臺灣博碩士論文加值系統

肝損傷是由多個因素如酒精、化學藥物和病毒所導致，若長期傷害肝臟則會造成肝細胞損傷伴隨著脂肪浸潤、脂肪肝、肝發炎等病狀，最終可能惡化成肝纖維化、肝硬化甚至肝癌，可見護肝的重要性。台灣藜 (Chenopodium formosanum Koidz)，俗稱紅藜，富含豐富蛋白質、膳食纖維、必需胺基酸營養，並含有機能性成分甜菜色素、多酚類，其中多酚類又以芸香苷 (rutin) 為主，具有清除自由基之能力、抗氧化、抗發炎和護肝等功效。本研究探討紅藜萃取物與其功效成分 rutin 對酒精性和化學性肝損傷之改善效果。利用酒精液態飼料誘導肝損傷與腹腔注射四氯化碳誘導肝損傷之動物模式，分別餵食紅藜全穀粉末、紅藜殼酒萃物、紅藜殼水萃物及 rutin給予損傷小鼠，經六週試驗，探討紅藜對肝損傷的改善效果。結果顯示，紅藜萃取物和 rutin 均能降低酒精所提高血清中肝損傷指標 aspartate aminotransferase (AST)、alanine aminotransferase (ALT) 活性和血清中脂質堆積 triglyceride (TG)、total cholesterol (TC)，並能降低血清中肝臟中的 TG 含量，並降低脂質生合成 ACC蛋白表現量，提高抗氧酵素 superoxide dismutase (SOD)、catalase (CAT) 活性和 glutathione (GSH) 含量，並顯著降低肝臟之 thiobarbituric acid reactive substances (TBARS)。在肝臟病理切片 H&E 染色中紅藜萃取物組僅只出現少許脂肪空泡及中央靜脈的周圍巨噬細胞浸潤，顯示紅藜萃取物達到預防酒精性脂肪肝之效果。在四氯化碳誘導肝損傷之結果中，紅藜萃取物和 rutin 均能降低血清中因四氯化碳所提高之肝損傷指標一 AST 與 ALT 活性降低血清中總蛋白和白蛋白/球蛋白比值降低血清中腎臟功能指標尿素氮和肌酸酐並提高抗氧化酵素 SOD、CAT 活性和抗氧化物質GSH 含量，顯著降低肝臟之 TBARS 含量，並降低發炎因子 tumor necrosis factor-α (TNF-α)、Interleukin 6 (IL-6) 及降低纖維化因子 transforming growth factor-β1 (TGF-β1)、α-smooth muscle actin (α-SMA)，達到改善四氯化碳誘導肝纖維化之效果。根據以上兩種動物模式誘導肝損傷結果，紅藜萃取物具有改善酒精誘導肝損傷和四氯化碳誘導肝損傷小鼠之效果，且 rutin 可作為其功效成分指標。

In 2015, Chronic liver disease and Cirrhosis are top ten causes of death in Taiwan. Liver injuty is caused by multiple factors, such as alcohol, chemicals and viruses. It may lead to hepatic failure, hepatic fibrosis, cirrhosis and eventually hepatic carcinoma. Thus, to protect liver is essential. Red Quinoa (Chenopodium formosanum Koidz), which is called Djulis in aboriginal village, contains high quantities of protein, dietary fiber, essential amino acid and other bioactive constitutions. Rutin is main polyphenols in Red Quinoa. It has effects on anti-radicals, anti-oxidation, anti-inflammatory and protecting liver. This study investigated the
effect of red quinoa extract and rutin on the improvement of alcoholic and chemical liver injury. Liver injury were induced by liquid alcoholic diet and CCl4 i.p. injection for 6 week and treated with red quinoa powder, red quinoa water extract, red quinoa
ethanol extract and rutin. In the results of alcoholic liver injury, red quinoa extract and rutin decreased the activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and the levels of serum triglyceride (TG) and cholesterol (TC). Moreover, they decreased the levels of TG and thiobarbituric acid reactive substances (TBARS) and increased the activities of antioxidant enzymes superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH) and Significantly in the liver. Furthermore, small amount of fat vacuoles and macrophages infiltrated around the central veins were found in the red quinoa extract groups in the H&E liver slice. In the results of carbon tetrachloride-induced liver injury, red quinoa extract and rutin
decreased the activities of AST and ALT and total protein, albumin/globulin ratio in serum. Besides, serum urea and creatinine were decreased by the treatment. The level of TBARS also was decreased in liver. According to the above two liver injury models, red quinoa extract has effects on improving alcohol-induced liver injury and carbon tetrachloride-induced liver injury in mice, and rutin might be a main effective compound in red quinoa extract.

中文摘要………………………………………………………………………….....Ⅰ
Abstract………………………………………………………………………………Ⅲ
縮寫表……………………………………………………………………………….ⅴ
前言…………………………………………………………………………………..1
第一章 文獻回顧……………………………………………………………………3
第一節 肝臟疾病……………………………………………………………...3
一、 肝損傷…………………………………………………………………3
二、 酒精性肝損傷…………………………………………………………4
(一) 酒精性肝損傷之作用機轉……………………………………...4
(二) 酒精性肝損傷誘發之動物模式………………………………...9
三、 化學性肝損傷……………………………………………………........11
(一) 四氯化碳誘導化學性肝損傷之作用機轉……………………..12
(二) 四氯化碳誘發肝損傷之動物模式……………………………..12
四、 酒精性與化學性誘發動物肝損傷模式之比較………………………15
第二節 台灣藜………………………………………………………………...16
一、 紅藜生長、分布特性介紹……………………………………………16
二、 紅藜營養成分與功效成分……………………………………………16
三、 紅藜保健之相關研究…………………………………………………20
第三節 紅藜預防肝損傷之潛力…………………………………...…………21
一、 Rutin 預防肝損傷之過去研究……………………………………….21
二、 Betanin 預防肝損傷之過去研究…………………………………….22
第二章 研究動機與架構……………………………………………………………24
第一節 研究動機與目的……………………………………………………...24
第二節 研究架構……………………………………………………………...25
第三章 材料與方法…………………………………………………………………27
第一節 實驗材料……………………………………………………………...27
一、 儀器與設備……………………………………………………………27
二、 藥品……………………………………………………………………28
第二節 實驗方法……………………………………………………………...29
一、 紅藜萃取物製備與rutin分析………………………………………..29
二、 紅藜萃取物對酒精和四氯化碳誘發肝損傷動物試驗模式……....…30
三、 血清和肝臟之生化測定分析…………………………………………34
四、 統計分析………………………………………………………………42
第四章 研究結果……………………………………………………………………43
第一節 紅藜萃取物製成其含量分析………………………………………….43
一、 紅藜營養成分分析表………………………………………………...43
二、 紅藜萃取物與其活性成分 rutin 之 HPLC 層析圖譜…………….43
三、 紅藜萃取物內 rutin 含量和萃取率…………………………….......43
第二節 紅藜萃取物與其rutin對酒精誘導肝損傷之影響…………………..43
一、 紅藜萃取物與對四氯化碳誘導肝損傷小鼠體重變化……………..43
二、 紅藜萃取物與對酒精性肝損傷小鼠體重與肝重/體重比值之影響.48
三、 紅藜萃取物對酒精性肝損傷小鼠血清中肝功能指標 AST、ALT 及 ALP活性之變化…………………………………………………….48
四、 紅藜萃取物對酒精性肝損傷小鼠血清與肝臟中脂質濃度之影響..48
五、 紅藜萃取物對酒精性肝損傷小鼠肝臟內脂質過氧化程度之影響..52
六、 紅藜萃取物對酒精性肝損傷小鼠肝臟病理之影響………………..52
七、 紅藜萃取物對酒精性肝損傷小鼠肝臟內 GSH 含量和抗氧化酵素活性之影響……………………………………………………………..52
八、 紅藜萃取物對酒精性肝損傷小鼠肝臟中之脂質代謝與生合成相關蛋白表現量之影響…………………………………….………………..61
第三節 紅藜萃取物與其rutin對四氯化碳誘導肝損傷之影響……………63
一、 紅藜萃取物與對四氯化碳誘導肝損傷小鼠體重變化……………..63
二、 紅藜萃取物與對四氯化碳誘導肝損傷小鼠體重、肝重與肝重/體重比值之影響……………………………………………………………..63
三、 紅藜萃取物對酒精性肝損傷小鼠血清中肝功能指標 AST、ALT 和 ALP 活性之變化…………………………………………………….63
四、 紅藜萃取物對酒精性肝損傷小鼠血清中肝功能指標總蛋白、白蛋白、球蛋白、白蛋白/球蛋白比值和總膽紅素之影響…………………..67
五、 紅藜萃取物對四氯化碳誘導肝損傷小鼠血清腎功能指標之影響..67
六、 紅藜萃取物四氯化碳誘導肝損傷小鼠肝臟內脂質過氧化程度之影響……………………………………………………………………...70
七、 紅藜萃取物對四氯化碳誘導肝損傷小鼠肝臟內抗氧化酵素活性和 GSH 含量之影響……………………………………………………70
八、 紅藜及其萃取物對四氯化碳誘導肝損傷小鼠肝臟病理之影響…..74
九、 紅藜及其萃取物對四氯化碳誘導肝損傷小鼠肝臟膠原堆積之影響……………………………………………………………………..74
十、 紅藜及其萃取物對四氯化碳誘導肝損傷小鼠肝臟中纖維化因子之影響……………………………………………………………………..81
十一、紅藜及其萃取物對四氯化碳誘導肝損傷小鼠肝臟中細胞激素之影響…………………………………………………………………………..81
第五章 討論
第一節 紅藜萃取物與其成分 rutin 對酒精性肝損傷小鼠之護肝效果…...85
第二節 紅藜及其萃取物與其成分 rutin 對四氯化碳誘導肝損傷小鼠之護肝
效果……………………………………………………………………92
第六章 結論………………………………………………………………………....93
第七章 參考文獻……………………………………………………………............95

世界衛生組織 (World Health Organization, WHO) 及其下屬的癌症研究機構
(International Agency for Research on Cancer , IARC) 發表2014年「全球癌
症報告」
行政院衛生福利部統計公布欄 (2017) 民國 105 年死因結果分析。
王煌輝 (2005) 肝功能判讀，中國內科醫學雜誌 3:3-12
行政院農業委員會 (2010) 農政與農情 99年7月(第217期)
郭耀綸、楊遠波、蔡碧仁、葛孟杰。2008。紅藜推廣手冊。行政院農業委員會林
務局資料
Addolorato G, Russell M, Albano E, Haber PS, Wands JR, Leggio L (2009) Understanding and treating patients with alcoholic cirrhosis: an update. Alcohol Clin Exp Res 33(7):1136-44 doi:10.1111/j.1530-0277.2009.00956.x
Alberts AW, Strauss AW, Hennessy S, Vagelos PR (1975) Regulation of synthesis of hepatic fatty acid synthetase: binding of fatty acid synthetase antibodies to polysomes. Proc Natl Acad Sci U S A 72(10):3956-60
Anji A, Kumari M (2008) Supplementing the liquid alcohol diet with chow enhances alcohol intake in C57 BL/6 mice. Drug Alcohol Depend 97(1-2):86-93 doi:10.1016/j.drugalcdep.2008.03.022
Bailey SM, Cunningham CC (2002) Contribution of mitochondria to oxidative stress associated with alcoholic liver disease. Free Radic Biol Med 32(1):11-6
Basu S (2003) Carbon tetrachloride-induced lipid peroxidation: eicosanoid formation and their regulation by antioxidant nutrients. Toxicology 189(1-2):113-27
Bataller R, Brenner DA (2005) Liver fibrosis. J Clin Invest 115(2):209-18 doi:10.1172/JCI24282
Bertola A, Mathews S, Ki SH, Wang H, Gao B (2013) Mouse model of chronic and binge ethanol feeding (the NIAAA model). Nat Protoc 8(3):627-37 doi:10.1038/nprot.2013.032
Best CH, Hartroft WS, et al. (1949) Liver damage produced by feeding alcohol or sugar and its prevention by choline. Br Med J 2(4635):1002-6, pl
Bode C, Bode JC (2003) Effect of alcohol consumption on the gut. Best Pract Res Clin Gastroenterol 17(4):575-92
Bondy SC (1992) Ethanol toxicity and oxidative stress. Toxicol Lett 63(3):231-41
Brandon-Warner E, Schrum LW, Schmidt CM, McKillop IH (2012) Rodent models of alcoholic liver disease: of mice and men. Alcohol 46(8):715-25 doi:10.1016/j.alcohol.2012.08.004
Buszewski B, Kawka S, Suprynowicz Z, Wolski T (1993) Simultaneous isolation of Rutin and Esculin from plant material and drugs using solid-phase extraction. J Pharm Biomed Anal 11(3):211-5
Cai Y, Sun M, Corke H (2003) Antioxidant activity of betalains from plants of the amaranthaceae. J Agric Food Chem 51(8):2288-94 doi:10.1021/jf030045u
Cheung PY, Zhang Q, Zhang YO, et al. (2006) Effect of WeiJia on carbon tetrachloride induced chronic liver injury. World J Gastroenterol 12(12):1912-7
Cho BO, Ryu HW, So Y, et al. (2013) Hepatoprotective effect of 2,3-dehydrosilybin on carbon tetrachloride-induced liver injury in rats. Food Chem 138(1):107-15 doi:10.1016/j.foodchem.2012.10.026
Chu C-C, Chen S-Y, Chyau C-C, Fu Z-H, Liu C-C, Duh P-D (2016) Protective effect of Djulis (Chenopodium formosanum) and its bioactive compounds against carbon tetrachloride-induced liver injury, in vivo. Journal of Functional Foods 26:585-597 doi:10.1016/j.jff.2016.08.025
Chua LS (2013) A review on plant-based rutin extraction methods and its pharmacological activities. J Ethnopharmacol 150(3):805-17 doi:10.1016/j.jep.2013.10.036
Chyau C-C, Chu C-C, Chen S-Y, Duh P-D (2015) Djulis (Chenopodiun formosaneum) and its bioactive compounds protect against oxidative stress in human HepG2 cells. Journal of Functional Foods 18:159-170 doi:10.1016/j.jff.2015.06.025
Curello S, Ceconi C, Bigoli C, Ferrari R, Albertini A, Guarnieri C (1985) Changes in the cardiac glutathione status after ischemia and reperfusion. Experientia 41(1):42-3
Day CP, Yeaman SJ (1994) The biochemistry of alcohol-induced fatty liver. Biochim Biophys Acta 1215(1-2):33-48
Deleve LD (1994) Dacarbazine toxicity in murine liver cells: a model of hepatic endothelial injury and glutathione defense. J Pharmacol Exp Ther 268(3):1261-70
Deschner EE, Ruperto J, Wong G, Newmark HL (1991) Quercetin and rutin as inhibitors of azoxymethanol-induced colonic neoplasia. Carcinogenesis 12(7):1193-6
Dufour DR, Lott JA, Nolte FS, Gretch DR, Koff RS, Seeff LB (2000) Diagnosis and monitoring of hepatic injury. I. Performance characteristics of laboratory tests. Clin Chem 46(12):2027-49
Duly AM, Alani B, Huang EY, et al. (2015) Effect of multiple binge alcohol on diet-induced liver injury in a mouse model of obesity. Nutr Diabetes 5:e154 doi:10.1038/nutd.2015.4
Dunn W, Shah VH (2016) Pathogenesis of Alcoholic Liver Disease. Clin Liver Dis 20(3):445-56 doi:10.1016/j.cld.2016.02.004
Edwards S, Kenna GA, Swift RM, Leggio L (2011) Current and promising pharmacotherapies, and novel research target areas in the treatment of alcohol dependence: a review. Curr Pharm Des 17(14):1323-32
Erdogan E, Ilgaz Y, Gurgor PN, Oztas Y, Topal T, Oztas E (2015) Rutin ameliorates methotrexate induced hepatic injury in rats. Acta Cir Bras 30(11):778-84 doi:10.1590/S0102-865020150110000009
Erlund I, Kosonen T, Alfthan G, et al. (2000) Pharmacokinetics of quercetin from quercetin aglycone and rutin in healthy volunteers. Eur J Clin Pharmacol 56(8):545-53
Friedman SL (2004) Mechanisms of disease: Mechanisms of hepatic fibrosis and therapeutic implications. Nat Clin Pract Gastroenterol Hepatol 1(2):98-105 doi:10.1038/ncpgasthep0055
Gao B, Bataller R (2011) Alcoholic liver disease: pathogenesis and new therapeutic targets. Gastroenterology 141(5):1572-85 doi:10.1053/j.gastro.2011.09.002
Gliszczynska-Swiglo A, Szymusiak H, Malinowska P (2006) Betanin, the main pigment of red beet: molecular origin of its exceptionally high free radical-scavenging activity. Food Addit Contam 23(11):1079-87 doi:10.1080/02652030600986032
Gonzalez-Vallinas M, Gonzalez-Castejon M, Rodriguez-Casado A, Ramirez de Molina A (2013) Dietary phytochemicals in cancer prevention and therapy: a complementary approach with promising perspectives. Nutr Rev 71(9):585-99 doi:10.1111/nure.12051
Gruebele A, Zawaski K, Kaplan D, Novak RF (1996) Cytochrome P4502E1- and cytochrome P4502B1/2B2-catalyzed carbon tetrachloride metabolism: effects on signal transduction as demonstrated by altered immediate-early (c-Fos and c-Jun) gene expression and nuclear AP-1 and NF-kappa B transcription factor levels. Drug Metab Dispos 24(1):15-22
Gustot T, Lemmers A, Moreno C, et al. (2006) Differential liver sensitization to toll-like receptor pathways in mice with alcoholic fatty liver. Hepatology 43(5):989-1000 doi:10.1002/hep.21138
Hafez MM, Al-Harbi NO, Al-Hoshani AR, et al. (2015) Hepato-protective effect of rutin via IL-6/STAT3 pathway in CCl4-induced hepatotoxicity in rats. Biol Res 48:30 doi:10.1186/s40659-015-0022-y
Halliwell B, Gutteridge JM (1986) Oxygen free radicals and iron in relation to biology and medicine: some problems and concepts. Arch Biochem Biophys 246(2):501-14
Han J, Gao C, Yang S, Wang J, Tan D (2014) Betanin attenuates carbon tetrachloride (CCl4)-induced liver injury in common carp (Cyprinus carpio L.). Fish Physiol Biochem 40(3):865-74 doi:10.1007/s10695-013-9892-5
Han S, Jiao J, Zhang W, et al. (2015) Dietary fiber prevents obesity-related liver lipotoxicity by modulating sterol-regulatory element binding protein pathway in C57BL/6J mice fed a high-fat/cholesterol diet. Sci Rep 5:15256 doi:10.1038/srep15256
Hartmann P, Seebauer CT, Schnabl B (2015) Alcoholic liver disease: the gut microbiome and liver cross talk. Alcohol Clin Exp Res 39(5):763-75 doi:10.1111/acer.12704
Hendrich AB (2006) Flavonoid-membrane interactions: possible consequences for biological effects of some polyphenolic compounds. Acta Pharmacol Sin 27(1):27-40 doi:10.1111/j.1745-7254.2006.00238.x
Hii CS, Howell SL (1985) Effects of flavonoids on insulin secretion and 45Ca2+ handling in rat islets of Langerhans. J Endocrinol 107(1):1-8
Hoek JB, Pastorino JG (2002) Ethanol, oxidative stress, and cytokine-induced liver cell injury. Alcohol 27(1):63-8
Hong YH, Huang YL, Liu YC, Tsai PJ (2016) Djulis (Chenopodium formosanum Koidz.) Water Extract and Its Bioactive Components Ameliorate Dermal Damage in UVB-Irradiated Skin Models. Biomed Res Int 2016:7368797 doi:10.1155/2016/7368797
Jimenez-Cruz A, Manuel Loustaunau-Lopez V, Bacardi-Gascon M (2006) The use of low glycemic and high satiety index food dishes in Mexico: a low cost approach to prevent and control obesity and diabetes. Nutr Hosp 21(3):353-6
Jung UJ, Lee MK, Park YB, Kang MA, Choi MS (2006) Effect of citrus flavonoids on lipid metabolism and glucose-regulating enzyme mRNA levels in type-2 diabetic mice. Int J Biochem Cell Biol 38(7):1134-45 doi:10.1016/j.biocel.2005.12.002
Kalyanaraman B (2013) Teaching the basics of redox biology to medical and graduate students: Oxidants, antioxidants and disease mechanisms. Redox Biol 1:244-57 doi:10.1016/j.redox.2013.01.014
Kim HY, Nam SY, Hong SW, Kim MJ, Jeong HJ, Kim HM (2015) Protective effects of rutin through regulation of vascular endothelial growth factor in allergic rhinitis. Am J Rhinol Allergy 29(3):e87-94 doi:10.2500/ajra.2015.29.4195
Klassen LW, Tuma D, Sorrell MF (1995) Immune mechanisms of alcohol-induced liver disease. Hepatology 22(1):355-7
Lands WE (1998) A review of alcohol clearance in humans. Alcohol 15(2):147-60
Lieber CS (1981) Metabolic effects of ethanol on the liver and other digestive organs. Clin Gastroenterol 10(2):315-42
Lieber CS (1982) Alcohol and the terminal hepatic venule. Gastroenterology 83(5):1158-9
Lieber CS (1994) Hepatic and metabolic effects of ethanol: pathogenesis and prevention. Ann Med 26(5):325-30
Lieber CS, DeCarli LM (1982) The feeding of alcohol in liquid diets: two decades of applications and 1982 update. Alcohol Clin Exp Res 6(4):523-31
Lieber CS, DeCarli LM, Sorrell MF (1989) Experimental methods of ethanol administration. Hepatology 10(4):501-10
Lieber CS, Lasker JM, DeCarli LM, Saeli J, Wojtowicz T (1988) Role of acetone, dietary fat and total energy intake in induction of hepatic microsomal ethanol oxidizing system. J Pharmacol Exp Ther 247(2):791-5
Lin JP, Yang JS, Lin JJ, et al. (2012) Rutin inhibits human leukemia tumor growth in a murine xenograft model in vivo. Environ Toxicol 27(8):480-4 doi:10.1002/tox.20662
Louvet A, Mathurin P (2015) Alcoholic liver disease: mechanisms of injury and targeted treatment. Nat Rev Gastroenterol Hepatol 12(4):231-42 doi:10.1038/nrgastro.2015.35
Lu Y, Cederbaum AI (2008) CYP2E1 and oxidative liver injury by alcohol. Free Radic Biol Med 44(5):723-38 doi:10.1016/j.freeradbiomed.2007.11.004
Lucey MR, Mathurin P, Morgan TR (2009) Alcoholic hepatitis. N Engl J Med 360(26):2758-69 doi:10.1056/NEJMra0805786
Luster MI, Simeonova PP, Gallucci RM, Bruccoleri A, Blazka ME, Yucesoy B (2001) Role of inflammation in chemical-induced hepatotoxicity. Toxicol Lett 120(1-3):317-21
Luster MI, Simeonova PP, Gallucci RM, Matheson JM, Yucesoy B (2000) Immunotoxicology: role of inflammation in chemical-induced hepatotoxicity. Int J Immunopharmacol 22(12):1143-7
Malhi H, Gores GJ (2008) Cellular and molecular mechanisms of liver injury. Gastroenterology 134(6):1641-54 doi:10.1053/j.gastro.2008.03.002
Mezey E, Caballeria J, Mitchell MC, Pares A, Herlong HF, Rodes J (1991) Effect of parenteral amino acid supplementation on short-term and long-term outcomes in severe alcoholic hepatitis: a randomized controlled trial. Hepatology 14(6):1090-6
Misra P, Chakrabarti R (2007) The role of AMP kinase in diabetes. Indian J Med Res 125(3):389-98
Miyazaki T, Karube M, Matsuzaki Y, et al. (2005) Taurine inhibits oxidative damage and prevents fibrosis in carbon tetrachloride-induced hepatic fibrosis. J Hepatol 43(1):117-25 doi:10.1016/j.jhep.2005.01.033
Nafees S, Rashid S, Ali N, Hasan SK, Sultana S (2015) Rutin ameliorates cyclophosphamide induced oxidative stress and inflammation in Wistar rats: role of NFkappaB/MAPK pathway. Chem Biol Interact 231:98-107 doi:10.1016/j.cbi.2015.02.021
Nanji AA, Zhao S, Sadrzadeh SM, Dannenberg AJ, Tahan SR, Waxman DJ (1994) Markedly enhanced cytochrome P450 2E1 induction and lipid peroxidation is associated with severe liver injury in fish oil-ethanol-fed rats. Alcohol Clin Exp Res 18(5):1280-5
Orman ES, Odena G, Bataller R (2013) Alcoholic liver disease: pathogenesis, management, and novel targets for therapy. J Gastroenterol Hepatol 28 Suppl 1:77-84 doi:10.1111/jgh.12030
Pandey KB, Rizvi SI (2010) Markers of oxidative stress in erythrocytes and plasma during aging in humans. Oxid Med Cell Longev 3(1):2-12 doi:10.4161/oxim.3.1.10476
Pikaar NA, Wedel M, van der Beek EJ, et al. (1987) Effects of moderate alcohol consumption on platelet aggregation, fibrinolysis, and blood lipids. Metabolism 36(6):538-43
Purohit V, Bode JC, Bode C, et al. (2008) Alcohol, intestinal bacterial growth, intestinal permeability to endotoxin, and medical consequences: summary of a symposium. Alcohol 42(5):349-61 doi:10.1016/j.alcohol.2008.03.131
Rajesh MG, Latha MS (2004) Preliminary evaluation of the antihepatotoxic activity of Kamilari, a polyherbal formulation. J Ethnopharmacol 91(1):99-104 doi:10.1016/j.jep.2003.12.011
Ramadori G, Armbrust T (2001) Cytokines in the liver. Eur J Gastroenterol Hepatol 13(7):777-84
Ramaiah SK (2007) A toxicologist guide to the diagnostic interpretation of hepatic biochemical parameters. Food Chem Toxicol 45(9):1551-7 doi:10.1016/j.fct.2007.06.007
Rasineni K, Penrice DD, Natarajan SK, et al. (2016) Alcoholic vs non-alcoholic fatty liver in rats: distinct differences in endocytosis and vesicle trafficking despite similar pathology. BMC Gastroenterol 16:27 doi:10.1186/s12876-016-0433-4
Rechnagel RO, Glende EA, Jr. (1973) Carbon tetrachloride hepatotoxicity: an example of lethal cleavage. CRC Crit Rev Toxicol 2(3):263-97 doi:10.3109/10408447309082019
Recknagel RO, Glende EA, Jr., Dolak JA, Waller RL (1989) Mechanisms of carbon tetrachloride toxicity. Pharmacol Ther 43(1):139-54
Ress C, Kaser S (2016) Mechanisms of intrahepatic triglyceride accumulation. World J Gastroenterol 22(4):1664-73 doi:10.3748/wjg.v22.i4.1664
Rouach H, Fataccioli V, Gentil M, French SW, Morimoto M, Nordmann R (1997) Effect of chronic ethanol feeding on lipid peroxidation and protein oxidation in relation to liver pathology. Hepatology 25(2):351-5 doi:10.1002/hep.510250216
Rusinski P, Kolacinski Z (2003) [Acute poisoning with selected hepatotoxic agents: biochemistry of toxic effect, clinical symptoms and treatment]. Przegl Lek 60(4):210-7
Schwartz JM, Reinus JF (2012) Prevalence and natural history of alcoholic liver disease. Clin Liver Dis 16(4):659-66 doi:10.1016/j.cld.2012.08.001
Seitz HK, Stickel F (2007) Molecular mechanisms of alcohol-mediated carcinogenesis. Nat Rev Cancer 7(8):599-612 doi:10.1038/nrc2191
Shen SC, Lee WR, Lin HY, et al. (2002) In vitro and in vivo inhibitory activities of rutin, wogonin, and quercetin on lipopolysaccharide-induced nitric oxide and prostaglandin E(2) production. Eur J Pharmacol 446(1-3):187-94
Shukla SD, Pruett SB, Szabo G, Arteel GE (2013) Binge ethanol and liver: new molecular developments. Alcohol Clin Exp Res 37(4):550-7 doi:10.1111/acer.12011
Sikder K, Kesh SB, Das N, Manna K, Dey S (2014) The high antioxidative power of quercetin (aglycone flavonoid) and its glycone (rutin) avert high cholesterol diet induced hepatotoxicity and inflammation in Swiss albino mice. Food Funct 5(6):1294-303 doi:10.1039/c3fo60526d
Slimestad R, Verheul M (2011) Properties of chalconaringenin and rutin isolated from cherry tomatoes. J Agric Food Chem 59(7):3180-5 doi:10.1021/jf104045k
Strack D, Vogt T, Schliemann W (2003) Recent advances in betalain research. Phytochemistry 62(3):247-69
Szabo G, Mandrekar P (2010) Focus on: Alcohol and the liver. Alcohol Res Health 33(1-2):87-96
Teli MR, Day CP, Burt AD, Bennett MK, James OF (1995) Determinants of progression to cirrhosis or fibrosis in pure alcoholic fatty liver. Lancet 346(8981):987-90
Tsai PJ, Sheu CH, Wu PH, Sun YF (2010) Thermal and pH stability of betacyanin pigment of Djulis (Chenopodium formosanum) in Taiwan and their relation to antioxidant activity. J Agric Food Chem 58(2):1020-5 doi:10.1021/jf9032766
Tsukamoto H, French SW, Benson N, et al. (1985) Severe and progressive steatosis and focal necrosis in rat liver induced by continuous intragastric infusion of ethanol and low fat diet. Hepatology 5(2):224-32
Ueno A, Lazaro R, Wang PY, Higashiyama R, Machida K, Tsukamoto H (2012) Mouse intragastric infusion (iG) model. Nat Protoc 7(4):771-81 doi:10.1038/nprot.2012.014
Venukumar MR, Latha MS (2002) Antioxidant activity ofcurculigo orchioides in carbon tetrachloride-induced hepatopathy in rats. Indian J Clin Biochem 17(2):80-7 doi:10.1007/BF02867976
Weber LW, Boll M, Stampfl A (2003) Hepatotoxicity and mechanism of action of haloalkanes: carbon tetrachloride as a toxicological model. Crit Rev Toxicol 33(2):105-36 doi:10.1080/713611034
Wilkin RJ, Lalor PF, Parker R, Newsome PN (2016) Murine Models of Acute Alcoholic Hepatitis and Their Relevance to Human Disease. Am J Pathol 186(4):748-60 doi:10.1016/j.ajpath.2015.12.003
Yang J, Guo J, Yuan J (2008) In vitro antioxidant properties of rutin. LWT - Food Science and Technology 41(6):1060-1066 doi:10.1016/j.lwt.2007.06.010
Yang RZ, Park S, Reagan WJ, et al. (2009) Alanine aminotransferase isoenzymes: molecular cloning and quantitative analysis of tissue expression in rats and serum elevation in liver toxicity. Hepatology 49(2):598-607 doi:10.1002/hep.22657
Yao Y, Suo T, Andersson R, et al. (2017) Dietary fibre for the prevention of recurrent colorectal adenomas and carcinomas. Cochrane Database Syst Rev 1:CD003430 doi:10.1002/14651858.CD003430.pub2
You KM, Jong HG, Kim HP (1999) Inhibition of cyclooxygenase/lipoxygenase from human platelets by polyhydroxylated/methoxylated flavonoids isolated from medicinal plants. Arch Pharm Res 22(1):18-24
Zakhari S (2006) Overview: how is alcohol metabolized by the body? Alcohol Res Health 29(4):245-54