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Biomedical subjects

K Nakao

Publications and source records attributed to K Nakao.

At least 55 records · Page 3Linked to original sources
PubMed2001

Phospholipase Cbeta4 and protein kinase Calpha and/or protein kinase CbetaI are involved in the induction of long term depression in cerebellar Purkinje cells.

Activation of the type-1 metabotropic glutamate receptor (mGluR1) signaling pathway in the cerebellum involves activation of phospholipase C (PLC) and protein kinase C (PKC) for the induction of cerebellar long term depression (LTD). The PLC and PKC isoforms that are involved in LTD remain unclear, however. One previous study found no change in LTD in PKCgamma-deficient mice, thus, in the present study, we examined cerebellar LTD in PLCbeta4-deficient mice. Immunohistochemical and Western blot analyses of cerebellum from wild-type mice revealed that PLCbeta1 was expressed weakly and uniformly, PLCbeta2 was not detected, PLCbeta3 was expressed predominantly in caudal cerebellum (lobes 7-10), and PLCbeta4 was expressed uniformly throughout. In PLCbeta4-deficient mice, expression of total PLCbeta, the mGluR1-mediated Ca(2+) response, and LTD induction were greatly reduced in rostral cerebellum (lobes 1-6). Furthermore, we used immunohistochemistry to localize PKCalpha, -betaI, -betaII, and -gamma in mouse cerebellar Purkinje cells during LTD induction. Both PKCalpha and PKCbetaI were found to be translocated to the plasmamembrane under these conditions. Taken together, these results suggest that mGluR1-mediated activation of PLCbeta4 in rostral cerebellar Purkinje cells induced LTD via PKCalpha and/or PKCbetaI.

Animals↗
PubMed2001

Spatial performance correlates with long-term potentiation of the dentate gyrus but not of the CA1 region in rats with fimbria-fornix lesions.

Although hippocampal long-term potentiation (LTP) is generally assumed to be a cellular mechanism of learning and memory, there has not been definitive evidence for this hypothesis. In the present study, therefore, we addressed the possible relationship between spatial learning ability and LTP by using rats with bilateral fimbria-fornix lesions. The animals were tested for spatial performance in spontaneous alternation behaviors with further in vivo investigation of LTP. The behavioral parameters of spatial memory showed a significant correlation with LTP in the dentate gyrus, but we found no evidence for a linkage with LTP in the CA1 region. Thus, LTP in the dentate gyrus may be important for spatial cognitive ability.

Animals↗
PubMed2001

Aldosterone induces angiotensin-converting-enzyme gene expression in cultured neonatal rat cardiocytes.

BACKGROUND: The cardiac renin-angiotensin-aldosterone system is activated in failing hearts in proportion to the severity of the disease. We hypothesized that a positive feedback mechanism might exist within this system and contribute to the progression of the heart failure. Methods and Results-- To test this hypothesis, we examined whether angiotensin II or aldosterone induces the expression of angiotensin-converting-enzyme (ACE) mRNA in cultured neonatal rat ventricular cardiocytes. Expression of ACE mRNA was detected and quantified using real-time reverse transcription-polymerase chain reaction. Exposure to angiotensin II (10(-5) mol/L) for 24 hours had no significant effect on the expression of ACE mRNA (0.7+/-0.5-fold versus control, P=NS), but similar treatment with aldosterone (10(-5) mol/L) induced a 23.3+/-7.9-fold increase (P<0.01) in ACE mRNA expression. The effect of aldosterone was both time- (maximal effect, 24 hours) and dose-dependent (EC(50), 4x10(-7) mol/L), and it was significantly (P<0.01) inhibited by spironolactone, a specific mineralocorticoid receptor antagonist. CONCLUSIONS: Aldosterone upregulates ACE mRNA expression, which is blocked by spironolactone in neonatal rat cardiocytes. Thus, spironolactone may suppress the progression of heart failure by blocking the effects of aldosterone and angiotensin II.

Aldosterone↗
PubMed2001

Requirement of phospholipase Cdelta4 for the zona pellucida-induced acrosome reaction.

Several phospholipase C (PLC) isoforms have been found in male and female mammalian gametes, and splicing isoforms of PLCdelta4 are predominantly expressed in testis. Here we report that male mice in which the PLCdelta4 gene had been disrupted either produced few small litters or were sterile. In vitro fertilization studies showed that insemination with PLCdelta4-/- sperm resulted in significantly fewer eggs becoming activated and that the calcium transients associated with fertilization were absent or delayed. PLCdelta4-/- sperm were unable to initiate the acrosome reaction, an exocytotic event required for fertilization and induced by interaction with the egg coat, the zona pellucida. These data demonstrate that PLCdelta4 functions in the acrosome reaction that is induced by the zona pellucida during mammalian fertilization.

Acrosome↗
PubMed2001

Stable operation of a 300-m laser interferometer with sufficient sensitivity to detect gravitational-wave events within our galaxy.

TAMA300, an interferometric gravitational-wave detector with 300-m baseline length, has been developed and operated with sufficient sensitivity to detect gravitational-wave events within our galaxy and sufficient stability for observations; the interferometer was operated for over 10 hours stably and continuously. With a strain-equivalent noise level of h approximately 5x10(-21)/sqrt[Hz], a signal-to-noise ratio of 30 is expected for gravitational waves generated by a coalescence of 1.4M-1.4M binary neutron stars at 10 kpc distance. We evaluated the stability of the detector sensitivity with a 2-week data-taking run, collecting 160 hours of data to be analyzed in the search for gravitational waves.

Astronomy↗
PubMed2001

Induction of JAB/SOCS-1/SSI-1 and CIS3/SOCS-3/SSI-3 is involved in gp130 resistance in cardiovascular system in rat treated with cardiotrophin-1 in vivo.

CIS (cytokine-inducible SH2 protein), SOCS (suppressor of cytokine signaling), or SSI (signal transducers and activators of transcription [STAT]-induced STAT inhibitor) proteins are a family of cytokine-inducible negative regulators of cytokine signaling via Janus kinase (JAK)-STAT pathways. Given the evidence that the JAK-STAT pathway plays a critical role in the cardiovascular system, the primary objective of this study was to assess the effects of the CIS family on JAK-STAT signaling in the cardiovascular system in rats treated with cardiotrophin-1 (CT-1), an interleukin-6 family of cytokines. Intravenous injection of 20 microgram/kg body weight of CT-1 induced a transient, marked increase in STAT3 activation in various tissues, including heart and lung, and subsequent upregulation of 2 members of the CIS family, JAK-binding protein (JAB)/SOCS-1/SSI-1 and CIS3/SOCS-3/SSI-3, in the same tissues. It was also observed that CIS3 was directly associated with JAK2 in vivo. Pretreatment with the same dose of CT-1 60 minutes before significantly attenuated the STAT3 activation induced by a second injection of CT-1. We previously reported that intravenous injection of CT-1 results in the nitric oxide (NO)-dependent hypotension accompanied by the induction of inducible NO synthase mRNA. In rats pretreated with CT-1, the induction of inducible NO synthase mRNA or hypotension by subsequent CT-1 injection was not observed. Forced expression of JAB or CIS3, but not other CISs, directly blocked CT-1-induced STAT3 activation in 293 cells. These results suggest that JAB and CIS3 serve as endogenous inhibitors of CT-1-mediated JAK-STAT signaling in the cardiovascular system in vivo.

Animals↗
PubMed2001

Dwarfism and early death in mice lacking C-type natriuretic peptide.

Longitudinal bone growth is determined by endochondral ossification that occurs as chondrocytes in the cartilaginous growth plate undergo proliferation, hypertrophy, cell death, and osteoblastic replacement. The natriuretic peptide family consists of three structurally related endogenous ligands, atrial, brain, and C-type natriuretic peptides (ANP, BNP, and CNP), and is thought to be involved in a variety of homeostatic processes. To investigate the physiological significance of CNP in vivo, we generated mice with targeted disruption of CNP (Nppc(-/-) mice). The Nppc(-/-) mice show severe dwarfism as a result of impaired endochondral ossification. They are all viable perinatally, but less than half can survive during postnatal development. The skeletal phenotypes are histologically similar to those seen in patients with achondroplasia, the most common genetic form of human dwarfism. Targeted expression of CNP in the growth plate chondrocytes can rescue the skeletal defect of Nppc(-/-) mice and allow their prolonged survival. This study demonstrates that CNP acts locally as a positive regulator of endochondral ossification in vivo and suggests its pathophysiological and therapeutic implication in some forms of skeletal dysplasia.

Animals↗
PubMed2001

Immature multipotent hemopoietic progenitors lacking long-term bone marrow-reconstituting activity in the aorta-gonad-mesonephros region of murine day 10 fetuses.

Previous studies indicated that multipotent progenitors exist in early fetuses that do not contain long-term reconstituting (LTR) activity. However, it remained unclear whether these multipotent progenitors are committed to the hemopoietic lineage or are immature mesodermal cells or hemangioblasts. In this study, we have succeeded in enriching the multipotent progenitors that are capable of generating myeloid, T, and B cells in the LFA-1(-) subpopulation of TER-119(-)c-kit(+)CD45(+) cells from the aorta-gonad-mesonephros (AGM) region of day 10 fetuses. We found that these day 10 AGM LFA-1(-) cells do not show the LTR activity, whereas day 11 AGM LFA-1(-) cells do have such an activity. These results strongly suggest that multipotent progenitors lacking LTR activity emerge as CD45(+) hemopoietic progenitor cells in the AGM region on the 10th day of gestation, and such p-Multi mature into hemopoietic stem cells by acquiring LTR activity.

Animals↗
PubMed2001

Genetic changes in colorectal carcinoma tumors with liver metastases analyzed by comparative genomic hybridization and DNA ploidy.

BACKGROUND: Liver metastases are found in 10% of primary colorectal malignancies, and they affects the prognosis of patients with colorectal carcinoma. The authors investigated DNA copy number aberrations by using comparative genomic hybridization (CGH) and DNA ploidy alterations by using flow cytometry (FCM) in patients with primary colorectal carcinoma (primary tumors). To determine whether there are characteristic DNA copy number alterations that contribute to liver metastasis, cytogenetic aberrations were examined by CGH and FCM. METHODS: The authors analyzed 35 primary tumors, including 16 primary tumors with liver metastasis, by using CGH and FCM. RESULTS: Increases in DNA copy numbers were detected in 6q (5 of 16 tumors), 7q (6 of 16 tumors), 8q (7 of 16 tumors), 9p (5 of 16 tumors), 13q (8 of 16 tumors), 20p (9 of 16 tumors), and 20q (15 of 16 tumors) in primary tumors with liver metastases. Decreases in DNA copy numbers were found in 17p (5 of 16 tumors), 18p (6 of 19 tumors), 18q (8 of 16 tumors), and 22q (5 of 16 tumors). In contrast, primary tumors without liver metastasis showed gains in chromosome arms 8q (2 of 19 tumors), 13q (2 of 19 tumors), 20p (6 of 19 tumors), and 20q (5 of 19 tumors); however, they showed no gains in 6q or 7q and showed losses in chromosome arms 17p (2 of 19 tumors), 18p (4 of 19 tumors), 18q (6 of 19 tumors), and 22q (5 of 19 tumors). There was a significant difference in the frequency of DNA copy number gains and losses in 6q (P < 0.05), 7q (P < 0.01), 8q (P < 0.05), 13q (P < 0.05), and 20q (P < 0.01), respectively, between primary tumors with and without liver metastases. The differences in the DNA index were not significant between the two groups of primary tumors. CONCLUSIONS: In liver metastases of primary tumors from patients with colorectal carcinoma, a correlation between DNA copy number aberrations and gains of chromosome arms 6q, 7q, 8q, 13q, and 20q is suggested.

Chromosome Aberrations↗
PubMed2001

cGMP-dependent protein kinase phosphorylates and inactivates RhoA.

Small GTPase Rho and cGMP/cGMP-dependent protein kinase (cGK) pathways exert opposing effects in specific systems such as vascular contraction and growth. However, the direct interaction between these pathways has remained elusive. We demonstrate that cGK phosphorylates RhoA in vitro at Ser188, the same residue phosphorylated by cAMP-dependent protein kinase. In HeLa cells transfected with constitutively active cGK (C-cGK), stress fiber formation induced by lysophosphatidic acid or V14RhoA was blocked. By contrast, C-cGK failed to inhibit stress fiber formation in cells transfected with mutant RhoA with substitution of Ser188 to Ala. C-cGK did not affect actin reorganization induced by Rac1 or Rho-associated kinase, one of the effectors for RhoA. Furthermore, C-cGK expression inhibited the membrane translocation of RhoA. Collectively, our findings suggest that cGK phosphorylates RhoA at Ser188 and inactivates RhoA signaling. The physiological relevance of the direct interaction between RhoA and cGK awaits further investigation.

Actins↗
PubMed2001

Geranylgeranylacetone induces antiviral gene expression in human hepatoma cells.

Geranylgeranylacetone (GGA), an isoprenoid compound, is used clinically as an anti-ulcer drug. Since some isoprenoids including retinoids have anti-tumor and anti-viral activities in a variety of cell types, we investigated whether GGA could induce anti-viral proteins in human hepatoma cells. The HuH-7 and HepG2 cells were treated with GGA, and expression of anti-viral proteins such as 2'5'-oligoadenylate synthetase (2'5'-OAS) and double-stranded RNA-dependent protein kinase (PKR) in these cells was analyzed. GGA stimulated 2'5'-OAS and PKR gene expression at the transcriptional level through the formation of interferon-stimulated gene factor 3 (ISGF3), which regulates both gene transcription. By Western blotting, GGA induced expression of signal transducers and activators of transcription 1, 2 (STAT1, STAT2) and p48 proteins, components of ISGF3, together with the phosphorylation of STAT1. These results suggest that GGA acts as a potent inducer of anti-viral gene expression by stimulating the ISGF3 formation in human hepatoma cells.

2',5'-Oligoadenylate Synthetase↗
PubMed2001

Attractin/mahogany/zitter plays a critical role in myelination of the central nervous system.

The rat zitter (zi) mutation induces hypomyelination and vacuolation in the central nervous system (CNS), which result in early-onset tremor and progressive flaccid paresis. By positional cloning, we found a marked decrease in Attractin (Atrn) mRNA in the brain of the zi/zi rat and identified zi as an 8-bp deletion at a splice donor site of Atrn. Atrn has been known to play multiple roles in regulating physiological processes that are involved in monocyte-T cell interaction, agouti-related hair pigmentation, and control of energy homeostasis. Rat Atrn gene encoded two isoforms, a secreted and a membrane form, as a result of alternative splicing. The zi mutation at the Atrn locus darkened coat color when introduced into agouti rats, as also described in mahogany (mg) mice, carrying the homozygous mutation at the Atrn locus. Transgenic rescue experiments showed that the membrane-type Atrn complemented both neurological alteration and abnormal pigmentation in zi/zi rats, but that the secreted-type Atrn complemented neither mutant phenotype. Furthermore, we discovered that mg mice exhibited hypomyelination and vacuolation in the CNS associated with body tremor. We conclude from these results that the membrane Atrn has a critical role in normal myelination in the CNS and would provide insights into the physiology of myelination as well as the etiology of myelin diseases.

Agouti Signaling Protein↗
PubMed2001

Aldosterone production is activated in failing ventricle in humans.

BACKGROUND: Recent reports have indicated that aldosterone is produced in extra-adrenal tissues in animals. The present study was designed to examine whether aldosterone is produced in human heart. METHODS AND RESULTS: Plasma levels of aldosterone, BNP, and angiotensin-converting enzyme were measured in anterior interventricular vein (AIV), coronary sinus (CS), and aortic root (Ao), respectively, in 20 patients with left ventricular systolic dysfunction (LVSD), 25 patients with LV diastolic dysfunction (LVDD), and 23 control subjects. Aldosterone levels were significantly higher in AIV and CS than Ao in LVSD (98+/-10 versus 72+/-9 pg/mL, P:<0.001, and 97+/-11 versus 72+/-9 pg/mL, P:<0.001, respectively) and LVDD (87+/-10 versus 71+/-9 pg/mL, P:<0.01, and 84+/-10 versus 71+/-9 pg/mL, P:<0.01, respectively) groups, but no differences were observed in levels for these sites in the control group. Levels of ACE activity and BNP also were higher in AIV than Ao in both LV dysfunction groups. The difference in aldosterone levels between AIV and Ao and those in BNP and angiotensin-converting enzyme had a significant positive correlation with LVEDP and a significant negative correlation with LV ejection fraction in the LVSD group. CONCLUSIONS: Production of aldosterone, angiotensin-converting enzyme, and BNP are activated in failing human ventricle in proportion to severity.

Adult↗
PubMed2001

Low sequence variation in the gene encoding the human beta-myosin heavy chain.

Over 40 different mutations in the cardiac myosin heavy chain gene (MYH7) have been associated with familial hypertrophic cardiomyopathy (FHC), but no study has analyzed variation at this locus within the normal human population. Here we determine the extent and distribution of nucleotide variation in the 5808-bp MYH7 coding sequence in 25 normal individuals without FHC. We identified six single-nucleotide polymorphisms, none of which changes the encoded amino acid. At one of these sites, the frequencies of both alleles are equal; at the other five sites, the frequency of the rarer allele varies from 0.02 to 0.08. The nucleotide diversity (pi) calculated from these data is 1.73x10(-4)+/-0.49x10(-4), which is lower than the nucleotide diversity found in most other human autosomal genes. Substitution analysis of homologous genes between human and rodent also indicates that the MYH7 sequence has evolved at a very slow rate. The rate of both synonymous and nonsynonymous substitutions, especially in the portion of the sequence that encodes the alpha-helical myosin rod, is extremely low. The low level of even silent sequence variation in MYH7 in comparisons between human sequences and between human and rodent sequences may be a consequence of strong selective pressure against mutations that cause cardiomyopathy.

Alleles↗
PubMed2001

Merits and demerits of operative procedure to the trachea in patients with differentiated thyroid cancer.

Local radical thyroidectomy, including cervical lymph node dissection and combined circumferential resection of the trachea, has been performed over the past 20 years in 31 patients with differentiated cancer invading the trachea. The 5- and 10-year survival rates for these patients were 77.4% and 66.7%, respectively. In 19 of the 31 (61%) cases the recurrent nerve was resected because of direct cancer invasion. Bilateral recurrent nerve palsy occurred in 12 patients, 3 of whom were managed postoperatively using a T-shaped tube for preservation of the larynx. Hoarseness remained in 21 patients. In two patients with recurrent cancer invasion of the larynx, partial laryngectomy and hemilaryngectomy were performed, and reconstruction was done using ear cartilage without postoperative dyspnea or dysphagia. Parathyroid function is an important factor in regard to the quality of life of patients. In 22 patients at least one of the parathyroids was preserved. Postoperative calcium administration was necessary in 14 patients. Our long-term observations indicate that local radical thyroidectomy with combined resection of the trachea can serve as a useful treatment for advanced differentiated cancer invading the airway.

Adult↗
PubMed2001

Changes in atrial natriuretic peptide and brain natriuretic peptide associated with hypobaric hypoxia-induced pulmonary hypertension in rats.

Experimental pulmonary hypertension induced in a hypobaric hypoxic environment (HHE) is characterized by structural remodeling of the heart and pulmonary arteries. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) both have diuretic, natriuretic, and hypotensive effects, and both are involved in cardiovascular homeostasis as cardiac hormones. To study the effects of HHE on the natriuretic peptide synthesis system, 170 male Wistar rats were housed in a chamber at the equivalent of the 5500-m altitude level for 1-12 weeks. After 1 week of HHE, pulmonary arterial pressure was significantly raised, and the ratio of left ventricle plus septum over right ventricle of the heart showed a significant decrease (compared with those of ground-level control rats). In both ventricular tissues, the expression of ANP messenger (m)RNA and BNP mRNA increased after exposure to HHE. The amounts of ANP and BNP had decreased significantly in right atrial tissue at 12 weeks of HHE (compared with those of the controls), whereas in ventricular tissues at the same time point, both levels had increased significantly. In in situ hybridization and immunohistochemical studies, the staining of the mRNAs for ANP and BNP and of ANP and BNP themselves was more intense in both ventricular tissues after exposure to HHE than before (i.e., in the controls). The results suggest that, in response to HHE, the changes in ventricular synthesis are similar for ANP and BNP. These changes may play a role in modulating pulmonary hypertension in HHE. However, under our conditions, pulmonary hypertension increased progressively throughout the HHE period.

Altitude Sickness↗