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)

Regulation of intracellular protein stability by the ubiquitin-dependent proteasome system plays a crucial role in cell function. HO-1 (haem oxygenase) is a stress response protein, which confers cytoprotection against oxidative injury and provides a vital function in maintaining tissue homoeostasis. In the present study, we found a novel action of proteasome inhibitors MG132 and MG262 on HO-1 induction, and characterized the underlying mechanisms. MG132 (> or =0.1 microM) treatment resulted in a marked time- and concentration-dependent induction of the steady-state level of HO-1 mRNA in RAW264.7 macrophages, followed by a corresponding increase in HO-1 protein. Actinomycin D and cycloheximide inhibited MG132-responsive HO-1 protein expression, indicating a requirement for transcription and de novo protein synthesis. The involvement of signal pathways in MG132-induced HO-1 gene expression was examined using chemical inhibitors. Antioxidant N -acetylcysteine and SB203580, an antioxidant and inhibitor of p38 MAPK (mitogen-activated protein kinase), abolished MG132-inducible HO-1 expression. Furthermore, MG132 activated the p38 MAPK pathway. The half-life of HO-1 protein was prolonged by MG132, indicating that the upregulation of HO-1 by proteasome inhibitor is partially attributable to the inhibition of protein degradation. MG132 can ablate IkappaBalpha degradation and NF-kappaB (nuclear factor kappaB) activation induced by lipopolysaccharide, similar to the effect of another NF-kappaB inhibitor pyrrolidine dithiocarbamate. We found HO-1 upregulation by MG132 and pyrrolidine dithiocarbamate is unrelated to their inhibition of NF-kappaB, since leptomycin B, another NF-kappaB inhibitor, did not elicit similar induction of HO-1. Taken together, we found a novel effect of proteasome inhibitor on induction of HO-1 expression. This action is ascribed to the activation of the p38 MAPK pathway, but is not dependent on NF-kappaB inhibition.
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PMID:Proteasome inhibitors up-regulate haem oxygenase-1 gene expression: requirement of p38 MAPK (mitogen-activated protein kinase) activation but not of NF-kappaB (nuclear factor kappaB) inhibition. 1473 Nov 12

Lung and skin are the organs directly exposed to environmental pollution. Ozone (O(3)) is a toxic, oxidant air pollutant, and exposure has been shown to induce antioxidant depletion as well as oxidation of lipids and proteins within the outermost skin layer (stratum corneum) and the lung respiratory tract lining fluids (RTLFs). To further define skin and lung responses to O(3) exposure, SKH-1 hairless mice were exposed to either 0.8 ppm of O(3) (a level occasionally reached in very polluted areas) or ambient air 6 h/day for 6 consecutive days. O(3) exposure resulted in the depletion of alpha-tocopherol in lung and plasma and induction in both skin and lung of heme oxygenase 1, cyclooxygenase 2, and proliferating cell nuclear antigen. O(3)-exposed animals showed a similar extent of upregulation of COX-2 and PCNA in lung and skin, whereas HO-1 was more responsive in skin than in lung (7-fold induction vs. 2-fold induction). In addition to these measures of response to oxidative stress, O(3) exposure led to the activation of nuclear factor kappaB measured as IkappaBalpha phosphorylation in both tissues. We conclude that in this model, O(3) at high pollutant levels is able to affect both lung and skin biology, inducing depletion of alpha-tocopherol and inducing stress-related responses in both skin epidermis and respiratory tract epithelium.
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PMID:In vivo ozone exposure induces antioxidant/stress-related responses in murine lung and skin. 1498 Jul 10

Activation of the inducible nitric oxide synthase (iNOS) pathway contributes to inflammation-induced osteoporosis by suppressing bone formation and causing osteoblast apoptosis. We investigated the mechanism of action by which YS-51S, a synthetic isoquinoline alkaloid, inhibits iNOS expression and nitric oxide (NO) production in ROS 17/28 osteoblast cells activated with the mixture of TNF-alpha, IFN-gamma and LPS (MIX). YS-51S, concentration- and time-dependently, increased heme oxygenase (HO-1) expression. Treatment with YS-51S 1 h prior to MIX significantly reduced MIX-induced NO production and iNOS expression with the IC50 to NO production of 47+/-3.3 microM. Electrophoretic mobility shift assay (EMSA) and western blot analysis showed that YS-51S inhibited MIX-mediated activation and translocation of NF-kappaB to nucleus by suppressing the degradation of its inhibitory protein IkappaBalpha in cytoplasm. YS-51S also reduced NF-kappaB-luciferase activity. In addition, an HO-1 inhibitor ZnPPIX, antagonized the inhibitory effect of YS-51S on iNOS expression and DNA strand break induced by MIX, indicating prevention of NO production by YS-51S is associated with HO-1 activity. Moreover, YS-51S inhibited the oxidation of cytochrome c(2+) by peroxynitrite (PN). Our results indicated that YS-51S may be beneficial in NO-mediated inflammatory conditions such as rheumatoid arthritis by alleviating iNOS expression and NO-mediated cell death of osteoblast with 1) inducing HO-1 expression, 2) interfering the activation of NF-kappaB and 3) quenching of PN.
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PMID:Heme oxygenase-1 induction by (S)-enantiomer of YS-51 (YS-51S), a synthetic isoquinoline alkaloid, inhibits nitric oxide production and nuclear factor-kappaB translocation in ROS 17/2.8 cells activated with inflammatory stimulants. 1792 May 33