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Biomedical subjects

Toru Kita

Publications and source records attributed to Toru Kita.

At least 127 records · Page 7Linked to original sources
PubMed2004

[Acceptance of memory impairment and satisfaction with life in patients with mild to moderate Alzheimer's disease].

In this study, we focused on acceptance of memory impairment and satisfaction with life in patients with mild to moderate Alzheimer's disease (AD). We interviewed 71 consecutive patients with AD and asked (1) whether they had memory loss, (2) whether they found trouble in life, and (3) how their daily life was. We categorized the patients into three groups based on awareness of memory loss and reference to the cause of memory loss. Cognitive functions were lower in patients who were not aware of memory loss. The rate of satisfaction with life was the highest in patients who were not aware of memory loss, and was the lowest in patients who complained of memory loss with reference to the cause of memory loss, indicating that patients could hardly accept their lives when memory impairment was a serious issue. However, in these patients, depression scores were not high, suggesting that they may somehow adapt themselves to their current status by defining the reason for memory loss. In patients who complained of memory impairment but did not refer to the cause of memory loss, there was a variation in awareness of memory loss and satisfaction with life. The present study indicated that we have to provide individual care and support for AD patients considering their level of acceptance of memory impairment.

Aged↗
PubMed2004

Mutations in Japanese subjects with primary hyperlipidemia--results from the Research Committee of the Ministry of Health and Welfare of Japan since 1996--.

Primary hyperlipidemia is caused by various molecular defects in lipid metabolism. The Research Committee on Primary Hyperlipidemia organized by the Ministry of Health and Welfare of Japan (present: the Ministry of Health, Labour and Welfare) has investigated reported mutations in Japanese patients with primary hyperlipidemia and related disorders (including hypolipidemia), and has created a database based on the questionnaire sent to the members of council board of the Japan Atherosclerosis Society. Mutations in the following genes were investigated: low density lipoprotein receptor, lecithin: cholesteryl acyltransferase, lipoprotein lipase (LPL), hepatic lipase, apolipoproteins A-I, A-II, A-IV, B, C-II, C-III and E, microsomal triglyceride transfer protein, and cholesterol ester transfer protein (CETP). Until 1998, 922 patients with primary hyperlipidemia and related disorders has been registered with the Research Committee, and 190 mutations in 15 genes had been reported, showing a marked variation in Japanese patients with primary hyperlipidemia and related disorders. So-called "common mutations" have been described in Japanese patients with familial hypercholesterolemia, LPL deficiency and CETP deficiency. The genetic defect of familial combined hyperlipidemia (FCHL) is still unknown although FCHL is speculated to be the most prevalent genetic hyperlipidemia, and further investigations should be performed to elucidate the molecular mechanisms of FCHL

Asian People↗
PubMed2004

Clinical features of familial hypercholesterolemia in Japan in a database from 1996-1998 by the research committee of the ministry of health, labour and welfare of Japan.

Familial hypercholesterolemia (FH) is one of the most common primary hyperlipidemias, characterized by a heterozygous or homozygous phenotype for a severe serum low-density lipoprotein (LDL)-cholesterol level and advanced atherosclerosis, leading to coronary artery diseases (CAD). Various kinds of mutations in the LDL receptor gene responsible for the genetic disease have been identified since the human LDL receptor gene has been identified. In this study, the clinical features of FH were investigated using a database based on nationwide surveillance for primary hyperlipidemia and related disorders by the Research Committee on Primary Hyperlipidemia. The clinical features and the frequencies of accompanying vascular diseases in 660 cases of FH homozygotes and heterozygotes showed that the incidence of CAD was negatively associated with plasma HDL-cholesterol levels, but not with plasma LDL-cholesterol levels, in 641 FH heterozygotes. Risk factor analyses revealed that hypertension, male, smoking, low HDL-cholesterol levels, age > 50 y, diabetes mellitus, and hypertriglyceridemia were positive risk factors for CAD. The summarized gene analysis in FH heterozygotes showed at least 4 mutations in the LDL receptor gene as common mutations in Japan. The average serum lipids and frequency of CAD based on each common mutation suggested that their clinical features are in part determined by responsive mutations in the LDL receptor gene.

Adolescent↗
PubMed2004

Heidenhain variant of Creutzfeldt-Jakob disease: diffusion-weighted MRI and PET characteristics.

Creutzfeldt-Jakob disease (CJD) is characterized by rapidly progressive dementia with a variety of neurological disorders and a fatal outcome. The authors present a case with visual disturbance as a leading symptom and rapid deterioration in global cognitive functions. The cerebrospinal fluid was positive for 14-3-3 protein, and diffusion-weighted magnetic resonance imaging (MRI) showed marked hyperintensity in the parieto-occipital cortices, where hypometabolism was clearly detected on positron emission tomography (PET). Pattern-reversal visual evoked potentials showed prolonged P100 latencies and increased N/5/P100 amplitudes. All these findings supported a diagnosis of the Heidenhain variant of CJD, whereas a long clinical course, a lack of myoclonus, and an absence of periodic synchronous discharges on electroencephalography were atypical. Diffusion-weighted MRI and PE1 in combination with visual evoked potential recording and 14-3-3 protein detection may be useful for the early diagnosis of CJD.

Brain↗
PubMed2003

Munc13-4 is a GTP-Rab27-binding protein regulating dense core granule secretion in platelets.

Platelets store self-agonists such as ADP and serotonin in dense core granules. Although exocytosis of these granules is crucial for hemostasis and thrombosis, the underlying mechanism is not fully understood. Here, we show that incubation of permeabilized platelets with unprenylated active mutant Rab27A-Q78L, wild type Rab27A, and Rab27B inhibited the secretion, whereas inactive mutant Rab27A-T23N and other GTPases had no effects. Furthermore, we affinity-purified a GTP-Rab27A-binding protein in platelets and identified it as Munc13-4, a homologue of Munc13-1 known as a priming factor for neurotransmitter release. Recombinant Munc13-4 directly bound to GTP-Rab27A and -Rab27B in vitro, but not other GTPases, and enhanced secretion in an in vitro assay. The inhibition of secretion by unprenylated Rab27A was rescued by the addition of Munc13-4, suggesting that Munc13-4 mediates the function of GTP-Rab27. Thus, Rab27 regulates the dense core granule secretion in platelets by employing its binding protein, Munc13-4.

Adenosine Diphosphate↗
PubMed2003

Upregulation of SR-PSOX/CXCL16 and recruitment of CD8+ T cells in cardiac valves during inflammatory valvular heart disease.

OBJECTIVE: SR-PSOX/CXCL16 is a transmembrane chemokine and is implicated in activated CD8+ T cell trafficking. In the present study, we examined the expression pattern of SR-PSOX/CXCL16 in the heart and investigated a potential role of SR-PSOX/CXCL16 in inflammatory valvular heart disease. METHODS AND RESULTS: Initial expression of SR-PSOX/CXCL16 in murine embryos was detected in endothelial cells lining endocardial cushions in the forming heart at E11.5. From mid-gestation to adult, expression of this gene in the heart was exclusively observed in valvular endothelial cells. Examination of SR-PSOX/CXCL16 expression in human cardiac valves demonstrated that SR-PSOX/CXCL16 was strongly expressed in valvular and neocapillary endothelial cells in patients with infective endocarditis. SR-PSOX/CXCL16 expression in neocapillary endothelial cells was also observed in patients with rheumatic and atherosclerotic valvular disease. Moreover, CD8+ T cells were distributed closely to endothelial cells expressing SR-PSOX/CXCL16. In vitro adhesion assays showed that SR-PSOX/CXCL16 induced adhesion of activated CD8+ T cells to vascular cell adhesion molecule-1 (VCAM-1) through very late antigen-4 (VLA-4) activation. Furthermore, SR-PSOX/CXCL16 stimulated interferon-gamma (IFN-gamma) production by CD8+ T cells. CONCLUSIONS: SR-PSOX/CXCL16 may be involved in CD8+ T cell recruitment through VLA-4 activation and stimulation of IFN-gamma production by CD8+ T cells during inflammatory valvular heart disease.

Animals↗
PubMed2003

Small-conductance Ca2+-dependent K+ channels are the target of spike-induced Ca2+ release in a feedback regulation of pyramidal cell excitability.

Cooperative regulation of inosiol-1,4,5-trisphosphate receptors (IP(3)Rs) by Ca(2+) and IP(3) has been increasingly recognized, although its functional significance is not clear. The present experiments first confirmed that depolarization-induced Ca(2+) influx triggers an outward current in visual cortex pyramidal cells in normal medium, which was mediated by apamin-sensitive, small-conductance Ca(2+)-dependent K(+) channels (SK channels). With IP(3)-mobilizing neurotransmitters bath-applied, a delayed outward current was evoked in addition to the initial outward current and was mediated again by SK channels. Calcium turnover underlying this biphasic SK channel activation was investigated. By voltage-clamp recording, Ca(2+) influx through voltage-dependent Ca(2+) channels (VDCCs) was shown to be responsible for activating the initial SK current, whereas the IP(3)R blocker heparin abolished the delayed component. High-speed Ca(2+) imaging revealed that a biphasic Ca(2+) elevation indeed underlays this dual activation of SK channels. The first Ca(2+) elevation originated from VDCCs, whereas the delayed phase was attributed to calcium release from IP(3)Rs. Such enhanced SK currents, activated dually by incoming and released calcium, were shown to intensify spike-frequency adaptation. We propose that spike-induced calcium release from IP(3)Rs leads to SK channel activation, thereby fine tuning membrane excitability in central neurons.

Animals↗
PubMed2003

Cell surface-anchored SR-PSOX/CXC chemokine ligand 16 mediates firm adhesion of CXC chemokine receptor 6-expressing cells.

Direct contacts between dendritic cells (DCs) and T cells or natural killer T (NKT) cells play important roles in primary and secondary immune responses. SR-PSOX/CXC chemokine ligand 16 (CXCL16), which is selectively expressed on DCs and macrophages, is a scavenger receptor for oxidized low-density lipoprotein and also the chemokine ligand for a G protein-coupled receptor CXC chemokine receptor 6 (CXCR6), expressed on activated T cells and NKT cells. SR-PSOX/CXCL16 is the second transmembrane-type chemokine with a chemokine domain fused to a mucin-like stalk, a structure very similar to that of fractalkine (FNK). Here, we demonstrate that SR-PSOX/CXCL16 functions as a cell adhesion molecule for cells expressing CXCR6 in the same manner that FNK functions as a cell adhesion molecule for cells expressing CX(3)C chemokine receptor 1 (CX(3)CR1) without requiring CX(3)CR1-mediated signal transduction or integrin activation. The chemokine domain of SR-PSOX/CXCL16 mediated the adhesion of CXCR6-expressing cells, which was not impaired by treatment with pertussis toxin, a Galphai protein blocker, which inhibited chemotaxis of CXCR6-expressing cells induced by SR-PSOX/CXCL16. Furthermore, the adhesion activity was up-regulated by treatment of SR-PSOX/CXCL16-expressing cells with a metalloprotease inhibitor, which increased surface expression levels of SR-PSOX/CXCL16. Thus, SR-PSOX/CXCL16 is a unique molecule that not only attracts T cells and NKT cells toward DCs but also supports their firm adhesion to DCs.

Animals↗
PubMed2003

Reinduction of T-type calcium channels by endothelin-1 in failing hearts in vivo and in adult rat ventricular myocytes in vitro.

BACKGROUND: In ventricular myocardium, the T-type Ca2+ current (ICa,T), which is temporarily observed during fetal and neonatal periods, has been shown to reappear in failing/remodeling hearts. However, its pathophysiological regulation has not been elucidated. METHODS AND RESULTS: We utilized Dahl salt-sensitive (DS) rats with hypertension at the stage of concentric left ventricular (LV) hypertrophy (11 weeks old, LVH) and at the heart failure stage (16 to 18 weeks old, CHF). Some were treated with bosentan (100 mg/kg per day) during the period from LVH to CHF. In LVH, neither the presence of ICa,T (measured in the freshly isolated LV myocytes) nor an increase in alpha-1G mRNA expression were detected. This condition was associated with increases in tissue angiotensin II (AII) but not with endothelin (ET)-1 peptides. In contrast, in CHF, when the tissue AII remained elevated and ET-1 de novo increased, ICa,T was recorded in most of the cells (-0.87+/-0.18 pA/pF at -30 mV, P<0.01 versus LVH). This was associated with a significant increase in the alpha-1G mRNA level. The chronic bosentan treatment eliminated both the elevation of alpha-1G mRNA level and ICa,T from the cells, whereas it did not affect the cell size and membrane capacitance. In addition, 48-hour exposure to ET-1 but not AII induced ICa,T in normal adult myocytes in culture from Sprague-Dawley rats. CONCLUSIONS: ICa,T channels reappear in failing but not in hypertrophied LV cardiomyocytes in a manner depending on the tissue ET-1 activation.

Angiotensin II↗
PubMed2003

Cutting edge: SR-PSOX/CXC chemokine ligand 16 mediates bacterial phagocytosis by APCs through its chemokine domain.

SR-PSOX and CXC chemokine ligand (CXCL)16, which were originally identified as a scavenger receptor and a transmembrane-type chemokine, respectively, are indicated to be identical. In this study, we demonstrate that membrane-bound SR-PSOX/CXCL16 mediates adhesion and phagocytosis of both Gram-negative and Gram-positive bacteria. Importantly, our prepared anti-SR-PSOX mAb, which suppressed chemotactic activity of SR-PSOX, significantly inhibited bacterial phagocytosis by human APCs including dendritic cells. Various scavenger receptor ligands inhibited the bacterial phagocytosis of SR-PSOX. In addition, the recognition specificity for bacteria was determined by only the chemokine domain of SR-PSOX/CXCL16. Thus, SR-PSOX/CXCL16 may play an important role in facilitating uptake of various pathogens and chemotaxis of T and NKT cells by APCs through its chemokine domain.

Animals↗
PubMed2003

Effects of endothelin-1 on mitochondrial function during the protection against myocardial cell apoptosis.

Endothelin-1 is a potent survival factor against myocardial cell apoptosis. While apoptotic stimuli often perturb mitochondrial function by decreasing the membrane potential as well as oxygen consumption, it is unknown whether ET-1 can rescue such perturbation by apoptotic stimuli. Administration of endothelin-1 inhibited the H(2)O(2)-induced release of cytochrome c from mitochondria to the cytosol in cardiac myocytes, indicating the involvement of the mitochondria-dependent pathway in the anti-apoptotic effect of endothelin-1. We showed here by cytofluorimetric analysis that endothelin-1 prevented the H(2)O(2)-induced decrease of membrane potential. However, endothelin-1 was unable to reverse the H(2)O(2)-mediated decrease in oxygen consumption and electron transport in the mitochondria of cardiac myocytes. Endothelin-1 was unable to rescue cardiac myocytes from apoptosis when administered after the decrease in mitochondrial membrane potential. These data suggest that endothelin-1 does not target the mitochondrial respiratory chain, but rather stabilizes the mitochondrial membrane during the protection against apoptosis.

Animals↗
PubMed2003

Direct demonstration of involvement of protein kinase Calpha in the Ca2+-induced platelet aggregation.

Platelets play critical roles in hemostasis and thrombosis through their aggregation following activation of integrin alphaIIbbeta3. However, the molecular mechanism of the integrin activation inside platelets remains largely unknown. Pharmacological experiments have demonstrated that protein kinase C (PKC) plays an important role in platelet aggregation. Because PKC inhibitors can have multiple substrates and given that non-PKC-phorbol ester-binding signaling molecules have been demonstrated to play important roles, the precise involvement of PKC in cellular functions requires re-evaluation. Here, we have established an assay for analyzing the Ca2+-induced aggregation of permeabilized platelets. The aggregation of platelets was inhibited by the addition of the arginine-glycine-aspartate-serine peptide, an integrin-binding peptide inhibitor of alphaIIbbeta3, suggesting that the aggregation was mediated by the integrin. The aggregation was also dependent on exogenous ATP and platelet cytosol, indicating the existence of essential cytosolic factors required for the aggregation. To examine the role of PKC in the aggregation assay, we immunodepleted PKCalpha and beta from the cytosol. The PKC-depleted cytosol lost the aggregation-supporting activity, which was recovered by the addition of purified PKCalpha. Furthermore, the addition of purified PKCalpha in the absence of cytosol did not support the aggregation, whereas the cytosol containing less PKC supported it efficiently, suggesting that additional factors besides PKC would also be required. Thus, we directly demonstrated that PKCalpha is involved in the regulation of Ca2+-induced platelet aggregation.

Blood Platelets↗
PubMed2003

Growth arrest-specific gene 6 is involved in glomerular hypertrophy in the early stage of diabetic nephropathy.

Nephropathy is one of the most common complications of diabetes mellitus. Glomerular hypertrophy is a hallmark in the early phase of the nephropathy. The mechanism of glomerular hypertrophy, however, remains incompletely understood. We have reported that Gas6 (growth arrest-specific gene 6) and its receptor, Axl, play a key role in the development of glomerulonephritis. Here we show the important role of Gas6/Axl in the pathogenesis of diabetic glomerular hypertrophy. In streptozotocin (STZ)-induced diabetic rats, mesangial and glomerular hypertrophy and an increase in the glomerular filtration rate (GFR) and albuminuria were observed after 12 weeks of STZ injection. The glomerular expression of Gas6 and Axl was increased in those rats. Administration of warfarin inhibited mesangial and glomerular hypertrophy and the increase in GFR and albuminuria in STZ rats. Moreover, we found less mesangial hypertrophy in STZ-treated Gas6 knockout mice than control mice. In vitro we found that stimulation of mesangial cells with Gas6 resulted in mesangial cell hypertrophy. Thus we have found a novel mechanism of glomerular hypertrophy through the Gas6/Axl-mediated pathway in the development of diabetic nephropathy. Inhibition of the Gas6/Axl pathway in diabetic patients might be beneficial to slow down the progression of diabetic nephropathy.

Albuminuria↗
PubMed2003

GATA-6 is involved in PPARgamma-mediated activation of differentiated phenotype in human vascular smooth muscle cells.

OBJECTIVE: Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a member of the nuclear receptor superfamily involved in the growth and differentiation of many cell types. Although the activation of PPARgamma in human vascular smooth muscle cells (VSMCs) inhibits the growth of these cells, the precise mechanism of this effect is unknown. PPARgamma-mediated growth inhibition of VSMCs is associated with the induction of the differentiated phenotype. A zinc finger transcription factor, GATA-6, has been implicated in the maintenance of the differentiated phenotype in VSMCs. METHODS AND RESULTS: The administration of 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2), a naturally occurring PPARgamma ligand, and troglitazone, a thiazolidinedione derivative, induced the expression of smooth muscle myosin heavy chain and smooth muscle alpha-actin, highly specific markers for differentiated VSMCs. Stimulation of proliferative VSMCs with PPARgamma ligands also increased the activity of the transfected wild-type smooth muscle myosin heavy chain promoter but not that of the mutant promoter, in which a GATA-6 binding site was mutated. Compatible with the role of GATA-6, both 15d-PGJ2 and troglitazone upregulated the DNA binding activity of GATA-6 in proliferative VSMCs. CONCLUSIONS: The activation of PPARgamma-dependent pathways induces the differentiated phenotype in proliferative VSMCs, and this induction is mediated, in part, through a GATA-6-dependent transcriptional mechanism.

Actins↗
PubMed2003

LOX-1 pathway affects the extent of myocardial ischemia-reperfusion injury.

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) was originally identified as a receptor for oxidized low-density lipoprotein predominantly expressed in endothelial cells. LOX-1 expression can be induced in cardiomyocytes and that activation of LOX-1 is involved in apoptosis. To investigate possible roles of LOX-1 in myocardial ischemia-reperfusion injury, rats were subjected to coronary artery ligation for 1h followed by reperfusion for 2h. Immunohistochemistry revealed that expression of LOX-1 in cardiac myocytes was induced following ischemia-reperfusion but not ischemia alone. Administration of anti-LOX-1 monoclonal antibody resulted in a nearly 50% reduction in myocardial infarction size compared with that of normal IgG or saline (P<0.05). These findings suggest that activation of the LOX-1 pathway is involved in determining the extent of myocardial ischemia-reperfusion injury and that inhibition of the LOX-1 pathway may provide a novel strategy for treatment of acute myocardial infarction in humans.

Animals↗
PubMed2003

Vortex-mediated mechanical stress induces integrin-dependent cell adhesion mediated by inositol 1,4,5-trisphosphate-sensitive Ca2+ release in THP-1 cells.

In the downstream regions of stenotic vessels, cells are subjected to a vortex motion under low shear forces, and atherosclerotic plaques tend to be localized. It has been reported that such a change of shear force on endothelial cells has an atherogenic effect by inducing the expression of adhesion molecules. However, the effect of vortex-induced mechanical stress on leukocytes has not been investigated. In this study, to elucidate whether vortex flow can affect the cell adhesive property, we have examined the effect of vortex-mediated mechanical stress on integrin activation in THP-1 cells, a monocytic cell line, and its signaling mechanisms. When cells are subjected to vortex flow at 400-2,000 rpm, integrin-dependent cell adhesion to vascular cell adhesion molecule-1 or fibronectin increased in a speed- and time-dependent manner. Next, to examine the role of Ca(2+) in this integrin activation, various pharmacological inhibitors involved in Ca(2+) signaling were tested to inhibit the cell adhesion. Pretreatment of cells with BAPTA-AM, thapsigargin +NiCl(2), or U-73122 (a phospholipase C inhibitor) inhibited cell adhesion induced by vortex-mediated mechanical stress. We also found that W7 (a calmodulin inhibitor) blocked the cell adhesion. However, pretreatment of cells with GdCl(3), NiCl(2), or ryanodine did not affect the cell adhesion. These data indicate that vortex-mediated mechanical stress induces integrin activation through calmodulin and inositol 1,4,5-trisphosphate-mediated Ca(2+) releases from intracellular Ca(2+) stores in THP-1 cells.

Calcium↗
PubMed2003

Glomerulonephritis induced by methicillin-sensitive Staphylococcus aureus infection.

A 57-year-old woman developed exacerbation of atopic dermatitis, fever, and nephrotic syndrome with microscopic hematuria. By bacteriological study, methicillin-sensitive Staphylococcus aureus (MSSA) was detected from each culture of pharyngeal mucus, stool, and blood samples. Renal biopsy specimens showed endocapillary proliferative glomerulonephritis with massive IgA deposition in the mesangium and along the capillary loops. After antistaphylococcal therapy with antibiotics, MSSA was negative for each culture and urinary protein decreased. Nine months after the first renal biopsy, a re-biopsy was performed, which revealed apparent disappearance of both endocapillary cell proliferation and IgA deposition. It is known that methicillin-resistant S. aureus (MRSA) infection causes glomerulonephritis through T-cell stimulation by superantigen presented by MRSA. The present results suggest that not only MRSA but also MSSA can cause this type of glomerulonephritis.

Anti-Bacterial Agents↗