OBJECTIVES: This study aimed at evaluating the serum redox status in type 2 diabetes mellitus (T2DM) accompanied with an imbalance in iron concentrations. METHODS: Diabetic patients were grouped according to serum iron levels [normal (DNFe), low (DLFe), and high (DHFe)], and their clinical and redox parameters [total sulfhydryl groups (tSH), uric acid (UA), and total bilirubin (tBILI) as non-enzymatic antioxidants, and malondialdehyde (MDA) and advanced oxidation products of proteins (AOPP) as markers of oxidative stress] were determined. RESULTS: Glucose and HbA1c levels in the T2DM patients did not differ in function of serum iron. T2DM was associated with reduced tSH levels. In the diabetic patients, tSH, UA, and tBILI negatively correlated with MDA, as well as HbA1c with UA. Accordingly, AOPP and MDA were higher in the diabetic groups compared to the controls. The reduced antioxidant capacity was particularly pronounced in the DLFe group, which was further characterized by lower levels of UA and tBILI compared to the other groups. Subsequently, the level of MDA in the DLFe group was higher compared to the DNFe and DHFe groups. The positive correlation between serum iron levels and the antioxidants UA and tBILI, in conjunction with the negative correlation between serum iron levels and the markers of oxidative stress in the diabetic patients, corroborated the indication that comparatively higher level of oxidative stress is present when T2DM coexists with decreased iron levels. CONCLUSIONS: T2DM-associated redox imbalance is characterized by a decrease in serum total sulfhydryl groups and low serum iron-associated reduction in uric acid and total bilirubin levels, accompanied by increased oxidative stress markers. The relatively noninvasive and simple determination of these parameters may be of considerable interest in monitoring the pathophysiological processes in T2DM patients, and may provide useful insights into the effects of potential therapeutic or nutritional interventions.
- MeSH
- antioxidancia * metabolismus MeSH
- bilirubin metabolismus MeSH
- biologické markery MeSH
- diabetes mellitus 2. typu * komplikace MeSH
- glykovaný hemoglobin MeSH
- kyselina močová MeSH
- lidé MeSH
- oxidace-redukce MeSH
- oxidační stres MeSH
- produkty pokročilé oxidace proteinů metabolismus MeSH
- thyreotropin metabolismus MeSH
- železo MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Gilbert's syndrome, also known as benign hyperbilirubinaemia, was described more than 100 years ago. It has usually been considered a physiological abnormality characterised by a mild elevation of the systemic level of unconjugated bilirubin, in the absence of any underlying liver or overt haemolytic disease. However, since the re-discovery of the potent antioxidant effects of bilirubin in the late 1980s, as well as multiple intracellular signalling pathways affected by bilirubin, an ever-increasing body of evidence suggests that individuals with Gilbert's syndrome may benefit from the mild hyperbilirubinaemia and are actually protected from the development of a wide variety of "diseases of civilisation" such as cardiovascular diseases, certain cancers, and autoimmune or neurodegenerative diseases. This review analyses the current state of medical knowledge given recent discoveries in this rapidly developing field, as well as their possible clinical significance, and provides a new perspective on this condition.
- MeSH
- antioxidancia MeSH
- bilirubin metabolismus MeSH
- Gilbertova nemoc * metabolismus MeSH
- hyperbilirubinemie metabolismus MeSH
- játra metabolismus MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
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.
- MeSH
- bilirubin metabolismus MeSH
- diabetes mellitus 2. typu * genetika MeSH
- genotyp MeSH
- glukuronosyltransferasa genetika metabolismus MeSH
- hemoxygenasa-1 genetika metabolismus MeSH
- lidé MeSH
- polymorfismus genetický * MeSH
- promotorové oblasti (genetika) MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
Bilirubin has several physiological functions, both beneficial and harmful. In addition to reactive oxygen species-scavenging activities, bilirubin has potent immunosuppressive effects associated with long-term pathophysiological sequelae. It has been recently recognized as a hormone with endocrine actions and interconnected effects on various cellular signaling pathways. Current studies show that bilirubin also decreases adiposity and prevents metabolic and cardiovascular diseases. All in all, the physiological importance of bilirubin is only now coming to light, and strategies for increasing plasma bilirubin levels to combat chronic diseases are starting to be considered. This review discusses the beneficial effects of increasing plasma bilirubin, incorporates emerging areas of bilirubin biology, and provides key concepts to advance the field.
- MeSH
- bilirubin * metabolismus farmakologie MeSH
- hemoxygenasa-1 metabolismus MeSH
- kardiovaskulární nemoci * MeSH
- lidé MeSH
- reaktivní formy kyslíku metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Research Support, N.I.H., Extramural MeSH
Ikterus je jedním z nejčastěji řešených problémů na novorozeneckých odděleních, rozvíjí se až u 60 % donošených a 80 % nezralých novorozenců. Vysoká prevalence novorozenecké hyperbilirubinemie je způsobena nerovnováhou mezi produkcí a eliminací bilirubinu. Hlavním cílem terapie novorozeneckého ikteru je prevence trvalého poškození mozku a současně minimalizace invazivního vyšetřování a nadbytečného užívání fototerapie. Tento článek zahrnuje aktuální doporučení pro management hyperbilirubinemie novorozenců nad 35. týden gestace vydaný Americkou pediatrickou asociací v roce 2022.
Jaundice is one of the most frequent problem in neonatal wards, it affects up to 60 % term infants and 80 % of premature infants. The high prevalence of neonatal hyperbilirubinemia is caused by an imbalance favoring the production of bilirubin over its elimination. The main goal of treatment for neonatal jaundice is the prevention of permanent brain damage while simultaneously minimizing invasive examinations and excessive use of phototherapy. This article includes the current recommendation for the management of hyperbilirubinemia in newborns of more than 35 weeks of gestation, which was issued by the American Pediatric Association in 2022.
- MeSH
- bilirubin metabolismus škodlivé účinky účinky záření MeSH
- fototerapie MeSH
- lidé MeSH
- novorozenec MeSH
- novorozenecká hyperbilirubinemie * diagnóza etiologie terapie MeSH
- rizikové faktory MeSH
- Check Tag
- lidé MeSH
- novorozenec MeSH
- Publikační typ
- přehledy MeSH
Závěrečná zpráva o řešení grantu Agentury pro zdravotnický výzkum MZ ČR
nestr.
Fototerapie je standardním léčebným postupem u zavážné novorozenecké žloutenky. Tato léčba však může být doprovázena závažnými zdravotními dopady, které zahrnují zvýšení celkové mortality, zvýšený výskyt některých nádorových onemocnění, diabetu mellitu 1. typu, obzvláště u novorozenců s velmi nízkou porodní hmotností. I přes široké používání fototerapie v klinické neonatologii je velmi málo známo o biologických účincích oxidačních produktů bilirubinu, které vznikají během fototerapie novorozenecké žloutenky, a zcela chybí studie, které by se systematicky zabývaly celým procesem fotooxidace bilirubinu. Všechny tyto aspekty přitom mohou vysvětlit pozorované nežádoucí účinky fototerapie. Cílem předkládaného projektu je tedy systematické studium procesu fotooxidace bilirubinu za použití interdisciplinárního přístupu, který kombinuje biologické a chemické vědní obory.; Phototherapy is a golden standard treatment of severe neonatal jaundice. However, this treatment modality might be associated with significant health issues including increased overall mortality, increased risk of certain cancers or type 1 diabetes mellitus, especially in very low weight birth neonates. Despite a widespread use of phototherapy in clinical neonatology, only little is known about bilirubin oxidation products generated during phototherapy, and almost no studies have been performed to systematically explore the whole process of bilirubin photooxidation. All these aspects may account for observed clinical side effects. Thus, these issues are the main aim of the current project which combines interdisciplinary approach between life and basic sciences.
- MeSH
- bilirubin chemie metabolismus škodlivé účinky účinky záření MeSH
- fototerapie škodlivé účinky MeSH
- hemoxygenasa-1 MeSH
- novorozenec MeSH
- novorozenecká žloutenka terapie MeSH
- oxid uhelnatý MeSH
- oxidace-redukce účinky záření MeSH
- rizikové faktory MeSH
- Check Tag
- novorozenec MeSH
- Konspekt
- Pediatrie
- NLK Obory
- biochemie
- perinatologie a neonatologie
- NLK Publikační typ
- závěrečné zprávy o řešení grantu AZV MZ ČR
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.
- MeSH
- bilirubin metabolismus MeSH
- cirkadiánní rytmus fyziologie MeSH
- lidé MeSH
- ligandy MeSH
- NADPH-oxidasy metabolismus MeSH
- receptory buněčného povrchu metabolismus MeSH
- signální transdukce * MeSH
- superoxidy metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
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.
- MeSH
- bilirubin metabolismus MeSH
- cirkadiánní rytmus fyziologie MeSH
- lidé MeSH
- ligandy MeSH
- NADPH-oxidasy metabolismus MeSH
- receptory buněčného povrchu metabolismus MeSH
- signální transdukce * MeSH
- superoxidy metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Unlike any protein studied so far, the active site of bilirubin oxidase from Myrothecium verrucaria contains a unique type of covalent link between tryptophan and histidine side chains. The role of this post-translational modification in substrate binding and oxidation is not sufficiently understood. Our structural and mutational studies provide evidence that this Trp396-His398 adduct modifies T1 copper coordination and is an important part of the substrate binding and oxidation site. The presence of the adduct is crucial for oxidation of substituted phenols and it substantially influences the rate of oxidation of bilirubin. Additionally, we bring the first structure of bilirubin oxidase in complex with one of its products, ferricyanide ion, interacting with the modified tryptophan side chain, Arg356 and the active site-forming loop 393-398. The results imply that structurally and chemically distinct types of substrates, including bilirubin, utilize the Trp-His adduct mainly for binding and to a smaller extent for electron transfer.
- MeSH
- bilirubin metabolismus MeSH
- Hypocreales metabolismus MeSH
- konformace proteinů MeSH
- molekulární modely * MeSH
- oxidace-redukce MeSH
- oxidoreduktasy působící na CH-CH vazby metabolismus MeSH
- transport elektronů fyziologie MeSH
- vazba proteinů fyziologie MeSH
- vazebná místa MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Bilirubin byl po dlouhou dobu považován jen za nepříznivý marker zejména jaterních chorob. Dnes však již víme, že se jedná o molekulu s významnými antioxidačními a dalšími biologickými vlastnosti. Bilirubin působí protizánětlivě, ovlivňuje řadu intracelulárních signalizačních faktorů, moduluje fosforylaci bílkovin. Těmito mechanizmy se patrně spolupodílí na ochraně před rozvojem mnoha civilizačních onemocnění. O jeho protektivním vlivu na aterogenezi dnes již není pochyb, sérové koncentrace bilirubinu však mají negativní vztah i k riziku rozvoje diabetu, obezity, arteriální hypertenze, metabolického syndromu, či nealkoholové steatohepatitidy. Z klinických studií vyplývá, že každé mikromolární zvýšení sérových koncentrací bilirubinu je asociováno s významnými benefity. Jedinci s mírně zvýšenými koncentracemi bilirubinu v krvi pozorovanými u Gilbertova syndromu (benigní hyperbilirubinemie) mají rizika těchto chorob výrazně snížena, zatímco ti, kteří mají sérové koncentrace bilirubinu nízké, jsou rozvojem těchto chorob ohroženi podstatně více.
For long time bilirubin was considered only an ominous sign of liver diseases. However, based on recent research, bilirubin is nowadays known as a potent antioxidant molecule, possessing additional biological activities. Bilirubin is a powerful anti-inflammatory compound, modulates number of intracelullar signaling pathways, affects protein phosphorylation. All these mechanisms may account for the protective effects of bilirubin against development of many civilization diseases. Its salutary effects on atherogenesis are generally accepted, but its serum concentrations have negative relationship also to risk of diabetes, obesity, arterial hypertension, metabolic syndrome or non-alcoholic steatohepatitis. Based on clinical studies, it is clear now that each micromolar increase of serum bilirubin concentrations is associated with significant health benefits. Subjects with mildly elevated serum bilirubin concentrations, such in Gilbert syndrome (benign hyperbilirubinemia), have much lower risk of these diseases, whereas those with low serum bilirubin levels are at much higher risk.
