interacts_with DB00328?
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 ) and class I histone deacetylase ( HDAC ) may results in a better control of pancreatic ductal adenocarcinoma . The impact of the concomitant HDAC and P35354 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 , MS-275 and celecoxib ) or Q13547 /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 /3 and P35354 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 and O15379 inhibition induced the expression of P35354 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 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 ) -axis and the serotonergic system . The Q9Y251 -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 ) 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 ) -1 and P35354 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 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 showed intermediate safety ( 2.59 mg/kg ) . In in vitro experiments , indometacin inhibited P23219 about 1.7 times more potently than P35354 . NS-398 inhibited P35354 with an IC50 of 0.32 microM , but never affected P23219 activity , even at 100 microM . In the same assay system , meloxicam inhibited P35354 about 12 times more selectively than P23219 . 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 over P23219 . Thus , meloxicam may belong to a group of P35354 selective anti-inflammatory agents with a better safety profile than conventional P23219 and P35354 nonselective anti-inflammatory agents . DB01281 inhibits effector T cells through regulatory T cells and TGF-β . The P10747 costimulatory receptor is a critical regulator of T cell function , making it an attractive therapeutic target for the treatment of immune-mediated diseases . DB01281 , now approved for use in humans , prevents naive T cell activation by binding to P33681 proteins and blocking engagement of P10747 . However , DB01281 suppresses inflammation even if administered when disease is established , suggesting alternative mechanisms . We identified a novel , P10747 -independent mechanism by which DB01281 inhibits activated T cells . We show that in vitro , DB01281 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 . Parallel in vivo experiments using an allergic airway inflammation model demonstrated that this novel mechanism required both macrophages and regulatory T cells . Furthermore , DB01281 was ineffective in P84022 -deficient mice , supporting a requirement for TGF-β signaling . Thus , in addition to preventing naive T cells from being fully activated , DB01281 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 and may be particularly important in the ability of DB01281 to treat chronic inflammatory disease . Peroxisome proliferator-activated receptor-gamma activation inhibits tumor metastasis by antagonizing P84022 -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 -γ ) inhibits transforming growth factor β ( TGF-β ) -induced EMT in lung cancer cells and prevents metastasis by antagonizing P84022 function . Activation of Q07869 -γ by synthetic ligands ( troglitazone and rosiglitazone ) or by a constitutively active form of Q07869 -γ prevents TGF-β-induced loss of P12830 expression and inhibits the induction of mesenchymal markers ( vimentin , P19022 , fibronectin ) and matrix metalloproteases . Consistently , activation of Q07869 -γ also inhibited EMT-induced migration and invasion of lung cancer cells . Furthermore , effects of Q07869 -γ ligands were attenuated by siRNA-mediated knockdown of Q07869 -γ , indicating that the ligand-induced responses are Q07869 -γ dependent . Selective knockdown of Q15796 and P84022 by siRNA showed that TGF-β-induced EMT is P84022 dependent in lung cancer cells . Activation of Q07869 -γ inhibits TGF-β-induced Smad transcriptional activity but had no effect on the phosphorylation or nuclear translocation of Smads . Consistently , Q07869 -γ activation prevented TGF-β-induced transcriptional repression of P12830 promoter and inhibited transcriptional activation of P19022 promoter . Finally , treatment of mice with troglitazone or knockdown of P84022 in tumor cells significantly inhibited TGF-β-induced experimental metastasis in SCID-Beige mice . Together , with the low toxicity profile of Q07869 -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 ) have been used as anti-inflammatory and anticancerous drugs in the recent years . Thalidomide and IMiDs inhibit the cytokines tumour necrosis factor-alpha ( P01375 ) , interleukins ( IL ) 1-beta , 6 , 12 , and granulocyte macrophage-colony stimulating factor ( GM- P04141 ) . 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 ) . 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 ( SLX ) which catalyzes thrombin inhibition by P01008 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 and HCII simultaneously , can inhibit TF and TG with less systemic anticoagulation than comparable antithrombotic doses of HEP . DB01098 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 , 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 inhibitor rosuvastatin on P14780 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 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 attenuates neointima formation without affecting early P14780 activity in a rat model of vascular injury . DB00328 ameliorates high glucose-induced proliferation and invasion via modulation of e-cadherin in pancreatic cancer cells . DB00328 , an inhibitor of cyclooxygenase-2 ( P35354 ) , 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 but not P35354 in PC cells . Additionally , the P12830 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 was knocked down ( Si-E-cad ) . Moreover , the protein levels of P08253 , P14780 , and P15692 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 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 ) and subsequent suppression of prostaglandin metabolism . Agents that both enhance P15428 expression and suppress cyclooxygenase-2 ( P35354 ) production may more effectively prevent CAC . Synthetic triterpenoids are a class of small molecules that suppress P35354 as well as inflammatory cytokine signaling . Here , we found that administration of the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-C28-methyl ester ( CDDO-Me ) suppresses CAC in mice . In a spontaneous , inflammation-driven intestinal neoplasia model , deletion of Q13485 specifically in T cells led to progressive production of inflammatory cytokines , including P01375 -α , IFN-γ , P35228 , P05231 , IL-1β ; as well as activation of P42224 and P40763 ; along with suppression of P15428 expression . Oral administration of CDDO-Me to mice with Q13485 -deficient T cells increased survival and suppressed intestinal epithelial neoplasia by decreasing production of inflammatory mediators and increasing expression of P15428 . Induction of P15428 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 induction was not observed in P84022 -/- 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 , P08254 , P39900 , P50281 , Q99542 , and P01033 are strongly induced in obese adipose tissues compared with lean tissues . In contrast , P09237 and P35625 mRNAs are markedly decreased in obesity . Interestingly , enzymatic activities of P39900 and of a new identified adipocyte-derived 30-kDa metalloproteinase are enhanced in obese adipose tissue fractions , demonstrating that MMP/ P01033 balance is shifted toward increased matrix degradation in obesity . Finally , we analyze the modulation of P08253 , Q99542 , and P01033 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 ) 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 , a transcription factor that is thought to play a major role in the adipogenic program . Such findings support a role for the MMP/ P01033 system in the control of proteolytic events and adipogenesis during obesity-mediated fat mass development . DB06212 , 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 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 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 is a promising pharmacological tool in the treatment of renal edema . P54252 represses transcription via chromatin binding , interaction with histone deacetylase 3 , and histone deacetylation . P54252 ( P01008 ) , the disease protein in spinocerebellar ataxia type 3 ( P54252 ) , has been associated with the ubiquitin-proteasome system and transcriptional regulation . Here we report that normal P01008 binds to target DNA sequences in specific chromatin regions of the matrix metalloproteinase-2 ( P08253 ) gene promoter and represses transcription by recruitment of the histone deacetylase 3 ( O15379 ) , the nuclear receptor corepressor ( NCoR ) , and deacetylation of histones bound to the promoter . Both normal and expanded P01008 physiologically interacted with O15379 and NCoR in a P54252 cell model and human pons tissue ; however , normal P01008 -containing protein complexes showed increased histone deacetylase activity , whereas expanded P01008 -containing complexes had reduced deacetylase activity . Consistently , histone analyses revealed an increased acetylation of total histone H3 in expanded P01008 -expressing cells and human P54252 pons . Expanded P01008 lost the repressor function and displayed altered DNA/chromatin binding that was not associated with recruitment of O15379 , NCoR , and deacetylation of the promoter , allowing aberrant P08253 transcription via the transcription factor GATA-2 . For transcriptional repression normal P01008 cooperates with O15379 and requires its intact ubiquitin-interacting motifs ( UIMs ) , whereas aberrant transcriptional activation by expanded P01008 is independent of the UIMs but requires the catalytic cysteine of the ubiquitin protease domain . These findings demonstrate that normal P01008 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 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 , MHY219 , Inhibits the Migration of Human Prostate Cancer Cells via Q13547 . Histone deacetylase ( HDAC ) inhibitors are considered novel agents for cancer chemotherapy . We previously investigated MHY219 , a new HDAC inhibitor , and its potent anticancer activity in human prostate cancer cells . In the present study , we evaluated MHY219 molecular mechanisms involved in the regulation of prostate cancer cell migration . Similar to suberanilohydroxamic acid ( DB02546 ) , MHY219 inhibited Q13547 enzyme activity in a dose-dependent manner . MHY219 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 . MHY219 significantly inhibited the Q13547 protein levels in LNCaP and DU145 cells at high concentrations . However , inhibitory effects of MHY219 on HDAC proteins levels varied based on the cell type . MHY219 significantly inhibited LNCaP and DU145 cells migration by down-regulation of matrix metalloprotease-1 ( P03956 ) and P08253 and induction of tissue inhibitor of metalloproteinases-1 ( P01033 ) . These results suggest that MHY219 may potentially be used as an anticancer agent to block cancer cell migration through the repression of P03956 and P08253 , which is related to the reduction of Q13547 . 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 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 ) -2 specific inhibitor . CONCLUSIONS : P36551 inhibitors such as indometacin inhibit regulation of epithelial permeability by reducing DB00917 . P23219 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 dependent manner . Celecoxib with chemotherapy in colorectal cancer . P35354 ( P35354 ) is the enzyme that normally synthesizes prostaglandins during an inflammatory response . Many primary and metastatic cancers express P35354 , and its presence is correlated with tumor angiogenesis , more invasive tumor phenotype , resistance to apoptosis , and systemic immunosuppression . The expression of P35354 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 inhibitors , such as sulindac ( DB00605 ) . Advanced solid tumor patients treated with indomethacin ( DB00328 ) survive twice as long as do such patients who receive supportive care alone . The U.S . Food and Drug Administration has approved specific P35354 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 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 inhibitors in both prevention and treatment of a diverse range of human cancers . Expression of P20839 and P12268 after transplantation and initiation of immunosuppression . BACKGROUND : DB01024 ( 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 + 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 ( 50-88 % , P < 0.0005 ) and decreased P12268 ( 42-56 % , P < 0.0005 ) expression . In P01730 + cells , however , P12268 increased ( 15 % , P=0.009 ) . These changes are probably related to glucocorticoid effects . Two weeks posttransplant , DB00603 -treated patients displayed elevated P20839 and 2 in reticulocytes , suggesting enzyme induction in these cells during prolonged DB00603 therapy . Patients with acute rejection during follow-up demonstrated higher P12268 expression in P01730 + cells pretransplant than nonrejecting patients ( median expression 1.26 vs. 0.87 respectively , P=0.017 ) . CONCLUSIONS : Knowledge of changes in P20839 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 in P01730 + cells pretransplant may be an indicator of immune activation . P01375 -α-accelerated degradation of type I collagen in human skin is associated with elevated matrix metalloproteinase ( MMP ) -1 and P08254 ex vivo . P01375 ( P01375 ) -α induces matrix metalloproteinases ( MMPs ) that may disrupt skin integrity . We have investigated the effects and mechanisms of exogenous P01375 -α on collagen degradation by incubating human skin explants in defined serum-free media with or without P01375 -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 -α ( p < 0.005 ) and accomplished by MMPs ( p < 0.005 ) . Levels of the collagenases P22894 and P45452 were insignificant and neither P08253 nor P50281 were associated with increased collagen degradation . P01375 -α increased secretion of P03956 ( p < 0.01 ) but had no impact on P03956 quantities in the tissue . Immunohistochemical analysis confirmed similar tissue P03956 expression with or without P01375 -α with epidermis being the major source of P03956 . Increased tissue-derived collagenolytic activity with P01375 -α exposure was blocked by neutralizing P03956 monoclonal antibody and was not due to down-regulation of tissue inhibitor of metalloproteinase-1 . P01375 -α increased production ( p < 0.01 ) , tissue levels ( p < 0.005 ) and catalytic activity of the endogenous P03956 activator P08254 . Type I collagen degradation correlated with P08254 tissue levels ( rs=0.68 , p < 0.05 ) and was attenuated with selective P08254 inhibitor . Type I collagen formation was down-regulated in cultured compared with native skin explants but was not reduced further by P01375 -α . P01375 -α had no significant effect on epidermal apoptosis . Our data indicate that P01375 -α augments collagenolytic activity of P03956 , possibly through up-regulation of P08254 leading to gradual loss of type I collagen in human skin . Expression of cyclooxygenase-2 ( P35354 ) 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 , 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 (+) , 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 ) -2 and epidermal growth factor receptor ( P00533 ) . RESULTS : For the pre-RT evaluation , fourteen ( 70 % ) and eleven ( 55 % ) patients showed positive immunoreactivity for P35354 and P00533 , respectively . Among the seven patients whose median percentage residual tumor at mid-RT ( P30518 ) was greater than 0.5 , seven ( 100 % , p=0.0515 ) and five ( 71.4 % , p=0.3742 ) patients showed positive immunoreactivity for P35354 and P00533 , respectively . The logistic regression analysis showed that positive immunoreactivity for both P35354 and P00533 at pre-RT were associated with P30518 ( p=0.0782 ) . For the mid-RT evaluation , eight cases showed an interval increase in the distribution of immunoreactivity for P35354 , and six out of the eight patients had a P30518 greater than 0.5 ( p=0.2222 ) . CONCLUSION : The poor mid-RT tumor response was associated with the coexpression of P35354 and P00533 . DB01098 , a new P04035 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 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 ) -alpha were determined by immunoassay and real time-PCR . The mRNA levels of endothelial nitric oxide synthase ( P29474 ) 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 also inhibited increases in intestinal P01375 protein and mRNA expression after DSS administration , respectively . The mucosal mRNA levels of P29474 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 transcription . Antiinflammatory effect of lactic acid bacteria : inhibition of cyclooxygenase-2 by suppressing nuclear factor-kappaB in Raw264.7 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 ) expression in Raw264.7 macrophage cells . The treatment of Raw264.7 cells with L. casei 3260 significantly inhibited the secretion of tumor necrosis factor-alpha ( P01375 ) and prostaglandins E2 ( DB00917 ) , followed by suppression of P35354 . 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 Raw264.7 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 through inhibiting the NF-kappaB activation by LPS may be associated with the antiinflammatory effects of L. casei 3260 on Raw264.7 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 ( P35354 ) 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 ( sCD14 ) in a randomized , placebo-controlled trial of the P35354 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 sCD14-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 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 -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 HepG2 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-LC3 ) puncta formation , gene and protein expression of autophagy biomarker P10415 /adenovirus E1B 19 kDa interacting protein 3 ( Q12983 ) , invasion biomarker P50281 , and inflammation biomarker cyclooxygenase ( P36551 ) -2 . Gene silencing of P50281 abrogated ConA-induced formation of autophagic acidic vacuoles and ConA-induced expressions of Q12983 and P35354 . DB01017 was also shown to inhibit ConA-induced signal transducer and activator of transcription 3 ( P40763 ) phosphorylation as well as gene expression of Q8WY41 , a biomarker believed to colocalize with P50281 and the specific silencing of which further inhibited ConA-induced P40763 phosphorylation . Collectively , our data demonstrate that part of minocycline 's effects on autophagy could be exerted through the inhibition of P50281 signaling functions , which contribute to the autophagy and inflammatory phenotype of ConA-activated HepG2 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 ) on HCC97‑H hepatocellular carcinoma ( HCC ) in mice . The polyclonal antibodies against the B‑cell epitopes of Q9Y251 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 activity , HCC growth , the expression of P15692 / P09038 and the value of micro‑vessel density ( P53602 ) . 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 , decrease Q9Y251 activity , suppress the expressions of P15692 and P09038 , reduce the P53602 , and markedly shrink the HCC volume . Based on these findings , Q96HU1 vaccine based on the B‑cell epitopes of Q9Y251 seemed to provide theoretical evidence for further study of the synthesized Q9Y251 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/NGA1/D1S210 and NGA5 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 , P23634 , P50993 ) , an ion channel ( VDAC4 ) , antithrombine III ( P01008 ) , and prostaglandin synthase ( P35354 ) . 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 ) and cyclooxygenase ( P36551 ) 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 isoforms was determined by semiquantitative immunoblotting . The mRNA expression of components of P01160 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 , respectively . There developed aldosterone escape in the experimental group . Accordingly , the renal content and the urinary excretion of NO increased . The expression of P29475 was increased in the inner medulla . Neither the expression of P29474 nor that of P35228 was changed . The expression and the catalytic activity of soluble guanylyl cyclase remained unaltered . The mRNA expression of P01160 was increased . Neither the expression of P16066 or P17342 nor the activity of particulate guanylyl cyclase was altered in the papilla . The protein expression of P35354 was increased in the inner medulla , while that of P23219 remained unchanged . In conclusion , the upregulation of P29475 , P01160 , and P35354 may be causally related with the aldosterone escape .