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Projects / Programmes source: ARIS

Bilirubin as protective factor against the development of chronic degenerative disease: serum biomarker and potential for pharmacological modulation

Research activity

Code Science Field Subfield
3.06.00  Medical sciences  Cardiovascular system   

Code Science Field
B007  Biomedical sciences  Medicine (human and vertebrates) 

Code Science Field
3.02  Medical and Health Sciences  Clinical medicine 
Keywords
bilirubin, biomarker, biliverdin, cardiovascular diseases, neurodegenerative diseases, prevention, lifestyle modification
Evaluation (rules)
source: COBISS
Researchers (19)
no. Code Name and surname Research area Role Period No. of publicationsNo. of publications
1.  35380  PhD Jure Borišek  Chemistry  Researcher  2017 - 2019  61 
2.  36896  Barbara Buh    Technical associate  2017 - 2018 
3.  30141  PhD Maša Černelič Bizjak  Psychology  Researcher  2017 - 2020  262 
4.  04537  PhD Mladen Franko  Control and care of the environment  Researcher  2017 - 2020  608 
5.  11373  PhD Dimitar Hristovski  Computer science and informatics  Researcher  2017 - 2020  152 
6.  24263  PhD Zala Jenko Pražnikar  Public health (occupational safety)  Researcher  2017 - 2020  233 
7.  27826  PhD Mihaela Jurdana  Neurobiology  Researcher  2017 - 2020  206 
8.  15169  PhD Damijana Mojca Jurič  Neurobiology  Researcher  2017 - 2020  103 
9.  26484  PhD Andrej Kastrin  Medical sciences  Researcher  2017 - 2018  151 
10.  31463  PhD Dorota Agnieszka Korte  Control and care of the environment  Researcher  2017 - 2020  158 
11.  17935  Jožica Košir    Technical associate  2017 - 2020 
12.  08095  PhD Mojca Kržan  Neurobiology  Researcher  2017 - 2020  272 
13.  26511  PhD Mitja Martelanc  Chemistry  Researcher  2018  73 
14.  29497  PhD Nikola Minovski  Pharmacy  Researcher  2017 - 2020  119 
15.  09775  PhD Marjana Novič  Chemistry  Researcher  2017 - 2020  618 
16.  24764  PhD Ana Petelin  Cardiovascular system  Researcher  2017 - 2020  234 
17.  31817  PhD Mojca Stubelj  Public health (occupational safety)  Researcher  2017 - 2020  208 
18.  10974  PhD Irena Zajc  Biochemistry and molecular biology  Technical associate  2019 - 2020  134 
19.  29416  PhD Lovro Žiberna  Neurobiology  Head  2017 - 2020  249 
Organisations (4)
no. Code Research organisation City Registration number No. of publicationsNo. of publications
1.  0104  National Institute of Chemistry  Ljubljana  5051592000  21,237 
2.  0381  University of Ljubljana, Faculty of Medicine  Ljubljana  1627066  48,704 
3.  1540  University of Nova Gorica  Nova Gorica  5920884000  14,352 
4.  2413  Universita del Litorale, Facolta di Scienze della Salute  Izola  1810014005  9,341 
Abstract
Bilirubin is present in various chemical forms in the blood, namely, conjugated with glucuronic acid (direct bilirubin), unconjugated bound to serum albumin (indirect bilirubin) and unconjugated-unbound (free bilirubin). The bioactive form is the free bilirubin, which is not measured routinely in the clinical setting, but has been recently identified to be around 10 nM in serum. Importantly, nanomolar concentrations of bilirubin can protect cells from the 10,000-fold molar excess of oxidants when both substances are added exogenously to cell culture. This remarkable effect has been explained that bilirubin acting as antioxidant, is itself oxidized to biliverdin, and then recycled by biliverdin reductase back to bilirubin. All in all, bilirubin is an endogenous antioxidant with anti-inflammatory and anti-thrombotic activity, and is inversely correlated with disease risk of the cardiovascular system, such as ischemic heart disease, hypertension, diabetes type II, metabolic syndrome, obesity, among others. Importantly, some positive lifestyle modifications, e.g. weight loss or cessation of smoking, lead to higher levels of serum bilirubin. We hypothesize that bilirubin has the potential to be used as a biomarker for cardiovascular pre-disease states and that serum bilirubin levels can be modulated. In this project we will include a large sample of healthy volunteers and volunteer-patients (heart failure patients and Parkinson's disease) and measure in their serum all forms of bilirubin, including free bilirubin and free biliverdin. We will introduce a new parameter B / B (ratio of free bilirubin / biliverdin free) as a potential biomarker for development of chronic degenerative diseases, especially cardiovascular and neurodegenerative, which involve in its aetiology increased oxidative stress and chronic inflammation. In addition to the collected blood serum samples, we will in certain volunteers collect also new biological fluids, obtained in a less invasive manner, and determine bilirubin, e.g. saliva, and lacrimal fluid. The aim of the project is to determine how to moderatley increase serum bilirubin levels, in order to enhance its protective activity. Namely, we will investigate the following hypotheses: positive lifestyle changes (due to lower consumption of bilirubin due to reduced oxidative stress and reduces inflammation) - a prospective study in volunteers, which will decide for at least one substantial amendment in their lives: (i) smoking cessation; ii) loss of excess weight; iii) an increase in physical activity; iv) improvement of diet; v) reduction of psychosocial stress. pharmacological interventions (increase in serum bilirubin) by increasing the synthesis of bilirubin (induction biliverdin reductase (BVR) and heme oxidase-1 (HO-1), which are responsible for the synthesis of bilirubin), inhibition of uptake in liver cells (inhibition of organic anion transporters (OATP) and bilitranslocase (BTL), inhibition of its metabolism in liver cells (inhibition of UDP-glucuronosyltransferase (UGT1A1), or through displacement from albumin (the interaction of the active substance with bilirubin bound to albumin). These studies will take place in the computer models (in silico), in cell culture (in vitro) and animal models (in vivo). The aim is to identify new clinical indications for drugs that are already registered in the market with an established safety profile (drug repurposing).
Significance for science
The project will contribute significantly to new research directions in medicine: - we will do the first study on a larger volunteer sample to investigate the relationship of free bilirubin (the biologically active form that is not measured in routine clinical analysis) and total serum bilirubin (which is routinely determined in the clinical laboratory). This opens the perspective to use free bilirubin routinely in serum analysis. - we will do the first study to determine the role of free biliverdin levels with the development of new clinical parameter B / B (free bilirubin / free biliverdin). In case of favorable results, there is a big potential in a lot of diseases since the changes in the B / B values will reflect the extent of oxidative stress and inflammation, as well as the ability of endogenous antioxidant response. - development of new less invasive methods for collecting biological fluids (saliva, tear fluid) for the assessment of serum bilirubin. This could lead into the development of new "point-of-care" appliances for healthy individuals and/or patients for use at home. This opens opportunities for other scientific discipline, who are orientied in the development of biosensors and new detection methods. - drug-repurposing approach: many drugs are available on the market with established drug safety profiles, which could be used for new indications. - a new way of monitoring non-pharmacological approaches used on the patients, such as the introduction of a healthy lifestyle, e.g. monitoring the antioxidant status in the introduction of diet, weight loss, reduction of psycho-social stress, healthy sleep. This opens up many research opportunities for many who are engaged in preventive medicine, healthy way of living. At the same time, the possibility of monitoring the psycho-social stress also provides a bridge between medicine and social sciences.
Significance for the country
Monitoring  of the quality of the lifestyle in a quantitative manner through the measurement of various forms of bilirubin in a small blood sample (in an affordable manner) opens up opportunities to develop new appliances that people could have at home. This can lead to the emergence of new products for companies dealing with the biomedical equipment.
Most important scientific results Interim report, final report
Most important socioeconomically and culturally relevant results Interim report, final report
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