第一節 結論
在本研究中，使用不同癌化程度的重組人類肝細胞株，偵測不同誘發劑誘發細胞中轉錄 因子活性，代表特定肝病模式。觀察藥物對AP-1與NF-?B的影響，並選擇具有抑制轉錄因子活 性，具新藥開發潛力的植物萃取物或化合物作為研究的目標。在諸多搜尋之中，小檗鹼具有抑 制乙醛誘發之NF-?B的活性，原因為其能干擾上游訊息傳導路線的活化，並抑制轉錄因子控制 下游基因的表現，對細胞生長造成抑制。希望藉由此模式作為未來研究的起點，進一步推展到 體內試驗，希望小檗鹼也可以發揮類似的功能
第二節 建議
未來將進一步研究小檗鹼和乙醛在分子生物學上對NF-?B的作用，了解NF-?B在此扮演的 角色，以及對被這兩個轉錄因子所調控的基因做研究，釐清作用發生的原因與結果，並推動相 關的動物實驗，觀察小檗鹼在生物體內產生的作用是否也能和體外的模式一樣具有類似的功 能，希望小檗鹼可以對肝病的預防和治療有所貢獻並且為未來新藥開發的過程提供一個良好的 範本。
Quercetin、 Rutin、 Hyperin、 Kaempferol、 Morin、 Galangin、 Silibinin、 3-Hydroxyflavone、 Baicalein、 Baicalin、 Chrysin、
Luteolin、 Apigenin、 Flavone、 Hesperetin、 Hesperidin、 Eriocitrin、 Naringenin、 Naringin、 (+)-Catechin、 (-)-Epicatechin、
Gentisin、 Puerarin、 Formononetin、 glycyrrhizin、 18-a-Glycyrrhetinic acid、 18-b-Glycyrrhetinic acid、 Stigmasterol 、 Ginsenoside Rb1、 Ginsenoside Rb2、 Ginsenoside Rc、 Ginsenoside Rd、 Ginsenoside Re 、 Ginsenoside Rg1、 Silymarin、
berberrin、 Berberine-Cl、 Berberine-SO4、 Emodin、 Rhein、 Paeoniflorin、 Paeonol、 Evodiamine
5-Azacytidine、 5-Fluorouracil、 Aminopterin、 Camptothecin、 Cis-platinum(II) diamine dichloride、 Colchicine、 Cystine β-D-arabinofuranoside、hydrochloride、 Daunorubcin-hydrochloride、 Etoposide、 Mitomycin C、 Paciltaxel、 Vinblastine sulfate salt、 Vinblastine sulfate salt、 Sandoststin、 Forane、 Diprivan、 Ultane
A
B
C
0
Relative AP-1 activation fold
0
Relative AP-1 activity fold
0 (A) Chang liver/AP-1 細胞（B）HepG2/AP-1 細胞在去除血清的培養基培養，經過
24 小時後，以濃度為 0.2、0.5、1、5、10、25、50、100 ng/mL 的 TPA 刺激細 A
B
TPA (ng/mL) TPA (ng/mL)
Mock 0.2 0.5 1 5 10 25 50 100 200
表一、在 Chang liver/AP-1 及 HepG2/AP-1 細胞中皆能抑制 TPA 誘發 AP-1 活性的中藥。
Butylidenephthalide
Evodiamine, Rutaecarpine, deoxyevodiamine
Berberine(EC50=24.4μM), Palmatine, Coptisine
Berberine(EC50=24.4μM), Palmatine, Coptisine Guvacine, Isoguvacine, Arecoline, Arecaidine β-Emdesmol, Magnolol, Honokiol
Emodin(EC50=30μM), Aloe-emodin,(-)-Epicatechin,
0
10、25、50、100 ng/mL 的溶液作用 16 小時後，以 Reporter assay 測量 NF-?B 的活性，
並以未加藥的組別的平均值作為基準，觀察不同濃度的 LPS 造成的劑量作用。以上實 驗為三次實驗的平均值±標準差。
LPS (ng/ml) Mock
Relative NF -?B activity
Relative NF -?B activity Relative NF -?B activity
圖十三、小檗鹼可以抑制 HepG2 細胞中乙醛所誘發的 NF-?B 活性。
(A)小檗鹼可以抑制 HepG2 細胞中乙醛所誘發的 NF-?B 活性，以 0.1、1、5、25、
50、100 µM 的小檗鹼與 5 µM 的乙醛作用，在 8 小時呈現的作用圖譜。以乙醛 在 HepG2 細胞中誘發的 NF-?B 活化倍率作為基準。以上實驗值為三次實驗的平 均值±標準差。
0 0.5 1
mock Ace5uM 1 5 25 50 100
conc(uM)
Relative NFkB activity
Mock Acet 50 µM 1 5 25 50 100 Berberine (µM)
Relative NF -?B activity
圖十四、小檗鹼可以抑制 HepG2 細胞中乙醛誘發的 I-?B 磷酸化。
細胞在預先以濃度為 1、5、25、50、100 µM 的小檗鹼處理 30 分鐘後，再加 入濃度為 5 µM 的乙醛作用 30 分鐘；觀察乙醛和小檗鹼對細胞的影響，ERK 蛋白質在此作為細胞中蛋白質總量的控制組。以上為一次實驗呈現的結果。
I-?B
phospho-I-?B
ERK Acetaldehyde
Berberine
Concentration(μM)
+
mock 5μM 1 1 5 25 50 100
- -
- +
+ + +
+
+ +
+
+
+ +
(
3’-CCCGACAGGG-5’ 5’ -GGGGTATCCT-3’ 5’ -GGGTTTCTCC-3’
TNF-α
圖十六、小檗鹼在 48 小時可以抑制乙醛誘發 HepG2 細胞分泌 IL-1ß。
（A）人類 IL-1ß 基因啟動子區域中 NF-?B 的結合序列（B）IL-1ß 的標準品在 Cytokine ELISA 中呈現的標準曲線；橫軸為濃度（pg/mL），縱軸為在 405 nm
GGGAAAAT
參考文獻:
行政院衛生署。中華民國八十九年國人十大死因之調查。中華民國九十年。
行政院衛生署。中華民國八十八年國人十大死因之調查。中華民國八十九年。
賴羿如。肝細胞轉形之分子機制與分子療程之探討。中國醫藥學院醫學研究所碩士論文。中華民國九十年。
Abiru S, Nakao K, Ichikawa T, Migita K, Shigeno M, Sakamoto M, Ishikawa H. Acetaldehyde prevents nuclear factor-kappa B activation and hepatic inflammation in ethanol-fed rats. Lab Invest. 1999. 79: 799-806.
Ahmad, N. and Mukhtar, H. Green tea polyphenols and cancer : biologic mechanisms and practical implications. Nutr Rev. 1999. 57: 78-83.
Anis KV, Rajeshkumar NV, Kuttan R. Inhibition of chemical carcinogenesis by berberine in rats and mice.
J Pharm Pharmacol. 2001. 53: 763-768.
Ann M. Bode, Wei-Ya Ma, Young-Joon Surh, and Zigang Dong.Inhibition of epidermal growth factor-a induced cell transformation and Activator Protein 1 activation by [6]-Gingerol. Canc Res 2001. 61: 850-853.
Anping Chen and Bernard H. Davis. The DNA Binding protein BTEB mediates acetaldehyde-induced, jun n-terminal kinase-dependent ai(i) collagen gene expression in rat hepatic stellate cells. Mol Cell Biol, 2000. 20: 2818-2826.
Anping Chen, Li Zhang, Jianye XU and Jun Tang. The antioxidant (-)-epigallocatechin-3-gallate inhibits activated hepaticstellate cell growth and suppresses acetaldehyde-induced gene expression. Biochem. J. 2002. 368: 695-704.
Arnott CH, Scott KA, Moore RJ, Hewer A, Phillips DH, Parker P, Balkwill FR,Owens DM. Tumour necrosis factor-alpha mediates tumour promotion via a PKC alpha- and AP-1-dependent pathway. Oncogene. 2002. 21:
4728-4738.
Arsura M, Panta GR, Bilyeu JD, Cavin LG, Sovak MA, Oliver AA, Factor V, Heuchel R, Mercurio F, Thorgeirsson SS, Sonenshein GE. Transient activation of NF-kappaB through a TAK1/IKK kinase pathway by TGF-beta 1 inhibits AP-1/SMAD signaling and apoptosis: implications in liver tumor formation. Oncogene. 2003. 22: 412-425.
Bae, H. W., Geiser, A. G., Kim, D. H., Chung, M. T., Burmester, J. K., Sporn, M. B., Roberts, A. B. and Kim, S. J.
Characterization of the promoter region of the human transforming growth factor-ß type II receptor gene. J Biol Chem. 1995. 270: 29460-29468.
Bedossa, P., Paradis, V.,. Transforming growth factor-b:a key-role in liver fibrogenesis. J Hepatol. 1995. 22: 37-42.
Bird, G.L.A., Sheron, N., Goka, J., Alexandra, G., Williams,R.S. Increased plasma tumor necrosis factor insevere alcoholic hepatitis. Ann Intern Med. 1990. 112: 917-920.
Bissell, D.M., Wang, S.S., Jarnagin, W.R., Roll, F.J. Cell-specific expression of TGF-ß1 in rat liver-evidence for autocrine regulation of hepatocytes proliferation. J Clin Invest. 1995. 33: 447-455.
Bode, C., Fukin, H., Bode, J.C.,. Hidden endotoxin in plasma of patients with alcoholic liver disease. Eur J Gastrol Hepatol. 1993. 5: 257-262.
Border, W.A., Noble, N.A.,. Mechanisms of disease: transforming growth factor beta in tissue fibrosis. N Engl J Med.
1994. 331: 1286-1292.
Cao Q, Mak KM, Lieber CS. Dilinoleoylphosphatidylcholine decreases acetaldehyde-induced TNF-alpha generation in Kupffer cells of ethanol-fed rats. Bio Biop Res Comm. 2002. 299: 459-464.
Casini, A., Galli, G., Salzano, R., Rotella, C. M. and Surrenti, C. Acetaldehydeprotein adducts, but not lactate and pyruvate, stimulate gene transcription of collagen and Fibronectin in hepatic fat-storing cells. J. Hepatol. 1993. 19:
385-392.
Chen A, Davis BH. Chi CW, Chang YF, Chao TW, Chiang SH, P'eng FK, Lui WY, Liu TY. Flowcytometric analysis of the effect of berberine on the expression of glucocorticoid receptors in human hepatoma HepG2 cells. Life Sci.
1994. 54: 2099-2107.
Chen A, Zhang L, Xu J, Tang J. The antioxidant (-)-epigallocatechin-3-gallate inhibits activated hepatic stellate cell growth and suppres ses acetaldehyde-induced gene expression. Biochem J. 2002. 368: 695-704.
Chen J, Clemens DL, Cederbaum AI, Gao B. Ethanol inhibits the JAK-STAT signaling pathway in freshly isolated rat hepatocytes but not in cultured hepatocytes or HepG2 cells: evidence for a lack of involvement of ethanol metabolism. Clin Biochem. 2001. 34: 203-209.
Chen N, Ma WY, She QB, Wu E, Liu G, Bode AM, Dong Z. Transactivation of the epidermal growth factor receptor is involved in 2-O-tetradecanoylphorbol-13-acetate-induced signal transduction.J Biol Chem. 2001. 276:
Chen, A. and Davis, B. H. The DNA binding protein BTEB mediates acetaldehyde-induced, jun N-terminal
kinase-dependent aI(I) collagen gene expression in rat hepatic stellate cells. Mol Cell Biol. 2000. 20: 2818-2826.
Chen, A. and Davis, B. H. UV irradiation activates JNK and increases aI(I)collagen gene expression in rat hepatic stellate cells. J Biol Chem. 1999. 274: 158-164.
Chuanshu Huang, Yi Huang, Jingxia Li, Wenwei Hu, Robeena Aziz, Moon-shong Tang, Nanjun Sun, John Cassady, and Gary D. Stoner Inhibition of Benzo(a)pyrene Diol-Epoxide-induced Transactivation of Activated Protein -1 and Nuclear Factor kappa B by Black Raspberry Extracts. Canc Res. 2002. 62: 6857-6863.
Chunfang, G., Gressner, G., Zoremba, M., Gressner, A.M., TGF expression in isolated and cultured rat hepatocytes. J Cell Phys. 1996. 167: 394-405.
Chung YW, Jeong DW, Won JY, Choi EJ, Choi YH, Kim IY.H(2)O(2)-induced AP-1 activation and its effect on p21(WAF1/CIP1)
-mediated G2/M arrest in a p53-deficient human lung cancer cell. Bio Biop Res Comm. 2002. 293:
1248-1253.
Clemens DL, Forman A, Jerrells TR, Sorrell MF, Tuma DJ. Relationship between acetaldehyde levels and cell survival in ethanol-metabolizing hepatoma cells. Hepatol. 2002. 35: 1196-1204.
Colburn N. Transgenic mice demonstrate AP-1 (activator protein-1) transactivation is required for tumor promotion.
Proc Natl Acad Sci U S A. 1999. 96: 9827-9832.
Dharwan. A, Young MR, Colburn NH. The role of AP-1, NF-kappaB and ROS/NOS in skin carcinogenesis: the JB6 model is predictive.Mol Cell Bio. 2002. 20: 185-193.
Dong Z, Cmarik JL, Wendel EJ, Colburn NH. Differential transformation efficiency but not AP-1 induction under anchorage-dependent and -independent conditions.Carcinog. 1994. 15: 1001-1004.
Dong, W., Simeonova, P.P., Gallucci R. Cytokine expression in hepatocytes: role of oxidant stress. J. Interf Cyto Res.
1998a. 18: 629-638.
Dong, W., Simeonova, P.P., Gallucci, R., et al.,, Toxic metals stimulate inflammatory cytokines in hepatocytes through oxidative stress mechanisms. Tox Appl Pharmacol. 1998b. 151: 359-366.
Eric J. Thompson, Jacalyn MacGowan, Matthew R. Young, Nancy Colburn, and G. Tim Bowden. A Dominant Negative c-jun Specifically Blocks Okadaic Acid-induced Skin Tumor Promotion. Canc Res. 2002. 62: 3044-3047.
Friedman, S. L. Molecular regulation of hepatic fibrosis, an integrated cellularresponse to tissue injury. J Biol Chem.
2000 . 275: 2247-2250.
Fukuda K, Hibiya Y, Mutoh M, Koshiji M, Akao S, Fujiwara H. Inhibition of activator protein 1 activity by berberine in human hepatoma cells. Planta Med. 1999. 381-383.
Gao, C., Gressner, G., Zoremba, M., Gressner, A.M. Transforming growth factor-ß expression in isolated andcultured rat hepatocyte. J. Cell Physiol. 1996. 167: 394-405.
Gong, W., Pecci, A., Roth, S., Lahme, B., Beato, M. and Gressner, A. M. Transformation-dependent susceptibility of rat hepatic stellate cells to apoptosisinduced by soluble Fas ligand. Hepatol. 1998. 28: 492-502.
Guangming Liu, Ann Bode, Wei-Ya Ma, Shengmin Sang, Chi-Tang Ho, and Zigang Dong.Two Novel Glycosides from the fruits of Morinda Citrifolia (Noni) inhibit AP-1transactivation and tell transformation in the mouse epidermal cell line. Canc Res. 2001. 61: 5749-5756.
Gukovskaya AS, Mouria M, Gukovsky I, Reyes CN, Kasho VN, Faller LD, Pandol SJ. Ethanol metabolism and transcription factor activation in pancreatic acinar cells in rats. Gastroenterol. 2002. 122: 106-118.
Gutierrez-Ruiz MC, Quiroz SC, Souza V, Bucio L, Hernandez E, Olivares IP, Llorente L, Vargas-Vorackova F,
Kershenobich D. Cytokines, growth factors, and oxidative stress in HepG2 cells treated with ethanol, acetaldehyde, and LPS. Toxicol. 1999. 134: 197-207.
H, Nishino H. Anti-tumor-promoting effects of glycoglycerolipid analogues on two-stage mouseskin carcinogenesis.
Canc Lett. 2000. 161: 201-205.
Hamasaki K, Nakata K, Eguchi K. Aspirin and NS-398 inhibit hepatocyte growth factor-induced invasiveness of human hepatoma cells.Hepatol. 2002. 35: 1117-1124.
Han, Y., Meng, T., Murray, N.R., Fields, A.P., Brasier, A.R.,. Interleukin 1 induced nuclear factor-kappa B Ikappa- B-alpha auto-regulatory feedback loop in hepatocytes. A role for protein kinase c-alpha in post-transcriptional regulatoryof I-kappa B-alpha resynthesis. J Biol Chem. 1999. 274: 939-947.
Hidekazu Tsukamoto and Shelly C. Lu Current concepts in the pathogenesis of alcoholic liver injury. FAEBS J 2001. 15:
1335-1349.
Huang C, Schmid PC, Ma WY, Schmid HH, Dong Z. Phosphatidylinositol-3 kinase is necessary for
12-O-tetradecanoylphorbol-13-acetate-induced cell transformation and activatedprotein 1 activation. J Biol Chem.
1997. 272: 4187-4194.
Huang ZZ, Chen C, Zeng Z, Yang H, Oh J, Chen L, Lu SC. Mechanism and significance of increased glutathione level in human hepatocellular carcinoma and liver regeneration. FASEB J. 2001. 15: 19-21.
Hwang JM, Wang CJ, Chou FP, Tseng TH, Hsieh YS, Lin WL, Chu CY. Inhibitory effect of berberine on tert-butyl hydroperoxide-induced oxidative damage in rat liver. Arch Toxicol. 2002. 76: 664-670.
Iizuka N, Miyamoto K, Hazama S, Yoshino S, Yoshimura K, Okita K, Fukumoto T, Yamamoto S, Tangoku A, Oka M.
Anticachectic effects of Coptidis rhizoma, an anti-iNF-lammatory herb, on esophageal cancer cells that produce interleukin 6. Cancer Lett. 2000. 158: 35-41.
Ishikawa T, Nakatsuru Y, Zarkovic M, Shamsuddin AM. Inhibition of skin cancer by IP6 in vivo: initiation-promotion model. Antican Res. 1999. 19: 3749-3752.
J, Fernandez-Checa JC. Enhanced DNA binding and activation of transcription factors NF-kappa B and AP-1 by acetaldehyde in HEPG2 cells. J Biol Chem. 2000. 275: 14684-14690.
Janbaz KH, Gilani AH. Studies on preventive and curative effects of berberine on chemical-induced hepatotoxicity in rodents. Fito. 2000. 71: 25-33.
Jirtle, R.L., Hankins, G.R., Reisenbichler, H., Boyer, J. Regulation of mannose 6-phosphate:insulin -like factor-II receptors and transforming growth factor beta during promotion with phenobarbital. Carcinog. 1994. 15: 1473-1478.
Jokelainen K, Thomas P, Lindros K, Nanji AA. Acetaldehyde inhibits NF-kappaB activation through IkappaBalpha preservation in rat Kupffer cells. Bio Biop Res Comm. 1998. 253: 834-836.
Juan Roma´n, Ame´rica Gime´nez, Jose´ Maria Lluis, Marta Gasso´ , Mireia Rubio, Joan Caballeria,Albert Pare´s, Joan Rode´s, and Jose´ C. Ferna´ndez-Checa Enhanced dna binding and activation of transcription factors NF-?B and AP-1 by acetaldehyde in HepG2 cells. J Bio Chem 2000. 275: 14684-14690.
Kang BY, Chung SW, Cho D, Kim TS. Involvement of p38 mitogen-activated protein kinase in the induction of
interleukin-12 p40 production in mouse macrophages by berberine, a benzodioxoloquinolizine alkaloid. Bio Pharm.
2002. 63: 1901-1910.
Kao, Y. H., Hiipakka, R. A. and Liao, S. Modulation of endocrine systems andfood intake by green tea epigallocatechin gallate. Endocrinol. 2000. 141: 980-987.
Kato, J., Mogi, Y., Kohgo, Y., Takimoto, R., Kobune, M.,Hisai, H., Nakamura, T., Takada, K., Niitsu, Y.,. Suppresive effect of ethanol on the expression of hepatic asialoglycoprotein receptors augmented by interleukin 1 beta, interleukin 6 and tumor necrosis factor-alpha. J Gastroenterol. 1998. 36: 855-859.
Kershenobich D. Metadoxine prevents damage produced by ethanol and acetaldehyde in hepatocyte and hepatic stella te cells in culture. Pharmacol Res. 2001. 44: 431-436.
Khoruts, A., Stanke, L., McClain, C.F., Logan, G., Allen, J.I. Circulating tumor necrosis factor, interleukin-1 and interleukin-6 concentrations in chronic alcoholic patients. Hepatol . 1991. 13: 267-276.
Kim SA, Kwon Y, Kim JH, Muller MT, Chung IK. Induction of topoisomerase II-mediated DNA cleavage by a protoberberine alkaloid, berberrubine. Biochem J. 1998. 37: 16316-16324.
Kim WH, Hong F, Jaruga B, Hu Z, Fan S, Liang TJ, Gao B. Lindros KO, Jokelainen K, Nanji AA. Lands, W.E.M.,.
Cellular signals in alcohol induced liver injury. Alco Clin Exp Res. 1995. 19: 928-938.
Kuo CL, Chou CC, Yung BY. Berberine complexes with DNA in the berberine-induced apoptosis in human leukemic HL-60 cells. Canc Lett. 1995. 93: 193-200.
Lee, K. S., Buck, M., Houglum, K. and Chojkier, M. Activation of hepatic stellate cells by TGF-a and collagen type I is mediated by oxidative stress through c-myb expression. J Clin Invest. 1995. 96: 2461-2468.
Liu G, Bibus DM, Bode AM, Ma WY, Holman RT, Dong Z. Omega-3 but not omega-6 fatty acids inhibit AP-1 activity and cell transformation in JB6 cells. Proc Natl Acad Sci U S A. 2001. 98: 7510-7515.
Li XK, Motwani M, Tong W, Bornmann W, Schwartz GK. Huanglian, A chinese herbal extract, inhibits cell growth by suppressing the expression of cyclin B1 and inhibiting CDC2 kinase activity in human cancer cells. Mol Pharmacol.
2000. 58: 1287-1293.
Lin JG, Chung JG, Wu LT, Chen GW, Chang HL, Wang TF. Effects of berberine on arylamine N-acetyltransferase activity in human colon tumor cells. Am J Chin Med. 1999. 27: 265-275.
Liu P, Kimmoun E, Legrand A, Sauvanet A, Degott C, Lardeux B, Bernuau D. Activation of NF-kappa B, AP-1 and
Luster, M.I., Germolec, D.R., Yoshida, I., Kayama, F., Thompson, M.,. Endotoxin-induced cytokine gene expression and excretion in the liver. Hepatol. 1994. 19: 7509-7511.
Masamune A, Kikuta K, Satoh M, Satoh A, Shimo segawa T. Alcohol activates activator protein -1 and mitogen-activated protein kinases in rat pancreatic stellate cells. J Pharm Exp Ther. 2002. 33: 36-42.
Masamune A, Sakai Y, Kikuta K, Satoh M, Satoh A, Shimosegawa T. Activated rat pancreatic stellate cells express intercellular adhesion molecule-1 (ICAM-1) in vitro. Panc. 25: 2002. 350-355.
Michael D. Wheeler and Ronald G. Thurman. Up-regulation of cd14 in liver due to acute ethanol involves oxidant-dependent AP-1 pathway. J Bio chem. 2003. 278: 664-670.
Mitani N, Murakami K, Yamaura T, Ikeda T, Saiki I. Inhibitory effect of berberine on the mediastinal lymphonode metastasis produced by orthotopic implantation of Lewis lung carcinoma. Canc Lett. 2001. 165: 35-42.
MR, Chung IK. Down-regulation of DNA topois omerase II alpha in human colorectal carcinoma cells resistant to a protoberberine alkaloid, berberrubine. Mol Pharm. 2002. 61: 879-882.
Murakami A, Nakamura Y, Torikai K, Tanaka T, Koshiba T, Koshimizu K, Kuwahara S, Takahashi Y, Ogawa K, Yano M, Tokuda H, Nishino H, Mimaki Y, Sashida. Inhibitors of both nuclear factor-kappaB and activator protein-1 activation lock the neoplastic transformation response. Canc Res. 1997. 57: 3569-3576.
Nanyue Chen, Masaaki Nomura, Qing-Bai She, Wei-Ya Ma, Ann M. Bode, Linan Wang, Richard A. Flavell, and Zigang Dong. Suppression of Skin Tumorigenesis in c-Jun NH2-Terminal Kinase-2-Deficient Mice. Canc Res 2001. 61:
3908-3912.
Neuman, M.G., Shear, N.H., Bellentani, S., Tiribelli, C., Role of cytokines in ethanol-induced cytotoxicity in vitro in HepG2 cells. Gastrol. 1998. 115: 157-166.
Niemela O. Distribution of ethanol-induced protein adducts in vivo: relationship to tissue injury. Free Radic Biol Med.
2001. 31: 954-960.
Niemela O, Parkkila S, Bradford B, Iimuro Y, Pasanen M, Thurman RG. Effect of Kupffer cell inactivation on ethanol-induced protein adducts in the liver. Free Radic Biol Med. 2002. 32: 1533-1538.
Nijhara R, Jana SS, Goswami SK, Rana A, Majumdar SS, Kumar V, Sarkar DP. Sustained activation of
mitogen-activated protein kinases and activator protein1 by the hepatitis B virus X protein in mouse hepatocytes in
Nijhara R, Jana SS, Goswami SK, Kumar V, Sarkar DP. An internal segment (residues 58-119) of the hepatitis B virus X protein issufficient to activate MAP kinase pathways in mouse liver. FEBS Lett. 2001. 504: 59-64.
Nilsson M, Ford J, Bohm S, Toftgard R. Characterization of a nuclear factor that binds juxtaposed with ATF3/Jun on a composite response element specifically mediating induced transcription inresponse to an epidermal growth factor/Ras/Raf signaling pathway.Cell Grow Diff. 1997. 8: 913-920.
Oberhammer, F., Nagy, P., Tiefenbacher, R., Fro¨ schl, G., Bouzahzah, B., Thorgeirsson, S.S., Carr, B. The antiandrogen cyproterone acetate induces synthesis of TGF -ß in the parenchymal cells of the liver accompanied by and enhanced sensitivity to undergo apoptosis and necrosis without inflammation. Hepatol. 1996. 23: 329-337.
Olivares, I.P., Bucio, L., Souza, V., Ca´rabez, A., Gutie´rrez- Ruiz, M.C. Comparative study of the damage produced by acute ethanol and acetaldehyde treatment in a human fetal hepatic cell line. Toxicol. 120: 1997.
Pennington HL, Hall PM, Wilce PA, Worrall S. Ethanol feeding enhances inflammatory cytokine expression in lipopolysaccharide-induced hepatitis.J Gastroenterol Hepatol.1997. 12: 305-313.
Pinkel D. Cancer cells, chemotherapy and gene clusters. Nat Genet. 2000. 24: 208-209.
Rice-Evans, C. Implications of the mechanisms of action of tea polyphenols as antioxidants in vitro for chemoprevention in humans. Proc Soc Exp Biol Med. 1999. 220: 262-266.
Rice-Evans, C. Implications of the mechanisms of action of tea polyphenols as antioxidants in vitro for chemoprevention in humans. Proc Soc Exp Biol Med. 1999. 220: 262-266.