Biomedical subjects

K Yamada

Publications and source records attributed to K Yamada.

At least 145 records · Page 8Linked to original sources

PubMed2002

The phytochemical lindleyin, isolated from Rhei rhizoma, mediates hormonal effects through estrogen receptors.

Some plant compounds or herb mixtures are popular alternatives to conventional therapies and contain organic compounds that bind to some nuclear receptors, such as the estrogen receptor (ER), to exert various biological effects. We studied the effect of various herbal extracts on ERalpha and ERbeta isoforms. One herbal extract, Rhei rhizoma (rhubarb), acts as an agonist to both ERalpha and ERbeta. The phytochemical lindleyin, a major component of rhubarb, might contribute to this estrogenic activity through ERalpha and ERbeta. 4-Hydroxytamoxifen, an ER antagonist, completely reversed the estrogenic activity of lindleyin. Lindleyin binds to ERalpha in vitro, as demonstrated using a fluorescent polarization assay. The in vivo effect of rhubarb extract was studied using a vitellogenin assay system in the freshwater fish, Japanese medaka (Oryzias latipes). There were marked increases in serum vitellogenin levels in male medaka exposed to rhubarb extract. We conclude that lindleyin, a component of some herbal medicines, is a novel phytoestrogen and might trigger many of the biological responses evoked by the physiological estrogens.

Cells, Cultured↗

PubMed2002

Effect of an Na+/H+ exchange inhibitor, SM-20550, on ischemic preconditioning in rabbits.

The effects of SM-20550 [N-(aminoiminomethyl)-1,4-dimethyl-1H-indole-2-carboxamide methanesulfonic acid], an Na+/H+ exchange inhibitor, on ischemic preconditioning (IPC) were studied in a rabbit model of myocardial ischemia and reperfusion injury. Anesthetized rabbits underwent occlusion of the coronary artery (30 min) followed by reperfusion (5 h). In SM-20550-treated animals, SM-20550 was intravenously administered at 0.03 mg/kg or 0.1 mg/kg before ischemia (30 min). Treatment with SM-20550 at 0.03 mg/kg had a nonsignificant tendency to reduce infarct size (18%). In contrast, 0.1 mg/kg of SM-20550 significantly reduced infarct size by 62%. In animals with IPC, the condition was induced by 2 or 5 min of ischemia and 10 min of reperfusion prior to sustained ischemia (30 min). Although 5 min of IPC significantly reduced infarct size by 72%, 2 min of IPC reduced infarct size by only 27%, which was not significant. The combination of 5 min of IPC and 0.1 mg/kg of SM-20550 significantly reduced infarct size by 78%. This reduction in infarct size was similar to that produced by 0.1 mg/kg SM-20550 or 5 min of IPC alone. Moreover, the combination of 2 min of IPC and 0.03 mg/kg of SM-20550 significantly reduced infarct size by 64%, although neither 0.03 mg/kg SM-20550 nor 2 min of IPC alone reduced infarct size significantly. These results indicate that an Na+/H+ exchange inhibitor SM-20550, does not antagonize the cardioprotective effect of IPC. SM-20550 and IPC appeared to act synergistically to exert a combined cardioprotective effect.

Amidines↗

PubMed2001

Therapeutic effect of S-allylmercaptocysteine on acetaminophen-induced liver injury in mice.

S-allylmercaptocysteine is one of the water-soluble organosulfur compounds in ethanol extracts of garlic (Allium sativum L.). We had demonstrated earlier that treatment with S-allylmercaptocysteine before acetaminophen administration protects mice against acetaminophen-induced hepatotoxicity. In this study, we examined the therapeutic effect of S-allylmercaptocysteine treatment after acetaminophen administration. A single dose of S-allylmercaptocysteine (200 mg/kg, p.o.) to mice 0.5 h after acetaminophen administration (500 mg/kg, p.o.) significantly suppressed both the increase in plasma alanine aminotransferase activity and the hepatic necrosis, and also reduced acetaminophen-induced mortality from 43% to 0%. These data indicate that S-allylmercaptocysteine is useful as an antidote for acetaminophen overdose. S-allylmercaptocysteine significantly suppressed hepatic cytochrome P450 2E1 (CYP2E1) activity and induction of inducible 70-kDa heat shock protein, a marker of acetaminophen arylation of protein. These results suggest that S-allylmercaptocysteine exerts its protective effect by inhibition of CYP2E1 activity, which leads to the suppression of acetaminophen arylation of hepatic protein.

Acetaminophen↗

PubMed2001

Pig kidney transplantation in baboons: anti-Gal(alpha)1-3Gal IgM alone is associated with acute humoral xenograft rejection and disseminated intravascular coagulation.

BACKGROUND: Kidneys harvested from miniature swine or pigs transgenic for human decay-accelerating factor (hDAF) were transplanted into baboons receiving an anti-CD154 monoclonal antibody (mAb) and either a whole body irradiation (WBI)- or cyclophosphamide (CPP)-based immunosuppressive regimen. METHODS: Group 1 baboons (n=3) underwent induction therapy with WBI and thymic irradiation, pretransplantation antithymocyte globulin, and immunoadsorption of anti-Gal(alpha)1-3Gal (Gal) antibody (Ab). After transplantation of a miniature swine kidney, maintenance therapy comprised cobra venom factor, mycophenolate mofetil, and an anti-CD154 mAb (for 14-28 days). In group 2 (n=2), WBI was replaced by CPP in the induction protocol. Group 3 (n=3) animals received the group 2 regimen, but underwent transplantation with hDAF pig kidneys. RESULTS: Group 1 and 2 animals developed features of disseminated intravascular coagulation (DIC), with reductions of fibrinogen and platelets and increases of prothrombin time, partial thromboplastin time, and fibrin split products. Graft survival was for 6-13 days. Histology showed mild acute humoral xenograft rejection (AHXR) of the kidneys, but severe rejection of the ureters. Group 3 animals developed features of DIC in two of three cases during the fourth week, with AHXR in the third case. Graft survival was for 28 (n=1) or 29 (n=2) days. Histology of day 15 biopsy specimens showed minimal focal mononuclear cellular infiltrates, with predominantly CD3+ cells. By days 28 and 29, kidneys showed mild-to-moderate features of AHXR. In all groups, the humoral response was manifest by reappearance of anti-Gal IgM below baseline level, with no or low return of anti-Gal IgG. All excised kidneys showed IgM deposition, but no complement and no or minimal IgG deposition. No baboon showed a rebound of anti-Gal Ab immediately after excision of the graft, and anti-Gal Ab increased over pretransplantation levels only when anti-CD154 mAb was discontinued. CONCLUSIONS: DIC was observed with WBI- or CPP-based therapy, and after miniature swine or hDAF kidney transplantation. AHXR+/-DIC was observed in all recipients even in the absence of complement and no or low levels of anti-Gal IgG, but was significantly delayed in the hDAF recipients. These results confirm our earlier observation that CD154 blockade prevents T cell-dependent sensitization in baboons to pig antigens, but that baseline natural anti-Gal Ab production is not inhibited. We suggest that IgM deposition, even in the absence of IgG and complement, leads to endothelial cell activation with the development of DIC, even when there are only minimal histologic changes of AHXR.

Acute Disease↗

PubMed2001

Effects of common polymorphisms on the properties of recombinant human methylenetetrahydrofolate reductase.

Methylenetetrahydrofolate reductase (MTHFR) catalyzes the conversion of methylenetetrahydrofolate to methyltetrahydrofolate, the major methyl donor for the conversion of homocysteine to methionine. Two common polymorphisms of the human enzyme have been identified: 677C>T, which leads to the substitution of Ala-222 by valine, and 1298A>C, which leads to the replacement of Glu-429 by alanine; the former polymorphism is the most frequent genetic cause of mild hyperhomocysteinemia, a risk factor for cardiovascular disease. By using a baculovirus expression system, recombinant human MTHFR has been expressed at high levels and purified to homogeneity in quantities suitable for biochemical characterization. The Glu429Ala protein has biochemical properties that are indistinguishable from the wild-type enzyme. The Ala222Val MTHFR, however, has an enhanced propensity to dissociate into monomers and to lose its FAD cofactor on dilution; the resulting loss of activity is slowed in the presence of methyltetrahydrofolate or adenosylmethionine. This biochemical phenotype is in good agreement with predictions made on the basis of studies comparing wild-type Escherichia coli MTHFR with a mutant, Ala177Val, homologous to the Ala222Val mutant human enzyme [Guenther, B. D., et al. (1999) Nat. Struct. Biol. 6, 359-365].

Animals↗

PubMed2001

Association studies of the CT repeat polymorphism in the 5' upstream region of the cholecystokinin B receptor gene with panic disorder and schizophrenia in Japanese subjects.

The tetrapeptide of cholecystokinin (CCK), CCK-4, is known to induce panic attacks in human subjects, while CCK-8 is reported to have a therapeutic effect on schizophrenia symptoms. Recently, we have identified a novel microsatellite polymorphism in the 5' upstream region of the CCK gene and shown a significant association between this polymorphism and panic disorder. In this study, we have investigated the CCK-B receptor (CCKBR) gene, which is the main constituent of the CCK receptor in the CNS. Recently, a dinucleotide repeat, (CT)(n), in the 5' regulatory region of the CCKBR gene was reported to be associated with panic disorder in Canadian samples. To evaluate an association of the CT repeat with panic disorder and schizophrenia, we genotyped 71 subjects with panic disorder, 154 schizophrenics and 199 controls. However, no evidence of allelic association was found between the polymorphic repeat of the CCKBR gene and either panic disorder or schizophrenia (P = 0.186 and 0.987, respectively). Together with the negative reports on association analyses using other polymorphisms of the CCKBR gene and Japanese samples, the present results exclude a major genetic contribution of the CCKBR gene to susceptibilities to panic disorder and schizophrenia in Japanese cohorts.

5' Flanking Region↗

PubMed2001

Karyotype analysis of 161 unrelated schizophrenics: no increased rates of X chromosome mosaicism or inv(9), using ethnically matched and age-stratified controls.

Chromosomal aberrations have long been studied in an effort to identify susceptibility genes in schizophrenia. The two most frequently detected abnormalities are X chromosome mosaicism in female patients and pericentric inversions of chromosome 9 [inv(9)]. Chromosome X aneuploidies are known to be age dependent but differences due to ethnicity remain undetermined. In the case of inv(9), its prevalence in the general population varies with ethnicity. To evaluate the importance of these karyotypic changes in schizophrenia, cytogenetic analysis was performed on 161 unrelated schizophrenics of Japanese origin. We observed an increase in the incidence of X chromosome mosaicism in female schizophrenics with age. However, when compared with age matched female controls (92 individuals), no significant differences between patient and control samples were detected. Moreover, this study showed that there is no significant difference in the incidence of X chromosome loss between Japanese and Caucasian populations. The four cases with inv(9) (2.5%) detected in this study, did not differ significantly from the reported incidence of between 1.7 and 2.1% seen in the general Japanese population. We also observed a small number of additional karyotypic changes, none of which were recurrent. This is the first report to examine the comparative rates of X mosaicism in female schizophrenics and age matched controls.

Adolescent↗

PubMed2001

Three novel mutations of the RPGR gene exon ORF15 in three Japanese families with X-linked retinitis pigmentosa.

We describe three new mutations in a recently identified exon, ORF15, of the retinitis pigmentosa GTPase regulator gene (RPGR) in three unrelated Japanese families (Families 1-3) with X-linked retinitis pigmentosa (XLRP). The affected males had typical retinitis pigmentosa (RP), whereas the obligate carrier females showed a wide clinical spectrum, ranging from minor symptoms to severe visual disability. Some carrier females in Families 1 and 2 showed typical RP, most carriers manifested high myopia and astigmatism, and their corrected visual acuity was insufficient. They showed an impairment of cone function following the rod dysfunction and accompanied by refractive errors. Microsatellite analysis of Family 1 revealed that the RP in the family was linked to the RP3 locus. Although one patient in the family had no mutation in the previously published exons 1-19 including exon 15a, he had a single-nucleotide insertion in exon ORF15 (g.ORF15 + 753-754 insG). Likewise, patients in Families 2 and 3 had two-base insertion/deletion in the exon, i.e., g.ORF15 + 833-834delGG and g.ORF15 + 861-862insGG, respectively. These insertional/deletional mutations observed in the three families are all different and new, and are predicted to lead to a frameshift, resulting in a truncated protein. These findings may support the previous hypothesis that RPGR-ORF15 is a mutational hot spot.

Adult↗

PubMed2001

Extremely large group-velocity dispersion of line-defect waveguides in photonic crystal slabs.

We reveal experimentally waveguiding characteristics and group-velocity dispersion of line defects in photonic crystal slabs as a function of defect widths. The defects have waveguiding modes with two types of cutoff within the photonic band gap. Interference measurements show that they exhibit extraordinarily large group dispersion, and we found waveguiding modes whose traveling speed is 2 orders of magnitude slower than that in air. These characteristics can be tuned by controlling the defect width, and the results agree well with theoretical calculations, indicating that we can design light paths with made-to-order dispersion.

Journal Article↗

PubMed2001

Confirmation of genetic homogeneity of syndactyly type 1 in an Iranian family.

Syndactyly type 1 (SD1) is the most common type of syndactyly, inherited in an autosomal dominant fashion and characterized by complete or partial webbings between the third and fourth fingers and/or between the second and third toes. We recently encountered an Iranian family in which 33 members in six generations were affected with SD1. As a locus of SD1 in a German family has recently been assigned to chromosome 2q34-q36, we performed a linkage analysis of the Iranian SD1 in order to know whether the disorder is genetically homogeneous. With the analysis on 15 affected and 16 unaffected persons in the Iranian family, using dinucleotide repeat polymorphisms as markers, we mapped the SD1 locus to 2q34-q36 with a maximum LOD score of 6.92 at a recombination fraction straight theta = 0.00 (penetrance = 1.00) for the D2S2179 locus. The result not only confirmed the gene assignment, but also suggests genetic homogeneity of the disease.

Alleles↗

PubMed2001

Role of hydrophilic interaction in binding of hydroxylated 3-deoxy C(19) steroids to the active site of aromatase.

As part of our investigation into the structure-activity relationship of a novel class of aromatase inhibitors, C(19) steroids having no oxygen function at C-3, we tested aromatase inhibition activity of polar diol compounds 4,19-dihydroxyandrost-5-en-17-ones (25 and 27) and 6,19-dihydroxyandrost-4-en-17-ones (36 and 37). 4alpha,19-Diol 25 was synthesized from tert-butyldimethylsilyoxyandrost-4-ene steroid (9) through its OsO(4) oxidation, giving the 4alpha,5alpha-dihydroxy derivative 12, as a key reaction. Acetylation of 5beta,6alpha-dihydroxy-19-acetate 30 and its 5alpha,6beta-analogue 31 followed by dehydration with SOCl(2) and alkaline hydroxysis gave 6alpha,19-diol 36 and its 6beta-isomer 37, respectively. The stereochemistry of a hydroxy group at C-4 of compound 25 and that at C-6 of compounds 36 and 37 were determined on the basis of (1)H NMR spectroscopy in each case. 4beta,19-Diol 27, previously synthesized, was identified as an extremely powerful competitive inhibitor of aromatase (K(i) = 3.4 nM). In contrast, its 4alpha,19-dihydroxy isomer 25 and other series of diol compounds, 6,19-dihydroxy-4-en-17-one steroids, were moderate to poor competitive inhibitors (K(i) = 110-800 nM). Through this series of analyses, it was concluded that hydrophilic interaction of a 4beta,19-diol function with the active site of aromatase plays a critical role in the tight binding of 3-deoxy-5-ene steroids.

Androstenediols↗

PubMed2001

Epidermal growth factor down-regulates connexin-43 expression in cultured rat cortical astrocytes.

Astrocytes are coupled via gap junction channels, predominantly formed by connexin-43 (Cx43), and contribute to neuronal function in the normal and diseased brain. In this study, we demonstrate that epidermal growth factor (EGF), applied to cortical astrocytes, results in a decrease in the expression of Cx43 mRNA and protein. We have further shown that the decrease is associated with the receptor tyrosine kinase pathway and the MEK inhibitor prevents EGF-stimulated down-regulation of Cx43 expression. These findings demonstrate a previously unknown function of EGF on cultured astrocytes, which may be relevant to the regulation of astrocytic growth and differentiation.

Animals↗

PubMed2001

Different onsets of oxidative damage to DNA and lipids in bone marrow and liver in rats given total body irradiation.

We examined time-dependent changes in antioxidant vitamins and oxidative damage to DNA and lipids in the bone marrow, liver, and plasma of rats given total body irradiation (TBI) with X-rays at 3 Gy. The oxidative damage to DNA and lipids was evaluated by measuring increases of 8-hydroxydeoxyguanosine (8OHdG) in DNA and 4-hydroxy-2-nonenal (HNE), respectively. After the TBI, marked increases in 8OHdG and HNE were detected at 3 to 5 h in the bone marrow, while gradual increases in these parameters were detected after a few days in the liver. These changes in 8OHdG and HNE were well correlated within each tissue. In the bone marrow, levels of both vitamin C and vitamin E were decreased by the TBI; however, the changes in vitamin C were earlier and greater than those in vitamin E. In the liver, the level of vitamin C did not decrease, but that of vitamin E decreased due to the TBI. Changes in HNE, vitamin C, and vitamin E in the plasma were similar to those in the liver. Within each tissue, the time of decrease in antioxidants was almost the same as that of the increase in oxidative damage. An increase in total iron due to the TBI was also detected in these tissues. In particular, the total iron in the bone marrow was markedly increased at a few hours after the TBI, with a slight increase in transferrin and no increase in ferritin. Exposure studies performed on cells or isolated DNA showed that an increase in 8OHdG was detected immediately after irradiation at more than 100 Gy in bone marrow cells and at less than 10 Gy in isolated DNA, suggesting that an increase in 8OHdG is undetectable even in bone marrow immediately after the TBI at 3 Gy. These results indicate that the onset of oxidative damage to DNA and lipids was delayed after TBI at 3 Gy, that it was quite different in the bone marrow and the liver, and that an increase in iron and decrease in antioxidant vitamins were involved in the mechanism of oxidative damage.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed2001

Cervical posterior fusion with wave-shaped rod under local anesthesia for cervical spondylotic myelopathy: review of 12 patients.

STUDY DESIGN: Clinical evaluation of cervical interspinous fusion under local anesthesia in elderly patients with cervical spondylotic myelopathy. OBJECTIVES: To evaluate the effectiveness of cervical posterior fusion with wave-shaped rods inserted under local anesthesia for elderly high-risk patients with cervical spondylotic myelopathy. SUMMARY OF BACKGROUND DATA: A substantial number of patients cannot undergo surgical interventions under general anesthesia because of their general medical complications. Although such patients would become unable to walk, which might induce a worsening of their general condition, conservative treatments had been adopted as the only treatment for these patients. The authors have obtained satisfactory results by means of posterior interspinous fusion under local anesthesia even in the high-risk patients with severe cervical spondylotic myelopathy. The aims of this surgical technique were to adjust cervical alignment and to stabilize the motion segment(s) without decompression. PATIENTS AND METHODS: Between May 1989 and August 1998, 12 elderly patients (3 men and 9 women) with cervical spondylotic myelopathy were treated with posterior interspinous fusion using wave-shaped rods inserted under local anesthesia. The average age at the surgery was 76.9 years. The average follow-up period was 5 years 6 months. All patients were unable to walk without any assistance because of their advanced myelopathy. It was felt that all of them would be unable to accept general anesthesia because of their generally poor medical conditions. Preoperative severity of the clinical symptoms and postoperative recovery were evaluated by a scoring system proposed by the Japanese Orthopaedic Association, which had 17 points at full mark. RESULTS: The average duration of the surgical procedure was 122.8 minutes. The average total blood loss was 118.6 g. No instrument failures were denoted. Neither neural deterioration nor major complication was observed relating to the surgery. Radiographic bony union of the grafted bone was achieved in all patients. Progression of myelopathy was arrested in all 12 patients, and clinical symptoms were improved in 10 patients. The mean Japanese Orthopaedic Association scores had increased from 5.0 to 10.2 points. CONCLUSIONS: Twelve high-risk patients with cervical spondylotic myelopathy were treated with posterior interspinous fusion using wave-shaped rods inserted under local anesthesia. This method was evaluated as an effective surgical salvage without any mortal complications even in the elderly high-risk patients.

Aged↗

PubMed2001

Electronic and steric control in regioselective addition reactions of organolithium reagents with enaldimines.

A reaction mode of imines derived from naphthalene-1-carbaldehyde and acyclic alpha,beta-unsaturated aldehydes with organolitium reagents was dependent on the characteristic nature of a substituent on the imine nitrogen atom. An imine having an electron-withdrawing aryl group on the nitrogen atom behaves as a 1,2-directing imine toward organolithium reagents. In contrast, an imine bearing an alkyl or a bulky aryl group favors 1,4-addition of organolithium reagents. Electronic and steric tuning of a substituent on the imine nitrogen atom for a reaction mode was rationalized on the basis of molecular orbital calculations.

Journal Article↗

PubMed2001

Potent and selective ET-A antagonists. 2. Discovery and evaluation of potent and water soluble N-(6-(2-(aryloxy)ethoxy)-4-pyrimidinyl)sulfonamide derivatives.

In the preceding article,(1) we outlined the discovery and structure-activity relationship of a potent and selective ET(A) receptor antagonist 1 and its related compounds. Metabolites of 1 having potent selective ET(A) receptor antagonist activity were identified. This study suggested the metabolic pathways of 1 were considerably affected by species. Consequently, structural modification of 1 intended to improve the complexity of the metabolic pathway, and water solubility was performed. The subsequent introduction of a hydroxyl group into the tert-butyl moiety of 1 led to the discovery of our new clinical candidate, 6b, which showed a higher water solubility, a uniform metabolic pathway among species, and very high affinity and selectivity for the human ET(A) receptor (K(i) for ET(A) receptor: 0.015 +/- 0.004 nM; for ET(B) receptor: 41 +/- 21 nM).

Animals↗

PubMed2001

Potent and selective ET-A antagonists. 1. Syntheses and structure-activity relationships of N-(6-(2-(aryloxy)ethoxy)-4-pyrimidinyl)sulfonamide derivatives.

Modifications to the ET(A/B) mixed type compounds 1 (Ro. 46-2005) and 2 (bosentan) were performed. Introduction of a pyrimidine group into 1 resulted in a dramatic increase in affinity for the ET(A) receptor, and the subsequent optimization of substituents on the pyrimidine ring led us to the discovery of N-(6-(2-((5-bromo-2-pyrimidinyl)oxy)ethoxy)-5-(4-methylphenyl)-4-pyrimidinyl)-4-tert-butylbenzenesulfonamide (7k), which showed an extremely high affinity for the human cloned ET(A) receptor (K(i) = 0.0042 +/- 0.0038 nM) and an ET(A/B) receptor selectivity up to 29 000 (K(i) = 130 +/- 50 nM for the human cloned ET(B) receptor). The compound was designed on the hypothesis that the hydrogen atom of the hydroxyl group in 1 and 2 played a role not as a proton donor but as an acceptor in the possible hydrogen bonding with Tyr129. Since the incorporation of a pyrimidinyl group into the hydroxyethoxy side chain of the nonselective antagonist (1) dramatically enhanced both the ET(A) receptor affinity and selectivity, and since similar results were obtained from the benzene analogues, we put forward the hypothesis that a "pyrimidine binding pocket" might exist in the ET(A) receptor.

Animals↗

PubMed2001

Highly efficient oligosaccharide synthesis on water-soluble polymeric primers by recombinant glycosyltransferases immobilised on solid supports.

Recombinant beta-1,4-galactosyltranferase (beta 1,4-GalT) and alpha-2,6-sialytransferase (alpha 2,6-SiaT) immobilised covalently with activated Sepharose beads were employed for the practical synthesis of a trisaccharide derivative, Neu-5Ac alpha(2-->6)Gal beta(1-->4)GlcNAc beta-O-(CH2)6-NH2, on a water-soluble primer having GlcNAc residues through a alpha-chymotrypsin-sensitive linker.

Chymotrypsin↗