MH_dev_153

Q99717 REA regulates Akt 2 expression and insulin-induced glucose uptake in Q9BTT4 myotubes . P01308 REA - induced glucose uptake by skeletal muscle results from Akt 2 activation and is severely impaired during insulin resistance . Recently , we and others have demonstrated that Q9UK05 improves glucose homeostasis in diabetic and non-diabetic rodents . However , the mechanism by which Q9UK05 modulates insulin action remains unknown . Here we demonstrate that Q99717 REA , a transcription factor activated by Q9UK05 , and Akt 2 , are upregulated in differentiated Q9BTT4 myotubes . Q99717 REA , rather than Q15797 REA /8 , is downregulated " in vivo " and " in vitro " by dexamethasone . Q99717 REA knockdown decreased Akt 2 expression and serine phosphorylation and insulin-induced glucose uptake , and increased the expression of the lipid phosphatase Ship 2 . Additionally , binding of Q99717 REA to Akt 2 gene is decreased in dexamethasone-treated rats and increased in Q9BTT4 myotubes compared to myoblasts . The present study indicates that Q99717 REA regulates glucose uptake in skeletal muscle by controlling Akt 2 expression and phosphorylation . These finding reveals Q99717 REA as a potential target for the therapeutic of type 2 diabetes .

Suppression of NF-kappaB activity by sulfasalazine is mediated by direct inhibition of IkappaB kinases alpha and beta . BACKGROUND & AIMS : Activation of NF-kappaB / Rel has been implicated in the pathogenesis of inflammatory bowel disease ( Q9UKU7 ) . Various drugs used in the treatment of Q9UKU7 , such as glucocorticoids , DB00244 , and sulfasalazine , interfere with NF-kappaB / Rel signaling . The aim of this study was to define the molecular mechanism by which sulfasalazine inhibits NF-kappaB activation . METHODS : The effects of sulfasalazine and its moieties on NF-kappaB signaling were evaluated using electromobility shift , transfection , and immune complex kinase assays . The direct effect of sulfasalazine on O15111 REA ( IKK ) activity was investigated using purified recombinant O15111 REA and - beta proteins . RESULTS : NF-kappaB / Rel activity induced by tumor necrosis factor alpha , 12 - O-tetradecanoylphorbol - 13 - acetate , or overexpression of NF-kappaB-inducing kinase , O15111 REA , O14920 REA , or constitutively active O15111 REA and O14920 REA mutants was inhibited dose dependently by sulfasalazine . Sulfasalazine inhibited tumor necrosis factor alpha-induced activation of endogenous IKK in Jurkat T cells and SW620 colon cells , as well as the catalytic activity of purified O15111 REA and O14920 REA in vitro . In contrast , the moieties of sulfasalazine , DB00244 , and sulfapyridine or DB00233 MEN had no effect . Activation of extracellular signal-related kinase ( P29323 REA ) 1 and 2 , c-Jun-N-terminal kinase ( JNK ) 1 , and p38 was unaffected by sulfasalazine . The decrease in substrate phosphorylation by O15111 REA and - beta is associated with a decrease in autophosphorylation of IKKs and can be antagonized by excess adenosine triphosphate . CONCLUSIONS : These data identify sulfasalazine as a direct inhibitor of O15111 REA and - beta by antagonizing adenosine triphosphate binding . The suppression of NF-kappaB activation by inhibition of the IKKs contributes to the well-known anti-inflammatory and immunosuppressive effects of sulfasalazine .

Long-term follow-up after cyclophosphamide and cyclosporine-A therapy in steroid-dependent and - resistant nephrotic syndrome . A retrospective study was made on 37 children with idiopathic nephrotic syndrome ( P01308 REA ) . At the beginning , all patients were steroid sensitive but received more than one steroid course ( median 4 ) . Following several relapses , they became steroid dependent or steroid resistant . Group 1 consisted of 22 children [ 3 focal segmental glomerulosclerosis ( FSGS ) , 19 minimal-change NS ( MCNS ) ] who received cyclophosphamide ( CP ) orally for 2.5 + / - 0.5 months . Group 2 consisted of 15 children ( 7 FSGS , 8 MCNS ) who received cyclosporine-A ( Q13216 REA ) for 28 + / - 15 months . The level of proteinuria decreased significantly and remained low during the follow-up . The relapse-free period was significantly longer in the CP group ( CP 30 + / - 21.5 ; Q13216 REA 26.2 + / - 18 months , p < 0.001 ) . The relapse rate decreased significantly in both groups and remained in this lower level during the follow-up ( from 3.4 + / - 2.8 to 0.1 + / - 0.2 / year in group 1 , and from 3.7 + / - 3.1 to 0.6 + / - 0.8 / year in group 2 ) . At the end of the 5 - year follow-up , 20/22 patients ( 90.9 % ) and 10/15 patients ( 66.6 % ) were in remission in groups 1 and 2 respectively , with or without treatment ( p < 0.05 ) . In the long term , both CP and Q13216 REA is effective second-line therapy following steroid monotherapy in P01308 REA patients , but the relapse rate was lower and the relapse free period was significantly longer in the CP-treated group .

Constructing glucagon like peptide - 1 receptor fused with derivatives of GFP for visualizing protein-protein interaction in living cells . The glucagon-like peptide - 1 receptor ( P43220 REA ) mediates important antidiabetogenic effects on peripheral tissues . It appears to be one of the most promising therapeutic targets for treatment of diabetes mellitus type 2 . Surprisingly , very little is known about the cellular mechanisms that regulate receptor function in living cells . One of the approaches how to study receptor dynamics is by using tagged fluorescent proteins . In this study , YFP-tagged P0C6A0 ( YFP - P0C6A0 ) receptor and P27918 REA - tagged P0C6A0 ( P27918 REA - P0C6A0 ) receptor for visualizing protein-protein interaction in living cells were constructed and localized in CHO cells . Cells expressing YFP - P0C6A0 and P27918 REA - P43220 REA showed characteristic P0C6A0 mediated increase in DB02527 , similar to cells expressing a wild type P43220 REA . This means that both types of receptors are functional and localized in plasma membrane .

Impaired MEK signaling and SERCA expression promote ER stress and apoptosis in insulin-resistant macrophages and are reversed by exenatide treatment . Accumulation of toxic lipids evokes the unfolded protein response ( UPR ) and apoptotic death of macrophages and vascular cells in atherosclerotic plaques . Primary macrophages from insulin-resistant ob / ob and insulin receptor ( Insr ) ( - / - ) mice display increased apoptosis in response to loading with free cholesterol or oxysterol , but underlying mechanisms have not been elucidated . We show increased activation of all three major branches of the UPR in response to free cholesterol or oxysterol loading in insulin-resistant macrophages . Inhibition and rescue experiments revealed that defective MEK / extracellular signal \ x { 2013 } related kinase ( P29323 REA ) / DB02527 - responsive element-binding protein ( CREBP ) signaling in insulin-resistant macrophages leads to decreased expression of sarcoplasmic endoplasmic reticulum ( ER ) Ca ( 2 + ) - ATPase , depletion of ER calcium stores , P19525 REA - like ER kinase activation , and ER stress-associated apoptosis . Activation of macrophage glucagon-like peptide 1 ( P0C6A0 ) receptor via the antidiabetic drug exenatide led to improvements in both P29323 REA and AKT signaling and reversed the increase in UPR and apoptosis of insulin-resistant macrophages in atherosclerotic lesions of ob / ob.Ldlr ( - / - ) and Insr ( - / - ) . Ldlr ( - / - ) mice . Increased signaling via P43220 REA or the CREBP activator protein kinase A thus offers a way to rescue insulin-resistant macrophages from excessive ER stress responses and apoptosis in insulin resistance and type 2 diabetes .

Neuroprotective effect of the glucagon-like peptide - 1 receptor agonist , synthetic exendin - 4 , in streptozotocin-induced diabetic rats . BACKGROUND AND PURPOSE : Glucagon-like peptide - 1 ( P0C6A0 ) receptors are widely expressed in neural tissues and diminish neuronal degeneration or induce neuronal differentiation . The aim of this study was to investigate the effect of the P0C6A0 pathway on peripheral nerves in streptozotocin-induced diabetic rats . EXPERIMENTAL APPROACH : Diabetic and nondiabetic rats were treated with the P43220 REA agonist , synthetic exendin - 4 ( i . p . , 1 nmol · kg ( - 1 ) · day ( - 1 ) ) or placebo for 24 weeks , and current perception threshold values , DB02527 levels and nerve fibre size in the sciatic nerve were measured . We also investigated P43220 REA expression , quantitative changes in P09936 REA - positive intraepidermal nerve fibres and cleaved caspase 3 - stained Schwann cells by immunohistochemistry . KEY RESULTS : P43220 REA expression was detected in the sciatic nerve and skin . After exendin - 4 treatment , the increase seen in current perception threshold values at 2000 and 250 Hz in diabetic rats was reduced . Also , the decrease in myelinated fibre size or axon / fibre area ratio in the sciatic nerve and the loss of intraepidermal nerve fibre in the skin of diabetic rats were ameliorated . These responses were closely associated with the attenuation of Schwann cell apoptosis and improvement in the DB02527 level in exendin - 4 - treated diabetic rats , compared with placebo-treated animals . CONCLUSION AND IMPLICATIONS : DB01276 SUB may prevent peripheral nerve degeneration induced by diabetes in an animal model , supporting the hypothesis that P0C6A0 may be useful in peripheral neuropathy . The neuroprotection is probably attributable to P43220 REA activation , antiapoptotic effects and restoration of DB02527 content .

Glucagon-like peptide - 1 inhibits adipose tissue macrophage infiltration and inflammation in an obese mouse model of diabetes . AIMS / HYPOTHESIS : Obesity and insulin resistance are associated with low-grade chronic inflammation . Glucagon-like peptide - 1 ( P0C6A0 ) is known to reduce insulin resistance . We investigated whether P0C6A0 has anti-inflammatory effects on adipose tissue , including adipocytes and adipose tissue macrophages ( Q13315 REA ) . METHODS : We administered a recombinant adenovirus ( rAd ) producing P0C6A0 ( rAd - P0C6A0 ) to an ob / ob mouse model of diabetes . We examined insulin sensitivity , body fat mass , the infiltration of Q13315 REA and metabolic profiles . We analysed the mRNA expression of inflammatory cytokines , lipogenic genes , and M1 and M2 macrophage-specific genes in adipose tissue by real-time quantitative PCR . We also examined the activation of nuclear factor κB ( NF-κB ) , extracellular signal-regulated kinase 1/2 and Jun N-terminal kinase ( JNK ) in vivo and in vitro . RESULTS : Fat mass , adipocyte size and mRNA expression of lipogenic genes were significantly reduced in adipose tissue of rAd - P0C6A0 - treated ob / ob mice . Macrophage populations ( F4 /8 0 ( + ) and F4 /8 0 ( + ) CD11b ( + ) CD11c ( + ) cells ) , as well as the expression and production of P05231 REA , P01375 REA - α and monocyte chemoattractant protein - 1 , were significantly reduced in adipose tissue of rAd - P0C6A0 - treated ob / ob mice . Expression of M1 - specific mRNAs was significantly reduced , but that of M2 - specific mRNAs was unchanged in rAd - P0C6A0 - treated ob / ob mice . NF-κB and JNK activation was significantly reduced in adipose tissue of rAd - P0C6A0 - treated ob / ob mice . Lipopolysaccharide-induced inflammation was reduced by the P43220 REA agonist , exendin - 4 , in 3T3 - Q9NUQ9 adipocytes and Q13315 REA . CONCLUSIONS / INTERPRETATION : We suggest that P0C6A0 reduces macrophage infiltration and directly inhibits inflammatory pathways in adipocytes and Q13315 REA , possibly contributing to the improvement of insulin sensitivity .

Molecular physiology of glucagon-like peptide - 1 insulin secretagogue action in pancreatic β cells . P01308 REA secretion from pancreatic β cells is stimulated by glucagon-like peptide - 1 ( P0C6A0 ) , a blood glucose-lowering hormone that is released from enteroendocrine L cells of the distal intestine after the ingestion of a meal . P0C6A0 mimetics ( e . g . , DB01276 SUB ) and P0C6A0 analogs ( e . g . , DB06655 ) activate the β cell P43220 REA ( P43220 REA ) , and these compounds stimulate insulin secretion while also lowering levels of blood glucose in patients diagnosed with type 2 diabetes mellitus ( T2DM ) . An additional option for the treatment of T2DM involves the administration of dipeptidyl peptidase-IV ( DPP-IV ) inhibitors ( e . g . , Januvia , DB04876 ) . These compounds slow metabolic degradation of intestinally released P0C6A0 , thereby raising post-prandial levels of circulating P0C6A0 substantially . Investigational compounds that stimulate P0C6A0 secretion also exist , and in this regard a noteworthy advance is the demonstration that small molecule Q8TDV5 agonists ( e . g . , AR231453 ) stimulate L cell P0C6A0 secretion while also directly stimulating β cell insulin release . In this review , we summarize what is currently known concerning the signal transduction properties of the β cell P43220 REA as they relate to insulin secretion . Emphasized are the cyclic AMP , protein kinase A , and Epac 2 - mediated actions of P0C6A0 to regulate DB00171 - sensitive K ⁺ channels , voltage-dependent K ⁺ channels , O94759 REA cation channels , intracellular Ca ⁺ release channels , and Ca ⁺ - dependent exocytosis . We also discuss new evidence that provides a conceptual framework with which to understand why P43220 REA agonists are less likely to induce hypoglycemia when they are administered for the treatment of T2DM .

The development of DB01276 SUB ( exenatide ) from the venom of the Gila monster as an anti-diabetic agent . The development of DB01276 SUB ( synthetic exendin - 4 ; exenatide ) as a treatment of diabetes arose from two , parallel lines of investigation . The development of the ' incretin concept ' which hypothesised that hormones from the gut contributed to the insulin secretion in response to meals , led to the identification of glucagon-like peptide 1 ( P0C6A0 ) as an important ' incretin ' hormone . P0C6A0 not only increases insulin secretion but increases β-cell proliferation and survival , suppresses glucagon secretion , delays gastric emptying and suppresses appetite , all of these actions contributing to a potential anti-diabetic effect . However , P0C6A0 has a very short half due to its rapid breakdown by dipeptidyl peptidase IV and ectopeptidases . A systematic investigation of the composition and activity of venom from the Gila monster , Heloderma suspectum , led to the isolation of a 39 - amino acid peptide , designated exendin - 4 , showing 53 % structural homology with P0C6A0 ( 7-36 ) . Exendin - 4 mimicked P0C6A0 through stimulating the P43220 REA . The much greater stability of exendin - 4 led to its experimental and clinical evaluation as an anti-diabetic agent and its introduction to the market in 2005 .

Class I HDACs are mediators of smoke carcinogen-induced stabilization of P26358 REA and serve as promising targets for chemoprevention of lung cancer . DNA methylation is an early event in bronchial carcinogenesis and increased DNA methyltransferase ( P26358 REA ) 1 protein expression is a crucial step in the oncogenic transformation of epithelia . Here , we investigate the role of class I histone deacetylases ( HDAC ) 1 to 3 in the stabilization of P26358 REA protein and as a potential therapeutic target for lung cancer chemoprevention . Long-term exposure of immortalized bronchial epithelial cells ( HBEC - 3KT ) to low doses of tobacco-related carcinogens led to oncogenic transformation , increased HDAC expression , cell-cycle independent increased P26358 REA stability , and DNA hypermethylation . Overexpression of HDACs was associated with increased P26358 REA stability and knockdown of HDACs reduced P26358 REA protein levels and induced P26358 REA acetylation . This suggests a causal relationship among increased class I HDACs levels , upregulation of P26358 REA protein , and subsequent promoter hypermethylation . Targeting of class I HDACs with valproic acid ( DB00313 MEN ) was associated with reduced HDAC expression and a profound reduction of P26358 REA protein level . Treatment of transformed bronchial epithelial cells with DB00313 MEN resulted in reduced colony formation , demethylation of the aberrantly methylated Q96HF1 promoter , and derepression of Q96HF1 transcription . These data suggest that inhibition of HDAC activity may reverse or prevent carcinogen-induced transformation . Finally , immunohistochemistry on human lung cancer specimens revealed a significant increase in P26358 REA , Q13547 REA , Q92769 REA , and O15379 REA expression , supporting our hypotheses that class I HDACs are mediators of P26358 REA stability . In summary , our study provides evidence for an important role of class I HDACs in controlling the stability of P26358 REA and suggests that HDAC inhibition could be an attractive approach for lung cancer chemoprevention .

P01308 REA signal transduction pathways and insulin-induced gene expression . P01308 REA regulates metabolic activity , gene transcription , and cell growth by modulating the activity of several intracellular signaling pathways . P01308 REA activation of one mitogen-activated protein kinase cascade , the MEK / P29323 REA kinase cascade , is well described . However , the effect of insulin on the parallel p38 pathway is less well understood . The present work examines the effect of inhibiting the p38 signaling pathway by use of specific inhibitors , either alone or in combination with insulin , on the activation of P27361 REA / 2 and on the regulation of gene transcription in rat hepatoma cells . Activation of P27361 REA / 2 was induced by insulin and was dependent on the activation of Q02750 REA , the kinase upstream of P29323 REA in this pathway . Treatment of cells with p38 inhibitors also induced P27361 REA / 2 activation / phosphorylation . The addition of p38 inhibitors followed by insulin addition resulted in a greater than additive activation of P27361 REA / 2 . The two genes studied , c-Fos and Pip 92 , are immediate-early genes that are dependent on the P27361 REA / 2 pathway for insulin-regulated induction because the insulin effect was inhibited by pretreatment with a Q02750 REA inhibitor . The addition of p38 inhibitors induced transcription of both genes in a dose-dependent manner , and insulin stimulation of both genes was enhanced by prior treatment with p38 inhibitors . The ability of the p38 inhibitors to induce P27361 REA / 2 and gene transcription , both alone and in combination with insulin , was abolished by prior inhibition of Q02750 REA . These data suggest possible cross-talk between the p38 and P27361 REA / 2 signaling pathways and a potential role of p38 in insulin signaling .

[ DB01276 SUB : first once weekly P43220 REA agonist ( exenatide P10586 REA ) ] . DB01276 SUB is a new galenic formulation ( long-acting release ) of exenatide , the first agonist of Glucagon-Like Peptide - 1 ( P0C6A0 ) receptors having been commercialized for the management of type 2 diabetes . The microsphere technology permits a prolonged absorption of exenatide from the subcutaneous depot , which allows one injection per week instead of two injections per day with the initial formulation of exenatide ( DB01276 SUB ) . The clinical development programme DURATION showed that exenatide 2 mg once weekly more markedly reduces glycated haemoglobin ( HbA ( 1c ) ) , with a similar weight loss but a better digestive tolerance profile ( less nausea and vomiting after treatment initiation ) , compared with the twice daily 10 microg exenatide . When compared to other glucose-lowering agents , once weekly exenatide is more efficacious than sitagliptin , pioglitazone or basal insulin ( glargine or detemir ) , with the advantage of producing weight loss and lowering arterial blood pressure . It does not induce hypoglycaemia and does not necessarily require home blood glucose monitoring , two advantages compared with insulin therapy . DB01276 SUB is currently only reimbursed in Belgium after failure of and in addition to metformin-sulfonylurea combination .

A novel pathway links oxidative stress to loss of insulin growth factor - 2 ( P01344 REA ) imprinting through NF-κB activation . Genomic imprinting is the allele-specific expression of a gene based on parental origin . Loss of imprinting ( LOI ) of P01308 REA - like Growth Factor 2 ( P01344 REA ) during aging is important in tumorigenesis , yet the regulatory mechanisms driving this event are largely unknown . In this study oxidative stress , measured by increased NF-κB activity , induces LOI in both cancerous and noncancerous human prostate cells . Decreased expression of the enhancer-blocking element CCCTC-binding factor ( P49711 REA ) results in reduced binding of P49711 REA to the H19 - ICR ( imprint control region ) , a major factor in the allelic silencing of P01344 REA . This ICR then develops increased DNA methylation . Assays identify a recruitment of the canonical pathway proteins NF-κB p65 and p50 to the P49711 REA promoter associated with the co-repressor Q13547 REA explaining gene repression . An IκBα super-repressor blocks oxidative stress-induced activation of NF-κB and P01344 REA imprinting is maintained . In vivo experiments using IκBα mutant mice with continuous NF-κB activation demonstrate increased P01344 REA LOI further confirming a central role for canonical NF-κB signaling . We conclude P49711 REA plays a central role in mediating the effects of NF-κB activation that result in altered imprinting both in vitro and in vivo . This novel finding connects inflammation found in aging prostate tissues with the altered epigenetic landscape .

DB04868 MEN and MEK inhibitors induce synthetic lethality through paradoxical activation of RAF in drug-resistant chronic myeloid leukemia . We show that imatinib , nilotinib , and dasatinib possess weak off-target activity against RAF and , therefore , drive paradoxical activation of P15056 REA and CRAF in a DB01367 - dependent manner . Critically , because DB01367 is activated by P11274 REA - P00519 REA , in drug-resistant chronic myeloid leukemia ( CML ) cells , DB01367 activity persists in the presence of these drugs , driving paradoxical activation of P15056 REA , CRAF , MEK , and P29323 REA , and leading to an unexpected dependency on the pathway . Consequently , nilotinib synergizes with MEK inhibitors to kill drug-resistant CML cells and block tumor growth in mice . Thus , we show that imatinib , nilotinib , and dasatinib drive paradoxical RAF / MEK / P29323 REA pathway activation and have uncovered a synthetic lethal interaction that can be used to kill drug-resistant CML cells in vitro and in vivo .

HRAS 1 and P01308 REA genes are relocated but not structurally altered as a result of the t ( 7 ; 11 ) ( p15 ;p 15 ) in a clone from a patient with acute myeloid leukaemia ( M4 ) . A patient whose leukaemic cells carried the rare t ( 7 ; 11 ) ( p15 ;p 15 ) was diagnosed as having acute myelomonocytic leukaemia ( AML-M 4 ) , and supports the association of this specific translocation with forms of acute myeloid leukaemia showing differentiation . Blast phase chronic myeloid leukaemia was excluded by lack of involvement of the P00519 REA and P11274 REA genes . Chromosome in situ hybridization studies showed that both the HRAS 1 and P01308 REA genes were present on the terminal part of chromosome 11p which was translocated to chromosome 7p . Neither HRAS 1 nor P01308 REA were structurally rearranged . Field inversion gel electrophoresis showed that a 400 kb fragment encompassing HRAS 1 was structurally entire in leukaemic DNA . Because the P01308 REA gene , which was also translocated , is probably located proximal to HRAS 1 on chromosome 11p , it is unlikely that HRAS 1 was near the chromosome 11 breakpoint or involved in this leukaemia .

PEGylated exendin - 4 , a modified P0C6A0 analog exhibits more potent cardioprotection than its unmodified parent molecule on a dose to dose basis in a murine model of myocardial infarction . A Site-specifically PEGylated exendin - 4 ( denoted as PEG-Ex 4 ) is an exendin - 4 ( denoted as Ex4 ) analog we developed by site-specific PEGylation of exendin - 4 with a high molecular weight trimeric poly ( ethylene glycol ) ( tPEG ) . It has been shown to possess prolonged half-life in vivo with similar receptor binding affinity compared to unmodified exendin - 4 by our previous work . This study is sought to test whether PEG-Ex 4 is suitable for treating myocardial infarction ( MI ) . In the MI model , PEG-Ex 4 was administered every 3 days while equivalent amount of Ex4 was administered every 3 days or twice daily . Animal survival rate , heart function , remodeling and neoangiogenesis were evaluated and compared . Tube formation was examined in endothelial cells . In addition , Western blotting and histology were performed to determine the markers of cardiac hypertrophy and angiogenesis and to explore the possible molecular mechanism involved . PEG-Ex 4 and Ex4 showed comparable binding affinity to P43220 REA . In MI mice , PEG-Ex 4 given at 3 days interval achieved similar extent of protection as Ex4 given twice daily , while Ex4 given at 3 days interval failed to produce protection . PEG-Ex 4 elevated endothelial tube formation in vitro and capillary density in the border area of MI . PEG-Ex 4 increased Akt activity and P15692 REA production in a P43220 REA dependent manner in endothelial cells and antagonism of P43220 REA , Akt or P15692 REA abolished the protection of PEG-Ex 4 in the MI model . PEG-Ex 4 is a potent long-acting P43220 REA agonist for the treatment of chronic heart disease . Its protection might be attributed to enhanced angiogenesis mediated by the activation of Akt and P15692 REA .

P15056 REA inhibitors suppress apoptosis through off-target inhibition of JNK signaling . DB08881 MEN and dabrafenib selectively inhibit the P15056 REA ( P15056 REA ) kinase , resulting in high response rates and increased survival in melanoma . Approximately 22 % of individuals treated with vemurafenib develop cutaneous squamous cell carcinoma ( cSCC ) during therapy . The prevailing explanation for this is drug-induced paradoxical P29323 REA activation , resulting in hyperproliferation . Here we show an unexpected and novel effect of vemurafenib / PLX 4720 in suppressing apoptosis through the inhibition of multiple off-target kinases upstream of c-Jun N-terminal kinase ( JNK ) , principally Q9NYL2 . JNK signaling is suppressed in multiple contexts , including in cSCC of vemurafenib-treated patients , as well as in mice . Expression of a mutant Q9NYL2 that can not be inhibited reverses the suppression of JNK activation and apoptosis . Our results implicate suppression of JNK-dependent apoptosis as a significant , independent mechanism that cooperates with paradoxical P29323 REA activation to induce cSCC , suggesting broad implications for understanding toxicities associated with P15056 REA inhibitors and for their use in combination therapies . DOI : http://dx.doi.org/10.7554/eLife.00969.001 .

Identification of an acetylation-dependant P12956 REA / FLIP complex that regulates FLIP expression and HDAC inhibitor-induced apoptosis . FLIP is a potential anti-cancer therapeutic target that inhibits apoptosis by blocking caspase 8 activation by death receptors . We report a novel interaction between FLIP and the DNA repair protein P12956 REA that regulates FLIP protein stability by inhibiting its polyubiquitination . Furthermore , we found that the histone deacetylase ( HDAC ) inhibitor DB02546 MEN ( DB02546 MEN ) enhances the acetylation of P12956 REA , thereby disrupting the FLIP / P12956 REA complex and triggering FLIP polyubiquitination and degradation by the proteasome . Using in vitro and in vivo colorectal cancer models , we further demonstrated that DB02546 MEN - induced apoptosis is dependant on FLIP downregulation and caspase 8 activation . In addition , an Q9UBN7 - specific inhibitor Tubacin recapitulated the effects of DB02546 MEN , suggesting that Q9UBN7 is a key regulator of P12956 REA acetylation and FLIP protein stability . Thus , HDAC inhibitors with anti - Q9UBN7 activity act as efficient post-transcriptional suppressors of FLIP expression and may , therefore , effectively act as ' FLIP inhibitors ' .

Regulation of Na + / H + exchanger P48764 REA by glucagon-like peptide 1 receptor agonist exendin - 4 in renal proximal tubule cells . The gut incretin hormone glucagon-like peptide 1 ( P0C6A0 ) is released in response to ingested nutrients and enhances insulin secretion . In addition to its insulinotropic properties , P0C6A0 has been shown to have natriuretic actions paralleled by a diminished proton secretion . We therefore studied the role of the P43220 REA agonist exendin - 4 in modulating the activity of Na ( + ) / H ( + ) exchanger P48764 REA in LLC-PK ( 1 ) cells . We found that P48764 REA - mediated Na ( + ) - dependent intracellular pH ( pH ( i ) ) recovery decreased approximately 50 % after 30 - min treatment with 1 nM exendin - 4 . Pharmacological inhibitors and DB02527 analogs that selectively activate protein kinase A ( PKA ) or the exchange protein directly activated by DB02527 ( O95398 REA ) demonstrated that regulation of P48764 REA activity by exendin - 4 requires activation of both DB02527 downstream effectors . This conclusion was based on the following observations : 1 ) the PKA antagonist H - 89 completely prevented the effect of the PKA activator but only partially blocked the exendin - 4 - induced P48764 REA inhibition ; 2 ) the Q02750 REA / 2 inhibitor U - 0126 abolished the effect of the O95398 REA activator but only diminished the exendin - 4 - induced P48764 REA inhibition ; 3 ) combination of H - 89 and U - 0126 fully prevented the effect of exendin - 4 on P48764 REA ; 4 ) no additive effect in the inhibition of P48764 REA activity was observed when exendin - 4 , PKA , and O95398 REA activators were used together . Mechanistically , the inhibitory effect of exendin - 4 on pH ( i ) recovery was associated with an increase of P48764 REA phosphorylation . Conversely , this inhibition took place without changes in the surface expression of the transporter . We conclude that P43220 REA agonists modulate sodium homeostasis in the kidney , most likely by affecting P48764 REA activity .

Histone deacetylase inhibitors increase microRNA - 146a expression and enhance negative regulation of interleukin - 1β signaling in osteoarthritis fibroblast-like synoviocytes . OBJECTIVE : MiR - 146a exerts negative control on inflammatory responses by suppressing cytokine-induced expression of interleukin - 1 receptor-associated kinase - 1 ( P51617 REA ) and tumor necrosis factor receptor-associated factor 6 ( Q9Y4K3 REA ) by impairing NF-κB activity and inhibiting the expression of target genes . Recent study suggests that histone deacetylases ( HDACs ) are involved in the regulation of microRNA ( miRNA ) expression . Therefore , we determined whether HDAC inhibitors can increase miR - 146a expression , thereby inhibiting interleukin - 1β ( IL - 1β ) - induced signaling in osteoarthritis fibroblast-like synoviocytes ( OA-FLS ) . METHOD : MiRNA expression was analyzed using real-time PCR . IL - 1β - induced downstream signals and cytokine expression were evaluated using Western blotting and ELISA . Transcription factors regulating promoter activation were identified using chromatin immunoprecipitation assays . RESULTS : IL - 1β treatment of OA-FLS induced a mild ( 1.7- fold ) increase in miR - 146a expression that was unable to appropriately downregulate P51617 REA and Q9Y4K3 REA expression . HDAC inhibitors , DB02546 MEN ( vorinostat ) , and LBH 589 ( DB06603 ) significantly ( 6.1- and 5.4- fold ) elevated miR - 146a expression by increasing the binding of the transcription factor NF-κB to the miR - 146a promoter , and negatively regulated IL - 1β - induced IKK / IκB / p65 phosphorylation signaling and P05231 REA secretion . The increase in miR - 146a expression induced by the HDAC inhibitors was prevented by transfection of miR - 146a inhibitor or Q13547 REA ( class I HDAC ) , P56524 REA ( class IIa HDAC ) , and Q9UBN7 ( class IIb HDAC ) overexpression , suggesting that they were due to inhibition of HDAC activity . CONCLUSIONS : Our study demonstrated that HDAC inhibitor treatment in OA-FLS significantly increased miR - 146a expression and mediated markedly negative regulation to inhibit IL - 1β - induced signaling and cytokine secretion . Our results indicate the potential rationale of anti-inflammatory effects for HDAC inhibitors .

Tumor suppressor function of P09936 REA is associated with epigenetic regulation in prostate cancer - - novel predictor of biochemical recurrence after radical surgery . BACKGROUND : The expression level of protein G product 9.5 ( P09936 REA ) is downregulated because of promoter CpG hypermethylation in several tumors . We speculated that impaired regulation of P09936 REA through epigenetic pathways is associated with the pathogenesis of prostate cancer . METHODS : CpG methylation of the P09936 REA gene was analyzed in cultured prostate cancer cell lines , 226 localized prostate cancer samples from radical prostatectomy cases , and 80 benign prostate hyperplasia ( BPH ) tissues . RESULTS : Following 5 - aza - 2 ' - deoxycytidune treatment , increased P09936 REA mRNA transcript expression was found in the LNCaP and PC3 cell lines . With bisulfite DNA sequencing , partial methylation of the P09936 REA promoter was shown in LNCaP whereas complete methylation was found in PC3 cells . After transfection of P09936 REA siRNA , cell viability was significantly accelerated in LNCaP but not in PC3 cells as compared with control siRNA transfection . Promoter methylation of P09936 REA was extremely low in only one of 80 BPH tissues , whereas it was found in 37 of 226 prostate cancer tissues . Expression of the mRNA transcript of P09936 REA was significantly lower in methylation ( + ) than methylation ( - ) prostate cancer tissues . Multivariate analysis of biochemical recurrence ( P11274 REA ) after an radical prostatectomy revealed pT category and P09936 REA methylation as prognostically relevant . Further stratification with the pT category in addition to methylation status identified a stepwise reduction of P11274 REA - free probability . CONCLUSION : This is the first clinical and comprehensive study of inactivation of the P09936 REA gene via epigenetic pathways in primary prostate cancer . Q9P2X3 REA : CpG methylation of P09936 REA in primary prostate cancer might become useful as a molecular marker for early clinical prediction of P11274 REA after radical prostatectomy .

Improvement of psoriasis during exenatide treatment in a patient with diabetes . CONTEXT AND AIM : Psoriasis is an immune-mediated skin disorder frequently associated with obesity and type 2 diabetes ( T2D ) . This report is of a clinically significant improvement in psoriasis lesions in a patient with T2D during treatment with a P43220 REA agonist ( exenatide ) . OBSERVATION : A 61 - year-old male patient ( BMI : 25.5 kg / m ( 2 ) ) with T2D treated with metformin and sulphonylureas had also complained , since 1980 , of extensive psoriasis that required multiple steroid-based treatments [ Psoriasis Area and Sensitivity Index ( PASI ) score : 11 ] . In September 2008 , his diabetes treatment was intensified with exenatide ( DB01276 SUB ( ® ) ) to improve poor glycaemic control . The patient , as expected , lost weight and reduced HbA ( 1c ) levels from 65 mmol / mol to 56 mmol / mol . However , after just 1 month of treatment with exenatide , the patient also reported a dramatic improvement in psoriatic plaques that was confirmed at the 1 - year follow-up ( PASI : estimated at 3-4 ) . Withdrawal of exenatide was associated with weight gain , deterioration of glycaemic control and deterioration of psoriasis ( PASI : > 10 ) . After reinstating exenatide treatment , the patient again reported a prompt improvement in psoriasis ( PASI : 3.1 ) . CONCLUSION : There was a major and rapid improvement in psoriasis in our patient with T2D following treatment with exenatide . A possible mechanism might be through direct modulation of the immune system by P43220 REA agonists .

Large-cell neuroendocrine carcinoma of the ampulla of Vater . Large-cell neuroendocrine carcinoma is a high-grade neuroendocrine carcinoma , originally described in the lung . The tumor rarely occurs in extrapulmonary sites like the gastrointestinal tract , and only few examples have been described in the ampulla of Vater . A new case of large-cell neuroendocrine carcinoma of the ampulla of Vater in a 60 - year-old man is reported . After pancreatoduodenectomy , macroscopic examination revealed ulcerated tumor in the region of the ampulla of Vater . Microscopically , the tumor exhibited organoid , predominantly nested growth pattern , consisting of large , polygonal cells with pleomorphic nuclei . Average number of mitoses was 36 per 10 high-power fields . Small and large areas of necrosis were identified . Immunohistochemically , the tumor cells were positive for synaptophysin , chromogranin A , P09936 REA , neuron-specific enolase , pancytokeratin , CK8 and somatostatin and negative for CK7 , CK20 , S - 100 , Q15669 REA - 1 , HMB - 45 , CD117 , P12830 REA and regulatory peptides . Ki - 67 proliferative index was 41 % . Histone deacetylase ( HDAC ) analysis showed almost identical results for Q13547 REA , Q92769 REA and O15379 REA - - 60 , 60.3 and 61 % , respectively . Two months after surgery , liver metastases occurred , confirming highly aggressive behavior of large-cell neuroendocrine carcinoma .

Novel P0C6A0 mimetics developed to treat type 2 diabetes promote progenitor cell proliferation in the brain . One of the symptoms of diabetes is the progressive development of neuropathies . One mechanism to replace neurons in the CNS is through the activation of stem cells and neuronal progenitor cells . We have tested the effects of the novel P0C6A0 mimetics exenatide ( exendin - 4 ; DB01276 SUB ) and liraglutide ( DB06655 ; DB06655 ) , which are already on the market as treatments for type 2 diabetes , on the proliferation rate of progenitor cells and differentiation into neurons in the dentate gyrus of brains of mouse models of diabetes . P0C6A0 analogues were injected subcutaneously for 4 , 6 , or 10 weeks once daily in three mouse models of diabetes : ob / ob mice , db / db mice , or high-fat-diet-fed mice . Twenty-four hours before perfusion , animals were injected with 5 ' - bromo - 2 ' - deoxyuridine ( BrdU ) to mark dividing progenitor cells . By using immunohistochemistry and stereological methods , the number of progenitor cells or doublecortin-positive young neurons in the dentate gyrus was estimated . We found that , in all three mouse models , progenitor cell division was enhanced compared with nondiabetic controls after chronic i . p . injection of either liraglutide or exendin - 4 by 100-150 % ( P < 0.001 ) . We also found an increase in young neurons in the DG of high-fat-diet-fed mice after drug treatment ( P < 0.001 ) . The P43220 REA antagonist exendin ( 9-36 ) reduced progenitor cell proliferation in these mice . The results demonstrate that P0C6A0 mimetics show promise as a treatment for neurodegenerative diseases such as Alzheimer ' s disease , because these novel drugs cross the blood-brain barrier and increase neuroneogenesis .

New insights into the role of DB02527 in the production and function of the incretin hormone glucagon-like peptide - 1 ( P0C6A0 ) . The proglucagon gene ( gcg ) encodes both glucagon and glucagon-like peptide - 1 ( P0C6A0 ) , produced in pancreatic alpha cells and intestinal endocrine L cells , respectively . The incretin hormone P0C6A0 stimulates insulin secretion and pro-insulin gene transcription . P0C6A0 also enhances pancreatic beta-cell proliferation , inhibits cell apoptosis , and has been utilized in the trans-differentiation of insulin producing cells . A long-term effective P43220 REA agonist , DB01276 SUB , has now been developed as the drug in treating type II diabetes and potentially other metabolic disorders . The expression of gcg and the production of P0C6A0 can be activated by the elevation of the second messenger cyclic AMP ( DB02527 ) . Recent studies suggest that in addition to protein kinase A ( PKA ) , exchange protein activated by DB02527 ( Epac ) , another effector of DB02527 , and the crosstalk between PKA and the Wnt signaling pathway , are involved in DB02527 - stimulated gcg transcription and P0C6A0 production as well . Finally , functions of P0C6A0 in pancreatic beta cells are also mediated by PKA , Epac , as well as the effector of the Wnt signaling pathway . Together , these novel findings bring us a new insight into the role of DB02527 in the production and function of the incretin hormone P0C6A0 .

Exenatide blocks P23458 REA - P42224 REA in pancreatic beta cells . Exenatide ( Ex - 4 ) is an antidiabetic drug that acts through the glucagon-like peptide 1 receptor and has recently been approved for the treatment of type 2 diabetes mellitus . Ex - 4 also has been shown to affect beta cell gene expression and increase beta cell mass in rodent models of type 1 diabetes mellitus , but the mechanisms are not fully understood . We therefore analyzed the pathways affected by Ex - 4 in human islets by using oligonucleotide microarrays and the PathwayStudio software ( Ariadne Genomics , Rockville , MD ) . We identified the P23458 REA - P42224 REA pathway as a novel target of Ex - 4 and confirmed the Ex - 4 - mediated down-regulation of P23458 REA and P42224 REA by quantitative reverse transcription-polymerase chain reaction in human islets and P01308 REA - 1 cells . P23458 REA - P42224 REA is the major signaling pathway mediating the interferon gamma effects on beta cell apoptosis in type 1 diabetes mellitus . Thus , these findings suggest that Ex - 4 treatment may also be beneficial in type 1 diabetes mellitus , where it may help protect beta cells from cytokine-induced cell death by inhibiting P23458 REA - P42224 REA .

Constitutive NF-kappaB activation confers interleukin 6 ( P05231 REA ) independence and resistance to dexamethasone and Janus kinase inhibitor DB08877 MEN in murine plasmacytoma cells . Myeloma cells are dependent on P05231 REA for their survival and proliferation during the early stages of disease , and independence from P05231 REA is associated with disease progression . The role of the NF-κB pathway in the P05231 REA - independent growth of myeloma cells has not been studied . Because human herpesvirus 8 - encoded P13646 REA selectively activates the NF-κB pathway , we have used it as a molecular tool to examine the ability of the NF-κB pathway to confer P05231 REA independence on murine plasmacytomas . We demonstrated that ectopic expression of P13646 REA , but not its NF-κB-defective mutant or a structural homolog , protected plasmacytomas against P05231 REA withdrawal-induced apoptosis and resulted in emergence of P05231 REA - independent clones that could proliferate long-term in vitro in the absence of P05231 REA and form abdominal plasmacytomas with visceral involvement when injected intraperitoneally into syngeneic mice . These P05231 REA - independent clones were dependent on NF-κB activity for their survival and proliferation but were resistant to dexamethasone and DB08877 MEN , a selective P23458 REA / 2 inhibitor . Ectopic expression of human T cell leukemia virus 1 - encoded Tax protein , which resembles P13646 REA in inducing constitutive NF-κB activation , similarly protected plasmacytoma cells against P05231 REA withdrawal-induced apoptosis . Although P13646 REA is known to up-regulate P05231 REA gene expression , its protective effect was not due to induction of endogenous P05231 REA production but instead was associated with sustained expression of several antiapoptotic members of the Bcl 2 family upon P05231 REA withdrawal . Collectively , these results demonstrate that NF-κB activation can not only promote the emergence of P05231 REA independence during myeloma progression but can also confer resistance to dexamethasone and DB08877 MEN .

Targeting eIF 4GI translation initiation factor affords an attractive therapeutic strategy in multiple myeloma . BACKGROUND : Deregulation of protein synthesis is integral to the malignant phenotype and translation initiation is the rate limiting stage . Therefore , eIF 4F translation initiation complex components are attractive therapeutic targets . METHODS : Protein lysates of myeloma cells ( cell lines / patients ' bone marrow samples ) untreated / treated with bevacizumab were assayed for eIF 4GI expression , regulation ( P15559 REA / proteosome dependent fragmentation ) ( WB , DB00266 MENMAX DB00266 MEN , qPCR ) and targets ( WB ) . eIF 4GI was inhibited by knockdown and 4EGI - 1 . Cells were tested for viability ( ELISA ) , death ( FACS ) and eIF 4GI targets ( WB ) . RESULTS : Previously , we have shown that manipulation of P15692 REA in myeloma cells attenuated P06730 REA dependent translation initiation . Here we assessed the significance of eIF 4GI to MM cells . We demonstrated increased expression of eIF 4GI in myeloma cells and its attenuation upon P15692 REA inhibition attributed to elevated P15559 REA / proteasome dependent fragmentation and diminished mRNA levels . Knockdown of eIF 4GI was deleterious to myeloma cells phenotype and expression of specific molecular targets ( Q99717 REA / ERα / HIF 1α / c-Myc ) . Finally , we showed that the small molecule 4EGI - 1 inhibits eIF 4GI and causes a reduction in expression of its molecular targets in myeloma . CONCLUSION : Our findings substantiate that translation initiation of particular targets in MM is contingent on the function of eIF 4GI , critical to cell phenotype , and mark it as a viable target for pharmacological intervention .

Influence of a 3 - day regimen of azithromycin on the disposition kinetics of cyclosporine A in stable renal transplant patients . Some macrolide antibiotics have been shown to produce significant drug-drug interactions through the inhibition of cytochrome P450 ( CYP ) enzymes . In renal transplant patients these interactions pose potentially serious problems for the safe administration of cyclosporine A ( Q13216 REA ) , a substrate of P08684 REA . The effects of azithromycin on Q13216 REA disposition kinetics were evaluated in eight stable renal transplant patients . Patients had been stabilized on individualized doses of Q13216 REA which remained unchanged throughout the study . DB00207 MEN was administered for 3 days . Baseline measurements of Q13216 REA disposition kinetics were taken prior to azithromycin treatment ( study day 2 ) and after 3 days ( study day 5 ) of azithromycin treatment ( 500mg / day , orally ) . The key parameters of interest were the area under the Q13216 REA blood concentration versus time curve ( AUC ) measured for 24h after the morning dose of Q13216 REA on both days 2 and 5 , and the C ( max ) values of Q13216 REA . The geometric mean ratios ( GMRs ) of those parameters ( day 5 / day 2 ) and their 90 % confidence intervals ( 90 % CI ) were 107 ( 98,116 ) and 119 ( 104,136 ) , respectively . The 7 % increase in exposure level and 19 % increase in peak plasma concentration are not likely to be clinically significant . It is concluded that azithromycin ( 500mg / dayx 3 days ) does not alter the disposition kinetics of Q13216 REA in a clinically significant way , and that Q13216 REA dosage adjustments are not warranted in renal transplant patients taking these two drugs together .

DB08877 MEN for the treatment of primary myelofibrosis . PURPOSE : The pharmacology , pharmacokinetics , pharmacogenomics , clinical efficacy , and safety profile of ruxolitinib for the treatment of primary myelofibrosis are reviewed . SUMMARY : DB08877 MEN , an oral tyrosine kinase inhibitor that targets the Janus-associated kinases ( JAKs ) 1 and 2 , has been recently approved for the treatment of patients with intermediate - or high-risk myelofibrosis . Unlike previous treatment options for patients with myelofibrosis , ruxolitinib offers a targeted therapy option for these patients who often suffer with severe and debilitating symptoms associated with the disease process . After oral administration , ruxolitinib is rapidly absorbed and can be given without regard to meals . DB08877 MEN is primarily metabolized by the cytochrome P - 450 ( CYP ) 3A4 isoenzyme system ; therefore , if concomitant use with a strong P08684 REA inhibitor is unavoidable , an initial dosage reduction is warranted . Two Phase III randomized trials comparing ruxolitinib to either placebo or best available therapy found a rapid and sustained response in the reduction of spleen size and improvements in constitutional symptoms and quality of life , with one study demonstrating an improvement in overall survival . The most commonly reported serious adverse effects of ruxolitinib are anemia and thrombocytopenia . DB08877 MEN is administered as an oral tablet given twice daily , with the initial starting dosage based on the baseline platelet count . Dosage reductions are based on the development of thrombocytopenia . CONCLUSION : By directly targeting both P23458 REA and O60674 REA through small-molecule inhibition , ruxolitinib elicits a reduction in splenomegaly and disease-related symptoms in patients with intermediate - or high-risk myelofibrosis while maintaining an acceptable toxicity profile and a low treatment-discontinuation rate .

Targeting Q01196 REA / Q06455 - histone deacetylase repressor complex : a novel mechanism for valproic acid-mediated gene expression and cellular differentiation in Q01196 REA / Q06455 - positive acute myeloid leukemia cells . In t (8 ; 21 ) acute myeloid leukemia ( AML ) , the Q01196 REA / Q06455 fusion protein promotes leukemogenesis by recruiting class I histone deacetylase ( HDAC ) - containing repressor complex to the promoter of Q01196 REA target genes . Valproic acid ( DB00313 MEN ) , a commonly used antiseizure and mood stabilizer drug , has been shown to cause growth arrest and induce differentiation of malignant cells via HDAC inhibition . DB00313 MEN causes selective proteasomal degradation of Q92769 REA but not other class I HDACs ( i . e . , HDAC 1 , 3 , and 8 ) . Therefore , we raised the question of whether this drug can effectively target the leukemogenic activity of the Q01196 REA / Q06455 fusion protein that also recruits Q13547 REA , a key regulator of normal and aberrant histone acetylation . We report here that DB00313 MEN treatment disrupts the Q01196 REA / Q06455 - Q13547 REA physical interaction , stimulates the global dissociation of Q01196 REA / Q06455 - Q13547 REA complex from the promoter of Q01196 REA / Q06455 target genes , and induces relocation of both Q01196 REA / Q06455 and Q13547 REA protein from nuclear to perinuclear region . Furthermore , we show that mechanistically these effects associate with a significant inhibition of HDAC activity , histone H3 and H4 hyperacetylation , and recruitment of RNA polymerase II , leading to transcriptional reactivation of target genes ( i . e . , P08700 REA ) otherwise silenced by Q01196 REA / Q06455 fusion protein . Ultimately , these pharmacological effects resulted in significant antileukemic activity mediated by partial cell differentiation and caspase-dependent apoptosis . Taken together , these data support the notion that DB00313 MEN might effectively target Q01196 REA / Q06455 - driven leukemogenesis through disruption of aberrant Q13547 REA function and that DB00313 MEN should be integrated in novel therapeutic approaches for Q01196 REA / Q06455 - positive AML .

Synergism between bosutinib ( DB06616 MEN ) and the Chk 1 inhibitor ( PF - 00477736 ) in highly imatinib-resistant P11274 REA / ABL ⁺ leukemia cells . Interactions between the dual P11274 REA / P00519 REA and Src inhibitor bosutinib and the Chk 1 inhibitor PF - 00477736 were examined in P11274 REA / P00519 REA ( + ) leukemia cells , particularly imatinib-resistant cells , including those with the T315I mutation . Bosutinib blocked PF - 00477736 - induced P27361 REA / 2 activation and sharply increased apoptosis in association with Mcl - 1 inhibition , p34 ( cdc 2 ) dephosphorylation , BimEL up-regulation , and DNA damage in imatinib-resistant CML or Ph ( + ) ALL cell lines . Inhibition of Src or Q02750 REA by shRNA significantly enhanced PF - 0047736 lethality . Bosutinib / PF - 00477736 co-treatment also potentiated cell death in P28906 REA ( + ) CML patient samples , including dasatinib-resistant blast crisis cells exhibiting both T315I and E355G mutations , but was minimally toxic to normal P28906 REA ( + ) cells . Finally , combined in vivo treatment significantly suppressed BaF 3 / T315I tumor growth and prolonged survival in an allogeneic mouse model . Together , these findings suggest that this targeted combination strategy warrants attention in IM-resistant CML or Ph ( + ) ALL .

Calorie restriction promotes mammalian cell survival by inducing the Q96EB6 deacetylase . A major cause of aging is thought to result from the cumulative effects of cell loss over time . In yeast , caloric restriction ( CR ) delays aging by activating the Sir 2 deacetylase . Here we show that expression of mammalian Sir 2 ( Q96EB6 ) is induced in CR rats as well as in human cells that are treated with serum from these animals . P01308 REA and insulin-like growth factor 1 ( DB01277 ) attenuated this response . Q96EB6 deacetylates the DNA repair factor P12956 REA , causing it to sequester the proapoptotic factor Bax away from mitochondria , thereby inhibiting stress-induced apoptotic cell death . Thus , CR could extend life-span by inducing Q96EB6 expression and promoting the long-term survival of irreplaceable cells .

Neonatal intramuscular injection of plasmid encoding glucagon-like peptide - 1 affects anxiety behaviour and expression of the hippocampal glucocorticoid receptor in adolescent rats . Early-life endocrine intervention may programme hippocampal glucocorticoid receptor ( GR ) expression and cause psychiatric disorders in later life . Glucagon-like peptide - 1 ( P0C6A0 ) has been implicated in the regulation of neuroendocrine and behavioural responses , but it is yet to be determined whether and how neonatal P0C6A0 overexpression may modify hippocampal GR expression and thus programme adolescent behaviour in rats . Two-day old pups were injected intramuscularly with vacant plasmid ( VP ) or plasmid DNA encoding secretory P0C6A0 ( GP ) . Anxiety-related behaviour was assessed in the elevated plus maze ( EPM ) test at 8 weeks of age . Plasma corticosterone levels were measured with enzyme immunoassay ( EIA ) . Protein and mRNA levels were determined by western blot and real-time polymerase chain reaction ( PCR ) , respectively . The DNA methylation status of the GR exon 1 ( 7 ) promoter was determined by bisulphate sequencing PCR ( BSP ) . GP rats exhibited anxiolytic behaviour compared with their VP counterparts . Hippocampal P43220 REA ( P43220 REA ) and GR mRNA expression were significantly elevated in GP rats without a significant difference in plasma corticosterone . Significant reduction in DNA methyltransferase 1 ( P26358 REA ) expression was observed in GP rats disconnected with alterations in DNA methylation of the GR exon 1 ( 7 ) promoter . Nevertheless , mRNA expression of nerve growth factor-inducible protein A ( P18146 REA ) was significantly elevated in GP rats . These results suggest that neonatal intramuscular injection of plasmid DNA encoding P0C6A0 affects anxiety behaviour in adolescent rats , probably through P18146 REA - activated upregulation of hippocampal GR expression .

Two-dimensional liquid crystalline growth within a phase-field-crystal model . By using a two-dimensional phase-field-crystal ( P27918 REA ) model , the liquid crystalline growth of the plastic triangular phase is simulated with emphasis on crystal shape and topological defect formation . The equilibrium shape of a plastic triangular crystal ( PTC ) grown from an isotropic phase is compared with that grown from a columnar or smectic-A ( Q13216 REA ) phase . While the shape of a PTC nucleus in the isotropic phase is almost identical to that of the classical P27918 REA model , the shape of a PTC nucleus in Q13216 REA is affected by the orientation of stripes in the Q13216 REA phase , and irregular hexagonal , elliptical , octagonal , and rectangular shapes are obtained . Concerning the dynamics of the growth process , we analyze the topological structure of the nematic order , which starts from nucleation of +1/2 and -1/2 disclination pairs at the PTC growth front and evolves into hexagonal cells consisting of + 1 vortices surrounded by six satellite -1/2 disclinations . It is found that the orientational and the positional order do not evolve simultaneously ; the orientational order evolves behind the positional order , leading to a large transition zone , which can span over several lattice spacings .

Exenatide twice daily : a review of its use in the management of patients with type 2 diabetes mellitus . Exenatide , administered subcutaneously twice daily ( DB01276 SUB ( ® ) ) , is a synthetic version of the natural peptide exendin - 4 , which is a glucagon-like peptide - 1 ( P0C6A0 ) receptor agonist ( incretin mimetic ) . Exenatide binds to the P43220 REA with the same affinity as P0C6A0 , but has a much longer half-life , since it is not degraded by the enzyme dipeptidyl peptidase - 4 . Exenatide twice daily enhances glucose-dependent insulin secretion , suppresses inappropriately elevated glucagon secretion , slows gastric emptying and reduces caloric intake . In well-designed clinical trials , adjunctive subcutaneous exenatide 5 or 10 μg twice daily for 16-52 weeks significantly and dose-dependently improved glycaemic control and reduced mean body weight compared with placebo in patients with type 2 diabetes inadequately controlled with oral antihyperglycaemic drugs ( OADs ) and / or basal insulin . The improvements in glycaemic control and reductions in body weight were stably maintained during long-term therapy ( up to 3.5 years ) . The efficacy of adjunctive exenatide twice daily was generally similar to that of basal , prandial or biphasic insulin , sulfonylureas , rosiglitazone and lixisenatide , and less than that of liraglutide , taspoglutide or exenatide once weekly with respect to reductions in glycated haemoglobin . Exenatide twice daily was generally well tolerated ; mild to moderate nausea and vomiting , which decreased with time on therapy , were the most common adverse events . In patients not receiving concomitant sulfonylureas or insulin , the incidence of hypoglycaemia was low ; when it did occur , it was generally mild in severity . Thus , adjunctive exenatide twice daily is a valuable option in the treatment of type 2 diabetes inadequately controlled with OADs and / or basal insulin .

Novel cinnamyl hydroxyamides and 2 - aminoanilides as histone deacetylase inhibitors : apoptotic induction and cytodifferentiation activity . Four novel series of cinnamyl-containing histone deacetylase ( HDAC ) inhibitors 1-4 are described , containing hydroxamate ( 1 and 3 ) or 2 - aminoanilide ( 2 and 4 ) derivatives . When screened against class I ( maize HD1 - B and human Q13547 REA ) and class II ( maize HD1 - A and human P56524 REA ) HDACs , most hydroxamates and 2 - aminoanilides displayed potent and selective inhibition toward class I enzymes . Immunoblotting analyses performed in U937 leukemia cells generally revealed high acetyl-H 3 and low acetyl-α-tubulin levels . Exceptions are compounds 3 f-i , 3 m-o , and 4 k , which showed higher tubulin acetylation than DB02546 MEN . In U937 cells , cell-cycle blockade in either the G₂ / M or G₁ / S phase was observed with 1-4 . Five hydroxamates ( compounds 1 h-l ) effected a two - to greater than threefold greater percent apoptosis than DB02546 MEN , and in the CD11c cytodifferentiation test some 2 - aminoanilides belonging to both series 2 and 4 were more active than MS - 275 . The highest-scoring derivatives in terms of apoptosis ( 1 k , 1 l ) or cytodifferentiation ( 2 c , 4 n ) also showed antiproliferative activity in U937 cells , thus representing valuable tools for study in other cancer contexts .

Association between severe toxicity of nilotinib and P22309 REA polymorphisms in Japanese patients with chronic myelogenous leukemia . BACKGROUND : DB04868 MEN is a P11274 REA - P00519 REA kinase inhibitor approved for the treatment of Philadelphia chromosome-positive chronic myelogenous leukemia ( CML ) . The P22309 REA ( P22309 REA ) polymorphism P22309 REA * 28 ( * 28 ) / * 28 has been linked to an increased risk of hyperbilirubinemia in patients with CML who receive nilotinib . Beside * 28 , P22309 REA * 6 ( * 6 ) is another important variant allele in Japanese patients because it is associated with adverse events of irinotecan , metabolized by P22309 REA . We retrospectively investigated the association between severe toxicity of nilotinib and P22309 REA polymorphisms ( * 6 and * 28 ) in Japanese patients with CML . PATIENTS AND METHODS : Eight patients with cytogenetically confirmed CML who were receiving nilotinib were studied to explore the association of P22309 REA polymorphisms with severe nilotinib-related toxicity . Genotyping analyses were determined for * 6 and * 28 . RESULTS : All 3 patients with the * 6 / * 6 or * 6 / * 28 genotype had severe toxicity , including QT interval prolongation ( grade 3 ) , elevated lipase levels ( grade 3 ) plus hyperbilirubinemia ( grade 2 ) , and anemia ( grade 3 ) plus hepatic cyst hemorrhage ( grade 2 ) in 1 patient each . Among the 5 patients with the * 6 / * 1 or * 1 / * 1 genotype , 1 had elevated lipase levels ( grade 3 ) and another had severe pain in the lower extremities ( grade 3 ) . CONCLUSION : These findings suggest that P22309 REA polymorphisms are important determinants of severe toxicity of nilotinib in Japanese patients .

P35568 REA regulation in health and disease . The global incidence of diabetes is increasing at epidemic rates . Estimates suggest there are currently 150 million people with diabetes and this number is expected to double in the next 20 years . Type 2 diabetes accounts for 95 % of all cases and is characterized in part by impaired sensitivity to insulin or ' insulin resistance ' . Defects in the insulin signalling pathways underpin this resistance . In the current article we discuss the regulation of P01308 REA Receptor Substrate - 1 ( P35568 REA ) , a protein that plays a pivotal role in insulin signalling and whose function is impaired in subjects with insulin resistance . Coordination of P35568 REA function is multi-faceted , involving phosphorylation of P35568 REA at multiple serine / threonine residues . This controls many aspects of P35568 REA , including its interaction with the insulin receptor and subsequent tyrosine phosphorylation , as well as its subcellular distribution and targeting for degradation by the proteasome . Such tight control ensures appropriate transduction and attenuation of the insulin signal , thereby regulating insulin action in healthy individuals . Emerging evidence indicates that ' diabetogenic factors ' associated with insulin resistance , such as TNFalpha and elevated circulating fatty acids , impact on insulin signalling at the level of P35568 REA serine / threonine phosphorylation . The expression and / or activity of several kinases , such as O15111 REA beta ( IKKbeta ) and salt-induced kinase 2 ( Q9H0K1 ) , and the phosphorylation of P35568 REA at key sites , such as Ser 307 and Ser 789 , are increased in states of insulin resistance . Identifying the pathways by which such factors activate these and other kinases , and defining the precise roles of specific serine / threonine phosphorylation events in P35568 REA regulation , represent important goals which may eventually provide a rationale for therapeutic intervention .