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Biomedical subjects

K Kato

Publications and source records attributed to K Kato.

At least 217 records · Page 12Linked to original sources
PubMed2001

Bisoprolol improves survival in rats with heart failure.

The cardioprotective effects of bisoprolol were studied in a rat model of severe heart failure induced by autoimmune myocarditis. Twenty-eight days after immunization, Lewis rats were divided into four groups: 0.1 mg/kg/day bisoprolol (Group 0.1), 1.0 mg/kg/day bisoprolol (Group 1) and 10 mg/kg/day bisoprolol (Group 10), and vehicle (0.5% methylcellulose; Group V) (all groups, n = 13). After oral administration for 1 month, heart weight, mean blood pressure, heart rate, central venous pressure, peak left ventricular pressure, left ventricular end-diastolic pressure, +/- dP/dt, and area of fibrosis were measured. Although bisoprolol reduced heart rate (399+/-11/min in Group V, 382+/-10/min in Group 0.1, 348+/-8/min in Group 1 and 302+/-9/min in Group 10) and increased survival (62% in Group V, 69% in Group 0.1, and 100% in Group 1 and Group 10) in a dose-dependent manner, this drug did not change heart weight, the area of myocardial fibrosis or hemodynamic parameters. These observations suggested that bisoprolol may improve survival independently of its effect on left ventricular function by reducing sudden death in patients with severe heart failure.

Adrenergic beta-Antagonists↗
PubMed2001

Congenital dyserythropoietic anemia type 1 with fetal onset of severe anemia.

We report a patient with congenital dyserythropoietic anemia type 1 with characteristic anomalies and two novel clinicopathologic presentations: intrauterine onset of severe anemia resulting in cardiac failure and relatively mild dyserythropoietic features on bone marrow aspiration in contrast to severity of anemia. After repeated transfusions and a trial of erythropoietin administration, the patient died from respiratory infection at age 7 months. Autopsy revealed characteristic dyserythropoietic features of the bone marrow by light microscopy and electron microscopy, which confirmed a diagnosis of congenital dyserythropoietic anemia type 1.

Anemia, Dyserythropoietic, Congenital↗
PubMed2001

Mitotic checkpoint protein hsMAD2 as a marker predicting liver metastasis of human gastric cancers.

hsMAD2, the human homologue of mitotic arrest deficient 2 (MAD2), is a key component of the mitotic checkpoint system. Recently, mutations and decreased expression of mitotic checkpoint genes including hsMAD2 have been reported in cancer cell lines with defective mitotic checkpoint. However, the genetic alterations in the genomic hsMAD2 gene have not been determined in gastric cancers. Moreover, the biological implications of the overexpressed hsMAD2 in primary cancers are unknown. In this study, we analyzed 32 primary gastric cancers with polymerase chain reaction (PCR) amplification of all exons, including flanking intronic sequences, of the genomic hsMAD2 gene followed by direct DNA sequencing. We also measured the hsMAD2 protein levels in cancer and normal tissues by semi-quantitative immunoblotting. No mutations were found in the coding sequences, although three single nucleotide polymorphisms (SNPs) were identified in the noncoding sequences in 13 of 32 patients. These SNPs were not associated with either hsMAD2 expression or disease progression. The semi-quantitative western blot analysis showed hsMAD2 was significantly overexpressed in gastric cancer tissues compared with corresponding normal tissues (P < 0.001). The calculated ratio of the hsMAD2 protein in cancer tissue (C) to that in corresponding normal tissue (N) (C / N ratio) was significantly higher in patients with well differentiated adenocarcinoma (P = 0.0274) or with synchronous liver metastasis (P = 0.0025). A C / N ratio greater than 3 was observed more frequently in patients with synchronous liver metastasis. Therefore, C / N ratio > 3 may be clinically important as a predictive indicator for metachronous liver metastasis of gastric cancers.

Adenocarcinoma↗
PubMed2001

Virological properties and nucleotide sequences of Cas-E-type endogenous ecotropic murine leukemia viruses in South Asian wild mice, Mus musculus castaneus.

Two types of endogenous ecotropic murine leukemia viruses (MuLVs), termed AKV- and Cas-E-type MuLVs, differ in nucleotide sequence and distribution in wild mouse subspecies. In contrast to AKV-type MuLV, Cas-E-type MuLV is not carried by common laboratory mice. Wild mice of Mus musculus (M. m.) castaneus carry multiple copies of Cas-E-type endogenous MuLV, including the Fv-4(r) gene that is a truncated form of integrated MuLV and functions as a host's resistance gene against ecotropic MuLV infection. Our genetic cross experiments showed that only the Fv-4(r) gene was associated with resistance to ecotropic F-MuLV infection. Because the spontaneous expression of infectious virus was not detected in M. m. castaneus, we generated mice that did not carry the Fv-4(r) gene but did carry a single or a few endogenous MuLV loci. In mice not carrying the Fv-4(r) gene, infectious MuLVs were isolated in association with three of six Cas-E-type endogenous MuLV loci. The isolated viruses showed a weak syncytium-forming activity for XC cells, an interfering property of ecotropic MuLV, and a slight antigenic variation. Two genomic DNAs containing endogenous Cas-E-type MuLV were cloned and partially sequenced. All of the Cas-E-type endogenous MuLVs were closely related, hybrid-type viruses with an ecotropic env gene and a xenotropic long terminal repeat. Duplications and a deletion were found in a restricted region of the hypervariable proline-rich region of Env glycoprotein.

Amino Acid Sequence↗
PubMed2001

Identification of major phosphorylation sites of Epstein-Barr virus nuclear antigen leader protein (EBNA-LP): ability of EBNA-LP to induce latent membrane protein 1 cooperatively with EBNA-2 is regulated by phosphorylation.

Epstein-Barr virus (EBV) nuclear antigen leader protein (EBNA-LP) is a phosphoprotein suggested to play important roles in EBV-induced immortalization of B cells. One of the potential functions of EBNA-LP is a cooperative induction with EBNA-2 of viral and cellular gene expression, including that of the genes for viral latent membrane protein 1 (LMP-1) and cellular cyclin D2. We report here that the phosphorylation of EBNA-LP by cellular kinase(s) is critical to its ability to cooperate with EBNA-2 in up-regulating the expression of LMP-1 in a B-lymphoma cell line. Our conclusion is based on the following observations. (i) Mass-spectrometric analysis of purified EBNA-LP and mutational analyses of EBNA-LP revealed that the serine residue at position 35 in the W2 repeat domain is the major phosphorylation site of EBNA-LP in vivo. (ii) Substitutions of this site in each W2 repeat domain with alanine markedly reduced the ability of the protein to induce LMP-1 expression in combination with EBNA-2 in Akata cells. (iii) Replacement at the major phosphorylation sites with glutamic acids restored the wild-type phenotype. It is well established that this substitution mimics constitutive phosphorylation. These results indicated that the coactivator function of EBNA-LP is regulated by phosphorylation.

Alanine↗
PubMed2001

Helicobacter pylori infection prevents erosive reflux oesophagitis by decreasing gastric acid secretion.

BACKGROUND: Helicobacter pylori infection is less prevalent and atrophic gastritis is less extensive in patients with reflux oesophagitis than those without it, but few studies have examined this relationship directly. AIMS: We investigated the relationship between H pylori infection, acid secretion, and reflux oesophagitis in Japanese subjects. SUBJECTS: A total of 105 patients with erosive reflux oesophagitis were compared with 105 sex and age matched patients without reflux oesophagitis. METHODS: The diagnosis of H pylori infection was made by histological examination of gastric mucosal biopsy specimens, rapid urease test, and detection of serum IgG antibodies. Acid secretion was assessed by the endoscopic gastrin test. RESULTS: H pylori infection was present in 36 patients with erosive reflux oesophagitis (34.3%) and in 80 control subjects (76.2%) (odds ratio 0.163, 95% confidence interval 0.09-0.29). Overall acid secretion was significantly greater in patients with reflux oesophagitis. Among H pylori positive patients, acid secretion was greater in patients with reflux oesophagitis than those without oesophagitis. CONCLUSION: In Japan, erosive reflux oesophagitis occurs most often in the absence of H pylori infection and gastric hyposecretion. Even in the presence of H pylori infection, reflux oesophagitis is more likely to develop in patients without gastric hyposecretion. H pylori infection may inhibit reflux oesophagitis by inducing hypoacidity.

Adolescent↗
PubMed2001

Inhibition by adenylyl cyclase-cAMP system of ET-1-induced HSP27 in osteoblasts.

We have previously reported that endothelin-1 (ET-1) stimulates heat shock protein (HSP) 27 induction in osteoblast-like MC3T3-E1 cells and that p38 mitogen-activated protein (MAP) kinase acts at a point downstream from protein kinase C (PKC) in HSP27 induction. In the present study, we investigated the effect of the adenylyl cyclase-cAMP system on ET-1-stimulated induction of HSP27 in MC3T3-E1 cells. Dibutyryl-cAMP (DBcAMP) dose dependently inhibited the HSP27 accumulation stimulated by ET-1. Forskolin and cholera toxin significantly suppressed the ET-1-stimulated accumulation of HSP27. However, dideoxyforskolin, a forskolin derivative that does not activate cAMP, failed to suppress the ET-1-induced HSP27 accumulation. Forskolin reduced the p38 MAP kinase phosphorylation induced by ET-1 or 12-O-tetradecanoylphorbol-13-acetate (TPA). PGE(1), an extracellular agonist that activates cAMP production, reduced the ET-1-induced HSP27 accumulation. In addition, the phosphorylation of p38 MAP kinase induced by ET-1 or TPA was suppressed by PGE(1). Forskolin, DBcAMP, and PGE(1) suppressed the ET-1-stimulated increase in the mRNA level for HSP27. These results indicate that the adenylyl cyclase-cAMP system has an inhibitory role in ET-1-stimulated HSP27 induction in osteoblasts and that the effect is exerted at the point between PKC and p38 MAP kinase in osteoblasts.

Adenylyl Cyclase Inhibitors↗
PubMed2001

Orexin depolarizes rat hypothalamic paraventricular nucleus neurons.

Orexins, also called hypocretins, are newly discovered hypothalamic peptides that are thought to be involved in various physiological functions. In spite of the fact that orexin receptors, especially orexin receptor 2, are abundant in the hypothalamic paraventricular nucleus (PVN), the effects of orexins on PVN neurons remain unknown. Using a whole cell patch-clamp recording technique, we investigated the effects of orexin-B on PVN neurons of rat brain slices. Bath application of orexin-B (0.01-1.0 microM) depolarized 80.8% of type 1 (n = 26) and 79.2% of type 2 neurons tested (n = 24) in the PVN in a concentration-dependent manner. The effects of orexin-B persisted in the presence of TTX (1 microM), indicating that these depolarizing effects were generated postsynaptically. Addition of Cd(2+) (1 mM) to artificial cerebrospinal fluid containing TTX (1 microM) significantly reduced the depolarizing effect in type 2 neurons. These results suggest that orexin-B has excitatory effects on the PVN neurons mediated via a depolarization of the membrane potential.

Animals↗
PubMed2001

Up-regulation of p27Kip1 by progestins is involved in the growth suppression of the normal and malignant human endometrial glandular cells.

Progestins are known to suppress the growth of normal human endometrial glands and endometrial carcinomas possessing PRs. To elucidate the molecular mechanisms of progestin-induced growth inhibition, the expression and functional involvement of p27Kip1 (p27), a cyclin-dependent-kinase inhibitor, was investigated using cultured normal endometrial glandular cells and endometrial carcinoma cell lines (Ishikawa; PR-positive, KLE; PR-negative). Growth of the normal endometrial glandular cells and Ishikawa cells was suppressed by treatment with progesterone and medroxyprogesterone acetate, respectively, in association with an increase in p27 protein expression. Immunoprecipitation revealed that progestins accelerated the complex formation of p27 and cdk2 in both types of cells. However, treatment with progestins did not show any marked alterations in the mRNA expression of p27 in either normal glandular cells or Ishikawa cells. On the other hand, p27 protein degradation experiments indicated that treatment with progesterone and medroxyprogesterone acetate prolonged the degradation time of the normal endometrial glandular cells and Ishikawa cells, respectively. Forced expression of the p27 protein using a p27 expression plasmid reduced the growth activity of normal endometrial glandular cells. These findings suggest that p27 is functionally involved in progestin-induced growth suppression of normal and malignant endometrial epithelial cells and that up-regulation of the p27 protein by progestins possibly occurs via posttranslational mechanisms.

Cell Cycle Proteins↗
PubMed2001

Oral administration of dimethylarsinic acid, a main metabolite of inorganic arsenic, in mice promotes skin tumorigenesis initiated by dimethylbenz(a)anthracene with or without ultraviolet B as a promoter.

Concerning arsenic-induced tumorigenesis, an animal model must be developed for understanding the mechanism of human carcinogenesis by arsenics. To determine whether orally administered dimethylarsinic acid (DMA) promotes and causes the progression of skin tumorigenesis, an animal protocol by topical application of dimethylbenz(a)anthracene (DMBA) with or without UVB, a tumor promoter, in hairless mice was used. The administration of DMA by the oral route promoted not only the formation of papillomas induced by DMBA alone but also the formation of malignant tumors induced by way of the formation of atypical keratoses by treatment with DMBA and UVB. A phenomenon, the progression of keratoses-->atypical keratoses-->squamous cell carcinomas (SCCs), observed in the present study may resemble the development of tumors in arsenic-exposed humans. We also discussed the involvement of a reactive oxygen species (ROS), e.g., the dimethylarsenic peroxy radical [(CH3)2AsOO.], produced during the metabolic processing of DMA, in skin and in multi-organ tumorigenesis.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2001

Application of combined reagent solution to the oxidative refolding of recombinant human interleukin 6.

Human interleukin 6 (hIL-6), which is a cytokine involved in diverse biological activities, consists of a four-helix bundle with two disulfide bonds. For the clinical use of hIL-6 in cancer therapy, designing of commercial-scale production systems of recombinant hIL-6 (rhIL-6) expressed by E. coli has been attempted. Since rhIL-6 has been produced as inclusion bodies in the expression systems reported to date, establishment of a strategy to achieve a high yield of refolding of this recombinant protein is quite desirable. It has been reported that oxidation of rhIL-6 under a completely denaturing condition suppresses aggregation during the refolding process [Ejima et al., Biotechnol. Bioeng., 62, 301-310 (1999)]. In this protocol, however, small but significant amounts of unidentified by-products unavoidably arose, which might be problematic in the therapeutic use of rhIL-6. In the present study, detailed characterization of the individual by-products has been performed on inspection of peptide maps, and the by-products found to originate from improperly formed disulfide bonds, most of which are disulfide-linked dimers. In order to minimize these by-products, combined solutions of urea and LiCl were used for oxidative refolding of rhIL-6. It was demonstrated that combined use of 1-2 M urea and 1-3 M LiCl effectively suppresses the formation of the by-products as well as aggregates. We propose that the use of the combined reagents can be an alternative method for refolding of rhIL-6 for clinical purposes.

Chromatography, High Pressure Liquid↗
PubMed2001

[Structural basis of the interaction between immunoglobulins and Fc receptors provided by NMR spectroscopy].

Fc gamma Receptors (Fc gamma R) are membrane glycoproteins that bind the Fc portion of immunoglobulin G (IgG). The cross linking of Fc gamma R-bound IgG by multivalent antigens allows clustering of the Fc gamma R and initiates a variety of effector mechanisms which play a key role in immune defenses against pathogens. The Fc region is composed of two identical polypeptide chains, which are related to each other by a two-fold axis. Recent elucidation of the crystal structure of human Fc gamma RII provided two distinct views of modes of IgG-Fc gamma R interactions, which is controversial against each other. Nuclear magnetic resonance (NMR) spectroscopy provides a unique and irreplaceable tool to solve these issues. We recently studied the interaction between the Fc fragment of mouse IgG2b and the extracellular domain of mouse Fc gamma RII by this method. We showed that Fc gamma RII binds to a negatively charged area of the CH2 domain, corresponding to the lower hinge region, and that the binding of Fc gamma RII onto one of the two symmetrically related sites on the Fc induces a conformational change in the other site. This conformational change may account for the 1:1 stoichiometry that we and others observed between Fc gamma R and Fc. We therefore propose a model that explains why the interaction between IgG molecules and Fc gamma R does not trigger cellular responses in the absence of cross linking by multivalent antigens and does not lead to spontaneous inflammatory responses that would be deleterious for the organism.

Animals↗
PubMed2001

[Effect of gallic acid derivatives on secretion of Th1 cytokines and Th2 cytokines from anti CD3-stimulated spleen cells].

As reported previously (Kosuge et al., Yakugaku Zasshi, 120, 408 (2000)), methyl gallate, a gallic acid derivative, which has been one of compounds isolated from extracts of Psidium geneus Myrtaceae, selectively suppresses Th2 cytokine secretion. In the present study, to examine more effective compounds than methyl gallate, the effects of various gallic acid derivatives on the secretion of helper T cell subtype specific cytokines from anti CD3-stimulated spleen cells were investigated. Ten micrograms/ml of methyl gallate and ethyl gallate remarkably suppressed the secretion of IL-4 and IL-5, Th2 cytokines, but did not suppress meaningfully the secretion of IFN-gamma, a Th1 cytokine. On the other hand, the other gallic acid derivatives suppressed the secretion of both IL-4 and IFN-gamma. Ten micrograms/ml of methyl gallate suppressed the secretion of IL-2, a Th1 cytokine, but the same concentration of ethyl gallate did not suppress it. In conclusion, it seemed that ethyl gallate was the most selective inhibitor for the secretion of Th2 cytokines among gallic acid derivatives used in this study.

Animals↗
PubMed2001

Short-term physical training improves ventilatory response to exercise after coronary arterial bypass surgery.

The issue of whether exercise training improves exercise hyperpnea in patients after coronary arterial bypass graft (CABG) surgery has not been fully explored. Effects of short-term physical training on ventilatory response and cardiac output during exercise in patients following coronary arterial bypass grafting surgery is studied. Thirty-four patients underwent exercise training for 2 weeks after the second postoperative week (Ex group); 23 stayed sedentary (Sed group). Ventilatory and cardiac output response during the cardiopulmonary exercise test was measured before and after the training period. The minute ventilation-carbon dioxide output (VE-VCO2) slope decreased from 38.9+/-8.1 to 35.1+/-6.7 (p<0.05) in the Ex group, but failed to decrease in the Sed group (39.7+/-11.1 to 41.5+/-11.4). Cardiac output during exercise at 20W and at peak exercise, and peak oxygen pulse (VO2/HR) increased significantly only in the Ex group after training. There was a correlation between improvement of the VE-VCO2 slope and peak cardiac output during the training interval (r=-0.47) in the Ex group. Short-term physical training after CABG improves ventilatory response to exercise and increases cardiac output during exercise. Improvement of cardiac output is correlated with a decreased value of the VE-VCO2 slope.

Aged↗
PubMed2001

Changes in the occurrence of mechanical alternans after long-term beta-blocker therapy in patients with chronic heart failure.

Mechanical alternans has been observed in patients with severe congestive heart failure, and the phenomenon is considered to be a terminal sign. Therapeutic strategies for chronic heart failure have significantly developed, but it is uncertain whether patients with mechanical alternans can be effectively treated or not. Seventeen consecutive patients with dilated cardiomyopathy were enrolled: 11 were treated with beta-blockers on conventional therapeutic regimens and 6 patients were not indicated for or were unable to continue beta-blockade. Mechanical alternans was detected during cardiac catheterization in the patients under physiologic tachycardia (110 beats/min) and stepwise dobutamine loading. In the initial study, mechanical alternans occurred in 70.6% of the patients: 8 of the 11 being treated with beta-blockers and 4 of the 6 without beta-blockade therapy. In the second study, none of the patients taking beta-blockers showed mechanical alternans under the same protocol; the occurrence of mechanical alternans did not change in the patients who were not being treated with beta-blockers. The left ventricular ejection fraction increased in patients whose mechanical alternans could not be induced during the follow up, but decreased in the patients in whom mechanical alternans was repeatedly inducible. It is concluded that mechanical alternans is associated with the failing myocardium and may be potentially correctable.

Adrenergic beta-Antagonists↗
PubMed2001

Disulfide bond formation in refolding of thermophilic fungal protein disulfide isomerase.

Disulfide bond formation in the refolding of thermophilic fungal protein disulfide isomerase (PDI) was investigated. It was revealed that (i) a disulfide bond buried inside the molecule is preferentially formed and contributes to the thermal stability and the isomerizing power of PDI, and (ii) formation of disulfide bonds in active sites located on the molecular surface causes deformation of the optimum conformation resulting in a decrease in the thermal stability.

Journal Article↗
PubMed2001

Protein kinase inhibitors can suppress stress-induced dissociation of Hsp27.

We previously showed that the aggregated form of Hsp27 in cultured cells becomes dissociated as a result of phosphorylation with various types of stress. In order to clarify the signal transduction cascade involved, the effects of various inhibitors of protein kinases and dithiothreitol on the dissociation of Hsp27 were here examined by means of an immunoassay after fractionation of cell extracts by sucrose density gradient centrifugation. The dissociation of Hsp27 induced by exposure of U251 MG human glioma cells to metals (NaAsO2 and CdCl2), hypertonic stress (sorbitol and NaCI), or anisomycin, an activator of p38 mitogen-activated protein (MAP) kinase, was completely suppressed by the presence of SB 203580 or PD 169316, inhibitors of p38 MAP kinase, but not by PD 98059 and Uo 126, inhibitors of MAP kinase kinase (MEK), nor by staurosporine, Go 6983, and bisindolylmaleimide I, inhibitors of protein kinase C. Phorbol ester (PMA)-induced dissociation of Hsp27 was completely suppressed by staurosporine, Go 6983, or bisindolylmaleimide I and partially suppressed by SB 203580, or PD 169316 but not by PD 98059 or Uo 126, indicating mediation by 2 cascades. The presence of 1 mM dithiothreitol in the culture medium during exposure to chemicals suppressed the dissociation of Hsp27 induced by arsenite and CdCl2 but not by other chemicals. These results suggest that the phosphorylation of Hsp27 is catalyzed by 2 protein kinases, p38 MAP kinase-activated protein (MAPKAP) kinase-2/3 and protein kinase C. In addition, metal-induced signals are sensitive to reducing power.

Anisomycin↗