Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
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

Epidemiological evidence indicates several health benefits of the consumption of broccoli, especially related to chemoprevention. Because broccoli contains high amounts of selenium and glucosinolates (particularly glucoraphanin and isothiocyanate sulforaphane), which can produce redox-regulated cardioprotective protein thioredoxin (Trx), it was reasoned that consumption of broccoli could be beneficial to the heart. To test this hypothesis, a group of rats were fed broccoli (slurry made with water) through gavaging; control animals were gavaged water only. After 30 days, the rats were sacrificed; isolated hearts perfused via working mode were made ischemic for 30 min followed by 2 h of reperfusion. The results demonstrated significant cardioprotection with broccoli as evidenced by improved postischemic ventricular function, reduced myocardial infarct size, and decreased cardiomyocyte apoptosis accompanied by reduced cytochrome c release and increased pro-caspase 3 activities. Ischemia/reperfusion reduced both RNA transcripts and protein levels of the thioredoxin superfamily including Trx1, Trx2, glutaredoxin Grx1, Grx2, and peroxiredoxin (Prdx), which were either restored or enhanced with broccoli. Broccoli enhanced the expression of Nrf2, a cytosolic suppressor of Keap1, suggesting a role of antioxidant response element (ARE) in the induction of Trx. Additionally, broccoli induced the expression of another cardioprotective protein, heme oxygenase (HO)-1, which could be transactivated during the activation of Trx. Examination of the survival signal revealed that broccoli caused the phosphorylation of Akt and the induction of Bcl2 in concert with the activation of redox-sensitive transcription factor NF kappa B and Src kinase, indicating a role of Akt, Bcl2, and cSrc in the generation of survival signal. Taken together, the results of the present study indicate that the consumption of broccoli triggers cardioprotection by generating a survival signal through the activation of several survival proteins and by redox cycling of thioredoxins.
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PMID:Broccoli: a unique vegetable that protects mammalian hearts through the redox cycling of the thioredoxin superfamily. 2241 31

The products of vitagenes such as heat shock protein 32 (Hsp32, heme oxygenase 1) and Hsp70, the family of inducible cytoprotective proteins regulated by the Keap1/Nrf2/ARE pathway, and small molecule antioxidants such as glutathione provide the cell with powerful means to counteract and survive various conditions of stress. Among these protective systems, the heat shock proteins represent a highly conserved and robust way for preservation of correct protein conformation, recovery of damaged proteins, and cell survival. Their regulation is dependent on the redox status of the cell, thus redox regulation is rapidly evolving as an important metabolic modulator of cellular functions, and is being increasingly implicated in many chronic inflammatory and degenerative diseases. Protein thiols play a key role in redox sensing, and regulation of cellular redox state is crucial mediator of multiple metabolic, signalling and transcriptional processes in the brain. Nitric oxide, and reactive nitrogen species induce the transcription of vitagenes and Keap1/Nrf2/ARE-dependent genes whose functional products protect against a wide array of subsequent challenges. Emerging interest is now focusing on exogenous small molecules that are capable of activating these systems as a novel target to minimize deleterious consequences associated with free radical-induced cell damage, such as during neurodegeneration. This chapter describes methods that can be used to assess the expression of heat shock proteins and the cellular glutathione redox status and discusses their relevance to mechanisms modulating the onset and progression of neurodegenerative diseases.
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PMID:Practical approaches to investigate redox regulation of heat shock protein expression and intracellular glutathione redox state. 1855 31

The Nrf2/anti-oxidant response element (ARE) pathway plays an important role in regulating cellular anti-oxidants, including haem oxygenase-1 (HO-1). Various kinases have been implicated in the pathways leading to Nrf2 activation. Here, we investigated the effect of epigallocatechin (EGC) on ARE-mediated gene expression in human monocytic cells. EGC time and dose dependently increased HO-1 mRNA and protein expression but had minimal effect on expression of other ARE-regulated genes, including NAD(P)H:quinone oxidoreductase 1, glutathione cysteine ligase and ferritin. siRNA knock down of Nrf2 significantly inhibited EGC-induced HO-1 expression. Furthermore, inhibition of PKC by Ro-31-8220 dose dependently decreased EGC-induced HO-1 mRNA expression, whereas MAP kinase and phosphatidylinositol-3-kinase pathway inhibitors had no significant effect. EGC stimulated phosphorylation of PKCalphabeta and delta in THP-1 cells. PKCdelta inhibition significantly decreased EGC-induced HO-1 mRNA expression, whereas PKCalpha- and beta-specific inhibitors had no significant effect. These results demonstrate for the first time that EGC-induced HO-1 expression occurs via PKCdelta and Nrf2.
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PMID:Epigallocatechin activates haem oxygenase-1 expression via protein kinase Cdelta and Nrf2. 1858 7

Disturbance of the microcirculation and generation of reactive oxygen species are crucial in producing acute gastric mucosal lesions (AGML). To understand the protective mechanism against mucosal injury and oxidative stress in the stomach, we investigated sequential expression and localization of a product of lipid peroxidation and a chemical mediator of the oxidative response array, 4-hydroxynonenal (HNE), transcriptional factor, NF-E2-related factor (Nrf2), and the inducible heme oxygenase (HO-1) in the injured stomach. AGML was produced by intragastric administration of 0.6 N HCl in male rats. Expression and localization of HNE, Nrf2, and HO-1 were investigated by Western blotting, immunohistochemistry, real-time RT-PCR, and in situ hybridization histochemistry. Mucosal lesions and expression of HNE and HO-1 were assessed by prior treatment with the PGI2 analog beraprast or after sensory denervation by pretreatment with capsaicin. Mucosal lesions were assessed by prior treatment with a HO-1 inhibitor, zinc protoporphyrin (ZnPP). After AGML, increased generation of HNE was observed in the injured mucosa and the surrounding submucosa, followed by nuclear translocation of Nrf2 and upregulation of HO-1 in the macrophages located in the margin of the injured mucosa and in the submucosa. Pretreatment with beraprost attenuated AGML and downregulated the expression of HNE and HO-1, while sensory denervation aggravated AGML and upregulated the expression of HNE and HO-1. Pretreatment with ZnPP also aggravated AGML. The sequential HNE-Nrf2-HO-1 pathway in the gastric mucosal cells and the macrophages is involved in an adaptive mechanism against oxidative stress after AGML.
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PMID:Adaptive HNE-Nrf2-HO-1 pathway against oxidative stress is associated with acute gastric mucosal lesions. 1861 59

Our previous study showed that a methanol extract of Inula helenium had the potential to induce detoxifying enzymes such as quinone reductase (QR) and glutathione S-transferase (GST) activity. In this study the methanol extract was further fractionated using silica gel chromatography and vacuum liquid chromatography, to yield pure compounds alantolactone and isoalantolactone as QR inducers. Alantolactone caused a dose-dependent induction of antioxidant enzymes including QR, GST, gamma-glutamylcysteine synthase, glutathione reductase, and heme oxygenase 1 in hepa1c1c7 mouse hepatoma cells. The compound increased the luciferase activity of HepG2-C8 cells, transfectants carrying antioxidant response element (ARE)-luciferase gene, in a dose-dependent manner, suggesting ARE-mediated transcriptional activation of antioxidant enzymes. Alantolactone also stimulated the nuclear accumulation of Nrf2 that was inhibited by phosphatidylinositol 3-kinase (PI3K) inhibitors. In conclusion, alantolactone appears to induce detoxifying enzymes via activation of PI3K and JNK signaling pathways, leading to translocation of Nrf2, and subsequent interaction between Nrf2 and ARE in the encoding genes.
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PMID:Nrf2-mediated induction of detoxifying enzymes by alantolactone present in Inula helenium. 1870 92

Nitric oxide (NO) produced by inducible NO synthase (iNOS) during infection plays a crucial role in host defense mechanisms, via its antimicrobial and cytoprotective activities. Infection of Salmonella typhimurium in mice induces excessive production of NO, as a host defense response. We found much greater bacterial growth and apoptotic changes in iNOS-deficient (iNOS-/-) mice than in wild-type mice. However, the mechanism of NO-mediated cytoprotection during Salmonella infection remained unclear. An important signaling mechanism induced by NO is heme oxygenase (HO)-1, a significant cytoprotective molecule produced by oxidative stress. Thus, we sought to clarify NO-dependent cytoprotective and antimicrobial host defense, with a particular focus on the signaling mechanism of HO-1 induction. We recently discovered a nitrated cyclic nucleotide, 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP), which is formed via NO possibly with reactive oxygen species. We observed strong immunoreactivity for 8-nitro-cGMP in Salmonella-infected wild-type mouse liver and peritoneal macrophages in culture but not in iNOS-/- mouse liver and macrophages. Moreover, a higher apoptosis was observed in iNOS-/- macrophages compared with wild-type macrophages after Salmonella infection, but the difference was nullified when iNOS-/- cells were treated with 8-nitro-cGMP. Finally, authentic 8-nitro-cGMP induced HO-1 in cultured macrophages infected with Salmonella. The signaling function of 8-nitro-cGMP appears to be mediated by its unique reaction with the sulfhydryl group of cysteine, thus forming a proteinS-cGMP adduct, which is an important mechanism of post-translational modification of proteins called protein S-guanylation. More importantly, we found 8-nitro-cGMP-dependent S-guanylation of Keap1, a regulatory protein of transcription factor Nrf2, which regulates the transcription of HO-1. In this review, we focus on a unique mechanism of NO-mediated host defense via formation of a novel signaling molecule, 8-nitro-cGMP in microbial infections.
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PMID:[New paradigm of host defense against intracellular pathogens by nitric oxide]. 1922 48

Ebselen, an organoselenium compound that acts as a glutathione peroxidase mimetic, has been demonstrated to possess antioxidant and anti-inflammatory activities. However, the molecular mechanism underlying this effect is not fully understood in auditory cells. The purpose of the present study is to investigate the protective effect of ebselen against cisplatin-induced toxicity in HEI-OC1 auditory cells, organotypic cultures of cochlear explants from two-day postnatal rats (P(2)) and adult Balb/C mice. Pretreatment with ebselen ameliorated apoptotic death induced by cisplatin in HEI-OC1 cells and organotypic cultures of Corti's organ. Ebselen pretreatment also significantly suppressed cisplatin-induced increases in intracellular reactive oxygen species (ROS), intracellular reactive nitrogen species (RNS) and lipid peroxidation levels. Ebselen dose-dependently increased the expression level of an antioxidant response element (ARE)-luciferase reporter in HEI-OC1 cells through the translocation of Nrf2 into the nucleus. Furthermore, we found that pretreatment with ebselen significantly restored Nrf2 function, whereas it ameliorated the cytotoxicity of cisplatin in cells transfectants with either a pcDNA3.1 (control) or a DN-Nrf2 (dominant-negative) plasmid. We also observed that Nrf2 activation by ebselen increased the expression of phase II antioxidant genes, including heme oxygenase (HO-1), NAD(P)H:quinine oxidoreductase, and gamma-glutamylcysteine synthetase (gamma-GCS). Treatment with ebselen resulted in an increased expression of HO-1 and intranuclear Nrf2 in hair cells of organotypic cultured cochlea. After intraperitoneal injection with cisplatin, auditory brainstem responses (ABRs) threshold was measured on 8th day in Balb/C mice. ABR threshold shift was marked occurred in mice injected with cisplatin (16 mg/kg, n=5; Click and 8-kHz stimuli, p<0.05; 4, 16 and 32 kHz, p<0.01), whereas that of animal group which was treated with cisplatin and ebselen was not significantly changed. These results suggest that ebselen activates the Nrf2-ARE signaling pathway, which ultimately prevents free radical stresses from cisplatin and further contributes to protect auditory sensory hair cells from free radicals produced by cisplatin.
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PMID:Ebselen attenuates cisplatin-induced ROS generation through Nrf2 activation in auditory cells. 1928 52

Here we have assessed the effects of extracellular matrix (ECM) composition and rigidity on mechanical properties of the human airway smooth muscle (ASM) cell. Cell stiffness and contractile stress showed appreciable changes from the most relaxed state to the most contracted state: we refer to the maximal range of these changes as the cell contractile scope. The contractile scope was least when the cell was adherent upon collagen V, followed by collagen IV, laminin, and collagen I, and greatest for fibronectin. Regardless of ECM composition, upon adherence to increasingly rigid substrates, the ASM cell positively regulated expression of antioxidant genes in the glutathione pathway and heme oxygenase, and disruption of a redox-sensitive transcription factor, nuclear erythroid 2 p45-related factor (Nrf2), culminated in greater contractile scope. These findings provide biophysical evidence that ECM differentially modulates muscle contractility and, for the first time, demonstrate a link between muscle contractility and Nrf2-directed responses.
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PMID:Cell stiffness, contractile stress and the role of extracellular matrix. 1932 44

High mobility group box-1 protein (HMGB1), primarily from the nucleus, is released into the extracellular milieu either passively from necrotic cells or actively through secretion by monocytes/macrophages. Extracellular HMGB1 acts as a potent inflammatory agent by promoting the release of cytokines such as tumor necrosis factor (TNF)-alpha, has procoagulant activity, and is involved in death due to sepsis. Accordingly, HMGB1 is an appropriate therapeutic target. In this study, we found that an extract of Prunus mume Sieb. et Zucc. (Ume) fruit (Ume extract), an abundant source of triterpenoids, strongly inhibited HMGB1 release from lipopolysaccharide (LPS)-stimulated macrophage-like RAW264.7 cells. The inhibitory effect on HMGB1 release was enhanced by authentic oleanolic acid (OA), a naturally occurring triterpenoid. Similarly, the HMGB1 release inhibitor in Ume extract was found to be OA. Regarding the mechanisms of the inhibition of HMGB1 release, the OA or Ume extract was found to activate the transcription factor Nrf2, which binds to the antioxidative responsive element, and subsequently the heme oxygenase (HO)-1 protein was induced, indicating that the inhibition of HMGB1 release from LPS-stimulated RAW264.7 cells was mediated via the Nrf2/HO-1 system; an essentially antioxidant effect. These results suggested that natural sources of triterpenoids warrant further evaluation as 'rescue' therapeutics for sepsis and other potentially fatal systemic inflammatory disorders.
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PMID:Mechanism of HMGB1 release inhibition from RAW264.7 cells by oleanolic acid in Prunus mume Sieb. et Zucc. 1936 Mar 20


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