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Biomedical subjects

Satoshi Ogawa

Publications and source records attributed to Satoshi Ogawa.

At least 19 recordsLinked to original sources
PubMed2006

Up-regulation of 150-kDa oxygen-regulated protein by celecoxib in human gastric carcinoma cells.

Induction of apoptosis by nonsteroidal anti-inflammatory drugs, such as celecoxib, is involved in their antitumor activity. An endoplasmic reticulum chaperone, 150-kDa oxygen-regulated protein (ORP150) is essential for the maintenance of cellular viability under hypoxia and is reported to be overexpressed in clinically isolated tumors. We here found that ORP150 was up-regulated by celecoxib in human gastric carcinoma cells. In conjunction with the suppression of tumor growth, orally administered celecoxib up-regulated ORP150 in xenograft tumors. Both the ATF4 and ATF6 pathways were activated by celecoxib, and suppression of ATF4 and ATF6 mRNA expression by small interfering RNA (siRNA) inhibited the celecoxib-dependent up-regulation of ORP150. Celecoxib administration led to an increase in the intracellular concentration of Ca2+, whereas 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester, an intracellular Ca2+ chelator, inhibited the up-regulation of ORP150 and the activation of the ATF4 and ATF6 pathways. These results suggest that these Ca2+-activated pathways are involved in the celecoxib-mediated up-regulation of ORP150. Clones overexpressing ORP150 were less susceptible to celecoxib-induced, but not staurosporine-induced, apoptosis and displayed less up-regulation of C/EBP homologous transcription factor (CHOP), a transcription factor with apoptosis-inducing activity. In contrast, siRNA for ORP150 stimulated apoptosis and expression of CHOP in the presence of celecoxib but not staurosporine. These results suggest that up-regulation of ORP150 in cancer cells inhibits celecoxib-induced apoptosis, thereby decreasing the potential antitumor activity of celecoxib.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2006

Pael receptor induces death of dopaminergic neurons in the substantia nigra via endoplasmic reticulum stress and dopamine toxicity, which is enhanced under condition of parkin inactivation.

Selective loss of dopaminergic neurons is the final common pathway in Parkinson's disease. Expression of Parkin associated endothelin-receptor like receptor (Pael-R) in mouse brain was achieved by injecting adenoviral vectors carrying a modified neuron-specific promoter and Cre recombinase into the striatum. Upregulation of Pael-R in the substantia nigra pars compacta of mice by retrograde infection induced endoplasmic reticulum (ER) stress leads to death of dopaminergic neurons. The role of ER stress in dopaminergic neuronal vulnerability was highlighted by their decreased survival in mice deficient in the ubiquitin-protein ligase Parkin and the ER chaperone ORP150 (150 kDa oxygen-regulated protein). Dopamine-related toxicity was also a key factor, as a dopamine synthesis inhibitor blocked neuronal death in parkin null mice. These data suggest a model in which ER- and dopamine-related stress are major contributors to decreased viability of dopaminergic neurons in a setting relevant to Parkinson's disease.

Adenoviridae↗
PubMed2006

Nerve growth factor is critical for cardiac sensory innervation and rescues neuropathy in diabetic hearts.

BACKGROUND: Molecular mechanisms regulating the cardiac sensory nervous system remain poorly understood. Cardiac sensory nerve impairment causes silent myocardial ischemia, a main cause of sudden death in diabetes mellitus (DM). The present study focused on the roles of nerve growth factor (NGF) in the regulation of the cardiac sensory nervous system and analyzed the mechanism of silent myocardial ischemia in DM. METHODS AND RESULTS: We screened neurotrophic factors and found that cardiac sensory nerves developed in parallel with NGF synthesized in the heart. Cardiac nociceptive sensory nerves that were immunopositive for calcitonin gene-related peptide, dorsal root ganglia (DRG), and the dorsal horn were markedly retarded in NGF-deficient mice, whereas cardiac-specific overexpression of NGF rescued these deficits. DM was induced with streptozotocin in wild-type and transgenic mice overexpressing NGF in the heart. Downregulation of NGF, calcitonin gene-related peptide-immunopositive cardiac sensory denervation, and atrophic changes in DRG were observed in DM-induced wild-type mice, whereas these deteriorations were reversed in DM-induced NGF transgenic mice. Cardiac sensory function, measured by myocardial ischemia-induced c-Fos expression in DRG, was also downregulated by DM in the wild-type mice but not in NGF transgenic mice. Direct gene transfer of NGF in the diabetic rat hearts improved impaired cardiac sensory innervation and function, determined by electrophysiological activity of cardiac afferent nerves during myocardial ischemia. CONCLUSIONS: These findings demonstrate that the development and regulation of the cardiac sensory nervous system are dependent on NGF synthesized in the heart and that DM-induced NGF reduction causes cardiac sensory neuropathy.

Afferent Pathways↗
PubMed2006

Chondromodulin-I maintains cardiac valvular function by preventing angiogenesis.

The avascularity of cardiac valves is abrogated in several valvular heart diseases (VHDs). This study investigated the molecular mechanisms underlying valvular avascularity and its correlation with VHD. Chondromodulin-I, an antiangiogenic factor isolated from cartilage, is abundantly expressed in cardiac valves. Gene targeting of chondromodulin-I resulted in enhanced Vegf-A expression, angiogenesis, lipid deposition and calcification in the cardiac valves of aged mice. Echocardiography showed aortic valve thickening, calcification and turbulent flow, indicative of early changes in aortic stenosis. Conditioned medium obtained from cultured valvular interstitial cells strongly inhibited tube formation and mobilization of endothelial cells and induced their apoptosis; these effects were partially inhibited by chondromodulin-I small interfering RNA. In human VHD, including cases associated with infective endocarditis, rheumatic heart disease and atherosclerosis, VEGF-A expression, neovascularization and calcification were observed in areas of chondromodulin-I downregulation. These findings provide evidence that chondromodulin-I has a pivotal role in maintaining valvular normal function by preventing angiogenesis that may lead to VHD.

Aged↗
PubMed2006

Methoxyflavones protect cells against endoplasmic reticulum stress and neurotoxin.

Enhanced endoplasmic reticulum (ER) stress leads to cell death in various pathophysiological situations. During a search for compounds that regulate ER stress, we identified methoxyflavones, a group of flavonoids, as strong protective agents against ER stress. Analysis in mouse insulinoma MIN6 cells revealed that methoxyflavones mildly activated the eukaryotic initiation factor 2alpha and nuclear factor erythroid 2-related factor pathways, but not the XBP1 pathway, and induced downstream genes, including glucose-regulated protein (GRP) 78, a molecular chaperone in the ER. The protective effect of methoxyflavones was enhanced by agents that increase intracellular cAMP levels such as forskolin, dibutyryl-cAMP and IBMX, but suppressed by the protein kinase A (PKA) inhibitor H-89, suggesting involvement of the PKA pathway in the regulation of ER stress by methoxyflavones. Consistent with the results in cultured cells, pretreatment of mice with tangeretin, a methoxyflavone, enhanced expression of GRP78 and HO-1 without causing ER stress in renal tubular epithelium and prevented tunicamycin-induced cell death. Furthermore, preadministration of tangeretin in mice enhanced expression of GRP78 in the substantia nigra pars compacta and protected dopaminergic neurons against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a neurotoxin that induces both oxidative and ER stress. These results suggest that methoxyflavones play an important role in the regulation of ER stress and could be a therapeutic target for the ER stress-related diseases.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2006

Clinical implications of "pure" Hisian pacing in addition to para-Hisian pacing for the diagnosis of supraventricular tachycardia.

BACKGROUND: Para-Hisian pacing is an effective method of differentiating between pathways for retrograde conduction over the accessory pathway (AP) and over the atrioventricular node (AVN). When performing para-Hisian pacing, the pacing spike sometimes captures only the His bundle, which we named "pure" Hisian pacing (Hc). OBJECTIVE: We evaluated the significance of pure Hisian pacing for predicting the pathways of ventriculoatrial conduction. METHODS: In 62 patients with supraventricular tachycardia, both para-Hisian and pure Hisian pacing were carried out during the sinus rhythm, resulting in three different types of electrocardiographic complexes with wide (local ventricular myocardial capture), slightly narrow (both local myocardial and His bundle capture), and very narrow QRS widths (Hc). A change of atrial activation sequence as demonstrated by these pacing modes indicated the presence of multiple retrograde pathways. The diagnosis of retrograde pathways by para-Hisian pacing with or without Hc was evaluated. RESULTS: In 22 patients with AVN reentrant tachycardia, para-Hisian pacing alone was able to correctly predict ventriculo-atrial conduction exclusively through the AVN without requiring findings from Hc. In 40 AP patients, para-Hisian pacing showed a pattern of retrograde conduction through the AVN in six, through both the AVN and AP in 10, and through an AP in 24 patients. Four of these 24 patients were diagnosed as having multiple pathways (AP+AVN or dual APs) by the addition of Hc. CONCLUSION: Pure Hisian pacing can help disclose another pathway for retrograde conduction in AP patients, which is unpredicted by ordinary para-Hisian pacing.

Atrioventricular Node↗
PubMed2006

Coronary artery disease and a functional polymorphism of hTERT.

Genetic variation, a -1327T/C polymorphism, of human telomerase reverse transcriptase (hTERT) is associated with leukocyte telomere length in healthy subjects, but clinical significances of this functional polymorphism are not clear. Recently, the relationship between the telomere system and coronary artery disease (CAD) was reported. We investigated the association between the -1327T/C polymorphism and (a) susceptibility to CAD and (b) telomere length in CAD patients. In a case-control study, 104 patients confirmed by coronary angiography and 115 age- and sex-matched controls were enrolled. There was a higher frequency of the -1327C/C genotype in CAD patients (51.9%) compared with controls (36.5%, p = 0.0218). Among the 104 CAD patients, leukocyte telomere length in the -1327C/C genotype (7.62+/-2.19 kb, mean+/-SD) was shorter than that in the -1327T/C and -1327T/T genotypes (8.74+/-2.92, p = 0.0287). These findings suggest that the -1327C/C genotype is a genetic risk factor for CAD and relates to shorter telomere length among CAD patients.

Case-Control Studies↗
PubMed2006

Antigen-specific effects of autoantibodies against sarcolemmal Na-K-ATPase pump in immunized cardiomyopathic rabbits.

OBJECTIVES: We examine antigen-specific actions of autoantibodies directed against sarcolemmal Na-K-ATPase. BACKGROUND: Autoantibodies against some receptors or pumps were detected in patients with dilated cardiomyopathy. Although immunoglobulin adsorption therapy improved cardiac function in such patients, direct pathogenic effects of autoantibodies remain to be proven. METHODS: Japanese white rabbits were immunized once a month with purified Na-K-ATPase (NKA rabbits, n=10) or a synthetic peptide corresponding to the second extracellular loop of beta1-adrenergic receptors (beta rabbits, n=10), respectively. Control rabbits (n=10) received vehicle in the same manner. RESULTS: At 6 months, cardiac hypertrophy along with increased left ventricular end-diastolic pressure was observed in both NKA and beta rabbits, and inhibitory G protein level increased in both NKA and beta rabbits. Histological findings showed similar myocyte hypertrophy and interstitial fibrosis in both rabbits. Enzymatic activities of Na-K-ATPase were lower in NKA rabbits than in other groups. Immunoblotting showed that alpha3-isoform of Na-K-ATPase was selectively reduced in myocardium from NKA rabbits. CONCLUSIONS: Our present findings suggested that isoform-specific alterations of myocardial Na-K-ATPase activity were induced by immunizing rabbits. This was not secondary change due to cardiac hypertrophy. Thus, autoantibodies against sarcolemmal Na-K-ATPase have antigen-specific effect on the heart in vivo.

Analysis of Variance↗
PubMed2006

Immunoneutralization of gonadotropin-releasing hormone type-III suppresses male reproductive behavior of cichlids.

To investigate the roles of gonadotropin-releasing hormone (GnRH) types in reproductive behaviors, antisera against GnRH1, GnRH2 and GnRH3 were stereotaxically administered into the intracerebroventricular region to neutralize the three native GnRH types in the brain of male tilapia Oreochromis niloticus. Reproductive behaviors (nest-building and aggressive behaviors), and morphological changes of the three GnRH systems were investigated by immunocytochemistry. GnRH1, GnRH2 and GnRH3 immunoreactive fibers were significantly decreased following injections of GnRH antisera indicating successful neutralization of their respective endogenous GnRH peptides. GnRH1- and GnRH2-immunoneutralization did not inhibit reproductive behaviors but GnRH3-immunoneutralization significantly decreased nest-building ability (Saline: 26.5 +/- 3.7%/day versus GnRH3: 6.1 +/- 2.9%/day, P < 0.001), nest size (Saline: 0.67 +/- 0.09 points versus GnRH3: 0.10 +/- 0.05 points, P < 0.0002) and aggressive behavior (Saline: 2.34 +/- 0.19 points versus GnRH3 1.06 +/- 0.12 points, P < 0.0001). These observations provide evidence that GnRH3 is a potent neuromodulator of reproductive behaviors in male tilapia.

Aggression↗
PubMed2006

A rat model of human FENIB (familial encephalopathy with neuroserpin inclusion bodies).

FENIB (familial encephalopathy with neuroserpin inclusion bodies) is caused by intracellular accumulation/polymerization of mutant neuroserpins in the endoplasmic reticulum (ER). Transgenic rats overexpressing megsin (Tg meg), a newly identified serine protease inhibitor (serpin), demonstrated intraneuronal periodic-acid Schiff (PAS)-positive inclusions distributed throughout deeper layers of cerebral cortex, CA1 of the hippocampus, and substantia nigra. Hippocampal extracts from Tg meg rats showed increased expression of ER stress proteins, and activation of caspases-12 and -3, associated with decreased neuronal density. Enhanced ER stress was also observed in dopaminergic neurons in the substantia nigra, in parallel with decreased neuronal viability and motor coordination. In each case, PAS-positive inclusions were also positive for megsin. These data suggest that overexpression of megsin results in ER stress, eventuating in the formation of PAS-positive inclusions. Tg meg rats provide a novel model of FENIB, where accumulation of serpins in the ER induces selective dysfunction/loss of specific neuronal populations.

Animals↗
PubMed2006

Identification of novel saponins from edible seeds of Japanese horse chestnut (Aesculus turbinata Blume) after treatment with wooden ashes and their nutraceutical activity.

Natural seeds of Japanese horse chestnut (Aesculus turbinata Blume) contain large amounts of mixed triterpenoidal saponins called escins. Recent studies have shown that escins have several biological activities including anti-inflammatory action and inhibitory effects on the absorption of ethanol and glucose. For the edible utilization of the seeds, natural seeds are usually treated with wooden ashes to remove harshness. Here, we found the novel compounds derived from escins in the edible seeds after the food processing with wooden ashes. The instrumental analyses revealed the chemical structures of escins and the derivatives. These compounds are identified as four types of deacetylescins Ia, IIa, Ib, and IIb as well as two types of desacylescins I and II. To determine their biological activity, the purified compounds were tested for their potential nutraceutical activity. The oral glucose tolerance test in mice revealed that a single oral administration of the isolated components of deacetylescins at a dose of 100 mg/kg was clearly effective in attenuating the elevation of blood glucose levels. The inhibitory effects of escins and their derivatives were in the order of escins>deacetylescins>desacylescins. Moreover, we found the inhibitory activity of those compounds on pancreatic lipase. Escins were the most potent in inhibiting the enzyme activity, and followed by desacylescins and then deacetylescins. Taken together, our results suggest the potential usefulness of novel saponins including deacetylescins and desacylescins from edible seeds as novel sources for nutraceutical foods with anti-obese effects.

Aesculus↗
PubMed2006

Pulsatile cardiac tissue grafts using a novel three-dimensional cell sheet manipulation technique functionally integrates with the host heart, in vivo.

We devised a method of fabricating easily transplantable scaffoldless 3D heart tissue, made with a novel cell-sheet (CS) technology from cultured cardiomyocytes using a fibrin polymer coated dish. In the present study, we tested in vivo electrical communication which is essential for improving heart function between the host heart and the grafted CS. The epicardial surface of the ventricle of an anesthetized open-chest nude rat was ablated by applying a heated metal. Bilayered CS was obtained from neonatal rat primary culture. CS was transplanted onto the injured myocardial surface (sMI) (sMI+sheet group). The rats were allowed to recover for 1 to 4 weeks, to stabilize the grafts. Action potentials (APs) from the excised perfused heart were monitored by the fluorescence signal of di-4ANEPPS with a high speed charge-coupled device camera. The APs were observed under epicardial pacing of the host heart or the CS grafts. The pacing threshold of the current output was measured in the sMI+sheet group and in the nongrafted sMI group at the center of the sMI and in the normal zone (Nz). Bidirectional AP propagation between the sMI and Nz was observed in the sMI+sheet group (n=14), but was blocked at the marginal area of the sMI in the sMI group (n=9). The ratio of the pacing threshold (sMI/Nz) was significantly lower in the sMI+sheet than in the sMI group (3.0+/-0.7, 19.0+/-6.1 respectively P<0.05). There were neither spontaneous nor pacing-induced arrhythmias in these two groups. Bidirectional smooth AP propagation between the host heart and the grafted CS was observed. This finding suggested functional integration of this CS graft with the host heart without serious arrhythmia.

Action Potentials↗
PubMed2006

Neurogenic potential of progenitors derived from human circulating CD14+ monocytes.

We previously reported a primitive cell fraction derived from human circulating CD14+ monocytes, named monocyte-derived multipotential cells (MOMC), that can differentiate along mesenchymal lineages, including bone, cartilage, fat, skeletal muscle and cardiac muscle. In this study, we investigated whether MOMC can differentiate into the neuronal lineage. MOMC were fluorescently labelled and cocultivated with a primary culture of rat neurons for up to 4 weeks. The protein and gene expressions of neuron-specific markers in the human MOMC were evaluated over time using immunohistochemistry, in situ hybridization and reverse transcription followed by PCR. Shortly after cocultivation with rat neurons, nearly all the MOMC expressed early neuroectodermal markers, Mash1, Neurogenin2 and NeuroD, together with nestin, an intermediate filament expressed in neurogenesis. After 14 days of coculture, a subpopulation of MOMC displayed a multipolar morphology with elongated neurites and expressed mature neuron-specific markers, including neurofilament, microtubule-associated protein type 2, beta3-tubulin, NeuN and Hu. Transdifferentiation of monocytes into the neuroectodermal lineage was shown by the simultaneous expression of proneural markers and CD45/CD14 early in the differentiation process. The cocultivated MOMC retained their proliferative capacity for at least 16 days. Finally, the neuronal differentiation of MOMC was observed when they were cultured with neurons without cell-to-cell contact. The capacity of MOMC to differentiate into both mesodermal and neuroectodermal lineages suggests that circulating CD14+ monocytes are more multipotential than previously thought.

Animals↗
PubMed2006

Deletion of SERP1/RAMP4, a component of the endoplasmic reticulum (ER) translocation sites, leads to ER stress.

Stress-associated endoplasmic reticulum (ER) protein 1 (SERP1), also known as ribosome-associated membrane protein 4 (RAMP4), is a Sec61-associated polypeptide that is induced by ER stress. SERP1-/- mice, made by targeted gene disruption, demonstrated growth retardation, increased mortality, and impaired glucose tolerance. Consistent with high levels of SERP1 expression in pancreas, pancreatic islets from SERP1-/- mice failed to rapidly synthesize proinsulin in response to a glucose load. In addition, reduced size and enhanced ER stress were observed in the anterior pituitary of SERP1-/- mice, and growth hormone production was slowed in SERP1-/- pituitary after insulin stimulation. Experiments using pancreatic microsomes revealed aberrant association of ribosomes and the Sec61 complex and enhanced ER stress in SERP1-/- pancreas. In basal conditions, the Sec61 complex in SERP1-/- microsomes was more cofractionated with ribosomes, compared with SERP1+/+ counterparts, in high-salt conditions. In contrast, after glucose stimulation, the complex showed less cofractionation at an early phase (45 min) but more at a later phase (120 min). Although intracellular insulin/proinsulin levels were not significantly changed in both genotypes, these results suggest that subtle changes in translocation efficiency play an important role in the regulation of ER stress and rapid polypeptide synthesis.

Animals↗
PubMed2006

Randomized study of angiotensin II type 1 receptor blocker vs dihydropiridine calcium antagonist for the treatment of paroxysmal atrial fibrillation in patients with hypertension.

BACKGROUND: Mega trials of rhythm vs rate control could not demonstrate the usefulness of available antiarrhythmic drugs, so a more effective and safer therapy for atrial fibrillation (AF) is now required. One candidate is the so-called "upstream therapy", which refers to the blockade of upstream modifying elements (renin - angiotensin system, cathecholamines, oxidative stress etc) that contribute to the arrhythmogenic substrate. METHODS AND RESULTS: The Japanese Rhythm Management Trial II for Atrial Fibrillation (J-RHYTHM II study) is a randomized comparative evaluation of an angiotensin II type 1 blocker (candesartan) and a dihydropiridine calcium blocker (amlodipine), both combined with antithrombotic therapy, as an antiarrhythmic therapy for the treatment of paroxysmal AF (PAF) associated with hypertension. To test the usefulness of this therapy, this study will reveal the recurrence rate of asymptomatic as well as symptomatic PAF during 1-year of treatment with candesartan or amlodipine, using daily transtelephonic monitoring. CONCLUSIONS: The J-RHYTHM II study will follow 400 patients with PAF and hypertension who were treated at approximately 50 sites throughout Japan, and will provide clinically important information.

Amlodipine↗
PubMed2006

Altered action potential dynamics in electrically remodeled canine atria: evidence for altered intracellular Ca2+ handling.

BACKGROUND: Electrical instability following sustained rapid excitation has been attributed to altered ion channels. Alterations of Ca(2+) handling could also contribute to abnormal dynamics of action potential, favoring the initiation and perpetuation of arrhythmia. METHODS AND RESULTS: Transmembrane action potentials and twitch force (TF) were recorded from normal (n=6) and remodeled (6-week atrial pacing at 400 beats/min, n=6) canine atria. When the cycle length (CL) was suddenly prolonged in normal atria, both TF and action potential duration (APD) increased on the first beat, and decreased subsequently. Opposite changes were observed with sudden CL shortening. These dynamics in both APD and TF were abolished by ryanodine, but augmented by cyclopiazonic acid, an inhibitor of the sarcoplasmic reticulum (SR) Ca(2+) pump. In remodeled atria (RA), dynamic changes in APD were also concordant with dynamic changes in TF. The transient increases in APD and TF were enhanced, and the transient decreases were reduced compared to normal atria. The maximal slopes of APD and TF restitution curves were flatter and the magnitude of alternans was reduced in RA. The protein expression of SR Ca(2+) ATPase and SR Ca(2+)-release channel in RA was significantly reduced. CONCLUSION: Altered Ca(2+) handling may underlie abnormal APD dynamics in RA.

Action Potentials↗
PubMed2006

Novel method of displaying coronary CT angiography: Angiographic view.

Background A method of displaying coronary computed tomography (CT) angiography, which enables evaluation of coronary artery disease (CAD) with fewer images and is understandable to the third person, is preferable. Methods and Results A maximum intensity projection image was created in which contrast media in the ventricles is eliminated, enabling an overview of CAD in a single 3-dimensional (D) image that can be rotated to be viewed at various angles and is easily understood by a third person. Conclusions A novel method of displaying coronary CT angiography in a single 3-D image has been developed and we believe it should become available for many workstations.

Coronary Angiography↗