MH_dev_32

Effects of neuropeptides on human lung fibroblast proliferation and chemotaxis . An increase in subepithelial mesenchymal cells and associated connective tissue is a feature of bronchial asthma . We determined whether neuropeptides could modulate fibroblast activity , particularly with respect to proliferation and chemotaxis . Human lung fibroblasts were cultured with neurokinin A ( P20366 REA ) , DB05875 ( SP ) , vasoactive intestinal peptide ( P01282 REA ) , and calcitonin-gene-related peptide ( P8 0511 ) . After 48 h , fibroblast proliferation was measured by a colorimetric assay based on the uptake and subsequent release of methylene blue . The chemotactic response to neuropeptides was determined with the use of a modified Boyden chamber . Both P20366 REA and SP ( 10 ( - 7 ) - 10 ( - 4 ) M ) stimulated human lung fibroblast proliferation in Q03591 REA and IMR - 90 fibroblasts . P01282 REA and P8 0511 had no effect on fibroblast proliferation . P20366 REA alone stimulated fibroblast chemotaxis maximally at 10 ( - 10 ) M . P08473 REA ( NEP ) activity of 0.52 and 5.2 pmol / 10 ( 6 ) cells was assayed in IMR - 90 and Hs68 fibroblasts , respectively . DB02557 MEN ( 5 x 10 ( - 6 ) - 10 ( - 5 ) M ) , an NEP inhibitor , enhanced fibroblast proliferation in a dose-dependent manner . Thus neuropeptides have the potential to cause activation of mesenchymal cells , and neuropeptide release may contribute to the structural abnormalities observed in asthmatic airways .

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 .

Natriuretic peptide receptor A signaling regulates stem cell recruitment and angiogenesis : a model to study linkage between inflammation and tumorigenesis . Natriuretic peptide receptor A ( NPRA ) , the signaling receptor for the cardiac hormone , atrial natriuretic peptide ( P01160 REA ) , is expressed abundantly in inflamed / injured tissues and tumors . NPRA deficiency substantially decreases tissue inflammation and inhibits tumor growth . However , the precise mechanism of NPRA function and whether it links inflammation and tumorigenesis remains unknown . Since both injury repair and tumor growth require stem cell recruitment and angiogenesis , we examined the role of NPRA signaling in tumor angiogenesis as a model of tissue injury repair in this study . In in vitro cultures , aortas from NPRA-KO mice show significantly lower angiogenic response compared to wild-type counterparts . The NPRA antagonist that decreases NPRA expression , inhibits lipopolysaccharide-induced angiogenesis . The reduction in angiogenesis correlates with decreased expression of vascular endothelial growth factor and chemokine ( C-X-C motif ) receptor 4 ( P61073 REA ) implicating a cell recruitment defect . To test whether NPRA regulates migration of cells to tumors , DB05914 ( MSCs ) were administered i . v . , and the results showed that MSCs fail to migrate to the tumor microenvironment in NPRA-KO mice . However , coimplanting tumor cells with MSCs increases angiogenesis and tumorigenesis in NPRA-KO mice , in part by promoting expression of P61073 REA and its ligand , stromal cell-derived factor 1α . Taken together , these results demonstrate that NPRA signaling regulates stem cell recruitment and angiogenesis leading to tumor growth . Thus , NPRA signaling provides a key linkage between inflammation and tumorigenesis , and NPRA may be a target for drug development against cancers and tissue injury repair .

Suppression of 3 - deoxyglucosone and heparin-binding epidermal growth factor-like growth factor mRNA expression by an aldose reductase inhibitor in rat vascular smooth muscle cells . Reactive carbonyl compounds and oxidative stress have been recently shown to up-regulate the expression of heparin-binding epidermal growth factor-like growth factor ( HB - P01133 REA ) , a potent mitogen for vascular smooth muscle cells ( SMCs ) produced by SMC themselves . Because the polyol pathway has been reported to influence the formation of carbonyl compounds and the oxidative stress in various cells , we conducted this study to investigate whether the polyol pathway affects HB - P01133 REA expression along with the generation of carbonyl compounds and the oxidative stress in SMCs . We found that , compared with those cultured with 5.5 mM glucose , SMCs cultured with 40 mM glucose showed the accelerated thymidine incorporation , elevated levels of intracellular sorbitol , 3 - deoxyglucosone ( 3 - DG ) , advanced glycation end products ( AGEs ) , and thiobarbituric acid-reactive substances ( TBARS ) along with the enhanced expression of HB - P01133 REA mRNA . An aldose reductase inhibitor ( Q9Y4X5 REA ) , Q9NYY3 - 860 , significantly inhibited all of these abnormalities , while aminoguanidine suppressed 3 - DG levels and HB - P01133 REA mRNA expression independent of sorbitol levels . The results suggest that the polyol pathway may play a substantial role in SMC hyperplasia under hyperglycemic condition in part by affecting HB - P01133 REA mRNA expression via the production of carbonyl compounds and oxidative stress .

Selective inhibition of the tumor marker O60218 REA by antiinflammatory N-phenylanthranilic acids and glycyrrhetic acid . A human aldose reductase-like protein , O60218 REA in the aldo-keto reductase ( AKR ) superfamily , was recently identified as a tumor marker of several types of cancer . DB02383 MEN , an aldose reductase inhibitor ( Q9Y4X5 REA ) , is known to be the most potent inhibitor of the enzyme . In this study , we compared the inhibitory effects of other ARIs including flavonoids on O60218 REA and aldose reductase to evaluate their specificity . However , ARIs showed lower inhibitory potency for O60218 REA than for aldose reductase . In the search for potent and selective inhibitors of O60218 REA from other drugs used clinically , we found that non-steroidal antiinflammatory N-phenylanthranilic acids , diclofenac and glycyrrhetic acid competitively inhibited O60218 REA , showing K ( i ) values of 0.35- 2.9 microM and high selectivity to this enzyme ( 43-57 fold versus aldose reductase ) . Molecular docking studies of mefenamic acid and glycyrrhetic acid in the O60218 REA - nicotinamide adenine dinucleotide phosphate ( NADP ( + ) ) complex and site-directed mutagenesis of the putative binding residues suggest that the side chain of Val 301 and a hydrogen-bonding network among residues Val 301 , Gln 114 and Ser 304 are important for determining the inhibitory potency and selectivity of the non-steroidal antiinflammatory drugs . Thus , the potent and selective inhibition may be related to the cancer chemopreventive roles of the drugs , and their structural features may facilitate the design of new anti-cancer agents targeting O60218 REA .

DB00175 MEN - induced proangiogenic effects depend upon extracellular P09038 REA . The P04035 REA inhibitors ( statins ) have been shown to exert several protective effects on the vasculature that are unrelated to changes in the cholesterol profile , and to induce angiogenesis . The proangiogenic effect exerted by statins has been attributed to the activation of the PI3K / Akt pathway in endothelial cells ; however , it is unclear how statins activate this pathway . DB00175 MEN - mediated activation of Akt and MAPK occurs rapidly ( within 10 min . ) and at low doses ( 10 nM ) . Here , we hypothesized that P09038 REA contributes to the proangiogenic effect of statins . We found that pravastatin , a hydrophilic statin , induced phosphorylation of the FGF receptor ( FGFR ) in human umbilical vein endothelial cells . SU5402 , an inhibitor of FGFR , abolished pravastatin-induced PI3K / Akt and MAPK activity . Likewise , anti - P09038 REA function-blocking antibodies inhibited Akt and MAPK activity . Moreover , depletion of extracellular P09038 REA by heparin prevented pravastatin-induced phosphorylation of Akt and MAPK . Treatment with P09038 REA antibody inhibited pravastatin-enhanced endothelial cell proliferation , migration and tube formation . These observations indicate that pravastatin exerts proangiogenic effects in endothelial cells depending upon the extracellular P09038 REA .

Coronary atherosclerosis : current therapeutic approaches and future trends . Invasive cardiovascular procedures , such as percutaneous translumenal coronary angioplasty ( PTCA ) and aorto-coronary bypass surgery ( ACBS ) , that are currently employed in treating the coronary stenosis or occlusion caused by atherosclerosis represent a major therapeutic advance for managing coronary heart disease ( Q8NE62 ) . However , the cellular proliferative response and associated intimal hyperplasia that can follow the damage to blood vessels that occurs with these procedures leads to late complications which can not be effectively controlled by presently available drugs . Hence , a new approach is required for managing these complications , termed " restenosis " ( in the case of PTCA ) or " stenosis " ( in the case of ACBS ) . Existing drug therapy is reviewed and some new approaches to this problem are provided herein . Further studies of growth factors and other substances that influence the cellular proliferative response that follows injury to the blood vessel wall could lead to the development of effective therapy . Inhibition of intimal hyperplasia and / or acceleration of endothelial cell re-growth provide a basis for such new approaches . Platelet-derived growth factor ( PDGF ) and basic fibroblast growth factor ( P09038 REA ) , as well as DB00435 ( s ) ( EDRF ) and calcitonin gene-related peptide ( P8 0511 ) are among the substances discussed . Modification of certain currently available drugs ( e . g . Ca ( 2 + ) - antagonists ) could also be of value in meeting this therapeutic demand .

P05231 REA - P40763 REA - HIF signaling and therapeutic response to the angiogenesis inhibitor sunitinib in ovarian clear cell cancer . PURPOSE : Ovarian clear cell adenocarcinoma ( OCCA ) is an uncommon histotype that is generally refractory to platinum-based chemotherapy . We analyze here the most comprehensive gene expression and copy number data sets , to date , to identify potential therapeutic targets of OCCA . EXPERIMENTAL DESIGN : Gene expression and DNA copy number were carried out using primary human OCCA tumor samples , and findings were confirmed by immunohistochemistry on tissue microarrays . Circulating interleukin ( IL ) 6 levels were measured in serum from patients with OCCA or high-grade serous cancers and related to progression-free and overall survival . Two patients were treated with sunitinib , and their therapeutic responses were measured clinically and by positron emission tomography . RESULTS : We find specific overexpression of the P05231 REA - P40763 REA - HIF ( interleukin 6 - signal transducer and activator of transcription 3 - hypoxia induced factor ) pathway in OCCA tumors compared with high-grade serous cancers . Expression of P12272 REA and high levels of circulating P05231 REA in OCCA patients may explain the frequent occurrence of hypercalcemia of malignancy and thromboembolic events in OCCA . We describe amplification of several receptor tyrosine kinases , most notably MET , suggesting other potential therapeutic targets . We report sustained clinical and functional imaging responses in two OCCA patients with chemotherapy-resistant disease who were treated with sunitinib , thus showing significant parallels with renal clear cell cancer . CONCLUSIONS : Our findings highlight important therapeutic targets in OCCA , suggest that more extensive clinical trials with sunitinib in OCCA are warranted , and provide significant impetus to the growing realization that OCCA is molecularly and clinically distinct to other forms of ovarian cancer .

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 .

DB01645 MEN 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 MEN 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 .

Atrial natriuretic peptide : a possible mediator involved in dexamethasone ' s inhibition of cell proliferation in multiple myeloma . Atrial natriuretic peptide ( P01160 REA ) has been recognized for several decades for its role of regulating blood pressure . Recently , cumulating evidences show that P01160 REA plays an anticancer role in various solid tumors via blocking the kinase cascade of Ras - Q02750 REA / 2 - P27361 REA / 2 with the result of inhibition of DNA synthesis . P01160 REA , as well as its receptors ( P16066 REA and P17342 ) has been identified present in the embryonic stem cell and a wide range of cancer cells . Various lymphoid organs , such as lymph nodes , have been detected the presence of P01160 REA . Multiple myeloma ( MM ) , though the therapies have evolved significantly , is still an incurable disease as B lymphocyte cell neoplasm . Dexamethasone is the cornerstone in treatment of MM via inactivation of Ras - Q02750 REA / 2 - P27361 REA / 2 cascade reaction . Coincidently , dexamethasone can increase the expression of P01160 REA markedly . Nevertheless , the role of P01160 REA in MM is unclear . Based on these results above , we raise the hypothesis that P01160 REA is involved in mediating dexamethasone ' s inhibition of proliferation in MM cells , which suggests that P01160 REA may be a potential agent to treat MM .

P03372 REA alpha augments changes in hemostatic gene expression in HepG 2 cells treated with estradiol and phytoestrogens . Phytoestrogens are popular alternatives to estrogen therapy however their effects on hemostasis in post-menopausal women are unknown . The aim of this study was to determine the effect of the phytoestrogens , genistein , daidzein and equol on the expression of key genes from the hemostatic system in human hepatocyte cell models and to determine the role of estrogen receptors in mediating any response seen . HepG 2 cells and Hep 89 cells ( expressing estrogen receptor alpha ( ERα ) ) were incubated for 24 h with 50 nM 17β - estradiol , genistein , daidzein or equol . Tissue plasminogen activator ( tPA ) , plasminogen activator inhibitor - 1 ( P05121 REA ) , Factor VII , fibrinogen γ , protein C and protein S mRNA expression were determined using TaqMan PCR . DB01645 MEN and equol increased tPA and P05121 REA expression in Hep 89 cells with fold changes greater than those observed for estradiol . In HepG 2 cells ( which do not express ERα ) , P05121 REA and tPA expression were unchanged . Increased expression of Factor VII was observed in phytoestrogen treated Hep 89 cells but not in similarly treated HepG 2s . P00734 REA gene expression was increased in equol and daidzein treated HepG 2 cells in the absence of the classical estrogen receptors . These data suggest that phytoestrogens can regulate the expression of coagulation and fibrinolytic genes in a human hepatocyte cell line ; an effect which is augmented by ERα .

Molecular targets and regulators of cardiac hypertrophy . Cardiac hypertrophy is one of the main ways in which cardiomyocytes respond to mechanical and neurohormonal stimuli . It enables myocytes to increase their work output , which improves cardiac pump function . Although cardiac hypertrophy may initially represent an adaptive response of the myocardium , ultimately , it often progresses to ventricular dilatation and heart failure which is one of the leading causes of mortality in the western world . A number of signaling modulators that influence gene expression , apoptosis , cytokine release and growth factor signaling , etc . are known to regulate heart . By using genetic and cellular models of cardiac hypertrophy it has been proved that pathological hypertrophy can be prevented or reversed . This finding has promoted an enormous drive to identify novel and specific regulators of hypertrophy . In this review , we have discussed the various molecular signal transduction pathways and the regulators of hypertrophic response which includes calcineurin , cGMP , NFAT , natriuretic peptides , histone deacetylase , P05231 REA cytokine family , Gq / P49842 signaling , PI3K , MAPK pathways , Na / H exchanger , DB01367 , polypeptide growth factors , P01160 REA , NO , P01375 REA , Q07869 REA and JAK / P35610 REA pathway , microRNA , Cardiac angiogenesis and gene mutations in adult heart . Augmented knowledge of these signaling pathways and their interactions may potentially be translated into pharmacological therapies for the treatment of various cardiac diseases that are adversely affected by hypertrophy . The purpose of this review is to provide the current knowledge about the molecular pathogenesis of cardiac hypertrophy , with special emphasis on novel researches and investigations .

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 REA , P21397 REA , P23560 REA , NOS 3 , P05231 REA , P12036 , P31645 REA , P21964 REA , P48454 REA 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 .

MEK inhibition in non-small cell lung cancer . P01116 REA mutations are the most common mutations in non-small cell lung cancer ( NSCLC ) with adenocarcinoma histology . P01116 REA mutations result in the activation of the RAF-MEK - P29323 REA pathway , and agents that target RAF-MEK - P29323 REA pathways have been investigated in P01116 REA mutant NSCLC . The two agents furthest in development are selumetinib and trametinib . DB08911 MEN has greater binding for the Q02750 REA / 2 allosteric site , and generally has superior pharmacokinetics . A randomized phase II trial of docetaxel with and without selumetinib revealed that the combination resulted numerically superior overall survival , and a statistically significant improvement in progression-free survival and objective response rate . However , a concerning rate of hospital admission , grade 3 or 4 neutropenia , and febrile neutropenia was observed with the combination . Trials have investigated MEK inhibitors as single agents and in combination with erlotinib , and the data do not support the further development . The activity of MEK inhibitors appears to be similar in patients with P01116 REA mutant and wild-type NSCLC suggesting P01116 REA mutation status is not a reliable biomarker for efficacy . It is possible that mutations of genes in addition to P01116 REA mutations impact the activity of MEK inhibitors , or specific subsets of P01116 REA mutations may be resistant or susceptible to MEK inhibition . Other potential explanations are gene amplifications , alternative RNA splicing of genes resulting in activation of their protein products , and deregulation of noncoding RNAs and consequent altered protein expression .

Mobilisation of haematopoietic stem cells in paediatric patients , prior to autologous transplantation following administration of plerixafor and DB00099 . Previous chemotherapy and radiation exposure can make adequate stem cell mobilisation prior to autologous transplant extremely difficult in paediatrics . DB06809 MEN , a selective reversible P61073 REA antagonist interferes with P61073 REA interaction with P48061 REA alpha ( P48061 REA ) . Combination with granulocyte-colony stimulating factor ( DB00099 ) amplifies G - P04141 REA affects in mobilising haematopoietic stem cells . Whilst licensed for use with G - P04141 REA for enhancement of mobilisation of haematopoietic stem cells in adults , paediatric data for use of plerixafor remain limited . We present a retrospective review of outcomes seen with plerixafor and G - P04141 REA to mobilise stem cells heavily pre-treated paediatric patients with cancer .

A randomized , placebo-controlled study of the effects of the p38 MAPK inhibitor SB - DB05250 MEN on blood biomarkers of inflammation in P48444 REA patients . The p38 mitogen-activated protein kinase ( MAPK ) signaling upregulates inflammation and is known to be increased in chronic obstructive pulmonary disease ( P48444 REA ) . The authors assessed the pharmacology of the novel p38 MAPK inhibitor SB - DB05250 MEN using blood biomarkers in P48444 REA . Seventeen P48444 REA patients ( forced expiratory volume in 1 second 50 % - 80 % predicted ) using short-acting bronchodilators participated in a double-blind , double-dummy , randomized , crossover study . Patients received single oral doses of SB - DB05250 MEN 7.5 mg and 25 mg , prednisolone 10 mg and 30 mg , and placebo . Blood was obtained predose and at 1 , 2 , 6 , and 24 hours postdose . Whole-blood sorbitol-induced phosphorylated ( p ) heat shock protein ( HSP ) 27 levels as a marker of p38 pathway activation and lipopolysaccharide-induced tumor necrosis factor ( P01375 REA ) - alpha production were assessed . Both doses of SB - DB05250 MEN , but not prednisolone , significantly ( P < . 0001 ) reduced weighted mean ( WM ) pHSP 27 ( 0-6 hours ) by 58 % compared with placebo . WM P01375 REA production ( 0-24 hours ) was significantly reduced compared with placebo by SB - DB05250 MEN 25 mg ( 40 % , P = . 005 ) and 7.5 mg ( 33.4 % , P = . 02 ) , while prednisolone 30 mg and 10 mg caused 81.5 % and 58.2 % suppression , respectively ( both P < . 0001 ) . SB - DB05250 MEN inhibited the p38 MAPK pathway to a greater degree than prednisolone did . SB - DB05250 MEN inhibited P01375 REA production . SB - DB05250 MEN is a potent p38 MAPK inhibitor that potentially suppresses inflammation in P48444 REA .

Steroid hormone receptors and coregulators in endocrine-resistant and estrogen-independent breast cancer cells . Resistance to hormonal therapy is often a problem in the treatment of breast cancer patients . It has been suggested that resistance could be explained by altered nuclear hormone receptor or coregulator levels or inappropriately increased agonist activity of selective estrogen receptor modulator ( SERM ) . To test these hypotheses , we have established novel MCF - 7 cell line-derived in vitro models of anti-estrogen - and progestin-resistant and estrogen-independent breast cancer by long-term culture in the presence of toremifene and medroxyprogesterone acetate ( DB00603 SUB ) and in the absence of estradiol , respectively . Using cell growth and multiprobe ribonuclease protection assays , the expression of 5 nuclear hormone receptors and 9 coregulators as well as the alterations in the cell proliferation and target gene transcription in response to hormonal treatments were studied . P06401 REA ( PR ) expression was decreased and silencing mediator for retinoid acid and thyroid hormone receptors ( Q9Y618 REA ) and amplified in breast cancer - 1 ( Q9Y6Q9 REA ) expression increased in anti-estrogen-resistant cells . Estrogen caused PR and ERbeta upregulation in all cell lines , but we did not observe increased agonist activity of anti-estrogen measured by regulation of these estrogen target genes . Basal ERalpha levels and estrogenic growth response were decreased and p300 / CBP-associated factor ( pCAF ) and Q9Y6Q9 REA upregulated by estrogen in progestin-resistant cells , but coregulator levels were unchanged . Estrogen-independent cells were still estrogen-responsive and PR , nuclear receptor corepressor ( O75376 REA ) and Q9Y618 REA expression was increased whereas steroid receptor coactivator - 1 ( P12931 REA - 1a ) and CBP-related protein p300 ( p300 ) expression decreased . Their growth was inhibited by toremifene , but estradiol was able to abrogate this effect , which might have interesting clinical implications concerning the use of postmenopausal hormone replacement therapy .

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 .

DB01037 MENMAX DB01037 MEN transdermal system : in the treatment of major depressive disorder . The monamine oxidase ( MAO ) inhibitor selegiline is selective for P27338 REA at the low oral dosages used in the treatment of Parkinson ' s disease . However , P21397 REA is also inhibited at the high oral dosages needed to effectively treat depression ( not an approved indication ) , necessitating a tyramine-restricted diet . The selegiline transdermal system was designed to deliver antidepressant drug concentrations to the CNS , without substantially impairing small intestine P21397 REA activity . At the target dose of 6 mg / 24 hours , tyramine dietary restrictions are not needed . Short-term treatment with fixed ( 6 mg / 24 hours ) or flexible ( 6 , 9 or 12 mg / 24 hours ) doses of selegiline transdermal system was superior to placebo on most measures of antidepressant activity in 6 - or 8 - week , randomised , double-blind , multicentre studies in adult outpatients with major depressive disorder ( MDD ) . Likewise , long-term treatment with a fixed dose of selegiline transdermal system 6 mg / 24 hours was superior to placebo as maintenance therapy in a 52 - week , randomised , double-blind , multicentre , relapse-prevention trial in patients with MDD . DB01037 MEN transdermal system therapy was generally well tolerated in placebo-controlled studies ; application site reactions , mostly of mild to moderate severity , were the most commonly reported adverse events . The incidence of sexual adverse effects and weight gain was low and similar to that with placebo .

Curcumin sensitizes acute promyelocytic leukemia cells to unfolded protein response-induced apoptosis by blocking the loss of misfolded O75376 REA protein . Acute promyelocytic leukemia ( APL ) is characterized by accumulation of apoptosis-resistant immature promyelocytic cells in the bone marrow and peripheral blood . We have shown that endoplasmic reticulum ( ER ) - associated degradation ( ERAD ) and protease-mediated degradation of misfolded nuclear receptor corepressor ( O75376 REA ) confer resistance to unfolded protein response ( UPR ) - induced apoptosis in APL . These findings suggest that therapeutic inhibition of O75376 REA misfolding or degradation may promote growth arrest in APL cells by sensitizing them to UPR-induced apoptosis . On the basis of this hypothesis , we tested the effects of several known protein conformation-modifying agents on the growth and survival of APL cells and identified curcumin , a natural component of turmeric , as a potent growth inhibitor of APL cells . Curcumin selectively inhibited the growth and promoted apoptosis in both primary and secondary leukemic cells derived from APL . The curcumin-induced apoptosis of APL cells was triggered by an amplification of ER stress , possibly from the accumulation of misfolded O75376 REA protein in the ER . Curcumin promoted this net accumulation of aberrantly phosphorylated misfolded O75376 REA protein by blocking its ERAD and protease-mediated degradation , which then led to the activation of UPR-induced apoptosis in APL cells . The activation of UPR by curcumin was manifested by phosphorylation of protein kinase RNA-like endoplasmic reticulum kinase ( Q9NZJ5 ) and eukaryotic translation initiation factor 2 alpha ( eIF 2α ) , and upregulation of C / EBP homologous protein ( P35638 REA ) and O75807 REA , the principal mediators of proapoptotic UPR . These findings identify the therapeutic potential of curcumin in APL and further establish the rationale of misfolded O75376 REA protein as an attractive molecular target in APL .

Natriuretic peptide / natriuretic peptide receptor-A ( P16066 REA ) system has inhibitory effects in renal fibrosis in mice . OBJECT : This study was designed to examine whether natriuretic peptide / natriuretic peptide receptor-A ( P16066 REA ) system attenuates renal fibrosis in a unilateral ureteral obstruction ( UUO ) model and also examined the mechanism involved . METHODS : Three groups were studied : untreated UUO in wild-type mice ; untreated UUO in P16066 REA KO mice ; and P01160 REA treated ( 0.05 microg / kg / min ) UUO in wild-type mice . We measured histological and immunohistochemical findings ( alpha-SMA and F4 /8 0 ) , tissue cGMP levels , various mRNA expression levels by real-time PCR analysis , and transcription factor levels ( AP - 1 and NF-kappaB ) in renal tissue . RESULTS : Compared with wild-type UUO mice , NPRA-KO UUO mice had abnormal morphological findings ( fibrous area : + 26 % , alpha-SMA expression : + 30 % ) with lower tissue cGMP levels and increases in the mRNA expression levels of TGF-beta , collagen I , collagen III , P05121 REA , renin and angiotensinogen , whereas there were no differences in F4 /8 0 positive cells or the mRNA expression levels of P05362 REA , osteopontin , or P13500 REA between the two groups . In contrast , P01160 REA pre-treatment significantly improved morphological changes with increase of tissue cGMP levels and reduction in the mRNA expression level of TGF-beta , collagen I , collagen III , P05121 REA , P05362 REA , osteopontin , P13500 REA , renin , and angiotensinogen . NPRA-KO UUO mice had higher AP - 1 levels than wild-type UUO mice and P01160 REA pre-treatment reduced AP - 1 and NF-kappaB activity . CONCLUSION : The endogenous natriuretic peptide / P16066 REA system may inhibit renal fibrosis partly via inhibition of the angiotensin / AP - 1 / TGF-beta / collagen pathway and exogenous P01160 REA pre-treatment may inhibit it partly via both the angiotensin / AP - 1 / TGF-beta / collagen and NF-kappaB / inflammatory pathways .

DB00594 MEN derivatives induce apoptosis by depleting ER Ca ( 2 + ) stores in vascular endothelial cells . BACKGROUND AND PURPOSE : DB00594 MEN derivatives are blockers of the Na ( + ) / H ( + ) exchanger ( NHE ) and at micromolar concentrations have protective effects on cardiac and brain ischaemia / reperfusion injury but at higher concentrations also induce apoptosis . Here , we aimed to elucidate the mechanism related to this cytotoxic action . EXPERIMENTAL APPROACH : We quantified the expression of genes associated with endoplasmic reticulum ( ER ) stress and measured changes in luminal ER Ca ( 2 + ) concentration ( [ Ca ( 2 + ) ] ( ER ) ) with a ' cameleon ' indicator , D1ER . KEY RESULTS : DB00594 MEN derivatives induced apoptosis in vascular endothelial cells , an effect that increased at alkaline extracellular pH . The potency order for cytotoxicity was 5 - ( N , N-hexamethylene ) - amiloride ( HMA ) > 5 - ( N-methyl-N-isobutyl ) amiloride > 5 - ( N-ethyl-N-isopropyl ) amiloride ( EIPA ) > > amiloride . HMA dose-dependently increased the transcription of the ER stress genes P35638 REA and O75807 REA and rapidly depleted [ Ca ( 2 + ) ] ( ER ) , mimicking the effects of the sarco / endoplasmic reticulum ATPase ( SERCA ) inhibitor thapsigargin . The P19634 REA - specific inhibitor HOE 694 inhibited NHE activity by 87 % but did not alter [ Ca ( 2 + ) ] ( ER ) . The decrease in [ Ca ( 2 + ) ] ( ER ) evoked by amiloride derivatives was also observed in HeLa cells and was mirrored by an increase in cytosolic Ca ( 2 + ) concentration . CONCLUSIONS AND IMPLICATIONS : DB00594 MEN derivatives disrupt ER and cytosolic Ca ( 2 + ) homeostasis by a mechanism unrelated to NHE inhibition , most likely by interfering with the activity of SERCA . We propose that ER Ca ( 2 + ) depletion and subsequent ER stress provide a rationale framework for the apoptotic effects of amiloride derivatives .