interacts_with DB00819?
The role of aquaporin-1 ( P29972 ) expression in a murine model of lipopolysaccharide-induced acute lung injury . A murine model of lipopolysaccharide ( LPS ) -induced acute lung injury ( ALI ) was used to evaluate whether aquaporin-1 ( P29972 ) is involved in lung inflammation and lung edema formation . Swiss strain mice ( n = 122 ) had LPS ( 5 mg/kg ) instilled intratracheally ( IT ) , and were then treated with either 0.9 % saline or dexamethasone ( 5 mg/kg/day ) . Mice were euthanized at 2 days and 7 days after treatment . Inflammatory cytokines ( P01375 , P05231 ) , protein concentration in bronchoalveolar lavage ( BAL ) fluid , lung wet-to-dry weight ratio , histology , immunohistochemistry , and P29972 Western blot were performed . Lung wet-to-dry weight ratio and lung vascular permeability were also measured in the P29972 knockout mice ( n = 9 ) that received IT LPS ( 5 mg/kg ) at 2 days . Intratracheal instillation of LPS produced a severe lung injury at 2 days , characterized by elevation of P01375 , P05231 in the BAL fluid , and by histological changes consistent with increased lung vascular permeability and neutrophil infiltration . P29972 -immunoreactivity in the pulmonary capillary endothelium was reduced at 2 days and 7 days . Administration of dexamethasone improved LPS-induced ALI and retained expression of P29972 . However , depletion of P29972 did not affect lung edema formation , lung vascular permeability , or lung histology . The results suggest that although P29972 expression is decreased after lung injury , depletion of P29972 does not alter lung inflammation and lung edema induced by LPS . DB06693 can cause P55008 arrest and induce apoptosis in pulmonary artery smooth muscle cells through a P46527 -independent pathway . Advanced pulmonary arterial hypertension is characterized by extensive vascular remodeling that is usually resistant to vasodilator therapy . DB06693 is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A ( HMG- DB01992 ) reductase , the rate-limiting step for cholesterol synthesis . P04035 inhibitors have been shown to upregulate the cyclin-dependent kinase inhibitor P46527 and to block cell proliferation through cholesterol-independent pathways . The aim of this study was to determine the effect of mevastatin on DNA synthesis , cell cycle progression , and cell proliferation in rat pulmonary artery smooth muscle cells ( PASMCs ) . We found that mevastatin induced P55008 arrest and decreased DNA synthesis in rat PASMCs and did so in association with an increase in both total and cyclin E-bound P46527 . This caused a marked decrease in cyclin E kinase activity , which suggests an important role for P46527 in the ability of mevastatin to induce P55008 arrest . However , in PASMCs lacking functional P46527 , mevastatin still decreased cyclin E kinase activity , caused P55008 arrest , and decreased DNA synthesis . In P46527 -deficient PASMCs , mevastatin induced a greater reduction of cyclin E protein levels ( to 35 % of control ) than in wild-type cells ( to 70 % of control ) and also reduced the phosphorylation of cdk2 on threonine 160 . DB06693 also caused apoptosis in both wild-type and P46527 -deficient PASMCs and was able to do so at a dose that did not induce cell cycle arrest . These data suggest that P04035 inhibitors can both inhibit cell proliferation and induce apoptosis in PASMCs through P46527 -independent pathways and may be important therapeutic agents in pulmonary arterial hypertension . DB00819 inhibits stimulated feline liver and gallbladder bicarbonate secretion . Bile acidification is a key factor in preventing calcium carbonate precipitation and gallstone formation . P00918 ( CA II ) , that is inhibited by acetazolamide , plays a role in regulation of the acid-base balance in many tissues . This study examines the effect of acetazolamide on secretin- and vasoactive intestinal peptide ( P01282 ) -stimulated gallbladder mucosal bicarbonate and acid secretion . Gallbladders in anaesthetized cats were perfused with a bicarbonate buffer bubbled with CO2 in air . In 20 experiments P01282 ( 10 microg kg(-1) h(-1) ) and in 10 experiments secretin ( 4 microg kg(-1) h(-1) ) were infused continuously intravenous ( i.v. ) . Hepatic bile and samples from the buffer before and after perfusion of the gallbladder were collected for calculation of ion and fluid transport . During basal conditions a continuous secretion of H+ by the gallbladder mucosa was seen . Intravenous infusion of vasoactive intestinal peptide ( P01282 ) and secretin caused a secretion of bicarbonate from the gallbladder mucosa ( P < 0.01 ) . This secretion was reduced by intraluminal ( i.l. ) acetazolamide ( P < 0.01 ) . Bile flow was enhanced by infusion of P01282 and secretin ( P < 0.01 ) but this stimulated outflow was not affected by i.v. acetazolamide . The presence of CA II in the gallbladder was demonstrated by immunoblotting . Biliary CA activity has an important function in the regulation of P01282 - and secretin-stimulated bicarbonate secretion across the gallbladder mucosa . MAPK induces P29972 expression in astrocytes following injury . P55087 ( P55087 ) is the principle water channel and the primary route for water transport across astrocytic membranes . P55087 co-localizes with Kir4.1 channels at astrocytic endfeet , and it has been suggested that these channels cooperate in K(+) and water homeostasis . In response to injury , two additional aquaporins , P29972 and AQP9 , can be detected in astrocytes , yet neither is found in cultured astrocytes , and therefore their contribution to astrocyte water uptake and biology is poorly investigated . In this study , we used a cortical stab wound assay to demonstrate an upregulation of P29972 following injury in reactive glia . We were able to mimic such injury in astrocytic cultures and show that P29972 expression is induced within 16 h following injury in vitro . This induction could be blocked by inhibition of Q02750 /2 using U0126 , and suggests that P29972 is specifically induced in reactive astrocytes via the mitogen-activated protein kinases signaling pathway . Effect of acetazolamide on aquaporin-1 and fluid flow in cultured choroid plexus . DB00819 ( AZA ) , used in treatment of early or infantile hydrocephalus , is effective in some cases , while its effect on the choroid plexus ( CP ) remains ill-defined . The drug reversibly inhibits aquaporin-4 ( P55087 ) , the most ubiquitous " water pore " in the brain , and perhaps modulation of P29972 ( located apically on CP cells ) by AZA may reduce cerebrospinal fluid ( P04141 ) production . We sought to elucidate the effect of AZA on P29972 and fluid flow in CP cell cultures.CP tissue culture from 10-day Sprague-Dawley rats and a TRCSF-B cell line were grown on Transwell permeable supports and treated with 100 μM AZA . Fluid assays to assess direction and extent of fluid flow , and P29972 expression patterns by immunoblot , Immuncytochemistry ( ICC ) , and quantitative reverse transcriptase polymerase chain reaction ( qRT-PCR ) were performed.Immunoblots and ICC analyses showed a decrease in P29972 protein shortly after AZA treatment ( lowest at 12 h ) , with transient P29972 reduction mediated by mRNA expression ( lowest at 6 h ) . Transwell fluid assays indicated a fluid shift at 2 h , before significant changes in P29972 mRNA or protein levels.Timing of AZA effect on P29972 suggests the drug alters protein transcription , while affecting fluid flow by a concomitant method . It is plausible that other mechanisms account for these phenomena , as the processes may occur independently . Archaebacterial elongation factor is ADP-ribosylated by diphtheria toxin . Archaebacteria have been defined as a ' third primary kingdom ' of cells in addition to the urkaryotes and the eubacteria . While the latter two correspond approximately to the conventional categories eukaryotes and prokaryotes respectively , the Archaebacteria have up to now comprised four groups of microorganisms : the methanogenic bacteria , the extremely halophilic bacteria and the two thermoacidophilic genera Sulfolobus and Thermoplasma . Based on ribosomal RNA sequence homologies and lipid composition , they apparently form a distinct group . Furthermore they possess or lack typical biochemical markers of both the eukaryotes and the prokaryotes , as well as having unique properties not found elsewhere . Altogether , this indicates that they are not closer to either one of the classical categories . One clear-cut difference between prokaryotes and eukaryotes is the diphtheria toxin reaction , which catalyses the covalent binding of adenosine diphosphate-ribose ( DB02059 ) to the eukaryotic peptide elongation factor P13639 in contrast to the homologous prokaryotic factor EF-G . We report here that diphtheria toxin also catalyses the ADP-riboslation of archaebacterial elongation factors . In this respect , these factors have to be assigned to the P13639 type ; we suppose that the ADP-ribosylatable structure arising so early in evolution is of fundamental importance for the elongation process . Hyperosmolar mannitol simulates expression of aquaporins 4 and 9 through a p38 mitogen-activated protein kinase-dependent pathway in rat astrocytes . The membrane pore proteins , aquaporins ( AQPs ) , facilitate the osmotically driven passage of water and , in some instances , small solutes . Under hyperosmotic conditions , the expression of some AQPs changes , and some studies have shown that the expression of P29972 and P55064 is regulated by MAPKs . However , the mechanisms regulating the expression of P55087 and AQP9 induced by hyperosmotic stress are poorly understood . In this study , we observed that hyperosmotic stress induced by mannitol increased the expression of P55087 and AQP9 in cultured rat astrocytes , and intraperitoneal infusion of mannitol increased P55087 and AQP9 in the rat brain cortex . In addition , a p38 MAPK inhibitor , but not P29323 and JNK inhibitors , suppressed their expression in cultured astrocytes . AQPs play important roles in maintaining brain homeostasis . The expression of P55087 and AQP9 in astrocytes changes after brain ischemia or traumatic injury , and some studies have shown that p38 MAPK in astrocytes is activated under similar conditions . Since mannitol is commonly used to reduce brain edema , understanding the regulation of AQPs and p38 MAPK in astrocytes under hyperosmotic conditions induced with mannitol may lead to a control of water movements and a new treatment for brain edema . Retinoic acid treatment enhances the acetylcholine contents in the human teratocarcinoma cell line NTera-2 . Human NTera-2/clone D1 teratocarcinoma cells are induced by retinoic acid ( RA ) to differentiate into postmitotic cells with morphological and biochemical characteristics of embryonic human neurones . Currently only limited information concerning peptide-contents and neurotransmitter pools of these cells is available . Zeller and Strauss [ Int. J. Dev. Neurosci. 1995;13(5):437 ] described an increase in choline acetyltransferase ( P28329 ) activity in RA-treated , but not in untreated NTera-2 cells , suggesting the induction of a cholinergic phenotype during treatment with RA . In the present study we investigated the effect of RA-differentiation on the amount of the neurotransmitters acetylcholine ( ACh ) , and dopamine in NTera-2 in order to specify the transmitter phenotype induced by RA-differentiation . We found that a 4-week treatment of NTera-2 cells with 10 microM RA markedly increased the ACh-content of these cells , while dopamine levels were unchanged . Depolarisation with potassium ( 60 mM ) enhanced ACh-outflow in the differentiated cells in a Ca(++) dependent way . Also neuropeptides like DB05875 and P01303 were detectable in the undifferentiated NTera-2 cells , while vasointestinal peptide ( P01282 ) could not be found in either precursor or RA-differentiated cells . Differentiation was accompanied by a marked reduction of neutral endopeptidase enzyme activity and aminopeptidase activity . From these observations it was concluded that RA induces a cholinergic neurochemical differentiation of this human teratocarcinoma cell line , and that these cells might provide a model system to investigate cholinergic properties of human origin . Polymorphisms associated with egg number at 300 days of age in chickens . We looked for variations that could be associated with chicken egg number at 300 days of age ( EN300 ) in seven genes of the hypothalamic-pituitary-gonadal axis , including gonadotrophin-releasing hormone-I ( DB00644 ) , P30968 ( GnRHR ) , neuropeptide Y ( P01303 ) , dopamine D2 receptor ( P14416 ) , vasoactive intestinal polypeptide ( P01282 ) , P01282 receptor-1 ( VIPR-1 ) , prolactin ( PRL ) , and the QTL region between 87 and 105 cM of the Z chromosome . Ten mutations in the seven genes were chosen to do marker-trait association analyses in a population comprising 1310 chickens , which were obtained from a company located in Guangdong Province of China . The C1704887T of VIPR-1 was found to have a highly significant association with EN300 . The T5841629C of P14416 and the C1715301T of VIPR-1 were significantly associated with EN300 . A highly significant association was also found between the C1704887T-C1715301T haplotypes of VIPR-1 and EN300 . H1H3 had the highest EN300 . Four PCR-RFLP variations in the candidate QTL region were selected to investigate their genetic effects on EN300 . The haplotypes of T32742468C-G32742603A in this region showed a highly significant association with EN300 . Bioinformatics analyses showed that both T32742468C and G32742603A were located in intron 1 of the SH3-domain P62993 -like 2 ( Q99962 ) gene . We conclude that five SNPs , including C1704887T and C1715301T of VIPR-1 , T5841629C of P14416 , and T32742468C and G32742603A of Q99962 , would be useful as markers for breeding to increase chicken EN300 . DB06698 ameliorates olanzapine-induced weight gain through modulation of histaminergic , P01303 and AMPK pathways . Olanzapine is widely used to treat schizophrenia and other disorders , but causes adverse obesity and other metabolic side-effects . Both animal and clinical studies have shown that co-treatment with betahistine ( a histaminergic H1 receptor agonist and H3 receptor antagonist ) is effective for ameliorating olanzapine-induced weight gain/obesity . To reveal the mechanisms underlying these effects , this study investigated the effects of co-treatment of olanzapine and betahistine ( O+B ) on expressions of histaminergic H1 receptor ( P35367 ) , AMP-activated protein kinase ( AMPK ) , neuropeptide Y ( P01303 ) , and proopiomelanocortin ( P01189 ) in the hypothalamus associated with reducing olanzapine-induced weight gain . Olanzapine significantly upregulated the mRNA and protein expressions of P35367 , while O+B co-treatment significantly downregulated the P35367 levels , compared to the olanzapine-only treatment group . The P01303 mRNA expression was significantly enhanced by olanzapine , but it was significantly reversed by O+B co-treatment . The hypothalamic P35367 expression was positively correlated with total food intake , and P01303 expression . Olanzapine also increased AMPKα activation measured by the AMPKα phosphorylation ( pAMPKα ) /AMPKα ratio compared with controls , whereas O+B co-treatment decreased the pAMPKα/AMPKα ratio , compared with olanzapine only treatment . The pAMPKα/AMPKα ratio was positively correlated with total food intake and P35367 expression . Although olanzapine administration decreased the P01189 mRNA level , this level was not affected by O+B co-treatment . Therefore , these results suggested that co-treatment with betahistine may reverse olanzapine-induced body weight gain via the P35367 - P01303 and P35367 -pAMPKα pathways . Newly recognized DB00644 receptors : function and relative role . Hypothalamic gonadotropin releasing hormone ( DB00644 I ) and its pituitary receptor are responsible for the CNS regulation of reproduction . However , a second DB00644 ( DB00644 II ) is also expressed in humans and a gene that resembles the Q96P88 in fish has been identified in humans and monkeys . The amino-acid sequence of this newly identified , seven-transmembrane , G-protein-coupled receptor in monkeys differs from the human DB00644 I receptor by having a C-terminal , cytoplasmic tail . DB00644 II is approximately 400-fold more potent at DB00644 II receptors than DB00644 I receptors . DB00644 I directly inhibits proliferation of human tumor cells , and DB00644 II and its receptor might have a similar role . Limited progress has been made , however , because of difficulty translating the mRNA that encodes the human Q96P88 . Nevertheless , such receptors are likely to exist in humans because DB00644 II is more inhibitory to tumor cell replication than DB00644 I , and DB00644 I and DB00644 II have reciprocal effects on human decidual stromal cells in culture . The focus of this review is the identity of a possible translatable , functional Q96P88 in humans . The two possibilities considered are either that Q96P88 mRNA is expressed that encodes either 5 or 7 transmembrane domains or that a DB00644 II-responsive complex is formed by the DB00644 I receptor and fragments derived from the Q96P88 . DB08626 -induced neprilysin inhibition raises amyloid beta levels in rabbit cortex and cerebrospinal fluid . Studies on the pathogenesis of Alzheimer 's disease ( AD ) suggest overproduction of amyloid beta ( Abeta ) may not be the only pathogenic route to AD . Decreased degradation of Abeta is another possible disease mechanism . P08473 is a neutral endopeptidase that has been proposed to be the major enzyme responsible for Abeta degradation . Studies have reported correlations between Abeta deposition and neprilysin activity in the human brain . This study shows that intracerebroventricular infusion of thiorphan , a neprilysin inhibitor , raises cortical and cerebrospinal fluid ( P04141 ) Abeta concentrations in rabbits . Rabbits treated with thiorphan for 5 days had levels of P04141 and cortical Abeta40 that were 147 and 142 % of the control group , respectively . Results for Abeta42 showed a similar trend . The results indicate that age-related decreases of neprilysin could lead to increased brain concentrations of Abeta , plaque formation , and AD . Concomitant oral and intravenous pharmacokinetics of trametinib , a MEK inhibitor , in subjects with solid tumours . AIMS : The aim of this phase 1 , single centre , open label study in four patients with solid tumours was to determine the absolute bioavailability of a 2 mg oral dose of trametinib . DB08911 is an orally bioavailable , reversible and selective allosteric inhibitor of Q02750 and P36507 activation and kinase activity . METHODS : A microtracer study approach , in which a 5 μg radiolabelled i.v. microdose of trametinib was given concomitantly with an unlabelled 2 mg oral tablet formulation , was used to recover i.v. and oral pharmacokinetic parameters , simultaneously . RESULTS : The least-squares mean ( 90 % confidence interval ) absolute bioavailability of trametinib ( 2 mg tablet ) was 72.3 % ( 50.0 % , 104.6 % ) . Median tmax after oral administration was 1.5 h and the geometric mean terminal half-life was 11 days . The geometric mean clearance and volume of distribution after i.v. administration were 3.21 l h(-1) and 976 l , respectively , resulting in a terminal elimination half-life of 11 days . CONCLUSIONS : DB08911 absolute bioavailability was moderate to high , whereas first pass metabolism was low . Aberrant accentuation of neurofibrillary degeneration in the hippocampus of Alzheimer 's disease with amyloid precursor protein 717 and presenilin-1 gene mutations . This study reports correlation of the hippocampal neurofibrillary tangles ( NFT ) density with beta-amyloid ( Abeta ) precursor protein ( P05067 ) 717 mutation , presenilin ( PS ) -1 mutation and apolipoprotein E ( P02649 ) e4 alleles ( E4 ) , being graded as 3 forms ( no-E4 , one-E4 and two-E4 ) in autopsied brains from patients with familial and non-familial Alzheimer 's disease ( AD ) . We studied the density of NFT-free neurons , intracellular NFT ( I-NFT ) , extracellular NFT ( E-NFT ) and total NFT ( I-NFT plus E-NFT ) in the six hippocampal subdivisions : cornu ammonis ( CA ) 1- P22748 , subiculum and entorhinal cortex . The P05067 mutation cases showed significantly higher total NFT density in the P00915 - P00918 region , and the P49768 mutation cases also showed higher density of total NFT in the P00915 - P07451 than non-familial cases . Moreover , high densities of the E-NFT contributed to these high total NFT densities . Non-familial AD cases showed a stereotypical NFT distribution with entorhinal accentuation in the hippocampus irrespective of E4 frequency . Thus , P05067 and P49768 mutations predominantly affect the CA regions with profound neurodegeneration , which contributes early and severe clinical features of familial AD . Glutamatergic regulation of the p70S6 kinase in primary mouse neurons . Brief glutamatergic stimulation of neurons from fetal mice , cultured in vitro for 6 days , activates the P42345 -S6 kinase , P27361 /2 and Akt pathways , to an extent approaching that elicited by brain-derived neurotrophic factor . In contrast , sustained glutamatergic stimulation inhibits P29323 , Akt , and S6K . Glutamatergic activation of S6K is calcium/calmodulin-dependent and is prevented by inhibitors of calcium/calmodulin-dependent protein kinase 2 , phosphatidylinositol 3-OH-kinase and by rapamycin . 2-Amino-5-phosphonovaleric acid , an inhibitor of N'-methyl-D-aspartate receptors , abolishes glutamatergic activation of P27361 /2 but not the activation of P42345 -S6K ; the latter is completely abolished by inhibitors of voltage-dependent calcium channels . Added singly , dopamine gives slight , and norepinephrine a more significant , activation of P29323 and S6K ; both catecholeamines , however , enhance glutamatergic activation of S6K but not P29323 . After 12 days in culture , the response to direct glutamatergic activation is attenuated but can be uncovered by suppression of gamma-aminobutyric acid interneurons with bicuculline in the presence of the weak K(+) channel blocker 4-aminopyridine ( DB06637 ) . This selective synaptic activation of P42345 -S6K is also resistant to APV and inhibited by Ca(2+) channel blockers and higher concentrations of glutamate . P13639 ( P13639 ) is phosphorylated and inhibited by the eEF2 kinase ( P62158 kinase III ) ; the latter is inhibited by the S6K or Rsk . DB11562 / DB06637 or DB00761 -induced depolarization reduces , whereas higher concentrations of glutamate increases , P13639 phosphorylation . Thus the P42345 -S6K pathway in neurons , a critical component of the late phase of LTP , is activated by glutamatergic stimulation in a calcium/calmodulin-dependent fashion through a calcium pool controlled by postsynaptic voltage-dependent calcium channels , whereas sustained stimulation of extrasynaptic glutamate receptors is inhibitory . Electrostatic steering at acetylcholine binding sites . The electrostatic environments near the acetylcholine binding sites on the nicotinic acetylcholine receptor ( nAChR ) and acetylcholinesterase were measured by diffusion-enhanced fluorescence energy transfer ( DEFET ) to determine the influence of long-range electrostatic interactions on ligand binding kinetics and net binding energy . Changes in DEFET from variously charged Tb3+ -chelates revealed net potentials of -20 mV at the nAChR agonist sites and -14 mV at the entrance to the P22303 active site , in physiological ionic strength conditions . The potential at the alphadelta-binding site of the nAChR was determined independently in the presence of DB01199 to be -14 mV ; the calculated potential at the alphagamma-site was approximately threefold stronger than at the alphadelta-site . By determining the local potential in increasing ionic strength , Debye-Hückel theory predicted that the potentials near the nAChR agonist binding sites are constituted by one to three charges in close proximity to the binding site . Examination of the binding kinetics of the fluorescent acetylcholine analog dansyl- P13671 -choline at ionic strengths from 12.5 to 400 mM revealed a twofold decrease in association rate . Debye-Hückel analysis of the kinetics revealed a similar charge distribution as seen by changes in the potentials . To determine whether the experimentally determined potentials are reflected by continuum electrostatics calculations , solutions to the nonlinear Poisson-Boltzmann equation were used to compute the potentials expected from DEFET measurements from high-resolution models of the nAChR and P22303 . These calculations are in good agreement with the DEFET measurements for P22303 and for the alphagamma-site of the nAChR . We conclude that long-range electrostatic interactions contribute -0.3 and -1 kcal/mol to the binding energy at the nAChR alphadelta- and alphagamma-sites due to an increase in association rates . Identification of a novel pituitary-specific chicken gonadotropin-releasing hormone receptor and its splice variants . In all vertebrates , DB00644 regulates gonadotropin secretion through binding to a specific receptor on the surface of pituitary gonadotropes . At least two forms of DB00644 exist within a single species , and several corresponding DB00644 receptors ( GNRHRs ) have been isolated with one form being pituitary specific . In chickens , only one type of widely expressed P30968 has previously been identified . The objectives of this study were to isolate a chicken pituitary-specific P30968 and to determine its expression pattern during a reproductive cycle . Using a combined strategy of PCR and rapid amplification of cDNA ends ( RACE ) , a new P30968 ( chicken Q96P88 ) and two splice variants were isolated in domestic fowl ( Gallus gallus domesticus ) . Q8N1N2 -length Q96P88 and one of its splice variant mRNAs were expressed exclusively in the pituitary , whereas mRNA of the other splice variant was expressed in most brain tissues examined . The deduced amino acid sequence of full-length chicken Q96P88 reveals a seven transmembrane domain protein with 57 % -65 % homology to nonmammalian GNRHRs . Semiquantitative real-time PCR revealed that mRNA levels of full-length chicken Q96P88 in the pituitary correlate with the reproductive status of birds , with maximum levels observed during the peak of lay and 4 wk postphotostimulation in females and males , respectively . Furthermore , DB00644 stimulation of GH3 cells that were transiently transfected with cDNA that encodes chicken Q96P88 resulted in a significant increase in inositol phosphate accumulation . In conclusion , we isolated a novel P30968 and its splice variants in chickens , and spatial and temporal gene expression patterns suggest that this receptor plays an important role in the regulation of reproduction . Is phentermine an inhibitor of monoamine oxidase ? A critical appraisal . DB00191 produces a spectrum of concentration-dependent biochemical effects . It interacts with NE transporters at 0.1 microM , DA transporters at about 1 microM , 5-HT transporters at 15 microM and P21397 at about 100 microM . When administered at typical anorectic doses , phentermine primarily interacts with DA and NE transporters and does not produce biochemical or neurochemical effects which would occur if it were inhibiting P21397 . Some other explanation other than MAO inhibition must be sought to explain how oral phentermine increases platelet 5-HT , since platelet P27338 does not metabolize platelet 5-HT , and since amphetamine-type drugs are even weaker inhibitors of P27338 than P21397 . Clinical studies in humans have shown that amphetamine , which is a more potent inhibitor of P21397 than phentermine , does not inhibit P21397 at therapeutic doses . Neither phentermine alone , fluoxetine alone or their combined use have been associated with cardiac valvulopathy , and clinical experience has shown their combined use to be free of significant adverse effects . Viewed collectively , there appears to be no data to support the hypothesis that phentermine inhibits MAO at typical therapeutic doses . Expression of aquaporins in Xenopus laevis oocytes and glial cells as detected by diffusion-weighted 1H NMR spectroscopy and photometric swelling assay . Expression of aquaporins ( AQP ) and water permeability were studied in Xenopus laevis oocytes and immobilized glial cells by a pulsed-field gradient spin echo NMR technique and a photometric swelling assay . Oocytes injected with poly(A) RNA from P13671 -BU-1 cells showed increased swelling behavior under hypoosmotic stress due to expressed water channels as compared to control oocytes . The swelling could be reversibly inhibited by HgCl2 . Furthermore , the intracellular relaxation time and the apparent intracellular diffusion coefficient of water in oocytes were determined by diffusion-weighted 1H NMR experiments to be P24752 =36 ms and Dapp , intra=0.18x10-3 mm2/s . In immobilized P13671 and F98 cells the mean exchange time of intracellular water was found to be 51 ms which increased to 75 ms upon chronic treatment ( 4 days ) in hypertonic medium . Additional hybrid depletion experiments with antisense oligonucleotides directed against P29972 were performed on oocytes and P13671 cells . Moreover , different water channel subtypes of glial cells were assessed by a reverse transcriptase polymerase chain reaction assay . With this , the mRNA encoding P29972 could be detected in primary cultures and glial cell lines , whereas P55087 mRNA was found in astroglia-rich primary cultures , but not in F98 and P13671 cells . Our results show that water permeability in glial cells is mainly mediated by water channels which play an important role in the regulation of water flow in brain under normal and pathological conditions . Agents with selective estrogen receptor ( ER ) modulator activity induce apoptosis in vitro and in vivo in ER-negative glioma cells . Tamoxifen , a member of the selective estrogen receptor modulator ( SERM ) family , is widely used in the treatment of estrogen receptor ( ER ) -expressing breast cancer . It has previously been shown that high-dose tamoxifen has cytotoxic activity against glioma cells , but whether this effect is drug specific or represents a general property of SERMs is unknown . In this study , we demonstrate that tamoxifen and DB05487 , a novel benzopyranone with SERM activity , induce glioma cell apoptosis in a dose- and time-dependent manner . Moreover , administration of tamoxifen and DB05487 suppresses tumor growth in vivo and extends animal survival in glioma xenograft models . None of the eight glioma cell lines examined express either P03372 or -beta , suggesting the mechanism for tamoxifen- and DB05487 -induced glioma cell apoptosis is independent of the ER signaling pathway . Complementary DNA microarray expression profiling allowed us to identify a subset of genes specifically regulated by tamoxifen and DB05487 , and not by other apoptotic stimuli , including nuclear factor ( NF ) -kappaB with its target genes IEX-3 , P04179 , P05231 , and P10145 . We demonstrate that suppression of NF-kappaB activation markedly enhances SERM-induced apoptosis , suggesting a role for NF-kappaB in protecting glioma cells from SERM-induced cytotoxicity . These findings demonstrate for the first time that a SERM other than tamoxifen can induce glioma cell apoptosis in vitro and in vivo and that the clinical efficacy of SERMs for the treatment of malignant gliomas could potentially be enhanced by simultaneous inhibition of the NF-kappaB pathway . DB00819 inhibits osmotic water permeability by interaction with aquaporin-1 . DB09145 channel proteins , known as aquaporins , are transmembrane proteins that mediate osmotic water permeability . In a previous study , we found that acetazolamide could inhibit osmotic water transportation across Xenopus oocytes by blocking the function of aquaporin-1 ( P29972 ) . The purpose of the current study was to confirm the effect of acetazolamide on water osmotic permeability using the human embryonic kidney 293 ( HEK293 ) cells transfected with pEGFP/ P29972 and to investigate the interaction between acetazolamide and P29972 . The fluorescence intensity of HEK293 cells transfected with pEGFP/ P29972 , which corresponds to the cell volume when the cells swell in a hyposmotic solution , was recorded under confocal laser fluorescence microscopy . The osmotic water permeability was assessed by the change in the ratio of cell fluorescence to certain cell area . DB00819 , at concentrations of 1 and 10muM , inhibited the osmotic water permeability in HEK293 cells transfected with pEGFP/ P29972 . The direct binding between acetazolamide and P29972 was detected by surface plasmon resonance . P29972 was prepared from rat red blood cells and immobilized on a CM5 chip . The binding assay showed that acetazolamide could directly interact with P29972 . This study demonstrated that acetazolamide inhibited osmotic water permeability through interaction with P29972 . Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual 's response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome . Cutting edge : resistance to apoptosis and continuous proliferation of dendritic cells deficient for P01375 receptor-1 . The individual roles of the two TNFRs on dendritic cells ( DC ) are poorly understood . Investigating bone marrow-derived DC from TNFR-deficient mice , we found that cultures from P19438 (-/-) mice continue to form proliferating clusters for 6-9 mo . In contrast , DC derived from wild-type , P20333 (-/-) , or P19438 /2(-/-) mice survived for only 3-4 wk . DC obtained from these P19438 (-/-) long term cultures ( LTC ) mice show an unusual mixed immature/mature phenotype . The continuous proliferation of the LTC is GM- P04141 dependent and correlates with decreased protein levels of the cyclin-dependent kinase inhibitors p27( P46527 ) and P38936 (CIP1) . Prolonged survival of P19438 (-/-) DC appears to be independent from NF-kappaB and Bcl-2 pathways and is rather enabled by the down-regulation of CD95 , resulting in the resistance to P48023 -induced apoptosis . These data point to proapoptotic signals mediated via P19438 and antiapoptotic signals mediated via P20333 in DC . DB00819 : future perspective in topical glaucoma therapeutics . Through this review it is contemplated that acetazolamide ( Q9Y6V0 ) , an age-old treatment for glaucoma with a myriad of side effects and inadequate topical effectiveness , may be formulated into a topically effective agent by utilizing various newer formulation approaches of ocular drug delivery . Even though it has a poor solubility and penetration power , various studies mentioned in the review indicate that it is possible to successfully formulate topically effective Q9Y6V0 by using : ( i ) high concentration of the drug , ( ii ) surfactant gel preparations of Q9Y6V0 , ( iii ) Q9Y6V0 loaded into liposomes , ( iv ) cyclodextrins to increase the solubility and hence bioavailability of Q9Y6V0 , and ( v ) viscolyzers and other polymers either alone or in combination with cyclodextrins . With the advent of newer topical carbonic anhydrase inhibitors ( CAIs ) like dorzolamide and brinzolamide , a localized effect with fewer side effects is expected . But whenever absorbed systemically , a similar range of adverse effects ( attributable to sulphonamides ) may occur upon use . Furthermore , oral Q9Y6V0 is reported to be more physiologically effective than 2 % dorzolamide hydrochloride administered topically , even though in isolated tissues dorzolamide appears to be the most active as it shows the lowest IC(50) values for P00918 and P22748 [ M.F. Surgue , J. Ocular Pharmacol. Ther. 12 ( 1996 ) 363-376 ] . Hence , there exists considerable scope for the development of more/equally effective and inexpensive topically effective formulations of Q9Y6V0 . The use of various formulation technologies discussed in this review can provide a fresh impetus to research in this area .