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)

NADPH-cytochrome P450 oxidoreductase (CYPOR), a flavoprotein localized in the nuclear envelope and endoplasmic reticulum of most cell types, is responsible for transferring electrons from NADPH to the cytochromes P450 as well as heme oxygenase, squalene epoxidase, and cytochrome b(5). CYPOR is encoded by a single gene and, similar to many housekeeping genes, has a TATA-less, GC-rich promoter with multiple Sp1 consensus sites. The current work has delineated the importance of multiple cis-acting elements contained within the proximal promoter for basal expression of the CYPOR gene. Transcription factor binding sites within this region included two upstream Sp1 motifs, a SEC element containing overlapping Sp1/Egr-1/CACCC box motifs, and a novel site designated the OxidoReductase Upstream element (ORU). Mutational modification of the ORU element, leading to a loss of protein binding, resulted in an approximately 90% decrease in transcriptional activity in H4IIE cells. Similarly, inactivation of the Egr-1/CACCC segment of the SEC element dramatically reduced promoter activity to less than 10% of wild-type, while mutagenesis of the contiguous Sp1 site did not affect basal transcription. Although both Sp1 sites contained within the minimal promoter were required for optimal expression in H4IIE cells, loss of these sites was compensated for by those Sp1 motifs located upstream of position 206, suggesting that Sp1 was acting as a position-independent enhancer. Hence, the CYPOR promoter was distinguished from the majority of TATA-less promoters in that Sp1 was not a primary transcriptional regulator and by the fact that the Sp1 binding site closest to the transcription start site was nonfunctional. Furthermore, both the SEC and ORU elements were essential for basal expression; however, the ORU element exhibited cell-specific differences in regulatory activity. Thus, several mechanisms appear to be in place to selectively alter the expression of the CYPOR gene.
 ...
PMID:Molecular basis for cell-specific regulation of the NADPH-cytochrome P450 oxidoreductase gene. 1086 47

Transcription factor HIF-1 is a key determinant of oxygen-dependent gene regulation. Suppression of HIF-1alpha is important for exploring HIF-1-dependent processes and for interfering with hypoxia-induced pathophysiological events. This study applied RNA-interference targeting HIF-1alpha to the human lung A549 cell line. Transfection of HIF-1alpha-siRNA reduced HIF-1alpha synthesis as measured on mRNA and protein level by realtime RT-PCR, Western blot, and immuncytochemistry. A time kinetic for hypoxic stabilization of HIF-1alpha protein and its inhibition by HIF-1alpha-siRNA is included. Hypoxic induction of HIF-1-controlled target genes as heme oxygenase I (HO-1), phosphoglycerate kinase (PGK), and vascular endothelial growth factor (VEGF) was markedly attenuated by HIF-1alpha-siRNA treatment. Correspondingly, gene activation via hypoxia-responsive-element, as shown by reporter gene assay, was inhibited by HIF-1alpha-siRNA. Moreover, this approach was found to suppress the shift from from S-phase to G1-phase observed in A549 cells in response to hypoxia, supporting a role of HIF-1alpha in oxygen-dependent cell cycle regulation.
 ...
PMID:RNA interference for HIF-1alpha inhibits its downstream signalling and affects cellular proliferation. 1468 Aug 3

Intraocular neovascularization is the leading cause of severe visual loss and anti-vascular endothelial growth factor (VEGF) therapy is currently performed for choroidal neovascularization (CNV). Despite its potent anti-angiogenic effect, there are concerns about its long-term safety. Non-steroidal anti-inflammatory drugs (NSAIDs) are common therapeutic agents used for treating inflammatory diseases, and their anti-stress effects are attracting attention now. We studied the effects of topical NSAIDs on CNV, focusing on anti-stress proteins. Cultured retinal pigment epithelium (RPE) cells were treated with NSAIDs: bromfenac, indomethacin, or vehicle control. Transcription factor NF-E2-related factor 2 (Nrf2) and its downstream anti-oxidant protein heme oxygenase (HO)-1 were assessed using western blot and immunohistochemistry. As a result, NSAIDs induced translocation of Nrf2 into the nucleus and the robust expression of HO-1 in a dose- and time-dependent manner. Flow cytometric analysis revealed that bromfenac inhibited H(2)O(2)-induced apoptosis in cultured RPE cells. Next, we studied the effects of topical bromfenac on laser-induced CNV model in rat. The expressions of Nrf2 and HO-1, infiltrations of ED-1-positive macrophages at CNV lesions and size were analyzed. VEGF in the ocular fluid of these rats was also measured using enzyme-linked immunosorbent assay. Rats administered an inhibitor of HO-1 stannic mesoporphyrin (SnMP) were also studied. The results showed that topical bromfenac led to translocation of Nrf2 and induction of HO-1 in CNV lesions and that the number of infiltrating macrophages at the CNV lesion decreased. The sizes of CNV lesions were significantly smaller in bromfenac-treated rats than control CNV, and the effects were diminished by SnMP. VEGF increased in the ocular fluid after laser treatment and was inhibited by bromfenac and SnMP canceling these effects. NSAIDs inhibit CNV through the novel anti-stress protein HO-1-dependent pathway, indicating its potential therapeutic value for various intraocular angiogenic diseases including CNV.
 ...
PMID:NSAIDs inhibit neovascularization of choroid through HO-1-dependent pathway. 2170 68

The Chinese herbal medicine formula Tao Hong Si Wu decoction (THSWD) is traditionally used for the prevention and treatment of ischemic stroke. Transcription factor NF-E2-related factor 2 (Nrf2) regulates a battery of phase II enzymes and is known as the major mechanism of cellular defense against oxidative stress. The present study aimed to explore the potential effect of THSWD on the Nrf2 signaling pathway and the consequent effect during cerebral ischemia-reperfusion (I/R) injury. We found that THSWD reduced infarct volume and improved neurological function in a rat stroke model induced by middle cerebral artery occlusion (MCAO). Additionally, heme oxygenase 1 (HO-1), a key endogenous antioxidant enzyme regulated by Nrf2, was significantly further induced by THSWD in this in vivo model. In neuronal-like PC12 cells, THSWD remarkably up-regulated HO-1 expression and promoted Nrf2 nuclear translocation. Furthermore, phosphatidylinositol 3-kinase (PI3K)/Akt kinase was found to be involved in the upstream of Nrf2 regulation. In an in vitro oxygen-glucose deprivation/reperfusion (OGD-Rep) model, THSWD treatment significantly reduced cell death induced by OGD-Rep insult. Importantly, the protective action was attenuated while PI3K activity was inhibited by a specific inhibitor, LY294002, and the Nrf2 signaling pathway was blocked by antioxidant response element (ARE) decoy oligonucleotides. Collectively, these results demonstrated that THSWD exhibited notable neuroprotective properties in vitro and in vivo and activation of PI3K/Akt and the Nrf2 signaling pathway may be, at least in part, responsible for the protection. This study provides a better understanding of the molecular mechanism underlying the traditional use of the Chinese herbal medicine formula THSWD.
...
PMID:Chinese herbal medicine formula tao hong si wu decoction protects against cerebral ischemia-reperfusion injury via PI3K/Akt and the Nrf2 signaling pathway. 2514 59