UMLS:C0027819 - FACTA Search

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

Query: UMLS:C0027819 (neuroblastoma)
27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Anandamide (arachidonylethanolamide; AnNH) has important neuromodulatory and immunomodulatory activities. This lipid is rapidly taken up and hydrolyzed to arachidonate and ethanolamine in many organisms. As yet, AnNH inactivation has not been studied in humans. Here, a human brain fatty-acid amide hydrolase (FAAH) has been characterized as a single protein of 67 kDa with a pI of 7.6, showing apparent Km and Vmax values for AnNH of 2.0 +/- 0.2 microM and 800 +/- 75 pmol.min-1.mg of protein-1, respectively. The optimum pH and temperature for AnNH hydrolysis were 9.0 and 37 degreesC, respectively, and the activation energy of the reaction was 43.5 +/- 4.5 kJ.mol-1. Hydro(pero)xides derived from AnNH or its linoleoyl analogues by lipoxygenase action were competitive inhibitors of human brain FAAH, with apparent Ki values in the low micromolar range. One of these compounds, linoleoylethanolamide is the first natural inhibitor (Ki = 9.0 +/- 0.9 microM) of FAAH as yet discovered. An FAAH activity sharing several biochemical properties with the human brain enzyme was demonstrated in human neuroblastoma CHP100 and lymphoma U937 cells. Both cell lines have a high affinity transporter for AnNH, which had apparent Km and Vmax values for AnNH of 0.20 +/- 0.02 microM and 30 +/- 3 pmol.min-1.mg of protein-1 (CHP100 cells) and 0.13 +/- 0.01 microM and 140 +/- 15 pmol.min-1.mg of protein-1 (U937 cells), respectively. The AnNH carrier of both cell lines was activated up to 170% of the control by nitric oxide.
...
PMID:Anandamide hydrolysis by human cells in culture and brain. 982 13

Anandamide is an endogenous compound that acts as an agonist at cannabinoid receptors. It is inactivated via intracellular degradation after its uptake into cells by a carrier-mediated process that depends upon a concentration gradient. The fate of anandamide in those cells containing an amidase called fatty-acid amide hydrolase (FAAH) is hydrolysis to arachidonic acid and ethanolamine. The active site nucleophilic serine of FAAH is inactivated by a variety of inhibitors including methylarachidonylfluorophosphonate (MAFP) and palmitylsulfonyl fluoride. In the current report, the net uptake of anandamide in cultured neuroblastoma (N18) and glioma (C6) cells, which contain FAAH, was decreased by nearly 50% after 6 min of incubation in the presence of MAFP. Uptake in laryngeal carcinoma (Hep2) cells, which lack FAAH, is not inhibited by MAFP. Free anandamide was found in all MAFP-treated cells and in control Hep2 cells, whereas phospholipid was the main product in N18 and C6 control cells when analyzed by TLC. The intracellular concentration of anandamide in N18, C6, and Hep2 cells was up to 18-fold greater than the extracellular concentration of 100 nm, which strongly suggests that it is sequestered within the cell by binding to membranes or proteins. The accumulation of anandamide and/or its breakdown products was found to vary among the different cell types, and this correlated approximately with the amount of FAAH activity, suggesting that the breakdown of anandamide is in part a driving force for uptake. This was shown most clearly in Hep2 cells transfected with FAAH. The uptake in these cells was 2-fold greater than in vector-transfected or untransfected Hep2 cells. Therefore, it appears that FAAH inhibitors reduce anandamide uptake by cells by shifting the anandamide concentration gradient in a direction that favors equilibrium. Because inhibition of FAAH increases the levels of extracellular anandamide, it may be a useful target for the design of therapeutic agents.
...
PMID:The cellular uptake of anandamide is coupled to its breakdown by fatty-acid amide hydrolase. 1111 29

Fatty acid amide hydrolase (FAAH) is critical for degradation of several important fatty acid amides including anandamide, an endocannabinoid, as well as oleamide, a sleep-inducing factor. These compounds play roles in diverse physiological processes ranging from memory and learning to the regulation of blood pressure. The mechanisms that regulate FAAH expression have not been characterized. A 5'-region of the mouse FAAH with promoter activity was isolated from 1.8 kbp of genomic sequence. Characterization of +1 of transcription of FAAH by RNA ligase mediated-rapid amplification of cDNA ends showed that FAAH mRNA is transcribed from multiple transcription start sites lacking a TATA-box element. Functional analysis of the FAAH upstream sequence fused to a luciferase reporter gene revealed a FAAH-promoter construct with tissue specific activity. A 674-bp FAAH-promoter construct was active in N18TG2 (N18) neuroblastoma cells and C6 glioma cells, lines that have endogenous FAAH activity. The same 674-bp FAAH-promoter construct was not active in C2C12 or L6 myogenic cells, two lines that do not have FAAH activity.
...
PMID:Characterization of the 5'-sequence of the mouse fatty acid amide hydrolase. 1169 37

The identification of guanine nucleotide binding proteins (G proteins) in guinea-pig tissues was assessed by the adenosine diphosphate-ribosylation of the alpha subunit by Bordetella pertussis toxin using [alpha32P]nicotinamide adenine dinucleotide as the substrate followed by sodium dodecyl sulphate - polyacrylamide gel electrophoresis and autoradiography. Three tissues (inferior colliculus, neuroblastoma cells, and the organ of Corti) contained G0alpha (39 kD), as well as Gi2alpha (40 kD) and Gi1alpha and/or Gi3alpha (41 kD). The stria vascularis and the VIIIth nerve contained mainly Gi2alpha, Gi1alpha and/or Gi3alpha, but G0alpha was barely detectable. A purified preparation of outer hair cells from the organ of Corti contained all three pertussis toxin substrates including G0alpha, with the Gi2alpha (40 kD) subunit being the most prominent. The immunocytochemical localization of the G0alpha subunit was determined by light microscopy after incubating isolated outer hair cells, Hensen cells and the stria vascularis with affinity-purified anti-G0alpha antibodies. In hair cells a positive reaction was observed along the plasma membrane and around the perimeter of the cuticular plate (zona adherens). Positive reaction was also observed within the infracuticular network extending from the cuticular plate towards the nucleus in outer hair cells. Finally, the base of the outer hair cells also contained G0alpha. However, it is likely that the G0alpha that is present in this cell region is not within the hair cell itself, but rather in nerve terminals which remained attached during dissection.
...
PMID:The Identification and Localization of the Guanine Nucleotide Binding Protein G0 in the Auditory System. 1210 31

Compound 24, an alkyl-substituted amino acid amide, previously found to activate pertussis toxin-sensitive G proteins in cell membranes and membrane protein fractions, was used as a tool to determine the mechanism/location of nicotine inhibition of amyloid beta peptide-stimulated phospholipase A2 and D activities in a human neuroblastoma cell line, LA-N-2, in vitro. In contrast to our previous findings with amyloid beta peptide, these phospholipase activations by compound 24 were not inhibited by (-)-nicotine, cholera toxin or tetanus toxin pretreatment. The contrasting activation of these phospholipases by amyloid beta peptide and compound 24 are discussed.
...
PMID:Activation of phospholipases A2 and D of a human neuroblastoma cell line (LA-N-2) by N-dodecyl-L-lysine amide (compound 24), a putative G protein activator: characteristics of inhibition by (-)-nicotine. 1251 13

Elevated production of hydrogen peroxide (H2O2) in the central nervous system has been implicated in the pathogenesis of several neurodegenerative diseases, including Parkinson's disease, ischemic reperfusion, stroke, and Alzheimer's disease. Pyruvic acid has a critical role in energy metabolism and a capability to nonenzymatically decarboxylate H2O2 into H2O. This study examined the effects of glycolytic regulation of pyruvic acid on H2O2 toxicity in murine neuroblastoma cells. Glycolytic energy substrates including D-(+)-glucose, D-(-) fructose and the adenosine transport blocker dipyridamole, were not effective in providing protection against H2O2 toxicity, negating energy as a factor. On the other hand, pyruvic acid completely prevented H2O2 toxicity, restoring the loss of ATP and cell viability. H2O2 toxicity was also attenuated by D-fructose 1,6 diphosphate (FBP), phospho (enol) pyruvate (PEP), niacinamide, beta-nicotinamide adenine dinucleotide (beta-NAD+), and reduced form (beta-NADH). Both FBP and PEP exerted positive kinetic effects on pyruvate kinase (PK) activity. Interestingly, only pyruvic acid and beta-NADH exhibited powerful stoichiometric H2O2 antioxidant properties. Further, beta-NADH may exert positive effects on PK activity. Subsequent pyruvic acid accumulation can lead to the recycling of beta-NAD+ through lactate dehydrogenase and beta-NADH through glyceraldehyde-3-phosphate dehydrogenase. It was concluded from these studies that intracellular pyruvic acid and beta-NADH appear to act in concert through glycolysis, to enhance H2O2 intracellular antioxidant capacity in neuroblastoma cells. Future research will be required to examine whether similar effects are observed in primary neuronal culture or intact tissue.
...
PMID:Cytoprotection of pyruvic acid and reduced beta-nicotinamide adenine dinucleotide against hydrogen peroxide toxicity in neuroblastoma cells. 1271 24

1. The ability of the endogenous fatty acid amide, cis-oleamide (ODA), to bind to and activate cannabinoid CB(1) and CB(2) receptors was investigated. 2. ODA competitively inhibited binding of the nonselective cannabinoid agonist [(3)H]CP55,940 and the selective CB(1) antagonist [(3)H]SR141716A to rat whole-brain membranes with K(i) values of 1.14 microm (0.52-2.53 microm, Hill slope=0.80, n=6) and 2.63 microm (0.62-11.20 microm, Hill slope=0.92, n=4), respectively. AEA inhibited [(3)H]CP55,940 binding in rat whole-brain membranes with a K(i) of 428 nm (346-510 nm, Hill slope=-1.33, n=3). 3. ODA competitively inhibited [(3)H]CP55,940 binding in human CB(1) (hCB(1)) cell membranes with a K(i) value of 8.13 microm (4.97-13.32 microm, n=2). In human CB(2) transfected (hCB(2)) HEK-293T cell membranes, 100 microm ODA produced only a partial (42.5+/-7%) inhibition of [(3)H]CP55,940 binding. 4. ODA stimulated [(35)S]GTPgammaS binding in a concentration-dependent manner (EC(50)=1.64 microm (0.29-9.32 microm), R(2)=0.99, n=4-9), with maximal stimulation of 188+/-9% of basal at 100 microm. AEA stimulated [(35)S]GTPgammaS binding with an EC(50) of 10.43 microm (4.45-24.42 microm, R(2)=1.00, n=3, 195+/-4% of basal at 300 microm). Trans-oleamide (trans-ODA) failed to significantly stimulate [(35)S]GTPgammaS binding at concentrations up to 100 microm. 5. ODA (10 microm)-stimulated [(35)S]GTPgammaS binding was reversed by the selective CB(1) antagonist SR141716A (IC(50)=2.11 nm (0.32-13.77 nm), R(2)=1.00, n=6). 6. The anatomical distribution of ODA-stimulated [(35)S]GTPgammaS binding in rat brain sections was indistinguishable from that of HU210. Increases of similar magnitude were observed due to both agonists in the striatum, cortex, hippocampus and cerebellum. 7. ODA (10 microm) significantly inhibited forskolin-stimulated cyclic AMP (cAMP) accumulation in mouse neuroblastoma N1E 115 cells (P=0.02, n=11). ODA-mediated inhibition was completely reversed by 1 microm SR141716A (P<0.001, n=11) and was also reversed by pretreatment with 300 ng ml(-1) pertussis toxin (P<0.001, n=6). 8. These data demonstrate that ODA is a full cannabinoid CB(1) receptor agonist. Therefore, in addition to allosteric modulation of other receptors and possible entourage effects due to fatty acid amide hydrolase inhibition, the effects of ODA may be mediated directly via the CB(1) receptor.
...
PMID:Oleamide is a selective endogenous agonist of rat and human CB1 cannabinoid receptors. 1469 Oct 53

The effects of increasing mitochondrial oxidative phosphorylation (OXPHOS), by enhancing electron transport chain components, were evaluated on 1-methyl-4-phenylpyridinium (MPP+) toxicity in brain neuroblastoma cells. Although glucose is a direct energy source, ultimately nicotinamide and flavin reducing equivalents fuel ATP produced through OXPHOS. The findings indicate that cell respiration/mitochondrial O(2) consumption (MOC) (in cells not treated with MPP+) is not controlled by the supply of glucose, coenzyme Q(10) (Co-Q(10)), NADH+, NAD or nicotinic acid. In contrast, MOC in whole cells is highly regulated by the supply of flavins: riboflavin, flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN), where cell respiration reached up to 410% of controls. In isolated mitochondria, FAD and FMN drastically increased complex I rate of reaction (1300%) and (450%), respectively, having no effects on complex II or III. MPP+ reduced MOC in whole cells in a dose-dependent manner. In isolated mitochondria, MPP+ exerted mild inhibition at complex I, negligible effects on complexes II-III, and extensive inhibition of complex IV. Kinetic analysis of complex I revealed that MPP+ was competitive with NADH, and partially reversible by FAD and FMN. Co-Q(10) potentiated complex II ( approximately 200%), but not complex I or III. Despite positive influence of flavins and Co-Q(10) on complexes I-II function, neither protected against MPP+ toxicity, indicating inhibition of complex IV as the predominant target. The nicotinamides and glucose prevented MPP+ toxicity by fueling anaerobic glycolysis, evident by accumulation of lactate in the absence of MOC. The data also define a clear anomaly of neuroblastoma, indicating a preference for anaerobic conditions, and an adverse response to aerobic. An increase in CO(2), CO(2)/O(2) ratio, mitochondrial inhibition or O(2) deprivation was not directly toxic, but activated metabolism through glycolysis prompting depletion of glucose and starvation. In conclusion, the results of this study indicate that the mechanism of action for MPP+, involves the inhibition of complex I and and more specifically complex IV, leading to impaired OXPHOS and MOC. Moreover, flavin dervatives control the rate of complex I/cellular respiration and Co-Q10 augments complex II [corrected].
...
PMID:Effects of enhancing mitochondrial oxidative phosphorylation with reducing equivalents and ubiquinone on 1-methyl-4-phenylpyridinium toxicity and complex I-IV damage in neuroblastoma cells. 1500 52

Oleamide is an endogenous sleep-inducing lipid that has been isolated from the cerebrospinal fluid of sleep-deprived mammals. Oleamide is the best-understood member of the primary fatty acid amide family. One key unanswered question regarding oleamide and all other primary acid amides is the pathway by which these molecules are produced. One proposed pathway involves oleoyl-CoA and N-oleoylglycine as intermediates: oleic acid --> oleoyl-CoA --> N-oleoylglycine --> oleamide. The first and third reactions are known reactions, catalyzed by acyl-CoA synthetase and peptidylglycine alpha-amidating monooxygenase (PAM). Oleoyl-CoA formation from oleic acid has been demonstrated in vitro and in vivo while, to date, N-oleoylglycine cleavage to oleamide has been established only in vitro. PAM catalyzes the final step in alpha-amidated peptide biosynthesis, and its proposed role in primary fatty acid amide biosynthesis has been controversial. Mouse neuroblastoma N(18)TG(2) cells are an excellent model system for the study of oleamide biosynthesis because these cells convert [(14)C]-oleic acid to [(14)C]-oleamide and express PAM in a regulated fashion. We report herein that growth of the N(18)TG(2) cells in the presence of [(14)C]-oleic acid under conditions known to stimulate PAM expression generates an increase in [(14)C]-oleamide or in the presence of a PAM inhibitor generates [(14)C]-N-oleoylglycine. This represents the first identification of N-oleoylglycine from a biological source. In addition, N(18)TG(2) cell growth in the presence of N-oleoylglycine yields oleamide. These results strongly indicate that N-oleoylglycine is an intermediate in oleamide biosynthesis and provide further evidence that PAM does have a role in primary fatty acid amide production in vivo.
...
PMID:Oleic acid derived metabolites in mouse neuroblastoma N18TG2 cells. 1544 56

While many investigations measuring oxidized nicotinamide adenine dinucleotide (NAD+) and reduced nicotinamide adenine dinucleotide (NADH) have been carried out on several mammalian tissues and blood cells, few reports have dealt with monolayers of cultured cells. Here we show a novel method to measure NAD+ and NADH in monolayers of a neuroblastoma cell line. The method was established by modifying a single extraction procedure originally developed for erythrocytes and an enzymatic cycling assay using a dye that absorbs in visible range. The following modifications were made. (i) Addition of 0.05% of a detergent, Triton X-100, to carbonate-bicarbonate extraction buffer enabled us to accurately measure cellular [NADH]/([NAD+]+[NADH]). (ii) Addition of N-ethyldibenzopyrazine ethyl sulfate salt (phenazine ethosulfate) immediately before the incubation suppressed the gradual decline of the sensitivity of the assay. The procedure presented here provides a simple and inexpensive measurement of NAD+ and NADH in cell monolayers.
...
PMID:Determination of oxidized and reduced nicotinamide adenine dinucleotide in cell monolayers using a single extraction procedure and a spectrophotometric assay. 1570 43

<< Previous 1 2 3 4 5 Next >>