Makoto Nishida

Osaka University, Suika, Ōsaka, Japan

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Publications (146)631.85 Total impact

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    ABSTRACT: While aging is unavoidable, the aging mechanism is still unclear because of its complexity. Smoking causes premature death and is considered as an environmental aging accelerator. In the present study, we focused on the influence of smoking to the serum concentration of anti-aging protein α-klotho (αKl) and the β-klotho-associated protein fibroblast growth factor (FGF)-21 in men. Subjects consisted of apparently healthy men over 40 years of age who underwent health examination. Physical and biochemical parameters, including the levels of several cytokines and growth factors, were obtained from the subjects. Among middle-aged men (46.1 ± 5.1 years), serum levels of FGF-21, soluble αKl (sαKl), and inflammation-related cytokine interleukin (IL)-6 were significantly higher in smokers than in never-smokers. Serum levels of FGF-21 increased and correlated with alanine transaminase, γ guanosine-5'-triphosphate, and total cholesterol only in smokers, suggesting FGF-21 as a metabolic disorder-related factor in smokers. In aged men (60.3 ± 1.7 years), although the serum levels of sαKl in never-smokers were low, smokers showed highly increased serum levels of sαKl. Serum levels of sαKl was correlated with IL-6 in middle-aged never-smokers, suggesting sαKl regulates IL-6. However, this correlation was disrupted in smokers and aged men.
    Scientific Reports 09/2015; 5:14230. DOI:10.1038/srep14230 · 5.58 Impact Factor
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    ABSTRACT: CD36 is an important transporter of long-chain fatty acids (LCFAs) in the myocardium. As we have reported previously, CD36-deficient patients demonstrate a marked reduction in myocardial uptake of (123)I-15-(p-iodophenyl)-(R, S)-methyl pentadecanoic acid (BMIPP), which is an analog of LCFAs, while myocardial (18)F-fluorodeoxy-glucose (FDG) uptake is increased. However, it has not been clarified whether energy provision is preserved in patients with CD36 deficiency. The aims of the current study were to investigate the myocardial uptake of glucose and alterations in myocardial metabolites in wild-type (WT) and CD36 knockout (KO) mice. High-resolution positron emission tomography (PET) demonstrated markedly enhanced glucose uptake in KO mouse hearts compared with those of WT mice in real-time. The myocardial protein expression of glucose transporter protein 1 (GLUT1) was significantly enhanced in KO mice compared to WT mice, whereas that of GLUT4 was not altered. While the myocardial expression of genes involved in fatty acid metabolism did not increase in KO mice, that of genes related to glucose utilization compensatorily increased in KO mice. The metabolomic analysis of cardiac tissues revealed that the myocardial concentrations of ATP and phosphocreatine were maintained, even in KO mice. The concentration of 3-hydroxybutyric acid and mRNA expression of hydroxybutyrate dehydrogenase in the heart were significantly higher in KO than in WT mice. These data suggest that high-energy phosphate might be preserved by the increased utilization of glucose and ketone bodies in CD36KO mouse hearts under conditions of deficient LCFA uptake. Copyright © 2015. Published by Elsevier Inc.
    Metabolism 06/2015; 64(9). DOI:10.1016/j.metabol.2015.05.017 · 3.89 Impact Factor
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    ABSTRACT: In this study, we investigated the relationship between several growth factors and inflammation development. Serum concentrations of epiregulin, amphiregulin, betacellulin, TGF-α, fibroblast growth factor 2, placental growth factor (PLGF), and tenascin C were increased in rheumatoid arthritis patients. Furthermore, local blockades of these growth factors suppressed the development of cytokine-induced arthritis in mice by inhibiting chemokine and IL-6 expressions. We found that epiregulin expression was early and followed by the induction of other growth factors at different sites of the joints. The same growth factors then regulated the expression of epiregulin at later time points of the arthritis. These growth factors were increased in patients suffering from multiple sclerosis (MS) and also played a role in the development of an MS model, experimental autoimmune encephalomyelitis. The results suggest that the temporal expression of growth factors is involved in the inflammation development seen in several diseases, including rheumatoid arthritis and MS. Therefore, various growth factor pathways might be good therapeutic targets for various inflammatory diseases. Copyright © 2015 by The American Association of Immunologists, Inc.
    The Journal of Immunology 01/2015; 194(3):1039-46. DOI:10.4049/jimmunol.1400562 · 4.92 Impact Factor

  • Atherosclerosis 08/2014; 235(2):e104-e105. DOI:10.1016/j.atherosclerosis.2014.05.281 · 3.99 Impact Factor

  • Atherosclerosis 08/2014; 235(2):e169-e170. DOI:10.1016/j.atherosclerosis.2014.05.490 · 3.99 Impact Factor
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    ABSTRACT: Objective In adults, gender and obesity play significant roles in the regulation of blood pressure (BP). This study investigated the effects of gender and body mass index (BMI) on BP during adolescence. Design and setting A cross-sectional and longitudinal study involving 6838 students under twenty years old (median, eighteen years old; male, 4624; female, 2214) at Osaka University visited the Healthcare Center for their matriculation health examination from April to May in the years 2008, 2009, and 2010, and re-visited the Healthcare Center for their student health examination from May to June in the years 2011, 2012, and 2013. Methods Height, body weight, and BP were measured in students both on and 3 years after admission to Osaka University. Results On admission, the slope of the regression line for BMI and systolic BP (SBP) in non-underweight students was significantly different between genders. SBP and diastolic BP (DBP) increased in both genders during the observation period. Among male students who had a normal BMI on admission, those who had an increase in BMI of over 4% during the observation period showed a greater increase in SBP than those who had a change in BMI of −4% to 4%. On the other hand, female students showed no change in BP with the increase in BMI. Conclusions The magnitude of BP elevation with increased BMI was associated with gender during adolescence. This may be a cause of the higher prevalence of hypertension in adult males.
    Obesity Research & Clinical Practice 07/2014; 9(2). DOI:10.1016/j.orcp.2014.07.001 · 1.18 Impact Factor

  • 35th Annual Scientific Meeting of the; 06/2014
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    ABSTRACT: Background: Smoking and metabolic syndrome (MetS) are major public health problems in modern society and are important risk factors of cardiovascular disease (CVD). The association of smoking, MetS, and CVD is widely reported, but reports targeted to women are few. In the present study, we evaluated risk factors, including visceral fat area (VFA), for CVD and development of subclinical atherosclerosis in female smokers especially. Methods and results: Subjects consisted of 162 apparent healthy female and male smokers, and 315 age-matched never-smokers who underwent a health examination in the Osaka University Health Care Center. For female smokers, lifestyle and carotid intima-media thickness (IMT) were evaluated. Triglycerides were significantly higher and high-density lipoprotein-cholesterol significantly lower in smokers than in never-smokers for both men and women. However, VFA was significantly high only in smoking women when compared with never-smokers. Multivariate analysis revealed that age, body mass index, and smoking were the independent predictors of high VFA in women. In addition, annual IMT increase was significantly higher in smokers than never-smokers in women. Conclusions: VFA was notably high in female smokers, but the difference was not observed in men. Smoking habit is an important risk factor of visceral fat accumulation and progression of subclinical atherosclerosis in women.
    Circulation Journal 03/2014; 78(5). DOI:10.1253/circj.CJ-13-1134 · 3.94 Impact Factor
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    ABSTRACT: Aim: Small intestine-derived chylomicrons and chylomicron remnants, which are predominant in patients with postprandial hypertriglyceridemia, chylomicron syndrome and/or familial dyslipidemia, carry one molecule of apolipoprotein B-48(apo B-48) per lipoprotein particle. We investigated the reference interval for the apo B-48 concentration. Methods: We studied 516 individuals who provided written informed consent and confirmed that they were not taking any medications. BMI, waist circumference, blood pressure and the fasting serum concentrations of LDL-C, triglyceride(TG), HDL-C and apo B-48 were measured. The Apo B-48 concentrations were compared according to sex, a pre- or postmenopausal status, dyslipidemia(LDL-C ≥140 mg/dL, TG ≥150 mg/dL, HDL-C <40 mg/dL), metabolic syndrome(MetS) and the number of risk factors. Results: The fasting apo B-48 concentrations(mean±SD) were significantly higher in men than in women(3.8±3.3 μg/mL vs 2.4±1.9 μg/mL, p<0.001), subjects with a BMI of ≥25 kg/m(2) versus a BMI of <25 kg/m(2) (4.4±3.7 μg/mL vs 2.8±2.4 μg/mL, p<0.001) and those with versus without MetS(6.5±4.3 μg/mL vs 3.0±2.6 μg/mL, p<0.001). High apo B-48 concentrations were also observed in correlation with the number of risk factors for the MetS. The upper reference limit of apo B-48 was estimated to be 5.7 μg/mL among the 332 patients with normolipidemia, excluding those exhibiting a mean value above ±2.58 standard deviations(SDs), as the mean and range of mean ±1.96 SD were calculated to be 2.04 μg/mL(reference value) and 0.74 to 5.65 μg/mL(reference interval), respectively. Conclusions: Based on our study of normolipidemic patients, the upper reference limit for the fasting apo B-48 concentration is estimated to be 5.7 μg/mL.
    Journal of atherosclerosis and thrombosis 02/2014; 21(6). DOI:10.5551/jat.22558 · 2.73 Impact Factor
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    ABSTRACT: To clarify the probability of low serum testosterone level as a risk factor for metabolic syndrome (MS) in middle-aged men, we measured serum total testosterone (TT) and assessed several metabolic factors because the direct risk for MS has not been investigated fully in men. This study comprised 1150 men aged ≥30 years. Physical and laboratory variables were assessed. Analyses were conducted to determine the association between serum TT level and incidence risk of MS and MS factors by a separate logistic regression model. Mean (± standard deviation [SD]) serum TT level was 5.4 ± 1.7 ng/mL in the 1150 men, and only 92 men (8.0%) were classified as having MS by the Japanese criteria. In age-adjusted analyses, higher levels of serum TT were independently associated with a lower risk of MS (odds ratio, per SD decrement of TT, 2.3; 95% confidence interval [CI], 1.7-2.9). MS risk increased by lower quintile of TT: ORs were 15.1 (95% CI, 4.6-50.0) for first quintile, 8.8 (95% CI, 2.6-29.9) for second quintile, 5.8 (95% CI, 1.7-20.5) for third quintile, and 5.0 (95% CI, 1.4-17.9) for fourth quintile compared with highest quintile of TT. Age-adjusted ORs for the incidence of dichotomous components of MS per SD decrement of TT were 1.8 (95% CI, 1.5-2.3) for waist circumference, 1.6 (95% CI, 1.1-2.2) for dyslipidemia, and 1.5 (95% CI, 1.2-1.8) for hypertension. We found that higher probability of MS was associated with lower levels of serum TT level in relatively healthy middle-aged Japanese men.
    Urology 10/2013; 82(4):814-9. DOI:10.1016/j.urology.2013.06.023 · 2.19 Impact Factor
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    ABSTRACT: [This corrects the article on p. e70755 in vol. 8.].
    PLoS ONE 08/2013; 8(8). DOI:10.1371/annotation/8d40f661-efc4-4590-8922-b3a6f5374e12 · 3.23 Impact Factor
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    ABSTRACT: Atherosclerotic lesions of the coronary arteries are the pathological basis for myocardial infarction and ischemic cardiomyopathy. Progression of heart failure after myocardial infarction is associated with cardiac remodeling, which has been studied by means of coronary ligation in mice. However, this ligation model requires excellent techniques. Recently, a new murine model, HypoE mouse was reported to exhibit atherogenic Paigen diet-induced coronary atherosclerosis and myocardial infarction; however, the HypoE mice died too early to make possible investigation of cardiac remodeling. Therefore, we aimed to modify the HypoE mouse model to establish a novel model for ischemic cardiomyopathy caused by atherosclerotic lesions, which the ligation model does not exhibit. In our study, the sustained Paigen diet for the HypoE mice was shortened to 7 or 10 days, allowing the mice to survive longer. The 7-day Paigen diet intervention starting when the mice were 8 weeks old was adequate to permit the mice to survive myocardial infarction. Our murine model, called the "modified HypoE mouse", was maintained until 8 weeks, with a median survival period of 36 days, after the dietary intervention (male, n = 222). Echocardiography demonstrated that the fractional shortening 2 weeks after the Paigen diet (n = 14) significantly decreased compared with that just before the Paigen diet (n = 6) (31.4±11.9% vs. 54.4±2.6%, respectively, P<0.01). Coronary angiography revealed multiple diffuse lesions. Cardiac remodeling and fibrosis were identified by serial analyses of cardiac morphological features and mRNA expression levels in tissue factors such as MMP-2, MMP-9, TIMP-1, collagen-1, and TGF-β. Modified HypoE mice are a suitable model for ischemic cardiomyopathy with multiple diffuse lesions and may be considered as a novel and convenient model for investigations of cardiac remodeling on a highly atherogenic background.
    PLoS ONE 08/2013; 8(8):e70755. DOI:10.1371/journal.pone.0070755 · 3.23 Impact Factor
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    ABSTRACT: Progranulin (PGRN) is a multifunctional protein known to be involved in inflammation. However, the relation between PGRN and atherosclerosis remains elusive. The aim of this study was to define the role of PGRN in the development of atherosclerosis.Methods and ResultsFirst, we checked the expression levels of PGRN in human atherosclerotic plaques. Immunohistochemical analysis showed that PGRN is strongly expressed in foam cells of atherosclerotic plaques. We also found that PGRN is expressed more abundantly in macrophages than in the smooth muscle cells of atherosclerotic lesions in ApoE(-/-) mice fed a high-fat diet for 12 weeks. Next, PGRN(-/-)ApoE(-/-) mice were generated to investigate the effect of PGRN on the development of atherosclerosis. PGRN(-/-)ApoE(-/-) mice exhibited severe atherosclerotic lesions compared to PGRN(+/+)ApoE(-/-) mice, despite their anti-atherogenic lipid profile. These results are partly due to enhanced expression of inflammatory cytokines, adhesion molecules, and decreased expression of endothelial nitric oxide synthase. In addition, lack of PGRN leads to accumulate excessive cholesterol in the macrophages and alter HDL-associated proteins. PGRN seems to be involved in the pathogenesis of atherosclerosis, possibly by various anti-atherogenic effects, including modulation of local and/or systemic inflammation.
    Cardiovascular Research 07/2013; 100(1). DOI:10.1093/cvr/cvt178 · 5.94 Impact Factor
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    ABSTRACT: The IL-6-triggered positive feedback loop for NFκB signaling (or the IL-6 amplifier/Imflammation amplifier) was originally discovered as a synergistic-activation signal that follows IL-17/IL-6 stimulation in nonimmune cells. Subsequent results from animal models have shown that the amplifier is activated by stimulation of NFκB and STAT3 and induces chemokines and inflammation via an NFκB loop. However, its role in human diseases is unclear. Here, we combined two genome-wide mouse screens with SNP-based disease association studies, revealing 1,700 genes related to the IL-6 amplifier, 202 of which showed 492 indications of association with ailments beyond autoimmune diseases. We followed up on ErbB1 from our list. Blocking ErbB1 signaling suppressed the IL-6 amplifier, whereas the expression of epiregulin, an ErbB1 ligand, was higher in patients with inflammatory diseases. These results indicate that the IL-6 amplifier is indeed associated with human diseases and disorders and that the identified genes may make for potential therapeutic targets.
    Cell Reports 02/2013; 3(5). DOI:10.1016/j.celrep.2013.01.028 · 8.36 Impact Factor
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    ABSTRACT: We isolated the human adipose-specific and most abundant gene transcript, apM1 (Maeda, K, et al., Biochem. Biophys. Res. Commun. 221, 286-289, 1996). The apM1 gene product was a kind of soluble matrix protein, which we named adiponectin. To quantitate the plasma adiponectin concentration, we have produced monoclonal and polyclonal antibodies for human adiponectin and developed an enzyme-linked immunosorbent assay (ELISA) system. Adiponectin was abundantly present in the plasma of healthy volunteers in the range from 1.9 to 17.0 mg/ml. Plasma concentrations of adiponectin in obese subjects were significantly lower than those in non-obese subjects, although adiponectin is secreted only from adipose tissue. The ELISA system developed in this study will be useful for elucidating the physiological and pathophysiological role of adiponectin in humans. (C) 1999 Academic Press
    Biochemical and Biophysical Research Communications 08/2012; 425(3):560-564. · 2.30 Impact Factor
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    ABSTRACT: We isolated the human adipose-specific and most abundant gene transcript, apM1 (Maeda, K., et al.,Biochem. Biophys. Res. Commun.221, 286–289, 1996). The apM1 gene product was a kind of soluble matrix protein, which we named adiponectin. To quantitate the plasma adiponectin concentration, we have produced monoclonal and polyclonal antibodies for human adiponectin and developed an enzyme-linked immunosorbent assay (ELISA) system. Adiponectin was abundantly present in the plasma of healthy volunteers in the range from 1.9 to 17.0 mg/ml. Plasma concentrations of adiponectin in obese subjects were significantly lower than those in non-obese subjects, although adiponectin is secreted only from adipose tissue. The ELISA system developed in this study will be useful for elucidating the physiological and pathophysiological role of adiponectin in humans.
    Biochemical and Biophysical Research Communications 08/2012; 425(3):560-4. DOI:10.1016/j.bbrc.2012.08.024 · 2.30 Impact Factor
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    ABSTRACT: Background: Smoking is a major risk factor for cardiovascular disease. Also, inflammatory activation and metabolic disorder are the mediators of smoking-induced atherosclerotic progression. The aim of the present study was to investigate whether current smoking and smoking cessation alter inflammatory or metabolic status and affect subclinical atherosclerosis in apparently healthy men. Methods and results: Classical risk factors and smoking habit were evaluated in 354 men who completed health examinations annually without any current medications. Carotid intima-media thickness (IMT) was followed for 27.1±4.5 months. At baseline, both maximum and mean IMT significantly changed during 2-year follow-up. They tended to increase along with progression of smoking habit, with significantly greater maximum IMT in current smokers compared with never smokers. Both maximum and mean IMT significantly changed during 2-year follow-up, and tended to increase with progression of smoking habit, with maximum IMT being greatest for current smokers. Past smokers tended to have greater IMT increase than never smokers. Among smoking habit and some atherosclerotic risk markers that showed significant correlation with maximum IMT increase, stepwise regression showed that smoking habit and serum low-density lipoprotein-cholesterol (LDL-C) level were the only independent predictors. Conclusions: Significant 2-year progression of subclinical atherosclerosis was associated with continuous smoking and LDL-C. This was only partly moderated in past smokers despite complete reversal of inflammatory activation, suggesting another crucial factor for inhibiting accelerated progression of subclinical atherosclerosis in men.
    Circulation Journal 08/2012; 76(12). DOI:10.1253/circj.CJ-11-1506 · 3.94 Impact Factor
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    ABSTRACT: Aim: Remnant lipoproteins are atherogenic and are accumulated in patients with type III hyperlipidemia (HL). Although type III HL is diagnosed by phenotyping apolipoprotein (apo) E, this procedure is time-consuming and inconvenient for routine clinical use. Clinical indices for screening type III HL in untreated HL patients have been proposed; however, in clinical settings, HL patients are promptly treated with lipid-lowering agents without diagnosing the underlying cause. We investigated whether existing clinical indices for screening type III HL as well as the apo B-48/triglyceride (TG) ratio, which was suggested to be related to the accumulation of small chylomicron (CM) remnants, are useful after the initiation of lipid-lowering therapies. Methods: In 25 normolipidemic subjects and 191 treated HL patients (type I, n =6; IIa, 62; IIb, 66; III, 12; IV, 22; and V, 23) from Osaka University Hospital and related hospitals, fasting low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), TG, and apolipoproteins were measured and clinical indices were evaluated statistically. Results: Apo B-48 levels were significantly higher in patients with type I, III, and V HL, and TG levels were significantly higher in patients with type I and V HL. The apo B-48/TG ratio was significantly higher only in patients with type III HL compared with other types of HL (p<0.001), and was statistically significant among the other clinical indices (AUC-ROC value, 0.895; cut-off value, 0.110). Conclusion: The apo B-48/TG ratio is a novel and useful marker for detecting type III HL even after the initiation of lipid-lowering interventions.
    Journal of atherosclerosis and thrombosis 08/2012; 19(9):862-71. DOI:10.5551/jat.13052 · 2.73 Impact Factor
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    ABSTRACT: High density lipoprotein (HDL) has multi-antiatherogenic effects such as antioxidation and anti-inflammation, in addition to being a key mediator of reverse cholesterol transport. Probucol, known as a lipid lowering drug, is also a potent antioxidant, but it decreases serum HDL cholesterol (HDL-C) levels. To elucidate the effect of probucol on antioxidant properties of HDL, we investigated the function of HDL derived from patients with heterozygous familial hypercholesterolemia (FH) who have been treated with probucol. Probucol-treated FH patients (n=21) showed a 47% reduction of serum HDL-C levels compared to probucol-untreated FH patients (n=15). High performance liquid chromatography (HPLC) analysis revealed that probucol diminished HDL particle size compared to the non-treated group. Antioxidant capacity of HDL was evaluated by its effect to protect reference LDL from oxidation induced in the presence of an oxidizing agent, AAPH. The HDL derived from the probucol-treated group demonstrated a significantly prolonged time to start oxidation by 112%, decreased the maximum oxidation rate by 14%, and lowered the maximum concentration of conjugated dienes formation by 15%. Furthermore, HDL-associated paraoxonase 1 (PON1) activity, but not platelet-activating factor acetyl-hydrolase (PAF-AH) correlated with these measurements of HDL anti-oxidative activity. Treatment with probucol in vitro and inhibition of PON1 activity demonstrated that probucol in HDL particles and increase of PON1 activity might largely contribute to the increase of HDL anti-oxidative activity. Probucol reduced HDL-C levels and HDL particle size in patients with heterozygous FH, while it concomitantly enhanced HDL anti-oxidative properties, possibly through increasing PON1 activity.
    Journal of atherosclerosis and thrombosis 07/2012; 19(7):643-56. DOI:10.5551/jat.12807 · 2.73 Impact Factor
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    ABSTRACT: Aim: Apolipoprotein B-48 (apoB-48) is a major apolipoprotein of intestine-derived chylomicrons (CM) and CM remnants (CMR). Clinically overt hypothyroidism (OH) has been associated with premature and accelerated coronary atherosclerosis. To clarify the clinical significance of apoB-48 measurement in patients with thyroid disease, we investigated the correlations between the serum apoB-48 level and thyroid hormones. Methods: From outpatients of Osaka University Hospital, patients with OH, subjects with subclinical hypothyroidism (SH) and subjects with normal thyroid function were collected and analyzed by measuring serum TSH, FT4 and FT3 levels. Serum apoB-48 levels were measured by a chemiluminescence enzyme immunoassay and the correlations with thyroid hormone levels or lipid profiles were assessed. These levels were compared among subjects with OH, SH and healthy controls. Results: Serum apoB-48 level was correlated with TSH, total cholesterol (TC) and triglycerides (TG), but negatively with FT4 and FT3 level. LDL-C and HDL-C levels were not correlated with serum apoB-48 levels. Serum apoB-48 in patients with OH (7.4 ± 5.9 µg/mL) was significantly higher than in those with hyperthyroidism (5.1 ± 3.5 µg/mL; p<0.01) and normal subjects (4.7 ± 3.7 µg/mL; p<0.01), but decreased after levo-thyroxine replacement. ApoB-48, TG and TSH were significantly higher in SH subjects than normal subjects, suggesting that serum apoB-48 level depends on the thyroid function status, similar to TC, LDL-C and TG. Conclusion: Increased serum apoB-48 concentrations and CMR may contribute to the increased risk of atherosclerosis and premature coronary artery disease in the hypothyroid state.
    Journal of atherosclerosis and thrombosis 07/2012; 19(10). DOI:10.5551/jat.12757 · 2.73 Impact Factor

Publication Stats

13k Citations
631.85 Total Impact Points


  • 1987-2015
    • Osaka University
      • • Health Care Center
      • • Graduate School of Medicine
      • • Department of Internal Medicine
      • • School of Medicine
      Suika, Ōsaka, Japan
  • 1994-2012
    • Osaka City University
      • • Department of Cardiovascular Medicine
      • • Graduate School of Medicine
      • • Second Department of Internal Medicine
      Ōsaka, Ōsaka, Japan
  • 2010
    • University of Texas Medical Branch at Galveston
      Galveston, Texas, United States