動脈硬化是一種發展緩慢且複雜的發炎疾病，由前人研究發現山苦瓜可能有抗發炎效果，因此本研究探討山苦瓜凍乾粉末和山苦瓜乙酸乙酯萃取物對於apoE剔除小鼠發炎與動脈硬化的影響。實驗一將18週大雄C57BL/6J apoE剔除小鼠分為6組，分別餵予一般商業飼料(n=5)、20％高脂飼料(n=10)、20％高脂飼料含5％山苦瓜凍乾粉末(n=10)、或含1％山苦瓜乙酸乙酯萃取物(n=10)、或含0.5％clofibrate(n=5)、或含0.00123％Thiazolidinedione (n=5)，餵食18週，犧牲後收集心血管、血液，分析血清黏著分子、發炎因子，並將主動脈封蠟包埋橫切分析內皮增厚程度，結果顯示山苦瓜凍乾粉末和山苦瓜乙酸乙酯萃取物對血清黏著分子、發炎因子並無顯著影響，但胸主動脈內皮增厚程度以餵食山苦瓜乙酸乙酯萃取物組顯著低於高脂組，新生內層與中層面積比率低了57% (p<0.05)，顯示山苦瓜乙酸乙酯萃取物可能具有改善動脈硬化的效果。實驗二改用較年輕的小鼠，且主動脈改用縱切觀察脂肪堆積情形，將6-10週大雄C57BL/6J apoE剔除小鼠分為3組分別餵予20％高脂飼料(n=11)、20％高脂飼料含5％山苦瓜凍乾粉末(n=11)、或含1％山苦瓜乙酸乙酯萃取物(n=11)，餵食8週，犧牲前一週分析白血球黏著分子Mac-1(CD11b/CD18)，犧牲後收集主動脈血管、血液，分析血清發炎因子、8-iso-Prostaglandin F2α和主動脈縱切脂肪堆積，結果顯示山苦瓜凍乾粉末和山苦瓜乙酸乙酯萃取物對血清發炎因子、白血球Mac-1、8-iso-PGF2α並無顯著影響，但山苦瓜乙酸乙酯萃取物組在主動脈縱切脂肪堆積顯著比高脂組低了28％(p<0.05)，再次證明山苦瓜乙酸乙酯萃取物具有改善動脈硬化的效果。

Atherosclerosis is a complex and slowly inflammatory disease. Ethyl acetate extract of bitter gourd has been found to have anti-inflammatory activity. To investigate the effects of bitter gourd (Momordica charantia L.) on atherosclerosis and inflammation, we conducted two experiments. Experiment 1, 18-wk-old C57BL/6J apoE knockout mice were assigned to 6 dietary groups as follows: (1) chow diet(n=5) (2) high fat (20%) diet(n=10) (3) high fat plus 5% wild bitter gourd powder(n=10) (4) high fat plus 1% ethyl acetate extract of bitter gourd powder(n=10) (5) high fat plus 0.5% clofibrate(n=5) (6) high fat plus 0.00123% Thiazolidinedione (n=5). After 18 weeks of feeding, the serum levels of adhesion molecules and cytokines were not significantly different among the 6 groups, but the aorta intima/media area ratio in mice fed ethyl acetate extract of bitter gourd powder were 57% less than those fed the high fat diet without supplementation(p<0.05). Experiment 2, Young (6-10 wk-old) C57BL/6J apoE knockout mice were assigned to 3 dietary groups as follows:(1) high fat (20%) diet(n=11) (2) high fat plus 5% wild bitter gourd powder(n=11) (3) high fat plus 1% ethyl acetate extract of bitter gourd powder(n=11). After 8 weeks of feeding, the Mac-1(CD11b/CD18) expression within leukocytes and the serum levels of cytokines and 8-iso-Prostaglandin F2α were not significantly different among the 3 groups, but the en face atherosclerotic lesion of aorta in mice fed ethyl acetate extract of bitter gourd powder were 28% less than those fed the high fat diet without supplementation(p<0.05)

Akira, S., Hirano, T., Taga, T., & Kishimoto, T. (1990). Biology of multifunctional cytokines: Il 6 and related molecules (il 1 and tnf). FASEB J, 4, 2860-2867.
Andreassen, A. K., Nordφy, I., Simonsen, S., Ueland, T., Muller, F., Frφland, S. S., et al. (1998). Levels of circulating adhesion molecules in congestive heart failure and after heart transplantation. The American Journal of Cardiology, 81, 604-608.
Basch, E., Gabardi, S., & Ulbricht, C. (2003). Bitter melon (momordica charantia): A review of efficacy and safety. Am J Health-Syst Pharm, 60, 356-359.
Berliner, J. A., & Heinecke, J. W. (1996). The role of oxidized lipoproteins in atherogenesis. Free Radical Biology and Medicine, 20, 707-727.
Blankenberg, S., Barbaux, S., & Tiret, L. (2003). Adhesion molecules and atherosclerosis. Atherosclerosis, 170, 191-203.
Calleja, L., Paris, M. A., Paul, A., Vilella, E., Joven, J., Jimenez, A., et al. (1999). Low-cholesterol and high-fat diets reduce atherosclerotic lesion development in apoe-knockout mice. Arterioscler Thromb Vasc Biol, 19, 2368-2375.
Chen, C.-C., Sun, Y.-T., Chen, J.-J., & Chiu, K.-T. (2000). TNF-α-induced cyclooxygenase-2 expression in human lung epithelial cells: Involvement of the phospholipase C-r2, protein kinase C-α, tyrosine kinase, NF-κB-inducing kinase, and I-κB kinase 1/2 pathway. J Immunol, 165, 2719-2728.
Chen, Q., Chan, L. L. Y., & Li, E. T. S. (2003). Bitter melon (momordica charantia) reduces adiposity, lowers serum insulin and normalizes glucose tolerance in rats fed a high fat diet. J. Nutr., 133, 1088-1093.
Collins, A. R., Meehan, W. P., Kintscher, U., Jackson, S., Wakino, S., Grace Noh, et al. (2001). Troglitazone inhibits formation of early atherosclerotic lesions in diabetic and nondiabetic low density lipoprotein receptor–deficient mice. Arterioscler Thromb Vasc Biol., 21, 365-371.
Dinarello, C. A. (1991). Interleukin-1 and interleukin-1 antagonism. Blood, 77, 1627-1652.
Dinarello, C. A., & Cannon, J. G. (1986). Tumor necrosis factor(cachectin) is an endogenous pyrogen and induces production of interleukin 1. J. Exp. Med, 163, 1433-1450.
Dutta, P., & Chakravarty, A. (1981). Vicine, a favism-inducing toxin from momordica charantia linn. Seeds. Indian J chem, 20B, 669-671.
Ehlers, M. R. W. (2000). Cr3: A general purpose adhesion-recognition receptor essential for innate immunity. Microbes and Infection, 289-294.
Francis, G. A., Annicotte, J.-S. b., & Auwerx, J. (2003a). Ppar agonists in the treatment of atherosclerosis. Current Opinion in Pharmacology, 3, 186-191.
Francis, G. A., Fayard, E., Picard, F. e. e., & Auwerx, J. (2003b). Nuclear receptors and the control of metabolism. Annu. Rev. Physiol., 65, 261-311.
Gniwotta, C., Morrow, J. D., Roberts, L. J., II, & Kuhn, H. (1997). Prostaglandin f2-like compounds, f2-isoprostanes, are present in increased amounts in human atherosclerotic lesions. Arterioscler Thromb Vasc Biol, 17, 3236-3241.
Guo, Z., Mitchell-Raymundo, F., Yang, H., Ikeno, Y., Nelson, J., Diaz, V., et al. (2002). Dietary restriction reduces atherosclerosis and oxidative stress in the aorta of apolipoprotein e-deficient mice. Mechanisms of Ageing and Development, 123, 1121-1131.
Harris, E. S., McIntyre, T. M., Prescott, S. M., & Zimmerman, G. A. (2000). The leukocyte integrins. J. Biol. Chem., 275(31), 23409-23412.
Hashimoto, J. K. R. a. T. (2001). Peroxisomal β-oxidation and peroxisome proliferator-activated receptorα:An adaptive metabolic system. Annu. Rev. Nutr., 21, 193-230.
Hegele, R. A. (1996). The pathogenesis of atherosclerosis. Clinica Chimica Acta, 246, 21-38.
Hope, S. A., & Meredith, I. T. (2003a). Cellular adhesion molecules and cardiovascular disease. Part i. Their expression and role in atherogenesis. Internal Mwdicine Journal, 33, 380-386.
Hope, S. A., & Meredith, I. T. (2003b). Cellular adhesion molecules and cardiovascular disease.Part ii. Their association with conventional and emerging risk factors, acute coronary events and cardiovascular risk prediction. Internal Medicine Journal, 33, 450-462.
Hsueh, W. A., & Law, R. E. (2001). Ppar and atherosclerosis effects on cell growth and movement. Arterioscler Thromb Vasc Biol., 21, 1891-1895.
Hubbard, A. r. K., & Rothlein, R. (2000). Intercellular adhesion molecule-1 (icam-1) expression and cell signaling cascades. Free Radical Biology and Medicine, 28, 1379-1386.
Huber, S. A., Sakkinen, P., Conze, D., Hardin, N., & Tracy, R. (1999). Interleukin-6 exacerbates early atherosclerosis in mice. Arterioscler Thromb Vasc Biol., 19, 2364-2367.
Jayasooriya, A. P., Sakono, M., Yukizaki, C., Kawano, M., Yamamoto, K., & Fukuda, N. (2000). Effects of momordica charantia powder on serum glucose levels and various lipid parameters in rats fed with cholesterol-free and cholesterol-enriched diets. Journal of Ethnopharmacology, 72, 331-336.
Jiang, C., Ting, A. T., & Seed, B. (1998). Ppar-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature, 391, 82-86.
JM, O., & AR., S. (2000). Ppar gamma and the treatment of insulin resistance. Trends Endocrinol Metab., 11, 362-368.
JW Pierce, Read, M., Ding, H., Luscinskas, F., & Collins, T. (1996). Salicylates inhibit i kappa b-alpha phosphorylation, endothelial- leukocyte adhesion molecule expression, and neutrophil transmigration. J. Immunol, 156, 3961-3969.
Kaplan, M., Hayek, T., Raz, A., Coleman, R., Dornfeld, L., Vaya, J., et al. (2001). Pomegranate juice supplementation to atherosclerotic mice reduces macrophage lipid peroxidation, cellular cholesterol accumulation and development of atherosclerosis. J. Nutr., 131, 2082-2089.
Kishimoto, T., Akira, S., Narazaki, M., & Taga, T. (1995). Interleukin-6 family of cytokines and gp130. Blood, 86, 1243-1254.
Konstantopoulos, K., & McIntire, L. V. (1996). Effects of fluid dynamic forces on vascular cell adhesion. J. Clin. Invest., 98, 2661-2665.
Kopf, M., Ramsay, A., Brombacher, F., Baumann, H., Freer, G., Galanos, C., et al. (1995). Pleiotropic defects of il-6-deficient mice including early hematopoiesis, t and b cell function, and acute phase responses. Ann. N.Y. Acad. Sci, 762, 308-318.
Kubo, N., Boisvert, W. A., Ballantyne, C. M., & Curtiss, L. K. (2000). Leukocyte cd11b expression is not essential for the development of atherosclerosis in mice. J. Lipid Res., 41, 1060-1066.
Law, R. E., Goetze, S., Xi, X.-P., Jackson, S., Kawano, Y., Demer, L., et al. (2000). Expression and function of pparg in rat and human vascular smooth muscle cells. Circulation, 101, 1311-1318.
Law, R. E., Meehan, W. P., Xi, X.-P., Graf, K., Wuthrich, D. A., Coats, W., et al. (1996). Troglitazone inhibits vascular smooth muscle cell growth and intimal hyperplasia. J. Clin. Invest., 98, 1897-1905.
Le, J., Weinstein, D., Gubler, U., & Vilcek, J. (1987). Induction of membrane-associated interleukin 1 by tumor necrosis factor in human fibroblasts. J. Immunol, 138, 2137-2142.
Lee, C.-H., Chawla, A., Urbiztondo, N., Liao, D., Boisvert, W. A., & Evans, R. M. (2003). Transcriptional repression of atherogenic in.Ammation: Modulation by ppar. Science, 302, 453-457.
Lee, S. H., Soyoola, E., Chanmugam, P., Hart, S., Sun, W., Zhong, H., et al. (1992). Selective expression of mitogen-inducible cyclooxygenase in macrophages stimulated with lipopolysaccharide. J. Biol. Chem., 267, 25934-25938.
Lee, T.-S., Shiao, M.-S., Pan, C.-C., & Chau, L.-Y. (1999). Iron-deficient diet reduces atherosclerotic lesions in apoe-deficient mice. Circulation, 99, 1222-1229.
Leeuwenberg, J. F. M., Smeets, E. F., NEEFJES, J. J., SHAFFER, M. A., CINEK4, T., JEUNHOMME, T. M. A. A., et al. (1992). E-selectin and intercellular adhesion molecule-l are released by activated human endothelial cells in vitro. Immunology, 77, 543-549.
Levi, Z., Shaish, A., Yacov, N., Levkovitz, H., Trestman, S., Gerber, Y., et al. (2003). Rosiglitazone(pparγ-agonist) attenuates atherogenesis with no effect on hyperglycaemia in a combined diabetes-atherosclerosis mouse model. Diabetes Obes Metab, 5, 45-50.
Lind, L. (2003). Circulating markers of inflammation and atherosclerosis. atherosclerosis, 169, 203-214.
Lishko, V. K., Yakubenko, V. P., & Ugarova, T. P. (2003). The interplay between integrins m 2 and 5 1 during cell migration to fibronectin. Experimental Cell Research, 283, 116-126.
Maggs, D. G., Buchanan, T. A., Burant, C. F., Cline, G., Gumbiner, B., Hsueh, W. A., et al. (1998). Metabolic effects of troglitazone monotherapy in type 2 diabetes mellitus: A randomized, double-blind, placebo-controlled trial. Ann Intern Med., 128, 176-185.
Marx, N., Sukhova, G. K., Collins, T., Libby, P., & Plutzky, J. (1999). Pparα activators inhibit cytokine-induced vascular cell adhesion molecule-1 expression in human endothelial cells. Circulation, 99, 3125-3131.
Meir, K. S., & Leitersdorf, E. (2004). Atherosclerosis in the apolipoprotein e-deficient mouse a decade of progress. Arterioscler Thromb Vasc Biol., 24, 1006-1014.
Morrow, J. D., Hill, K. E., Burk, R. F., Nammour, T. M., Badr, K. F., & Roberts Lj, II. (1990). A series of prostaglandin f2-like compounds are produced in vivo in humans by a non-cyclooxygenase, free radical-catalyzed mechanism. PNAS, 87, 9383-9387.
Morrow, J. D., & Roberts, L. J. (1997). The isoprostanes:Unique bioactive products of lipid peroxidation. Prog. Lipid Res., 36, 1-21.
Murata, T., He, S., Hangai, M., Ishibashi, T., Xi, X.-P., Kim, S., et al. (2000). Peroxisome proliferator-activated receptor-g ligands inhibit choroidal neovascularization. Investigative Ophthalmology & Visual Science, 41, 2309-2317.
Nakashima, Y., Plump, A. S., Raines, E. W., Breslow, J. L., & Ross, R. (1994). Apoe-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree. Arterioscler Thromb., 14, 133-140.
Nawroth, P. P., Bank, I., Handley, D., Cassimeris, J., & Chess, L. (1986). Tumor necrosis factor/cachectin interacts with endothelial cell receptors to induce release of interleukin 1. J. Exp. Med, 163, 1363-1375.
Ng, T., Wong, C., Li, W., & Yeung, H. (1986). Isolation and characterization of a galactose binding lectin with insulinomimetic activities. From the seeds of the bitter gourd momordica charantia (family cucurbitaceae). Int J Pept Protein Res, 28, 163-172.
Pasceri, V., Wu, H. D., Willerson, J. T., & Yeh, E. T. H. (2000). Modulation of vascular inflammation in vitro and in vivo by peroxisome proliferator–activated receptor-γ activators. Circulation, 101, 235-238.
Petruzzelli, L., Takami, M., & Humes, H. D. (1999). Structure and function of cell adhesion molecules. Am J Med., 106, 467-476.
Phillips, J. W., Barringhaus, K. G., Sanders, J. M., Yang, Z., Chen, M., Hesselbacher, S., et al. (2003). Rosiglitazone reduces the accelerated neointima formation after arterial injury in a mouse injury model of type 2 diabetes. Circulation, 108, 1994-1999.
Pratico, D., Iuliano, L., Mauriello, A., Spagnoli, L., Lawson, J. A., Maclouf, J., et al. (1997). Localization of distinct f2-isoprostanes in human atherosclerotic lesions. J. Clin. Invest., 100(8), 2028-2034.
Pratico, D., Lawson, J. A., & FitzGerald, G. A. (1995). Cylooxygenase-dependent formation of the isoprostane, 8-epi prostaglandin F2α. J. Biol. Chem., 270, 9800-9808.
Price, D. T., & Loscalzo, J. (1999). Cellular adhesion molecules and atherogenesis. Am J Med., 107, 85-97.
Ricote, M., Li, A. C., Willson, T. M., Kelly, C. J., & Glass, C. K. (1998). The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature, 391, 79-82.
Roberts, L. J., II, Moore, K. P., Zackert, W. E., Oates, J. A., & Morrow, J. D. (1996). Identification of the major urinary metabolite of the f2-isoprostane 8-iso-prostaglandin f2alpha in humans. J. Biol. Chem., 271, 20617-20620.
Ross, R. (1999). Atherosclerosis-an inflammatory disease. The New England Journal of Medicine, 340, 115-126.
Schoonjans, K., Staels, B., & Auwerx, J. (1996). The peroxisome proliferator activated receptors(ppars) and their effects on lipid metabolism and adipocyte differentiation. Biochimica et Biophysica Acta, 1302, 93-109.
Senanayake, G. V. K., Maruyama, M., Shibuya, K., Sakono, M., Fukuda, N., Morishita, T., et al. (2004). The effects of bitter melon(momordica charantia) on serum and liver triglyceride levels in rats. Journal of Ethnopharmacology, 91, 257-262.
Staels, B., Koenig, W., Habib, A. d., Merval, R. g., Lebret, M., & Torra, I. s. P. (1998). Activation of human aortic smooth-muscle cells is inhibited by ppara but not by pparg activators. Circulation, 393, 790-793.
Steinberg, D. (1997). Low density lipoprotein oxidation and its pathobiological significance. J. Biol. Chem., 272, 20963-20966.
Stocker, R., & Keaney, J. F. (2004). Role of oxidative modifications in atherosclerosis. the American Physiological Society, 84, 1381-1478.
Stocker, R., & O'Halloran, R. A. (2004). Dealcoholized red wine decreases atherosclerosis in apolipoprotein e gene-deficient mice independently of inhibition of lipid peroxidation in the artery wall. Am J Clin Nutr, 79, 123-130.
Toomey, S., Roche, H., Fitzgerald, D., & Belton, O. (2003). Regression of pre-established atherosclerosis in the apoe./. Mouse by conjugated linoleic acid. Biochemical Society transations, 31, 1075-1079.
Tsuzuki, T., Igarashi, M., Komai, M., & Miyazawa, T. (2003). A metabolic conversion of 9,11,13-eleostearic acid (18:3) to 9,11-conjugated linoleic acid (18:2) in the rat. J. Nutr. Sci. Vitaminol., 49, 195-200.
Ugarova, T. P., & Yakubenko, V. P. (2001). Recognition of fibrinogen by leukocyte integrins. Ann NY Acad Sci, 936, 368-385.
Waddington, E., Puddey, I. B., & Croft, K. D. (2004). Red wine polyphenolic compounds inhibit atherosclerosis in apolipoprotein e-deficient mice independently of effects on lipid peroxidation. Am J Clin Nutr, 79, 54-61.
Wang, A. M., Creasey, A. A., Ladner, M. B., Lin, L. S., Strickler, J., Arsdell, J. N., et al. (1985). Molecular cloning of the complementary DNA for human tumor necrosis factor. 228, 149-154.
Wanga, H.-H., Hunga, T.-M., Weib, J., & Chiang, A.-N. (2004). Fish oil increases antioxidant enzyme activities in macrophages and reduces atherosclerotic lesions in apoe-knockout mice. Cardiovascular Research, 61, 169-176.
Weissberg, P. L. (2000). Atherogenesis:Current understanding of the causes of atheroma. Heart, 83, 247-252.
Xia, M., Ling, W. H., Ma, J., Kitts, D. D., & Zawistowski, J. (2003). Supplementation of diets with the black rice pigment fraction attenuates atherosclerotic plaque formation in apolipoprotein e deficient mice. J. Nutr., 133, 744-751.
Zapolska-Downar, D., Zapolski-Downar, A., Markiewski, M., Ciechanowicz, A., Kaczmarczyk, M., & Naruszewicz, M. (2001). Selective inhibition by probucol of vascular cell adhesion molecule-1 (vcam-1) expression in human vascular endothelial cells. Atherosclerosis, 155, 123-130.
Zhang, L. (1999). The αmβ2 integrin and its role in neutrophil function. Cell Research, 9, 171-178.
φsterud, B., & Bjφrklid, E. (2003). Role of monocyte in atherogenesis. American physiological society, 83, 1069-1112.
林弼玉. (2003). 以巨噬細胞株為模式探討苦瓜中影響前列腺素E2合成之區分物. 國立台灣師範大學碩士論文.
莊佳穎. (2004). 山苦瓜活化過氧化體增殖活化受器PPARs之成分分離與鑑定. 台大微生物與生化研究所碩士論文.
趙哲毅. (2003). 苦瓜活化過氧化體增殖劑活化受器及改變脂質代謝相關基因之表現. 台大微生物與生化研究所博士論文.
謝婉郁. (2005). 山苦瓜改善血糖血脂代謝異常之效應探討. 國立台灣大學微生物與生化學研究所碩士論文.