甲基化在肝纤维化过程中的作用及其机制的研究进展
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摘要
目的总结DNA甲基化和组蛋白甲基化在肝纤维化中的作用机制。方法综述国内外有关探究肝纤维化过程中DNA甲基化和组蛋白甲基化的文献并进行分析总结。结果 DNA甲基化和组蛋白甲基化都是表观遗传学的重要组成部分,在肝纤维化过程中通过上调或下调某些基因表达,导致后续通路激活或失活,如PTEN、SEPT9、Smad7等在肝纤维化中呈高甲基化且表达降低,Spp1在肝纤维化中就呈低甲基化且表达增加。结论甲基化通过改变基因的表观遗传学从而影响基因的表达,通过对甲基化在肝脏疾病中的作用及机制进行系统而深入的研究可为肝脏疾病的治疗提供新的方向和靶向治疗的位点。
Objective To summarize mechanism of DNA methylation and histone methylation in liver fibrosis.Method The literatures on the DNA methylation and histone methylation during the liver fibrosis were reviewed and analyzed.Results The DNA methylation and histone methylation were the important components of epigenetics.The up-regulation or down-regulation of genes during the liver fibrosis leaded to the activation or inactivation of the subsequent pathways.For example,the PTEN,SEPT9,Smad7,etc.were hypermethylated and the expressions were decreased in the liver fibrosis.The Spp1 was hypomethylated and the expression was increased in the liver fibrosis.Conclusions Methylation affects expression of genes by altering epigenetics of genes.Systematic and in-depth study of role and mechanism of methylation in liver diseases provides a new direction and locations for some target treatments for liver disease.
Objective To summarize mechanism of DNA methylation and histone methylation in liver fibrosis.Method The literatures on the DNA methylation and histone methylation during the liver fibrosis were reviewed and analyzed.Results The DNA methylation and histone methylation were the important components of epigenetics.The up-regulation or down-regulation of genes during the liver fibrosis leaded to the activation or inactivation of the subsequent pathways.For example,the PTEN,SEPT9,Smad7,etc.were hypermethylated and the expressions were decreased in the liver fibrosis.The Spp1 was hypomethylated and the expression was increased in the liver fibrosis.Conclusions Methylation affects expression of genes by altering epigenetics of genes.Systematic and in-depth study of role and mechanism of methylation in liver diseases provides a new direction and locations for some target treatments for liver disease.
引文
1 Lin L, Zhou F, Shen S, et al. Fighting liver fibrosis with naturally occurring antioxidants. Planta Med, 2018 Oct 12. doi:10.1055/a-0757-0008.
2 Moran-Salvador E, Mann J. Epigenetics and liver fibrosis. Cell Mol Gastroenterol Hepatol, 2017,4(1):125-134.
3 Iwaisako K, Jiang C, Zhang M, et al. Origin of myofibroblasts in the fibrotic liver in mice. Proc Natl Acad Sci USA, 2014, 111(32):E3297-E3305.
4 Lee UE, Friedman SL. Mechanisms of hepatic fibrogenesis. Best Pract Res Clin Gastroenterol, 2011, 25(2):195-206.
5 Pinter M, Trauner M, Peck-Radosavljevic M, et al. Cancer and liver cirrhosis:implications on prognosis and management. ESMO Open, 2016, 1(2):e000042.
6 Hackl C, Schlitt HJ, Renner P, et al. Liver surgery in cirrhosis and portal hypertension. World J Gastroenterol, 2016, 22(9):2725-2735.
7 European Association For The Study Of The Liver, European Organisation For Research And Treatment Of Cancer. EASLEORTC clinical practice guidelines:management of hepatocellular carcinoma. J Hepatol, 2012, 56(4):908-943.
8 Piscaglia AC, Campanale M, Gasbarrini A, et al. Stem cell-based therapies for liver diseases:state of the art and new perspectives.Stem Cells Int, 2010, 2010:259461.
9 Miyamoto T, Nakauchi H. Generation of functional organs from pluripotent stem cells. Rinsho Ketsueki, 2015, 56(10):2213-2219.
10 Liu X, Xu J, Brenner DA, et al. Reversibility of liver fibrosis and inactivation of fibrogenic myofibroblasts. Curr Pathobiol Rep,2013,1(3):209-214.
11 Xu J, Liu X, Koyama Y, et al. The types of hepatic myofibroblasts contributing to liver fibrosis of different etiologies. Front Pharmacol, 2014, 5:167.
12 Ren JJ, Huang TJ, Zhang QQ, et al. Insulin-like growth factor binding protein related protein 1 knockdown attenuates hepatic fibrosis via the regulation of MMPs/TIMPs in mice. Hepatobiliary Pancreat Dis Int, 2018 Aug 29. pii:S1499-3872(18)30189-9.
13 Page A, Paoli P, Moran Salvador E, et al. Hepatic stellate cell transdifferentiation involves genome-wide remodeling of the DNA methylation landscape. J Hepatol, 2016, 64(3):661-673.
14 Mann J, Chu DC, Maxwell A, et al. MeCP2 controls an epigenetic pathway that promotes myofibroblast transdifferentiation and fibrosis. Gastroenterology, 2010,138(2):705-714.
15 Correia NC, Girio A, Antunes I, et al. The multiple layers of nongenetic regulation of PTEN tumour suppressor activity. Eur J Cancer, 2014, 50(1):216-225.
16 Kumar P, Raeman R, Chopyk DM, et al. Adiponectin inhibits hepatic stellate cell activation by targeting the PTEN/AKTpathway. Biochim Biophys Acta Mol Basis Dis. 2018, 1864(10):3537-3545.
17 Pitha-Rowe I, Liby K, Royce D, et al. Synthetic triterpenoids attenuate cytotoxic retinal injury:cross-talk between Nrf2 and PI3K/AKT signaling through inhibition of the lipid phosphatase PTEN. Invest Ophthalmol Vis Sci, 2009, 50(11):5339-5347.
18 Tao H, Huang C, Yang JJ, et al. MeCP2 controls the expression of RASAL1 in the hepatic fibrosis in rats. Toxicology, 2011, 290(2-3):327-333.
19 Takashima M, Parsons CJ, Ikejima K, et al. The tumor suppressor protein PTEN inhibits rat hepatic stellate cell activation. J Gastroenterol, 2009,44(8):847-855.
20 Bian EB, Huang C, Ma TT, et al. DNMT1-mediated PTEN hypermethylation confers hepatic stellate cell activation and liver fibrogenesis in rats. Toxicol Appl Pharmacol, 2012, 264(1):13-22.
21 Estey MP, Kim MS, Trimble WS. Septins. Curr Biol, 2011, 21(10):R384-R387.
22 Fan Y, Du Z, Steib CJ, et al. Effect of SEPT6 on the biological behavior of hepatic stellate cells and liver fibrosis in rats and its mechanism. Lab Invest, 2018 Oct 12. doi:10.1038/s41374-018-0133-5.
23 Peterson EA, Petty EM. Conquering the complex world of human septins:implications for health and disease. Clin Genet, 2010,77(6):511-524.
24 Gonzalez ME, Peterson EA, Privette LM, et al. High SEPT9_v1expression in human breast cancer cells is associated with oncogenic phenotypes. Cancer Res, 2007, 67(18):8554-8564.
25 McDade SS, Hall PA, Russell SE. Translational control of SEPT9isoforms is perturbed in disease. Hum Mol Genet, 2007,16(7):742-752.
26 Connolly D, Yang Z, Castaldi M, et al. Septin 9 isoform expression,localization and epigenetic changes during human and mouse breast cancer progression. Breast Cancer Res, 2011, 13(4):R76.
27 Lofton-Day C, Model F, Devos T, et al. DNA methylation biomarkers for blood-based colorectal cancer screening. Clin Chem, 2008, 54(2):414-423.
28 Dietrich D, Jung M, Puetzer S, et al. Diagnostic and prognostic value of SHOX2 and SEPT9 DNA methylation and cytology in benign, paramalignant and malignant pleural effusions. PLoS One,2013, 8(12):e84225.
29 Powrozek T, Krawczyk P, Kucharczyk T, et al. Septin 9 promoter region methylation in free circulating DNA-potential role in noninvasive diagnosis of lung cancer:preliminary report. Med Oncol, 2014, 31(4):917.
30 Kuo IY, Chang JM, Jiang SS, et al. Prognostic CpG methylation biomarkers identified by methylation array in esophageal squamous cell carcinoma patients. Int J Med Sci, 2014,11(8):779-787.
31 Andresen K, Boberg KM, Vedeld HM, et al. Four DNA methylation biomarkers in biliary brush samples accurately identify the presence of cholangiocarcinoma. Hepatology, 2015,61(5):1651-1659.
32 Dayeh T, Volkov P, Salo S, et al. Genome-wide DNA methylation analysis of human pancreatic islets from type 2 diabetic and nondiabetic donors identifies candidate genes that influence insulin secretion. PLoS Genet, 2014,10(3):e1004160.
33 Grutzmann R, Molnar B, Pilarsky C, et al. Sensitive detection of colorectal cancer in peripheral blood by septin 9 DNA methylationassay. PLoS One, 2008, 3(11):e3759.
34 deVos T, Tetzner R, Model F, et al. Circulating methylated SEPT9DNA in plasma is a biomarker for colorectal cancer. Clin Chem,2009,55(7):1337-1346.
35 Payne SR. From discovery to the clinic:the novel DNA methylation biomarker(m)SEPT9 for the detection of colorectal cancer in blood. Epigenomics, 2010, 2(4):575-585.
36 Wu Y, Bu F, Yu H, et al. Methylation of Septin9 mediated by DNMT3a enhances hepatic stellate cells activation and liver fibrogenesis. Toxicol Appl Pharmacol, 2017, 315:35-49.
37 Nakamura M, Kubo M, Yanai K, et al. Anti-patched-1 antibodies suppress hedgehog signaling pathway and pancreatic cancer proliferation. Anticancer Res, 2007, 27(6A):3743-3747.
38 Spicer LJ, Sudo S, Aad PY, et al. The hedgehog-patched signaling pathway and function in the mammalian ovary:a novel role for hedgehog proteins in stimulating proliferation and steroidogenesis of theca cells..Reproduction, 2009, 138(2):329-339.
39 Rimkus TK, Carpenter RL, Qasem S, et al. Targeting the sonic hedgehog signaling pathway:review of smoothened and GLI inhibitors. Cancers(Basel), 2016, 8(2):pii:E22.
40 Cohen MM Jr. Hedgehog signaling update. Am J Med Genet A,2010.152A(8):1875-1914.
41 Choi SS, Syn WK, Karaca GF, et al. Leptin promotes the myofibroblastic phenotype in hepatic stellate cells by activating the hedgehog pathway. J Biol Chem, 2010, 285(47):36551-36560.
42 Yang JJ, Tao H, Huang C, et al. DNA methylation and MeCP2regulation of PTCH1 expression during rats hepatic fibrosis. Cell Signal, 2013,25(5):1202-1211.
43 Liu Y, Meyer C, Muller A, et al. IL-13 induces connective tissue growth factor in rat hepatic stellate cells via TGF-(3-independent Smad signaling. J Immunol, 2011, 187(5):2814-2823.
44 Ma L, Zeng Y, Wei J, et al. Knockdown of LOXL1 inhibits TGF-β1-induced proliferation and fibrogenesis of hepatic stellate cells by inhibition of Smad2/3 phosphorylation. Biomed Pharmacother,2018,107:1728-1735.
45 Ramos-Tovar E, Flores-Beltran RE, Galindo-Gomez S, et al. Stevia rebaudiana tea prevents experimental cirrhosis via regulation of NF-κB, Nrf2, transforming growth factor beta, Smad7, and hepatic stellate cell activation. Phytother Res, 2018 Sep 24. doi:10.1002/ptr.6197.
46 Latella G, Vetuschi A, Sferra R, et al. Targeted disruption of Smad3confers resistance to the development of dimethylnitrosamineinduced hepatic fibrosis in mice. Liver Int, 2009, 29(7):997-1009.
47 Bian EB, Huang C, Wang H, et al. Repression of Smad7 mediated by DNMT1 determines hepatic stellate cell activation and liver fibrosis in rats. Toxicol Lett, 2014, 224(2):175-185.
48 De Luca A, Pierno S, Liantonio A, et al. Enhanced dystrophic progression in mdx mice by exercise and beneficial effects of taurine and insulin-like growth factor-1. J Pharmacol Exp Ther,2003, 304(1):453-463.
49 Heinemeier KM, Skovgaard D, Bayer ML, et al. Uphill running improves rat Achilles tendon tissue mechanical properties and alters gene expression without inducing pathological changes. J Appl Physiol(1985), 2012,113(5):827-836.
50 Gotshall RW. Exercise-induced bronchoconstriction. Drugs, 2002,62(12):1725-1739.
51 Weber MA, Nagel AM, Jurkat-Rott K, et al. Sodium(23Na)MRI detects elevated muscular sodium concentration in Duchennemuscular dystrophy. Neurology, 2011, 77(23):2017-2024.
52 Mariappan YK, Glaser KJ, Ehman RL. Magnetic resonance elastography:a review. Clin Anat, 2010, 23(5):497-511.
53 Shankar H, Reddy S. Two-and three-dimensional ultrasound imaging to facilitate detection and targeting of taut bands in myofascial pain syndrome. Pain Med, 2012, 13(7):971-975.
54 Lorena D, Darby IA, Gadeau AP, et al. Osteopontin expression in normal and fibrotic liver. Altered liver healing in osteopontindeficient mice. J Hepatol, 2006, 44(2):383-390.
55 Sahai A, Malladi P, Melin-Aldana H, et al. Upregulation of osteopontin expression is involved in the development of nonalcoholic steatohepatitis in a dietary murine model. Am J Physiol Gastrointest Liver Physiol, 2004,287(1):G264-G273.
56 Ramaiah SK, Rittling S. Role of osteopontin in regulating hepatic inflammatory responses and toxic liver injury. Expert Opin Drug Metab Toxicol, 2007, 3(4):519-526.
57 Komatsu Y, Waku T, Iwasaki N, et al. Global analysis of DNA methylation in early-stage liver fibrosis. BMC Med Genomics,2012,5:5.
58 Ding M, Cui S, Li C, et al. Loss of the tumor suppressor Vhlh leads to upregulation of Cxcr4 and rapidly progressive glomerulonephritis in mice, Nat Med, 2006,12(9):1081-1087.
59 Bernstein BE, Humphrey EL, Erlich RL, et al. Methylation of histone H3 Lys 4 in coding regions of active genes. Proc Natl Acad Sci USA, 2002, 99(13):8695-8700.
60 Kouzarides T. Chromatin modifications and their function. Cell,2007,128(4):693-705.
61 Tammen SA, Friso S, Choi SW. Epigenetics:the link between nature and nurture. Mol Aspects Med, 2013, 34(4):753-764.
62 Suganuma T, Workman JL. Signals and combinatorial functions of histone modifications. Annu Rev Biochem, 2011, 80:473-499.
63 Perugorria MJ, Wilson CL, Zeybel M, et al. Histone methyltransferase ASH1 orchestrates fibrogenic gene transcription during myofibroblast transdifferentiation. Hepatology, 2012, 56(3):1129-1139.
64 Zeybel M, Luli S, Sabater L, et al. A proof-of-concept for epigenetic therapy of tissue fibrosis:inhibition of liver fibrosis progression by3-deazaneplanocin A. Mol Ther, 2017, 25(1):218-231.
65 Rankin EB, Giaccia AJ. The role of hypoxia-inducible factors intumorigenesis. Cell Death Differ, 2008,15(4):678-685.
66 Wang Y, Huang Y, Guan F, et al. Hypoxia-inducible factor-1alpha and MAPK co-regulate activation of hepatic stellate cells upon hypoxia stimulation. PLoS One, 2013, 8(9):e74051.
67 Deng J, Huang Q, Wang Y, et al. Hypoxia-inducible factor-1alpha regulates autophagy to activate hepatic stellate cells. Biochem Biophys Res Commun, 2014, 454(2):328-334.
68 Zhou X, Sun H, Chen H, et al. Hypoxia induces trimethylated H3lysine 4 by inhibition of JARID1A demethylase. Cancer Res, 2010,70(10):4214-4221,
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72 Hussain M, Rao M, Humphries AE, et al. Tobacco smoke induces polycomb-mediated repression of Dickkopf-1 in lung cancer cells.Cancer Res, 2009, 69(8):3570-3578.
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75 Takahashi YH, Shilatifard A. Structural basis for H3K4 trimethylation by yeast Setl/COMPASS. Adv Enzyme Regul, 2010, 50(1):104-110.
76 Tian W, Fan Z, Li J, et al. Myocardin-related transcription factor A(MRTF-A)plays an essential role in hepatic stellate cell activation by epigenetically modulating TGF-βsignaling. Int J Biochem Cell Biol, 2016, 71:35-43.
2 Moran-Salvador E, Mann J. Epigenetics and liver fibrosis. Cell Mol Gastroenterol Hepatol, 2017,4(1):125-134.
3 Iwaisako K, Jiang C, Zhang M, et al. Origin of myofibroblasts in the fibrotic liver in mice. Proc Natl Acad Sci USA, 2014, 111(32):E3297-E3305.
4 Lee UE, Friedman SL. Mechanisms of hepatic fibrogenesis. Best Pract Res Clin Gastroenterol, 2011, 25(2):195-206.
5 Pinter M, Trauner M, Peck-Radosavljevic M, et al. Cancer and liver cirrhosis:implications on prognosis and management. ESMO Open, 2016, 1(2):e000042.
6 Hackl C, Schlitt HJ, Renner P, et al. Liver surgery in cirrhosis and portal hypertension. World J Gastroenterol, 2016, 22(9):2725-2735.
7 European Association For The Study Of The Liver, European Organisation For Research And Treatment Of Cancer. EASLEORTC clinical practice guidelines:management of hepatocellular carcinoma. J Hepatol, 2012, 56(4):908-943.
8 Piscaglia AC, Campanale M, Gasbarrini A, et al. Stem cell-based therapies for liver diseases:state of the art and new perspectives.Stem Cells Int, 2010, 2010:259461.
9 Miyamoto T, Nakauchi H. Generation of functional organs from pluripotent stem cells. Rinsho Ketsueki, 2015, 56(10):2213-2219.
10 Liu X, Xu J, Brenner DA, et al. Reversibility of liver fibrosis and inactivation of fibrogenic myofibroblasts. Curr Pathobiol Rep,2013,1(3):209-214.
11 Xu J, Liu X, Koyama Y, et al. The types of hepatic myofibroblasts contributing to liver fibrosis of different etiologies. Front Pharmacol, 2014, 5:167.
12 Ren JJ, Huang TJ, Zhang QQ, et al. Insulin-like growth factor binding protein related protein 1 knockdown attenuates hepatic fibrosis via the regulation of MMPs/TIMPs in mice. Hepatobiliary Pancreat Dis Int, 2018 Aug 29. pii:S1499-3872(18)30189-9.
13 Page A, Paoli P, Moran Salvador E, et al. Hepatic stellate cell transdifferentiation involves genome-wide remodeling of the DNA methylation landscape. J Hepatol, 2016, 64(3):661-673.
14 Mann J, Chu DC, Maxwell A, et al. MeCP2 controls an epigenetic pathway that promotes myofibroblast transdifferentiation and fibrosis. Gastroenterology, 2010,138(2):705-714.
15 Correia NC, Girio A, Antunes I, et al. The multiple layers of nongenetic regulation of PTEN tumour suppressor activity. Eur J Cancer, 2014, 50(1):216-225.
16 Kumar P, Raeman R, Chopyk DM, et al. Adiponectin inhibits hepatic stellate cell activation by targeting the PTEN/AKTpathway. Biochim Biophys Acta Mol Basis Dis. 2018, 1864(10):3537-3545.
17 Pitha-Rowe I, Liby K, Royce D, et al. Synthetic triterpenoids attenuate cytotoxic retinal injury:cross-talk between Nrf2 and PI3K/AKT signaling through inhibition of the lipid phosphatase PTEN. Invest Ophthalmol Vis Sci, 2009, 50(11):5339-5347.
18 Tao H, Huang C, Yang JJ, et al. MeCP2 controls the expression of RASAL1 in the hepatic fibrosis in rats. Toxicology, 2011, 290(2-3):327-333.
19 Takashima M, Parsons CJ, Ikejima K, et al. The tumor suppressor protein PTEN inhibits rat hepatic stellate cell activation. J Gastroenterol, 2009,44(8):847-855.
20 Bian EB, Huang C, Ma TT, et al. DNMT1-mediated PTEN hypermethylation confers hepatic stellate cell activation and liver fibrogenesis in rats. Toxicol Appl Pharmacol, 2012, 264(1):13-22.
21 Estey MP, Kim MS, Trimble WS. Septins. Curr Biol, 2011, 21(10):R384-R387.
22 Fan Y, Du Z, Steib CJ, et al. Effect of SEPT6 on the biological behavior of hepatic stellate cells and liver fibrosis in rats and its mechanism. Lab Invest, 2018 Oct 12. doi:10.1038/s41374-018-0133-5.
23 Peterson EA, Petty EM. Conquering the complex world of human septins:implications for health and disease. Clin Genet, 2010,77(6):511-524.
24 Gonzalez ME, Peterson EA, Privette LM, et al. High SEPT9_v1expression in human breast cancer cells is associated with oncogenic phenotypes. Cancer Res, 2007, 67(18):8554-8564.
25 McDade SS, Hall PA, Russell SE. Translational control of SEPT9isoforms is perturbed in disease. Hum Mol Genet, 2007,16(7):742-752.
26 Connolly D, Yang Z, Castaldi M, et al. Septin 9 isoform expression,localization and epigenetic changes during human and mouse breast cancer progression. Breast Cancer Res, 2011, 13(4):R76.
27 Lofton-Day C, Model F, Devos T, et al. DNA methylation biomarkers for blood-based colorectal cancer screening. Clin Chem, 2008, 54(2):414-423.
28 Dietrich D, Jung M, Puetzer S, et al. Diagnostic and prognostic value of SHOX2 and SEPT9 DNA methylation and cytology in benign, paramalignant and malignant pleural effusions. PLoS One,2013, 8(12):e84225.
29 Powrozek T, Krawczyk P, Kucharczyk T, et al. Septin 9 promoter region methylation in free circulating DNA-potential role in noninvasive diagnosis of lung cancer:preliminary report. Med Oncol, 2014, 31(4):917.
30 Kuo IY, Chang JM, Jiang SS, et al. Prognostic CpG methylation biomarkers identified by methylation array in esophageal squamous cell carcinoma patients. Int J Med Sci, 2014,11(8):779-787.
31 Andresen K, Boberg KM, Vedeld HM, et al. Four DNA methylation biomarkers in biliary brush samples accurately identify the presence of cholangiocarcinoma. Hepatology, 2015,61(5):1651-1659.
32 Dayeh T, Volkov P, Salo S, et al. Genome-wide DNA methylation analysis of human pancreatic islets from type 2 diabetic and nondiabetic donors identifies candidate genes that influence insulin secretion. PLoS Genet, 2014,10(3):e1004160.
33 Grutzmann R, Molnar B, Pilarsky C, et al. Sensitive detection of colorectal cancer in peripheral blood by septin 9 DNA methylationassay. PLoS One, 2008, 3(11):e3759.
34 deVos T, Tetzner R, Model F, et al. Circulating methylated SEPT9DNA in plasma is a biomarker for colorectal cancer. Clin Chem,2009,55(7):1337-1346.
35 Payne SR. From discovery to the clinic:the novel DNA methylation biomarker(m)SEPT9 for the detection of colorectal cancer in blood. Epigenomics, 2010, 2(4):575-585.
36 Wu Y, Bu F, Yu H, et al. Methylation of Septin9 mediated by DNMT3a enhances hepatic stellate cells activation and liver fibrogenesis. Toxicol Appl Pharmacol, 2017, 315:35-49.
37 Nakamura M, Kubo M, Yanai K, et al. Anti-patched-1 antibodies suppress hedgehog signaling pathway and pancreatic cancer proliferation. Anticancer Res, 2007, 27(6A):3743-3747.
38 Spicer LJ, Sudo S, Aad PY, et al. The hedgehog-patched signaling pathway and function in the mammalian ovary:a novel role for hedgehog proteins in stimulating proliferation and steroidogenesis of theca cells..Reproduction, 2009, 138(2):329-339.
39 Rimkus TK, Carpenter RL, Qasem S, et al. Targeting the sonic hedgehog signaling pathway:review of smoothened and GLI inhibitors. Cancers(Basel), 2016, 8(2):pii:E22.
40 Cohen MM Jr. Hedgehog signaling update. Am J Med Genet A,2010.152A(8):1875-1914.
41 Choi SS, Syn WK, Karaca GF, et al. Leptin promotes the myofibroblastic phenotype in hepatic stellate cells by activating the hedgehog pathway. J Biol Chem, 2010, 285(47):36551-36560.
42 Yang JJ, Tao H, Huang C, et al. DNA methylation and MeCP2regulation of PTCH1 expression during rats hepatic fibrosis. Cell Signal, 2013,25(5):1202-1211.
43 Liu Y, Meyer C, Muller A, et al. IL-13 induces connective tissue growth factor in rat hepatic stellate cells via TGF-(3-independent Smad signaling. J Immunol, 2011, 187(5):2814-2823.
44 Ma L, Zeng Y, Wei J, et al. Knockdown of LOXL1 inhibits TGF-β1-induced proliferation and fibrogenesis of hepatic stellate cells by inhibition of Smad2/3 phosphorylation. Biomed Pharmacother,2018,107:1728-1735.
45 Ramos-Tovar E, Flores-Beltran RE, Galindo-Gomez S, et al. Stevia rebaudiana tea prevents experimental cirrhosis via regulation of NF-κB, Nrf2, transforming growth factor beta, Smad7, and hepatic stellate cell activation. Phytother Res, 2018 Sep 24. doi:10.1002/ptr.6197.
46 Latella G, Vetuschi A, Sferra R, et al. Targeted disruption of Smad3confers resistance to the development of dimethylnitrosamineinduced hepatic fibrosis in mice. Liver Int, 2009, 29(7):997-1009.
47 Bian EB, Huang C, Wang H, et al. Repression of Smad7 mediated by DNMT1 determines hepatic stellate cell activation and liver fibrosis in rats. Toxicol Lett, 2014, 224(2):175-185.
48 De Luca A, Pierno S, Liantonio A, et al. Enhanced dystrophic progression in mdx mice by exercise and beneficial effects of taurine and insulin-like growth factor-1. J Pharmacol Exp Ther,2003, 304(1):453-463.
49 Heinemeier KM, Skovgaard D, Bayer ML, et al. Uphill running improves rat Achilles tendon tissue mechanical properties and alters gene expression without inducing pathological changes. J Appl Physiol(1985), 2012,113(5):827-836.
50 Gotshall RW. Exercise-induced bronchoconstriction. Drugs, 2002,62(12):1725-1739.
51 Weber MA, Nagel AM, Jurkat-Rott K, et al. Sodium(23Na)MRI detects elevated muscular sodium concentration in Duchennemuscular dystrophy. Neurology, 2011, 77(23):2017-2024.
52 Mariappan YK, Glaser KJ, Ehman RL. Magnetic resonance elastography:a review. Clin Anat, 2010, 23(5):497-511.
53 Shankar H, Reddy S. Two-and three-dimensional ultrasound imaging to facilitate detection and targeting of taut bands in myofascial pain syndrome. Pain Med, 2012, 13(7):971-975.
54 Lorena D, Darby IA, Gadeau AP, et al. Osteopontin expression in normal and fibrotic liver. Altered liver healing in osteopontindeficient mice. J Hepatol, 2006, 44(2):383-390.
55 Sahai A, Malladi P, Melin-Aldana H, et al. Upregulation of osteopontin expression is involved in the development of nonalcoholic steatohepatitis in a dietary murine model. Am J Physiol Gastrointest Liver Physiol, 2004,287(1):G264-G273.
56 Ramaiah SK, Rittling S. Role of osteopontin in regulating hepatic inflammatory responses and toxic liver injury. Expert Opin Drug Metab Toxicol, 2007, 3(4):519-526.
57 Komatsu Y, Waku T, Iwasaki N, et al. Global analysis of DNA methylation in early-stage liver fibrosis. BMC Med Genomics,2012,5:5.
58 Ding M, Cui S, Li C, et al. Loss of the tumor suppressor Vhlh leads to upregulation of Cxcr4 and rapidly progressive glomerulonephritis in mice, Nat Med, 2006,12(9):1081-1087.
59 Bernstein BE, Humphrey EL, Erlich RL, et al. Methylation of histone H3 Lys 4 in coding regions of active genes. Proc Natl Acad Sci USA, 2002, 99(13):8695-8700.
60 Kouzarides T. Chromatin modifications and their function. Cell,2007,128(4):693-705.
61 Tammen SA, Friso S, Choi SW. Epigenetics:the link between nature and nurture. Mol Aspects Med, 2013, 34(4):753-764.
62 Suganuma T, Workman JL. Signals and combinatorial functions of histone modifications. Annu Rev Biochem, 2011, 80:473-499.
63 Perugorria MJ, Wilson CL, Zeybel M, et al. Histone methyltransferase ASH1 orchestrates fibrogenic gene transcription during myofibroblast transdifferentiation. Hepatology, 2012, 56(3):1129-1139.
64 Zeybel M, Luli S, Sabater L, et al. A proof-of-concept for epigenetic therapy of tissue fibrosis:inhibition of liver fibrosis progression by3-deazaneplanocin A. Mol Ther, 2017, 25(1):218-231.
65 Rankin EB, Giaccia AJ. The role of hypoxia-inducible factors intumorigenesis. Cell Death Differ, 2008,15(4):678-685.
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