UMLS:C0406810 - FACTA Search

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Query: UMLS:C0406810 (NAME)
13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glucuronidation is responsible for the clearance of a diverse range of drug and chemicals whose topology confers properties that complicate in vitro-in vivo clearance correlations as compared to those possible for oxidative metabolism. The active site of the UGTs faces the inside of the luminal space of the endoplasmic reticulum, thus presenting diffusional barriers for substrates, the cosubstrate, UDPGA, and resultant glucuronide products. Transport processes for the cosubstrate UDPGA and glucuronidated products likely contribute to the well-known latency phenomena in which exogenous detergents or alamethicin are required for maximal UGT activity in microsomes. This complicates the extrapolation of results of in vitro clearance studies to the in vivo situation. Even with activation, the microsomal-based clearance values still underestimate the actual in vivo UGT-mediated clearance; therefore latency is not the only explanation for the poor correlation. Recent data indicate that hepatocytes are a promising in vitro system that can be used for the early evaluation of human clearance behavior of drug candidates. Both induction and inhibition of UGT-mediated clearance are a source of clinical drug-drug interactions. Emerging evidence indicates that the same mechanisms identified in the regulation of CYP enzymes also are involved in regulation of the UGTs, i.e., CAR, AH and probably PXR mediate regulation of UGT1A1, 1A6 and UGT2B7, respectively. In contrast to CYP-mediated interactions, with a few exceptions, the magnitude of UGT-mediated interactions are less than 2-fold because of the relatively high UGT Km values and substrate overlap among the multiple isozymes.
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PMID:Complexities of glucuronidation affecting in vitro in vivo extrapolation. 1236 90

We examined whether Ca(2+) mobilizers induce endothelium-dependent contraction and relaxation (EDC and EDR) in isolated rabbit intrapulmonary arteries. Ionomycin (10(-7) M) and A-23187 (10(-7) M), both Ca(2+) ionophores, and thapsigargin (10(-6) M), an endoplasmic reticulum Ca(2+)-ATPase inhibitor, caused a contraction in the non-contracted preparations, and a transient relaxation followed by a transient contraction and sustained relaxation in the precontracted preparations. Endothelium-removal abolished the contraction and transient relaxation (EDC and EDR) but not sustained relaxation (endothelium-independent relaxation, EIR). In the noncontracted preparations, ionomycin-induced EDC was significantly attenuated by quinacrine (10(-5) M), manoalide (10(-6) M), both phospholipase A(2) inhibitors, indomethacin (10(-5) M) and aspirin (10(-4) M), both COX inhibitors, and ozagrel (10(-5) M), a TXA(2) synthetase inhibitor. In the precontracted arteries, EDR was markedly reduced by L-NAME (10(-4) M), a NOS inhibitor, and methylene blue (10(-6) M), a guanylate cyclase inhibitor, and was enhanced by indomethacin, aspirin and ozagrel, probably due to inhibition of EDC. ZM230487, a 5-lipoxygenase inhibitor, had no effect on EDR. EIR was not affected by L-NAME, indomethacin or ZM230487. Arachidonic acid (10(-6) M) evoked EDC sensitive to indomethacin and ozagrel. L-Arginine (10(-3) M) caused EDR sensitive to L-NAME in the ionomycin-stimulated preparations. In conclusion, Ca(2+) mobilizers cause EDC and EDR via production of TXA(2) and NO, respectively.
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PMID:Role of intracellular Ca2+ in endothelium-dependent contraction and relaxation of rabbit intrapulmonary arteries. 1258 21

The relationship between nitric oxide (NO) and intracellular Ca2+ in hypoxic-ischemic brain damage is not known in detail. Here we used rat striatal slices perfused under low-oxygen and Ca2+-free conditions and cultured human astrocytoma cells incubated under similar conditions as models to study the dynamics of intracellular NO and Ca2+ in hypoxia-induced tissue damage. Exposure of rat striatal slices for 70 min to low oxygen tension elicited a delayed and sustained increase in the release of 45Ca2+. This was potentiated by the NO donors sodium nitroprusside (SNP) and spermine-NO and inhibited by N-omega-nitro-L-arginine methyl ester (L-NAME) or by the NO scavenger 2-phenyl-4,4,5,5 tetramethylimidazoline-1-oxyl-3-oxide (PTIO). A membrane-permeant form of heparin in combination with either ruthenium red (RR) or ryanodine (RY) also inhibited 45Ca2+ release. In human astrocytoma U-373 MG cells, hypoxia increased intracellular Ca2+ concentration ([Ca2+]i) by 67.2 +/- 13.1% compared to normoxic controls and this effect was inhibited by L-NAME, PTIO or heparin plus RR. In striatal tissue, hypoxia increased NO production and LDH release and both effects were antagonized by L-NAME. Although heparin plus RR or RY antagonized hypoxia-induced increase in LDH release they failed to counteract increased NO production. These data therefore indicate that NO contributes to hypoxic damage through increased intracellular Ca2+ mobilization from endoplasmic reticulum and suggest that the NO-Ca2+ signalling might be a potential therapeutic target in hypoxia-induced neuronal degeneration.
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PMID:Potentiation of intracellular Ca2+ mobilization by hypoxia-induced NO generation in rat brain striatal slices and human astrocytoma U-373 MG cells and its involvement in tissue damage. 1260 59

Visceral organs display differential sensitivity to ischemia and reperfusion injury, but the cellular mechanisms underlying these differential responses are not completely understood. A significant response to ischemia identified in brain is stress to the endoplasmic reticulum (ER), as indicated by PKR-like endoplasmic reticulum eIF2alpha kinase (PERK)-mediated phosphorylation of eIF2alpha. To determine the generality of this response, we evaluated the PERK pathway in brain, GI tract, heart, liver, lung, kidney, pancreas and skeletal muscle following a clinically relevant, 10 min cardiac arrest-induced whole body ischemia and either 10 or 90 min reperfusion. The potential role of nitric oxide (NO) on PERK activation was investigated by conducting ischemia and reperfusion in the presence and absence of the NO synthase inhibitor nitro-L-arginine methyl ester (L-NAME). Organ stress could be ranked with respect to the degree of eIF2alpha phosphorylation at 10 min reperfusion. Brain, kidney and GI tract were reactive organs, showing 15 to 20-fold increases in eIF2alpha(P) compared to controls. Moderately reactive organs included liver and heart, showing <10-fold increases in eIF2alpha(P). Pancreas, lung and skeletal muscle were nonreactive. Although treatment of cultured neuroblastoma 104 cells with the NO-donor S-nitroso-N-acetyl-penicillamine (SNAP) activated PERK, administration of L-NAME had no effect on PERK activation or eIF2alpha phosphorylation in organs following ischemia and reperfusion. Thus, PERK is activated differentially in reperfused organs independent of NO. These results suggest that ER stress may play a role in differential responses of viscera to ischemia and reperfusion. ER stress in viscera may contribute to the pathophysiology of resuscitation from cardiac arrest and during organ transplantation procedures.
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PMID:PERK is activated differentially in peripheral organs following cardiac arrest and resuscitation. 1602 20

1 Recent evidence supports additional subtypes of vasodilator beta-adrenoceptor (beta-AR) besides the 'classical' beta(2). The aim of this study was to investigate the distribution of beta-ARs in the wall of rat mesenteric resistance artery (MRA), to establish the relative roles of beta-ARs in smooth muscle and other cell types in mediating vasodilatation and to analyse this in relation to the functional pharmacology. 2 We first examined the vasodilator beta-AR subtype using 'subtype-selective' agonists against the, commonly employed, phenylephrine-induced tone. Concentration-related relaxation was produced by isoprenaline (pEC(50): 7.70+/-0.1) (beta(1) and beta(2)). Salbutamol (beta(2)), BRL 37344 (beta(3)) and CGP 12177 (atypical beta) caused relaxation but were 144, 100 and 263 times less potent than isoprenaline; the 'beta(3)-adrenoceptor agonist' CL 316243 was ineffective. 3 In arteries precontracted with 5-HT or U 46619, isoprenaline produced concentration-related relaxation but salbutamol, BRL 37344, CGP 12177 and CL 316243 did not. SR 59230A, CGP 12177 and BRL 37344 caused a parallel rightward shift in the concentration-response curve to phenylephrine indicating competitive alpha(1)-AR antagonism, explaining the false-positive 'vasodilator' action against phenylephrine-induced tone. Endothelial denudation but not L-NAME slightly attenuated isoprenaline-mediated vasodilatation in phenylephrine and U 46619 precontracted MRA. 4 The beta-AR fluorescent ligand BODIPY TMR-CGP 12177 behaved as an irreversible beta(1)-AR antagonist in MRA and bound to the surface and inside vascular smooth muscle cells in intact vascular wall. Beta-ARs in smooth muscle cells were observed in a perinuclear location, consistent with the location of Golgi and endoplasmic reticulum. 5 Binding of BODIPY TMR-CGP 12177 was inhibited by BAAM (1 microM) in all three vascular tunics, confirming the presence of beta-ARs in adventitia, media and intima. Binding in adventitia was observed in both neuronal and non-neuronal cell types. Lack of co-localisation with a fluorescent ligand for alpha-ARs confirms the selectivity of BODIPY TMR-CGP 12177 for beta-ARs over alpha-ARs. 6 Our results support the presence of functional vasodilator beta(1)-ARs and show that they are mainly located in smooth muscle cells. Furthermore, we have demonstrated, for the first time, the usefulness of BODIPY TMR-CGP 12177 for identifying beta-AR distribution in the 'living' vascular wall.
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PMID:Direct demonstration of beta1- and evidence against beta2- and beta3-adrenoceptors, in smooth muscle cells of rat small mesenteric arteries. 1611 91

The division of one cell into two requires the coordination of multiple components. We describe a gene, car-1, whose product may provide a link between disparate cellular processes. Inhibition of car-1 expression in Caenorhabditis elegans embryos causes late cytokinesis failures: cleavage furrows ingress but subsequently regress and the spindle midzone fails to form, even though midzone components are present. The localized accumulation of membrane that normally develops at the apex of the cleavage furrow during the final phase of cytokinesis does not occur and organization of the endoplasmic reticulum is aberrant, indicative of a disruption in membrane trafficking. The car-1 gene has homologues in a number of species, including proteins that associate with RNA binding proteins. CAR-1 localizes to P-granules (germ-line specific ribonucleoprotein particles) and discrete, developmentally regulated cytoplasmic foci. These foci also contain DCAP-1, a protein involved in decapping mRNAs. Thus, CAR-1, a protein likely to be associated with RNA metabolism, plays an essential role in the late stage of cytokinesis, suggesting a novel link between RNA, membrane trafficking and cytokinesis in the C. elegans embryo.
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PMID:CAR-1, a protein that localizes with the mRNA decapping component DCAP-1, is required for cytokinesis and ER organization in Caenorhabditis elegans embryos. 1626 65

Passage of spermatozoa through the epididymis is obligatory for sperm maturation processes and is based on spontaneous phasic contractions (SC) of the epididymal duct. Here, the functional role of cyclic GMP (cGMP) signaling in modulating SC in the bovine epididymal caput and corpus region was examined by muscle tension recording and immunological and autoradiographic techniques. The cGMP-analog 8-bromo (Br)-cGMP, as well as the nitric oxide (NO) donor sodium nitroprusside and the natriuretic peptides (NPs) atrial NP and C-type NP, displayed distally increasing SC-relaxant effects. In agreement, a distally increasing epididymal expression of the cGMP-dependent protein kinase I (PKG I), endothelial NO synthase (eNOS), and the atrial NP receptor was found. Immunoreactivity for PKG, soluble guanylate cyclase, and eNOS could be localized to the epididymal muscle cells as well as to the epithelial basal cells only at the corpus level. The SC-relevant action of NO and the NPs was cGMP dependent, and the action of 8-Br-cGMP, in turn, was modified by epithelial and luminal factors. The NOS inhibitor L-NAME (N(omega)-nitro-L-arginine methyl ester) caused an increase in SC frequency, indicating basal activity of NO generating enzymes. The SC-inhibitory effect of 8-Br-cGMP was clearly reduced by the PKG inhibitor Rp-8-Br-cGMPS as well as by iberiotoxin, thapsigargin, and indomethacin, pointing to PKG as main SC-relevant target of cGMP, and to large-conductance calcium-activated K(+) channels, the sarcoplasmic-endoplasmic reticulum Ca(2+)-ATPase and cyclooxygenase-1 as possible targets of PKG. These data support an essential role of cGMP signaling in the control of epididymal peristalsis, thereby enabling fine tuning of sperm transport and maturation.
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PMID:Regulation of spontaneous contractile activity in the bovine epididymal duct by cyclic guanosine 5'-monophosphate-dependent pathways. 1643 52

The targeting of messenger RNAs (mRNAs) to specific subcellular sites for local translation plays an important role in diverse cellular and developmental processes in eukaryotes, including axis formation, cell fate determination, spindle pole regulation, cell motility, and neuronal synaptic plasticity. Recently, a new conserved class of Lsm proteins, the Scd6 family, has been implicated in controlling mRNA function. Depletion or mutation of members of the Scd6 family, Caenorhabditis elegans CAR-1 and Drosophila melanogaster trailer hitch, lead to a variety of developmental phenotypes, which in some cases can be linked to alterations in the endoplasmic reticulum (ER). Scd6/Lsm proteins are RNA binding proteins and are found in RNP complexes associated with translational control of mRNAs, and these complexes can colocalize with the ER. These findings raise the possibility that localization and translational regulation of mRNAs at the ER plays a role in controlling the organization of this organelle.
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PMID:CAR-1 and trailer hitch: driving mRNP granule function at the ER? 1663 42

In the early 1960s, phenobarbital (PB) was shown to induce hepatic drug metabolism and the induction was implicated in the molecular mechanism of drug tolerance development. Since then, it has become evident that PB not only induces drug metabolism, but also triggers pleiotropic effects on liver function, such as cell growth and communication, proliferation of the endoplasmic reticulum, tumor promotion, glucose metabolism, steroid/thyroid hormone metabolism, and bile acid synthesis. Upon activation by PB and numerous PB-type inducers, the nuclear receptor CAR mediates those pleiotropic actions by regulating various hepatic genes, utilizing multiple regulatory mechanisms.
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PMID:Phenobarbital confers its diverse effects by activating the orphan nuclear receptor car. 1668 49

Using female 4-week-old Sprague-Dawley rats, we investigated the effects of 14 weeks of progressive strength isometric training on endothelium dysfunction after estrogen deficiency. We also proposed possible mechanism(s) by which such training acted on endothelium-dependent vasodilation in thoracic aortic rings. Rats were randomly divided into 4 groups of 8 rats: a sham operated group, an ovariectomized sedentary group receiving 17beta-estradiol vehicle s.c. daily, an ovariectomized sedentary group receiving a daily injection of 20 microg.kg(-1) 17beta-estradiol s.c., and an ovariectomized exercised group receiving daily s.c. vehicle. Vascular reactivity of aortic rings have been evaluated by a cumulative dose of acetylcholine (ACh), in the presence or absence of L-NAME (N-nitro-L-arginine methyl ester), indomethacin, thapsigargin, iberiotoxin, apamin, and tetraethylammonium. Ovariectomy markedly decreased the relaxation caused by ACh, whereas 17beta-estradiol treatment induced a significant increase in the relaxation elicited by ACh. Isometric exercise enhanced relaxation due to ACh. This enhancement was attenuated in the presence of L-NAME, indomethacin, thapsigargin, iberiotoxin, and apamin. Our data indicated, for the first time, that the endothelium-dependent relaxant response to ACh was markedly improved in trained ovariectomized rats. This increased vasodilation is mediated by nitric oxide, cyclooxygenase, sarco-endoplasmic reticulum Ca2+-ATPase pathways, and endothelium-derived hyperpolarizing factor. Finally, this study suggested that resistance training may provide benefits in addressing vascular dysfunction consequent to a decline in estrogen levels after menopause. However, any benefits for age-related vascular dysfunction remain to be demonstrated.
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PMID:Beneficial effects of isometric strength training on endothelial dysfunction in rats. 1711 Oct 17

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