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)

The accumulation of advanced oxidation protein products (AOPPs) has been linked to vascular lesions in diabetes, chronic renal insufficiency, and atherosclerosis. However, the signaling pathway involved in AOPPs-induced endothelial cells (ECs) perturbation is unknown and was investigated. AOPPs modified human serum albumin (AOPPs-HSA) bound to the receptor for advanced glycation end products (RAGE) in a dose-dependent and saturable manner. AOPPs-HSA competitively inhibited the binding of soluble RAGE (sRAGE) with its preferential ligands advanced glycation end products (AGEs). Incubation of AOPPs, either prepared in vitro or isolated from uremic serum, with human umbilical vein ECs induced superoxide generation, activation of NAD(P)H oxidase, ERK 1/2 and p38, and nuclear translocation of NF-kappaB. Activation of signaling pathway by AOPPs-ECs interaction resulted in overexpression of VCAM-1 and ICAM-1 at both gene and protein levels. This AOPPs-triggered biochemical cascade in ECs was prevented by blocking RAGE with either anti-RAGE IgG or excess sRAGE, but was not affected by the neutralizing anti-AGEs IgG. These data suggested that AOPPs might be new ligands of endothelial RAGE. AOPPs-HSA activates vascular ECs via RAGE-mediated signals.
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PMID:Advanced oxidation protein products activate vascular endothelial cells via a RAGE-mediated signaling pathway. 1857 17

Differentiation of monocytes into macrophages is accompanied by increased cell adhesiveness, due in part to the activation of alpha4beta1 integrins. Here we report that the sustained alpha4beta1 activation associated with macrophage differentiation results from expression of beta1 integrin subunits that lack alpha2-6-linked sialic acids, a carbohydrate modification added by the ST6Gal-I sialyltransferase. During differentiation of U937 monocytic cells and primary human CD14(+) monocytes, ST6Gal-I is down-regulated, leading to beta1 hyposialylation and enhanced alpha4beta1-dependent VCAM-1 binding. Importantly, ST6Gal-I down-regulation results from cleavage by the BACE1 secretase, which we show is dramatically up-regulated during macrophage differentiation. BACE1 up-regulation, ST6Gal-I shedding, beta1 hyposialylation, and alpha4beta1-dependent VCAM-1 binding are all temporally correlated and share the same signaling mechanism (protein kinase C/Ras/ERK). Preventing ST6Gal-I down-regulation (and therefore integrin hyposialylation), through BACE1 inhibition or ST6Gal-I constitutive overexpression, eliminates VCAM-1 binding. Similarly, preventing integrin hyposialylation inhibits a differentiation-induced increase in the expression of an activation-dependent conformational epitope on the beta1 subunit. Collectively, these results describe a novel mechanism for alpha4beta1 regulation and further suggest an unanticipated role for BACE1 in macrophage function.
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PMID:Proteolytic shedding of ST6Gal-I by BACE1 regulates the glycosylation and function of alpha4beta1 integrins. 1865 Apr 47

IL-4-mediated proangiogenic and proinflammatory vascular responses have been implicated in the pathogenesis of chronic lung diseases such as asthma. Although it is well known that hypoxia induces pulmonary angiogenesis and vascular alterations, the underlying mechanism of IL-4 on the pulmonary vasculature under hypoxic conditions remains unknown. In this context, we designed the present study to determine the functional importance of IL-4 for pulmonary angiogenesis under hypoxic conditions using IL-4 knockout (KO) animals. Our results show that hypoxia significantly increased IL-4R alpha expression in wild-type (WT) control lungs. Even though hypoxia significantly up-regulated vascular endothelial growth factor (VEGF) receptor expression in the lungs of both genotypes, hypoxia-induced VEGF, VCAM-1, HIF-1alpha, and ERK phosphorylation were significantly diminished in IL-4 KO lungs as compared with WT control lungs. In addition, hypoxia-induced pulmonary angiogenesis and proliferating activities in the airway and pulmonary artery were significantly suppressed in IL-4 KO lungs as compared with WT control lungs. We also isolated primary lung fibroblasts from these genotypes and stimulated these cells with hypoxia. Hypoxia-induced VEGF production was significantly suppressed in lung fibroblasts from IL-4 KO mice. These in vitro results are in accordance with the in vivo data. Furthermore, we observed a significant increase of hypoxia-induced pulmonary angiogenesis in STAT6 KO mice similar to that in WT controls. In conclusion, IL-4 has proangiogenic properties in the lung under hypoxic conditions via the VEGF pathway, and this is independent of the STAT6 pathway.
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PMID:IL-4 is proangiogenic in the lung under hypoxic conditions. 1938 Jul 95

In this study, we examined the effect of Cd on the expression of vascular cell adhesion molecule-1 (VCAM-1) and its mechanisms in bEnd.3 cells. The treatment with Cd increased protein and mRNA expressions of VCAM-1 and increased the phosphorylations of p38, JNK, and ERK. The Cd-induced VCAM-1 expression was significantly suppressed by either a specific p38 mitogen-activated protein kinase (MAPK) inhibitor (SB202190) or a JNK inhibitor (SP600125), but not by an ERK inhibitor (U0126). These results suggest that Cd induces the expression of VCAM-1, at least in part, via p38 and JNK pathways in bEnd.3 cells.
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PMID:Cadmium stimulates the expression of vascular cell adhesion molecule-1 (VCAM-1) via p38 mitogen-activated protein kinase (MAPK) and JNK activation in cerebrovascular endothelial cells. 1960 71

Cardiac progenitor cells are a potential source of cell therapy for heart failure. Although recent studies have shown that transplantation of cardiac stem/progenitor cells improves function of infarcted hearts, the precise mechanisms of the improvement in function remain poorly understood. The present study demonstrates that transplantation of sheets of clonally expanded stem cell antigen 1-positive (Sca-1-positive) cells (CPCs) ameliorates cardiac dysfunction after myocardial infarction in mice. CPC efficiently differentiated into cardiomyocytes and secreted various cytokines, including soluble VCAM-1 (sVCAM-1). Secreted sVCAM-1 induced migration of endothelial cells and CPCs and prevented cardiomyocyte death from oxidative stress through activation of Akt, ERK, and p38 MAPK. Treatment with antibodies specific for very late antigen-4 (VLA-4), a receptor of sVCAM-1, abolished the effects of CPC-derived conditioned medium on cardiomyocytes and CPCs in vitro and inhibited angiogenesis, CPC migration, and survival in vivo, which led to attenuation of improved cardiac function following transplantation of CPC sheets. These results suggest that CPC transplantation improves cardiac function after myocardial infarction through cardiomyocyte differentiation and paracrine mechanisms mediated via the sVCAM-1/VLA-4 signaling pathway.
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PMID:Transplantation of cardiac progenitor cells ameliorates cardiac dysfunction after myocardial infarction in mice. 1962 Jul 70

Exposure to persistent organic pollutants, such as polychlorinated biphenyls (PCBs), can lead to chronic inflammation and the development of vascular diseases. Because cell adhesion molecules (CAMs) of the cerebrovascular endothelium regulate infiltration of inflammatory cells into the brain, we have explored the molecular mechanisms by which ortho-substituted polychlorinated biphenyls (PCBs), such as PCB153, can upregulate CAMs in brain endothelial cells. Exposure to PCB153 increased expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), as well as elevated adhesion of leukocytes to brain endothelial cells. These effects were impeded by inhibitors of EGFR, JAKs, or Src activity. In addition, pharmacological inhibition of NADPH oxidase or disruption of lipid rafts by cholesterol depleting agents blocked PCB153-induced phosphorylation of JAK and Src kinases and upregulation of CAMs. In contrast, silencing of caveolin-1 by siRNA interference did not affect upregulation of ICAM-1 and VCAM-1 in brain endothelial cells stimulated by PCB153. Results of the present study indicate that lipid raft-dependent NADPH oxidase/JAK/EGFR signaling mechanisms regulate the expression of CAMs in brain endothelial cells and adhesion of leukocytes to endothelial monolayers. Due to its role in leukocyte infiltration, induction of CAMs may contribute to PCB-induced cerebrovascular disorders and neurotoxic effects in the CNS.
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PMID:NADPH oxidase and lipid raft-associated redox signaling are required for PCB153-induced upregulation of cell adhesion molecules in human brain endothelial cells. 1963 55

Very recently, we identified two distinct mesenchymal stem cell (MSC) subsets in primary bone marrow (BM) that differ in their expression pattern (CD271(bright)MSCA-1(dim)CD56(+) and CD271(bright)MSCA-1(bright)CD56(-)) and morphology as well as in their clonogenic and differentiation capacity. Here we analyzed the cell surface antigen expression in these subsets in more detail and compared the profiles with the expression pattern on cultured MSCs. Most of the tested antigens, including CD13, CD15, CD73, CD140b, CD144, CD146, and CD164, are expressed at similar levels in both primary BM populations. However, a number of markers were differentially expressed. Of these, CD166 (ALCAM), CD200, and CD106 (VCAM-1) showed an almost selective expression on either CD271(bright)MSCA-1(dim)CD56(+) (increased CD166 and CD200 expression) or CD271(bright)MSCA-1(bright)CD56(-) (increased CD106 expression) MSCs, respectively. Additional markers with elevated expression on CD56(+) MSCs include F9-3C2F1, HEK-3D3, HEK5-1B3, and W1C3 antigens, whereas CD10, CD26, CD106, 7C5G1, 9A3G2, 56A1C2, 66E2D11, HEK-3D6, HEK4-1A1, HEK4-2D6, W1D6, W4A5, W7C6, and W8B2 (MSCA-1) antigens showed increased expression in the CD56(-) population. The majority of the analyzed markers found on primary MSCs were also expressed on cultured MSCs. However, in contrast to primary MSCs, HEK7-1C4, W1C3, W1D6, and W4A5 antigens were absent on the cultured counterparts. 7G5G1 and 9A3G2 antigens showed reduced, and HEK-3D6, F9-3C2, and HEK-3D3 showed increased expression on cultured cells. The extended knowledge about the phenotype of the two subsets and the identification of novel MSC markers may result in the isolation of attractive starting populations for applications in regenerative medicine.
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PMID:Phenotypic characterization of distinct human bone marrow-derived MSC subsets. 1979 40

The natural product sesamin has been known to act as a potent antioxidant and prevent endothelial dysfunction. We here found that sesamin increased in vitro angiogenic processes, such as endothelial cell proliferation, migration, and tube formation, as well as neovascularization in an animal model. This compound elicited the activation of multiple angiogenic signal modulators, such as ERK, Akt, endothelial nitric oxide synthase (eNOS), NO production, FAK, and p38 MAPK, but not Src. The MEK inhibitor PD98059 and the PI3K inhibitor Wortmannin specifically inhibited sesamin-induced activation of the ERK and Akt/eNOS pathways. These inhibitors reduced angiogenic events, with high specificity for MEK/ERK-dependent cell proliferation and migration and PI3K/Akt-mediated tube formation. Moreover, inhibition of p38 MAPK effectively inhibited sesamin-induced cell migration. The angiogenic activity of sesamin was not associated with VEGF expression. Furthermore, this compound did not induce vascular permeability and upregulated ICAM-1 and VCAM-1 expression, which are hallmarks of vascular inflammation. These results suggest that sesamin stimulates angiogenesis in vitro and in vivo through the activation of MEK/ERK-, PI3K/Akt/eNOS-, p125(FAK)-, and p38 MAPK-dependent pathways, without increasing vascular inflammation, and may be used for treating ischemic diseases and tissue regeneration.
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PMID:Angiogenic activity of sesamin through the activation of multiple signal pathways. 1991 68

Vitamin D is thought to exert a protective effect on renal disease progression, but the underlying molecular mechanism remains unclear. We investigated whether paricalcitol ameliorates tubular dysfunction and fibrosis in gentamicin (GM)-induced renal injury. Two groups of rats were treated with GM (100 mg x kg(-1) x day(-1)), one of which was cotreated with paricalcitol (0.3 microg x kg(-1) x day(-1)) for 14 days and the other was not. The control group was treated with vehicle only. HK-2 cells were cultured with GM in the absence or presence of paricalcitol. Paricalcitol restored impaired renal function and the downregulated renal sodium transporters and aquaporin-1 expression caused by GM. ED-1-expressing monocyte/macrophage accumulation induced by GM was attenuated by paricalcitol treatment. Paricalcitol prevented upregulated inflammatory cytokines (TNF-alpha, IL-1beta, INF-gamma) and adhesion molecules (monocyte chemoattractant protein-1, ICAM-1, VCAM-1) induced by GM. In addition, paricalcitol effectively reversed TGF-beta1-induced epithelial-to-mesenchymal transition (EMT) process and extracellular matrix accumulation in GM-induced nephropathy. Increased collagen deposition and fibrosis in GM-treated kidney were ameliorated by paricalcitol. Paricalcitol also attenuated the upregulated NF-kappaB and phosphorylated ERK1/2 expression in HK-2 cells cultured with GM. In conclusion, paricalcitol prevents GM-induced renal injury by inhibiting renal inflammation and fibrosis, the mechanism of which is the interruption of NF-kappaB/ERK signaling pathway and preservation of tubular epithelial integrity via inhibiting EMT process.
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PMID:Renoprotective effects of paricalcitol on gentamicin-induced kidney injury in rats. 1994 33

Lipopolysaccharide (LPS)/Toll-like receptor 4 (TLR4)-mediated signaling pathways have caught the attention of strategies designed for rheumatoid arthritis (RA). In this study, we identified that cPLA(2)alpha acted as a modulator of LPS-induced VCAM-1 expression and THP-1 (human acute monocytic leukemia cell line) adherence. Treatment of RA synovial fibroblasts (RASFs) with LPS, a TLR4 agonist, promoted the VCAM-1 expression and THP-1 adherence which were decreased by pretreatment with a selective cytosolic phospholipase A(2) (cPLA(2)) inhibitor (AACOCF(3)), implying the involvement of cPLA(2)alpha in these responses. This notion was further confirmed by knockdown of cPLA(2)alpha expression by transfection with cPLA(2)alpha small interfering RNA (siRNA) leading to a decrease in VCAM-1 expression and THP-1 adherence induced by LPS. Subsequently, the LPS-stimulated cPLA(2)alpha phosphorylation was attenuated by pretreatment with a MEK1/2 inhibitor (U0126), suggesting that LPS-stimulated cPLA(2)alpha phosphorylation and activity are mediated through an ERK-dependent mechanism. Moreover, COX-2-derived PGE(2) production appeared to involve in LPS-induced VCAM-1 expression which was attenuated by pretreatment with selective COX-2 inhibitors (NS-398 and celecoxib), transfection with COX-2 siRNA, or PGE(2) receptor antagonists. In addition, pretreatment with ecosapentaenoic acid (EPA), a substrate competitor of arachidonic acid (AA), also blocked LPS-induced VCAM-1 mRNA and protein expression, and THP-1 adherence. Collectively, these results suggest that LPS-induced VCAM-1 expression and adhesion of THP-1 cells are mediated through the TLR4/ERK/cPLA(2)alpha phosphorylation and COX-2 expression/PGE(2) synthesis in RASFs.
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PMID:TLR4-dependent induction of vascular adhesion molecule-1 in rheumatoid arthritis synovial fibroblasts: Roles of cytosolic phospholipase A(2)alpha/cyclooxygenase-2. 2011 84


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