Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The hypothesis that copper modulates the activity of intracellular signal transduction pathways to affect transcription, which ultimately disrupts normal development was investigated. Preliminary analysis of transcriptomes from HepG2 cells exposed to copper for 4 and 24 h identified 19 and 7 up-regulated genes (twofold; p <or= 0.05), respectively. Among the up-regulated genes, several have been previously reported to be responsive to metals or oxidative stress. Differentially expressed genes were grouped by the functional categories based on gene ontology (GO). Significantly enriched GO categories (p < 0.01) included copper ion homeostasis, cadmium and copper ion binding, and heme oxygenase and oxidoreductase activities. Real-time RT-PCR confirmed the effect of copper on the levels of MT2A, HSPA1A, CYP1A1 and HMOX1 expression.
Mol Cell Biochem 2005 Nov
PMID:Expression of copper-responsive genes in HepG2 cells. 1628 23

Heme is a crucial component of many pharmacological and toxicological processes, and studies have suggested that heme deficiency may play a role in cellular ageing. A model of ageing neurons was established using prolonged cultures of BALB/c mouse primary cortical neurons. Aged neurons displayed a senescent phenotype and a marked up-regulation of cathepsin-L expression. Down-regulation of the candidate neuron-specific genes for N-methyl-D-aspartate (NMDA) receptor subunits (NMDAzeta1 and -epsilon2) and neurofilament light peptide (NF-L) were found to be characteristic of the aging process as reported in vivo (Brain Res 907:71-83, 2001; Brain Res Mol Brain Res 99:40-45, 2002). In contrast, the genes for the controlling enzymes of heme synthesis and degradation (5-aminolevulinate synthase 1 and heme oxygenase 1, respectively) were up-regulated, implying depletion of a regulatory heme pool. Inhibition of heme synthesis (by 70-80%) at different enzymic steps by succinyl acetone and N-methylprotoporphyrin IX resulted in the earlier lowered expression of NMDAzeta1 and -epsilon2 and NF-L. Exogenous hemin added to heme-depleted cells rescued the expression of these neuron-specific genes. Culture of cortical neurons from BALB/c Fech(m1Pas) mutant mice demonstrating depressed heme synthesis showed premature senescence and reduced expression of NMDAzeta1 and -epsilon2 receptor subunits and NF-L compared with wild-type cells. Our findings suggest that reduced availability of heme in neurons associated with senescence may have significant effects on synaptic function.
Mol Pharmacol 2006 Mar
PMID:Heme deficiency is associated with senescence and causes suppression of N-methyl-D-aspartate receptor subunits expression in primary cortical neurons. 1630 32

Carbon monoxide (CO) is proposed to play a role in placental vascular control, as the placenta produces and responds to CO. The mechanism by which CO is formed by the placenta is unclear but could be through heme oxygenase (HO) degradation of heme, lipid peroxidation, or both. Human placental cotyledons were perfused with Kreb s solution to remove blood. Chorionic villi segments were prepared for measurements of CO production in the absence/presence of an exogenous supply of heme substrate (methemalbumin), inhibitors of HO, or inhibitors of lipid peroxidation. HO inhibitors used were chromium mesoporphyrin (CrMP) (0.1 mM, 0.3 mM), and azalanstat (0.1 mM, 0.3 mM). The lipid peroxidation inhibitors used were EDTA (0.1 mM, 0.3 mM) and deferoxamine (0.1 mM). Incubation of villi segments with methemalbumin (0.15 mM, 0.3 mM, 0.45 mM) resulted in a concentration-dependent increase in CO formation above the basal, endogenous rate. CrMP and azalanstat inhibited basal endogenous CO production, whereas EDTA and deferoxamine enhanced CO formation above basal level. These results demonstrate that endogenous CO was formed by human chorionic villi from heme, primarily through the action of HO, and are consistent with the hypothesis that HO plays a role in the regulation of placental vasculature by the formation of heme-derived CO.
Cell Mol Biol (Noisy-le-grand) 2005 Oct 03
PMID:The source of endogenous carbon monoxide formation in human placental chorionic villi. 1630 66

The stress-inducible protein heme oxygenase-1 exerts potent antiinflammatory, antiapoptotic and cytoprotective effects in vitro and in vivo. Another important mediator of cytoprotection, the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway activates many proteins involved in the maintenance of cellular homeostasis. Since activation of heme oxygenase-1 and PI3K/Akt both protect the cellular environment, we postulated that PI3K/Akt can regulate the induction of heme oxygenase-1 by proinflammatory stress. The treatment of primary murine macrophage cells (RAW 264.7) with lipopolysaccharide induced heme oxygenase-1 protein and mRNA expression, and increased the phosphorylation of Akt and p38 mitogen activated protein kinase (p38 MAPK). These cellular effects of lipopolysaccharide were markedly diminished by pre-treatment with wortmannin, a specific inhibitor of PI3K. Furthermore, lipopolysaccharide-inducible heme oxygenase expression was blocked by SB203580, a specific inhibitor of p38 MAPK. Both wortmannin and SB203580 decreased lipopolysaccharide-inducible NF-E2-related factor (Nrf2) DNA binding activity. Transfection of macrophages with dominant negative mutants of PI3K, Akt and Nrf2, as well as wortmannin treatment, significantly reduced the transcriptional activity of a minimal heme oxygenase-1 promoter luciferase construct (D33HO-1luc). We demonstrate, to our knowledge for the first time, that upon proinflammatory stimulation heme oxygenase-1 gene expression in macrophages depends on PI3K/Akt and p38 MAPK acting upstream of Nrf2-dependent promoter activation.
Cell Mol Biol (Noisy-le-grand) 2005 Oct 03
PMID:Phosphatidylinositol 3-kinase/Akt pathway mediates heme oxygenase-1 regulation by lipopolysaccharide. 1630 68

Several drugs and stress are involved in the triggering of attacks in acute porphyrias. The central nervous system is extremely sensitive to free radical damage because of a relatively low antioxidant capacity. We have demonstrated that mice brain cholinergic system was altered by the effect of some porphyrinogenic agents. The aim of this work was to investigate how known porphyrinogenic drugs affect delta-Aminolevulinic acid synthetase (ALA-S), which is the response of heme oxygenase (HO) to this challenge and to evaluate if the xenobiotics studied develop stress oxidative in mice brain. HO activity was 50-70% induced after chronic Enflurane and Isoflurane anaesthesia, dietary Griseofulvin and starvation. An increase in mRNA HO expression was caused by chronic anaesthesia and Veronal treatments; instead allylisopropilacetamide (AIA) reduced mRNA expression. ALA-S activity was induced by acute administration of anaesthetics (89%), veronal (240%) and ethanol (80%), while ALA-S mRNA expression augmented by chronic administration of enflurane, AIA and veronal. Stress markers such as superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase activities and malondialdehyde and reduced glutathione levels showed different responses depending on the xenobiotic assayed. In conclusion, some of the drugs studied produced oxidative stress in brain that was confirmed through HO induction and this could be one of the factors leading to porphyric neuropathy.
Cell Mol Biol (Noisy-le-grand) 2005 Oct 03
PMID:Heme oxygenase, aminolevulinate acid synthetase and the antioxidant system in the brain of mice treated with porphyrinogenic drugs. 1630 71

Distribution and enzymatic activity of haem oxygenase (HO) was investigated in the stomach of healthy guinea pigs or animals subjected to in vivo cobalt-induced oxidative stress. The physiological role of HO-1 and HO-2 isoenzymes in fundic and antral area of the stomach was assessed by studying the action of HO substrate--hemin--on ionic currents of single smooth muscle cells. The data obtained suggest that HO-1 induction might serve in the guinea-pig stomach as genetically determined defense mechanism aimed to combat toxic stress-related pathology in order to preserve the functional performance of the organ.
Cell Mol Biol (Noisy-le-grand) 2005 Oct 03
PMID:HO-1 induction in the guinea-pig stomach: protection of smooth muscle functional performance during cobalt-induced oxidative stress. 1630 72

Hemin and other heme derivatives, e.g. heme-L-lysinate (HLL) and heme-L-arginate, have been used extensively to upregulate expression of heme oxygenase and production of endogenous carbon monoxide. Hemin administration has been shown to markedly decrease high blood pressure in spontaneously hypertensive rats (SHR), but not in normotensive Wistar-Kyoto or Sprague Dawley (SD) rats. While methodology to measure serum heme levels has been established long ago, metabolism of the injected hemin or heme derivatives when used to lower blood pressure has not been investigated. In this study, metabolism of hemin or HLL after injected into the rat was monitored by measuring changes in circulatory heme levels. SHR (12-20 weeks old) had significantly higher blood pressure than age-matched SD rats. In both strains, serum heme level was negligible. Hemin or HLL injection (15 mg/kg/day, i.p.) for 5-13 days significantly lowered blood pressure of 12-weeks SHR. High blood pressure was not lowered in SHR older than 20 weeks until hemin or HLL injection period was beyond 5 days. This anti-hypertensive effect of hemin and HLL was synchronized with an increase in serum heme level, from undetectable to 4.3 micromol/l. On the other hand, hemin or HLL had no effect on blood pressure of age-matched SD rats, despite serum heme level rose to the same extent as in the treated SHR. There was no significant difference between hemin and HLL injections in terms of changes in blood pressure and serum heme level in all rats. Our study for the first time correlated changes in serum heme levels with blood pressure levels after injection of hemin or HLL in SHR and SD rats. Hemin and HLL had similar effects on blood pressure change and serum heme level. By determining serum heme levels following the administration of hemin or HLL, we can better understand mechanisms for the blood pressure lowering effect of hemin therapy. Application of this heme monitoring technology will also pave the way for clinical application of hemin therapy in treatment of different types of hypertension pathologies.
Cell Mol Biol (Noisy-le-grand) 2005 Oct 03
PMID:Monitoring circulatory heme level in hemin therapy for lowering blood pressure in rats. 1630 73

Acute respiratory distress syndrome (ARDS) is a devastating disease process characterized by severe acute lung injury, inflammatory cell recruitment to the lung, upregulation of pro-inflammatory cytokines and increased oxidative stress. Epithelial cell injury, diffuse alveolar damage and surfactant dysfunction ensue leading to refractory hypoxemic respiratory failure. There are no specific effective therapies for ARDS and novel therapeutic approaches are desperately needed. In this study we assessed the role of the cytoprotective and anti-inflammatory enzyme heme oxygenase (HO)-1 in a model of nebulized endotoxin-induced acute lung injury. HO-1 null (HO-1(-/-)) mice exhibited severe physiologic lung dysfunction following lipopolysaccharide (LPS) nebulization, but had similar inflammatory responses as wild-type (WT) mice. However, a dramatic reduction in surfactant protein-B (SP-B) expression was observed in the lungs of LPS-treated HO-1(-/-) mice compared with similarly treated WT mice. Using reciprocal bone marrow transplantation (BMT) to generate HO-1-chimeric mice, we found that absence of HO-1 in the lung parenchyma, not in bone marrow-derived inflammatory cells, was responsible for enhanced SP-B downregulation and severe physiologic lung dysfunction. These findings have implications for our understanding of the pathophysiology of ARDS and may guide future therapeutic strategies.
Cell Mol Biol (Noisy-le-grand) 2005 Oct 03
PMID:Absence of heme oxygenase-1 expression in the lung parenchyma exacerbates endotoxin-induced acute lung injury and decreases surfactant protein-B levels. 1630 74

Transforming growth factor-beta (TGF-beta) is implicated in a variety of kidney diseases where it promotes extracellular matrix (ECM) deposition and pro-inflammatory events, but it also stabilizes and attenuates tissue injury through the activation of cytoprotective proteins, including heme oxygenase-1 (HO-1). HO-1 catalyzes the conversion of heme into carbon monoxide (CO), iron, and biliverdin, which is subsequently converted to bilirubin. The beneficial effects of HO-1 induction include decreasing pro-oxidants (heme), increasing anti-oxidants (biliverdin and bilirubin), and producing a vasodilator with anti-apoptotic and anti-inflammatory properties (CO). The reaction products of HO-1 may also have antifibrogenic properties. The purpose of this study is to explore the effects of HO-1 expression and its reaction products on fibronectin, an ECM protein, in the kidney. The results demonstrate that kidneys of HO-1 knockout mice express significantly more fibronectin protein as compared to heterozygote mice. A potent inducer of HO-1, hemin, significantly decreases fibronectin protein with a concomitant increase in HO-1 protein. Cells expressing HO-1, via TGF-beta1 induction, have reduced fibronectin expression. Bilirubin, a product of the heme oxygenase reaction, attenuates TGF-beta1-mediated increases in fibronectin expression. These results indicate that HO-1 induction and activity may modulate the production of ECM components and suggest a potential role for TGF-beta-mediated HO-1 induction in attenuating renal fibrosis.
Cell Mol Biol (Noisy-le-grand) 2005 Sep 30
PMID:Induction of heme oxygenase-1 modulates the profibrotic effects of transforming growth factor-beta in human renal tubular epithelial cells. 1630 85

Hyperglycemia represents the main cause of complication of diabetes mellitus and oxidative stress, resulting from increased generation of reactive oxygen species (ROS), and plays a crucial role in their pathogenesis. Impairment of vascular responses in diabetic rats, as a result of an increase in superoxide (O2-), formation is a major complication in diabetes. Since heme oxygenase (HO) expression regulates the level of ROS by increasing antioxidant, such as glutathione and bilirubin, we investigated whether upregulation of HO-1 modulates the levels of iNOS and eNOS and altered vascular responses to phenylephrine (PE) and acetylcholine (Ach) in aorta and femoral arteries of diabetic (streptozotocin (STZ)-induced) rats. Our results showed that iNOS expression was increased, but HO activity was reduced, in diabetic compared to nondiabetic rats (p<0.05). Upregulation of HO-1 expression by cobalt protoporphyrin (CoPP), an inducer of HO-1 protein and activity, conferred an increase in eNOS and differentially decreased iNOS protein levels (p<0.05). Isolated aortic and femoral arteries obtained from diabetic rats exhibited contraction to PE and relaxation to Ach, which were markedly increased and decreased, respectively. However, HO-1 induction in diabetic rats normalized relaxation compared to controls. Therefore, overexpression of HO-1 may mediate an increase in eNOS and a decrease in iNOS, potentially contributing to restoration of vascular responses in diabetic rats.
Cell Mol Biol (Noisy-le-grand) 2005 Sep 30
PMID:Heme oxygenase-1 gene expression increases vascular relaxation and decreases inducible nitric oxide synthase in diabetic rats. 1630 87


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