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

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neutral endopeptidase (NEP; EC 3.4.24.11) is a type-2 cell-surface metalloproteinase known by a variety of eponyms, including enkephalinase, common acute lymphoblastic leukemia antigen (CALLA), and CD10. Identified substrates are largely neural or humoral oligopeptide agonists, and the enzyme functions to terminate signaling by degrading the ligand, analogous to the acetylcholine/acetylcholinesterase system. Targeted disruption of the NEP locus in mice results in enhanced lethality to endotoxin shock with a pronounced gene-dosage effect. The site(s) of action appears downstream from release of TNF and IL-1, as NEP-deficient animals demonstrate increased sensitivity to these mediators as well. This unexpected finding indicates an important protective role for NEP in septic shock.
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PMID:Neutral endopeptidase modulates septic shock. 860 28

According to the latest research the therapy of dementia includes following strategies: Above all there is a necessity for thoroughly diagnostic tests to exclude diseases which secondary induce reduced brain function. The early onset of non pharmacological treatments e.g. "brain-jogging" is essential. Pharmacological therapy with nootropics (e.g. Codergocrin, Nicergolin, Ginkgo biloba, Piracetam, Pyritinol, Naftidrofuryl) is recommended as early as possible, because they have no relevant side effects. Calcium antagonists may also be administered because of their neuroprotective properties. One pharmacological approach to enhance cholinergic functions involves inhibiting ACH-degradation by inhibiting acetylcholinesterase. Although this relatively new therapy has benefits, in some patients it has not been effective and has a potential to cause serious adverse (hepatic) events; only mild to medium severe dementias of Alzheimer's disease should be treated with this therapeutic principle. In the case of personality disorders there are psychotherapy and the administration of psychoactive drugs necessary.
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PMID:[Therapy approaches in cerebral cognitive deficits--neuropsychiatric aspects]. 909 14

Because of the low basal output, measurement of acetylcholine (ACh) release from enteric neurons usually requires cholinesterase inhibition, a condition which is known to interfere with feed-back mechanisms regulating ACh release. In this study, we resorted to a highly sensitive HPLC-ED method to determine the minimum requirement of physostigmine to achieve reliable quantitation of spontaneous endogenous ACh overflow from the guinea-pig isolated colon. Furthermore, in order to assess the degree of interference by physostigmine with cholinergic function, we assessed the effect of scopolamine and oxotremorine (in the presence of physostigmine) on spontaneous ACH overflow (to detect the presence of autoreceptors) and also measured the efficiency of the peristaltic reflex with different physostigmine concentrations. Spontaneous endogenous ACh overflow was detectable only with physostigmine concentrations > or = 10 nM. ACh overflow increased with increasing physostigmine concentrations (10 nM-10 microM range). Scopolamine significantly enhanced the facilitatory effect of physostigmine concentrations > or = 10 nM; conversely, oxotremorine inhibited ACh overflow. Peristaltic efficiency was not significantly affected by physostigmine concentrations < or = 300 nM. In conclusion, this modified HPLC-ED method allows ACh detection with minimal physostigmine concentrations (10-30 nM), which do not interfere with peristaltic activity, do not saturate autoreceptor feed-back mechanisms and therefore improve the assessment of cholinergic function in colonic enteric neurons.
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PMID:Acetylcholine detection by a modified HPLC-ED method improves the assessment of cholinergic function in the myenteric plexus of the guinea-pig colon. 929 79

The effect of subchronic administration of the acetylcholinesterase (AChE) inhibitor heptastigmine (HEP 0.6 mg/kg s.c. daily for 15 days) was investigated on cortical extracellular acetylcholine (ACh) levels and on memory function in aged male rats (26 months old at the beginning of the experiments) using microdialysis and behavioural techniques. Twenty-four hours after the last treatment, cortical ACh levels were significantly higher in rats subchronically treated with HEP than in rats treated with saline and AChE activity was still inhibited in cortex, hippocampus and striatum. The injection of a challenge dose of HEP (0.6 mg/kg s.c.) 24 h after the last treatment produced a faster and a more sustained increase of ACh in the cortex of subchronically treated rats compared to those repeatedly injected with saline. However, the maximum increase of ACh levels after injection of the challenge was comparable in both groups. In an object recognition test in which the pretest and test phase were spaced by 45 days, HEP prevented the deterioration of spatial memory occurring during this period, but had no effect on non-spatial memory. The present results suggest that moderate inhibition of brain AChE is able to maintain high levels of cortical extracellular ACh in aged rats and that this increase matches facilitatory effect of HEP on spatial memory.
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PMID:Effect of the subchronic treatment with the acetylcholinesterase inhibitor heptastigmine on central cholinergic transmission and memory impairment in aged rats. 959 54

The effects of single intraperitoneal injection of two cholinesterase inhibitors, physostigmine (PHY; 0.01, 0.025, 0.05, 0. 1, 0.2 mg/kg) and heptylphysostigmine (HEP; 0.5, 2, 6 mg/kg) on electroencephalographic (EEG) activity and flash visual evoked potentials (f-VEP) in the occipital cortex were compared in DBA/2 mice. EEG spectral analysis of awake periods showed that PHY at all doses and HEP at 2 mg/kg induced an increase of power in the 4.25- to 7-Hz frequency band. Furthermore, PHY at the higher doses and HEP at all doses induced a decrease of power in the 7.25- to 12-Hz frequency band, while the lower doses of PHY (0.01, 0.025 mg/kg) produced an increase of this band. EEG effects elicited by the two drugs were similar, when doses displaying analogous biochemical effects (acetylcholinesterase inhibition) were used (i.e. 0.01 and 0. 025 mg/kg of PHY versus 0.5 and 2 mg/kg of HEP). PHY and HEP induced similar changes in f-VEPs. Amplitudes of early and late components (P1N1, N1P2, P4N4 and particularly N1P3) were enhanced, while amplitudes of middle components were depressed after all doses. The peak latency measures were generally delayed, even though, after the lower doses, a trend to a latency reduction was evident in late components. This finding might indicate a possible effect on stimulus speed diffusion by 'low therapeutic' doses, analogous to the ones used in men. Our data show that both drugs are effective in modifying EEG and f-VEP parameters connected with brain cholinergic function, although in a very narrow dose range.
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PMID:Effects of cholinergic drugs on neocortical EEG and flash-visual evoked potentials in the mouse. 1042 Jan 1

Rat pheochromocytoma PC12 cells undergo neuronal differentiation in response to nerve growth factor (NGF). The differentiation involves protein kinase cascades that include the kinases MEK and ERK, as well as activation of the transcription factors c-Jun and c-Fos. We show here, that exposure of PC12 cells to mannosylerythritol lipid (MEL), a yeast extracellular glycolipid, enhances the activity of acetylcholinesterase and interrupts the cell cycle at the G1 phase, with resulting outgrowth of neurites and partial cellular differentiation. Treatment with MEL stimulates the phosphorylation of ERK to a similar extent as treatment with NGF, although, the appearance of phosphorylated ERK is somewhat delayed. Both the MEL-induced outgrowth of neurites and the increase in the activity of acetylcholinesterase are prevented by PD98059, a specific inhibitor of MEK. Northern blotting analysis of c-jun transcripts and analysis of transcription in PC12 cells of a c-jun/CAT reporter construct demonstrated a significant increase in the rate of transcription of the c-jun gene upon treatment with MEL. The sequence elements required for the MEL-mediated activation of transcription of the c-jun gene are located between nucleotides -126 and -79 in the 5' flanking region. Our results suggest that MEL induces characteristics of neuronal differentiation in PC12 cells, with transactivation of the c-jun gene, via an ERK-related signal cascade that is partially overlapping the pathways activated in response to NGF. These results might provide the groundwork for the use of microbial extracellular glycolipids as novel reagents for the treatment of cancer cells.
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PMID:Mannosylerythritol lipid induces characteristics of neuronal differentiation in PC12 cells through an ERK-related signal cascade. 1116 72

Hirschsprung's disease (HD) is characterised by the absence of ganglion cells and the presence of hypertrophic nerve trunks in the distal bowel. It has been suggested that aganglionosis may be caused by failure of differentiation as a result of microenvironmental change after neuronal migration has occurred. Recently, it was reported that cell-adhesion molecules (CAMs) and fibroblast growth factors (FGFs) stimulate neurite outgrowth through activation of FGF receptors (FGFRs) in neurons. The aim of this study was to investigate the expression of CAMs FGFs, and FGFRs in ganglionic (NG) and aganglionic (AG) segments of HD in order to understand the role of CAM-FGF signalling in the pathogenesis of HD. Specimens from NG and AG segments of bowel from 11 patients with HD were obtained at the time of definitive pull-through operation, snap-frozen in OCT compound, and stored at -70 degrees C. Aganglionosis was confirmed by Haematoxylin and eosin staining and acetylcholinesterase histochemistry; 8-micron cryosections were immunostained using the standard streptavidinbiotin-immunoperoxidase method. The following antibodies were used as the first antibody; FGF2 and FGF7 for FGFs, FGFR1 and FGFR2 for FGFRs, NCAM, L1CAM, and N-cadherin for CAMs. FGF2, FGF7, and FGFR2 were expressed in neuronal tissue of NG segments as well as in hypertrophic nerves of AG segments. There was a lack of FGFRI expression in neuronal tissue of both NG and AG bowel. Immunoreactivity with all three CAMs was detected in ganglion cells in NG bowel and in hypertrophic nerve trunks in AG bowel. In contrast the numbers of CAM-positive nerve fibres in muscle layers were markedly decreased in AG bowel compared to NG bowel. The markedly decreased expression of CAMs on nerve fibres within the muscle of AG bowel suggests that CAM-FGF signalling is altered in HD, resulting in failure of enteric neuroblast migration.
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PMID:Cell-adhesion molecules and fibroblast growth factor signalling in Hirschsprung's disease. 1140 66

Chlorpyrifos oxon (CPO) activates extracellular signal-regulated kinase (ERK 44/42) in Chinese hamster ovary (CHOK1) cells but the mechanism is not defined. This study tests the hypothesis that diacylglycerol (DAG) is the secondary messenger responsible for CPO-induced ERK 44/42 activation. It is known that DAG is sequentially hydrolyzed by DAG lipase and monoacylglycerol (MAG) lipase, both of which are organophosphate sensitive. Inhibition of these enzymes might therefore lead to the accumulation of DAG and MAG, of which only DAG is a secondary messenger. The experiments show that treatment of CHOK1 cells with CPO significantly inhibits DAG/MAG lipase activity and elevates cellular DAG levels. Pretreatment of CHOK1 cells with CPO or a carbamate known to be a DAG lipase inhibitor, followed by treatment with a cell-permeable DAG (1,2-dihexanoyl-sn-glycerol), results in synergistic activation of ERK 44/42. CPO-potentiated DAG-induced ERK 44/42 activation is both time and concentration dependent. This activation is blocked by inhibitors of protein kinase C and mitogen-activated protein kinase kinase, suggesting that these enzymes are important in CPO/DAG cellular signaling. Activation by a stable DAG analogue (phorbol ester) was not altered by CPO, suggesting that DAG metabolism is the probable target for CPO-potentiated DAG-induced ERK 44/42 activation. These observations support the hypothesis that CPO potentiates DAG signaling in CHOK1 cells by inhibiting a CPO-sensitive DAG lipase, thereby providing a potential mechanism of toxicity not associated with acetylcholinesterase inhibition.
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PMID:Chlorpyrifos oxon potentiates diacylglycerol-induced extracellular signal-regulated kinase (ERK 44/42) activation, possibly by diacylglycerol lipase inhibition. 1178 Oct 77

In the course of examining the actions of major human bile acids on cholinergic receptors, we discovered that conjugates of lithocholic acid are partial muscarinic agonists. In the present communication, we report that conjugates of deoxycholic acid (DC) act as cholinergic muscarinic receptor antagonists. Chinese hamster ovary (CHO) cells expressing rat M3-muscarinic receptors were used to test bile acids for inhibition of radioligand [N- (3)H-methylscopolamine ((3)H-NMS)] binding; alteration of inositol phosphate (IP) formation; mitogen-activated protein (MAP) kinase phosphorylation and cell toxicity. We observed approximately 18.8, 30.3 and 37.1% inhibition of (3)H-NMS binding with DC and its glycine (DCG) and taurine (DCT) conjugates, respectively (all 100 micromol/l, p < 0.01). DCT and DCG inhibited acetylcholine-induced increases in IP formation and MAP kinase phosphorylation (p44 and p42 ERK). DCG and DCT did not alter trypan blue exclusion or lactate dehydrogenase release from CHO-M3 cells. We observed the following rank order of potency (IC(50) micromol/l) for inhibition of (3)H-NMS by muscarinic antagonists and bile acids: NMS (0.0004) > 4-DAMP (0.009) > atropine (0.012) > DCT (170) > DCG (250). None of the bile acids tested were hydrolyzed by recombinant cholinesterase. At concentrations achieved in human bile, DC derivatives are natural muscarinic antagonists.
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PMID:Deoxycholic acid conjugates are muscarinic cholinergic receptor antagonists. 1211 52

Multiple endocrine neoplasia (MEN) 2B is a hereditary syndrome including medullary thyroid carcinoma (MTC), pheochromocytoma, gastrointestinal (GI) disorders, marfanoid facies, and multiple ganglioneuromas. MTC is the major cause of mortality, and often appears during the 1st decade of life. RET proto-oncogene mutations are responsible for MEN 2B. Other RET mutations cause MEN 2A syndrome, familial MTC, or Hirschsprung's disease. We studied three MEN 2B patients with the aim of delineating the best diagnostic and therapeutic protocol. The gold standards for diagnosis are histochemical study of the rectal mucosa and molecular analysis of RET, which in familial cases detects MEN 2B at a preclinical stage so that early total prophylactic thyroidectomy can be performed. In non-familial cases, the diagnosis can be suggested by the presence of GI symptoms, ganglioneuromas, and/or the typical facies. The intestinal innervation pattern, analyzed with the acetylcholinesterase technique, is pathognomonic for MEN 2B. In our protocol a rectal biopsy is, therefore, the first measure. The surgical treatment of MEN 2B is total thyroidectomy with cervical lymphadenectomy of the central compartment of the neck. When possible, this intervention should be performed prophylactically before 1 year of age.
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PMID:Diagnostic and therapeutic approach to multiple endocrine neoplasia type 2B in pediatric patients. 1241 60


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