MH_dev_222

DB00144 MEN synthase - 1 and - 2 are localized to mitochondria-associated membranes . We report the subcellular localization of enzymes involved in phosphatidylserine biosynthesis in mammalian cells . Several lines of evidence suggest that phosphatidylserine synthase - 1 ( PSS 1 ) is highly enriched in mitochondria-associated membranes ( MAM ) and is largely excluded from the bulk of the endoplasmic reticulum ( ER ) . Taking advantage of the substrate specificity of PSS 1 , we showed that ( i ) MAM contain choline exchange activity , whereas this activity is very low in the bulk of the ER , ( ii ) serine exchange activity is inhibited by choline to a much greater extent in MAM than in ER , and ( iii ) MAM use phosphatidylcholine and phosphatidylethanolamine as substrates for phosphatidylserine biosynthesis , whereas the ER utilizes only phosphatidylethanolamine . According to immunoblotting of proteins from both CHO - P04264 REA cells and murine liver , PSS 1 is localized to MAM , and in hepatoma cells stably expressing PSS 1 this protein is highly enriched in MAM . Since the ER contains serine and ethanolamine exchange activities , we had predicted that Q9BVG9 would account for the serine exchange activity in the ER . Unexpectedly , using immunoblotting experiments , we found that ( i ) Q9BVG9 of CHO - P04264 REA cells is present only in MAM and ( ii ) Q9BVG9 is restricted to MAM of McArdle cells expressing recombinant Q9BVG9 . These data leave open the question of which enzyme imparts PSS activity to the ER and suggest that a third isoform of PSS might be located in the ER .

Cell cycle actions of parathyroid hormone-related protein in non-small cell lung carcinoma . P12272 REA ( P12272 REA ) , a paraneoplastic protein expressed by two-thirds of human non-small cell lung cancers , has been reported to slow progression of lung carcinomas in mouse models and to lengthen survival of patients with lung cancer . This study investigated the effects of ectopic expression of P12272 REA on proliferation and cell cycle progression of two human lung adenocarcinoma cell lines that are normally P12272 REA negative . Stable transfection with P12272 REA decreased H1944 cell DNA synthesis , measured by thymidine incorporation , bromodeoxyuridine uptake , and MTT proliferation assay . A substantial fraction of P12272 REA - positive cells was arrested in or slowly progressing through P55008 . P12004 REA D2 and cyclin A2 protein levels were 60-70 % lower in P12272 REA - expressing cells compared with control cells ( P < 0.05 , N = 3 independent clones per group ) , while expression of p27 ( Kip 1 ) , a cyclin-dependent kinase inhibitor , was increased by 35 + / - 9 % ( mean + / - SE , P < 0.05 ) in the presence of P12272 REA . Expression of other cyclins , including cyclins D1 and D3 , and cyclin-dependent kinases was unaffected by P12272 REA . P12272 REA did not alter the phosphorylation state of Rb , but decreased cyclin-dependent kinase ( CDK ) 2 - cyclin A2 complex formation . Ectopic expression of P12272 REA stimulated P29323 REA phosphorylation . In MV522 cells , P12272 REA had similar effects on DNA synthesis , cyclin A2 expression , P06400 REA levels , P24941 REA - cyclin A2 association , and P29323 REA activation . In summary , P12272 REA appears to slow progression of lung cancer cells into S phase , possibly by decreasing activation of P24941 REA . Slower cancer cell proliferation could contribute to slower tumor progression and increased survival of patients with P12272 REA - positive lung cancer .

Modeling of Q14654 REA and inhibition mechanism of the natural ligand , ellagic acid , using molecular docking . Diabetes mellitus is a disorder in which blood sugar ( glucose ) levels are abnormally high because the body does not produce enough insulin to meet its needs . Post-prandial hyperglycemia ( PPHG ) is an independent risk factor for the development of macro vascular complications . It is now recognized that normalizing post-prandial blood glucose is more difficult than normalizing fasting glucose . DB01345 channels are the most widely distributed type of ion channel and are found in virtually all living organisms . The function of KATP channels is best understood in pancreatic beta cells , the membrane potential of which is responsive to external glucose concentration . Beta cells show a remarkably complex electrical bursting behavior in response to an increase in glucose level . DB00731 and DB00222 MENMAX DB00222 MEN are a class of insulin secretagog agents that lowers blood glucose levels by stimulating insulin secretion from the pancreas . These compounds interact with the DB00171 - sensitive potassium ( K + DB00171 ) channel in pancreatic beta cells . However , the side effects of these drugs overpass their uses , and the need to identify compounds with less adverse effects is exigent . In our research study , we used the natural compound ellagic acid , which is an already proven anti-carcinogen , anti-mutagen , and anticancer initiator , for its anti-diabetic activity in comparison to the two commercial drugs ( DB00731 and DB00222 MEN ) . The drugs and the compounds were docked to the DB00171 - dependent potassium channel and their energy value showed that the compound had higher binding value than the commercial drugs . Then an ADME / Tox analysis for the compound was carried out which showed that ellagic can be a possible lead molecule .

Characterisation of the cellular and molecular responses of ovine oocytes and their supporting somatic cells to pre-ovulatory levels of LH and DB00094 during in vitro maturation . The response of Graafian follicles to pre-ovulatory surge levels of DB00094 and LH in vivo triggers the terminal differentiation of granulosa cells and oocyte maturation . In polyovular species , the LH-driven signalling uses the epidermal growth factor ( P01133 REA ) - like ligands P15514 REA , O14944 REA and P35070 REA to promote oocyte maturation and cumulus expansion . This experimental series used a physiologically relevant ovine in vitro maturation ( IVM ) system to evaluate the impact of exposure to pre-ovulatory levels ( 100 ng / ml ) of LH and DB00094 on ovine cumulus cell expression of P01133 REA - like ligands in vitro . The serum-free sheep IVM system supported high levels ( 91.4 % ) of gonadotrophin-induced maturation of cumulus-enclosed oocytes and embryo development to the blastocyst stage ( 34.5 % ) . Results were equivalent to a serum-based IVM system ( 85.1 % IVM , 25.8 % blastocyst rate ; P > 0.05 ) but were significantly different ( P < 0.05 ) to serum-free medium without gonadotrophins ( 69.5 % IVM ; 8.0 % blastocyst rate ) . Ovine P35070 REA was cloned and sequenced . Gonadotrophin-induced P15514 REA , O14944 REA , P35070 REA and P00533 REA expressions were quantified in cumulus and mural granulosa cells during IVM . A rapid induction of P15514 REA expression was apparent in both cell types within 30 min of gonadotrophin exposure in vitro . P22888 REA ( LHR ) was detected in mural cells and P23945 REA in both cumulus and mural granulosa cells . The data confirm the involvement of P15514 REA and P00533 REA during gonadotrophin-induced cumulus expansion , oocyte maturation and the acquisition of developmental competence by sheep oocytes matured in vitro .

Effect of progesterone on intracellular Ca2 + homeostasis in human myometrial smooth muscle cells . Although it is well known that progesterone alters uterine contractility and plays an important role in maintenance of pregnancy , the biochemical mechanisms by which progesterone alters uterine contractility in human gestation are less clear . In this investigation we sought to identify progesterone-induced adaptations in human myometrial smooth muscle cells that may alter Ca2 + signaling in response to contractile agents . Cells were treated with vehicle or the progesterone analog medroxyprogesterone acetate ( DB00603 SUB ) for 5 days , and intracellular free Ca2 + concentration ( [ Ca2 + ] i ) was quantified after treatment with oxytocin ( OX ) or endothelin ( ET ) - 1 . OX - and ET - 1 - induced increases in [ Ca2 + ] i were significantly attenuated in cells pretreated with DB00603 SUB in a dose-dependent manner . P06401 REA antagonists prevented the attenuated Ca2 + transients induced by DB00603 SUB . P25101 REA and ETB receptor subtypes were expressed in myometrial cells , and treatment with DB00603 SUB resulted in significant downregulation of P25101 REA and ETB receptor binding . DB00603 SUB did not alter ionomycin-stimulated increases in [ Ca2 + ] i and had no effect on inositol trisphosphate-dependent or - independent release of Ca2 + from internal Ca2 + stores . We conclude that adaptations of Ca2 + homeostasis in myometrial cells during pregnancy may include progesterone-induced modification of receptor-mediated increases in [ Ca2 + ] i .

Heterozygous missense mutations in the insulin gene are linked to permanent diabetes appearing in the neonatal period or in early infancy : a report from the French ND ( Neonatal Diabetes ) Study Group . OBJECTIVE : Permanent neonatal diabetes ( P01160 REA ) is defined by chronic hyperglycemia due to severe nonautoimmune insulin deficiency diagnosed in the first months of life . Several genes , including Q14654 REA and Q09428 REA , which encode the two subunits of the DB00171 - sensitive K ( + ) channel ( K ( DB00171 ) channel ) can cause P01160 REA . Mutations in the insulin ( P01308 REA ) gene have been recently described in families with neonatal diabetes . Our study aimed to investigate the genetic anomalies and clinical heterogeneity in P01160 REA patients who are negative for a K ( DB00171 ) channel mutation . RESEARCH DESIGN AND METHODS : We screened the P01308 REA gene by direct sequencing in 38 P01160 REA patients and in one child with nonautoimmune early-infancy diabetes , where no mutation in GCK , Q14654 REA , and Q09428 REA was identified . A detailed clinical phenotyping of the patients was carried out to specify the diabetes features in those found with an P01308 REA mutation . RESULTS : We identified three missense mutations in the P01308 REA gene in four probands . Two of four mutations were inherited in a dominant manner , and the familial description evidenced a marked variability in age of diagnosis and disease progression . In our cohort , the P01308 REA mutations may represent approximately 10 % of all permanent neonatal diabetes cases , having a later presentation of diabetes and no associated symptoms compared with cases with K ( DB00171 ) channel mutations . CONCLUSIONS ; Heterozygous P01308 REA gene mutations can cause isolated permanent early-infancy diabetes and should be assessed in neonatal as well as in childhood diabetes appearing like type 1 , when autoimmune markers are absent . New pharmacogenomic strategies may be applicable , since residual beta-cell function is still present in some patients .

Antivascular agents for non-small-cell lung cancer : current status and future directions . BACKGROUND : Despite improvements in surgery and chemo ( radio ) therapy which have allowed for modest advances in the treatment of patients with non-small-cell lung cancer ( NSCLC ) , survival remains poor and further improvements are needed . Attention over recent years has focused , therefore , on targeted therapies , with notable success in the development of antivascular drugs . OBJECTIVE : To summarize the current knowledge on antivascular therapy in patients with NSCLC . METHOD : Review of randomized controlled trials exploring treatment of NSCLC patients with antivascular drugs . RESULTS / CONCLUSION : DB00112 MEN , a humanized monoclonal antibody against the vascular endothelial growth factor ( P15692 REA ) , when added to cytotoxic chemotherapy , was the first treatment to prolong the overall survival of patients with advanced NSCLC beyond 12 months , a significant breakthrough in the management of advanced NSCLC . Small-molecule tyrosine kinase inhibitors and alternative antivascular strategies such as P15692 REA - trap and vascular disrupting agents are also being investigated and have shown promise in clinical trials . This review summarizes the most recent and important findings in antivascular agents in NSCLC .

Atrial natriuretic peptide binds to P01160 REA - Q96GN5 receptors in neuroblastoma cells or is degraded extracellularly at the DB00133 - DB00120 bond . P01160 REA - Q96GN5 receptors for atrial natriuretic peptide ( P01160 REA ) showed the following rank order of affinity in intact human neuroblastoma cells NB-OK - 1 : human P01160 REA - ( 99-126 ) approximately human P01160 REA - ( 102-126 ) approximately rat P01160 REA - ( 99-126 ) ( P04264 REA 17-32 pM ) > human P01160 REA - ( 103-126 ) > porcine brain natriuretic peptide ( DB04899 ) . Analogues truncated at the C-terminal extremity or devoid of a disulphide bridge , such as rat P01160 REA - ( 103-123 ) , rat C - P01160 REA - ( 102-121 ) , rat P01160 REA - ( 111-126 ) , rat P01160 REA - ( 99-109 ) and rat [ desCys 105 , Cys 121 ] P01160 REA - ( 104-126 ) and chicken P23582 REA , were not recognized . The occupancy of these high affinity P01160 REA - Q96GN5 receptors led to marked cyclic GMP accumulation in the presence of 3 - isobutyl 1 - methylxanthine . An ectoenzymic activity , partly shed in the incubation medium , provoked the stepwise release of DB00120 - DB00125 - [ 125I ] DB00135 , DB00125 - [ 125I ] DB00135 and [ 125I ] DB00135 from rat [ 125I ] P01160 REA - ( 99-126 ) , at an optimal pH of 7.0 . Its inhibition by 1,10- phenanthroline , DB00974 and bacitracin but not by thiorphan suggests the contribution of at least one neutral metalloendopeptidase , distinct from EC 3.4 . 24.11 , for which P01160 REA showed high affinity .

Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen DB00977 ( EE ) and bisphenol-A ( Q03001 REA ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 REA ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( DB00603 SUB ) of the hypothalamus . Animals were treated during early puberty , from P01160 REA 23 to P01160 REA 30 , with EE and Q03001 REA given orally every day . They were then sacrificed and perfused on P01160 REA 37 or P01160 REA 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 REA 37 , ER-labelled neurons were higher in males than in females in the ARC and DB00603 SUB . EE and Q03001 REA increased ER-labelled neurons in the ARC and DB00603 SUB . At P01160 REA 90 , females showed higher ER-labelled neurons in the VMH . EE and Q03001 REA increased ER-labelled neurons in the DB00603 SUB in females . EE increased testosterone in males at P01160 REA 37 and estradiol in females at P01160 REA 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats .

P03372 REA - immunoreactive neurons contain calcitonin gene-related peptide , methionine-enkephalin or tyrosine hydroxylase in the female rat preoptic area . We have shown in our previous studies that estrogen treatment selectively influences calcitonin gene-related peptide ( P8 0511 ) - , methionine-enkephalin ( DB00134 - Enk ) - and tyrosine hydroxylase ( TH ) - immunoreactive ( IR ) intensities in the neurons of the periventricular preoptic nucleus ( Q9H237 REA ) and the medial preoptic area ( DB00603 SUB ) of the female rat . In the present study , we examined whether estrogen receptor ( ER ) - IR neurons in the Q9H237 REA and DB00603 SUB contain P8 0511 , DB00134 - Enk , or TH using a double-labeling immunohistochemical method and investigated changes in the number of double-labeling cells upon treatment with estrogen . Brain sections of ovariectomized rats and ovariectomized and estrogen-treated rat were stained using the avidin-biotin-peroxidase complex method followed by the peroxidase-anti-peroxidase method . The sections were first incubated with an anti-ER antibody in conjunction with nickel diaminobenzidine which produces a dark blue reaction product in the nucleus . Subsequently , P8 0511 , DB00134 - Enk or TH antisera were applied to these sections and the resulting brown diaminobenzidine reaction product in the cytoplasm was examined . Neurons that were double-labeled for ER and P8 0511 , DB00134 - Enk or TH were investigated in the Q9H237 REA and DB00603 SUB . The number of doubly labeled ER / P8 0511 - and ER / TH-IR neurons was large , whereas the number of ER / DB00134 - Enk-IR neurons was small . These results suggest that ER in the Q9H237 REA and DB00603 SUB may be more closely related to the mechanism of changes in P8 0511 - and TH-IR intensities upon estrogen treatment than that in DB00134 - Enk-IR intensity .

DB01645 potentiates the P01160 REA effect on a K ( + ) - conductance in P29320 REA - 293 cells . P29320 REA - 293 cells are known to reflect many features of the late distal tubule . Furthermore , they have the ability to release urodilatin , the structural analog to P01160 REA . RT-PCR was performed to test for the expression of natriuretic peptide receptors . While the mRNA for the human P01160 REA receptor ( P16066 REA , P16066 REA ) could be amplified , the P09543 - specific receptor P20594 REA ( P20594 REA ) and the receptor specific for guanylins , P25092 REA , could not be detected . In patch clamp experiments the effects of P01160 REA ( 10 nM ) on membrane voltage ( V ( m ) ) were monitored and P29320 REA - 293 cells depolarized by 2.3 + / - 0.5 mV ( n = 14 ) . In the presence of the P01133 REA receptor blocker genistein ( 10 microM ) the effect of P01160 REA was increased by 65 % to 3.9 + / - 0.8 mV ( n = 14 ) . After removal of genistein the P01160 REA - mediated depolarization further increased by 147 % to 5.7 + / - 1.0 mV ( n = 14 ) . P01160 REA given repetitively without genistein had no increasing depolarizing effect in P29320 REA - 293 cells with time . The P01160 REA effect could be fully blocked by 1 mM Ba ( 2 + ) and by 1 microM of the specific PKG inhibitor KT5823 indicating that P01160 REA inhibits a K ( + ) - conductance via a cGMP-dependent protein kinase . DB01645 itself hyperpolarized the membrane voltage of P29320 REA - 293 cells by -3.9 + / - 0.6 mV ( n = 11 ) and this effect could also be fully blocked by Ba ( 2 + ) ( -0.3 + / - 0.1 mV , n = 5 ) , indicating that genistein activates a K ( + ) - conductance which contributes significantly to the membrane potential of P29320 REA - 293 cells .

Gene network profiling before and after transplantation in alcoholic cirrhosis liver transplant recipients . The main objective of this study was to define a gene network profile network in liver transplant recipients with alcoholic cirrhosis before and after liver transplantation . Genes were selected from data obtained in a previous study of liver transplant recipients with alcoholic cirrhosis . Selected up-regulated genes were further validated by quantitative real-time polymerase chain reaction in different groups of liver transplant recipients with alcoholic cirrhosis ( n = 5 ) . Selected genes up-regulated before transplantation were : Q07011 REA ( tumor necrosis factor [ P01375 REA ] receptor superfamily , member 9 ) ; P14784 REA ( interleukin - 2 receptor beta ) ; Q92843 ( P10415 REA - like 2 ) ; Q96PH1 ( NADPH ) oxidase , EF-hand calcium binding domain 5 ) ; P50542 REA ( peroxisomal biogenesis factor 5 ) ; P37231 REA ( peroxisome proliferator-activated receptor gamma ) ; Q96Q05 REA ( O14920 REA binding protein ) ; Q9NYR9 ( NFKappaBeta inhibitor interacting Ras-like 2 ) ; P05112 REA ( interleukin - 4 ) ; IL - 4R ( interleukin 4 receptor ) ; P07327 REA ( alcohol dehydrogenase 1A , class 1 ) ; O75891 REA ( aldehyde dehydrogenase 1 family , member Q9NUQ9 ) ; P05164 REA ( myeloperoxidase ) ; P01160 REA ( natriuretic peptide precursor A ) ; Q16548 ( P10415 REA - related protein A1 ) ; P24522 REA ( growth arrest and DNA-damage-inducible alpha ) ; P55061 ( P55061 ) ; P42336 REA ( phosphoinositide - 3 - kinase , catalytic , alpha polypeptide ) ; P38484 REA ( interferon gamma receptor 2 ) ; O60674 REA ( Janus Kinase 2 ) ; FAS ( Fas , P01375 REA receptor superfamily , member 6 ) ; Q92844 REA ( TRAF family member-associated NFKB activator ) ; O95551 REA ( O95551 REA ) ; and P08758 REA ( annexin A5 ) .

DB05025 MEN , a coinducer of heat shock proteins for the potential treatment of amyotrophic lateral sclerosis . Recent years have seen an explosion of research into increasingly prevalent neurodegenerative diseases . DB05025 MEN ( BRX - 220 ) , being developed by CytRx Corp , is an oral therapeutic candidate for the treatment of amyotrophic lateral sclerosis ( P35858 REA ) , the most common form of motor neuron disease . P35858 REA is a fatal , incurable disorder , which can present as sporadic ( 90 to 95 % of cases ) or familial ( 5 to 10 % of cases ) forms . The etiology of sporadic P35858 REA remains unknown and much of the understanding of P35858 REA pathogenesis has been derived through study of its familial forms ; in particular , through study of autosomal dominant mutations in the P00441 REA ( copper / zinc superoxide dismutase ) gene , which cause approximately 20 % of familial P35858 REA cases . Under conditions of excessive stress , arimoclomol induces amplification of the cytoprotective heat shock response in order to protect motor neurons from death . Comprehensive in vivo and in vitro studies demonstrated its effect in the prevention of neuronal loss and promotion of motor neuron survival , even after symptom onset . Clinical trials have reported good tolerability and safety . This paper discusses the rationale for arimoclomol use in P35858 REA , the preclinical and clinical evidence collected to date , the likelihood of its promising preclinical results translating to humans , and the relevance of this research for neurodegeneration as a whole .

Involvement of retinoic acid receptor alpha in the stimulation of tissue-type plasminogen-activator gene expression in human endothelial cells . Retinoids stimulate tissue-type plasminogen-activator ( t-PA ) gene expression in human endothelial cells , and are likely to do so by binding to one or more nuclear retinoid receptors . The present study was initiated to identify the retinoid receptor ( s ) involved in this process . Expression and regulation of retinoic acid receptors ( RARs ) and retinoid X receptors ( RXRs ) were analyzed by Northern-blot analysis of total or poly ( A ) - rich RNA prepared from cultured human umbilical vein endothelial cells ( HUVEC ) . Prior to any exposure to retinoids , HUVEC express two transcripts for P10276 REA ( 3.6 kb and 2.8 kb ) , and low levels of transcripts for P10826 REA ( 3.4 kb and 3.2 kb ) and P13631 REA ( 3.3 kb and 3.1 kb ) . Two RXR subtypes were identified , RXR-alpha ( 4.8 kb ) and , at a much lower concentration , RXR-beta ( 2.4 kb ) ; no evidence for the presence of RXR-gamma was found . Furthermore , HUVEC express cellular retinol-binding protein I ( P09455 REA ) and cellular retinoic-acid-binding protein I ( P29762 REA ) mRNA . Exposure of HUVEC to 1 microM retinoic acid or the DB04942 MEN , Ch55 , led to the induction of the two P10826 REA mRNAs , RXR-alpha mRNA and P09455 REA mRNA , whereas the expression of the other receptor and P29762 REA transcripts did not change appreciably . Using retinoid analogues that bind preferentially to one of the RAR or RXR subtypes , we found evidence that P10276 REA is involved in the retinoid-induced t-PA expression in HUVEC . This conclusion was strengthened by experiments in which blocking of P10276 REA with a specific P10276 REA antagonist , Ro 41-5253 , was demonstrated to suppress the induction of t-PA by retinoids .

Drug insight : Use of docetaxel in prostate and urothelial cancers . Taxanes have emerged as a potent class of chemotherapeutic agents in many malignancies , with two taxanes now in clinical use . Their mechanism of action against tumor cells is by alteration of microtubule dynamics , which causes cell-cycle arrest during mitosis . DB01248 MEN binds to the microtubules with a higher affinity than paclitaxel , and over a broader range of cell-cycle activities . It has also been shown to promote apoptosis via P10415 REA phosphorylation . In hormone-refractory prostate cancer , docetaxel has been studied as both a single agent and in combination with estramustine , and in different treatment schedules , with demonstrated efficacy . Two phase III trials have confirmed a survival benefit , making docetaxel the first chemotherapy agent with proven efficacy against prostate cancer . In urothelial cancer , docetaxel has demonstrated activity and has been investigated as a single agent and in combination regimens . A phase III trial comparing docetaxel and cisplatin to methotrexate , vinblastine , doxorubicin , and cisplatin was inferior when evaluating response rates and overall survival . More recent phase II trials combining docetaxel with two additional agents have shown promise , but confirmatory trials are needed .

Morphological and functional changes in innervation of a fast forelimb muscle in P00441 REA - G85R mice . Muscle endplates become denervated in mice that express mutations of human superoxide dismutase 1 ( hSOD 1 ) , models of familial amyotrophic lateral sclerosis . This denervation is especially marked in fast limb muscles , and precedes death of motor neuron somata . This study used mice that expressed yellow fluorescent protein ( YFP ) in neurons to investigate changes in the morphology and function of axons and motor terminals innervating a fast forelimb muscle ( epitrochleoanconeus , P25101 REA ) in presymptomatic and symptomatic hSOD 1 - G85R mice , compared to those in mice that express wild-type ( wt ) hSOD 1 . The percentage of endplates ( identified using fluorescently-labeled α-bungarotoxin ) innervated by motor terminals remained high in presymptomatic P00441 REA - G85R mice , but fell to ~ 50 % in symptomatic mice . The number of large diameter ( ≥ 4 μm ) axons in the P25101 REA nerve also decreased as mice became symptomatic , and endplate innervation correlated best with the number of large diameter axons . Motor terminal function was assessed using changes in terminal YFP fluorescence evoked by trains of action potentials ; different components of the pH-dependent YFP signals reflect stimulation-induced Ca2 + entry and vesicular exo / endocytosis . Most visible motor terminals ( > 90 % ) remained capable of responding to nerve stimulation in both pre - and symptomatic hSOD 1 - G85R mice , but with functional alterations . Responses in presymptomatic terminals suggested reduced acidification and increased vesicular release , whereas symptomatic terminals exhibited increased acidification and reduced vesicular release . The fact that most remaining terminals were able to respond to nerve stimulation suggests that motor terminal-protective therapies might contribute to preserving neuromuscular function in fALS mice .

Pharmacological profile of astemizole-derived compounds at the histamine H1 and H4 receptor - - H1 / H4 receptor selectivity . DB00637 MEN , a P35367 REA antagonist shows high affinity to the histamine H1 receptor but only a moderate affinity to the histamine H4 receptor . This study aims to modify the astemizole to keep high affinity to the histamine H1 receptor and to increase affinity to the histamine H4 receptor . Therefore , 13 astemizole-derived compounds and astemizole-JNJ 7777120 - derived hybrid compounds were synthesized and pharmacologically characterized at the histamine H1 and H4 receptors . The new compounds show affinity to the histamine H1 receptor in the pK i range from 5.3 to 8.8 , whereas the affinity of these compounds to the histamine H4 receptor was surprisingly rather low ( pK i from 4.4 to 5.6 ) . Three representative compounds were docked into the histamine H1 receptor and molecular dynamic studies were performed to explain the binding mode and the experimental results on a molecular level . Furthermore , taking into account the binding mode of compounds with high affinity to the histamine H4 receptor , a H1 / H4 - pharmacophore hypothesis was developed .

P35367 REA mRNA is expressed in capsaicin-insensitive sensory neurons with neuropeptide Y-immunoreactivity in guinea pigs . P35367 REA mRNA-expressing sensory neurons in guinea pigs are unmyelinated and are not immunoreactive to DB05875 and calcitonin gene-related peptide ( P8 0511 ) [ Mol . Brain Res . 66 ( 1999 ) 24 ] , which are implicated in the nociceptive transmission of the primary sensory system . In this study , we examined whether these H1 receptor mRNA-expressing neurons are sensitive to capsaicin by using in situ hybridization histochemistry . Of lumbar dorsal root ganglion ( Q86YR7 ) neurons in control animals , 17 % were positive for P8 0511 . In guinea pigs neonatally treated with capsaicin ( 50 mg / kg ) , few P8 0511 - immunoreactive neurons were seen in the DRGs . However , the percentages of H1 receptor mRNA-expressing neurons ( 15-20 % ) and the intensity of the mRNA signals in these neurons were not affected by neonatal capsaicin treatment . We also revealed the presence of both capsaicin-sensitive and insensitive neuropeptide Y ( P01303 REA ) - immunoreactive neurons in the DRGs . These neurons were exclusively small . H1 receptor mRNA was expressed in P01303 REA - immunoreactive neurons in naive guinea pig DRGs . These results suggest that H1 receptor mRNA is expressed in capsaicin-insensitive Q86YR7 neurons with P01303 REA - immunoreactivity in guinea pigs .

DB00741 response to stress is associated with myocardial remodeling in salmonid fishes . Cardiac disease is frequently reported in farmed animals , and stress has been implicated as a factor for myocardial dysfunction in commercial fish rearing . DB00741 is a major stress hormone in teleosts , and this hormone has adverse effects on the myocardium . Strains of rainbow trout ( Oncorhynchus mykiss ) selected for divergent post-stress cortisol levels [ high responsive ( HR ) and low responsive ( LR ) ] have been established as a comparative model to examine how fish with contrasting stress-coping styles differ in their physiological and behavioral profiles . We show that the mean cardiosomatic index ( CSI ) of adult HR fish was 34 % higher than in LR fish , mainly because of hypertrophy of the compact myocardium . To characterize the hypertrophy as physiological or pathological , we investigated specific cardiac markers at the transcriptional level . HR hearts had higher mRNA levels of cortisol receptors ( MR , GR1 and GR2 ) , increased P53805 levels [ suggesting enhanced pro-hypertrophic nuclear factor of activated T-cell ( NFAT ) signaling ] and increased P15692 REA gene expression ( reflecting increased angiogenesis ) . Elevated collagen ( Col 1a2 ) expression and deposition in HR hearts supported enhanced fibrosis , whereas the heart failure markers P01160 REA and DB04899 were not upregulated in HR hearts . To confirm our results outside the selection model , we investigated the effect of acute confinement stress in wild-type European brown trout , Salmo trutta . A positive correlation between post-stress cortisol levels and CSI was observed , supporting an association between enhanced cortisol response and myocardial remodeling . In conclusion , post-stress cortisol production correlates with myocardial remodeling , and coincides with several indicators of heart pathology , well-known from mammalian cardiology .

Suppression of parathyroid hormone-related protein messenger RNA expression by medroxyprogesterone acetate in breast cancer tissues . The level of parathyroid hormone-related protein ( P12272 REA ) expressed in breast cancer tissue is closely related to the incidence of bone metastasis . We examined the P12272 REA mRNA expression in breast cancer tissues by coamplification polymerase chain reaction ( PCR ) in mole ratio to internal standard beta-actin mRNA . The P12272 REA expression was higher in premenopausal patients than in postmenopausal patients ( P < 0.05 ) . More pronounced difference by menopause found in estrogen receptor ( ER ) positive groups ( P < 0.001 ) indicated that the P12272 REA expression in breast cancer tissue is hormonally regulated and might be altered by endocrine agents . To clarify the changes of P12272 REA expression by endocrine therapy of breast cancer , we measured P12272 REA expression in the breast cancer tissue incubated for 24 h with 1 x 10 (-8 ) M of estradiol ( E2 ) , 1 x 10 ( - 6 ) M of tamoxifen ( TAM ) and 1 x 10 ( - 5 ) M of medroxyprogesterone acetate ( DB00603 SUB ) . The P12272 REA expression was decreased significantly by DB00603 SUB ( P < 0.005 ) , while E2 and TAM did not change the P12272 REA expression . P06401 REA ( PgR ) mRNA expression was also examined to confirm that the breast cancer tissue responds to E2 and TAM . The results were well compatible with the better therapeutic effect of DB00603 SUB reported for the treatment of breast cancer with bone metastases . As a potential candidate for the receptor that mediates the suppressive effect of DB00603 SUB , androgen receptor ( AR ) is suggested most probable . Present results also demonstrated that the clinical response of individual tumors is closely associated with the early in vitro changes of gene expression detected in the cancer specimen .

Is olomoucine , a weak P24941 REA inhibitor , able to induce apoptosis in cancer cells ? DB02116 MEN ( OLO ) , a substituted purine analogue , is a much weaker inhibitor of cyclin-dependent kinases than other closely related DB00171 derivatives . It has been recently reported that OLO did not affect the viability of normal human MRC - 5 fibroblasts , but it inhibited the proliferation of human HL - 60 leukemia cells . Therefore , it was interesting to explore the antiproliferative effect of OLO and to characterize its action on distinct human cancer cells differing in the functional status of the cell cycle . Human HeLa cervical carcinoma and HL - 60 leukemia cells were continuously exposed to increasing concentrations of OLO for 24 h and 48 h or alternatively , cells after treatment for 24 h were postincubated in a drug-free medium . Surprisingly , OLO more strongly affected the proliferation of HL - 60 cells than that of HeLa cells . Flow cytometric analyses revealed that OLO at higher doses increases the frequency of a hypoploid HL - 60 cell population representing cells undergoing apoptosis . These results substantiated the data of the determination of the number of viable cells . Moreover , OLO at higher doses modulates the cell cycle progression of tested cancer cells . Detailed analyses of the DNA concentration in single cells revealed that OLO-mediated reduction of the number of G ( 1 ) - phase cells was accompanied by an increase of the frequency of G ( 2 ) - phase cells . The kinetics of these changes differed between both tested cancer cell lines , suggesting that some cancer cells exhibit increased susceptibility to OLO action . It remains to clarify whether the strong proapoptotic effect of OLO observed in HL - 60 cells depends on their differentiation status .

Comparative linkage mapping of genes on sheep chromosome 3 provides evidence of chromosomal rearrangements in the evolution of the Bovidae . Three genes - - parathyroid hormone-like hormone ( P12272 REA ) , insulin-like growth factor 1 ( IGF 1 ) , and retinoic acid receptor gamma ( P13631 REA ) - - have been mapped to sheep ( Ovis aries ) chromosome 3 ( OAR 3 ) . The order and genetic distances between loci on OAR 3 are similar to those on cattle ( Bos taurus ) chromosome 5 , as expected from their close evolutionary relationship . The OAR 3 linkage map shows conserved synteny with human chromosome 12 , but there are at least two rearrangements in gene order between the species .

P22888 REA expression in leiomyomatosis peritonealis disseminata . BACKGROUND : Leiomyomatosis peritonealis disseminata has been attributed to estrogen stimulation and is seen only rarely in postmenopausal women . In such cases , pathogenesis is uncertain . CASE : Leiomyomatosis peritonealis disseminata tumors were resected from a postmenopausal woman . She was receiving tamoxifen therapy for breast cancer and had bilateral ovarian Brenner tumors . Estrogen and progesterone receptors were detected . Immunohistochemical analysis indicated that LH receptors were present . CONCLUSION : DB00044 MEN receptors were identified in leiomyomatosis peritonealis disseminata in one woman . Levels of DB00094 and LH increase after menopause , and immunohistochemical analysis showed the presence of LH receptors , so gonadotropin rather than estrogen stimulation might have contributed to development of leiomyomatosis peritonealis disseminata in this uncommon case .