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Biomedical subjects

H Sakurai

Publications and source records attributed to H Sakurai.

At least 109 records · Page 6Linked to original sources

[A case of cardiac myxoma with multiple brain hemorrhage].

A case of cardiac myxoma with multiple brain hemorrhage is reported. A 57-year-old male had complained of lower abdominal pain, diarrhea and fever for 3 days. On admission, he was in a condition of disseminated intravascular coagulation and sepsis. An abdominal CT scan showed infarction in the right kidney and spleen and an echocardiogram also showed myxoma in the left atrium. Although he presented no neurological symptoms, the brain CT showed multiple brain hemorrhage in the bilateral brain hemispheres. Total resection of the tumor was carried out for the improvement of the patient's general condition. Vimentin, S-100 protein and neuron specific enolase was positive in immunological staining and the pathological diagnosis was myxoma. Postoperative recovery of consciousness was poor and left hemiparesis developed. CT showed the increase of hematoma but angiography showed no cerebral aneurysm. The symptoms improved with conservative therapy. However the enhanced lesion remained in the right parietal lobe and an operation was performed 5 months later. The myxoma cell could not be found in the pathological examination, so tumor embolism, cerebral infarction, hemorrhagic infarction due to DIC, hematoma enlargement caused by heparinization during operation were suspected to have occurred in this order without tumor growth.

Brain↗

[Reoperation for late postoperative right ventricular outflow tract obstruction].

Between February 1993 and July 2000, 18 patients with a mean age of 7.9 years underwent re-operation for critical stenosis of the right ventricular outflow tract. Their diagnoses of these patients included tetralogy of Fallot (n = 7), transposition of the great arteries (n = 6), truncus arteriosus communis (n = 3), and double outlet right ventricle with pulmonary stenosis (n = 2). The first operations were extracardiac conduit operations (n = 9), arterial switch operations (n = 6) and patch reconstruction of the right ventricular outflow tract (n = 3). At re-operation, the right ventricular outflow tract obstruction was released completely and reconstructed using a monocusp ventricular outflow patch (n = 14), valved pericardial roll (n = 2), or bovine pericardial patch sparing the native pulmonary valve annulus (n = 2). There were no early deaths, although one patient died of arrhythmia 2.6 years after re-operation. The pressure gradient across the right ventricular outflow tract, right ventricular systolic pressure, and right ventricle to systemic systolic pressure ratio were satisfactorily relieved (84.3 +/- 19.0 vs. 16.7 +/- 19.7 mmHg, 109.2 +/- 20.5 vs. 48.7 +/- 16.7 mmHg, 0.92 +/- 0.25 vs. 0.43 +/- 0.16; p < 0.001, p < 0.001, p < 0.001, respectively). The right ventricular end-diastolic volume index and right ventricular ejection fraction were also improved (166.3 +/- 85.2 vs. 105.6 +/- 28.8% of normal, 38.3 +/- 12.6 vs. 50.9 +/- 8.8%; p < 0.05, p < 0.005, respectively). Re-operation should be done before the development of marked right ventricular dysfunction, while it can still be performed at a low risk with satisfactory results.

Child↗

Alternative splicing and gene structure of the transforming growth factor beta-activated kinase 1.

We have identified a fourth splice variant of the TGF beta-activated kinase (TAK1), called TAK1-d, and identified an error in the previously published TAK1-c sequence. Our data shows that the c and d variants encode proteins whose carboxyl ends differ markedly from those of variants a and b. Analysis of the human TAK1 gene sequence, located at 6q16.1-q16.3, shows that the coding sequence is organised in 17 exons. The four splice variants result from alternative splicing of exons 12 and 16, the reading frame of exon 17 being determined by the presence or absence of exon 16. Study of the relative levels of expression of the four splice variants showed significant variations between tissues. Our evidence suggests that the alternative splicing of the TAK1 mRNA may have important functional implications.

Alternative Splicing↗

Functional connections between mediator components and general transcription factors of Saccharomyces cerevisiae.

The yeast Gal11 protein is an important component of the Mediator complex in RNA polymerase II-directed transcription. Gal11 and the general transcription factor (TF) IIE are involved in regulation of the protein kinase activity of TFIIH that phosphorylates the carboxyl-terminal domain of RNA polymerase II. We have previously shown that Gal11 binds the small and large subunits of TFIIE at two Gal11 domains, A and B, respectively, which are important for normal function of Gal11 in vivo. Here we demonstrate that Gal11 binds directly to TFIIH through domain A in vitro. A null mutation in GAL11 caused lethality of cells when combined with temperature-sensitive mutations in the genes encoding TFIIE or the carboxyl-terminal domain kinase, indicating the presence of genetic interactions between Gal11 and these proteins. Mutational depletion of Gal11 or TFIIE caused inefficient opening of the transcription initiation region, but had no significant effect on TATA-binding protein occupancy of the TATA sequence in vivo. These results suggest that the functions of Gal11 and TFIIE are necessary after recruitment of TATA-binding protein to the TATA box presumably at the step of stable preinitiation complex formation and/or promoter melting. We illustrate genetic interactions between Gal11 and other Mediator components such as Med2 and Pgd1/Hrs1/Med3.

Base Sequence↗

Effect of duration of infusion of stress-like concentrations of cortisol on follicular development and the preovulatory surge of LH in sheep.

Stress-like levels of cortisol suppress follicular growth and development and block or delay the preovulatory surge of LH when cortisol is continuously administered during the late luteal and early follicular phases of the ovine oestrous cycle. We postulated that cortisol infusion of shorter duration would have a similar effect. To test this hypothesis the oestrous cycles of mature ewes were synchronized using progestin-treated vaginal pessaries. Ewes were randomly assigned to one of four treatment groups. Animals received cortisol (0.1mg/kg/h; n=8) or vehicle alone (n=8) beginning 5 days before, and continuing for 5 days after, pessary removal (PR). Additional groups received cortisol only during the 5 days period before (n=7), or the 5 days period after (n=8), PR. Continuous delivery of cortisol established stable serum concentrations of cortisol of 72.0+/-2.5ng/ml within 6h of initiation of infusion. Serum concentrations of oestradiol increased progressively during the period after PR in control animals receiving vehicle alone and the preovulatory surge of LH was evident in all control animals (eight of eight) 55.5+/-5.0h after PR. In contrast, follicular development and the preovulatory surge of LH were evident during the period of cortisol infusion in only one of eight animals receiving stress-like levels of cortisol over the entire 10-day infusion period. Similarly, neither follicular development nor surge-like secretion of LH were evident during the infusion period in animals (zero of eight) receiving cortisol during the 5-day period after PR. This cortisol-dependent suppression of ovarian activity in sheep receiving stress-like levels of cortisol during the 5 days after PR was temporary and follicular development, the ovulatory surge of LH, and subsequent luteal function were evident in six of eight ewes after cessation of cortisol delivery. Similarly, follicular development and the preovulatory surge of LH were noted within 5 days after PR in four of seven ewes receiving cortisol only during the 5-day period prior to PR. Collectively, these data indicate that stress-like levels of cortisol reduce fertility of sheep by suppressing follicular development and the preovulatory surge of LH. Additionally, cortisol delivery during the follicular phase has a more profound suppressive effect on follicular development than cortisol administration during the luteal phase.

Animals↗

A role for Timeless in epithelial morphogenesis during kidney development.

Central to the process of epithelial organogenesis is branching morphogenesis into tubules and ducts. In the kidney, this can be modeled by a very simple system consisting of isolated ureteric bud (UB) cells, which undergo branching morphogenesis in response to soluble factors present in the conditioned medium of a metanephric mesenchyme cell line. By employing a targeted screen to identify transcription factors involved early in the morphogenetic program leading to UB branching, we identified the mammalian ortholog of Timeless (mTim) as a potential immediate early gene (IEG) important in this process. In the embryo, mTim was found to be expressed in patterns very suggestive of a role in epithelial organogenesis with high levels of expression in the developing lung, liver, and kidney, as well as neuroepithelium. In the embryonic kidney, the expression of mTim was maximal in regions of active UB branching, and a shift from the large isoform of mTim to a smaller isoform occurred as the kidney developed. Selective down-regulation of mTim resulted in profound inhibition of embryonic kidney growth and UB morphogenesis in organ culture. A direct effect on the branching UB was supported by the observation that down-regulation of mTim in the isolated UB (cultured in the absence of mesenchyme) resulted in marked inhibition of morphogenesis, suggesting a key role for Tim in the epithelial cell morphogenetic pathway leading to the formation of branching tubules.

Animals↗

Molecular cloning and characterization of a copper chaperone for copper/zinc superoxide dismutase from the rat.

Copper chaperone is an essential cytosolic factor that maintains copper homeostasis in living cells. Cytosolic metallochaperones have been recently identified in plant, yeast, rodents, and human cells. During our investigation, we found a new member of the copper chaperone family for copper/zinc superoxide dismutase, which was cloned from rats. The new copper chaperone was named rCCS (rat Copper Chaperone for Superoxide dismutase). The cDNA of rCCS was found to have a length of 1094 bp, and the protein analyzed from the cDNA was deduced to contain 274 amino acids. The amino acid sequence of rCCS consists of three domains: A metal binding domain, which has a MXCXXC motif in domain I, a homolog of the Cu/Zn SOD in domain II, and a CXC motif in domain III. The binding of rCCS to Cu/Zn SOD was analyzed by GST column binding assay, and the domain II of rCCS was found to be essential for binding to Cu/Zn SOD, which in turn activates Cu/Zn SOD.

Amino Acid Sequence↗

Role of hyaluronan and CD44 in in vitro branching morphogenesis of ureteric bud cells.

Mutual interaction between the metanephric mesenchyme (MM) and the ureteric bud (UB) in the developing kidney leads to branching morphogenesis and the formation of the ureteric tree. A UB-derived cell line, stimulated by conditioned medium derived from an embryonic MM cell line (or, similarly, by 10% fetal calf serum), forms branching tubules under three-dimensional culture conditions (H. Sakurai et al., 1997, Proc. Natl. Acad. Sci. USA 94, 6279-6284). The formation of branching tubules in this simple in vitro system for early nephrogenesis is highly sensitive to the matrix environment, a key component of which is the glycosaminoglycan hyaluronan (HA). Consistent with this, we found that HA in the extracellular environment markedly stimulated the formation of cellular processes and multicellular cords (early steps in branching morphogenesis) and also acted as a cell survival factor. Inhibition of HA binding to the cells by addition of blocking antibodies to CD44, the principal cell surface receptor for HA, or degradation of HA by the addition of Streptomyces hyaluronidase resulted in decreased cell survival and diminished morphogenesis, indicating that the HA-CD44 axis plays a central role in in vitro branching morphogenesis. Analysis of the expression of a large number of genes displayed on a cDNA array revealed that significant changes in gene expression in cells undergoing morphogenesis in the presence of HA were limited to a small subset of genes regulating apoptosis, proliferation, and morphogenesis. This included upregulation by HA of its receptor, CD44, which was found to largely localize to the tips of branching cellular processes. In the embryonic kidney, HA was found near the developing ureteric tree and CD44 was expressed basolaterally in UB-derived structures. In addition, both UB and MM appear to express HA synthase, suggesting their ability to secrete HA. We propose that HA promotes branching morphogenesis by creating a positive feedback loop that results in (1) enhanced interaction of HA-CD44 at branching tips (possibly leading to localization of HA binding morphoregulatory factors at the tips) and (2) an activated transcriptional program favoring cell survival/proliferation and migration/morphogenesis of cells through matrix by the expression of key morphoregulatory molecules. Furthermore, since HA, hyaluronidase, and CD44 have been functionally implicated in branching morphogenesis in this model, and since HA, CD44, and HA synthase are all expressed in an appropriate spatiotemporal fashion in the developing kidney, we propose that these molecules may, together, constitute a morphoregulatory pathway that plays a key role in sequential cycles of branching morphogenesis in the UB.

Animals↗

The effect of 6-methylthiohexyl isothiocyanate isolated from Wasabia japonica (wasabi) on 4-(methylnitrosamino)-1-(3-pyridyl)-1-buatnone-induced lung tumorigenesis in mice.

The present study was undertaken to estimate the effect of 6-methylthiohexyl isothiocyanate (6MHITC) isolated from Wasabia japonica (wasabi) pretreatment on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone(NNK)-induced lung tumorigenesis in mice. Pretreatment with 6MHITC for 4 consecutive days at a daily dose of 5 micromol significantly inhibited NNK-induced O(6)-methylguanine formation in lungs at 4 h after the injection. In conjugation with this inhibitory effect, 6MHITC suppressed the increase in proliferating nuclear cell antigen level as well as ornithine decarboxylase activity at a promotion stage of NNK-induced lung tumorigenesis. Finally, this treatment of 6MHITC suppressed the NNK-induced lung tumorigenesis in mice. These results suggest that 6MHITC inhibits the development of lung tumors in mice treated with NNK, due to the suppression of initiation stage.

Animals↗

Phosphorylation-dependent activation of TAK1 mitogen-activated protein kinase kinase kinase by TAB1.

TAK1 is a mitogen-activated protein kinase kinase kinase (MAP3K) that is involved in the c-Jun N-terminal kinase/p38 MAPKs and NF-kappaB signaling pathways. Here, we characterized the molecular mechanisms of TAK1 activation by its specific activator TAB1. Autophosphorylation of two threonine residues in the activation loop of TAK1 was necessary for TAK1 activation. Association with TAK1 and induction of TAK1 autophosphorylation required the C-terminal 24 amino acids of TAB1, but full TAK1 activation required additional C-terminal Ser/Thr rich sequences. These results demonstrated that the association between the kinase domain of TAK1 and the C-terminal TAB1 triggered the phosphorylation-dependent TAK1 activation mechanism.

Adaptor Proteins, Signal Transducing↗

Effect of stress-like concentrations of cortisol on the feedback potency of oestradiol in orchidectomized sheep.

The effect of stress-like concentrations of cortisol on oestradiol-induced change in LH secretion and GnRH receptor expression was evaluated in orchidectomized sheep (wethers). Twenty-four wethers were assigned at random to one of the four treatment groups in a 2x2 factorial design (n=6 wethers/group). Wethers received cortisol (90 microg/kg/h; groups 2 and 4) or a comparable volume of cortisol delivery vehicle (groups 1 and 3) by continuous infusion for 48 h. During the final 24 h of infusion, wethers received oestradiol (6 ng/kg/h; groups 3 and 4) or oestradiol delivery vehicle (groups 1 and 2). The pattern of LH secretion was assessed during a 3-h period of intensive blood collection beginning 21 h after initiation of oestradiol infusion. Although neither cortisol nor oestradiol alone affected (P>0.05) mean serum concentration of LH or LH pulse frequency, serum LH and the frequency of secretory episodes of LH were significantly reduced (P<0.05) in wethers receiving cortisol and oestradiol in combination. Anterior pituitary tissue was collected at the end of the infusion period. Oestradiol increased (P<0.05) tissue concentrations of GnRH receptor and GnRH receptor mRNA. Although cortisol alone did not affect (P>0.05) basal concentrations of receptor or receptor mRNA, the magnitude of oestradiol-induced increase in GnRH receptor and GnRH receptor mRNA was significantly reduced in wethers receiving cortisol and oestradiol concurrently. Conversely, steady-state concentrations of mRNA encoding the LHbeta and FSHbeta subunits were increased (P<0.05) in wethers receiving cortisol. These observations demonstrate that stress-like concentrations of cortisol act in concert with oestradiol to suppress LH secretion. In addition, cortisol blocks oestradiol-dependent increase in pituitary tissue concentrations of GnRH receptor and GnRH receptor mRNA.

Animals↗

Speciation of insulin-mimetic VO(IV)-containing drugs in blood serum.

The biospeciations of three potential insulin-mimetic VO(IV) compounds, VO(maltolate)2, VO(picolinate)2 and VO(6-Me-picolinate)2, in blood serum were assessed via modelling calculations, using the stability constants reported in the literature for the binary insulin-mimetic complexes and their ternary complexes formed with the most important low molecular mass binders in the serum: oxalic acid, lactic acid, citric acid and phosphate. The binding capabilities of two high molecular mass serum proteins, albumin and transferrin, were also taken into account.

Citric Acid↗

An orally active antidiabetic vanadyl complex, bis(1-oxy-2-pyridinethiolato)oxovanadium(IV), with VO(S2O2) coordination mode; in vitro and in vivo evaluations in rats.

According to Pearson's HSAB (hard and soft acids and bases) rule, the vanadyl ion is classified as a hard acid. However, vanadyl-cysteine methyl ester and dithiocarbamate complexes with VO(S2N2) and VO(S4) coordination modes, respectively, that contain bonds with a combination of hard acid (VO2+) and soft base (sulfur) have been found to form stable complexes and exhibit insulin-mimetic activities in in vitro and in vivo evaluations. Based on such observations, a purple bis(1-oxy-2-pyridinethiolato)oxovanadium(IV) (VO(OPT)) complex with VO(S2O2) coordination mode was prepared and found to have a strong insulin-mimetic activity in in vitro evaluation, which followed in vivo effectiveness on intraperitoneal injection and oral administration. Then, we examined the real-time ESR analysis of vanadyl species in the blood of live rats given VO(OPT) by use of the blood circulation monitoring-ESR method. The clearance of vanadyl species from the blood in terms of half-life (t(1/2)) was determined as 15 min in VO(OPT)-treated rats, while t(1/2) of VOSO4-treated rats was 5 min, indicating the long-term acting character of VO(OPT). On the basis of the results, VO(OPT) with VO(S2O2) coordination mode is proposed to be a potent orally active insulin-mimetic complex in treating insulin-dependent diabetes mellitus in experimental animals.

Adipocytes↗

Shape coexistence and the N = 28 shell closure far from stability

The masses of 31 neutron-rich nuclei in the range A = 29-47 have been measured. The precision of 19 masses has been significantly improved and 12 masses were measured for the first time. The neutron-rich Cl, S, and P isotopes are seen to exhibit a change in shell structure around N = 28. Comparison with shell model and relativistic mean field calculations demonstrate that the observed effects arise from deformed prolate ground state configurations associated with shape coexistence. Evidence for shape coexistence is provided by the observation of an isomer in 43S.

Journal Article↗

Caffeine enhanced radiosensitivity of rat tumor cells with a mutant-type p53 by inducing apoptosis in a p53-independent manner.

The radiosensitizing effects of caffeine on two rat yolk sac tumor cell lines with a different p53 status were investigated. A reduction of radiation-induced G(2) arrest was caused by caffeine at a concentration of 2 mM in both cell lines. The reduction of survival was observed in a combination of radiation and 2 mM caffeine only in a lower radiation dose range, but not in a higher dose range in NMT-1 with a wild type p53. Radiosensitization of caffeine was recognized even in a higher dose range for cells with a mutant-type p53. Apoptosis, which was not prominent after irradiation alone or caffeine treatment alone, was induced by irradiation in combination with caffeine in cells with a mutant-type p53 through a p53-independent pathway.

Animals↗

Cell to cell interaction between mesangial cells and macrophages induces the expression of monocyte chemoattractant protein-1 through nuclear factor-kappaB activation.

The interaction between mesangial cells (MCs) and monocytes/macrophages (Mo/Mo) is an important pathogenic feature of glomerulonephritis. However, its mechanism is not fully elucidated. Studies to date have focused on the interactions through mediators. In the present study, to obtain insight into the mechanism of the interaction between MCs and Mo/Mo, we examined the significance of the cell to cell interaction of these cells in the context of monocyte chemoattractant protein-1 (MCP-1) expression using cell contact cultures or co-culture without contact. Our results revealed that the cellular adhesion of cultured macrophages to MCs induced the expression of MCP-1, which was mainly observed in the MCs. In addition, the induction of MCP-1 was, at least in part, mediated by nuclear factor kappa-B activation which occurs preferentially in the MCs. Because MCP-1 is suggested to play an important role in glomerulonephritis, this novel cell to cell interaction between the MCs and Mo/Mo could be important in glomerulonephritis.

Animals↗