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Kozaki Y.,Kinjo Gakuin University | Umetsu R.,Kinjo Gakuin University | Mizukami Y.,Kinjo Gakuin University | Yamamura A.,Kinjo Gakuin University | And 4 more authors.
Journal of Physiological Sciences | Year: 2015

Repeated cold stress (RCS) is known to transiently induce functional disorders associated with hypotension and hyperalgesia. In this study, we investigated the effects of RCS (24 and 4 °C alternately at 30-min intervals during the day and 4 °C at night for 2 days, followed by 4 °C on the next 2 consecutive nights) on the thresholds for cutaneous mechanical pain responses and on peripheral expression of “pain-related genes” in SHRSP5/Dmcr rats, which are derived from stroke-prone spontaneously hypertensive rats. To define genes peripherally regulated by RCS, we detected changes in the expression of pain-related genes in dorsal root ganglion cells by PCR-based cDNA subtraction analysis or DNA microarray analysis, and confirmed the changes by RT-PCR. We found significantly changed expression in eight pain-related genes (upregulated: Fyn, St8sia1, and Tac 1; downregulated: Ctsb, Fstl1, Itpr1, Npy, S100a10). At least some of these genes may play key roles in hyperalgesia induced by RCS. © 2015, The Physiological Society of Japan and Springer Japan.

Moriya T.,Nagoya University | Kitamori K.,Kinjo Gakuin University | Naito H.,Nagoya University | Yanagiba Y.,Nagoya University | And 11 more authors.
Environmental Health and Preventive Medicine | Year: 2012

Objectives: The aim of this study was to identify the molecular mechanisms underlying high-fat and high-cholesterol (HFC) diet-induced steatohepatitis and associated liver fibrosis progression in a novel stroke-prone, spontaneously hypertensive 5/Dmcr (SHRSP5/Dmcr) rat model. Methods: SHRSP5/Dmcr rats were given the control or HFC-diet for 2, 8, and 16 weeks. Plasma and hepatic gene expression of key molecules involved in fatty acid oxidation, inflammation, oxidative stress, and fibrosis were subsequently analyzed. Results: Rats fed the HFC-diet showed increased plasma tumor necrosis factor-α (TNF-α) and hepatic p50/p65 signals, but reduced hepatic Cu2+/Zn 2+-superoxide dismutase across the treatment period and reduced plasma total adiponectin at 8 weeks. In HFC-diet-fed rats, transforming growth factor-β1 (TGF-β1) was elevated prior to the appearance of obvious liver fibrosis pathology at 2 weeks, followed by elevations in platelet-derived growth factor-B (PDGF-B) and α-smooth muscle actin (α-SMA), corresponding to evident liver fibrosis, at 8 weeks and by α1 type I collagen production at 16 weeks. The HFC-diet increased hepatic total cholesterol accumulation, although hepatic triglyceride declined by 0.3-fold from 2 to 16 weeks due to reduced hepatic triglyceride synthesis, as suggested by the diacylglycerol acyltransferase 1 and 2 measurements. Conclusions: TNF-α and p50/p65 molecular signals appeared to be major factors for HFC-diet-induced hepatic inflammation and oxidative stress facilitating liver disease progression. While the up-regulation of TGF-β1 prior to the appearance of any evident liver fibrosis could be an early signal for progressive liver fibrosis, elevated PDGF-B and α-SMA levels signified evident liver fibrosis at 8 weeks, and subsequent increased α1 type I collagen production and reduced triglyceride synthesis indicated extensive liver fibrosis at 16 weeks in this novel SHRSP5/Dmcr model. © The Japanese Society for Hygiene 2012.

Kitamori K.,Nagoya University | Kitamori K.,Kinjo Gakuin University | Naito H.,Nagoya University | Tamada H.,Nagoya University | And 11 more authors.
Environmental Health and Preventive Medicine | Year: 2012

Objectives Patients with nonalcoholic fatty liver disease are increasing worldwide, and preventive measures are an urgent need and primary concern today. Aim This study aimed to develop and clarify the usefulness of the SHRSP5/Dmcr rat, derived from a stroke-prone spontaneously hypertensive rat, as a novel animal model for time-course analysis of steatohepatitis and the severe fibrosis progression often observed in the disease. Methods Ten-week-old male SHRSP5/Dmcr rats were divided into six groups: half were fed a high-fat and highcholesterol- containing diet (HFC diet), and the others the control, stroke-prone (SP) diet for 2, 8, and 14 weeks. Results The HFC diet significantly increased serum transaminase and gamma glutamyl transpeptidase activities, tumor necrosis factor alpha levels, and serum and hepatic total cholesterol levels over time. In contrast, this diet decreased serum albumin, glucose, and adiponectin levels throughout or the later stage of the feeding period, but did not influence serum insulin levels. Histopathologically, the HFC diet increased microvesicular steatosis, and focal or spotty necrosis with lymphocyte infiltrations were observed in the liver at 2 weeks, macrovesicular steatosis, ballooned hepatocytes with Mallory- Denk body formation in some, and multilobular necrosis and fibrosis at 8 weeks. Interestingly, this fibrosis formed a honeycomb network at 14 weeks. These changes are very similar to those observed in patients with non-alcoholic steatohepatitis. Conclusions SHRSP5/Dmcr rats appear to be a useful model for analyzing the time-dependent changes of HFC diet-induced steatohepatitis and fibrosis progression. © The Japanese Society for Hygiene 2011.

Yamaguchi T.,Life Science Research Center | Kitamori K.,Nagoya University | Kitamori K.,Kinjo Gakuin University | Ichihara G.,Nagoya University | And 8 more authors.
Clinical and Experimental Pharmacology and Physiology | Year: 2013

Obesity is associated with high chronic cardiac workload due to the need to supply more blood to peripheral tissue, and frequently leads to left ventricular (LV) dysfunction. The present study examined serial changes in cardiac function in the SHR/NDmcr-cp (SHR/cp) strain, an experimental model of obesity plus hypertension and metabolic syndrome. Transthoracic echocardiography was used to define cardiac dimensions and function in male spontaneously hypertensive rats (SHR/lean), SHR/cp and Wistar-Kyoto rats. We also assessed age-related changes in plasma and LV adipocytokine levels in this model. Although there were no significant differences in LV end-diastolic diameter and end-systolic diameter among the three rat strains until 24 weeks of age, these parameters were significantly higher and LV fractional shortening (%FS) was significantly lower in SHR/cp compared with SHR/lean at 32 weeks of age. At the same age, pronounced interstitial fibrosis and infiltration of macrophages and T lymphocytes into the LV was noted in SHR/cp relative to the other strains. In the myocardium, adiponectin levels were significantly lower and resistin levels and the expression of proinflammatory cytokines (tumour necrosis factor-α and interleukin-6) were significantly higher in SHR/cp than SHR/lean at 32 weeks of age. Using echocardiography, we demonstrated reduced systolic function in 32-week-old SHR/cp. Changes in myocardial cytokine concentrations could be involved in worsening of cardiac function in our animal model of metabolic syndrome. © 2013 Wiley Publishing Asia Pty Ltd.

Katakura M.,The University of Shimane | Hashimoto M.,The University of Shimane | Inoue T.,The University of Shimane | Mamun A.A.,The University of Shimane | And 5 more authors.
Molecules | Year: 2014

The omega-3 polyunsaturated fatty acids (?-3 PUFAs) docosahexaenoic acid (DHA) and/or eicosapentaenoic acid (EPA) protect against diabetic nephropathy by inhibiting inflammation. The aim of this study was to assess the effects of highly purified DHA and EPA or EPA only administration on renal function and renal eicosanoid and docosanoid levels in an animal model of metabolic syndrome, SHR.Cg-Leprcp/NDmcr (SHRcp) rats. Male SHRcp rats were divided into 3 groups. Control (5% arabic gum), TAK-085 (300 mg/kg/day, containing 467 mg/g EPA and 365 mg/g DHA), or EPA (300 mg/kg/day) was orally administered for 20 weeks. The urinary albumin to creatinine ratio in the TAK-085-administered group was significantly lower than that in other groups. The glomerular sclerosis score in the TAK-085-administered group was significantly lower than that in the other groups. Although DHA levels were increased in total kidney fatty acids, the levels of nonesterified DHA were not significantly different among the 3 groups, whereas the levels of protectin D1, resolvin D1, and resolvin D2 were significantly increased in the TAK-085-administered group. The results show that the use of combination therapy with DHA and EPA in SHRcp rats improved or prevented renal failure associate with metabolic syndrome with decreasing triglyceride levels and increasing ?-3 PUFA lipid mediators. © 2014 by the authors; licensee MDPI, Basel, Switzerland.

Hashimoto M.,The University of Shimane | Inoue T.,The University of Shimane | Katakura M.,The University of Shimane | Tanabe Y.,The University of Shimane | And 4 more authors.
Neurochemical Research | Year: 2013

Metabolic syndrome is implicated in the decline of cognitive ability. We investigated whether the prescription n-3 fatty acid administration improves cognitive learning ability in SHR.Cg-Lepr cp /NDmcr (SHR-cp) rats, a metabolic syndrome model, in comparison with administration of eicosapentaenoic acid (EPA, C20:5, n-3) alone. Administration of TAK-085 [highly purified and concentrated n-3 fatty acid formulation containing EPA ethyl ester and docosahexaenoic acid (DHA, C22:6, n-3) ethyl ester] at 300 mg/kg body weight per day for 13 weeks reduced the number of reference memory-related errors in SHR-cp rats, but EPA alone had no effect, suggesting that long-term TAK-085 administration improves cognitive learning ability in a rat model of metabolic syndrome. However, the working memory-related errors were not affected in either of the rat groups. TAK-085 and EPA administration increased plasma EPA and DHA levels of SHR-cp rats, associating with an increase in EPA and DHA in the cerebral cortex. The TAK-085 administration decreased the lipid peroxide levels and reactive oxygen species in the cerebral cortex and hippocampus of SHR-cp rats, suggesting that TAK-085 increases antioxidative defenses. Its administration also increased the brain-derived neurotrophic factor levels in the cortical and hippocampal tissues of TAK-085-administered rats. The present study suggests that long-term TAK-085 administration is a possible therapeutic strategy for protecting against metabolic syndrome-induced learning decline. © 2013 The Author(s).

Hashimoto M.,The University of Shimane | Katakura M.,The University of Shimane | Nabika T.,The University of Shimane | Tanabe Y.,The University of Shimane | And 4 more authors.
Medical Gas Research | Year: 2011

Background: Hydrogen (H2), a potent free radical scavenger, selectively reduces the hydroxyl radical, which is the most cytotoxic of the reactive oxygen species (ROS). An increase in oxygen free radicals induces oxidative stress, which is known to be involved in the development of metabolic syndrome. Therefore, we investigated whether hydrogen-rich water (HRW) affects metabolic abnormalities in the metabolic syndrome rat model, SHR.Cg-Lepr cp /NDmcr (SHR-cp). Methods. Male SHR-cp rats (5 weeks old) were divided into 2 groups: an HRW group was given oral HRW for 16 weeks, and a control group was given distilled water. At the end of the experiment, each rat was placed in a metabolic cage for 24 h, fasted for 12 h, and anesthetized; the blood and kidneys were then collected. Results: Sixteen weeks after HRW administration, the water intake and urine flow measured in the metabolic cages were significantly higher in the HRW group than in the control group. The urinary ratio of albumin to creatinine was significantly lower and creatinine clearance was higher in the HRW group than in the control group. After the 12-h fast, plasma urea nitrogen and creatinine in the HRW group were significantly lower than in the control group. The plasma total antioxidant capacity was significantly higher in the HRW group than in the control group. The glomerulosclerosis score for the HRW group was significantly lower than in the control group, and a significantly positive correlation was observed between this score and plasma urea nitrogen levels. Conclusion: The present findings suggest that HRW conferred significant benefits against abnormalities in the metabolic syndrome model rats, at least by preventing and ameliorating glomerulosclerosis and creatinine clearance. © 2011 Hashimoto et al; licensee BioMed Central Ltd.

PubMed | Disease Model Cooperative Research Association, Jahangirnagar University and The University of Shimane
Type: | Journal: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie | Year: 2016

The effects of cholesterol-lowering statins, which substantially benefit future cardiovascular events, on fatty acid metabolism have remained largely obscured. In this study, we investigated the effects of atorvastatin on fatty acid metabolism together with the effects of TAK-085 containing highly purified eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) ethyl ester on atorvastatin-induced n-3 polyunsaturated fatty acid lowering in SHR.Cg-Lepr

Kunimasa K.,Mukogawa Women's University | Miura C.,Mukogawa Women's University | Mori H.,Mukogawa Women's University | Tsuchikura S.,Disease Model Cooperative Research Association | And 4 more authors.
Clinical and Experimental Pharmacology and Physiology | Year: 2010

1. Atherosclerosis is commonly observed in obesity. Obese atherosclerosis-prone animals may be a promising tool for understanding the pathophysiology of obesity-associated atherosclerosis. However, most rat strains are resistant to atherosclerosis. The aim of the present study was to assess the susceptibility of two obese hypertensive rat models, namely SHRSP.Z-Leprfa/IzmDmcr rats (SHRSP-fatty) and SHR.Cg-Leprcp/NDmcr rats (SHR-cp), to arterial lipid deposition, an initial stage of atherosclerosis, by comparing these strains with non-obese stroke-prone spontaneously hypertensive rats (SHRSP). 2. Eight-week-old male SHRSP, SHRSP-fatty and SHR-cp were fed a high-fat and high-cholesterol diet containing 20% palm oil, 5% cholesterol and 2% cholic acid for 5 weeks. Bodyweight, blood pressure and fasting serum levels of total cholesterol and triglycerides were measured in 12-week-old rats. Oil red O staining was used to visualize lipid deposition in the mesenteric artery. 3. The bodyweight of 12-week-old SHRSP-fatty and SHR-cp was higher than that of SHRSP (P < 0.005). Systolic blood pressure in SHRSP and SHRSP-fatty was higher than in SHR-cp (P < 0.005). Serum total cholesterol and triglyceride levels were elevated in SHRSP-fatty (P < 0.005) and SHR-cp (P < 0.05) compared with levels in SHRSP. Lipid deposition in the mesenteric artery was significantly greater in SHRSP-fatty than in SHRSP (37.7 ± 4.9 vs 13.1 ± 2.8%, respectively; P < 0.005), but markedly reduced in SHR-cp (1.8 ± 0.4%; P < 0.05). 4. The results of the present study indicate that SHRSP-fatty are highly susceptible to arterial lipid deposition, whereas SHR-cp are resistant. Thus, SHRSP-fatty may be a useful obese rat model in which to investigate atherosclerotic processes. © 2010 The Authors. Clinical and Experimental Pharmacology and Physiology © 2010 Blackwell Publishing Asia Pty Ltd.

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