MH_dev_333

Q16739 REA - 100 , a novel galectin - 3 antagonist , modulates Q8WXI8 - 1 , Q13794 REA , and cell cycle to induce myeloma cell death . Q16739 REA - 100 is a galectin - 3 antagonist with an acceptable human safety profile that has been demonstrated to have an antimyeloma effect in the context of bortezomib resistance . In the present study , the mechanisms of action of Q16739 REA - 100 are elucidated in myeloma cell lines and primary tumor cells . Q16739 REA - 100 induced inhibition of proliferation , accumulation of cells in sub-G ( 1 ) and G ( 1 ) phases , and apoptosis with activation of both caspase - 8 and - 9 pathways . Dose - and time-dependent decreases in Q8WXI8 - 1 and BCL-X ( L ) levels also occurred , accompanied by a rapid induction of Q13794 REA protein , whereas BCL - 2 , Q07812 REA , Q16611 REA , O43521 REA , Q92934 REA , P55957 REA , and PUMA remained unchanged . The cell-cycle inhibitor P38936 REA ( Cip 1 ) was up-regulated by Q16739 REA - 100 , whereas the procycling proteins CYCLIN E2 , CYCLIN D2 , and Q00534 REA were all reduced . Reduction in signal transduction was associated with lower levels of activated P25963 REA , O15111 REA , and AKT as well as lack of P25963 REA and AKT activation after appropriate cytokine stimulation ( insulin-like growth factor - 1 , tumor necrosis factor-alpha ) . Primary myeloma cells showed a direct reduction in proliferation and viability . These data demonstrate that the novel therapeutic molecule , Q16739 REA - 100 , is a potent modifier of myeloma cell biology targeting apoptosis , cell cycle , and intracellular signaling and has potential for myeloma therapy .

Q14653 REA and Q92985 REA phosphorylation in virus-infected cells does not require double-stranded RNA-dependent protein kinase R or Ikappa B kinase but is blocked by Vaccinia virus E3L protein . Induction of interferon-alpha ( IFNalpha ) gene expression in virus-infected cells requires phosphorylation-induced activation of the transcription factors Q14653 REA and Q92985 REA . However , the kinase ( s ) that targets these proteins has not been identified . Using a combined pharmacological and genetic approach , we found that none of the kinases tested was responsible for Q969Q1 REA phosphorylation in cells infected with Newcastle disease virus ( NDV ) . Although the broad-spectrum kinase inhibitor staurosporine potently blocked Q14653 REA and - 7 phosphorylation , inhibitors for protein kinase C , protein kinase A , MEK , SAPK , IKK , and protein kinase R ( P19525 REA ) were without effect . Both O15111 REA and P19525 REA have been implicated in IFN induction , but cells genetically deficient in O15111 REA , P19525 REA , or the P19525 REA - related genes Q9NZJ5 , O75460 REA , or Q9P2K8 REA retained the ability to phosphorylate Q92985 REA and induce IFNalpha . Interestingly , P19525 REA mutant cells were defective for response to double-stranded ( ds ) RNA but not to virus infection , suggesting that dsRNA is not the only activating viral component . Consistent with this notion , protein synthesis was required for Q92985 REA phosphorylation in virus-infected cells , and the kinetics of phosphorylation and viral protein production were similar . Despite evidence for a lack of involvement of dsRNA and P19525 REA , vaccinia virus E3L protein , a dsRNA-binding protein capable of inhibiting P19525 REA , was an effective Q14653 REA and - 7 phosphorylation inhibitor . These results suggest that a novel cellular protein that is activated by viral products in addition to dsRNA and is sensitive to E3L inhibition is responsible for Q969Q1 REA activation and reveal a novel mechanism for the anti-IFN effect of E3L distinct from its inhibition of P19525 REA .

DB00125 metabolic enzymes , nitric oxide and infection . DB00435 ( NO ) is synthesized from arginine by NO synthase ( NOS ) , and the availability of arginine is one of the rate-limiting factors in cellular NO production . DB00155 MEN that is formed as a by-product of the NOS reaction can be recycled to arginine by successive actions of argininosuccinate synthetase ( AS ) and argininosuccinate lyase ( AL ) , forming the citrulline-NO cycle . AS and sometimes AL have been shown to be coinduced with inducible NOS ( P35228 REA ) in various cell types including activated macrophages , microglia , vascular smooth muscle cells , glial cells , neuronal PC12 cells , retinal pigment epithelial cells , and pancreatic beta-cells . Coinduction of endothelial NOS ( P29474 REA ) , AS , and AL are observed in human umbilical vein endothelial cells . In contrast , arginase can downregulate NO production by decreasing intracellular arginine concentrations . P35228 REA and arginase activities are regulated reciprocally in macrophages by cytokines , and this may guarantee the efficient production of NO . In contrast , P35228 REA and arginase isoforms ( type I and / or II ) are coinduced in immunostimulated macrophages , but not in PC12 cells and glial cells . These results indicate that NO production is modulated by the recycling and degradation of arginine . Arginase also plays an important role in regulation of polyamine and proline synthesis .

Acute ethanol preexposure promotes liver regeneration after partial hepatectomy in mice by activating P05091 REA . It is known that chronic ethanol significantly impairs liver regeneration . However , the effect of acute ethanol exposure on liver regeneration remains largely unknown . To address this question , C57Bl6 / J mice were exposed to acute ethanol ( 6 g / kg intragastrically ) for 3 days , and partial hepatectomy ( PHx ) was performed 24 h after the last dose . Surprisingly , acute ethanol preexposure promoted liver regeneration . This effect of ethanol did not correlate with changes in expression of cell cycle regulatory genes ( e . g . , cyclin D1 , P38936 REA , and p27 ) but did correlate with protection against the effect of PHx on indices of impaired lipid and carbohydrate metabolism . DB00898 preexposure protected against inhibition of the oxidant-sensitive mitochondrial enzyme , aconitase . The activity of aldehyde dehydrogenase 2 ( P05091 REA ) was significantly increased by ethanol preexposure . The effect of ethanol was blocked by inhibiting ( DB02115 MEN ) and was mimicked by activating ( Alda - 1 ) P05091 REA . Lipid peroxides are also substrates for P05091 REA ; indeed , alcohol preexposure blunted the increase in lipid peroxidation ( 4OH - nonenal adducts ) caused by PHx . Taken together , these data suggest that acute preoperative ethanol exposure " preconditions " the liver to respond more rapidly to regenerate after PHx by activating mitochondrial P05091 REA , which prevents oxidative stress in this compartment .

The biology of serotonin receptors : focus on migraine pathophysiology and treatment . Serotonin receptors are highly heterogeneous and they have been regrouped within seven different families ( 5 - HT1 - P34969 REA ) . With the exception of the 5 - Q9H205 REA which is a ligand-gated ion channel , all others are G-protein coupled receptors with each family sharing structural , pharmacological and transductional characteristics . 5 - HT receptors have been implicated in the regulation of several psychiatric and neurological disorders related to serotonergic neurotransmission , and specific receptor subtypes have recently been associated with either the pathogenesis or the treatment of migraine headache . In this respect , activation of vascular P41595 REA and / or P34969 REA receptors , possibly as a consequence of the sudden rise in 5 - HT levels reported at the onset of a migraine attack , would hypothetically result in dilation of cerebral blood vessels and concomitant activation of sensory trigeminovascular afferents , hence initiating the manifestation of head pain . At this stage in the migraine process , activation of specific subtypes of 5 - HT1 receptors has proven clinically effective in relieving migraine pain . Neural P28221 REA and / or P30939 REA receptors localized pre-junctionally on trigeminovascular afferents appear to mediate the DB00669 MEN - induced inhibition of the neurogenic inflammatory response , with possible additional sites of action for brain penetrant 5 - HT1 receptor agonists in inhibiting the transmission of pain centrally . In contrast , activation of vascular P28222 REA receptors would constrict meningeal vessels hence recovering their pre-migraine diameter . The recent availability of subtype selective P28221 REA and P30939 REA receptor agonists should allow a further test of the neural / vascular hypothesis and could possibly lead to antimigraine drugs with a safer cardiovascular profile .

[ Pharmacological and clinical profile of mitiglinide calcium hydrate ( Glufast ) , a new insulinotropic agent with rapid onset ] . DB01252 MEN calcium hydrate ( mitiglinide , Glufast ) is a new insulinotropic agent of the glinide class with rapid onset . DB01252 MEN is thought to stimulate insulin secretion by closing the DB00171 - sensitive K ( + ) ( K ( DB00171 ) ) channels in pancreatic beta-cells , and its early insulin release and short duration of action would be effective in improving postprandial hyperglycemia . In studies of various cloned K ( DB00171 ) channels , mitiglinide shows a higher selectivity for the beta-cell type of Q09428 REA / Kir 6.2 than the cardiac and smooth muscle types of K ( DB00171 ) channels in comparison with glibenclamide and glimepiride . In vitro and in vivo studies demonstrated the insulinotropic effect of mitiglinide is more potent than that of nateglinide , and mitiglinide surpassed in controlling postprandial hyperglycemia in normal and diabetic animals . In clinical trials , treatment with mitiglinide provided lasting improvement of postprandial hyperglycemia in Type 2 diabetic patients and decreased the fasting plasma glucose levels and HbA ( 1C ) values . The incidence of adverse events related to mitiglinide were nearly equivalent to placebo ; in particular there was no difference with the frequency of hypoglycemia . The results from these studies indicated that mitiglinide could be expected to possess good therapeutic features of being effective in reducing postprandial glucose excursions in the early stage of Type 2 diabetes and less incidence of events suggestive of hypoglycemia .

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 .

NSA 9 , a human prothrombin kringle - 2 - derived peptide , acts as an inhibitor of kringle - 2 - induced activation in EOC 2 microglia . In neurodegenerative diseases , such as Alzheimer ' s and Parkinson ' s , microglial cell activation is thought to contribute to CNS injury by producing neurotoxic compounds . P00734 REA and kringle - 2 increase levels of NO and the mRNA expression of P35228 REA , IL - 1beta , and P01375 REA in microglial cells . In contrast , the human prothrombin kringle - 2 derived peptide NSA 9 inhibits NO release and the production of pro-inflammatory cytokines such as IL - 1beta , P01375 REA , and P05231 REA in LPS-activated EOC 2 microglia . In this study , we investigated the anti-inflammatory effects of NSA 9 in human prothrombin - and kringle - 2 - stimulated EOC 2 microglia . Treatment with 20-100 muM of NSA 9 attenuated both prothrombin - and kringle - 2 - induced microglial activation . NO production induced by MAPKs and NF-kappaB was similarly reduced by inhibitors of P29323 REA ( PD98059 ) , p38 ( SB203580 ) , NF-kappaB ( DB06151 ) , and NSA 9 . These results suggest that NSA 9 acts independently as an inhibitor of microglial activation and that its effects in EOC 2 microglia are not influenced by the presence of kringle - 2 .

Ras-dependent P29323 REA activation by the human G ( s ) - coupled serotonin receptors Q13639 REA ( b ) and P34969 REA ( a ) . Receptor tyrosine kinases activate mitogen-activated protein ( Q96HU1 ) kinases through Ras , P04049 REA , and MEK . Receptor tyrosine kinases can be transactivated by G protein-coupled receptors coupling to G ( i ) and G ( q ) . The human G protein-coupled serotonin receptors 5 - HT ( 4 ( b ) ) and 5 - HT ( 7 ( a ) ) couple to G ( s ) and elevate intracellular DB02527 . Certain G ( s ) - coupled receptors have been shown to activate Q96HU1 kinases through a protein kinase A - and Rap 1 - dependent pathway . We report the activation of the extracellular signal-regulated kinases ( ERKs ) 1 and 2 ( Q8TCB0 and Q8NFH3 Q96HU1 kinase ) through the human serotonin receptors 5 - HT ( 4 ( b ) ) and 5 - HT ( 7 ( a ) ) in COS - 7 and human embryonic kidney HEK 293 cells . In transfected HEK 293 cells , 5 - HT-induced activation of P27361 REA / 2 is sensitive to H89 , which indicates a role for protein kinase A . The observed activation of P27361 REA / 2 does not require transactivation of epidermal growth factor receptors . Furthermore , 5 - HT induced activation of both Ras and Rap 1 . Whereas the presence of P47736 REA did not influence the 5 - HT-mediated activation of P27361 REA / 2 , the activation of P27361 REA / 2 was abolished in the presence of dominant negative Ras ( RasN 17 ) . P27361 REA / 2 activation was reduced in the presence of " dominant negative " Raf 1 ( RafS 621A ) and slightly reduced by dominant negative B-Raf , indicating the involvement of one or more Raf isoforms . These findings suggest that activation of P27361 REA / 2 through the human G ( s ) - coupled serotonin receptors 5 - HT ( 4 ( b ) ) and 5 - HT ( 7 ( a ) ) in HEK 293 cells is dependent on Ras , but independent of Rap 1 .

c7E3 Fab inhibits human tumor angiogenesis in a SCID mouse human skin xenograft model . The alphavbeta 3 integrin plays an important role in tumor growth and angiogenesis . Inhibition of this receptor by intact bivalent antibodies has been shown to inhibit angiogenesis and tumor growth . In this study we tested the chimeric Fab of DB00054 MENMAX DB00054 MEN ( c7E3 Fab ) , an antibody reactive with human platelet P08514 REA / IIIa and alphavbeta 3 to determine if it would inhibit in vivo angiogenesis and tumor growth in a SCID mouse / human skin tumor growth and angiogenesis model . c7E3 Fab inhibited human tumor angiogenesis and tumor growth . These data suggest monovalent antibody fragments devoid of antibody effector function can have efficacy in preclinical models of angiogenesis .

Novel and emerging drugs for acute myeloid leukemia : pharmacology and therapeutic activity . For the last twenty years , significant progress in Molecular and Cellular Biology has resulted in a better characterization and understanding of the biology and prognosis of acute myeloid leukemia ( AML ) . These achievements have provided new opportunities for the development of innovative , more effective therapies . Novel agents potentially useful in the treatment of patients with AML include new formulations of established drugs , newer nucleoside analogs , molecular target drugs , monoclonal antibodies and other agents . Three newer nucleoside analogs , clofarabine , troxacitabine and sapacitabine have been recently investigated in patients with AML . Two methylation inhibitors , 5 - azacyticline and decitabine are pyrimidine nucleoside analogs of cytidine which can be incorporated into RNA and / or DNA . Lower doses of these agents are active in AML and have been extensively investigated , especially in secondary AML and AML in elderly patients . DB04960 and lonafarnib are orally available farnesyltransferase inhibitors with in vitro and in vivo activity against AML . In recent years , P36888 REA inhibitors , lestaurinib , DB05465 MEN and PKC 412 have been developed and tested in AML . The preclinical observations and clinical studies indicate that P36888 REA inhibitors are promising agents in the treatment of P36888 REA mutated AML patients , especially when used in combinations with chemotherapy . Several newer MDR inhibitors , including valspodar ( PSC - 833 ) and zosuquidar trihydrochloride have been also tested for the treatment of relapsed AML . This article reviews the various classes of AML targets and drugs that are under early phase clinical evaluation , especially those that are likely to enter clinical practice in the near future .

c-Src modulates estrogen-induced stress and apoptosis in estrogen-deprived breast cancer cells . The emergence of anti-estrogen resistance in breast cancer is an important clinical phenomenon affecting long-term survival in this disease . Identifying factors that convey cell survival in this setting may guide improvements in treatment . Estrogen ( E2 ) can induce apoptosis in breast cancer cells that have been selected for survival after E2 deprivation for long periods ( MCF -7:5 C cells ) , but the mechanisms underlying E2 - induced stress in this setting have not been elucidated . Here , we report that the c-Src kinase functions as a key adapter protein for the estrogen receptor ( ER , P03372 REA ) in its activation of stress responses induced by E2 in MCF -7:5 C cells . E2 elevated phosphorylation of c-Src , which was blocked by 4 - hydroxytamoxifen ( DB04468 MEN ) , suggesting that E2 activated c-Src through the ER . We found that E2 activated the sensors of the unfolded protein response ( UPR ) , IRE 1α ( O75460 REA ) and Q9NZJ5 kinase ( Q9NZJ5 ) , the latter of which phosphorylates eukaryotic translation initiation factor - 2α ( eIF 2α ) . E2 also dramatically increased reactive oxygen species production and upregulated expression of heme oxygenase P09601 REA ( P09601 REA ) , an indicator of oxidative stress , along with the central energy sensor kinase AMPK ( P54646 REA ) . Pharmacologic or RNA interference-mediated inhibition of c-Src abolished the phosphorylation of eIF 2α and AMPK , blocked E2 - induced ROS production , and inhibited E2 - induced apoptosis . Together , our results establish that c-Src kinase mediates stresses generated by E2 in long-term E2 - deprived cells that trigger apoptosis . This work offers a mechanistic rationale for a new approach in the treatment of endocrine-resistant breast cancer .

20 - hydroxy -5,8 , 11,14- eicosatetraenoic acid mediates endothelial dysfunction via O15111 REA - dependent endothelial nitric-oxide synthase uncoupling . Endothelial dysfunction and activation occur in the vasculature and are believed to contribute to the pathogenesis of cardiovascular diseases . We have shown that 20 - hydroxy -5,8 , 11,14- eicosatetraenoic acid ( 20 - HETE ) , a cytochrome P450 4A - derived eicosanoid that promotes vasoconstriction in the microcirculation , uncouples endothelial nitric-oxide synthase ( P29474 REA ) and reduces nitric oxide ( NO ) levels via the dissociation of the 90 - kDa heat shock protein ( HSP 90 ) from P29474 REA . It also causes endothelial activation by stimulating nuclear factor-kappaB ( NF-kappaB ) and increasing levels of pro-inflammatory cytokines . In this study , we examined signaling mechanisms that may link 20 - HETE-induced endothelial dysfunction and activation . Under conditions in which 20 - HETE inhibited NO production , it also stimulated inhibitor of NF-kappaB ( IkappaB ) phosphorylation . Both effects were prevented by inhibition of tyrosine kinases and mitogen-activated protein kinase ( MAPK ) / extracellular signal-regulated kinase ( P29323 REA ) . It is noteworthy that inhibitor of O15111 REA ( IKK ) activity negated the 20 - HETE-mediated inhibition of NO production . Immunoprecipitation experiments revealed that treatment of ionophore-stimulated cells with 20 - HETE brings about a decrease in HSP 90 - P29474 REA association and an increase in HSP 90 - IKKbeta association , suggesting that the activation by 20 - HETE of NF-kappaB is linked to its action on P29474 REA . Furthermore , addition of inhibitors of tyrosine kinase MAPK and IKK restored the 20 - HETE-mediated impairment of acetylcholine-induced relaxation in rat renal interlobar arteries . The results indicate that 20 - HETE mediates P29474 REA uncoupling and endothelial dysfunction via the activation of tyrosine kinase , MAPK , and IKK , and these effects are linked to 20 - HETE-mediated endothelial activation .

Glycoprotein IIb / IIIa inhibition attenuates platelet-activating factor-induced platelet activation by reducing protein kinase C activity . Glycoprotein ( GP ) IIb / IIIa inhibition may abolish activated leukocyte-induced platelet activation , in which leukocyte-released platelet-activating factor ( Q15004 ) is a major mediator . The present study thus investigated if and how P08514 REA / IIIa inhibitors interfere with Q15004 - induced platelet activation . Platelet and leukocyte activation were monitored by flow cytometry and immunoblotting . P08514 REA / IIIa inhibitors ( c7E3 , non-peptide SR121566 , and MAb RFGP 56 ) attenuated Q15004 - induced , but not adenosine diphosphate ( ADP ) - or thrombin receptor activating peptide ( TRAP ) - induced platelet P16109 REA expression in whole blood . P08514 REA / IIIa blockade enhanced ADP - or TRAP-induced leukocyte CD11b expression , but not the response to Q15004 . P08514 REA / IIIa blockade attenuated Q15004 - induced , but enhanced ADP - or TRAP-induced platelet-leukocyte aggregation . Under the present experimental conditions , thromboxane A2 receptor antagonism did not significantly influence Q15004 - induced platelet activation , and P08514 REA / IIIa inhibition did not interfere with calcium mobilization / influx in platelets . Protein kinase C ( PKC ) blockade inhibited Q15004 - induced platelet P16109 REA expression , and Q15004 - induced PKC activity was reduced by P08514 REA / IIIa inhibition . Q15004 ( = 1 micro m ) did not induce Q02750 REA / 2 or P29323 REA 1/2 phosphorylation , whilst thrombin induced marked responses , which were enhanced by P08514 REA / IIIa blockade . Thus , P08514 REA / IIIa inhibition attenuates Q15004 - induced platelet activation via inhibiting PKC activity . P08514 REA / IIIa blockade enhances thrombin-induced platelet Q02750 REA / 2 and P29323 REA 1/2 activation , and augments ADP - and TRAP-induced leukocyte activation by enhancing platelet-leukocyte aggregation .

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 SUB 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 .

DB09341 - and interleukin - 1beta - induced beta-cell apoptosis requires Ca2 + influx and extracellular signal-regulated kinase ( P29323 REA ) 1/2 activation and is prevented by a sulfonylurea receptor 1 / inwardly rectifying K + channel 6.2 ( Q09428 REA / Kir 6.2 ) selective potassium channel opener in human islets . Increasing evidence indicates that a progressive decrease in the functional beta-cell mass is the hallmark of both type 1 and type 2 diabetes . The underlying causes , beta-cell apoptosis and impaired secretory function , seem to be partly mediated by macrophage production of interleukin ( IL ) - 1beta and / or high-glucose-induced beta-cell production of IL - 1beta . Treatment of type 1 and type 2 diabetic patients with the potassium channel opener diazoxide partially restores insulin secretion . Therefore , we studied the effect of diazoxide and of the novel potassium channel opener NN414 , selective for the beta-cell potassium channel Q09428 REA / Kir 6.2 , on glucose - and IL - 1beta - induced apoptosis and impaired function in human beta-cells . Exposure of human islets for 4 days to 11.1 and 33.3 mmol / l glucose , 2 ng / ml IL - 1beta , or 10 and 100 micromol / l of the sulfonylurea tolbutamide induced beta-cell apoptosis and impaired glucose-stimulated insulin secretion . The deleterious effects of glucose and IL - 1beta were blocked by 200 micromol / l diazoxide as well as by 3 and 30 micromol / l NN414 . By Western blotting with phosphospecific antibodies , glucose and IL - 1beta were shown to activate the extracellular signal-regulated kinase ( P29323 REA ) 1/2 , an effect that was abrogated by 3 micromol / l NN414 . Similarly , 1 micromol / l of the mitogen-activated protein kinase / P29323 REA kinase 1/2 inhibitor PD098059 or 1 micromol / l of the l-type Ca ( 2 + ) channel blocker nimodipine prevented glucose - and IL - 1beta - induced P29323 REA activation , beta-cell apoptosis , and impaired function . Finally , islet release of IL - 1beta in response to high glucose could be abrogated by nimodipine , NN414 , or PD098059 . Thus , in human islets , glucose - and IL - 1beta - induced beta-cell secretory dysfunction and apoptosis are Ca ( 2 + ) influx and P29323 REA dependent and can be prevented by the beta-cell selective potassium channel opener NN414 .

DB00233 SUB inhibits O15111 REA alpha phosphorylation of P25963 REA in mouse intestinal epithelial cells . P01375 REA alpha ( TNFalpha ) - stimulated nuclear factor ( NF ) kappaB activation plays a key role in the pathogenesis of inflammatory bowel disease ( Q9UKU7 ) . Phosphorylation of NFkappaB inhibitory protein ( IkappaB ) leading to its degradation and NFkappaB activation , is regulated by the multimeric O15111 REA complex , including IKKalpha and IKKbeta . We recently reported that DB00244 ( DB00244 ) inhibits TNFalpha-regulated IkappaB degradation and NFkappaB activation . To determine the mechanism of DB00244 inhibition of IkappaB degradation , we studied young adult mouse colon ( YAMC ) cells by immunodetection and in vitro kinase assays . We show DB00244 inhibits TNFalpha-stimulated phosphorylation of P25963 REA in intact YAMC cells . Phosphorylation of a glutathione S-transferase - P25963 REA fusion protein by cellular extracts or immunoprecipitated IKKalpha isolated from cells treated with TNFalpha is inhibited by DB00244 . Recombinant IKKalpha and IKKbeta autophosphorylation and their phosphorylation of glutathione S-transferase - P25963 REA are inhibited by DB00244 . However , IKKalpha serine phosphorylation by its upstream kinase in either intact cells or cellular extracts is not blocked by DB00244 . Surprisingly , immunodepletion of cellular extracts suggests IKKalpha is predominantly responsible for P25963 REA phosphorylation in intestinal epithelial cells . In summary , DB00244 inhibits TNFalpha-stimulated IKKalpha kinase activity toward P25963 REA in intestinal epithelial cells . These findings suggest a novel role for DB00244 in the management of Q9UKU7 by disrupting TNFalpha activation of NFkappaB .

DB04998 MEN inhibits activation of nuclear factor-kappaB ( NF-kappaB ) by forming a complex with NF-kappaB essential modulator ( Q9Y6K9 REA ) and nucleolin . DB04998 MEN , also known as DB04998 MEN , is an experimental anticancer drug that recently entered human clinical trials . It is a member of a novel class of antiproliferative agents known as G-rich oligonucleotides ( P09341 REA ) , which are non-antisense , guanosine-rich phosphodiester oligodeoxynucleotides that form stable G-quadruplex structures . The biological activity of GROs results from their binding to specific cellular proteins as aptamers . One important target protein of GROs has been previously identified as nucleolin , a multifunctional protein expressed at high levels by cancer cells . Here , we report that DB04998 MEN also associates with nuclear factor-kappaB ( NF-kappaB ) essential modulator ( Q9Y6K9 REA ) , which is a regulatory subunit of the inhibitor of kappaB ( IkappaB ) kinase ( IKK ) complex , and also called IKKgamma . In the classic NF-kappaB pathway , the IKK complex is required for phosphorylation of P25963 REA and subsequent activation of the transcription factor NF-kappaB . We found that treatment of cancer cells with DB04998 MEN inhibits IKK activity and reduces phosphorylation of P25963 REA in response to tumor necrosis factor-alpha stimulation . Using a reporter gene assay , we showed that DB04998 MEN blocks both tumor necrosis factor-alpha-induced and constitutive NF-kappaB activity in human cancer cell lines derived from cervical , prostate , breast , and lung carcinomas . In addition , we showed that , in DB04998 MEN - treated cancer cells , Q9Y6K9 REA is coprecipitated by nucleolin , indicating that both proteins are present in the same complex . Our studies suggest that abrogation of NF-kappaB activity may contribute to the anticancer effects of DB04998 MEN and that nucleolin may play a previously unknown role in regulating the NF-kappaB pathway .

Combining the P36888 REA inhibitor PKC 412 and the triterpenoid CDDO-Me synergistically induces apoptosis in acute myeloid leukemia with the internal tandem duplication mutation . Mutations of the P36888 REA receptor tyrosine kinase consisting of internal tandem duplications ( ITD ) have been detected in blasts from 20 % to 30 % of patients with acute myeloid leukemia ( AML ) and are associated with a poor prognosis . P36888 REA / ITD results in constitutive autophosphorylation of the receptor and factor-independent survival in leukemia cell lines . The C - 28 methyl ester of the oleane triterpenoid ( CDDO-Me ) is a multifunctional molecule that induces apoptosis of human myeloid leukemia cells . Here , we report that CDDO-Me blocks targeting of NFkappaB to the nucleus by inhibiting O15111 REA beta-mediated phosphorylation of P25963 REA . Moreover , CDDO-Me blocked constitutive activation of the signal transducer and activator of transcription 3 . We report the potent and selective antiproliferative effects of CDDO-Me on P36888 REA / ITD-positive myeloid leukemia cell lines and primary AML cells . The present studies show that CDDO-Me treatment results in caspase - 3 - mediated induction of apoptosis of P36888 REA / ITD-expressing cells and its antiproliferative effects are synergistic with PKC 412 , a P36888 REA - tyrosine kinase inhibitor currently in clinical trials . Taken together , our studies indicate that CDDO-Me greatly enhanced the efficacy of the P36888 REA inhibitor PKC 412 , suggesting that combining two separate pathway inhibitors might be a viable therapeutic strategy for AML associated with a P36888 REA / ITD mutation .