Editorial

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2 pages, 186 KiB

Open AccessEditorial

Bilirubin 2022: The Past, the Present and the Future

by Cristina Bellarosa and Claudio Tiribelli

Antioxidants 2022, 11(9), 1632; https://doi.org/10.3390/antiox11091632 - 23 Aug 2022

Viewed by 1379

Abstract

The present Special Issue (SI) addresses the double-faced Janus behavior of bilirubin [...] Full article

(This article belongs to the Special Issue Bilirubin and Oxidative Stress)

Research

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20 pages, 3394 KiB

Open AccessArticle

Long-Term Effects of Biliverdin Reductase a Deficiency in Ugt1^−/− Mice: Impact on Redox Status and Metabolism

by Giulia Bortolussi, Xiaoxia Shi, Lysbeth ten Bloemendaal, Bhaswati Banerjee, Dirk R. De Waart, Gabriele Baj, Weiyu Chen, Ronald P. Oude Elferink, Ulrich Beuers, Coen C. Paulusma, Roland Stocker, Andrés F. Muro and Piter J. Bosma

Antioxidants 2021, 10(12), 2029; https://doi.org/10.3390/antiox10122029 - 20 Dec 2021

Cited by 4 | Viewed by 2885

Abstract

Accumulation of neurotoxic bilirubin due to a transient neonatal or persistent inherited deficiency of bilirubin glucuronidation activity can cause irreversible brain damage and death. Strategies to inhibit bilirubin production and prevent neurotoxicity in neonatal and adult settings seem promising. We evaluated the impact [...] Read more.

Accumulation of neurotoxic bilirubin due to a transient neonatal or persistent inherited deficiency of bilirubin glucuronidation activity can cause irreversible brain damage and death. Strategies to inhibit bilirubin production and prevent neurotoxicity in neonatal and adult settings seem promising. We evaluated the impact of Bvra deficiency in neonatal and aged mice, in a background of unconjugated hyperbilirubinemia, by abolishing bilirubin production. We also investigated the disposal of biliverdin during fetal development. In Ugt1^−/− mice, Bvra deficiency appeared sufficient to prevent lethality and to normalize bilirubin level in adults. Although biliverdin accumulated in Bvra-deficient fetuses, both Bvra^−/− and Bvra^−/−Ugt1^−/− pups were healthy and reached adulthood having normal liver, brain, and spleen histology, albeit with increased iron levels in the latter. During aging, both Bvra^−/− and Bvra^−/−Ugt1^−/− mice presented normal levels of relevant hematological and metabolic parameters. Interestingly, the oxidative status in erythrocytes from 9-months-old Bvra^−/− and Bvra^−/−Ugt1^−/− mice was significantly reduced. In addition, triglycerides levels in these 9-months-old Bvra^−/− mice were significantly higher than WT controls, while Bvra^−/−Ugt1^−/− tested normal. The normal parameters observed in Bvra^−/−Ugt1^−/− mice fed chow diet indicate that Bvra inhibition to treat unconjugated hyperbilirubinemia seems safe and effective. Full article

(This article belongs to the Special Issue Bilirubin and Oxidative Stress)

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10 pages, 295 KiB

Open AccessArticle

Association of Serum Bilirubin and Functional Variants of Heme Oxygenase 1 and Bilirubin UDP-Glucuronosyl Transferase Genes in Czech Adult Patients with Non-Alcoholic Fatty Liver Disease

by Jaromír Petrtýl, Karel Dvořák, Jan Stříteský, Martin Leníček, Alena Jirásková, Václav Šmíd, Martin Haluzík, Radan Brůha and Libor Vítek

Antioxidants 2021, 10(12), 2000; https://doi.org/10.3390/antiox10122000 - 15 Dec 2021

Cited by 8 | Viewed by 2156

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disorder worldwide. The aim of our study was to assess the role of bilirubin, and the heme oxygenase 1 (HMOX1) and bilirubin UDP-glucuronosyl transferase (UGT1A1) promoter gene variants, [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disorder worldwide. The aim of our study was to assess the role of bilirubin, and the heme oxygenase 1 (HMOX1) and bilirubin UDP-glucuronosyl transferase (UGT1A1) promoter gene variants, which are involved in bilirubin homeostasis, in the NAFLD development in adult patients. The study was performed on 84 patients with NAFLD and 103 age/sex-matched controls. Routine biochemistry, inflammatory markers, adipokines, and the fibrosis/steatohepatitis stage were determined in the NAFLD patients. The (GT)n/(TA)n dinucleotide variations in HMOX1/UGT1A1 gene promoters, respectively, were analyzed by fragment analysis. Compared to controls, serum bilirubin concentrations in NAFLD patients tended to be decreased, while the prevalence of phenotypic Gilbert syndrome was significantly low. Genetic variations in HMOX1 and UGT1A1 gene promoters did not differ between NAFLD patients and controls, and no relationship was found in the NAFLD patients between these gene variants and any of the laboratory or histological parameters. In conclusion, metabolism of bilirubin is dysregulated in NAFLD patients, most likely due to increased oxidative stress, since frequencies of the major functional variants in the HMOX1 or UGT1A1 gene promoters did not have any effect on development of NAFLD in adult patients. Full article

(This article belongs to the Special Issue Bilirubin and Oxidative Stress)

16 pages, 2262 KiB

Open AccessArticle

The Effects of Bilirubin and Lumirubin on the Differentiation of Human Pluripotent Cell-Derived Neural Stem Cells

by Nikola Capková, Veronika Pospíšilová, Veronika Fedorová, Jan Raška, Kateřina Pospíšilová, Matteo Dal Ben, Aleš Dvořák, Jitka Viktorová, Dáša Bohačiaková and Libor Vítek

Antioxidants 2021, 10(10), 1532; https://doi.org/10.3390/antiox10101532 - 27 Sep 2021

Cited by 7 | Viewed by 3070

Abstract

The ‘gold standard’ treatment of severe neonatal jaundice is phototherapy with blue–green light, which produces more polar photo-oxidation products that are easily excreted via the bile or urine. The aim of this study was to compare the effects of bilirubin (BR) and its [...] Read more.

The ‘gold standard’ treatment of severe neonatal jaundice is phototherapy with blue–green light, which produces more polar photo-oxidation products that are easily excreted via the bile or urine. The aim of this study was to compare the effects of bilirubin (BR) and its major photo-oxidation product lumirubin (LR) on the proliferation, differentiation, morphology, and specific gene and protein expressions of self-renewing human pluripotent stem cell-derived neural stem cells (NSC). Neither BR nor LR in biologically relevant concentrations (12.5 and 25 µmol/L) affected cell proliferation or the cell cycle phases of NSC. Although none of these pigments affected terminal differentiation to neurons and astrocytes, when compared to LR, BR exerted a dose-dependent cytotoxicity on self-renewing NSC. In contrast, LR had a substantial effect on the morphology of the NSC, inducing them to form highly polar rosette-like structures associated with the redistribution of specific cellular proteins (β-catenin/N-cadherin) responsible for membrane polarity. This observation was accompanied by lower expressions of NSC-specific proteins (such as SOX1, NR2F2, or PAX6) together with the upregulation of phospho-ERK. Collectively, the data indicated that both BR and LR affect early human neurodevelopment in vitro, which may have clinical relevance in phototherapy-treated hyperbilirubinemic neonates. Full article

(This article belongs to the Special Issue Bilirubin and Oxidative Stress)

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12 pages, 287 KiB

Open AccessArticle

Oxidative Stress and Related Biomarkers in Gilbert’s Syndrome: A Secondary Analysis of Two Case-Control Studies

by Karl-Heinz Wagner, Nazlisadat Seyed Khoei, Claudia Anna Hana, Daniel Doberer, Rodrig Marculescu, Andrew Cameron Bulmer, Marlies Hörmann-Wallner and Christine Mölzer

Antioxidants 2021, 10(9), 1474; https://doi.org/10.3390/antiox10091474 - 15 Sep 2021

Cited by 8 | Viewed by 3877

Abstract

Bilirubin is an important antioxidant and a modulator of biological functions. However, most of the protection against oxidative stress was shown in vitro or ex vivo. The aim of this case-control study was to investigate whether subjects with Gilbert’s syndrome (GS) experience different [...] Read more.

Bilirubin is an important antioxidant and a modulator of biological functions. However, most of the protection against oxidative stress was shown in vitro or ex vivo. The aim of this case-control study was to investigate whether subjects with Gilbert’s syndrome (GS) experience different levels of lipid and protein oxidation (as well as differences in oxidative stress related markers) compared to healthy controls. GS subjects (n = 119) demonstrated higher serum levels of unconjugated bilirubin (p < 0.001), a lower BMI (p < 0.001), 37% higher antioxidant potential assessed as ferric reducing ability potential (p < 0.001), higher advanced oxidation protein products (p < 0.01) andlower apolipoprotein B (p < 0.05), hs-C-reactive protein (p < 0.05), interleukin 6 (p < 0.001) and interleukin 1 beta (p < 0.05) values compared to healthy controls (n = 119). Furthermore, the resting heart rate was significantly lower in the GS group (p < 0.05). Stronger protective effects for GS subjects were demonstrated in the older subgroup (n = 104, average age 50 years) compared to those of the younger group (n = 134, average age 27 years). Although not all markers related to oxidative stress were different between the groups (e.g., malondialdehyde, homocysteine, oxLDL, and myeloperoxidase; p > 0.05), the observed differences contribute to the explanation of why GS serves as an important protector in the pathogenesis of metabolic, oxidative stress related diseases. Full article

(This article belongs to the Special Issue Bilirubin and Oxidative Stress)

11 pages, 758 KiB

Open AccessArticle

Bilirubin Links HO-1 and UGT1A1*28 Gene Polymorphisms to Predict Cardiovascular Outcome in Patients Receiving Maintenance Hemodialysis

by Yang Ho, Tzen-Wen Chen, Tung-Po Huang, Ying-Hwa Chen and Der-Cherng Tarng

Antioxidants 2021, 10(9), 1403; https://doi.org/10.3390/antiox10091403 - 31 Aug 2021

Cited by 4 | Viewed by 2161

Abstract

Serum bilirubin levels, which are determined by a complex interplay of various enzymes, including heme oxygenase-1 (HO-1) and uridine diphosphate–glucuronosyl transferase (UGT1A1), may be protective against progression of cardiovascular disease (CVD) in hemodialysis patients. However, the combined effect of HO-1 and UGT1A1*28 [...] Read more.

Serum bilirubin levels, which are determined by a complex interplay of various enzymes, including heme oxygenase-1 (HO-1) and uridine diphosphate–glucuronosyl transferase (UGT1A1), may be protective against progression of cardiovascular disease (CVD) in hemodialysis patients. However, the combined effect of HO-1 and UGT1A1*28 gene polymorphisms on CVD outcomes among hemodialysis patients is still unknown. This retrospective study enrolled 1080 prevalent hemodialysis patients and the combined genetic polymorphisms of HO-1 and UGT1A1 on serum bilirubin were analyzed. Endpoints were CVD events and all-cause mortality. Mean serum bilirubin was highest in patients with S/S + S/L of the HO-1 promoter and UGT1A1 7/7 genotypes (Group 1), intermediate in those with S/S + S/L of the HO-1 promoter and UGT1A1 7/6 + 6/6 genotypes (Group 2), and lowest in the carriers with the L/L HO-1 promoter and UGT1A1 7/6 + 6/6 genotypes (Group 3) (p < 0.001). During a median follow-up of 50 months, 433 patients developed CVD. Compared with patients in Group 3, individuals among Groups 1 and 2 had significantly lower risks for CVD events (adjusted hazard ratios (aHRs) of 0.35 for Group 1 and 0.63 for Group 2), respectively. Compared with the lower bilirubin tertile, the aHRs were 0.72 for the middle tertile and 0.40 for the upper tertile for CVD events. We summarized that serum bilirubin as well as HO-1 and UGT1A1 gene polymorphisms were associated with CVD among patients receiving chronic hemodialysis. Full article

(This article belongs to the Special Issue Bilirubin and Oxidative Stress)

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Review

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16 pages, 1106 KiB

Open AccessReview

Bilirubin as a Therapeutic Molecule: Challenges and Opportunities

by Christopher A. Adin

Antioxidants 2021, 10(10), 1536; https://doi.org/10.3390/antiox10101536 - 28 Sep 2021

Cited by 26 | Viewed by 5401

Abstract

There is strong evidence that serum free bilirubin concentration has significant effects on morbidity and mortality in the most significant health conditions of our times, including cardiovascular disease, diabetes, and obesity/metabolic syndrome. Supplementation of bilirubin in animal and experimental models has reproduced these [...] Read more.

There is strong evidence that serum free bilirubin concentration has significant effects on morbidity and mortality in the most significant health conditions of our times, including cardiovascular disease, diabetes, and obesity/metabolic syndrome. Supplementation of bilirubin in animal and experimental models has reproduced these protective effects, but several factors have slowed the application bilirubin as a therapeutic agent in human patients. Bilirubin is poorly soluble in water, and is a complex molecule that is difficult to synthesize. Current sources of this molecule are animal-derived, creating concerns regarding the risk of virus or prion transmission. However, recent developments in nanoparticle drug delivery, biosynthetic strategies, and drug synthesis have opened new avenues for applying bilirubin as a pharmaceutical agent. This article reviews the chemistry and physiology of bilirubin, potential clinical applications and summarizes current strategies for safe and efficient drug delivery. Full article

(This article belongs to the Special Issue Bilirubin and Oxidative Stress)

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16 pages, 1174 KiB

Open AccessReview

Serum Bilirubin Levels in Overweight and Obese Individuals: The Importance of Anti-Inflammatory and Antioxidant Responses

by Lovro Žiberna, Zala Jenko-Pražnikar and Ana Petelin

Antioxidants 2021, 10(9), 1352; https://doi.org/10.3390/antiox10091352 - 26 Aug 2021

Cited by 15 | Viewed by 5933

Abstract

Obesity is a chronic condition involving low-grade inflammation and increased oxidative stress; thus, obese and overweight people have lower values of serum bilirubin. Essentially, bilirubin is a potent endogenous antioxidant molecule with anti-inflammatory, immunomodulatory, antithrombotic, and endocrine properties. This review paper presents the [...] Read more.

Obesity is a chronic condition involving low-grade inflammation and increased oxidative stress; thus, obese and overweight people have lower values of serum bilirubin. Essentially, bilirubin is a potent endogenous antioxidant molecule with anti-inflammatory, immunomodulatory, antithrombotic, and endocrine properties. This review paper presents the interplay between obesity-related pathological processes and bilirubin, with a focus on adipose tissue and adipokines. We discuss potential strategies to mildly increase serum bilirubin levels in obese patients as an adjunctive therapeutic approach. Full article

(This article belongs to the Special Issue Bilirubin and Oxidative Stress)

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