MH_dev_256

DB06655 MEN : clinical pharmacology and considerations for therapy . DB06655 MEN is a United States Food and Drug Administration ( FDA ) - approved glucagon-like peptide - 1 ( P0C6A0 ) analog that is 97 % homologous to native human P0C6A0 . The additional 16 - carbon fatty acid chain causes noncovalent binding to albumin , which slows absorption from the injection site and protects the molecule from degradation by the enzyme dipeptidyl peptidase - 4 , allowing for protraction of action . Albumin binding and an elimination half-life of 13 hours combine to allow for once-daily dosing . DB06655 MEN 1.2 and 1.8 mg / day given as monotherapy for up to 52 weeks produced mean reductions in hemoglobin A1c ( A1C ) of 0.6- 1.6 % ; combination therapy of liraglutide with oral antidiabetic agents demonstrated mean A1C reductions up to 1.5 % . The satiety effect of P43220 REA agonists and documented weight loss as great as 3.38 kg in clinical trials may make liraglutide ideal for obese patients with type 2 diabetes mellitus . Like other incretin-based agents , preliminary studies suggest liraglutide may also increase β-cell mass and function . Hypoglycemia is rare with liraglutide and tends to occur when used in combination with sulfonylureas ; liraglutide in combination with insulin is not yet FDA approved . The pharmacokinetic parameters of liraglutide are unaffected by age , sex , race , or ethnicity , and no special recommendations for altered dosing of liraglutide need apply to populations with hepatic or renal impairment . Results from clinical trials have not shown an increased risk of medullary thyroid cancer , pancreatitis , or poor cardiovascular outcomes with liraglutide treatment . Ongoing , long-term monitoring studies continue to evaluate the safety of liraglutide treatment in these outcomes .

Further evidence for a functional role of the glutamate receptor gene Q14832 REA in schizophrenia . In recent years , evidence has been accumulating indicating a major role of glutamate in the pathogenesis and pathophysiology of schizophrenia . Of particular importance in this regard are the metabotropic glutamate receptors ( GRM ) . Thus , a recently published trial of the amino acid analogue DB05096 MEN , which exerts its effects through the activation of the glutamate receptors Q14832 REA / Q14416 REA , showed an improvement of positive and negative symptoms comparable to treatment with olanzapine . A functional variant of Q14832 REA has been described which modulates synaptic glutamate levels . We assessed whether this functional variant rs6465084 is related to schizophrenia in a large sample of patients and controls . We found an increased frequency of the A allele ( p= 0.027 ) and the AA genotype ( p= 0.024 ) in schizophrenia patients . Moreover , in an assessment of schizophrenia endophenotypes , patients of the AA genotype performed poorly in the digit symbol test , a measure of attention ( p= 0.008 ) . Our results provide further evidence for the potential importance of the glutamate receptor Q14832 REA in schizophrenia , and indicate that the novel antipsychotic DB05096 MEN may actually be targeting a pathogenic pathway of schizophrenia .

Evaluation of a microarray for genotyping polymorphisms related to xenobiotic metabolism and DNA repair . We present an oligonucleotide microarray ( " MetaboChip " ) based on the arrayed primer extension ( P27695 REA ) technique , allowing genotyping of single nucleotide polymorphisms ( SNPs ) in genes of interest for cancer susceptibility and pharmacogenetics . P27695 REA consists of a sequencing reaction primed by an oligonucleotide anchored with its 5 ' end to a glass slide and terminating one nucleotide before the polymorphic site . The extension with one fluorescently labeled dideoxynucleotide complementary to the template reveals the polymorphism . Ninety-three SNPs in 42 genes were selected among those resequenced in the context of the SNP 500 project , using a set of 102 reference DNA samples from the Coriell Biorepository . Selected SNPs belong to the following genes : P00325 REA , P05091 REA , P27695 REA , CDKN 2A , P21964 REA , P04798 REA , P05177 REA , Q16678 REA , P11509 REA , P33261 REA , P11712 REA , P05181 REA , P08684 REA , P14416 REA , P21917 REA , P07099 REA , P07992 REA , P18074 REA , Q92889 REA , P28715 REA , P30550 REA , O15217 REA , P21266 REA , P09211 REA , GSTT 2 , LIG 3 , Q00987 REA , P16455 REA , P05164 REA , NAT 1 , NAT 2 , P15559 REA , O15527 REA , P12004 REA , P06746 REA , Q01959 REA , P04179 REA , P04637 REA , P18887 REA , O43543 REA , O43542 REA , and O15287 REA . We assessed the performance of P27695 REA by comparing the results obtained with MetaboChip against those reported by the SNP 500 . Among 88 SNPs that yielded signals , 6 showed less than 99 % of concordance , whereas 82 performed accurately , showing that P27695 REA is a reliable and sensitive genotyping method .

The presence and function of dopamine type 2 receptors in boar sperm : a possible role for dopamine in viability , capacitation , and modulation of sperm motility . Several studies have shown that dopamine and other catecholamines are present in oviduct luminal fluid . We recently reported that dopamine type 2 receptors ( P14416 REA ) are present in a wide range of mammalian sperm , suggesting a role for dopaminergic signaling in events such as fertilization , capacitation , and sperm motility . In the present study , we used Western blot analysis to show that boar sperm express P14416 REA and that their activation with dopamine ( 100 nM ) has a positive effect on cell viability that can be correlated with AKT / P31749 REA phosphorylation . DB01200 SUB ( 100 nM ) and dopamine ( 100 nM and 10 muM ) increased tyrosine phosphorylation during the capacitation period . Immunofluorescence analysis indicated that P14416 REA localization is dynamic and depends on the capacitation stage , colocalizing with tyrosine phosphorylated proteins in the acrosome and midpiece region of capacitated boar sperm . This association was confirmed by coimmunoprecipitation analysis . We also showed that bromocriptine ( 100 nM ) and low-concentration dopamine ( 100 nM and 10 muM ) increased total and progressive motility of sperm . However , high concentrations of dopamine ( 1 mM ) decreased tyrosine phosphorylation and motility in in vitro sperm capacitation assays . This can be explained by the presence of the dopamine transporters ( Q01959 REA , official symbol Q01959 REA ) in sperm , as demonstrated by Western blot analysis and immunocytochemistry . Taken together , our results support the idea that dopamine may have a fundamental role during sperm capacitation and motility in situ in the female upper reproductive tract .

Serotonin skews human macrophage polarization through P41595 REA and P34969 REA . Besides its role as a neurotransmitter , serotonin ( 5 - hydroxytryptamine , 5HT ) regulates inflammation and tissue repair via a set of receptors ( 5HT ( 1-7 ) ) whose pattern of expression varies among cell lineages . Considering the importance of macrophage polarization plasticity for inflammatory responses and tissue repair , we evaluated whether 5HT modulates human macrophage polarization . 5HT inhibited the LPS-induced release of proinflammatory cytokines without affecting P22301 REA production , upregulated the expression of M2 polarization-associated genes ( P05120 REA , P07996 REA , Q9NY15 , Q86Y22 REA ) , and reduced the expression of M1 - associated genes ( P08476 REA , P41597 REA , P39900 REA , P05121 REA , P29016 REA , O94788 REA ) . Whereas only 5HT ( 7 ) mediated the inhibitory action of 5HT on the release of proinflammatory cytokines , both 5HT ( 2B ) and 5HT ( 7 ) receptors mediated the pro-M 2 skewing effect of 5HT . In fact , blockade of both receptors during in vitro monocyte-to-macrophage differentiation preferentially modulated the acquisition of M2 polarization markers . 5HT ( 2B ) was found to be preferentially expressed by anti-inflammatory M2 ( P09603 REA ) macrophages and was detected in vivo in liver Kupffer cells and in tumor-associated macrophages . Therefore , 5HT modulates macrophage polarization and contributes to the maintenance of an anti-inflammatory state via 5HT ( 2B ) and 5HT ( 7 ) , whose identification as functionally relevant markers for anti-inflammatory / homeostatic human M2 macrophages suggests their potential therapeutic value in inflammatory pathologies .

Gene expression results in lipopolysaccharide-stimulated monocytes depend significantly on the choice of reference genes . BACKGROUND : Gene expression in lipopolysaccharide ( LPS ) - stimulated monocytes is mainly studied by quantitative real-time reverse transcription PCR ( RT-qPCR ) using P04406 REA ( glyceraldehyde 3 - phosphate dehydrogenase ) or P60709 REA ( beta-actin ) as reference gene for normalization . Expression of traditional reference genes has been shown to vary substantially under certain conditions leading to invalid results . To investigate whether traditional reference genes are stably expressed in LPS-stimulated monocytes or if RT-qPCR results are dependent on the choice of reference genes , we have assessed and evaluated gene expression stability of twelve candidate reference genes in this model system . RESULTS : Twelve candidate reference genes were quantified by RT-qPCR in LPS-stimulated , human monocytes and evaluated using the programs geNorm , Normfinder and BestKeeper . geNorm ranked P23284 REA ( cyclophilin B ) , P61769 REA ( beta - 2 - microglobulin ) and P62937 REA ( cyclophilin A ) as the best combination for gene expression normalization in LPS-stimulated monocytes . Normfinder suggested P20226 REA ( TATA-box binding protein ) and P61769 REA as the best combination . Compared to these combinations , normalization using P04406 REA alone resulted in significantly higher changes of P01375 REA ( tumor necrosis factor-alpha ) and P22301 REA ( interleukin 10 ) expression . Moreover , a significant difference in P01375 REA expression between monocytes stimulated with equimolar concentrations of LPS from N . meningitides and E . coli , respectively , was identified when using the suggested combinations of reference genes for normalization , but stayed unrecognized when employing a single reference gene , P60709 REA or P04406 REA . CONCLUSIONS : Gene expression levels in LPS-stimulated monocytes based on RT-qPCR results differ significantly when normalized to a single gene or a combination of stably expressed reference genes . Proper evaluation of reference gene stabiliy is therefore mandatory before reporting RT-qPCR results in LPS-stimulated monocytes .

Cyclophilin inhibitors as a novel HCV therapy . A critical role of Cyclophilins , mostly P62937 REA ( CyPA ) , in the replication of HCV is supported by a growing body of in vitro and in vivo evidence . CyPA probably interacts directly with nonstructural protein 5A to exert its effect , through its peptidyl-prolyl isomerase activity , on maintaining the proper structure and function of the HCV replicase . The major proline substrates are located in domain II of NS5A , centered around a " DY " dipeptide motif that regulates CyPA dependence and DB00091 MENMAX DB00091 MEN resistance . Importantly , DB00091 MEN A derivatives that lack immunosuppressive function efficiently block the CyPA-NS 5A interaction and inhibit HCV in cell culture , an animal model , and human trials . Given the high genetic barrier to development of resistance and the distinctness of their mechanism from that of either the current standard of care or any specifically targeted antiviral therapy for HCV ( P35610 REA - C ) , CyP inhibitors hold promise as a novel class of anti-HCV therapy .

Predicting the possibility of two newly isolated phenetheren ring containing compounds from Aristolochia manshuriensis as P24941 REA inhibitors . Aristolochia manshuriensis has been used for centuries in Chinese medicinal system for their versatile medicinal uses . Recent studies have revealed two new aristolactames ( compound A and B ) with γ-lactame ring fused with the phenentherene ring as potent inhibitors of human Cycline Dependent Kinase 2 ( P24941 REA ) . Studies on aristolactames and related compounds claim for their P24941 REA inhibition without delineating the involved mechanism and structural basis of interaction . Molecular structural model was used to we propose a structural basis of P24941 REA inhibition . We showed that these compounds ( A and B ) can successfully dock into the inhibitor binding pockets of human P24941 REA . Predicted binding affinities are comparable to known inhibitors of P24941 REA . Results were in agreement with the earlier biochemical studies . Hence , suggest that studied compounds A and B can be a promising scaffold for rational design of novel and potential drugs against cancer . ABBREVIATIONS : P24941 REA - cyclin-dependent kinase 2 , OLO - DB02116 MEN , NW1 - Cyclohexylmethyloxy - 5 - Nitroso-Pyrimidine - 2 , 4 - Diamine , CMG - DB02407 .

Agonism at P41595 REA receptors is not a class effect of the ergolines . Restrictive cardiac valvulopathies observed in Parkinson patients treated with the ergoline dopamine agonist pergolide have recently been associated with the agonist efficacy of the drug at 5 - hydroxytryptamine 2B ( P41595 REA ) receptors . To evaluate whether agonism at P41595 REA receptors is a phenomenon of the class of the ergolines , we studied P41595 REA receptor-mediated relaxation in porcine pulmonary arteries to five ergolines which are used as antiparkinsonian drugs . DB01186 and cabergoline were potent full agonists in this tissue ( pEC 50 8.42 and 8.72 ) . DB01200 SUB acted as a partial agonist ( pEC 50 6.86 ) . Lisuride and terguride , however , failed to relax the arteries but potently antagonized 5 - HT-induced relaxation ( pKB 10.32 and 8.49 ) . Thus , agonism at P41595 REA receptors seems not to be a class effect of the ergolines .

Increase in proinflammatory cytokines in peripheral blood without haemostatic changes after LPS inhalation . INTRODUCTION : Bronchoalveolar fibrin deposition is a characteristic of various lung disorders including acute lung injury , acute respiratory distress syndrome and sepsis . It is secondary to the activation of coagulation and inhibition of fibrinolysis in the alveolar space , and can be stimulated by lipopolysaccharide ( LPS ) inhalation . The aim of this study was to determine the relation between compartmental stress in the lung and systemic response after LPS inhalation by measuring haemostatic parameters . PATIENTS AND METHODS : 12 healthy subjects underwent a bronchial challenge test with LPS ; sequential dosages were performed for 5 biological markers ( P05231 REA ( P05231 REA ) , C-Reactive Protein ( CRP ) , P00734 REA Fragments 1 and 2 ( F 1 + 2 ) , cortisol and P00747 REA Activator Inhibitor 1 ( P05121 REA ) before endotoxin inhalation and 2 , 4 , 6 , 8 and 24 hours afterwards . RESULTS : P05231 REA and CRP levels in the peripheral blood were higher after LPS inhalation ; there was no activation of coagulation and no increase in P05121 REA level . CONCLUSION : This study confirms that despite systemic release of proinflammatory cytokines , LPS inhalation does not induce systemic haemostatic response to LPS challenge .

Dissociable fronto-striatal effects of dopamine D2 receptor stimulation on cognitive versus motor flexibility . Genetic and pharmacological studies suggest an important role of the dopamine D2 receptor ( P14416 REA ) in flexible behavioral adaptation , mostly shown in reward-based learning paradigms . Recent evidence from imaging genetics indicates that also intentional cognitive flexibility , associated with lateral frontal cortex , is affected by variations in P14416 REA signaling . In the present functional magnetic resonance imaging ( Q9BWK5 ) study , we tested the effects of a direct pharmacological manipulation of P14416 REA stimulation on intentional flexibility in a task-switching context , requiring switches between cognitive task rules and between response hands . In a double blind , counterbalanced design , participants received either a low dose of the P14416 REA agonist bromocriptine or a placebo in two separate sessions . DB01200 SUB modulated the blood-oxygen-level-dependent ( BOLD ) signal during rule switching : rule-switching-related activity in the left posterior lateral frontal cortex and in the striatum was increased compared to placebo , at comparable performance levels . Fronto-striatal connectivity under bromocriptine was slightly increased for rule switches compared to rule repetitions . Hand-switching-related activity , in contrast , was reduced under bromocriptine in sensorimotor regions . Our results provide converging evidence for an involvement of P14416 REA signaling in fronto-striatal mechanisms underlying intentional flexibility , and indicate that the neural mechanisms underlying different types of flexibility ( cognitive vs motor ) are affected differently by increased dopaminergic stimulation .

Phosphatidylinositol 3 - kinase / Akt pathway regulates tuberous sclerosis tumor suppressor complex by phosphorylation of tuberin . Normal cellular functions of hamartin and tuberin , encoded by the Q92574 REA and P49815 REA tumor suppressor genes , are closely related to their direct interactions . However , the regulation of the hamartin-tuberin complex in the context of the physiologic role as tumor suppressor genes has not been documented . Here we show that insulin or insulin growth factor ( IGF ) 1 stimulates phosphorylation of tuberin , which is inhibited by the phosphatidylinositol 3 - kinase ( PI3K ) inhibitor LY294002 but not by the mitogen-activated protein kinase inhibitor PD98059 . Expression of constitutively active PI3K or active Akt , including Akt 1 and Akt 2 , induces tuberin phosphorylation . We further demonstrate that Akt / P31749 REA associates with hamartin-tuberin complexes , promoting phosphorylation of tuberin and increased degradation of hamartin-tuberin complexes . The ability to form complexes , however , is not blocked . Akt also inhibits tuberin-mediated degradation of p27 ( kip 1 ) , thereby promoting P24941 REA activity and cellular proliferation . Our results indicate that tuberin is a direct physiological substrate of Akt and that phosphorylation of tuberin by PI3K / Akt is a major mechanism controlling hamartin-tuberin function .

[ Meloxicam ( DB00814 MEN ) : a review of its pharmacological and clinical profile ] . Meloxicam ( DB00814 MEN ) is a new nonsteroidal anti-inflammatory drug ( NSAID ) derived from enolic acid , exhibiting selectivity for cyclooxygenase ( P36551 REA ) - 2 over P23219 REA . Meloxicam has shown potent anti-inflammatory and analgesic activity together with low gastrointestinal toxicity in animal models . It is a potent inhibitor not only of acute exudation in adjuvant arthritis in the rat , but also of bone and cartilage destruction . The therapeutic range of meloxicam in the rat , with regard to inhibition of adjuvant arthritis , was several times greater than that of other NSAIDs . Meloxicam in therapeutic doses was found to have no effect on bleeding time or platelet aggregation in healthy volunteers . In clinical studies , meloxicam has shown reliable efficacy against rheumatoid arthritis , osteoarthritis , lumbago ( low back pain ) , scapulohumeral periarthritis , and neck-shoulder-arm syndrome with low gastrointestinal toxicity .

Q9GZP0 inhibition by DB05139 MEN ameliorates tubulointerstitial fibrosis following experimental glomerulonephritis . BACKGROUND : Arresting or regressing kidney scarring is of major clinical relevance . Q9GZP0 ( Q9GZP0 ) is widely expressed in fibrotic kidneys . Administration of the Q9GZP0 neutralizing fully human monoclonal antibody DB05139 MEN in the acute phase of progressive anti-Thy 1.1 glomerulonephritis reduced glomerular and secondary tubulointerstitial damage . METHODS : Using this model , we now assessed the effects of DB05139 MEN ( n = 15 ) vs irrelevant control IgG ( n = 17 ) administered on days 17 , 28 and 35 after disease induction , i . e . after acute glomerular damage had subsided . RESULTS : In vitro , DB05139 MEN inhibited the Q9GZP0 - but not the PDGF-B-induced proliferation of rat renal fibroblasts . Following the first DB05139 MEN injection on day 17 , exposure to therapeutic levels was maintained until day 49 . Proteinuria in the DB05139 MEN - treated group was transiently reduced between days 49 and 77 ( - 19 to - 23 % in comparison with the controls ; P < 0.05 ) . On day 100 , DB05139 MEN treatment reduced the number of rats that had doubled their serum creatinine ( DB05139 MEN : 40 vs controls : 71 % ; P < 0.05 ) . Compared with controls , the DB05139 MEN animals , on day 100 , significantly lowered glomerular expression of vimentin and collagens as well as tubulointerstitial damage scores , interstitial fibrosis , vimentin and cortical Q9GZP0 mRNA levels . CONCLUSIONS : Q9GZP0 antagonism , even after the phase of acute glomerular damage , exerts beneficial effects on the course of tubulointerstitial damage , i . e . the final common pathway of most renal diseases .

DB06626 MEN modulates hypoxia-induced blood-retina barrier permeability and expression of growth factors . This study investigates the effects of the multikinase inhibitor axitinib on the expression of vascular endothelial growth factor ( P15692 REA ) receptors 1/2 ( P17948 REA / 2 ) and platelet-derived growth factor ( PDGF ) receptor beta ( P09619 REA - β ) , hypoxia-induced increased tissue permeability , occludin , zonula occludens protein 1 ( ZO - 1 ) , P15692 REA , and PDGF expression of human retinal pigment epithelial ( Q96AT9 ) cells and human umbilical vein endothelial cells ( HUVECs ) . Primary human Q96AT9 cells and HUVECs were exposed to hypoxia and axitinib . Viability of cells , tissue permeability , and expression of occludin , ZO - 1 , P15692 REA , PDGF , P17948 REA / 2 and P09619 REA - β , and their mRNAs , were investigated by reverse transcription-polymerase chain reaction , enzyme-linked immunosorbent assay , western blotting , and immunohistochemistry . Treatment with axitinib reduced expression of P17948 REA / 2 and P09619 REA - β . Hypoxia decreased cell viability , occludin , and ZO - 1 expression and increased tissue permeability , expression , and secretion of P15692 REA and PDGF . DB06626 MEN significantly reduced hypoxia-induced effects on HUVEC and Q96AT9 cells . Our in vitro results suggest that axitinib may have promising properties as a potential treatment for diabetic macular edema .

Transient , P41595 REA receptor-mediated facilitation in neuropathic pain : Up-regulation of PKCγ and engagement of the DB01221 receptor in dorsal horn neurons . Spinal nociception can be facilitated by 5 - HT2 receptors in neuropathic pain . We investigated the involvement of glutamate receptors in dorsal neuron hyperexcitation that is promoted by P41595 REA receptor ( 5 - HT2BR ) after spinal nerve ligation ( Q16658 REA ) in the rat . Augmentation of C-fiber-evoked potentials by spinal superfusion with 5 - HT2BR agonist BW 723C86 in nerve-ligated rats was impeded by co-administration of DB01221 receptor ( NMDAR ) antagonist D-AP 5 , but not by Q13255 REA / 5 antagonist Q96BJ3 or Q14416 REA / 3 antagonist LY 341495 . Evoked potentials were increased by cis-ACPD in nerve-injured rats , irrespective of simultaneous 5 - HT2BR blockade by SB204741 . In uninjured rats , NMDAR agonist cis-ACPD enhanced evoked potentials in the presence of BW 723C86 but not if administered alone or during exposure to protein kinase C γ ( PKCγ ) inhibitor peptide . Triple immunofluorescence labelings revealed co-localization of NMDAR and 5 - HT2BR in PKCγ-expressing perikarya in lamina II neurons . As a result of Q16658 REA , PKCγ was transiently and bilaterally up-regulated in synaptic fraction from dorsal horn homogenates , peaking at day 2 and returning to basal levels by day 9 . Chronic blockade of 5 - HT2BR with selective antagonist SB 204741 after Q16658 REA bilaterally decreased the following : ( i ) PKCγ up-regulation in synaptic fraction , ( ii ) phosphorylation of NMDAR subunit Q9UHB4 ( serine 889 ) in synaptic fraction , and ( iii ) co-localization of both PKCγ and phosphorylated Q9UHB4 with postsynaptic marker P78352 REA . Chronic delivery of SB 204741 bilaterally attenuated thermal and mechanical allodynia occurring after Q16658 REA , particularly at day 2 post injury . These findings suggest that transient activation of the PKCγ / NMDAR pathway is critically involved in 5 - HT2BR - mediated facilitation in the Q16658 REA model of neuropathic pain .

Pro-fibrogenic potential of Q9GZP0 in liver fibrosis . BACKGROUND / AIMS : We analyzed the expression of platelet-derived growth factor D ( Q9GZP0 ) in an experimental bile duct-ligated ( BDL ) rat model and assessed its biological function in cultured hepatic stellate cells ( P19526 REA ) and myofibroblasts ( MFB ) . METHODS : The mRNA for PDGF-A , - B , - C , - D and for PDGF receptor-alpha and - beta chains ( PDGFRalpha and PDGFRbeta ) in normal and fibrotic rat livers was assessed quantitatively . Protein levels of Q9GZP0 were quantified by immunoblotting and immunohistochemistry . RESULTS : The relative mRNA expression of all PDGF isoforms and receptors upregulated upon BDL and PDGF-A , - B and - D expression was significantly higher than that of Q9NRA1 . Q9GZP0 and PDGFRbeta protein also increased markedly . Immunostaining revealed that Q9GZP0 is localized along the fibrotic septa of the periportal - and perisinusoidal areas . Besides PDGF-B , Q9GZP0 is the second most potent PDGF isoform in PDGFRbeta signaling within P19526 REA / MFB , evidenced by PDGFRbeta autophosphorylation and activation of the downstream signaling molecules P27361 REA / 2 - , JNK - , p38 MAPK , and P31749 REA / Akt while Q9NRA1 effects were minimal . Q9GZP0 exerted mitogenic and fibrogenic effects in both cultured P19526 REA and MFB comparable to PDGF-B but PDGF-A and - C showed only marginal fibrogenic effects . CONCLUSIONS : Q9GZP0 possesses potential pathogenetic properties for P19526 REA activation and matrix remodeling in liver fibrosis .

Effects of 1 - beta-D-arabinofuranosylcytosine incorporation on elongation of specific DNA sequences by P06746 REA . DB00987 MEN ( ara-C ) is an effective antileukemic agent which acts as an inhibitor of DNA synthesis . The precise mechanism responsible for this inhibitory effect , however , remains unclear . The present work has examined the effects of the triphosphate derivative , ara - P53007 REA , on purified P06746 REA . These studies were performed on M13 phage DNA templates of defined sequence . The results demonstrate that ara-C is incorporated into DNA by P06746 REA . The results also demonstrate that the incorporated ara-C residue acts as a relative chain terminator . Moreover , the relative chain terminating effects of ara-C are sequence specific . In this regard , DNA strand elongation was progressively slowed at sequences of two , three , and four contiguous sites for cytosine incorporation . We also demonstrate that the inhibitory effects of ara-C are reversed by competition with deoxycytidine-triphosphate for incorporation into the DNA strand . Taken together , these findings are consistent with structural differences of the incorporated arabinosyl moiety which alter reactivity of the 3 ' - terminus and thereby inhibit chain elongation . These findings also provide new insights regarding the inhibitory effects of ara-C on elongation of specific DNA sequences .

Exendin - 4 stimulates islet cell replication via the IGF 1 receptor activation of mTORC 1 / P23443 REA . P43220 REA ( P43220 REA ) agonists , such as exendin - 4 , potentiate glucose-stimulated insulin secretion and are currently used in the management of type 2 diabetes . Interestingly , P43220 REA agonists also have the ability to augment β-cell mass . In this report , we provide evidence that in the presence of glucose , exendin - 4 stimulates rodent islet cell DNA replication via the activation of ribosomal protein S6 kinase 1 ( P23443 REA ) and that this is mediated by the protein kinase B ( P31749 REA ) - dependent activation of P42345 REA complex 1 ( mTORC 1 ) . We show that activation of this pathway is caused by the autocrine or paracrine activation of the IGF 1 receptor ( P08069 REA ) , as siRNA-mediated knockdown of the P08069 REA effectively blocked exendin - 4 - stimulated P31749 REA and mTORC 1 activation . In contrast , pharmacological inactivation of the epidermal growth factor receptor has no discernible effect on exendin - 4 - stimulated P31749 REA or mTORC 1 activation . Therefore , we conclude that P43220 REA agonists stimulate β-cell proliferation via the P31749 REA - dependent stimulation of mTORC 1 / P23443 REA whose activation is mediated through the autocrine / paracrine activation of the P08069 REA . This work provides a better understanding of the molecular basis of GLP 1 agonist-induced β-cell proliferation which could potentially be exploited in the identification of novel drug targets that increase β-cell mass .

5 - hydroxytryptamine 2B receptor regulates cell-cycle progression : cross-talk with tyrosine kinase pathways . In this paper , we present evidence that activation of 5 - hydroxytryptamine 2B ( P41595 REA ) receptors by serotonin ( 5 - HT ) leads to cell-cycle progression through retinoblastoma protein hyperphosphorylation and through activation of both cyclin D1 / cdk 4 and cyclin E / cdk 2 kinases by a mechanism that depends on induction of cyclin D1 and cyclin E protein levels . The induction of cyclin D1 expression , but not that of cyclin E , is under mitogen-activated protein kinase ( MAPK ) control , indicating an independent regulation of these two cyclins in the P41595 REA receptor mitogenesis . Moreover , by using the specific platelet-derived growth factor receptor ( P09619 REA ) inhibitor AG 1296 or by overexpressing a kinase-mutant P09619 REA , we show that P09619 REA kinase activity is essential for P41595 REA - triggered MAPK / cyclin D1 , but not cyclin E , signaling pathways . P41595 REA receptor activation also increases activity of the Src family kinase , c-Src , Fyn , and c-Yes . Strikingly , c-Src , but not Fyn or c-Yes , is the crucial molecule between the G ( q ) protein-coupled P41595 REA receptor and the cell-cycle regulators . Inhibition of c-Src activity by 4 - amino - 5 - ( 4 - methylphenyl ) - 7 - ( t-butyl ) pyrazolo [ 3,4- d ] pyrimidine ( P50391 REA ) or depletion of c-Src is sufficient to abolish the 5 - HT-induced ( i ) P09619 REA tyrosine kinase phosphorylation and MAPK activation , ( ii ) cyclin D1 and cyclin E expression levels , and ( iii ) thymidine incorporation . This paper elucidates a model of P41595 REA receptor mitogenesis in which c-Src acts alone to control cyclin E induction and in concert with the receptor tyrosine kinase P09619 REA to induce cyclin D1 expression via the MAPK / P29323 REA pathway .

Proapoptotic and antiproliferative potential of selective cyclooxygenase - 2 inhibitors in human liver tumor cells . Recent studies have shown increased levels of cyclooxygenase - 2 ( P35354 REA ) in a variety of human malignancies , including hepatocellular carcinoma ( HCC ) , but so far it is unknown whether P35354 REA contributes to the malignant growth and whether inhibition of P35354 REA function modifies the malignant potential of liver tumors . P23219 REA and P35354 REA expression was determined in 4 liver tumor cell lines ( Hep 3B , HuH - 7 , Hep G2 , Sk-hep 1 ) by Northern hybridization and Western immunoblot . The functional effects of the nonselective inhibitor sulindac sulfide and the P35354 REA selective inhibitors SC - 58635 and meloxicam were examined by 3 ( 4,5- dimethylthiazol - 2 - yl ) -2,5- diphenyl tetrazoliumbromide ( MTT ) - assays and BrdU uptake , morphology , and TUNEL analysis of apoptosis . Apoptosis regulating proteins were analyzed by Western immunoblot . P23219 REA and P35354 REA expression was demonstrable in all tested liver tumor cell lines . Sulindac sulfide ( 50 to 400 micromol / L ) , SC - 58635 ( 6,25 to 400 micromol / L ) , and meloxicam ( 6.25 to 400 micromol / L ) led to a significant time - and dose-dependent reduction of cell numbers of up to 80 % ( P < . 05 ) . At equimolar concentrations the effect was more pronounced when P35354 REA was selectively blocked . P35354 REA inhibition induced apoptosis and reduced tumor cell proliferation . Apoptosis after P35354 REA inhibition with SC - 58635 ( 50 micromol / L ) was independent of BCL - 2 , Q07812 REA , and the phosphorylation status of AKT / P31749 REA and Q92934 REA , but correlated with activation of caspase - 9 , caspase - 3 , and caspase - 6 . In conclusion , selective inhibition of P35354 REA leads to a marked growth inhibition of human liver tumor cells , based on the induction of apoptosis and inhibition of proliferation and , thus , may offer therapeutic and preventive potential in human hepatocarcinogenesis .

Effects on thrombin generation of single injections of DB02351 MEN in patients with calf vein thrombosis . STUDY OBJECTIVE : To determine whether single injections of DB02351 MEN , a direct thrombin inhibitor , can inhibit thrombin generation in patients with calf vein thrombosis and , if so , if the inhibition is sustained . DESIGN : Phase II open label cohort study . SETTING : Tertiary-care referral centres , university affiliated hospitals . PATIENTS : 10 patients with venographically-demonstrated calf vein thrombosis . INTERVENTION : Patients received a single injection of DB02351 MEN , either 1.0 mg / kg subcutaneously or 0.6 mg / kg as a 15 min intravenous infusion . P00734 REA fragment ( F1 + + 2 ) levels , as an index of thrombin generation , were measured before as well as 6 h post - and 24 h post - DB02351 MEN administration . Patients were followed with non-invasive tests to detect thrombus extension into the proximal veins . RESULTS : There was a significant reduction in the levels of F1 + 2 with both regimens , 6 h after DB02351 MEN . The F1 + 2 levels 24 h post - DB02351 MEN showed a significant increase relative to the 6 h post - DB02351 MEN results . One patient developed thrombus extension into the popliteal vein and was treated with conventional anticoagulants . CONCLUSION : The single injections of DB02351 MEN used in the study produced incomplete and temporary suppression of F1 + 2 . Complete and permanent inhibition of thrombin generation with DB02351 MEN in patients with calf vein thrombosis may require higher doses , multiple subcutaneous injections and / or prolonged intravenous infusion .