interacts_with DB09073?
Inhibition of cyclin-dependent kinases , GSK-3beta and CK1 by hymenialdisine , a marine sponge constituent . BACKGROUND : Over 2000 protein kinases regulate cellular functions . Screening for inhibitors of some of these kinases has already yielded some potent and selective compounds with promising potential for the treatment of human diseases . RESULTS : The marine sponge constituent hymenialdisine is a potent inhibitor of cyclin-dependent kinases , glycogen synthase kinase-3beta and casein kinase 1 . DB02950 competes with DB00171 for binding to these kinases . A P24941 -hymenialdisine complex crystal structure shows that three hydrogen bonds link hymenialdisine to the Glu81 and Leu83 residues of P24941 , as observed with other inhibitors . DB02950 inhibits Q00535 /p35 in vivo as demonstrated by the lack of phosphorylation/down-regulation of Pak1 kinase in E18 rat cortical neurons , and also inhibits GSK-3 in vivo as shown by the inhibition of P46821 phosphorylation . DB02950 also blocks the in vivo phosphorylation of the microtubule-binding protein tau at sites that are hyperphosphorylated by GSK-3 and Q00535 /p35 in Alzheimer 's disease ( cross-reacting with Alzheimer's-specific AT100 antibodies ) . CONCLUSIONS : The natural product hymenialdisine is a new kinase inhibitor with promising potential applications for treating neurodegenerative disorders . The potential role of bevacizumab in early stages and locally advanced non-small cell lung cancer . Improving outcomes for early-stage non-small cell lung cancer ( NSCLC ) is a major research area considering that a significant percentage of such patients develop recurrent disease within 5 years of complete lung resection . Adjuvant chemotherapy prolongs survival , with an absolute improvement in 5-year overall survival of about 5 % with drawbacks such as treatment toxicity . Approximately , one third of patients with newly diagnosed NSCLC have locally advanced disease not amenable for surgical resection - in this setting of patients concurrent chemoradiation is the standard of therapy . However , the treatment of locally advanced NSCLC is still controversial and clinical outcomes are disappointing , and so new approaches are required to improve the clinical benefit in this setting of patients . Vascular endothelial growth factor ( P15692 ) is a key angiogenic factor implicated in tumor blood vessels formation and permeability , and tumor P15692 overexpression in patients with early stage lung cancer has been associated with worse relapse free and overall survival . Several agents have been developed that inhibit P15692 or its receptor signalling system . DB00112 is the first recombinant humanized monoclonal antibody binding P15692 to demonstrate clinical benefit or rather a survival prolongation in combination with chemotherapy in the treatment of non-squamous advanced NSCLC patients . These positive results led to a large number of clinical trials to evaluate bevacizumab in combination with other targeted agents in advanced disease , and to define the role of this agent in early stage NSCLC such as the impact of bevacizumab integration in chemoradiotherapy strategy for locally advanced disease . Selective inhibition of the tumor marker O60218 by antiinflammatory N-phenylanthranilic acids and glycyrrhetic acid . A human aldose reductase-like protein , O60218 in the aldo-keto reductase ( AKR ) superfamily , was recently identified as a tumor marker of several types of cancer . DB02383 , an aldose reductase inhibitor ( Q9Y4X5 ) , is known to be the most potent inhibitor of the enzyme . In this study , we compared the inhibitory effects of other ARIs including flavonoids on O60218 and aldose reductase to evaluate their specificity . However , ARIs showed lower inhibitory potency for O60218 than for aldose reductase . In the search for potent and selective inhibitors of O60218 from other drugs used clinically , we found that non-steroidal antiinflammatory N-phenylanthranilic acids , diclofenac and glycyrrhetic acid competitively inhibited O60218 , showing K(i) values of 0.35-2.9 microM and high selectivity to this enzyme ( 43-57 fold versus aldose reductase ) . Molecular docking studies of mefenamic acid and glycyrrhetic acid in the O60218 -nicotinamide adenine dinucleotide phosphate ( NADP(+) ) complex and site-directed mutagenesis of the putative binding residues suggest that the side chain of Val301 and a hydrogen-bonding network among residues Val301 , Gln114 and Ser304 are important for determining the inhibitory potency and selectivity of the non-steroidal antiinflammatory drugs . Thus , the potent and selective inhibition may be related to the cancer chemopreventive roles of the drugs , and their structural features may facilitate the design of new anti-cancer agents targeting O60218 . DB08901 circumvents P09038 -driven resistance to imatinib in CML . P09038 induces imatinib resistance in CML cells via reactivation of P22607 - DB01367 -MAPK signaling . The potential role of PD0332991 ( DB09073 ) in the treatment of multiple myeloma . INTRODUCTION : Multiple myeloma ( MM ) remains an incurable malignancy indicating a need for continued investigation of novel therapies . Recent studies have highlighted the role of cyclin-dependent kinases ( CDK ) in the pathogenesis of MM . PD0332991 ( DB09073 ) is an orally bioavailable , highly selective inhibitor of the P11802 /6-cyclin complex and downstream retinoblastoma protein ( Rb ) activation pathway that induces cell cycle arrest in the P55008 phase . AREAS COVERED : In this review , the authors summarize the role of the P11802 /6 signaling pathway in MM . They also summarize the development of PD0332991 as a specific inhibitor of P11802 /6 , and the reported preclinical and clinical data supporting the potential role of PD0332991 in MM . EXPERT OPINION : While PD0332991 is essentially cytostatic , inducing prolonged P55008 arrest , it enhances the cytotoxic effect of other agents effective in MM , including bortezomib and lenalidomide , as confirmed in early phase clinical trials . However , with a plethora of other drugs of different classes being tested in MM , further development of PD0332991 will depend on defining the most efficacious combination with least toxicity . An unexplored opportunity remains the potential protective effect of PD0332991 against lytic bone lesions of MM . The next few years are likely to better define the place of PD0332991 in the treatment of MM . PPARgamma activation abolishes LDL-induced proliferation of human aortic smooth muscle cells via SOD-mediated down-regulation of superoxide . Native LDL would be a mitogenic and chemotactic stimulus of VSMC proliferation and differentiation in the atherosclerotic lesion where endothelial disruption occurred . In previous studies , our group investigated the molecular mechanisms by which LDL induces P10145 production and by which PPARalpha activation abolishes LDL effects in human aortic SMCs ( hAoSMCs ) . Herein is the first report of PPARgamma activation by troglitazone ( TG ) exerting its inhibitory effects on LDL-induced cell proliferation via generation not of H(2)O(2) , but of O2(.-) , and the subsequent activation of Erk1/2 in hAoSMCs . Moreover , in this study TG abolished the LDL-accelerated G(1)-S progression to control levels via down-regulation of active cyclinD1/ P11802 and cyclinE/ P24941 complexes and up-regulation of P38936 (Cip1) expression . TG exerted its anti-proliferative effects through the up-regulation of basal superoxide dismutase ( SOD ) expression . This data suggests that the regulation of O2(.-) is located at the crossroads between LDL signaling and cell proliferation . The role of tumor suppressor dysregulation in prostate cancer progression . P10275 activity is essential for prostate cancer development and progression . While there are classically defined roles for the retinoblastoma ( P06400 ) and p53 tumor suppressor pathways in maintenance of cell cycle control and the DNA damage response , recent studies have demonstrated a direct role of these two pathways in regulating AR expression and function . While the role of Pten deregulation in prostate cancer has provided much insight in to the mechanisms underlying prostate cancer initiation and progression , emerging roles for P06400 and p53 are likely to further expand upon our understanding of tumor suppressor/nuclear receptor interaction . As disconnecting mitogenic signaling from AR-mediated gene transcription underlies the progression to castrate resistant prostate cancer ( CRPC ) , functional inactivation of these two tumor suppressor pathways represents one mechanism through which AR protein levels can be upregulated and AR-mediated gene transcription can become aberrant . Importantly , recent advances in small molecule inhibitor design and discovery have led to the identification of agents capable of targeting these two prominent pathways and restoring the function of deregulated wild-type P06400 and p53 protein . While such agents have undergone extensive study in many solid tumor types , the additional importance of P06400 and p53 in restraining transcription of the AR gene within the prostate provides impetus for examining how loss of these two tumor suppressor proteins can facilitate transition of prostate cancers to CRPC . As will be reviewed in this article , restoration of P06400 and p53 functions are not only important in regard to shortterm cell cycle regulation and response to genomic stresses , but likely have direct implications for deregulation of the AR locus . DAPk1 inhibits NF-κB activation through P01375 -α and P27352 -γ-induced apoptosis . Recent studies have shown DAPk as a molecular modulator induced by the second messenger , responsible for controlling cell destiny decisions , but the detailed mechanism mediating the role of DAPk1 during cell death is still not fully understood . In this present report , we attempted to characterize the effects of P01375 -α and P27352 -γ on DAPk1 in human ovarian carcinoma cell lines , OVCAR-3 . Both P01375 -α and P27352 -γ significantly induce DAPk1 levels in a time-dependent manner . At the same time , they both arrested cell cycle progression in the G(0)-G(1) and G2/M phase , down-regulated cyclin D1 , P11802 and NF-κB expression , while also up-regulating p27 and p16 expression . Subsequently , the efficacy of the combined treatment with DAPk1 was investigated . In the presence of DAPk1 , P01375 -α or P27352 -γ-induced apoptosis was additively increased , while P01375 -α or P27352 -γ-induced NF-κB activity was inhibited . Conversely , P01375 -α or P27352 -γ-dependent NF-κB activity was further enhanced by the inhibition of DAPk1 with its specific siRNA . The activity of NF-κB was dependent on the level of DAPk1 , indicating the requirement of DAPk1 for the activation of NF-κB . Low levels of DAPk1 expression were frequently observed in different human patient 's tissue and cancer cell lines compared to normal samples . In addition , over-expression of DAPk1 from either P01375 -α or P27352 -γ-treatment cells suppressed the anti-apoptosis protein P98170 as well as P35354 and P05362 , more than control . Taken together , our data findings suggest that DAPk1 can mediate the pro-apoptotic activity of P01375 -α and P27352 -γ via the NF-κB signaling pathways . Sense p16 and antisense Q03405 bicistronic construct inhibits angiogenesis and induces glioma cell death . High-grade gliomas comprise the most malignant type of primary brain tumor and are relatively frequent in adults . Recent studies have indicated that the loss of p16 , an inhibitor of P11802 , promotes the acquisition of malignant characteristics in gliomas . A correlation between overexpression of urokinase-type plasminogen activator receptor ( Q03405 ) and glioblastoma invasion has also been established . Moreover , Q03405 /integrin binding has been shown to initiate or potentiate integrin signaling through focal adhesion kinase and/or src kinases . Our previous studies demonstrated that downregulation of Q03405 expression and restoration of p16 regress glioma growth in nude mice and downregulate alphavbeta3 integrin receptor expression . Here , we show the effect of a bicistronic construct on alphavbeta5 integrin receptor expression , angiogenesis and the biochemical pathway that causes glioma cell death . The U251 glioblastoma and a glioblastoma xenograft cell line transduced with a recombinant replication-defective adenovirus vector containing the cDNA of wild-type p16 and antisense RNA of Q03405 significantly inhibited human mammary epithelial cell capillary formation and vascular endothelial growth factor ( P15692 ) expression . Inactivation of anti-apoptotic molecules such as Akt , PARP , activation of caspases and accumulation of heteroduplex chromosomal DNA in pre- P55008 phase of the cell cycle was demonstrated by Western blotting , caspase activity assay and FACS analysis . Nuclear DNA fragmentation upon induction of apoptosis was scored using the TUNEL assay . Significant downregulation of alphavbeta5 integrin receptor expression was also confirmed by FACS analysis , immunoprecipitation and RT-PCR . Taken together , the results demonstrate that the sense p16 and anti-sense Q03405 bicistronic construct significantly inhibits angiogenesis , induces apoptosis by deregulation of the PI3K-Akt pathway and downregulates alphavbeta5 integrin receptor expression . Implicating P21583 complexes in organogenesis in Caenorhabditis elegans . Development of the Caenorhabditis elegans foregut ( pharynx ) is regulated by a network of proteins that includes the Retinoblastoma protein ( P06400 ) ortholog LIN-35 ; the ubiquitin pathway components P0CG48 -18 and Q9Y4X5 ; and PHA-1 , a cytoplasmic protein . Loss of pha-1 activity impairs pharyngeal development and body morphogenesis , leading to embryonic arrest . We have used a genetic suppressor approach to dissect this complex pathway . The lethality of pha-1 mutants is suppressed by loss-of-function mutations in sup-35/ztf-21 and sup-37/ztf-12 , which encode Zn-finger proteins , and by mutations in sup-36 . Here we show that sup-36 encodes a divergent Skp1 family member that binds to several F-box proteins and the microtubule-associated protein Q02083 -1/τ . Like P60880 -35 , P60880 -36 levels were negatively regulated by P0CG48 -18- Q9Y4X5 . We also found that P60880 -35 and P60880 -37 physically associated and that P60880 -35 could bind microtubules . Thus , P60880 -35 , P60880 -36 , and P60880 -37 may function within a pathway or complex that includes cytoskeletal components . Additionally , P60880 -36 may regulate the subcellular localization of P60880 -35 during embryogenesis . We carried out a genome-wide RNAi screen to identify additional regulators of this network and identified 39 genes , most of which are associated with transcriptional regulation . Twenty-three of these genes acted via the LIN-35 pathway . In addition , several S-phase kinase-associated protein (Skp)1-Cullin-F-Box ( P21583 ) components were identified , further implicating P21583 complexes as part of the greater network controlling pharyngeal development . Oligodendroglia are protected from antibody-mediated complement injury by normal immunoglobulins ( " DB00028 " ) . High-dose intravenous immunoglobulin ( DB00028 ) treatment has become a promising immune therapy that can modulate the immune system at several levels , including the complement cascade . In relation to inflammatory demyelinating disease , there is some clinical evidence for the suppression of disease activity by DB00028 , while a role in promoting remyelination after experimental myelin damage has been described . Antibody and complement deposition have been implicated in the immune attack in some cases of multiple sclerosis ( MS ) , and to investigate the mechanisms of action of DB00028 , we studied the effect of DB00028 using the model of complement-mediated cell injury on oligodendroglia in vitro . There was no effect on direct complement lysis of the oligodendroglial cell line CG4 , but antibody-dependent complement damage was inhibited in a dose-dependent manner by DB00028 . These results were confirmed with primary cultures of oligodendrocyte precursor cells ( OPC ) and oligodendrocytes . The addition of excess C1 , P01024 , and C4 did not influence the inhibitory effect of DB00028 , implying that binding of these complement components does not play a role , in contrast to other experimental models of complement damage . F(ab')2 immunoglobulin fragments were at least partially responsible for the effect . We conclude that DB00028 may be protective in antibody-mediated complement injury of oligodendrocytes and their progenitors , and that this effect is likely to be mediated via antibody binding , rather than interference with complement activation . Inhibition of inflammatory mechanisms , as opposed to a direct effect on remyelinating cells , may underlie the role of DB00028 in promoting myelin repair in experimental models . P10275 rediscovered : the new biology and targeting the androgen receptor therapeutically . Discoveries over the past decade suggest that castration-resistant prostate cancer ( CRPC ) is sensitive , but not resistant to , further manipulation of the androgen-androgen receptor ( AR ) axis . Several new therapies that target this axis have demonstrated clinical activity . In this article , preclinical and clinical findings occurring in the field of AR-targeted therapies are reviewed . Reviews of scientific and clinical development are divided into those occurring prereceptor ( androgen production and conversion ) and at the level of the receptor ( AR aberrations and therapies targeting AR directly ) . Intracrine androgen production and AR amplification , among others , are among the principal aberrancies driving CRPC growth . Phase III data with abiraterone acetate and phase II data with DB08899 , along with other similar therapies , confirm for the clinician that the scientific findings related to persistent AR signaling in a castrate milieu can be harnessed to produce significant clinical benefit for patients with the disease . Studies aimed at optimizing the timing of their use and exploring the mechanisms of resistance to these therapies are under way . The clinical success of therapies that directly target androgen synthesis as well as the most common aberrancies of the AR confirm that prostate cancer retains dependence on AR signaling , even in the castrate state . Prostanoid production in Saccharomyces cerevisiae provides a novel assay for nonsteroidal anti-inflammatory drugs . Prostanoids are a large family of lipid mediators originating from prostaglandin H synthase ( PGHS ) activity on the 20-carbon polyunsaturated fatty acids dihomo-gamma-linolenic acid ( DB00154 ) , arachidonic acid ( AA ) and eicosapentaenoic acid . The two mouse PGHS isoforms , P23219 and P35354 , were expressed in Saccharomyces cerevisiae ( yeast ) , as was a signal-peptide-deleted version of P23219 ( PGHS-1MA ) . P23219 showed high activity with both AA and DB00154 as substrate , whereas P35354 activity was high with DB00154 but low with AA . Signal peptide removal reduced the activity of PGHS-1MA by > 50 % relative to P23219 , but the residual activity indicated that correct targeting to the lumen of the endoplasmic reticulum may not be necessary for enzyme function . Coexpression of P23219 with cDNAs encoding mouse prostaglandin I synthase and thromboxane A synthase , and with Trypanosoma brucei genomic DNA encoding prostaglandin F synthase in AA-supplemented yeast cultures resulted in production of the corresponding prostanoids , prostaglandin I(2) , thromboxane A(2) and prostaglandin F(2alpha) . The inhibitory effects of nonsteroidal anti-inflammatory drugs ( NSAIDs ) on prostanoid production were tested on yeast cells expressing P23219 in AA-supplemented culture . Dose-dependent inhibition of prostaglandin H(2) production by aspirin , ibuprofen and indomethacin demonstrated the potential utility of this simple expression system in screening for novel NSAIDs . JTE-522 , a selective P35354 inhibitor , inhibits cell proliferation and induces apoptosis in RL95-2 cells . AIM : To investigate whether JTE-522 [ 4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide ] , a selective P35354 inhibitor , can induce apoptosis and inhibit cell proliferation in human endometrial cancer cell line RL95-2 cells and to explore the molecular mechanisms . METHODS : [ 3-(4,5)-dimethylthiazol-2-yl ] -2,5-diphenyl tetrazolium bromide ( MTT ) , DNA ladder , enzyme-linked immunosorbent assay ( ELISA ) , flow cytometry , RT-PCR , and Western blot analysis were employed to investigate effect of JTE-522 on human endometrial cancer cell line RL95-2 cells and the related molecular mechanisms . RESULTS : JTE-522 inhibited the growth of RL95-2 cells and induced the apoptosis . Furthermore , it arrested G0/ P55008 phase and inhibited S phase in RL95-2 cells . JTE-522 inhibited the expressions of P35354 mRNA , phosphorylated Rb , and P11802 proteins , while increased the levels of p53 , P38936 , cyclin D1 proteins , and the activity of caspase-3 in RL95-2 cells . CONCLUSION : JTE-522 inhibits cell proliferation and induces apoptosis in RL95-2 cells , which may be associated with the activation of caspase-3-like proteases , down-regulation of the expression of P35354 mRNA , phosphorylated Rb , and P11802 proteins , and up-regulation of the expressions of p53 , P38936 , and cyclin D1 proteins . DB00051 plus methotrexate or standard therapy is more effective than methotrexate or standard therapies alone in the treatment of fatigue in patients with active , inadequately treated rheumatoid arthritis . OBJECTIVES : Fatigue is an important systemic symptom of rheumatoid arthritis ( RA ) but has rarely been evaluated consistently after initiation of treatment in RA patients . This study examined the effects of adalimumab ( HUMIRA , Abbott Laboratories , Abbott Park , IL , USA ) , a fully human , anti-tumor necrosis factor ( anti- P01375 ) monoclonal antibody , on reducing fatigue in patients with RA . METHODS : A total of 1526 patients with RA were enrolled in 3 randomized , placebo-controlled clinical trials of adalimumab versus placebo plus methotrexate ( MTX ) or placebo plus standard antirheumatic therapies . Fatigue was assessed with the Functional Assessment of Chronic Illness Therapy ( FACIT ) fatigue scale questionnaire ( which has been validated in RA ) at baseline , mid-study , and at the end of the study . Logistic regression models were constructed using baseline demographic variables to test for treatment effect . In addition , sensitivity analyses were performed to determine the robustness of the data . RESULTS : At baseline in the 3 trials , patients ' fatigue ranged from 27.9-29.7 , representing considerable fatigue on the FACIT fatigue scale . Fatigue was significantly and consistently reduced in adalimumab-treated patients in the 3 clinical trials . Relative to placebo plus MTX , the adalimumab 40-mg-every-other-week dosage group reported statistically significantly less fatigue at all time points post-baseline . Improvements between adalimumab and placebo ranged from 3-7 points across all 3 trials , with a 3-4-point change representing a minimum clinically important difference . CONCLUSION : DB00051 treatment was shown to significantly reduce fatigue in patients with moderate to severe RA . Changes in fatigue in all 3 trials were found to be clinically important . Characterization of proapoptotic compounds from the bark of Garcinia oblongifolia . Twenty compounds from Garcinia oblongifolia were screened for proapoptotic activity using FRET-based HeLa- P01024 sensor cells . Among them , oblongifolins F and G ( 1 and 2 ) , 1,3,5-trihydroxy-13,13-dimethyl-2H-pyran[7,6-b]xanthone ( 3 ) , nigrolineaxanthone T ( 4 ) , and garcicowin B ( 5 ) showed significant proapoptotic activity at a concentration of 10 μM . Bioassessments were then performed to evaluate the potential of these compounds for therapeutic application . All five compounds showed significant cytotoxicity and caspase-3-activating ability in cervical cancer HeLa cells , with compounds 1 and 2 having the highest potencies . All five compounds specifically induced caspase-dependent apoptosis , which could be prevented by the pan-caspase inhibitor zVAD-fmk . In particular , 3 induced apoptosis through mitotic arrest . Compounds 1-5 displayed similar IC50 values ( 3.9-16.5 μM ) against the three cancer cell lines HeLa , MDA-MB-435 , and HepG2 . In addition , compounds 1 , 2 , and 4 exhibited similar and potent IC50 values ( 2.4-5.1 μM ) against several breast and colon cancer cell lines , including those overexpressing either P04626 or P-glycoprotein . P04626 and P-glycoprotein are known factors that confer resistance to anticancer drugs in cancer cells . This is the first study on the cytotoxicity , caspase-3-activing ability , and specificity of proapoptotic compounds isolated from G. oblongifolia in HeLa cells . The potential application of these compounds against P04626 - or P-glycoprotein-overexpressing cancer cells was investigated . DB09073 ( PD 0332991 ) : targeting the cell cycle machinery in breast cancer . INTRODUCTION : The cyclin D-cyclin-dependent kinases 4 and 6 ( P11802 /6 ) -retinoblastoma ( P06400 ) pathway , governing the cell cycle restriction point , is frequently altered in breast cancer and is a potentially relevant target for anticancer therapy . DB09073 ( PD 0332991 ) , a potent and selective inhibitor of P11802 and Q00534 , inhibits proliferation of several P06400 -positive cancer cell lines and xenograft models . AREAS COVERED : The basic features and abnormalities of the cell cycle in breast cancer are described , along with their involvement in estrogen signaling and endocrine resistance . The pharmacological features of palbociclib , its activity in preclinical models of breast cancer and the potential determinants of response are then illustrated , and its clinical development in breast cancer described . A literature search on the topic was conducted through PubMed and the proceedings of the main cancer congresses of recent years . EXPERT OPINION : The combination of palbociclib with endocrine agents is a very promising treatment and Phase III clinical trials are ongoing to confirm its efficacy . Further , potentially useful combinations are those with drugs targeting mitogenic signaling pathways , such as P04626 - and PI3K-inhibitors . Combination with chemotherapy seems more problematic , as antagonism has been reported in preclinical models . The identification of predictive factors , already explored in preclinical studies , must be further refined and validated in clinical trials . Apotransferrin decreases the response of oligodendrocyte progenitors to PDGF and inhibits the progression of the cell cycle . In the CNS , transferrin ( Tf ) is expressed by the oligodendroglial cells ( OLGcs ) and is essential for their development . We have previously shown that apotransferrin ( aTf ) accelerates maturation of OLGcs in vivo as well as in vitro . The mechanisms involved in this action appear to be complex and have not been completely elucidated . The aim of this study was to investigate if Tf participates in the regulation of the cell cycle of oligodendroglial progenitor cells ( OPcs ) . Primary cultures of OPcs were treated with aTf and/or with different combinations of mitogenic factors . Cell cycle progression was studied by BrdU incorporation , flow cytometry and by the expression of cell cycle regulatory proteins . Apotransferrin decreased the number of BrdU+ cells , increasing the cell cycle time and decreasing the number of cells in S phase . The cell cycle inhibitors p27kip1 , p21cip1 and p53 were increased , and in agreement with these results , the activity of the complexes involved in P55008 -S progression ( cyclin D/ P11802 , cyclin E/ P24941 ) , was dramatically decreased . Apotransferrin also inhibited the mitogenic effects of PDGF and PDGF/IGF on OPcs , but did not affect their proliferation rate in the presence of P09038 , P09038 /PDGF or P09038 /IGF . Our results indicate that inhibition of the progression of the cell cycle of OPcs by aTf , even in the presence of PDGF , leads to an early beginning of the differentiation program , evaluated by different maturation markers ( O4 , GC and MBP ) and by morphological criteria . The modulation by aTf of the response of OPcs to PDGF supports the idea that this glycoprotein might act as a key regulator of the OLGc lineage progression . FIPSDock : a new molecular docking technique driven by fully informed swarm optimization algorithm . The accurate prediction of protein-ligand binding is of great importance for rational drug design . We present herein a novel docking algorithm called as FIPSDock , which implements a variant of the Fully Informed Particle Swarm ( FIPS ) optimization method and adopts the newly developed energy function of AutoDock 4.20 suite for solving flexible protein-ligand docking problems . The search ability and docking accuracy of FIPSDock were first evaluated by multiple cognate docking experiments . In a benchmarking test for 77 protein/ligand complex structures derived from GOLD benchmark set , FIPSDock has obtained a successful predicting rate of 93.5 % and outperformed a few docking programs including particle swarm optimization ( Q9P0Z9 )@AutoDock , SODOCK , AutoDock , DOCK , Glide , GOLD , FlexX , Surflex , and MolDock . More importantly , FIPSDock was evaluated against Q9P0Z9 @AutoDock , SODOCK , and AutoDock 4.20 suite by cross-docking experiments of 74 protein-ligand complexes among eight protein targets ( P24941 , P03372 , F2 , Q16539 , P22894 , P45452 , Q07343 , and O76074 ) derived from Sutherland-crossdock-set . Remarkably , FIPSDock is superior to Q9P0Z9 @AutoDock , SODOCK , and AutoDock in seven out of eight cross-docking experiments . The results reveal that FIPS algorithm might be more suitable than the conventional genetic algorithm-based algorithms in dealing with highly flexible docking problems . Mice deficient in phosphodiesterase-4A display anxiogenic-like behavior . RATIONALE : Phosphodiesterases ( PDEs ) are a super family of enzymes responsible for the halting of intracellular cyclic nucleotide signaling and may represent novel therapeutic targets for treatment of cognitive disorders . DB05876 is of considerable interest to cognitive research because it is highly expressed in the brain , particularly in the cognition-related brain regions . Recently , the functional role of Q07343 and Q08499 , two of the four DB05876 subtypes ( P27815 , B , C , and D ) , in behavior has begun to be identified ; however , the role of P27815 in the regulation of behavior is still unknown . OBJECTIVES : The purpose of this study was to characterize the functional role of P27815 in behavior . METHODS : The role of P27815 in behavior was evaluated through a battery of behavioral tests using P27815 knockout ( KO ) mice ; urine corticosterone levels were also measured . RESULTS : P27815 KO mice exhibited improved memory in the step-through-passive-avoidance test . They also displayed anxiogenic-like behavior in elevated-plus maze , holeboard , light-dark transition , and novelty suppressed feeding tests . Consistent with the anxiety profile , P27815 KO mice had elevated corticosterone levels compared with wild-type controls post-stress . Interestingly , P27815 KO mice displayed no change in object recognition , Morris water maze , forced swim , tail suspension , and duration of anesthesia induced by co-administration of xylazine and ketamine ( suggesting that P27815 KO may not be emetic ) . CONCLUSIONS : These results suggest that P27815 may be important in the regulation of emotional memory and anxiety-like behavior , but not emesis . P27815 could possibly represent a novel therapeutic target in the future for anxiety or disorders affecting memory .