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

In humans, the head-up tilted position results in central hypovolaemia which mimicks haemorrhage and is associated with cardiovascular changes that can be divided into two stages. 1) One stage with increase in HR and vascular resistance and a slight increase in MAP. 2) Another stage with decrease in HR, vascular resistance and MAP and appearance of presyncopal symptoms (hypovolaemic shock). The first stage is "sympathoexcitatory" as plasma NA originating from postganglionic vasoconstrictory sympathetic neurons increase. Limb vascular resistance contributes to the increase in TPR at this time. The second stage is "sympathoinhibitory" in nature as plasma NA slightly decreases, or remains unchanged, while plasma A, originating from the adrenal medulla, raises. This pattern is a reflection of a differentiated sympathetic response as an increase in the activity of the nerves innervating the adrenals and decrease in renal sympathetic nerves has been reported by others. There is a decrease in limb as well as total vascular resistance. The secretion of potent vasoactive peptides may contribute to the circulatory changes taken place during head-up tilt. The head-up tilted position is associated with central hypovolaemia which is reliably monitored by electrical impedance. There is a close relation between the increase in thoracic electrical impedance and the decrease in plasma ANP which is regulated by atrial stretch. Also, from recording of technetium labeled red blood cells and measurements of haematocrite the decrease in CBV is reflected by thoracic electrical impedance. In contrast, CVP reflects changes in CBV during the initial head-up tilt only, whereafter CVP usually is unchanged or may even increase. After the initial head-up tilt the decrease in the CBV is caused by further reduction in plasma volume as shown by increase in haematocrite and unchanged distribution of labeled red blood cells. This mechanism is reflected by application of regional electrical impedance measurements at a low and high frequency current. The low frequency current, passing extracellular fluid only, changing more than the high frequency current that passes extra as well as intracellular fluid. Central hypovolaemia was found to stimulate the pituitary-adrenal axis, and the development of hypotension strongly increases plasma ACTH, beta-END, cortisol and PRL. Blocking histaminergic receptors did not change the pituitary-adrenal response to central hypovolaemia, while the sympathoadrenal response was affected by histaminergic receptor blockade. The H2-receptor antagonist cimetidine inhibited plasma A, while the H1-receptor antagonist mepyramine attenuated plasma NA and reduced cardiovascular tolerance, and also induced some sedation. A possible effect of sedation and anxiolysis was investigated by administration of the GABAergic drug diazepam. This drug did not change the cardiovascular response to head-up tilt, but reduced the increase in plasma cortisol. This indicates that the appearance of presyncopal symptoms is not related to "stress" but associated with the cardiovascular effects of central hypovolaemia. Another endogenous substance, serotonin (5-HT), may be also involved in cardiovascular as well as endocrine regulation. We investigated the effect of blocking three main receptors on the development and effects of hypovolaemic shock. Methysergide (5-Ht1+2-receptor antagonist) attenuated plasma NA, beta-END, PRL and PRA during tilt with a slight reduction of cardiovascular tolerance. The 5-HT2-receptor antagonist ketanserin reduced cardiovascular tolerance without significant effects on the hormonal responses. The 5-HT3-receptor antagonist ondansetron inhibited the plasma CGRP and adrenalin response to central hypovolaemia without influencing cardiovascular tolerance. It is concluded that the head-up tilted model in humans can be applied to study cardiovascular and endocrine mechanisms until the development of hypovolaemic shock.(ABSTRACT TRUNCATED)
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PMID:Neuroendocrine mechanisms during reversible hypovolaemic shock in humans with emphasis on the histaminergic and serotonergic system. 880 74

Cyclic AMP is involved in the differentiation of oligodendrocyte and Schwann cell progenitors into mature myelin producing cells. The involvement of MAP kinases in this pathway was investigated in the D6P2T cell line. This cell line can be induced to display a differentiated phenotype characterized by myelin basic protein gene expression by increased cyclic AMP. Blocking MAP kinase activity with inhibitors of the activating kinase, MEK, by expression of a dominant negative MAP kinase or by expression of the MAP kinase inactivating phosphatase Mkp-1 all blocked the activation of the myelin basic protein promoter in D6P2T cells. In addition, blocking MAP kinase activation during differentiation of an oligodendrocyte-like cell line, CG4, also leads to inhibition of MBP expression. These findings suggest a role for MAP kinase in the cyclic AMP stimulated expression of the myelin basic protein gene during differentiation.
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PMID:Involvement of MAP kinase in the cyclic AMP induction of myelin basic protein gene expression. 982 68

Apoptosis of arterial cells induced by oxidized low density lipoproteins (OxLDL) is thought to contribute to the progression of atherosclerosis. However, most data on apoptotic effects and mechanisms of OxLDL were obtained with extensively oxidized LDL unlikely to occur in early stages of atherosclerotic lesions. We now demonstrate that mildly oxidized LDL generated by incubation with oxygen radical-producing xanthine/xanthine oxidase (X/XO) induces apoptosis in primary cultures of human coronary endothelial and SMC, as determined by TUNEL technique, DNA laddering, and FACS analysis. Apoptosis was markedly reduced when X/XO-LDL was generated in the presence of different oxygen radical scavengers. Apoptotic signals were mediated by intramembrane domains of both Fas and tumor necrosis factor (TNF) receptors I and II. Blocking of Fas ligand (FasL) reduced apoptosis by 50% and simultaneous blocking of FasL and TNF receptors by 70%. Activation of apoptotic receptors was accompanied by an increase of proapoptotic and a decrease in antiapoptotic proteins of the Bcl-2 family and resulted in marked activation of class I and II caspases. Mildly oxidized LDL also activated MAP and Jun kinases and increased p53 and other transcription factors (ATF-2, ELK-1, CREB, AP-1). Inhibitors of Map and Jun kinase significantly reduced apoptosis. Our results provide the first evidence that OxLDL-induced apoptosis involves TNF receptors and Jun activation. More important, they demonstrate that even mildly oxidized LDL formed in atherosclerotic lesions may activate a broad cascade of oxygen radical-sensitive signaling pathways affecting apoptosis and other processes influencing the evolution of plaques. Thus, we suggest that extensive oxidative modifications of LDL are not necessary to influence signal transduction and transcription in vivo.
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PMID:Mildly oxidized low density lipoprotein activates multiple apoptotic signaling pathways in human coronary cells. 1102 84

Classical experiments performed on the embryo of the mollusc Ilyanassa obsoleta demonstrate that the 3D macromere acts as an embryonic organizer, by signaling to other cells and inducing them to assume the correct pattern of cell fates. We have discovered that MAP kinase signaling is activated in the cells that require the signal from 3D for normal differentiation. Preventing specification of the D quadrant lineage by removing the polar lobe disrupts the pattern of MAPK activation, as does ablation of the 3D macromere itself. Blocking MAPK activation with the MAP Kinase inhibitor U0126 produces larvae that differentiate the same limited complement of tissues as D quadrant deletions. Our results suggest that the MAP Kinase signaling cascade transduces the inductive signal from 3D and specifies cell fate among the cells that receive the signal.
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PMID:MAPK signaling by the D quadrant embryonic organizer of the mollusc Ilyanassa obsoleta. 1109 10

Primary cultures of rat cerebellar neurons were used to study mechanisms of arsenic neurotoxicity. Exposure to 5, 10, or 15 microM sodium arsenite reduced cerebellar neuron viability and induced nuclear fragmentation and condensation as well as DNA degradation to oligonucleosome fragments. Exposure to 1 or 5 mM dimethylarsinic acid caused similar changes. Therefore, both inorganic arsenite and organic dimethylarsinic acid induce apoptosis in cerebellar neurons, with the inorganic form being more toxic. Cotreatment with cycloheximide or actinomycin D, inhibitors of protein or RNA synthesis, respectively, or with the caspase inhibitor zVAD, completely blocked arsenite-induced cerebellar neuron apoptosis. This implies that arsenite-induced cerebellar neuron apoptosis requires new gene expression and caspase activation. Interestingly, sodium arsenite selectively activated p38 and JNK3, but not JNK1 or JNK2 in cerebellar neurons. Blocking the p38 or JNK signaling pathways using the inhibitors SB203580 or CEP-1347 protected cerebellar neurons against arsenite-induced apoptosis. These data suggest that arsenite neurotoxicity may be due to apoptosis caused by activation of p38 and JNK3 MAP kinases.
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PMID:Arsenic induces apoptosis in rat cerebellar neurons via activation of JNK3 and p38 MAP kinases. 1144 28

Leukocyte infiltration in the CNS after trauma or inflammation is triggered in part by upregulation of the chemokine, monocyte chemoattractant protein-1 (MCP-1), in astrocytes. However the signals that induce the upregulation of MCP-1 in astrocytes are unknown. We have investigated the roles for ATP P2X7 receptor activation because ATP is an intercellular signaling transmitter that is released in both trauma and inflammation and P2X7 receptors are involved in immune system signaling. Astrocytes in primary cell culture and acutely isolated from the hippocampus were immunopositive for P2X7 receptors. In astrocyte cultures, application of the selective P2X7 agonist, benzoyl-benzoyl ATP (Bz-ATP), activated MAP kinases extracellular signal receptor-activated kinase 1 (ERK1), ERK2, and p38. Purinergic antagonists depressed this activation with a profile suggesting P2X7 receptors. Bz-ATP also increased MCP-1 expression in cultured astrocytes, and again P2X7 antagonists prevented this increase. Blocking either the ERK1/ERK2 or the p38 pathway (with PD98059 or SB203580, respectively) significantly inhibited Bz-ATP-induced MCP-1 expression. Coapplication of both antagonists caused a greater depression. We also tested the roles for ATP receptor activation in inducing MCP-1 upregulation in corticectomy, an in vivo model of trauma. This model of cortical trauma was previously shown to increase MCP-1 expression in vivo principally in astrocytes. Suramin, a wide-spectrum purinergic receptor antagonist, significantly depressed the rapid (3 hr) trauma-induced increase in MCP-1 mRNA. These data indicate that purinergic transmitter receptors in astrocytes are important in regulating chemokine synthesis. The regulation of MCP-1 in astrocytes by ATP may be important in mediating communication with hematopoietic inflammatory cells.
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PMID:P2X7-like receptor activation in astrocytes increases chemokine monocyte chemoattractant protein-1 expression via mitogen-activated protein kinase. 1154 24

In this study, we show that the ETS transcription factor ER81 directly binds to and activates the promoter of the matrix metalloproteinase gene, MMP-1. Further, the oncoprotein HER2/Neu synergizes with ER81 to stimulate MMP-1 transcription. The activation of ER81 by HER2/Neu is mediated by MAP kinases, which phosphorylate ER81 in its N-terminal activation domain. Four respective phosphorylation sites have been identified. Blocking phosphorylation at these sites decreases ER81 transcriptional activity, which can be further diminished by abolishment of phosphorylation at two non-MAP kinase sites. Altogether, our results reveal mechanisms of how phosphorylation of ER81 regulates the expression of target genes such as MMP-1, which may be important for many physiological processes from embryogenesis to adulthood as well as for tumor metastasis.
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PMID:HER2/Neu-mediated activation of the ETS transcription factor ER81 and its target gene MMP-1. 1159 30

The reasons for annual variability in the composition of phytoplankton assemblages are poorly understood but may include competition for resources and allelopathic interactions. We show that domination by the patch-forming dinoflagellate, Peridinium gatunense, or, alternatively, a bloom of a toxic cyanobacterium, Microcystis sp., in the Sea of Galilee may be accounted for by mutual density-dependent allelopathic interactions. Over the last 11 years, the abundance of these species in the lake displayed strong negative correlation. Laboratory experiments showed reciprocal, density-dependent, but nutrient-independent, inhibition of growth. Application of spent P. gatunense medium induced sedimentation and, subsequently, massive lysis of Microcystis cells within 24 hr, and sedimentation and lysis were concomitant with a large rise in the level of McyB, which is involved in toxin biosynthesis by Microcystis. P. gatunense responded to the presence of Microcystis by a species-specific pathway that involved a biphasic oxidative burst and activation of certain protein kinases. Blocking this recognition by MAP-kinase inhibitors abolished the biphasic oxidative burst and affected the fate (death or cell division) of the P. gatunense cells. We propose that patchy growth habits may confer enhanced defense capabilities, providing ecological advantages that compensate for the aggravated limitation of resources in the patch. Cross-talk via allelochemicals may explain the phytoplankton assemblage in the Sea of Galilee.
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PMID:Dinoflagellate-cyanobacterium communication may determine the composition of phytoplankton assemblage in a mesotrophic lake. 1240 Nov 72

During ischemia/reperfusion (I/R), cardiomyocytes are exposed to sudden lack of nutrients and successively to radical oxygen species (ROS). In the present study, we used the HL-5 cardiac atrial myocyte cell line exposed to serum/glucose depletion added or not in H(2)O(2) to mimic ROS during ischemia, then replaced in their standard culture medium to simulate reperfusion. We investigated the effects of serum/glucose depletion combined or not to ROS exposure on AKT and MAP kinases activation to address the role of each event with respect to apoptosis. We demonstrate that serum/glucose depletion per se did not induce apoptosis when compared to ROS exposure. In particular, ROS recruited p38MAPK and JNK pathways. SB202190 preventing p38MAPK activity, partially protected HL-5 from apoptosis while blocking JNK, thanks to JNKI, further enhanced apoptosis. Blocking phosphatidylinositol (PI) 3-kinase with LY294002 or ERKs with U0126 was without consequence on apoptosis. Finally, BCL-2 and BCL-X(L/S) expression levels were analyzed in cells exposed to 1 h ischemia followed by 12-h reperfusion in the presence or not of SB202190; BCL-2, but not BCL-X(L/S), expression was decreased in ROS treated cells but SB202190 failed to restore BCL-2 level. Our data suggest that p38MAPK activation primarily mediates ROS-induced apoptosis while concomitant JNK activation would represent a scavenger pathway for cells trying to escape apoptosis.
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PMID:Characterization of apoptosis signal transduction pathways in HL-5 cardiomyocytes exposed to ischemia/reperfusion oxidative stress model. 1259 6

Peripheral T cells can be polarized towards type 1 or type 2 cytokine immune responses during TCR engagement. Because T cell selection by peptide plus self-MHC in the thymus requires TCR engagement, we hypothesized that type 1 cytokines may polarize developing T cells. We cultured thymi from BBDR rats in adult thymus organ cultures (ATOC) under type 1 cytokine conditions in the absence of exogenous antigen. Type 1 cytokine-conditioned ATOC generated cells that spontaneously secreted high levels of IFNgamma, but not IL-4. A second exposure to type 1 cytokines further increased IFNgamma secretion by these cells, most of which were blasts that expressed the activation markers CD25, CD71, CD86, and CD134. Studies using blocking antibodies and pharmacological inhibitors suggested that both IL-18 and cognate TCR-MHC/ligand interactions were important for activation. Blocking anti-MHC class I plus anti-MHC class II antibodies, neutralizing anti-IL-18 antibody, and the p38 MAP-kinase inhibitor SB203580 each reduced IFNgamma production by approximately 75-80%. Cyclosporin A, which prevents TCR signaling, inhibited IFNgamma production by approximately 50%. These data demonstrate that exposure to type 1 cytokines during intrathymic development can polarize differentiating T cells, and suggest a mechanism by which intrathymic exposure to type 1 cytokines may modulate T cell development.
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PMID:Type 1 cytokines polarize thymocytes during T cell development in adult thymus organ cultures. 1260 10


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