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The Journal of Clinical Investigation Feb 1986Studies with synthetic metal-porphyrin complexes in which the central iron atom of heme is replaced by other elements indicate that those heme analogues that cannot be... (Review)
Review
Studies with synthetic metal-porphyrin complexes in which the central iron atom of heme is replaced by other elements indicate that those heme analogues that cannot be enzymatically degraded to bile pigments possess novel biological properties that may have considerable clinical as well as experimental value. Such studies have revealed the important role that the central metal atom plays in determining the physiological and pharmacological properties of metal-porphyrin complexes; and they have demonstrated that the form in which animals and humans are exposed to trace metals, i.e., inorganic, organified, porphyrin-chelated, etc., can be of great importance in determining the biological responses that such elements elicit, especially with respect to actions on heme synthesis and degradation and cytochrome P-450 formation and function. Study of the biological properties of synthetic metalloporphyrins represents a potentially fruitful area of research and the results may have significant value for basic as well as clinical disciplines.
Topics: 5-Aminolevulinate Synthetase; Animals; Bilirubin; Cobalt; Cytochrome P-450 Enzyme System; Enzyme Induction; Erythrocytes; Heme; Heme Oxygenase (Decyclizing); Humans; Kidney; Liver; Metalloporphyrins; Protoporphyrins; Tin
PubMed: 3511095
DOI: 10.1172/JCI112309 -
BMC Gastroenterology Jul 2020Pigmented bile salts darken the small-bowel lumen and are present with bile acid, which is involved in the development of bowel habits. The small-bowel water content...
BACKGROUND
Pigmented bile salts darken the small-bowel lumen and are present with bile acid, which is involved in the development of bowel habits. The small-bowel water content (SBWC) in the ileum could represent the colonic environment, but no studies have focused on this feature. However, measurement of crude SBWC can be challenging because of the technical difficulty of the endoscopic approach without preparation. Our aim was to evaluate optically active bile pigments in the SBWC of patients with abnormal bowel habits using capsule endoscopy (CE) to investigate the impact of bile acid on bowel habits.
METHODS
The study population included 37 constipated patients, 20 patients with diarrhea, and 77 patients with normal bowel habits who underwent CE between January 2015 and May 2018. Patients with secondary abnormal bowel habits were excluded. In addition to conventional imaging, we used flexible spectral imaging color enhancement (FICE) setting 1 imaging, in which the effects of bile pigments on color are suppressed. Intergroup color differences of SBWC in the ileum (ΔE) were evaluated from conventional and FICE setting 1 images. Color values were assessed using the CIE L*a*b* color space. Differences in SBWC lightness (black to white, range 0-100) were also evaluated.
RESULTS
The ΔE values from the comparison of conventional images between patients with constipation and with normal bowel habits and between patients with diarrhea and with normal bowel habits were 12.4 and 11.2, respectively. These values decreased to 4.4 and 3.3, respectively, when FICE setting 1 images were evaluated. Patients with constipation and diarrhea had significantly brighter (34.4 versus 27.6, P < .0001) and darker (19.6 versus 27.6, P < .0001) SBWC lightness, respectively, than patients with normal bowel habits. The FICE setting 1 images did not reveal significant differences in SBWC lightness between those with constipation and with normal bowel habits (44.1 versus 43.5, P = .83) or between those with diarrhea and with normal bowel habits (39.1 versus 43.5, P = .20).
CONCLUSIONS
Differences in SBWC color and darkness in the ileum appear to be attributable to bile pigments. Therefore, bile pigments in SBWC may reflect bowel habits.
Topics: Bile Pigments; Capsule Endoscopy; Habits; Humans; Image Enhancement; Retrospective Studies; Water
PubMed: 32703159
DOI: 10.1186/s12876-020-01382-0 -
Kidney360 May 2022Bilirubin is the end product of the catabolism of heme the heme oxygenase pathway. Heme oxygenase generates carbon monoxide (CO) and biliverdin from the breakdown of... (Review)
Review
Bilirubin is the end product of the catabolism of heme the heme oxygenase pathway. Heme oxygenase generates carbon monoxide (CO) and biliverdin from the breakdown of heme, and biliverdin is rapidly reduced to bilirubin by the enzyme biliverdin reductase (BVR). Bilirubin has long been thought of as a toxic product that is only relevant to health when blood levels are severely elevated, such as in clinical jaundice. The physiologic functions of bilirubin correlate with the growing body of evidence demonstrating the protective effects of serum bilirubin against cardiovascular and metabolic diseases. Although the correlative evidence suggests a protective effect of serum bilirubin against many diseases, the mechanism by which bilirubin offers protection against cardiovascular and metabolic diseases remains unanswered. We recently discovered a novel function for bilirubin as a signaling molecule capable of activating the peroxisome proliferator-activated receptor (PPAR) transcription factor. This review summarizes the new finding of bilirubin as a signaling molecule and proposes several mechanisms by which this novel action of bilirubin may protect against cardiovascular and kidney diseases.
Topics: Bilirubin; Biliverdine; Carbon Monoxide; Heme; Heme Oxygenase (Decyclizing); Humans; Kidney Diseases; PPAR alpha; Transcription Factors
PubMed: 36128497
DOI: 10.34067/KID.0000062022 -
American Journal of Physiology. Renal... Jul 2014Unconjugated bilirubin is an endogenous circulating antioxidant, bound to albumin, and therefore is retained in the vascular compartment. Bilirubin has well-documented... (Review)
Review
Unconjugated bilirubin is an endogenous circulating antioxidant, bound to albumin, and therefore is retained in the vascular compartment. Bilirubin has well-documented neurotoxic effects in infants; however, current evidence indicates mildly elevated bilirubin is associated with protection from cardiovascular disease and all-cause mortality in adults. Recent clinical studies show mildly elevated bilirubin is associated with protection from kidney damage and dysfunction, in addition to cardiovascular events and all-cause mortality in patients undergoing hemodialysis. This is the first review to examine the clinical evidence and summarize the potential mechanisms of action that link bilirubin to protection from kidney damage, subsequent kidney failure, and dialysis-related mortality. With this understanding, it is hoped that new therapies will be developed to prevent renal dysfunction and mortality from cardiovascular disease in at-risk individuals.
Topics: Animals; Bilirubin; Biomarkers; Cardiovascular Diseases; Disease Progression; Humans; Kidney; Kidney Diseases; Renal Dialysis; Risk Assessment; Risk Factors; Treatment Outcome; Up-Regulation
PubMed: 24761005
DOI: 10.1152/ajprenal.00039.2014 -
PloS One 2016Numerous clinical and population studies have demonstrated that increased serum bilirubin levels protect against cardiovascular and metabolic diseases such as obesity...
Numerous clinical and population studies have demonstrated that increased serum bilirubin levels protect against cardiovascular and metabolic diseases such as obesity and diabetes. Bilirubin is a potent antioxidant, and the beneficial actions of moderate increases in plasma bilirubin have been thought to be due to the antioxidant effects of this bile pigment. In the present study, we found that bilirubin has a new function as a ligand for PPARα. We show that bilirubin can bind directly to PPARα and increase transcriptional activity. When we compared biliverdin, the precursor to bilirubin, on PPARα transcriptional activation to known PPARα ligands, WY 14,643 and fenofibrate, it showed that fenofibrate and biliverdin have similar activation properties. Treatment of 3T3-L1 adipocytes with biliverdin suppressed lipid accumulation and upregulated PPARα target genes. We treated wild-type and PPARα KO mice on a high fat diet with fenofibrate or bilirubin for seven days and found that both signal through PPARα dependent mechanisms. Furthermore, the effect of bilirubin on lowering glucose and reducing body fat percentage was blunted in PPARα KO mice. These data demonstrate a new function for bilirubin as an agonist of PPARα, which mediates the protection from adiposity afforded by moderate increases in bilirubin.
Topics: Adiposity; Animals; Bilirubin; Cell Line; Gene Knockout Techniques; Lipid Metabolism; Male; Mice; Models, Molecular; PPAR alpha; Protein Binding; Protein Conformation
PubMed: 27071062
DOI: 10.1371/journal.pone.0153427 -
Redox Biology Nov 2021Plasma concentrations of bilirubin, a product of heme catabolism formed by biliverdin reductase A (BVRA), inversely associate with the risk of metabolic diseases...
BACKGROUND & AIMS
Plasma concentrations of bilirubin, a product of heme catabolism formed by biliverdin reductase A (BVRA), inversely associate with the risk of metabolic diseases including hepatic steatosis and diabetes mellitus in humans. Bilirubin has antioxidant and anti-inflammatory activities and may also regulate insulin signaling and peroxisome proliferator-activated receptor alpha (PPARα) activity. However, a causal link between bilirubin and metabolic diseases remains to be established. Here, we used the global Bvra gene knockout (Bvra) mouse as a model of deficiency in bilirubin to assess its role in metabolic diseases.
APPROACH & RESULTS
We fed mice fat-rich diets to induce hepatic steatosis and insulin resistance. Bile pigments were measured by LC-MS/MS, and hepatic lipids by LC-MS/MS (non-targeted lipidomics), HPLC-UV and Oil-Red-O staining. Oxidative stress was evaluated measuring F-isoprostanes by GC-MS. Glucose metabolism and insulin sensitivity were verified by glucose and insulin tolerance tests, ex vivo and in vivo glucose uptake, and Western blotting for insulin signaling. Compared with wild type littermates, Bvra mice contained negligible bilirubin in plasma and liver, and they had comparable glucose metabolism and insulin sensitivity. However, Bvra mice exhibited an inflamed and fatty liver phenotype, accompanied by hepatic accumulation of oxidized triacylglycerols and F-isoprostanes, in association with depletion of α-tocopherol. α-Tocopherol supplementation reversed the hepatic phenotype and observed biochemical changes in Bvra mice.
CONCLUSIONS
Our data suggests that BVRA deficiency renders mice susceptible to oxidative stress-induced hepatic steatosis in the absence of insulin resistance.
Topics: Animals; Bilirubin; Chromatography, Liquid; F2-Isoprostanes; Fatty Liver; Insulin; Insulin Resistance; Liver; Mice; Mice, Inbred C57BL; Mice, Knockout; Tandem Mass Spectrometry
PubMed: 34610553
DOI: 10.1016/j.redox.2021.102152 -
Molecules (Basel, Switzerland) Mar 2023In this work we review research activities on a few of the most relevant structural aspects of bilirubin (BR) and biliverdin (BV). Special attention is paid to the... (Review)
Review
In this work we review research activities on a few of the most relevant structural aspects of bilirubin (BR) and biliverdin (BV). Special attention is paid to the exocyclic C=C bonds being in mostly rather than configurations, and to the overall conformation being essentially different for BR and BV due to the presence or absence of the double C=C bond at C-10. In both cases, racemic mixtures of each compound of either or configuration are present in achiral solutions; however, imbalance between the two configurations may be easily achieved. In particular, results based on chiroptical spectroscopies, both electronic and vibrational circular dichroism (ECD and VCD) methods, are presented for chirally derivatized BR and BV molecules. Finally, we review deracemization experiments monitored with ECD data from our lab for BR in the presence of serum albumin and anesthetic compounds.
Topics: Biliverdine; Bilirubin; Circular Dichroism; Molecular Conformation; Vibration; Stereoisomerism
PubMed: 36985535
DOI: 10.3390/molecules28062564 -
Recent Patents on CNS Drug Discovery 2014Liver growth factor (LGF) is a hepatic mitogen purified by our group in 1986. In the following years we demonstrated its activity both in "in vivo" and "in vitro"... (Review)
Review
Liver growth factor (LGF) is a hepatic mitogen purified by our group in 1986. In the following years we demonstrated its activity both in "in vivo" and "in vitro" systems, stimulating hepatocytes mitogenesis as well as liver regeneration in several models of liver injury. Furthermore, we established its chemical composition (albumin-bilirubin complex) and its mitogenic actions in liver. From 2000 onwards we used LGF as a tissue regenerating factor in several models of extrahepatic diseases. The use of Liver growth factor as a neural tissue regenerator has been recently protected (Patent No US 2014/8,642,551 B2). LGF administration stimulates neurogenesis and neuron survival, promotes migration of newly generated neurons, and induces the outgrowth of striatal dopaminergic terminals in 6-hidroxydopamine-lesioned rats. Furthermore, LGF treatment raises striatal dopamine levels and protects dopaminergic neurons in hemiparkinsonian animals. LGF also stimulates survival of grafted foetal neural stem cells in the damaged striatum, reduces rotational behaviour and improves motor coordination. Interestingly, LGF also exerts a neuroprotective role both in an experimental model of cerebellar ataxia and in a model of Friedrich´s ataxia. Microglia seem to be the cellular target of LGF in the CNS. Moreover, the activity of the factor could be mediated by the stimulation of MAPK´s signalling pathway and by regulating critical proteins for cell survival, such as Bcl-2 and phospho-CREB. Since the factor shows neuroprotective and neurorestorative effects we propose LGF as a patented novel therapeutic tool that may be useful for the treatment of Parkinson´s disease and cerebellar ataxias. Currently, our studies have been extended to other neurological disorders such as Alzheimer's disease (Patent No: US 2014/0113859 A1).
Topics: Animals; Bilirubin; Disease Models, Animal; Humans; Nerve Regeneration; Neurodegenerative Diseases; Serum Albumin; Serum Albumin, Human
PubMed: 25537484
DOI: 10.2174/1574889809666141224123303 -
HPB Surgery : a World Journal of... 1996After partial ligation of the common bile duct (CBD) of guinea pigs, 14 of 16 animals developed pigment gallstones within one week (S group). Intraperitoneal injection...
After partial ligation of the common bile duct (CBD) of guinea pigs, 14 of 16 animals developed pigment gallstones within one week (S group). Intraperitoneal injection of Vit. E and C, each 10 mg/kg daily from 3 days before CBD ligation to one week after the operation (S+V group), decreased the gallstone incidence to 5/14 (exact probability < 0.01). The gallstone incidence in the control group, that only received laparotomy without ligation of the CBD, was 0/15. Biochemical analysis of the gallbladder bile showed that stricture of the CBD was associated with a significant increase in levels of unconjugated bilirubin (UCB) and Ca2+ (p < 0.05 and < 0.01). Simultaneously the scavenging rate (SR) of superoxide radical in bile significantly decreased (p < 0.05). Comparing S+V group with S group, the effect of Vit. E and C on the concentrations of UCB and Ca2+ in bile was not significant (both p > 0.05), but Vit. E and C normalized the SR, and the difference between S group and S+V group was significant (p < 0.05). These results suggested that Vit. E and C, known as antioxidants, enhanced the ability to scavenge oxygen radical in S+V group; and that in addition to the increases of UCB and Ca2+ concentrations, the participation of oxygen radicals might be of importance for pigment gallstone formation induced by bile duct obstruction.
Topics: Animals; Ascorbic Acid; Bile; Bile Pigments; Cholelithiasis; Common Bile Duct; Disease Models, Animal; Drug Evaluation, Preclinical; Free Radical Scavengers; Guinea Pigs; Incidence; Injections, Intraperitoneal; Ligation; Male; Oxidants; Vitamin E
PubMed: 9184859
DOI: 10.1155/1996/20687 -
Annals of Noninvasive Electrocardiology... Mar 2020
Topics: Bilirubin; Electrocardiography; Humans; Nutrition Surveys
PubMed: 32125055
DOI: 10.1111/anec.12755