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Pharmacology & Pharmacy 2015年第10期6卷 461-470页

作者： Shigeko Fujimoto Sakata Koichi Matsuda Yoko Horikawa yasuto sasaki Faculty of Nutrition Kobe Gakuin University Kobe Japan

An increase in total homocysteine (Hcy) levels (protein-bound and free Hcy in the serum) has been identified as a risk factor for vascular diseases. Hcy is a product of the methionine cycle and is a precursor of glutathione in the transsulfuration pathway. The methionine cycle mainly occurs in the liver, with Hcy being exported out of the liver and subsequently bound to serum proteins. When the non-specific adenosine receptor agonist 5’-N-ethylcarboxamide-adenosine (NECA;0.1 or 0.3 mg/kg body weight) was intraperitoneally administered to mice that had been fasted for 16 h, total Hcy levels in the serum significantly increased 1 h after its administration. The NECA treatment may have inhibited transsulfuration because glutathione levels were significantly decreased in the liver. After the intraperitoneal administration of a high dose of NECA (0.3 mg/kg body weight), elevations in total Hcy levels in the serum continued for up to 10 h. The mRNA expression of methionine metabolic enzymes in the liver was significantly reduced 6 h after the administration of NECA. NECA-induced elevations in total serum Hcy levels may be maintained in the long term through the attenuated expression of methionine metabolic enzymes.

关键词： Adenosine 5’-N-Ethylcarboxamide-Adenosine Glutathione Homocysteine

Protective Effects of Nobiletin on Hypertension and Cerebral Thrombosis in Stroke-Prone Spontaneously Hypertensive Rats (SHRSP)

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Food and Nutrition Sciences 2012年第11期3卷 1539-1546页

作者： Miyako Ikemura yasuto sasaki John C. Giddings Junichiro Yamamoto Formerly Department of Haematology College of Medicine Cardiff University Cardiff UK. Laboratory of Physiology Faculty of Nutrition Kobe Gakuin University Kobe Japan

Some citrus flavonoids have been reported to possess antioxidant activities that moderate endothelial dysfunction and show protective effects on cardiovascular disease. We have investigated the protective effects of nobiletin (5,6,7,8,3’,4’-hexamethoxy flavone) derived from the peel of Citrus depressa Hayata (Shiikuwasha), a citrus fruit produced in Okinawa prefecture in Japan on hypertension and thrombogenicity in cerebral vessels of stroke-prone spontaneously hypertensive rats (SHRSP). Nobiletin was added to the diet of male SHRSP (7 weeks old) for 4 weeks. The age-related increase in systolic blood pressure usually observed in SHRSP was significantly suppressed in the treated animals. Thrombogenesis in pial blood vessels, determined using a He-Ne laser technique, and antioxidant activity, assessed by measuring urinary 8-hydroxy-2’-deoxyguanosine (8-OHdG), were significantly reduced after treatment. Urinary nitric oxide (NO) metabolites and acetylcholine-induced endothelial relaxation were increased after dietary intervention. These results strongly suggested that antihypertensive and antithrombotic effects of nobiletin may be related to an increase in bioavailable NO, possibly mediated by the scavenging of reactive oxygen species (ROS).

关键词： Nitric Oxide (NO) Nobiletin Reactive Oxygen Species (ROS) Stroke-Prone Spontaneously Hypertensive Rat (SHRSP) Thrombosis

The Adenosine Receptor Agonist 5’-N-Ethylcarboxamide-Adenosine Increases Glucose 6-Phosphatase Expression and Gluconeogenesis

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Pharmacology & Pharmacy 2014年第1期5卷 19-23页

作者： Koichi Matsuda Yoko Horikawa yasuto sasaki Shigeko F. Sakata Faculty of Nutrition Kobe Gakuin University Kobe Japan.

Intraperitoneal administration of the non-selective adenosine receptor agonist 5’-N-ethylcarboxamide-adenosine (NECA) (0.1 or 0.3 mg/kg) increased fasting serum glucose levels in mice. To clarify the mechanism responsible for this, the expression of liver glucose 6-phosphatase (G6Pase: a gluconeogenic enzyme) was analyzed, and it was found that G6Pase mRNA was increased by NECA treatment. Administration of 0.3 mg/kg NECA resulted in elevated serum glucose levels at 1 h and were further elevated at 6 h. Administration of 0.1 mg/kg NECA increased serum glucose levels at 1 h and had returned to control levels by 6 h. The increase in fasting serum glucose levels induced by NECA are thought to be caused, in part, by elevated G6Pase expression.

关键词： 5’-N-Ethylcarboxamide-Adenosine Glucose 6-Phosphatase Gluconeogenesis

Myricetin and Hesperidin Inhibit Cerebral Thrombogenesis and Atherogenesis in Apoe-/-and Ldlr-/-Mice

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Food and Nutrition Sciences 2018年第1期9卷 20-31页

作者： yasuto sasaki Kanae Hyodo Ayana Hoshino Eri Kisa Koichi Matsuda Yoko Horikawa John C. Giddings Laboratory of Physiology Faculty of Nutrition Kobe Gakuin University Kobe Japan Laboratory of Biochemistry Faculty of Nutrition Kobe Gakuin University Kobe Japan Department of Haematology School of Medicine Cardiff University Cardiff UK

Flavonoids have been reported to possess strong antioxidant activities that moderate endothelial dysfunction and demonstrate protective effects on cardiovascular disease. Our previous studies confirmed that flavonoids, including hesperidin, naringin and nobiletin, inhibited thrombogenesis and hypertension in stroke prone spontaneously hypertensive rats (SHRSP) by protecting the endothelium from the adverse effects of free radical formation. We have now further investigated the protective effects of myricetin and hesperidin on cerebral thrombosis and atherogenesis in apolipoprotein E (apoE) and lowdensity lipoprotein receptor (LDLR) deficient (Apoe-/- and Ldlr-/- double knockout) mice. Three groups of mice were fed high fat diet alone and high fat diet mixed with myricetin (100 mg/kg/day and 200 mg/kg/day) or glucosyl hesperidin (G-hesperidin;250 mg/kg/day and 500 mg/kg/day) for 8 weeks. There were no differences in body weight related to administration of the flavonoids. Thrombotic tendency was assessed using a He-Ne laser technique in the murine cerebral pial vessels. In addition, atherogenesis was quantified histologically after dissection of the aorta from each mouse and staining with Oil Red O solution. The percentages of stained area to whole area of dissected aorta were calculated as indices of anti-atherogenic activity. Both myricetin and G-hesperidin significantly inhibited thrombogenesis in vivo and significantly inhibited atherogenesis compared to control mice (p < 0.001). These findings demonstrated that daily intake of myricetin and hesperidin suppressed the development of atherogenesis and thrombogenesis, possibly associated with the potent antioxidant effects of the flavonoids.

关键词： Myricetin Hesperidin Atherosclerosis Apoe-/- and Ldlr-/- Mice Thrombosis