Language：Japanese   Publisher：(公財)腸内細菌学会  

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Language：Japanese   Publisher：(公財)腸内細菌学会  

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The SHRSP5/Dmcr is a useful animal model for the development of nonalcoholic steatohepatitis (NASH) pathology when fed a high-fat, high-cholesterol diet, and further drug interventions can lead to concomitant cardiovascular disease. While SHRSP5/Dmcr rats have been used for basic research related to NASH, details of their bile acid metabolism in this condition are unknown. In this study, we aimed to clarify the changes in the serum bile acid (BA) fractions associated with NASH and found that glycine-conjugated and unconjugated bile acid increased with worsening NASH and cardiovascular disease while taurine-conjugated BA relatively decreased.

DOI： 10.18926/AMO/64358

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Authorship：Last author,　Corresponding author  

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Language：Japanese   Publisher：(一社)日本サルコペニア・フレイル学会  

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BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a progressive subtype of non-alcoholic fatty liver disease (NAFLD) that is closely related to cardiovascular disease (CVD). Nitric oxide (NO) plays a critical role in the control of various biological processes. Dysfunction of the NO signaling pathway is associated with various diseases such as atherosclerosis, vascular inflammatory disease, and diabetes. Recently, it has been reported that NO is related to lipid and cholesterol metabolism. Chronic NO synthase (NOS) inhibition accelerates NAFLD by increasing hepatic lipid deposition. However, the detailed relationship between NO and abnormal lipid and cholesterol metabolism in NAFLD/NASH has not been completely explained. We aimed to determine the effects of NOS inhibition by N omega-nitro-L-arginine methyl ester hydrochloride (L-NAME), a NOS inhibitor, on NASH and CVD via lipid and cholesterol metabolism. METHODS: Stroke-prone spontaneously hypertensive rats were fed a high-fat and high-cholesterol diet for 8 weeks and administered L-NAME for the last 2 weeks. Following blood and tissue sampling, biochemical analysis, histopathological staining, quantitative RT-PCR analysis, and western blotting were performed. RESULTS: L-NAME markedly increased hepatic triglyceride (TG) and cholesterol levels by promoting TG synthesis and cholesterol absorption from the diet. L-NAME increased the mRNA levels of inflammatory markers and fibrotic areas in the liver. Cholesterol secretion from the liver was promoted in rats administered L-NAME, which increased serum cholesterol. L-NAME significantly increased the level of oxidative stress marker and lipid deposition in the arteries. CONCLUSIONS: NOS inhibition simultaneously aggravates NASH and atherosclerosis via hepatic lipid and cholesterol metabolism.

DOI： 10.1007/s43440-022-00380-1

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Osteoarthritis is a progressive disease characterized by cartilage destruction in the joints. Matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) play key roles in osteoarthritis progression. In this study, we screened a chemical compound library to identify new drug candidates that target MMP and ADAMTS using a cytokine-stimulated OUMS-27 chondrosarcoma cells. By screening PCR-based mRNA expression, we selected 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide as a potential candidate. We found that 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide attenuated IL-1β-induced MMP13 mRNA expression in a dose-dependent manner, without causing serious cytotoxicity. Signaling pathway analysis revealed that 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide attenuated ERK- and p-38-phosphorylation as well as JNK phosphorylation. We then examined the additive effect of 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide in combination with low-dose betamethasone on IL-1β-stimulated cells. Combined treatment with 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide and betamethasone significantly attenuated MMP13 and ADAMTS9 mRNA expression. In conclusion, we identified a potential compound of interest that may help attenuate matrix-degrading enzymes in the early osteoarthritis-affected joints.

DOI： 10.3390/ijms23052681

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Language：English   Publishing type：Research paper (scientific journal)  

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

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Authorship：Corresponding author   Language：English  

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Language：English   Publishing type：Research paper (scientific journal)  

Idiopathic pulmonary fibrosis (IPF) is the most common and most deadly form of interstitial lung disease. Osteopontin (OPN), a matricellular protein with proinflammatory and profibrotic properties, plays a major role in several fibrotic diseases, including IPF; OPN is highly upregulated in patients' lung samples. In this study, we knocked down OPN in a bleomycin (BLM)-induced pulmonary fibrosis (PF) mouse model using small interfering RNA (siRNA) to determine whether the use of OPN siRNA is an effective therapeutic strategy for IPF. We found that fibrosing areas were significantly smaller in specimens from OPN siRNA-treated mice. The number of alveolar macrophages, neutrophils, and lymphocytes in bronchoalveolar lavage fluid was also reduced in OPN siRNA-treated mice. Regarding the expression of epithelial-mesenchymal transition (EMT)-related proteins, the administration of OPN-siRNA to BLM-treated mice upregulated E-cadherin expression and downregulated vimentin expression. Moreover, in vitro, we incubated the human alveolar adenocarcinoma cell line A549 with transforming growth factor (TGF)-β1 and subsequently transfected the cells with OPN siRNA. We found a significant upregulation of Col1A1, fibronectin, and vimentin after TGF-β1 stimulation in A549 cells. In contrast, a downregulation of Col1A1, fibronectin, and vimentin mRNA levels was observed in TGF-β1-stimulated OPN knockdown A549 cells. Therefore, the downregulation of OPN effectively reduced pulmonary fibrotic and EMT changes both in vitro and in vivo. Altogether, our results indicate that OPN siRNA exerts a protective effect on BLM-induced PF in mice. Our results provide a basis for the development of novel targeted therapeutic strategies for IPF.

DOI： 10.1016/j.biopha.2021.111633

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Language：English   Publishing type：Research paper (scientific journal)  

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Language：Japanese   Publishing type：Research paper (bulletin of university, research institution)  

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BACKGROUND: High-density lipoprotein (HDL) containing apolipoprotein E (apoE-rich HDL) represents a small portion of plasma HDL. We recently established a method for measuring plasma apoE-rich HDL. This study aimed to investigate the relationship between metabolic syndrome (MetS) and apoE-rich HDL levels. METHODS: The apoE-rich HDL-cholesterol (HDL-C) levels and metabolic characteristics of 113 patients were analyzed. RESULTS: The MetS group (n = 58) had significantly lower apoE-rich HDL-C and a lower apoE-rich HDL-C/HDL-C ratio (apoE-HDL (%)) compared to the non-MetS group. The prevalence of MetS was increased when apoE-HDL (%) decreased. In simple regression analyses, apoE-HDL (%) was significantly inversely correlated with visceral fat area (rs = -0.370, P < 0.001) and plasma triglycerides (rs = -0.447, P < 0.001) and positively correlated with low-density lipoprotein (LDL) mean particle size (rs = 0.599, P < 0.001) and HDL mean particle size (rs = 0.512, P < 0.001). Stepwise multiple regression analysis revealed that LDL mean particle size, a component of the atherogenic lipoprotein profile, was an independent predictor of apoE-HDL (%) (adjusted R2 = 0.409). CONCLUSIONS: Plasma apoE-rich HDL levels might be a valuable indicator of MetS. These findings may help further understand HDL subfraction analysis in cardiometabolic diseases.

DOI： 10.1016/j.cca.2020.08.020

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BACKGROUND AND AIMS: Nonalcoholic steatohepatitis (NASH) is linked to an increased risk of cardiovascular disease, regardless of the risk factors in metabolic syndrome. However, the intermediary factors between NASH and cardiovascular disease are still unknown. A previous study revealed that serum and hepatic bile acid (BA) levels are increased in some NASH patients. We aimed to examine whether NASH and cardiovascular disease were aggravated by BA using an animal model. METHOD AND RESULTS: From 10 to 18 weeks of age, SHRSP5/Dmcr rats divided into 3 groups were fed 3 types of high-fat and high-cholesterol (HFC) diets which were changed in the cholic acid (CA) concentration (0%, 2%, or 4%). The nitro oxide synthase inhibition (L-NAME) was administered intraperitoneally from 16 to 18 weeks of age. The 4% CA groups showed the worst LV dysfunction and myocardial fibrosis, and demonstrated severe hepatic fibrosis and lipid depositions. In addition, a large amount of lipid accumulation was observed in the aortas of the 4% CA group, and NFκB and VCAM-1 gene expression levels were increased. These findings were not seen in the 0% CA group. CONCLUSION: In the SHRSP5/Dmcr rat model, NASH and cardiovascular disease were aggravated with increasing BAs concentrations in an HFC diet.

DOI： 10.1016/j.yexmp.2020.104437

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Longdom Group  

DOI： 10.35248/2155-9600.19.9.763

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

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Language：English   Publishing type：Research paper (scientific journal)  

Non-alcoholic steatohepatitis (NASH) is linked to increased cardiovascular risk, independent of the broad spectrum of metabolic syndrome risk factors. Stroke-prone (SP) spontaneously hypertensive rats (SHRSP5/Dmcr) fed a high-fat and high-cholesterol (HFC) diet developed hepatic lesions similar to those in human NASH pathology. These rats simultaneously developed lipid deposits in the mesenteric arteries, cardiac fibrosis, endothelial dysfunction and left ventricle (LV) diastolic dysfunction. However, the intermediary factors between NASH and cardiovascular disease are still unknown. We investigated whether NASH aggravates nitric oxide (NO) synthase inhibition-induced arteriosclerosis in SHRSP5/Dmcr rats. Wistar Kyoto and SHRSP5/Dmcr rats were divided into 4 groups of 5 and fed the stroke-prone (SP) or HFC diets for 8 weeks. To induce NO synthase inhibition, Nω -nitro-L-arginine methyl ester hydrochloride (L-NAME) mixed with drinking water was administered in the final 2 weeks. The NASH+L-NAME group demonstrated the following characteristics related to arteriosclerosis and myocardial ischaemia: (a) LV systolic dysfunction with asynergy, (b) replacement fibrosis caused by the shedding of cardiomyocytes and (c) arterial lipid deposition and coronary occlusion secondary to endothelial dysfunction. These characteristics were not observed in the NASH or non-NASH+L-NAME groups. The SHRSP5/Dmcr rat model demonstrates that NASH significantly aggravates cardiovascular risk.

DOI： 10.1111/iep.12301

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japan Atherosclerosis Society  

Aim: Non-alcoholic steatohepatitis (NASH) increases cardiovascular risk regardless of risk factors in metabolic syndrome. However, the intermediary factors between NASH and vascular disease are still unknown because a suitable animal model has never been established. The stroke-prone (SP) spontaneously hypertensive rat, SHRSP5/Dmcr, simultaneously develops hypertension, acute arterial lipid deposits in mesenteric arteries, and NASH when feed with a high-fat and high-cholesterol (HFC) diet. We investigated whether SHRSP5/Dmcr affected with NASH aggravates the cardiac or vascular dysfunction. Method: Wister Kyoto and SHRSP5/Dmcr rats were divided into 4 groups of 5 rats each, and fed with a SP or HFC diet. After 8 weeks of HFC or SP diet feeding, glucose and insulin resistance, echocardiography, blood biochemistry, histopathological staining, and endothelial function in aorta were evaluated. Results: We demonstrate that SHRSP5/Dmcr rats fed with a HFC diet presented with cardiac and vascular dysfunction caused by cardiac fibrosis, endothelial dysfunction, and left ventricular diastolic dysfunction, in association with NASH and hypertension. These cardiac and vascular dysfunctions were aggravated and not associated with the presence of hypertension, glucose metabolism disorder, and/or obesity. Conclusions: SHRSP5/Dmcr rats may be a suitable animal model for elucidating the organ interaction between NASH and cardiac or vascular dysfunction.

DOI： 10.5551/jat.40956

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DOI： 10.14326/abe.7.47

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：IOP PUBLISHING LTD  

The summation of the muscle force caused by an increase in the firing rate is named a tetanic contraction (tetanus), and the minimum stimulation frequency necessary to evoke an unfused/fused tetanus is related to the contraction time (CT) and relaxation time (RT) of the twitch. In particular, the fusion index (FI) is a very useful indicator, and it is used to evaluate the change in the muscle fiber component ratio. However, the measurement of the FI is invasive, because most patients experience pain during the electrical stimulation for tetanus. We expect that the twitch parameters CT and RT can substitute for the FI in the future. We found that the minimum stimulation frequency necessary to evoke the unfused/fused tetanus can be estimated from the twitch parameters as a first step. The results showed that (1) the minimum stimulation frequencies calculated from twitch parameters during unfused/fused tetanus were very similar to those calculated from FI parameters, and (2) they were also strongly correlated with FI parameters regardless of fiber components. The basic characteristics of tetanic progression in different fiber types could be estimated from twitch parameters.

DOI： 10.1088/1361-6579/aa5bd1

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Language：Japanese   Publisher：Japanese Society for Medical and Biological Engineering  

<p>By simultaneously measuring Mechanomyoram (MMG) and Electromyogram (EMG), it is possible to accurate assessment of skeletal muscle contraction. However, MMG measurement has been rarely used for reasons such as having to fix body. Therefore, the authors developed MMG/EMG hybrid transducer system. The device was small and light (47x34x24 mm, 34 g). It was capable of MMG/EMG measurement without requiring any accessory, because sensor section, transducer and storage were integrated. Attachment to the skin was used a dedicated belt conforming to device shape. In addition, hybrid transducer was communicated with operation terminal via Bluetooth(R), and measurement control software collectively controlled five hybrid transducers and could set measurement parameters such as sampling time. MMG/EMG waveforms were monitored in real-time, and data were output in CSV format. By MMG/EMG hybrid transducer system, everyone could simply measure regardless of any field. ACKNOWLEDGEMENT: This research was partially supported by Okayama Prefecture.</p>

DOI： 10.11239/jsmbe.55Annual.252

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier B.V.  

Background Respiratory muscle strength has been used as a tool for evaluating respiratory rehabilitation in chronic obstructive pulmonary disease. However, mouth pressure measurement evaluated by maximum expiratory mouth pressure (PEmax) or inspiratory mouth pressure (PImax) offers an indirect method for measuring respiratory muscle strength. We demonstrated the evaluation of diaphragm contractility using a mechanomyogram (MMG), which is the mechanical signal generated by the motion of the diaphragm induced by the electric stimulation of the phrenic nerve. Methods Study participants were 21 young and 20 elderly subjects with no symptoms of respiratory disease. The elderly subjects were divided into non-smoker or smoker groups. The smoker group was defined as subjects having a Brinkman Index of greater than 300. We measured basic spirometric parameters, mouth pressure (PEmax, PImax), and diaphragmatic MMG. Results Diaphragmatic MMG showed more clear contrast between young subjects and elderly non-smoker or smoker subjects than the conventional method for respiratory muscle contraction (PEmax, PImax). In addition, the diaphragmatic MMG strongly correlated with inspiratory muscle strength. Conclusions Diaphragmatic MMG may reflect diaphragmatic contractility more directly and sensitively than the conventional method.

DOI： 10.1016/j.resinv.2016.06.001

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER INTERNATIONAL PUBLISHING AG  

Purpose: The aim of this study is to investigate the relationship between arterial pulse amplitude change under increased shear stress and the presence of ischemic heart disease (IHD).
Methods: This study comprised 31 subjects, including 14 subjects with IHD. We investigated the change in brachial artery pulse amplitude during flow-mediated dilation (FMD) using ultrasonography.
Results: The arterial pulse amplitude increased during FMD in 19 subjects, whereas it decreased in 12 subjects. There was a marked difference in the change in arterial pulse amplitude (the maximum amplitude of the arterial pulse amplitude during FMD/the arterial pulse amplitude at baseline) between subjects with and without IHD (0.98 +/- 0.53 and 1.37 +/- 0.53, p = 0.028). Furthermore, decreased arterial pulse amplitude during FMD was a significant predictor of IHD after adjustment of age, blood pressure, the presence of each type of coronary risks, the value of FMD and sex (p = 0.0001).
Conclusions: The decrease of arterial pulsation amplitude during FMD was a useful predictive parameter for IHD.

DOI： 10.1186/s40064-016-2794-0

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER INTERNATIONAL PUBLISHING AG  

Purpose: The aim of this study is to investigate the relationship between arterial pulse amplitude change under increased shear stress and the presence of ischemic heart disease (IHD).
Methods: This study comprised 31 subjects, including 14 subjects with IHD. We investigated the change in brachial artery pulse amplitude during flow-mediated dilation (FMD) using ultrasonography.
Results: The arterial pulse amplitude increased during FMD in 19 subjects, whereas it decreased in 12 subjects. There was a marked difference in the change in arterial pulse amplitude (the maximum amplitude of the arterial pulse amplitude during FMD/the arterial pulse amplitude at baseline) between subjects with and without IHD (0.98 +/- 0.53 and 1.37 +/- 0.53, p = 0.028). Furthermore, decreased arterial pulse amplitude during FMD was a significant predictor of IHD after adjustment of age, blood pressure, the presence of each type of coronary risks, the value of FMD and sex (p = 0.0001).
Conclusions: The decrease of arterial pulsation amplitude during FMD was a useful predictive parameter for IHD.

DOI： 10.1186/s40064-016-2794-0

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Language：Japanese  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society for Medical and Biological Engineering  

<p>Electromyogram (EMG) is recorded electrical muscle contraction, mechanomyogram (MMG) indicates cross-sectional area change of muscle, reflect mechanical muscle contraction. By simultaneously measuring both signals, it is possible to multifaceted evaluation of muscle contraction. However, MMG measurement at voluntary movement was difficult. Therefore, the authors developed MMG / EMG hybrid transducer capable of simultaneous measurement of MMG and EMG. This study evaluated MMG and EMG of rectus femoris (RF) and hamstrings using recumbent bicycle of easy load regulation. As result, dMMGbase (baseline of displacement MMG) indicated cross-sectional area change of muscle at pushing down and pulling up of pedal. In addition, EMG and dMMGbase increased with pushing down of pedal in RF, dMMGacc (acceleration dMMGbase) showing muscle contraction force was output simultaneously. Each signal of hamstrings had output that antagonize RF. By simultaneously measuring MMG and EMG at recumbent bicycle pedaling, it was possible to evaluate muscle contraction of voluntary movement.</p>

DOI： 10.11239/jsmbe.54Annual.P2-C04-1

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Glucocorticoids are stress hormones that modulate metabolic, inflammatory and cardiovascular processes. We recently characterized DahlS. Z-Leprfa/Leprfa (DS/obese) rats, derived from a cross between Dahl salt-sensitive (DS) and Zucker rats, as a new animal model of metabolic syndrome (MetS). We have now investigated the effects of glucocorticoid receptor (GR) blockade on cardiac and adipose tissue pathology and gene expression, as well as on glucose metabolism in this model. DS/obese rats were treated with the GR blocker RU486 (2 mg kg(-1) per day, subcutaneous) for 4 weeks beginning at 9 weeks of age. Age-matched homozygous lean (DahlS. Z-Lepr(+)/Lepr(+), or DS/lean) littermates of DS/obese rats served as controls. Treatment of DS/obese rats with RU486 attenuated left ventricular (LV) fibrosis and diastolic dysfunction, as well as cardiac oxidative stress and inflammation, without affecting hypertension or LV hypertrophy. Administration of RU486 to DS/obese rats also inhibited the upregulation of GR and 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) expression at the mRNA and protein levels in the heart; it attenuated adiposity and adipose tissue inflammation, as well as the upregulation of GR and 11 beta-HSD1 mRNA and protein expression in adipose tissue; it ameliorated fasting hyperinsulinemia as well as insulin resistance and glucose intolerance. Our results thus implicate the glucocorticoid-GR axis in the pathophysiology of MetS, and they suggest that GR blockade has therapeutic potential for the treatment of this condition.

DOI： 10.1038/hr.2015.77

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER PHYSIOLOGICAL SOC  

Restraint stress stimulates sympathetic nerve activity and can affect adiposity and metabolism. However, the effects of restraint stress on cardiovascular and metabolic disorders in metabolic syndrome (MetS) have remained unclear. We investigated the effects of chronic restraint stress and beta-adrenergic receptor (beta-AR) blockade on cardiac and adipose tissue pathology and metabolic disorders in a rat model of MetS. DahlS. Z-Lepr(fa)/Lepr(fa) (DS/obese) rats, derived from a cross between Dahl salt-sensitive and Zucker rats. Rats were exposed to restraint stress (restraint cage, 2 h/day) for 4 wk from 9 wk of age with or without daily subcutaneous administration of the beta-AR blocker propranolol (2 mg/kg). Age-matched homozygous lean littermates of DS/obese rats (DahlS. Z-Lepr(+)/Lepr(+) rats) served as control animals. Chronic restraint stress exacerbated hypertension as well as left ventricular hypertrophy, fibrosis, diastolic dysfunction, and oxidative stress in a manner sensitive to propranolol treatment. Restraint stress attenuated body weight gain in DS/obese rats, and this effect tended to be reversed by propranolol (P = 0.0682). Restraint stress or propranolol did not affect visceral or subcutaneous fat mass. However, restraint stress potentiated cardiac and visceral adipose tissue inflammation in DS/obese rats, and these effects were ameliorated by propranolol. Restraint stress also exacerbated glucose intolerance, insulin resistance, and abnormal lipid metabolism in a manner sensitive to propranolol. In addition, restraint stress increased urinary norepinephrine excretion, and propranolol attenuated this effect. Our results thus implicate beta-ARs in the exacerbation of cardiac and adipose tissue pathology and abnormal glucose and lipid metabolism induced by restraint stress in this model of MetS.

DOI： 10.1152/ajpheart.00906.2014

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NAGOYA UNIV, SCH MED  

Oxidative stress and the mineralocorticoid receptor (MR) are implicated in the pathogenesis of salt-induced left ventricular (LV) diastolic dysfunction associated with metabolic syndrome (MetS). We recently characterized DahlS. Z-Leprfa/Leprfa (DS/obese) rats, derived from a cross between Dahl salt-sensitive and Zucker rats, as a new animal model of MetS. We investigated the pathophysiological roles of increased oxidative stress and MR activation in cardiac injury with this model. DS/obese rats were treated with the antioxidant tempol (1 mmol/L in drinking water) or the selective MR antagonist eplerenone (15 mg/kg per day, per os) for 5 weeks beginning at 10 weeks of age. The increased systolic blood pressure and LV hypertrophy that develop in untreated DS/obese rats were substantially ameliorated by eplerenone but not by tempol. Eplerenone also attenuated LV fibrosis and diastolic dysfunction more effectively than did tempol in DS/obese rats, whereas cardiac oxidative stress and inflammation were reduced similarly by both drugs. Both the ratio of plasma aldosterone concentration to plasma renin activity and cardiac expression of the MR and serum/glucocorticoid-regulated kinase 1 genes were decreased to a greater extent by eplerenone than by tempol. Our results indicate that both increased oxidative stress and MR activation in the heart may contribute to the development of LV remodeling and diastolic dysfunction in DS/obese rats. The superior cardioprotective action of eplerenone is likely attributable to its greater antihypertensive effect, which is likely related to its greater inhibition of aldosterone-MR activity in the cardiovascular system.

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Angiotensin receptor blockers (ARBs) are often supplemented with calcium channel blockers (CCBs) for treatment of hypertension. We recently showed that the L/N-type CCB cilnidipine has superior cardioprotective effects compared with the L-type CCB amlodipine in Dahl salt-sensitive (DS) rats. We have now compared the effects of the ARB valsartan combined with cilnidipine or amlodipine on cardiac pathophysiology in DS rats. DS rats fed a high-salt diet from 6 weeks of age were treated with vehicle, valsartan alone (10 mg kg(-1) per day), or valsartan combined with either cilnidipine (1 mg kg(-1) per day) or amlodipine (1 mg kg(-1) per day) from 7 to 11 weeks. The salt-induced increase in systolic blood pressure apparent in the vehicle group was attenuated similarly in the three drug treatment groups. Valsartan-cilnidipine attenuated left ventricular (LV) fibrosis and diastolic dysfunction as well as cardiac oxidative stress and inflammation to a greater extent than did valsartan alone or valsartan-amlodipine. In addition, the increases in urinary excretion of dopamine and epinephrine as well as in cardiac renin-angiotensin-aldosterone-system (RAAS) gene expression apparent in vehicle-treated rats were attenuated to a greater extent by valsartan-cilnidipine than by the other two treatments. Valsartan-cilnidipine thus attenuated LV remodeling and diastolic dysfunction more effectively than did valsartan or valsartan-amlodipine in rats with salt-sensitive hypertension, and this superior cardioprotective action of valsartan-cilnidipine compared with valsartan-amlodipine is likely attributable, at least in part, to the greater antioxidant and antiinflammatory effects associated with both greater inhibition of cardiac RAAS gene expression and N-type calcium channel blockade.

DOI： 10.1038/hr.2014.136

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

Background: Pioglitazone is a thiazolidinedione drug that acts as an insulin sensitizer. We recently characterized DahlS. Z-Lepr(fa)/Lepr(fa) (DS/obese) rats, derived from a cross between Dahl salt-sensitive and Zucker rats, as a new animal model of metabolic syndrome. We have now investigated the effects of pioglitazone on cardiac and adipose tissue pathology in this model.
Methods and results: DS/obese rats were treated with pioglitazone (2.5 mg/kg per day, per os) from 9 to 13 weeks of age. Age-matched homozygous lean (DahlS. Z-Lepr(+)/Lepr(+), or DS/lean) littermates served as controls. Pioglitazone increased body weight and food intake in DS/obese rats. It also ameliorated left ventricular (LV) hypertrophy, fibrosis, and diastolic dysfunction as well as attenuated cardiac oxidative stress and inflammation, without lowering blood pressure, in DS/obese rats, but it had no effect on these parameters in DS/lean rats. In addition, pioglitazone increased visceral and subcutaneous fat mass but alleviated adipocyte hypertrophy and inflammation in visceral adipose tissue in DS/obese rats. Furthermore, pioglitazone increased the serum concentration of adiponectin, induced activation of AMP-activated protein kinase (AMPK) in the heart, as well as ameliorated glucose intolerance and insulin resistance in DS/obese rats.
Conclusions: Treatment of DS/obese rats with pioglitazone exacerbated obesity but attenuated LV hypertrophy, fibrosis, and diastolic dysfunction, with these latter effects being associated with the activation of cardiac AMPK signaling likely as a result of the stimulation of adiponectin secretion. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.ijcard.2014.11.099

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

Background-Metabolic syndrome (MetS) enhances salt sensitivity of blood pressure and is an important risk factor for cardiovascular disease. The effects of dietary salt restriction on cardiac pathology associated with metabolic syndrome remain unclear.
Methods and Results-We investigated whether dietary salt restriction might ameliorate cardiac injury in DahlS. Z-Leprfa/Leprfa (DS/ obese) rats, which are derived from a cross between Dahl salt-sensitive and Zucker rats and represent a model of metabolic syndrome. DS/obese rats were fed a normal-salt (0.36% NaCl in chow) or low-salt (0.0466% NaCl in chow) diet from 9 weeks of age and were compared with similarly treated homozygous lean littermates (DahlS. Z-Lepr+/Lepr+, or DS/lean rats). DS/ obese rats fed the normal-salt diet progressively developed hypertension and showed left ventricular hypertrophy, fibrosis, and diastolic dysfunction at 15 weeks. Dietary salt restriction attenuated all of these changes in DS/obese rats. The levels of cardiac oxidative stress and inflammation and the expression of cardiac renin-angiotensin-aldosterone system genes were increased in DS/obese rats fed the normal-salt diet, and dietary salt restriction downregulated these parameters in both DS/obese and DS/lean rats. In addition, dietary salt restriction attenuated the increase in visceral adipose tissue inflammation and the decrease in insulin signaling apparent in DS/ obese rats without reducing body weight or visceral adipocyte size. Dietary salt restriction did not alter fasting serum glucose levels but it markedly decreased the fasting serum insulin concentration in DS/obese rats.
Conclusions-Dietary salt restriction not only prevents hypertension and cardiac injury but also ameliorates insulin resistance, without reducing obesity, in this model of metabolic syndrome.

DOI： 10.1161/JAHA.114.001312

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Purpose: The physiological role of vasomotion, rhythmic oscillations in vascular tone or diameter, and its underlying mechanisms are unknown. We investigated the characteristics of brachial artery vasomotion in patients with ischemic heart disease (IHD).
Methods: We performed a retrospective study of 37 patients with IHD. Endothelial function was assessed using flow-mediated dilation (FMD), and power spectral analysis of brachial artery diameter oscillations during FMD was performed. Frequency-domain components were calculated by integrating the power spectrums in three frequency bands (in ms(2)) using the MemCalc (GMS, Tokyo, Japan): very-low frequency (VLF), 0.003-0.04 Hz; low frequency (LF), 0.04-0.15 Hz; and high frequency (HF), 0.15-0.4 Hz. Total spectral power (TP) was calculated as the sum of all frequency bands, and each spectral component was normalized against TP.
Results: Data revealed that HF/TP closely correlated with FMD (r = -0.33, p = 0.04), whereas VLF/TP and LF/TP did not. We also explored the relationship between elevated C-reactive protein (CRP) levels and vasomotion. HF/TP was significantly increased in subjects with high CRP levels (CRP;&gt;0.08 mg/dL) compared with subjects with low CRP levels (0.052 +/- 0.026 versus 0.035 +/- 0.022, p&lt;0.05). The HF/TP value closely correlated with CRP (r = 0.24, p = 0.04), whereas the value of FMD did not (r = 0.023, p = 0.84). In addition, elevated CRP levels significantly increased the value of HF/TP after adjustment for FMD and blood pressure (beta = 0.33, p&lt;0.05).
Conclusion: The HF component of brachial artery diameter oscillation during FMD measurement correlated well with FMD and increased in the presence of elevated CRP levels in subjects with IHD.

DOI： 10.1371/journal.pone.0110013

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The aim of this study was to evaluate the add-on effect of aliskiren to valsartan on endothelial-dependent vasodilation in hypertensive patients with ischemic heart disease (IHD). After 4 weeks of treatment with 80 mg of valsartan, 28 patients were allocated to either continued treatment with valsartan or an add-on treatment with valsartan plus 150 mg of aliskiren. Aliskiren significantly decreased plasma renin activity, whereas endothelium-dependent vasodilation measured by flow-mediated dilation (FMD) did not change. In contrast, heart rate significantly decreased (73.1 ± 9.8 to 66.3 ± 7.0 beats per minute at baseline and 24 weeks, respectively [P = .009]) and the standard deviation of the R-R intervals (SDNN) significantly increased in the aliskiren group. The add-on aliskiren to valsartan therapy may not improve endothelial functions, although it significantly reduced resting heart rate via regulation of the autonomic nervous system in hypertensive patients with IHD.

DOI： 10.1111/jch.12366

PubMed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

We recently characterized DahlS.Z-Lepr(fa)/Lepr(fa) (DS/obese) rats, derived from a cross between Dahl salt-sensitive rats and Zucker rats, as a new animal model of metabolic syndrome (MetS). Although the phenotype of DS/obese rats is similar to that of humans with MetS, the pathophysiological and metabolic characteristics in each cell type remain to be clarified. Hence, the establishment of induced pluripotent stem cells (iPSCs) derived from MetS rats is essential for investigations of MetS in vitro. Reports of rat iPSCs (riPSCs), however, are few because of the difficulty of comparing to other rodents such as mouse. Recently, the advantage of using mesenchymal stromal cells (MSCs) as a cell source for generating iPSCs was described. We aimed to establish riPSCs from MSCs in adipose tissues of both DS/obese rats and their lean littermates, DahlS.Z-Lepr(+)/Lepr(+) (DS/lean) rats using lentivirus vectors with only three factors Oct4, Klf4, and Sox2 without c-Myc. The morphology, gene expression profiles, and protein expression of established colonies showed embryonic stem cell (ESCs)like properties, and the differentiation potential into cells from all three germ layers both in vitro and in vivo (teratomas). Both riPSCs became adipocytes after induction of adipogenesis by insulin, T3, and dexamethasone. Real-time PCR analysis also revealed that both riPSCs and the adipose tissue from DS/obese and DS/lean rats possess similar expression patterns of adipocyte differentiation-related genes. We succeeded in generating riPSCs effectively from MSCs of both DS/obese and DS/ lean rats. These riPSCs may well serve as highly effective tools for the investigation of MetS pathophysiology in vitro.

DOI： 10.1371/journal.pone.0104462

Web of Science

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We conducted a retrospective study of 60 patients with ischemic heart disease (31 with diabetes and 29 without diabetes) to investigate the impact of diabetes on diurnal body temperature patterns. We found that the increase of axillary body temperature in the evening was reduced in the presence of diabetes, which was associated with autonomic neuropathy.

DOI： 10.1007/s10286-013-0223-9

PubMed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NAGOYA UNIV, SCH MED  

Aging is accelerated by metabolic and cardiovascular diseases, and the risk of these diseases increases with age. Obesity is an important risk factor for many age-related diseases and is linked to reduced telomere length in white blood cells. We investigated whether cardiac senescence might be enhanced in DahlS.Z-Lepr(fa)/Lepr(fa) (DS/obese) rats, which we recently established as a new animal model of metabolic syndrome. The heart of DS/obese rats was compared with that of homozygous lean littermates (DahlS.Z-Lepr(+)/Lepr(+), or DS/lean, rats). DS/obese rats manifested hypertension as well as left ventricular hypertrophy, fibrosis, and diastolic dysfunction at 18 weeks of age. Myocardial oxidative stress and inflammation were increased in DS/obese rats compared with DS/lean rats. Telomere length in myocardial cells did not differ between the two rat strains, whereas telomerase activity and expression of the telomerase reverse transcriptase gene were increased in DS/obese rats. Expression of the senescence-associated genes for checkpoint kinase 2 (Chk2), p53, and p21 as well as that of genes related to the renin-angiotensin-aldosterone system were also up-regulated in the DS/obese rat heart. Our results indicate that DS/obese rats undergo premature cardiac senescence as well as cardiac remodeling in association with the development of diastolic dysfunction in these animals.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NAGOYA UNIV, SCH MED  

We previously showed that selective mineralocorticoid receptor (MR) blockade by eplerenone is cardioprotective in Dahl salt-sensitive (DS) rats. To clarify the consequences of glucocorticoid-mediated MR activation in these animals, we investigated the effects of exogenous corticosterone on blood pressure as well as cardiac remodeling and function after adrenalectomy. DS rats were subjected to adrenalectomy at 6 weeks of age and thereafter fed a high-salt diet and administered corticosterone (20 mg/kg per day) or vehicle. Systolic blood pressure was higher in the corticosterone group than in the vehicle group at 7 weeks and thereafter. By 11 weeks, corticosterone had reduced left ventricular (LV) mass and induced LV diastolic dysfunction. The ratio of collagen type I to type III mRNA levels in the left ventricle was increased in the corticosterone group compared with the vehicle group. Administration of a non-antihypertensive dose of the MR antagonist spironolactone (20 mg/kg per day) from 6 weeks inhibited the effects of corticosterone on both the collagen type I to type III mRNA ratio and diastolic function without affecting the decrease in LV mass. Spironolactone attenuated both the increase in NADPH oxidase activity in the left ventricle and coronary vascular inflammatory responses apparent in the corticosterone group. These results indicate that exogenous glucocorticoids induce hypertension, cardiac remodeling, and diastolic dysfunction in adrenalectomized DS rats fed a high-salt diet. The cardiac effects of exogenous glucocorticoids are likely attributable, at least in part, to myocardial oxidative stress and coronary vascular inflammation induced by glucocorticoid-activated MRs..

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE CIRCULATION SOC  

Background: Differences in regulating factors and the clinical implications of body temperature variability (BTV) between subjects with and without diabetes have not been clarified to date.
Methods and Results: In 66 subjects with ischemic heart disease (33 with diabetes and 33 without diabetes), BTV, the difference between the highest and lowest temperature measurements, and body temperature standard deviation (BT SD) were measured from axillary body temperature (ABT) records of 3 consecutive days and followed for 16.4 +/- 8.4 months. In subjects without diabetes BTV and BT SD were closely associated with endothelial function as evaluated on flow-mediated dilation (BTV, R=0.33, P=0.026; BT SD, R=0.41, P=0.029), whereas there was a poor association in subjects with diabetes. In the absence of an interrelationship between vascular function and thermoregulation, the contribution of inflammation to BTV was increased in subjects with diabetes (BTV, 0.59 +/- 0.21 degrees C for C-reactive protein [CRP] &lt;0.08 mg/dl vs. 0.79 +/- 0.28 degrees C for CRP &gt;0.08 mg/dl, P=0.014). Event-free survival analysis showed that in subjects with diabetes higher BT SD was associated with shorter event-free survival (log-rank P=0.012), but this relationship was not found in subjects without diabetes.
Conclusions: In subjects with diabetes, the interrelationship between thermoregulation and vascular function was disrupted and the effect of inflammation on thermoregulation was enhanced, so that BTV had a sufficient predictive value for cardiovascular events in diabetic subjects.

DOI： 10.1253/circj.CJ-12-1591

Web of Science

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Language：English   Publishing type：Research paper (scientific journal)  

Background: Endothelial dysfunction and autonomic nervous system imbalance are both risk markers of atherosclerotic vascular damage. The relationship between these 2 factors, however, has not been clarified concisely. Methods and Results: Flow-mediated dilation (FMD) was measured in 47 patients with ischemic heart disease (IHD
mean age, 68.1±7.1 years) using an ultrasound semi-automatic measuring system (UNEXEF18G), and autonomic nervous system activity was evaluated by simultaneous measurements of heart rate variability. FMD was significantly correlated with standard deviation of normal-to-normal beats (r=0.33, P=0.022) and the power ratio of low-frequency power to high-frequency power (LF/HF
r=-0.38, P=0.0087). Furthermore, multiple regression analysis indicated that LF/HF was the most important predictor of the magnitude of FMD. This interaction was severely blunted by β-blockers and the presence of diabetes. Moreover, standardized FMD according to autonomic nervous system activity was a better predictor of future cardiovascular events than FMD. Subjects with cardiovascular events had a significantly smaller corrected FMD (event (+), 3.62±0.41
event (-), 5.10±2.35
P=0.001), and the higher corrected FMD was associated with longer event-free survival. Conclusions: Autonomic nervous system activity is an important regulatory factor of FMD in subjects with IHD. Assessment of this interaction can help provide more accurate risk stratification of subjects with IHD.

DOI： 10.1253/circj.CJ-12-1043

Scopus

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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DOI： 10.1016/j.jelekin.2009.02.007

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Publisher：慶應義塾大学出版  

CiNii Article

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society for Medical and Biological Engineering  

Isometric force response curve by electrically stimulated skeletal muscle contraction of twitch is important in order to judge the ability of the skeletal muscle and to distinguish disease state. In this report, we introduce a new mathematical model of the isometric force response curve, in order to estimate the muscle contraction behavior accurately. The new mathematical model of force response curve was expressed by a difference of fundamental function which was expressed by products of a step response function and a logistic function. The mathematical model was applied to the force response curve by electrically stimulated muscle contraction of twitch, using the rat gastrocnemius muscle (GC), intermediate vastus muscle (VI) and soleus muscle (SOL) . The results indicate new mathematical model showed better agreement with the force response curve of twitch than previous mathematical model in the rat skeletal muscle which has different muscle fiber type only changes the model parameters.

DOI： 10.11239/jsmbe.47.199

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Other Link： http://search.jamas.or.jp/link/ui/2009345502

Language：Japanese  

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Society of Biomechanisms  

<p>Mechanomyogram (MMG) which measures the slight vibration of muscle contraction can evaluate the mechanical function of the muscle. There are few reports describing the surface displacement (displacement-MMGs) along the cross-section direction during tetanus. Using the laser displacement sensor, we recorded the displacement-MMGs of the human Rectus Femoris (type Ⅱ superiority) and Abductor Pollicis Brevis (type I superiority) during tetanus with a 30-s continuous electrostimulation at the frequency ranging from 0.2 to 50 [Hz], and discussed the contraction properties of these mixed fiber-type skeletal muscles. Three male and one female subjects (21- to 25-year-old) without medical histories of muscular disease joined the experiment repeatedly. The results showed that incomplete tetanus in the mixed fiber-type skeletal muscles were induced by two steps, and the displacement-MMG amplitude was affected by the component ratio of the area of muscle fiber. Furthermore, according to contraction and relaxation time of muscle force in type I, II twitches, the frequency regions of the first phase of incomplete tetanus and the second almost corresponded with those of type I and type II, respectively.</p>

DOI： 10.3951/biomechanisms.19.23

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J-GLOBAL

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OBJECTIVE: This study was conducted to determine if interleukin-6 (IL-6) and interleukin-1beta (IL-1beta) mRNA expression increase in response to muscle contraction caused by repetitive electrical stimulation of the rat masseter muscle. METHODS: Male Wistar rats weighing 140-160 g were divided randomly into the following three groups: electrical stimulation (ES) group (n=21), carrageenan injection (CI) group (n=24), and ES under dantrolene sodium (muscle relaxant) injection (ESDI) group (n=7). ES or CI was done to the left masseter; and mock ES or mock CI to the right. Muscle tissues on both sides were sampled for total RNA isolation. Real-time RT-PCR was performed, with the cyclophilin A (CypA) mRNA level in each sample as an internal control. Mean relative IL-6 (il-6/cypA) and IL-1beta (il-1beta/cypA) mRNA levels were compared between the experimental and mock-treated sides within each group. RESULTS: Mean IL-6/CypA levels in the ES- or CI-treated muscle significantly increased, without any significant incremental change observed in either mock-treated muscle. Interestingly, the increase in the il-6/cypA level caused by the ES was suppressed by the injection of dantrolene sodium in the ESDI group. Furthermore, the mean il-1beta/cypA level in the CI-treated masseter also significantly increased without any significant incremental change observed in the mock-treated muscle. However, there was no significant difference in the mean il-1beta/cypA levels in the masseter between the ES- and the mock-treated sides. CONCLUSIONS: These results show that IL-6 mRNA expression in the rat masseter muscle was accelerated by the CI or by repetitive muscle contraction induced by ES. Since the mRNA level of IL-1beta, a well-known proinflammatory cytokine, was not altered by the contraction, the accelerated IL-6 mRNA expression elicited by the muscle contraction does not seem to be related to local inflammation.

DOI： 10.1016/j.archoralbio.2006.10.025

PubMed

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Society of Biomechanisms  

<p>It is known that the MMG (mechanomyogram) reflects the mechanical function of the muscle, but its generating mechanism has not been sufficiently clarified. In this study, when the gastrocnemius of the rat was electrically stimulated, the acceleration-MMG and the displacement on the surface of the muscle were measured using an accelerometer and a laser displacement transducer, respectively, and the intramuscular pressure was simultaneously measured using an optical fiber inserted into the muscle. The generating mechanism of the acceleration-MMG was suggested by the comparative reviews of the following data obtained from the muscle where the induced twitching occurred: the latencies, propagation velocities and amplitudes among the acceleration-MMG, displacement and pressure. Dantrolene, which suppresses the emission of Ca^2＋ from the sarcoplasmic reticulum, was also injected intramuscularly and the measurements were similarly carried out. The following conclusions were obtained: (1) the MMG measured by the accelerometer can be dynamically transformed into the displacement of the surface; (2) the MMG consists of the propagation and composition of the shear wave caused by the change of intramuscular pressure with the muscle contraction;(3) the location of neuromuscular junction can be estimated from the latency of the MMG and the intramuscular pressure wave.</p>

DOI： 10.3951/biomechanisms.18.209

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Language：English   Publisher：(一社)日本循環器学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

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Language：Japanese   Publisher：バイオメカニズム学会  

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Other Link： http://search.jamas.or.jp/link/ui/2009039118

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Other Link： http://search.jamas.or.jp/link/ui/2008276054

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Other Link： http://search.jamas.or.jp/link/ui/2008276073

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Language：Japanese   Publisher：バイオメカニズム学会  

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Other Link： http://search.jamas.or.jp/link/ui/2008300397

Language：Japanese   Publisher：社団法人日本生体医工学会  

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Venue：高松  

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