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http://dx.doi.org/10.6116/kjh.2013.28.4.49.

Anti-fibrotic Effect of Mori Folium Extract in Hepatic Stellate Cells  

Byun, Sung Hui (College of Korean Medicine, Daegu Haany University)
Park, Sang Mi (College of Korean Medicine, Daegu Haany University)
Kim, Sang Chan (College of Korean Medicine, Daegu Haany University)
Cho, Il Je (College of Korean Medicine, Daegu Haany University)
Publication Information
The Korea Journal of Herbology / v.28, no.4, 2013 , pp. 49-55 More about this Journal
Abstract
Objectives : Mori Folium was popularly used as one of the traditional medicinal herbs. Although M. Folium has been cultivated for rearing silkworm historically, it's use has been expanded as natural therapeutic agent for the treatment of filariasis, diabetes and dropsy in East Asia. However, little has been known about the effect of M. Folium on liver fibrosis. Therefore, we would like to explore an anti-fibrogenic potential of M. Folium extract (MFE) using immortalized human hepatic stellate cell line, LX-2 cells. Methods : We examined the effects of MFE on the transforming growth factor ${\beta}1$ ($TGF{\beta}1$)-induced liver fibrosis in LX-2 cells. Cell viability, Smad binding element-driven luciferase activity, phosphorylations level of Smad 2/3, and expression level of $TGF{\beta}1$-dependent target genes were monitored in the MFE-treated LX-2 cells. Results : Up to 30 ${\mu}g/ml$ MFE treatment did not show any possible toxic effect in LX-2 cells. MFE inhibited $TGF{\beta}1$-inducible Smad binding element-driven luciferase activity and decreased the $TGF{\beta}1$-inducible phosphorylations of Smad 2 and Smad 3 in hepatic stellate cell in a dose dependent manner. Furthermore, increases of plasminogen activator inhibitor type 1, $TGF{\beta}1$ and matrix metalloproteinases 2 genes by $TGF{\beta}1$ were also attenuated by MFE treatment. Conclusions : These findings suggested that MFE would be used as a potential therapeutic agent for the treatment liver fibrosis, which might be mediated by the inhibition of $TGF{\beta}1$-inducible Smad 2/3 transactivation and target genes expression.
Keywords
Mori Folium; LX-2 cells; Liver fibrosis; $TGF{\beta}1$; Smad;
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1 Bataller B, Brenner DA. Hepatic Fibrosis. In : Arias IM, Alter HJ, Boyer JL, Cohen DE, Fausto N, Shafritz DA, Wolkoff AW, eds. The liver biology and pathobiology. 5th ed. Oxford : Wiley-Blackwell. 2009 : 433-52.
2 Lee JS, Kim JH. The role of activated hepatic stellate cells in liver fibrosis, portal hypertension and cancer angiogenesis. Korean J Hepatol. 2007 ; 13 : 309-19.   과학기술학회마을   DOI   ScienceOn
3 Sanderson N, Factor V, Nagy P, Kopp J, Kondaiah P, Wakefield L, Roberts AB, Sporn MB, Thorgeirsson SS. Hepatic expression of mature transforming growth factor b1 in transgenic mice results in multiple tissue lesions. Proc Natl Acad Sci USA. 1995 ; 92 : 2572-6.   DOI   ScienceOn
4 Liu C, Gaca MD, Swenson E, Vellucci VF, Reiss M, Wells RG. Smads 2 and 3 are differentially activated by transforming growth factor-$\beta$ (TGF-$\beta$) in quiescent and activated hepatic stellate cells. Constitutive nuclear localization of Smads in activated cells is TGF-$\beta$ independent. J Biol Chem. 2003 ; 278 : 11721-8.   DOI   ScienceOn
5 Jablonska E, Markart P, Zakrzewicz D, Preissner KT, Wygrecka M. Transforming growth factor-$\beta1$ induces expression of human coagulation factor XII via Smad3 and JNK signaling pathways in human lung fibroblasts. J Biol Chem. 2010 ; 285 : 11638-51.   DOI   ScienceOn
6 Dennler S, Itoh S, Vivien D, ten Dijke P, Huet S, Gauthier JM. Direct binding of Smad3 and Smad4 to critical TGF$\beta$-inducible elements in the promoter of human plasminogen activator inhibitortype 1 gene. EMBO J. 1998 ; 17 : 3091-100.   DOI   ScienceOn
7 Cho IJ, Kim SH, Kim SG. Inhibition of $TGF\beta1$-mediated PAI-1 induction by oltipraz through selective interruption of Smad 3 activation. Cytokines. 2006 ; 35 : 284-94.   DOI   ScienceOn
8 Cho IJ, Kim YW, Han CY, Kim EH, Anderson RA, Lee YS, Lee CH, Hwang SJ, Kim SG. E-cadherin antagonizes transforming growth factor $\beta1$ gene induction in hepatic stellate cells by inhibiting RhoA-dependent Smad3 phosphorylation. Hepatology. 2010 ; 52 : 2053-64.   DOI   ScienceOn
9 The Korean Medical Dictionary Compliation Committee. The Korean Medical Dictionary. Seoul : Jungdam. 1998 : 727.
10 Park SM, Byun SH, Kim YW, Cho IJ, Kim SC. Inhibitory effect of Mori Folium ethanol extract on pro-inflammatory mediator in lipopolysaccharide-activated RAW 264.7 cells. Kor J Herbology. 2012 ; 27 : 31-8.   과학기술학회마을   DOI   ScienceOn
11 Jang MH, Kim H, Shin MC, Lim BV, Lee TH, Jung SB, Kim CJ, Kim EH. Administration of Folium Mori extract decreases nitric oxide synthase expression in the hypothalamus of streptozotocininduced diabetic rats. Jpn J Pharmacol. 2002 ; 90 : 189-92.   DOI   ScienceOn
12 Sugimoto M, Arai H, Tamura Y, Murayama T, Khaengkhan P, Nishio T, Ono K, Ariyasu H, Akamizu T, Ueda Y, Kita T, Harada S, Kamei K, Yokode M. Mulberry leaf ameliorates the expression profile of adipocytokines by inhibiting oxidative stress in white adipose tissue in b/db mice. Atherosclerosis. 2009 ; 204 : 388–94.   DOI   ScienceOn
13 Harauma A, Murayama T, Ikeyama K, Sano H, Arai H, Takano R, Kita T, Hara S, Kamei K, Yokode M. Mulberry leaf powder prevents atherosclerosis in apolipoprotein E-deficient mice. Biochem Biophys Res Commun. 2007 ; 358 : 751-6.   DOI   ScienceOn
14 Sattayasai J, Tiamkao S, Puapairoj P. Biphasic effects of Morus alba leaves green tea extract on mice in chronic forced swimming model. Phytother Res. 2008 ; 22 : 487-92.   DOI   ScienceOn
15 Dooley S, Delvoux B, Streckert M, Bonzel L, Stopa M, ten Dijke P, Gressner AM. Transforming growth factor beta signal transduction in hepatic stellate cells via Smad2/3 phosphorylation, a pathway that is abrogated during in vitro progression to myofibroblasts. TGF beta signal transduction during transdifferentiation of hepatic stellate cells. FEBS Lett. 2001 ; 502 : 4-10.   DOI   ScienceOn
16 Piek E, Ju WJ, Heyer J, Escalante-Alcalde D, Stewart CL, Weinstein M, Deng C, Kucherlapati R, Bottinger EP, Roberts AB. Functional characterization of transforming growth factor beta signaling in Smad2- and Smad3-deficient fibroblasts. J Biol Chem. 2001 ; 276 : 19945-53.   DOI   ScienceOn
17 Massague J, Chen YG. Controlling TGF-beta signaling. Genes Dev. 2000 ; 14 : 627-44.
18 Dooley S, Hamzavi J, Breitkopf K, Wiercinska E, Said HM, Lorenzen J, Ten Dijke P, Gressner AM. Smad7 prevents activation of hepatic stellate cells and liver fibrosis in rats. Gastroenterology. 2003 ; 125 : 178-91.   DOI   ScienceOn
19 Liu X, Wang W, Hu H, Tang N, Zhang C, Liang W, Wang M. Smad3 specific inhibitor, naringenin, decreases the expression of extracellular matrix induced by TGF-beta1 in cultured rat hepatic stellate cells. Pharm Res. 2006 ; 23 : 82-9.   DOI   ScienceOn
20 Kang KW, Kim YG, Cho MK, Bae SK, Kim CW, Lee MG, Kim SG. Oltipraz regenerates cirrhotic liver through CCAAT/enhancer binding protein-mediated stellate cell inactivation. FASEB J. 2002 ; 16 : 1988–90.
21 Inagaki Y, Mamura M, Kanamaru Y, Greenwel P, Nemoto T, Takehara K, Ten Dijke P, Nakao A. Constitutive phosphorylation and nuclear localization of Smad 3 are correlated with increased collagen gene transcription in activated hepatic stellate cells. J Cell Physiol. 2001 ; 187 : 117-23.   DOI
22 Doi K, Kojima T, Makino M, Kimura Y, Fujimoto Y. Studies on the constituents of the leaves of Morus alba L. Chem Pharm Bull (Tokyo). 2001 ; 49 : 151-3.   DOI   ScienceOn
23 Hernandez-Ortega LD, Alcantar-Diaz BE, Ruiz-Corro LA, Sandoval-Rodriguez A, Bueno-Topete M, Armendariz-Borunda J, Salazar-Montes AM. Quercetin improves hepatic fibrosis reducing hepatic stellate cells and regulating pro-fibrogenic/anti-fibrogenic molecules balance. J Gastroenterol Hepatol. 2012 ; 27 : 1865-72.   DOI   ScienceOn
24 Marcolin E, San-Miguel B, Vallejo D, Tieppo J, Marroni N, Gonzalez-Gallego J, Tunon MJ. Quercetin treatment ameliorates inflammation and fibrosis in mice with nonalcoholic steatohepatitis. J Nutr. 2012 ; 142 : 1821-8.   DOI
25 Kanter M. Protective effect of quercetin on liver damage induced by biliary obstruction in rats. J Mol Histol. 2010 ; 41 : 395-402.   DOI
26 Lee HS, Jung KH, Park IS, Kwon SW, Lee DH, Hong SS. Protective effect of morin on dimethylnitrosamine-induced hepatic fibrosis in rats. Dig Dis Sci. 2009 ; 54 : 782-8.   DOI   ScienceOn