Looking to the horizon: the role of bilirubin in the development and prevention of age-related chronic diseases

Watchko, 2013, Bilirubin-induced neurologic damage–mechanisms and management approaches, N. Engl. J. Med., 369, 2021, 10.1056/NEJMra1308124

Barateiro, 2013, Unconjugated bilirubin restricts oligodendrocyte differentiation and axonal myelination, Mol. Neurobiol., 47, 632, 10.1007/s12035-012-8364-8

Qaisiya, 2014, Bilirubin mediated oxidative stress involves antioxidant response activation via Nrf2 pathway, Cell. Signal., 26, 512, 10.1016/j.cellsig.2013.11.029

Rao, 2006, Bilirubin exhibits a novel anti-cancer effect on human adenocarcinoma, Biochem. Biophys. Res. Commun., 342, 1279, 10.1016/j.bbrc.2006.02.074

Stocker, 1987, Bilirubin is an antioxidant of possible physiological importance, Science, 235, 1043, 10.1126/science.3029864

Bulmer, 2013, Bilirubin and beyond: a review of lipid status in Gilbert's syndrome and its relevance to cardiovascular disease protection, Prog. Lipid. Res., 52, 193, 10.1016/j.plipres.2012.11.001

Stocker, 1989, Antioxidant properties of conjugated bilirubin and biliverdin: biologically relevant scavenging of hypochlorous acid, Free Radic. Res. Commun., 6, 57, 10.3109/10715768909073428

Bulmer, 2007, The anti-mutagenic and antioxidant effects of bile pigments in the Ames Salmonella test, Mutat. Res., 629, 122, 10.1016/j.mrgentox.2007.01.008

Molzer, 2012, In vitro antioxidant capacity and antigenotoxic properties of protoporphyrin and structurally related tetrapyrroles, Free Radic. Res., 46, 1369, 10.3109/10715762.2012.715371

Molzer, 2013, Extracellular and intracellular anti-mutagenic effects of bile pigments in the Salmonella typhimurium reverse mutation assay, Toxicol. In Vitro, 27, 433, 10.1016/j.tiv.2012.08.004

Molzer, 2013, Bilirubin and related tetrapyrroles inhibit food-borne mutagenesis: a mechanism for antigenotoxic action against a model epoxide, J. Nat. Prod., 76, 1958, 10.1021/np4005807

De Flora, 1994, Structural basis of antimutagenicity of chemicals towards 4-nitroquinoline 1-oxide in Salmonella typhimurium, Mutagenesis, 9, 39, 10.1093/mutage/9.1.39

Camoirano, 1994, Experimental databases on inhibition of the bacterial mutagenicity of 4-nitroquinoline 1-oxide and cigarette smoke, Mutat. Res., 317, 89, 10.1016/0165-1110(94)90019-1

Vitek, 2002, Gilbert syndrome and ischemic heart disease: a protective effect of elevated bilirubin levels, Atherosclerosis, 160, 449, 10.1016/S0021-9150(01)00601-3

Vitek, 2005, Impact of serum bilirubin on human diseases, Pediatrics, 115, 1411, 10.1542/peds.2004-1796

Vitek, 2007, The heme catabolic pathway and its protective effects on oxidative stress-mediated diseases, Adv. Clin. Chem., 43, 1, 10.1016/S0065-2423(06)43001-8

Vitek, 2009, Bilirubin chemistry and metabolism; harmful and protective aspects, Curr. Pharm. Des., 15, 2869, 10.2174/138161209789058237

Schwertner, 2008, Gilbert syndrome, UGT1A1*28 allele, and cardiovascular disease risk: possible protective effects and therapeutic applications of bilirubin, Atherosclerosis, 198, 1, 10.1016/j.atherosclerosis.2008.01.001

Lin, 2010, Serum bilirubin and genes controlling bilirubin concentrations as biomarkers for cardiovascular disease, Clin. Chem., 56, 1535, 10.1373/clinchem.2010.151043

Bulmer, 2008, Improved resistance to serum oxidation in Gilbert's syndrome: a mechanism for cardiovascular protection, Atherosclerosis, 199, 390, 10.1016/j.atherosclerosis.2007.11.022

Horsfall, 2011, Serum bilirubin and risk of respiratory disease and death, JAMA, 305, 691, 10.1001/jama.2011.124

Vitek, 2002, Gilbert syndrome and ischemic heart disease: a protective effect of elevated bilirubin levels, Atherosclerosis, 160, 449, 10.1016/S0021-9150(01)00601-3

Vitek, 2008, Protective effects of serum bilirubin on peripheral vascular disease, Ann. Hepatol., 7, 94, 10.1016/S1665-2681(19)31897-6

Vitek, 2005, The impact of intestinal microflora on serum bilirubin levels, J. Hepatol., 42, 238, 10.1016/j.jhep.2004.10.012

Temme, 2001, Serum bilirubin and 10-year mortality risk in a Belgian population, Cancer Causes Control, 12, 887, 10.1023/A:1013794407325

Zucker, 2004, Serum bilirubin levels in the U.S. population: gender effect and inverse correlation with colorectal cancer, Hepatology, 40, 827, 10.1002/hep.1840400412

Cox, 2013, Association of SNPs in the UGT1A gene cluster with total bilirubin and mortality in the Diabetes Heart Study, Atherosclerosis, 229, 155, 10.1016/j.atherosclerosis.2013.04.008

Vitek, 2012, The role of bilirubin in diabetes, metabolic syndrome, and cardiovascular diseases, Front. Pharmacol., 3, 55, 10.3389/fphar.2012.00055

Wagner, 2012, A global view on the development of non communicable diseases, Prev. Med., 54, S38, 10.1016/j.ypmed.2011.11.012

Klatskin, 1961, Bile pigment metabolism, Annu. Rev. Med., 12, 211, 10.1146/annurev.me.12.020161.001235

Schmid, 1975, The enzymatic formation of bilirubin, Ann. N. Y. Acad. Sci., 244, 533, 10.1111/j.1749-6632.1975.tb41553.x

Ryter, 2006, Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications, Physiol. Rev., 86, 583, 10.1152/physrev.00011.2005

Rigato, 2005, Bilirubin and the risk of common non-hepatic diseases, Trends Mol. Med., 11, 277, 10.1016/j.molmed.2005.04.008

Brodersen, 1979, Bilirubin. Solubility and interaction with albumin and phospholipid, J. Biol. Chem., 254, 2364, 10.1016/S0021-9258(17)30230-2

Brodersen, 1980, Binding of bilirubin to albumin, CRC Crit. Rev. Clin. Lab. Sci., 11, 305, 10.3109/10408368009105860

Kamisako, 2000, Recent advances in bilirubin metabolism research: the molecular mechanism of hepatocyte bilirubin transport and its clinical relevance, J. Gastroenterol., 35, 659, 10.1007/s005350070044

Arias, 2012, Liver function from Y to Z, J. Clin. Invest., 122, 2763, 10.1172/JCI64587

Isselbacher, 1956, Enzymatic mechanisms of hormone metabolism. II. Mechanism of hormonal glucuronide formation, Recent Prog. Hormone Res., 12, 134

Keitel, 2003, A common Dubin-Johnson syndrome mutation impairs protein maturation and transport activity of MRP2 (ABCC2), Am. J. Physiol. Gastrointest. Liver Physiol., 284, G165, 10.1152/ajpgi.00362.2002

Vitek, 2003, Enterohepatic cycling of bilirubin as a cause of ‘black’ pigment gallstones in adult life, Eur. J. Clin. Invest., 33, 799, 10.1046/j.1365-2362.2003.01214.x

Lester, 1961, Enterohepatic circulation of bilirubin, Nature, 192, 372, 10.1038/192372a0

Gilbertsen, 1962, Enterohepatic circulation of unconjugated bilirubin in man, Nature, 196, 141, 10.1038/196141a0

Vitek, 2006, Identification of bilirubin reduction products formed by Clostridium perfringens isolated from human neonatal fecal flora, J. Chromatogr. B. Analyt. Technol. Biomed. Life Sci., 833, 149, 10.1016/j.jchromb.2006.01.032

Vitek, 2000, Intestinal colonization leading to fecal urobilinoid excretion may play a role in the pathogenesis of neonatal jaundice, J. Pediatr. Gastroenterol. Nutr., 30, 294, 10.1097/00005176-200003000-00015

Stocker, 2004, Antioxidant activities of bile pigments, Antioxid. Redox Signal., 6, 841, 10.1089/ars.2004.6.841

Berk, 1974, Comparison of plasma bilirubin turnover and carbon monoxide production in man, J. Lab. Clin. Med., 83, 29

Fulks, 2009, Mortality associated with bilirubin levels in insurance applicants, J. Insur. Med., 41, 49

Ong, 2014, The relationship between total bilirubin levels and total mortality in older adults: the United States National Health and Nutrition Examination Survey (NHANES) 1999–2014, PLOS ONE, 9, e94479, 10.1371/journal.pone.0094479

Ajja, 2011, Usefulness of serum bilirubin and cardiorespiratory fitness as predictors of mortality in men, Am. J. Cardiol., 108, 1438, 10.1016/j.amjcard.2011.06.067

Horsfall, 2012, Cardiovascular events as a function of serum bilirubin levels in a large, statin-treated cohort, Circulation, 126, 2556, 10.1161/CIRCULATIONAHA.112.114066

Horsfall, 2013, Gilbert's syndrome and the risk of death: a population-based cohort study, J. Gastroenterol. Hepatol., 28, 1643, 10.1111/jgh.12279

Vasovic, 2014, Prediction of cardiovascular mortality in functional disabled elderly–a possible new score, J. Med. Biochem., 33, 181, 10.2478/jomb-2013-0026

Breimer, 1995, Serum bilirubin and risk of ischemic heart disease in middle-aged British men, Clin. Chem., 41, 1504, 10.1093/clinchem/41.10.1504

Novotny, 2003, Inverse relationship between serum bilirubin and atherosclerosis in men: a meta-analysis of published studies, Exp. Biol. Med., 228, 568, 10.1177/15353702-0322805-29

Chen, 2011, Serum bilirubin links UGT1A1*28 polymorphism and predicts long-term cardiovascular events and mortality in chronic hemodialysis patients, Clin. J. Am. Soc. Nephrol., 6, 567, 10.2215/CJN.06130710

Zhu, 2012, Association of arterial stiffness with serum bilirubin levels in established coronary artery disease, Intern. Med., 51, 2083, 10.2169/internalmedicine.51.7701

Ohnaka, 2010, Inverse associations of serum bilirubin with high sensitivity C-reactive protein, glycated hemoglobin, and prevalence of type 2 diabetes in middle-aged and elderly Japanese men and women, Diabetes Res. Clin. Pract., 88, 103, 10.1016/j.diabres.2009.12.022

Vitek, 2007, The heme catabolic pathway and its protective effects on oxidative stress-mediated diseases, Adv. Clin. Chem., 43, 1, 10.1016/S0065-2423(06)43001-8

Vitek, 2009, Bilirubin chemistry and metabolism; harmful and protective aspects, Curr. Pharm. Des., 15, 2869, 10.2174/138161209789058237

Bulmer, 2013, Bilirubin and beyond: a review of lipid status in Gilbert's syndrome and its relevance to cardiovascular disease protection, Prog. Lipid Res., 52, 193, 10.1016/j.plipres.2012.11.001

Boon, 2014, Circulating bilirubin and defense against kidney disease and cardiovascular mortality: mechanisms contributing to protection in clinical investigations, Am. J. Physiol. Renal Physiol., 307, F123, 10.1152/ajprenal.00039.2014

Wallner, 2013, Haem catabolism: a novel modulator of inflammation in Gilbert's syndrome, Eur. J. Clin. Invest., 43, 912, 10.1111/eci.12120

Kunutsor, 2015, Circulating total bilirubin and risk of incident cardiovascular disease in the general population, Arterioscler. Thromb. Vasc. Biol., 35, 716, 10.1161/ATVBAHA.114.304929

Schwertner, 1994, Association of low serum concentration of bilirubin with increased risk of coronary artery disease, Clin. Chem., 40, 18, 10.1093/clinchem/40.1.18

Vitek, 2002, Gilbert syndrome and ischemic heart disease: a protective effect of elevated bilirubin levels, Atherosclerosis, 160, 449, 10.1016/S0021-9150(01)00601-3

Vitek, 2006, The inverse association of elevated serum bilirubin levels with subclinical carotid atherosclerosis, Cerebrovasc. Dis., 21, 408, 10.1159/000091966

Kang, 2013, Elevated serum bilirubin levels are inversely associated with coronary artery atherosclerosis, Atherosclerosis, 230, 242, 10.1016/j.atherosclerosis.2013.06.021

Tanaka, 2009, Low serum bilirubin concentration is associated with coronary artery calcification (CAC), Atherosclerosis, 206, 287, 10.1016/j.atherosclerosis.2009.02.010

Mahabadi, 2014, Association of bilirubin with coronary artery calcification and cardiovascular events in the general population without known liver disease: the Heinz Nixdorf Recall study, Clin. Res. Cardiol., 103, 647, 10.1007/s00392-014-0697-z

Cure, 2013, The effect of Gilbert's syndrome on the dispersions of QT interval and P-wave: an observational study, Anadolu Kardiyol. Derg., 13, 559

Qin, 2008, Bilirubin would be the indispensable component for some of the most important therapeutic effects of Calculus Bovis (Niuhuang), Chin. Med. J. (Engl.), 121, 480, 10.1097/00029330-200803010-00024

Ma, 2012, The novel antidote Bezoar Bovis prevents the cardiotoxicity of toad (Bufo bufo gargarizans Canto) venom in mice, Exp. Toxicol. Pathol., 64, 417, 10.1016/j.etp.2010.10.007

Ma, 2012, Bilirubin attenuates bufadienolide-induced ventricular arrhythmias and cardiac dysfunction in guinea-pigs by reducing elevated intracellular Na+ levels, Cardiovasc. Toxicol., 12, 83, 10.1007/s12012-011-9142-y

Perlstein, 2008, Serum total bilirubin level and prevalent lower-extremity peripheral arterial disease: National Health and Nutrition Examination Survey (NHANES) 1999 to 2004, Arterioscler. Thromb. Vasc. Biol., 28, 166, 10.1161/ATVBAHA.107.153262

Perlstein, 2008, Serum total bilirubin level, prevalent stroke, and stroke outcomes: NHANES 1999–2004, Am. J. Med., 121, 781, 10.1016/j.amjmed.2008.03.045

Balta, 2014, Bilirubin levels and their association with carotid intima media thickness and high-sensitivity C-reactive protein in patients with psoriasis vulgaris, Am. J. Clin. Dermatol., 15, 137, 10.1007/s40257-014-0069-5

Erdogan, 2006, Low serum bilirubin levels are independently and inversely related to impaired flow-mediated vasodilation and increased carotid intima-media thickness in both men and women, Atherosclerosis, 184, 431, 10.1016/j.atherosclerosis.2005.05.011

Chen, 2011, TGR5: a novel target for weight maintenance and glucose metabolism, Exp. Diabetes Res., 2011, 853501, 10.1155/2011/853501

Kim, 2012, Serum total bilirubin concentration is inversely correlated with Framingham risk score in Koreans, Arch. Med. Res., 43, 288, 10.1016/j.arcmed.2012.05.003

Ben-Amotz, 2014, Intraperitoneal bilirubin administration decreases infarct area in a rat coronary ischemia/reperfusion model, Front. Physiol., 5, 53, 10.3389/fphys.2014.00053

Bakrania, 2014, Hyperbilirubinemia modulates myocardial function, aortic ejection and ischemic stress-resistance in the Gunn rat, Am. J. Physiol. Heart Circ. Physiol., 307, H1142, 10.1152/ajpheart.00001.2014

Horsfall, 2011, Serum bilirubin and risk of respiratory disease and death, JAMA, 305, 691, 10.1001/jama.2011.124

Lenicek, 2014, The relationship between serum bilirubin and Crohn's disease, Inflamm. Bowel Dis., 20, 481, 10.1097/01.MIB.0000440817.84251.98

Vitek, 2010, Association of systemic lupus erythematosus with low serum bilirubin levels, Scand. J. Rheumatol., 39, 480, 10.3109/03009741003742748

Fischman, 2010, Bilirubin as a protective factor for rheumatoid arthritis: an NHANES study of 2003–2006 data, J. Clin. Med. Res., 2, 256

Vitek, 2010, Serum bilirubin levels and UGT1A1 promoter variations in patients with schizophrenia, Psychiatry Res., 178, 449, 10.1016/j.psychres.2009.12.008

Peng, 2011, Serum bilirubin concentrations and multiple sclerosis, J. Clin. Neurosci., 18, 1355, 10.1016/j.jocn.2011.02.023

Bian, 2013, Effects of total bilirubin on the prevalence of osteoporosis in postmenopausal women without potential liver disease, J. Bone Miner. Metab., 31, 637, 10.1007/s00774-013-0452-y

Breslin, 2013, Bilirubin influences the clinical presentation of pre-eclampsia, Eur. J. Obstet. Gyn. Reprod. Biol., 170, 111, 10.1016/j.ejogrb.2013.05.024

Coumbe, 2014, Cardiovascular risk and psoriasis: beyond the traditional risk factors, Am. J. Med., 127, 12, 10.1016/j.amjmed.2013.08.013

Scalzi, 2008, Cardiovascular disease risk awareness in systemic lupus erythematosus patients, Arthritis Rheum., 58, 1458, 10.1002/art.23419

Kayahan, 2012, Evaluation of early atherosclerosis in patients with inflammatory bowel disease, Dig. Dis. Sci., 57, 2137, 10.1007/s10620-012-2148-x

Anagnostis, 2009, Atherosclerosis and osteoporosis: age-dependent degenerative processes or related entities?, Osteoporos. Int., 20, 197, 10.1007/s00198-008-0648-5

Garcia-Gomez, 2014, Inflammation, lipid metabolism and cardiovascular risk in rheumatoid arthritis: a qualitative relationship?, World J. Orthop., 5, 304, 10.5312/wjo.v5.i3.304

Christiansen, 2010, Risk of arterial cardiovascular diseases in patients with multiple sclerosis: a population-based cohort study, Neuroepidemiology, 35, 267, 10.1159/000320245

McDonald, 2013, Measures of cardiovascular risk and subclinical atherosclerosis in a cohort of women with a remote history of preeclampsia, Atherosclerosis, 229, 234, 10.1016/j.atherosclerosis.2013.04.020

Unsal, 2013, Detection of subclinical atherosclerosis and diastolic dysfunction in patients with schizophrenia, Neuropsychiatr. Dis. Treat., 9, 1531, 10.2147/NDT.S52030

Ghoorah, 2013, Increased cardiovascular risk in patients with chronic obstructive pulmonary disease and the potential mechanisms linking the two conditions: a review, Cardiol. Rev., 21, 196, 10.1097/CRD.0b013e318279e907

Stocker, 1987, Bilirubin is an antioxidant of possible physiological importance, Science, 235, 1043, 10.1126/science.3029864

Wu, 1996, Antioxidation of human low density lipoprotein by unconjugated and conjugated bilirubins, Biochem. Pharmacol., 51, 859, 10.1016/0006-2952(95)02395-X

Wu, 1994, Unconjugated bilirubin inhibits the oxidation of human low density lipoprotein better than Trolox, Life Sci., 54, P477, 10.1016/0024-3205(94)90140-6

Vítek, 2013, Relationship between serum bilirubin and uric acid to oxidative stress markers in Italian and Czech populations, J. Appl. Biomed., 11, 209, 10.2478/v10136-012-0030-y

Vitek, 2007, Urinary excretion of oxidative metabolites of bilirubin in subjects with Gilbert syndrome, J. Gastroenterol. Hepatol., 22, 841, 10.1111/j.1440-1746.2006.04564.x

Kalousova, 2005, Decreased levels of advanced glycation end-products in patients with Gilbert syndrome, Cell. Mol. Biol., 51, 387

Boon, 2012, Reduced circulating oxidized LDL is associated with hypocholesterolemia and enhanced thiol status in Gilbert syndrome, Free Radic. Biol. Med., 52, 2120, 10.1016/j.freeradbiomed.2012.03.002

Datla, 2007, Induction of heme oxygenase-1 in vivo suppresses NADPH oxidase derived oxidative stress, Hypertension, 50, 636, 10.1161/HYPERTENSIONAHA.107.092296

Lanone, 2005, Bilirubin decreases nos2 expression via inhibition of NAD(P)H oxidase: implications for protection against endotoxic shock in rats, FASEB J., 19, 1890, 10.1096/fj.04-2368fje

Schwertner, 2000, Comparison of various lipid, lipoprotein, and bilirubin combinations as risk factors for predicting coronary artery disease, Atherosclerosis, 150, 381, 10.1016/S0021-9150(99)00387-1

Tapan, 2011, Decreased small dense LDL levels in Gilbert's syndrome, Clin. Biochem., 44, 300, 10.1016/j.clinbiochem.2010.12.003

Wallner, 2013, Protection from age-related increase in lipid biomarkers and inflammation contributes to cardiovascular protection in Gilbert's syndrome, Clin. Sci., 125, 257, 10.1042/CS20120661

Kotani, 2014, The relationship between gamma-glutamyltransferase (GGT), bilirubin (Bil) and small dense low-density lipoprotein (sdLDL) in asymptomatic subjects attending a clinic for screening dyslipidaemias, Ann. Acad. Med. Singap., 43, 216, 10.47102/annals-acadmedsg.V43N4p216

Ocadlik, 2011, Relationship between unconjugated hyperbilirubinemia and lipoprotein spectrum, Neuro Endocrinol. Lett., 32, 360

Oda, 2014, A decrease in total bilirubin predicted hyper-LDL cholesterolemia in a health screening population, Atherosclerosis, 235, 334, 10.1016/j.atherosclerosis.2014.05.927

Kamisako, 2013, Relationship between serum bilirubin and remnant lipoprotein cholesterol level, Clin. Lab., 59, 435, 10.7754/Clin.Lab.2012.120608

Kohli, 2012, Triglycerides: how much credit do they deserve?, Med. Clin. North. Am., 96, 39, 10.1016/j.mcna.2011.11.006

Sharma, 2009, Thinking beyond low-density lipoprotein cholesterol: strategies to further reduce cardiovascular risk, Vasc. Health Risk Manag., 5, 793, 10.2147/VHRM.S5684

Miller, 2008, Impact of triglyceride levels beyond low-density lipoprotein cholesterol after acute coronary syndrome in the PROVE IT-TIMI 22 trial, J. Am. Coll. Cardiol., 51, 724, 10.1016/j.jacc.2007.10.038

McNamara, 2001, Remnant-like particle (RLP) cholesterol is an independent cardiovascular disease risk factor in women: results from the Framingham Heart Study, Atherosclerosis, 154, 229, 10.1016/S0021-9150(00)00484-6

Andersson, 2009, Acute effect of weight loss on levels of total bilirubin in obese, cardiovascular high-risk patients: an analysis from the lead-in period of the Sibutramine Cardiovascular Outcome trial, Metabolism, 58, 1109, 10.1016/j.metabol.2009.04.003

Belo, 2014, Body fat percentage is a major determinant of total bilirubin independently of UGT1A1*28 polymorphism in young obese, PLOS ONE, 9, e98467, 10.1371/journal.pone.0098467

Inoguchi, 2007, Relationship between Gilbert syndrome and prevalence of vascular complications in patients with diabetes, JAMA, 298, 1398, 10.1001/jama.298.12.1398-b

Puri, 2013, Serum bilirubin level is inversely associated with nonalcoholic steatohepatitis in children, J. Pediatr. Gastroenterol. Nutr., 57, 114, 10.1097/MPG.0b013e318291fefe

Salomone, 2013, Unconjugated bilirubin, a potent endogenous antioxidant, is decreased in patients with non-alcoholic steatohepatitis and advanced fibrosis, J. Gastroenterol. Hepatol., 28, 1202, 10.1111/jgh.12155

Kwak, 2012, Serum bilirubin levels are inversely associated with nonalcoholic fatty liver disease, Clin. Mol. Hepatol., 18, 383, 10.3350/cmh.2012.18.4.383

Dong, 2014, Bilirubin increases insulin sensitivity in leptin-receptor deficient and diet-induced obese mice through suppression of ER stress and chronic inflammation, Endocrinology, 155, 818, 10.1210/en.2013-1667

Guzek, 2012, Inverse association of serum bilirubin with metabolic syndrome and insulin resistance in Polish population, Przeg. Epidemiol., 66, 495

Dullaart, 2014, The inverse association of incident cardiovascular disease with plasma bilirubin is unaffected by adiponectin, Atherosclerosis, 235, 380, 10.1016/j.atherosclerosis.2014.05.938

Kubota, 2002, Disruption of adiponectin causes insulin resistance and neointimal formation, J. Biol. Chem., 277, 25863, 10.1074/jbc.C200251200

Cure, 2013, The evaluation of relationship between adiponectin levels and epicardial adipose tissue thickness with low cardiac risk in Gilbert's syndrome: an observational study, Anadolu Kardiyol. Derg., 13, 791

Lee, 2014, Serum bilirubin as a predictor of incident metabolic syndrome: a 4-year retrospective longitudinal study of 6205 initially healthy Korean men, Diabetes Metab., 40, 305, 10.1016/j.diabet.2014.04.006

Jung, 2014, Higher serum bilirubin level as a protective factor for the development of diabetes in healthy Korean men: a 4 year retrospective longitudinal study, Metabolism, 63, 87, 10.1016/j.metabol.2013.09.011

Kwon, 2011, Inverse association between total bilirubin and metabolic syndrome in rural Korean women, J. Womens Health, 20, 963, 10.1089/jwh.2010.2453

Chan, 2013, Plasma total bilirubin levels predict amputation events in type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, Diabetologia, 56, 724, 10.1007/s00125-012-2818-4

Jiraskova, 2011, Association of low bilirubin levels and promoter variations in UGT1A1 gene with diabetes mellitus type 2, Hepatol. Int., 5, 37

Bossard, 2014, Serum bilirubin levels and risk of prediabetes in young and healthy adults, Int. J. Cardiol., 171, e24, 10.1016/j.ijcard.2013.11.125

Mishra, 2014, A critical and comprehensive insight on heme oxygenase and related products including carbon monoxide, bilirubin, biliverdin and ferritin in type-1 and type-2 diabetes, Curr. Pharm. Des., 20, 1370, 10.2174/13816128113199990559

Deetman, 2014, The relationship of the anti-oxidant bilirubin with free thyroxine is modified by insulin resistance in euthyroid subjects, PLOS ONE, 9, e90886, 10.1371/journal.pone.0090886

Libby, 2009, Inflammation in atherosclerosis: from pathophysiology to practice, J. Am. Coll. Cardiol., 54, 2129, 10.1016/j.jacc.2009.09.009

Najib-Farah, 1937, Defensive role of bilirubinemia in pneumococcal infection, Lancet, 229, 505, 10.1016/S0140-6736(00)75817-X

Basiglio, 2010, Complement activation and disease: protective effects of hyperbilirubinaemia, Clin. Sci., 118, 99, 10.1042/CS20080540

Haga, 1996, Unconjugated bilirubin inhibits in vitro cytotoxic T lymphocyte activity of human lymphocytes, Biochim. Biophys. Acta, 1317, 65, 10.1016/0925-4439(96)00039-7

Rocuts, 2010, Bilirubin promotes de novo generation of T regulatory cells, Cell Transplant, 19, 443, 10.3727/096368909X484680

Eklund, 2009, Proinflammatory cytokines in CRP baseline regulation, Adv. Clin. Chem., 48, 111, 10.1016/S0065-2423(09)48005-3

Hwang, 2011, Relationship between bilirubin and C-reactive protein, Clin. Chem. Lab. Med., 49, 1823, 10.1515/cclm.2011.662

Vitek, 2007, Relationship between serum bilirubin and markers of inflammation and oxidative stress, J. Gastroenterol. Hepatol., 22, A235

Gullu, 2005, High serum bilirubin concentrations preserve coronary flow reserve and coronary microvascular functions, Arterioscler. Thromb. Vasc. Biol., 25, 2289, 10.1161/01.ATV.0000185806.61430.7c

Verma, 2003, C-reactive protein and atherothrombosis-beyond a biomarker: an actual partaker of lesion formation, Am. J. Physiol. Regul. Integr. Comp. Physiol., 285, R1253, 10.1152/ajpregu.00170.2003

Bisht, 2014, Endogenous tetrapyrroles influence leukocyte responses to lipopolysaccharide in human blood: pre-clinical evidence demonstrating the anti-inflammatory potential of biliverdin, J. Clin. Cell. Immunol., 5, 1000218

Kundur, 2014, Unconjugated bilirubin inhibits collagen induced platelet activation, Platelets, 25, 45, 10.3109/09537104.2013.764405

Sansanayudh, 2014, Mean platelet volume and coronary artery disease: a systematic review and meta-analysis, Int. J. Cardiol., 175, 433, 10.1016/j.ijcard.2014.06.028

Kim, 2014, Platelet volume indices are associated with high residual platelet reactivity after antiplatelet therapy in patients undergoing percutaneous coronary intervention, J. Atheroscler. Thromb., 21, 445, 10.5551/jat.20156

Cure, 2013, The effects of Gilbert's syndrome on the mean platelet volume and other hematological parameters, Blood Coagul. Fibrinolysis, 24, 484, 10.1097/MBC.0b013e32835e4230

Tiker, 2005, Relationship between serum bilirubin and coagulation test results in 1-month-old infants, Indian J. Pediatr., 72, 205, 10.1007/BF02859256

Gutierrez, 2013, Endothelial dysfunction over the course of coronary artery disease, Eur. Heart J., 34, 3175, 10.1093/eurheartj/eht351

Mazzone, 2009, Bilirubin inhibits the TNF alpha-related induction of three endothelial adhesion molecules, Biochem. Biophys. Res. Commun., 386, 338, 10.1016/j.bbrc.2009.06.029

Mazzone, 2009, Bilirubin effect on endothelial adhesion molecules expression is mediated by the NF-kappaB signaling pathway, Biosci. Trends, 3, 151

Mazzone, 2010, Unconjugated bilirubin modulates nitric oxide production via iNOS regulation, Biosci. Trends, 4, 244

Keshavan, 2005, Unconjugated bilirubin inhibits VCAM-1-mediated transendothelial leukocyte migration, J. Immunol., 174, 3709, 10.4049/jimmunol.174.6.3709

Tapan, 2009, Soluble CD40 ligand and soluble P-selectin levels in Gilbert's syndrome: a link to protection against atherosclerosis?, Clin. Biochem., 42, 791, 10.1016/j.clinbiochem.2009.02.005

Jirásková, 2012, Association of serum bilirubin and promoter variations in HMOX1 and UGT1A1 genes with sporadic colorectal cancer, Int. J. Cancer, 131, 1549, 10.1002/ijc.27412

Stoeckius, 2012, Essential roles of raf/extracellular signal-regulated kinase/mitogen-activated protein kinase pathway, YY1, and Ca2+ influx in growth arrest of human vascular smooth muscle cells by bilirubin, J. Biol. Chem., 287, 15418, 10.1074/jbc.M111.266510

Ollinger, 2005, Bilirubin–a natural inhibitor of vascular smooth muscle cell proliferation, Circulation, 112, 1030, 10.1161/CIRCULATIONAHA.104.528802

Ollinger, 2007, Bilirubin and biliverdin treatment of atherosclerotic diseases, Cell Cycle, 6, 39, 10.4161/cc.6.1.3700

Moraes, 2012, Heme modulates smooth muscle cell proliferation and migration via NADPH oxidase: a counter-regulatory role for heme oxygenase system, Atherosclerosis, 224, 394, 10.1016/j.atherosclerosis.2012.07.043

Cesaratto, 2007, Bilirubin-induced cell toxicity involves PTEN activation through an APE1/Ref-1-dependent pathway, J. Mol. Med., 85, 1099, 10.1007/s00109-007-0204-3

Dong, 2013, Inhibition of PTEN expression and activity by angiotensin II induces proliferation and migration of vascular smooth muscle cells, J. Cell. Biochem., 114, 174, 10.1002/jcb.24315

Li, 2013, Decreased serum bilirubin is associated with arterial stiffness in men, Nutr. Metab. Cardiovasc. Dis., 23, 375, 10.1016/j.numecd.2011.09.004

Zhang, 2013, Serum total bilirubin is inversely associated with brachial-ankle pulse wave velocity in men with hypertension, Heart Vessels, 28, 453, 10.1007/s00380-012-0261-6

Erdogan, 2006, Low serum bilirubin levels are independently and inversely related to impaired flow-mediated vasodilation and increased carotid intima-media thickness in both men and women, Atherosclerosis, 184, 431, 10.1016/j.atherosclerosis.2005.05.011

Caliskan, 2007, Low serum bilirubin concentrations are associated with impaired aortic elastic properties, but not impaired left ventricular diastolic function, Int. J. Clin. Pract., 61, 218, 10.1111/j.1742-1241.2006.00907.x

Erdogan, 2012, Increased serum bilirubin level is related to good collateral development in patients with chronic total coronary occlusion, Intern. Med., 51, 249, 10.2169/internalmedicine.51.6417

Yoshino, 2011, Relationship between bilirubin concentration, coronary endothelial function, and inflammatory stress in overweight patients, J. Atheroscler. Thromb., 18, 403, 10.5551/jat.6346

Dekker, 2011, The bilirubin-increasing drug atazanavir improves endothelial function in patients with type 2 diabetes mellitus, Arterioscler. Thromb. Vasc. Biol., 31, 458, 10.1161/ATVBAHA.110.211789

Brown, 2002, Venous collagenosis and arteriolar tortuosity in leukoaraiosis, J. Neurol. Sci., 203–204, 159, 10.1016/S0022-510X(02)00283-6

Ben-Assayag, 2012, Leukoaraiosis is a chronic atherosclerotic disease, Scientific World Journal, 2012, 532141, 10.1100/2012/532141

Park, 2007, Significant association between leukoaraiosis and metabolic syndrome in healthy subjects, Neurology, 69, 974, 10.1212/01.wnl.0000266562.54684.bf

Park, 2012, Association between serum total bilirubin level and leukoaraiosis in Korean adults, Clin. Biochem., 45, 289, 10.1016/j.clinbiochem.2011.12.023

Kang, 2012, Mean platelet volume (MPV) is associated with leukoaraiosis in the apparently healthy elderly, Arch. Gerontol. Geriatr., 54, e118, 10.1016/j.archger.2011.10.010

Hsu, 2006, Tissue-specific effects of statins on the expression of heme oxygenase-1 in vivo, Biochem. Biophys. Res. Commun., 343, 738, 10.1016/j.bbrc.2006.03.036

Szabó, 2014, Statins alter the hepatobiliary transport of unconjugated and conjugated bilirubin in sandwich-cultured rat hepatocytes, Toxicol. In Vitro, 28, 1136, 10.1016/j.tiv.2014.05.016

Hu, 2012, Effects of statin treatments and polymorphisms in UGT1A1 and SLCO1B1 on serum bilirubin levels in Chinese patients with hypercholesterolaemia, Atherosclerosis, 223, 427, 10.1016/j.atherosclerosis.2012.06.002

Ong, 2011, Association of lower total bilirubin level with statin usage: the United States National Health and Nutrition Examination Survey 1999–2008, Atherosclerosis, 219, 728, 10.1016/j.atherosclerosis.2011.07.094

Vítek, 2011, Statin use and serum bilirubin levels, Atherosclerosis, 219, 969, 10.1016/j.atherosclerosis.2011.09.001

de Sauvage Nolting, 2011, Serum bilirubin levels in familial hypercholesterolemia: a new risk marker for cardiovascular disease?, J. Lipid Res., 52, 1755, 10.1194/jlr.P013193

Zhang, 2005, In vitro inhibition of UDP glucuronosyltransferases by atazanavir and other HIV protease inhibitors and the relationship of this property to in vivo bilirubin glucuronidation, Drug Metab. Dispos., 33, 1729, 10.1124/dmd.105.005447

Rotger, 2005, Gilbert syndrome and the development of antiretroviral therapy-associated hyperbilirubinemia, J. Infect. Dis., 192, 1381, 10.1086/466531

Martinez, 2015, Differential body composition effects of protease inhibitors recommended for initial treatment of hiv infection: a randomized clinical trial, Clin. Infect. Dis., 60, 811, 10.1093/cid/ciu898

Morcos, 2008, Vivo-morpholinos: a non-peptide transporter delivers morpholinos into a wide array of mouse tissues, Biotechniques, 45, 613, 10.2144/000113005

Vera, 2010, Moderate hyperbilirubinemia improves renal hemodynamics in ANG II-dependent hypertension, Am. J. Physiol. Regul. Integr. Comp. Physiol., 299, R1044, 10.1152/ajpregu.00316.2010

Moulton, 2009, Gene knockdowns in adult animals: PPMOs and vivo-morpholinos, Molecules, 25, 1304, 10.3390/molecules14031304

Smit, 2014, Using genetic variation for establishing causality of cardiovascular risk factors: overcoming confounding and reverse causality, Neth. Heart J., 22, 186, 10.1007/s12471-014-0534-z

Ching, 2002, Serum levels of micronutrients, antioxidants and total antioxidant status predict risk of breast cancer in a case control study, J. Nutr., 132, 303, 10.1093/jn/132.2.303

Guillemette, 2001, Association of genetic polymorphisms in UGT1A1 with breast cancer and plasma hormone levels, Cancer Epidemiol. Biomarkers Prev., 10, 711

Shatalova, 2006, [Association of polymorphisms in SULT1A1 and UGT1A1 Genes with breast cancer risk and phenotypes in Russian women], Mol. Biol. (Mosk.), 40, 263, 10.1134/S0026893306020075

Muraca, 1984, Influence of sex and sex steroids on bilirubin uridine diphosphate-glucuronosyltransferase activity of rat liver, Gastroenterology, 87, 308, 10.1016/0016-5085(84)90705-4

Russo, 2006, The role of estrogen in the initiation of breast cancer, J. Steroid Biochem. Mol. Biol., 102, 89, 10.1016/j.jsbmb.2006.09.004

ESHRE Capri Workshop Group, 2006, Hormones and cardiovascular health in women, Hum. Reprod. Update, 12, 483, 10.1093/humupd/dml028

Yong, 2010, Associations between polymorphisms in glucuronidation and sulfation enzymes and mammographic breast density in premenopausal women in the United States, Cancer Epidemiol. Biomarkers Prev., 19, 537, 10.1158/1055-9965.EPI-09-0898

Ko, 1994, Serum albumin, bilirubin, and uric acid and the anatomic site-specific incidence of colon cancer, J. Natl. Cancer Inst., 86, 1874, 10.1093/jnci/86.24.1874

Bajro, 2012, Promoter length polymorphism in UGT1A1 and the risk of sporadic colorectal cancer, Cancer Genet., 205, 163, 10.1016/j.cancergen.2012.01.015

Lacko, 2010, Genetic polymorphism in the conjugating enzyme UGT1A1 and the risk of head and neck cancer, Int. J. Cancer, 127, 2815, 10.1002/ijc.25296

Karakosta, 2014, UGT1A1*28 polymorphism in chronic lymphocytic leukemia: the first investigation of the polymorphism in disease susceptibility and its specific cytogenetic abnormalities, Acta Haematol., 132, 59, 10.1159/000355714

Bonassi, 2011, Micronuclei frequency in peripheral blood lymphocytes and cancer risk: evidence from human studies, Mutagenesis, 26, 93, 10.1093/mutage/geq075

Wallner, 2012, Effects of unconjugated bilirubin on chromosomal damage in individuals with Gilbert's syndrome measured with the micronucleus cytome assay, Mutagenesis, 27, 731, 10.1093/mutage/ges039

Grant, 2004, Bilirubin UDP-glucuronosyltransferase 1A1 (UGT1A1) gene promoter polymorphisms and HPRT, glycophorin A, and micronuclei mutant frequencies in human blood, Mutat. Res., 560, 1, 10.1016/j.mrgentox.2004.01.010

Wallner, 2013, Anti-genotoxic potential of bilirubin in vivo: damage to DNA in hyperbilirubinemic human and animal models, Cancer Prev. Res., 6, 1056, 10.1158/1940-6207.CAPR-13-0125

Kim, 1997, UDP-glucuronosyltransferase-mediated protection against in vitro DNA oxidation and micronucleus formation initiated by phenytoin and its embryotoxic metabolite 5-(p-hydroxyphenyl)-5-phenylhydantoin, J. Pharmacol. Exp. Ther., 280, 200

Vienneau, 1995, Potential genoprotective role for UDP-glucuronosyltransferases in chemical carcinogenesis: initiation of micronuclei by benzo(a)pyrene and benzo(e)pyrene in UDP-glucuronosyltransferase-deficient cultured rat skin fibroblasts, Cancer Res., 55, 1045

Gunn, 1938, Hereditary acholuric jaundice in a new mutant strain of rats, J. Hered., 29, 137, 10.1093/oxfordjournals.jhered.a104478

Arimoto, 1993, Binding of polycyclic planar mutagens to chlorophyllin resulting in inhibition of the mutagenic activity, Mutat. Res., 287, 293, 10.1016/0027-5107(93)90022-8

Orlov, 2014, Circular dichroism study of the interaction between mutagens and bilirubin bound to different binding sites of serum albumins, Spectrochim. Acta A Mol. Biol. Spectrosc., 126, 68, 10.1016/j.saa.2014.01.139

Molzer, 2013, Interaction between TNFone and tetrapyrroles may account for their anti-genotoxic effects–a novel mechanism for DNA-protection, J. Porphyrins Phthalocyanines, 17, 1157, 10.1142/S1088424613500995

Keshavan, 2004, Unconjugated bilirubin induces apoptosis in colon cancer cells by triggering mitochondrial depolarization, Int. J. Cancer, 112, 433, 10.1002/ijc.20418

Ollinger, 2007, Bilirubin inhibits tumor cell growth via activation of ERK, Cell Cycle, 6, 3078, 10.4161/cc.6.24.5022

Molzer, 2013, In vitro DNA-damaging effects of intestinal and related tetrapyrroles in human cancer cells, Exp. Cell Res., 319, 536, 10.1016/j.yexcr.2012.12.003

Markesbery, 2007, Damage to lipids, proteins, DNA, and RNA in mild cognitive impairment, Arch. Neurol., 64, 954, 10.1001/archneur.64.7.954

Kim, 2012, Serum total bilirubin concentration is inversely correlated with Framingham risk score in Koreans, Arch. Med. Res., 43, 288, 10.1016/j.arcmed.2012.05.003

Butterfield, 2001, Evidence of oxidative damage in Alzheimer's disease brain: central role for amyloid beta-peptide, Trends Mol. Med., 7, 548, 10.1016/S1471-4914(01)02173-6

Butterfield, 2013, Amyloid beta-peptide (1–42)-induced oxidative stress in Alzheimer disease: importance in disease pathogenesis and progression, Antioxid. Redox Signal., 19, 823, 10.1089/ars.2012.5027

Kimpara, 2000, Increased bilirubins and their derivatives in cerebrospinal fluid in Alzheimer's disease, Neurobiol. Aging, 21, 551, 10.1016/S0197-4580(00)00128-7

Barone, 2014, The Janus face of the heme oxygenase/biliverdin reductase system in Alzheimer disease: it's time for reconciliation, Neurobiol. Dis., 62, 144, 10.1016/j.nbd.2013.09.018

Schipper, 2004, Heme oxygenase-1: transducer of pathological brain iron sequestration under oxidative stress, Ann. N.Y. Acad. Sci., 1012, 84, 10.1196/annals.1306.007

Scigliano, 1997, Increased plasma bilirubin in Parkinson patients on L-dopa: evidence against the free radical hypothesis?, Ital. J. Neurol. Sci., 18, 69, 10.1007/BF01999565

Li, 2014, Decreased serum bilirubin is associated with silent cerebral infarction, Arterioscler. Thromb. Vasc. Biol., 34, 946, 10.1161/ATVBAHA.113.303003

Peng, 2011, Serum bilirubin concentrations and multiple sclerosis, J. Clin. Neurosci., 18, 1355, 10.1016/j.jocn.2011.02.023

Ilzecka, 2003, Serum bilirubin concentration in patients with amyotrophic lateral sclerosis, Clin. Neurol. Neurosurg., 105, 237, 10.1016/S0303-8467(03)00031-3

Muller, 1991, Coincidence of schizophrenia and hyperbilirubinemia, Pharmacopsychiatr, 24, 225, 10.1055/s-2007-1014472

Miyaoka, 2000, Schizophrenia-associated idiopathic unconjugated hyperbilirubinemia (Gilbert's syndrome), J. Clin. Psychiatry, 61, 868, 10.4088/JCP.v61n1110

Yao, 1998, Reduced status of plasma total antioxidant capacity in schizophrenia, Schizophr. Res., 32, 1, 10.1016/S0920-9964(98)00030-9

Pae, 2004, Decreased plasma antioxidants in schizophrenia, Neuropsychobiology, 50, 54, 10.1159/000077942

Vitek, 2010, Serum bilirubin levels and UGT1A1 promoter variations in patients with schizophrenia, Psychiatry. Res., 178, 449, 10.1016/j.psychres.2009.12.008

Oren, 2002, Effects of light on low nocturnal bilirubin in winter depression: a preliminary report, Biol. Psychiatry, 51, 422, 10.1016/S0006-3223(01)01254-9

Oren, 1998, Tweaking the human circadian clock with light, Science, 279, 333, 10.1126/science.279.5349.333

Seta, 2006, Heme oxygenase-2 is a critical determinant for execution of an acute inflammatory and reparative response, Am. J. Pathol., 169, 1612, 10.2353/ajpath.2006.060555

Biomarkers Definitions Working Group, 2001, Biomarkers and surrogate endpoints: preferred definitions and conceptual framework, Clin. Pharmacol. Ther., 69, 89, 10.1067/mcp.2001.113989

Knasmuller, 2008, Use of conventional and -omics based methods for health claims of dietary antioxidants: a critical overview, Br. J. Nutr., 99, ES3, 10.1017/S0007114508965752

Weber, 2006, Role of B-type natriuretic peptide (BNP) and NT-proBNP in clinical routine, Heart, 92, 843, 10.1136/hrt.2005.071233

Gillett, 2009, International Expert Committee report on the role of the A1c assay in the diagnosis of diabetes: Diabetes Care 2009;32(7):1327–1334, Clin. Biochem. Rev., 30, 197

Keller, 2009, Sensitive troponin I assay in early diagnosis of acute myocardial infarction, N. Engl. J. Med., 361, 868, 10.1056/NEJMoa0903515

Ridker, 2003, Clinical application of C-reactive protein for cardiovascular disease detection and prevention, Circulation, 107, 363, 10.1161/01.CIR.0000053730.47739.3C

European Food Safety Authority (EFSA) Panel on Dietetic Products, 2011, Guidance on the scientific requirements for health claims related to antioxidants, oxidative damage and cardiovascular health, EFSA J., 9, 2474, 10.2903/j.efsa.2011.2474

Sistrom, 2004, Proportions, odds, and risk, Radiology, 230, 12, 10.1148/radiol.2301031028

Kundur, 2015, Bilirubin, platelet activation and heart disease: a missing link to cardiovascular protection in Gilbert's syndrome?, Atherosclerosis, 239, 73, 10.1016/j.atherosclerosis.2014.12.042

Dore, 1999, Bilirubin, formed by activation of heme oxygenase-2, protects neurons against oxidative stress injury, Proc. Natl. Acad. Sci. U.S.A., 96, 2445, 10.1073/pnas.96.5.2445

Baranano, 2002, Biliverdin reductase: a major physiologic cytoprotectant, Proc. Natl. Acad. Sci. U.S.A., 99, 16093, 10.1073/pnas.252626999

Sedlak, 2004, Bilirubin benefits: cellular protection by a biliverdin reductase antioxidant cycle, Pediatrics, 113, 1776, 10.1542/peds.113.6.1776