20081216_02潘子明_紅麴於預防醫學之應用

1. 紅麴在預防醫學上之應用 Tzu-Ming Pan President Health Food Society of Taiwan Committee member Health Food Evaluation Committee, DOH Professor and Director Institute of Microbiology and Biochemistry, NTU 2008.12.16 於 2008 紅麴國際研討會

2. Welcome to National Taiwan University 歡迎蒞臨臺灣大學

4. 系所成立數 2000-2007 88 98 54 1 2 ─ 2007 87 96 54 3 ─ ─ 2006 84 96 54 1 ─ ─ 2005 83 96 54 2 4 ─ 2004 81 92 54 4 5 ─ 2003 77 87 54 3 3 1 2002 74 84 53 2 2 1 2001 72 82 52 1 2 ─ 2000 博士班 碩士班 大學部 博士班 碩士班 大學部 累 計 成 立 數 每 年 度 成 立 數 年度

5. 歷年在學人數 1979-2007 4,909 10,192 774 ─ 16,916 32,791 2007 4,582 10,007 1,033 ─ 16,611 32,233 2006 4,266 9,584 1,152 ─ 16,538 31,540 2005 3,856 9,003 1,305 ─ 16,519 30,683 2004 3,484 8,383 1,448 0 16,515 29,830 2003 3,195 7,664 1,498 1 16,414 28,772 2002 2,900 7,095 1,456 17 16,036 27,504 2001 2,744 6,729 1,212 114 15,952 26,751 2000 2,594 5,976 946 416 15,634 25,566 1999 190 1,246 ─ 1,305 10,778 13,519 1979 進修學士班 夜間部 日間學制 博士班 碩士班 學士班 總計 年度

16. 各國健康食品許可證圖樣

17. Look Here

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21. 健康食品保健功效通過概況 （ 97.11.20 ，共 138 件） 調節血脂 (45 項 ) 32.6% 胃腸道功能 (39 項 ) 28.2% 免疫調節 (18 項 ) 13.0% 護肝功能 (15 項 ) 10.9 % 牙齒保健 (6 項 ) 4.4 % 抗疲勞 (5 項 ) 3.6% 不易形成脂肪、改善骨質疏鬆各 2 項 (1.5%) 調節血糖 (4 項 ) (2.9%) 延緩衰老及調節血壓各 1 項 (0.7%)

23. 1997 至 2006 年我國生技產業投資金額統計 資料來源：經濟部生物技術與醫藥工業發展推動小組， 2007 。

24. 2005 至 2006 年我國生技產業投資金額比較 資料來源，經濟部生物技術與醫藥工業發展推動小組， 2007 。 製藥產業 醫療器材產業 新興生技產業

25. 我國保健機能性食品市場之供需分析 ＊ : 2007 年預估 資料來源：中華民國海關進出口統計資料； 2007 年保健機能性食品普查結果 12,750 2.2 9.79 540 120.0 24.0 445 2007(e) ＊ 10,850 2.2 8.36 470 108.0 21.0 380 2006 9,750 2.1 6.951 410 98.3 18.8 331 2005 8,500 2.1 6.048 360 90.0 17.9 288 2004 7,600 1.9 4.75 309 76.6 16.8 250 2003 6,700 1.8 3.96 262 55.7 13.8 220 2002 員工人數 ( 人 ) 研發佔營 收比重 (%) 研發投入 ( 億元 ) 國內總需 求市場 ( 億元 ) 進口值 ( 億元 ) 出口值 ( 億元 ) 產值 ( 億元 ) 年份

28. 紅麴之製造過程

29. Production processes 紅麴生產步驟 Rice -> Washing -> Leaching -> Steaming -> or other 洗淨 瀝乾 蒸米 Substrate 大米或其他基質 Inoculuming ->Culture -> Red mold rice 接種 培養 紅麴米成品

31. 培養於試管中之紅麴菌 顯微鏡下 之紅麴菌 培養於培養皿中之紅麴菌

32. Carbohydrate 碳水化合物 55.3% Monacolin K 0.8% (variable) Reducing sugar 還原糖 0.9% Others 11.8% Protein 蛋白質 19.3% Lipid 脂肪 3.5% Ash 灰份 4.3% Moisture 水份 4.0% Composition of red mold rice 紅麴米組成份

35. Structure of pigments 紅麴色素之結構

36. Supplement of RMR in rice

37. 台灣煙酒公司 RMR in wine

38. Grape wine with RMR

39. Beer with RMR

40. Vinegar with RMR 穀盛股份有限公司 600 mL

41. Soy sauce with RMR

42. Miso with RMR

43. Bean cured with RMR

44. Bread with RMR

45. Oil with RMR 佳格食品股份有限公司 2 L

46. Sausage with RMR

47. Noodle with RMR

48. Dietary supplement with RMR

49. Look Here Capsules of RMR 衛署健食字第 A00078 號

50. RMR product 資料來源：食品所 ITIS 計畫整理 Application of red mold rice (1) 紅麴米之應用 (1) Baking food Oil Meat product Food from soybean Fermented food Drinking Wine Dairy product 02 紅露酒 01 紅麴葡萄酒 01 飲用醋 02 蜂蜜紅麴酵素 01 奶粉 02 高屏羊乳 ( 水蜜桃口味 ) 01 紅麴雞爪 02 紅麴香腸 03 紅麴養生肉絲 04 紅麴肉圓 05 紅麴貢丸 01 火鍋料 01 紅豆腐乳 02 農產醃漬品 ( 山藥、苦瓜 ..) 01 紅麴蜂蜜蛋糕 02 紅麴麵包、土司 03 紅麴杏仁脆片 01 紅麴油 03 紅麴啤酒

51. 資料來源：食品所 ITIS 計畫整理 Application of red mold rice (2) 紅麴米之應用 (2) Noodle Food from rice Leisure food 01 紅麴桂圓凍 02 紅麴養生麻糬 01 紅麴麵條 02 紅麴麵線 01 紅麴魷魚頭 02 紅麴魷魚片 Vegetant food Flavoring Health food 03 紅麴章魚花 01 紅麴米 02 紅麴粽 01 紅麴素肉排 02 紅麴素肉鬆 03 培根火腿片 ( 素 ) 01 紅麴醬油 ( 膏 ) 02 紅麴料理醋 05 紅麴醬 04 紅麴粉 03 紅麴甜辣醬 01 膠囊 02 錠劑 03 茶包 04 液狀 05 顆粒 06 粉末 Ice product 01 冰棒 RMR product

53. 臺灣大學紅麴相關研究 飼料添加之應用 (2 papers and 1 patent) 應用蛋白質體學 探討生化特性 (6 papers) 新加工技術之探討 (2 papers) Monascus purpureus 二次代謝產 物之分析研究 (2 papers) 變異株之誘導 分離與篩選 (3 papers) 二次代謝產 物之生產 (3 papers) 預防醫學研究 (6 papers)

55. Application of red mold rice in preventive medicine 紅麴在預防醫學上之應用 Aniya et al. Gen Pharmacol Dimerumic acid Protection of liver damage 1999 Author Journal Published Bioactive Ingredient Function Year 玉田英明 食品與科學 Unknown Blood glucose lowering 1988 Tsuji et al. Jpn J Nutri GABA Blood pressure lowering 1992 Monacolins Pigment Monacolin K 1999 1996 1979 Heber Am J Clin Nutr Cholesterol lowering (clinical test) Yasukawa et al. Oncology Cancer cell inhibition Endo J Antibiot (Tokyo) Cholesterol lowering

56. Application of red mold rice in preventive medicine 紅麴在預防醫學上之應用 Wang and Pan Appl Microbiol Biotechnol Amino acids and others Antifatigue 2006 Wang and Pan Appl Microbiol Biotechnol Monacolin K Hypolipidemic Effects 2006 Author Journal Published Bioactive Ingredient Function Year Jeon et al. Life Sci Water extract Inhibitive effects on preadipocyte differentiation 2004 Monacolins Water extract 2003 2000 Rhyu et al. J Ethnopharmacol Anti-immflation Wei et al. J Nutr Biochem Anti-atherosclerotic effect

57. Application of red mold rice in preventive medicine 紅麴在預防醫學上之應用 Lee and Pan Appl Microbiol Biotechnol Monacolins,GABA, Antioxidant etc. Anti-Azeheimer’s Disease (cell model) 2008 Lee and Pan J Neurosci Research Monacolins,GABA, Antioxidant etc. Anti-Azeheimer’s Disease (animal model) 2007 Lee and Pan J Agric Food Chem Monacolins (fermented from Dioscorea ) Hypolipidemic and anti-atherosclerotic effect 2007 Author Journal Published Bioactive Ingredient Function Year Chen and Pan Int J Obesity Monacolins, Antioxidant etc. Anti-Obesity 2008

59. O verall anti-cholesterol benefits of red mold rice produced by Monascus purpureus NTU 568 (4 week) ↓ TC ↓TG ↓LDL-C ↓ L DL-C/HDL-C 31. 2% 3 0 . 1 % 36 . 0 % 3 9 . 2 % ↑ HDL-C 1 1 . 6 % In vivo hypolipidemic effects and safety of low dosage monascus powder in a hamster model of hyperlipidemia, Appl. Microb. & Biotech. (2006) 70: 533-540.

60. The microscopy photos (400 X and 100 X) of liver biopsy of experimental hamster ( 實驗動物肝臟切片鏡檢結果 ) 實驗組 ( HChol-M1 組 ) 以 400 X 及 100 X 鏡檢之結果 In vivo hypolipidemic effects and safety of low dosage monascus powder in a hamster model of hyperlipidemia, Appl. Microb. & Biotech. (2006) 70: 533-540.

64. Swimming test ( 游泳試驗 ) Effect of red mold rice on antifatigue and exercise-related changes in lipid peroxidation in endurance exercise, Appl. Microb. & Biotech. (2006) 70: 247-253. 129.4  10.9 c 104.2  9.6 b 78.0  6.4 a Swimming time (min) 65.90 486.2  40.3 a 435.2  33.3 a High dosage gr. 33.59 477.1  41.2 a 421.1  32.9 a Low dosage gr. - 491.4  33.4 a 427.3  30.1 a Control After test Before test Increase in swimming time (%) Body wt (g) Group

65. Lactic acid and glucose in blood ( 乳酸與血糖 ) Effect of red mold rice on antifatigue and exercise-related changes in lipid peroxidation in endurance exercise, Appl. Microb. & Biotech. (2006) 70: 247-253. High dosage gr. Low dosage gr. Control Group 27.63  1.17 a 27.72  0.99 a 29.52  1.44 a Before swimming Lactic acid (mg/dL) 28.89  1.62 c (+4.56%) 31.41  1.80 b (+13.31%) 45.00  0.90 a (+ 52.44% ) After swimming (change%) 117.67  11.06 b (-3.02%) 121.33  10.50 a 111.33  8.50 b (-7.48%) 120.33  4.62 a 76.67  8.08 a (-38.17% ) 124.00  13.08 a After swimming (change%) Before swimming Glucose in blood (mg/dL)

66. Urine nitrogen and haemoblobin ( 尿氮與紅血球 ) Effect of red mold rice on antifatigue and exercise-related changes in lipid peroxidation in endurance exercise, Appl. Microb. & Biotech. (2006) 70: 247-253. High dosage gr. Low dosage gr. Control Group 17.74  0.91 b 17.26  0.81 ab 16.37  1.02 a Before swimming Urine nitrogen (mg/dL) 20.53  1.09 b (+15.7%) 20.33  0.83 b (+17.8%) 21.87  0.75 a (+33.6%) After swimming (change%) 13.28  0.35 b (-13.3%) 15.31  0.38 a 13.70  0.55 ab (-12.4%) 15.64  0.34 a 14.20  0.21 a (-10.1%) 15.80  0.55 a After swimming (change%) Before swimming Haemoblobin (g/dL)

69. 這隻可以拜天公

70. 專家預測未來十年中國肥胖人口數將超兩億

72. 肥胖引起健康問題非常嚴重，然而世界仍有約八億人口沒有足夠糧食

74. Obesity Trends* Among U.S. Adults BRFSS, 1985 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14%

75. Obesity Trends* Among U.S. Adults BRFSS, 1986 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14%

76. Obesity Trends* Among U.S. Adults BRFSS, 1987 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14%

77. Obesity Trends* Among U.S. Adults BRFSS, 1988 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14%

78. Obesity Trends* Among U.S. Adults BRFSS, 1989 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14%

79. Obesity Trends* Among U.S. Adults BRFSS, 1990 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14%

80. Obesity Trends* Among U.S. Adults BRFSS, 1991 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19%

81. Obesity Trends* Among U.S. Adults BRFSS, 1992 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19%

82. Obesity Trends* Among U.S. Adults BRFSS, 1993 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19%

83. Obesity Trends* Among U.S. Adults BRFSS, 1994 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19%

84. Obesity Trends* Among U.S. Adults BRFSS, 1995 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19%

85. Obesity Trends* Among U.S. Adults BRFSS, 1996 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19%

86. Obesity Trends* Among U.S. Adults BRFSS, 1997 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19% ≥20%

87. Obesity Trends* Among U.S. Adults BRFSS, 1998 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19% ≥20%

88. Obesity Trends* Among U.S. Adults BRFSS, 1999 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19% ≥20%

89. Obesity Trends* Among U.S. Adults BRFSS, 2000 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19% ≥20%

90. Obesity Trends* Among U.S. Adults BRFSS, 2001 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19% 20%–24% ≥25%

91. (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) Obesity Trends* Among U.S. Adults BRFSS, 2002 No Data <10% 10%–14% 15%–19% 20%–24% ≥25%

92. Obesity Trends* Among U.S. Adults BRFSS, 2003 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19% 20%–24% ≥25%

93. Obesity Trends* Among U.S. Adults BRFSS, 2004 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19% 20%–24% ≥25%

94. Obesity Trends* Among U.S. Adults BRFSS, 2005 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%

95. Obesity Trends* Among U.S. Adults BRFSS, 2006 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%

96. Obesity Trends* Among U.S. Adults BRFSS, 2007 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%

99. In vitro model -Cell experiment ( 生體外試驗 - 細胞試驗 )

101. Adipogenesis ( 前脂肪細胞分化– Oil Red O stain) 各萃取物確實能減少細胞中之油滴形成，與 TG 含量測定結果相符，顯示紅麴發酵產物萃取物確實具抑制前脂肪細胞分化之效果。

102. in vivo experiments -Animal experiment ( 生體內試驗 - 動物試驗 )

105. Effects of 6 wk of Monascus fermented products supplementation to a high-fat diet on the body weight and body fat mass of male Wistar rats ( 餵食紅麴發酵產物對高油脂飲食之雄性 Wistar 大鼠體重及 腎臟周圍與副睪周圍體脂肪 體脂肪之影響 ) * p < 0.05, ** p < 0.01, *** p < 0.001 ： 顯著不同於 HF 組 C: 正常飲食對照組， HF: 高油脂飲食對照組， L: 高油脂飲食 + lovastatin ， R: 高油脂飲食 + 0.4% 未發酵在來米， RL: 高油脂飲食 + 0.4% 紅麴米， RH: 高油脂飲食 + 2% 紅麴米 2.19* ± 8.76 2.03*** ± 8.12 27.0** ± 118.9 39.6*** ± 439.1 18.4 ± 320.3 RH 1.42* ± 9.49 1.98* ± 9.68 20.7* ± 134.3 29.5* ± 459.3 10.8 ± 325.0 RL 1.73 ± 11.45 1.47 ± 11.56 41.3 ± 156.5 34.3 ± 487.5 12.4 ± 331.0 R 1.43* ± 9.50 1.12 ± 10.42 35.3 ± 141.1 35.2 ± 472.4 17.8 ± 331.3 L 2.94 ± 11.89 3.94 ± 13.21 25.4 ± 171.0 33.0 ± 504.8 20.5 ± 333.8 HF 1.37*** ± 7.69 1.99*** ± 7.01 24.0*** ± 115.3 20.6*** ± 439.8 16.0 ± 324.5 C Epididymal fat pads weight (g) Perirenal fat pads weight (g) Weight gain Final body weight (g) Initial body weight (g)

106. Effects of 6 wk of Monascus fermented products supplementation to a high-fat diet on the body weight and body fat mass of male Wistar rats ( 餵食紅麴發酵產物對高油脂飲食之雄性 Wistar 大鼠體重及 腎臟周圍與副睪周圍體脂肪 之影響 ) * p < 0.05, ** p < 0.01, *** p < 0.001 ： 顯著不同於 HF 組 C: 正常飲食對照組， HF: 高油脂飲食對照組， L: 高油脂飲食 + lovastatin ， R: 高油脂飲食 + 0.4% 未發酵在來米， RL: 高油脂飲食 + 0.4% 紅麴米， RH: 高油脂飲食 + 2% 紅麴米 餵食紅麴發酵產物組其 體重及脂肪組織重量 皆呈顯著下降 -21.5% -30.5% -38.5% -26.7% -26.3% -20.2% 2.19* ± 8.76 2.03*** ± 8.12 27.0** ± 118.9 39.6*** ± 439.1 18.4 ± 320.3 RH 1.42* ± 9.49 1.98* ± 9.68 20.7* ± 134.3 29.5* ± 459.3 10.8 ± 325.0 RL 1.73 ± 11.45 1.47 ± 11.56 41.3 ± 156.5 34.3 ± 487.5 12.4 ± 331.0 R 1.43* ± 9.50 1.12 ± 10.42 35.3 ± 141.1 35.2 ± 472.4 17.8 ± 331.3 L 2.94 ± 11.89 3.94 ± 13.21 25.4 ± 171.0 33.0 ± 504.8 20.5 ± 333.8 HF 1.37*** ± 7.69 1.99*** ± 7.01 24.0*** ± 115.3 20.6*** ± 439.8 16.0 ± 324.5 C Epididymal fat pads weight (g) Perirenal fat pads weight (g) Weight gain Final body weight (g) Initial body weight (g)

107. Effects of 6 wk of Monascus fermented products supplementation to a high-fat dit on the food intake, calorie intake, feed efficiency and fat absorption of male Wistar rats ( 餵食紅麴發酵產物對高油脂飲食之雄性 Wistar 大鼠 攝食量、熱量攝取量、飼料效率及脂質吸收率 之影響 ) * p < 0.05, ** p < 0.01, *** p < 0.001 ：顯著不同於 HF 組 0.69 ± 96.10 2.75** ± 14.30 6.2** ± 95.6 1.29** ± 19.71 RH 2.14 ± 95.17 1.75* ± 15.09 7.6 ± 102.5 1.56 ± 21.14 RL 1.03 ± 95.51 3.35 ± 16.73 6.4 ± 107.0 1.32 ± 22.06 R 1.12 ± 96.08 3.02 ± 16.48 10.4* ± 98.0 2.15* ± 20.21 L 0.72 ± 95.84 1.64 ± 17.94 9.2 ± 109.8 1.89 ± 22.64 HF 5.51*** ± 81.51 2.0*** ± 10.20 4.1*** ± 89.7 1.23*** ± 26.85 C Fat absorption (%) Feed efficiency (%) Calorie intake (kcal/d) Food intake (g/d)

108. Effects of 6 wk of Monascus fermented products supplementation to a high-fat dit on the food intake, calorie intake, feed efficiency and fat absorption of male Wistar rats ( 餵食紅麴發酵產物對高油脂飲食之雄性 Wistar 大鼠 攝食量、熱量攝取量、飼料效率及脂質吸收率 之影響 ) * p < 0.05, ** p < 0.01, *** p < 0.001 ：顯著不同於 HF 組 -12.9% -12.9% -15.9% -20.3% 餵食紅麴發酵產物高劑量組其 攝食量、熱量攝取量、飼料效率 皆呈顯著下降，但脂質吸收率無顯著變化 0.69 ± 96.10 2.75** ± 14.30 6.2** ± 95.6 1.29** ± 19.71 RH 2.14 ± 95.17 1.75* ± 15.09 7.6 ± 102.5 1.56 ± 21.14 RL 1.03 ± 95.51 3.35 ± 16.73 6.4 ± 107.0 1.32 ± 22.06 R 1.12 ± 96.08 3.02 ± 16.48 10.4* ± 98.0 2.15* ± 20.21 L 0.72 ± 95.84 1.64 ± 17.94 9.2 ± 109.8 1.89 ± 22.64 HF 5.51*** ± 81.51 2.0*** ± 10.20 4.1*** ± 89.7 1.23*** ± 26.85 C Fat absorption (%) Feed efficiency (%) Calorie intake (kcal/d) Food intake (g/d)

109. Lipolysis activity – glycerol release 成熟脂肪細胞脂解作用之測定 ( 甘油釋放濃度 ) *** * ** 餵食紅麴發酵產物對高油脂飲食之雄性 Wistar 大鼠脂肪組織脂解作用之影響 . * p < 0.05, ** p < 0.01, *** p < 0.001 ：顯著不同於 HF 組 (A) Perirenal fat pads ( 腎臟周圍脂肪組織 ) (B) Epididymal fat pads ( 副睪周圍脂肪組織 ) ** ** **

110. Lipolysis activity – glycerol release 成熟脂肪細胞脂解作用之測定 ( 甘油釋放濃度 ) *** * ** 餵食紅麴發酵產物對高油脂飲食之雄性 Wistar 大鼠脂肪組織脂解作用之影響 . * p < 0.05, ** p < 0.01, *** p < 0.001 ：顯著不同於 HF 組 (A) Perirenal fat pads ( 腎臟周圍脂肪組織 ) (B) Epididymal fat pads ( 副睪周圍脂肪組織 ) ** ** ** 攝食高熱量飲食再餵食 0.4% 及 2% 紅麴米，可顯著 提升腎臟周圍脂肪組織 (12.3% 及 17.3%) 與副睪周圍組織 (29.0% 及 30.0%) 之脂解作用活性

111. Effects of RMR supplement on the lipidic and glycemic parameters in male Wistar rats fed high fat diet. ( 餵食 6 週高油脂飲食與紅麴發酵產物對雄性 Wistar 大鼠 血清脂質 之影響 ) * p < 0.05, ** p < 0.01 ：顯著不同於 HF 組 0.06** ± 0.20 4.75* ± 30.01 1.93** ± 6.02 10.57 ± 82.64 6.48* ± 52.55 RH 0.15** ± 0.35 4.94 ± 27.84 2.23* ± 9.14 11.89 ± 75.41 5.72* ± 51.55 RL 0.35 ± 1.09 4.08 ± 22.37 5.05 ± 23.47 26.87 ± 96.70 8.83 ± 65.18 R 0.14* ± 0.42 3.78 ± 22.44 2.61* ± 9.02 15.84 ± 87.56 4.16* ± 48.97 L 0.42 ± 1.11 3.56 ± 22.39 6.75 ± 23.93 14.12 ± 94.56 5.75 ± 65.23 HF 0.13** ± 0.29 7.70* ± 29.19 3.92* ± 8.06 18.82 ± 76.63 8.45* ± 52.57 C LDL-C/HDL-C HDL-C (mg/dL) LDL-C (mg/dL) TG (mg/dL) TC (mg/dL)

112. Effects of RMR supplement on the lipidic and glycemic parameters in male Wistar rats fed high fat diet. ( 餵食 6 週高油脂飲食與紅麴發酵產物對雄性 Wistar 大鼠 血清脂質 之影響 * p < 0.05, ** p < 0.01 ：顯著不同於 HF 組 降低 降低 升高 降低 降低 降低 降低 升高 0.06** ± 0.20 4.75* ± 30.01 1.93** ± 6.02 10.57 ± 82.64 6.48* ± 52.55 RH 0.15** ± 0.35 4.94 ± 27.84 2.23* ± 9.14 11.89 ± 75.41 5.72* ± 51.55 RL 0.35 ± 1.09 4.08 ± 22.37 5.05 ± 23.47 26.87 ± 96.70 8.83 ± 65.18 R 0.14* ± 0.42 3.78 ± 22.44 2.61* ± 9.02 15.84 ± 87.56 4.16* ± 48.97 L 0.42 ± 1.11 3.56 ± 22.39 6.75 ± 23.93 14.12 ± 94.56 5.75 ± 65.23 HF 0.13** ± 0.29 7.70* ± 29.19 3.92* ± 8.06 18.82 ± 76.63 8.45* ± 52.57 C LDL-C/HDL-C HDL-C (mg/dL) LDL-C (mg/dL) TG (mg/dL) TC (mg/dL)

113. Effects of RMR supplement on the weight and cellularity of perirenal adipose tissues in male Wistar rats fed high fat diet. ( 餵食紅麴發酵產物對高油脂飲食之雄性 Wistar 大鼠 腎臟周圍脂肪組織 之影響 ) * p < 0.05, ** p < 0.01, *** p < 0.001 ：顯著不同於 HF 組 7.90 ± 20.26 1.17 ± 2.57 1289.6** ± 5361.8 2.03*** ± 8.12 RH 9.14 ± 21.28 0.85 ± 2.23 1369.1* ± 5842.2 1.98* ± 9.68 RL 17.78 ± 21.63 1.50 ± 1.85 1529.8 ± 7319.2 1.47 ± 11.56 R 5.58 ± 18.29 0.39 ± 1.73 559.0 ± 6636.4 1.12 ± 10.42 L 8.45 ± 21.65 0.72 ± 1.70 1708.3 ± 7527.5 3.94 ± 13.21 HF 7.92 ± 16.80 1.12 ± 2.44 1153.8** ± 5108.2 1.99*** ± 7.01 C Cell number x 10 6 / total tissue Cell number x 10 6 / g tissue Cell cross-sectional area (µm²) Perirenal fat pads weight (g)

114. Effects of RMR supplement on the weight and cellularity of perirenal adipose tissues in male Wistar rats fed high fat diet. ( 餵食紅麴發酵產物對高油脂飲食之雄性 Wistar 大鼠 腎臟周圍脂肪組織 之影響 ) * p < 0.05, ** p < 0.01, *** p < 0.001 ：顯著不同於 HF 組 降低 26.7% 降低 22.8% 降低 38.5% 降低 28.8% 餵食紅麴發酵產物組其腎臟周圍脂肪組織 重量及細胞平均截面積 皆呈顯著下降，但細胞數目無顯著變化 7.90 ± 20.26 1.17 ± 2.57 1289.6** ± 5361.8 2.03*** ± 8.12 RH 9.14 ± 21.28 0.85 ± 2.23 1369.1* ± 5842.2 1.98* ± 9.68 RL 17.78 ± 21.63 1.50 ± 1.85 1529.8 ± 7319.2 1.47 ± 11.56 R 5.58 ± 18.29 0.39 ± 1.73 559.0 ± 6636.4 1.12 ± 10.42 L 8.45 ± 21.65 0.72 ± 1.70 1708.3 ± 7527.5 3.94 ± 13.21 HF 7.92 ± 16.80 1.12 ± 2.44 1153.8** ± 5108.2 1.99*** ± 7.01 C Cell number x 10 6 / total tissue Cell number x 10 6 / g tissue Cell cross-sectional area (µm²) Perirenal fat pads weight (g)

115. Effects of RMR supplement on the weight and cellularity of epididymal adipose tissues in male Wistar rats fed high fat diet. ( 餵食紅麴發酵產物對高油脂飲食之雄性 Wistar 大鼠 副睪周圍脂肪組織 之影響 ) * p < 0.05, ** p < 0.01, *** p < 0.001 ：顯著不同於 HF 組 11.21 ± 30.67 0.71 ± 3.40 206.8*** ± 4021.5 2.19* ± 8.76 RH 10.74 ± 33.82 0.90 ± 3.54 537.3 ± 4158.7 1.42* ± 9.49 RL 12.60 ± 31.64 1.14 ± 2.81 1069.9 ± 5163.9 1.73 ± 11.45 R 9.13 ± 28.83 0.99 ± 3.09 811.8* ± 4600.6 1.43* ± 9.50 L 6.65 ± 31.14 0.43 ± 2.67 747.7 ± 5209.6 2.94 ± 11.89 HF 5.01 ± 28.99 0.82* ± 3.85 567.5*** ± 3812.1 1.37*** ± 7.69 C Cell number x 10 6 / total tissue Cell number x 10 6 / g tissue Cell cross-sectional area (µm²) Epididymal fat pads weight (g)

116. Effects of RMR supplement on the weight and cellularity of epididymal adipose tissues in male Wistar rats fed high fat diet. ( 餵食紅麴發酵產物對高油脂飲食之雄性 Wistar 大鼠 副睪周圍脂肪組織 之影響 ) * p < 0.05, ** p < 0.01, *** p < 0.001 ：顯著不同於 HF 組 降低 20.2% 降低 22.8% 餵食紅麴發酵產物組其副睪周圍 脂肪組織重量及細胞平均截面積 皆呈顯著下降，但細胞數目無顯著變化 降低 26.3% 11.21 ± 30.67 0.71 ± 3.40 206.8*** ± 4021.5 2.19* ± 8.76 RH 10.74 ± 33.82 0.90 ± 3.54 537.3 ± 4158.7 1.42* ± 9.49 RL 12.60 ± 31.64 1.14 ± 2.81 1069.9 ± 5163.9 1.73 ± 11.45 R 9.13 ± 28.83 0.99 ± 3.09 811.8* ± 4600.6 1.43* ± 9.50 L 6.65 ± 31.14 0.43 ± 2.67 747.7 ± 5209.6 2.94 ± 11.89 HF 5.01 ± 28.99 0.82* ± 3.85 567.5*** ± 3812.1 1.37*** ± 7.69 C Cell number x 10 6 / total tissue Cell number x 10 6 / g tissue Cell cross-sectional area (µm²) Epididymal fat pads weight (g)

117. 餵食 6 週高油脂飲食與紅麴發酵產物對雄性 Wistar 大鼠血糖及血清胰島素之影響 25.5** ± 89.7 31.7 ± 180.5 RH 27.0* ± 92.2 20.5 ± 184.7 RL 15.2 ± 135.2 40.4 ± 204.5 R 28.3 ± 106.0 30.2 ± 194.9 L 37.1 ± 131.6 33.0 ± 218.6 HF 34.1** ± 86.7 26.5 ± 194.4 C Insulin (pmole/L) Glucose (mg/dL)

118. 餵食 6 週高油脂飲食與紅麴發酵產物對雄性 Wistar 大鼠 血糖及血清胰島素 之影響 降低 30.0% 降低 31.8% 25.5** ± 89.7 31.7 ± 180.5 RH 27.0* ± 92.2 20.5 ± 184.7 RL 15.2 ± 135.2 40.4 ± 204.5 R 28.3 ± 106.0 30.2 ± 194.9 L 37.1 ± 131.6 33.0 ± 218.6 HF 34.1** ± 86.7 26.5 ± 194.4 C Insulin (pmole/L) Glucose (mg/dL)

126. Surgery for i.c.v. Aβ1-40 infusion 輸注類澱粉樣蛋白 Aβ1-40 之手術

127. (1) The surgery process of intracerebroventricular infusion of Aβ40 (1): put the rat into the stereotaxic frame (Narishige, Tokyo, Japan) 大鼠腦部進行定位置：將大鼠置於動物立體定位儀上

128. (2) (3) The surgery process of intracerebroventricular infusion of Aβ40 (2): Cut the hull of the rat 於頭蓋骨位置劃開外皮並挖除頭蓋骨之硬殼膜

129. Bregma Lambda (4) 尋找頭蓋骨上之 bregma ( 前囪 , 顱骨冠狀縫與矢狀縫會合處 ) The surgery process of intracerebroventricular infusion of Aβ40 (3): Find the position of bregma 尋找頭蓋骨上之 bregma

130. (5) The surgery process of intracerebroventricular infusion of Aβ40 (4): Using stereotaxic frame to find the position of bregma 以定位儀定出 bregma 之座標

131. (6) (7) The surgery process of intracerebroventricular infusion of Aβ40 (5): Penetrating in bregma 以 bregma 為原點，進行側腦室定位：縱軸 0.8 mm ，橫軸 1.4 mm ，深度 4.0 mm

132. (8) The surgery process of intracerebroventricular infusion of Aβ40 (6): bury brain infusion kit into 4-mm deepness in bregma 將 Brain Infusion Kit 插入深度 4.0 mm 之側腦室位置

133. (9) (10) The surgery process of intracerebroventricular infusion of Aβ40 (7): Seam the scotch 將 infusion pump 黏合於頭蓋骨上，並將 Alzet osmotic mini-pump 塞至頸部之皮下

134. Volume ： 234 μ L Injection rate ： 0.26 μ L/hr Injection period ： 28 days Brain Infusion Kit II ： 3-5 mm The osmotic mini-pump (2004, Durect Co., Cupertino, CA, USA) used to result in an animal model of AD with impaired memory was filled with Aβ 1-40 solution or the vehicle solution. 滲透壓式迷你馬達

135. The surgery process of intracerebroventricular infusion of Aβ40 (8): Observe the cicatrization condition 手術完成後觀察傷口癒合情形

136. Grouping of animal in this experiment 動物之分群 For the convenience of comparison, the conc. of monacolin K in low dosage of red mold rice group is the same as that in lovastatin group 為比較方便，低劑量紅麴組所含之 monacolin K 與 lovastatin 組相同，均為 1.43 mg/kg rat per day - 755 (7.15) + RH - 151 (1.43) + RL 1.43 - + LS - - + A β - - - V-N Lovastatin (mg/kg rat per day) RMR (monacolin K) (mg/kg rat per day) A β 40 infusion Groups

138. Passive-avoidance task 被動迴避試驗

139. The experiment schedule for passive avoidance task 被動迴避試驗施行時期

140. Instrument of passive-avoidance task 被動迴避試驗設備

141. RL and RH groups are able to ensure staying in light chamber for longer time as compared with Aβ-infused group. 低劑量紅麴組與高劑量紅麴組明顯比輸注類澱粉樣蛋白組，在明室停留時間較長

142. Reference memory task 參考記憶試驗

143. Equipment for Morris water-maze task 水迷宮試驗設備 23 o C 140 cm 45 cm 25 cm 2 cm 10 cm A black circular tank (diameter: 140 cm, height: 45 cm) was used as the apparatus of water maze in which a movable escape platform (diameter: 10 cm, height: 25 cm) was located inside the tank. 水迷宮試驗使用一圓形貯水池，其內放一可移動之休息平台

144. The experiment schedule for reference memory task 參考記憶試驗施行時期

145. In each training trial, the rat was put into one of four different starting positions (sp) in the water tank. The escape platform was located at the set position in the middle of quadrant IV during the period of reference memory task. 每次試驗將老鼠置於四個起始點之ㄧ，參考記憶試驗係將休息平台固定放置於第四象限 Escape platform sp 1 sp 2 sp 3 sp 4 sp 5 Quadrant I Quadrant II Quadrant III Quadrant IV

146. The dietary administration of RMR (RL and RH groups) significantly decreases escape latency from the 2nd trial to the 9th trial as compared with that of the Aβ group ( p< 0.05). 攝食紅麴組 ( 低劑量及高劑量組 ) 在第 2 至第 9 次試驗均顯著比輸注類澱粉樣蛋白組花較少時間即能找到休息平台。 21st day 22nd day 23rd day

147. Probe test 空間性探測試驗

148. The experiment schedule for probe test 空間性探測試驗 施行時期

149. Probe test 空間性探測試驗施行方法 I II III IV Rat 進入點 Starting Point 1 將休息平臺移出泳池，將大鼠由第一象限之進入點 1 進入泳池，游泳 90 sec ，記錄大鼠於原參考記憶試驗中休息平臺放置之象限 ( 第四象限 ) 中所停留之時間與全程游泳之路徑。

150. Administration with RMR of one-fold dosage or five-fold dosage respectively results in significant increase on search time in the target quadrant by 38.2% ( p< 0.05) and 48.0% ( p< 0.01) as compared with Aβ group. 攝食紅麴一倍及五倍劑量組於目標象限之游泳時間顯著比輸注類澱粉樣蛋白大鼠多出 38.2% 及 48.0% 。

151. Effect of RMR on performance in the swimming pathway 空間性記憶試驗中大鼠之游泳路徑 directly swam to the target quadrant and linger for a long time 較集中在目標象限

152. Working memory task 工作記憶試驗

153. The experiment schedule for working memory task 工作記憶試驗 施行時期

154. I II III IV P2 P3 P4 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 3 5 4 1 2 P2 P3 P4 1st day 2nd day 3rd day Session Entrance Exit The rat was put into the water tank at one of the 5 different starting positions in each trail. 休息平臺每日放置於不同象限 ( 第一、二或三象限 ) ，每天訓練 5 次，大鼠頭向外依序隨機分別進入 5 個進入點，每次 90 sec The first trial of each session per day was recorded as an informative practice trial. 每日的第 1 次訓練為認知訓練，故不列入計算。

155. Effect of RMR on working memory task in the Aβ40-infused rats RMR 提高在工作記憶試驗之學習能力 Both RL and RH groups are able to perform learning ability as fast as vehicle group. RL and RH group significantly decrease escape latency time by 57.3% and 58.9% as compared to Aβ group ( p< 0.01). 攝食紅麴組游泳時間比輸注類澱粉樣蛋白組明顯降低 57.3% 及 58.9%

156. Biochemistry assay 生理與生化指標變化

157. The experiment schedule for biochemical assay 生理與生化指標變化施行時期

159. Effect of RMR on the formation of iNOS expression in the hippocampus of Aβ40-infused rats. Importantly, iNOS expression of hippocampus in RL and RH groups are lower than that in lovastatin group 對於抗發炎的效果 lovastatin 餵食組較 1 倍與 5 倍劑量之紅麴餵食組差。

160. Effect of RMR on the Aβ40 accumulation in the hippocampus of Aβ40-infused rats. Immunohistochemical stain was carried out using the non-biotin hydrogen peroxidase kit. RL group and RH group including fewer Aβ40 accumulation in hippocampus than Aβ group. 紅麴米的 RL 組與 RH 組則有較為顯著降低 Aβ40 累積量的效果。紅麴米降低 Aβ40 於海馬迴組織之累積量的原因主要歸因於其對氧化壓力與發炎反應的抑制。輸注至腦部的 Aβ40 不受氧化發炎物質促進而沈積。使 Aβ40 無法對於腦部造成損傷，進而有效改善記憶學習的能力。

170. 台灣保健食品未來展望

176. 2007 年 8 月號 57-72 頁

177. 2008 年 2 月號 41-66 頁

181. Thank you for your attention Tzu-Ming Pan [email_address]