Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Carbon monoxide (CO) generated by catalysis of heme by heme oxygenase is increased in the exhaled air of asthmatic patients. Based on recent studies demonstrating that asthma is an inflammatory disease associated with increased oxidants and that CO confers cytoprotection in oxidant-induced lung injury and inflammation, we sought to better understand the functional role of CO in asthma by using an aeroallergen model. Mice were sensitized to ovalbumin, challenged with aerosolized ovalbumin, and maintained in either CO (250 parts/million) or room air for 48 h. The differential effects of CO on bronchoalveolar lavage (BAL) fluid cell types were observed, with a marked attenuation of BAL fluid eosinophils in the CO-treated animals at 24 and 48 h. A marked reduction of the proinflammatory cytokine interleukin-5 was observed in the CO-treated mice, with no significant changes for other proinflammatory cytokines. These differential effects of CO were also observed with leukotrienes (LTs) and prostaglandins in that CO significantly decreased BAL fluid PGE2, and LTB4 but exerted negligible effect on thromboxane B2 or LTC4/D4/E4. Our data suggest a putative immunoregulatory role for CO in aeroallergen-induced inflammation in mice.
Am J Physiol Lung Cell Mol Physiol 2001 Jul
PMID:Carbon monoxide attenuates aeroallergen-induced inflammation in mice. 1140 64

Spinal cord tissue contains two enzyme systems capable of producing monoxide gases which in turn are linked to the stimulation of soluble guanylate cyclase, nitric oxide synthase (NOS) which produces NO and heme oxygenase (HO) which produces CO. Reports from several laboratories link these two enzyme systems to pain of inflammatory and neuropathic etiologies. Additional studies have demonstrated that the activation of the NOS system by morphine limits the spinal analgesic action of this drug. In this study we first employed the hot plate model of pain to demonstrate that the NOS inhibitor L-NAME and the HO inhibitor Sn-P potentiate the analgesic actions of intrathecally administered morphine while having no intrinsic analgesic action at the doses used. We then determined that L-NAME loses its ability to potentiate morphine in nNOS null-mutant mice, while Sn-P no longer potentiates morphine in mice lacking a functional HO-2 gene. The intrathecal injection of the cGMP analog 8-Br cGMP caused hyperalgesia in the hot plate assay. Focusing on the possible involvement of cGMP metabolism, we documented that morphine stimulates cGMP production in a spinal cord slice model in a concentration dependent and naloxone reversible manner. Both L-NAME and Sn-P were potent inhibitors of morphine-stimulated cGMP production. Buffer containing either CO or the NO donor compound SNAP stimulated cGMP production as well. In spinal cord slices from either nNOS or HO-2 null-mutant animals morphine did not stimulate cGMP production. Taken together our data suggest that spinal monoxide generation modifies the acute analgesic actions of morphine.
Brain Res Mol Brain Res 2001 Nov 01
PMID:Spinal cord nitric oxide synthase and heme oxygenase limit morphine induced analgesia. 1168 80

ICF (immunodeficiency, centromeric region instability and facial anomalies) is a recessive disease caused by mutations in the DNA methyltransferase 3B gene (DNMT3B). Patients have immunodeficiency, chromosome 1 (Chr1) and Chr16 pericentromeric anomalies in mitogen-stimulated lymphocytes, a small decrease in overall genomic 5-methylcytosine levels and much hypomethylation of Chr1 and Chr16 juxtacentromeric heterochromatin. Microarray expression analysis was done on B-cell lymphoblastoid cell lines (LCLs) from ICF patients with diverse DNMT3B mutations and on control LCLs using oligonucleotide arrays for approximately 5600 different genes, 510 of which showed a lymphoid lineage-restricted expression pattern among several different lineages tested. A set of 32 genes had consistent and significant ICF-specific changes in RNA levels. Half of these genes play a role in immune function. ICF-specific increases in immunoglobulin (Ig) heavy constant mu and delta RNA and cell surface IgM and IgD and decreases in Ig(gamma) and Ig(alpha) RNA and surface IgG and IgA indicate inhibition of the later steps of lymphocyte maturation. ICF-specific increases were seen in RNA for RGS1, a B-cell specific inhibitor of G-protein signaling implicated in negative regulation of B-cell migration, and in RNA for the pro-apoptotic protein kinase C eta gene. ICF-associated decreases were observed in RNAs encoding proteins involved in activation, migration or survival of lymphoid cells, namely, transcription factor negative regulator ID3, the enhancer-binding MEF2C, the iron regulatory transferrin receptor, integrin beta7, the stress protein heme oxygenase and the lymphocyte-specific tumor necrosis factor receptor family members 7 and 17. No differences in promoter methylation were seen between ICF and normal LCLs for three ICF upregulated genes and one downregulated gene by a quantitative methylation assay [combined bisulfite restriction analysis (COBRA)]. Our data suggest that DNMT3B mutations in the ICF syndrome cause lymphogenesis-associated gene dysregulation by indirect effects on gene expression that interfere with normal lymphocyte signaling, maturation and migration.
Hum Mol Genet 2001 Dec 01
PMID:DNA methyltransferase 3B mutations linked to the ICF syndrome cause dysregulation of lymphogenesis genes. 1174 35

The absorption and fluorescence characteristics of tin(IV) mesoporphyrin (SnMP) and its analog tin(IV) protoporphyrin (SnPP) were studied in a series of organic solvents. Fluorescence quantum yields were calculated using the Strickler-Berg equation. Good correlation was found between calculated values and measured relative values. Fluorescence lifetime, radiative lifetime and non-radiative lifetime were also calculated. The parameters showed variation depending on ligation as well as H-bonding. Unusual long lifetime and high quantum yields were found in alcohol solvents. This finding might contribute to elucidation of the nature of tin porphyrins to inhibit heme oxygenase.
Spectrochim Acta A Mol Biomol Spectrosc 2001 Oct
PMID:Solvent effects on the absorption and fluorescence characteristics of tin(IV) mesoporphyrin. 1176 38

Heme oxygenase-1, the major inducible isoform of heme oxygenase (HO), can be induced by heme and numerous other physical and chemical factors, many of which cause cellular 'stress'. This has led to the realization that HO-1 is a major highly conserved stress or heat shock protein. Recent work has implicated activation of mitogen-activated protein kinases and other kinases in the mechanism of induction of HO-1, and suggested that signal transduction pathways through tyrosine kinases are involved in induction of HO-1 gene expression by stress inducers. We hypothesized that phenylarsine oxide (PAO), an inhibitor of protein tyrosine phosphatases (PTPs), might up-regulate the HO-1 gene. Here, we show that a remarkably brief (1-15 min) exposure of normal hepatocytes to low concentrations (0.5-3 microM) of PAO produces a marked increase in mRNA and protein of HO-1. This increase is comparable to the level obtained by addition of heme (20 microM), and occurs without producing changes in cellular glutathione levels or stabilization of HO-1 message. Preincubation of cells with inhibitors of protein synthesis decreased the ability of PAO to increase levels of HO-1 mRNA, suggesting that the inductive effect requires de novo protein synthesis. Addition of thiol donors abrogated the PAO-mediated induction of HO-1 in a dose dependent fashion. Addition of genistein, a tyrosine kinase inhibitor, blunted the induction produced by both PAO and heme. After brief incubations with PAO or heme, cell extracts showed comparable increases in levels of protein tyrosine phosphorylation in general, and specifically in ZAP70 kinase. Our results are consistent with the proposition that induction of HO-1 by PAO involves inhibition of specific PTP(s), and that the mechanisms of induction of HO-1 by PAO and by heme may share some common pathways.
Mol Cell Biochem 2001 Oct
PMID:Induction of heme oxygenase-1 by phenylarsine oxide. Studies in cultured primary liver cells. 1176 35

Heme oxygenase-1 (HO-1) is a redox-sensitive inducible protein that provides efficient cytoprotection against oxidative stress. Curcumin, a polyphenolic natural compound that possesses anti-tumor and anti-inflammatory properties, has been reported recently to induce potently HO-1 expression in vascular endothelial cells (Free Rad Biol Med 28:1303-1312, 2000). Here, we extend our previous findings by showing that caffeic acid phenethyl ester (CAPE), another plant-derived phenolic agent, markedly increases heme oxygenase activity and HO-1 protein in astrocytes. The effect seems to be related to the peculiar chemical structures of curcumin and CAPE, because analogous antioxidants containing only portions of these two molecules were totally ineffective. At a final concentration of 30 microM, both curcumin and CAPE maximally up-regulated heme oxygenase activity while promoting marked cytotoxicity at higher concentrations (50-100 microM). Similar results were obtained with Curcumin-95, a mixture of curcuminoids commonly used as a dietary supplement. Incubation of astrocytes with curcumin or CAPE at concentrations that promoted maximal heme oxygenase activity resulted in an early increase in reduced glutathione followed by a significant elevation in oxidized glutathione contents. A curcumin-mediated increase in heme oxygenase activity was not affected by the glutathione precursor and thiol donor N-acetyl-L-cysteine. These data suggest that regulation of HO-1 expression by polyphenolic compounds is evoked by a distinctive mechanism which is not necessarily linked to changes in glutathione but might depend on redox signals sustained by specific and targeted sulfydryl groups. This study identifies a novel class of natural substances that could be used for therapeutic purposes as potent inducers of HO-1 in the protection of tissues against inflammatory and neurodegenerative conditions.
Mol Pharmacol 2002 Mar
PMID:Caffeic acid phenethyl ester and curcumin: a novel class of heme oxygenase-1 inducers. 1185 35

Modulation of the cytochrome P450 (CYP) monooxygenase system (P450) by arsenite was investigated in male, adult Sprague-Dawley rats treated with a single dose (75 micromol/kg, sc) of sodium arsenite (As3+). Total CYP content and P450-dependent 7-pentoxyresorufin O-pentylation (PROD) and 7-ethoxyresorufin O-deethylation (EROD) activities of liver microsomes decreased maximally (33, 35, and 50% of control, respectively) 1 day after As3+ treatment. Maximum decreases of CYP content and P450 catalytic activities corresponded with maximum increases of microsomal heme oxygenase (HO) activity and with increased total plasma bilirubin concentrations. EROD activity increased maximally in lung (300%) 5 days after a single dose of As3+. Lung CYP1A1 mRNA and protein levels also increased maximally 5 days after treatment. A small but significant increase in EROD activity (65%) was observed in lung microsomes 24 h following a 1 h infusion of bilirubin (7.5 mg/kg) into rats. However, administration of bilirubin to the lung via intratracheal injection (0.25 and 2.5 mg/kg) did not increase CYP1A1 monooxygenase activity or mRNA. This study demonstrates that P450 is modulated in an isozyme (CYP1A1 vs CYP2B1/2) selective manner in rat lung after acute As3+ administration. Administration of bilirubin, a potential aryl hydrocarbon receptor (AHR) ligand, by infusion or intratracheal instillation did not upregulate pulmonary CYP1A1 at the mRNA level under our treatment conditions.
J Biochem Mol Toxicol 2002
PMID:Acute sodium arsenite administration induces pulmonary CYP1A1 mRNA, protein and activity in the rat. 1197 25

Modulation of hepatic and extrahepatic detoxication enzymes Cyp1a1, Cyp2a5, glutathione S-transferse Ya (GSTYa) and NAD(P)H:quinone oxidoreductase (QOR) dependent catalytic activity and mRNA levels were investigated at 1, 2, or 4 days in liver, lung, or kidney of male, adult CD57 Bl/6 mice treated sc with a single dose (85 micromol/kg) of sodium arsenite (As3+). Maximum decreases of total hepatic cytochrome P450 (CYP) monooxygenase content and catalytic activities, occurring at 24 h, corresponded with maximum increases of heme oxygenase (HO-1) in all tissues, as well as maximum plasma total bilirubin. Extrahepatic increases in CYP were observed only in non-AHR dependent isozymes in the kidney, where both Cyp2a5 mRNA and catalytic activity increased maximally 24 h after treatment. In contrast, no significant changes in Cyp2b1/2-dependent PROD or mRNA activity and decreases in Cyp1a1-dependent-EROD activity were noted 1, 2, or 4 days after treatment. Increases in QOR catalytic activities were observed in all tissues examined with increased mRNA in kidney. On the other hand, GSTYa catalytic activity and mRNA increases were only detected in kidney. This study demonstrates the differential modulation of CYP, QOR, and GST-Ya, important drug metabolizing enzymes after acute As3+ administration. The induction of Cyp2a5, QOR, and GSTYa catalytic activity and gene expression occurred primarily in kidney during or shortly after conditions of oxidant stress.
J Biochem Mol Toxicol 2002
PMID:Acute sodium arsenite treatment induces Cyp2a5 but not Cyp1a1 in the C57Bl/6 mouse in a tissue (kidney) selective manner. 1197 26

Nitric oxide (NO) has received wide attention as a biological signaling molecule that uses cyclic GMP as a cellular second messenger. Other work has supported roles for cysteine oxidation or nitrosylation as signaling events. Recent studies in bacteria and mammalian cells now point to the existence of at least two other pathways independent of cGMP. For the E. coli SoxR protein, signaling occurs by nitrosylation of its binuclear iron-sulfur clusters, a reaction that is unprecedented in gene activation. In intact cells, these nitrosylated centers are very rapidly replaced by unmodified iron-sulfur clusters, a result that points to the existence of an active repair pathway for this type of protein damage. Exposure of mammalian cells to NO elicits an adaptive resistance that confers elevated resistance of the cells to higher levels of NO. This resistance in many cell types involves the important defense protein heme oxygenase 1, although the mechanism by which this enzyme mediates NO resistance remains unknown. Induction of heme oxygenase in some cell types occurs through the stabilization of its mRNA. NO-induced stabilization of mRNA is mediated by pre-existing proteins and points to the existence of an important new signaling pathway that counteracts the damage and stress exerted by this free radical.
Mol Cell Biochem
PMID:Signal transduction by nitric oxide in cellular stress responses. 1216 22

Carbon monoxide (CO), a gaseous second messenger, arises in biological systems during the oxidative catabolism of heme by the heme oxygenase (HO) enzymes. HO exists as constitutive (HO-2, HO-3) and inducible isoforms (HO-1), the latter which responds to regulation by multiple stress-stimuli. HO-1 confers protection in vitro and in vivo against oxidative cellular stress. Although the redox active compounds that are generated from HO activity (i.e. iron, biliverdin-IXalpha, and bilirubin-IXa) potentially modulate oxidative stress resistance, increasing evidence points to cytoprotective roles for CO. Though not reactive, CO regulates vascular processes such as vessel tone, smooth muscle proliferation, and platelet aggregation, and possibly functions as a neurotransmitter. The latter effects of CO depend on the activation of guanylate cyclase activity by direct binding to the heme moiety of the enzyme, stimulating the production of cyclic 3':5'-guanosine monophosphate. CO potentially interacts with other intracellular hemoprotein targets, though little is known about the functional significance of such interactions. Recent progress indicates that CO exerts novel anti-inflammatory and anti-apoptotic effects dependent on the modulation of the p38 mitogen activated protein kinase (MAPK)-signaling pathway. By virtue of these effects, CO confers protection in oxidative lung injury models, and likely plays a role in HO-1 mediated tissue protection.
Mol Cell Biochem
PMID:Heme oxygenase/carbon monoxide signaling pathways: regulation and functional significance. 1216 41


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