interacts_with DB00277?
Levels of angiopoietins 1 and 2 in induced sputum supernatant in patients with P48444 . Pathological features of chronic obstructive pulmonary disease ( P48444 ) include lung vascular remodeling and angiogenesis . Q15389 ( Ang-1 ) , is an essential mediator of angiogenesis by establishing vascular integrity , whereas angiopoietin-2 ( Ang-2 ) acts as its natural inhibitor . We determined the levels of angiopoietins in sputum supernatants of patients with P48444 and investigated their possible association with mediators and cells involved in the inflammatory and remodeling process . Fifty-nine patients with P48444 , 25 healthy smokers and 20 healthy non-smokers were studied . All subjects underwent lung function tests , sputum induction for cell count identification and Ang-1 , Ang-2 , P15692 , TGF-β1 , P08253 , LTB4 , P10145 , albumin measurement in sputum supernatants . Airway vascular permeability ( AVP ) index was also assessed . Ang-2 levels were significantly higher in patients with P48444 compared to healthy smokers and healthy non-smokers [ median , interquartile ranges pg/ml , 267 ( 147-367 ) vs. 112 ( 67-171 ) and 98 ( 95-107 ) , respectively ; p < 0.001 ] . Regression analysis showed a significant association between Ang-2 levels and AVP index , P15692 , P10145 and P08253 levels in P48444 , the strongest being with P15692 . Our results indicate that induced sputum Ang-2 levels are higher in P48444 compared to healthy smokers and healthy non-smokers . Moreover , Ang-2 is associated with AVP , P10145 , P08253 , and P15692 , indicating a possible role for Ang-2 in the pathogenesis of the disease . Dependence on phosphoinositide 3-kinase and DB01367 -RAF pathways drive the activity of RAF265 , a novel RAF/ P35968 inhibitor , and RAD001 ( DB01590 ) in combination . Activation of phosphatidylinositol-3-kinase ( PI3K ) -AKT and Kirsten rat sarcoma viral oncogene homologue ( P01116 ) can induce cellular immortalization , proliferation , and resistance to anticancer therapeutics such as epidermal growth factor receptor inhibitors or chemotherapy . This study assessed the consequences of inhibiting these two pathways in tumor cells with activation of P01116 , PI3K-AKT , or both . We investigated whether the combination of a novel RAF/vascular endothelial growth factor receptor inhibitor , RAF265 , with a mammalian target of rapamycin ( P42345 ) inhibitor , RAD001 ( everolimus ) , could lead to enhanced antitumoral effects in vitro and in vivo . To address this question , we used cell lines with different status regarding P01116 , P42336 , and P15056 mutations , using immunoblotting to evaluate the inhibitors , and MTT and clonogenic assays for effects on cell viability and proliferation . Subcutaneous xenografts were used to assess the activity of the combination in vivo . RAD001 inhibited P42345 downstream signaling in all cell lines , whereas RAF265 inhibited RAF downstream signaling only in P15056 mutant cells . In vitro , addition of RAF265 to RAD001 led to decreased AKT , S6 , and P06730 binding protein 1 phosphorylation in HCT116 cells . In vitro and in vivo , RAD001 addition enhanced the antitumoral effect of RAF265 in HCT116 and H460 cells ( both P01116 mut , P42336 mut ) ; in contrast , the combination of RAF265 and RAD001 yielded no additional activity in A549 and MDAMB231 cells . The combination of RAF and P42345 inhibitors is effective for enhancing antitumoral effects in cells with deregulation of both DB01367 -RAF and PI3K , possibly through the cross-inhibition of 4E binding protein 1 and S6 protein . Effect of lipoteichoic acid on P60568 and P05113 release from T lymphocytes in asthma and P48444 . Susceptibility to infections with gram-positive bacteria , which are an important trigger of exacerbations , is increased in P48444 and asthma . Unraveling the underlying mechanisms may help developing therapeutic strategies to reduce exacerbation rates . The aim of this study was to evaluate the effects of lipoteichoic acid ( P01374 ) , a danger signal from gram-positive bacteria , on T cell cytokines related to bacterial infection defense in P48444 and asthma . T cell populations within peripheral blood mononuclear cells ( PBMCs ) were ex-vivo activated towards T(H)2/T(C)2 subtypes and subsequently stimulated with P01374 . P60568 and P05113 concentrations in cell culture supernatants were measured by ELISA comparative between non-smokers ( NS ) , current smokers without airflow limitation ( S ) , smokers with moderate to severe P48444 and mild to moderate asthmatics ( A ) ( each n=10 ) . P60568 and P05113 baseline levels were without differences between the cohorts . After T cell activation , P60568 and P05113 releases were increased in all cohorts , however , for P60568 this increase was significantly higher in S and by trend in P48444 compared to the other groups . P01374 time-dependently suppressed P60568 release in NS , S and P48444 but not in A . P01374 reduced P05113 release in P48444 and A but not in NS and S. Summarized , P01374 reduces T(H)2/T(C)2 cytokines indicating immunosuppressive effects , which are dysregulated in P48444 and asthma . This implies a misguided response to gram-positive bacterial infections , which might help to explain the increased susceptibility to bacterial infections in P48444 and asthma . Targeting eIF4GI 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 , eIF4F 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 eIF4GI expression , regulation ( P15559 /proteosome dependent fragmentation ) ( WB , DB00266 , qPCR ) and targets (WB). eIF4GI was inhibited by knockdown and 4EGI-1 . Cells were tested for viability ( ELISA ) , death ( FACS ) and eIF4GI targets ( WB ) . RESULTS : Previously , we have shown that manipulation of P15692 in myeloma cells attenuated P06730 dependent translation initiation . Here we assessed the significance of eIF4GI to MM cells . We demonstrated increased expression of eIF4GI in myeloma cells and its attenuation upon P15692 inhibition attributed to elevated P15559 /proteasome dependent fragmentation and diminished mRNA levels . Knockdown of eIF4GI was deleterious to myeloma cells phenotype and expression of specific molecular targets ( Q99717 /ERα/HIF1α/c-Myc ) . Finally , we showed that the small molecule 4EGI-1 inhibits eIF4GI 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 eIF4GI , critical to cell phenotype , and mark it as a viable target for pharmacological intervention . DB00501 induces interleukin-18 production through H2-agonist activity in monocytes . The present study demonstrates a possible mechanism for the improvement of gastrointestinal cancer patients ' prognosis by the histamine receptor type 2 ( P25021 ) antagonist cimetidine . This agent , but not the P25021 antagonists ranitidine and famotidine , induced the production of an antitumor cytokine , interleukin ( IL ) -18 , by human monocytes and dendritic cells ( DC ) . In fact , ranitidine and famotidine antagonized cimetidine-induced Q14116 production . DB00501 induced the activation of caspase-1 , which is reported to modify immature Q14116 to mature/active Q14116 , and the elevation of intracellular DB02527 , leading to the activation of protein kinase A ( PKA ) . The PKA inhibitor H89 abolished the Q14116 production induced by cimetidine . Moreover , the effects of cimetidine on Q14116 production were reproduced in peripheral blood mononuclear cells from wild-type mice , but not in those from P25021 knockout mice . In conclusion , cimetidine , a partial agonist for P25021 , has a pharmacological profile different from ranitidine and famotidine , possibly contributing to its antitumor activity on gastrointestinal cancers . Desmopressin ( DB00035 ) induces NO production in human endothelial cells via V2 receptor- and DB02527 -mediated signaling . The hemostatic agent desmopressin ( DB00035 ) also has strong vasodilatory effects . DB00035 is a selective agonist for the vasopressin V2 receptor ( P30518 ) , which is coupled to DB02527 -dependent signaling . DB00035 -induced vasodilation may be due to endothelial NO synthase ( P29474 ) activation . This hypothesis implies DB02527 -mediated P29474 activation . It also implies wide extrarenal , endothelial P30518 expression . We show that in human umbilical vein endothelial cells ( HUVECs ) the DB02527 -raising agents forskolin and epinephrine increase NO production , as measured by a l-NMMA-inhibitable rise in cellular cGMP content . They also increase P29474 enzymatic activity , in a partly calcium-independent manner . DB02527 -mediated P29474 activation is associated with phosphorylation of residue Ser1177 , in a phosphatidyl inositol 3-kinase ( PI3K ) -independent manner . HUVECs do not express P30518 . However , after heterologous P30518 expression , DB00035 induces DB02527 -dependent P29474 activation via Ser1177 phosphorylation . We have previously found P30518 expression in cultured lung endothelial cells . By real time quantitative RT-PCR , we now find a wide P30518 distribution notably in heart , lung and skeletal muscle . These results indicate that DB00035 and other DB02527 -raising agents can activate P29474 via PI3K-independent Ser1177 phosphorylation in human endothelial cells . This mechanism most likely accounts for DB00035 -induced vasodilation . Targeting the epigenome in the treatment of asthma and chronic obstructive pulmonary disease . Epigenetic modification of gene expression by methylation of DNA and various post-translational modifications of histones may affect the expression of multiple inflammatory genes . Acetylation of histones by histone acetyltransferases activates inflammatory genes , whereas histone deacetylation results in inflammatory gene repression . Corticosteroids exert their antiinflammatory effects partly by inducing acetylation of antiinflammatory genes , but mainly by recruiting histone deacetylase-2 ( Q92769 ) to activated inflammatory genes . Q92769 deacetylates acetylated glucocorticoid receptors so that they can suppress activated inflammatory genes in asthma . In chronic obstructive pulmonary disease ( P48444 ) , there is resistance to the antiinflammatory actions of corticosteroids , which is explained by reduced activity and expression of Q92769 . This can be reversed by a plasmid vector , which restores Q92769 levels , but may also be achieved by low concentrations of theophylline . Oxidative stress causes corticosteroid resistance by reducing Q92769 activity and expression by activation of phosphoinositide-3-kinase-delta , resulting in Q92769 phosphorylation via a cascade of kinases . DB00277 reverses corticosteroid resistance by directly inhibiting oxidant-activated O00329 and is mimicked by O00329 knockout or by selective inhibitors . Other treatments may also interact in this pathway , making it possible to reverse corticosteroid resistance in patients with P48444 , as well as in smokers with asthma and some patients with severe asthma in whom similar mechanisms operate . Other histone modifications , including methylation , tyrosine nitration , and ubiquitination may also affect histone function and inflammatory gene expression , and better understanding of these epigenetic pathways could led to novel antiinflammatory therapies , particularly in corticosteroid-resistant inflammation . Histone deacetylase-2 and airway disease . The increased expression of inflammatory genes in inflammatory lung diseases is regulated by acetylation of core histones , whereas histone deacetylase-2 ( Q92769 ) suppresses inflammatory gene expression . Corticosteroids suppress inflammatory genes in asthma by inhibiting histone acetyltransferase and in particular by recruiting Q92769 to the nuclear factor-kappaB-activated inflammatory gene complex . This involves deacetylation of the acetylated glucocorticoid receptor . In P48444 , severe asthma and asthmatics who smoke , Q92769 is reduced , thus preventing corticosteroids from suppressing inflammation . The reduction in Q92769 appears to be secondary to increased oxidative and nitrative stress in the lungs . Antioxidants and inhibitors of nitric oxide synthesis may therefore restore corticosteroid sensitivity in P48444 , but this can also be achieved by low concentrations of theophylline and curcumin , which act as HDAC activators . DB00277 is a direct inhibitor of oxidant-activated phosphoinositide-3-kinase-delta , which is involved in inactivation of Q92769 . In the future selective O00329 inhibitors and more direct activators of Q92769 may be used to treat corticosteroid-resistant inflammatory diseases of the lung , including P48444 , severe asthma and asthma in smokers . Influence of immunomodulatory drugs on the cytotoxicity induced by monoclonal antibody 17-1A and interleukin-2 . Patients treated with monoclonal antibodies and cytokines for cancer receive often co-medication , which may influence treatment efficacy . Therefore , we investigated with a flowcytometric cytotoxicity assay the effect of several immunomodulatory drugs on antibody dependent cellular cytotoxicity ( ADCC ) , interleukin-2 ( P60568 ) induced cytotoxicity and P60568 -induced-ADCC . We found that dexamethasone markedly inhibited the P60568 induced cytotoxicity and the P60568 -induced-ADCC . DB00904 , a P46098 serotonin receptor antagonist augmented significantly ADCC . Clemastine , a histamine type-2 receptor antagonist augmented the P60568 -induced-ADCC . The P01375 antagonist thalidomide suppressed ADCC whereas pentoxifylline proved to be ineffective . Other tested drugs namely ibuprofen and indomethacin , both prostaglandin E2 antagonists , cimetidine a histamine type-2 receptor antagonist , the opioid pethidine , prostaglandin E2 and histamine exerted minor effects or had no influence on the tested parameters . We conclude that glucocorticosteroids should be avoided with monoclonal antibody and cytokine treatment . According to our in vitro data the other drugs tested did not have a negative impact on cellular cytotoxicity and ADCC . Inhibition of inducible nitric oxide synthase in respiratory diseases . DB00435 ( NO ) is a key physiological mediator and disturbed regulation of NO release is associated with the pathophysiology of almost all inflammatory diseases . A multitude of inhibitors of NOSs ( nitric oxide synthases ) have been developed , initially with low or even no selectivity against the constitutively expressed NOS isoforms , P29474 ( endothelial NOS ) and P29475 ( neuronal NOS ) . In the meanwhile these efforts yielded potent and highly selective P35228 ( inducible NOS ) inhibitors . Moreover , P35228 inhibitors have been shown to exert beneficial anti-inflammatory effects in a wide variety of acute and chronic animal models of inflammation . In the present mini-review , we summarize some of our current knowledge of inhibitors of the P35228 isoenzyme , their biochemical properties and efficacy in animal models of pulmonary diseases and in human disease itself . Moreover , the potential benefit of P35228 inhibition in animal models of P48444 ( chronic obstructive pulmonary disease ) , such as cigarette smoke-induced pulmonary inflammation , has not been explicitly studied so far . In this context , we demonstrated recently that both a semi-selective P35228 inhibitor { L-NIL [ N6-(1-iminoethyl)-L-lysine hydrochloride ] } and highly selective P35228 inhibitors ( GW274150 and BYK402750 ) potently diminished inflammation in a cigarette smoke mouse model mimicking certain aspects of human P48444 . Therefore , despite the disappointing results from recent asthma trials , P35228 inhibition could still be of therapeutic utility in P48444 , a concept which needs to be challenged and validated in human disease . Role of breast regression protein-39 in the pathogenesis of cigarette smoke-induced inflammation and emphysema . The exaggerated expression of chitinase-like protein P36222 , the human homologue of breast regression protein-39 ( BRP-39 ) , was reported in a number of diseases , including chronic obstructive pulmonary disease ( P48444 ) . However , the in vivo roles of P36222 in normal physiology or in the pathogenesis of specific diseases such as P48444 remain poorly understood . We hypothesized that BRP-39/ P36222 plays an important role in the pathogenesis of cigarette smoke ( CS ) -induced emphysema . To test this hypothesis , 10-week-old wild-type and BRP-39 null mutant mice ( BRP-39(-/-) ) were exposed to room air ( RA ) and CS for up to 10 months . The expression of BRP-39 was significantly induced in macrophages , airway epithelial cells , and alveolar Type II cells in the lungs of CS-exposed mice compared with RA-exposed mice , at least in part via an Q14116 signaling-dependent pathway . The null mutation of BRP-39 significantly reduced CS-induced bronchoalveolar lavage and tissue inflammation . However , CS-induced epithelial cell apoptosis and alveolar destruction were further enhanced in the absence of BRP-39 . Consistent with these findings in mice , the tissue expression of P36222 was significantly increased in the lungs of current smokers compared with the lungs of ex-smokers or nonsmokers . In addition , serum concentrations of P36222 were significantly higher in smokers with P48444 than in nonsmokers or smokers without P48444 . These studies demonstrate a novel regulatory role of BRP-39/ P36222 in CS-induced inflammation and emphysematous destruction . These studies also underscore that maintaining physiologic concentrations of P36222 in the lung is therapeutically important in preventing excessive inflammatory responses or emphysematous alveolar destruction . Q92769 promotes P06730 sumoylation and activates mRNA translation gene specifically . Histone deacetylases ( HDACs ) are best known as transcription corepressors through deacetylating histone tails . Here we show that Q92769 is also involved in cap-dependent mRNA translation by promoting sumoylation of eukaryotic translation initiation factor 4E ( P06730 ) , which is independent of its deacetylase activity . By stimulating P06730 sumoylation , Q92769 induces the formation of the active eukaryotic initiation factor 4F ( eIF4F ) complex and induces the protein synthesis of a subset of P06730 -responsive genes that are essential for cell proliferation and preventing apoptosis . These data demonstrate that Q92769 has an unexpected sumoylation-promoting activity and regulates cap-dependent mRNA translation . How corticosteroids control inflammation : Quintiles Prize Lecture 2005 . Corticosteroids are the most effective anti-inflammatory therapy for many chronic inflammatory diseases , such as asthma but are relatively ineffective in other diseases such as chronic obstructive pulmonary disease ( P48444 ) . Chronic inflammation is characterised by the increased expression of multiple inflammatory genes that are regulated by proinflammatory transcription factors , such as nuclear factor-kappaB and activator protein-1 , that bind to and activate coactivator molecules , which then acetylate core histones to switch on gene transcription . Corticosteroids suppress the multiple inflammatory genes that are activated in chronic inflammatory diseases , such as asthma , mainly by reversing histone acetylation of activated inflammatory genes through binding of liganded glucocorticoid receptors ( GR ) to coactivators and recruitment of histone deacetylase-2 ( Q92769 ) to the activated transcription complex . At higher concentrations of corticosteroids GR homodimers also interact with DNA recognition sites to active transcription of anti-inflammatory genes and to inhibit transcription of several genes linked to corticosteroid side effects . In patients with P48444 and severe asthma and in asthmatic patients who smoke Q92769 is markedly reduced in activity and expression as a result of oxidative/nitrative stress so that inflammation becomes resistant to the anti-inflammatory actions of corticosteroids . DB00277 , by activating HDAC , may reverse this corticosteroid resistance . This research may lead to the development of novel anti-inflammatory approaches to manage severe inflammatory diseases .