MH_dev_249

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 MEN competes with DB00171 for binding to these kinases . A P24941 REA - hymenialdisine complex crystal structure shows that three hydrogen bonds link hymenialdisine to the Glu 81 and Leu 83 residues of P24941 REA , as observed with other inhibitors . DB02950 MEN inhibits Q00535 REA / p35 in vivo as demonstrated by the lack of phosphorylation / down-regulation of Pak 1 kinase in E18 rat cortical neurons , and also inhibits GSK - 3 in vivo as shown by the inhibition of P46821 phosphorylation . DB02950 MEN also blocks the in vivo phosphorylation of the microtubule-binding protein tau at sites that are hyperphosphorylated by GSK - 3 and Q00535 REA / 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 REA ) is a key angiogenic factor implicated in tumor blood vessels formation and permeability , and tumor P15692 REA 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 REA or its receptor signalling system . DB00112 MEN is the first recombinant humanized monoclonal antibody binding P15692 REA 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 REA by antiinflammatory N-phenylanthranilic acids and glycyrrhetic acid . A human aldose reductase-like protein , O60218 REA in the aldo-keto reductase ( AKR ) superfamily , was recently identified as a tumor marker of several types of cancer . DB02383 MEN , an aldose reductase inhibitor ( Q9Y4X5 REA ) , is known to be the most potent inhibitor of the enzyme . In this study , we compared the inhibitory effects of other ARIs including flavonoids on O60218 REA and aldose reductase to evaluate their specificity . However , ARIs showed lower inhibitory potency for O60218 REA than for aldose reductase . In the search for potent and selective inhibitors of O60218 REA from other drugs used clinically , we found that non-steroidal antiinflammatory N-phenylanthranilic acids , diclofenac and glycyrrhetic acid competitively inhibited O60218 REA , showing K ( i ) values of 0.35- 2.9 microM and high selectivity to this enzyme ( 43-57 fold versus aldose reductase ) . Molecular docking studies of mefenamic acid and glycyrrhetic acid in the O60218 REA - nicotinamide adenine dinucleotide phosphate ( NADP ( + ) ) complex and site-directed mutagenesis of the putative binding residues suggest that the side chain of Val 301 and a hydrogen-bonding network among residues Val 301 , Gln 114 and Ser 304 are important for determining the inhibitory potency and selectivity of the non-steroidal antiinflammatory drugs . Thus , the potent and selective inhibition may be related to the cancer chemopreventive roles of the drugs , and their structural features may facilitate the design of new anti-cancer agents targeting O60218 REA .

DB08901 MEN circumvents P09038 REA - driven resistance to imatinib in CML . P09038 REA induces imatinib resistance in CML cells via reactivation of P22607 REA - DB01367 - MAPK signaling .

The potential role of PD0332991 ( DB09073 SUB ) 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 SUB ) is an orally bioavailable , highly selective inhibitor of the P11802 REA / 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 REA / 6 signaling pathway in MM . They also summarize the development of PD0332991 as a specific inhibitor of P11802 REA / 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 REA 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 Erk 1/2 in hAoSMCs . Moreover , in this study TG abolished the LDL-accelerated G ( 1 ) - S progression to control levels via down-regulation of active cyclinD 1 / P11802 REA and cyclinE / P24941 REA complexes and up-regulation of P38936 REA ( Cip 1 ) 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 REA activity is essential for prostate cancer development and progression . While there are classically defined roles for the retinoblastoma ( P06400 REA ) 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 REA 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 REA and p53 protein . While such agents have undergone extensive study in many solid tumor types , the additional importance of P06400 REA 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 REA 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 .

DAPk 1 inhibits NF-κB activation through P01375 REA - α and P27352 REA - 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 DAPk 1 during cell death is still not fully understood . In this present report , we attempted to characterize the effects of P01375 REA - α and P27352 REA - γ on DAPk 1 in human ovarian carcinoma cell lines , OVCAR - 3 . Both P01375 REA - α and P27352 REA - γ significantly induce DAPk 1 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 REA and NF-κB expression , while also up-regulating p27 and p16 expression . Subsequently , the efficacy of the combined treatment with DAPk 1 was investigated . In the presence of DAPk 1 , P01375 REA - α or P27352 REA - γ-induced apoptosis was additively increased , while P01375 REA - α or P27352 REA - γ-induced NF-κB activity was inhibited . Conversely , P01375 REA - α or P27352 REA - γ-dependent NF-κB activity was further enhanced by the inhibition of DAPk 1 with its specific siRNA . The activity of NF-κB was dependent on the level of DAPk 1 , indicating the requirement of DAPk 1 for the activation of NF-κB . Low levels of DAPk 1 expression were frequently observed in different human patient ' s tissue and cancer cell lines compared to normal samples . In addition , over-expression of DAPk 1 from either P01375 REA - α or P27352 REA - γ-treatment cells suppressed the anti-apoptosis protein P98170 REA as well as P35354 REA and P05362 REA , more than control . Taken together , our data findings suggest that DAPk 1 can mediate the pro-apoptotic activity of P01375 REA - α and P27352 REA - γ via the NF-κB signaling pathways .

Sense p16 and antisense Q03405 REA 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 REA , promotes the acquisition of malignant characteristics in gliomas . A correlation between overexpression of urokinase-type plasminogen activator receptor ( Q03405 REA ) and glioblastoma invasion has also been established . Moreover , Q03405 REA / 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 REA expression and restoration of p16 regress glioma growth in nude mice and downregulate alphavbeta 3 integrin receptor expression . Here , we show the effect of a bicistronic construct on alphavbeta 5 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 REA significantly inhibited human mammary epithelial cell capillary formation and vascular endothelial growth factor ( P15692 REA ) 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 alphavbeta 5 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 REA bicistronic construct significantly inhibits angiogenesis , induces apoptosis by deregulation of the PI3K - Akt pathway and downregulates alphavbeta 5 integrin receptor expression .

Implicating P21583 REA 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 REA ) ortholog LIN - 35 ; the ubiquitin pathway components P0CG48 - 18 and Q9Y4X5 REA ; 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 Skp 1 family member that binds to several F-box proteins and the microtubule-associated protein Q02083 REA - 1 / τ . Like P60880 REA - 35 , P60880 REA - 36 levels were negatively regulated by P0CG48 - 18 - Q9Y4X5 REA . We also found that P60880 REA - 35 and P60880 REA - 37 physically associated and that P60880 REA - 35 could bind microtubules . Thus , P60880 REA - 35 , P60880 REA - 36 , and P60880 REA - 37 may function within a pathway or complex that includes cytoskeletal components . Additionally , P60880 REA - 36 may regulate the subcellular localization of P60880 REA - 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 REA ) components were identified , further implicating P21583 REA complexes as part of the greater network controlling pharyngeal development .

Oligodendroglia are protected from antibody-mediated complement injury by normal immunoglobulins ( " DB00028 MEN " ) . High-dose intravenous immunoglobulin ( DB00028 MEN ) 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 MEN , 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 MEN , we studied the effect of DB00028 MEN 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 MEN . These results were confirmed with primary cultures of oligodendrocyte precursor cells ( OPC ) and oligodendrocytes . The addition of excess C1 , P01024 REA , and C4 did not influence the inhibitory effect of DB00028 MEN , 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 MEN 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 MEN in promoting myelin repair in experimental models .

P10275 REA 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 MENMAX DB08899 MEN , 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 MEN ) , arachidonic acid ( AA ) and eicosapentaenoic acid . The two mouse PGHS isoforms , P23219 REA and P35354 REA , were expressed in Saccharomyces cerevisiae ( yeast ) , as was a signal-peptide-deleted version of P23219 REA ( PGHS - 1MA ) . P23219 REA showed high activity with both AA and DB00154 MEN as substrate , whereas P35354 REA activity was high with DB00154 MEN but low with AA . Signal peptide removal reduced the activity of PGHS - 1MA by > 50 % relative to P23219 REA , 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 REA 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 REA 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 REA 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 REA 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 REA mRNA , phosphorylated Rb , and P11802 REA proteins , while increased the levels of p53 , P38936 REA , 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 REA mRNA , phosphorylated Rb , and P11802 REA proteins , and up-regulation of the expressions of p53 , P38936 REA , and cyclin D1 proteins .

DB00051 MEN 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 REA ) 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 MEN 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 REA 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 HepG 2 . 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 REA or P-glycoprotein . P04626 REA 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 REA - or P-glycoprotein-overexpressing cancer cells was investigated .

DB09073 SUB ( PD 0332991 ) : targeting the cell cycle machinery in breast cancer . INTRODUCTION : The cyclin D-cyclin-dependent kinases 4 and 6 ( P11802 REA / 6 ) - retinoblastoma ( P06400 REA ) pathway , governing the cell cycle restriction point , is frequently altered in breast cancer and is a potentially relevant target for anticancer therapy . DB09073 SUB ( PD 0332991 ) , a potent and selective inhibitor of P11802 REA and Q00534 REA , inhibits proliferation of several P06400 REA - 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 REA - 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 REA , cyclin E / P24941 REA ) , 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 REA , P09038 REA / PDGF or P09038 REA / 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 REA ) @AutoDock , SODOCK , AutoDock , DOCK , Glide , GOLD , FlexX , Surflex , and MolDock . More importantly , FIPSDock was evaluated against Q9P0Z9 REA @AutoDock , SODOCK , and AutoDock 4.20 suite by cross-docking experiments of 74 protein-ligand complexes among eight protein targets ( P24941 REA , P03372 REA , F2 , Q16539 REA , P22894 REA , P45452 REA , Q07343 REA , and O76074 REA ) derived from Sutherland-crossdock-set . Remarkably , FIPSDock is superior to Q9P0Z9 REA @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 MEN 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 REA and Q08499 REA , two of the four DB05876 MEN subtypes ( P27815 REA , B , C , and D ) , in behavior has begun to be identified ; however , the role of P27815 REA in the regulation of behavior is still unknown . OBJECTIVES : The purpose of this study was to characterize the functional role of P27815 REA in behavior . METHODS : The role of P27815 REA in behavior was evaluated through a battery of behavioral tests using P27815 REA knockout ( KO ) mice ; urine corticosterone levels were also measured . RESULTS : P27815 REA 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 REA KO mice had elevated corticosterone levels compared with wild-type controls post-stress . Interestingly , P27815 REA 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 REA KO may not be emetic ) . CONCLUSIONS : These results suggest that P27815 REA may be important in the regulation of emotional memory and anxiety-like behavior , but not emesis . P27815 REA could possibly represent a novel therapeutic target in the future for anxiety or disorders affecting memory .