Biomedical subjects

Yoichi Nakamura

Publications and source records attributed to Yoichi Nakamura.

71 records · Page 4Linked to original sources

PubMed2003

Direct evidence for increased hydroxyl radicals in angiotensin II-induced cardiac hypertrophy through angiotensin II type 1a receptor.

Oxidative stress is known to contribute to numerous cardiac disease processes. However, the contribution of reactive oxygen species to cardiac hypertrophy has not yet been fully investigated. The aim of the present study was therefore to determine whether levels of reactive oxygen species were increased in angiotensin II-induced cardiac hypertrophy. We continuously administered angiotensin II (1.1 mg/kg per day) into wild-type and angiotensin II type-1a receptor knockout mice for 2 weeks. The angiotensin II treatment increased blood pressure and heart weight/body weight ratio in wild-type mice but not in knockout mice. The generation of hydroxyl radicals in heart tissue homogenate was directly assessed with electron spin resonance spectroscopy using a spin trapping agent, alpha-phenyl-N-tert butylnitrone. Angiotensin II significantly increased hydroxyl radical production 2.2-fold (p < 0.01) in the hearts of wildtype mice but not in knockout mice. The present study provided direct evidence for increased production of hydroxyl radicals in angiotensin II-induced cardiac hypertrophy through angiotensin II type-1a receptor. These findings in this study may provide important insights into the development of hypertrophy and the transition of hypertrophy to heart failure.

Angiotensin II↗

PubMed2003

Retrospective analysis of safety and efficacy of low-dose docetaxel 60 mg/m2 in advanced non-small cell lung cancer patients previously treated with platinum-based chemotherapy.

The efficacy and toxicity of low-dose docetaxel (60 mg/m2) were evaluated in patients with relapsed non-small-cell lung cancer (NSCLC) after platinum-containing chemotherapy. Docetaxel 60 mg/m2 was infused during 1 hour with no routine premedication, with courses repeated at 3-week intervals. Twenty-seven patients were analyzed retrospectively. The median age was 56 years (range, 32-72); 22 patients (81.5%) had adenocarcinoma, 26 (96.3%) had stage IV disease, and 23 (85.2%) were Eastern Cooperative Oncology Group performance status 0 to 1. Five patients (18.5%) had a partial response. Median progression-free survival time for all patients was 1.9 months, and median survival time was 9.4 months. The predominant toxicity was neutropenia, which was grade III or IV in 63% of patients. No neutropenic fever was observed. Other hematologic toxicities were mild (all grade II). Thus, low-dose docetaxel (60 mg/m2) yielded a response rate comparable to that achieved with moderate- to high-dose docetaxel (75-100 mg/m2) as second-line chemotherapy in platinum-pretreated NSCLC, and had less toxicity. Further investigation of the optimal docetaxel dose as second-line chemotherapy in NSCLC is warranted.

Adult↗

PubMed2003

Early-phase neutrophilia in cigarette smoke-induced acute eosinophilic pneumonia.

Although cigarette smoking is a recognized cause of acute eosinophilic pneumonia (AEP), and an increase in eosinophils in the lung is a common occurrence in AEP, early-phase neutrophilia in AEP is not well understood. We describe three cases of cigarette smoke (menthol type)-induced AEP with neutrophilia in the lungs or blood. Increased in-vitro production of the neutrophil chemoattractant interleukin (IL)-8 by human bronchial epithelial cells (HBECs) was correlated with neutrophilia. We suggest that IL-8 released from HBECs is involved in neutrophilia in the lung in AEP, and is newly recognized as an important factor in the early phase of AEP development.

Acute Disease↗

PubMed2003

Three cases of the gastrosplenic and the hepatomesenteric trunks.

Three common branches of the celiac trunk are the left gastric artery, the splenic artery and the common hepatic artery. The variation of the three branches of the celiac trunk has an importance for the arterial supply to the digestive organs of the upper abdomen. In this study, we present three cases of the gastrosplenic and the hepatomesenteric trunks in Japanese cadavers. Especially, in Case 1, the left inferior phrenic artery arose from the gastrosplenic trunk and the left hepatic artery arose from the left gastric artery. In Cases 2 and 3, the common hepatic artery penetrated the pancreatic parenchyma before reaching liver. In Case 3, the right hepatic artery arose from the hepatomesenteric trunk.

Cadaver↗

PubMed2003

Effect of human airway trypsin-like protease on intracellular free Ca2+ concentration in human bronchial epithelial cells.

It has been shown that human airway trypsin-like protease (HAT) is localized in human bronchial epithelial cells (HBEC), and trypsin activates protease-activated receptor-2 (PAR-2). Activation of PAR-2 activates G-protein followed by an increase of intracellular free Ca2+, [Ca2+]in. This study was undertaken to clarify whether HAT can activate PAR-2 in HBEC or not. RT-PCR showed that HAT mRNA is expressed in HBEC, and PAR-2 mRNA is the most strongly expressed of the known PARs in HBEC. Both PAR-2 agonist peptide (PAR-2 AP) and HAT increased [Ca2+]in in HBEC in a biphasic fashion; a prompt, sharp increase (peak I) and a sustained low plateau (peak II). PAR-2 AP over 100-200 microM and HAT over 200-300 mU/ml (0.08-0.12 microM) induced both peak I and II, and PAR-2 AP below 100 microM and HAT below 200 mU/ml induced only peak II. Both PAR-2 AP-induced and HAT-induced peak I were induced by Ca2+ mobilization from intracellular stores, because they appeared even in Ca2+-free medium. Both PAR-2 AP-induced and HAT-induced peak II were induced by an influx of extracellular Ca2+, because they were abolished in Ca2+-free medium. The Ca2+ response to HAT was desensitized by exposure of HBEC to PAR-2 AP. These results indicate that HBEC have a functional PAR-2, and HAT regulates cellular functions of HBEC via activation of PAR-2.

Adult↗

PubMed2002

Short-term prophylaxis with deoxyspergualin prevents testicular autoimmunity in mice.

The effects of the treatment with the immunosuppressant deoxyspergualin on the development of experimental autoimmune orchitis were studied. The results showed that C3H/He mice immunized with testicular germ cells and treated daily with either 0.3 or 3 mg/kg body weight deoxyspergualin during days 15-20 post-immunization developed experimental autoimmune orchitis lesions with a significantly lower incidence and severity than did the control mice treated under the same experimental conditions with phosphate buffered saline (PBS). The effects of deoxyspergualin were clearly dose-dependent, and the higher dose of the drug also markedly reduced the degree of delayed type hypersensitivity responses against testicular germ cells. These data suggest that deoxyspergualin may be worthy of consideration for the prevention/treatment of human immunoinflammatory orchitis.

Animals↗

PubMed2002

Demonstration of expression of mRNA for particular AMPA and kainate receptor subunits in immature and mature cultured rat calvarial osteoblasts.

Reverse transcription polymerase chain reaction revealed expression of mRNA for particular subunits of ionotropic glutamate receptors (iGluR) in primary cultures of rat calvarial osteoblastic cells under immature to mature states. These included GluR3, KA1 and KA2 subunits, in addition to NR1 and NR2D subunits. These results suggest that glutamate may play an unidentified role in mechanisms associated with cellular development through particular subunits of iGluR in rat calvarial osteoblasts.

Animals↗

PubMed2002

Carvedilol decreases elevated oxidative stress in human failing myocardium.

BACKGROUND: Oxidative stress has been implicated in the pathogenesis of heart failure. However, direct evidence of oxidative stress generation in the human failing myocardium has not been obtained. Furthermore, the effect of carvedilol, a vasodilating beta-blocker with antioxidant activity, on oxidative stress in human failing hearts has not been assessed. This study was therefore designed to determine whether levels of lipid peroxides are elevated in myocardia of patients with dilated cardiomyopathy (DCM) and whether carvedilol reduces the lipid peroxidation level. Methods and Results- Endomyocardial biopsy samples obtained from 23 patients with DCM and 13 control subjects with normal cardiac function were studied immunohistochemically for the expression of 4-hydroxy-2-nonenal (HNE)-modified protein, which is a major lipid peroxidation product. Expression of HNE-modified protein was found in all myocardial biopsy samples from patients with DCM. Expression was distinct in the cytosol of cardiac myocytes. Myocardial HNE-modified protein levels in patients with DCM were significantly increased compared with the levels in control subjects (P<0.0001). Endomyocardial biopsy samples from 11 patients with DCM were examined before and after treatment (mean, 9+/-4 months) with carvedilol (5 to 30 mg/d; mean dosage, 22+/-8 mg/d). After treatment with carvedilol, myocardial HNE-modified protein levels decreased by 40% (P<0.005) along with amelioration of heart failure. CONCLUSIONS: Oxidative stress is elevated in myocardia of patients with heart failure. Administration of carvedilol resulted in a decrease in the oxidative stress level together with amelioration of cardiac function.

Adrenergic beta-Antagonists↗

PubMed2002

Constitutive expression of heterologous N-methyl-D-aspartate receptor subunits in rat adrenal medulla.

An RT-PCR analysis revealed constitutive expression of mRNA for N-methyl-D-aspartate (NMDA) receptor (NR)-1, NR-2C, and NR-2D subunits in rat adrenal and pituitary glands, in addition to brain and retina. Constitutive expression of mRNA was detected for the NR-2A subunit in pituitary but not adrenal gland. Although on Western blotting assays adrenal medulla exhibited expression of NR-1 subunit protein without expression of NR-2C and NR-2D subunit proteins, an immunohistochemical investigation clearly showed selective localization of proteins for NR-1, NR-2C, and NR-2D subunits in adrenal medulla but not in adrenal cortex. Prior treatment with different glycosidases invariably resulted in a marked increase in immunoreactivity to the anti-NR-1 antibody in both hippocampus and adrenal medulla. An intraperitoneal injection of a blocker of NMDA receptor channel, but not NMDA itself, led to marked potentiation of DNA binding activity of the transcription factor activator protein-1 in adrenal nuclear extracts 2 hr after administration. These results suggest that heteromeric NMDA receptor channels may be constitutively and functionally expressed with glycosylation of NR-1 subunit under the influence of tonic stimulation by circulating agonists such as L-glutamate in rat adrenal medulla.

Adrenal Medulla↗

PubMed2002

Potentiation of nuclear activator protein-1 DNA binding following brief exposure to N-methyl-D-aspartate in immature cultured rat hippocampal neurons.

Similar potentiation was seen with the nuclear transcription factor activator protein-1 (AP1) binding in rat hippocampal neurons cultured for 3 and 9 DIV, when determined immediately after exposure to 500 microM N-methyl-D-aspartate (NMDA) for 60-120 min. Growth-associated protein-43 was markedly expressed in hippocampal neurons cultured for 3-5 DIV, with a decline up to 9 DIV. In immature neurons cultured for 3 DIV, NMDA was effective in significantly potentiating AP1 binding even in the presence of Mg(2+) with less potency than in the absence of Mg(2+) when determined immediately after sustained exposure for 120 min. When determined 120 min after brief exposure for 5 min, by contrast, NMDA significantly potentiated AP1 binding at a range of 100-500 microM only in the absence of Mg(2+) in immature neurons cultured for 3 DIV. At least 60 min was required for significant potentiation of AP1 binding as an interval between brief exposure and subsequent cell harvest. Dizocilpine abolished the potentiation determined 120 min after brief exposure to 500 microM NMDA, and both dantrolene and nifedipine were similarly effective in significantly preventing the potentiation at 10-50 microM. These results suggest that NMDA may potentiate AP1 binding following a sustained increase in intracellular free Ca(2+) concentrations through influxes across NMDA-operated and L-type voltage-sensitive Ca(2+) channels, in addition to release from intracellular Ca(2+) stores, in immature cultured rat hippocampal neurons.

Animals↗

PubMed2002

Anti-inflammatory effects of long-lasting locally-delivered human recombinant tissue factor pathway inhibitor after balloon angioplasty.

BACKGROUND: Tissue factor pathway inhibitor (TFPI) has anti-proliferative and anti-migratory effects on cultured smooth muscle cells (SMC) in addition to its anti-thrombotic activity. Here, we assess how long locally delivered recombinant TFPI (rTFPI) remains detectable at the delivery sites and clarify the main mechanism by which rTFPI blocks neointimal growth in vivo. METHODS: The iliac arteries of 85 Japanese white rabbits were injured using a Cutting Balloon. First, to establish the efficacy of local delivery of rTFPI, 5 groups of 3 rabbits each were examined immediately or 1, 2, 4 or 7 days after delivery. They were treated locally with a total amount of 200 microg of rTFPI given at 40 microg per pulse per minute by means of a Pulse Spray catheter. Thereafter, 34 rabbits which had received 200 microg of rTFPI after cutting angioplasty were compared to the same number of controls regarding thrombosis, inhibition of neointimal proliferation and inflammation. RESULTS: A total of 2.6+/-1.6 ng rTFPI persisted on the injured vessel 4 days after delivery. rTFPI was still present on 48 % of the cut sites 7 days after delivery, despite its short half-life in plasma. Thrombosis in the rTFPI-treated group was significantly reduced compared to the controls. The number of macrophages present within the media and intima was significantly decreased at day 7 after delivery of rTFPI. Furthermore, the number of Ki-67-positive cells 14 days after rTFPI delivery was significantly lower than in controls although there were no significant differences between them after 2 days. CONCLUSIONS: Local delivery of rTFPI decreased the degree of neointimal formation 4 weeks after TFPI delivery because of anti-inflammatory and anti-proliferative effects in addition to, or rather than, via anti-thrombosis.

Angioplasty, Balloon↗

PubMed2002

Blockade by ferrous iron of Ca2+ influx through N-methyl-D-aspartate receptor channels in immature cultured rat cortical neurons.

Rat cortical neurons cultured for 3 days in vitro were loaded with the fluorescent indicator fluo-3 for assessment of intracellular free calcium ion (Ca2+) concentrations with the aid of a confocal laser-scanning microscope. In the absence of added MgCl2, the addition of NMDA induced a rapid but sustained increase in the number of fluorescent neurons in a concentration-dependent manner at a concentration range of 1-100 micro m with the increase by KCl being transient. The addition of FeCl2, but not FeCl3, markedly inhibited the increase by NMDA in a reversible manner at concentrations of 10-200 micro m, without affecting that by KCl. Extensive analyses revealed clear differentiation between inhibitions by ferrous iron and other channel blockers known to date. The inhibition by FeCl2 was completely prevented by the addition of two different iron chelators. Exposure to NMDA alone did not lead to cell death in immature cultured neurons, however, while further addition of FeCl2 invariably induced neuronal cell death 24 h after exposure. These results give support to our previous proposal that NMDA receptor complex may contain a novel site sensitive to blockade by ferrous iron in rat brain.

Animals↗

PubMed2002

Differential effects of lowering culture temperature on mediator release from lipopolysaccharide-stimulated neonatal rat microglia.

OBJECTIVE: Therapeutic moderate hypothermia has the potential for neuronal protection against brain injury. Microglia, a type of immune-related cell in the brain, may play a certain role in neuronal damage subsequent to injury. We examined the effects of culture temperature changes from 37 degrees C to 33 degrees C or 30 degrees C on mediator release, including nitric oxide, interleukin-6, and tumor necrosis factor-alpha from lipopolysaccharide-stimulated microglia harvested from neonatal rats. DESIGN: Laboratory study. SETTING: University medical school. SUBJECTS: Microglial cells isolated from primary cultures of rat brains. INTERVENTIONS: The production of nitric oxide was measured by a nitrite accumulation method in a culture medium, whereas cytokines, interleukin-6, and tumor necrosis factor-alpha were measured by enzyme-linked immunosorbent assay. MEASUREMENT AND MAIN RESULTS: At 30 degrees C and 33 degrees C, nitric oxide production stimulated by lipopolysaccharide decreased to 10 and 30% of control (37 degrees C), respectively, 24 hrs after the stimulation, and the decrease was sustained for 48 hrs. Interleukin-6 production at 30 degrees C and 33 degrees C was also reduced to 30% of control 6 hrs after the activation. Such responses lasted throughout the study. However, tumor necrosis factor-alpha release at 30 degrees C and 33 degrees C was depressed for only 6 hrs after stimulation, followed by subsequent elevation to concentrations similar to those at 37 degrees C. Microglial morphologic activation, showing changes from round to bipolar, reached a peak at 6 hrs in the 37 degrees C group, returning to round 12 hrs after lipopolysaccharide application. In 30 degrees C and 33 degrees C, the zenith was detected at 6 hrs, with activation remaining even 12 hrs after the stimulation, suggesting prolongation of the microglial response to lipopolysaccharide, which was inconsistent with changes in tumor necrosis factor release. CONCLUSIONS: Decreasing culture temperature inhibits the production of nitric oxide and interleukin-6 from activated microglia. Differences were found in the degree or time course change between tumor necrosis factor-alpha and the other mediators. Also, the time course of morphologic changes in microglia was dependent on culture temperature. Further studies are required to define the mechanisms for such differences in mediator release from cooled microglia and also to clarify the inconsistency between morphologic change and its function in the cell.

Animals↗

PubMed2002

Regulating factors for microglial activation.

Microglia, residential macrophages in the central nervous system, can release a variety of factors including cytokines, chemokines, etc. to regulate the communication among neuronal and other types of glial cells. Microglia play immunological roles in mechanisms underlying the phagocytosis of invading microorganisms and removal of dead or damaged cells. When microglia are hyperactivated due to a certain pathological imbalance, they may cause neuronal degeneration. Pathological activation of microglia has been reported in a wide range of conditions such as cerebral ischemia, Alzheimer's disease, prion diseases, multiple sclerosis, AIDS dementia, and others. Nearly 5000 papers on microglia can be retrieved on the Web site PubMed at present (November 2001) and half of them were published within the past 5 years. Although it is not possible to read each paper in detail, as many factors as possible affecting microglial functions in in vitro culture systems are presented in this review. The factors are separated into "activators" and "inhibitors," although it is difficult to classify many of them. An overview on these factors may help in the development of a new strategy for the treatment of various neurodegenerative diseases.

Animals↗

PubMed2002

Cigarette smoke-induced acute eosinophilic pneumonia accompanied with neutrophilia in the blood.

Smoking causes various changes in the lung. This report describes a case of cigarette smoke-induced acute eosinophilic pneumonia (CS-AEP) with neutrophilia in the blood. However, the precise mechanism is unknown, so we examined the effect of exposure to cigarette smoke extracts on the production of interleukin (IL)-4, IL-5, IL-8, IL-18, granulocyte macrophage-colony stimulating factor (GM-CSF), and vascular endothelial growth factor (VEGF) by human bronchial epithelial cells (HBECs) obtained from the patient. We found that IL-8 released from HBECs was involved in neutrophilia in the blood, and is a new factor in the development of AEP, especially in the early phase.

Acute Disease↗

PubMedDate not supplied

Corrosion casts of convoluted testicular arteries in mice and rats.

The preparation of vascular corrosion casts enables us to observe the minute features of blood vessels. For mice and rats, reports on the macroscopical appearance of testicular arteries with the cast technique have been quite limited. Therefore, in the present study, we tried to prepare corrosion casts of such arteries in order to observe the three-dimensional structures in mice and rats. Vascular casts of testicular arteries were produced by intravenous injection of a polymethylmethacrylate solution, followed by treatment of the whole animal bodies with NaOH. Additionally, the gross appearance of human testicular arteries in cadavers was compared with that of the vascular casts. The results showed that the testicular arteries of humans, mice, and rats run from the abdominal aorta to the testes, with various configurations (straight, meandering, spiral, or coiled forms), and each species exhibits a specific pattern. The specific forms of testicular arteries may play several roles in protection of normal spermatogenesis, such as allowing wide mobility of the testes on physical attack, heat emission with the entwined pampiniform plexus, and reduction of the blood flow rate. The great extension of the testicular arteries during the fetal period from the upper abdomen to the scrotum when the testes descend might be another feature of the specific development of their running configuration.

Animals↗

PubMedDate not supplied

Toluene diisocyanate (TDI) induces production of inflammatory cytokines and chemokines by bronchial epithelial cells via the epidermal growth factor receptor and p38 mitogen-activated protein kinase pathways.

Toluene diisocyanate (TDI) is known as one of causes of occupational asthma and hypersensitivity pneumonitis. To investigate the stimulatory effect on bronchial epithelial cells in response to TDI, the authors examined production of cytokines by the bronchial epithelial cell line BEAS-2B and intercellular signal transduction stimulated by TDI-human serum albumin (HSA) conjugate. The production of interleukin (IL)-8, granulocyte-macrophage colony-stimulating factor (GM-CSF), and regulated on activation normal T cell expressed and secreted (RANTES) from the bronchial epithelial cells were augmented by the TDI-HSA conjugate. Extracellular signal-regulated kinase (Erk) 1/2 and p38 mitogen-activated protein kinase (MAPK) were phosphorylated by the TDI-HSA conjugate. AG1478, SB203580, and dexamethasone prevented augmentation of these cytokine production. TDI-HSA conjugate did not augment release of epidermal growth factor (EGF) ligands from BEAS-2B. These results suggest that TDI directly induces production of proinflammatory cytokines and chemokines through p38 MAPK and EGF receptor (EGFR)-Erk pathway without an autocrine mechanism. Thus, TDI was shown to have a stimulatory effect on bronchial epithelial cells, suggesting the potent role of bronchial epithelial cells in TDI-induced asthma.

Allergens↗