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Mahin D. Maines - One of the best experts on this subject based on the ideXlab platform.
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Biliverdin Reductase: a target for cancer therapy?
Frontiers in pharmacology, 2015Co-Authors: Peter E. M. Gibbs, Tihomir Miralem, Mahin D. MainesAbstract:Biliverdin Reductase (BVR) is a multifunctional protein that is the primary source of the potent antioxidant, bilirubin. BVR regulates activities/functions in the insulin/IGF-1/IRK/PI3K/MAPK pathways. Activation of certain kinases in these pathways is/are hallmark(s) of cancerous cells. The protein is a scaffold/bridge and intracellular transporter of kinases that regulate growth and proliferation of cells, including PKCs, ERK and Akt, and their targets including NF-κB, Elk1, HO-1, and iNOS. The scaffold and transport functions enable activated BVR to relocate from the cytosol to the nucleus or to the plasma membrane, depending on the activating stimulus. This enables the Reductase to function in diverse signaling pathways. And, its expression at the transcript and protein levels are increased in human tumors and the infiltrating T-cells, monocytes and circulating lymphocytes, as well as the circulating and infiltrating macrophages. These functions suggest that the cytoprotective role of BVR may be permissive for cancer/tumor growth. In this review, we summarize the recent developments that define the pro-growth activities of BVR, particularly with respect to its input into the MAPK signaling pathway and present evidence that BVR-based peptides inhibit activation of protein kinases, including MEK, PKCδ, and ERK as well as downstream targets including Elk1 and iNOS, and thus offers a credible novel approach to reduce cancer cell proliferation.
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Biliverdin Reductase: More than a Namesake – The Reductase, Its Peptide Fragments, and Biliverdin Regulate Activity of the Three Classes of Protein Kinase C
Frontiers in pharmacology, 2012Co-Authors: Peter E. M. Gibbs, Cicerone Tudor, Mahin D. MainesAbstract:The expanse of human Biliverdin Reductase (hBVR) functions in the cells is arguably umatched by any single protein. hBVR is a Ser/Thr/Tyr kinase, a scaffold protein, a transcription factor and an intracellular transporter of gene regulators. hBVR is an upstream activator of the insulin/IGF-1 signaling pathway and of PKC kinases in the two major arms of the pathway. In addition, it is the sole means for generating the antioxidant bilirubin-IXα. hBVR is essential for activation of ERK1/2 kinases by upstream MAPKK-MEK and by PKCδ, as well as the nuclear import and export of ERK1/2. Small fragments of hBVR are potent activators and inhibitors of the ERK kinases and PKCs: as such, they suggest the potential application of BVR-based technology in therapeutic settings. Presently, we have reviewed the function of hBVR in cell signaling with an emphasis on regulation of PKCδ activity.
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the coordinated increased expression of Biliverdin Reductase and heme oxygenase 2 promotes cardiomyocyte survival a Reductase based peptide counters β adrenergic receptor ligand mediated cardiac dysfunction
The FASEB Journal, 2011Co-Authors: Bo Ding, Peter E. M. Gibbs, Paul S Brookes, Mahin D. MainesAbstract:HO-2 oxidizes heme to CO and Biliverdin; the latter is reduced to bilirubin by Biliverdin Reductase (BVR). In addition, HO-2 is a redox-sensitive K/Ca2-associated protein, and BVR is an S/T/Y kinase. The two enzymes are components of cellular defense mechanisms. This is the first reporting of regulation of HO-2 by BVR and that their coordinated increase in isolated myocytes and intact heart protects against cardiotoxicity of β-adrenergic receptor activation by isoproterenol (ISO). The induction of BVR mRNA, protein, and activity and HO-2 protein was maintained for ≥96 h; increase in HO-1 was modest and transient. In isolated cardiomyocytes, experiments with cycloheximide, proteasome inhibitor MG-132, and siBVR suggested BVR-mediated stabilization of HO-2. In both models, activation of BVR offered protection against the ligand's stimulation of apoptosis. Two human BVR-based peptides known to inhibit and activate the Reductase, KKRILHC281 and KYCCSRK296, respectively, were tested in the intact heart. Perfusion of the heart with the inhibitory peptide blocked ISO-mediated BVR activation and augmented apoptosis; conversely, perfusion with the activating peptide inhibited apoptosis. At the functional level, peptide-mediated inhibition of BVR was accompanied by dysfunction of the left ventricle and decrease in HO-2 protein levels. Perfusion of the organ with the activating peptide preserved the left ventricular contractile function and was accompanied by increased levels of HO-2 protein. Finding that BVR and HO-2 levels, myocyte apoptosis, and contractile function of the heart can be modulated by small human BVR-based peptides offers a promising therapeutic approach for treatment of cardiac dysfunctions.—Ding, B., Gibbs, P. E. M., Brookes, P. S., Maines, M. D. The coordinated increased expression of Biliverdin Reductase and heme oxygenase-2 promotes cardiomyocyte survival; a Reductase-based peptide counters β-adrenergic receptor ligand-mediated cardiac dysfunction.
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Pleiotropic functions of Biliverdin Reductase: cellular signaling and generation of cytoprotective and cytotoxic bilirubin.
Trends in Pharmacological Sciences, 2009Co-Authors: Jaime Kapitulnik, Mahin D. MainesAbstract:Degradation of heme requires its conversion to Biliverdin (BV) by heme oxygenase, followed by reduction of BV to the free-radical quencher bilirubin (BR) by Biliverdin Reductase (BVR). It is now recognized that human BVR (hBVR) is a dual-specificity kinase (Ser/Thr and Tyr) upstream activator of the insulin/insulin growth factor-1 (IGF-1) and mitogen-activated protein kinase (MAPK) signaling pathways. hBVR is also a basic-leucine-zipper (bZip) DNA/chromatin-binding transcription factor, an activator and anchor protein for translocation of protein kinase C βII and ζ isozymes within cell compartments, and a kinase kinase for their activation. hBVR is essential for MAPK–extracellular signal-regulated kinase (ERK)1/2 (MEK)–eukaryotic-like protein kinase (Elk) signaling and has been identified as the cytoplasm-nuclear heme transporter of ERK1/2 and hematin, the key components of stress-responsive gene expression. Here, we discuss the recently uncovered functions of hBVR in cell signaling and regulation of gene expression, and the role of BR in cellular signaling, cytoprotection and cytotoxicity.
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Biliverdin Reductase: PKC interaction at the cross-talk of MAPK and PI3K signaling pathways.
Antioxidants & redox signaling, 2007Co-Authors: Mahin D. MainesAbstract:Biliverdin Reductase (BVR) was characterized some 25 years ago as a unique dual-cofactor/pH-dependent enzyme that catalyzes the reduction of Biliverdin-IXa. Our knowledge of functions of BVR has increased enormously in recent years. hBVR functions in the IR/IGF-1–controlled regulation of the MAPK and PI3K cascades that are linked by the PKC enzymes. The first of the two culminates in the activation of transcription factors for oxidative stress–responsive genes, including ho-1, where BVR functions as both a bZip (basic leucine zipper) transcription factor and a kinase. The second pathway amplifies the insulin/growth-factor signal for protein/DNA synthesis and glucose transport downstream of PI3K. hBVR is a transactivator of PKC-βII, and thus an integral component of the “activation loop” linking MAPK, PKC-βII, and PI3K to insulin/growth-factor signaling. The emergence of Biliverdin and bilirubin as a newly defined category of modulators of cell signaling and kinase activity further underscores the critical...
Cesare Mancuso - One of the best experts on this subject based on the ideXlab platform.
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The Heme Oxygenase/Biliverdin Reductase System as Effector of the Neuroprotective Outcomes of Herb-Based Nutritional Supplements.
Frontiers in pharmacology, 2019Co-Authors: Emanuela Mhillaj, Vincenzo Cuomo, Luigia Trabace, Cesare MancusoAbstract:Over the last few years, several preclinical studies have shown that some herbal products, such as ferulic acid, ginkgo biloba and resveratrol, exert neuroprotective effects through the modulation of the heme oxygenase/Biliverdin Reductase system. Unfortunately, sufficient data supporting the shift of knowledge from preclinical studies to humans, particularly in neurodegenerative diseases, are not yet available in the literature. The purpose of this review is to summarize the studies and the main results achieved on the potential therapeutic role of the interaction between the heme oxygenase/Biliverdin Reductase system with ferulic acid, ginkgo biloba and resveratrol. Some critical issues have also been reported, mainly concerning the safety profile and the toxicological sequelae associated to the supplementation with the herbs mentioned above, based on both current literature and specific reports issued by the competent Regulatory Authorities.
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the heme oxygenase Biliverdin Reductase system as effector of the neuroprotective outcomes of herb based nutritional supplements
Frontiers in Pharmacology, 2019Co-Authors: Emanuela Mhillaj, Cesare Mancuso, Vincenzo Cuomo, Luigia TrabaceAbstract:Over the last few years, several preclinical studies have shown that some herbal products, such as ferulic acid, ginkgo biloba and resveratrol, exert neuroprotective effects through the modulation of the heme oxygenase/Biliverdin Reductase system. Unfortunately, sufficient data supporting the shift of knowledge from preclinical studies to humans, particularly in neurodegenerative diseases, are not yet available in the literature. The purpose of this review is to summarize the studies and the main results achieved on the potential therapeutic role of the interaction between the heme oxygenase/Biliverdin Reductase system with ferulic acid, ginkgo biloba and resveratrol. Some critical issues have also been reported, mainly concerning the safety profile and the toxicological sequelae associated to the supplementation with the herbs mentioned above, based on both current literature and specific reports issued by the competent Regulatory Authorities.
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The heme oxygenase/Biliverdin Reductase system in skin cancers.
Journal of biological regulators and homeostatic agents, 2015Co-Authors: Vincenzo Arena, Ilaria Pennacchia, Giuseppe Guerriero, Cesare MancusoAbstract:The heme oxygenase/Biliverdin Reductase (HO/BVR) pathway enhances cell stress response by degrading excess heme or producing antioxidant and cytoprotective molecules. Recently, members of the HO/BVR system have been proposed as biomarkers for the early diagnosis of free radical-related diseases. In this study, the presence of both the inducible and constitutive HO isoforms (HO-1 and HO-2, respectively) and BVR was evaluated by immunohistochemistry in human skin cancer samples. Moderate/strong immunoreactivities against HO-1, HO-2 and BVR were detected in 100% of the nodular malignant melanoma samples, whereas in basal cell carcinoma specimens these figures were 62%, 88% and 60%, respectively, with a faint/moderate degree of expression. Faint/moderate HO-1, HO-2 and BVR immunoreactivities were detected in 33%, 66% and 100% of melanocytic nevi samples, respectively. In conclusion, HO-1 and HO-2 and BVR were expressed in the cytosols of skin cancer cells, whereas perilesional normal epidermis showed only faint staining, thus leading to the hypothesis that the HO/BVR system is activated in skin cancers.
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the heme oxygenase Biliverdin Reductase system in skin cancers
Journal of Biological Regulators and Homeostatic Agents, 2015Co-Authors: Vincenzo Arena, Ilaria Pennacchia, Giuseppe Guerriero, Cesare MancusoAbstract:The heme oxygenase/Biliverdin Reductase (HO/BVR) pathway enhances cell stress response by degrading excess heme or producing antioxidant and cytoprotective molecules. Recently, members of the HO/BVR system have been proposed as biomarkers for the early diagnosis of free radical-related diseases. In this study, the presence of both the inducible and constitutive HO isoforms (HO-1 and HO-2, respectively) and BVR was evaluated by immunohistochemistry in human skin cancer samples. Moderate/strong immunoreactivities against HO-1, HO-2 and BVR were detected in 100% of the nodular malignant melanoma samples, whereas in basal cell carcinoma specimens these figures were 62%, 88% and 60%, respectively, with a faint/moderate degree of expression. Faint/moderate HO-1, HO-2 and BVR immunoreactivities were detected in 33%, 66% and 100% of melanocytic nevi samples, respectively. In conclusion, HO-1 and HO-2 and BVR were expressed in the cytosols of skin cancer cells, whereas perilesional normal epidermis showed only faint staining, thus leading to the hypothesis that the HO/BVR system is activated in skin cancers.
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Biliverdin Reductase-A: a novel drug target for atorvastatin in a dog pre-clinical model of Alzheimer disease
Journal of neurochemistry, 2011Co-Authors: Eugenio Barone, Fabio Di Domenico, Rukhsana Sultana, Cesare Mancuso, Michael Paul Murphy, Elizabeth Head, D. A. ButterfieldAbstract:Biliverdin Reductase-A (BVR-A) is a pleiotropic enzyme involved in cellular stress responses. It not only transforms Biliverdin-IX alpha into the antioxidant bilirubin-IX alpha but through its serine/threonine/tyrosine kinase activity is able to modulate cell signaling networks. BVR-A's involvement in neurodegenerative disorders such as Alzheimer disease (AD) and amnestic mild cognitive impairment was previously described. Statins have been proposed to reduce risk of AD. In this study we evaluated the effect of atorvastatin treatment (80 mg/day for 14.5 months) on BVR-A in the parietal cortex, cerebellum and liver of a well characterized pre-clinical model of AD, the aged beagle. We found that atorvastatin significantly increased BVR-A protein levels, phosphorylation and activity only in parietal cortex. Additionally, we found significant negative correlations between BVR-A and oxidative stress indices, as well as discrimination learning error scores. Furthermore, BVR-A up-regulation and post-translational modifications significantly correlated with β-secretase protein levels in the brain, suggesting a possible role for BVR-A in Aβ formation.
Eugenio Barone - One of the best experts on this subject based on the ideXlab platform.
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Biliverdin Reductase-A Mediates the Beneficial Effects of Intranasal Insulin in Alzheimer Disease
Molecular neurobiology, 2018Co-Authors: Eugenio Barone, Fabio Di Domenico, D. Allan Butterfield, Antonella Tramutola, Francesca Triani, Silvio Calcagnini, Cristian Ripoli, Silvana Gaetani, Claudio Grassi, Tommaso CassanoAbstract:Impairment of Biliverdin Reductase-A (BVR-A) is an early event leading to brain insulin resistance in AD. Intranasal insulin (INI) administration is under evaluation as a strategy to alleviate brain insulin resistance; however, the molecular mechanisms underlying INI beneficial effects are still unclear. We show that INI improves insulin signaling activation in the hippocampus and cortex of adult and aged 3×Tg-AD mice by ameliorating BVR-A activation. These changes were associated with a reduction of nitrosative stress, Tau phosphorylation, and Aβ oligomers in brain, along with improved cognitive functions. The role of BVR-A was strengthened by showing that cells lacking BVR-A: (i) develop insulin resistance if treated with insulin and (ii) can be recovered from insulin resistance only if treated with a BVR-A-mimetic peptide. These novel findings shed light on the mechanisms underlying INI treatment effects and suggest BVR-A as potential therapeutic target to prevent brain insulin resistance in AD.
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Biliverdin Reductase-A correlates with inducible nitric oxide synthasein in atorvastatin treated aged canine brain.
Neural regeneration research, 2013Co-Authors: Fabio Di Domenico, Marzia Perluigi, Eugenio BaroneAbstract:Alzheimer's disease is a neurodegenerative disorder characterized by progressive cognitive impairment and neuropathology. Recent preclinical and epidemiological studies proposed statins as a possible therapeutic drug for Alzheimer's disease, but the exact mechanisms of action are still unknown. Biliverdin Reductase-A is a pleiotropic enzyme involved in cellular stress responses. It not only transforms Biliverdin-IX alpha into the antioxidant bilirubin-IX alpha but its serine/threonine/tyrosine kinase activity is able to modulate cell signaling networks. We previously reported the beneficial effects of atorvastatin treatment on Biliverdin Reductase-A and heme oxygenase-1 in the brains of a well characterized pre-clinical model of Alzheimer's disease, aged beagles, together with observed improvement in cognition. Here we extend our knowledge of the effects of atorvastatin on inducible nitric oxide synthase in parietal cortex, cerebellum and liver of the same animals. We demonstrated that atorvastatin treatment (80 mg/day for 14.5 months) to aged beagles selectively increased inducible nitric oxide synthase in the parietal cortex but not in the cerebellum. In contrast, inducible nitric oxide synthase protein levels were significantly decreased in the liver. Significant positive correlations were found between Biliverdin Reductase-A and inducible nitric oxide synthase as well as heme oxygenase-1 protein levels in the parietal cortex. The opposite was observed in the liver. Inducible nitric oxide synthase up-regulation in the parietal cortex was positively associated with improved Biliverdin Reductase-A functions, whereas the oxidative-induced impairment of Biliverdin Reductase-A in the liver negatively affected inducible nitric oxide synthase expression, thus suggesting a role for Biliverdin Reductase-A in atorvastatin-dependent inducible nitric oxide synthase changes. Interestingly, increased inducible nitric oxide synthase levels in the parietal cortex were not associated with higher oxidative/nitrosative stress levels. We hypothesize that Biliverdin Reductase-A-dependent inducible nitric oxide synthase regulation strongly contributes to the cognitive improvement observed following atorvastatin treatment.
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Biliverdin Reductase-A: a novel drug target for atorvastatin in a dog pre-clinical model of Alzheimer disease
Journal of neurochemistry, 2011Co-Authors: Eugenio Barone, Fabio Di Domenico, Rukhsana Sultana, Cesare Mancuso, Michael Paul Murphy, Elizabeth Head, D. A. ButterfieldAbstract:Biliverdin Reductase-A (BVR-A) is a pleiotropic enzyme involved in cellular stress responses. It not only transforms Biliverdin-IX alpha into the antioxidant bilirubin-IX alpha but through its serine/threonine/tyrosine kinase activity is able to modulate cell signaling networks. BVR-A's involvement in neurodegenerative disorders such as Alzheimer disease (AD) and amnestic mild cognitive impairment was previously described. Statins have been proposed to reduce risk of AD. In this study we evaluated the effect of atorvastatin treatment (80 mg/day for 14.5 months) on BVR-A in the parietal cortex, cerebellum and liver of a well characterized pre-clinical model of AD, the aged beagle. We found that atorvastatin significantly increased BVR-A protein levels, phosphorylation and activity only in parietal cortex. Additionally, we found significant negative correlations between BVR-A and oxidative stress indices, as well as discrimination learning error scores. Furthermore, BVR-A up-regulation and post-translational modifications significantly correlated with β-secretase protein levels in the brain, suggesting a possible role for BVR-A in Aβ formation.
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Oxidative and Nitrosative Modifications of Biliverdin Reductase-A in the Brain of Subjects with Alzheimer's Disease and Amnestic Mild Cognitive Impairment
Journal of Alzheimer's disease : JAD, 2011Co-Authors: Eugenio Barone, Fabio Di Domenico, Marzia Perluigi, Giovanna Cenini, Rukhsana Sultana, Paolo Preziosi, Cesare Mancuso, Raffaella Coccia, D. Allan ButterfieldAbstract:Biliverdin Reductase-A (BVR-A) is a pleiotropic enzyme and plays pivotal role in the antioxidant defense against free radicals as well as in cell homeostasis. Together with heme oxygenase, BVR-A forms a powerful system involved in the cell stress response during neurodegenerative disorders including Alzheimer's disease (AD), whereas due to the serine/threonine/tyrosine kinase activity the enzyme regulates glucose metabolism and cell proliferation. In this paper, we report results that demonstrate BVR-A undergoes post-translational oxidative and nitrosative modifications in the hippocampus, but not cerebellum, of subjects with AD and amnestic mild cognitive impairment (MCI). A significant increase of nitrated BVR-A was demonstrated only in AD and MCI hippocampi, whereas no significant modifications were found in cerebellar tissue. In addition, a significant reduction in protein carbonyl-derivatives of BVR-A was found in both AD and MCI hippocampi (15% and 18%, respectively). Biliverdin Reductase-bound 4-hydroxynonenals were not modified in hippocampi and cerebella from AD and MCI subjects. These results supported the hypothesis of a prevalence of nitrosative stress-induced modifications on BVR-A structure, and this evidence was confirmed by a significant upregulation of inducible nitric oxide synthase in hippocampal tissue of subjects with AD and MCI that was not present in cerebellum. In conclusion, nitrosative stress-induced modifications on hippocampal BVR-A are an early event in the pathogenesis of AD since they appear also in MCI subjects and could contribute to the antioxidant and metabolic derangement characteristic of these neurodegenerative disorders.
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Biliverdin Reductase-A protein levels and activity in the brains of subjects with Alzheimer disease and mild cognitive impairment
Biochimica et Biophysica Acta - Molecular Basis of Disease, 2011Co-Authors: Eugenio Barone, Fabio Di Domenico, Marzia Perluigi, Giovanna Cenini, Rukhsana Sultana, Chiara Cini, Paolo Preziosi, Cesare Mancuso, D. Allan ButterfieldAbstract:Biliverdin Reductase-A is a pleiotropic enzyme involved not only in the reduction of Biliverdin-IX -alpha into bilirubin-IX-alpha, but also in the regulation of glucose metabolism and cell growth secondary to its serine/threonine/tyrosine kinase activity. Together with heme oxygenase, whose metabolic role is to degrade heme into Biliverdin-IX-alpha, it forms a powerful system involved in the cell stress response during neurodegenerative disorders. In this paper, an up-regulation of the Biliverdin Reductase-A protein levels was found in the hippocampus of the subjects with Alzheimer disease and arguably its earliest form, mild cognitive impairment. Moreover a significant reduction in the phosphorylation of serine, threonine and tyrosine residues of Biliverdin Reductase-A was found, and this was paralleled by a marked reduction in its Reductase activity. Interestingly, the levels of both total and phosphorylated Biliverdin Reductase-A was unchanged as well as its enzymatic activity in the cerebella. These results demonstrated a dichotomy between Biliverdin Reductase-A protein levels and activity in the hippocampus of subjects affected by Alzheimer disease and mild cognitive impairment, and this effect likely is attributable to a reduction in the phosphorylation of serine, threonine and tyrosine residues of Biliverdin Reductase-A. Consequently, not just the increased levels of Biliverdin Reductase-A, but also its changed activity and phosphorylation state, should be taken into account when considering potential biomarkers for Alzheimer disease and mild cognitive impairment.
Anthony Disantagnese - One of the best experts on this subject based on the ideXlab platform.
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THE OXIDOReductase, Biliverdin Reductase, IS INDUCED IN INCREASE IN ACTIVITY HUMAN RENAL CARCINOMA - pH AND COFACTOR-SPECIFIC
1999Co-Authors: Win D. Maines, Robert D. Mayer, Erdal Erturk, Tian J. Huang, Anthony DisantagneseAbstract:Purpose: Biliverdin Reductase is an oxidoReductase unique among all enzymes characterized to date in having dual pWdual cofactor requirement - NADH and NADPH at 6.7 and 8.7, respectively. The protein shows extensive microheterogeneity that is caused by post-translational modification. The Reductase converts the heme degradation product, Biliverdin, to bilirubin. Bilirubin has been shown to inhibit responses of human lymphocytes, including phytohemagglutinininduced proliferation, interleukin-2 production, and antibody dependent and independent cell mediated cytotoxicity. In addition to acting as an antioxidant, it inhibits protein phosphorylation and activity of enzymes such as protein kinase C and NADPH oxidase. This research was to evaluate whether renal cell carcinoma differs from normal tissue in regard to the expression and activity of the Reductase. Materials and Methods: kidney tissue with or without visible renal carcinoma and normal kidney tissue from a brain dead patient were frozen at -8OC shortly after removal. Ten pm. tissue sections were used for immunostaining of Biliverdin Reductase, pooled isolated tumors and surrounding tissue that did not contain visible tumor were used for Northern blot analysis of mRNA and Western blot analysis of protein. Enzyme activity was also measured in these preparations at pH 6.7 with NADH, and at pH 8.7 with NADPH. Ten additional formalin fixed specimens of renal cell carcinoma were also used for immunostaining. Results: There was a striking increase in the Reductase protein levels, as visualized by immunostaining in tumor tissue cells. The increase was also evident by Western blotting, and involved in increased transcription of Biliverdin Reductase as suggested by Northern blot analysis. The protein would also be detected in the infiltrating monocytes, macrophages, T cells and neutrophils as well as in circulating lymphocytes. The enzyme activity was nearly doubled in the tumor tissue, but selectively with NADH as the cofactor. Conclusion: Increases in Biliverdin Reductase expression and activity only with NADH is found in renal cell carcinoma. The net effects of this change are uncertain at present but several pathways, which could be affected by the Reductase, may alter local physiology. Biliverdin Reductase as a zinc metalloprotein may directly interact with other regulatory proteins, generation of increased bilirubin may alter immune function and increased enzyme activity may deplete NADH with contrasting consequence of blocking free radical formation and depleting cellular ATP. To the benefit of the host, the latter could culminate in tumor cell death.
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THE OXIDOReductase, Biliverdin Reductase, IS INDUCED IN HUMAN RENAL CARCINOMA - pH AND COFACTOR-SPECIFIC INCREASE IN ACTIVITY
The Journal of urology, 1999Co-Authors: Mahin D. Maines, Robert D. Mayer, Erdal Erturk, Tian J. Huang, Anthony DisantagneseAbstract:ABSTRACTPurpose: Biliverdin Reductase is an oxidoReductase unique among all enzymes characterized to date in having dual pH/dual cofactor requirement - NADH and NADPH at 6.7 and 8.7, respectively. The protein shows extensive microheterogeneity that is caused by post-translational modification. The Reductase converts the heme degradation product, Biliverdin, to bilirubin. Bilirubin has been shown to inhibit responses of human lymphocytes, including phytohemagglutinin-induced proliferation, interleukin-2 production, and antibody dependent and independent cell mediated cytotoxicity. In addition to acting as an antioxidant, it inhibits protein phosphorylation and activity of enzymes such as protein kinase C and NADPH oxidase. This research was to evaluate whether renal cell carcinoma differs from normal tissue in regard to the expression and activity of the Reductase.Materials and Methods: kidney tissue with or without visible renal carcinoma and normal kidney tissue from a brain dead patient were frozen at −...
Tian J. Huang - One of the best experts on this subject based on the ideXlab platform.
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Nuclear localization of Biliverdin Reductase in the rat kidney: response to nephrotoxins that induce heme oxygenase-1.
The Journal of pharmacology and experimental therapeutics, 2001Co-Authors: Mahin D. Maines, James F. Ewing, Tian J. Huang, Nariman PanahianAbstract:Biliverdin Reductase catalyzes the reduction of Biliverdin, the product of heme oxygenase (HO) activity, to bilirubin. The Reductase is unique among all enzymes characterized to date in being dual pH/cofactor-dependent. Until now the enzyme was assumed to be a noninducible cytosolic protein. This report, for the first time, demonstrates induction and nuclear localization of Reductase in rat kidney in response to HO-1 inducers: bacterial lipopolysaccharide (LPS) and bromobenzene. The study also demonstrates that nuclear localization requires an intact nuclear localization signal and is responsive to cGMP. Specifically 16 h after treatment of rats (i.p.) with LPS (5 mg/kg), there was an increase in nuclear Biliverdin Reductase as determined by immunostaining, Western blotting, and activity analysis. Induction and nuclear localization of the Reductase in kidney was also observed in bromobenzene-treated rats (2 mmol/kg, s.c., 24 h). The Reductase message levels, however, were not increased in response to either treatment, suggesting post-transcriptional activation of the Reductase by LPS and bromobenzene. The mechanism of nuclear transport of the Reductase was examined using HeLa cells transfected with the hemagglutinin-tagged Reductase construct. When cells were treated with 8-Br-cGMP the protein translocated into the nucleus. Mutation of the putative nuclear localization signal domain of the Reductase blocked nuclear transport of the protein. We suggest the significance of nuclear localization of the Reductase may relate to: 1) chain-breaking antioxidant activity of bilirubin; 2) inhibition of superoxide formation by bilirubin; and 3) modulation of the signal transduction pathways.
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THE OXIDOReductase, Biliverdin Reductase, IS INDUCED IN INCREASE IN ACTIVITY HUMAN RENAL CARCINOMA - pH AND COFACTOR-SPECIFIC
1999Co-Authors: Win D. Maines, Robert D. Mayer, Erdal Erturk, Tian J. Huang, Anthony DisantagneseAbstract:Purpose: Biliverdin Reductase is an oxidoReductase unique among all enzymes characterized to date in having dual pWdual cofactor requirement - NADH and NADPH at 6.7 and 8.7, respectively. The protein shows extensive microheterogeneity that is caused by post-translational modification. The Reductase converts the heme degradation product, Biliverdin, to bilirubin. Bilirubin has been shown to inhibit responses of human lymphocytes, including phytohemagglutinininduced proliferation, interleukin-2 production, and antibody dependent and independent cell mediated cytotoxicity. In addition to acting as an antioxidant, it inhibits protein phosphorylation and activity of enzymes such as protein kinase C and NADPH oxidase. This research was to evaluate whether renal cell carcinoma differs from normal tissue in regard to the expression and activity of the Reductase. Materials and Methods: kidney tissue with or without visible renal carcinoma and normal kidney tissue from a brain dead patient were frozen at -8OC shortly after removal. Ten pm. tissue sections were used for immunostaining of Biliverdin Reductase, pooled isolated tumors and surrounding tissue that did not contain visible tumor were used for Northern blot analysis of mRNA and Western blot analysis of protein. Enzyme activity was also measured in these preparations at pH 6.7 with NADH, and at pH 8.7 with NADPH. Ten additional formalin fixed specimens of renal cell carcinoma were also used for immunostaining. Results: There was a striking increase in the Reductase protein levels, as visualized by immunostaining in tumor tissue cells. The increase was also evident by Western blotting, and involved in increased transcription of Biliverdin Reductase as suggested by Northern blot analysis. The protein would also be detected in the infiltrating monocytes, macrophages, T cells and neutrophils as well as in circulating lymphocytes. The enzyme activity was nearly doubled in the tumor tissue, but selectively with NADH as the cofactor. Conclusion: Increases in Biliverdin Reductase expression and activity only with NADH is found in renal cell carcinoma. The net effects of this change are uncertain at present but several pathways, which could be affected by the Reductase, may alter local physiology. Biliverdin Reductase as a zinc metalloprotein may directly interact with other regulatory proteins, generation of increased bilirubin may alter immune function and increased enzyme activity may deplete NADH with contrasting consequence of blocking free radical formation and depleting cellular ATP. To the benefit of the host, the latter could culminate in tumor cell death.
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THE OXIDOReductase, Biliverdin Reductase, IS INDUCED IN HUMAN RENAL CARCINOMA - pH AND COFACTOR-SPECIFIC INCREASE IN ACTIVITY
The Journal of urology, 1999Co-Authors: Mahin D. Maines, Robert D. Mayer, Erdal Erturk, Tian J. Huang, Anthony DisantagneseAbstract:ABSTRACTPurpose: Biliverdin Reductase is an oxidoReductase unique among all enzymes characterized to date in having dual pH/dual cofactor requirement - NADH and NADPH at 6.7 and 8.7, respectively. The protein shows extensive microheterogeneity that is caused by post-translational modification. The Reductase converts the heme degradation product, Biliverdin, to bilirubin. Bilirubin has been shown to inhibit responses of human lymphocytes, including phytohemagglutinin-induced proliferation, interleukin-2 production, and antibody dependent and independent cell mediated cytotoxicity. In addition to acting as an antioxidant, it inhibits protein phosphorylation and activity of enzymes such as protein kinase C and NADPH oxidase. This research was to evaluate whether renal cell carcinoma differs from normal tissue in regard to the expression and activity of the Reductase.Materials and Methods: kidney tissue with or without visible renal carcinoma and normal kidney tissue from a brain dead patient were frozen at −...