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)

Familial paraganglioma is a dominantly inherited disorder characterised by the development of highly vascular tumours in the head and neck. Recently, a relationship between hereditary tumours derived from the autonomic nervous system and germline mutations in the gene encoding succinate dehydrogenase complex subunit D (SDHD) is increasingly a subject of study. Familial paraganglioma syndrome is embryologically related to phaeochromocytoma, another neuroendocrine tumour that shows great aetiological and genetic heterogeneity. Some hereditary phaeochromocytomas may be associated with germline mutations in VHL, RET and NF1 genes in genetic disorders such as von Hippel-Lindau disease (VHL), multiple endocrine neoplasia type 2 (MEN 2) and neurofibromatosis type 1 (NF 1), respectively. However, there are many cases that cannot be explained by mutations in these genes. In this report, we describe two previously unreported mutations in two patients from 25 unrelated kindreds with phaeochromocytoma and/or paraganglioma disorders and with or without familial antecedents: a mutation featuring the change of tryptophan to a termination codon in exon 2, and a 4-bp deletion in exon 4 that results in a truncated protein. We also describe one missense substitution of uncertain significance. The patients had previously tested negative for germline mutations in VHL and RET genes and had not been previously selected. The involvement of SDHD mutations in familial phaeochromocytoma and/or paraganglioma predisposition is of considerable interest since other studies have shown these alterations to be associated with highly expressed angiogenic factors.
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PMID:Identification of novel SDHD mutations in patients with phaeochromocytoma and/or paraganglioma. 1211 39

A liquid chromatographic-electrospray ionization ion trap mass spectrometry (LC/MS) method has been developed to measure the biosynthetic incorporation of specific precursors into NAD. The stable isotope-labeled precursors tryptophan, quinolinic acid, nicotinic acid, and nicotinamide were added to the media of human liver tumor cells (SK-HEP) grown in culture. The cells were harvested, the NAD was extracted, and the ratio of labeled to unlabeled NAD was measured using the newly developed LC/MS assay. The quantity of NAD formed from each precursor relative to an internal standard (fully labeled 13C, 15N-labeled NAD prepared from baker's yeast) was measured. The detection limit (signal-to-noise ratio 5:1) of the LC/MS method was 37 fmol (25 pg) of NAD and was linear from 20.0 ng to 25 pg. All reported NAD levels were normalized relative to cellular protein measurements. At 50 microM precursor concentrations, nicotinamide was the dominant precursor and NAD levels in the cell rose well above normal levels. Other precursors were minimally incorporated. The same methods were applied to NAD biosynthesized by macrophages derived from peripheral blood monocytes. However, the NAD concentration in macrophages was about 5% of that in SK-HEP cells and the incorporation of stable isotope-labeled substrates remained below measurable levels.
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PMID:LC/MS analysis of NAD biosynthesis using stable isotope pyridine precursors. 1212 56

Celsior, a new preservation solution in thoracic organ transplantation was evaluated for efficacy in cold preservation of human hepatocytes and compared with University of Wisconsin solution (UW) and histidine-tryptophan-ketoglutarate solution (HTK, Custodiol). Human hepatocyte cultures were preserved at 4 degrees C in Celsior, UW and HTK for 2, 6, 12, 24 and 48 h with 6 h of reperfusion. Levels of lactate dehydrogenase (LDH; cell necrosis), 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT; mitochondrial function), and adenosine 5'-triphosphate (ATP; loss of intracellular energy) were measured. Cell necrosis, mitochondrial dysfunction, and loss of ATP were significantly ( P<0.001, P<0.001, P<0.002, respectively) lower in Celsior than in HTK. The amount of cell necrosis and mitochondrial dysfunction in Celsior solution (CS) and UW was equal ( P=n.s.) up to 24 h and significantly lower in UW after 48 h ( P<0.001). Additionally, the intracellular level of ATP was significantly higher after ischemia ( P<0.001) and reperfusion from long-term ischemia (24, 48 h) ( P<0.002). We can conclude that Celsior was superior to HTK and equal to UW in the protection of human hepatocytes against cold preservation injury from ischemia and reperfusion. Furthermore, Celsior was effective in long-term preservation of human hepatocytes.
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PMID:Celsior solution compared with University of Wisconsin solution (UW) and histidine-tryptophan-ketoglutarate solution (HTK) in the protection of human hepatocytes against ischemia-reperfusion injury. 1269 41

Biological effects of ultraviolet A (UVA) irradiation have been ascribed to the photochemical generation of singlet oxygen. Not all effects described in the literature, however, are explicable solely by the generation of singlet oxygen, but rather resemble effects elicited by hydrogen peroxide (H2O2). Here, we show that when cells are kept in cell culture media during exposure to UVA, stress kinases, including ERK 1 and ERK 2 as well as Akt (protein kinase B), are activated, whereas there is no or only minor activation when cells are kept in phosphate-buffered saline during irradiation. Indeed, the exposure of cell culture media to UVA (30 J/cm2) results in the generation of significant amounts of H2O2, with concentrations of about 100 microM. H2O2 concentrations are at least three-fold higher in HEPES-buffered culture media after UVA irradiation. From experiments with solutions of riboflavin, tryptophan or HEPES, as well as combinations thereof, it is concluded that riboflavin mediates the photooxidation of either tryptophan or HEPES, resulting in the generation of H2O2. Thus, if signaling effects of UVA radiation are to be investigated in cell culture systems, riboflavin and HEPES/tryptophan should be avoided during irradiation because of artificial H2O2 generation. It should be taken into account, however, that in vivo tryptophan and riboflavin might play an important role in the generation of reactive oxygen species by UVA as both substances are abundant in living tissues.
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PMID:Irradiation of cells with ultraviolet-A (320-400 nm) in the presence of cell culture medium elicits biological effects due to extracellular generation of hydrogen peroxide. 1274 33

In the present study, we investigated whether activation of protease-activated receptor type 2 (PAR-2) with SLIGRL (SL)NH2, a short mimetic agonistic peptide, directly stimulates pepsinogen secretion from gastric-isolated, pepsinogen-secreting (chief) cells. Immunostaining of gastric-dispersed chief cells with a specific anti-PAR-2 antibody demonstrated expression of PAR-2 receptors on membrane and cytoplasm. SL-NH2 and trypsin potently stimulated pepsinogen secretion (EC50 = 0.3 nM) and caused Ca2+ mobilization (EC50 = 0.6 nM). In contrast to SL-NH2, the scramble peptide LSIGRL-NH2 failed to stimulate pepsinogen release. Exposure to SL-NH2 also resulted in ERK1/2 phosphorylation and activation. Exposure of chief cells to phosphotyrosine kinase inhibitors and 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one, a selective MEK inhibitor, significantly reduced secretion induced by SL-NH2. Pepsinogen secretion induced by SL-NH2 was desensitized by pretreating the cells with the mimetic peptide and trypsin, and exposure to SL-NH2 abrogates pepsinogen secretion induced by carbachol and CCK-8, but not secretion induced by secretin and vasointestinal peptide. Exposure to Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 (substance P) but not to calcitonin gene-related peptide increased pepsinogen release. The neurokinin-1 receptor antagonist, N-acetyl-l-tryptophan 3,5-bis(trifluoromethyl)benzyl ester, inhibited substance P-stimulated pepsinogen secretion, whereas it did not affect secretion induced by SL-NH2. Collectively, these data indicate that PAR-2 is expressed on gastric chief cells and that its activation causes a Ca2+-ERK-dependent stimulation of pepsinogen secretion.
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PMID:PAR-2 modulates pepsinogen secretion from gastric-isolated chief cells. 1274 62

During influenza virus infection, viral ribonucleoproteins (vRNPs) are replicated in the nucleus and must be exported to the cytoplasm before assembling into mature viral particles. Nuclear export is mediated by the cellular protein Crm1 and putatively by the viral protein NEP/NS2. Proteolytic cleavage of NEP defines an N-terminal domain which mediates RanGTP-dependent binding to Crm1 and a C-terminal domain which binds to the viral matrix protein M1. The 2.6 A crystal structure of the C-terminal domain reveals an amphipathic helical hairpin which dimerizes as a four-helix bundle. The NEP-M1 interaction involves two critical epitopes: an exposed tryptophan (Trp78) surrounded by a cluster of glutamate residues on NEP, and the basic nuclear localization signal (NLS) of M1. Implications for vRNP export are discussed.
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PMID:Crystal structure of the M1 protein-binding domain of the influenza A virus nuclear export protein (NEP/NS2). 1297 Jan 77

Adenosine 5'-triphosphate (ATP) depletion is a major cause of cellular injury during ischemia and reperfusion in organ transplantation. Therefore, histidine-tryptophan-ketoglutarate solution (HTK; alpha-ketoglutarate) and University of Wisconsin solution (UW; adenosine) were supplied with energy substrates to achieve graft viability. Nevertheless, their efficacy for maintaining the ATP level, particularly in human liver endothelial cells, was uncertain. Furthermore, it is of interest whether a high ATP level is beneficial in human liver endothelial cell viability. We used human liver endothelial cells between the 3rd and 6th passages in a cell culture model. Human liver endothelial cells were exposed to hypothermic preservation (4 degrees C) in HTK and UW for 2, 6, 12, 24 and 48 h with subsequent reperfusion of 6 h. ATP and lactate dehydrogenase (LDH) were measured after each interval. In comparison to HTK, UW demonstrates a statistically significantly higher level of ATP after each interval of ischemia (p < 0.001) and reperfusion (p < 0.002). Additionally, UW-preserved human liver endothelial cells exceed the ATP level of the warm control during all intervals of ischemia. The loss of cell viability (LDH) was statistically significantly higher after ischemia (p < 0.01) and reperfusion (p < 0.01) in HTK than in UW except after the interval of 48 h. In conclusion, adenosine was more effective than alpha-ketoglutarate in maintaining a high ATP level in human liver endothelial cells after ischemia and reperfusion. Different pathways of energy substrate utilization were a contributing factor. The beneficial effect of the higher ATP level caused by adenosine to human liver endothelial cell viability was limited to 24 h of ischemia. Beyond this ischemia time we could not prove a favorable impact of adenosine on human liver endothelial cells.
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PMID:Value of energy substrates in HTK and UW to protect human liver endothelial cells against ischemia and reperfusion injury. 1473 Feb 20

Reperfusion injuries after organ transplantation affect graft function and influence long-term graft survival. As hypothermic storage, which minimizes the extent of unspecific tissue injury after ischemia and reperfusion, is significantly influenced by the composition of preservation solutions, strategies to optimize the different components may lead to longer graft survival. In the present study the effects of the preservation solution B2 on early renal function and histopathological changes were compared to histidine-tryptophan-ketoglutarate solution (HTK, Bretschneider) in a model of isolated blood-perfused porcine kidneys. B2-preserved kidneys displayed a lower renal resistance and significantly better creatinine clearance as compared to HTK. Mean differences were also found for filtration fraction and sodium fraction reabsorption. The functional data were also related to histopathological changes. Together, these data indicate that the recently developed preservation solution B2 offers new principles of preservation and is a useful preservation solution for experimental isolated perfused kidney models. B2 may also be an interesting model for optimizing preservation within other organ perfusion models.
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PMID:Protective effects of B2 preservation solution in comparison to a standard solution (histidine-tryptophan-ketoglutarate/Bretschneider) in a model of isolated autologous hemoperfused porcine kidney. 1498 62

Celsior solution (CS), a new preservation solution in thoracic organ transplantation, was evaluated for its efficacy in cold preservation of human liver endothelial cells (HLEC) and was compared to University of Wisconsin solution (UW) and histidine-tryptophan-ketoglutarate solution (HTK, Custodiol). HLEC cultures were preserved at 4 degrees C in CS, UW, and HTK, for 2, 6, 12, 24, and 48 hours, with 6 hours of reperfusion. Levels of lactate dehydrogenase (LDH), 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and adenosine 5'-triphosphate (ATP) were measured after each interval of ischemia and the respective phase of reperfusion. Preservation injury of HLEC as measured by LDH release, intracellular ATP level, and MTT reduction were overall significantly (P <or= .01, P <or= .01, P < .05, respectively) lower in UW than in CS and HTK. CS demonstrates a modest superiority to HTK in HLEC preservation. Furthermore, cold preservation remains the main cause of preservation injury of HLEC regardless of the preservation solution used. Additionally, the maintenance of a high intracellular ATP level of HLEC after ischemia and reperfusion, as shown by UW, could be taken as a beneficial effect, particularly in long-term ischemia. In conclusion, our cell culture model reveals the order of efficacy to protect HLEC against preservation injury as: UW >> CS > HTK.
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PMID:UW is superior to Celsior and HTK in the protection of human liver endothelial cells against preservation injury. 1555 36

C-reactive protein (CRP) is significantly associated with the risk of ischemic cardiovascular disease in epidemiological studies. To explore if CRP has a functional role, we investigated its effect on the gene expression profile of vascular endothelial cells. Human vascular endothelial cells (human umbilical vein endothelial cells and human aortic endothelial cells) were incubated with CRP at various concentrations (0-10 mug/ml). Microarray analysis showed that a total of 11 genes increased (IL-8, core promoter element binding protein, activin A, monocyte chemoattractant protein 1, Exostoses 1, Cbp/p300-interacting transactivator with Glu/Asp-rich COOH-terminal domain 2, plasminogen activator inhibitor 1, fibronectin-1, gravin, connexin43, and sortilin-related receptor-1) and 6 genes decreased (methionine adenosyltransferase 2A, tryptophan-rich basic protein, reticulocalbin 1, membrane-associated RING-CH protein VI, cytoplasmic dynein1, and annexin A(1)) by more than twofold for their mRNA levels. IL-8 was the most significantly upregulated gene (13.6-fold), which demonstrated a clear dose- and time-dependent pattern revealed by quantitative real-time PCR. Cell adhesion assay showed that CRP enhanced the monocyte adhesion to endothelial cell monolayer by 2-fold (P < 0.01), which was partially blocked by an anti-IL-8 antibody (34.2% inhibition, P < 0.01). Inhibition of ERK MAPK pathway using U0126 prevented CRP-induced IL-8 upregulation, and Western blot analysis revealed a rapid activation of ERK1/2 after CRP stimulation. These data showed that CRP can significantly influence gene expressions in vascular endothelium. The CRP-responsive genes suggested that CRP may have a broad functional role in cell growth and differentiation, vascular remodeling and solid tumor development.
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PMID:Effect of C-reactive protein on gene expression in vascular endothelial cells. 1559 Oct 95


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