Hajime Nakamura

Tazuke Kofukai Medical Research Institute, Kitano Hospital, Ōsaka, Ōsaka, Japan

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Publications (188)935.37 Total impact

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    ABSTRACT: Airway remodelling in bronchial asthma (BA) and COPD has been quantitatively assessed by analysing the airway wall area and the luminal area on cross-sectional CT images. To date, there have been no reports on assessment of the longitudinal structure of the airway lumen. Quantitative airway analysis using CT was performed on three groups consisting of 29 patients with BA, 58 patients with COPD and 59 healthy controls. To assess the longitudinal shape irregularity of the airway lumen, new quantitative CT parameters, validated by a phantom study, were established. The internal radii of imaginary inscribed spheres in the airway lumen were measured as a function of distance from the level of the carina to the fifth-order branches of the right posterior basal bronchus. The gaps of these radii from the regression line were calculated as parameters to reflect the longitudinal airway lumen shape irregularity. These new parameters were compared among the study groups as well as with the conventional parameters of airway wall thickening and luminal area. Longitudinal airway lumen shape irregularity was significantly greater in patients with COPD than in those with BA and healthy controls. Wall thickening was significantly greater, and luminal area smaller, in patients with BA than in those with COPD and healthy controls. These results were consistent even among the BA and COPD subgroups with similar airflow limitation. The combination of cross-sectional and longitudinal airway structure analyses using CT images may suggest differences in the characteristics of airway remodelling between COPD and asthma. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
    Thorax 05/2015; DOI:10.1136/thoraxjnl-2014-206651 · 8.56 Impact Factor
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    ABSTRACT: The role of urinary (U-) thioredoxin (Trx), a class of small redox proteins, in physiological and pathological conditions, in addition to its gender specificity, has been insufficiently determined in chronic kidney disease (CKD) patients, especially in diabetes mellitus (DM) nephropathy. U-Trx was measured cross-sectionally in 110 CKD outpatients with estimated glomerular filtration rate (eGFR) of >15 mL/min/1.73 m(2) , namely, in 57 type 2 DM patients (male (M): n=41, female (F): n=16) and 53 non-DM patients (M: n=33, F: n=20), as well as 30 healthy controls (M: n=11, F: n=19). Comparisons were made among controls, DM and non-DM, and between M and F, and clinical parameters were compared in each group. In addition, a comparison between average U-Trx level and the changes of renal function during a one-year period was performed. U-Trx was significantly higher in females than in males in controls (p<0.05) and in non-DM patients (p<0.05). Multiple regression analysis revealed that urinary protein (UP)/creatinine (Cr) ratio, female sex and HbA1c were independent factors affecting U-Trx among all subjects (adjusted R(2) =0.468). In DM patients, U-Trx was negatively correlated with eGFR, especially in males, and positively correlated with UP/Cr and NAG in both sexes (all p<0.01), as well as with systolic blood pressure in all (p<0.05). Average U-Trx was positively correlated with the rate of annual eGFR decline of male (p<0.01) but not female DM patients. U-Trx might have a gender-specific physiological and pathological role and be a potent marker of renal damage in DM nephropathy. This article is protected by copyright. All rights reserved.
    Nephrology 01/2015; 20(5). DOI:10.1111/nep.12403 · 1.86 Impact Factor
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    Fu-Cheng Luo · Jia Zhou · Tao Lv · Lei Qi · Sheng-Dong Wang · Hajime Nakamura · Junji Yodoi · Jie Bai
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    ABSTRACT: Oxidative stress is a major determinant of acute kidney injury (AKI); however, the effects of the AKI on renal redox system are unclear and few existing AKI markers are suitable for evaluating oxidative stress. We measured urinary levels of the redox regulatory protein thioredoxin 1 (TRX1) in patients with various kinds of kidney disease and in mice with renal ischemia/reperfusion injury. Urinary TRX1 levels were markedly higher in patients with AKI than in those with chronic kidney disease or in healthy subjects. In a receiver operating characteristic curve analysis to differentiate between AKI and other renal diseases, the area under the curve for urinary TRX1 was 0.94 (95% confidence interval, 0.90-0.98), and the sensitivity and specificity were 0.88 and 0.88, respectively, at the optimal cutoff value of 43.0 μg/g creatinine. Immunostaining revealed TRX1 to be diffusely distributed in the tubules of normal kidney, but to be shifted to the brush borders or urinary lumen in injured tubules in both mice and humans with AKI. Urinary TRX1 in AKI was predominantly in the oxidized form. In cultured human proximal tubular epithelial cells, hydrogen peroxide specifically and dose-dependently increased TRX1 levels in the culture supernatant, while decreasing intracellular levels. These findings suggest that urinary TRX1 is an oxidative stress-specific biomarker useful in distinguishing AKI from chronic kidney disease and healthy kidneys.
    American journal of physiology. Renal physiology 10/2014; 307(12):ajprenal.00381.2013. DOI:10.1152/ajprenal.00381.2013 · 3.30 Impact Factor
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    Fu-Cheng Luo · Jia Zhou · Tao Lv · Lei Qi · Sheng-Dong Wang · Hajime Nakamura · Junji Yodoi · Jie Bai
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    Fu-Cheng Luo · Jia Zhou · Tao Lv · Lei Qi · Sheng-Dong Wang · Hajime Nakamura · Junji Yodoi · Jie Bai
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    Fu-Cheng Luo · Jia Zhou · Tao Lv · Lei Qi · Sheng-Dong Wang · Hajime Nakamura · Junji Yodoi · Jie Bai
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    ABSTRACT: Thioredoxin (TRX) is a redox regulating protein which has protective effects against oxidative stress-induced damage to cells and tissues. In this study, we investigated the effects of orally administered TRX derived from edible yeast, Saccharomyces cerevisiae, on gastric mucosa. First, we examined the digestibility of orally administered yeast TRX in mice, and detected yeast TRX in the stomach for 4 h after administration. Next, we investigated the mitigation of gastric mucosal injury after the oral administration of yeast TRX in water-immersion restraint stress and HCl/ethanol-induced gastric ulcer models. Furthermore, we conducted DNA microarray analysis, using the HCl/ethanol-induced model, which revealed that several groups of genes related to tissue repair were upregulated in ulcer regions in the stomachs of rats administered with yeast TRX. These results demonstrated the viability of the use of oral administrations of yeast TRX to protect the gastric mucosa.
    Bioscience Biotechnology and Biochemistry 07/2014; 78(7):1221-1230. DOI:10.1080/09168451.2014.915733 · 1.21 Impact Factor
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    ABSTRACT: Although supplementation with the selenocompound, sodium selenite has been shown to stimulate the concanavalin A-induced T-cell mitogenic response, the mechanisms responsible remain unclear. This study was conducted to evaluate the relationships between the induction of apoptosis, formation of tumor necrosis factor (TNF)-alpha and reactive oxygen species (ROS), activation of apoptosis signal-regulating kinase (ASK) 1 and the thioredoxin (Trx) system when mitogenesis was stimulated by selenite. TNF-alpha was dose-dependently released by mouse splenocytes treated with selenite, and apoptosis was induced when TNF-alpha was added at the indicated concentrations. However, supplementation with selenite at low concentrations inhibited the accumulation of ROS with the increased expression of Trx reductase 1 and induction of apoptosis in wild-type splenocytes, and also at high concentrations in Trx-1-transgenic mouse splenocytes. The suppression of apoptosis was accompanied by a decrease in the expression of phospho-ASK1. These results suggest that the stimulation of T-cell mitogenesis by selenite may be partly attributed to the inhibited accumulation of ROS due to a reduced Trx-1/TR1 system, the inactivation of ASK1, and the suppression of apoptosis.
    Biological & Pharmaceutical Bulletin 01/2014; 37(8):1352-8. DOI:10.1248/bpb.b14-00286 · 1.78 Impact Factor
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    ABSTRACT: Nonalcoholic steatohepatitis (NASH) is a common liver disease that can progress to cirrhosis. Oxidative stress is one of the central mechanisms causing hepatocellular injury in the disease. In this study, antioxidant therapy using both vitamins C and E was conducted in patients with NASH. Vitamin E 300 mg/day and vitamin C 300 mg/day were administered orally to 23 patients with NASH for 12 months. Body mass index was measured during therapy. Serum levels of alanine aminotransferase, thioredoxin (an oxidative stress marker), and high-sensitivity C-reactive protein were measured before treatment and after 12 months in all patients. Ten of the 23 patients underwent liver biopsy before and after treatment. Body mass index remained unchanged during treatment with vitamins C and E. Serum alanine aminotransferase, thioredoxin, and high-sensitivity C-reactive protein levels were decreased significantly at 12 months compared with pretreatment. Liver biopsies showed improved necroinflammatory activity in eight cases and improved fibrosis staging in 4. Serum alanine aminotransferase, thioredoxin, and high-sensitivity C-reactive protein levels, and liver histology were clearly improved with vitamin C and E therapy. These findings suggest that combination therapy using these vitamins may be useful in patients with NASH to minimize damage from oxidative stress and slow the processes leading to cirrhosis.
    Hepatic Medicine: Evidence and Research 03/2013; 5:11-6. DOI:10.2147/HMER.S41258
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    ABSTRACT: Multifunctional redox protein human thioredoxin (TRX-1) is reduced by thioredoxin reductase (TRX-R). The aim of the present study was to examine the distribution of TRX-1 and TRX-R expressions in gallbladder carcinoma (GBC) to clarify their usefulness as prognostic factors after surgical resection. Immunohistochemical staining for TRX-1 and TRX-R was performed in GBC tissue from 38 patients who underwent surgical resection, and TRX-1/TRX-R localization in relation to outcome was examined. TRX-1 protein levels were significantly higher in GBC samples than in cholecystolithiasis samples (P = 0.0174). TRX-1 expression was observed in 100% (38/38) of tumour samples and in the nucleus in 76% (29/38), with nuclear expression in the invasion front observed in 45% (13/29). TRX-R expression was only detected in the cytoplasm of cancer cells and in the invasion front in 28 samples. In all of the samples, the depth of tumour invasion, lymph node metastasis, surgical margin, curability and nuclear expression of TRX-1 in the invasion front were significant prognostic factors by univariate analysis. In 27 selected patients who underwent curative resection, both TRX-1 nuclear expression and TRX-R cytoplasmic expression in the invasion front was a significantly prognostic factor. TRX-1 nuclear expression in the GBC invasion front is a significant prognostic marker. Patients with both TRX-1 nuclear expression and TRX-R cytoplasmic expression in the tumour invasion front should be observed carefully even if after curative resection.
    HPB 09/2012; 14(9):573-82. DOI:10.1111/j.1477-2574.2012.00482.x · 2.05 Impact Factor
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    ABSTRACT: Preterm delivery (PTD) is the leading cause of infant mortality and morbidity. However, the mechanism at the molecular level is still unknown. Placental inflammatory response and oxidative stress are associated with PTD. Thioredoxin-1 (TRX-1) regulates oxidative stress, inflammation, and the activities of transcription factors. The objective was to detect in placental tissues the expressions of TRX-1 and the TRX-1-related molecules: tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2), thioredoxin-1-binding protein-2 (TBP-2), hypoxia inducible transcription factor 1α (HIF-1α), and forkhead box protein O3A (FoxO3A). PTD was defined as gestation of <37 weeks and term delivery (TD) as ≥37 weeks. The expressions of TRX-1 and TRX-1-related molecules were examined in placental tissues by real-time polymerase chain rection and western blot. The expressions of TRX-1, TNF-α, COX-2, HIF-1α, and FoxO3A in the placenta of PTD were significantly higher as compared with TD, but no difference was observed in TBP-2 expression. These results indicate that TRX-1 may be adaptively induced by the effects of inflammation and oxidative stress, suggesting protective roles for TRX-1 against these effects in the placenta of PTD.
    Redox report: communications in free radical research 09/2012; 17(5):187-93. DOI:10.1179/1351000212Y.0000000021 · 1.71 Impact Factor
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    ABSTRACT: Abstract Aims: Accumulating evidence indicates that oxidative stress is associated with inflammation, and the cellular redox status can determine the sensitivity and the final outcome in response to inflammatory stimuli. To control the redox balance, mammalian cells contain a variety of oxidoreductases belonging to the thioredoxin superfamily. The large number of these enzymes suggests a complex mechanism of redox regulation in mammals, but the precise function of each family member awaits further investigations. Results: We generated mice deficient in transmembrane thioredoxin-related protein (TMX), a transmembrane oxidoreductase in the endoplasmic reticulum (ER). When exposed to lipopolysaccharide (LPS) and d-(+)-galactosamine (GalN) to induce inflammatory liver injury, mutant mice were highly susceptible to the toxicants and developed severe liver damage. LPS-induced production of inflammatory mediators was equivalent in both wild-type and TMX(-/-) mice, whereas neutralization of the proinflammatory cytokine tumor necrosis factor-α suppressed the toxic effects of LPS/GalN in the mutant mice. Liver transcriptional profiles revealed enhanced activation of the p53-signaling pathway in the TMX(-/-) mice after LPS/GalN treatment. Furthermore, TMX deficiency also caused increased sensitivity to thioacetamide, which exerts its hepatotoxicity through the generation of reactive oxygen species. Innovation: The present study is the first to address the role of the oxidoreductase TMX in inflammatory liver injury. The phenotype of mice deficient in TMX suggests a functional link between redox regulation in the ER and susceptibility to oxidative tissue damage. Conclusion: We conclude that TMX plays a major role in host defense under the type of inflammatory conditions associated with oxidative stress. Antioxid. Redox Signal. 00, 000-000.
    Antioxidants & Redox Signaling 08/2012; DOI:10.1089/ars.2011.4430 · 7.67 Impact Factor
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    Fu-Cheng Luo · Lei Qi · Tao Lv · Sheng-Dong Wang · Hua Liu · Hajime Nakamura · Junji Yodoi · Jie Bai
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    ABSTRACT: There are few efficacious interventions to combat morphine dependence. Thioredoxin-1 (Trx-1) and heat shock protein 70 (Hsp70) are emerging as important modulators of neuronal function. They have been shown to be involved in cellular protective mechanisms against a variety of toxic stressors. This study was designed to investigate the effects of geranylgeranylacetone (GGA), a pharmacological inducer of Trx-1 and Hsp70, on morphine-induced hyperlocomotion, rewarding effect, and withdrawal syndrome. Trx-1 and Hsp70 expression was increased in the frontal cortex, hippocampus, ventral tegmental area, and nucleus accumbens of mice after GGA treatment. GGA administration reduced morphine-induced motor activity and inhibited conditioned place preference. GGA markedly attenuated the morphine-naloxone-induced withdrawal signs, including jumping, rearing, and forepaw tremor. Furthermore, the activation of cAMP-responsive element-binding protein and the expression of ΔFosB and cyclin-dependent kinase 5 were decreased in the nucleus accumbens by GGA treatment after morphine withdrawal. In the nucleus accumbens, GGA enhanced morphine-induced expression of Trx-1 and Hsp70 after morphine withdrawal. These results suggest that strengthening the expression of Trx-1 and Hsp70 in the brain by using noncytotoxic pharmacological inducers may provide a novel therapeutic strategy for morphine dependence. GGA could be a safe and novel therapeutic agent for morphine dependence.
    Free Radical Biology and Medicine 04/2012; 52(7):1218-27. DOI:10.1016/j.freeradbiomed.2012.01.004 · 5.71 Impact Factor
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    Fu-Cheng Luo · Jia Zhou · Tao Lv · Lei Qi · Sheng-Dong Wang · Hajime Nakamura · Junji Yodoi · Jie Bai
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    ABSTRACT: Formaldehyde (FA), a common environmental pollutant, has toxic effects on central nervous system. The detailed mechanisms on FA-induced neurotoxicity have not been fully elucidated. In this study, we found that glucose regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) expression, biomarkers of endoplasmic reticulum (ER) stress, were increased and pro-caspase-12 was decreased after PC12 cells exposure to FA. These results suggest that FA actually induces ER stress. Thioredoxin-1 (Trx-1) has various biological activities, including the control of redox balance, the modulation of ER stress and inhibition of apoptosis. In the present study, Trx-1 expression was increased at early stage, but decreased at late stage after FA treatment. Knockdown of Trx-1 expression increased the susceptibility of PC12 cells to FA-induced neurotoxicity. We also found that ginsenoside Rg1 had the potential to induce Trx-1 expression and attenuated neurotoxicity induced by FA. ER stress caused by FA was suppressed by ginsenoside Rg1. These data indicate that Trx-1 is a therapeutic candidate for protecting against FA-induced neurotoxicity.
    NeuroToxicology 02/2012; 33(3):290-8. DOI:10.1016/j.neuro.2012.02.004 · 3.05 Impact Factor
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    ABSTRACT: Thioredoxin (TRX) catalyzes the reduction of disulfide bonds in proteins via the NADPH-dependent thioredoxin reductase system. Reducing the disulfide bonds of allergenic proteins in food by TRX lowers the allergenicity. We established in this study a method to prepare TRX-enriched extracts from the edible yeast, Saccharomyces cerevisiae, on a large and practical scale, with the objective of developing TRX-containing functional foods to mitigate food allergy. Treating with the yeast TRX-enriched extracts together with NADPH and yeast thioredoxin reductase enhanced the pepsin cleavage of β-lactoglobulin and ovomucoid (OM). We also examined whether yeast TRX can mitigate the allergenicity of OM by conducting immediate allergy tests on guinea pigs. The treatment with TRX reduced the anaphylactic symptoms induced by OM in these tests. These results indicate that yeast TRX was beneficial against food allergy, raising the possibility that yeast TRX-enriched extracts can be applied to food materials for mitigating food allergy.
    Bioscience Biotechnology and Biochemistry 10/2011; 75(10):1872-9. DOI:10.1271/bbb.100734 · 1.21 Impact Factor
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    ABSTRACT: Thioredoxin (TRX) is a redox-active protein that regulates reactive oxidative metabolism and plays a crucial role in the antioxidant system in regulating the reduction/oxidation balance by scavenging reactive oxygen species, which is implicated in the mechanism of asthma. As for the mechanisms by which TRX exerts its beneficial effects, some studies have shown that TRX suppresses allergic inflammation in animal models of asthma. Recently, we reported that TRX directly modulated the chemotaxis of eosinophils, which have been shown to play a pivotal role in the mechanism of allergic airway inflammation, in the absence of T helper (Th)1 or Th2 cytokines. Further, serum TRX levels in patients with asthma were significantly increased in patients with attacks compared with those in the asymptomatic period. This review focuses on TRX in allergic reactions and discusses the physiological role of TRX.
    International Archives of Allergy and Immunology 06/2011; 155 Suppl 1:142-6. DOI:10.1159/000327501 · 2.43 Impact Factor

Publication Stats

9k Citations
935.37 Total Impact Points

Institutions

  • 2006–2015
    • Tazuke Kofukai Medical Research Institute, Kitano Hospital
      Ōsaka, Ōsaka, Japan
    • National Institute of Advanced Industrial Science and Technology
      Tsukuba, Ibaraki, Japan
  • 1991–2012
    • Kyoto University
      • • Institute for Virus Research
      • • Department of Gastroenterology and Hepatology
      • • Graduate School of Medicine / Faculty of Medicine
      Kioto, Kyōto, Japan
  • 2005
    • Kumamoto University
      Kumamoto, Kumamoto, Japan
    • Hamamatsu Rosai Hospital
      Hamamatu, Shizuoka, Japan
  • 2003
    • Kurume University
      • Department of Internal Medicine
      Куруме, Fukuoka, Japan
    • National Cerebral and Cardiovascular Center
      Ōsaka, Ōsaka, Japan
  • 2002
    • Hokkaido University
      • Graduate School of Pharmaceutical Sciences
      Sapporo, Hokkaidō, Japan
    • Shimane University
      • Department of Ophthalmology
      Matsu, Shimane, Japan
    • Akita University
      Akita, Akita, Japan
  • 2001
    • Kyoto Prefectural University of Medicine
      Kioto, Kyōto, Japan
  • 1998
    • Karolinska Institutet
      • Department of Medical Biochemistry and Biophysics
      Solna, Stockholm, Sweden
  • 1996
    • Stanford University
      • Department of Genetics
      Stanford, California, United States