Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.11.18 (MAP)
 7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oxidative stress has been implicated in the pathogenesis of stroke, traumatic brain injuries, and neurodegenerative diseases affecting both neuronal and glial cells in the CNS. In this study we have demonstrated that reactive oxygen species (ROS) dramatically induce the expression of two neuropeptide genes, the opioid proenkephalin (pENK) and the opioid-related proorphanin FQ (pOFQ; also known as pronociceptin) in primary astrocytes. Hydrogen peroxide (H2O2) treatment dose-dependently increased pENK and pOFQ mRNA levels with a maximal effect ( approximately 15-fold increase) being detected at 50 microM concentration. Exposing the astrocyte cultures to hypoxia and subsequent re-oxygenation also led to a profound elevation of pOFQ and pENK mRNA levels. Western blot analysis and immunocytochemistry revealed that H2O2 treatment elicited the phosphorylation and nuclear translocation of ERK 1/2 and p38 MAP kinases. Blockade of the p38 or the ERK MAP kinase pathways (by SB202190 and PD98059, respectively) prevented the H2O2-induced increase in pENK and pOFQ mRNA levels indicating a central role for these cascades in the regulation of pOFQ and pENK genes in response to oxidative stress. Regulation of pOFQ and pENK gene expression by ERK and p38 activation may be mediated through the transcription factor cAMP-response element binding protein (CREB). We observed CREB phosphorylation in response to H2O2, which was also prevented by SB202190 and PD98059. The nuclear factor-kappaB (NF-kappaB) pathway appears to be involved exclusively in the induction of pOFQ transcription by H2O2, as NF-kappaB inhibitors antagonized the effect of oxidative stress on pOFQ, but not on pENK expression. The profound induction of these genes by oxidative stress and these other factors may suggest a role for orphanin FQ and enkephalin in injury and stress responses of the CNS and neuropathophysiological conditions involving reactive oxygen species.
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PMID:Oxidative stress induces proorphanin FQ and proenkephalin gene expression in astrocytes through p38- and ERK-MAP kinases and NF-kappaB. 1159 55

In the central nervous system, glial cells play an important role in inflammatory and immune responses, and opioid peptides have been identified as essential mediators between the nervous and the immune systems. We report the profound upregulation of the opioid-related nociceptin/orphanin FQ (N/OFQ) by inflammatory mediators in astrocytes. The bacterial endotoxin, lipopolysaccharide (LPS), and the proinflammatory cytokines, interleukin-beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha), induced levels of N/OFQ mRNA and immunoreactivity. HPLC analysis of the immunoreactivity in astrocyte extracts revealed that a large molecular weight precursor for N/OFQ is being synthesized and released in response to LPS and astrocytes appear to lack the enzymes required to process the precursor protein. Western blot analysis showed that LPS treatment elicited the activation of ERK 1/2 and p38 MAP kinases. Blockade of the p38 or the ERK MAP kinase pathways prevented the LPS-induced increase in N/OFQ mRNA levels indicating a role for these cascades in the regulation of N/OFQ genes in response to LPS. Regulation of N/OFQ gene expression by ERK and p38 activation may be mediated through the transcription factor CREB. We observed CREB phosphorylation in response to LPS, which was also prevented by SB202190 and PD98059. The NFkappaB pathway also appears to be involved in the induction of N/OFQ transcription by LPS, since NFkappaB inhibitors antagonized the effect of LPS on N/OFQ expression. Regulation of N/OFQ by inflammatory mediators in astrocytes may suggest a role for N/OFQ in neural-glial communication and in inflammatory responses in certain neuropathophysiological conditions.
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PMID:Inflammatory mediators increase the expression of nociceptin/orphanin FQ in rat astrocytes in culture. 1220 90

Ceramide is generated in response to inflammatory mediators and oxidative stress. Since these stimuli dramatically increase nociceptin/orphanin FQ (N/OFQ) gene expression in astrocytes we evaluated the regulation of N/OFQ by ceramide and the signaling mechanisms involved. We found that ceramide induced N/OFQ mRNA levels 22-fold after 24 h. In astrocytes ceramide stimulated the JNK, p38 and ERK MAP kinase pathways and also led to the activation of the transcription factors CREB and NFkappaB. Using specific inhibitors of signaling pathways we determined that N/OFQ gene induction is mediated by ERK and p38 MAP kinases. ERK activation may be induced by protein kinase C and it leads to CREB phosphorylation. The NFkappaB pathway also appears to be crucial for ceramide-induced N/OFQ gene expression.
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PMID:Regulation of nociceptin/orphanin FQ gene expression in astrocytes by ceramide. 1239 8

Nociceptin/orphanin FQ (N/OFQ) is the endogenous ligand for the N/OFQ peptide receptor (NOP) and has been shown previously to produce bradycardia and hypotension in rodents. In this study we have measured the effects of intravenous N/OFQ, and the NOP antagonists [Nphe(1)]N/OFQ(1-13)-NH(2) ([Nphe(1)]) and [Nphe(1),Arg(14),Lys(15)]N/OFQ-NH(2) (UFP-101) on cardiovascular parameters and plasma catecholamine concentrations. Female Hartley guinea pigs were anesthetized with pentobarbital and ventilated artificially. MAP and HR were measured via a femoral arterial catheter and ECG, respectively. Plasma catecholamine concentrations were measured by HPLC. Animals received saline, N/OFQ (0.25, 1.25, 6.25 and 25 nmol cumulatively at 10-min intervals), [Nphe(1)] (600 nmol) and UFP-101 (60 nmol) i.v. in various combinations. After establishing a stable baseline, MAP and HR measurements and blood sampling were performed at the beginning and 3 min following each drug administration. N/OFQ significantly decreased MAP, HR and the plasma noradrenaline concentrations in a dose dependent manner (maximally by 29.1+/-1.8%, 13.8+/-0.8% and 46.6+/-7.8%, respectively) To the contrary, N/OFQ tended to increase plasma adrenaline concentration but did not affect plasma dopamine concentrations. There was a significant correlation between percent change in MAP (0.69, P<0.01) or HR (0.84, P<0.01) and that in plasma noradrenaline. [Nphe(1)], but not UFP-101, alone significantly decreased MAP. [Nphe(1)] partially antagonized N/OFQ-induced hypotension, bradycardia and the decrease in plasma concentration of noradrenaline. UFP-101 fully prevented the effects of N/OFQ in this model. In conclusion, the present study shows that intravenous N/OFQ, via NOP receptors, elicits hypotension and bradycardia also in the anaesthetized guinea pig and that the decrease in MAP and HR are positively correlated with the decrease in the plasma noradrenaline level.
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PMID:Effects of nociceptin/orphanin FQ receptor ligands on blood pressure, heart rate, and plasma catecholamine concentrations in guinea pigs. 1269 Apr 25