Abstract
Liver fibrosis is a pathological manifestation induced by chronic liver injury and may cause cirrhosis and liver cancer with the chronic progression of fibrosis. During the onset and progression of liver fibrosis, the activation of hepatic stellate cells (HSCs) is the core mechanism for the secretion of many extracellular matrices to induce fibrosis. Lignans are reportedly the main effective components of Schisandra chinensis with good anti-fibrosis effects. In this study, we compared the inhibiting effects of the seven lignan components from S. chinensis on HSC activation. We found that the seven lignans inhibited the activation of human HSCs (LX-2) in various degrees. Among all lignans, schisanhenol showed the best effect in inhibiting the activation of LX-2 with a dose–effect relationship. Sal also inhibited the phosphorylations of Smad1, Smad2, Smad3, extracellular regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK), p38, and nuclear transcription factor-κB (NF-κB), as well as downregulated Smad4. All these findings suggested that schisanhenol may ameliorate liver fibrosis by inhibiting the transforming growth factor β (TGF-β)/Smad and mitogen-activated protein kinase (MAPK) signaling pathways. Remarkably, schisanhenol may be a potential anti-liver fibrosis drug and warrants further research.
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References
Wallace K, Burt A, Wright M (2008) Liver fibrosis. Biochem J 411:1–18. https://doi.org/10.1042/BJ20071570
Friedrich-Rust M, Wunder K, Kriener S, Sotoudeh F, Richter S, Bojunga J, Herrmann E, Poynard T, Dietrich CF, Vermehren J, Zeuzem S, Sarrazin C (2009) Liver fibrosis in viral hepatitis: noninvasive assessment with acoustic radiation force impulse imaging versus transient elastography. Radiology 252:595–604. https://doi.org/10.1148/radiol.2523081928
Amarapurka DN, Amarapurkar AD, Patel ND, Agal S, Baigal R, Gupte P, Pramanik S (2006) Nonalcoholic steatohepatitis (NASH) with diabetes: predictors of liver fibrosis. Ann Hepatol 5:30–33
Nahon P, Kettaneh A, Tengher-Barna I, Ziol M, de Lédinghen V, Douvin C, Marcellin P, Ganne-Carrié N, Trinchet JC, Beaugrand M (2008) Assessment of liver fibrosis using transient elastography in patients with alcoholic liver disease. J Hepatol 49:1062–1068. https://doi.org/10.1016/j.jhep.2008.08.011
Sherman IA, Pappas SC, Fisher MM (1990) Hepatic microvascular changes associated with development of liver fibrosis and cirrhosis. Am J Physiol 258:460–465. https://doi.org/10.1111/j.1748-1716.1990.tb08843.x
Affo S, Yu LX, Schwabe RF (2017) The role of cancer-associated fibroblasts and fibrosisin liver cancer. Annu Rev Pathol 12:153–186. https://doi.org/10.1146/annurev-pathol-052016-100322
Chen RJ, Wu HH, Wang YJ (2015) Strategies to prevent and reverse liver fibrosis in humans and laboratory animals. Arch Toxikol 89:1727–1750. https://doi.org/10.1007/s00204-015-1525-6
Liu X, Hu H, Yin JQ (2010) Therapeutic strategies against TGF-β signaling pathway in hepatic fibrosis. Liver Int 26:8–22. https://doi.org/10.1111/j.1478-3231.2005.01192.x
Friedman SL (2008) Hepatic stellate cells: Protean, multifunctional, and enigmatic cells of the liver. Physiol Rev 88:125–172. https://doi.org/10.1152/physrev.00013.2007
Sato M, Suzuki S, Senoo H (2003) Hepatic stellate cells: unique characteristics in cell biology and phenotype. Cell Struct Funct 28:105–112. https://doi.org/10.1247/csf.28.105
Senoo H (2004) Structure and function of hepatic stellate cells. Med Electron Microsc 37:3–15. https://doi.org/10.1007/s00795-003-0230-3
Xu F, Liu C, Zhou D, Zhang L (2016) TGF/Smad pathways and its regulation in hepatic fibrosis. J Histochem Cytochem 64:157–167. https://doi.org/10.1369/0022155415627681
Dewidar B, Soukupova J, Fabregat I, Dooley S (2015) TGF-β in hepatic stellate cell activation and liver fibrogenesis: updated. Curr Pathobiol Rep 3:291–305. https://doi.org/10.1007/s40139-015-0089-8
Kitamura Y, Ninomiya H (2010) Smad expression of hepatic stellate cells in liver cirrhosis in vivo and hepatic stellate cell line in vitro. Pathol Int 53:18–26. https://doi.org/10.1046/j.1440-1827.2003.01431.x
Zhou J, Zhong DW, Wang QW, Miao XY, Xu XD (2010) Paclitaxel ameliorates fibrosis in hepatic stellate cells via inhibition of TGF-β/Smad activity. World J Gastroenterol 16:3330–3334. https://doi.org/10.1140/epjc/s2005-02407-6
Lee JH, Jang EJ, Seo HL, Ku SK, Lee JR, Shin SS, Park SD, Kim SC, Kim YW (2014) Sauchinone attenuates liver fibrosis and hepatic stellate cell activation through TGF-β/Smad signaling pathway. Chem Biol Interact 224:58–67. https://doi.org/10.1016/j.cbi.2014.10.005
Takahashi M, Matsui A, Inao M, Mochida S, Fujiwara K (2003) ERK/MAPK-dependent PI3K/Akt phosphorylation through VEGFR-1 after VEGF stimulation in activated hepatic stellate cells. Hepatol Res 26:232–236. https://doi.org/10.1016/s1386-6346(03)00112-8
Thirunavukkarasu C, Watkins SC, Gandhi CR (2010) Mechanisms of endotoxin-induced NO, IL-6, and TNF-α production in activated rat hepatic stellate cells: role of p38 MAPK. Hepatology 44:389–398. https://doi.org/10.1002/hep.21254
Hong IH, Park SJ, Goo MJ, Lee HR, Park JK, Ki MR, Kim SH, Lee EM, Kim AY, Jeong KS (2014) JNK1 and JNK2 regulate α-SMA in hepatic stellate cells during CCl4-induced fibrosis in the rat liver. Pathol Int 63:483–491. https://doi.org/10.1111/pin.12094
Deng X, Chen X, Cheng W, Shen Z, Bi K (2008) Simultaneous LC–MS quantification of 15 lignans in Schisandra chinensis (Turcz.) Baill. Fruit Chromatographia 67:559–566. https://doi.org/10.1365/s10337-008-0589-3
Li Y, Chen J, Li F, Qu S, Yu X, Sui D (2014) Protective effects of extract fructus Schisandrae Chinensis on hepatic injury in experimental hepatic fibrosis rats. J Jilin Univ 3:285–288. https://doi.org/10.13481/j.1671-587x.20140215
Wang Y, Qi H, Hu Y, Wang S (2008) Inhibitory effect of Schisandrol A on KC mediated hepatic fibrosis. J Fourth Mil Med Univ 29:816–818. https://doi.org/10.3321/j.issn:1000-2790.2008.09.014
Cao Y, Xia YZ, Chen J, Chen X (2016) Anti-fibrotic effect of Schizandrin A on human hepatic stellate cells. Chin J Clin Pharmacol 21:878–883
Chen Q, Zhang H, Cao Y, Li Y, Sun S, Zhang J, Zhang G (2017) Schisandrin B attenuates CCl4-induced liver fibrosis in rats by regulation of Nrf2-ARE and TGF-β/Smad signaling pathways. Drug Des Dev Ther 11:2179–2191. https://doi.org/10.2147/DDDT.S137507
Inman GJ, Nicolás FJ, Callahan JF, Harling JD, Gaster LM, Reith AD, Laping NJ, Hill CS (2002) SB-431542 is a potent and specific inhibitor of transforming growth factor-beta superfamily type I activin receptor-like kinase (ALK) receptors ALK4, ALK5, and ALK7. Mol Pharmacol 62:65–74. https://doi.org/10.1124/mol.62.1.65
Alessi DR, Cuenda A, Cohen P, Dudley DT, Saltiel AR (1995) PD98059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and in vivo. J Biol Chem 270:27489–27494. https://doi.org/10.1074/jbc.270.46.27489
Wang Y, Ji HX, Xing SH, Pei DS, Guan QH (2007) SP600125, a selective JNK inhibitor, protects ischemic renal injury via suppressing the extrinsic pathways of apoptosis. Life Sci 80:2067–2075. https://doi.org/10.1016/j.lfs.2007.03.010
Barancík M, Bohácová V, Kvackajová J, Hudecová S, Krizanová O, Breier A (2001) SB203580, a specific inhibitor of p38-MAPK pathway, is a new reversal agent of P-glycoprotein-mediated multidrug resistance. Eur J Pharm Sci 14:29–36. https://doi.org/10.1016/S0928-0987(01)00139-7
Duan Y, Ma X, Zou W, Wang C, Bahbahan IS, Ahuja TP, Tolstikov V, Zern MA (2010) Differentiation and characterization of metabolically functioning hepatocytes from human embryonic stem cells. Stem Cells 28:674–686. https://doi.org/10.1002/stem.704
Zaret KS, Grompe M (2008) Generation and regeneration of cells of the liver and pancreas. Science 322:1490–1494. https://doi.org/10.1126/science.1161431
Wang QL, Tao YY, Yuan JL, Shen L, Liu CH (2010) Salvianolic acid B prevents epithelial-to-mesenchymal transition through the TGF-β1 signal transduction pathway. BMC Cell Biol 11:31–46. https://doi.org/10.1186/1471-2121-11-31
Lin TJ, Liu GT, Pan Y (1992) Protective effect of Schisanhenol against oxygen radical induced mitochondrial toxicity on rat heart and liver. Biomed Environ Sci 5:57–64
Wang B, Fang X, Gao F, Hu Z, Li L (2017) Protective effect of Schisanhenol on Parkinson’s disease mice induced by oxotremorine. J Qiqihar Univ Med 38:1735–1737. https://doi.org/10.3969/j.issn.1002-1256.2017.15.001
Zhou SY, Deng ZR, Tan L, Wang L, Yang H (2014) Protection effect of Schisanhenol on learning and memory acquired disorder induced by Scopolamine in mice. Chin Pharm J 49:2088–2091. https://doi.org/10.11669/cpj.2014.23.008
Lin TJ, Liu GT, Pan Y, Liu Y, Xu GZ (1991) Protection by Schisanhenol against Adriamycin toxicity in rat heart mitochondria. Biochem Pharmacol 42:1805–1810. https://doi.org/10.1016/0006-2952(91)90519-B
Wang R, Yu XY, Guo ZY, Wang YJ, Wu Y, Yuan TF (2012) Inhibitory effects of Salvianolic acid B on CCl4-induced hepatic fibrosis through regulating NF-κB/IκBα signaling. J Ethnopharmacol 144:592–598. https://doi.org/10.1016/j.jep.2012.09.048
Kitade Y, Watanabe S, Masaki T, Nishiokaa M, Nishinob H (2002) Inhibition of liver fibrosis in LEC rats by a carotenoid, lycopene, or a herbal medicine, Sho-saiko-to. Hepatol Res 22:196–205. https://doi.org/10.1016/S1386-6346(01)00132-2
Harrison SA, Torgerson S, Hayashi P, Ward J, Schenker S (2003) Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis. Am J Gastroenterol 98:2485–2490. https://doi.org/10.1016/j.amjgastroenterol.2003.08.005
Puche JE, Saiman Y, Friedman SL (2013) Hepatic stellate cells and liver fibrosis. Compr Physiol 3:1473–1492. https://doi.org/10.1002/cphy.c120035
Gäbele E, Brenner DA, Rippe RA (2003) Liver fibrosis: signals leading to the amplification of the fibrogenic hepatic stellate cell. Front Biosci 8:d69–77. https://doi.org/10.2741/887
Schnabl B, Kweon YO, Frederick JP, Wang XF, Rippe RA, Brenner DA (2001) The role of Smad3 in mediating mouse hepatic stellate cell activation. Hepatology 34:89–100. https://doi.org/10.1053/jhep.2001.25349
Erin M, Izabela C, Andreea B, Faye H, Christine M, Peter TD, Maria T (2011) Endoglin promotes TGF-β/Smad1 signaling in scleroderma fibroblasts. J Cell Physiol 226:3340–3348. https://doi.org/10.1002/jcp.22690
Sashidhar SN, Andreea MB, Maria T (2011) CCN2 is required for the TGF-β induced activation of Smad1-Erk1/2 signaling network. PLoS ONE 6:e21911. https://doi.org/10.1371/journal.pone.0021911
Nakao A, Imamura T, Souchelnytskyi S, Kawabata M, Ishisaki A, Oeda E, Tamaki K, Hanai J, Heldin CH, Miyazono K, ten Dijke P (1997) TGF-β receptor-mediated signaling through Smad2, Smad3 and Smad4. EMBO J 16:5353–5362. https://doi.org/10.1093/emboj/16.17.5353
Karathanasi V, Tosios KI, Nikitakis NG, Piperi E, Koutlas I, Trimis G, Sklavounou A (2013) TGF-β1, Smad2/3, Smad1/5/8, and Smad4 signaling factors are expressed in ameloblastomas, adenomatoid odontogenic tumors, and calcifying cystic odontogenic tumors: an immunohistochemical study. J Oral Pathol Med 42:415–423. https://doi.org/10.1111/jop.12016
Hall MC, Young DA, Waters JG, Rowan AD, Chantry A, Edwards DR, Clark IM (2003) The comparative role of AP1 and Smad factors in the regulation of TIMP-1 and MMP-1 gene expression by TGF-β1. J Biol Chem 278:10304–10313. https://doi.org/10.1074/jbc.M212334200
Finnson KW, Parker WL, Chi Y, Hoemann CD, Goldring MB, Antoniou J, Philip A (2010) Endoglin differentially regulates TGF-β-induced Smad2/3 and Smad1/5 signalling and its expression correlates with extracellular matrix production and cellular differentiation state in human chondrocytes. Osteoarthr Cartilage 18:1518–1527. https://doi.org/10.1016/j.joca.2010.09.002
Lai CF, Chaudhary L, Fausto A, Halstead LR, Ory DS, Avioli LV, Cheng SL (2001) ERK is essential for growth, differentiation, integrin expression, and cell function in human osteoblastic cells. J Biol Chem 276:14443–14450. https://doi.org/10.1074/jbc.M010021200
Schramek H, Feifel E, Marschitz I, Golochtchapova N, Gstraunthaler G, Montesano R (2003) Loss of active MEK1-ERK1/2 restores epithelial phenotype and morphogenesis in transdifferentiated MDCK cells. Am J Physiol Cell Physiol 285:C652–661. https://doi.org/10.1152/ajpcell.00463.2002
Liu Y, Zhu H, Su Z, Sun C, Yin J, Yuan H, Sandoghchian S, Jiao Z, Wang S, Xu H (2012) IL-17 contributes to cardiac fibrosis following experimental autoimmune myocarditis by a PKCβ/ERK1/2/NF-κB-dependent signaling pathway. Int Immunol 24:605–612. https://doi.org/10.1093/intimm/dxs056
Lan R, Geng H, Polichnowski AJ, Singha PK, Saikumar P, McEwen DG, Griffin KA, Koesters R, Weinberg JM, Bidani AK, Kriz W, Venkatachalam MA (2012) PTEN loss defines a TGF-β-induced tubule phenotype of failed differentiation and JNK signaling during renal fibrosis. Am J Physiol Renal Physiol 302:F1210. https://doi.org/10.1152/ajprenal.00660.2011
Daoud G, Amyot M, Rassart E, Masse A, Simoneau L, Lafond J (2005) ERK1/2 and p38 regulate trophoblasts differentiation in human term placenta. J Physiol 566:409–423. https://doi.org/10.1113/jphysiol.2005.089326
Zavadil J, Cermak L, Soto-Nieves N, Böttinger EP (2004) Integration of TGF-β/Smad and Jagged1/Notch signaling in epithelial-to-mesenchymal transition. EMBO J 23:1155–1165. https://doi.org/10.1038/sj.emboj.7600069
Leong KG, Niessen K, Kulic I, Raouf A, Eaves C, Pollet I, Karsan A (2007) Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin. J Exp Med 204:2935–2948. https://doi.org/10.1084/jem.20071082
Kavian N, Servettaz A, Weill B, Batteux F (2012) New insights into the mechanism of Notch signaling in fibrosis. Open Rheumatol J 6:96–102. https://doi.org/10.2174/1874312901206010096
Huang Y, Li X, Wang Y, Wang H, Huang C, Li J (2014) Endoplasmic reticulum stress-induced hepatic stellate cell apoptosis through calcium-mediated JNK/p38 MAPK and Calpain/Caspase-12 pathways[J]. Mol Cell Biochem 394:1–12. https://doi.org/10.1007/s11010-014-2073-8
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This work is supported by National Natural Foundation of China (Grant No.81530101, No.81703681).
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He, X., Chen, J., Mu, Y. et al. The effects of inhibiting the activation of hepatic stellate cells by lignan components from the fruits of Schisandra chinensis and the mechanism of schisanhenol. J Nat Med 74, 513–524 (2020). https://doi.org/10.1007/s11418-020-01394-w
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DOI: https://doi.org/10.1007/s11418-020-01394-w