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)

Albumin has been shown to activate the mitogen activated protein kinase (MAPK) pathway in proximal tubular cells (PTECs) of the kidney. Megalin, the putative receptor for albumin has potential signalling properties. However, the mechanisms by which megalin signals are unclear. The adaptor phosphoprotein Disabled-2 (Dab2) is known to interact with the cytoplasmic tail of megalin and may be involved in albumin-mediated MAPK signalling. In this study, we investigated the role of Dab2 in albumin-mediated MAPK signalling and further studied the role of Dab2 in albumin-induced TGFbeta-1 secretion, a MAPK dependent event. We used RNA interference to knockdown Dab2 protein abundance in HKC-8 cells a model of human PTECs. Albumin activated ERK1,2 and Elk-1 in a MEK-1 dependent manner and resulted in secretion of TGFbeta-1. In the absence of albumin, knockdown of Dab2 resulted in a trend towards increase in pERK1,2 consistent with its putative role as an inhibitor of cell proliferation. However albumin-induced ERK1,2 activation was completely abolished by Dab2 knockdown. Dab2 knockdown did not however result in inhibition of albumin-induced TGFbeta-1 secretion. These results suggest that Dab2 is a ligand dependent bi-directional regulator of ERK1,2 activity by demonstrating that in addition to its more traditional role as an inhibitor of ERK1,2 it may also activate ERK1,2.
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PMID:Role played by disabled-2 in albumin induced MAP Kinase signalling. 1807 May 91

Dehydroepiandrosterone (DHEA) activates a plasma membrane receptor on vascular endothelial cells and phosphorylates ERK 1/2. We hypothesize that ERK1/2-dependent vascular endothelial proliferation underlies part of the beneficial vascular effect of DHEA. DHEA (0.1-10 nm) activated ERK1/2 in bovine aortic endothelial cells (BAECs) by 15 min, causing nuclear translocation of phosphorylated ERK1/2 and phosphorylation of nuclear p90 ribosomal S6 kinase. ERK1/2 phosphorylation was dependent on plasma membrane-initiated activation of Gi/o proteins and the upstream MAPK kinase because the effect was seen with albumin-conjugated DHEA and was blocked by pertussis toxin or PD098059. A 15-min incubation of BAECs with 1 nm DHEA (or albumin-conjugated DHEA) increased endothelial proliferation by 30% at 24 h. This effect was not altered by inhibition of estrogen or androgen receptors or nitric oxide production. There was a similar effect of DHEA to increase endothelial migration. DHEA also increased the formation of primitive capillary tubes of BAECs in vitro in solubilized basement membrane. These rapid DHEA-induced effects were reversed by the inhibition of either Gi/o-proteins or ERK1/2. Additionally, DHEA enhanced angiogenesis in vivo in a chick embryo chorioallantoic membrane assay. These findings indicate that exposure to DHEA, at concentrations found in human blood, causes vascular endothelial proliferation by a plasma membrane-initiated activity that is Gi/o and ERK1/2 dependent. These data, along with previous findings, define an important vascular endothelial cell signaling pathway that is activated by DHEA and suggest that this steroid may play a role in vascular function.
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PMID:Dehydroepiandrosterone stimulates endothelial proliferation and angiogenesis through extracellular signal-regulated kinase 1/2-mediated mechanisms. 1829 99

This work describes the preparation, physicochemical characterization, mechanical properties and in vitro biological properties of two bioresorbable aliphatic segmented poly(esterurethane urea)s (SPEUU) based on poly(epsilon-caprolactone) diol (PCL diol), 1,6-hexamethylene diisocyanate and two novel urea-diol chain extenders. To strengthen the interactions through hydrogen bonding in the hard segments of SPEUU, novel chain extenders containing urea groups were synthesized and used in the SPEUU formulation. The different chemical structures of the chain extenders modulated the phase separation of soft and hard segments, as demonstrated by the thermal behavior. The hard segment association was enhanced using a diurea-diol chain extender. The biological interactions between the obtained materials and blood were studied by in vitro methods. Research on the protein adsorption, platelet adhesion and thrombus formation is presented. Studies of protein adsorption onto polymeric surfaces showed that SPEUU adsorbed more albumin than fibrinogen. Studies on platelet adhesion and thrombus formation of SPEUU-coated coverslips indicated the antithrombogenic behavior of these surfaces. The synthesized SPEUU revealed no signs of cytotoxicity to Chinese hamster ovary cells, showing satisfactory cytocompatibility.
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PMID:Segmented poly(esterurethane urea)s from novel urea-diol chain extenders: synthesis, characterization and in vitro biological properties. 1835 73

Many chemotherapeutic and biologic agents used for advanced breast cancer exhibit activity alone or in combination, but the small number of randomized trials, coupled with the significant heterogeneity of patient and tumor characteristics, have precluded the development of standardized, evidence-based approaches to therapy for advanced disease. This expert faculty roundtable discussion focused on chemotherapy regimens used in pretreated patients. Given the increasing data on taxanes in this setting, a specific need was identified that led to the theme of standard and novel taxanes in this discussion. Numerous factors can predict response and long-term outcome: tumor characteristics like hormone and HER2 receptor status and grade and clinical characteristics like age, functional status, disease-free interval, previous adjuvant therapy, and sites or burden of metastatic disease. The choice of therapeutic agents or combinations, therefore, relies not only on randomized or phase II trial results but also on patient context in relation to these variables. After anthracycline and taxane therapy, agents such as capecitabine, vinorelbine, gemcitabine, and platinum agents and combinations thereof can be active. Taxanes themselves also possess activity, with a dependency on a specific agent and schedule. Albumin-bound paclitaxel has demonstrated superiority to certain taxane agents and schedules and has demonstrated activity after taxane exposure. This discussion highlights basic paradigms by which standard taxanes and albumin-bound paclitaxel can be evaluated as possible therapeutic or investigative options, along with nontaxane agents, emerging biologic agents, and combinations.
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PMID:Novel taxane formulations in the treatment of breast cancer: a thought leader discussion and consensus roundtable. 1850 Oct 57

In this study, we synthesized and characterized two methoxy poly(ethylene glycol)-block-poly(caprolactone) (MePEG-b-PCL) amphiphilic diblock copolymers, both based on MePEG with a molecular weight of 5000 g/mol (114 repeat units) and PCL block lengths of either 19 or 104 repeat units. Nanoparticles were formed from these copolymers by a nanoprecipitation and dialysis technique. The MePEG(114)-b-PCL(19) copolymer was water soluble and formed micelles that had a hydrodynamic diameter of 40 nm at all copolymer concentrations tested, and displayed a relatively low core microviscosity. The practically water insoluble MePEG(114)-b-PCL(104) copolymer formed nanoparticles with a larger hydrodynamic diameter, which was dependent on copolymer concentration, and possessed a higher core microviscosity than the MePEG(114)-b-PCL(19) micelles, characteristic of nanospheres. The micelles solubilized a maximum of 1.6% w/w of the hydrophobic anticancer agent, paclitaxel (PTX), and released 92% of their drug payload over 7 days, as compared to the nanospheres, which solubilized a maximum of 3% w/w of PTX and released 60% over the same period of time. Both types of nanoparticles were found to be hemocompatible, causing only minimal hemolysis and no changes in plasma coagulation times as compared to control. Upon in vitro incubation in human plasma, PTX solubilized by micelles had a plasma distribution similar to free drug. The majority of PTX was associated with the lipoprotein deficient plasma (LPDP) fraction, which primarily consists of albumin and alpha-1-acid glycoprotein. In contrast, nanospheres were capable of retaining more of the encapsulated drug with significantly less PTX partitioning into the LPDP fraction.
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PMID:In vitro human plasma distribution of nanoparticulate paclitaxel is dependent on the physicochemical properties of poly(ethylene glycol)-block-poly(caprolactone) nanoparticles. 1876 53

Impairment of proximal tubular endocytosis of glomerular-filtered proteins including albumin results in the development of proteinuria/albuminuria in patients with chronic kidney disease. However, the mechanisms regulating the proximal tubular function are largely unknown. This study aimed to investigate the role of angiotensin II type 1A receptor (AT(1A)R)- and insulin-mediated signaling pathways in regulating the expression of megalin, a multiligand endocytic receptor in proximal tubule cells (PTCs). Opossum kidney PTC-derived OK cells that stably express rat AT(1A)R but are deficient in endogenous angiotensin II receptors (AT(1A)R-OK cells) were used for this study. Treatment of the cells with angiotensin II suppressed mRNA and protein expression of megalin at 3- and 24-h incubation time points, respectively. Cellular uptake and degradation of albumin and receptor-associated protein, megalin's endocytic ligands were suppressed 24 h after angiotensin II treatment. The AT(1A)R-mediated decrease in megalin expression was partially prevented by ERK inhibitors. Insulin competed with the AT(1A)R-mediated ERK activation and decrease in megalin expression. Inhibitors of phosphatidylinositol 3-kinase (PI3K), a major component of insulin signaling, also suppressed megalin expression, and activation of the insulin receptor substrate (IRS)/PI3K system was prevented by angiotensin II. Collectively the AT(1A)R-mediated ERK signaling is involved in suppressing megalin expression in the OK cell line, and insulin competes with this pathway. Conversely, the insulin-IRS/PI3K signaling, with which angiotensin II competes, tends to stimulate megalin expression. In conclusion, there is AT(1A)R- and insulin-mediated competitive signaling cross talk to regulate megalin expression in cultured PTCs.
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PMID:Regulation of megalin expression in cultured proximal tubule cells by angiotensin II type 1A receptor- and insulin-mediated signaling cross talk. 1892 21

Tissue engineering of implantable cellular constructs is an emerging cellular therapy for hepatic disease. In this study, we tested the ability of poly(epsilon-caprolactone) (PCL) nanofiber scaffold to support and maintain hepatic differentiation of human cord blood-derived unrestricted somatic stem cells (USSCs) in vitro. USSCs, self-renewing pluripotent cells, were isolated from human cord blood. The electrospun PCL nanofiber porous scaffold was constructed of uniform, randomly oriented nanofibers. USSCs were seeded onto PCL nanofiber scaffolds, and were induced to differentiate into hepatogenic lineages by culturing with differentiation factors for 6 weeks. RT-PCR analysis of endoderm and hepatic-specific gene expression, immunohistochemical detection of cytokeratin 18 (CK-18), alpha-fetoprotein, albumin, glycogen storage and indocyanine green uptake confirmed the differentiation of USSCs into endoderm and hepatocyte-like cells. In the present study, we show that hepatocyte-like cells differentiated from USSCs on the PCL nanofiber scaffold can be candidate for tissue engineering and cell therapy of hepatic tissues.
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PMID:In vitro differentiation of human cord blood-derived unrestricted somatic stem cells into hepatocyte-like cells on poly(epsilon-caprolactone) nanofiber scaffolds. 1909 33

We describe a system that permits conditional mobilization of a Sleeping Beauty (SB) transposase allele by Cre recombinase to induce cancer specifically in a tissue of interest. To demonstrate its potential for developing tissue-specific models of cancer in mice, we limit SB transposition to the liver by placing Cre expression under the control of an albumin enhancer/promoter sequence and screen for hepatocellular carcinoma (HCC)-associated genes. From 8,060 nonredundant insertions cloned from 68 tumor nodules and comparative analysis with data from human HCC samples, we identify 19 loci strongly implicated in causing HCC. These encode genes, such as EGFR and MET, previously associated with HCC and others, such as UBE2H, that are potential new targets for treating this neoplasm. Our system, which could be modified to drive transposon-based insertional mutagenesis wherever tissue-specific Cre expression is possible, promises to enhance understanding of cancer genomes and identify new targets for therapeutic development.
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PMID:A conditional transposon-based insertional mutagenesis screen for genes associated with mouse hepatocellular carcinoma. 1947 87

The pathogenesis of chronic obstructive pulmonary disease (COPD) is characterized by pulmonary inflammation associated with lung neutrophilia and elevated levels of pro-inflammatory mediators in the bronchoalveolar lavage fluid or sputum of patients. Recent findings revealed that mitogen-activated protein kinase (MAPK) signaling cascade is involved in the inflammatory response of lung injury. In the present study we could elucidate the role of extracellular signal-related MAPK in the murine model of LPS-induced acute lung injury by using U0126, a specific inhibitor of MEK1/2, upstream kinases of ERK. Phosphorylation of ERK was inhibited by U0126 in vivo as well as in vitro. In freshly isolated human peripheral blood mononuclear cells U0126 dose-dependently blocked the release of IL-2 and TNF-alpha. For in vivo studies mice were exposed to aerosolized LPS to induce an acute lung injury mimicking some aspects of COPD. This led to a recruitment of neutrophils to the lung and to the release of pro-inflammatory cytokines into bronchoalveolar lavage. Pretreatment of mice with U0126 significantly reduced lung neutrophilia and diminished levels of TNF-alpha and chemotactic MIP-2 and KC in bronchoalveolar fluid. U0126 also decreased albumin levels in BAL fluid, a marker of vascular leakage. Histological examination of lung tissues revealed that ERK MAPK inhibition using U0126 efficiently attenuated LPS-induced pulmonary inflammatory responses. These data suggest that ERK signaling plays an important role in acute lung injury and pharmacologic inhibition of ERK provides a promising new therapeutic strategy for lung inflammatory diseases and in particular COPD.
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PMID:Inhibition of the MAP kinase ERK protects from lipopolysaccharide-induced lung injury. 1942 37

Lemierre's syndrome is a rare but a life threatening condition which affects young healthy individuals, was first described by Dr.Andre Lemierre in 1936. Incidence rates are between 0.6 and 2.3 per million population. It is found more commonly in males, with a male to female ratio of approximately 2:1. Its pathogenesis consists of the development of infectious thrombophlebitis in the internal jugular vein or one of its branches caused by a focal sepsis, mostly localized in the oropharynx, leading to generalized multiorgan metastatic infections, generally to the lung. This computerized tomography (CT) neck with intravenous contrast is from a 24 year old female who presented with a two day history of fever, hypotension and respiratory failure. The physical exam was positive for diminished breath sounds bilaterally on lung exam. Complete blood count revealed a leukocytosis of 16,200 u/L with 70% neutrophils and 9% bands, hemoglobin of 13.4mg/dl and severe thrombocytopenia with a platelet count of 34,000 u/L; comprehensive metabolic panel revealed sodium 140mmol/L, potassium 2.9mmol/L, bicarbonate 26mmol/L, blood urea nitrogen (BUN) 16mg/dl, creatinine 0.8mg/dl, calcium 7.2 mg/dl, albumin 2.4g/dl, total bilurubin 3.1mg/dl, AST 81 U/L, ALK 101 U/L, ALT 35U/L. CT chest revealed multiple cavitary opacities in both lungs. Blood cultures were positive for Fusobacterium necrophorum. CT scan neck showed a filling defect of the right internal jugular vein consistent with a thrombus and multiple enlarged cervical lymph nodes. Treatment is medical with intravenous antibiotics and anticoagulation. References: 1. Carlson ER, Bergamo DF, Coccia CT. Lemierre's syndrome: two cases of a forgotten disease. J Oral Maxillofac Surg 1994; 52:74-78. 2. Moore-Gillon J, Lee TH, Eykyn SJ, Phillips I. Necrobacillosis: a forgotten disease. BMJ 1984;288:1526-1527. 3. Jones C, Siva TM, Seymour FK, O'Reilly BJ. Lemierre's syndrome presenting with peritonsillar abscess and VIth cranial nerve palsy. J Laryngol Otol 2006;120:502-504 4. Mohammed Iqbal Syed et al. Lemierre Syndrome: Two Cases and a Review. Laryngoscope, 117:1605-1610, 2007 5. Vohra A, Saiz E, Ratzan KR. A young woman with a sore throat, septicaemia, and respiratory failure. Lancet 1997; 350:928.
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PMID:"A forgotten disease": a case of Lemierre syndrome. 1946 52


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