glomerular response to exogenous vasopressin (VP) in vivo between normotensive and hypertensive rats, we examined the effects of 14-day continuous infusion of VP (1.0 ng/kg/min) on the physiological and histological aspects in 7-week-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. VP infusion did not result in significant changes in systolic blood pressure, heart rate, serum electrolytes, serum creatinine, urinary protein and N-acetyl-beta-glucosaminidase levels in both strains of rats. VP infusion significantly reduced daily urine volume associated with significant concentration of the urine in WKY rats but not SHR. Kidney and heart weights did not differ significantly after VP infusion between both strains. Glomerular mesangial expansion was significantly enhanced in VP infused SHR, but glomerular cellularity was not different between both strains following treatment. Competitive reverse transcription-polymerase chain reaction revealed that the level of glomerular transforming growth factor (TGF)-beta1 mRNA was significantly higher in SHR than WKY rats, and that this difference was significantly augmented after VP infusion in SHR. VP infusion, however, did not change the level of glomerular mRNAs of platelet-derived growth factor (PDGF) B-chain in both strains. Then, exogenous VP infusion contributes to the glomerular mesangial expansion in SHR, which involved overexpression of glomerular TGF-beta1 without any pressor effect. In contrast, the significant changes of glomerular expansion and TGF-beta1 level were not shown in WKY rats. These findings suggest that the glomerular response to the exogenous VP is preferentially enhanced in SHR.

Animals↗
PubMed2000

Flap transfers for the treatment of perichondrial ring injuries with soft tissue defects.

Seven cases (six fresh) of perichondrial ring injury with skin defects were treated using flap transfers. The study included four boys and three girls ranging in age from 2 to 9 years (average 6). They were followed up for an average of 8 years and 10 months. The period from injury to flap coverage was 8-12 days, with an average of 10 days in the fresh cases. Fracture was noted in four cases, with one an epiphyseal fracture. Peroneal flaps were transferred in four cases, latissimus dorsi myocutaneous flaps in two, and gastrocnemius muscle flap in one. Six flaps survived perfectly, and one failed due to venous thrombosis. This latter case was treated with a cross leg flap. Postoperative radiographic assessments confirmed partial growth plate arrest in the chronic case, but all the fresh cases had no postoperative growth disturbance. Flap coverage, for perichondrial ring injuries with wide skin defects, is a useful method not only for skin coverage, but for the prevention of growth disturbances as well.

Accidents, Traffic↗
PubMed2000

Testosterone modulates serum leptin concentrations in a male patient with hypothalamic hypogonadism.

Serial measurements of body mass index (BMI), serum concentrations of testosterone (T), estradiol (E) and leptin (L) were performed before and after gonadotropin (Gn) therapy in an 18-year-old male subject (BMI 25.4 kg/m2) with idiopathic hypothalamic hypogonadism (IHH). We also measured the BMI and serum concentrations of L in 99 age-matched healthy subjects. Serum L correlated significantly with BMI in control subjects (r=0.84, p<0.0001). Baseline serum concentrations of L in our case were markedly high and both T and E were very low, but Gn therapy resulted in a gradual decrease in L and improvement in T and E, finally reaching the control levels of BMI-matched subjects. Our results demonstrate that T is a powerful negative modulator of serum L independent of BMI in conditions associated with low T levels, such as IHH.

Adolescent↗
PubMed2000

Dermal absorption of N,N-dimethylacetamide in human volunteers.

OBJECTIVES: We investigated the potential for the dermal absorption of N,N-dimethylacetamide (DMAC: CAS No. 127-19-5) vapor, the biological half-life of N-methylacetamide (NMAC) in urine as the biological exposure item of DMAC, and the adjustment method for urinary concentrations. METHODS: Twelve healthy male volunteers (mean age 25.2 years, range 21-43 years) were exposed to DMAC for 4 h on two occasions at intervals of 96 h or above. Each volunteer sat inside a whole-body-type exposure chamber for the dermal exposure experiment or outside the chamber for the inhalation exposure experiment. The temperature and relative humidity in the chamber were controlled at approximately 26 degrees C and 40% in order to keep the skin (90% naked) of the volunteers dry. DMAC concentrations were 6.1 +/- 1.3 ppm for dermal exposure and 6.1 +/- 1.3 ppm for inhalation exposure. Urine samples were collected from 0 h through 36 h and at 48 h and 72 h after the exposure. Extrapolations from exposure concentrations for 4 h to 10 ppm for 8 h were performed. RESULTS: Mean dermal absorption was estimated to be 40.4% of the total DMAC uptake. The biological half-lives of urinary NMAC were 9.0 +/- 1.4 h and 5.6 +/- 1.3 h via skin and lung, respectively. Mean NMAC in urine just after 5 consecutive workdays (8 h/day) at 10 ppm DMAC exposure was assumed to be 33.7 mg/g x Cr (18.6-70.0 mg/g x Cr). Creatinine-adjusted NMAC concentration in urine for each volunteer within 12 h after the exposure was more closely correlated with the total excretion amount of NMAC up to 36 h than with urinary-volume-adjusted or specific-gravity-adjusted NMAC concentration in both the dermal and inhalation exposure experiments. CONCLUSIONS: DMAC vapor was significantly absorbed through the skin. Estimated NMAC values indicate that 20 mg/g x Cr NMAC seems to be appropriate as the biological exposure index.

Acetamides↗
PubMed2000

Involvement of muscarinic cholinergic and alpha2-adrenergic mechanisms in growth hormone secretion during exercise in humans.

The purpose of this study was to examine the role of muscarinic cholinergic and alpha2-adrenergic mechanisms in growth hormone (GH) secretion during exercise in humans. The GH responses induced during moderate-intensity exercise (using a cycle ergometer at 60% maximal oxygen uptake, VO2max, for 30 min) without treatment (control) and after the administration of a muscarinic cholinergic antagonist (atropine 1 mg) or after an alpha2-adrenergic antagonist (yohimbine 15 mg) were compared in seven healthy men. Although, serum GH concentration had increased significantly after exercise in the control experiment [mean peak GH concentration 52.64 (SEM 18.60) ng x ml(-1)], the increase was suppressed by the administration of either atropine [mean peak GH concentration 8.64 (SEM 7.47) ng x ml(-1)] or yohimbine [mean peak GH concentration 17.50 (SEM 7.89) ng x ml(-1)]. The area under the curve of serum GH concentration against time was significantly lower in the experiment using these drugs [with atropine, mean area 458 (SEM 409) ng x ml(-1) min], with yohimbine mean area 946 (SEM 435) ng x ml(-1) min] than in the control experiment [mean area 3135 (SEM 1098) ng x ml(-1) x min]. These results suggest that muscarinic cholinergic and alpha2-adrenergic mechanisms are involved in GH secretion during exercise in humans.

Adrenergic alpha-2 Receptor Antagonists↗
PubMed2000

Collateral sprouting mechanism after end-to-side nerve repair in the rat.

The collateral sprouting mechanisms of axons from an uninjured donor nerve after end-to-side nerve repair was investigated in motor nerves of rats, with special reference to the neurotrophins related to nerve regeneration. In addition, growth cone formation at the tip of the regenerating nerve was examined. A transected medial gastrocnemius nerve (MGN) was transferred to the side of an intact lateral gastrocnemius nerve (LGN) using a Y-shaped silicone tube. At 3, 7, or 14 days later, the MGN with the LGN was transected and was stained immunohistologically. Expression of neurotrophin-3 (NT-3) and Trk C (receptor of NT-3) was most significantly observed 3 days postoperatively around the site of coaptation. Brain-derived neurotrophic factor (BDNF) and Trk B (receptor of BDNF) was weakly detected at the coaptation site 3 days after-operation. Growth-associated protein 43 (GAP-43), which is a marker of growth cone formation, was observed at the site of coaptation in the LGN 7 days postoperatively and in the MGN at the site of coaptation at 14 days. We concluded that motor nerve regeneration due to collateral sprouting of axons after end-to-side nerve repair is possible. We thus demonstrated the involvement of at least one neurotrophin, NT-3, in the process of collateral sprouting of motor nerves.

Animals↗
PubMed2000

Differentiation induction in non-lymphocytic leukemia cells upon treatment with mycophenolate mofetil.

Inosine 5'-monophosphate (IMP) dehydrogenase catalyzes the rate-limiting reaction of guanine nucleotide biosynthesis and has been implicated in the reaction of cell growth and differentiation. We investigated the ability of mycophenolate mofetil, a prodrug of mycophenolic acid, to induce differentiation in HL-60 and U937 leukemic cells as well as in fresh leukemia cells from patients with non-lymphocytic leukemia. Treatment with mycophenolate mofetil reduced the intracellular guanosine 5'-triphosphate (GTP) levels and induced morphologic and functional differentiation in HL-60 and U937 cells dose-dependently. HL-60 and U937 cells developed macrophage-like cytoplasm as well as the expression of CD11b and CD14 antigens and the ability to oxidize nitroblue tetrazorium (NBT). These changes became evident when the intracellular GTP levels decreased to approximately 20-30% of the untreated control level and were abrogated by the addition of guanosine. In the fresh leukemic cells, differentiation induction was shown in the cells derived from seven of 13 patients. The fresh leukemia cells responding to mycophenolate mofetil revealed significant higher positivity to CD11b, CD14, and NBT before treatment and significantly reduced intracellular GTP levels after treatment compared to the non-responding cells. These findings suggest that mycophenolate mofetil induces differentiation in HL-60 and U937 cells and some fresh leukemia cells with moderate tendency to maturation, by causing a decrease in the intracellular GTP levels. Mycophenolate mofetil could be a promising differentiation inducer in vivo.

Adult↗
PubMed2000

Differential effect of chronic inhibition of calcium channel and angiotensin II type 1-receptor on aldosterone synthesis in spontaneously hypertensive rats.

We have investigated the in vivo effect of chronic blockade of Ca(2+)-channels and angiotensin II type 1 (AT(1))-receptors on aldosterone (Aldo)-synthesis in the adrenal glands of spontaneously hypertensive rats (SHR). Male SHR were administered Ca(2+)-antagonist, amlodipine (10 mg/kg per day) or AT(1)-receptor-antagonist, TCV-116 (1 mg/kg per day) from 7 until 11 weeks of age. Systolic blood pressure (SBP) and heart rate (HR) were significantly higher in SHR than Wistar-Kyoto (WKY) rats. Both treatments resulted in equivalent and significant reduction in SBP in SHR. Aldo-secretion in SHR, which was significantly higher than in WKY rats, was profoundly suppressed by TCV-116 compared with amlodipine. Both treatments resulted in thickening of the zona glomerulosa, which immunohistochemically contains Aldo, at the end of therapy. Competitive reverse transcription-polymerase chain reaction (RT-PCR) showed that CYP11A (P450scc) mRNA regulating the first step of Aldo-synthesis was significantly reduced from week 9 of age by amlodipine, and that CYP11B2 (P450aldo) mRNA regulating the last step of Aldo-synthesis was potently suppressed from 9 weeks of age by TCV-116. Our results indicate that chronic treatment with different antihypertensive agents directly modulates adrenocortical aldosterone synthesis in SHR in vivo via different mechanisms.

Adrenal Cortex↗
PubMed2000

Direct silicone intubation using Nunchaku-style tube (NST-DSI) to treat lacrimal passage obstruction.

PURPOSE: To confirm the usefulness of direct silicone intubation using a Nunchaku-style tube (NST-DSI) for the treatment of lacrimal passage obstruction. METHODS: Included in this retrospective study were 54 cases (45 patients) of adult-onset lacrimal passage obstruction on which NST-DSI was performed. The cases were subdivided into two groups: 29 cases of common canalicular obstruction (the canalicular obstruction group) and 25 cases of nasolacrimal duct obstruction (the duct obstruction group). RESULTS: At the final examination, irrigating fluid passed readily through the lacrimal passage in 39 (72.2%) of the 54 cases. Twenty-two cases (75.9%) were successful in the canalicular obstruction group (29 cases) whereas 17 cases (68.0%) were successful in the duct obstruction group (25 cases). CONCLUSION: NST-DSI is an effective alternative to treat both common canalicular obstruction and nasolacrimal duct obstruction. We regard NST-DSI as the first choice for the treatment of lacrimal passage obstruction.

Adult↗