MH_dev_102

The anti-tumor effect of HDAC inhibition in a human pancreas cancer model is significantly improved by the simultaneous inhibition of cyclooxygenase 2 . Pancreatic ductal adenocarcinoma is the fourth leading cause of cancer death worldwide , with no satisfactory treatment to date . In this study , we tested whether the combined inhibition of cyclooxygenase - 2 ( P35354 REA ) and class I histone deacetylase ( HDAC ) may results in a better control of pancreatic ductal adenocarcinoma . The impact of the concomitant HDAC and P35354 REA inhibition on cell growth , apoptosis and cell cycle was assessed first in vitro on human pancreas BxPC - 3 , PANC - 1 or CFPAC - 1 cells treated with chemical inhibitors ( DB02546 MEN , MS - 275 and celecoxib ) or Q13547 REA / 2/3 / 7 siRNA . To test the potential antitumoral activity of this combination in vivo , we have developed and characterized , a refined chick chorioallantoic membrane tumor model that histologically and proteomically mimics human pancreatic ductal adenocarcinoma . The combination of Q13547 REA / 3 and P35354 REA inhibition significantly impaired proliferation of BxPC - 3 cells in vitro and stalled entirely the BxPC - 3 cells tumor growth onto the chorioallantoic membrane in vivo . The combination was more effective than either drug used alone . Consistently , we showed that both Q13547 REA and O15379 REA inhibition induced the expression of P35354 REA via the NF-kB pathway . Our data demonstrate , for the first time in a Pancreatic Ductal Adenocarcinoma ( PDAC ) model , a significant action of HDAC and P35354 REA inhibitors on cancer cell growth , which sets the basis for the development of potentially effective new combinatory therapies for pancreatic ductal adenocarcinoma patients .

Nongenomic , glucocorticoid receptor-mediated regulation of serotonin transporter cell surface expression in embryonic stem cell derived serotonergic neurons . Depressive disorders have been linked to the combined dysregulation of the hypothalamus-pituitary-adrenal ( Q9Y251 REA ) - axis and the serotonergic system . The Q9Y251 REA - axis and serotonergic ( 5 - HT ) neurons exert reciprocal regulatory actions . It has been reported that glucocorticoid-glucocorticoid receptor ( GR ) signaling influences serotonin transporter ( 5 - HTT ) transcription but data also points to the fact that 5 - HTT expression is regulated nongenomically via redistribution of 5 - HTT from the cell surface into intracellular compartments . In order to analyze the acute effects of glucocorticoids on 5 - HTT cell surface localization we differentiated serotonergic neurons from mouse embryonic stem ( ES ) cells derived from the C57BL / 6N blastocysts . These postmitotic 5 - HT neurons express all relevant serotonergic markers following the application of a growth factor-based differentiation protocol . Increasing concentrations of the GR agonist dexamethasone ( DB00514 MEN ) resulted in enhanced , dose-dependent 5 - HTT cell surface localization in the presence of the protein synthesis inhibitor cycloheximide already 1h after incubation . Inhibition of GR function by the specific GR-antagonist mifepristone abolished the increase in 5 - HTT cell surface localization . Hence , our data account for a nongenomic upregulation of 5 - HTT cell surface expression by glucocorticoid-GR interaction which likely constitutes a rapid physiological response to increased levels of glucocorticoids as seen during stress . Taken together , we provide a cellular model to analyze and dissect glucocorticoid - P31645 interactions on a molecular level that corresponds to in vivo animal models using C57BL / 6N mice .

Evaluation of pharmacological profile of meloxicam as an anti-inflammatory agent , with particular reference to its relative selectivity for cyclooxygenase - 2 over cyclooxygenase - 1 . We studied the anti-inflammatory activity of meloxicam on rat carrageenin-induced pleurisy and its toxicity for rat gastric mucosa , relative to its in vitro inhibitory potency against partially purified cyclooxygenase ( P36551 REA ) - 1 and P35354 REA preparations in order to clarify the pharmacological profile of the compound as an anti-inflammatory agent . In rat carrageenin-induced pleurisy , the plasma exudation rate peaked at 5 h , at which time P35354 REA was detectable in cells from the pleural exudate . Meloxicam and piroxicam ( 1 and 3 mg / kg ) and NS - 398 ( 3 mg / kg ) showed almost equal anti-inflammatory potency against 5 - hour pleurisy . A single oral administration of the compounds caused a dose-dependent increase in the number of rats with gastric mucosal erosion . The ED50 value for meloxicam ( 5.92 mg / kg ) was significantly higher than that for piroxicam ( 1.76 mg / kg ) , indicating that meloxicam is safer . DB00328 SUB showed intermediate safety ( 2.59 mg / kg ) . In in vitro experiments , indometacin inhibited P23219 REA about 1.7 times more potently than P35354 REA . NS - 398 inhibited P35354 REA with an IC50 of 0.32 microM , but never affected P23219 REA activity , even at 100 microM . In the same assay system , meloxicam inhibited P35354 REA about 12 times more selectively than P23219 REA . Piroxicam , however , inhibited both isoforms almost equally . These results indicate that meloxicam is a potent anti-inflammatory agent with low gastric toxicity . One reason for its in vivo pharmacological profile may be related to its relative selectivity for P35354 REA over P23219 REA . Thus , meloxicam may belong to a group of P35354 REA selective anti-inflammatory agents with a better safety profile than conventional P23219 REA and P35354 REA nonselective anti-inflammatory agents .

DB01281 MEN inhibits effector T cells through regulatory T cells and TGF-β . The P10747 REA costimulatory receptor is a critical regulator of T cell function , making it an attractive therapeutic target for the treatment of immune-mediated diseases . DB01281 MEN , now approved for use in humans , prevents naive T cell activation by binding to P33681 REA proteins and blocking engagement of P10747 REA . However , DB01281 MEN suppresses inflammation even if administered when disease is established , suggesting alternative mechanisms . We identified a novel , P10747 REA - independent mechanism by which DB01281 MEN inhibits activated T cells . We show that in vitro , DB01281 MEN synergizes with NO from bone marrow-derived macrophages to inhibit T cell proliferation . Depletion of regulatory T cells ( Tregs ) or interference with TGF-β signaling abrogated the inhibitory effect of DB01281 MEN . Parallel in vivo experiments using an allergic airway inflammation model demonstrated that this novel mechanism required both macrophages and regulatory T cells . Furthermore , DB01281 MEN was ineffective in P8 4022 - deficient mice , supporting a requirement for TGF-β signaling . Thus , in addition to preventing naive T cells from being fully activated , DB01281 MEN can turn off already activated effector T cells by an NO / regulatory T cell / TGF-β-dependent pathway . This mechanism is similar to cell-extrinsic effects of endogenous P16410 REA and may be particularly important in the ability of DB01281 MEN to treat chronic inflammatory disease .

Peroxisome proliferator-activated receptor-gamma activation inhibits tumor metastasis by antagonizing P8 4022 - mediated epithelial-mesenchymal transition . Epithelial-mesenchymal transition ( EMT ) was shown to confer tumor cells with abilities essential for metastasis , including migratory phenotype , invasiveness , resistance to apoptosis , evading immune surveillance , and tumor stem cell traits . Therefore , inhibition of EMT can be an important therapeutic strategy to inhibit tumor metastasis . Here , we show that activation of peroxisome proliferator-activated receptor γ ( Q07869 REA - γ ) inhibits transforming growth factor β ( TGF-β ) - induced EMT in lung cancer cells and prevents metastasis by antagonizing P8 4022 function . Activation of Q07869 REA - γ by synthetic ligands ( troglitazone and rosiglitazone ) or by a constitutively active form of Q07869 REA - γ prevents TGF-β-induced loss of P12830 REA expression and inhibits the induction of mesenchymal markers ( vimentin , P19022 REA , fibronectin ) and matrix metalloproteases . Consistently , activation of Q07869 REA - γ also inhibited EMT-induced migration and invasion of lung cancer cells . Furthermore , effects of Q07869 REA - γ ligands were attenuated by siRNA-mediated knockdown of Q07869 REA - γ , indicating that the ligand-induced responses are Q07869 REA - γ dependent . Selective knockdown of Q15796 REA and P8 4022 by siRNA showed that TGF-β-induced EMT is P8 4022 dependent in lung cancer cells . Activation of Q07869 REA - γ inhibits TGF-β-induced Smad transcriptional activity but had no effect on the phosphorylation or nuclear translocation of Smads . Consistently , Q07869 REA - γ activation prevented TGF-β-induced transcriptional repression of P12830 REA promoter and inhibited transcriptional activation of P19022 REA promoter . Finally , treatment of mice with troglitazone or knockdown of P8 4022 in tumor cells significantly inhibited TGF-β-induced experimental metastasis in SCID-Beige mice . Together , with the low toxicity profile of Q07869 REA - γ ligands , our data show that these ligands may serve as potential therapeutic agents to inhibit metastasis .

Pharmacological properties of thalidomide and its analogues . Thalidomide and its immunomodulatory imide drugs ( IMiDs ) analogues DB00480 ( DB00480 , DB00480 ) and CC - 4047 ( Actimid , DB08910 MEN ) have been used as anti-inflammatory and anticancerous drugs in the recent years . Thalidomide and IMiDs inhibit the cytokines tumour necrosis factor-alpha ( P01375 REA ) , interleukins ( IL ) 1 - beta , 6 , 12 , and granulocyte macrophage-colony stimulating factor ( GM - P04141 REA ) . They also costimulate primary human T , NKT and NK lymphocytes inducing their proliferation , cytokine production , and cytotoxic activity . On the other hand , the compounds are anti-angiogenic , anti-proliferative , and pro-apoptotic . Thalidomide analogues have been used as inhibitors of alpha glucosidase and could be potential drugs for diabetes treatment . In this review , we explore the current trend of the different structures , the new patents , and the possible new applications in different pathologies .

Prevention of thrombus formation and growth by antithrombin III and heparin cofactor II-dependent thrombin inhibitors : importance of heparin cofactor II . DB01109 ( HEP ) prevents thrombus formation ( TF ) and thrombus growth ( TG ) , by accelerating thrombin ( THR ) inhibition by antithrombin III ( P01008 REA ) . Recent studies suggest that dermatan sulphate which catalyzes thrombin inhibition by heparin cofactor II ( HCII ) , can inhibit TF and TG as effectively as HEP . This study compared the antithrombotic effects of HEP and another agent , DB06271 MENMAX DB06271 MEN ( SLX ) which catalyzes thrombin inhibition by P01008 REA and HCII simultaneously . TF was induced in rabbit jugular veins , using the stasis / hypercoagulation model . TG was measured as the accretion of 125I - fibrin onto existing thrombi in rabbit jugular veins . HEP and SLX inhibited TF when given in doses of 10 and 5 anti-thrombin U / kg , respectively . SLX ( 16 anti-thrombin U / kg or 260 micrograms / kg ) was more effective than HEP ( 120 anti-thrombin U / kg or 800 micrograms / kg ) in preventing TG when administered either as a bolus or by continuous infusion . These data suggest that agents which accelerate THR inhibition by both P01008 REA and HCII simultaneously , can inhibit TF and TG with less systemic anticoagulation than comparable antithrombotic doses of HEP .

DB01098 MEN reduces neointima formation in a rat model of balloon injury . BACKGROUND : Processes of restenosis , following arterial injury , are complex involving different cell types producing various cytokines and enzymes . Among those enzymes , smooth muscle cell-derived matrix metalloproteinases ( MMPs ) are thought to take part in cell migration , degrading of extracellular matrix , and neointima formation . P14780 REA , also known as gelatinase B , is expressed immediately after vascular injury and its expression and activity can be inhibited by statins . Using an established in vivo model of vascular injury , we investigated the effect of the P04035 REA inhibitor rosuvastatin on P14780 REA expression and neointima formation . MATERIALS AND METHODS : 14 - week old male Sprague Dawley rats underwent balloon injury of the common carotid artery . Half of the animals received rosuvastatin ( 20 mg / kg body weight / day ) via oral gavage , beginning 3 days prior to injury . Gelatinase activity and neointima formation were analyzed 3 days and 14 days after balloon injury , respectively . 14 days after vascular injury , proliferative activity was assessed by staining for Ki67 . RESULTS : After 14 days , animals in the rosuvastatin group showed a decrease in total neointima formation ( 0.194 ± 0.01 mm2 versus 0.124 ± 0.02 mm2 , p < 0.05 ) as well as a reduced intima / media ratio ( 1.26 ± 0.1 versus 0.75 ± 0.09 , p < 0.05 ) . Balloon injury resulted in increased activity of P14780 REA 3 days after intervention for both rosuvastatin treated animals and controls with no significant difference observed between the groups . There was a trend towards a reduction in the number of Ki67 - positive cells 14 days after injury . CONCLUSIONS : DB01098 MEN attenuates neointima formation without affecting early P14780 REA activity in a rat model of vascular injury .

DB00328 SUB ameliorates high glucose-induced proliferation and invasion via modulation of e-cadherin in pancreatic cancer cells . DB00328 SUB , an inhibitor of cyclooxygenase - 2 ( P35354 REA ) , has been shown to exert anticancer effects in a variety of cancers . However , the effect and mechanism of indometacin on high glucose ( HG ) - induced proliferation and invasion of pancreatic cancer ( PC ) cells remain unclear . Multiple lines of evidence suggest that a large portion of pancreatic cancer ( PC ) patients suffer from either diabetes or HG which contributing PC progression . In this study , we report that indometacin down-regulated HG-induced proliferation and invasion via up-regulating P12830 REA but not P35354 REA in PC cells . Additionally , the P12830 REA transcriptional repressors , Snail and Slug , were also involved in the process . Furthermore , the proliferation and invasion of PC cells , incubated in HG medium and treated with indometacin were significantly increased when P12830 REA was knocked down ( Si-E-cad ) . Moreover , the protein levels of P08253 REA , P14780 REA , and P15692 REA were increased in PC cells transfected with Si-E-cad . Finally , the activation of the PI3K / AKT / GSK - 3β signaling pathway was demonstrated to be involved in indometacin reversing HG-induced cell proliferation and invasion in PC cells . In conclusion , these results suggest that indometacin plays a key role in down-regulating HG-induced proliferation and invasion in PC cells . Our findings indicate that indometacin could be used as a novel therapeutic strategy to treat PC patients who simultaneously suffer from diabetes or HG .

Synthetic triterpenoid induces P15428 REA expression and suppresses inflammation-driven colon carcinogenesis . Colitis-associated colon cancer ( CAC ) develops as a result of inflammation-induced epithelial transformation , which occurs in response to inflammatory cytokine-dependent downregulation of 15 - hydroxyprostaglandin dehydrogenase ( P15428 REA ) and subsequent suppression of prostaglandin metabolism . Agents that both enhance P15428 REA expression and suppress cyclooxygenase - 2 ( P35354 REA ) production may more effectively prevent CAC . Synthetic triterpenoids are a class of small molecules that suppress P35354 REA as well as inflammatory cytokine signaling . Here , we found that administration of the synthetic triterpenoid 2 - cyano -3,12- dioxooleana -1,9 ( 11 ) - dien-C 28 - methyl ester ( CDDO-Me ) suppresses CAC in mice . In a spontaneous , inflammation-driven intestinal neoplasia model , deletion of Q13485 REA specifically in T cells led to progressive production of inflammatory cytokines , including P01375 REA - α , IFN-γ , P35228 REA , P05231 REA , IL - 1β ; as well as activation of P42224 REA and P40763 REA ; along with suppression of P15428 REA expression . Oral administration of CDDO-Me to mice with Q13485 REA - deficient T cells increased survival and suppressed intestinal epithelial neoplasia by decreasing production of inflammatory mediators and increasing expression of P15428 REA . Induction of P15428 REA by CDDO-Me was dose dependent in epithelial cells and was abrogated following treatment with TGF-β signaling inhibitors in vitro . Furthermore , CDDO-Me-dependent P15428 REA induction was not observed in P8 4022 - / - mice . Similarly , CDDO-Me suppressed azoxymethane plus dextran sodium sulfate-induced carcinogenesis in wild-type animals , highlighting the potential of small molecules of the triterpenoid family as effective agents for the chemoprevention of CAC in humans .

Matrix metalloproteinases are differentially expressed in adipose tissue during obesity and modulate adipocyte differentiation . Matrix metalloproteinases ( MMPs ) are essential for proper extracellular matrix remodeling , a process that takes place during obesity-mediated adipose tissue formation . Here , we examine expression profiles and the potential role of MMPs and their tissue inhibitors ( TIMPs ) in adipose tissue remodeling during obesity . Expression patterns are studied by Northern blot and real-time PCR in two genetic models of obesity ( ob / ob and db / db mice ) and in a diet-induced model of obesity ( AKR mice ) . Of the MMPs and TIMPs studied , mRNA levels for P08253 REA , P08254 REA , P39900 REA , P50281 REA , Q99542 REA , and P01033 REA are strongly induced in obese adipose tissues compared with lean tissues . In contrast , P09237 REA and P35625 REA mRNAs are markedly decreased in obesity . Interestingly , enzymatic activities of P39900 REA and of a new identified adipocyte-derived 30 - kDa metalloproteinase are enhanced in obese adipose tissue fractions , demonstrating that MMP / P01033 REA balance is shifted toward increased matrix degradation in obesity . Finally , we analyze the modulation of P08253 REA , Q99542 REA , and P01033 REA during 3T3 - Q9NUQ9 preadipocyte differentiation , and we explore the effect of inhibition of MMP activity on in vitro adipogenesis . We find that the synthetic MMP inhibitor BB - 94 ( DB03880 MEN ) decreases adipose conversion of 3T3 - Q9NUQ9 and primary rat preadipocytes . BB - 94 represses differentiation without affecting mitotic clonal expansion but prevents the early expression of P17676 REA , a transcription factor that is thought to play a major role in the adipogenic program . Such findings support a role for the MMP / P01033 REA system in the control of proteolytic events and adipogenesis during obesity-mediated fat mass development .

DB06212 MEN , a selective oral vasopressin V2 receptor antagonist , ameliorates podocyte injury in puromycin aminonucleoside nephrotic rats . BACKGROUND : Proteinuria caused by glomerular disease is characterized by podocyte injury . P30518 REA antagonists are effective in reducing albuminuria , although their actions on glomerular podocytes have not been explored . The objective of this study was to evaluate the effects of tolvaptan , a selective oral V2 receptor antagonist , on podocytes in a puromycin aminonucleoside ( PAN ) - induced nephrosis rat model . METHODS : Rats were allocated to a control , PAN nephrosis , or tolvaptan-treated PAN nephrosis group ( n = 9 per group ) . Urinary protein excretion and serum levels of total protein , albumin , creatinine , and total cholesterol were measured on day 10 . The influence of tolvaptan on podocytes was examined in renal tissues by immunofluorescence and electron microscopy . RESULTS : PAN induced massive proteinuria and serum creatinine elevation on day 10 , both of which were significantly ameliorated by tolvaptan . Immunofluorescence studies of the podocyte-associated proteins nephrin and podocin revealed granular staining patterns in PAN nephrosis rats . In tolvaptan-treated rats , nephrin and podocin expressions retained their normal linear pattern . Electron microscopy showed foot process effacement was ameliorated in tolvaptan-treated rats . CONCLUSIONS : DB06212 MEN is protective against podocyte damage and proteinuria in PAN nephrosis . This study indicates that tolvaptan exerts a renoprotective effect by affecting podocyte morphology and probably function in PAN nephrosis . DB06212 MEN is a promising pharmacological tool in the treatment of renal edema .

P54252 REA represses transcription via chromatin binding , interaction with histone deacetylase 3 , and histone deacetylation . P54252 REA ( P01008 REA ) , the disease protein in spinocerebellar ataxia type 3 ( P54252 REA ) , has been associated with the ubiquitin-proteasome system and transcriptional regulation . Here we report that normal P01008 REA binds to target DNA sequences in specific chromatin regions of the matrix metalloproteinase - 2 ( P08253 REA ) gene promoter and represses transcription by recruitment of the histone deacetylase 3 ( O15379 REA ) , the nuclear receptor corepressor ( NCoR ) , and deacetylation of histones bound to the promoter . Both normal and expanded P01008 REA physiologically interacted with O15379 REA and NCoR in a P54252 REA cell model and human pons tissue ; however , normal P01008 REA - containing protein complexes showed increased histone deacetylase activity , whereas expanded P01008 REA - containing complexes had reduced deacetylase activity . Consistently , histone analyses revealed an increased acetylation of total histone H3 in expanded P01008 REA - expressing cells and human P54252 REA pons . Expanded P01008 REA lost the repressor function and displayed altered DNA / chromatin binding that was not associated with recruitment of O15379 REA , NCoR , and deacetylation of the promoter , allowing aberrant P08253 REA transcription via the transcription factor GATA - 2 . For transcriptional repression normal P01008 REA cooperates with O15379 REA and requires its intact ubiquitin-interacting motifs ( UIMs ) , whereas aberrant transcriptional activation by expanded P01008 REA is independent of the UIMs but requires the catalytic cysteine of the ubiquitin protease domain . These findings demonstrate that normal P01008 REA binds target promoter regions and represses transcription of a GATA - 2 - dependent target gene via formation of histone-deacetylating repressor complexes requiring its UIM-associated function . Expanded P01008 REA aberrantly activates transcription via its catalytic site and loses the ability to form deacetylating repressor complexes on target chromatin regions .

A New Histone Deacetylase Inhibitor , MHY 219 , Inhibits the Migration of Human Prostate Cancer Cells via Q13547 REA . Histone deacetylase ( HDAC ) inhibitors are considered novel agents for cancer chemotherapy . We previously investigated MHY 219 , a new HDAC inhibitor , and its potent anticancer activity in human prostate cancer cells . In the present study , we evaluated MHY 219 molecular mechanisms involved in the regulation of prostate cancer cell migration . Similar to suberanilohydroxamic acid ( DB02546 MEN ) , MHY 219 inhibited Q13547 REA enzyme activity in a dose-dependent manner . MHY 219 cytotoxicity was higher in LNCaP ( IC50 = 0.67 μM ) than in DU145 cells ( IC50 = 1.10 μM ) and PC3 cells ( IC50 = 5.60 μM ) after 48 h of treatment . MHY 219 significantly inhibited the Q13547 REA protein levels in LNCaP and DU145 cells at high concentrations . However , inhibitory effects of MHY 219 on HDAC proteins levels varied based on the cell type . MHY 219 significantly inhibited LNCaP and DU145 cells migration by down-regulation of matrix metalloprotease - 1 ( P03956 REA ) and P08253 REA and induction of tissue inhibitor of metalloproteinases - 1 ( P01033 REA ) . These results suggest that MHY 219 may potentially be used as an anticancer agent to block cancer cell migration through the repression of P03956 REA and P08253 REA , which is related to the reduction of Q13547 REA .

The protective effect of rebamipide on paracellular permeability of rat gastric epithelial cells . BACKGROUND : Barrier function in gastric epithelial cells is essential for the gastric defence mechanism against acid back-diffusion into the mucosal layer . Our previous study indicated that trans-epithelial resistance ( Q9NZ01 ) of rat gastric epithelial cells was rapidly increased when the cells were exposed to acid . This response to acid was diminished by indometacin . AIM : Evaluate the effects of a mucoprotective agent , rebamipide , on the nonsteroidal anti-inflammatory drug ( NSAID ) - induced increase of gastric epithelial permeability . METHODS : Rat gastric epithelial cells were plated on tissue culture inserts . Cells were exposed to a NSAID ( indometacin , 10-7 M ) . Trans-epithelial permeability was measured by Q9NZ01 and diffusion rate of 14C - mannitol . The effect of rebamipide was evaluated by measuring Q9NZ01 . Endogenous prostaglandin E2 ( DB00917 ) production in culture medium was also measured . RESULTS : DB00328 SUB gradually and significantly decreased Q9NZ01 and increased 14C - manitol permeability . Rebamipide reversed the indometacin-induced changes in epithelial permeability and induced DB00917 synthesis . This induction was blocked by either indometacin or a Cyclooxygenase ( P36551 REA ) - 2 specific inhibitor . CONCLUSIONS : P36551 REA inhibitors such as indometacin inhibit regulation of epithelial permeability by reducing DB00917 . P23219 REA has an important role in the gastric defense mechanism . Rebamipide suppressed an indometacin-induced increase in gastric epithelial permeability by increasing DB00917 levels in a P35354 REA dependent manner .

Celecoxib with chemotherapy in colorectal cancer . P35354 REA ( P35354 REA ) is the enzyme that normally synthesizes prostaglandins during an inflammatory response . Many primary and metastatic cancers express P35354 REA , and its presence is correlated with tumor angiogenesis , more invasive tumor phenotype , resistance to apoptosis , and systemic immunosuppression . The expression of P35354 REA is associated with a worse prognosis . Inhibition of prostaglandin synthesis may be beneficial in human malignancy . Regular consumption of nonsteroidal anti-inflammatory drugs ( NSAIDs ) decreases the incidence of , and mortality rate resulting from , a number of types of gastrointestinal cancers . Premalignant colonic lesions regress following the administration of nonspecific P36551 REA inhibitors , such as sulindac ( DB00605 ) . Advanced solid tumor patients treated with indomethacin ( DB00328 SUB ) survive twice as long as do such patients who receive supportive care alone . The U . S . Food and Drug Administration has approved specific P35354 REA inhibitors for the treatment of arthritis , pain , and familial adenomatous polyposis . Preclinical studies show that these drugs block angiogenesis , suppress solid tumor metastases , and slow the growth of implanted gastrointestinal cancer cell lines . The P35354 REA inhibitors have safely and effectively been combined with chemotherapeutic agents in experimental studies . Ongoing clinical trials are currently assessing the potential therapeutic role of P35354 REA inhibitors in both prevention and treatment of a diverse range of human cancers .

Expression of P20839 REA and P12268 REA after transplantation and initiation of immunosuppression . BACKGROUND : DB01024 MEN ( DB00603 ) mediates immunosuppressive effects by inhibiting inosine monophosphate dehydrogenase ( IMPDH ) . Induction of IMPDH activity has been observed in whole blood and erythrocyte samples during immunosuppressive therapy . Information concerning the mechanisms for increased IMPDH activity is limited and the potential implications of induction have been debated . METHODS : Whole blood , P01730 REA + cell , and reticulocyte samples were collected from 30 renal transplant patients pre - and posttransplantation . The expressions of two IMPDH isoforms , type 1 and 2 , were analyzed by real-time reverse-transcription polymerase chain reaction and quantified using a housekeeping gene index . The IMPDH activity was determined by ultraviolet high-performance liquid chromatography . RESULTS : Transplantation and the initiation of immunosuppressive therapy was associated with increased P20839 REA ( 50-88 % , P < 0.0005 ) and decreased P12268 REA ( 42-56 % , P < 0.0005 ) expression . In P01730 REA + cells , however , P12268 REA increased ( 15 % , P= 0.009 ) . These changes are probably related to glucocorticoid effects . Two weeks posttransplant , DB00603 - treated patients displayed elevated P20839 REA and 2 in reticulocytes , suggesting enzyme induction in these cells during prolonged DB00603 therapy . Patients with acute rejection during follow-up demonstrated higher P12268 REA expression in P01730 REA + cells pretransplant than nonrejecting patients ( median expression 1.26 vs . 0.87 respectively , P= 0.017 ) . CONCLUSIONS : Knowledge of changes in P20839 REA and 2 expression after transplantation and initiation of immunosuppression is important considering the action of DB00603 on IMPDH and the potential for pharmacodynamic monitoring of DB00603 by measuring IMPDH activity . The expression of P12268 REA in P01730 REA + cells pretransplant may be an indicator of immune activation .

P01375 REA - α-accelerated degradation of type I collagen in human skin is associated with elevated matrix metalloproteinase ( MMP ) - 1 and P08254 REA ex vivo . P01375 REA ( P01375 REA ) - α induces matrix metalloproteinases ( MMPs ) that may disrupt skin integrity . We have investigated the effects and mechanisms of exogenous P01375 REA - α on collagen degradation by incubating human skin explants in defined serum-free media with or without P01375 REA - α ( 10ng / ml ) in the absence or presence of the nonselective MMP inhibitor DB02255 for 8 days . The basal culture conditions promoted type I collagen catabolism that was accelerated by P01375 REA - α ( p < 0.005 ) and accomplished by MMPs ( p < 0.005 ) . Levels of the collagenases P22894 REA and P45452 REA were insignificant and neither P08253 REA nor P50281 REA were associated with increased collagen degradation . P01375 REA - α increased secretion of P03956 REA ( p < 0.01 ) but had no impact on P03956 REA quantities in the tissue . Immunohistochemical analysis confirmed similar tissue P03956 REA expression with or without P01375 REA - α with epidermis being the major source of P03956 REA . Increased tissue-derived collagenolytic activity with P01375 REA - α exposure was blocked by neutralizing P03956 REA monoclonal antibody and was not due to down-regulation of tissue inhibitor of metalloproteinase - 1 . P01375 REA - α increased production ( p < 0.01 ) , tissue levels ( p < 0.005 ) and catalytic activity of the endogenous P03956 REA activator P08254 REA . Type I collagen degradation correlated with P08254 REA tissue levels ( rs = 0.68 , p < 0.05 ) and was attenuated with selective P08254 REA inhibitor . Type I collagen formation was down-regulated in cultured compared with native skin explants but was not reduced further by P01375 REA - α . P01375 REA - α had no significant effect on epidermal apoptosis . Our data indicate that P01375 REA - α augments collagenolytic activity of P03956 REA , possibly through up-regulation of P08254 REA leading to gradual loss of type I collagen in human skin .

Expression of cyclooxygenase - 2 ( P35354 REA ) in tumour and stroma compartments in cervical cancer : clinical implications . This study aims at investigating the relationship between cyclooxygenase - 2 expression in tumour vs stroma inflammatory compartment and its possible clinical role . The study included 99 stage IB-IV cervical cancer patients : immunostaining of tumour tissue sections was performed with rabbit antiserum against cyclooxygenase - 2 . CD3 , P01730 REA , CD8 , CD25 , Mast Cell Tryptase monoclonal antibodies were used to characterise stroma inflammatory cells in nine cervical tumours . An inverse relation was found between cyclooxygenase - 2 levels ( cyclooxygenase - 2 IDV ) of tumour vs stroma compartment ( r = -0.44 , P < 0.0001 ) . The percentage of cases showing high tumour / stromal cyclooxygenase - 2 IDV ratio was significantly higher in patients who did not respond to treatment ( 93.3 % ) with respect to patients with partial ( 60.5 % ) , and complete ( 43.7 % ) response ( P= 0.009 ) . Cases with a high tumour / stroma cyclooxygenase - 2 IDV ratio had a shorter overall survival rate than cases with a low tumour / stroma cyclooxygenase - 2 IDV ( P < 0.0001 ) . In the multivariate analysis advanced stage and the status of tumour / stroma cyclooxygenase - 2 IDV ratio retained an independent negative prognostic role . The proportion of CD3 ( + ) , P01730 REA ( + ) , and CD25 ( + ) cells was significantly lower in tumours with high tumour / stroma cyclooxygenase - 2 IDV ratio , while a higher percentage of mast cells was detected in tumours showing high tumour / stroma cyclooxygenase - 2 IDV ratio . Our study showed the usefulness of assessing cyclooxygenase - 2 status both in tumour and stroma compartment in order to identify cervical cancer patients endowed with a very poor chance of response to neoadjuvant therapy and unfavourable prognosis .

Correlation between tumor volume response to radiotherapy and expression of biological markers in patients with cervical squamous cell carcinoma . OBJECTIVE : To determine the factors associated with tumor volume response to radiotherapy ( RT ) in cervical cancer patients , and the relationship between the tumor volume response and alteration of the expression of biological markers during RT . METHODS : Twenty consecutive patients with cervical squamous cell carcinoma who received definitive RT were enrolled . Tumor volumes were calculated by Q9BWK5 examinations performed at the start of RT ( pre-RT ) , at the fourth week of RT ( mid-RT ) , and 1 month after RT completion ( post-RT ) . Two serial punch biopsies were performed at pre - and mid-RT , and immunohistochemical staining was performed for cyclooxygenase ( P36551 REA ) - 2 and epidermal growth factor receptor ( P00533 REA ) . RESULTS : For the pre-RT evaluation , fourteen ( 70 % ) and eleven ( 55 % ) patients showed positive immunoreactivity for P35354 REA and P00533 REA , respectively . Among the seven patients whose median percentage residual tumor at mid-RT ( P30518 REA ) was greater than 0.5 , seven ( 100 % , p= 0.0515 ) and five ( 71.4 % , p= 0.3742 ) patients showed positive immunoreactivity for P35354 REA and P00533 REA , respectively . The logistic regression analysis showed that positive immunoreactivity for both P35354 REA and P00533 REA at pre-RT were associated with P30518 REA ( p= 0.0782 ) . For the mid-RT evaluation , eight cases showed an interval increase in the distribution of immunoreactivity for P35354 REA , and six out of the eight patients had a P30518 REA greater than 0.5 ( p= 0.2222 ) . CONCLUSION : The poor mid-RT tumor response was associated with the coexpression of P35354 REA and P00533 REA .

DB01098 MEN , a new P04035 REA inhibitor , reduces the colonic inflammatory response in dextran sulfate sodium-induced colitis in mice . The aim of the present study was to elucidate the beneficial effects of rosuvastatin , a new P04035 REA inhibitor , on colonic mucosal damage and on the inflammatory response in a dextran sulfate sodium ( DSS ) colitis model . Acute colitis was induced using 8 % DSS in female BALB / c mice . Colonic mucosal inflammation was evaluated clinically , biochemically , and histologically . Mucosal protein contents and mRNA levels of tumor necrosis factor ( P01375 REA ) - alpha were determined by immunoassay and real time-PCR . The mRNA levels of endothelial nitric oxide synthase ( P29474 REA ) were determined by real-time PCR . Disease activity scores in DSS-induced colitis model mice , as determined by weight loss , stool consistency , and blood in stool , were significantly lower in the rosuvastatin-treated mice than in control mice . Shortening of the colon was significantly reversed by rosuvastatin . Increases in tissue-associated myeloperoxidase activity and thiobarbituric acid-reactive substances after DSS administration were both significantly inhibited by treatment with rosuvastatin . DB01098 MEN also inhibited increases in intestinal P01375 REA protein and mRNA expression after DSS administration , respectively . The mucosal mRNA levels of P29474 REA were decreased after DSS administration , but preserved in mice treated with rosuvastatin . These results suggest that rosuvastatin prevents the development of DSS-induced colitis in mice via the inhibition of mucosal inflammatory responses associated with the preservation of P29474 REA transcription .

Antiinflammatory effect of lactic acid bacteria : inhibition of cyclooxygenase - 2 by suppressing nuclear factor-kappaB in Raw 264.7 macrophage cells . Lactobacillus casei 3260 ( L . casei 3260 ) was evaluated in relation to the inflammatory response mediated by lipopolysaccharide ( LPS ) - induced nuclear factor-kappaB ( NF-kappaB ) and cyclooxygenase - 2 ( P35354 REA ) expression in Raw 264.7 macrophage cells . The treatment of Raw 264.7 cells with L . casei 3260 significantly inhibited the secretion of tumor necrosis factor-alpha ( P01375 REA ) and prostaglandins E2 ( DB00917 ) , followed by suppression of P35354 REA . To clarify the molecular mechanism , the inhibitory effect of L . casei 3260 on the NF-kappaB signaling pathway was examined based on the luciferase reporter activity . Although the treatment of Raw 264.7 cells with L . casei 3260 did not affect the transcriptional activity of NF-kappaB , it did inhibit NF-kappaB activation , as determined by the cytosolic p65 release and degradation of I-kappaBalpha . Therefore , these findings suggest that the suppression of P35354 REA through inhibiting the NF-kappaB activation by LPS may be associated with the antiinflammatory effects of L . casei 3260 on Raw 264.7 cells .

Elevated macrophage migration inhibitory factor and decreased transforming growth factor-beta levels in major depression - - no influence of celecoxib treatment . OBJECTIVES : The involvement of an immune process in the pathophysiology of major depression disorder ( MDD ) was substantiated by studies demonstrating elevated levels of proinflammatory cytokines and prostaglandin E ( 2 ) ( PGE ( 2 ) ) . P35354 REA ( P35354 REA ) inhibitors lead to a reduced production of PGE ( 2 ) and have been shown to improve depressive symptoms . We investigated the three immune parameters macrophage migration inhibitory factor ( MIF ) , transforming growth factor-β ( TGF-β ) and soluble P08571 REA ( sCD 14 ) in a randomized , placebo-controlled trial of the P35354 REA inhibitor celecoxib as add-on therapy in patients with MDD treated with reboxetine . METHODS : Thirty-two patients with depression and 20 healthy controls participated in the study . The patients were treated with reboxetine and celecoxib or placebo . Immune parameters were measured from serum at baseline , after three and five weeks using ELISA . RESULTS : Celecoxib as add-on strategy resulted in a significant reduction of Hamilton Depression Scale scores compared to placebo . Depressed patients showed significantly elevated MIF ( p < 0.001 ) and reduced TGF-β ( p = 0.006 ) concentrations at baseline . There was no difference in sCD 14 - concentrations . There was no difference between the placebo and the celecoxib group and no change over time . LIMITATIONS : Limitations of the study are the relatively small sample size and lack of functional assessment of Q9Y251 REA axis in parallel . CONCLUSIONS : MIF is a promising new candidate in the neuro-immune interplay that may link depressive symptoms , altered immune state and Q9Y251 REA - axis dysregulation . Reduced levels of TGF-β replicate previous findings and support the importance of this regulatory cytokine in major depressive disorder .

DB00759 derivative minocycline inhibits autophagy and inflammation in concanavalin-a-activated human hepatoma cells . Inhibition of soluble matrix metalloproteinase ( MMP ) activity is among the non-antibiotic cellular effects exerted by the anti-inflammatory tetracycline derivative minocycline . The impact of minocycline on the signal transduction functions of membrane-bound MMPs is however unknown . We assessed minocycline in a concanavalin-A ( ConA ) - activated human HepG 2 hepatoma cell model , a condition known to increase the expression of membrane type - 1 MMP ( MT-MMP ) and to trigger inflammatory and autophagy processes . We found that minocycline inhibited ConA-induced formation of autophagic acidic vacuoles , green fluorescent microtubule-associated protein 1 light chain 3 ( GFP-LC 3 ) puncta formation , gene and protein expression of autophagy biomarker P10415 REA / adenovirus E1B 19 kDa interacting protein 3 ( Q12983 ) , invasion biomarker P50281 REA , and inflammation biomarker cyclooxygenase ( P36551 REA ) - 2 . Gene silencing of P50281 REA abrogated ConA-induced formation of autophagic acidic vacuoles and ConA-induced expressions of Q12983 and P35354 REA . DB01017 was also shown to inhibit ConA-induced signal transducer and activator of transcription 3 ( P40763 REA ) phosphorylation as well as gene expression of Q8WY41 , a biomarker believed to colocalize with P50281 REA and the specific silencing of which further inhibited ConA-induced P40763 REA phosphorylation . Collectively , our data demonstrate that part of minocycline ' s effects on autophagy could be exerted through the inhibition of P50281 REA signaling functions , which contribute to the autophagy and inflammatory phenotype of ConA-activated HepG 2 cells .

Multiple antigenic polypeptide composed of heparanase B ‑ cell epitopes shrinks human hepatocellular carcinoma in mice . The purpose of this study was to evaluate the anti ‑ growth effect of the self ‑ designed multiple antigenic polypeptide ( Q96HU1 ) vaccine comprising B ‑ cell epitopes of heparanase ( Q9Y251 REA ) on HCC 97 ‑ H hepatocellular carcinoma ( HCC ) in mice . The polyclonal antibodies against the B ‑ cell epitopes of Q9Y251 REA were prepared by immunizing rabbits with freshly synthesized Q96HU1 vaccine . HCC ‑ bearing models were constructed on BALB / c nude mice . Anti ‑ Q96HU1 antibodies were administrered to the models to assess the effects on Q9Y251 REA activity , HCC growth , the expression of P15692 REA / P09038 REA and the value of micro ‑ vessel density ( P53602 REA ) . The anti ‑ Q96HU1 antibodies were harvested , purified and identified . These antibodies were able to specifically bind with the dominant epitopes of the precursor protein and large subunit monomer of Q9Y251 REA , decrease Q9Y251 REA activity , suppress the expressions of P15692 REA and P09038 REA , reduce the P53602 REA , and markedly shrink the HCC volume . Based on these findings , Q96HU1 vaccine based on the B ‑ cell epitopes of Q9Y251 REA seemed to provide theoretical evidence for further study of the synthesized Q9Y251 REA Q96HU1 vaccine in the treatment of HCC .

Recombinational and physical mapping of the locus for primary open-angle glaucoma ( Q99972 ) on chromosome 1q23 - q25 . Primary open-angle glaucoma ( POAG ) is a leading cause of irreversible blindness in industrialized countries . A locus for juvenile-onset POAG , Q99972 , has been mapped to 1q21 - q31 in a 9 - cM interval . With recombinant haplotypes , we have now reduced the Q99972 interval to a maximum of 3 cM , between the D1S452 / NGA 1 / D1S210 and NGA 5 loci . These loci are 2.8 Mb apart on a 4.7- Mb contig that we have completed between the D1S2851 and D1S218 loci and that includes 96 YAC clones and 48 STSs . The new Q99972 interval itself is now covered by 25 YACs , 30 STSs , and 16 restriction enzyme site landmarks . The lack of a NotI site suggests that the region has few CpG islands and a low gene content . This is compatible with its predominant cytogenetic location on the 1q24 G-band . Finally , we have excluded important candidate genes , including genes coding for three ATPases ( P05026 REA , P23634 REA , P50993 REA ) , an ion channel ( VDAC 4 ) , antithrombine III ( P01008 REA ) , and prostaglandin synthase ( P35354 REA ) . Our results provide a basis to identify the Q99972 gene .

Altered regulation of renal nitric oxide , atrial natriuretic peptide and cyclooxygenase systems in aldosterone escape in rats . The present study was aimed to determine whether there is an altered role of local nitric oxide ( NO ) , atrial natriuretic peptide ( P01160 REA ) and cyclooxygenase ( P36551 REA ) systems in the kidney in association with the aldosterone escape . Male Sprague-Dawley rats were used . DB04630 ( 200 microg / day ) was infused through entire time course . The control group was kept on a low sodium diet ( 0.02 mEq / day ) , and the experimental group was supplied with a higher sodium diet ( 2 . / day ) . Four days after beginning the regimen , the kidneys were taken . The protein expression of NO synthase ( NOS ) and P36551 REA isoforms was determined by semiquantitative immunoblotting . The mRNA expression of components of P01160 REA system was determined by real-time polymerase chain reaction . The activities of soluble and particulate guanylyl cyclases were determined by the amount of cGMP generated in responses to sodium nitroprusside and P01160 REA , respectively . There developed aldosterone escape in the experimental group . Accordingly , the renal content and the urinary excretion of NO increased . The expression of P29475 REA was increased in the inner medulla . Neither the expression of P29474 REA nor that of P35228 REA was changed . The expression and the catalytic activity of soluble guanylyl cyclase remained unaltered . The mRNA expression of P01160 REA was increased . Neither the expression of P16066 REA or P17342 nor the activity of particulate guanylyl cyclase was altered in the papilla . The protein expression of P35354 REA was increased in the inner medulla , while that of P23219 REA remained unchanged . In conclusion , the upregulation of P29475 REA , P01160 REA , and P35354 REA may be causally related with the aldosterone escape .