Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dehydroepiandrosterone (DHEA) improves vascular function, but the mechanism of this effect is unclear. Since nitric oxide (NO) regulates vascular function, we hypothesized that DHEA affects the vasculature by increasing endothelial NO production. Physiological concentrations of DHEA stimulated NO release from intact bovine aortic endothelial cells (BAEC) within 5min. This effect was mediated by activation of endothelial nitric oxide synthase (eNOS) in BAEC and human umbilical vein endothelial cells (HUVEC). Dehydroepiandrosterone increased cyclic GMP (cGMP) levels in BAEC, consistent with its effect on NO production. Albumin-conjugated DHEA also stimulated NO release, suggesting that DHEA stimulates eNOS by a plasma membrane-initiated signal. Tamoxifen blocked estrogen-stimulated NO release from BAEC, but did not inhibit the DHEA effect. Pertussis toxin abolished the acute effect of DHEA on NO release. Dehydroepiandrosterone had no effect on intracellular calcium fluxes. However, inhibition of tyrosine kinases or the mitogen-activated protein (MAP) kinase kinase (MEK) blocked NO release and cGMP production in response to DHEA. These findings demonstrate that physiological concentrations of DHEA acutely increase NO release from intact vascular endothelial cells, by a plasma membrane-initiated mechanism. This action of DHEA is mediated by a steroid-specific, G-protein coupled receptor, which activates eNOS in both bovine and human cells. The release of NO is independent of intracellular calcium mobilization, but depends on tyrosine- and MAP kinases. This cellular mechanism may underlie some of the cardiovascular protective effects proposed for DHEA.
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PMID:Dehydroepiandrosterone stimulates nitric oxide release in vascular endothelial cells: evidence for a cell surface receptor. 1518 94

Albumin has been shown to be expressed in osteoblastic cells. The role of albumin in osteoblastic cells was investigated. Osteoblastic MC3T3-E1 cells with subconfluent monolayers were cultured for 24 or 48 h in a medium without fetal bovine serum (FBS) in the presence or absence of albumin (0.5 or 1.0 mg/ml of medium) or insulin-like growth factor-I (IGF-I; 10(-9) or 10(-8) M). The number of osteoblastic cells was significantly increased by culture for 48 h in the presence of albumin (0.5 or 1.0 mg/ml) or IGF-I (10(-9) or 10(-8) M). The effect of albumin (0.5 or 1.0 mg/ml) in increasing the cell number was not significantly modulated in the presence of IGF-I (10(-9) or 10(-8) M). Protein content in osteoblastic cells was significantly increased by culture with albumin (1.0 mg/ml). This effect was not significantly altered in the presence of IGF-I (10(-9) or 10(-8) M). Alkaline phosphatase activity was significantly decreased by culture with albumin (0.5 or 1.0 mg/ ml), while it was significantly increased in the presence of IGF-I (10(-9) or 10(-8) M). The effect of IGF-I in increasing the enzyme activity was not significantly altered in the presence of albumin (0.5 or 1.0 mg/ ml). The effect of albumin (0.5 mg/ ml) plus IGF-I (10(-9) M) in increasing the cell number was completely prevented in the presence of PD98059, suggesting that the effect of albumin or IGF-I is partly mediated through mitogen-activated protein (MAP) kinase cascade. The expression of Runx2 (type 1) mRNA using transcription-polymerase chain reaction (RT-PCR) analysis in osteoblastic cells was significantly decreased by culture for 24 or 48 h with albumin (0.5 or 1.0 mg/ml) or IGF-I (10(-9) M). alpha1 (I) collagen mRNA expression in osteoblastic cells was significantly increased by culture for 24 h with albumin (0.5 or 1.0 mg/ml) or IGF-I (10(-9) M). Albumin (0.5, 1.0, or 2.0 mg/ml) did not have a significant effect on osteoclast-like cell formation induced by culture with parathyroid hormone (PTH; 10(-7) M) in mouse marrow culture. This study demonstrates that albumin has a role in the regulation of Runx2 or alpha1 (I) collagen mRNA expression, which may be mediated through intracellular signaling pathway, in osteoblastic cells.
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PMID:Albumin regulates Runx2 and alpha1 (I) collagen mRNA expression in osteoblastic cells: comparison with insulin-like growth factor-I. 1614 6

Signal transduction via the endothelial receptor for advanced glycation end products (RAGE) plays a key role in vascular inflammation. Recent observations have shown that the myeloperoxidase-H2O2-chloride system of activated phagocytes is highly up-regulated under inflammatory conditions where hypochlorous acid (HOCl) is formed as the major oxidant. Albumin, an in vivo carrier for myeloperoxidase is highly vulnerable to oxidation and a major representative of circulating advanced oxidized proteins during inflammatory diseases. Immunohistochemical studies performed in the present study revealed marked colocalization of HOCl-modified epitopes with RAGE and albumin in sections of human atheroma, mainly at the endothelial lining. We show that albumin modified with physiologically relevant concentrations of HOCl, added as reagent or generated by the myeloperoxidase-H2O2-chloride system, is a high affinity ligand for RAGE. Albumin, modified by HOCl in the absence of free amino acids/carbohydrates/lipids to exclude formation of AGE-like structures, induced a rapid, RAGE-dependent activation of extracellular signal-regulated kinase 1/2 and up-regulation of the proinflammatory mediator monocyte chemoattractant protein-1. Cellular activation could be blocked either by a specific polyclonal anti-RAGE IgG and/or a specific mitogen-activated protein-kinase kinase inhibitor. The present study demonstrates that HOCl-modified albumin acts as a ligand for RAGE and promotes RAGE-mediated inflammatory complications.
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PMID:Hypochlorite-modified albumin colocalizes with RAGE in the artery wall and promotes MCP-1 expression via the RAGE-Erk1/2 MAP-kinase pathway. 1721 39

Following acute brain injury, albumin may gain access to the brain parenchyma. Clinical studies indicate a protective role for albumin in stroke but an increase in mortality associated with albumin administration following traumatic brain injury. We investigated the effects of albumin on astrocyte and microglial activation, and the role of mitogen-activated protein kinases (MAPK) in these responses. Albumin activated ERK1/2, p38 MAPK and JNK signaling pathways in astrocytes, and induced the production of interleukin (IL)-1beta, inducible nitric oxide (NO) synthase, the NO metabolite nitrite, and the chemokine CX3CL1 while reducing the level of S100B. The release of inflammatory markers by astrocytes was partially dependent on p38 MAPK and ERK1/2 pathways, but not JNK. In microglia, albumin exposure activated all three MAPK pathways and produced an increase in IL-1beta and nitrite. Inhibition of p38 MAPK in microglia leads to an increased level of IL1beta, while inhibition of all three MAPKs suppressed the release of nitrite. These results suggest that albumin activates astrocytes and microglia, inducing inflammatory responses involved both in the mechanisms of cellular injury and repair via activation of MAPK pathways, and thereby implicate glial activation in the clinical responses to administration of albumin.
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PMID:Albumin activates astrocytes and microglia through mitogen-activated protein kinase pathways. 1996 38