The Experts below are selected from a list of 1092 Experts worldwide ranked by ideXlab platform
Augustine M K Choi - One of the best experts on this subject based on the ideXlab platform.
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Physiol Rev 86: 583–650, 2006; doi:10.1152/physrev.00011.2005. Heme Oxygenase-1/Carbon Monoxide: From Basic Science to Therapeutic Applications
2013Co-Authors: Stefan W. Ryter, Augustine M K Choi, Jawed Alam, Enzymatic A. Activity, Its Measurement, Biochemical B. Properties, C. Genetics, Subcellular E. Localization, F. PhylogenyAbstract:C. Gene/promoter regulation 603 IV. Functional Properties of Heme Oxygenase-Derived Iron 608 A. HO-derived iron and gene regulation 608 B. Antiapoptotic roles of HO-derived iron and ferritin 609 V. Functional Properties of Heme Oxygenase-Derived Bile Pigments 611 A. Metabolism of biliverdin and bilirubin 611 B. Protective effects in vitro and in vivo 612 VI. Carbon Monoxide 613 A. Properties, environmental or endogenous sources, and toxicity 613 B. Mechanisms of CO-dependent cell signaling 614 C. CO releasing molecules: biochemical properties 615 D. Vasodilation 616 E. Antiapoptotic, anti-inflammatory, and antiproliferative mechanisms 618 F. Neurotransmission 620 VII. Protective Roles of Heme Oxygenase-1/Carbon Monoxide in Disease Models 622 A. Inflammatory diseases 622 B. Lung injury models 624 C. Cardiovascular injury/disease 626 D. Ischemia/reperfusion 62
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heme oxygenase 1 carbon monoxide from metabolism to molecular therapy
American Journal of Respiratory Cell and Molecular Biology, 2009Co-Authors: Stefan W. Ryter, Augustine M K ChoiAbstract:Heme oxygenase-1 (HO-1), a ubiquitous inducible stress-response protein, serves a major metabolic function in heme turnover. HO activity cleaves heme to form biliverdin-IXα, carbon monoxide (CO), and iron. Genetic experiments have revealed a central role for HO-1 in tissue homeostasis, protection against oxidative stress, and in the pathogenesis of disease. Four decades of research have witnessed not only progress in elucidating the molecular mechanisms underlying the regulation and function of this illustrious enzyme, but also have opened remarkable translational applications for HO-1 and its reaction products. CO, once regarded as a metabolic waste, can act as an endogenous mediator of cellular signaling and vascular function. Exogenous application of CO by inhalation or pharmacologic delivery can confer cytoprotection in preclinical models of lung/vascular injury and disease, based on anti-apoptotic, anti-inflammatory, and anti-proliferative properties. The Bile Pigments, biliverdin and bilirubin, end products of heme degradation, have also shown potential as therapeutics in vascular disease based on anti-inflammatory and anti-proliferative activities. Further translational and clinical trials research will unveil whether the HO-1 system or any of its reaction products can be successfully applied as molecular medicine in human disease.
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heme oxygenase 1 carbon monoxide from basic science to therapeutic applications
Physical Review, 2006Co-Authors: Stefan W. Ryter, Jawed Alam, Augustine M K ChoiAbstract:The heme oxygenases, which consist of constitutive and inducible isozymes (HO-1, HO-2), catalyze the rate-limiting step in the metabolic conversion of heme to the Bile Pigments (i.e., biliverdin and bilirubin) and thus constitute a major intracellular source of iron and carbon monoxide (CO). In recent years, endogenously produced CO has been shown to possess intriguing signaling properties affecting numerous critical cellular functions including but not limited to inflammation, cellular proliferation, and apoptotic cell death. The era of gaseous molecules in biomedical research and human diseases initiated with the discovery that the endothelial cell-derived relaxing factor was identical to the gaseous molecule nitric oxide (NO). The discovery that endogenously produced gaseous molecules such as NO and now CO can impart potent physiological and biological effector functions truly represented a paradigm shift and unraveled new avenues of intense investigations. This review covers the molecular and biochemical characterization of HOs, with a discussion on the mechanisms of signal transduction and gene regulation that mediate the induction of HO-1 by environmental stress. Furthermore, the current understanding of the functional significance of HO shall be discussed from the perspective of each of the metabolic by-products, with a special emphasis on CO. Finally, this presentation aspires to lay a foundation for potential future clinical applications of these systems.
Stefan W. Ryter - One of the best experts on this subject based on the ideXlab platform.
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Physiol Rev 86: 583–650, 2006; doi:10.1152/physrev.00011.2005. Heme Oxygenase-1/Carbon Monoxide: From Basic Science to Therapeutic Applications
2013Co-Authors: Stefan W. Ryter, Augustine M K Choi, Jawed Alam, Enzymatic A. Activity, Its Measurement, Biochemical B. Properties, C. Genetics, Subcellular E. Localization, F. PhylogenyAbstract:C. Gene/promoter regulation 603 IV. Functional Properties of Heme Oxygenase-Derived Iron 608 A. HO-derived iron and gene regulation 608 B. Antiapoptotic roles of HO-derived iron and ferritin 609 V. Functional Properties of Heme Oxygenase-Derived Bile Pigments 611 A. Metabolism of biliverdin and bilirubin 611 B. Protective effects in vitro and in vivo 612 VI. Carbon Monoxide 613 A. Properties, environmental or endogenous sources, and toxicity 613 B. Mechanisms of CO-dependent cell signaling 614 C. CO releasing molecules: biochemical properties 615 D. Vasodilation 616 E. Antiapoptotic, anti-inflammatory, and antiproliferative mechanisms 618 F. Neurotransmission 620 VII. Protective Roles of Heme Oxygenase-1/Carbon Monoxide in Disease Models 622 A. Inflammatory diseases 622 B. Lung injury models 624 C. Cardiovascular injury/disease 626 D. Ischemia/reperfusion 62
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Bile Pigments in pulmonary and vascular disease
Frontiers in Pharmacology, 2012Co-Authors: Stefan W. RyterAbstract:The Bile Pigments, biliverdin and bilirubin, are endogenously-derived substances generated during enzymatic heme degradation. These compounds have been shown to act as chemical antioxidants in vitro. Bilirubin formed in tissues circulates in the serum, prior to undergoing hepatic conjugation and biliary excretion. The excess production of bilirubin has been associated with neurotoxicity, in particular to the newborn. Nevertheless, clinical evidence suggests that mild states of hyperbilirubinemia may be beneficial in protecting against cardiovascular disease in adults. Pharmacological application of either bilirubin and/or its biological precursor biliverdin, can provide therapeutic benefit in several animal models of cardiovascular and pulmonary disease. Furthermore, biliverdin and bilirubin can confer protection against ischemia/reperfusion injury and graft rejection secondary to organ transplantation in animal models. Several possible mechanisms for these effects have been proposed, including direct antioxidant and scavenging effects, and modulation of signaling pathways regulating inflammation, apoptosis, cell proliferation, and immune responses. The practicality and therapeutic-effectiveness of Bile pigment application to humans remains unclear.
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doi: 10.3389/fphar.2012.00039 Edited by:
2012Co-Authors: Leo Otterbein, Mahin D Maines, Harvard Medical, Stefan W. RyterAbstract:The Bile Pigments, biliverdin, and bilirubin, are endogenously derived substances generated during enzymatic heme degradation. These compounds have been shown to act as chemical antioxidants in vitro. Bilirubin formed in tissues circulates in the serum, prior to undergoing hepatic conjugation and biliary excretion. The excess production of bilirubin has been associated with neurotoxicity, in particular to the newborn. Nevertheless, clinical evidence suggests that mild states of hyperbilirubinemia may be beneficial in protecting against cardiovascular disease in adults. Pharmacological application of either bilirubin and/or its biological precursor biliverdin, can provide therapeutic benefit in several animal models of cardiovascular and pulmonary disease. Furthermore, biliverdin and bilirubin can confer protection against ischemia/reperfusion injury and graft rejection secondary to organ transplantation in animal models. Several possible mechanisms for these effects have been proposed, including direct antioxidant and scavenging effects, and modulation of signaling pathways regulating inflammation, apoptosis, cell proliferation, and immune responses.The practicality and therapeutic-effectiveness of Bile pigment application to humans remains unclear
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heme oxygenase 1 carbon monoxide from metabolism to molecular therapy
American Journal of Respiratory Cell and Molecular Biology, 2009Co-Authors: Stefan W. Ryter, Augustine M K ChoiAbstract:Heme oxygenase-1 (HO-1), a ubiquitous inducible stress-response protein, serves a major metabolic function in heme turnover. HO activity cleaves heme to form biliverdin-IXα, carbon monoxide (CO), and iron. Genetic experiments have revealed a central role for HO-1 in tissue homeostasis, protection against oxidative stress, and in the pathogenesis of disease. Four decades of research have witnessed not only progress in elucidating the molecular mechanisms underlying the regulation and function of this illustrious enzyme, but also have opened remarkable translational applications for HO-1 and its reaction products. CO, once regarded as a metabolic waste, can act as an endogenous mediator of cellular signaling and vascular function. Exogenous application of CO by inhalation or pharmacologic delivery can confer cytoprotection in preclinical models of lung/vascular injury and disease, based on anti-apoptotic, anti-inflammatory, and anti-proliferative properties. The Bile Pigments, biliverdin and bilirubin, end products of heme degradation, have also shown potential as therapeutics in vascular disease based on anti-inflammatory and anti-proliferative activities. Further translational and clinical trials research will unveil whether the HO-1 system or any of its reaction products can be successfully applied as molecular medicine in human disease.
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heme oxygenase 1 carbon monoxide from basic science to therapeutic applications
Physical Review, 2006Co-Authors: Stefan W. Ryter, Jawed Alam, Augustine M K ChoiAbstract:The heme oxygenases, which consist of constitutive and inducible isozymes (HO-1, HO-2), catalyze the rate-limiting step in the metabolic conversion of heme to the Bile Pigments (i.e., biliverdin and bilirubin) and thus constitute a major intracellular source of iron and carbon monoxide (CO). In recent years, endogenously produced CO has been shown to possess intriguing signaling properties affecting numerous critical cellular functions including but not limited to inflammation, cellular proliferation, and apoptotic cell death. The era of gaseous molecules in biomedical research and human diseases initiated with the discovery that the endothelial cell-derived relaxing factor was identical to the gaseous molecule nitric oxide (NO). The discovery that endogenously produced gaseous molecules such as NO and now CO can impart potent physiological and biological effector functions truly represented a paradigm shift and unraveled new avenues of intense investigations. This review covers the molecular and biochemical characterization of HOs, with a discussion on the mechanisms of signal transduction and gene regulation that mediate the induction of HO-1 by environmental stress. Furthermore, the current understanding of the functional significance of HO shall be discussed from the perspective of each of the metabolic by-products, with a special emphasis on CO. Finally, this presentation aspires to lay a foundation for potential future clinical applications of these systems.
Frank R Sharp - One of the best experts on this subject based on the ideXlab platform.
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hypoxia ischemia but not hypoxia alone induces the expression of heme oxygenase 1 hsp32 in newborn rat brain
Journal of Cerebral Blood Flow and Metabolism, 1997Co-Authors: Marcelle Bergeron, Donna M Ferriero, Hendrik J Vreman, David K Stevenson, Frank R SharpAbstract:Heme oxygenase (HO) is the rate-limiting enzyme in the degradation of heme to produce Bile Pigments and carbon monoxide. The HO-1 isozyme is induced by a variety of agents such as heat, heme, and hydrogen peroxide. Evidence suggests that the Bile Pigments serve as antioxidants in cells with compromised defense mechanisms. Because hypoxia-ischemia (HI) increases the level of oxygen free radicals, the induction of HO-1 expression in the brain during ischemia could modulate the response to oxidative stress. To study the possible involvement of HO-1 in neonatal hypoxia-induced ischemic tolerance, we examined the brains of newborn rat pups exposed to 8% O2 (for 2.5 to 3 hours), and the brain of chronically hypoxic rat pups with congenital cardiac defects (Wistar Kyoto; WKY/ NCr). Heme oxygenase-1 immunostaining did not change after either acute or chronic hypoxia, suggesting that HO-1 is not a good candidate for explaining hypoxia preconditioning in newborn rat brain. To study the role of HO-1 in neonatal HI, 1-week-old rats were subjected to right carotid coagulation and exposure to 8% O2/92% N2 for 2.5 hours. Whereas HO enzymatic activity was unchanged in ipsilateral cortex and subcortical regions compared with the contralateral hemisphere or control brains, immunocytochemistry and Western blot analysis showed increased HO-1 staining in ipsilateral cortex, hippocampus, and striatum at 12 to 24 hours up to 7 days after HI. Double fluorescence immunostaining showed that HO-1 was expressed mostly in ED-1 positive macrophages. Because activated brain macrophages have been associated with the release of several cytotoxic molecules, the presence of HO-1 positive brain macrophages may determine the tissue vulnerability after HI injury.
Karl-heinz Wagner - One of the best experts on this subject based on the ideXlab platform.
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Extracellular and intracellular anti-mutagenic effects of Bile Pigments in the Salmonella typhimurium reverse mutation assay.
Toxicology in Vitro, 2012Co-Authors: Christine Mölzer, Hedwig Huber, Marlies Wallner, Amelia C. Bulmer, Kurt Diem, Karl-heinz WagnerAbstract:In vitro anti-genotoxic properties of Bile Pigments have been explored and confirmed recently. Despite these reports mechanisms to explain DNA protection by endogenous Bile Pigments remain unclear. Surprisingly, the quantification of cellular pigment absorption which could represent a fundamental prerequisite for intracellular (e.g., anti-mutagenic) effects, has not been explored. Therefore, we aimed to measure the amounts of un-/conjugated bilirubin as well as biliverdin absorbed into colonies of Salmonella typhimurium, utilising HPLC analyses, and to observe whether intracellular compound concentrations could predict anti-genotoxic effects. HPLC analyses confirmed that bacterial Bile pigment absorption was concentration-dependent. Plate Bile pigment concentrations were inversely associated with genotoxicity of all tested mutagens, irrespective of strain and test conditions. However, protection against frame-shift mutation in strain TA98 most strongly depended on the bacterial absorption of bilirubin and biliverdin, which indicates that Bile Pigments can protect by intercepting mutations extracellularly and specifically inhibit frame-shift mutations intracellularly.
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The anti-mutagenic properties of Bile Pigments
Mutation Research-reviews in Mutation Research, 2008Co-Authors: Andrew C. Bulmer, Joanne T. Blanchfield, K. Ried, Karl-heinz WagnerAbstract:Bile Pigments, including bilirubin and biliverdin, are endogenous compounds belonging to the porphyrin family of molecules. In the past, Bile Pigments and bilirubin in particular were thought of as useless by-products of heme catabolism that can be toxic if they accumulate. However, in the past 20 years, research probing the physiological relevance of Bile Pigments has been mounting, with evidence to suggest Bile Pigments possess significant antioxidant and anti-mutagenic properties. More specifically, Bile Pigments are potent peroxyl radical scavengers and inhibit the mutagenic effects of a number of classes of mutagens (polycyclic aromatic hydrocarbons, heterocyclic amines, oxidants). Coincidentally, persons with elevated circulating bilirubin concentrations have a reduced prevalence of cancer and cardio-vascular disease. Despite the encouraging in vitro anti-mutagenic effects of Bile Pigments, relatively little research has been conducted on their inhibitory capacity in bacterial and cultured cell assays of mutation, which might link the existing in vitro and in vivo observations. This is the first review to summarise the published data and it is our hope it will stimulate further research on these potentially preventative compounds.
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the anti mutagenic and antioxidant effects of Bile Pigments in the ames salmonella test
Mutation Research-genetic Toxicology and Environmental Mutagenesis, 2007Co-Authors: Andrew C. Bulmer, Joanne T. Blanchfield, Istvan Toth, Jeff S Coombes, K. Ried, Karl-heinz WagnerAbstract:The aim of this study was to explore the potential pro- and anti-mutagenic effects of endogenous Bile Pigments unconjugated bilirubin (BR), biliverdin (BV) and a synthetic, water soluble conjugate, bilirubin ditaurate (BRT) in the Ames Salmonella test. The Bile Pigments were tested over a wide concentration range (0.01-2 mu mol/plate) in the presence of three bacterial strains (TA98, TA100, TA102). A variety of mutagens including benzo[alpha]pyrene (B[alpha]P), 2,4,7 trinitrofluorenone (TNFone), 2-aminotluorene (2-AF), sodium azide (NaN3) and tertiary-butyl hydroperoxide (t-BuOOH), were used to promote the formation of mutant revertants. Tests were conducted with (B[alpha]P, 2-AF, t-BuOOH) and without (TNFone, NaN3, t-BuOOH) metabolic activation incorporating the addition of the microsomal liver preparation, S9. The Bile Pigments alone did not induce mutagenicity in any of the strains tested (p > 0.05). Anti-mutagenic effects of the Bile Pigments were observed in the presence of all mutagens except for NaN3 and the anti-mutagenic effects appeared independent of the strain tested. For TNFone induced genotoxicity, the order of effectiveness was BR >= BRT > BV. However, the order was BV >= BRT >= BR for 2-AF. Antioxidant testing in the TA102 strain revealed Bile Pigments could effectively inhibit the genotoxic effect of t-BuOOH induced oxidative stress. The apparent antioxidant and anti-mutagenic behaviour of Bile Pigments further suggests their presence in biological systems is of possible physiological importance. (c) 2007 Elsevier B.V. All rights reserved.
Marcelle Bergeron - One of the best experts on this subject based on the ideXlab platform.
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hypoxia ischemia but not hypoxia alone induces the expression of heme oxygenase 1 hsp32 in newborn rat brain
Journal of Cerebral Blood Flow and Metabolism, 1997Co-Authors: Marcelle Bergeron, Donna M Ferriero, Hendrik J Vreman, David K Stevenson, Frank R SharpAbstract:Heme oxygenase (HO) is the rate-limiting enzyme in the degradation of heme to produce Bile Pigments and carbon monoxide. The HO-1 isozyme is induced by a variety of agents such as heat, heme, and hydrogen peroxide. Evidence suggests that the Bile Pigments serve as antioxidants in cells with compromised defense mechanisms. Because hypoxia-ischemia (HI) increases the level of oxygen free radicals, the induction of HO-1 expression in the brain during ischemia could modulate the response to oxidative stress. To study the possible involvement of HO-1 in neonatal hypoxia-induced ischemic tolerance, we examined the brains of newborn rat pups exposed to 8% O2 (for 2.5 to 3 hours), and the brain of chronically hypoxic rat pups with congenital cardiac defects (Wistar Kyoto; WKY/ NCr). Heme oxygenase-1 immunostaining did not change after either acute or chronic hypoxia, suggesting that HO-1 is not a good candidate for explaining hypoxia preconditioning in newborn rat brain. To study the role of HO-1 in neonatal HI, 1-week-old rats were subjected to right carotid coagulation and exposure to 8% O2/92% N2 for 2.5 hours. Whereas HO enzymatic activity was unchanged in ipsilateral cortex and subcortical regions compared with the contralateral hemisphere or control brains, immunocytochemistry and Western blot analysis showed increased HO-1 staining in ipsilateral cortex, hippocampus, and striatum at 12 to 24 hours up to 7 days after HI. Double fluorescence immunostaining showed that HO-1 was expressed mostly in ED-1 positive macrophages. Because activated brain macrophages have been associated with the release of several cytotoxic molecules, the presence of HO-1 positive brain macrophages may determine the tissue vulnerability after HI injury.