Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.14.99.3 (heme oxygenase)
 4,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Keap1-Nrf2-ARE signalling pathway has emerged as an important regulator of the mammalian defence system to enable detoxification and clearance of foreign chemicals. Recent studies by our group using paracetamol (APAP), diethylmaleate and buthionine sulphoximine have shown that for a given xenobiotic molecule, Nrf2 induction in the murine liver is associated with protein reactivity and glutathione depletion. Here, we have investigated, in vivo, whether the ability of four murine hepatotoxins, paracetamol, bromobenzene (BB), carbon tetrachloride (CCl4) and furosemide (FS) to deplete hepatic glutathione (GSH) is related to induction of hepatic Nrf2 nuclear translocation and Nrf2-dependent gene expression. Additionally, we studied whether hepatic Nrf2 nuclear translocation is a general response during the early stages of acute hepatic chemical stress in vivo. Male CD-1 mice were administered APAP (3.5 mmol/kg), FS (1.21 mmol/kg), BB (4.8 mmol/kg) and CCl4 (1 mmol/kg) for 1, 5 and 24h. Each compound elicited significant serum ALT increases after 24h (ALT U/L: APAP, 3036+/-1462; BB, 5308+/-2210; CCl4, 5089+/-1665; FS, 2301+/-1053), accompanied by centrilobular damage as assessed by histopathology. Treatment with APAP also elicited toxicity at a much earlier time point (5h) than the other hepatotoxins (ALT U/L: APAP, 1780+/-661; BB, 161+/-15; CCl4, 90+/-23; FS, 136+/-27). Significant GSH depletion was seen with APAP (9.6+/-1.7% of control levels) and BB (52.8+/-6.2% of control levels) 1h after administration, but not with FS and CCl4. Western Blot analysis revealed an increase in nuclear Nrf2, 1h after administration of BB (209+/-10% control), CCl4 (146+/-3% control) and FS (254+/-41% control), however this was significantly lower than the levels observed in the APAP-treated mice (462+/-36% control). The levels of Nrf2-dependent gene induction were also analysed by quantitative real-time PCR and Western blotting. Treatment with APAP for 1h caused a significant increase in the levels of haem oxygenase-1 (HO-1; 2.85-fold) and glutamate cysteine ligase (GCLC; 1.62-fold) mRNA. BB and FS did not affect the mRNA levels of either gene after 1h of treatment; however CCl4 significantly increased HO-1 mRNA at this time point. After 24h treatment with the hepatotoxins, there was evidence for the initiation of a late defence response. BB significantly increased both HO-1 and GCLC protein at this time point, CCl4 increased GCLC protein alone, although FS did not alter either of these proteins. In summary, we have demonstrated that the hepatotoxins BB, CCl4 and FS can induce a small but significant increase in Nrf2 accumulation in hepatic nuclei. However, this was associated with modest changes in hepatic GSH, a delayed development of toxicity and was insufficient to activate an early functional adaptive response to these hepatotoxins.
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PMID:Investigation of the effect of a panel of model hepatotoxins on the Nrf2-Keap1 defence response pathway in CD-1 mice. 1807 5

The constitutive isoform of heme oxygenase, HO-2, is highly expressed in the brain and in cerebral vessels. HO-2 functions in the brain have been evaluated using pharmacological inhibitors of the enzyme and HO-2 gene deletion in in vivo animal models and in cultured cells (neurons, astrocytes, cerebral vascular endothelial cells). Rapid activation of HO-2 via post-translational modifications without upregulation of HO-2 expression or HO-1 induction coincides with the increase in cerebral blood flow aimed at maintaining brain homeostasis and neuronal survival during seizures, hypoxia, and hypotension. Pharmacological inhibition or gene deletion of brain HO-2 exacerbates oxidative stress induced by seizures, glutamate, and inflammatory cytokines, and causes cerebral vascular injury. Carbon monoxide (CO) and bilirubin, the end products of HO-catalyzed heme degradation, have distinct cytoprotective functions. CO, by binding to a heme prosthetic group, regulates the key components of cell signaling, including BK(Ca) channels, guanylyl cyclase, NADPH oxidase, and the mitochondria respiratory chain. Cerebral vasodilator effects of CO are mediated via activation of BK(Ca) channels and guanylyl cyclase. CO, by inhibiting the major components of endogenous oxidant-generating machinery, NADPH oxidase and the cytochrome C oxidase of the mitochondrial respiratory chain, blocks formation of reactive oxygen species. Bilirubin, via redox cycling with biliverdin, is a potent oxidant scavenger that removes preformed oxidants. Overall, HO-2 has dual housekeeping cerebroprotective functions by maintaining autoregulation of cerebral blood flow aimed at improving neuronal survival in a changing environment, and by providing an effective defense mechanism that blocks oxidant formation and prevents cell death caused by oxidative stress.
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PMID:Cerebroprotective functions of HO-2. 1828 71

Endothelial dysfunction underlies cardiovascular disease (CVD) in humans and is reported in animal models of developmental origins of such disease. We have investigated whether impaired antioxidant defences and NO generation underlie the genesis of endothelial dysfunction and operate as part of the normal processes of developmental plasticity regulating the induction of phenotype in the offspring. Female Wistar rats were fed either a control (C, 18% protein) or protein-restricted (PR, 9% protein) diet throughout pregnancy. Dams and pups were returned to standard laboratory chow post partum. In male offspring, PR resulted in a reduced endothelial responsiveness to acetylcholine (P < 0.05) in resistance arteries, with vascular remodelling evident from a reduction in smooth muscle content. mRNA expression of endothelial NO synthase (eNOS) was increased (P < 0.05) but there was no change in mRNA levels of manganese superoxide dismutase (MnSOD) or glutamate cysteine ligase (GCL) expression. Interestingly, expression of the antioxidant enzyme haem oxygenase-1 (HO-1) was reduced in the liver (P < 0.05). Female PR offspring also showed a reduced endothelial responsiveness but exhibited no changes in expression of eNOS, iNOS, soluble guanylate cyclase (sGC) or antioxidant genes. Thus, in this model of the developmental origins of CVD, the structure and function of resistance arteries in offspring is altered in complex ways which cannot simply be explained by attenuation in vascular eNOS or in antioxidant protection afforded by GCL or MnSOD. The dysfunction in male offspring may partially be counteracted by an up-regulation of eNOS expression; however, PR does lead to reduced HO-1 expression in these offspring, which may affect both their growth and vascular function. Our findings have established that PR induces significant phenotypic changes in male offspring that may be indicative of an adaptive response during development.
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PMID:Endothelial dysfunction and reduced antioxidant protection in an animal model of the developmental origins of cardiovascular disease. 1882 46

Cudratricusxantone A (CTXA), isolated from the roots of Cudrania tricuspidata Bureau (Moraceae), has potent hepatoprotective, antiproliferative, and monoamine oxidase inhibitory effects. In this study, we examined whether CTXA could protect HT22-immortalized hippocampal cells against glutamate-induced oxidative stress through the induction of heme oxygenase (HO)-1 expression. CTXA induced the expression of HO-1 and increased HO activity dose- and time-dependently. CTXA also suppressed glutamate-induced ROS generation in HT22 cells. Interestingly, treatment of neuronal cells with CTXA enhanced cellular resistance to glutamate oxidative stress. The protective effect of CTXA was abrogated by tin protoporphyrin IX, an HO inhibitor. In addition, treatment with the HO-1 inducer, cobalt protoporphyrin IX, and bilirubin, one of the enzymatic products of HO-1, produced comparable protection. These results demonstrate that CTXA protects neuronal cells from glutamate-induced oxidative stress via the induction of HO-1.
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PMID:Cudratricusxanthone A protects mouse hippocampal cells against glutamate-induced neurotoxicity via the induction of heme oxygenase-1. 1868 28

Lavandulyl flavanones of Sophora flavescens roots are anti-malarial, anti-inflammatory, and cytotoxic. Here, we examined whether four lavandulyl flavanones, (2S)-2'-methoxykurarinone (1), sophoraflavanone G (2), leachianone A (3), and (-)-kurarinone (4), isolated from S. flavescens could protect HT22 immortalized hippocampal cells against glutamate-induced oxidative stress. Compounds 1 and 2 induced the expression of heme oxygenase (HO)-1 and increased HO activity dose- and time-dependently. These two compounds also suppressed glutamate-induced reactive oxygen species generation in HT22 cells, whereas compounds 3 and 4 were not protective. These two lavandulyl flavanones (compounds 1, 2) may protect against glutamate-induced neurotoxicity via HO-1 induction.
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PMID:Lavandulyl flavanones from Sophora flavescens protect mouse hippocampal cells against glutamate-induced neurotoxicity via the induction of heme oxygenase-1. 1882 64

The bioassay-guided fractionation of a MeOH extract of the heartwood of Caesalpinia sappan L. provided two neuroprotective compounds, sappanchalcone (2) and 4-O-methylepisappanol (3), together with a methoxychalcone, isoliquiritigenin 2'-methyl ether (1), and three aromatic compounds, 4-O-methylsappanol (4), caesalpine J (5), pluchoic acid (6). At concentrations of 20-40 microM, compound 2 showed significant cytoprotective effects against glutamate-induced oxidative stress through the induction of heme oxygenase (HO)-1 in HT22-immortalized hippocampal cells. Compound 3 also showed moderate neuroprotective effect at 40 microM, but compounds 1, 4-6 did not show any protective effects against glutamate-induced cytotoxicity in HT22 cells.
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PMID:Cytoprotective constituents of the heartwood of Caesalpinia sappan on glutamate-induced oxidative damage in HT22 cells. 1942 Jul 70

Oxidative injury contributes to neuronal degeneration in many central nervous system (CNS) diseases, such as Parkinson's disease, Alzheimer's disease, epilepsy and ischemia. Inducible heme oxygenase (HO)-1 acts against oxidants that are thought to play a role in the pathogenesis of these diseases. Lindenenyl acetate, isolated by bioassay-guided fractionation of the MeOH extract of the roots of Lindera strychnifolia, showed potent neuroprotective effects on glutamate-induced neurotoxicity by inducing the expression of HO-1 and increasing the activity of HO in mouse hippocampal HT22 cells. Furthermore, lindenenyl acetate caused the nuclear accumulation of nuclear factor-E2-related factor 2 (Nrf2) and increased the promoter activity of antioxidant response elements (ARE) in mouse hippocampal HT22 cells. In addition, we found that treatment of the cells with extracellular signal-regulated kinase (ERK) inhibitor (U0126) reduced lindenenyl acetate-induced HO-1 expression. Lindenenyl acetate also increased ERK phosphorylation. These results suggest that lindenenyl acetate increases cellular resistance to glutamate-induced oxidative injury in mouse hippocampal HT22 cells, presumably through the ERK pathway-Nrf2/ARE-dependent HO-1 expression.
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PMID:Cytoprotective effects of lindenenyl acetate isolated from Lindera strychnifolia on mouse hippocampal HT22 cells. 1944 2

Glutamate is the principal cerebral excitatory neurotransmitter and dilates cerebral arterioles to match blood flow to neural activity. Arterial contractility is regulated by local and global Ca(2+) signals that occur in smooth muscle cells, but modulation of these signals by glutamate is poorly understood. Here, using high-speed confocal imaging, we measured the Ca(2+) signals that occur in arteriole smooth muscle cells of newborn piglet tangential brain slices, studied signal regulation by glutamate, and investigated the physiological function of heme oxygenase (HO) and carbon monoxide (CO) in these responses. Glutamate elevated Ca(2+) spark frequency by approximately 188% and reduced global intracellular Ca(2+) concentration ([Ca(2+)](i)) to approximately 76% of control but did not alter Ca(2+) wave frequency in brain arteriole smooth muscle cells. Isolation of cerebral arterioles from brain slices abolished glutamate-induced Ca(2+) signal modulation. In slices treated with l-2-alpha-aminoadipic acid, a glial toxin, glutamate did not alter Ca(2+) sparks or global [Ca(2+)](i) but did activate Ca(2+) waves. This shift in Ca(2+) signal modulation by glutamate did not occur in slices treated with d-2-alpha-aminoadipic acid, an inactive isomer of l-2-alpha-aminoadipic acid. In the presence of chromium mesoporphyrin, a HO blocker, glutamate inhibited Ca(2+) sparks and Ca(2+) waves and did not alter global [Ca(2+)](i). In isolated arterioles, CORM-3 [tricarbonylchloro(glycinato)ruthenium(II)], a CO donor, activated Ca(2+) sparks and reduced global [Ca(2+)](i). These effects were blocked by 1H-(1,2,4)-oxadiazolo-(4,3-a)-quinoxalin-1-one, a soluble guanylyl cyclase inhibitor. Collectively, these data indicate that glutamate can modulate Ca(2+) sparks, Ca(2+) waves, and global [Ca(2+)](i) in arteriole smooth muscle cells via mechanisms that require astrocytes and HO. These data also indicate that soluble guanylyl cyclase is involved in CO activation of Ca(2+) sparks in arteriole smooth muscle cells.
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PMID:Glutamate regulates Ca2+ signals in smooth muscle cells of newborn piglet brain slice arterioles through astrocyte- and heme oxygenase-dependent mechanisms. 1996 53

Glutamate-induced oxidative injury causes neuronal degeneration related to many central nervous system diseases, such as Parkinson's disease, Alzheimer's disease, epilepsy and ischemia. The bioassay-guided fractionation of the EtOH extract of the root bark of Dictamnus dasycarpus Trucz. provided one neuroprotective limonoid, obacunone, together with a degraded limonoid, fraxinellone and two alkaloids, dictamine and haplopine. At concentrations of 100-150 microM, obacunone showed the potent neuroprotective effects on glutamateinduced neurotoxicity and induced the expression of heme oxygenase (HO)-1 in the mouse hippocampal HT22 cells. In addition, we found that obacunone increased p38 MAPK phosphorylation and induced HO-1 expression via p38 MAPK pathway. These results suggest that obacunone isolated from the root bark of D. dasycarpus increases cellular resistance to glutamate-induced oxidative injury in mouse hippocampal HT22 cells, presumably through the p38 MAPK pathway-dependent HO-1 expression. These results suggest that obacunone could be the effective candidates for the treatment of ROS-related neurological diseases.
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PMID:Neuroprotective effects of constituents of the root bark of Dictamnus dasycarpus in mouse hippocampal cells. 2080 31

Threohydroxyaspartate (THA) causes glutamate excitotoxicity in motor neurons in organotypic culture of rat spinal cord. Some drugs, including sulforaphane (SF) and riluzole, can protect motor neuron against excitotoxicity. It has been demonstrated that SF is a potent inducer of Phase II enzymes, while riluzole is a classic anti-glutamate agent. The objective of the current study is to investigate whether the combination of SF and riluzole is superior to either one used alone. In our study, the combination of SF with riluzole not only stimulates the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), reduced nicotinamide adenine dinucleotide phosphate (NADPH): quinone oxidoreductase 1 (NQO1) and heme oxygenase 1 (HO-1), but also reduces the extracellular accumulation of glutamate. When used at optimal doses, SF (10 microM) and riluzole (5 microM), either alone or in combination, all exert significant and similar neuroprotection, as measured by the number of motor neuron, medium malondialdehyde (MDA) level and lactate dehydrogenase (LDH) level. When used at low doses, the combination is better than each agent used alone. In conclusion, these results suggest the potential utility of combination use of SF and riluzole for protection of motor neuron against excitotoxicity.
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PMID:Protective effect of combination of sulforaphane and riluzole on glutamate-mediated excitotoxicity. 2082 60


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