MH_dev_269

Fetzima ( levomilnacipran ) , a drug for major depressive disorder as a dual inhibitor for human serotonin transporters and beta-site amyloid precursor protein cleaving enzyme - 1 . Pharmacological management of Major Depressive Disorder includes the use of serotonin reuptake inhibitors which targets serotonin transporters ( P31645 REA ) to increase the synaptic concentrations of serotonin . Beta-site amyloid precursor protein cleaving enzyme - 1 ( P56817 REA - 1 ) is responsible for amyloid β plaque formation . Hence it is an interesting target for Alzheimer ' s disease ( AD ) therapy . This study describes molecular interactions of a new Food and Drug Administration approved antidepressant drug named ' Fetzima ' with P56817 REA - 1 and P31645 REA . Fetzima is chemically known as levomilnacipran . The study has explored a possible link between the treatment of Depression and AD . ' Autodock 4.2 ' was used for docking study . The free energy of binding ( ΔG ) values for ' levomilnacipran - P31645 REA ' interaction and ' levomilnacipran - P56817 REA ' interaction were found to be -7.47 and -8.25 kcal / mol , respectively . DB08918 MENMAX DB08918 MEN was found to interact with S438 , known to be the most important amino acid residue of serotonin binding site of P31645 REA during ' levomilnacipran - P31645 REA ' interaction . In the case of ' levomilnacipran - P56817 REA ' interaction , levomilnacipran interacted with two very crucial aspartic acid residues of P56817 REA - 1 , namely , D32 and D228 . These residues are accountable for the cleavage of amyloid precursor protein and the subsequent formation of amyloid β plaques in AD brain . Hence , Fetzima ( levomilnacipran ) might act as a potent dual inhibitor of P31645 REA and P56817 REA - 1 and expected to form the basis of a future dual therapy against depression and AD . It is an established fact that development of AD is associated with Major Depressive Disorder . Therefore , the design of new P56817 REA - 1 inhibitors based on antidepressant drug scaffolds would be particularly beneficial .

Chronic atrial fibrillation alters the functional properties of If in the human atrium . INTRODUCTION : Despite the evidence that the hyperpolarization-activated current ( If ) is highly modulated in human cardiomyopathies , no definite data exist in chronic atrial fibrillation ( cAF ) . We investigated the expression , function , and modulation of If in human cAF . METHODS AND RESULTS : Right atrial samples were obtained from sinus rhythm ( SR , n = 49 ) or cAF ( duration > 1 year , n = 31 ) patients undergoing corrective cardiac surgery . Among f-channel isoforms expressed in the human atrium ( O60741 REA , 2 and 4 ) , Q9Y3Q4 REA mRNA levels measured by RT-PCR were significantly reduced . However , protein expression was preserved in cAF compared to SR ( + 85 % for Q9Y3Q4 REA ) ; concurrently , miR - 1 expression was significantly reduced . In patch-clamped atrial myocytes , current-specific conductance ( gf ) was significantly increased in cAF at voltages around the threshold for If activation ( - 60 to - 80 mV ) ; accordingly , a 10 - mV rightward shift of the activation curve occurred ( P < 0.01 ) . β-Adrenergic and Q13639 REA receptor stimulation exerted similar effects on If in cAF and SR cells , while the P01160 REA - mediated effect was significantly reduced ( P < 0.02 ) , suggesting downregulation of natriuretic peptide signaling . CONCLUSIONS : In human cAF modifications in transcriptional and posttranscriptional mechanisms of HCN channels occur , associated with a slight yet significant gain-of-function of If , which may contribute to enhanced atrial ectopy .

Role of DB05875 signaling in enhanced nociceptive sensitization and local cytokine production after incision . Substance P ( SP ) signaling facilitates nociceptive sensitization in various inflammatory and chronic pain models and we postulated that SP signaling might also contribute to the development of post-incisional hyperalgesia . These studies used mice with a deletion of the pre-protachykinin A gene ( ppt-A ( - / - ) ) which codes for SP to determine the role of SP signaling in post-incisional pain and in the increased cytokine and nerve growth factor ( P01138 REA ) expression observed in the incised skin . SP deficient ppt-A ( - / - ) mice displayed reduced mechanical allodynia and heat hyperalgesia compared to the wild-type ( wt ) mice at all post-incision time points , despite similar baseline values ( p < 0.001 ) . Furthermore , the P25103 REA antagonist LY303870 attenuated mechanical allodynia produced by incision in the wt mice ( p < 0.001 ) . Incision also up-regulated P05231 REA , P01375 REA and KC levels but not IL - 1beta after 2h in the wt mice skin . However , ppt-A ( - / - ) mice had more skin P01138 REA levels 2h post-incision . Subcutaneous hind paw SP injection produced acute and transient elevations of IL - 1beta , P05231 REA , and KC but modest elevations in P01375 REA levels in the wt mice . Systemic LY303870 reversed the SP-induced elevations of these cytokines . Hind paw injection of P05231 REA and P01138 REA dose dependently produced less mechanical allodynia in the ppt-A ( - / - ) compared to wt mice . Additionally , SP produced mechanical allodynia in a dose-dependent fashion in wt mice . Therefore , SP supports nociceptive sensitization after hind paw incision and potentially participates directly in modulating the intensity of inflammatory response in peri-incisional tissue .

Substance P induces rapid and transient membrane blebbing in U373MG cells in a P38936 REA - activated kinase-dependent manner . U373MG astrocytoma cells endogenously express the full-length neurokinin 1 receptor ( P25103 REA ) . Substance P ( SP ) , the natural ligand for P25103 REA , triggers rapid and transient membrane blebbing and we report that these morphological changes have different dynamics and intracellular signaling as compared to the changes that we have previously described in HEK 293 - P25103 REA cells . In both cell lines , the SP-induced morphological changes are Gq-independent , and they require the Rho , Rho-associated coiled-coil kinase ( ROCK ) signaling pathway . Using confocal microscopy we have demonstrated that tubulin is phosphorylated subsequent to cell stimulation with SP and that tubulin accumulates inside the blebs . DB01394 , a tubulin polymerization inhibitor , blocked SP-induced blebbing in U373MG but not in HEK 293 - P25103 REA cells . Although P38936 REA - activated kinase ( PAK ) is expressed in both cell lines , SP induced rapid phosphorylation of PAK in U373MG , but failed to phosphorylate PAK in HEK 293 - P25103 REA cells . The cell-permeable Rho inhibitor P01024 REA transferase inhibited SP-induced PAK phosphorylation , but the ROCK inhibitor Y27632 had no effect on PAK phosphorylation , suggesting that Rho activates PAK in a ROCK-independent manner . Our study demonstrates that SP triggers rapid changes in cell morphology mediated by distinct intracellular signaling mechanisms in U373MG versus HEK 293 - P25103 REA cells .

Q8N0V5 V ( Mgat 5 ) - mediated N-glycosylation negatively regulates Th1 cytokine production by T cells . The differentiation of naive P01730 REA ( + ) T cells into either proinflammatory Th1 or proallergic Th2 cells strongly influences autoimmunity , allergy , and tumor immune surveillance . We previously demonstrated that beta 1,6 GlcNAc-branched complex-type ( Q8N0V5 V ( Mgat 5 ) ) N-glycans on TCR are bound to galectins , an interaction that reduces TCR signaling by opposing agonist-induced TCR clustering at the immune synapse . Mgat 5 ( - / - ) mice display late-onset spontaneous autoimmune disease and enhanced resistance to tumor progression and metastasis . In this study we examined the role of beta 1,6 GlcNAc N-glycan expression in Th1 / Th2 cytokine production and differentiation . beta 1,6 GlcNAc N-glycan expression is enhanced by TCR stimulation independent of cell division and declines at the end of the stimulation cycle . DB00075 - activated splenocytes and naive T cells from Mgat 5 ( - / - ) mice produce more P01579 REA and less P05112 REA compared with wild-type cells , the latter resulting in the loss of P05112 REA - dependent down-regulation of IL - 4Ralpha . DB02034 MEN , an inhibitor of Q16706 REA , blocked beta 1,6 GlcNAc N-glycan expression and caused a similar increase in P01579 REA production by T cells from humans and mice , but no additional enhancement in Mgat 5 ( - / - ) T cells . Mgat 5 deficiency did not alter P01579 REA / P05112 REA production by polarized Th1 cells , but caused an approximately 10 - fold increase in P01579 REA production by polarized Th2 cells . These data indicate that negative regulation of TCR signaling by beta 1,6 GlcNAc N-glycans promotes development of Th2 over Th1 responses , enhances polarization of Th2 cells , and suggests a mechanism for the increased autoimmune disease susceptibility observed in Mgat 5 ( - / - ) mice .

Polymorphisms influencing olanzapine metabolism and adverse effects in healthy subjects . OBJECTIVE : The pharmacokinetics of olanzapine and response to treatment could be affected by polymorphisms in genes coding for drug-metabolizing enzymes , transporters , or receptors . The aim of this study was to identify genetic markers predictive of pharmacokinetics , pharmacodynamics , and adverse effects of olanzapine . METHODS : Sixty-three healthy volunteers receiving a single 5 - mg oral dose of olanzapine were genotyped for 39 genetic variants that could be related to the response to olanzapine . All genetic variants were analyzed by PharmaChip , but P14416 REA Taq 1A polymorphism was determined by real-time polymerase chain reaction . Olanzapine was measured using high-performance liquid chromatography combined with tandem mass spectrometry . The relationship of gender and polymorphisms with olanzapine pharmacokinetics , the change in prolactin levels , and the incidence of adverse effects were evaluated by multiple regression analysis . RESULTS : The pharmacokinetics of olanzapine was influenced by polymorphisms in P20815 REA , P21266 REA , and Q13224 REA . P01236 REA levels were affected by gender and polymorphisms in P14416 REA and 5 - P28223 REA . Polymorphisms in P11712 REA , P51580 REA , P22309 REA , P08183 REA , and 5 - P28223 REA were related to some adverse effects of olanzapine . CONCLUSIONS : Several polymorphisms can explain differences in the pharmacokinetics , pharmacodynamics , and safety of olanzapine in healthy subjects . Whether these genetic factors influence the risk of therapeutic failure or tolerability in patients remains to be established .

Efficacy and safety of repeated dosing of netupitant , a neurokinin - 1 receptor antagonist , in treating overactive bladder . AIM : NK - 1 receptors in sensory nerves , the spinal cord and bladder smooth muscle participate in complex sensory mechanisms that regulate bladder activity . This study was designed to assess the efficacy and safety of a new P25103 REA antagonist , netupitant , in patients with OAB . METHODS : This was a phase II , multicenter , double-blind study in which adults with OAB symptoms > 6 months were randomized to receive 1 of 3 doses of netupitant ( 50 , 100 , 200 mg ) or placebo once daily for 8 weeks . The primary efficacy endpoint was percentage change from baseline in average number of daily micturitions at week 8 . Urinary incontinence , urge urinary incontinence ( UUI ) , and urgency episodes were also assessed . RESULTS : The primary efficacy endpoint was similar in the treatment groups ( -13.85 for placebo to -16.17 in the netupitant 200 mg group ) with no statistically significant differences between netupitant and placebo . The same was true for most secondary endpoints although a significant difference for improvement in UUI episodes and a trend for the greatest decrease in urgency episodes were seen in the netupitant 100 mg group . DB09048 SUB was well tolerated with most treatment emergent adverse events ( AEs ) being mild . While the overall incidence of AEs increased with netupitant dose , there was no evidence for this dose dependency based on relationship to treatment , intensity , or time to onset . CONCLUSIONS : The study failed to demonstrate superiority of netupitant versus placebo in decreasing OAB symptoms , despite a trend favoring netupitant 100 mg . There were no safety concerns with daily administration of netupitant over 8 weeks .

Functional identification of NR2 subunits contributing to DB01221 receptors on DB05875 receptor-expressing dorsal horn neurons . DB01221 receptors are important elements in pain signaling in the spinal cord dorsal horn . They are heterotetramers typically composed of two Q9UHB4 and two of four NR2 subunits : Q12879 REA - 2D . Mice lacking specific NR2 subunits show deficits in pain transmission yet subunit location in the spinal cord remains unclear . We have combined electrophysiological and pharmacological approaches to investigate the composition of functional DB01221 receptors expressed by lamina I , DB05875 receptor-expressing ( P25103 REA + ) neurons , as well as P25103 REA - neurons . Under low Mg2 + conditions ( 100 microM ) , the conductance of DB01221 receptors at - 90 mV ( g ( - 90 mV ) ) with Q12879 REA or Q13224 REA subunits ( Q12879 REA / B ) is low compared to conductance measured at the membrane potential where the inward current is maximal or maximal inward current ( MIC ) ( ratio of approximately 0.07 calculated from Kuner and Schoepfer , 1996 ) . For Q14957 REA or O15399 REA subunits ( Q14957 REA / D ) , the ratio is higher ( ratio approximately 0.4 ) . P25103 REA + and P25103 REA - neurons express DB01221 receptors that give ratios approximately 0.28 and 0.16 , respectively , suggesting both types of subunits are present in both populations of neurons , with P25103 REA + neurons expressing a higher percentage of Q14957 REA / D type DB01221 receptors . This was confirmed using EAB 318 , an Q12879 REA / B preferring antagonist , and UBP 141 , a mildly selective Q14957 REA / D antagonist to increase and decrease the g ( - 90 mV ) / g ( MIC ) ratios in both subpopulations of neurons .

Application of HapMap data to the evaluation of 8 candidate genes for pediatric slow transit constipation . BACKGROUND : Slow transit constipation ( P52823 ) affects up to 3 % of all children and is an increasingly recognized cause of chronic constipation in children . We conducted a pilot study to investigate whether genes encoding neurotransmitters ( P20366 REA , Q9UHF0 , P01282 REA , NOS 1 ) and receptors ( P25103 REA , P21452 REA , P29371 REA , P10721 REA ) could be responsible for P52823 . METHODS : One hundred seventeen tag single nucleotide polymorphisms ( SNPs ) , distributed among the candidate genes , were selected from HapMap data and genotyped using Sequenom ( San Diego , CA ) technology in 35 affected families . Evaluation of association was performed by transmission disequilibrium test and multilocus analysis . RESULTS : Five SNPs ( rs3771863 , rs4580655 , rs11722288 , rs4563545 , and rs3782221 ) in the P25103 REA , P29371 REA , P10721 REA , and NOS 1 genes were found to be potentially associated with P52823 , although the significance of these results does not withstand correction for multiple testing . CONCLUSIONS : Our data indicate that 5 SNPs in the NOS 1 , P25103 REA , P29371 REA , and P10721 REA genes could be involved in P52823 , especially rs3771863 in intron 1 of P25103 REA , which showed the highest association .

Distribution of polyamines and their biosynthetic enzymes in intestinal adaptation . P11926 REA ( ODC ) and the polyamines have been shown to be important for growth processes in the intestinal mucosa . The highest activity of ODC is found in the differentiated , nonproliferating villus-tip cells rather than in the rapidly proliferating undifferentiated crypt cells . During poststarvation refeeding and lactation , we now show that increases in ODC activity paralleled the time course of mucosal hyperplasia and thymidine incorporation . Increases in ODC ( threefold ) were similar in villus and crypt cells , and the villus-crypt gradient of decreasing ODC activity ( 40:1 ) was maintained . The activity of the other polyamine biosynthetic enzyme , S-adenosylmethionine decarboxylase ( P18827 REA ) , was highest in the crypt cells in the basal state and increased throughout the entire villus-crypt axis during refeeding and lactation , preserving a villus-crypt gradient opposite to that of ODC . During hyperplasia , all three polyamines increased . DB01917 MEN was highest in the villus-tip cells , paralleling ODC activity , whereas spermidine and spermine were highest in the crypt cells and paralleled the distribution of P18827 REA activity . Thus P18827 REA activity and spermidine and spermine content may play a more important role than ODC and putrescine in regulation of intestinal mucosal proliferation . It is also possible that the threefold increases in the low levels of ODC in the crypt cells are adequate to trigger cell proliferation , whereas the higher ODC levels in villus cells may represent an association with the differentiation of the enterocytes .

DB08810 MEN protects against ethanol-induced gastric mucosal injury in rats : role of 5 - hydroxytryptamine , prostaglandins and sulfhydryl compounds . This study was designed to determine the gastroprotective properties of cinitapride ( CNT ) , a novel prokinetic benzamide derivative agonist of Q13639 REA and 5 - HT1 receptors and 5 - HT2 antagonist , on mucosal injury produced by 50 % ( v / v ) ethanol . Results were compared with those for 5 - hydroxytryptamine ( 5 - HT : 10 mg kg - 1 ) . The possible involvements of gastric mucus secretion , endogenous prostaglandins ( PGs ) and sulfhydryl compounds ( SH ) in the protection mediated by CNT were also examined . Intraperitoneal administration of CNT ( 0.50 and 1 mg kg - 1 ) , 30 min before ethanol , significantly prevented gastric ulceration and increased the hexosamine content of gastric mucus . CNT ( 1 mg kg - 1 ) also produced a significant increase in gastric mucosal levels of DB00917 , but did not induce any significant changes in SH values . On the contrary , pretreatment with 5 - HT worsened ethanol-induced erosions , however , did not affect gastric mucus secretion , glycoprotein content or DB00917 levels , although the non-protein SH fraction was significantly decreased . The present results demonstrate that the gastroprotective effects of CNT could be partly explained by a complex PG dependent mechanism . We suggest that 5 - HT dependent mechanisms through 5 - HT2 receptor blockade and 5 - HT1 receptor activation could be also involved .

Effect of matrine on the expression of DB05875 receptor and inflammatory cytokines production in human skin keratinocytes and fibroblasts . Matrine is a kind of alkaloid found in certain Sophora plants , which has been extensively used in China for the treatment of viral hepatitis , cancer , cardiac diseases and skin diseases ( such as atopic dermatitis and eczema ) . It also has been confirmed that DB05875 ( SP ) and its receptor ( neurokinin - 1 receptor , P25103 REA ) are involved in the pathogenesis of inflammatory skin disorders . So the present study was designed to investigate the effect of matrine on the expression of P25103 REA and cytokines production induced by SP in HaCaT cells ( a human epidermal keratinocyte cell line ) and dermal fibroblasts . In addition , cell viability was also evaluated . The results showed that matrine inhibited the expression of P25103 REA in HaCaT cells and fibroblasts . SP induced the production of interleukin ( IL ) - 1beta , P10145 REA , interferon ( IFN ) - gamma , and monocyte chemotactic protein ( MCP ) - 1 in both cell types . Matrine 5-100 microg / mL had little effect on cell viability . It inhibited SP-induced IL - 1beta , P10145 REA and P13500 REA production in HaCaT cells and fibroblasts , while it increased the production of P01579 REA in HaCaT cells . Both SP and matrine had no effect on the secretion of P05231 REA . These findings suggest that matrine may have potential treatment function on SP related cutaneous inflammation by inhibition of the expression of DB05875 receptor and regulation of the production of inflammatory cytokines .

Substance P stimulates neovascularization in vivo and proliferation of cultured endothelial cells . We have investigated the possible effect of DB05875 ( SP ) , a main mediator of neurogenic inflammation , on the growth of capillary vessels in vivo , and on the proliferation of cultured endothelial cells in vitro . Slow release preparations of SP were implanted into the avascular cornea of New Zealand White rabbits and vessel growth was monitored daily through a slit lamp stereomicroscope . SP ( 1-5 micrograms / pellet ) induced a marked neovascularization . A selective P25103 REA agonist [ beta-Ala 4 , Sar 9 , DB00134 ( O2 ) 11 ] - SP ( 4-11 ) also induced neovascularization . The addition of SP to serum-free cultured endothelial cells , isolated from bovine adrenals ( P56817 REA ) and from human umbilical cord veins ( HUVE ) , increased proliferation of both cell lines in a concentration-dependent manner with maximal activity at 10 (-8 ) M ( P56817 REA ) and 10 ( - 10 ) M ( HUVE ) . The selective P25103 REA agonist induced a similar proliferative action on both cell lines , while the selective P21452 REA agonist [ beta-Ala 8 ] - P20366 REA ( 4-10 ) and the selective P29371 REA agonist [ MePhe 7 ] - NKB had no significant effect . Two different SP antagonists [ D-Pro 2 , D-Trp 7,9 ] - SP and [ D-Pro 4 , D-Trp 7,9 , Phe 11 ] - SP ( 4-11 ) blocked the response to SP . These findings indicate that SP can directly stimulate the process of neovascularization , probably through induction of endothelial cell proliferation . This hitherto unraveled activity of SP could play a key role in the trophic action produced by activation of the efferent function of peripheral endings of primary sensory neurons .

The effect of MDA and DB01454 MEN ( " DB01454 MEN " ) isomers in combination with pirenpirone on operant responding in mice . The behaviorally disruptive effects of the optical isomers of 1 - ( 3,4- methylenedioxyphenyl - 2 - aminopropane ) ( MDA ) and its N-methyl derivative ( DB01454 MEN ) were evaluated in 27 mice trained to bar-press for a liquid food reinforcement . In addition , a second study was conducted in which mice were pretreated with either saline or the P28223 REA antagonist , pirenpirone , prior to the administration of either DB01454 MEN or MDA using the same behavioral procedure . The results indicated that the behaviorally disruptive effects produced only by R ( - ) - MDA , but not those of S ( + ) - MDA , R ( - ) - MDA , nor of S ( + ) - DB01454 MEN , were significantly attenuated by pirenpirone . These findings support previous research findings which indicate that this isomer may be producing its behaviorally disruptive effects via an action on P28223 REA receptors .

beta-Carotene induces apoptosis and up-regulates peroxisome proliferator-activated receptor gamma expression and reactive oxygen species production in MCF - 7 cancer cells . Although the pharmacological role of beta-carotene in the prevention and treatment of many cancer cells has received increasing attention , the molecular mechanisms underlying such chemopreventive activity are not clear . Since peroxisome proliferator-activated receptor gamma ( P37231 REA ) has been implicated in regulating breast cancer cell differentiation and apoptosis , the effects of beta-carotene on the P37231 REA - mediated pathway and its association with reactive oxygen species production in MCF - 7 cells were investigated in the present study . The results demonstrated that beta-carotene significantly increased P37231 REA mRNA and protein levels in time-dependent manner . In addition , beta-carotene increased the cyclin-dependent kinase inhibitor P38936 REA ( P38936 REA / CIP 1 ) expression and decreased the prostanoid synthesis rate-limiting enzyme cyclooxygenase - 2 expression . DB07863 MEN ( GW9662 ) , an irreversible P37231 REA antagonist , partly attenuated the cell death caused by beta-carotene . Further , reactive oxygen species ( ROS ) production was induced by beta-carotene , resulting in mitochondrial dysfunction and cytochrome C release . DB00143 ( DB00143 ) treatment decreases the intracellular ROS and prevents cytochrome C release and cell apoptosis induced by beta-carotene . In total , these observations suggest that the synergistic effect of P37231 REA expression and ROS production may account for beta-carotene-mediated anticancer activities .

DB01079 MEN treatment for IBS : a model of indirect costs . Irritable bowel syndrome ( IBS ) has been associated with substantial time lost from work ( absenteeism ) and reduced productivity at work ( presenteeism ) , which are the indirect costs of illness . This article presents a productivity model demonstrating the indirect costs associated with IBS and the reduction in those costs for a cohort of female employees hypothetically treated with tegaserod , a new selective serotonin ( 5 - hydroxytryptamine [ 5 - HT ] ) type 4 ( Q13639 REA ) receptor agonist , which is approved by the US Food and Drug Administration for treating women with IBS-C . The model is based on economic and epidemiologic published literature and clinical trial results . In this model , tegaserod treatment resulted in 1882 dollars in avoided lost productivity per treated female employee . Considering only the benefits of decreased work loss and the costs of medical therapy , the model predicts a benefit / cost ratio of 3.75 in the base case . From an employer ' s perspective , medical therapy for IBS with tegaserod is cost-effective under a series of assumptions for the treatment of women with IBS with constipation .

Evaluation of cytokine production by equine alveolar macrophages exposed to lipopolysaccharide , Aspergillus fumigatus , and a suspension of hay dust . OBJECTIVE : To evaluate cytokine production by equine alveolar macrophages after exposure to lipopolysaccharide ( LPS ) , Aspergillus fumigatus , and hay dust , and determine the effect of clenbuterol on the cytokine response . ANIMALS : 6 horses . PROCEDURE : Alveolar macrophages were exposed to PBS solution ( negative control ) , LPS , hyphae and conidia of Aspergillus fumigatus ( AF ) , or a suspension of hay dust ( Q86SQ9 ) and incubated for 24 hours at 37 degrees C . Concentrations of tumor necrosis factor ( P01375 REA ) - alpha and interleukin ( IL ) - 1beta were measured in the supernatant . The procedure was repeated with cells that were concurrently incubated with 0.5 microM clenbuterol . RESULTS : Exposure to Q86SQ9 and AF significantly increased production of P01375 REA by equine alveolar macrophages . The increase in P01375 REA produced in response to Q86SQ9 and AF was 5 and 7 times as great , respectively , as the increase measured in response to LPS . The concentration of IL - 1beta in the supernatant was significantly increased after exposure of cells to AF . DB01407 MEN was effective at inhibiting P01375 REA production by cells exposed to LPS , Q86SQ9 , or AF . CONCLUSIONS AND CLINICAL RELEVANCE : Increased production of P01375 REA and IL - 1 indicated that the pro-inflammatory cytokines produced by alveolar macrophages in response to allergens may play a role in recurrent airway obstruction ( O75106 REA ) in horses . Equine alveolar macrophages are not only a primary pulmonary defense mechanism but may also influence the pathogenesis of equine O75106 REA . The beta 2 - adrenoceptor agonist clenbuterol , a drug that is commonly used for treatment of equine O75106 REA , promotes immediate bronchodilation and may also contribute to downward modulation of the inflammatory response .

P04629 REA and Q16620 REA receptors facilitate follicle assembly and early follicular development in the mouse ovary . Recent studies have demonstrated that neurotrophins ( NTs ) and their NTRK tyrosine kinase receptors , thought to be exclusively required for the development of the nervous system , are also involved in controlling ovarian development . Here , we show that primordial follicle formation is decreased in the absence of nerve growth factor ( P01138 REA ) or its receptor P04629 REA , and in the absence of Q16620 REA , the receptor for neurotrophin - 4 ( P34130 REA ) and brain-derived neurotrophic factor ( P23560 REA ) . This deficiency is not due to premature oocyte loss , because the ovaries of Ntrk 1 ( - / - ) and Ntrk 2 ( - / - ) mice do not show an increased rate of oocyte death antedating the initiation of folliculogenesis . Moreover , exposure of P01138 REA - deficient ovaries to P01138 REA rescues the defect in follicular assembly , if P04629 REA receptors are present , suggesting that the absence of NTs causes a delay , and not an irretrievable loss , of follicle formation . Both the number of secondary follicles and DB00094 MEN receptor ( P23945 REA ) expression are diminished in Ntrk 1 - and Ntrk 2 - null ovaries , but not in ovaries lacking the common NT receptor P08138 REA . Transient exposure of wild-type ovaries to P34130 REA increases Fshr gene expression and enhances the ability of the ovary to respond to DB00094 MEN with formation of cyclin D2 , a cell cycle protein mediating the proliferative actions of DB00094 MEN in the ovary . These results indicate that both P04629 REA and Q16620 REA receptors are necessary for the timely assembly of primordial follicles and for sustaining early follicular development . They also suggest that a mechanism by which Q16620 REA receptors facilitate subsequent follicle development is by inducing the formation of functional P23945 REA .

Standard - and high-dose etoposide , ifosfamide , carboplatin , and epirubicin in 107 patients with non-small-cell lung cancer : a mature follow-up report . BACKGROUND : We conducted a phase I-II trial to assess the activity of standard-dose ( P18827 REA ) and high-dose chemotherapy ( HDC ) with etoposide , ifosfamide , cis / carboplatin , and epirubicin ( P01282 REA - E , VIC-E ) in 107 patients with limited-stage ( LS , stage I-IIIB ) and extensive stage ( ES , stage IV ) non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS : Updated results of a previously published trial are presented . RESULTS : Response rates and survival after P01282 REA - E were comparable to those of other standard-dose combination chemotherapies in NSCLC . Treatment-related mortality ( TRM ) in P18827 REA was 3 % in LS-NSCLC , and 8 % in ES-NSCLC . TRM was 4 % in patients selected for HDC by response rate and performance score . Five-year survival in LS-NSCLC was 12 % after P18827 REA , and 18 % after HDC ; it was 0 % for both treatment protocols in ES-NSCLC . CONCLUSIONS : The activity of P01282 REA - E P18827 REA and VIC-E HDC is not superior to that of established protocols in the treatment of NSCLC . In view of the toxicity and TRM associated with this protocol , less aggressive regimens should be preferred for most patients . Whether selected patients with chemosensitive disease could benefit from P01282 REA - E P18827 REA and / or VIC-E HDC in an adjuvant or neo-adjuvant setting could not be determined within the scope of this study .

[ Role of neurokinin - 1 receptor in lung injury in rats with acute necrotizing pancreatitis ] . OBJECTIVE : To investigate the expression of neurokinin - 1 receptor ( P25103 REA ) in the lung tissue , and the relationship between expression of P25103 REA and lung injury in rats with acute necrotizing pancreatitis ( P01160 REA ) . METHODS : One hundred and twenty adult Sprague-Dawley rats were randomly divided into P01160 REA and control groups . Animals in group P01160 REA were induced by the retrograde intraductal infusion of 5 % sodium taurocholate ( 0.1 ml / kg ) , and animals in normal control group received laparotomy only . The accumulation of polymorphonuclear leukocytes in lung tissues was measured with myeloperoxidase ( P05164 REA ) assay . Lung endothelial barrier destruction was measured by lung capillary permeability ( LCP ) . Reverse transcription polymerase chain reaction ( RT-PCR ) was used to determine the mRNA expression of P25103 REA , western blot analysis was used to determine P25103 REA protein expression levels , and immunohistochemistry was used to localize expression site of P25103 REA . RESULTS : P25103 REA mRNA level was enhanced in the lung of P01160 REA compared with normal control group . Western blot analysis showed overexpression of P25103 REA protein level exited in P01160 REA group . Statistical analysis revealed correlation between P25103 REA mRNA and P05164 REA ( r = 0.83 , P < 0.01 ) and LCP ( r = 0.79 , P < 0.01 ) respectively . With immunohistochemistry staining , moderate to strong P25103 REA immunoreactivity was localized to alveolar membrane , I epithelium , II epithelium and polymorphonuclear leukocytes in the lung of P01160 REA . CONCLUSION : In P01160 REA , overexpression of P25103 REA contributes to disturbance of neuropeptides loop , resulting in aggregation of neutrophilic granulocyte and promoting deterioration of lung injury .