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1
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TGF-β signalling from cell membrane to nucleus through SMAD proteins
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Heldin, C.H.1
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Direct binding of Smad3 and Smad4 to critical TGF-β-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene
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This study identified the Smad binding sites (CAGA) in the promoter of the TGF-β target gene PAI-1
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• Dennler S, Itoh S, Vivien D, et al. (1998) Direct binding of Smad3 and Smad4 to critical TGF-β-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene. EMBO J 17:3091–3100. doi:10.1093/emboj/17.11.3091. This study identified the Smad binding sites (CAGA) in the promoter of the TGF-β target gene PAI-1
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Dennler, S.1
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Fine tuning and cross-talking of TGF-β signal by inhibitory Smads
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Park SH (2005) Fine tuning and cross-talking of TGF-β signal by inhibitory Smads. J Biochem Mol Biol 38:9–16
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Non-Smad TGF-β signals
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Moustakas, A.1
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Zhang YE (2009) Non-Smad pathways in TGF-β signaling. Cell Res 19:128–139. doi:10.1038/cr.2008.328
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Cell Res
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Zhang, Y.E.1
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7
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Liver fibrosis and repair: immune regulation of wound healing in a solid organ
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Pellicoro A, Ramachandran P, Iredale JP, Fallowfield JA (2014) Liver fibrosis and repair: immune regulation of wound healing in a solid organ. Nat Rev Immunol 14:181–194. doi:10.1038/nri3623
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Nat Rev Immunol
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Pellicoro, A.1
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9
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Anti-TGF-β strategies for the treatment of chronic liver disease
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Breitkopf K, Haas S, Wiercinska E et al (2005) Anti-TGF-β strategies for the treatment of chronic liver disease. Alcohol Clin Exp Res 29:121S–131S. doi:10.1097/01.alc.0000189284.98684.22
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Breitkopf, K.1
Haas, S.2
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10
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84866851052
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NADPH oxidase NOX4 mediates stellate cell activation and hepatocyte cell death during liver fibrosis development
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One of the first papers that demonstrate the role of NOX4 during liver fibrosis and TGF-β mediated apoptosis
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• Sancho P, Mainez J, Crosas-Molist E, et al. (2012) NADPH oxidase NOX4 mediates stellate cell activation and hepatocyte cell death during liver fibrosis development. PLoS One 7:1–14. doi:10.1371/journal.pone.0045285. One of the first papers that demonstrate the role of NOX4 during liver fibrosis and TGF-β mediated apoptosis
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Plos One
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Sancho, P.1
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11
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84862290446
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Liver fibrosis and hepatocyte apoptosis are attenuated by GKT137831, a novel NOX4/NOX1 inhibitor in vivo
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Jiang JX, Chen X, Serizawa N et al (2012) Liver fibrosis and hepatocyte apoptosis are attenuated by GKT137831, a novel NOX4/NOX1 inhibitor in vivo. Free Radic Biol Med 53:289–296. doi:10.1016/j.freeradbiomed.2012.05.007
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Jiang, J.X.1
Chen, X.2
Serizawa, N.3
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12
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84876928036
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A vitamin D receptor/SMAD genomic circuit gates hepatic fibrotic response
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This study demonstrates the ability of VDR to inhibit TGF-β effects on HSC activation and liver fibrosis by interacting with Smad3
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•• Ding N, Yu RT, Subramaniam N, et al. (2013) A vitamin D receptor/SMAD genomic circuit gates hepatic fibrotic response. Cell 153:601–613. doi:10.1016/j.cell.2013.03.028. This study demonstrates the ability of VDR to inhibit TGF-β effects on HSC activation and liver fibrosis by interacting with Smad3
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Cell
, vol.153
, pp. 601-613
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Ding, N.1
Yu, R.T.2
Subramaniam, N.3
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13
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84886921890
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Transforming growth factor-β-mediated connective tissue growth factor (CTGF) expression in hepatic stellate cells requires Stat3 signaling activation
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This work demonstrates Stat3 as important downstream signaling molecule to TGF-β/ALK5 in mediating CTGF expression
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• Liu Y, Liu H, Meyer C, et al. (2013) Transforming growth factor-β-mediated connective tissue growth factor (CTGF) expression in hepatic stellate cells requires Stat3 signaling activation. J Biol Chem 288:30708–19. doi:10.1074/jbc.M113.478685. This work demonstrates Stat3 as important downstream signaling molecule to TGF-β/ALK5 in mediating CTGF expression
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J Biol Chem
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Liu, Y.1
Liu, H.2
Meyer, C.3
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14
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84880165240
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Transforming growth factor-β induces expression of connective tissue growth factor in hepatic progenitor cells through Smad independent signaling
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This Study provides an evidence for the role of HPCs in liver fibrosis and suggests that the production of CTGF by TGF-β in HPCs is mediated by activated MAPK
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• Ding Z, Jin G, Liang H, et al. (2013) Transforming growth factor-β induces expression of connective tissue growth factor in hepatic progenitor cells through Smad independent signaling. Cell Signal 25:1981–92. doi:10.1016/j.cellsig.2013.05.027. This Study provides an evidence for the role of HPCs in liver fibrosis and suggests that the production of CTGF by TGF-β in HPCs is mediated by activated MAPK
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(2013)
Cell Signal
, vol.25
, pp. 1981-1992
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Ding, Z.1
Jin, G.2
Liang, H.3
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15
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84894875873
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Free cholesterol accumulation in hepatic stellate cells: Mechanism of liver fibrosis aggravation in nonalcoholic steatohepatitis in mice
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An elegant study demonstrating that free cholesterol in HSCs increases the availability of TLR4 and senstizes HSCs to TGF β action, thereby aggravating liver fibrosis in NASH
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•• Tomita K, Teratani T, Suzuki T, et al. (2013) Free cholesterol accumulation in hepatic stellate cells: Mechanism of liver fibrosis aggravation in nonalcoholic steatohepatitis in mice. Hepatology 59:154-69. doi:10.1002/hep.26604. An elegant study demonstrating that free cholesterol in HSCs increases the availability of TLR4 and senstizes HSCs to TGF β action, thereby aggravating liver fibrosis in NASH
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(2013)
Hepatology
, vol.59
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Tomita, K.1
Teratani, T.2
Suzuki, T.3
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16
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84902685435
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Acyl-CoA:Cholesterol acyltransferase 1 mediates liver fibrosis by regulating free cholesterol accumulation in hepatic stellate cells
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An interesting study illustrating Acyl-coA regulation as new therapeutic target to treat liver fibrosis
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•• Tomita K, Teratani T, Suzuki T, et al. (2014) Acyl-CoA:cholesterol acyltransferase 1 mediates liver fibrosis by regulating free cholesterol accumulation in hepatic stellate cells. J Hepatol 61:98–106. doi:10.1016/j.jhep.2014.03.018. An interesting study illustrating Acyl-coA regulation as new therapeutic target to treat liver fibrosis
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(2014)
J Hepatol
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, pp. 98-106
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Tomita, K.1
Teratani, T.2
Suzuki, T.3
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17
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84896754721
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Transcriptional repression of the transforming growth factor-β (TGF-β) pseudoreceptor BMP and activin membrane-bound inhibitor (BAMBI) by nuclear factor κB (NF-κB) p50 enhances TGF-β signaling in hepatic stellate cells
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Liu C, Chen X, Yang L et al (2014) Transcriptional repression of the transforming growth factor-β (TGF-β) pseudoreceptor BMP and activin membrane-bound inhibitor (BAMBI) by nuclear factor κB (NF-κB) p50 enhances TGF-β signaling in hepatic stellate cells. J Biol Chem 289:7082–7091. doi:10.1074/jbc.M113.543769
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J Biol Chem
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Liu, C.1
Chen, X.2
Yang, L.3
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18
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84875552564
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Up-regulation of RACK1 by TGF-β1 promotes hepatic fibrosis in mice
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Jia D, Duan F, Peng P et al (2013) Up-regulation of RACK1 by TGF-β1 promotes hepatic fibrosis in mice. PLoS ONE 8:e60115. doi:10.1371/journal.pone.0060115
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PLoS ONE
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Jia, D.1
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19
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RACK1-mediated translation control promotes liver fibrogenesis
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Liu M, Peng P, Wang J et al (2015) RACK1-mediated translation control promotes liver fibrogenesis. Biochem Biophys Res Commun 463:255–261. doi:10.1016/j.bbrc.2015.05.040
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Biochem Biophys Res Commun
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Liu, M.1
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20
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Effect of RhoA on transforming growth factor β1-induced rat hepatic stellate cell migration
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Li L, Wang J-Y, Yang C-Q, Jiang W (2012) Effect of RhoA on transforming growth factor β1-induced rat hepatic stellate cell migration. Liver Int 32:1093–1102. doi:10.1111/j.1478-3231.2012.02809.x
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Li, L.1
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21
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77954976056
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Neuropilin-1 promotes cirrhosis of the rodent and human liver by enhancing PDGF/TGF-β signaling in hepatic stellate cells
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This study reports participation of Neuropilin-1, the axonal guidance molecule, in liver cirrhosis via enhancing PDGF/TGF-β signaling in HSCs
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•• Cao S, Yaqoob U, Das A, et al. (2010) Neuropilin-1 promotes cirrhosis of the rodent and human liver by enhancing PDGF/TGF-β signaling in hepatic stellate cells. J Clin Invest 120:2379–2394. doi:10.1172/JCI41203. This study reports participation of Neuropilin-1, the axonal guidance molecule, in liver cirrhosis via enhancing PDGF/TGF-β signaling in HSCs
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J Clin Invest
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Cao, S.1
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22
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84886380249
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TGF-β1 up-regulates the expression of PDGF-β receptor mRNA and induces a delayed PI3K-, AKT-, and p70(S6 K) -dependent proliferative response in activated hepatic stellate cells
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Shah R, Reyes-Gordillo K, Arellanes-Robledo J et al (2013) TGF-β1 up-regulates the expression of PDGF-β receptor mRNA and induces a delayed PI3K-, AKT-, and p70(S6 K) -dependent proliferative response in activated hepatic stellate cells. Alcohol Clin Exp Res 37:1838–1848. doi:10.1111/acer.12167
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Shah, R.1
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23
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TRPV4 channel inhibits TGF-β1-induced proliferation of hepatic stellate cells
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Song Y, Zhan L, Yu M et al (2014) TRPV4 channel inhibits TGF-β1-induced proliferation of hepatic stellate cells. PLoS One 9:e101179. doi:10.1371/journal.pone.0101179
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PLoS One
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Song, Y.1
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24
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84908025562
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TGF-β1-elevated TRPM7 channel regulates collagen expression in hepatic stellate cells via TGF-β1/Smad pathway
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Fang L, Huang C, Meng X et al (2014) TGF-β1-elevated TRPM7 channel regulates collagen expression in hepatic stellate cells via TGF-β1/Smad pathway. Toxicol Appl Pharmacol 280:335–344. doi:10.1016/j.taap.2014.08.006
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Fang, L.1
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25
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77952699836
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Signal transducer and activator of transcription 3 protects from liver injury and fibrosis in a mouse model of sclerosing cholangitis
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An important work showing that inactivation of Stat3 in hepatocytes and cholangiocytes of Mdr2ko mice aggravated bile acid-induced liver injury and fibrosis
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•• Mair M, Zollner G, Schneller D, et al. (2010) Signal transducer and activator of transcription 3 protects from liver injury and fibrosis in a mouse model of sclerosing cholangitis. Gastroenterology 138:2499–2508. doi:10.1053/j.gastro.2010.02.049. An important work showing that inactivation of Stat3 in hepatocytes and cholangiocytes of Mdr2ko mice aggravated bile acid-induced liver injury and fibrosis
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Gastroenterology
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Mair, M.1
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Loss of SOCS3 in the liver promotes fibrosis by enhancing STAT3-mediated TGF-β1 production
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Ogata H, Chinen T, Yoshida T et al (2006) Loss of SOCS3 in the liver promotes fibrosis by enhancing STAT3-mediated TGF-β1 production. Oncogene 25:2520–2530. doi:10.1038/sj.onc.1209281
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Ogata, H.1
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27
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84908077833
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Stat3 signaling activation crosslinking of TGF-β1 in hepatic stellate cell exacerbates liver injury and fibrosis
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Xu M-Y, Hu J-J, Shen J et al (2014) Stat3 signaling activation crosslinking of TGF-β1 in hepatic stellate cell exacerbates liver injury and fibrosis. Biochim Biophys Acta 1842:1–9. doi:10.1016/j.bbadis.2014.07.025
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Xu, M.-Y.1
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28
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84868020504
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HGF regulates the activation of TGF-β1 in rat hepatocytes and hepatic stellate cells
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This study examines crosstalk between HGF and TGF-β suggesting that HGF decreases TGF-β levels through induction of plasmin
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• Narmada BC, Chia SM, Tucker-Kellogg L, Yu H (2013) HGF regulates the activation of TGF-β1 in rat hepatocytes and hepatic stellate cells. J Cell Physiol 228:393–401. doi:10.1002/jcp.24143. This study examines crosstalk between HGF and TGF-β suggesting that HGF decreases TGF-β levels through induction of plasmin
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J Cell Physiol
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Narmada, B.C.1
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Yu, H.4
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29
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84868211637
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Human antigen R contributes to hepatic stellate cell activation and liver fibrosis
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This study documents that RBP human antigen R (HuR) is fibrogenic by sensitizing activated HSC to PDGF and TGF-β
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• Woodhoo A, Iruarrizaga-Lejarreta M, Beraza N, et al. (2012) Human antigen R contributes to hepatic stellate cell activation and liver fibrosis. Hepatology 56:1870–1882. doi:10.1002/hep.25828 This study documents that RBP human antigen R (HuR) is fibrogenic by sensitizing activated HSC to PDGF and TGF-β
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Hepatology
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, pp. 1870-1882
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Woodhoo, A.1
Iruarrizaga-Lejarreta, M.2
Beraza, N.3
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30
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84901194840
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Pin1 induction in the fibrotic liver and its roles in TGF-β1 expression and Smad2/3 phosphorylation
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Yang JW, Hien TT, Lim SC et al (2014) Pin1 induction in the fibrotic liver and its roles in TGF-β1 expression and Smad2/3 phosphorylation. J Hepatol 60:1235–1241. doi:10.1016/j.jhep.2014.02.004
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J Hepatol
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Yang, J.W.1
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31
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MicroRNAs, transforming growth factor β-1, and tissue fibrosis
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Bowen T, Jenkins RH, Fraser DJ (2013) MicroRNAs, transforming growth factor β-1, and tissue fibrosis. J Pathol 229:274–285. doi:10.1002/path.4119
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Bowen, T.1
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32
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Profibrotic effect of miR-33a with Akt activation in hepatic stellate cells
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Li ZJ, Ou-Yang PH, Han XP (2014) Profibrotic effect of miR-33a with Akt activation in hepatic stellate cells. Cell Signal 26:141–148. doi:10.1016/j.cellsig.2013.09.018
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Li, Z.J.1
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33
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The role of the miR-31/FIH1 pathway in TGF-β-induced liver fibrosis
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Hu J, Chen C, Liu Q et al (2015) The role of the miR-31/FIH1 pathway in TGF-β-induced liver fibrosis. Clin Sci 129:305–317. doi:10.1042/CS20140012
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Hu, J.1
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34
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84879618751
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Transforming growth factor-β1 selectively inhibits hepatocyte growth factor expression via a micro-RNA-199-dependent posttranscriptional mechanism
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Another interesting study that shows the crosstalk between TGF-β and HGF and the capability of TGF-β to inhibit HGF by microRNA-199
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• Mungunsukh O, Day RM (2013) Transforming growth factor-β1 selectively inhibits hepatocyte growth factor expression via a micro-RNA-199-dependent posttranscriptional mechanism. Mol Biol Cell 24:2088–97. doi:10.1091/mbc.E13-01-0017. Another interesting study that shows the crosstalk between TGF-β and HGF and the capability of TGF-β to inhibit HGF by microRNA-199
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Mol Biol Cell
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Mungunsukh, O.1
Day, R.M.2
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35
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Activation of hepatic stellate cells is suppressed by microRNA-150
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Zheng J, Lin Z, Dong P et al (2013) Activation of hepatic stellate cells is suppressed by microRNA-150. Int J Mol Med 32:17–24. doi:10.3892/ijmm.2013.1356
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36
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84880951481
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MiR-133a mediates TGF-β-dependent derepression of collagen synthesis in hepatic stellate cells during liver fibrosis
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The study shows the antifibrotic role of MiR-133a in liver and illustrates its potential as target for diagnostics and therapy
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• Roderburg C, Luedde M, Vargas Cardenas D, et al. (2013) MiR-133a mediates TGF-β-dependent derepression of collagen synthesis in hepatic stellate cells during liver fibrosis. J Hepatol 58:736–742. doi: 10.1016/j.jhep.2012.11.022. The study shows the antifibrotic role of MiR-133a in liver and illustrates its potential as target for diagnostics and therapy
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J Hepatol
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Roderburg, C.1
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37
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Regulation of myofibroblast differentiation by miR-424 during epithelial-to-mesenchymal transition
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Xiao X, Huang C, Zhao C et al (2015) Regulation of myofibroblast differentiation by miR-424 during epithelial-to-mesenchymal transition. Arch Biochem Biophys 566:49–57. doi:10.1016/j.abb.2014.12.007
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38
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Expression of microRNA-454 in TGF-β1-stimulated hepatic stellate cells and in mouse livers infected with Schistosoma japonicum
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Zhu D, He X, Duan Y et al (2014) Expression of microRNA-454 in TGF-β1-stimulated hepatic stellate cells and in mouse livers infected with Schistosoma japonicum. Parasit Vectors 7:148. doi:10.1186/1756-3305-7-148
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39
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84864011802
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MicroRNA-146a modulates TGF-β1-induced hepatic stellate cell proliferation by targeting SMAD4
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The study shows the ability of MiR-146a to inhibit TGF-β activity through decreasing Smad4
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• He Y, Huang C, Sun X, et al. (2012) MicroRNA-146a modulates TGF-β1-induced hepatic stellate cell proliferation by targeting SMAD4. Cell Signal 24:1923–1930. doi:10.1016/j.cellsig.2012.06.003. The study shows the ability of MiR-146a to inhibit TGF-β activity through decreasing Smad4
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Cell Signal
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40
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MicroRNA-30 protects against carbon tetrachloride-induced liver fibrosis by attenuating transforming growth factor-β signaling in hepatic stellate cells
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Tu X, Zheng X, Li H et al (2015) MicroRNA-30 protects against carbon tetrachloride-induced liver fibrosis by attenuating transforming growth factor-β signaling in hepatic stellate cells. Toxicol Sci 146:157–169. doi:10.1093/toxsci/kfv081
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41
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KLF11 mediates a critical mechanism in TGF beta signaling that is inactivated by ERK-MAPK in pancreatic cancer cells
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Ellenrieder V, Buck A, Harth ANA et al (2004) KLF11 mediates a critical mechanism in TGF beta signaling that is inactivated by ERK-MAPK in pancreatic cancer cells. Gastroenterology 5085:607–620. doi:10.1053/S0016-5085(04)00864-9
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84933060092
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MicroRNA-17-5p activates hepatic stellate cells through targeting of Smad7
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The authors show that MiR-175-5p is targeting Smad7 during HSC activation, therewith enhancing TGF-β action and fibrogenesis
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• Yu F, Guo Y, Chen B, et al. (2015) MicroRNA-17-5p activates hepatic stellate cells through targeting of Smad7. Lab Investig 95:781–789. doi:10.1038/labinvest.2015.58. The authors show that MiR-175-5p is targeting Smad7 during HSC activation, therewith enhancing TGF-β action and fibrogenesis
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Sun X, He Y, Ma T-T et al (2014) Participation of miR-200a in TGF-β1-mediated hepatic stellate cell activation. Mol Cell Biochem 388:11–23. doi:10.1007/s11010-013-1895-0
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44
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• Meyer C, Godoy P, Bachmann A, et al. (2011) Distinct role of endocytosis for Smad and non-Smad TGF-β signaling regulation in hepatocytes. J Hepatol 55:369–378. doi:10.1016/j.jhep.2010.11.027. This work highlights the importance of endocytosis in regulating TGF-β signaling in hepatocytes
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This work shows Caveolin-1 as important hepatocyte fate determinant for TGF-β effects. Knockdown of Caveolin-1 sensitized hepatocytes for TGF-β mediated apoptosis through downregulating AKT phosphorylation
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• Meyer C, Liu Y, Kaul a, et al. (2013) Caveolin-1 abrogates TGF-β mediated hepatocyte apoptosis. Cell Death Dis 4:e466. doi:10.1038/cddis.2012.204. This work shows Caveolin-1 as important hepatocyte fate determinant for TGF-β effects. Knockdown of Caveolin-1 sensitized hepatocytes for TGF-β mediated apoptosis through downregulating AKT phosphorylation
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Caveolin-1 is required for TGF-β-induced transactivation of the EGF receptor pathway in hepatocytes through the activation of the metalloprotease TACE/ADAM17
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This study shows a link between TGF-β and the EGF receptor via Caveolin
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• Moreno-Càceres J, Caja L, Mainez J, et al. (2014) Caveolin-1 is required for TGF-β-induced transactivation of the EGF receptor pathway in hepatocytes through the activation of the metalloprotease TACE/ADAM17. Cell Death Dis 5:e1326. doi:10.1038/cddis.2014.294. This study shows a link between TGF-β and the EGF receptor via Caveolin
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Extracellular matrix modulates sensitivity of hepatocytes to fibroblastoid dedifferentiation and transforming growth factor-β-induced apoptosis
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This study demonstrates that cultured hepatocytes undergo cellular stress with activation of survival pathways, which protect against TGF-β dependent apoptosis
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•• Godoy P, Hengstler JG, Ilkavets I, et al. (2009) Extracellular matrix modulates sensitivity of hepatocytes to fibroblastoid dedifferentiation and transforming growth factor-β-induced apoptosis. Hepatology 49:2031–2043. doi:10.1002/hep.22880. This study demonstrates that cultured hepatocytes undergo cellular stress with activation of survival pathways, which protect against TGF-β dependent apoptosis
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90
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Hepatocyte-specific Smad7 expression attenuates TGF-β-mediated fibrogenesis and protects against liver damage
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This investigation shows that overexpression of TGF-β antagonist Smad7 in hepatocytes interferes with liver fibrogenesis in CCl4 treated mice
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•• Dooley S, Hamzavi J, Ciuclan L, et al. (2008) Hepatocyte-specific Smad7 expression attenuates TGF-β-mediated fibrogenesis and protects against liver damage. Gastroenterology 135:642–659. doi:10.1053/j.gastro.2008.04.038. This investigation shows that overexpression of TGF-β antagonist Smad7 in hepatocytes interferes with liver fibrogenesis in CCl4 treated mice
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91
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Transforming growth factor β signaling in hepatocytes participates in steatohepatitis through regulation of cell death and lipid metabolism in mice
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This paper convincingly shows participation of hepatocyte TGF-β signaling in the generation of a NASH phenotype in mice fed a high fat diet
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•• Yang L, Roh YS, Song J, et al. (2014) Transforming growth factor β signaling in hepatocytes participates in steatohepatitis through regulation of cell death and lipid metabolism in mice. Hepatology 59:483–495. doi:10.1002/hep.26698. This paper convincingly shows participation of hepatocyte TGF-β signaling in the generation of a NASH phenotype in mice fed a high fat diet
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92
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Transforming growth factor-β signaling in hepatocytes promotes hepatic fibrosis and carcinogenesis in mice with hepatocyte-specific deletion of TAK1
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This paper shows that TAK1 is a critical TGF-β signaling regulator in hepatocytes that reduces pro-apoptotic activity by activating cell survival pathways. Its abrogation leads to massive TGF-β mediated hepatocyte death, proliferative activity and inflammation mediated HCC development
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•• Yang L, Inokuchi S, Roh YS, et al. (2013) Transforming growth factor-β signaling in hepatocytes promotes hepatic fibrosis and carcinogenesis in mice with hepatocyte-specific deletion of TAK1. Gastroenterology 144:1042–1054.e4. doi:10.1053/j.gastro.2013.01.056. This paper shows that TAK1 is a critical TGF-β signaling regulator in hepatocytes that reduces pro-apoptotic activity by activating cell survival pathways. Its abrogation leads to massive TGF-β mediated hepatocyte death, proliferative activity and inflammation mediated HCC development
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Gastroenterology
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Luedde T, Kaplowitz N, Schwabe RF (2014) Cell death and cell death responses in liver disease: mechanisms and clinical relevance. Gastroenterology 147(765–783):e4. doi:10.1053/j.gastro.2014.07.018
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Reduced nicotinamide adenine dinucleotide phosphate oxidase 2 plays a key role in stellate cell activation and liver fibrogenesis in vivo
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−/− mice with lentiviral-GFP under the control of a hepatocyte-specific promoter. With that approach, the authors show that apoptosis and phagocytosis of hepatocytes directly induce HSC activation and initiation of fibrosis, and that NOX2, the phagocytic NADPH oxidase, plays a key role in this process
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−/− mice with lentiviral-GFP under the control of a hepatocyte-specific promoter. With that approach, the authors show that apoptosis and phagocytosis of hepatocytes directly induce HSC activation and initiation of fibrosis, and that NOX2, the phagocytic NADPH oxidase, plays a key role in this process
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Jiang, J.X.1
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The study shows that hepatocytes under stress send out signals termed Damage-associated molecular patterns to initiate cellular reactions in injured liver tissue; in this case HMGB1, which amplifies neutrophil-mediated injury via its receptor RAGE
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• Huebener P, Pradere J, Hernandez C, et al. (2015) The HMGB1/RAGE axis triggers neutrophil-mediated injury amplification following necrosis. 125:539–550. doi:10.1172/JCI76887.DAMP. The study shows that hepatocytes under stress send out signals termed Damage-associated molecular patterns to initiate cellular reactions in injured liver tissue; in this case HMGB1, which amplifies neutrophil-mediated injury via its receptor RAGE
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Signals from dying hepatocytes trigger growth of liver progenitors
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The study similarly shows that dying hepatocytes overexpress Hh ligands, which provide a survival signal for progenitor cells and myofibroblasts thus triggering wound healing/fibrogenesis
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• Jung Y, Witek RP, Syn W-K, et al. (2010) Signals from dying hepatocytes trigger growth of liver progenitors. Gut 59:655–665. doi:10.1136/gut.2009.204354. The study similarly shows that dying hepatocytes overexpress Hh ligands, which provide a survival signal for progenitor cells and myofibroblasts thus triggering wound healing/fibrogenesis
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Xie G, Diehl AM (2013) Evidence for and against epithelial-to-mesenchymal transition in the liver. Am J Physiol Gastrointest Liver Physiol 305:G881–G890. doi:10.1152/ajpgi.00289.2013
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Lee SJ, Kim KH, Park KK (2014) Mechanisms of fibrogenesis in liver cirrhosis: the molecular aspects of epithelial-mesenchymal transition. World J Hepatol 6:207–216. doi:10.4254/wjh.v6.i4.207
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Zeisberg M, Yang C, Martino M et al (2007) Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition. J Biol Chem 282:23337–23347. doi:10.1074/jbc.M700194200
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The study identifies FSP1, previously described as a marker to identify hepatocytes undergoing EMT during fibrogenesis, as a specific marker for a subpoulation of macrophages
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•• Österreicher CH, Penz-österreicher M, Grivennikov SI, Guma M (2010) Fibroblast-specific protein 1 identifies an inflammatory subpopulation of macrophages in the liver. doi:10.1073/pnas.1017547108. The study identifies FSP1, previously described as a marker to identify hepatocytes undergoing EMT during fibrogenesis, as a specific marker for a subpoulation of macrophages
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Fibroblast-specific protein 1 identifies an inflammatory subpopulation of macrophages in the liver
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102
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Hepatocytes do not undergo epithelial-mesenchymal transition in liver fibrosis in mice
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An interesting study using lineage tracing to confirm that there is no change of the morphology and no expression of EMT markers in hepatocytes of CCl4-treated mice challenging the concept that hepatocytes can undergo EMT
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•• Taura K, Miura K, Iwaisako K, et al. (2010) Hepatocytes do not undergo epithelial-mesenchymal transition in liver fibrosis in mice. Hepatology 51:1027–1036. doi:10.1002/hep.23368. An interesting study using lineage tracing to confirm that there is no change of the morphology and no expression of EMT markers in hepatocytes of CCl4-treated mice challenging the concept that hepatocytes can undergo EMT
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The ratio of transforming growth factor-β1/bone morphogenetic protein-7 in the progression of the epithelial-mesenchymal transition contributes to rat liver fibrosis
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Bi WR, Xu GT, Lv LX, Yang CQ (2014) The ratio of transforming growth factor-β1/bone morphogenetic protein-7 in the progression of the epithelial-mesenchymal transition contributes to rat liver fibrosis. Genet Mol Res 13:1005–1014. doi:10.4238/2014.February.20.2
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Bi WR, Jin CX, Xu GT, Yang CQ (2012) Bone morphogenetic protein-7 regulates Snail signaling in carbon tetrachloride-induced fibrosis in the rat liver. Exp Ther Med 4:1022–1026. doi:10.3892/etm.2012.720
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The study shows the ability of BMP-7 to attenuate liver fibrosis via inhibition of TGF-β1 signaling
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• Wang S-L, Yang C, Qi X-L, et al. (2013) Inhibitory effect of bone morphogenetic protein-7 on hepatic fibrosis in rats. Int J Clin Exp Pathol 6:897–903. The study shows the ability of BMP-7 to attenuate liver fibrosis via inhibition of TGF-β1 signaling
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ERK5 inhibition ameliorates pulmonary fibrosis via regulating Smad3 acetylation
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Interestingly, this study shows that ERK5 inhibition can antagonize TGF-β-mediated fibrogenic signaling through Smad3 acetylation instead through Smad3 phosphorylation
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• Kim S, Lim JH, Woo CH (2013) ERK5 inhibition ameliorates pulmonary fibrosis via regulating Smad3 acetylation. Am J Pathol 183:1758–1768. doi:10.1016/j.ajpath.2013.08.014. Interestingly, this study shows that ERK5 inhibition can antagonize TGF-β-mediated fibrogenic signaling through Smad3 acetylation instead through Smad3 phosphorylation
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Opposing roles for Smad2 and Smad3 in peritoneal fibrosis in vivo and in vitro
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A good study that expand our information about the specific roles that Smad2 and Smad3 play in organ fibrosis and confirm the results of Zhang et al (2014) in the liver
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• Duan W-J, Yu X, Huang X-R, et al. (2014) Opposing roles for Smad2 and Smad3 in peritoneal fibrosis in vivo and in vitro. Am J Pathol 184:2275–2284. doi:10.1016/j.ajpath.2014.04.014 A good study that expand our information about the specific roles that Smad2 and Smad3 play in organ fibrosis and confirm the results of Zhang et al (2014) in the liver
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Am J Pathol
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Chronic Toll-like receptor 4 stimulation in skin induces inflammation, macrophage activation, transforming growth factor-β signature gene expression, and fibrosis
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Targeting of αv integrin identifies a core molecular pathway that regulates fibrosis in several organs
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An elegant study that used Cre/Loxp technique to specifically target αv integrin in different organs. The results show that αv integrin depletion is effective in protecting the mice against CCl4-induced liver fibrosis and attentuated also renal and pulmonary fibrosis, highlighting αv integrin as general therapeutic target in variant fibrotic diseases
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•• Henderson NC, Arnold TD, Katamura Y, et al. (2013) Targeting of αv integrin identifies a core molecular pathway that regulates fibrosis in several organs. Nat Med 19:1617–24. doi:10.1038/nm.3282. An elegant study that used Cre/Loxp technique to specifically target αv integrin in different organs. The results show that αv integrin depletion is effective in protecting the mice against CCl4-induced liver fibrosis and attentuated also renal and pulmonary fibrosis, highlighting αv integrin as general therapeutic target in variant fibrotic diseases
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The study shows the detrimental effects of IL-20 during liver fibrosis in human and animals illustrating that blocking antibodies for IL-20 and IL-20R1 are potential therapeutic agents
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• Chiu YS, Wei CC, Lin YJ, et al. (2014) Il-20 and IL-20R1 antibodies protect against liver fibrosis. Hepatology 1003–1014. doi:10.1002/hep.27189. The study shows the detrimental effects of IL-20 during liver fibrosis in human and animals illustrating that blocking antibodies for IL-20 and IL-20R1 are potential therapeutic agents
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