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International Journal of Clinical... 2022To observe different roles of direct bilirubin (Dbil) on portopulmonary hypertension (POPH) and idiopathic pulmonary arterial hypertension (IPAH).
BACKGROUND
To observe different roles of direct bilirubin (Dbil) on portopulmonary hypertension (POPH) and idiopathic pulmonary arterial hypertension (IPAH).
METHODS
Thirty incident patients with POPH and 180 with IPAH (matched by the WHO functional classification in a 1 : 6 ratio) between March 2010 and December 2020 were included. The receiver operating curve and Kaplan-Meier method were applied to estimate the ability to distinguish between the two and survival, respectively. Univariate and forward multiple stepwise regression analyses were performed to access the relationship between pulmonary vascular resistance (PVR) and clinical indices.
RESULTS
Compared to IPAH, the POPH group had better hemodynamics including PVR (7.08 ± 3.95 vs. 14.89 ± 7.11, < 0.001) and higher total bilirubin (Tbil) and Dbil. Tbil and Dbil had a negative correlation with PVR in the POPH group ( = -0.394, =0.031; = -0.364, =0.048, respectively) but positive correlation in the IPAH group ( = 0.218, =0.003; = 0.178, =0.018, respectively). Increased neutrophil counts ( = 0.394, =0.031) and elevated NT-proBNP ( = 0.433, < 0.001) would help predict the elevation of PVR in POPH and IPAH groups independent of Dbil, respectively. Dbil could distinguish POPH from IPAH (AUC = 0.799, =0.009), and the ability was elevated when taking aspartate aminotransferase together (AUC = 0.835, < 0.001). The overall survival was better in POPH than in IPAH (7 dead cases of POPH and 96 of IPAH, =0.002). Survival was better in POPH than in IPAH in the group of Dbil ≥7 mol/L (=0.001) but showed no significant difference between POPH and IPAH in the group of Dbil <7 mol/L (=0.192).
CONCLUSIONS
The POPH group had a better hemodynamic profile than IPAH. Dbil was associated oppositely with the elevation of PVR in POPH and IPAH. Patients with POPH had better survival than those with IPAH in the total cohort and in the group of Dbil ≥7 mol/L, but limited dead cases of POPH should be noted.
Topics: Bilirubin; Familial Primary Pulmonary Hypertension; Humans; Hypertension; Liver Diseases; Vascular Resistance
PubMed: 35685569
DOI: 10.1155/2022/7021178 -
Annals of Noninvasive Electrocardiology... Mar 2020
Topics: Bilirubin; Electrocardiography; Humans; Nutrition Surveys
PubMed: 32154617
DOI: 10.1111/anec.12756 -
The Journal of Clinical Investigation Sep 1972Conjugates of bilirubin were studied in normal bile of man and rat, and in bile of liver patients. In general human bile was obtained by duodenal intubation. In addition...
Conjugates of bilirubin were studied in normal bile of man and rat, and in bile of liver patients. In general human bile was obtained by duodenal intubation. In addition T-tube bile was examined in patients operated on for mechanical obstruction. The bile pigment compositions of duodenal and T-tube bile were similar in two patients where comparison was possible. Obstruction of the bile duct in rats was used as an animal model for obstructive jaundice. Diazotized ethyl anthranilate was used for determination of total conjugated bile pigment and for thin-layer chromatography (t.l.c.) analysis of the derived azopigments. The available t.l.c. procedures are versatile and allow rapid and quantitative analysis. A variety of conjugated azopigments can be distinguished. With chloroform, negligible amounts of unconjugated bilirubin are extracted from bile of man. Therefore, the percentage of monoconjugated bile pigments present in the initial bile sample can be calculated from the percentage of azodipyrrole found after diazotization. Normal bile from man and rat yields similar azopigment patterns. The dominant component is azopigment-delta (azodipyrrole beta-D-monoglucuronoside). Small amounts of azopigments with complex conjugating structures (gamma-azopigments) are present in both cases. Human bile further yields small amounts of azopigments containing xylose or glucose (called azopigments-alpha(2) and -alpha(3), respectively). Monoconjugated bilirubin (estimated from the percentage of azodipyrrole) amounts of 22% of total bile pigments in human bile and to 39% in murine bile. In both, the bulk of bile pigment is bilirubin diglucuronoside. From bile of patients with acquired liver diseases a new azopigment group (beta-azopigment) was derived. The gamma-azopigment group was increased; the delta-azopigment group (containing azodipyrrole beta-D-monoglucuronoside) was decreased. No differentiation was possible between intra- and extrahepatic cholestasis. The percentage of beta-azopigment showed a positive correlation with serum bilirubin concentration (r = 0.6). Recovery of the diseases was accompanied by normalization of the azopigment patterns. In rats, hydrostatic or mechanical obstruction induced increases in beta- and gamma-azopigments and a decrease in delta-azopigment similar to the changes observed in bile of liver patients. Complete normalization was obtained 6 hr after relieving the hydrostatic obstruction (duration 15-21 hr). In contrast, with man after surgery for extrahepatic obstruction, T-tube bile was not normalized when the T-tube was withdrawn (10 days after operation). Hydrostatic obstruction in rats provides an easy model when postobstructive bile pigment composition and parameters have to be investigated. The present investigations stress the importance of the physiopathological state when studying bilirubin conjugation. Hindrance to bile secretion induced heterogeneity of bilirubin conjugates and stimulated the formation of complex structures.
Topics: Animals; Azo Compounds; Bile; Bile Pigments; Bilirubin; Body Temperature; Chemical and Drug Induced Liver Injury; Cholelithiasis; Cholestasis; Chromatography, Thin Layer; Diazonium Compounds; Duodenum; Hepatitis A; Humans; Hydrogen-Ion Concentration; Intubation; Liver Cirrhosis; Liver Diseases; Rats; ortho-Aminobenzoates
PubMed: 4639028
DOI: 10.1172/JCI107062 -
The Biochemical Journal Oct 1977Bilirubin and its conjugates were extracted from either dog gall-bladder bile or bile-containing human duodenal juice into chloroform containing 10mm-tetraheptylammonium...
Bilirubin and its conjugates were extracted from either dog gall-bladder bile or bile-containing human duodenal juice into chloroform containing 10mm-tetraheptylammonium chloride. The intact bilirubin tetrapyrroles were then separated by t.l.c. Structural elucidation was made after coupling of the individual pigments with diazonium salts. Four azopigments were detected: azopigment alpha(o) or dipyrrolic azobilirubin; azopigment delta or dipyrrolic azobilirubin monoglucuronide; azopigment alpha(3) or dipyrrolic azobilirubin monoglucoside; and, from dog gall-bladder bile, azopigment alpha(2). The last conjugate required further verification of its structure. After methanolysis, it was shown by combined g.l.c.-mass spectrometry to contain xylose in a 1:1 molar ratio with the azopigments of bilirubin. Human bile contained 86% bilirubin diglucuronide, 7% bilirubin monoglucuronide monoglucoside diester, 4% bilirubin monoglucuronide and 3% bilirubin. Dog gall-bladder bile had a considerably different composition; it contained 47% bilirubin diglucuronide, 40% bilirubin monoglucuronide monoglucoside diester, 8% bilirubin monoglucuronide, 4% bilirubin diglucoside, 1-2% bilirubin and traces of conjugates containing xylose. The total bilirubin content and proportions of the conjugates did not change in bile that was frozen and stored at -20 degrees C under N(2), whereas in the chloroform/tetraheptylammonium chloride extract, similarly stored, total pigment was slowly lost and the diglucuronide conjugate converted into the monoglucuronide.
Topics: Animals; Azo Compounds; Bile; Bilirubin; Chromatography, Gas; Chromatography, Thin Layer; Dogs; Duodenum; Gallbladder; Humans; Intestinal Secretions; Mass Spectrometry; Pyrroles; Time Factors
PubMed: 588243
DOI: 10.1042/bj1670001 -
PloS One 2016Although phototherapy was introduced as early as 1950's, the potential biological effects of bilirubin photoisomers (PI) generated during phototherapy remain unclear....
Although phototherapy was introduced as early as 1950's, the potential biological effects of bilirubin photoisomers (PI) generated during phototherapy remain unclear. The aim of our study was to isolate bilirubin PI in their pure forms and to assess their biological effects in vitro. The three major bilirubin PI (ZE- and EZ-bilirubin and Z-lumirubin) were prepared by photo-irradiation of unconjugated bilirubin. The individual photoproducts were chromatographically separated (TLC, HPLC), and their identities verified by mass spectrometry. The role of Z-lumirubin (the principle bilirubin PI) on the dissociation of bilirubin from albumin was tested by several methods: peroxidase, fluorescence quenching, and circular dichroism. The biological effects of major bilirubin PI (cell viability, expression of selected genes, cell cycle progression) were tested on the SH-SY5Y human neuroblastoma cell line. Lumirubin was found to have a binding site on human serum albumin, in the subdomain IB (or at a close distance to it); and thus, different from that of bilirubin. Its binding constant to albumin was much lower when compared with bilirubin, and lumirubin did not affect the level of unbound bilirubin (Bf). Compared to unconjugated bilirubin, bilirubin PI did not have any effect on either SH-SY5Y cell viability, the expression of genes involved in bilirubin metabolism or cell cycle progression, nor in modulation of the cell cycle phase. The principle bilirubin PI do not interfere with bilirubin albumin binding, and do not exert any toxic effect on human neuroblastoma cells.
Topics: Bilirubin; Cell Cycle; Cell Line; Cell Survival; Chromatography, High Pressure Liquid; Circular Dichroism; Gene Expression Regulation; Heme; Humans; Isomerism; Kinetics; Ligands; Light; Phototherapy; Serum Albumin; Spectrophotometry, Ultraviolet
PubMed: 26829016
DOI: 10.1371/journal.pone.0148126 -
Proceedings of the National Academy of... May 2021Biosyntheses of chlorophyll and heme in oxygenic phototrophs share a common trunk pathway that diverges with insertion of magnesium or iron into the last common...
Biosyntheses of chlorophyll and heme in oxygenic phototrophs share a common trunk pathway that diverges with insertion of magnesium or iron into the last common intermediate, protoporphyrin IX. Since both tetrapyrroles are pro-oxidants, it is essential that their metabolism is tightly regulated. Here, we establish that heme-derived linear tetrapyrroles (bilins) function to stimulate the enzymatic activity of magnesium chelatase (MgCh) via their interaction with GENOMES UNCOUPLED 4 (GUN4) in the model green alga A key tetrapyrrole-binding component of MgCh found in all oxygenic photosynthetic species, GUN4, also stabilizes the bilin-dependent accumulation of protoporphyrin IX-binding CHLH1 subunit of MgCh in light-grown cells by preventing its photooxidative inactivation. Exogenous application of biliverdin IXα reverses the loss of CHLH1 in the bilin-deficient heme oxygenase () mutant, but not in the mutant. We propose that these dual regulatory roles of GUN4:bilin complexes are responsible for the retention of bilin biosynthesis in all photosynthetic eukaryotes, which sustains chlorophyll biosynthesis in an illuminated oxic environment.
Topics: Bile Pigments; Chlamydomonas reinhardtii; Chlorophyll; Cyanobacteria; Heme Oxygenase (Decyclizing); Intracellular Signaling Peptides and Proteins; Lyases; Protoporphyrins
PubMed: 33975960
DOI: 10.1073/pnas.2104443118 -
The Libyan Journal of Medicine Jan 2010Gallstone disease is one of the major surgical problems in the Libyan population; it is probably related to diet, especially excessive consumption of meat. The study was...
Gallstone disease is one of the major surgical problems in the Libyan population; it is probably related to diet, especially excessive consumption of meat. The study was conducted to determine the composition of gallstones and their possible etiology in a Libyan population. The chemical composition of gallstones from 41 patients (six males and 35 females) was analyzed. The stones were classified into cholesterol, pigment, and mixed stones (MS). Cholesterol stones (CS) showed a significantly higher cholesterol content than pigment stones (PS) (p=0.0085) though not significantly higher than MS. Their phospholipid content and inorganic phosphates were higher than in the other types of stones and oxalate content was significantly elevated in comparison with MS (p=0.0471). In MS, the cholesterol, bile acids, and bilirubin were intermediate between cholesterol and PS, whereas triglycerides were significantly more than PS (p=0.0004). Bilirubin (0.0001) and bile acids (p=0.0009) were significantly higher than CS (p=0.0001). However, they contained the lowest amounts of sodium, potassium, magnesium, and oxalate. In PS, bilirubin (p=0.0001) was significantly higher than both groups. Bile acid content was significantly higher than CS (p=0.0001) but not significantly more than MS. They showed the highest values of calcium, sodium, potassium, magnesium, and chlorides compared to the other types of stones. High levels of cholesterol in stones and dyslipidemia associated with mixed as well as cholesterol gallstones suggest an etiological association and efforts to reduce dietary fat among the Libyan population may lead to decreased cholesterol and mixed gallstones.
Topics: Bile Acids and Salts; Bilirubin; Cholesterol; Female; Gallstones; Humans; Male; Triglycerides
PubMed: 28156296
DOI: 10.3402/ljm.v5i0.4627 -
Angewandte Chemie (International Ed. in... Apr 2016Fall colors have always been fascinating and are still a remarkably puzzling phenomenon associated with the breakdown of chlorophyll (Chl) in leaves. As discovered in... (Review)
Review
Fall colors have always been fascinating and are still a remarkably puzzling phenomenon associated with the breakdown of chlorophyll (Chl) in leaves. As discovered in recent years, nongreen bilin-type Chl catabolites are generated, which are known as the phyllobilins. Collaborative chemical-biological efforts have led to the elucidation of the key Chl-breakdown processes in senescent leaves and in ripening fruit. Colorless and largely photoinactive phyllobilins are rapidly produced from Chl, apparently primarily as part of a detoxification program. However, fluorescent Chl catabolites accumulate in some senescent leaves and in peels of ripe bananas and induce a striking blue glow. The structural features, chemical properties, and abundance of the phyllobilins in the biosphere suggest biological roles, which still remain to be elucidated.
Topics: Bile Pigments; Cell Death; Cellular Senescence; Chlorophyll; Oxidation-Reduction; Plants
PubMed: 26919572
DOI: 10.1002/anie.201508928 -
Journal of Hepatology Aug 2017Biliverdin and bilirubin were previously considered end products of heme catabolism; now, however, there is evidence for further degradation to diverse bioactive...
BACKGROUND & AIMS
Biliverdin and bilirubin were previously considered end products of heme catabolism; now, however, there is evidence for further degradation to diverse bioactive products. Z-BOX A and Z-BOX B arise upon oxidation with unknown implications for hepatocellular function and integrity. We studied the impact of Z-BOX A and B on hepatic functions and explored their alterations in health and cholestatic conditions.
METHODS
Functional implications and mechanisms were investigated in rats, hepatocytic HepG2 and HepaRG cells, human immortalized hepatocytes, and isolated perfused livers. Z-BOX A and B were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in acute and acute-on-chronic liver failure and hereditary unconjugated hyperbilirubinemia.
RESULTS
Z-BOX A and B are found in similar amounts in humans and rodents under physiological conditions. Serum concentrations increased ∼20-fold during cholestatic liver failure in humans (p<0.001) and in hereditary deficiency of bilirubin glucuronidation in rats (p<0.001). Pharmacokinetic studies revealed shorter serum half-life of Z-BOX A compared to its regio-isomer Z-BOX B (p=0.035). While both compounds were taken up by hepatocytes, Z-BOX A was enriched ∼100-fold and excreted in bile. Despite their reported vasoconstrictive properties in the brain vasculature, BOXes did not affect portal hemodynamics. Both Z-BOX A and B showed dose-dependent cytotoxicity, affected the glutathione redox state, and differentially modulated activity of Rev-erbα and Rev-erbβ. Moreover, BOXes-triggered remodeling of the hepatocellular cytoskeleton.
CONCLUSIONS
Our data provide evidence that higher-order heme degradation products, namely Z-BOX A and B, impair hepatocellular integrity and might mediate intra- and extrahepatic cytotoxic effects previously attributed to hyperbilirubinemia.
LAY SUMMARY
Degradation of the blood pigment heme yields the bile pigment bilirubin and the oxidation products Z-BOX A and Z-BOX B. Serum concentrations of these bioactive molecules increase in jaundice and can impair liver function and integrity. Amounts of Z-BOX A and Z-BOX B that are observed during liver failure in humans have profound effects on hepatic function when added to cultured liver cells or infused into healthy rats.
Topics: Acute-On-Chronic Liver Failure; Animals; Bile; Bilirubin; Biliverdine; Cholestasis; Glutathione; Heme; Hemodynamics; Hep G2 Cells; Humans; Hyperbilirubinemia; In Vitro Techniques; Liver; Liver Circulation; Male; Oxidation-Reduction; Pyrroles; Rats; Rats, Wistar
PubMed: 28412296
DOI: 10.1016/j.jhep.2017.03.037 -
American Journal of Physiology.... Jan 2015Metastable and equilibrium phase diagrams for unconjugated bilirubin IXα (UCB) in bile are yet to be determined for understanding the physical chemistry of pigment...
Metastable and equilibrium phase diagrams for unconjugated bilirubin IXα (UCB) in bile are yet to be determined for understanding the physical chemistry of pigment gallstone formation. Also, UCB is a molecule of considerable biomedical importance because it is a potent antioxidant and an inhibitor of atherogenesis. We employed principally a titrimetric approach to obtain metastable and equilibrium UCB solubilities in model bile systems composed of taurine-conjugated bile salts, egg yolk lecithin (mixed long-chain phosphatidylcholines), and cholesterol as functions of total lipid concentration, biliary pH values, and CaCl2 plus NaCl concentrations. Metastable and equilibrium precipitation pH values were obtained, and average pKa values of the two carboxyl groups of UCB were calculated. Added lecithin and increased temperature decreased UCB solubility markedly, whereas increases in bile salt concentrations and molar levels of urea augmented solubility. A wide range of NaCl and cholesterol concentrations resulted in no specific effects, whereas added CaCl2 produced large decreases in UCB solubilities at alkaline pH values only. UV-visible absorption spectra were consistent with both hydrophobic and hydrophilic interactions between UCB and bile salts that were strongly influenced by pH. Reliable literature values for UCB compositions of native gallbladder biles revealed that biles from hemolytic mice and humans with black pigment gallstones are markedly supersaturated with UCB and exhibit more acidic pH values, whereas biles from nonstone control animals and patients with cholesterol gallstone are unsaturated with UCB.
Topics: Animals; Bile; Bilirubin; Calcium Chloride; Cholesterol; Crigler-Najjar Syndrome; Disease Models, Animal; Gallstones; Hemolysis; Humans; Hydrogen-Ion Concentration; Hydrophobic and Hydrophilic Interactions; Lecithins; Mice; Micelles; Models, Chemical; Rats, Gunn; Rats, Sprague-Dawley; Sodium Chloride; Solubility; Spectrophotometry, Ultraviolet; Temperature; Urea
PubMed: 25359538
DOI: 10.1152/ajpgi.00277.2014