Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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The development of effective therapies for cystic fibrosis (CF) requires animal models that can appropriately reproduce the human disease phenotype. CF mouse models have demonstrated cAMP-inducible, non-CF transmembrane conductance regulator (non-CFTR) chloride transport in conducting airway epithelia, and this property is thought to be responsible for the lack of a spontaneous CF-like phenotype in the lung. Thus, an understanding of species diversity in airway epithelial electrolyte transport and CFTR function is critical to developing better models for CF. Two species currently being used in attempts to develop better animal models of CF include the pig and ferret. In the study reported here, we sought to comparatively characterize the bioelectric properties of in vitro polarized airway epithelia--from human, mouse, pig and ferret--grown at the air-liquid interface (ALI). Bioelectric properties analyzed include amiloride-sensitive Na(+) transport, 4,4'-diisothiocyanato-stilbene-2,2'-disulfonic acid (DIDS)-sensitive Cl(-) transport, and cAMP-sensitive Cl(-) transport. In addition, as an index for CFTR functional conservation, we evaluated the ability of four CFTR inhibitors, including glibenclamide, 5-nitro-2-(3-phenylpropyl-amino)-benzoic acid, CFTR (inh)-172, and CFTR(inh)-GlyH101, to block cAMP-mediated Cl(-) transport. Compared with human epithelia, pig epithelia demonstrated enhanced amiloride-sensitive Na(+) transport. In contrast, ferret epithelia exhibited significantly reduced DIDS-sensitive Cl(-) transport. Interestingly, although the four CFTR inhibitors effectively blocked cAMP-mediated Cl(-) secretion in human airway epithelia, each species tested demonstrated unique differences in its responsiveness to these inhibitors. These findings suggest the existence of substantial species-specific differences at the level of the biology of airway epithelial electrolyte transport, and potentially also in terms of CFTR structure/function.
Am J Respir Cell Mol Biol 2007 Mar
PMID:Bioelectric properties of chloride channels in human, pig, ferret, and mouse airway epithelia. 1700 35

Endogenous salicylic acid (SA) and its predominant conjugates, SA 2-O-beta-D-glucoside (SAG) and the glucose ester of SA (SGE), increase dramatically during plant defense responses. Here I report the isolation and characterization of an Arabidopsis thaliana UDP-glucose:SA glucosyltransferase1 (AtSGT1) gene using a tobacco SGT gene previously reported, whose product catalyzes the formation of both SAG and SGE. The recombinant AtSGT1 protein had significant activities with SA and benzoic acid, and synthesized SAG and SGE. Northern blot analysis showed that AtSGT1 was rapidly induced both by exogenous SA and infection with the bacterial pathogen Pseudomonas syringae, indicating that pathogen-inducible AtSGT1 expression is an early disease response and may be involved in the accumulation of glucosyl SA during pathogenesis.
Mol Cells 2006 Oct 31
PMID:Induction of a salicylic acid glucosyltransferase, AtSGT1, is an early disease response in Arabidopsis thaliana. 1708 77

The Fas pathway and oxidative stress mediate neuronal death in stroke and may contribute to neurodegenerative disease. We tested the hypothesis that these two factors synergistically produce spinal motor neuron degeneration in amyotrophic lateral sclerosis (ALS). Levels of reactive oxygen species were increased in motor neurons from ALS mice compared with wild-type mice at age 10 weeks, before symptom onset. The proapoptotic proteins Fas, Fas-associated death domain, caspase 8, and caspase 3 were also elevated. Oral administration of 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid (Neu2000), a potent antioxidant, blocked the increase in reactive oxygen species but only slightly reduced activation of proapoptotic proteins. Administration of lithium carbonate (Li(+)), a mood stabilizer that prevents apoptosis, blocked the apoptosis machinery without preventing oxidative stress. Neu2000 or Li(+) alone significantly enhanced survival time and motor function and together had an additive effect. These findings provide evidence that jointly targeting oxidative stress and Fas-mediated apoptosis can prevent neuronal loss and motor dysfunction in ALS.
Mol Pharmacol 2007 Apr
PMID:Concurrent administration of Neu2000 and lithium produces marked improvement of motor neuron survival, motor function, and mortality in a mouse model of amyotrophic lateral sclerosis. 1710 68

The present study investigated whether cAMP-dependent cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel current (i.e., I(Cl.CFTR) or I(Cl.cAMP)) would be expressed in pig cardiac myocytes using whole-cell patch technique and reverse transcription polymerase chain reaction (RT-PCR). It was found that the beta-adrenoceptor agonist isoproterenol activated a time-independent current in myocytes from the ventricle, but not the atrium of pig heart. Histamine and forskolin (an adenylate cyclase activator) induced a similar current in pig ventricular cells. The current induced by isoproterenol was blocked by the PKA inhibitor H-7, reduced by the replacement of external Cl(-) ion, and inhibited by the application of 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB), but not 4'-diisothiocynatostilbene-2,2'-disulfonic acid (DIDS), typical of I(Cl.CFTR). I(Cl.CFTR) showed a small difference in regional myocytes across the left ventricular wall from epicardium to endocardium. Isoproterenol-induced current was 3.1+/-0.2 (n=33), 2.8+/-0.2 (n=25) and 2.3+/-0.2 pA/pF (n=31) respectively in subepicardial, midmyocardial, and subendocardial myocytes (P<0.05, subepicardium vs. subendocardium). RT-PCR and Western blotting analysis revealed that significant differences in CFTR channel mRNA and protein levels were present in atrial and ventricular cells, but not in regional ventricular cells across the ventricular wall from subepicardium to subendocardium. These results indicate that the functional CFTR channel (i.e., I(Cl.CFTR)) is present in ventricular myocytes, but not in atrial cells of pig heart.
J Mol Cell Cardiol 2007 Jan
PMID:Evidence for cystic fibrosis transmembrane conductance regulator chloride current in swine ventricular myocytes. 1711 38

The characteristics of vitamin C (ascorbic acid, ASC) transport were studied in polarized cultured monolayers of the chick (Gallus gallus) renal proximal tubule in Ussing chambers. Under voltage clamp conditions, monolayers responded to apical addition of ASC in a dose-dependent manner, with positive short circuit currents (I(SC)), ranging from 3 microA/cm(2) at 5 microM ASC to a maximal response of 27 microA/cm(2) at 200 microM, and a half-maximal response at 40 microM. There was no effect of basolateral addition of ASC, indicating a polarized transport process. The oxidized form of ASC, dehydroascorbic acid had negligible effects. The I(SC) response to ASC was completely eliminated with Na(+) ion replacement, and was also eliminated by bilateral reduction of bath Cl(-), from 137 to 2.6 mM. There was significant inhibition of the I(SC) responses to 30 microM ASC by the flavanoid quercetin (50 microM) and by 100 microM 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) and 5-ethylisopropylamiloride (EIPA), blockers of anion exchangers and sodium-proton exchangers, respectively. There was no inhibition, however, by the chloride channel blocker 5-nitro-2(3-phenylpropylamino)benzoic acid (NPPB). Phorbol 12-myristate 13 acetate (PMA), the phorbol ester activator of protein kinase C, caused a 37% decrease in the I(SC) response to ASC. Chicken-specific primers to an EST homolog of the human vitamin C transporter SVCT1 (SLC23A1) were designed and used to probe transporter expression in these cells. RT-PCR analysis demonstrated the presence of chicken SVCT1 in both cultured cells and in freshly isolated proximal tubule fragments. These data indicate the presence of an electrogenic, sodium-dependent vitamin C transporter (SVCT1) in the chick renal proximal tubule. Vitamin C transport and conservation by the kidney is likely to be especially critical in birds, due to high plasma glucose levels and resulting high levels of reactive oxygen species.
Comp Biochem Physiol A Mol Integr Physiol 2007 Mar
PMID:Vitamin C transport and SVCT1 transporter expression in chick renal proximal tubule cells in culture. 1725 85

Nuclear receptors (NRs) are transcription factors whose activity is regulated by the binding of small lipophilic ligands, including hormones, vitamins, and metabolites. Pharmacological NR ligands serve as important therapeutic agents; for example, all-trans retinoic acid, an activating ligand for retinoic acid receptor alpha (RARalpha), is used to treat leukemia. Another RARalpha ligand, (E)-S,S-dioxide-4-(2-(7-(heptyloxy)-3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-6-yl)-1-propenyl)-benzoic acid (Ro 41-5253), is a potent antagonist that has been a useful and purportedly specific probe of RARalpha function. Here, we report that Ro 41-5253 also activates the peroxisome proliferator-activated receptor gamma (PPARgamma), a master regulator of adipocyte differentiation and target of widely prescribed antidiabetic thiazolidinediones (TZDs). Ro 41-5253 enhanced differentiation of mouse and human preadipocytes and activated PPARgamma target genes in mature adipocytes. Like the TZDs, Ro 41-5253 also down-regulated PPARgamma protein expression in adipocytes. In addition, Ro 41-5253 activated the PPARgamma-ligand binding domain in transiently transfected HEK293T cells. These effects were not prevented by a potent RARalpha agonist or by depleting cells of RARalpha, indicating that PPARgamma activation was not related to RARalpha antagonism. Indeed, Ro 41-5253 was able to compete with TZD ligands for binding to PPARgamma, suggesting that Ro 41-5253 directly affects PPAR activity. These results vividly demonstrate that pharmacological NR ligands may have "off-target" effects on other NRs. Ro 41-5253 is a PPARgamma agonist as well as an RARalpha antagonist whose pleiotropic effects on NRs may signify a unique spectrum of biological responses.
Mol Pharmacol 2007 May
PMID:A widely used retinoic acid receptor antagonist induces peroxisome proliferator-activated receptor-gamma activity. 1729 5

Salt and water absorption and secretion across the airway epithelium are important for maintaining the thin film of liquid lining the surface of the airway epithelium. Movement of Cl across the apical membrane involves the CFTR Cl channel; however, conductive pathways for Cl movement across the basolateral membrane have been little studied. Here, we determined the regulation and single-channel properties of the Cl conductance (G(Cl)) in airway surface epithelia using epithelial cultures from human or bovine trachea and freshly isolated ciliated cells from the human nasal epithelium. In Ussing chamber studies, a swelling-activated basolateral G(Cl) was found, which was further stimulated by forskolin and blocked by N-phenylanthranilic acid (DPC) = sucrose > flufenamic acid = niflumic acid = glibenclamide > CdCl(2) = 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB) = DIDS = ZnCl(2) > tamoxifen > 4,4'-dinitro-2,2'-stilbene-disulfonate disodium salt (DNDS). In whole cell patch-clamp experiments, three types of G(Cl) were identified: 1) a voltage-activated, DIDS- (but not Cd-) blockable and osmosensitive G(Cl); 2) an inwardly rectifying, hyperpolarization-activated and Cd-sensitive G(Cl); and 3) a forskolin-activated, linear G(Cl), which was insensitive to Cd and DIDS. In cell-attached patch-clamp recordings, the basolateral pole of isolated ciliated cells expressed three types of Cl channels: 1) an outwardly rectifying, swelling-activated Cl channel; 2) a strongly inwardly rectifying Cl channel; and 3) a forskolin-activated, low-conductance channel. We propose that, depending on the driving force for Cl across the apical membrane, basolateral Cl channels confine Cl(-) secretion or support transcellular Cl(-) absorption.
Am J Physiol Lung Cell Mol Physiol 2007 Jun
PMID:Basolateral Cl channels in primary airway epithelial cultures. 1732 86

Thiazolidinediones are synthetic agonists for the transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma) and are therapeutically used as insulin sensitizers. Besides therapeutical benefits, potential side effects such as the induction of cell death by thiazolidinediones deserve consideration. Although PPARgamma-dependent and -independent cell death in response to thiazolidinediones has been described, we provide evidence supporting a new mechanism to account for thiazolidinedione-initiated but PPARgamma-independent cell demise. In Jurkat T cells, ciglitazone and troglitazone provoked rapid and dose-dependent cell death, whereas rosiglitazone did not alter cell viability. We found induction of apoptosis by troglitazone, whereas ciglitazone caused necrosis. Because preincubation with the reactive oxygen species (ROS) scavengers manganese (III) tetrakis(4-benzoic acid) porphyrin and vitamin C significantly inhibited ciglitazone- and partially troglitazone-mediated cell death, we suggest that ROS contribute to cytotoxicity. Assuming that ROS originate from mitochondria, studies in submitochondrial particles demonstrated that all thiazolidinediones inhibited complex I of the mitochondrial respiratory chain. However, only ciglitazone and troglitazone lowered complex II activity as well. Pharmacological inhibition of complexes I and II documented that complex II inhibition in Jurkat cells caused massive apoptotic cell death, whereas inhibition of complex I provoked only marginally apoptosis after 4-h treatment. Therefore, inhibition of complex II by ciglitazone and troglitazone is the main trigger of cell death. ATP depletion by ciglitazone, in contrast to troglitazone, is responsible for induction of necrosis. Our results demonstrate that despite their similar molecular structure, thiazolidinediones differently affect cell death, which might help to explain some adverse effects occurring during thiazolidinedione-based therapies.
Mol Pharmacol 2007 Jun
PMID:Mechanism of thiazolidinedione-dependent cell death in Jurkat T cells. 1732 28

The Grand Canonical Monte Carlo method was used to analyse the phenomenon of adsorption of aromatic compounds (i.e. phenol, toluene, benzoic acid and salicylic acid) on the surface of the titania-silica (TiO2/SiO2) catalyst. We found that different types of interactions play important roles in the adsorption of molecules having polar and non-polar groups. Moreover, we found that the interactions between sorbate molecules are strong, and are the cause of multilayer adsorption occurring in the investigated temperature and pressure range.
J Mol Model 2007 Jul
PMID:Modeling the adsorption of aromatic compounds on the TiO2/SiO2 catalyst. 1734 Jan 10

We investigated the nonlinear dynamics of the pressure vs. hydraulic conductivity (L(p)) relationship in lung microvascular endothelial cells and demonstrate that heparan sulfates, an important component of the endothelial glycocalyx, participate in pressure-sensitive mechanotransduction that results in barrier dysfunction. The pressure vs. L(p) relationship was complex, possessing both time- and pressure-dependent components. Pretreatment of lung capillary endothelial cells with heparanase III completely abolished the pressure-induced increase in L(p). This extends our (7) previous observation regarding heparan sulfates as mechanotransducers for shear stress. Inhibition of nitric oxide (NO) synthase with L-NAME (N(G)-nitro-L-arginine methyl ester HCl) and intracellular scavenging of reactive oxygen species (ROS) by TBAP [tetrakis-(4-benzoic acid) porphorin] significantly attenuated the pressure-induced L(p) response. Intracellular NO/ROS were visualized using the fluorescent dye, 2'7'-dichlorofluorescein diacetate (DCFA), and cells demonstrated a pressure-induced increase in intracellular fluorescence. Heparanase pretreatment significantly reduced the pressure-induced increase in intracellular fluorescence, suggesting that cell-surface heparan sulfates directly participate in mechanotransduction that results in NO/ROS production and increased permeability. This is the first report to demonstrate a role for heparan sulfates in pressure-mediated mechanotransduction and barrier regulation. These observations may have important clinical implications during conditions where pulmonary microvascular pressure is elevated.
Am J Physiol Lung Cell Mol Physiol 2007 Jun
PMID:Heparan sulfates mediate pressure-induced increase in lung endothelial hydraulic conductivity via nitric oxide/reactive oxygen species. 1735 Oct 62


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