Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Marinobufagenin (MBG) is an endogenous mammalian cardiotonic steroid that is involved in the inhibition of the sodium pump Na(+)/K(+)-ATPase. Increased plasma levels of MBG have been reported in patients with preeclampsia. MBG increases microvascular barrier permeability in an animal model of preeclampsia. However, the mechanism by which MBG impairs endothelial permeability is unknown. We utilized rat lung microvascular endothelial cells (RLMEC) to examine alterations in MBG-induced monolayer permeability and the effect of MBG on the phosphorylation status of ERK1/2, Jnk, and p38. Apoptosis was evaluated by examining alterations in caspases 3/7, 8, and 9 and annexin-V staining. We also examined the effect of MBG on the endothelial adherens junctions of the RLMEC monolayer. MBG inhibited the proliferation, and increased the monolayer permeability, of RLMEC. These actions of MBG were attenuated by ERK, p38, and pan caspase inhibition. MBG significantly decreased the phosphorylation of ERK1/2 and activated the phosphorylation of Jnk and p38. MBG also significantly increased the expression of caspases 3/7, 8, and 9, indicating the activation of apoptosis. MBG-induced apoptosis signaling was not observed in cells pretreated with a p38 inhibitor. MBG treatment induced the disruption of endothelial cell junctions. This effect was prevented by a pan caspase inhibitor. In conclusion, 1) MBG induced an impairment of RLMEC proliferation; 2) the bufadienolide also caused endothelial hyperpermeability; and 3) these effects of MBG were mediated by the downregulation of ERK1/2, the upregulation of Jnk and p38, by the activation of apoptosis, and by the disruption of endothelial cell junctions.
 ...
PMID:Marinobufagenin causes endothelial cell monolayer hyperpermeability by altering apoptotic signaling. 1938 84

We compared short-term neonatal outcomes between premature infants with spontaneous preterm birth (s-PTB) and those delivered due to preeclampsia (PEC). Data were collected from women with singleton pregnancies admitted with spontaneous preterm labor (PTL) (2002 to 2005) and PEC (2005 to 2007). Patients delivering 24 to 36(6/7) weeks were analyzed. The incidence of adverse outcomes was compared. Chi-square and Fisher exact tests compared outcomes between neonates of varying gestational ages, and Poisson regression was used to control for confounders. Data describing 368 infants are included (PTL: n = 224; PEC: n = 144). Overall, s-PTB infants had less favorable outcomes at earlier gestational ages, and at later gestational ages those born preterm secondary to PEC (pec-PTB) had less favorable outcomes. s-PTB infants 24 to 27(6/7) weeks were 21% more likely to stay in the neonatal intensive care unit (NICU) > or = 8 days than pec-PTB infants (incident rate ratios [IRR] 0.79, P = 0.002, 95% confidence interval [CI] 0.68 to 0.92). Pec-PTB infants 32 to 33(6/7) weeks were 6 times more likely to stay in the NICU > or = 31 days than s-PTB infants (IRR 5.82, P = 0.03, 95% CI 1.20 to 28.31). Short-term neonatal outcomes differ by the etiology of preterm birth. These data can help facilitate proper patient counseling and allocation of resources. Future studies should address mechanisms by which the etiology of PTB leads to specific adverse outcomes, thus allowing for more direct interventional strategies.
 ...
PMID:Do neonatal outcomes differ depending on the cause of preterm birth? A comparison between spontaneous birth and iatrogenic delivery for preeclampsia. 1964 90

Interindividual variation in DNA-methylation level is widespread in the human genome, despite its critical role in regulating gene expression. The nature of this variation, including its tissue-specific nature, and the role it may play in human phenotypic variation and disease is still poorly characterized. The placenta plays a critical role in regulating fetal growth and development in ways that have lifelong effects on health. To identify genes with a high degree of interindividual DNA methylation variation in the human placenta, we surveyed the human genome using the Illumina GoldenGate Methylation Cancer panel targeting 1505 CpG sites of 807 genes. While many sites show a continuous pattern of methylation levels, WNT2, TUSC3 and EPHB4 were identified to have a polymorphic "on-or-off" pattern of DNA methylation variation at their promoter region which was confirmed by pyrosequencing. Methylation of these genes can be found in 7%-25% of over 100 placentas tested. The methylation state at the promoter of these genes is concordant with mRNA allelic expression. In three informative cases TUSC3 was observed to be methylated on the maternal allele, and it is thus possible this represents a polymorphically imprinted gene. Furthermore, TUSC3 promoter methylation showed evidence for association with preeclampsia. A biological significance of these methylation allelic polymorphisms (MAPs) to human placental diversity is further implied by their placental specificity and absence in mouse. An extended study of blood suggests that MAPs may also be found in other tissues, implicating their utility for tissue-specific association with complex disorders. The identification of such "epipolymorphism" in other tissues and their use in association studies, should improve our understanding of interindividual phenotypic variability and complex disease susceptibility.
 ...
PMID:Human placental-specific epipolymorphism and its association with adverse pregnancy outcomes. 1983 7

Angiogenesis is the growth of new capillaries from pre-existent microvasculature. A wide range of pathological conditions, from atherosclerosis to cancer, can be attributed to either excessive or deficient angiogenesis. Central to the physiological regulation of angiogenesis is the vascular endothelial growth factor (VEGF) system--its ligands and receptors (VEGFRs) are thus prime molecular targets of pro-angiogenic and anti-angiogenic therapies. Of growing interest as a prognostic marker and therapeutic target in angiogenesis-dependent diseases is soluble VEGF receptor-1 (sVEGFR1, also known as sFlt-1)--a truncated version of the cell membrane-spanning VEGFR1. For instance, it is known that sVEGFR1 is involved in the endothelial dysfunction characterizing the pregnancy disorder of pre-eclampsia, and sVEGFR1's therapeutic potential as an anti-angiogenic agent is being evaluated in pre-clinical models of cancer. This mini review begins with an examination of the protein domain structure and biomolecular interactions of sVEGFR1 in relation to the full-length VEGFR1. A synopsis of known and inferred physiological and pathological roles of sVEGFR1 is then given, with emphasis on the utility of computational systems biology models in deciphering the molecular mechanisms by which sVEGFR1's purported biological functions occur. Finally, we present the need for a systems biology perspective in interpreting circulating VEGF and sVEGFR1 concentrations as surrogate markers of angiogenic status in angiogenesis-dependent diseases.
 ...
PMID:A systems biology perspective on sVEGFR1: its biological function, pathogenic role and therapeutic use. 1984 Jan 94

During human pregnancy, trophoblasts play an important role in embryo implantation and placental development. Cytotrophoblast cells invade the uterine spiral arteries and differentiate into extravillous trophoblasts, resulting in the remodeling of the uterine vessels and fetoplacental vasculature. During early pregnancy, a physiologically hypoxic environment induces the production of angiogenic factors, such as vascular endothelial growth factor (VEGF), which are suggested to locally control the vascular remodeling. Endoglin, a cell-surface coreceptor for transforming growth factor-beta1, is highly expressed in endothelial cells and syncytiotrophoblasts, and can be associated with endothelial nitric oxide synthase and vascular homeostasis. Several studies have recently suggested that some pregnancy-related complications, such as preeclampsia, have their origins early in pregnancy as a result of abnormalities in implantation and placental development. Although angiogenic factors are recognized as key molecules in placental development, little is known about the mechanism(s) of their regulation in trophoblasts. In this study, we elucidated the mechanisms underlying the regulation of VEGF and endoglin production under hypoxic conditions in the trophoblast-derived cell line, BeWo. We evaluated the role of the AKT-MTOR cascade and ERK kinase in the expression of VEGF and endoglin in response to hypoxia using various kinase inhibitors and small interfering RNA targeted against hypoxia-inducible factor (HIF)-1alpha (listed as HIF1A in Hugo Database). Our results suggest that both the phosphatidylinositol 3-kinase-AKT-MTOR-HIF-1alpha and ERK-HIF-1alpha signaling pathways are crucial for increasing VEGF and endoglin expression in response to hypoxia in BeWo cells.
 ...
PMID:Role of extracellular signal-regulated kinase and AKT cascades in regulating hypoxia-induced angiogenic factors produced by a trophoblast-derived cell line. 2037 67

Inadequate trophoblast invasion of the spiral arteries in early pregnancy, an increased inflammatory response and changes in the immune answer to paternal antigens are considered aetiological factors in preeclampsia. Searching for factors related to these angiogenic, anti-angiogenic, immunologic and inflammatory mechanisms may provide methods to determine which patient will develop preeclampsia predating the onset of the clinical manifestations of the disease. Screening for preeclampsia in the first trimester has had Limited success. Currently, maternal characteristics, clinical history, maternal serum biochemistry and uterine artery Doppler sonography before 14 weeks are being investigated. Preeclampsia in a previous pregnancy is still the strongest predictor. In the second trimester, uterine artery Doppler has a detection rate around 60% but also a high false positive rate of 25%. First trimester uterine artery Doppler studies have high sensitivity but poor specificity with a high false positive rate. Combination of first trimester uterine artery Doppler with patient characteristics and maternal serum biochemistry, specifically placental protein 13 holds promise but further evaluation is needed. Maternal serum markers including inhibin A, activin A, soluble FMS-Like tyrosine kinase 1, endoglin, pregnancy associated plasma protein A and others, when used alone have proved poor predictors of preeclampsia. Most studies have been performed by a limited group of researchers in a population with a high risk and no validation studies of any method in other populations are available. Results are difficult to compare due to differences in methodology, and differences in the end point studied.There are still no good methods of preventing preeclampsia once a high risk has been determined.
 ...
PMID:Risk factors and prediction of preeclampsia. 2037 92

Phaeochromocytomas are catecholamine-secreting tumours that arise from chromaffin cells of the adrenal medulla and extra-adrenal sites. Extra-adrenal phaeochromocytomas are called paragangliomas. A diagnosis of phaeochromocytoma is suspected by typical paroxysmal symptoms, unusual or refractory hypertension, discovery of an adrenal incidentaloma or a family history of phaeochromocytoma or paraganglioma, possibly associated with other genetic syndromes (multiple endocrine neoplasia type 2 A or B, neurofibromatosis type 1 and von Hippel-Lindau disease). It can be confirmed by measurements of urinary or plasma fractionated catecholamines and metanephrines. The best diagnostic performances are achieved by metanephrines. Twenty-four hour urine fractionated metanephrines are still recommended as a screening test but some experts prefer plasma measurements in high-risk patients. Increased serum chromogranin-A levels, combined with high catecholamine or metanephrine in a patient with normal renal function is also a tool, virtually diagnostic of phaeochromocytoma. Recent studies have suggested that 25% of patients with phaeochromocytoma have germline mutations of several genes (NF1, VHL, SDHD, SDHB and RET). Thus, genetic testing should be carried out according to an algorithm of risk factors and specific characteristics. Once a biochemical diagnosis of phaeochromocytoma is made, a CT scan or MRI of the abdomen and pelvis should be performed first. If these investigations remain negative, the chest and neck should be explored. After anatomical imaging, functional imaging by 123I-MIBG should be considered. If the MIBG scan is negative, other imaging modalities have recently proven to be useful (PET, Octreoscan). After localization, the treatment of phaeochromocytoma is a surgical resection, which may be laparoscopic. Preoperative preparation with alpha- and beta-adrenergic blockade and/or calcium channel blockers associated with volume expansion is essential. Malignant phaeochromocytoma is rare and its treatment still unsatisfying. Phaeochromocytoma during pregnancy is also rare and its diagnosis easily missed because of its clinical resemblance to pre-eclampsia.
 ...
PMID:Phaeochromocytoma: state-of-the-art. 2051 23

An imbalance in circulating proangiogenic and antiangiogenic factors is postulated to play a causal role in preeclampsia (PE). We have described an inbred mouse strain, BPH/5, which spontaneously develops a PE-like syndrome including late-gestational hypertension, proteinuria, and poor feto-placental outcomes. Here we tested the hypothesis that an angiogenic imbalance during pregnancy in BPH/5 mice leads to the development of PE-like phenotypes in this model. Similar to clinical findings, plasma from pregnant BPH/5 showed reduced levels of free vascular endothelial growth factor (VEGF) and placental growth factor (PGF) compared to C57BL/6 controls. This was paralleled by a marked decrease in VEGF protein and Pgf mRNA in BPH/5 placentae. Surprisingly, antagonism by the soluble form of the FLT1 receptor (sFLT1) did not appear to be the cause of this reduction, as sFLT1 levels were unchanged or even reduced in BPH/5 compared to controls. Adenoviral-mediated delivery of VEGF(121) (Ad-VEGF) via tail vein at embryonic day 7.5 normalized both the plasma-free VEGF levels in BPH/5 and restored the in vitro angiogenic capacity of serum from these mice. Ad-VEGF also reduced the incidence of fetal resorptions and prevented the late-gestational spike in blood pressure and proteinuria observed in BPH/5. These data underscore the importance of dysregulation of angiogenic factors in the pathogenesis of PE and suggest the potential utility of early proangiogenic therapies in treating this disease.
 ...
PMID:Adenoviral delivery of VEGF121 early in pregnancy prevents spontaneous development of preeclampsia in BPH/5 mice. 2107 47

Eps15 Homology Domain-containing 3 (EHD3), a member of the EHD protein family that regulates endocytic recycling, is the first protein reported to be specifically expressed in the glomerular endothelium in the kidney; therefore we generated Ehd3(-/-) mice and assessed renal development and pathology. Ehd3(-/-) animals showed no overt defects, and exhibited no proteinuria or glomerular pathology. However, as the expression of EHD4, a related family member, was elevated in the glomerular endothelium of Ehd3(-/-) mice and suggested functional compensation, we generated and analyzed Ehd3(-/-); Ehd4(-/-) mice. These mice were smaller, possessed smaller and paler kidneys, were proteinuric and died between 3-24 weeks of age. Detailed analyses of Ehd3(-/-); Ehd4(-/-) kidneys demonstrated thrombotic microangiopathy (TMA)-like glomerular lesions including thickening and duplication of glomerular basement membrane, endothelial swelling and loss of fenestrations. Other changes included segmental podocyte foot process effacement, mesangial interposition, and abnormal podocytic and mesangial marker expression. The glomerular lesions observed were strikingly similar to those seen in human pre-eclampsia and mouse models of reduced VEGF expression. As altered glomerular endothelial VEGFR2 expression and localization and increased apoptosis was observed in the absence of EHD3 and EHD4, we propose that EHD-mediated endocytic traffic of key surface receptors such as VEGFR2 is essential for physiological control of glomerular function. Furthermore, Ehd3(-/-); Ehd4(-/-) mice provide a unique model to elucidate mechanisms of glomerular endothelial injury which is observed in a wide variety of human renal and extra-renal diseases.
 ...
PMID:Renal thrombotic microangiopathy in mice with combined deletion of endocytic recycling regulators EHD3 and EHD4. 2140 24

The placenta plays a central role in governing local circulatory system that mediates maternal condition and fetal growth. In early gestational phases, the placenta exerts properties of invasion and neovascularization for successful placentation. Extravillous invasive trophoblasts replace uterine endometrial vasculature and establish local blood pathway to obtain oxygen and nutrients from the mother. In later phases, the placenta promotes villous angiogenesis and vascular maturation that are finely controlled by angiogenic and antiangiogenic molecules. Among various molecules involved in placental neovascularization, vascular endothelial growth factor receptors (VEGFRs) and angiotensin II receptor type 1 (AT1) mediate important signaling pathways for maternal circulatory system and fetal growth. VEGFR1 and VEGFR2 are functional receptors for placental growth factor (PlGF) and VEGF, respectively, and PlGF-VEGFR1 and VEGF-VEGFR2 interactions are disturbed in many preeclamptic patients by excess amount of soluble form of VEGFR1 (also named sFlt1), a natural PlGF/VEGF antagonist. Recent studies have disclosed that excessive sFlt1 production in the placenta and aberrant AT1 signaling in the mother are closely associated with the pathology of preeclampsia and intrauterine growth restriction (IUGR). In this paper, neovascularization of the placenta and pathological events associated with disrupted balance between angiogenic and antiangiogenic signaling in preeclampsia are discussed.
 ...
PMID:Disrupted balance of angiogenic and antiangiogenic signalings in preeclampsia. 2149 Jul 87


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>