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Bilirubin

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 October 2022) | Viewed by 11767

Special Issue Editor

Prof. Dr. Libor Vitek

E-Mail Website
Guest Editor
Institute of Medical Biochemistry and Laboratory Diagnostics, 1st Faculty of Medicine, Charles University in Prague, Na Bojišti 3, 128 08 Prague, Czech Republic
Interests: bilirubin; heme catabolic pathway; carbon monoxide; bile acids; cholestasis; liver diseases; atherosclerosis; cancer

Special Issue Information

Dear Colleagues,

In recent years, progress in our knowledge of bilirubin metabolism has been enormous, and bilirubin seems to have a much wider impact on the functioning of the human body than ever imaginable. Although for long being considered only a waste product of the heme catabolic pathway, an ominous sign of an underlying liver disease, and also a culprit of encephalopathy in severely jaundiced newborn infants, we know now that bilirubin has versatile biological activities affecting processes such as atherogenesis, cancer formation, and immune responsiveness, which is in part due to its real endocrine action mediated by specific nuclear and cytoplasmic receptors.

Therefore, due to this rapid advance, the Special Issue of the International Journal of Molecular Sciences entitled ‘Bilirubin’ will aim to publish original articles and review papers on aspects related to the molecular mechanisms of Bilirubin.

Prof. Dr. Libor Vitek
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Bilirubin
  • heme catabolic pathway

Published Papers (6 papers)

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Research

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11 pages, 1289 KiB  
Article
Near-Infrared Autofluorescence (NIRAF) in Atherosclerotic Plaque Dissociates from Intraplaque Hemorrhage and Bilirubin
by Weiyu Chen, James Nadel, Sergey Tumanov and Roland Stocker
Int. J. Mol. Sci. 2023, 24(13), 10727; https://doi.org/10.3390/ijms241310727 - 27 Jun 2023
Viewed by 1002
Abstract
Near-infrared autofluorescence (NIRAF) in unstable atherosclerotic plaque has been suggested as a novel imaging technology for high-risk atherosclerosis. Intraplaque hemorrhage (IPH) and bilirubin, derived from the subsequent degradation of heme, have been proposed as the source of NIRAF, although their roles and the [...] Read more.
Near-infrared autofluorescence (NIRAF) in unstable atherosclerotic plaque has been suggested as a novel imaging technology for high-risk atherosclerosis. Intraplaque hemorrhage (IPH) and bilirubin, derived from the subsequent degradation of heme, have been proposed as the source of NIRAF, although their roles and the underlying mechanism responsible for NIRAF remain unclear. To test the proposed role of bilirubin as the source of NIRAF in high-risk atherosclerosis, Biliverdin reductase a gene and apolipoprotein E gene double-knockout (Bvra−/−Apoe−/−) mice were subjected to the Western diet and tandem stenosis (TS) surgery, as a model of both bilirubin deficiency and plaque instability. Human coronary arteries containing atherosclerotic plaques were obtained from heart transplant recipients. The NIRAF was determined by in vivo fluorescence emission computed tomography, and ex vivo infrared imaging. The cholesterol content was quantified by HPLC with UV detection. In Bvra+/+Apoe−/− TS mice, the NIRAF intensity was significantly higher in unstable plaque than in stable plaque, yet the NIRAF in unstable plaque was undistinguishable in Bvra+/+Apoe−/− and littermate Bvra−/−Apoe−/− TS mice. Moreover, the unstable plaque in TS mice exhibited a lower NIRAF compared with highly cellular plaque that lacked most of the features of unstable plaque. In human coronary arteries, the NIRAF associated with cholesterol-rich, calcified lesions, rather than just cholesterol-rich lesions. The NIRAF in atherosclerotic plaque can be dissociated from IPH and bilirubin, such that the compositional meaning of an elevated NIRAF remains obscure. Full article
(This article belongs to the Special Issue Bilirubin)
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9 pages, 272 KiB  
Article
Association of Low Serum Bilirubin Concentrations and Promoter Variations in the UGT1A1 and HMOX1 Genes with Type 2 Diabetes Mellitus in the Czech Population
by Alena Jirásková, Jan Škrha and Libor Vítek
Int. J. Mol. Sci. 2023, 24(13), 10614; https://doi.org/10.3390/ijms241310614 - 25 Jun 2023
Cited by 1 | Viewed by 862
Abstract
Bilirubin has potent biological beneficial effects, protecting against atherosclerosis, obesity, and metabolic syndrome. The aim of this study was to assess serum bilirubin concentrations and (TA)n and (GT)n microsatellite variations in the promoter regions of the UGT1A1 and HMOX1 genes, respectively, [...] Read more.
Bilirubin has potent biological beneficial effects, protecting against atherosclerosis, obesity, and metabolic syndrome. The aim of this study was to assess serum bilirubin concentrations and (TA)n and (GT)n microsatellite variations in the promoter regions of the UGT1A1 and HMOX1 genes, respectively, in patients with type 2 diabetes mellitus (T2DM). The study was carried out in 220 patients with T2DM and 231 healthy control subjects, in whom standard biochemical tests were performed. The (TA)n and (GT)n dinucleotide variations were determined by means of fragment (size-based) analysis using an automated capillary DNA sequencer. Compared to controls, both male and female patients with T2DM had lower serum bilirubin concentrations (9.9 vs. 12.9 μmol/L, and 9.0 vs. 10.6 μmol/L, in men and women, respectively, p < 0.001). Phenotypic Gilbert syndrome was much less prevalent in T2DM patients, as was the frequency of the (TA)7/7UGT1A1 genotype in male T2DM patients. (GT)nHMOX1 genetic variations did not differ between diabetic patients and controls. Our results demonstrate that the manifestation of T2DM is associated with lower serum bilirubin concentrations. Consumption of bilirubin due to increased oxidative stress associated with T2DM seems to be the main explanation, although (TA)n repeat variations in UGT1A1 partially contribute to this phenomenon. Full article
(This article belongs to the Special Issue Bilirubin)
17 pages, 1990 KiB  
Article
Bilirubin Prevents the TH+ Dopaminergic Neuron Loss in a Parkinson’s Disease Model by Acting on TNF-α
by Sri Jayanti, Rita Moretti, Claudio Tiribelli and Silvia Gazzin
Int. J. Mol. Sci. 2022, 23(22), 14276; https://doi.org/10.3390/ijms232214276 - 17 Nov 2022
Cited by 4 | Viewed by 2106
Abstract
Parkinson’s disease (PD), the fastest-growing movement disorder, is still challenged by the unavailability of disease-modifying therapy. Mildly elevated levels of unconjugated bilirubin (UCB, PubChem CID 5280352) have been shown to be protective against several extra-CNS diseases, and the effect is attributed to its [...] Read more.
Parkinson’s disease (PD), the fastest-growing movement disorder, is still challenged by the unavailability of disease-modifying therapy. Mildly elevated levels of unconjugated bilirubin (UCB, PubChem CID 5280352) have been shown to be protective against several extra-CNS diseases, and the effect is attributed to its well-known anti-oxidant and anti-inflammatory capability. We explored the neuroprotective effect of low concentrations of UCB (from 0.5 to 4 µM) in our PD model based on organotypic brain cultures of substantia nigra (OBCs-SN) challenged with a low dose of rotenone (Rot). UCB at 0.5 and 1 µM fully protects against the loss of TH+ (dopaminergic) neurons (DOPAn). The alteration in oxidative stress is involved in TH+ positive neuron demise induced by Rot, but is not the key player in UCB-conferred protection. On the contrary, inflammation, specifically tumor necrosis factor alpha (TNF-α), was found to be the key to UCB protection against DOPAn sufferance. Further work will be needed to introduce the use of UCB into clinical settings, but determining that TNF-α plays a key role in PD may be crucial in designing therapeutic options. Full article
(This article belongs to the Special Issue Bilirubin)
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17 pages, 1728 KiB  
Article
Activation of Alternative Bilirubin Clearance Pathways Partially Reduces Hyperbilirubinemia in a Mouse Model Lacking Functional Ugt1a1 Activity
by Bhaswati Banerjee, Olayemi Joseph Olajide, Giulia Bortolussi and Andrés F. Muro
Int. J. Mol. Sci. 2022, 23(18), 10703; https://doi.org/10.3390/ijms231810703 - 14 Sep 2022
Viewed by 1421
Abstract
Bilirubin is a heme catabolite and Ugt1a1 is the only enzyme involved in the biological elimination of bilirubin. Partially functional or non-functional Ugt1a1 may result in neuronal damage and death due to the accumulation of unconjugated bilirubin in the brain. The understanding of [...] Read more.
Bilirubin is a heme catabolite and Ugt1a1 is the only enzyme involved in the biological elimination of bilirubin. Partially functional or non-functional Ugt1a1 may result in neuronal damage and death due to the accumulation of unconjugated bilirubin in the brain. The understanding of the role of alternative bilirubin detoxification mechanisms that can reduce bilirubin toxicity risk is crucial for developing novel therapeutic strategies. To provide a proof-of-principle showing whether activation of alternative detoxification pathways could lead to life-compatible bilirubin levels in the absence of Ugt1a1 activity, we used Ugt1−/− hyperbilirubinemic mice devoid of bilirubin glucuronidation activity. We treated adult Ugt1−/− mice with TCPOBOP, a strong agonist of the constitutive androstane receptor (CAR). TCPOBOP treatment decreased plasma and liver tissue bilirubin levels by about 38%, and resulted in the transcriptional activation of a vast array of genes involved in bilirubin transport and metabolism. However, brain bilirubin level was unaltered. We observed ~40% degradation of bilirubin in the liver microsomes from TCPOBOP treated Ugt1−/− mice. Our findings suggest that, in the absence of Ugt1a1, the activation of alternative bilirubin clearance pathways can partially improve hyperbilirubinemic conditions. This therapeutic approach may only be considered in a combinatorial manner along with other treatments. Full article
(This article belongs to the Special Issue Bilirubin)
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16 pages, 6046 KiB  
Article
A Potential Role of Keratinocyte-Derived Bilirubin in Human Skin Yellowness and Its Amelioration by Sucrose Laurate/Dilaurate
by Bin Fang, Patrick D. Card, Junjun Chen, Lijuan Li, Timothy Laughlin, Bradley Jarrold, Wenzhu Zhao, Adam M. Benham, Arto T. Määttä, Timothy J. Hawkins and Tomohiro Hakozaki
Int. J. Mol. Sci. 2022, 23(11), 5884; https://doi.org/10.3390/ijms23115884 - 24 May 2022
Cited by 5 | Viewed by 2263
Abstract
Sallow and/or dull skin appearance is greatly attributable to the yellow components of skin tone. Bilirubin is a yellow chromophore known to be made in the liver and/or spleen and is transported throughout the body via the blood stream. Recent publications suggest bilirubin [...] Read more.
Sallow and/or dull skin appearance is greatly attributable to the yellow components of skin tone. Bilirubin is a yellow chromophore known to be made in the liver and/or spleen and is transported throughout the body via the blood stream. Recent publications suggest bilirubin may be synthesized in other cells/organs, including the skin. We found human keratinocytes express the transcripts involved in bilirubin biosynthesis. In parallel, we also found human keratinocytes could indeed synthesize bilirubin in monolayer keratinocytes and in a 3D human skin-equivalent model. The synthesized amount was substantial enough to contribute to skin yellowness. In addition, oxidative stress enhanced bilirubin production. Using UnaG, a protein that forms a fluorescent species upon binding to bilirubin, we also visualized the intracellular expression of bilirubin in keratinocytes. Finally, we screened a compound library and discovered that the sucrose laurate/dilaurate (SDL) combination significantly reduced bilirubin levels, as well as bilirubin-mediated yellowness. In conclusion, bilirubin is indeed synthesized in epidermal keratinocytes and can be upregulated by oxidative stress, which could contribute to chronic or transient yellow skin tone appearance. Application of SDL diminishes bilirubin generation and may be a potential solution to mitigate yellowish and/or dull skin appearance. Full article
(This article belongs to the Special Issue Bilirubin)
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Review

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13 pages, 474 KiB  
Review
Blue-Green (~480 nm) versus Blue (~460 nm) Light for Newborn Phototherapy—Safety Considerations
by Finn Ebbesen, Hendrik Jan Vreman and Thor Willy Ruud Hansen
Int. J. Mol. Sci. 2023, 24(1), 461; https://doi.org/10.3390/ijms24010461 - 27 Dec 2022
Cited by 2 | Viewed by 3462
Abstract
We have previously shown that the phototherapy of hyperbilirubinemic neonates using blue-green LED light with a peak wavelength of ~478 nm is 31% more efficient for removing unconjugated bilirubin from circulation than blue LED light with a peak wavelength of ~452 nm. Based [...] Read more.
We have previously shown that the phototherapy of hyperbilirubinemic neonates using blue-green LED light with a peak wavelength of ~478 nm is 31% more efficient for removing unconjugated bilirubin from circulation than blue LED light with a peak wavelength of ~452 nm. Based on these results, we recommended that the phototherapy of hyperbilirubinemic newborns be practiced with light of ~480 nm. Aim: Identify and discuss the most prominent potential changes that have been observed in the health effects of phototherapy using either blue fluorescent- or blue LED light and speculate on the expected effects of changing to blue-green LED light phototherapy. Search the phototherapy literature using the terms neonate, hyperbilirubinemia, and phototherapy in the PubMed and Embase databases. Transitioning from blue fluorescent light to blue-green LED light will expose neonates to less light in the 400–450 nm spectral range, potentially leading to less photo-oxidation and geno-/cytotoxicity, reduced risk of cancer, and decreased mortality in extremely low-birthweight neonates. The riboflavin level may decline, and the increased production and retention of bronze pigments may occur in predisposed neonates due to enhanced lumirubin formation. The production of pre-inflammatory cytokines may rise. Hemodynamic responses and transepidermal water loss are less likely to occur. The risk of hyperthermia may decrease with the use of blue-green LED light and the risk of hypothermia may increase. Parent–neonate attachment and breastfeeding will be positively affected because of the shortened duration of phototherapy. The latter may also lead to a significant reduction in the cost of phototherapy procedures as well as the hospitalization process. Full article
(This article belongs to the Special Issue Bilirubin)
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