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Trends in Molecular Medicine Apr 2023Bilirubin has several physiological functions, both beneficial and harmful. In addition to reactive oxygen species-scavenging activities, bilirubin has potent... (Review)
Review
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.
Topics: Humans; Bilirubin; Heme Oxygenase-1; Cardiovascular Diseases; Reactive Oxygen Species
PubMed: 36828710
DOI: 10.1016/j.molmed.2023.01.007 -
The Cochrane Database of Systematic... Mar 2023Phototherapy is a widely accepted, effective first-line therapy for neonatal jaundice. It is traditionally used continuously but intermittent phototherapy has been... (Review)
Review
BACKGROUND
Phototherapy is a widely accepted, effective first-line therapy for neonatal jaundice. It is traditionally used continuously but intermittent phototherapy has been proposed as an equally effective alternative with practical advantages of improved maternal feeding and bonding. The effectiveness of intermittent phototherapy compared with continuous phototherapy is unknown.
OBJECTIVES
To assess the safety and effectiveness of intermittent phototherapy compared with continuous phototherapy.
SEARCH METHODS
Searches were conducted on 31 January 2022 in the following databases: CENTRAL via CRS Web, MEDLINE and Embase via Ovid. We also searched clinical trials databases and the reference lists of retrieved articles for randomised controlled trials (RCTs) and quasi-randomised trials.
SELECTION CRITERIA
We included RCTs, cluster-RCTs and quasi-RCTs comparing intermittent phototherapy with continuous phototherapy in jaundiced infants (both term and preterm) up to the age of 30 days. We compared intermittent phototherapy with continuous phototherapy by any method and at any dose and duration as defined by the authors.
DATA COLLECTION AND ANALYSIS
Three review authors independently selected trials, assessed trial quality and extracted data from included studies. We performed fixed-effect analyses and expressed treatment effects as mean difference (MD), risk ratio (RR) and risk difference (RD) with 95% confidence intervals (CIs). Our primary outcomes of interest were rate of decline of serum bilirubin, and kernicterus. We used the GRADE approach to assess the certainty of evidence.
MAIN RESULTS
We included 12 RCTs (1600 infants) in the review. There is one ongoing study and four awaiting classification. There was little or no difference between intermittent phototherapy and continuous phototherapy with respect to rate of decline of bilirubin in jaundiced newborn infants (MD -0.09 micromol/L/hr, 95% CI -0.21 to 0.03; I² = 61%; 10 studies; 1225 infants; low-certainty evidence). One study involving 60 infants reported no incidence of bilirubin induced brain dysfunction (BIND). It is uncertain whether either intermittent or continuous phototherapy reduces BIND because the certainty of this evidence is very low. There was little or no difference in treatment failure (RD 0.03, 95% CI 0.08 to 0.15; RR 1.63, 95% CI 0.29 to 9.17; 1 study; 75 infants; very low-certainty evidence) or infant mortality (RD -0.01, 95% CI -0.03 to 0.01; RR 0.69, 95% CI 0.37 to 1.31 I² = 0%; 10 studies, 1470 infants; low-certainty evidence). AUTHORS' CONCLUSIONS: The available evidence detected little or no difference between intermittent and continuous phototherapy with respect to rate of decline of bilirubin. Continuous phototherapy appears to be more effective in preterm infants, however, the risks of continuous phototherapy and the potential benefits of a slightly lower bilirubin level are unknown. Intermittent phototherapy is associated with a decrease in the total number of hours of phototherapy exposure. There are theoretical benefits to intermittent regimens but there are important safety outcomes that were inadequately addressed. Large, well designed, prospective trials are needed in both preterm and term infants before it can be concluded that intermittent and continuous phototherapy regimens are equally effective.
Topics: Infant; Infant, Newborn; Humans; Jaundice, Neonatal; Phototherapy; Bilirubin; Family
PubMed: 36867730
DOI: 10.1002/14651858.CD008168.pub2 -
Circulation Research Mar 2023The rupture of atherosclerotic plaque contributes significantly to cardiovascular disease. Plasma concentrations of bilirubin-a byproduct of heme catabolism-inversely...
BACKGROUND
The rupture of atherosclerotic plaque contributes significantly to cardiovascular disease. Plasma concentrations of bilirubin-a byproduct of heme catabolism-inversely associate with risk of cardiovascular disease, although the link between bilirubin and atherosclerosis remains unclear.
METHODS
To assess the role of bilirubin in atherosclerotic plaque stability, we crossed with mice and used the tandem stenosis model of plaque instability. Human coronary arteries were obtained from heart transplant recipients. Analysis of bile pigments, heme metabolism, and proteomics were performed by liquid chromatography tandem mass spectrometry. MPO (myeloperoxidase) activity was determined by in vivo molecular magnetic resonance imaging, liquid chromatography tandem mass spectrometry analysis, and immunohistochemical determination of chlorotyrosine. Systemic oxidative stress was evaluated by plasma concentrations of lipid hydroperoxides and the redox status of circulating Prx2 (peroxiredoxin 2), whereas arterial function was assessed by wire myography. Atherosclerosis and arterial remodeling were quantified by morphometry and plaque stability by fibrous cap thickness, lipid accumulation, infiltration of inflammatory cells, and the presence of intraplaque hemorrhage.
RESULTS
Compared with tandem stenosis littermates, tandem stenosis mice were deficient in bilirubin, showed signs of increased systemic oxidative stress, endothelial dysfunction, as well as hyperlipidemia, and had a higher atherosclerotic plaque burden. Heme metabolism was increased in unstable compared with stable plaque of both and tandem stenosis mice and in human coronary plaques. In mice, deletion selectively destabilized unstable plaque, characterized by positive arterial remodeling and increased cap thinning, intraplaque hemorrhage, infiltration of neutrophils, and MPO activity. Proteomic analysis confirmed deletion enhanced extracellular matrix degradation, recruitment and activation of neutrophils, and associated oxidative stress in unstable plaque.
CONCLUSIONS
Bilirubin deficiency, resulting from global deletion, generates a proatherogenic phenotype and selectively enhances neutrophil-mediated inflammation and destabilization of unstable plaque, thereby providing a link between bilirubin and cardiovascular disease risk.
Topics: Humans; Animals; Mice; Plaque, Atherosclerotic; Bilirubin; Cardiovascular Diseases; Constriction, Pathologic; Proteomics; Atherosclerosis; Antioxidants; Hemorrhage; Heme; Apolipoproteins E; Lipids; Disease Models, Animal
PubMed: 36876485
DOI: 10.1161/CIRCRESAHA.122.322418 -
European Journal of Medical Research Oct 2022Bile pigments, such as bilirubin and biliverdin, are end products of the heme degradation pathway in mammals and are widely known for their cytotoxic effects. However,... (Review)
Review
Bile pigments, such as bilirubin and biliverdin, are end products of the heme degradation pathway in mammals and are widely known for their cytotoxic effects. However, recent studies have revealed that they exert cytoprotective effects through antioxidative, anti-inflammatory, and immunosuppressive properties. All these mechanisms are indispensable in the treatment of diseases in the field of emergency and critical care medicine, such as coronary ischemia, stroke, encephalomyelitis, acute lung injury/acute respiratory distress syndrome, mesenteric ischemia, and sepsis. While further research is required before the safe application of bile pigments in the clinical setting, their underlying mechanisms shed light on their utilization as therapeutic agents in the field of emergency and critical care medicine. This article aims to summarize the current understanding of bile pigments and re-evaluate their therapeutic potential in the diseases listed above.
Topics: Animals; Humans; Bile Pigments; Biliverdine; Antioxidants; Respiratory Distress Syndrome; Critical Care; Mammals
PubMed: 36309733
DOI: 10.1186/s40001-022-00863-0 -
Trends in Endocrinology and Metabolism:... Mar 2018Bilirubin is a component of the heme catabolic pathway that is essential for liver function and has been shown to reduce hepatic fat accumulation. High plasma bilirubin... (Review)
Review
Bilirubin is a component of the heme catabolic pathway that is essential for liver function and has been shown to reduce hepatic fat accumulation. High plasma bilirubin levels are reflective of liver disease due to an injurious effect on hepatocytes. In healthy liver, bilirubin is conjugated and excreted to the intestine and converted by microbes to urobilinoids, which are reduced to the predominant pigment in feces, stercobilin, or reabsorbed. The function of urobilinoids in the gut or their physiological relevance of reabsorption is not well understood. In this review, we discuss the relationship of hepatic bilirubin signaling to the intestinal microbiota and its regulation of the liver-gut axis, as well as its capacity to mediate these processes.
Topics: Animals; Bilirubin; Gastrointestinal Microbiome; Gastrointestinal Tract; Humans; Liver; Signal Transduction
PubMed: 29409713
DOI: 10.1016/j.tem.2018.01.002 -
The Keio Journal of Medicine Mar 1992There are two types of gallstones; cholesterol and pigment or bilirubinate. Cholesterol stones are formed in the gallbladder as a consequence of altered hepatocellular... (Review)
Review
There are two types of gallstones; cholesterol and pigment or bilirubinate. Cholesterol stones are formed in the gallbladder as a consequence of altered hepatocellular and gallbladder function. Overproduction of cholesterol by the liver is the major metabolic precedent of cholesterol gallstones and this may occur because of obesity, drugs, or other factors. Gallbladder factors which promote stone formation include hypomotility and the secretion of nucleating factors such as mucus glycoprotein. It is possible that both of these two factors are mediated by an increase in the prostaglandin production by the gallbladder mucosa. Pigment stones are either brown or black. Brown stones are formed of calcium bilirubinate and are usually associated with biliary infection. They occur in both the gallbladder and the bile ducts. Black pigment stones are extremely hard bilirubin polymers and are found mainly in the gallbladder. Biliary sludge is a necessary precedent of gallstones. It comprises cholesterol monohydrate crystals, glycoproteins and granules of calcium bilirubinate.
Topics: Bilirubin; Cholelithiasis; Cholesterol; Humans; Pigments, Biological
PubMed: 1583812
DOI: 10.2302/kjm.41.1 -
World Journal of Gastroenterology Jun 2002In this paper, we summarize the main progresses made in our group in the field of the mechanism of pigment gallstone formation. It was found that after treatment with... (Review)
Review
In this paper, we summarize the main progresses made in our group in the field of the mechanism of pigment gallstone formation. It was found that after treatment with free radicals, bilirubin (BR) was changed into free radical itself, and a semiquinone free radical and a superoxide free radical bound with metal were recognized, which was detected by ESR (electron spin resonance). By the means of NMR (nuclear magnetic resonance) and IR (Infra-red spectra), it was postulated that bilirubin polymerized through the reaction between the vinyl group and the hydroxyl group under the attack of free radicals. It was also found that bilirubin free radical were liable to calcify in a kinetic study. Because of its chemical properties, bilirubin free radical was shown to be cytotoxic to hepatocyte, which was demonstrated based on the following facts: induction of phospholipid peroxidation (LPO), leakage of lactate dehydrogenase (LDH) and decrease of glutathione. As to the mechanism of bilirubin-induced cytotoxicity, it was postulated that the main target of bilirubin free radical was the cell membrane, including phospholipid and membrane bound proteins, especially spectrin, a content of cytoskeleton. Based on the results mentioned above, it was deduced that bilirubin free radical is the key factor that initiates and promotes the formation of pigment gallstone, which is consistent with other researches in recent years.
Topics: Bilirubin; Cholelithiasis; Electron Spin Resonance Spectroscopy; Free Radicals; Humans; Pigments, Biological
PubMed: 12046060
DOI: 10.3748/wjg.v8.i3.413 -
World Journal of Gastroenterology Nov 2013This review considers the physiological and molecular biochemical mechanisms of bile formation. The composition of bile and structure of a bile canaliculus, biosynthesis... (Review)
Review
This review considers the physiological and molecular biochemical mechanisms of bile formation. The composition of bile and structure of a bile canaliculus, biosynthesis and conjugation of bile acids, bile phospholipids, formation of bile micellar structures, and enterohepatic circulation of bile acids are described. In general, the review focuses on the molecular physiology of the transporting systems of the hepatocyte sinusoidal and apical membranes. Knowledge of physiological and biochemical basis of bile formation has implications for understanding the mechanisms of development of pathological processes, associated with diseases of the liver and biliary tract.
Topics: Animals; Bile; Bile Pigments; Biliary Tract; Biological Transport; Carrier Proteins; Cellulose, Oxidized; Enterohepatic Circulation; Humans; Liver; Membrane Glycoproteins; Micelles; Phospholipids
PubMed: 24259965
DOI: 10.3748/wjg.v19.i42.7341 -
Pathology International Dec 2022The biliary system is a highly branched tubular network consisting of intrahepatic bile ducts (IHBDs) and extrahepatic bile ducts (EHBDs). IHBDs are derived from hepatic... (Review)
Review
The biliary system is a highly branched tubular network consisting of intrahepatic bile ducts (IHBDs) and extrahepatic bile ducts (EHBDs). IHBDs are derived from hepatic progenitor cells, while EHBDs originate directly from the endoderm through a separate branching morphogenetic process. Traits that are important for cancer are often found to overlap in developmental and other processes. Therefore, it has been suggested that intrahepatic cholangiocarcinomas (iCCAs) and extrahepatic cholangiocarcinomas (eCCAs) have different developmental mechanisms. While much evidence is being gathered on the mechanism of iCCAs, the evidence for eCCA is still very limited. The main reason for this is that there are very few appropriate animal models for eCCA. We can gain important insights from these animal models, particularly genetically engineered mouse models (GEMMs). GEMMs are immunocompetent and mimic human CCA subtypes with a specific mutational pattern, allowing the development of precancerous lesions, that is, biliary intraepithelial neoplasia (BilIN) and intraductal papillary neoplasm of the bile duct (IPNB). This review provides a summary of the pathogenesis and mechanisms of eCCA that can be revealed by GEMMs. Furthermore, we discuss several clinical questions, such as whether BilIN and IPNB really become malignant, whether the peribiliary gland is the origin of eCCAs, and others.
Topics: Animals; Mice; Humans; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Cholangiocarcinoma; Bile Ducts, Extrahepatic; Cell Transformation, Neoplastic; Bile Pigments
PubMed: 36349994
DOI: 10.1111/pin.13287