interacts_with DB01656?
Effects of pravastatin on the expression of DB00171 -binding cassette transporter A1 . In vitro inhibition of 3-hydroxy-3-methylglutaryl coenzyme A ( HMG- DB01992 ) reductase causes the suppression of liver X receptor ( LXR ) activity . Because LXR regulates the expression of DB00171 -binding cassette transporter ( DB01048 ) A1 , which is involved in the high-density lipoprotein-related reverse cholesterol transport pathway , we examined the effects of an P04035 inhibitor pravastatin on O95477 expression in vitro and in vivo . DB00175 ( 10 microM ) significantly reduced the transcript levels of murine O95477 gene by 35 % in RAW264.7 macrophages under a lipoprotein-deficient condition . The inhibition was due to the decreased mevalonic acid production because addition of exogenous mevalonic acid restored O95477 mRNA levels . In addition , cholesterol and 22(R)-hydroxycholesterol thoroughly blunted the inhibition . Furthermore , pravastatin did not decrease O95477 mRNA and protein levels in HepG2 hepatocytes even in the absence of exogenous LXR agonists . Oral dosing of pravastatin ( 0.1 % concentration in drinking water ) for 24 h or 2 weeks to mice did not decrease O95477 mRNA and protein levels in the liver and leukocytes . Interestingly , pravastatin significantly increased both hepatic and leukocyte LXRalpha mRNA levels . Thus , although P04035 inhibitors suppress O95477 mRNA expression in the absence of LXR agonists , in vivo inhibition of P04035 is unlikely to cause such suppression . Pathogenesis and treatment of thrombohemorrhagic diathesis in acute promyelocytic leukemia . Acute promyelocytic leukemia ( APL ) is a distinct subtype of myeloid leukemia characterized by t(15;17) chromosomal translocation , which involves the retinoic acid receptor-alpha ( P10276 ) . APL typically presents with a life-threatening hemorrhagic diathesis . Before the introduction of all-trans retinoic acid ( DB00755 ) for the cure of APL , fatal hemorrhages due , at least in part , to the APL-associated coagulopathy , were a major cause of induction remission failure . The laboratory abnormalities of blood coagulation found in these patients indicate the occurrence of a hypercoagulable state . Major determinants of the coagulopathy of APL are endogenous factors expressed by the leukemic cells , including procoagulant factors , fibrinolytic proteins , and non-specific proteolytic enzymes . In addition , these cells have an increased capacity to adhere to the vascular endothelium , and to secrete inflammatory cytokines [ i.e. interleukin-1beta ( IL-1beta ) and tumor necrosis factor ( P01375 ) ] , which in turn stimulate the expression of prothrombotic activities by endothelial cells and leukocytes . DB00755 can interfere with each of the principal hemostatic properties of the leukemic cell , thus reducing the APL cell procoagulant potential , in parallel to the induction of cellular differentiation . This effect occurs in vivo , in the bone marrow of APL patients receiving DB00755 , and is associated with the improvement of the bleeding symptoms . Therapy with arsenic trioxide ( ATO ) also beneficially affects coagulation in APL . However , early deaths from bleeding still remain a major problem in APL and further research is required in this field . In this review , we will summarize our current knowledge of the pathogenesis of the APL-associated coagulopathy and will overview the therapeutic approaches for the management of this complication . Bresol inhibits phosphodiesterase 4 gene expression and modulates the levels of select mediators of inflammation in human monocytic cells . Bresol-a poly-herbal formulation , has been reported to be effective against bronchial asthma and allergic rhinitis in children . In vivo studies have supported the anti-histaminic and anti-anaphylactic action of bresol . However , the mechanism of action of bresol in modulation of inflammation has not been studied at the cellular and molecular level . The present study was aimed to elucidate the mechanism(s) of action of bresol at the cellular and molecular levels , using human monocyte leukemia cells . The effects of bresol on phosphodiesterase 4B ( Q07343 ) gene expression were analyzed using human monocytic U937 leukemia cells . The ability of bresol to stimulate DB02527 formation in these cells , as well as its effects on mediators of inflammation like tumor necrosis factor-α ( TNFα ) , nitric oxide ( NO ) , and cycloxygenase-2 ( P35354 ) in lipopolysaccharide ( LPS ) -stimulated U937 cells , were also studied . The results here indicated that bresol exhibited potential anti-inflammatory properties by inhibiting LPS-induced Q07343 gene expression in the cells . Bresol also dose dependently activated DB02527 formation , and inhibited TNFα , NO , as well as P35354 formation in the LPS-stimulated cells . Based upon the results , we concluded that the reported anti-inflammatory activity of bresol might be attributed to its abilities to inhibit Q07343 and thus elevate DB02527 levels in human monocytes . The anti-inflammatory effects of bresol might also be a result of the capacity of bresol to modulate the formation of TNFα , NO , and P35354 in monocytes . Proinflammatory cytokines promote glial heme oxygenase-1 expression and mitochondrial iron deposition : implications for multiple sclerosis . Proinflammatory cytokines , pathological iron deposition , and oxidative stress have been implicated in the pathogenesis of multiple sclerosis ( MS ) and experimental autoimmune encephalomyelitis ( EAE ) . P09601 mRNA levels and mitochondrial uptake of [(55)Fe]Cl(3)-derived iron were measured in rat astroglial cultures exposed to interleukin-1beta ( IL-1beta ) or tumor necrosis factor-alpha ( P01375 ) alone or in combination with the heme oxygenase-1 ( P09601 ) inhibitors , tin mesoporphyrin ( DB04912 ) or dexamthasone ( DEX ) , or interferon beta1b ( P27352 -beta ) . P09601 expression in astrocytes was evaluated by immunohistochemical staining of spinal cord tissue derived from MS and control subjects . IL-1beta or P01375 promoted sequestration of non-transferrin-derived (55)Fe by astroglial mitochondria . P09601 inhibitors , mitochondrial permeability transition pore ( P55157 ) blockers and antioxidants significantly attenuated cytokine-related mitochondrial iron sequestration in these cells . IFN-beta decreased P09601 expression and mitochondrial iron sequestration in IL-1beta- and P01375 -challenged astroglia . The percentage of astrocytes coexpressing P09601 in affected spinal cord from MS patients ( 57.3 % +/- 12.8 % ) was significantly greater ( p < 0.05 ) than in normal spinal cord derived from controls subjects ( 15.4 % +/- 8.4 % ) . P09601 is over-expressed in MS spinal cord astroglia and may promote mitochondrial iron deposition in MS plaques . In MS , IFN-beta may attenuate glial P09601 gene induction and aberrant mitochondrial iron deposition accruing from exposure to proinflammatory cytokines . Direct intracerebral delivery of cintredekin besudotox ( P35225 -PE38QQR ) in recurrent malignant glioma : a report by the DB05305 Intraparenchymal Study Group . PURPOSE : Glioblastoma multiforme ( GBM ) is a devastating brain tumor with a median survival of 6 months after recurrence . Cintredekin besudotox ( CB ) is a recombinant protein consisting of interleukin-13 ( P35225 ) and a truncated form of Pseudomonas exotoxin ( PE38QQR ) . Convection-enhanced delivery ( DB01333 ) is a locoregional-administration method leading to high-tissue concentrations with large volume of distributions . We assessed the use of intracerebral DB01333 to deliver CB in patients with recurrent malignant glioma ( MG ) . PATIENTS AND METHODS : Three phase I clinical studies evaluated intracerebral DB01333 of CB along with tumor resection . The main objectives were to assess the tolerability of various concentrations and infusion durations ; tissue distribution ; and methods for optimizing delivery . All patients underwent tumor resection followed by a single intraparenchymal infusion ( in addition to the intraparenchymal one following resection ) , with a portion of patients who had a preresection intratumoral infusion . RESULTS : A total of 51 patients with MG were treated including 46 patients with GBM . The maximum tolerated intraparenchymal concentration was 0.5 microg/mL and tumor necrosis was observed at this concentration . Infusion durations of up to 6 days were well tolerated . Postoperative catheter placement appears to be important for optimal drug distribution . CB- and procedure-related adverse events were primarily limited to the CNS . Overall median survival for GBM patients is 42.7 weeks and 55.6 weeks for patients with optimally positioned catheters with patient follow-up extending beyond 5 years . CONCLUSION : CB appears to have a favorable risk-benefit profile . DB01333 is a complex delivery method requiring catheter placement via a second procedure to achieve accurate catheter positioning , better drug distribution , and better outcome . Regulation of hepatic lecithin:retinol acyltransferase activity by retinoic acid receptor-selective retinoids . The microsomal enzyme O95237 esterifies retinol and has been implicated in the hepatic storage of vitamin A . Previously , we showed that hepatic O95237 activity is negligible during vitamin A deficiency and that all-trans-retinoic acid ( all-trans-RA ) rapidly induces the activity of liver O95237 in retinoid-deficient rats . In the present studies , we have examined the ability of natural and synthetic retinoids to induce liver O95237 activity in retinoid-deficient rats . The natural retinoids retinol , all-trans-RA ( 100 microg ) , 9- DB00982 , or equal molar amounts of other retinoids were injected ip and O95237 specific activity was measured in liver homogenates 17-18 h later . In retinoid-deficient rats , liver O95237 activity was extremely low [ 0.13 +/- 0.03 pmol retinyl ester ( RE ) /min/mg liver protein , mean +/- SE ] . The natural retinoids retinol and all-trans-RA strongly induced O95237 activity ( 12.71 +/- 1.09 and 13.10 +/- 1.55 pmol RE/min/mg , respectively ) , whereas 9- DB00982 induced a lower level of O95237 activity ( 3.96 +/- 1.88 pmol RE/min/mg , P < 0.001 vs all-trans-RA ) . The retinoic acid receptor ( RAR ) -selective analog ( RAR pan-agonist ) all-trans-UAB8 and the P10276 -selective retinoid Am580 also strongly induced O95237 activity . In contrast , neither RXR-selective agonists nor retinoids having a retro structure were active . For retinoids with significant P10276 binding activity there was a strong direct correlation between receptor binding in vitro and the ability to induce hepatic O95237 activity in vivo ( r2 = 0.920 ) . These data implicate the RARs in the induction of hepatic O95237 and suggest a predominant role for P10276 -active ligands . Impaired pulmonary defense against Pseudomonas aeruginosa in P15692 gene inactivated mouse lung . Repeated bacterial and viral infections are known to contribute to worsening lung function in several respiratory diseases , including asthma , cystic fibrosis , and chronic obstructive pulmonary disease ( P48444 ) . Previous studies have reported alveolar wall cell apoptosis and parenchymal damage in adult pulmonary P15692 gene ablated mice . We hypothesized that P15692 expressed by type II cells is also necessary to provide an effective host defense against bacteria in part by maintaining surfactant homeostasis . Therefore , Pseudomonas aeruginosa ( PAO1 ) levels were evaluated in mice following lung-targeted P15692 gene inactivation , and alterations in P15692 -dependent type II cell function were evaluated by measuring surfactant homeostasis in mouse lungs and isolated type II cells . In P15692 -deficient lungs increased PAO1 levels and pro-inflammatory cytokines , TNFα and P05231 , were detected 24 h after bacterial instillation compared to control lungs . In vivo lung-targeted P15692 gene deletion ( 57 % decrease in total pulmonary P15692 ) did not alter alveolar surfactant or tissue disaturated phosphatidylcholine ( DSPC ) levels . However , sphingomyelin content , choline phosphate cytidylyltransferase ( Q9UPI3 ) mRNA , and P35247 expression were decreased . In isolated type II cells an 80 % reduction of P15692 protein resulted in decreases in total phospholipids ( PL ) , DSPC , DSPC synthesis , surfactant associated proteins ( SP ) -B and -D , and the lipid transporters , O95477 and Rab3D . TPA-induced DSPC secretion and apoptosis were elevated in P15692 -deficient type II cells . These results suggest a potential protective role for type II cell-expressed P15692 against bacterial initiated infection . Bronchodilators modulate inflammation in chronic obstructive pulmonary disease subjects . Chronic obstructive pulmonary disease ( P48444 ) is characterized by neutrophilic airway inflammation and oxidative stress . Leukotriene B₄ ( LTB₄ ) , a potent proinflammatory mediator , is synthesized by P09917 ( P09917 ) , which is activated by the presence of lipid hydroperoxides resulting from oxidative stress on biological membranes . We proposed to evaluate the effect of a four week treatment with two different bronchodilators of common practice in P48444 treatment , on the production of reactive oxygen species ( ROS ) , in particular superoxide anions , and of LTB₄ by peripheral blood neutrophils obtained from P48444 subjects . 24 subjects among the P48444 outpatients were enrolled , and randomized to receive either formoterol ( 12 μg bid ) or tiotropium ( 18 μg od ) . Peripheral blood neutrophils were obtained at the start and at the end of the treatment , and production of superoxide anions and of LTB₄ were evaluated as previously published . The results obtained showed a decrease in the unstimulated production of superoxide by isolated neutrophils in both groups , but tiotropium only was effective in modulating the production of LTB₄ , while formoterol caused an increased production of superoxide in response to fMLP , when compared to values obtained before treatment . In conclusion , tiotropium showed a better antiinflammatory activity profile when compared to formoterol in a clinical setting , reducing superoxide and LTB₄ production by peripheral neutrophils obtained from P48444 subjects . Anti-inflammatory properties of Septilin in lipopolysaccharide activated monocytes and macrophage . In vivo studies have suggested the immunomodulatory properties of Septilin , an herbal preparation . This drug is being used against various types of inflammatory disorders . However , the mechanism of action of Septilin in the modulation of inflammation is not explored using suitable in vitro models . Hence , we decided to study the modulatory role of Septilin in lipopolysaccharide ( LPS ) mediated signaling in macrophage and monocyte cells . It was observed from the present study that by employing tumor necrosis factor α ( P01375 -α ) bioassay and reverse transcription-polymerase chain reaction ( RT-PCR ) , Septilin inhibited P01375 -α production in LPS ( 1 μg/mL ) stimulated RAW 264.7 cells ( p < 0.05 ) . 80 % inhibition of P01375 -α was observed even at 2.5 % Septilin . Septilin at all the concentrations tested could also significantly block the LPS mediated nitric oxide ( NO ) production ( p < 0.01 ) and expression of inducible NO synthase ( P35228 ) gene . LPS mediated interleukin 6 ( P05231 ) and P10145 production was also blocked by Septilin at the concentrations tested . This herbal preparation could also inhibit cycloxygenase 2 ( P35354 ) activity and suppression of P35354 and phosphodiesterase 4 B ( Q07343 ) mRNA expression in a concentration dependent manner . Taken together , these findings from the present in vitro study suggest the anti-inflammatory and immunomodulatory properties of Septilin . Identification of the fused bicyclic 4-amino-2-phenylpyrimidine derivatives as novel and potent DB05876 inhibitors . 2-Phenyl-4-piperidinyl-6,7-dihydrothieno[3,4-d]pyrimidine derivative ( 2 ) was found to be a new DB05876 inhibitor with moderate Q07343 activity ( IC50=150 nM ) . A number of derivatives with a variety of 4-amino substituents and fused bicyclic pyrimidines were synthesized . Among these , 5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivative ( 18 ) showed potent Q07343 inhibitory activity ( IC50=25 nM ) . Finally , N-propylacetamide derivative ( 31b ) was determined as a potent inhibitor for both Q07343 ( IC50=7.5 nM ) and P01375 -α production in mouse splenocytes ( IC50=9.8 nM ) and showed good in vivo anti-inflammatory activity in the LPS-induced lung inflammation model in mice ( ID50=18 mg/kg ) . The binding mode of the new inhibitor ( 31e ) in the catalytic site of Q07343 is presented based on an X-ray crystal structure of the ligand-enzyme complex . Q9UBN7 -mediated selective autophagy regulates P48444 -associated cilia dysfunction . Chronic obstructive pulmonary disease ( P48444 ) involves aberrant airway inflammatory responses to cigarette smoke ( CS ) that are associated with epithelial cell dysfunction , cilia shortening , and mucociliary clearance disruption . Exposure to CS reduced cilia length and induced autophagy in vivo and in differentiated mouse tracheal epithelial cells ( MTECs ) . Autophagy-impaired ( Becn1+/- or Map1lc3B-/- ) mice and MTECs resisted CS-induced cilia shortening . Furthermore , CS increased the autophagic turnover of ciliary proteins , indicating that autophagy may regulate cilia homeostasis . We identified cytosolic deacetylase Q9UBN7 as a critical regulator of autophagy-mediated cilia shortening during CS exposure . Mice bearing an X chromosome deletion of Hdac6 ( Hdac6-/Y ) and MTECs from these mice had reduced autophagy and were protected from CS-induced cilia shortening . Autophagy-impaired Becn1-/- , Map1lc3B-/- , and Hdac6-/Y mice or mice injected with an Q9UBN7 inhibitor were protected from CS-induced mucociliary clearance ( MCC ) disruption . MCC was preserved in mice given the chemical chaperone 4-phenylbutyric acid , but was disrupted in mice lacking the transcription factor Q16236 , suggesting that oxidative stress and altered proteostasis contribute to the disruption of MCC . Analysis of human P48444 specimens revealed epigenetic deregulation of Q9UBN7 by hypomethylation and increased protein expression in the airways . We conclude that an autophagy-dependent pathway regulates cilia length during CS exposure and has potential as a therapeutic target for P48444 . Cross-talk between PKA-Cβ and p65 mediates synergistic induction of Q07343 by roflumilast and NTHi . Phosphodiesterase 4B ( Q07343 ) plays a key role in regulating inflammation . DB01656 , a phosphodiesterase (PDE)4-selective inhibitor , has recently been approved for treating severe chronic obstructive pulmonary disease ( P48444 ) patients with exacerbation . However , there is also clinical evidence suggesting the development of tachyphylaxis or tolerance on repeated dosing of roflumilast and the possible contribution of Q07343 up-regulation , which could be counterproductive for suppressing inflammation . Thus , understanding how Q07343 is up-regulated in the context of the complex pathogenesis and medications of P48444 may help improve the efficacy and possibly ameliorate the tolerance of roflumilast . Here we show that roflumilast synergizes with nontypeable Haemophilus influenzae ( NTHi ) , a major bacterial cause of P48444 exacerbation , to up-regulate PDE4B2 expression in human airway epithelial cells in vitro and in vivo . Up-regulated PDE4B2 contributes to the induction of certain important chemokines in both enzymatic activity-dependent and activity-independent manners . We also found that protein kinase A catalytic subunit β ( PKA-Cβ ) and nuclear factor-κB ( NF-κB ) p65 subunit were required for the synergistic induction of PDE4B2 . PKA-Cβ phosphorylates p65 in a DB02527 -dependent manner . Moreover , Ser276 of p65 is critical for mediating the PKA-Cβ-induced p65 phosphorylation and the synergistic induction of PDE4B2 . Collectively , our data unveil a previously unidentified mechanism underlying synergistic up-regulation of PDE4B2 via a cross-talk between PKA-Cβ and p65 and may help develop new therapeutic strategies to improve the efficacy of DB05876 inhibitor . DB01656 inhibits respiratory syncytial virus infection in human differentiated bronchial epithelial cells . Respiratory syncytial virus ( RSV ) causes acute exacerbations in P48444 and asthma . RSV infects bronchial epithelial cells ( P02100 ) that trigger RSV associated lung pathology . This study explores whether the phosphodiesterase 4 ( DB05876 ) inhibitor DB01656 N-oxide ( P59046 ) , alters RSV infection of well-differentiated P02100 ( WD- P02100 ) in vitro . WD- P02100 were RSV infected in the presence or absence of P59046 ( 0.1-100 nM ) . Viral infection ( staining of F and G proteins , nucleoprotein RNA level ) , mRNA of P05362 , ciliated cell markers ( digital high speed videomicroscopy , β-tubulin immunofluorescence , Foxj1 and Dnai2 mRNA ) , Goblet cells ( DB00233 ) , mRNA of P98088 and A8K7I4 , mRNA and protein level of P35225 , P05231 , P10145 , TNFα , formation of H2O2 and the anti-oxidative armamentarium ( mRNA of Nrf2 , P09601 , GPx ; total antioxidant capacity ( TAC ) were measured at day 10 or 15 post infection . P59046 inhibited RSV infection of WD- P02100 , prevented the loss of ciliated cells and markers , reduced the increase of P98088 and A8K7I4 and inhibited the increase of P35225 , P05231 , P10145 , TNFα and P05362 . Additionally P59046 reversed the reduction of Nrf2 , P09601 and GPx mRNA levels and consequently restored the TAC and reduced the H2O2 formation . P59046 inhibits RSV infection of WD- P02100 cultures and mitigates the cytopathological changes associated to this virus . Agents with selective estrogen receptor ( ER ) modulator activity induce apoptosis in vitro and in vivo in ER-negative glioma cells . Tamoxifen , a member of the selective estrogen receptor modulator ( SERM ) family , is widely used in the treatment of estrogen receptor ( ER ) -expressing breast cancer . It has previously been shown that high-dose tamoxifen has cytotoxic activity against glioma cells , but whether this effect is drug specific or represents a general property of SERMs is unknown . In this study , we demonstrate that tamoxifen and DB05487 , a novel benzopyranone with SERM activity , induce glioma cell apoptosis in a dose- and time-dependent manner . Moreover , administration of tamoxifen and DB05487 suppresses tumor growth in vivo and extends animal survival in glioma xenograft models . None of the eight glioma cell lines examined express either P03372 or -beta , suggesting the mechanism for tamoxifen- and DB05487 -induced glioma cell apoptosis is independent of the ER signaling pathway . Complementary DNA microarray expression profiling allowed us to identify a subset of genes specifically regulated by tamoxifen and DB05487 , and not by other apoptotic stimuli , including nuclear factor ( NF ) -kappaB with its target genes IEX-3 , P04179 , P05231 , and P10145 . We demonstrate that suppression of NF-kappaB activation markedly enhances SERM-induced apoptosis , suggesting a role for NF-kappaB in protecting glioma cells from SERM-induced cytotoxicity . These findings demonstrate for the first time that a SERM other than tamoxifen can induce glioma cell apoptosis in vitro and in vivo and that the clinical efficacy of SERMs for the treatment of malignant gliomas could potentially be enhanced by simultaneous inhibition of the NF-kappaB pathway . Rationalizing cyclooxygenase ( P36551 ) inhibition for maximal efficacy and minimal adverse events . New information indicates that cyclooxygenase-2 ( P35354 ) is constitutively expressed in several tissues , including brain , lung , pancreas , kidney , and ovary , and plays an important role in renal and gastrointestinal function . Selective P35354 inhibition has been associated in animal studies with impairment of ulcer healing and renal function and inhibition of prostacyclin , an effect that inhibits vasodilation without inhibiting platelet aggregation . The clinical consequences , if any , of these effects remain to be determined in long-term studies in humans . The premise that selective P35354 inhibitors will cause less gastrointestinal toxicity than nonsteroidal antiinflammatory drugs that inhibit both P36551 isoforms needs to take into account the low toxicity of nabumetone . The gastrointestinal safety profile of this nonacidic , dual P36551 inhibitor that does not undergo enterohepatic circulation has been evaluated in extensive clinical trials . The data submitted to the US Food and Drug Administration in the New Drug Application for nabumetone ( DB00461 ) , the comparative trials subsequently completed , the published databases of the comparative gastrointestinal toxicity of various nonsteroidal anti-inflammatory drugs ( NSAIDs ) , and the meta-analysis published in this issue of The American Journal of Medicine ( Schoenfeld , page 48S ) indicate that nabumetone has the lowest incidence of gastrointestinal toxicity among the extensively studied NSAIDs . Overall , the incidence is approximately 10-fold less than with comparator drugs . This rate is an appropriate current reference against which the gastrointestinal toxicity of P35354 inhibitors can be compared . Leukotriene A4 hydrolase . Inhibition by bestatin and intrinsic aminopeptidase activity establish its functional resemblance to metallohydrolase enzymes . DB03424 , an inhibitor of aminopeptidases , was also a potent inhibitor of leukotriene ( LT ) A4 hydrolase . On isolated enzyme its effects were immediate and reversible with a Ki = 201 +/- 95 mM . With erythrocytes it inhibited LTB4 formation greater than 90 % within 10 min ; with neutrophils it inhibited LTB4 formation by only 10 % during the same period , increasing to 40 % in 2 h . DB03424 inhibited P09960 hydrolase selectively ; neither P09917 nor 15-lipoxygenase activity in neutrophil lysates was affected . Purified P09960 hydrolase exhibited an intrinsic aminopeptidase activity , hydrolyzing L-lysine-p-nitroanilide and L-leucine-beta-naphthylamide with apparent Km = 156 microM and 70 microM and Vmax = 50 and 215 nmol/min/mg , respectively . Both P09960 and bestatin suppressed the intrinsic aminopeptidase activity of P09960 hydrolase with apparent Ki values of 5.3 microM and 172 nM , respectively . Other metallohydrolase inhibitors tested did not reduce P09960 hydrolase/aminopeptidase activity , with one exception ; captopril , an inhibitor of angiotensin-converting enzyme , was as effective as bestatin . The results demonstrate a functional resemblance between P09960 hydrolase and certain metallohydrolases , consistent with a molecular resemblance at their putative Zn2(+)-binding sites . The availability of a reversible , chemically stable inhibitor of P09960 hydrolase may facilitate investigations on the role of LTB4 in inflammation , particularly the process termed transcellular biosynthesis . DB06603 synergizes with bortezomib to induce endoplasmic reticulum stress and ubiquitinated protein accumulation in renal cancer cells . BACKGROUND : Inducing endoplasmic reticulum ( ER ) stress is a novel strategy used to treat malignancies . Inhibition of histone deacetylase ( HDAC ) 6 by the HDAC inhibitor DB06603 hinders the refolding of unfolded proteins by increasing the acetylation of heat shock protein 90 . We investigated whether combining DB06603 with the proteasome inhibitor bortezomib would kill cancer cells effectively by inhibiting the degradation of these unfolded proteins , thereby causing ubiquitinated proteins to accumulate and induce ER stress . METHODS : Caki-1 , ACHN , and 769-P cells were treated with DB06603 and/or bortezomib . Cell viability , clonogenicity , and induction of apoptosis were evaluated . The in vivo efficacy of the combination was evaluated using a murine subcutaneous xenograft model . The combination-induced ER stress and ubiquitinated protein accumulation were assessed . RESULTS : The combination of DB06603 and bortezomib induced apoptosis and inhibited renal cancer growth synergistically ( combination indexes < 1 ) . It also suppressed colony formation significantly ( p < 0.05 ) . In a murine subcutaneous tumor model , a 10-day treatment was well tolerated and inhibited tumor growth significantly ( p < 0.05 ) . Enhanced acetylation of the Q9UBN7 substrate alpha-tubulin was consistent with the suppression of Q9UBN7 activity by DB06603 , and the combination was shown to induce ER stress and ubiquitinated protein accumulation synergistically . CONCLUSIONS : DB06603 inhibits renal cancer growth by synergizing with bortezomib to induce ER stress and ubiquitinated protein accumulation . The current study provides a basis for testing the combination in patients with advanced renal cancer . Action of rolipram on specific DB05876 DB02527 phosphodiesterase isoforms and on the phosphorylation of DB02527 -response-element-binding protein ( CREB ) and p38 mitogen-activated protein ( Q96HU1 ) kinase in U937 monocytic cells . U937 monocytic cells are shown here to express a range of DB05876 , DB02527 -specific phosphodiesterase ( PDE ) isoenzymes : the long isoenzymes , PDE4A4 , PDE4D5 and PDE4D3 , plus the short isoenzyme , PDE4B2 . These isoenzymes provide around 76 % of the total DB02527 PDE activity of U937 cells . The specific activities of the total P27815 , Q07343 and Q08499 activities were 0.63+/-0.09 , 8.8+/-0.2 and 34.4+/-2.9 pmol/min per mg of protein respectively . The DB05876 selective inhibitor , rolipram , inhibited immunopurified Q07343 and Q08499 activities similarly , with IC(50) values of approx . 130 nM and 240 nM respectively . In contrast , rolipram inhibited immunopurified P27815 activity with a dramatically lower IC(50) value of around 3 nM . DB01954 increased phosphorylation of DB02527 -response-element-binding protein ( CREB ) in U937 cells in a dose-dependent fashion , which implied the presence of both high affinity ( IC(50) value approx. 1 nM ) and low affinity ( IC(50) value approx. 120 nM ) components . DB01954 dose-dependently inhibited the interferon-gamma ( P01579 ) -stimulated phosphorylation of p38 mitogen-activated protein ( Q96HU1 ) kinase in a simple monotonic fashion with an IC(50) value of approx . 290 nM . On this basis , it is suggested that rolipram inhibition of PDE4A4 is involved in regulating CREB phosphorylation but not P01579 -stimulated p38 Q96HU1 kinase phosphorylation . PDE4A4 was also selectively activated by challenge of U937 cells with either bacterial lipopolysaccharide ( LPS ) or P01579 through a process which was attenuated by both wortmannin and rapamycin . It is proposed that the PDE4A4 isoform is involved in compartmentalized DB02527 signalling responses in U937 monocytes .