Bilirubin and Epigenetic Modifications in Metabolic and Immunometabolic
Disorders

Mostafa    Moradi    Sarabi; Esmaeel       Babaeenezhad; Maral       Amini; Mozhgan       Kaviani; Fakhraddin       Naghibalhossaini
Abstract

Bilirubin is the main waste product of heme catabolism. At high concentrations, bilirubin may cause toxicity, especially in the brain, kidney, and erythrocytes. Membrane and mitochondrial dysfunction, oxidative stress, apoptosis, necrosis, endoplasmic reticulum stress, excitotoxicity, inflammation, and epigenetic modifications are the main mechanisms of toxicity triggered by bilirubin in susceptible organs. Many studies have shown that there is an interaction between bilirubin and epigenetic modifications in metabolic and immune diseases. In this review, we first outline the toxicity mediated by bilirubin and then summarize the current knowledge linking bilirubin and epigenetic modifications in metabolic and immunometabolic disorders.
Keywords: Bilirubin, DNA methylation, epigenetic modifications, metabolic disorders, immunometabolic disorder, Wilson’s disease (WD).
Graphical Abstract

[1] 
Gazzin, S.; Strazielle, N.; Tiribelli, C.; Ghersi-Egea, J.F. Transport and metabolism at blood-brain interfaces and in neural cells: Relevance to bilirubin-induced encephalopathy. Front. Pharmacol.,  2012, 3, 89.
[http://dx.doi.org/10.3389/fphar.2012.00089] [PMID: 22629246] 
[2] 
Wennberg, R.P.; Ahlfors, C.E.; Aravkin, A.Y. Intervention guidelines for neonatal hyperbilirubinemia: An evidence based quagmire. Curr. Pharm. Des.,  2009, 15(25), 2939-2945.
[http://dx.doi.org/10.2174/138161209789058228] [PMID: 19754370] 
[3] 
Stocker, R.; Yamamoto, Y.; McDonagh, A.F.; Glazer, A.N.; Ames, B.N. Bilirubin is an antioxidant of possible physiological importance. Science,  1987, 235(4792), 1043-1046.
[http://dx.doi.org/10.1126/science.3029864] [PMID: 3029864] 
[4] 
Watchko, J.F.; Tiribelli, C. Bilirubin-induced neurologic damage--mechanisms and management approaches. N. Engl. J. Med.,  2013, 369(21), 2021-2030.
[http://dx.doi.org/10.1056/NEJMra1308124] [PMID: 24256380] 
[5] 
Watchko, J.F. Kernicterus and the molecular mechanisms of bilirubin-induced CNS injury in newborns. Neuromolecular Med.,  2006, 8(4), 513-529.
[http://dx.doi.org/10.1385/NMM:8:4:513] [PMID: 17028373] 
[6] 
Rodrigues, C.M.P.; Solá, S.; Castro, R.E.; Laires, P.A.; Brites, D.; Moura, J.J. Perturbation of membrane dynamics in nerve cells as an early event during bilirubin-induced apoptosis. J. Lipid Res.,  2002, 43(6), 885-894.
[http://dx.doi.org/10.1016/S0022-2275(20)30462-4] [PMID: 12032163] 
[7] 
Johnston, M.V. Excitotoxicity in perinatal brain injury. Brain Pathol.,  2005, 15(3), 234-240.
[http://dx.doi.org/10.1111/j.1750-3639.2005.tb00526.x] [PMID: 16196390] 
[8] 
Vodret, S.; Bortolussi, G.; Jašprová, J.; Vitek, L.; Muro, A.F. Inflammatory signature of cerebellar neurodegeneration during neonatal hyperbilirubinemia in Ugt1 -/- mouse model. J. Neuroinflammation,  2017, 14(1), 64.
[http://dx.doi.org/10.1186/s12974-017-0838-1] [PMID: 28340583] 
[9] 
Sarabi, M.M.; Naghibalhossaini, F. Association of DNA methyltransferases expression with global and gene-specific DNA methylation in colorectal cancer cells. Cell Biochem. Funct.,  2015, 33(7), 427-433.
[http://dx.doi.org/10.1002/cbf.3126] [PMID: 26416384] 
[10] 
Roberti, A.; Valdes, A.F.; Torrecillas, R.; Fraga, M.F.; Fernandez, A.F. Epigenetics in cancer therapy and nanomedicine. Clin. Epigenetics,  2019, 11(1), 81.
[http://dx.doi.org/10.1186/s13148-019-0675-4] [PMID: 31097014] 
[11] 
Konsoula, Z.; Barile, F.A. Epigenetic histone acetylation and deacetylation mechanisms in experimental models of neurodegenerative disorders. J. Pharmacol. Toxicol. Methods,  2012, 66(3), 215-220.
[http://dx.doi.org/10.1016/j.vascn.2012.08.001] [PMID: 22902970] 
[12] 
Sakamoto, T.; Morishita, A.; Nomura, T.; Tani, J.; Miyoshi, H.; Yoneyama, H.; Iwama, H.; Himoto, T.; Masaki, T. Identification of microRNA profiles associated with refractory primary biliary cirrhosis. Mol. Med. Rep.,  2016, 14(4), 3350-3356.
[http://dx.doi.org/10.3892/mmr.2016.5606] [PMID: 27511723] 
[13] 
Liu, X.; Ni, S.; Li, C.; Xu, N.; Chen, W.; Wu, M.; van Wijnen, A.J.; Wang, Y. Circulating microRNA-23b as a new biomarker for rheumatoid arthritis. Gene,  2019, 712, 143911.
[http://dx.doi.org/10.1016/j.gene.2019.06.001] [PMID: 31176730] 
[14] 
Rogge, G.A.; Wood, M.A. The role of histone acetylation in cocaine-induced neural plasticity and behavior. Neuropsychopharmacology,  2013, 38(1), 94-110.
[http://dx.doi.org/10.1038/npp.2012.154] [PMID: 22910457] 
[15] 
Gou, P.; Qi, X.; Yuan, R.; Li, H.; Gao, X.; Wang, J.; Zhang, B. Tet1-mediated DNA demethylation involves in neuron damage induced by bilirubin in vitro. Toxicol. Mech. Methods,  2018, 28(1), 55-61.
[http://dx.doi.org/10.1080/15376516.2017.1357775] [PMID: 28805483] 
[16] 
Gao, S.; Ji, X.F.; Li, F.; Sun, F.K.; Zhao, J.; Fan, Y.C.; Wang, K. Aberrant DNA methylation of G-protein-coupled bile acid receptor Gpbar1 predicts prognosis of acute-on-chronic hepatitis B liver failure. J. Viral Hepat.,  2015, 22(2), 112-119.
[http://dx.doi.org/10.1111/jvh.12277] [PMID: 24995843] 
[17] 
Medici, V.; Shibata, N.M.; Kharbanda, K.K.; LaSalle, J.M.; Woods, R.; Liu, S.; Engelberg, J.A.; Devaraj, S.; Török, N.J.; Jiang, J.X.; Havel, P.J.; Lönnerdal, B.; Kim, K.; Halsted, C.H. Wilson’s disease: Changes in methionine metabolism and inflammation affect global DNA methylation in early liver disease. Hepatology,  2013, 57(2), 555-565.
[http://dx.doi.org/10.1002/hep.26047] [PMID: 22945834] 
[18] 
Yasar, U.; Greenblatt, D.J.; Guillemette, C.; Court, M.H. Evidence for regulation of UDP-glucuronosyltransferase (UGT) 1A1 protein expression and activity via DNA methylation in healthy human livers. J. Pharm. Pharmacol.,  2013, 65(6), 874-883.
[http://dx.doi.org/10.1111/jphp.12053] [PMID: 23647681] 
[19] 
Ji, H.; Wang, Y.; Liu, G.; Xu, X.; Dai, D.; Chen, Z.; Zhou, D.; Zhou, X.; Han, L.; Li, Y.; Zhuo, R.; Hong, Q.; Jiang, L.; Zhang, X.; Liu, Y.; Xu, L.; Chang, L.; Li, J.; An, P.; Duan, S.; Wang, Q. OPRK1 promoter hypermethylation increases the risk of Alzheimer’s disease. Neurosci. Lett.,  2015, 606, 24-29.
[http://dx.doi.org/10.1016/j.neulet.2015.08.027] [PMID: 26300544] 
[20] 
Bae, W.K.; Kang, K.; Yu, J.H.; Yoo, K.H.; Factor, V.M.; Kaji, K.; Matter, M.; Thorgeirsson, S.; Hennighausen, L. The methyltransferases enhancer of zeste homolog (EZH) 1 and EZH2 control hepatocyte homeostasis and regeneration. FASEB J.,  2015, 29(5), 1653-1662.
[http://dx.doi.org/10.1096/fj.14-261537] [PMID: 25477280] 
[21] 
Wang, Y.; Zhao, L.; Jiao, F.Z.; Zhang, W.B.; Chen, Q.; Gong, Z.J. Histone deacetylase inhibitor suberoylanilide hydroxamic acid alleviates liver fibrosis by suppressing the transforming growth factor-β1 signal pathway. Hepatobiliary Pancreat. Dis. Int.,  2018, 17(5), 423-429.
[http://dx.doi.org/10.1016/j.hbpd.2018.09.013] [PMID: 30249543] 
[22] 
Zhang, H.; Li, X.; Zhang, Q.; Yang, F.; Chu, X.; Zhang, D.; Wang, L.; Gong, Z. Role of histone deacetylase expression levels and activity in the inflammatory responses of patients with chronic hepatitis B. Mol. Med. Rep.,  2017, 15(5), 2744-2752.
[http://dx.doi.org/10.3892/mmr.2017.6290] [PMID: 28447718] 
[23] 
Nie, Y.L.; Meng, X.G.; Liu, J.Y.; Yan, L.; Wang, P.; Bi, H.Z.; Kan, Q.C.; Zhang, L.R. Histone modifications regulate the developmental expression of human hepatic UDP-glucuronosyltransferase 1A1. Drug Metab. Dispos.,  2017, 45(12), 1372-1378.
[http://dx.doi.org/10.1124/dmd.117.076109] [PMID: 29025858] 
[24] 
Gurba, P.E.; Zand, R. Bilirubin binding to myelin basic protein, histones and its inhibition in vitro of cerebellar protein synthesis. Biochem. Biophys. Res. Commun.,  1974, 58(4), 1142-1147.
[http://dx.doi.org/10.1016/S0006-291X(74)80262-7] [PMID: 4834691] 
[25] 
Vianello, E.; Zampieri, S.; Marcuzzo, T.; Tordini, F.; Bottin, C.; Dardis, A.; Zanconati, F.; Tiribelli, C.; Gazzin, S. Histone acetylation as a new mechanism for bilirubin-induced encephalopathy in the Gunn rat. Sci. Rep.,  2018, 8(1), 13690.
[http://dx.doi.org/10.1038/s41598-018-32106-w] [PMID: 30209300] 
[26] 
Amin, M.A.; Fawzi, M.; Sabri, D.; Sedrak, H.; Mausa, S. Liver specific serum Micro RNA122 as a prognostic marker in egyptian patients with liver cirrhosis. Arch. Hepatitis Res.,  2017, 3(1), 004-009.
[http://dx.doi.org/10.17352/ahr.000008] 
[27] 
Brandon-Warner, E.; Benbow, J.H.; Swet, J.H.; Feilen, N.A.; Culberson, C.R.; McKillop, I.H.; deLemos, A.S.; Russo, M.W.; Schrum, L.W. Adeno-associated virus serotype 2 vector-mediated reintroduction of microRNA-19b attenuates hepatic fibrosis. Hum. Gene Ther.,  2018, 29(6), 674-686.
[http://dx.doi.org/10.1089/hum.2017.035] [PMID: 29281894] 
[28] 
Shao, M.; Xu, Q.; Wu, Z.; Chen, Y.; Shu, Y.; Cao, X.; Chen, M.; Zhang, B.; Zhou, Y.; Yao, R.; Shi, Y.; Bu, H. Exosomes derived from human umbilical cord mesenchymal stem cells ameliorate IL-6-induced acute liver injury through miR-455-3p. Stem Cell Res. Ther.,  2020, 11(1), 37.
[http://dx.doi.org/10.1186/s13287-020-1550-0] [PMID: 31973730] 
[29] 
Huang, Y.H.; Yang, Y.L.; Huang, F.C.; Tiao, M.M.; Lin, Y.C.; Tsai, M.H.; Wang, F.S. MicroRNA-29a mitigation of endoplasmic reticulum and autophagy aberrance counteracts in obstructive jaundice-induced fibrosis in mice. Exp. Biol. Med. (Maywood),  2018, 243(1), 13-21.
[http://dx.doi.org/10.1177/1535370217741500] [PMID: 29105510] 
[30] 
Lin, S.H.; Song, W.; Cressatti, M.; Zukor, H.; Wang, E.; Schipper, H.M. Heme oxygenase-1 modulates microRNA expression in cultured astroglia: Implications for chronic brain disorders. Glia,  2015, 63(7), 1270-1284.
[http://dx.doi.org/10.1002/glia.22823] [PMID: 25820186] 
[31] 
Vaz, A.R.; Falcão, A.S.; Scarpa, E.; Semproni, C.; Brites, D. Microglia susceptibility to free bilirubin is age-dependent. Front. Pharmacol.,  2020, 11, 1012.
[http://dx.doi.org/10.3389/fphar.2020.01012] [PMID: 32765258] 
[32] 
Rieger, J.K.; Klein, K.; Winter, S.; Zanger, U.M. Expression variability of absorption, distribution, metabolism, excretion-related microRNAs in human liver: Influence of nongenetic factors and association with gene expression. Drug Metab. Dispos.,  2013, 41(10), 1752-1762.
[http://dx.doi.org/10.1124/dmd.113.052126] [PMID: 23733276] 
[33] 
Dennery, P.A.; Seidman, D.S.; Stevenson, D.K. Neonatal hyperbilirubinemia. N. Engl. J. Med.,  2001, 344(8), 581-590.
[http://dx.doi.org/10.1056/NEJM200102223440807] [PMID: 11207355] 
[34] 
Hansen, T.W.R. Mechanisms of bilirubin toxicity: Clinical implications; , 2002, pp. 765-778.
[35] 
Shapiro, S.M. Definition of the clinical spectrum of kernicterus and bilirubin-induced neurologic dysfunction (BIND). J. Perinatol.,  2005, 25(1), 54-59.
[http://dx.doi.org/10.1038/sj.jp.7211157] [PMID: 15578034] 
[36] 
Song, J.; Chang, A. Jaundice-associated acute kidney injury. NDT Plus,  2009, 2(1), 82-83.
[PMID: 25949296] 
[37] 
Krones, E.; Pollheimer, M.J.; Rosenkranz, A.R.; Fickert, P. Cholemic nephropathy – Historical notes and novel perspectives. 2018, 1356-1366.
[38] 
Lang, E.; Gatidis, S.; Freise, N.F.; Bock, H.; Kubitz, R.; Lauermann, C.; Orth, H.M.; Klindt, C.; Schuier, M.; Keitel, V.; Reich, M.; Liu, G.; Schmidt, S.; Xu, H.C.; Qadri, S.M.; Herebian, D.; Pandyra, A.A.; Mayatepek, E.; Gulbins, E.; Lang, F.; Häussinger, D.; Lang, K.S.; Föller, M.; Lang, P.A. Conjugated bilirubin triggers anemia by inducing erythrocyte death. Hepatology,  2015, 61(1), 275-284.
[http://dx.doi.org/10.1002/hep.27338] [PMID: 25065608] 
[39] 
Wennberg, R.P.; Ahlfors, C.E.; Rasmussen, L.F. The pathochemistry of kernicterus. Early Hum. Dev.,  1979, 3(4), 353-372.
[http://dx.doi.org/10.1016/0378-3782(79)90047-1] [PMID: 43803] 
[40] 
Karimzadeh, P.; Fallahi, M.; Kazemian, M.; Taslimi Taleghani, N.; Nouripour, S.; Radfar, M. Bilirubin induced encephalopathy. Iran. J. Child. Neurol.,  2020, 14(1), 7-19.
[PMID: 32021624] 
[41] 
Slusher, T.M.; Zamora, T.G.; Appiah, D.; Stanke, J.U.; Strand, M.A.; Lee, B.W.; Richardson, S.B.; Keating, E.M.; Siddappa, A.M.; Olusanya, B.O. Burden of severe neonatal jaundice: A systematic review and meta-analysis. BMJ Paediatr. Open,  2017, 1(1), e000105.
[http://dx.doi.org/10.1136/bmjpo-2017-000105] [PMID: 29637134] 
[42] 
Maisels, M.J. Neonatal hyperbilirubinemia and kernicterus - not gone but sometimes forgotten. Early Hum. Dev.,  2009, 85(11), 727-732.
[http://dx.doi.org/10.1016/j.earlhumdev.2009.09.003] [PMID: 19833460] 
[43] 
Brodersen, R. Bilirubin. Solubility and interaction with albumin and phospholipid. J. Biol. Chem.,  1979, 254(7), 2364-2369.
[http://dx.doi.org/10.1016/S0021-9258(17)30230-2] [PMID: 429290] 
[44] 
Ives, N.; Brewster, F.; Gardiner, R. Bilirubin transport at the blood-brain-barrier investigated using the oldendorf technique. Acta Neurol. Scand.,  1985, 72, 94.
[45] 
Lee, C.; Oh, W.; Stonestreet, B.S.; Cashore, W.J. Permeability of the blood brain barrier for 125I-albumin-bound bilirubin in newborn piglets. Pediatr. Res.,  1989, 25(5), 452-456.
[http://dx.doi.org/10.1203/00006450-198905000-00005] [PMID: 2717260] 
[46] 
Roger, C.; Koziel, V.; Vert, P.; Nehlig, A. Autoradiographic mapping of local cerebral permeability to bilirubin in immature rats: Effects of hyperbilirubinemia. Pediatr. Res.,  1996, 39(1), 64-71.
[http://dx.doi.org/10.1203/00006450-199601000-00009] [PMID: 8825387] 
[47] 
Gulati, A.; Mahesh, A.K.; Misra, P.K. Blood brain barrier permeability studies in control and icteric neonates. In: Pediatric Research; Williams & Wilkins, 1990; 27, p. 206A.
[48] 
Amit, Y.; Brenner, T. Age-dependent sensitivity of cultured rat glial cells to bilirubin toxicity. Exp. Neurol.,  1993, 121(2), 248-255.
[http://dx.doi.org/10.1006/exnr.1993.1092] [PMID: 8339775] 
[49] 
Hansen, T.W.R.; Cashore, W.J. Rates of bilirubin clearance from rat brain regions. Biol. Neonate,  1995, 68(2), 135-140.
[http://dx.doi.org/10.1159/000244229] [PMID: 8534773] 
[50] 
Wennberg, R.P.; Hance, A.J. Experimental bilirubin encephalopathy: Importance of total bilirubin, protein binding, and blood-brain barrier. Pediatr. Res.,  1986, 20(8), 789-792.
[http://dx.doi.org/10.1203/00006450-198608000-00018] [PMID: 3737293] 
[51] 
Watchko, J.F.; Daood, M.J.; Hansen, T.W.R. Brain bilirubin content is increased in P-glycoprotein-deficient transgenic null mutant mice. Pediatr. Res.,  1998, 44(5), 763-766.
[http://dx.doi.org/10.1203/00006450-199811000-00020] [PMID: 9803459] 
[52] 
Strazielle, N.; Khuth, S.T.; Ghersi-Egea, J.F. Detoxification systems, passive and specific transport for drugs at the blood-CSF barrier in normal and pathological situations. Adv. Drug Deliv. Rev.,  2004, 56(12), 1717-1740.
[http://dx.doi.org/10.1016/j.addr.2004.07.006] [PMID: 15381331] 
[53] 
Kapitulnik, J.; Gonzalez, F.J. Marked endogenous activation of the CYP1A1 and CYP1A2 genes in the congenitally jaundiced Gunn rat. Mol. Pharmacol.,  1993, 43(5), 722-725.
[PMID: 8502229] 
[54] 
Kapitulnik, J.; Hardwick, J.P.; Ostrow, J.D.; Webster, C.C.; Park, S.S.; Gelboin, H.V. Increase in a specific cytochrome P-450 isoenzyme in the liver of congenitally jaundiced Gunn rats. Biochem. J.,  1987, 242(1), 297-300.
[http://dx.doi.org/10.1042/bj2420297] [PMID: 3593244] 
[55] 
Abu-Bakar, A.; Moore, M.R.; Lang, M.A. Evidence for induced microsomal bilirubin degradation by cytochrome P450 2A5. Biochem. Pharmacol.,  2005, 70(10), 1527-1535.
[http://dx.doi.org/10.1016/j.bcp.2005.08.009] [PMID: 16183037] 
[56] 
Gazzin, S.; Zelenka, J.; Zdrahalova, L.; Konickova, R.; Zabetta, C.C.; Giraudi, P.J.; Berengeno, A.L.; Raseni, A.; Robert, M.C.; Vitek, L.; Tiribelli, C. Bilirubin accumulation and Cyp mRNA expression in selected brain regions of jaundiced Gunn rat pups. Pediatr. Res.,  2012, 71(6), 653-660.
[http://dx.doi.org/10.1038/pr.2012.23] [PMID: 22337225] 
[57] 
Hansen, T.W.R. Bilirubin brain toxicity. J. Perinatol.,  2001, 21(S1)(Suppl. 1), S48-S51.
[http://dx.doi.org/10.1038/sj.jp.7210634] [PMID: 11803417] 
[58] 
Brito, M.A.; Brites, D.; Butterfield, D.A. A link between hyperbilirubinemia, oxidative stress and injury to neocortical synaptosomes. Brain Res.,  2004, 1026(1), 33-43.
[http://dx.doi.org/10.1016/j.brainres.2004.07.063] [PMID: 15476695] 
[59] 
Ahdab-Barmada, M.; Moossy, J. The neuropathology of kernicterus in the premature neonate: Diagnostic problems. J. Neuropathol. Exp. Neurol.,  1984, 43(1), 45-56.
[http://dx.doi.org/10.1097/00005072-198401000-00004] [PMID: 6693927] 
[60] 
Barateiro, A.; Miron, V.E.; Santos, S.D.; Relvas, J.B.; Fernandes, A.; Ffrench-Constant, C.; Brites, D. Unconjugated bilirubin restricts oligodendrocyte differentiation and axonal myelination. Mol. Neurobiol.,  2013, 47(2), 632-644.
[http://dx.doi.org/10.1007/s12035-012-8364-8] [PMID: 23086523] 
[61] 
Fernandes, A.; Falcão, A.S.; Abranches, E.; Bekman, E.; Henrique, D.; Lanier, L.M.; Brites, D. Bilirubin as a determinant for altered neurogenesis, neuritogenesis, and synaptogenesis. Dev. Neurobiol.,  2009, 69(9), 568-582.
[http://dx.doi.org/10.1002/dneu.20727] [PMID: 19449315] 
[62] 
Zucker, S.D.; Goessling, W.; Bootle, E.J.; Sterritt, C. Localization of bilirubin in phospholipid bilayers by parallax analysis of fluorescence quenching. J. Lipid Res.,  2001, 42(9), 1377-1388.
[http://dx.doi.org/10.1016/S0022-2275(20)30269-8] [PMID: 11518756] 
[63] 
Schutta, H.S.; Johnson, L. Electron microscopic observations on acute bilirubin encephalopathy in Gunn rats induced by sulfadimethoxine. Lab. Invest.,  1971, 24(1), 82-89.
[PMID: 4322704] 
[64] 
Wennberg, R.P.; Johansson, B.B.; Folbergrová, J.; Siesjö, B.K. Bilirubin-induced changes in brain energy metabolism after osmotic opening of the blood-brain barrier. Pediatr. Res.,  1991, 30(5), 473-478.
[http://dx.doi.org/10.1203/00006450-199111000-00015] [PMID: 1754304] 
[65] 
Vogt, M.T.; Basford, R.E. The effect of bilirubin on the energy metabolism of brain mitochondria. J. Neurochem.,  1968, 15(11), 1313-1320.
[http://dx.doi.org/10.1111/j.1471-4159.1968.tb05909.x] [PMID: 4236753] 
[66] 
Soto Conti, C.P. Bilirubin: The toxic mechanisms of an antioxidant molecule. Arch. Argent. Pediatr.,  2021, 119(1), e18-e25.
[PMID: 33458986] 
[67] 
Watchko, J.F. Bilirubin-induced neurotoxicity in the preterm neonate. 2016, 43(2), 297-311.
[http://dx.doi.org/10.1016/j.clp.2016.01.007] 
[68] 
Bortolussi, G; Codarin, E; Antoniali, G; Vascotto, C; Vodret, S; Arena, S. Impairment of enzymatic antioxidant defenses is associated with bilirubin-induced neuronal cell death in the cerebellum of Ugt1 KO mice. 2015, 6(50), e1739.
[http://dx.doi.org/10.1038/cddis.2015.113] 
[69] 
Rawat, V.; Bortolussi, G.; Gazzin, S.; Tiribelli, C.; Muro, A.F. Bilirubin-induced oxidative stress leads to DNA damage in the cerebellum of hyperbilirubinemic neonatal mice and activates DNA double-strand break repair pathways in human cells. Oxid. Med. Cell. Longev.,  2018, 2018, 1801243.
[http://dx.doi.org/10.1155/2018/1801243] [PMID: 30598724] 
[70] 
Basu, S.; De, D.; Dev Khanna, H.; Kumar, A. Lipid peroxidation, DNA damage and total antioxidant status in neonatal hyperbilirubinemia. J. Perinatol.,  2014, 34(7), 519-523.
[http://dx.doi.org/10.1038/jp.2014.45] [PMID: 24674982] 
[71] 
Grojean, S.; Koziel, V.; Vert, P.; Daval, J.L. Bilirubin induces apoptosis via activation of NMDA receptors in developing rat brain neurons. Exp. Neurol.,  2000, 166(2), 334-341.
[http://dx.doi.org/10.1006/exnr.2000.7518] [PMID: 11085898] 
[72] 
Novelli, A.; Reilly, J.A.; Lysko, P.G.; Henneberry, R.C. Glutamate becomes neurotoxic via the N-methyl-D-aspartate receptor when intracellular energy levels are reduced. Brain Res.,  1988, 451(1-2), 205-212.
[http://dx.doi.org/10.1016/0006-8993(88)90765-2] [PMID: 2472189] 
[73] 
Slemmer, J.E.; De Zeeuw, C.I.; Weber, J.T. Don’t get too excited: Mechanisms of glutamate-mediated Purkinje cell death. Prog. Brain Res.,  2005, 148, 367-390.
[http://dx.doi.org/10.1016/S0079-6123(04)48029-7] [PMID: 15661204] 
[74] 
Johnston, M.V.; Hoon, A.H., Jr Possible mechanisms in infants for selective basal ganglia damage from asphyxia, kernicterus, or mitochondrial encephalopathies. J. Child Neurol.,  2000, 15(9), 588-591.
[http://dx.doi.org/10.1177/088307380001500904] [PMID: 11019789] 
[75] 
Greenamyre, T.; Penney, J.B.; Young, A.B.; Hudson, C.; Silverstein, F.S.; Johnston, M.V. Evidence for transient perinatal glutamatergic innervation of globus pallidus. J. Neurosci.,  1987, 7(4), 1022-1030.
[http://dx.doi.org/10.1523/JNEUROSCI.07-04-01022.1987] [PMID: 2883265] 
[76] 
Spencer, R.F.; Shaia, W.T.; Gleason, A.T.; Sismanis, A.; Shapiro, S.M. Changes in calcium-binding protein expression in the auditory brainstem nuclei of the jaundiced Gunn rat. Hear. Res.,  2002, 171(1-2), 129-141.
[http://dx.doi.org/10.1016/S0378-5955(02)00494-X] [PMID: 12204357] 
[77] 
Churn, S.B.; DeLorenzo, R.J.; Shapiro, S.M. Bilirubin induces a calcium-dependent inhibition of multifunctional Ca2+/calmodulin-dependent kinase II activity in vitro. Pediatr. Res.,  1995, 38(6), 949-954.
[http://dx.doi.org/10.1203/00006450-199512000-00020] [PMID: 8618799] 
[78] 
Shaia, W.T.; Shapiro, S.M.; Heller, A.J.; Galiani, D.L.; Sismanis, A.; Spencer, R.F. Immunohistochemical localization of calcium-binding proteins in the brainstem vestibular nuclei of the jaundiced Gunn rat. Hear. Res.,  2002, 173(1-2), 82-90.
[http://dx.doi.org/10.1016/S0378-5955(02)00631-7] [PMID: 12372637] 
[79] 
McDonald, J.W.; Shapiro, S.M.; Silverstein, F.S.; Johnston, M.V. Role of glutamate receptor-mediated excitotoxicity in bilirubin-induced brain injury in the Gunn rat model. Exp. Neurol.,  1998, 150(1), 21-29.
[http://dx.doi.org/10.1006/exnr.1997.6762] [PMID: 9514835] 
[80] 
Rodrigues, C.M.P.; Solá, S.; Brites, D. Bilirubin induces apoptosis via the mitochondrial pathway in developing rat brain neurons. Hepatology,  2002, 35(5), 1186-1195.
[http://dx.doi.org/10.1053/jhep.2002.32967] [PMID: 11981769] 
[81] 
Tiribelli, C.; Ostrow, J.D. The molecular basis of bilirubin encephalopathy and toxicity: Report of an EASL Single Topic Conference, Trieste, Italy, 1-2 October, 2005. 2004, 43(1), pp. 156-166.
[82] 
Lin, S.; Yan, C.; Wei, X.; Paul, S.M.; Du, Y. p38 MAP kinase mediates bilirubin-induced neuronal death of cultured rat cerebellar granule neurons. Neurosci. Lett.,  2003, 353(3), 209-212.
[http://dx.doi.org/10.1016/j.neulet.2003.09.053] [PMID: 14665418] 
[83] 
Qaisiya, M.; Brischetto, C.; Jašprová, J.; Vitek, L.; Tiribelli, C.; Bellarosa, C. Bilirubin-induced ER stress contributes to the inflammatory response and apoptosis in neuronal cells. Arch. Toxicol.,  2017, 91(4), 1847-1858.
[http://dx.doi.org/10.1007/s00204-016-1835-3] [PMID: 27578021] 
[84] 
Hankø, E.; Hansen, T.W.; Almaas, R.; Paulsen, R.; Rootwelt, T. Synergistic protection of a general caspase inhibitor and MK-801 in bilirubin-induced cell death in human NT2-N neurons. Pediatr. Res.,  2006, 59(1), 72-77.
[http://dx.doi.org/10.1203/01.pdr.0000191135.63586.08] [PMID: 16326984] 
[85] 
Silva, R.F.M.; Rodrigues, C.M.P.; Brites, D. Rat cultured neuronal and glial cells respond differently to toxicity of unconjugated bilirubin. Pediatr. Res.,  2002, 51(4), 535-541.
[http://dx.doi.org/10.1203/00006450-200204000-00022] [PMID: 11919342] 
[86] 
Silva, R.F.M.; Rodrigues, C.M.P.; Brites, D. Bilirubin-induced apoptosis in cultured rat neural cells is aggravated by chenodeoxycholic acid but prevented by ursodeoxycholic acid. J. Hepatol.,  2001, 34(3), 402-408.
[http://dx.doi.org/10.1016/S0168-8278(01)00015-0] [PMID: 11322201] 
[87] 
Hankø, E.; Hansen, T.W.; Almaas, R.; Lindstad, J.; Rootwelt, T. Bilirubin induces apoptosis and necrosis in human NT2-N neurons. Pediatr. Res.,  2005, 57(2), 179-184.
[http://dx.doi.org/10.1203/01.PDR.0000148711.11519.A5] [PMID: 15611354] 
[88] 
Brites, D. The evolving landscape of neurotoxicity by unconjugated bilirubin: Role of glial cells and inflammation. Front. Pharmacol.,  2012, 3, 88.
[http://dx.doi.org/10.3389/fphar.2012.00088] [PMID: 22661946] 
[89] 
Yueh, M.F.; Chen, S.; Nguyen, N.; Tukey, R.H. Developmental onset of bilirubin-induced neurotoxicity involves Toll-like receptor 2-dependent signaling in humanized UDP-glucuronosyltransferase1 mice. J. Biol. Chem.,  2014, 289(8), 4699-4709.
[http://dx.doi.org/10.1074/jbc.M113.518613] [PMID: 24403077] 
[90] 
El Chediak, A.; Janom, K.; Koubar, S.H. Bile cast nephropathy: When the kidneys turn yellow. Renal Replacement Ther.,  2020, 6(1), 1-7.
[http://dx.doi.org/10.1186/s41100-020-00265-0] 
[91] 
Sitprija, V.; Kashemsant, U.; Sriratanaban, A.; Arthachinta, S.; Poshyachinda, V. Renal function in obstructive jaundice in man: Cholangiocarcinoma model. Kidney Int.,  1990, 38(5), 948-955.
[http://dx.doi.org/10.1038/ki.1990.296] [PMID: 2176256] 
[92] 
Betjes, M.G.H.; Bajema, I. The pathology of jaundice-related renal insufficiency: Cholemic nephrosis revisited. J. Nephrol.,  2006, 19(2), 229-233.
[PMID: 16736428] 
[93] 
Chvez-Iiguez, J.S.; Meza-Ros, A.; Santos-Garcia, A.; Garca-Garca, G.; Armendriz-Borunda, J. Cholemic nephropathy: Hyperbilirubinemia and its impact on renal function. J. Renal Hepatic Disorders,  2019, 3(1), 33-39.
[http://dx.doi.org/10.15586/jrenhep.2019.52] 
[94] 
Bairaktari, E.; Liamis, G.; Tsolas, O.; Elisaf, M. Partially reversible renal tubular damage in patients with obstructive jaundice. Hepatology,  2001, 33(6), 1365-1369.
[http://dx.doi.org/10.1053/jhep.2001.25089] [PMID: 11391524] 
[95] 
Martínez-Cecilia, D.; Reyes-Díaz, M.; Ruiz-Rabelo, J.; Gomez-Alvarez, M.; Villanueva, C.M.; Álamo, J.; Muntané, J.; Padillo, F.J. Oxidative stress influence on renal dysfunction in patients with obstructive jaundice: A case and control prospective study. Redox Biol.,  2016, 8, 160-164.
[http://dx.doi.org/10.1016/j.redox.2015.12.009] [PMID: 26774750] 
[96] 
Sens, F.; Bacchetta, J.; Rabeyrin, M.; Juillard, L. Efficacy of extracorporeal albumin dialysis for acute kidney injury due to cholestatic jaundice nephrotoxicity. BMJ Case Rep.,  2016, 2016, bcr-2015-213257.
[http://dx.doi.org/10.1136/bcr-2015-213257] [PMID: 27389722] 
[97] 
Fickert, P.; Krones, E.; Pollheimer, M.J.; Thueringer, A.; Moustafa, T.; Silbert, D.; Halilbasic, E.; Yang, M.; Jaeschke, H.; Stokman, G.; Wells, R.G.; Eller, K.; Rosenkranz, A.R.; Eggertsen, G.; Wagner, C.A.; Langner, C.; Denk, H.; Trauner, M. Bile acids trigger cholemic nephropathy in common bile-duct-ligated mice. Hepatology,  2013, 58(6), 2056-2069.
[http://dx.doi.org/10.1002/hep.26599] [PMID: 23813550] 
[98] 
Krones, E.; Eller, K.; Pollheimer, M.J.; Racedo, S.; Kirsch, A.H.; Frauscher, B.; Wahlström, A.; Ståhlman, M.; Trauner, M.; Grahammer, F.; Huber, T.B.; Wagner, K.; Rosenkranz, A.R.; Marschall, H.U.; Fickert, P. NorUrsodeoxycholic acid ameliorates cholemic nephropathy in bile duct ligated mice. J. Hepatol.,  2017, 67(1), 110-119.
[http://dx.doi.org/10.1016/j.jhep.2017.02.019] [PMID: 28242240] 
[99] 
Alexandra Brito, M.; Silva, R.F.; Brites, D. Bilirubin toxicity to human erythrocytes: A review. Clin. Chim. Acta,  2006, 374(1-2), 46-56.
[http://dx.doi.org/10.1016/j.cca.2006.06.012] [PMID: 16887110] 
[100] 
Fadok, V.A.; Bratton, D.L.; Frasch, S.C.; Warner, M.L.; Henson, P.M. The role of phosphatidylserine in recognition of apoptotic cells by phagocytes. 1998, 5, 551, 562.
[http://dx.doi.org/10.1038/sj.cdd.4400404] 
[101] 
Brito, M.A.; Silva, R.; Tiribelli, C.; Brites, D. Assessment of bilirubin toxicity to erythrocytes. Implication in neonatal jaundice management. Eur. J. Clin. Invest.,  2000, 30(3), 239-247.
[http://dx.doi.org/10.1046/j.1365-2362.2000.00612.x] [PMID: 10692001] 
[102] 
Brito, M.A.; Silva, R.M.; Matos, D.C.; da Silva, A.T.; Brites, D.T. Alterations of erythrocyte morphology and lipid composition by hyperbilirubinemia. Clin. Chim. Acta,  1996, 249(1-2), 149-165.
[http://dx.doi.org/10.1016/0009-8981(96)06285-7] [PMID: 8737599] 
[103] 
Tayyab, S.; Ali, M.K. A comparative study on the extraction of membrane-bound bilirubin from erythrocyte membranes using various methods. J. Biochem. Biophys. Methods,  1999, 39(1-2), 39-45.
[http://dx.doi.org/10.1016/S0165-022X(98)00049-9] [PMID: 10344499] 
[104] 
Jones, P.A.; Baylin, S.B. The fundamental role of epigenetic events in cancer. Nat. Rev. Genet.,  2002, 3(6), 415-428.
[http://dx.doi.org/10.1038/nrg816] [PMID: 12042769] 
[105] 
Strom, P.; Snve, O.; Rossi, J.J. Epigenetics and microRNAs. Nature,  2007, 61, 17-23.
[106] 
Moradi Sarabi, M.; Zahedi, S.A.; Pajouhi, N.; Khosravi, P.; Bagheri, S.; Ahmadvand, H.; Shahryarhesami, S. The effects of dietary polyunsaturated fatty acids on miR-126 promoter DNA methylation status and VEGF protein expression in the colorectal cancer cells. Genes Nutr.,  2018, 13(1), 32.
[http://dx.doi.org/10.1186/s12263-018-0623-5] [PMID: 30598703] 
[107] 
Mokarram, P.; Shakiba-Jam, F.; Kavousipour, S.; Sarabi, M.M.; Seghatoleslam, A. Promoter methylation status of two novel human genes, UBE2Q1 and UBE2Q2, in colorectal cancer: A new finding in Iranian patients. Asian Pac. J. Cancer Prev.,  2015, 16(18), 8247-8252.
[http://dx.doi.org/10.7314/APJCP.2015.16.18.8247] [PMID: 26745068] 
[108] 
Maruyama, T.; Tanaka, K.; Suzuki, J.; Miyoshi, H.; Harada, N.; Nakamura, T.; Miyamoto, Y.; Kanatani, A.; Tamai, Y. Targeted disruption of G protein-coupled bile acid receptor 1 (Gpbar1/M-Bar) in mice. J. Endocrinol.,  2006, 191(1), 197-205.
[http://dx.doi.org/10.1677/joe.1.06546] [PMID: 17065403] 
[109] 
Thomas, C.; Gioiello, A.; Noriega, L.; Strehle, A.; Oury, J.; Rizzo, G.; Macchiarulo, A.; Yamamoto, H.; Mataki, C.; Pruzanski, M.; Pellicciari, R.; Auwerx, J.; Schoonjans, K. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab.,  2009, 10(3), 167-177.
[http://dx.doi.org/10.1016/j.cmet.2009.08.001] [PMID: 19723493] 
[110] 
Wang, Y.D.; Chen, W.D.; Yu, D.; Forman, B.M.; Huang, W. The G-protein-coupled bile acid receptor, Gpbar1 (TGR5), negatively regulates hepatic inflammatory response through antagonizing nuclear factor κ light-chain enhancer of activated B cells (NF-κB) in mice. Hepatology,  2011, 54(4), 1421-1432.
[http://dx.doi.org/10.1002/hep.24525] [PMID: 21735468] 
[111] 
Ahlbory-Dieker, D.L.; Stride, B.D.; Leder, G.; Schkoldow, J.; Trölenberg, S.; Seidel, H.; Otto, C.; Sommer, A.; Parker, M.G.; Schütz, G.; Wintermantel, T.M. DNA binding by estrogen receptor-alpha is essential for the transcriptional response to estrogen in the liver and the uterus. Mol. Endocrinol.,  2009, 23(10), 1544-1555.
[http://dx.doi.org/10.1210/me.2009-0045] [PMID: 19574448] 
[112] 
Villa, E.; Baldini, G.M.; Rossini, G.P.; Pasquinelli, C.; Melegari, M.; Cariani, E.; Tata, C.; Bellentani, S.; Ferrari, A.; Manenti, F. Ethanol-induced increase in cytosolic estrogen receptors in human male liver: A possible explanation for biochemical feminization in chronic liver disease due to alcohol. Hepatology,  1988, 8(6), 1610-1614.
[http://dx.doi.org/10.1002/hep.1840080623] [PMID: 3192175] 
[113] 
Fan, X.P.; Dou, C.Y.; Fan, Y.C.; Cao, C.J.; Zhao, Z.H.; Wang, K. Methylation status of the estrogen receptor 1 promoter predicts poor prognosis of acute-on-chronic hepatitis B liver failure. Rev. Esp. Enferm. Dig.,  2017, 109(12), 818-827.
[http://dx.doi.org/10.17235/reed.2017.4426/2016] [PMID: 29082740] 
[114] 
Basu, N.K.; Ciotti, M.; Hwang, M.S.; Kole, L.; Mitra, P.S.; Cho, J.W.; Owens, I.S. Differential and special properties of the major human UGT1-encoded gastrointestinal UDP-glucuronosyltransferases enhance potential to control chemical uptake. J. Biol. Chem.,  2004, 279(2), 1429-1441.
[http://dx.doi.org/10.1074/jbc.M306439200] [PMID: 14557274] 
[115] 
Gregory, P.A.; Lewinsky, R.H.; Gardner-Stephen, D.A.; Mackenzie, P.I. Coordinate regulation of the human UDP-glucuronosyltransferase 1A8, 1A9, and 1A10 genes by hepatocyte nuclear factor 1alpha and the caudal-related homeodomain protein 2. Mol. Pharmacol.,  2004, 65(4), 953-963.
[http://dx.doi.org/10.1124/mol.65.4.953] [PMID: 15044625] 
[116] 
Oda, S.; Fukami, T.; Yokoi, T.; Nakajima, M. Epigenetic regulation of the tissue-specific expression of human UDP-glucuronosyltransferase (UGT) 1A10. Biochem. Pharmacol.,  2014, 87(4), 660-667.
[http://dx.doi.org/10.1016/j.bcp.2013.11.001] [PMID: 24239897] 
[117] 
Kathawala, M.; Hirschfield, G.M. Insights into the management of Wilson’s disease. Therap. Adv. Gastroenterol.,  2017, 10(11), 889-905.
[http://dx.doi.org/10.1177/1756283X17731520] [PMID: 29147139] 
[118] 
Kim, T.S.; Pae, C.U.; Yoon, S.J.; Jang, W.Y.; Lee, N.J.; Kim, J.J.; Lee, S.J.; Lee, C.; Paik, I.H.; Lee, C.U. Decreased plasma antioxidants in patients with Alzheimer’s disease. Int. J. Geriatr. Psychiatry,  2006, 21(4), 344-348.
[http://dx.doi.org/10.1002/gps.1469] [PMID: 16534775] 
[119] 
Wang, T.; Wu, H.; Li, Y.; Szulwach, K.E.; Lin, L.; Li, X.; Chen, I.P.; Goldlust, I.S.; Chamberlain, S.J.; Dodd, A.; Gong, H.; Ananiev, G.; Han, J.W.; Yoon, Y.S.; Rudd, M.K.; Yu, M.; Song, C.X.; He, C.; Chang, Q.; Warren, S.T.; Jin, P. Subtelomeric hotspots of aberrant 5-hydroxymethylcytosine-mediated epigenetic modifications during reprogramming to pluripotency. Nat. Cell Biol.,  2013, 15(6), 700-711.
[http://dx.doi.org/10.1038/ncb2748] [PMID: 23685628] 
[120] 
Park, K.C.; Park, J.H.; Jeon, J.Y.; Kim, S.Y.; Kim, J.M.; Lim, C.Y.; Lee, T.H.; Kim, H.K.; Lee, H.G.; Kim, S.M.; Kwon, H.J.; Suh, J.S.; Kim, S.W.; Choi, S.H. A new histone deacetylase inhibitor improves liver fibrosis in BDL rats through suppression of hepatic stellate cells. Br. J. Pharmacol.,  2014, 171(21), 4820-4830.
[http://dx.doi.org/10.1111/bph.12590] [PMID: 24467283] 
[121] 
Murata, K.; Hamada, M.; Sugimoto, K.; Nakano, T. A novel mechanism for drug-induced liver failure: Inhibition of histone acetylation by hydralazine derivatives. J. Hepatol.,  2007, 46(2), 322-329.
[http://dx.doi.org/10.1016/j.jhep.2006.09.017] [PMID: 17156885] 
[122] 
Sheen-Chen, S.M.; Lin, C.R.; Chen, K.H.; Yang, C.H.; Lee, C.T.; Huang, H.W.; Huang, C.Y. Epigenetic histone methylation regulates transforming growth factor β-1 expression following bile duct ligation in rats. J. Gastroenterol.,  2014, 49(8), 1285-1297.
[http://dx.doi.org/10.1007/s00535-013-0892-0] [PMID: 24097032] 
[123] 
Rao, R.C.; Dou, Y. Hijacked in cancer: The KMT2 (MLL) family of methyltransferases. Nat. Rev. Cancer,  2015, 15(6), 334-346.
[http://dx.doi.org/10.1038/nrc3929] [PMID: 25998713] 
[124] 
Liang, W.; Lscher-Firzlaff, J.; Ullius, A.; Schneider, U.; Longerich, T.; Lscher, B. Loss of the epigenetic regulator Ash2l results in desintegration of hepatocytes and liver failure. Int. J. Clin. Exp. Pathol.,  2016, 9, 5167.
[125] 
El Samaloty, N.M.; Hassan, Z.A.; Hefny, Z.M.; Abdelaziz, D.H.A. Circulating microRNA-155 is associated with insulin resistance in chronic hepatitis C patients. Arab J. Gastroenterol.,  2019, 20(1), 1-7.
[http://dx.doi.org/10.1016/j.ajg.2019.01.011] [PMID: 30852102] 
[126] 
Qu, Y.; Zhang, Q.; Cai, X.; Li, F.; Ma, Z.; Xu, M.; Lu, L. Exosomes derived from miR-181-5p-modified adipose-derived mesenchymal stem cells prevent liver fibrosis via autophagy activation. J. Cell. Mol. Med.,  2017, 21(10), 2491-2502.
[http://dx.doi.org/10.1111/jcmm.13170] [PMID: 28382720] 
[127] 
Chen, S.; He, N.; Yu, J.; Li, L.; Hu, Y.; Deng, R.; Zhong, S.; Shen, L. Post-transcriptional regulation by miR-137 underlies the low abundance of CAR and low rate of bilirubin clearance in neonatal mice. Life Sci.,  2014, 107(1-2), 8-13.
[http://dx.doi.org/10.1016/j.lfs.2014.04.024] [PMID: 24792516] 
[128] 
Liu, H.H.; Li, A.J. MiR-340 suppresses CCl4-induced acute liver injury through exerting anti-inflammation targeting Sigirr. Eur. Rev. Med. Pharmacol. Sci.,  2020, 24(20), 10687-10695.
[PMID: 33155227] 
[129] 
Kumar, V.; Kumar, V.; Luo, J.; Mahato, R.I. Therapeutic potential of OMe-PS-miR-29b1 for treating liver fibrosis. Mol. Ther.,  2018, 26(12), 2798-2811.
[http://dx.doi.org/10.1016/j.ymthe.2018.08.022] [PMID: 30287074] 
[130] 
Katsushima, F.; Takahashi, A.; Sakamoto, N.; Kanno, Y.; Abe, K.; Ohira, H. Expression of micro-RNAs in peripheral blood mononuclear cells from primary biliary cirrhosis patients. Hepatol. Res.,  2014, 44(10), E189-E197.
[http://dx.doi.org/10.1111/hepr.12198] [PMID: 23834361] 
[131] 
Song, G.; Jia, H.; Xu, H.; Liu, W.; Zhu, H.; Li, S.; Shi, J.; Li, Z.; He, J.; Chen, Z. Studying the association of microRNA-210 level with chronic hepatitis B progression. J. Viral Hepat.,  2014, 21(4), 272-280.
[http://dx.doi.org/10.1111/jvh.12138] [PMID: 24597695] 
[132] 
Bihrer, V.; Waidmann, O.; Friedrich-Rust, M.; Forestier, N.; Susser, S.; Haupenthal, J.; Welker, M.; Shi, Y.; Peveling-Oberhag, J.; Polta, A.; von Wagner, M.; Radeke, H.H.; Sarrazin, C.; Trojan, J.; Zeuzem, S.; Kronenberger, B.; Piiper, A. Serum microRNA-21 as marker for necroinflammation in hepatitis C patients with and without hepatocellular carcinoma. PLoS One,  2011, 6(10), e26971.
[http://dx.doi.org/10.1371/journal.pone.0026971] [PMID: 22066022] 
[133] 
Matton, A.P.M.; Selten, J.W.; Roest, H.P.; de Jonge, J.; IJzermans, J.N.M.; de Meijer, V.E.; Porte, R.J.; van der Laan, L.J.W. Cell-free microRNAs as early predictors of graft viability during ex vivo normothermic machine perfusion of human donor livers. Clin. Transplant.,  2020, 34(3), e13790.
[http://dx.doi.org/10.1111/ctr.13790] [PMID: 31984571] 
[134] 
Eguchi, A.; Franz, N.; Kobayashi, Y.; Iwasa, M.; Wagner, N.; Hildebrand, F.; Takei, Y.; Marzi, I.; Relja, B. Circulating extracellular vesicles and their miR Barcode differentiate alcohol drinkers with liver injury and those without liver injury in severe trauma patients. Front. Med. (Lausanne),  2019, 6(FEB), 30.
[http://dx.doi.org/10.3389/fmed.2019.00030] [PMID: 30859103] 
[135] 
Nasser, M.Z.; Zayed, N.A.; Mohamed, A.M.; Attia, D.; Esmat, G.; Khairy, A. Circulating microRNAs (miR-21, miR-223, miR-885-5p) along the clinical spectrum of HCV-related chronic liver disease in Egyptian patients. Arab J. Gastroenterol.,  2019, 20(4), 198-204.
[http://dx.doi.org/10.1016/j.ajg.2019.11.003] [PMID: 31806407] 
[136] 
Ruoquan, Y.; Wanpin, N.; Qiangsheng, X.; Guodong, T.; Feizhou, H. Correlation between plasma miR-122 expression and liver injury induced by hepatectomy. J. Int. Med. Res.,  2014, 42(1), 77-84.
[http://dx.doi.org/10.1177/0300060513499093] [PMID: 24287929] 
[137] 
Fathi-Kazerooni, M.; Kazemnejad, S.; Khanjani, S.; Saltanatpour, Z.; Tavoosidana, G. Down-regulation of miR-122 after transplantation of mesenchymal stem cells in acute liver failure in mice model. Biologicals,  2019, 58, 64-72.
[http://dx.doi.org/10.1016/j.biologicals.2019.02.002] [PMID: 30824230] 
[138] 
Roy, S.; Benz, F.; Alder, J.; Bantel, H.; Janssen, J.; Vucur, M.; Gautheron, J.; Schneider, A.; Schüller, F.; Loosen, S.; Luedde, M.; Koch, A.; Tacke, F.; Luedde, T.; Trautwein, C.; Roderburg, C. Down-regulation of miR-192-5p protects from oxidative stress-induced acute liver injury. Clin. Sci. (Lond.),  2016, 130(14), 1197-1207.
[http://dx.doi.org/10.1042/CS20160216] [PMID: 27129188] 
[139] 
Roderburg, C.; Benz, F.; Vargas Cardenas, D.; Koch, A.; Janssen, J.; Vucur, M.; Gautheron, J.; Schneider, A.T.; Koppe, C.; Kreggenwinkel, K.; Zimmermann, H.W.; Luedde, M.; Trautwein, C.; Tacke, F.; Luedde, T. Elevated miR-122 serum levels are an independent marker of liver injury in inflammatory diseases. Liver Int.,  2015, 35(4), 1172-1184.
[http://dx.doi.org/10.1111/liv.12627] [PMID: 25039534] 
[140] 
Rahmel, T.; Rump, K.; Adamzik, M.; Peters, J.; Frey, U.H. Increased circulating microRNA-122 is associated with mortality and acute liver injury in the acute respiratory distress syndrome. BMC Anesthesiol.,  2018, 18(1), 75.
[http://dx.doi.org/10.1186/s12871-018-0541-5] [PMID: 29935532] 
[141] 
Zhang, J.; Huang, Y.; Wang, Q.; Ma, Y.; Qi, Y.; Liu, Z.; Deng, J.; Ruan, Q. Levels of human cytomegalovirus miR-US25-1-5p and miR-UL112-3p in serum extracellular vesicles from infants with HCMV active infection are significantly correlated with liver damage. Eur. J. Clin. Microbiol. Infect. Dis.,  2020, 39(3), 471-481.
[http://dx.doi.org/10.1007/s10096-019-03747-0] [PMID: 31749099] 
[142] 
Calkins, K.L.; Thamotharan, S.; Ghosh, S.; Dai, Y.; Devaskar, S.U. MicroRNA 122 reflects liver injury in children with intestinal failure-associated liver disease treated with intravenous fish oil. J. Nutr.,  2020, 150(5), 1144-1150.
[http://dx.doi.org/10.1093/jn/nxaa001] [PMID: 32072161] 
[143] 
Xing, L.; Xu, W.; Qu, Y.; Zhao, M.; Zhu, H.; Liu, H.; Wang, H.; Su, X.; Shao, Z. miR-150 regulates B lymphocyte in autoimmune hemolytic anemia/Evans syndrome by c-Myb. Int. J. Hematol.,  2018, 107(6), 666-672.
[http://dx.doi.org/10.1007/s12185-018-2429-z] [PMID: 29488168] 
[144] 
Tao, Y.C.; Wang, M.L.; Wang, M.; Ma, Y.J.; Bai, L.; Feng, P.; Chen, E.Q.; Tang, H. Quantification of circulating miR-125b-5p predicts survival in chronic hepatitis B patients with acute-on-chronic liver failure. Dig. Liver Dis.,  2019, 51(3), 412-418.
[http://dx.doi.org/10.1016/j.dld.2018.08.030] [PMID: 30274791] 
[145] 
Roderburg, C.; Koch, A.; Benz, F.; Vucur, M.; Spehlmann, M.; Loosen, S.H.; Luedde, M.; Rehse, S.; Lurje, G.; Trautwein, C.; Tacke, F.; Luedde, T. Serum levels of miR-143 predict survival in critically Ill patients. Dis. Markers,  2019, 2019, 4850472.
[http://dx.doi.org/10.1155/2019/4850472] [PMID: 31772686] 
[146] 
Shaker, O.G.; Senousy, M.A. Serum microRNAs as predictors for liver fibrosis staging in hepatitis C virus-associated chronic liver disease patients. J. Viral Hepat.,  2017, 24(8), 636-644.
[http://dx.doi.org/10.1111/jvh.12696] [PMID: 28211229] 
[147] 
Jiang, S.; Jiang, W.; Xu, Y.; Wang, X.; Mu, Y.; Liu, P. Serum miR-21 and miR-26a levels negatively correlate with severity of cirrhosis in patients with chronic hepatitis B. MicroRNA,  2019, 8(1), 86-92.
[http://dx.doi.org/10.2174/2211536607666180821162850] [PMID: 30147020] 
[148] 
Chen, C.; Zhang, L.; Huang, H.; Liu, S.; Liang, Y.; Xu, L.; Li, S.; Cheng, Y.; Tang, W. Serum miR-126-3p level is down-regulated in sepsis patients. Int. J. Clin. Exp. Pathol.,  2018, 11(5), 2605-2612.
[PMID: 31938374] 
[149] 
Qian, C.; Chen, S.X.; Ren, C.L.; Zhong, R.Q.; Deng, A.M.; Qin, Q. [Abnormal expression of miR-let-7b in primary biliary cirrhosis and its clinical significance]. Chung Hua Kan Tsang Ping Tsa Chih,  2013, 21(7), 533-536.
[PMID: 24074714] 
[150] 
Ayoub, S.E.; Shaker, O.G.; Abdelwahed, M.Y.; Ahmed, N.A.; Abdelhameed, H.G.; Bosilah, A.H.; Mohammed, S.R. Association of MicroRNA-155rs767649 polymorphism with susceptibility to preeclampsia. Int. J. Mol. Cell. Med.,  2019, 8(4), 247-257.
[PMID: 32587835] 
[151] 
Howell, L.S.; Ireland, L.; Park, B.K.; Goldring, C.E. MiR-122 and other microRNAs as potential circulating biomarkers of drug-induced liver injury. Expert Rev. Mol. Diagn.,  2018, 18(1), 47-54.
[http://dx.doi.org/10.1080/14737159.2018.1415145] [PMID: 29235390] 
[152] 
Koyama, S.; Kuragaichi, T.; Sato, Y.; Kuwabara, Y.; Usami, S.; Horie, T.; Baba, O.; Hakuno, D.; Nakashima, Y.; Nishino, T.; Nishiga, M.; Nakao, T.; Arai, H.; Kimura, T.; Ono, K. Dynamic changes of serum microRNA-122-5p through therapeutic courses indicates amelioration of acute liver injury accompanied by acute cardiac decompensation. ESC Heart Fail.,  2017, 4(2), 112-121.
[http://dx.doi.org/10.1002/ehf2.12123] [PMID: 28451447] 
[153] 
Ma, Z.H.; Sun, C.X.; Shi, H.; Fan, J.H.; Song, Y.G.; Cong, P.J.; Kong, X.M.; Hao, D.L. Detection of miR-122 by fluorescence real-time PCR in blood from patients with chronic hepatitis B and C infections. Cytokine,  2020, 131, 155076.
[http://dx.doi.org/10.1016/j.cyto.2020.155076] [PMID: 32289629] 
[154] 
Jiao, X.; Fan, Z.; Chen, H.; He, P.; Li, Y.; Zhang, Q.; Ke, C. Serum and exosomal miR-122 and miR-199a as a biomarker to predict therapeutic efficacy of hepatitis C patients. J. Med. Virol.,  2017, 89(9), 1597-1605.
[http://dx.doi.org/10.1002/jmv.24829] [PMID: 28401565] 
[155] 
Elmouttaleb, A.T.A.; Abd-elatif, D.M.; Soliman, G.M. Serum Micro RNA-122 as a biomarker for hepatocellular carcinoma in chronic hepatitis C virus patients. Res. Cancer Tumor,  2015, 4, 25-33.
[156] 
Waidmann, O.; Köberle, V.; Brunner, F.; Zeuzem, S.; Piiper, A.; Kronenberger, B. Serum microRNA-122 predicts survival in patients with liver cirrhosis. PLoS One,  2012, 7(9), e45652.
[http://dx.doi.org/10.1371/journal.pone.0045652] [PMID: 23029162] 
[157] 
Chen, Y.J.; Zhu, J.M.; Wu, H.; Fan, J.; Zhou, J.; Hu, J.; Yu, Q.; Liu, T.T.; Yang, L.; Wu, C.L.; Guo, X.L.; Huang, X.W.; Shen, X.Z. Circulating microRNAs as a fingerprint for liver cirrhosis. PLoS One,  2013, 8(6), e66577.
[http://dx.doi.org/10.1371/journal.pone.0066577] [PMID: 23805240] 
[158] 
Bihrer, V.; Friedrich-Rust, M.; Kronenberger, B.; Forestier, N.; Haupenthal, J.; Shi, Y.; Peveling-Oberhag, J.; Radeke, H.H.; Sarrazin, C.; Herrmann, E.; Zeuzem, S.; Waidmann, O.; Piiper, A. Serum miR-122 as a biomarker of necroinflammation in patients with chronic hepatitis C virus infection. Am. J. Gastroenterol.,  2011, 106(9), 1663-1669.
[http://dx.doi.org/10.1038/ajg.2011.161] [PMID: 21606975] 
[159] 
Starkey Lewis, P.J.; Dear, J.; Platt, V.; Simpson, K.J.; Craig, D.G.N.; Antoine, D.J.; French, N.S.; Dhaun, N.; Webb, D.J.; Costello, E.M.; Neoptolemos, J.P.; Moggs, J.; Goldring, C.E.; Park, B.K. Circulating microRNAs as potential markers of human drug-induced liver injury. Hepatology,  2011, 54(5), 1767-1776.
[http://dx.doi.org/10.1002/hep.24538] [PMID: 22045675] 
Cite As
Endocrine, Metabolic & Immune Disorders - Drug Targets

Bilirubin and Epigenetic Modifications in Metabolic and Immunometabolic Disorders

Abstract

Graphical Abstract
