Biomedical subjects

T Katagiri

Publications and source records attributed to T Katagiri.

At least 145 records · Page 8Linked to original sources

PubMed1997

Vitamin K2 and its derivatives induce apoptosis in leukemia cells and enhance the effect of all-trans retinoic acid.

Geranylgeraniol, a polyprenylalcohol composing the side chain of vitamin K2 (VK2), was previously reported to be a potent inducer of apoptosis in tumor cell lines (Ohzumi H et al, J Biochem 1995; 117: 11-13). We examined the apoptosis-inducing ability of VK2 (menaquinone 3 (MK3), MK4 and MK5) and its derivatives such as phytonadione (VK1), as well as polyprenylalcohols with side chains of various lengths including farnesol (C15-OH; FO), geranylgeraniol (C20-OH; GGO), and geranylfarnesol (C25-OH; GFO) toward leukemia cells in vitro. MK3, MK4, MK5 and GFO (at 10 microM) showed a potent apoptosis-inducing activity for all freshly isolated leukemia cells tested and for leukemia cell lines such as NB4, an acute promyelocytic leukemia (APL)-derived cell line and MDS92, a cell line derived from a patient with myelodysplastic syndrome, although there were some differences depending on the cells tested. In contrast, VK1 showed no effect on any of the leukemia cells. The combination of MK5 plus all-trans retinoic acid (ATRA) resulted in enhanced induction of apoptosis in both freshly isolated APL cells and NB4 cells as compared to each reagent alone. These data suggest the possibility of using VK2 and its derivatives for the treatment of myelogenous leukemias, including APL.

Apoptosis↗

PubMed1997

Elevation of circulating proadrenomedullin-N terminal 20-peptide in thyrotoxicosis.

BACKGROUND AND OBJECTIVE: Adrenomedullin (AM) is a recently discovered peptide which has potent vasodilatory activity. We have found that the plasma adrenomedullin level is elevated in hyperthyroidism, suggesting a potential role of AM in the decrease of vascular resistance in thyrotoxicosis. Proadrenomedullin, a precursor of adrenomedullin, yields another peptide termed proadrenomedullin-N terminal 20-peptide (PAMP). PAMP also has potent vasodilatory activity. Although the regulation of secretion of AM and PAMP is not fully understood and the mechanism by which the plasma AM level is elevated in hyperthyroidism remains unknown, it is of interest to determine the plasma concentration of PAMP in thyrotoxicosis. DESIGN AND PATIENTS: We measured the plasma concentration of immunoreactive AM and PAMP in newly recruited untreated thyrotoxic Graves' patients using specific antibodies to each peptide. RESULTS: Not only AM, but also the plasma concentration of PAMP in thyrotoxic patients was significantly (P < 0.01) elevated (4.7 +/- 0.9 pmol/l), compared to that in control subjects (2.6 +/- 0.8 pmol/l). The correlation was marginally significant between the plasma AM concentration and serum free thyroid hormone levels. The plasma PAMP level tended to be more elevated when thyrotoxicosis was severe but the correlation was not statistically significant. Correlation was not demonstrated between the AM and PAMP levels in thyrotoxic patients. CONCLUSIONS: Elevation of the plasma adrenomedullin and proadrenomedullin-N terminal 20-peptide levels raises the possibility of involvement of these vasodilatory peptides in the haemodynamic changes in thyrotoxicosis.

Adolescent↗

PubMed1997

Infrequent mutation of the H-cadherin gene on chromosome 16q24 in human breast cancers.

To investigate the molecular basis of altered expression of the H-cadherin gene, we used polymerase chain reaction-single strand conformation polymorphism and DNA sequencing to examine the H-cadherin gene in 48 primary breast cancers in which loss of the long arm of chromosome 16 had been detected. We identified no mutations other than somatic 5-bp deletion within the coding region in a single tumor. The very low frequency of mutation found in these experiments suggests that H-cadherin is usually not a primary target for carcinogenesis in human breast cancers, and that reduction of its expression is likely to be a consequence of some other genetic event(s).

Breast Neoplasms↗

PubMed1997

Isolation and mapping of karyopherin alpha 3 (KPNA3), a human gene that is highly homologous to genes encoding Xenopus importin, yeast SRP1 and human RCH1.

From a human fetal-brain cDNA library, we isolated and characterized a novel gene (KPNA3) encoding a protein highly homologous to certain nuclear transport proteins of Xenopus and human. The complete cDNA clone, designated karyopherin alpha 3, contained an open reading frame of 1,563 nucleotides encoding 521 amino acids. The predicted amino acid sequence showed 48%, 45% and 48% identity with Xenopus importin, yeast SRP1 and human RCH1, respectively. The similarities among these proteins suggest that karyopherin alpha 3 may be involved in the nuclear transport system. Eight repeats of the arm motif were well conserved among these proteins. The N-terminal region of the predicted karyopherin alpha 3 product was highly basic and the C-terminal region was strongly acidic. A 4.3-kb transcript was expressed in all adult human tissues examined by Northern blotting. The cDNA clone was assigned to chromosome band 13q14.3 by fluorescence in situ hybridization.

Amino Acid Sequence↗

PubMed1997

Cloning and chromosome assignment to 1q32 of a human cDNA (RAB7L1) encoding a small GTP-binding protein, a member of the RAS superfamily.

A full-length cDNA homologous to RAB7, a member of the RAB-related GTP-binding protein subfamily, was isolated from a human placenta cDNA library. This cDNA, designated RAB7L1, has an open reading frame of 609 nucleotides encoding 203 amino acids. Northern analysis showed that the mRNA is ubiquitously expressed in human tissues, although signal intensities were different among the various organs examined. This gene was located on chromosome band 1q32 by fluorescence in situ hybridization.

Amino Acid Sequence↗

PubMed1997

Protective effect of captopril on ischemic myocardium.

The protective effect and mechanism of action of the angiotensin-converting enzyme inhibitor (ACE-I) captopril was investigated in organelles from ischemic myocardial cells in a canine coronary ligation model. Sarcoplasmic reticulum (SR) and mitochondrial fractions were extracted from ischemic and nonischemic myocardial cells from captopril- and saline-treated (control) hearts. Heart rate, cardiac output, and right ventricular systolic blood pressure were similar in the captopril-treated and control groups. Left ventricular systolic blood pressure (LVPs) decreased gradually to 89% of the baseline value after captopril administration, and to 78% of the baseline value after ligation. Ca-ATPase activity in the SR, the respiratory control ratio (RCR) in the mitochondria, and dinitrophenol (DNP)-stimulated ATPase activity were significantly higher in ischemic myocardium from the captopril-treated group than from the saline-treated (control) group. The SH group content of both organelles was higher in the captopril-treated group. Our results suggest that, in addition to their hemodynamic effects, ACE-I agents containing SH groups protect the myocardium from ischemic damage by preventing enzyme oxidation.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1997

Effects of adenosine triphosphate on ventriculoatrial conduction--usefulness and problems in assessment of catheter ablation of accessory pathways.

The effects of adenosine triphosphate (ATP) on ventriculoatrial (VA) conduction were examined before and after accessory pathway (AP) ablation, with emphasis on assessment of the complication of dual atrioventricular (AV) node pathway. By evaluating the differences in the response to ATP of APs and other pathways, we assessed the usefulness and problems of this method. Of 59 patients who underwent AP ablation, 31 showed pre-excitation and 28 had concealed APs. A dual AV node pathway was found in 9 patients (15.3%) before ablation. After ablation, a dual AV node pathway was newly found in 9 patients. Thus, the total number of patients with a dual AV node pathway was 18 (30.5%). VA conduction over APs was not blocked in 26 of 29 patients, but the remaining 3 APs were blocked transiently by ATP. ATP caused VA block over the AV node in 15 of 16 patients and a dual AV node pathway in all 11 patients. In contrast, VA conduction over the retrograde fast pathway was blocked in 9 of 14 patients with AV node re-entrant tachycardia. ATP has little effect on APs, so observation of the response to ATP provides a more reliable and useful means of evaluating successful ablation. With this method, however, it is important to consider the possibility of the presence of ATP-sensitive APs and ATP-resistant retrograde fast pathways. The influence of ablation-induced injury has not been fully clarified. It is therefore essential to take into account various data, including the comparison between data obtained before and after ablation.

Adenosine Triphosphate↗

PubMed1997

Correlations between resting regional wall motion and regional myocardial blood flow (at rest and during exercise) in infarct-related myocardium--a study with [13N]ammonia positron emission tomography.

We evaluated quantitatively the correlations between resting wall motion and regional myocardial blood flow (RMBF; at rest and during exercise) in infarct-related myocardium. The study was performed in 28 subjects: 21 patients who had previously suffered myocardial infarction of the anteroseptal wall, and 7 normal individuals. Positron emission tomography (PET) with [13N]ammonia was performed at rest and during low-grade exercise (bicycle ergometer fixed at 25 W for 6.5 min), and RMBF was measured quantitatively from the radioactivity in myocardial tissue and arterial blood. Resting regional wall motion was calculated using the centerline method on left ventriculographic findings. Resting regional wall motion was correlated with RMBF both at rest and during exercise in the infarct areas (anterior walls; y = 2.74 +/- 4.25 x 10(-2)x, r = 0.43, at rest; and y = -2.48 + 3.04 x 10(-2)x, r = 0.48, during exercise, p < 0.05; septal walls; y = -3.61 + 5.64 x 10(-2)x, r = 0.62, at rest; and y = -3.46 + 4.31 x 10(-2)x, r = 0.62, during exercise, p < 0.01). In each infarct-related wall, the coefficient (the slope) during exercise was smaller than that at rest (3.04 vs 4.25 and 4.31 vs 5.64 in each), and the infarct areas with preserved wall motion showed higher RMBF during exercise than those with reduced wall motion. Our results may show that wall motion depends on viable but ischemic myocardium in infarct-related walls.

Adult↗

PubMed1997

Significance of downsloping ST-segment depression induced by low-level exercise in severe coronary artery disease. Assessment with myocardial ischemia and collateral perfusion.

Exercise-induced downsloping ST-segment depression is a common manifestation of severe myocardial ischemia. Although greater downsloping ST-segment depression is suspected to indicate more severe ischemia, its exact relationship to regional myocardial blood flow (RMBF) has not yet been clarified. We investigated the relationship between the magnitude of downsloping ST-segment depression and exercise-induced changes in RMBF and collateral perfusion. Nitrogen-13 ammonia positron emission tomography was performed in 6 healthy volunteers and 72 patients with angiographically proven coronary artery disease. The left ventricle was divided into 11 regions of interest, and RMBF in each region was measured at rest and during low-level supine bicycle exercise. Downsloping ST-segment depression of 0.1 mV or more at 80 milliseconds after the J point was accepted as significant. Low-level exercise induced downsloping depression of 0.1 to 0.2 mV in 10 patients (group D1) and downsloping depression of 0.2 mV or more in 8 patients (group D2). Multivessel disease was common in both group D1 (80% of patients) and group D2 (88% of patients). Collateral circulation was significantly more frequent in group D1 (90%) than in group D2 (13%, p < 0.01). Ischemic areas were larger and cardiac function was worse in group D2 than in group D1. The RMBF increased sufficiently in all regions (56 +/- 30%) with exercise in the healthy group. In group D1, RMBF was unchanged or decreased in ischemic areas (10 +/- 23%) but increased sufficiently in surrounding areas (50 +/- 32%). In group D2, RMBF was unchanged in ischemic areas (17 +/- 24%) and increased insufficiently in surrounding areas (41 +/- 21%). Therefore, exercise-induced downsloping ST-segment depression of 0.1 to 0.2 mV may reflect an underlying change in blood flow in viable myocardium with collateral perfusion, and downsloping depression of 0.2 mV or more may reflect more severely impaired myocardium without collateral perfusion.

Adult↗

PubMed1997

Reversal of early metabolic dysfunction in hypertensive rat left-ventricular myocytes by angiotensin-converting enzyme inhibition.

We evaluated the effects of angiotensin-converting enzyme (ACE) inhibition on metabolic changes in myocardial organelles, myocardial hypertrophy, and interstitial fibrosis in the early stage of hypertension. An ACE inhibitor, imidapril (2.5 mg/kg per day), a calcium-channel blocker, diltiazem (30 mg/kg per day), or vehicle was given to spontaneously hypertensive rats (SHRs) from 10 to 18 weeks of age. Single myocytes were isolated enzymatically from the left ventricles of these SHRs and normotensive Wistar-Kyoto (WKY) controls at 18 weeks of age. In single ventricular myocytes, enzyme activities in the sarcoplasmic reticulum (SR) and the sarcolemma (SL) and the mitochondrial respiratory control ratio (RCR) were determined. In 18-week-old SHRs receiving vehicle, myocardial hypertrophy and interstitial fibrosis developed, and SR Ca2+ AT-Pase activity and the mitochondrial RCR were significantly lower and SL Na+, K(+)-ATPase activity was significantly higher than in age-matched WKYs. However, compared with diltiazem, imidapril was better able to prevent the development of myocardial hypertrophy and interstitial fibrosis, to improve SR Ca(2+)-ATPase activity and the mitochondrial RCR, and to increase SL Na+, K(+)-ATPase activity. These results suggest that ACE inhibition can prevent the development of morphologic changes associated with hypertension-induced left ventricular remodeling, such as myocardial hypertrophy and interstitial fibrosis, and can counteract ongoing dysfunction of organelle metabolism early in the development of hypertension.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1997

The effects of dopamine, dobutamine and amrinone on mitochondrial function in cardiogenic shock.

The impairment of mitochondrial in non-infarcted myocardium under cardiogenic shock complicated by acute myocardial infarction was studied. We induced acute myocardial infarction in dogs by ligating the circumflex branch of the left coronary artery (LCX). On basis of left ventricular systolic pressure (LVPs) after 60 minutes, we divided the dogs into two groups: a group in which LVPs fell to below 70% of the pre-LCX ligation level, and a Control group in which LVPs remained more than 90%. The former group was further divided into four subgroups, depending on infusion of dopamine, dobutamine, amrinone or saline after 90 minutes. Mitochondria were prepared and mitochondrial respiratory activity determined. In the Saline group, hemodynamics became reduced to less than 70% of the preligation level after 120 minutes, however, in the Dopamine and Dobutamine groups, hemodynamics became restored to the preligation level. In the Amrinone group, LVPs decreased slightly, while cardiac output, LV Max. dp/dt and myocardial blood flow increased. In the Saline group, mitochondria in the non-infarcted myocardium functioned at a lower level of activity than that of the Control group. However, in the Dopamine, Dobutamine, and Amrinone groups, the mitochondria functioned at a higher level. Electron microscopy revealed mitochondrial damage in the Saline group only. The results indicate that an energy production disorder in the non-infarcted myocardium may have pathogenetic implications in cardiogenic shock associated with acute myocardial infarction, while dopamine, dobutamine, and amrinone improve mitochondrial function, and ultimately improve cardiac function.

Adenosine Triphosphatases↗

PubMed1997

Hemodynamic effects of warm bathing in a Hubbard tank and exercise loading in patients after myocardial infarction.

Hemodynamic parameters were measured during bathing and exercise testing in 43 patients with myocardial infarction (mean age: 60.2 years) to investigate the predictive parameters to determine when patients could safely resume bathing. Patients took a fresh water bath at 42 degrees C in the supine position for 5 min in a Hubbard tank. Group A showed an elevation of pulmonary capillary wedge pressure (PCWP) during bathing of 10 mmHg or more (23 patients, mean age: 61.7 years) and group B showed an elevation of less than 10 mmHg (20 patients, mean age: 60.5 years). Continuous multistep exercise tests were performed with a bicycle ergometer in the supine position, and hemodynamic parameters were measured at up to 50 W for 3 min on the day before the warm bathing test. There were no significant differences in the changes of arterial pressure and heart rate between the two groups. The PCWP at 3 min with a load of 50 W was significantly higher in group A (26.9 +/- 9.0 mmHg) than in group B (16.7 +/- 9.1 mmHg, p < 0.01). The stroke index (SI) during exercise testing was significantly lower in group A than in group B. The difference in the stroke index from baseline values (delta SI) at 3 min with a load of 50 W was significantly lower in group A (3.5 +/- 5.5 ml/m2/beat) than in group B (10.6 +/- 7.0 ml/m2/beat, p < 0.01). Similarly, delta CI and delta oxygen pulse during testing were significantly lower in group A than in group B. The physical work capacity and ejection fraction of the left ventricle of group A were significantly lower than those of group B, whereas the left ventricular end-diastolic pressure was higher in group A than in group B. CI, delta CI, SI, delta SI, METs, oxygen pulse, and delta oxygen pulse were examined by regression analysis and multivariate analysis to predict a significant elevation of delta PCWP during bathing. delta SI (p = 0.0032), delta CI (p = 0.0094), delta SI + METs (p = 0.0051), delta CI + METs (p = 0.0061), delta CI + delta SI (p = 0.0084), and delta CI + delta SI + METs (p = 0.0093) showed the highest correlations with delta PCWP. These findings suggest that changes in delta CI, delta SI, and METs are good predictive parameters for determining when patients may safely resume bathing. We suggest that patients with myocardial infarction, reduced cardiac function and a physical work capacity of approximately 4.0 METs, delta SI: 5 ml/m2/beat and delta CI: 2.4 l/min/m2 resume bathing only after careful consideration.

Adult↗

PubMed1996

Cloning and characterization of two novel human cDNAs (NELL1 and NELL2) encoding proteins with six EGF-like repeats.

From a human fetal-brain cDNA library we isolated two novel genes encoding peptides containing six EGF-like repeats. Both showed significant homologies with nel, a gene strongly expressed in neural tissues of chicken. The cDNAs, designated NELL1 (nel-like, type 1) and NELL2 (nel-like, type 2), contained open reading frames encoding 810 and 816 amino acids, respectively. NELL2 is strongly expressed in brain of adult and fetus but only weakly in fetal kidney. NELL1 and NELL2 were mapped by FISH to chromosomal bands 11p15.1-p15.2 and 12q13.11-q13.12, respectively.

Adult↗

PubMed1996

Localization of the gustatory pathway in the human midbrain.

The localization of the secondary gustatory pathway in the human brainstem still remains uncertain. Here we report two patients with small vascular lesions in the unilateral midbrain tegmentum who presented with taste disturbance on the ipsilateral side of the tongue. In both cases, the dorsomedial mesencephalic tegmental region lateral to the oculomotor nucleus, including the central tegmental tract and the ventral part of the periaqueductal gray, was involved commonly in the lesions. The secondary gustatory pathway arising from the nucleus of the solitary tract appears to run rostrally, without crossing, to the ipsilateral thalamic nucleus through the dorsomedial part of the tegmental region at the rostral level of the midbrain.

Adult↗

PubMed1996

Mutations in the BRCA2 gene in hepatocellular carcinomas.

To investigate whether the BRCA2 gene plays a role in carcinogenesis of hepatocellular carcinomas or pancreatic cancers in view of frequent losses of heterozygosity on chromosome 13q12-13 in those tumors, we screened the entire coding region of this gene for mutations in 60 hepatocellular carcinomas and 36 pancreatic cancers. No alteration was found in any of the pancreatic cancers examined, but three mutations were identified in hepatocellular carcinomas; one was a 6-bp somatic deletion within intron 6. The other two mutations we identified in hepatocellular carcinomas were missense mutations in the germ line, although all BRCA2 mutations thus far detected in patients with familial breast cancers likewise have been deletions. None of 194 other patients with cancers or 44 normal controls exhibited either mutation. Combined with our demonstration of BRCA2 expression in adult liver tissue, the evidence implies that inactivation of BRCA2 may play some role in development or progression of hepatocellular carcinoma and might predispose carriers of mutant alleles to liver malignancies.

Carcinoma, Hepatocellular↗

PubMed1996

Hematopoietic cell phosphatase, SHP-1, is constitutively associated with the SH2 domain-containing leukocyte protein, SLP-76, in B cells.

Src homology region 2 (SH2) domain-containing phosphatase 1 (SHP-1; previously named HCP, PTP1C, SH-PTP1, and SHP) is a cytosolic protein tyrosine phosphatase that contains two SH2 domains. Recent data have demonstrated that the gene encoding SHP-1 is mutated in motheaten (mc) and viable motheaten (mc') mice resulting in autoimmune disease. More recently, SHP-1 has been shown to negatively regulate B cell antigen receptor (BCR)-initiated signaling. To elucidate potential mechanisms of SHP-1 action in BCR signal transduction, we studied proteins that interact with SHP-1 in B cells. Both anti-SHP-1 antibody and the two SH2 domains of SHP-1 expressed as glutathione S-transferase fusion proteins precipitated at least three phosphoproteins of approximately 75, 110, and 150 kD upon anti-immunoglobulin M stimulation of the WEHI-231 immature B cell line. Binding of SHP-1 to the 75- and 110-kD proteins appeared to be mediated mainly by the NH2-terminal SH2 domain of SHP-1, whereas both the NH2- and COOH-terminal SH2 domains are required for maximal binding to the 150-kD protein. Immunoprecipitation and Western blot analysis revealed that the SHP-1-associated 75-kD protein is the hematopoietic cell-specific, SH2-containing protein SLP-76. Further, this protein-protein association was constitutively observed and stable during the early phase of BCR signaling. However, significant tyrosine phosphorylation of SLP-76 as well as of SHP-1 was observed after BCR ligation. Constitutive association of SHP-1 with SLP-76 could also be detected in normal splenic B cells. Collectively, these results suggest possible mechanisms by which SHP-1 may modulate signals delivered by BCR engagement.

Adaptor Proteins, Signal Transducing↗

PubMed1996

Bone morphogenetic protein-12 and -13 inhibit terminal differentiation of myoblasts, but do not induce their differentiation into osteoblasts.

Effects of bone morphogenetic protein (BMP)-12 and BMP-13, new members of the BMP family which belong to the transforming growth factor (TGF)-beta superfamily, on terminal differentiation of myoblasts were examined in C2C12 and L-6 myoblasts. When the myoblasts were cultured with BMP-12 or BMP-13, the expression of the myosin heavy chain and the formation of multinucleated myotubes mRNA in L-6 cells. The inhibitory effects of BMP-12 and BMP-13 on myogenic differentiation were similar to the effects of BMP-2, though their potencies were lower than BMP-2. Unlike BMP-2, neither BMP-12 nor BMP-13 induced alkaline phosphatase activity in C2C12 myoblasts. The differences in the biological activities of these new BMPs suggest that the intracellular signalling pathway used by BMP-12 and BMP-13 differs from that of BMP-2.

Alkaline Phosphatase↗

PubMed1996

Differential regulation of leukocyte function-associated antigen-1/ intercellular adhesion molecules-1-dependent adhesion and aggregation in HL-60 cells.

Activation of integrin and organization of cytoskeletal proteins are highly regulated in cell adhesion and aggregation. The interaction of leukocyte function-associated antigen-1 (LFA-1) and intercellular adhesion molecules-1 (ICAM-1) mediates cell adhesion and aggregation, which facilitate leukocyte trafficking to inflamed tissues and augment effector functions. We investigated how LFA-1/ICAM-1-mediated adhesion and aggregation are regulated in HL-60 cells induced to differentiate into neutrophils by retinoic acid (RA). Uninduced HL-60 cells did not bind to ICAM-1 even with stimulation by 12-0-tetradecanoyl phorbol-13-acetate, although they express LFA-1 on the cell surface. When cultured with RA for 24 hours, HL-60 cells were able to adhere to ICAM-1 constitutively. The induction of adhesion did not accompany any change in surface density of LFA-1, indicating that the avidity of LFA-1 was increased. The change in its avidity required de novo synthesis of proteins. Although ICAM-1 was intensely expressed on RA-induced HL-60 cells, these cells did not show any cellular aggregation. The HL-60 cells transfected with the active form of Ras (Val12) exhibited LFA-1/ICAM-1-dependent aggregation by RA stimulation without change in the avidity of LFA-1. In these Ras-transfectants, a cytoskeletal protein, paxillin, was tyrosine-phosphorylated, and the level of F-actin increased. Transforming growth factor (TGF) beta, as well as cytochalasin D, prevented both the tyrosine phosphorylation of paxillin and the aggregation without any effects on the avidity of LFA-1. Thus, an increase in the avidity of LFA-1 was not sufficient for the induction of aggregation, which required activation of Ras and reorganization of cytoskeletal proteins. These results suggest that distinct regulatory mechanisms control LFA-1/ICAM-1-dependent adhesion and aggregation in HL-60 cells differentiating into neutrophils.

Actins↗