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Prof. Libor Vítek
Charles University

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0 Gastroenterology
0 Hepatology
0 Oxidative Stress
0 bile acids
0 Bilirubin

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Bilirubin
Oxidative Stress
bile acids
Hepatology

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Journal article
Published: 18 June 2021 in Scientific Reports
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Unconjugated bilirubin (UCB) is the end-product of heme catabolism in the intravascular compartment. Although beneficial for human health when mildly elevated in the body, when present at greater than a critical threshold concentration, UCB exerts toxic effects that are related to its physico-chemical properties, particularly affecting the central nervous system. The aim of the present study was to characterize bilirubin-10-sulfonate (ranarubin), a naturally occurring bile pigment, including determination of its mixed acidity constants (pK a *). Thanks to the presence of the sulfonic acid moiety, this compound is more polar compared to UCB, which might theoretically solve the problem with an accurate determination of the UCB pK a * values of its propionic acid carboxylic groups. Bilirubin-10-sulfonate was synthesized by modification of a previously described procedure; and its properties were studied by mass spectrometry (MS), nuclear magnetic resonance (NMR), infrared (IR), and circular dichroism (CD) spectroscopy. Determination of pK a * values of bilirubin-10-sulfonate and UCB was performed by capillary electrophoresis with low pigment concentrations in polar buffers. The identity of the synthesized bilirubin-10-sulfonate was confirmed by MS, and the pigment was further characterized by NMR, IR, and CD spectroscopy. The pK a values of carboxylic acid moieties of bilirubin-10-sulfonate were determined to be 5.02, whereas those of UCB were determined to be 9.01. The physico-chemical properties of bilirubin-10-sulfonate were partially characterized with low pK a * values compared to those of UCB, indicating that bilirubin-10-sulfonate cannot be used as a surrogate pigment for UCB chemical studies. In addition, using a different methodological approach, the pK a * values of UCB were found to be in a mildly alkaline region, confirming the conclusions of a recent critical re-evaluation of this specific issue.

ACS Style

Adam Čepa; Veronika Dejmková; Ladislav Lešetický; Ivan Jelínek; Stanislav Smrček; Martin Štícha; Jana Jašprová; Marie Urbanová; Iryna Goncharova; Martin Dračínský; Eliška Procházková; Donald J. Ostrow; Libor Vítek. Physico-chemical characterization of bilirubin-10-sulfonate and comparison of its acid–base behavior with unconjugated bilirubin. Scientific Reports 2021, 11, 1 -11.

AMA Style

Adam Čepa, Veronika Dejmková, Ladislav Lešetický, Ivan Jelínek, Stanislav Smrček, Martin Štícha, Jana Jašprová, Marie Urbanová, Iryna Goncharova, Martin Dračínský, Eliška Procházková, Donald J. Ostrow, Libor Vítek. Physico-chemical characterization of bilirubin-10-sulfonate and comparison of its acid–base behavior with unconjugated bilirubin. Scientific Reports. 2021; 11 (1):1-11.

Chicago/Turabian Style

Adam Čepa; Veronika Dejmková; Ladislav Lešetický; Ivan Jelínek; Stanislav Smrček; Martin Štícha; Jana Jašprová; Marie Urbanová; Iryna Goncharova; Martin Dračínský; Eliška Procházková; Donald J. Ostrow; Libor Vítek. 2021. "Physico-chemical characterization of bilirubin-10-sulfonate and comparison of its acid–base behavior with unconjugated bilirubin." Scientific Reports 11, no. 1: 1-11.

Expert opinion
Published: 17 June 2021 in Journal of Hepatology
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Summary Bilirubin is a tetrapyrrolic compound originating from heme catabolism. Although originally considered only a waste product, potentially dangerous for human health, it becomes now increasingly evident that this molecule represents an important modulator of various biological functions in the human body. Bilirubin appears to have versatile functions, from cell signaling (behaving almost as a ¨real¨ hormonal substance), modulation of metabolism, to immune system affecting biological activities with apparent clinical and even therapeutic consequences. These activities may be the reason for the lower incidence of civilization illnesses (cardiovascular diseases, arterial hypertension, diabetes, obesity, metabolic syndrome, certain cancers, autoimmune, and neurodegenerative diseases) observed in subjects with a chronic mild unconjugated hyperbilirubinemia, a typical sign of the Gilbert syndrome. While higher serum concentrations of unconjugated bilirubin may serve as an important protective factor against these diseases, low levels of bilirubin are associated with the opposite effect.

ACS Style

Libor Vítek; Claudio Tiribelli. Bilirubin: The yellow hormone? Journal of Hepatology 2021, 1 .

AMA Style

Libor Vítek, Claudio Tiribelli. Bilirubin: The yellow hormone? Journal of Hepatology. 2021; ():1.

Chicago/Turabian Style

Libor Vítek; Claudio Tiribelli. 2021. "Bilirubin: The yellow hormone?" Journal of Hepatology , no. : 1.

Journal article
Published: 09 June 2021 in Molecules
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Statins have been widely used for the treatment of hypercholesterolemia due to their ability to inhibit HMG-CoA reductase, the rate-limiting enzyme of de novo cholesterol synthesis, via the so-called mevalonate pathway. However, their inhibitory action also causes depletion of downstream intermediates of the pathway, resulting in the pleiotropic effects of statins, including the beneficial impact in the treatment of cancer. In our study, we compared the effect of all eight existing statins on the expression of genes, the products of which are implicated in cancer inhibition and suggested the molecular mechanisms of their action in epigenetic and posttranslational regulation, and in cell-cycle arrest, death, migration, or invasion of the cancer cells.

ACS Style

Silvie Rimpelová; Michal Kolář; Hynek Strnad; Tomáš Ruml; Libor Vítek; Helena Gbelcová. Comparison of Transcriptomic Profiles of MiaPaCa-2 Pancreatic Cancer Cells Treated with Different Statins. Molecules 2021, 26, 3528 .

AMA Style

Silvie Rimpelová, Michal Kolář, Hynek Strnad, Tomáš Ruml, Libor Vítek, Helena Gbelcová. Comparison of Transcriptomic Profiles of MiaPaCa-2 Pancreatic Cancer Cells Treated with Different Statins. Molecules. 2021; 26 (12):3528.

Chicago/Turabian Style

Silvie Rimpelová; Michal Kolář; Hynek Strnad; Tomáš Ruml; Libor Vítek; Helena Gbelcová. 2021. "Comparison of Transcriptomic Profiles of MiaPaCa-2 Pancreatic Cancer Cells Treated with Different Statins." Molecules 26, no. 12: 3528.

Journal article
Published: 27 May 2021 in Scientific Reports
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Neonatal hyperbilirubinemia or jaundice is associated with kernicterus, resulting in permanent neurological damage or even death. Conventional phototherapy does not prevent hyperbilirubinemia or eliminate the need for exchange transfusion. Here we investigated the potential of therapeutic bile acids ursodeoxycholic acid (UDCA) and obeticholic acid (OCA, 6-α-ethyl-CDCA), a farnesoid-X-receptor (FXR) agonist, as preventive treatment options for neonatal hyperbilirubinemia using the hUGT1*1 humanized mice and Ugt1a-deficient Gunn rats. Treatment of hUGT1*1 mice with UDCA or OCA at postnatal days 10–14 effectively decreased bilirubin in plasma (by 82% and 62%) and brain (by 72% and 69%), respectively. Mechanistically, our findings indicate that these effects are mediated through induction of protein levels of hUGT1A1 in the intestine, but not in liver. We further demonstrate that in Ugt1a-deficient Gunn rats, UDCA but not OCA significantly decreases plasma bilirubin, indicating that at least some of the hypobilirubinemic effects of UDCA are independent of UGT1A1. Finally, using the synthetic, non-bile acid, FXR-agonist GW4064, we show that some of these effects are mediated through direct or indirect activation of FXR. Together, our study shows that therapeutic bile acids UDCA and OCA effectively reduce both plasma and brain bilirubin, highlighting their potential in the treatment of neonatal hyperbilirubinemia.

ACS Style

Lori W. E. van der Schoor; Henkjan J. Verkade; Anna Bertolini; Sanne de Wit; Elvira Mennillo; Eva Rettenmeier; André A. Weber; Rick Havinga; Petra Valášková; Jana Jašprová; Dicky Struik; Vincent W. Bloks; Shujuan Chen; Andrea B. Schreuder; Libor Vítek; Robert H. Tukey; Johan W. Jonker. Potential of therapeutic bile acids in the treatment of neonatal Hyperbilirubinemia. Scientific Reports 2021, 11, 1 -10.

AMA Style

Lori W. E. van der Schoor, Henkjan J. Verkade, Anna Bertolini, Sanne de Wit, Elvira Mennillo, Eva Rettenmeier, André A. Weber, Rick Havinga, Petra Valášková, Jana Jašprová, Dicky Struik, Vincent W. Bloks, Shujuan Chen, Andrea B. Schreuder, Libor Vítek, Robert H. Tukey, Johan W. Jonker. Potential of therapeutic bile acids in the treatment of neonatal Hyperbilirubinemia. Scientific Reports. 2021; 11 (1):1-10.

Chicago/Turabian Style

Lori W. E. van der Schoor; Henkjan J. Verkade; Anna Bertolini; Sanne de Wit; Elvira Mennillo; Eva Rettenmeier; André A. Weber; Rick Havinga; Petra Valášková; Jana Jašprová; Dicky Struik; Vincent W. Bloks; Shujuan Chen; Andrea B. Schreuder; Libor Vítek; Robert H. Tukey; Johan W. Jonker. 2021. "Potential of therapeutic bile acids in the treatment of neonatal Hyperbilirubinemia." Scientific Reports 11, no. 1: 1-10.

Journal article
Published: 28 April 2021 in Antioxidants & Redox Signaling
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Significance: As the central metabolic organ, the liver is exposed to a variety of potentially cytotoxic, pro-inflammatory, pro-fibrotic, and carcinogenic stimuli. To protect the organism from these deleterious effects, the liver has evolved a number of defense systems, which include antioxidant substrates and enzymes, anti-inflammatory tools, enzymatic biotransformation systems, and metabolic pathways. Recent advances: One of the pivotal systems that evolved during phylogenesis was the heme catabolic pathway. Comprising the important enzymes heme oxygenase and biliverdin reductase, this complex pathway has a number of key functions including enzymatic activities, but also cell signaling, and DNA transcription. It further generates two important bile pigments, biliverdin and bilirubin, as well as the gaseous molecule carbon monoxide. These heme degradation products have potent antioxidant, immunosuppressive, and cytoprotective effects. Recent data suggest that the pathway participates in the regulation of metabolic and hormonal processes implicated in the pathogenesis of hepatic and other diseases. Critical issues: This review discusses the impact of the heme catabolic pathway on major liver diseases, with particular focus on the involvement of cellular targeting and signaling in the pathogenesis of these conditions. Future directions: To utilize the biological consequences of the heme catabolic pathway, several unique therapeutic strategies have been developed. Research indicates that pharmaceutical, nutraceutical and lifestyle modifications positively affect the pathway, delivering potentially long-term clinical benefits. However, further well-designed studies are needed to confirm the clinical benefits of these approaches.

ACS Style

Libor Vitek. The protective role of the heme catabolic pathway in hepatic disorders. Antioxidants & Redox Signaling 2021, 1 .

AMA Style

Libor Vitek. The protective role of the heme catabolic pathway in hepatic disorders. Antioxidants & Redox Signaling. 2021; ():1.

Chicago/Turabian Style

Libor Vitek. 2021. "The protective role of the heme catabolic pathway in hepatic disorders." Antioxidants & Redox Signaling , no. : 1.

Journal article
Published: 04 April 2021 in Cancers
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Mitochondrial production of 2-hydroxyglutarate (2HG) can be catalyzed by wild-type isocitrate dehydrogenase 2 (IDH2) and alcohol dehydrogenase, iron-containing 1 (ADHFE1). We investigated whether biochemical background and substrate concentration in breast cancer cells promote 2HG production. To estimate its role in 2HG production, we quantified 2HG levels and its enantiomers in breast cancer cells using analytical approaches for metabolomics. By manipulation of mitochondrial substrate fluxes using genetic and pharmacological approaches, we demonstrated the existence of active competition between 2HG producing enzymes, i.e., IDH2 and ADHFE1. Moreover, we showed that distinct fractions of IDH2 enzyme molecules operate in distinct oxido-reductive modes, providing NADPH and producing 2HG simultaneously. We have also detected 2HG release in the urine of breast cancer patients undergoing adjuvant therapy and detected a correlation with stages of breast carcinoma development. In summary, we provide a background for vital mitochondrial production of 2HG in breast cancer cells with outcomes towards cancer biology and possible future diagnosis of breast carcinoma.

ACS Style

Jitka Špačková; Klára Gotvaldová; Aleš Dvořák; Alexandra Urbančoková; Kateřina Pospíšilová; David Větvička; Alberto Leguina-Ruzzi; Petra Tesařová; Libor Vítek; Petr Ježek; Katarína Smolková. Biochemical Background in Mitochondria Affects 2HG Production by IDH2 and ADHFE1 in Breast Carcinoma. Cancers 2021, 13, 1709 .

AMA Style

Jitka Špačková, Klára Gotvaldová, Aleš Dvořák, Alexandra Urbančoková, Kateřina Pospíšilová, David Větvička, Alberto Leguina-Ruzzi, Petra Tesařová, Libor Vítek, Petr Ježek, Katarína Smolková. Biochemical Background in Mitochondria Affects 2HG Production by IDH2 and ADHFE1 in Breast Carcinoma. Cancers. 2021; 13 (7):1709.

Chicago/Turabian Style

Jitka Špačková; Klára Gotvaldová; Aleš Dvořák; Alexandra Urbančoková; Kateřina Pospíšilová; David Větvička; Alberto Leguina-Ruzzi; Petra Tesařová; Libor Vítek; Petr Ježek; Katarína Smolková. 2021. "Biochemical Background in Mitochondria Affects 2HG Production by IDH2 and ADHFE1 in Breast Carcinoma." Cancers 13, no. 7: 1709.

Original research article
Published: 04 March 2021 in Frontiers in Pharmacology
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For severe unconjugated hyperbilirubinemia the gold standard treatment is phototherapy with blue-green light, producing more polar photo-oxidation products, believed to be non-toxic. The aim of the present study was to compare the effects of bilirubin (BR) and lumirubin (LR), the major BR photo-oxidation product, on metabolic and oxidative stress markers. The biological activities of these pigments were investigated on several human and murine cell lines, with the focus on mitochondrial respiration, substrate metabolism, reactive oxygen species production, and the overall effects on cell viability. Compared to BR, LR was found to be much less toxic, while still maintaining a similar antioxidant capacity in the serum as well as suppressing activity leading to mitochondrial superoxide production. Nevertheless, due to its lower lipophilicity, LR was less efficient in preventing lipoperoxidation. The cytotoxicity of BR was affected by the cellular glycolytic reserve, most compromised in human hepatoblastoma HepG2 cells. The observed effects were correlated with changes in the production of tricarboxylic acid cycle metabolites. Both BR and LR modulated expression of PPARα downstream effectors involved in lipid and glucose metabolism. Proinflammatory effects of BR, evidenced by increased expression of TNFα upon exposure to bacterial lipopolysaccharide, were observed in murine macrophage-like RAW 264.7 cells. Collectively, these data point to the biological effects of BR and its photo-oxidation products, which might have clinical relevance in phototherapy-treated hyperbilirubinemic neonates and adult patients.

ACS Style

Aleš Dvořák; Kateřina Pospíšilová; Kateřina Žížalová; Nikola Capková; Lucie Muchová; Marek Vecka; Nikola Vrzáčková; Jana Křížová; Jaroslav Zelenka; Libor Vítek. The Effects of Bilirubin and Lumirubin on Metabolic and Oxidative Stress Markers. Frontiers in Pharmacology 2021, 12, 1 .

AMA Style

Aleš Dvořák, Kateřina Pospíšilová, Kateřina Žížalová, Nikola Capková, Lucie Muchová, Marek Vecka, Nikola Vrzáčková, Jana Křížová, Jaroslav Zelenka, Libor Vítek. The Effects of Bilirubin and Lumirubin on Metabolic and Oxidative Stress Markers. Frontiers in Pharmacology. 2021; 12 ():1.

Chicago/Turabian Style

Aleš Dvořák; Kateřina Pospíšilová; Kateřina Žížalová; Nikola Capková; Lucie Muchová; Marek Vecka; Nikola Vrzáčková; Jana Křížová; Jaroslav Zelenka; Libor Vítek. 2021. "The Effects of Bilirubin and Lumirubin on Metabolic and Oxidative Stress Markers." Frontiers in Pharmacology 12, no. : 1.

Preprint
Published: 01 March 2021
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Mitochondrial production of 2-hydroxyglutarate (R-2HG) can be catalyzed by wild-type isocitrate dehydrogenase 2 (IDH2) and alcohol dehydrogenase, iron-containing 1 (ADHFE1). We investigated whether biochemical background and substrate concentration in breast cancer cells promote 2HG production. To estimate its role in 2HG production, we analyzed 2HG levels and its enantiomers in breast cancer cells using analytical approaches for metabolomics. By manipulation of mitochondrial substrate fluxes, including glutaminolysis, using genetic and pharmacological approaches we demonstrated the existence of an active competition between 2HG producing enzymes, i.e. IDH2 and ADHFE1. Moreover, we show that distinct fractions of IDH2 enzyme molecules operate in distinct oxido-reductive modes, providing NADPH and producing 2HG simultaneously. We have also detected 2HG release into breast cancer patient´s urine undergoing adjuvant therapy and detected a correlation with stages of breast carcinoma development. In summary, we provide a background for vital mitochondrial production of 2HG in breast cancer cells with outcomes towards cancer biology and possible future diagnosis of breast carcinoma.

ACS Style

Jitka Špačková; Klára Gotvaldová; Aleš Dvořák; Alexandra Urbančoková; Kateřina Pospíšilová; David Větvička; Alberto Andrés Leguina-Ruzzi; Petra Tesařová; Libor Vítek; Petr Ježek; Katarína Smolková. Biochemical Background in Mitochondria Affects 2HG Production by IDH2 and ADHFE1 in Breast Carcinoma. 2021, 1 .

AMA Style

Jitka Špačková, Klára Gotvaldová, Aleš Dvořák, Alexandra Urbančoková, Kateřina Pospíšilová, David Větvička, Alberto Andrés Leguina-Ruzzi, Petra Tesařová, Libor Vítek, Petr Ježek, Katarína Smolková. Biochemical Background in Mitochondria Affects 2HG Production by IDH2 and ADHFE1 in Breast Carcinoma. . 2021; ():1.

Chicago/Turabian Style

Jitka Špačková; Klára Gotvaldová; Aleš Dvořák; Alexandra Urbančoková; Kateřina Pospíšilová; David Větvička; Alberto Andrés Leguina-Ruzzi; Petra Tesařová; Libor Vítek; Petr Ježek; Katarína Smolková. 2021. "Biochemical Background in Mitochondria Affects 2HG Production by IDH2 and ADHFE1 in Breast Carcinoma." , no. : 1.

Journal article
Published: 09 February 2021 in Chemistry
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Carbon monoxide (CO) is an endogenously produced signaling molecule involved in the control of a vast array of physiological processes. One of the strategies to administer therapeutic amounts of CO is the precise spatial and temporal control over its release from photoactivatable CO-releasing molecules (photoCORMs). Here we present the synthesis and photophysical and photochemical properties of a small library of meso-carboxy BODIPY derivatives bearing different substituents at positions 2 and 6. We show that the nature of substituents has a major impact on both their photophysics and the efficiency of CO photorelease. CO was found to be efficiently released from π-extended 2,6-arylethynyl BODIPY derivatives possessing absorption spectra shifted to a more biologically desirable wavelength range. Selected photoCORMs were subjected to in vitro experiments that did not reveal any serious toxic effects, suggesting their potential for further biological research.

ACS Style

Esther Sánchez-Carnerero; Marina Russo; Andreas Jakob; Lucie Muchová; Libor Vítek; Petr Klán. Effects of Substituents on Photophysical and CO-Photoreleasing Properties of 2,6-Substituted meso-Carboxy BODIPY Derivatives. Chemistry 2021, 3, 238 -255.

AMA Style

Esther Sánchez-Carnerero, Marina Russo, Andreas Jakob, Lucie Muchová, Libor Vítek, Petr Klán. Effects of Substituents on Photophysical and CO-Photoreleasing Properties of 2,6-Substituted meso-Carboxy BODIPY Derivatives. Chemistry. 2021; 3 (1):238-255.

Chicago/Turabian Style

Esther Sánchez-Carnerero; Marina Russo; Andreas Jakob; Lucie Muchová; Libor Vítek; Petr Klán. 2021. "Effects of Substituents on Photophysical and CO-Photoreleasing Properties of 2,6-Substituted meso-Carboxy BODIPY Derivatives." Chemistry 3, no. 1: 238-255.

Journal article
Published: 30 October 2020 in International Journal of Molecular Sciences
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Background: Severe hyperbilirubinemia can cause permanent neurological damage in particular in neonates, whereas mildly elevated serum bilirubin protects from various oxidative stress-mediated diseases. The present work aimed to establish the intracellular unconjugated bilirubin concentrations (iUCB) thresholds differentiating between anti- and pro-oxidant effects. Methods: Hepatic (HepG2), heart endothelial (H5V), kidney tubular (HK2) and neuronal (SH-SY5Y) cell lines were exposed to increasing concentration of bilirubin. iUCB, cytotoxicity, intracellular reactive oxygen species (ROS) concentrations, and antioxidant capacity (50% efficacy concentration (EC50)) were determined. Results: Exposure of SH-SY5Y to UCB concentration > 3.6 µM (iUCB of 25 ng/mg) and >15 µM in H5V and HK2 cells (iUCB of 40 ng/mg) increased intracellular ROS production (p < 0.05). EC50 of the antioxidant activity was 21 µM (iUCB between 5.4 and 21 ng/mg) in HepG2 cells, 0.68 µM (iUCB between 3.3 and 7.5 ng/mg) in SH-SY5Y cells, 2.4 µM (iUCB between 3 and 6.7 ng/mg) in HK2 cells, and 4 µM (iUCB between 4.7 and 7.5 ng/mg) in H5V cells. Conclusions: In all the cell lines studied, iUCB of around 7 ng/mg protein had antioxidant activities, while iUCB > 25 ng/mg protein resulted in a prooxidant and cytotoxic effects. UCB metabolism was found to be cell-specific resulting in different iUCB.

ACS Style

Annalisa Bianco; Aleš Dvořák; Nikola Capková; Camille Gironde; Claudio Tiribelli; Christophe Furger; Libor Vitek; Cristina Bellarosa. The Extent of Intracellular Accumulation of Bilirubin Determines Its Anti- or Pro-Oxidant Effect. International Journal of Molecular Sciences 2020, 21, 8101 .

AMA Style

Annalisa Bianco, Aleš Dvořák, Nikola Capková, Camille Gironde, Claudio Tiribelli, Christophe Furger, Libor Vitek, Cristina Bellarosa. The Extent of Intracellular Accumulation of Bilirubin Determines Its Anti- or Pro-Oxidant Effect. International Journal of Molecular Sciences. 2020; 21 (21):8101.

Chicago/Turabian Style

Annalisa Bianco; Aleš Dvořák; Nikola Capková; Camille Gironde; Claudio Tiribelli; Christophe Furger; Libor Vitek; Cristina Bellarosa. 2020. "The Extent of Intracellular Accumulation of Bilirubin Determines Its Anti- or Pro-Oxidant Effect." International Journal of Molecular Sciences 21, no. 21: 8101.

Research article
Published: 01 October 2020 in The Journal of Organic Chemistry
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Phototherapy is a standard treatment for severe neonatal jaundice to remove toxic bilirubin from the blood. Here, the wavelength-dependent photochemistry of vinylneoxanthobilirubic acid methyl ester, a simplified model of a bilirubin dipyrrinone subunit responsible for a lumirubin-like structural rearrangement, was thoroughly investigated by liquid chromatography and mass and absorption spectroscopies, with the application of a multivariate curve resolution analysis method supplemented with quantum chemical calculations. Irradiation of the model chromophore leads to reversible Z → E photoisomerization followed by reversible photocyclization to a seven-membered ring system (formed as a mixture of diastereomers). Both the isomerization processes are efficient (ΦZE ∼ ΦEZ ∼ 0.16) when irradiated in the wavelength range of 360–410 nm, whereas the E-isomer cyclization (Φc = 0.006–0.008) and cycloreversion (Φ–c = 0.002–0.004) reactions are significantly less efficient. The quantum yields of all processes were found to depend strongly on the wavelength of irradiation, especially when lower energy photons were used. Upon irradiation in the tail of the absorption bands (490 nm), both the isomers exhibit more efficient photoisomerization (ΦZE ∼ ΦEZ ∼ 0.30) and cyclization (Φc = ∼0.07). In addition, the isomeric bilirubin dipyrrinone subunits were found to possess important antioxidant activities while being substantially less toxic than bilirubin.

ACS Style

Dominik Madea; Sadegh Mahvidi; David Chalupa; Taufiqueahmed Mujawar; Aleš Dvořák; Lucie Muchová; Jiří Janoš; Petr Slavíček; Jakub Švenda; Libor Vítek; Petr Klán. Wavelength-Dependent Photochemistry and Biological Relevance of a Bilirubin Dipyrrinone Subunit. The Journal of Organic Chemistry 2020, 85, 13015 -13028.

AMA Style

Dominik Madea, Sadegh Mahvidi, David Chalupa, Taufiqueahmed Mujawar, Aleš Dvořák, Lucie Muchová, Jiří Janoš, Petr Slavíček, Jakub Švenda, Libor Vítek, Petr Klán. Wavelength-Dependent Photochemistry and Biological Relevance of a Bilirubin Dipyrrinone Subunit. The Journal of Organic Chemistry. 2020; 85 (20):13015-13028.

Chicago/Turabian Style

Dominik Madea; Sadegh Mahvidi; David Chalupa; Taufiqueahmed Mujawar; Aleš Dvořák; Lucie Muchová; Jiří Janoš; Petr Slavíček; Jakub Švenda; Libor Vítek; Petr Klán. 2020. "Wavelength-Dependent Photochemistry and Biological Relevance of a Bilirubin Dipyrrinone Subunit." The Journal of Organic Chemistry 85, no. 20: 13015-13028.

Review
Published: 22 September 2020 in Antioxidants
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Bilirubin is a yellow endogenous derivate of the heme catabolism. Since the 1980s, it has been recognized as one of the most potent antioxidants in nature, able to counteract 10,000× higher intracellular concentrations of H2O2. In the recent years, not only bilirubin, but also its precursor biliverdin, and the enzymes involved in their productions (namely heme oxygenase and biliverdin reductase; altogether the “yellow players”—YPs) have been recognized playing a protective role in diseases characterized by a chronic prooxidant status. Based on that, there is an ongoing effort in inducing their activity as a therapeutic option. Nevertheless, the understanding of their specific contributions to pathological conditions of the central nervous system (CNS) and their role in these diseases are limited. In this review, we will focus on the most recent evidence linking the role of the YPs specifically to neurodegenerative and neurological conditions. Both the protective, as well as potentially worsening effects of the YP’s activity will be discussed.

ACS Style

Sri Jayanti; Libor Vítek; Claudio Tiribelli; Silvia Gazzin. The Role of Bilirubin and the Other “Yellow Players” in Neurodegenerative Diseases. Antioxidants 2020, 9, 900 .

AMA Style

Sri Jayanti, Libor Vítek, Claudio Tiribelli, Silvia Gazzin. The Role of Bilirubin and the Other “Yellow Players” in Neurodegenerative Diseases. Antioxidants. 2020; 9 (9):900.

Chicago/Turabian Style

Sri Jayanti; Libor Vítek; Claudio Tiribelli; Silvia Gazzin. 2020. "The Role of Bilirubin and the Other “Yellow Players” in Neurodegenerative Diseases." Antioxidants 9, no. 9: 900.

Research article
Published: 24 July 2020 in PLOS ONE
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Enzymatic assays based on bacterial 3α-hydroxysteroid dehydrogenase are the method of choice for quantification of total bile acids (BAs) in serum. Although non-specific, it is generally considered precise and robust. The aim of this study was to investigate how changes in the BA spectrum might affect the reliability of the method. We measured standard solutions of twenty-three human and murine BAs using a commercial enzymatic assay and compared the measured vs. expected concentrations. Additionally, total BA concentrations in rat and human cholestatic samples with an abnormal BA spectrum were measured using an enzymatic assay, and a more specific LC-MS/MS method. We observed a great variability in the response of individual BAs in the enzymatic assay. Relative signal intensities ranged from 100% in glycocholic acid (reference) to only 20% in α-muricholic acid. The enzymatic assay markedly underestimated the BA concentrations in both human and rat cholestatic sera when compared to the LC-MS/MS assay. Our study indicated that the performance of an enzymatic assay largely depends on the BA spectrum, and the total concentration of BAs can be markedly underestimated. Samples with an atypical BA spectrum (viz. in rodents) should preferably be measured by other methods.

ACS Style

Kateřina Žížalová; Marek Vecka; Libor Vítek; Martin Leníček. Enzymatic methods may underestimate the total serum bile acid concentration. PLOS ONE 2020, 15, e0236372 .

AMA Style

Kateřina Žížalová, Marek Vecka, Libor Vítek, Martin Leníček. Enzymatic methods may underestimate the total serum bile acid concentration. PLOS ONE. 2020; 15 (7):e0236372.

Chicago/Turabian Style

Kateřina Žížalová; Marek Vecka; Libor Vítek; Martin Leníček. 2020. "Enzymatic methods may underestimate the total serum bile acid concentration." PLOS ONE 15, no. 7: e0236372.

Journal article
Published: 10 March 2020 in Scientific Reports
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Although phototherapy (PT) is a standard treatment for neonatal jaundice, no validated clinical methods for determination of bilirubin phototherapy products are available. Thus, the aim of our study was to establish a such method for clinical use. To achieve this aim, a LC-MS/MS assay for simultaneous determination of Z-lumirubin (LR) and unconjugated bilirubin (UCB) was conducted. LR was purified after irradiation of UCB at 460 nm. The assay was tested on human sera from PT-treated neonates. Samples were separated on a HPLC system with a triple quadrupole mass spectrometer detector. The instrument response was linear up to 5.8 and 23.4 mg/dL for LR and UCB, respectively, with submicromolar limits of detection and validity parameters relevant for use in clinical medicine. Exposure of newborns to PT raised serum LR concentrations three-fold (p < 0.01), but the absolute concentrations were low (0.37 ± 0.16 mg/dL), despite a dramatic decrease of serum UCB concentrations (13.6 ± 2.2 vs. 10.3 ± 3.3 mg/dL, p < 0.01). A LC-MS/MS method for the simultaneous determination of LR and UCB in human serum was established and validated for clinical use. This method should help to monitor neonates on PT, as well as to improve our understanding of both the kinetics and biology of bilirubin phototherapy products.

ACS Style

Jana Jašprová; Aleš Dvořák; Marek Vecka; Martin Leníček; Ondřej Lacina; Petra Valášková; Miloš Zapadlo; Richard Plavka; Petr Klán; Libor Vítek. A novel accurate LC-MS/MS method for quantitative determination of Z-lumirubin. Scientific Reports 2020, 10, 1 -8.

AMA Style

Jana Jašprová, Aleš Dvořák, Marek Vecka, Martin Leníček, Ondřej Lacina, Petra Valášková, Miloš Zapadlo, Richard Plavka, Petr Klán, Libor Vítek. A novel accurate LC-MS/MS method for quantitative determination of Z-lumirubin. Scientific Reports. 2020; 10 (1):1-8.

Chicago/Turabian Style

Jana Jašprová; Aleš Dvořák; Marek Vecka; Martin Leníček; Ondřej Lacina; Petra Valášková; Miloš Zapadlo; Richard Plavka; Petr Klán; Libor Vítek. 2020. "A novel accurate LC-MS/MS method for quantitative determination of Z-lumirubin." Scientific Reports 10, no. 1: 1-8.

Journal article
Published: 28 February 2020 in Toxins
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Mycotoxins found in randomly selected commercial milk thistle dietary supplement were evaluated for their toxicity in silico and in vitro. Using in silico methods, the basic physicochemical, pharmacological, and toxicological properties of the mycotoxins were predicted using ACD/Percepta. The in vitro cytotoxicity of individual mycotoxins was determined in mouse macrophage (RAW 264.7), human hepatoblastoma (HepG2), and human embryonic kidney (HEK 293T) cells. In addition, we studied the bioavailability potential of mycotoxins and silibinin utilizing an in vitro transwell system with differentiated human colon adenocarcinoma cells (Caco-2) simulating mycotoxin transfer through the intestinal epithelial barrier. The IC50 values for individual mycotoxins in studied cells were in the biologically relevant ranges as follows: 3.57–13.37 nM (T-2 toxin), 5.07–47.44 nM (HT-2 toxin), 3.66–17.74 nM (diacetoxyscirpenol). Furthermore, no acute toxicity was obtained for deoxynivalenol, beauvericin, zearalenone, enniatinENN-A, enniatin-A1, enniatin-B, enniatin-B1, alternariol, alternariol-9-methyl ether, tentoxin, and mycophenolic acid up to the 50 nM concentration. The acute toxicity of these mycotoxins in binary combinations exhibited antagonistic effects in the combinations of T-2 with DON, ENN-A1, or ENN-B, while the rest showed synergistic or additive effects. Silibinin had a significant protective effect against both the cytotoxicity of three mycotoxins (T-2 toxin, HT-2 toxin, DAS) and genotoxicity of AME, AOH, DON, and ENNs on HEK 293T. The bioavailability results confirmed that AME, DAS, ENN-B, TEN, T-2, and silibinin are transported through the epithelial cell layer and further metabolized. The bioavailability of silibinin is very similar to mycotoxins poor penetration.

ACS Style

Van Nguyen Tran; Jitka Viktorova; Katerina Augustynkova; Nikola Jelenova; Simona Dobiasova; Katerina Rehorova; Marie Fenclova; Milena Stranska-Zachariasova; Libor Vitek; Jana Hajslova; Tomas Ruml. In Silico and In Vitro Studies of Mycotoxins and Their Cocktails; Their Toxicity and Its Mitigation by Silibinin Pre-Treatment. Toxins 2020, 12, 148 .

AMA Style

Van Nguyen Tran, Jitka Viktorova, Katerina Augustynkova, Nikola Jelenova, Simona Dobiasova, Katerina Rehorova, Marie Fenclova, Milena Stranska-Zachariasova, Libor Vitek, Jana Hajslova, Tomas Ruml. In Silico and In Vitro Studies of Mycotoxins and Their Cocktails; Their Toxicity and Its Mitigation by Silibinin Pre-Treatment. Toxins. 2020; 12 (3):148.

Chicago/Turabian Style

Van Nguyen Tran; Jitka Viktorova; Katerina Augustynkova; Nikola Jelenova; Simona Dobiasova; Katerina Rehorova; Marie Fenclova; Milena Stranska-Zachariasova; Libor Vitek; Jana Hajslova; Tomas Ruml. 2020. "In Silico and In Vitro Studies of Mycotoxins and Their Cocktails; Their Toxicity and Its Mitigation by Silibinin Pre-Treatment." Toxins 12, no. 3: 148.

Review article
Published: 04 February 2020 in Medicinal Research Reviews
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For long time bilirubin was only considered as a potentially dangerous sign of liver diseases, but it now appears clear that it is also a powerful signaling molecule. Together with potent antioxidant activities that were only reported in the last few decades, many other biological effects have now been clearly described. These include especially profound inhibitory effects on almost all effectors of the immune system, with their clinical consequences in the bilirubin‐mediated protection against autoimmune and inflammatory diseases. Separate from these, bilirubin activates various nuclear and cytoplasmic receptors, resembling the endocrine activities of actual hormonal substances. This is true for the “classical” hepatic nuclear receptors, including the aryl hydrocarbon receptor, or the constitutive androstane receptor; and also for some lesser‐explored receptors such as peroxisome proliferator‐activated receptors α and γ; Mas‐related G protein‐coupled receptor; or other signaling molecules including fatty acid binding protein 1, apolipoprotein D, or reactive oxygen species. All of these targets have broad metabolic effects, which in turn may offer protection against obesity, diabetes mellitus, and other metabolic diseases. The (mostly experimental) data are also supported by clinical evidence. In fact, data from the last three decades have convincingly demonstrated the protective effects of mildly elevated serum bilirubin concentrations against various “diseases of civilization.” Additionally, even tiny, micromolar changes of serum bilirubin concentrations have been associated with substantial alteration in the risks of these diseases. It is highly likely that all of the biological activities of bilirubin have yet to be exhaustively explored, and thus we can expect further clinical discoveries about this evolutionarily old molecule into the future.

ACS Style

Libor Vítek. Bilirubin as a signaling molecule. Medicinal Research Reviews 2020, 40, 1335 -1351.

AMA Style

Libor Vítek. Bilirubin as a signaling molecule. Medicinal Research Reviews. 2020; 40 (4):1335-1351.

Chicago/Turabian Style

Libor Vítek. 2020. "Bilirubin as a signaling molecule." Medicinal Research Reviews 40, no. 4: 1335-1351.

Original article
Published: 10 January 2020 in Journal of Cellular and Molecular Medicine
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Arthrospira platensis, a blue‐green alga, is a popular nutraceutical substance having potent antioxidant properties with potential anti‐carcinogenic activities. The aim of our study was to assess the possible anti‐angiogenic effects of A platensis in an experimental model of pancreatic cancer. The effects of an A platensis extract were investigated on human pancreatic cancer cells (PA‐TU‐8902) and immortalized endothelial‐like cells (Ea.hy926). PA‐TU‐8902 pancreatic tumours xenografted to athymic mice were also examined. In vitro migration and invasiveness assays were performed on the tested cells. Multiple angiogenic factors and signalling pathways were analysed in the epithelial, endothelial and cancer cells, and tumour tissue. The A platensis extract exerted inhibitory effects on both migration and invasion of pancreatic cancer as well as endothelial‐like cells. Tumours of mice treated with A platensis exhibited much lesser degrees of vascularization as measured by CD31 immunostaining (P = .004). Surprisingly, the VEGF‐A mRNA and protein expressions were up‐regulated in pancreatic cancer cells. A platensis inhibited ERK activation upstream of Raf and suppressed the expression of ERK‐regulated proteins. Treatment of pancreatic cancer with A platensis was associated with suppressive effects on migration and invasiveness with various anti‐angiogenic features, which might account for the anticancer effects of this blue‐green alga.

ACS Style

Ivana Marková; Renata Koníčková; Kateřina Vaňková; Martin Leníček; Michal Kolář; Hynek Strnad; Miluše Hradilová; Jana Šáchová; Jan Rasl; Zuzana Klímová; Tomáš Vomastek; Ivana Němečková; Petr Nachtigal; Libor Vítek. Anti‐angiogenic effects of the blue‐green alga Arthrospira platensis on pancreatic cancer. Journal of Cellular and Molecular Medicine 2020, 24, 2402 -2415.

AMA Style

Ivana Marková, Renata Koníčková, Kateřina Vaňková, Martin Leníček, Michal Kolář, Hynek Strnad, Miluše Hradilová, Jana Šáchová, Jan Rasl, Zuzana Klímová, Tomáš Vomastek, Ivana Němečková, Petr Nachtigal, Libor Vítek. Anti‐angiogenic effects of the blue‐green alga Arthrospira platensis on pancreatic cancer. Journal of Cellular and Molecular Medicine. 2020; 24 (4):2402-2415.

Chicago/Turabian Style

Ivana Marková; Renata Koníčková; Kateřina Vaňková; Martin Leníček; Michal Kolář; Hynek Strnad; Miluše Hradilová; Jana Šáchová; Jan Rasl; Zuzana Klímová; Tomáš Vomastek; Ivana Němečková; Petr Nachtigal; Libor Vítek. 2020. "Anti‐angiogenic effects of the blue‐green alga Arthrospira platensis on pancreatic cancer." Journal of Cellular and Molecular Medicine 24, no. 4: 2402-2415.

Review
Published: 01 September 2019 in Archives of Biochemistry and Biophysics
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Bilirubin is among the most potent of the endogenous antioxidants. Data developed over the last three decades have convincingly demonstrated the protective effects of mildly elevated serum bilirubin concentrations; whereas lower levels of it have been associated with an increased risk of various diseases of civilization, commonly accompanied with increased oxidative stress. Even tiny, micromolar changes of serum bilirubin concentrations have been associated with substantial modulation for the risk of these diseases. However, clinical data published in the current literature are influenced by many confounding factors that have not been properly controlled for. These include the use of improper reference intervals, which are mostly used as common intervals without any partitioning for gender, ethnicity, age, or other important factors (such as smoking). The clinical chemistry methods used for bilirubin determination have not been standardized; in fact, these methods are known to be among the least reliable of any used in clinical chemistry labs. As a result, the data from epidemiological studies are not always comparable. Therefore, it is highly recommended to conduct properly-designed large epidemiological studies. Based on this data, the establishment of decision limits is highly warranted, especially for the lower concentration values of serum bilirubin.

ACS Style

Libor Vítek. Bilirubin as a predictor of diseases of civilization. Is it time to establish decision limits for serum bilirubin concentrations? Archives of Biochemistry and Biophysics 2019, 672, 108062 .

AMA Style

Libor Vítek. Bilirubin as a predictor of diseases of civilization. Is it time to establish decision limits for serum bilirubin concentrations? Archives of Biochemistry and Biophysics. 2019; 672 ():108062.

Chicago/Turabian Style

Libor Vítek. 2019. "Bilirubin as a predictor of diseases of civilization. Is it time to establish decision limits for serum bilirubin concentrations?" Archives of Biochemistry and Biophysics 672, no. : 108062.

Journal article
Published: 18 August 2019 in Antioxidants
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Numerous in vitro assays are used to characterize the antioxidant properties of natural-based matrices. However, many of them generate contradictory and non-compliant results. In our study, we focused on the characterization of traditionally used biochemical (2,2'-azino-bis-(3-ethylbenzothiazoline-6 sulfonic acid) (ABTS), Oxygen Radical Absorption Capacity (ORAC), and 2,2-diphenyl-1-picrylhydrazyl (DPPH)) and cellular (CAA) antioxidant tests on a broad set of milk thistle dietary supplements containing silymarin. In addition to 26 commercially available preparations, also the natural silymarin extract available from Sigma Aldrich, St. Louis, MI, USA, and a model mixture of pure flavonoid/flavonolignans mimicking the silymarin composition were investigated as control samples. Significant differences in the antioxidant capacity of the supplements were observed. Unlike the DPPH, the results of the ABTS and ORAC methods correlated with the silymarin components determined by U-HPLC-HRMS/MS. The responses in CAA were considerably lower than in other assays. Silymarin exhibited a significantly higher antioxidant capacity than the artificially prepared flavonoid/flavonolignans mixture in all tests, indicating possible presence of other antioxidants of natural origin. The follow-up U-HPLC-HRMS/MS screening revealed the presence of tens of non-silymarin compounds with reported antioxidant activity (not only in the silymarin extract, but also in the milk thistle preparations). The sum of the total phenolics and the sum of the simple phenolics correlated with CAA results more than silymarin.

ACS Style

Jitka Viktorova; Milena Stranska-Zachariasova; Marie Fenclova; Libor Vitek; Jana Hajslova; Vladimir Kren; Tomas Ruml. Complex Evaluation of Antioxidant Capacity of Milk Thistle Dietary Supplements. Antioxidants 2019, 8, 317 .

AMA Style

Jitka Viktorova, Milena Stranska-Zachariasova, Marie Fenclova, Libor Vitek, Jana Hajslova, Vladimir Kren, Tomas Ruml. Complex Evaluation of Antioxidant Capacity of Milk Thistle Dietary Supplements. Antioxidants. 2019; 8 (8):317.

Chicago/Turabian Style

Jitka Viktorova; Milena Stranska-Zachariasova; Marie Fenclova; Libor Vitek; Jana Hajslova; Vladimir Kren; Tomas Ruml. 2019. "Complex Evaluation of Antioxidant Capacity of Milk Thistle Dietary Supplements." Antioxidants 8, no. 8: 317.

Journal article
Published: 31 July 2019 in Scientific Reports
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Herbal-based dietary supplements have become increasingly popular. The extract from milk thistle (Silybum marianum), is often used for the treatment of liver diseases. However, serious concerns exist regarding the efficacy, composition, as well as the safety of these over-the-counter preparations. Therefore, the aim of the present study was to investigate the composition as well as chemical and biological safety of 26 milk thistle-based dietary supplements purchased from both the U.S. and Czech markets between 2016 and 2017. The study was focused on a determination of the composition of active ingredients, as well as analyses of possible contaminants including: mycotoxins, plant alkaloids, and pesticide residues, as well as the microbial purity. High-throughput analyses were performed using advanced U-HPLC-HRMS techniques. Large differences in the silymarin content were observed among individual milk thistle preparations, often in contrast with the information provided by the manufacturers. In addition, substantial inter-batch differences in silymarin content were also demonstrated. In all milk thistle preparations tested, large numbers and high concentrations of mycotoxins and several pesticides, as well as the substantial presence of microbiological contamination were detected, pointing to serious safety issues. In conclusion, our results strongly indicate the need for strict controls of the composition, chemical contaminants, as well as the microbiological purity of commercial milk thistle extracts used for the treatment of liver diseases. Poor definition of these preparations together with contamination by biologically active substances may not only account for the inconsistency of clinical observations, but also be responsible for possible herbal-based dietary supplements-induced liver injury.

ACS Style

Marie Fenclova; Alena Novakova; Jitka Viktorova; Petra Jonatova; Zbynek Dzuman; Tomas Ruml; Vladimir Kren; Jana Hajslova; Libor Vitek; Milena Stranska-Zachariasova. Poor chemical and microbiological quality of the commercial milk thistle-based dietary supplements may account for their reported unsatisfactory and non-reproducible clinical outcomes. Scientific Reports 2019, 9, 1 -12.

AMA Style

Marie Fenclova, Alena Novakova, Jitka Viktorova, Petra Jonatova, Zbynek Dzuman, Tomas Ruml, Vladimir Kren, Jana Hajslova, Libor Vitek, Milena Stranska-Zachariasova. Poor chemical and microbiological quality of the commercial milk thistle-based dietary supplements may account for their reported unsatisfactory and non-reproducible clinical outcomes. Scientific Reports. 2019; 9 (1):1-12.

Chicago/Turabian Style

Marie Fenclova; Alena Novakova; Jitka Viktorova; Petra Jonatova; Zbynek Dzuman; Tomas Ruml; Vladimir Kren; Jana Hajslova; Libor Vitek; Milena Stranska-Zachariasova. 2019. "Poor chemical and microbiological quality of the commercial milk thistle-based dietary supplements may account for their reported unsatisfactory and non-reproducible clinical outcomes." Scientific Reports 9, no. 1: 1-12.