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Biomedical subjects

Yoichi Nakamura

Publications and source records attributed to Yoichi Nakamura.

At least 37 records · Page 2Linked to original sources
PubMed2005

Relationship between oxidative stress and systolic dysfunction in patients with hypertrophic cardiomyopathy.

BACKGROUND: Progression of hypertrophic cardiomyopathy (HCM) to left ventricular dilatation and systolic dysfunction sometimes occurs. However, the mechanism is not known. We examined whether oxidative stress was elevated in myocardia of HCM patients and whether the levels were correlated with left ventricular dilatation and systolic dysfunction. METHODS AND RESULTS: Endomyocardial biopsy samples obtained from the right ventricular side of the septum of 31 patients with HCM, and 10 control subjects 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 HCM. Expression was distinct in the cytosol of cardiomyocytes. The expression levels in patients with HCM were significantly increased compared with those in control subjects (P = .0005). The expression levels in patients with HCM were correlated with left ventricular end-diastolic diameter (r = 0.483, P = .0053) and end-systolic diameter (r = 0.500, P = .0037) determined by echocardiography. The expression levels were inversely correlated with left ventricular ejection fraction determined by left ventriculography (r = -0.640, P = .0001). CONCLUSION: Oxidative stress was elevated in myocardia of HCM patients and the levels were correlated with left ventricular dilatation and systolic dysfunction. Oxidative stress is involved in the pathogenesis of heart failure in patients with HCM.

Aldehydes↗
PubMed2005

Gefitinib, an EGFR tyrosine kinase inhibitor, directly inhibits the function of P-glycoprotein in multidrug resistant cancer cells.

Gefitinib (Iressa) is a selective epidermal growth factor receptor tyrosine kinase inhibitor and is used for the treatment of lung cancer. Recently, we discovered that it inhibits the breast cancer resistance protein, which is an ATP-binding cassette transporter. P-glycoprotein (Pgp) also pumps multiple types of drugs out of the cell using energy generated from ATP, and confers multidrug resistance on cancer cells. This study was designed to examine whether gefitinib inhibits the function of Pgp. We used multidrug resistant PC-6/PTX lung cancer and MCF-7/Adr breast cancer cells which overexpress Pgp and measured their drug sensitivity and drug-efflux function by tetrazolium assay and flowcytometry, respectively. In addition, the drug-stimulated ATPase activity of Pgp was measured using insect membranes that express human Pgp. Epidermal growth factor receptor was expressed in MCF-7/Adr, but not in PC-6/PTX cells, and the overexpression of Pgp did not confer resistance to gefitinib to both cell types. However, clinically achievable levels of gefitinib moderately reversed the Pgp-mediated resistance to paclitaxel and docetaxel in Pgp overexpressing cells. In addition, gefitinib increased the intracellular accumulation of the Pgp substrate rhodamine-123 in resistant cells, and activated ATPase in a preparation of pure Pgp-expressing membrane. These findings suggest that gefitinib directly interacts with Pgp and inhibits its function. Gefitinib may clinically inhibit the excretion of Pgp substrate drugs including anticancer agents, and its drug-interaction should therefore be considered.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

Gefitinib inhibits MUC5AC synthesis in mucin-secreting non-small cell lung cancer cells.

Gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is an active agent in non-small cell lung cancer, and rapidly relieves bronchorrhea in patients with bronchioloalveolar carcinoma before the improvement of radiological findings. In addition, epidermal growth factor regulates mucin secretion in normal airway goblet cells. The present study was designed to clarify whether gefitinib modifies mucin production in lung cancer cell lines apart from its anti-proliferative effects, using A549 adenocarcinoma and NCI-H292 mucoepidermoid carcinoma cells expressing EGFR and MUC5AC mRNA. Mucin synthesis was measured by RT-PCR and ELISA, and MAPK and Akt, the downstream targets of EGFR, were examined by Western blotting assay. The clinically-achievable concentration of 1muM gefitinib inhibited the growth of both cells by only 10%, but gefitinib suppressed MUC5AC mRNA levels subsequent to a decrease in intracellular and secreted MUC5AC protein. Gefitinib also inhibited the phosphorylation of MAPK and Akt, and the selective inhibitors PD98059 and LY294002 also suppressed MUC5AC protein synthesis. These findings suggest that gefitinib may inhibits MUC5AC synthesis, at least in part, through MAPK and Akt signaling pathways. Thus, gefitinib inhibits mucin production, which is encouraging for trials involving its use against bronchorrhea in patients with lung cancer.

Adenocarcinoma↗
PubMed2005

Engraftment of NOD/SCID/gammac(null) mice with multilineage neoplastic cells from patients with juvenile myelomonocytic leukaemia.

Several lines of evidence indicate the clonal nature of juvenile myelomonocytic leukaemia (JMML), involving myeloid, erythroid, megakaryocyte and B-lymphoid lineages. However, it is unclear whether the T-lymphocyte lineage is involved. We demonstrated that cells from six patients with JMML repopulated in non-obese diabetic/severe combined immunodeficient/gammac(null) mice and differentiated into granulocytes, monocytes, erythrocytes, B lymphocytes, T lymphocytes and natural killer cells. The percentage of human CD45 antigen-positive cells ranged from 41% to 73% in the murine bone marrow 12 weeks after transplantation. To examine the involvement of lymphocyte subpopulations, we purified human CD3(+), CD19(+) and CD56(+) cells from murine bone marrow cells transplanted from a patient with monosomy 7. Fluorescence in situ hybridization (FISH) showed the clonal marker in 96-100% of purified CD3(+), CD19(+) and CD56(+) subpopulations. These findings support the concept that JMML originates in transplantable multilineage haematopoietic stem cells. This novel murine xenotransplant model should be useful for investigating the nature of stem cells and testing new therapies for patients with JMML.

Animals↗
PubMed2005

Elevation of macrophage-derived chemokine in eosinophilic pneumonia: a role of alveolar macrophages.

Macrophage-derived chemokine (MDC/CCL22) and thymus-and activation-regulated chemokine (TARC/CCL17) are ligands for CC chemokine receptor 4. Recently, TARC has been reported to play a role in the pathogenesis of idiopathic eosinophilic pneumonia (IEP). The purpose of this study was to evaluate the role of MDC in IEP and other interstitial lung diseases (ILDs). MDC and TARC in the bronchoalveolar lavage fluid (BALF) were measured by enzyme-linked immunosorbent assay in patients with ILDs and healthy volunteers (HV). We also examined the expression of MDC mRNA in alveolar macrophages (AM) by real-time quantitative reverse transcriptase-polymerase chain reaction. Both MDC and TARC were detected only in BALF obtained from IEP patients. The concentration of MDC was higher than that of TARC in all cases. The level of MDC in IEP correlated with that of TARC. AM from IEP patients expressed a significantly higher amount of MDC than that from HV at the levels of protein and mRNA. MDC in BALF from IEP dramatically decreased when patients achieved remission. These findings suggest that MDC, in addition to TARC, might be involved in the pathogenesis of IEP, and AM play a role in the elevation of MDC in IEP.

Adult↗
PubMed2005

Neuronal and glial responses to polyamines in the ischemic brain.

The polyamines, putrescine, spermidine and spermine are present in most living cells, with the essentiality for normal cell function, cellular growth and differentiation. In the mammalian brain, polyamines are also present at relatively high concentrations with different regional distribution profiles. Cerebral ischemia is a leading cause of disability and mortality in humans, and believed to yield a cascade of cytotoxic molecules responsible for the death of viable cells in the brain. Polyamines have been implicated in the pathogenesis of ischemic brain damage. For example, polyamine biosynthesis is increased after the onset of cerebral ischemia through an induction of ornithine decarboxylase, a key enzyme in the polyamine biosynthetic pathway. The administration of a drug that inhibits ornithine decarboxylase activity prevents the development of ischemic brain damage, suggesting a critical role of the accumulation of polyamines in the ischemic brain in the pathogenesis of stroke. Both spermine and spermidine are linked to the development of glutamate-mediated neurotoxicity, for they can bind to the N-methyl-D-aspartate (NMDA)-sensitive subtype of glutamate receptors to potentiate cellular responses to glutamate. Moreover, polyamines are metabolized by polyamine oxidases after acetylation to produce different cytotoxic aldehydes and reactive oxygen species such as hydrogen peroxide, which possibly damage proteins, DNA and lipids. Polyamines have been extensively studied in the ischemic brain, particularly with respect to neuronal responses such as NMDA receptor-mediated excitotoxicity. However, little is known about glial responses to polyamines in the ischemic brain to date. In this review, we would summarize previous studies related to neuronal and glial responses to polyamines in the ischemic brain.

Animals↗
PubMed2005

Morphological observation of the horseshoe kidney with special reference to the vascular system in 2 Japanese cadavers.

Two cases of the horseshoe kidney in Japanese cadaver were reported in this paper. The kidneys and their associated vessels in the retroperitoneal cavity were carefully examined, and the histological examination of the isthmus was performed. In Case 1, four arteries arose from the abdominal aorta. One right and two left renal arteries were distributed to the apical, upper, middle and posterior regions of the kidney, respectively, and the artery of isthmus entered the lower segments and the isthmus. In Case 2, six arteries arose from the abdominal aorta. Among three arteries arose from the inferior end of the aorta and entered the lower segments and the isthmus. Histological study revealed that the isthmuses consisted of collecting tubes, glomeruli and urinary tubules and fibrous connective tissue. The incidence of the horseshoe kidney during the dissecting practice at Tokyo Medical University in a period of 24 years from 1980 to 2003 was estimated to be 0.16% (2 out of the 1,219 cadavers). The anatomical and embryological significance of this anomaly and its associated vascular system were discussed. And the histology of the parenchymal structure of the isthmus in the horseshoe kidney containing either fibrous connective tissue or renal parenchyma was also analyzed in this report.

Aged↗
PubMed2005

[Effect of steroid on antiemetic for side effect of anticancer chemotherapy].

The side effect of anticancer agents such as nausea and vomiting frequently interrupt chemotherapy. To reduce these side effects, 5-hydroxytryptamine (5-HT3) receptor antagonist or metoclopramide is administered combined with steroid. In this study, we examined the effect of 5-HT3 receptor antagonist on the frequency of nausea and vomiting in a male cancer patient treated with/without steroid. This patient in his sixties had esophageal cancer (stage IV). He was administered nedaplatin 100 mg/day for 1 day and then 5-fluorouracil (5-FU) 750 mg/day for 5 days combined with radiotherapy (60 Gy) as one cycle of this chemotherapy. In the first cycle, 5-HT3 receptor antagonist was administered, and in the second, the antagonist was administered after treatment with steroid. The blood levels of total bilirubin, GOT, GPT, BUN, Cre, Na, K and Cl were stable normally during both cycles of the chemotherapy, indicating that the hepatopathy and nephropathy which cause nausea and vomiting did not occur in these periods. The frequency and period of the nausea and vomiting were one-third decreased, respectively, by the combination of 5-HT3 receptor antagonist and steroid.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2005

[Case of interstitial cystitis accompanied by food allergy].

A case is a 62 years old woman who consulted her family physicion with pollakiuria and sharp pain at the time of urinary bladder distention. Since anti-H1-antagonist but not antibiotics was partially effective against the symptoms and some specific food ingestion appeared to increase the bladder pain, she was referred to our hospital. Treatment with spulatast tosilate and elimination of food products that revealed the presence of specific IgE antibodies and positive skin reactiont resulted favorable clinical response. Cystoscopic examination showed reduction in bladder capacity, mucosal injection and vascularization, besides pinpoint submucosal hemorrage and linear ulcer by hydrodistension. The diagnosis of interstitial cystitis was established by those evidences and histological findings. The patient got apparent remission after the bladder hydrodistension and is now in steady state with an addition of suplatast tosilate, a Th2 cytokine inhibitor, on the treatment mentioned above. Interstitial cystitis is a very rare disease which is characterized by cystitis-symptoms with normal urinary finding and non-effectiveness of antibiotics. The pathogenesis of the disease is unclear but considered as allergic inflammation. We report a case of interstitial cystitis accompanied by food allergy.

Anti-Allergic Agents↗
PubMed2004

Neuroprotective effects of ONO-1924H, an inhibitor of poly ADP-ribose polymerase (PARP), on cytotoxicity of PC12 cells and ischemic cerebral damage.

N-[3-(4-Oxo-3,4-dihydro-phthalazin-1-yl)phenyl]-4-(morpholin-4-yl) butanamide methanesulfonate monohydrate (ONO-1924H) is a novel inhibitor of poly ADP-ribose polymerase (PARP). In this study, we examined the effects of ONO-1924H on cytotoxicity induced by hydrogen peroxide in PC12 cells in vitro and cerebral damage and neurological deficits induced by middle cerebral artery (MCA) thrombus occlusion in vivo in rat. In the in vitro cytotoxicity assay, exposure to 0.5 mmol/L hydrogen peroxide induced cell death in differentiated PC12 cells. ONO-1924H, a PARP inhibitor (Ki=0.21 micromol/L), reduced cell death in a concentration-dependent manner that was correlated with inhibition of PARP activation. A 50% reduction in cell death (EC50) was achieved with 2.4 micromol/L ONO-1924H. In the MCA occlusion model, ONO-1924H was injected intravenously at doses of 3, 10 and 30 mg/kg/h for 3 h, and cerebral damage and neurological deficits were estimated 24 h after MCA occlusion. ONO-1924H treatment led to a significant decrease in cerebral damage in the 10 mg/kg/h-treated group (P < 0.05) and the 30 mg/kg/h-treated group (P < 0.01). Further, ONO-1924H at doses of 30 mg/kg/h significantly (P < 0.05) improved neurological deficits. These findings suggest that the novel PARP inhibitor, ONO-1924H, affords effective neuroprotection and is a useful therapeutic candidate for the treatment of ischemic stroke.

Animals↗
PubMed2004

Synthesis and secretion of interleukin-15 by freshly isolated human bronchial epithelial cells.

BACKGROUND: Interleukin-15 (IL-15), which shares many functional activities of IL-2, is proposed as a potential modulator of T and natural killer (NK) cell-mediated inflammatory diseases. Since IL-15 gene is expressed in various cell types including epithelial cells, we examined how proinflammatory modulators affect IL-15 gene expression in both freshly isolated human bronchial epithelial cells (HBECs) and the human bronchial epithelial cell line BEAS-2B. METHODS: HBECs were obtained from 25 patients with primary lung cancer by bronchial brushing under bronchofiberscopy. The expressions of IL-15 and its receptor were examined using reverse transcription-polymerase chain reaction (RT-PCR), Northern blot analysis and enzyme-linked immunosorbent assay. RESULTS: IL-15 mRNA was constitutively expressed in the cells and was upregulated by several proinflammatory cytokines such as IL-1beta, tumor necrosis factor-alpha, interferon-gamma (IFN-gamma) and lipopolysaccharide. In addition, IFN-gamma but not other cytokines induced the synthesis and secretion of IL-15 protein. Investigation of IL-15 receptor expression using RT-PCR showed that IL-15Ralpha and IL-2Rbeta chains but not IL-2Ralpha or gamma chain were constitutively expressed in these cells. CONCLUSIONS: Bronchial epithelial cells may contribute to T and NK cell-mediated airway inflammation through IL-15 production.

Blotting, Northern↗
PubMed2004

Phase II study of irinotecan combined with carboplatin in previously untreated non-small-cell lung cancer.

PURPOSE: Irinotecan, a topoisomerase I inhibitor, is an effective agent for non-small-cell lung cancer (NSCLC). To determine the efficacy and toxicity of irinotecan and carboplatin, we conducted a phase II study in 61 patients with advanced NSCLC. METHODS: Every 4 weeks, the patients received irinotecan 50 mg/m2 (days 1, 8 and 15) and carboplatin (day 1) with a target AUC of 5 mg min/ml using the Chatelut formula. RESULTS: All patients were evaluable for toxicity, and of 59 patients evaluable for response, 20 achieved a partial response and 26 showed no change. The overall response rate was 34% (95% confidence interval 23-48%). Grade 3 or 4 anemia, leukopenia, neutropenia, thrombocytopenia and diarrhea occurred in 32%, 32%, 60%, 25%, and 7%, respectively. The median survival time and 1-year, and 2-year survival rates were 10.0 months, 37.6%, and 15.2%, respectively. CONCLUSIONS: Irinotecan with carboplatin is effective for advanced NSCLC and safe.

Adult↗
PubMed2004

Highly enantioselective catalytic carbon dioxide incorporation reaction: nickel-catalyzed asymmetric carboxylative cyclization of bis-1,3-dienes.

A method for nickel-catalyzed asymmetric carbon dioxide (CO2) incorporation via carbon-carbon bond formation was developed. In the presence of a catalytic amount of Ni(acac)2 and MeO-MOP, various bis-1,3-dienes reacted with CO2 (1 atm) and a diorganozinc reagent (Me2Zn or Ph2Zn) to afford cyclic carboxylic acids in good yields (71-100%) and with high enantioselectivities (90-96% ee).

Journal Article↗
PubMed2004

Reversal of breast cancer resistance protein (BCRP/ABCG2)-mediated drug resistance by novobiocin, a coumermycin antibiotic.

Breast cancer resistance protein (BCRP/ABCG2) of an ATP-binding cassette half-transporter confers resistance against mitoxantrone and camptothecin derivatives of topotecan and irinotecan. Novobiocin, a coumermycin antibiotic, is known to enhance anticancer drug sensitivity of cancer cells in vitro and in vivo, the mechanism of which remains undetermined. Here we focused on drug efflux pump and examined whether novobiocin reversed drug resistance in multidrug-resistant cells highly expressing BCRP. To explore the reversal mechanisms, intracellular drug accumulation was measured by flow cytometry, and a topotecan transport study using plasma membrane vesicles was performed. We used PC-6/SN2-5H2 small cell lung cancer and MCF-7/MX breast cancer cells selected with SN-38 of the active irinotecan metabolite and mitoxantrone, respectively, and the BCRP cDNA transfectant MCF-7/clone 8 cells. These cells expressed high levels of BCRP mRNA but not other known transporters. Compared to the parental PC-6 cells, PC-6/SN2-5H2 cells were 141-, 173- and 57.2-fold resistant to topotecan, SN-38 and mitoxantrone, respectively. Novobiocin at 60 microM decreased the degree of the above resistance by approximately 26-fold in PC-6/SN2-5H2 cells, and similarly reversed resistance in MCF-7/MX, MCF-7/clone 8 and un-selected NCI-H460 cells highly expressing BCRP. Furthermore, novobiocin increased the intracellular topotecan accumulation in these cells and inhibited the topotecan transport into the membrane vesicles of PC-6/SN2-5H2 cells. No effects of novobiocin in these assay were observed in the parental PC-6 and MCF-7 cells. The kinetic parameters in the transport study indicated that novobiocin was a inhibitor for BCRP, resulting in competitive inhibition of BCRP-mediated topotecan transport. These findings suggest that novobiocin effectively overcomes BCRP-mediated drug resistance at acceptable concentrations.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed2004

Health benefits associated with exercise habituation in older Japanese men.

BACKGROUND AND AIMS: The purpose of this study was to compare the effects of exercise habituation (3-32 years, mean 13.2 years) on physical vitality among five different groups. METHODS: One hundred and two independent, community-dwelling elderly Japanese men, aged 64.6 +/- 6.6 years, were recruited as subjects. The vital age test battery consisted of various coronary heart disease risk factors and physical fitness elements. RESULTS: The results of analysis of variance revealed that vital age as an index of physical vitality was youngest in joggers (47.9 yr, N=18), intermediate in trekkers (55.8 yr, N=20) and walkers (59.1 yr, N=18), and oldest (69.6 yr, N=20) in patients with ischemic heart disease (IHD). The difference between chronological age and vital age was approximately 15 years (p<0.05) in joggers, and 8 years (p<0.05) in trekkers and walkers. The vital age of sedentary persons (N=26) was only 1.9 years (NS) younger than their chronological age, which was similar to the difference (vital age of 64.1 +/- 8.5 yr vs chronological age of 65.7 +/- 5.4 yr) previously observed in similarly aged exercising IHD patients. CONCLUSIONS: These results indicate that exercise habituation significantly affects the overall health status of most individuals, irrespective of mode of exercise. Among the three modes of exercise, jogging may be most beneficial. Furthermore, regularly exercising coronary patients may have physical vitality similar to that of sedentary men.

Aged↗
PubMed2004

Recovery of the susceptibility of isolated bacterium achieved by giving long-established antibiotics as prophylaxis against postoperative infections.

PURPOSE: To evaluate the effectiveness of operative antibiotic therapy we changed the antibiotics and examined the susceptibility of the postoperative infection. METHODS: We studied 4 593 patients who underwent gastrointestinal surgery during the last 12.5 years, and examined the changes in intraoperative antibiotics, the return of bacteria isolated from infectious sites, the trends in frequency of Methicillin-resistant Staphylococcus aureus (MRSA) isolation, and changes in the antibiotic susceptibility of Pseudomonas aeruginosa and Bacterioides fragilis. We changed the antibiotics to Cefazolin (CEZ) for upper gastrointestinal tract surgery and cholecystectomy, and to Cefotiam (CTM) for colonic, liver, and pancreatic surgery. We also reduced the period of drug administration. RESULTS: The rate of MRSA infections decreased, the rate of P. aeruginosa infections was always under 20% and the rate of B. fragilis infections increased. After the guidelines of drug susceptibility were prepared, the minimum inhibitory concentrations (MICs) of Cefsulodin (CFS) and Piperacillin (PIPC) for P. aeruginosa and of Latamoxef (LMOX) and PIPC for B. fragilis, decreased. CONCLUSION: The use of antibiotics considered comparatively old for the prophylaxis of postoperative infection prevented the emergence of MRSA-like resistant strains, influenced changes in Gram-negative bacteria drug susceptibility, and led to an overall reduction in multiple drug resistance.

Anti-Bacterial Agents↗
PubMed2004

Determinants of cardiorespiratory fitness in patients with chronic obstructive pulmonary disease, focusing on activities parallel to daily living.

OBJECTIVE: The purpose of this study was to examine whether activities parallel to daily living (APDL) constitute a determinant index of cardiorespiratory fitness in patients with chronic obstructive pulmonary disease (COPD). METHODOLOGY: Four functional physical fitness parameters were investigated in 38 male patients (mean age 69.8 +/- 6.7 years) with moderate to severe COPD. The parameters measured were muscular strength (grip strength), muscular endurance strength (arm curl, keeping a half-squat position) and regulation (walking around two cones). In addition, cardiorespiratory fitness was measured using a 6-min walking distance test (6MWD) and peak oxygen uptake (VO(2peak)) was measured during bicycle ergometer testing. Maximal inspiratory pressure (MIP) and maximal expiratory pressure were measured so as to quantify respiratory muscle strength. RESULTS: There were significant correlations (P < 0.05) between the VO(2peak), muscular endurance, pulmonary function and respiratory muscle strength. There were also significant correlations of VO(2peak) to muscular endurance, muscular strength, muscular endurance strength and regulation. In stepwise multiple regression analysis, per cent predicted forced expiratory volume in 1 s and MIP appeared to be significant determinants of VO(2peak), showing a total variance of 56% (P < 0.05). For the 6MWD, the significant determinants were forced vital capacity, MIP and performance in the half-squat test, showing a variance of 59% (P < 0.05). CONCLUSION: The results suggest that cardiorespiratory fitness is strongly affected by MIP, pulmonary function and muscular endurance strength, as APDL depend on lower-limb use.

Activities of Daily Living↗