interacts_with DB01285?
Effects of the inhibition of cyclo-oxygenase 1 or 2 or P09917 on the activation of the hypothalamic-pituitary-adrenal axis induced by interleukin-1beta in the male Rat . The limited entry of interleukin-1beta ( IL-1beta ) into the central nervous system has led to the hypothesis that IL-1beta acts , through IL-1beta receptors located notably on endothelial cells , on the release of prostaglandins which in turn stimulate the hypothalamic-pituitary-adrenal ( Q9Y251 ) axis . We used cyclo-oxygenase-1 ( P23219 ) and cyclo-oxygenase-2 ( P35354 ) and P09917 ( 5- P28300 ) inhibitors , before the injection of IL-1beta , to explore the role of arachidonic acid metabolic pathways on Q9Y251 axis activation . Adult male rats were i.m injected 20 min before i.p injection of IL-1beta , with ( i ) : a P23219 / P35354 inhibitor ( ketoprofen ) ; ( ii ) a P35354 selective inhibitor ( NS 398 ) ; or ( iii ) a 5- P28300 inhibitor ( BW A4C ) . Following this , rats were killed 90 min after i.p . IL-1beta injection and analysis for plasma adrenocorticotropic hormone ( DB01285 ) and corticosterone concentrations and determination of anterior pituitary pro-opio melanocortin ( P01189 ) gene transcription was conducted . Administration of the P23219 / P35354 inhibitor led to a complete blockage of DB01285 and corticosterone secretion and P01189 gene transcription . The P35354 inhibitor led to a complete blockade of DB01285 secretion and P01189 gene transcription but had no effect on corticosterone secretion . The 5- P28300 inhibitor had no significant effect on any parameter . These results demonstrate the crucial role of eicosanoid pathways in mediating the stimulation of the Q9Y251 axis induced by IL-1beta . Moreover , we found a clear dissociation of the effect of the blockage of COXs upon DB01285 and corticosterone secretion , suggesting that IL-1beta may act at the brain as well as at the adrenal cortex to stimulate the secretion of corticosterone . Differential changes of corticotropin releasing hormone ( P06850 ) concentrations in plasma and synovial fluids of patients with rheumatoid arthritis ( RA ) . DB01285 releasing hormone ( P06850 ) and DB01285 concentrations in plasma and P06850 and P05231 concentrations in synovial fluid in patients with rheumatoid arthritis ( RA ) were examined to clarify the relationship between cytokines and the hypothalamic-pituitary-adrenal axis ( Q9Y251 axis ) . Concentrations of serum amyloid A protein ( P0DJI8 ) , one of the acute phase proteins , were also measured as an indicator of inflammation . P06850 and P05231 concentrations in synovial fluid were higher in RA patients than in control patients ( osteoarthritis , OA ) . Plasma DB01285 and P06850 levels were significantly lower in RA patients than in OA patients . This suggests that P06850 secretion in synovial fluid is regulated differently from plasma P06850 secretion , as P06850 levels in synovial fluid and plasma showed opposite changes in RA patients . P0DJI8 levels were positively correlated with the levels of P06850 or P05231 in synovial fluid , whereas there was no correlation between P06850 and P05231 levels . The results suggest that P06850 and P05231 play important independent roles in producing P0DJI8 in synovial fluid . P30559 genetic variation relates to empathy and stress reactivity in humans . DB00107 , a peptide that functions as both a hormone and neurotransmitter , has broad influences on social and emotional processing throughout the body and the brain . In this study , we tested how a polymorphism ( rs53576 ) of the oxytocin receptor relates to two key social processes related to oxytocin : empathy and stress reactivity . Compared with individuals homozygous for the G allele of rs53576 ( GG ) , individuals with one or two copies of the A allele ( AG/AA ) exhibited lower behavioral and dispositional empathy , as measured by the " Reading the Mind in the Eyes " Test and an other-oriented empathy scale . Furthermore , AA/AG individuals displayed higher physiological and dispositional stress reactivity than GG individuals , as determined by heart rate response during a startle anticipation task and an affective reactivity scale . Our results provide evidence of how a naturally occurring genetic variation of the oxytocin receptor relates to both empathy and stress profiles . Intracellular retention and degradation of the epidermal growth factor receptor , two distinct processes mediated by benzoquinone ansamycins . Epidermal growth factor ( P01133 ) stimulates the growth of various types of cells via its cell surface tyrosine kinase receptor . The P01133 receptor ( P01133 -R ) has an oncogenic potential when overexpressed in a wide range of tumor cells . DB02424 ( GA ) and herbimycin ( HA ) , specific inhibitors of the cytosolic chaperone P08238 and its endoplasmic reticulum homologue GRP 94 , were shown to accelerate degradation of the P01133 -R and of its homologue p185(c-)(erbB-2) . Here we compared the effects of GA and HA on intracellular degradation and maturation of P01133 -R . By using an inhibitor of proteasomal degradation , we learned that GA , but not HA , blocks processing of newly synthesized P01133 -R . The effects of GA and HA on receptor degradation are mediated by the cytosolic portion of P01133 -R and could be conferred to the erythropoietin receptor ( P19235 ) , by employing the respective chimera . Neither HA nor GA affected stability of newly synthesized P01133 -R lacking the cytosolic domain ( Ex P01133 -R ) , but GA caused intracellular retention of this mutant . Taken together , our results imply that GA has two distinct targets of action on the P01133 -R , one for promoting its degradation and another for mediating its intracellular retention . Apparently , degradation of the P01133 -R mediated by GA or HA requires the presence of the P01133 -R cytosolic domain , whereas intracellular retention in the presence of GA is coupled to the extracellular domain of the P01133 -R . Invasion and metastasis of renal cell carcinoma . Renal cell carcinoma ( RCC ) represents over 80 % of kidney cancer , and about 30 % of the patients with RCC develop metastasis after the surgery . Invasion of basement membrane ( BM ) and extracellular matrix ( Q13201 ) is an essential event in tumor invasion and metastasis . Matrix metalloproteinases ( MMPs ) , which digest the main components of BM and Q13201 , are expressed in RCC . Q9Y251 , which degrades heparan sulfate proteoglycans , is predominantly expressed in high-grade RCCs with a positive correlation with pathological tumor stage and poor prognosis . Bone metastasis is common among the patients with RCC , and increased osteoclastic activity was observed at metastatic sites . Receptor activator of nuclear factor κB ligand ( O14788 ) , which plays an important role in osteoclastogenesis , is predominantly expressed in high-grade RCC and its expression level is associated with bone metastasis and prognosis . Epithelial-mesenchymal transition ( EMT ) , a switch of epithelial cells to sarcomatoid phenotype , is considered to be critical step during metastasis , and Snail , a major regulator of EMT , is predominantly expressed in high-grade RCC , and high Snail expression is a worse prognostic factor . Accordingly , heparanase , O14788 and Snail may be targets for the development of anti-tumor therapies for RCCs . Inhibition of the leukotriene synthetase of rat basophil leukemia cells by diethylcarbamazine , and synergism between diethylcarbamazine and piriprost , a P09917 inhibitor . DB00711 inhibited the formation of sulfidopeptide leukotrienes in rat basophil leukemia ( RBL ) cells ( 50 % inhibitory concentration , EC50 , 3 mM ) . Similar concentrations also inhibited the formation of leukotriene C4 ( LTC4 ) by LTC synthetase , a detergent-solubilized cell free particulate enzyme from RBL cells which is capable of coupling P09960 to glutathione . By contrast , the conversion of P09960 to LTC4 using enzymes from rat liver was at least ten times less sensitive to this inhibitor . The EC50 for inhibition of the leukotriene C synthetase of RBL cells was directly proportional to the P09960 concentration in the incubations , ranging from 1.5 mM at 10 microM P09960 to over 40 mM at 500 microM P09960 . Kinetic analysis revealed that the inhibition of the leukotriene C synthetase reaction by diethylcarbamazine was competitive with respect to P09960 . In contrast to diethylcarbamazine , piriprost ( U-60,257 ; 6,9-deepoxy-6,9-(phenylimino)-delta 6,8-prostaglandin I1 ) , which inhibits the formation of sulfidopeptide leuktrienes in RBL cells at the P09917 step ( EC50 5 microM ) , did not inhibit the leukotriene synthetase of these cells . On the other hand , low concentrations of piriprost , which had no demonstrable inhibitory activity on leukotriene formation by themselves , markedly synergized the inhibitory activity of diethylcarbamazine . These results are consistent with the interpretation that both piriprost and diethylcarbamazine inhibit leukotriene formation but that they act on sequential steps in the biosynthetic pathway in such a manner as to synergistically interfere with the availability or utilization of P09960 in the leukotriene C synthetase reaction . No stress response of the hypothalamo-pituitary-adrenal axis in parturient rats : lack of involvement of brain oxytocin . During parturition , the basal activity of the hypothalamo-pituitary-adrenal ( Q9Y251 ) axis of Wistar rats is strongly attenuated , whereas the oxytocin system is activated . We investigated the secretory responses of the Q9Y251 axis and oxytocin to exposure to a mild emotional stressor ( airpuff ) comparing virgin female , d 22 pregnant , and parturient rats . Furthermore , as the brain oxytocin system is activated in parturition and oxytocin has been shown to inhibit Q9Y251 axis responses in virgin rats , the role of brain oxytocin in the regulation of stress responses during parturition was investigated by intracerebroventricular administration of an oxytocin receptor antagonist before stressor exposure ( 0.75 micro g/5 micro l ) . In virgin female rats , exposure to airpuff increased DB01285 ( 2.5 +/- 0.34-fold ) and corticosterone ( 5.1 +/- 2.3-fold ) secretion , but in late pregnancy and parturition , the stress-induced increase in DB01285 ( pregnancy : 1.9 +/- 0.41-fold ; parturition : 1.3 +/- 0.13-fold ) and corticosterone secretion ( parturition : 1.8 +/- 0.40-fold ) were strongly attenuated . DB00107 secretion remained unchanged in response to airpuff in both virgin and parturient rats despite higher overall plasma concentrations in the latter . P30559 blockade in the brain elevated basal and stress-induced DB01285 secretion in virgin but not pregnant or parturient rats and had no effect on oxytocin secretion either in virgin or parturient rats . We conclude that the reactivity of the Q9Y251 axis to external stressors is strongly attenuated during parturition , and this can not be disinhibited by blocking the receptor-mediated action of brain oxytocin . The effect of choline and cystine on the utilisation of methionine for protein accretion , remethylation and trans-sulfuration in juvenile shrimp Penaeus monodon . This 35-d feeding experiment examined in juvenile shrimp Penaeus monodon ( 3·3 g initial body weight ) the effects of methionine ( DB00134 ) , choline and cystine on protein accretion and the activity of two key enzymes of remethylation ( betaine-homocysteine methyltransferase ; Q93088 ) and trans-sulfuration ( cystathionine β-synthase ; P35520 ) . The interaction between DB00134 and choline was tested using semi-purified diets either adequate or limiting ( 30 or 50 % ) in total sulphur amino acid ( P0DJI8 ) content with a constant cystine: DB00134 ratio . The diets contained either basal or excess choline ( 3 v. 7 g/kg feed ) . Cystine was added to two other 30 and 50 % DB00134 -limiting diets to adjust the P0DJI8 supply to that of the control diet in order to evaluate the interaction between DB00134 and cystine . As expected , N accretion was significantly lower with the P0DJI8 -limiting diets but increased back to control levels by the extra choline or cystine , demonstrating their sparing effect on DB00134 utilisation for protein accretion . We show , for the first time , the activities of Q93088 and P35520 in shrimp hepatopancreas . Only Q93088 responded to the P0DJI8 deficiencies , whereas the extra choline and cystine did not stimulate remethylation or down-regulate trans-sulfuration . Our data also suggest the capacity of P. monodon to synthesise taurine , being significantly affected by the cystine level in the 30 % P0DJI8 -limiting diets . Further research is warranted to better understand the metabolic regulation of taurine synthesis in shrimp and of the observed DB00134 -sparing effects . DB08626 -induced neprilysin inhibition raises amyloid beta levels in rabbit cortex and cerebrospinal fluid . Studies on the pathogenesis of Alzheimer 's disease ( AD ) suggest overproduction of amyloid beta ( Abeta ) may not be the only pathogenic route to AD . Decreased degradation of Abeta is another possible disease mechanism . P08473 is a neutral endopeptidase that has been proposed to be the major enzyme responsible for Abeta degradation . Studies have reported correlations between Abeta deposition and neprilysin activity in the human brain . This study shows that intracerebroventricular infusion of thiorphan , a neprilysin inhibitor , raises cortical and cerebrospinal fluid ( P04141 ) Abeta concentrations in rabbits . Rabbits treated with thiorphan for 5 days had levels of P04141 and cortical Abeta40 that were 147 and 142 % of the control group , respectively . Results for Abeta42 showed a similar trend . The results indicate that age-related decreases of neprilysin could lead to increased brain concentrations of Abeta , plaque formation , and AD . Electroacupuncture activates corticotrophin-releasing hormone-containing neurons in the paraventricular nucleus of the hypothalammus to alleviate edema in a rat model of inflammation . BACKGROUND : Studies show that electroacupuncture ( EA ) has beneficial effects in patients with inflammatory diseases . This study investigated the mechanisms of EA anti-inflammation , using a rat model of complete Freund 's adjuvant ( O75347 ) -induced hind paw inflammation and hyperalgesia . DESIGN : Four experiments were conducted on male Sprague-Dawley rats ( n = 6-7/per group ) . Inflammation was induced by injecting O75347 into the plantar surface of one hind paw . Experiment 1 examined whether EA increases plasma adrenocorticotropic hormone ( DB01285 ) levels . Experiments 2 and 3 studied the effects of the DB01285 and corticotropin-releasing hormone ( P06850 ) receptor antagonists , DB01285 (11-24) and astressin , on the EA anti-edema . Experiment 4 determined whether EA activates P06850 neurons in the paraventricular nucleus of the hypothalammus . EA treatment , 10 Hz at 3 mA and 0.1 ms pulse width , was given twice for 20 min each , once immediately post and again 2 hr post- O75347 . Plasma DB01285 levels , paw thickness , and paw withdrawal latency to a noxious thermal stimulus were measured 2 h and 5 h after the O75347 . RESULTS : EA significantly increased DB01285 levels 5 h ( 2 folds ) after O75347 compared to sham EA control , but EA alone in naive rats and O75347 alone did not induce significant increases in DB01285 . DB01285 (11-24) and astressin blocked EA anti-edema but not EA anti-hyperalgesia . EA induced phosphorylation of Q9UHB4 , an essential subunit of the N-methyl-D-aspartic acid ( DB01221 ) receptor , in P06850 -containing neurons of the paraventricular nucleus . CONCLUSION : The data demonstrate that EA activates P06850 neurons to significantly increase plasma DB01285 levels and suppress edema through P06850 and DB01285 receptors in a rat model of inflammation . Biological and immunological studies of bovine hypothalamic DB05394 . P06850 B ( CRF-B ) is a peptide(s) isolated from bovine hypothalamic extracts by Sephadex G-100 chromatography on the basis of its ability to stimulate secretion of adrenocorticotropin ( DB01285 ) in vitro and in vivo . It is similar in molecular size to the 41-residue ovine CRF ( oCRF ) or rat CRF ( rCRF ) recently elucidated and appears to be their bovine counterpart . Immunoreactivity of CRF-B was examined in homologous radioimmunoassays ( RIAs ) for oCRF or rCRF , using several anti-oCRF and anti-rCRF antibodies . CRF-B cross-reacted well with anti-oCRF antibodies but poorly with anti-rCRF antibodies . Purification of CRF-B with preparative isoelectric focusing yielded four CRF peaks , B-1 ( pH 4.7 ) , B-2 ( pH 5.5 ) , B-3 ( pH 6.3 ) , and B-4 ( pH 7.0 ) , which accounted for 16 , 30 , 46 , and 8 % of the total immunoreactivity , respectively . CRF B-2 , B-3 , and B-4 showed both immunological activity and biological activity in vitro ( cell culture assay ) and in vivo ( Arimura assay ) , whereas CRF B-1 showed only immunoreactivity . Their relative bioactivity/immunoreactivity ratios were 0 ( B-1 ) , 1 ( B-2 ) , 1 ( B-3 ) , and 3 ( B-4 ) . All of these CRF-B subtypes exhibited RIA displacement curves parallel to that for the oCRF standard and coeluted with oCRF on Sephadex G-100 chromatography , which suggests that their molecular modifications are relatively minor . Comparison of the effects of cytoprotective drugs on human plasma adrenocorticotropic hormone and cortisol levels with continual stress exposure . Cetraxate hydrochloride ( cetraxate ) , ecabet sodium ( ecabet ) , and sulpiride , which are cytoprotective drugs , have been used to treat peptic ulcers and acute or chronic gastritis . They are reported to improve mucosal blood flow in the stomach . One of the most important factors believed to cause gastric ulcers is mental and/or physiological stress . When people feel stress , the hypothalamo-pituitary-adrenal ( Q9Y251 ) axis is activated . Therefore , corticotropin-releasing hormone ( P06850 ) , adrenocorticotropic hormone ( DB01285 ) , and cortisol can be indicators of stress . We examined the effects of cetraxate , ecabet and sulpiride on the plasma levels of DB01285 and cortisol under stress conditions by repetitive blood sampling . Venous blood samples were taken before and 20-240 min after a single administration of the drugs or a placebo . A single dose of ecabet caused significant suppression of increases in plasma DB01285 -like immunoreactive substance ( IS ) levels at 90 to 120 min and cortisol levels at 240 min , compared with the response to placebo . DB00391 only suppressed increases in plasma cortisol levels at 180 to 240 min , compared with the response to placebo . A single dose of cetraxate had no effect on plasma DB01285 -IS and cortisol levels . Ecabet may have a modulatory effect on the Q9Y251 axis while sulpiride may have a partial modulatory effect on the Q9Y251 axis . These effects might be beneficial in stress-related disease . DB11582 suppresses osteoclastogenesis induced by O14788 and cancer cells through inhibition of inflammatory pathways : a new use for an old drug . BACKGROUND AND PURPOSE : Most patients with cancer die not because of the tumour in the primary site , but because it has spread to other sites . Common tumours , such as breast , multiple myeloma , and prostate tumours , frequently metastasize to the bone . To search for an inhibitor of cancer-induced bone loss , we investigated the effect of thiocolchicoside , a semi-synthetic colchicoside derived from the plant Gloriosa superba and clinically used as a muscle relaxant , on osteoclastogenesis induced by receptor activator of NF-κB ligand ( O14788 ) and tumour cells . EXPERIMENTAL APPROACH : We used RAW 264.7 ( murine macrophage ) cells , a well-established system for osteoclastogenesis , and evaluated the effect of thiocolchicoside on O14788 -induced NF-κB signalling and osteoclastogenesis as well as on osteoclastogenesis induced by tumour cells . KEY RESULTS : DB11582 suppressed osteoclastogenesis induced by O14788 , and by breast cancer and multiple myeloma cells . Inhibition of the NF-κB pathway was responsible for this effect since the colchicoside inhibited O14788 -induced NF-κB activation , activation of IκB kinase ( IKK ) and suppressed inhibitor of NF-κBα ( IκBα ) phosphorylation and degradation , an inhibitor of NF-κB . Furthermore , an inhibitor of the IκBα kinase γ or NF-κB essential modulator , the regulatory component of the IKK complex , demonstrated that the NF-κB signalling pathway is mandatory for osteoclastogenesis induced by O14788 . CONCLUSIONS AND IMPLICATIONS : Together , these data suggest that thiocolchicoside significantly suppressed osteoclastogenesis induced by O14788 and tumour cells via the NF-κB signalling pathway . Thus , thiocolchicoside , a drug that has been used for almost half a century to treat muscle pain , may also be considered as a new treatment for bone loss . Effects of short- and long-duration hypothyroidism on hypothalamic-pituitary-adrenal axis function in rats : in vitro and in situ studies . The purpose of this study is to assess the effects of hypothyroidism on the hypothalamic-pituitary-adrenal ( Q9Y251 ) axis ; the functional integrity of each component of the Q9Y251 axis was examined in short-term and long-term hypothyroidism . Neuropeptide synthesis , release , and content were evaluated in vitro both in the hypothalamus and anterior pituitary , and corticosterone release was assessed in primary adrenal cell cultures at 7 ( short-term ) and 60 days ( long-term hypothyroidism ) after thyroidectomy in male rats . Hypothyroid rats showed adrenal insufficiency in several parameters , which were associated with the duration of hypothyroidism . Cerebrospinal ( P04141 ) DB01285 was decreased in all hypothyroid animals , while P04141 corticosterone levels were significantly decreased only in long-term hypothyroidism . Long-term hypothyroid animals showed decreased corticotropin-releasing hormone ( P06850 ) mRNA expression in the hypothalamic paraventricular nucleus under both basal and stress conditions , decreased P06850 release from hypothalamic organ cultures after KCL and arginine vasopressin stimulation , as well as an increased number of anterior pituitary P06850 receptors . In contrast , short-term hypothyroid rats showed changes in anterior pituitary function with an increased responsiveness to P06850 that was associated with an increase in P06850 receptors . Although both short- and long-term hypothyroidism was associated with significant decreases in adrenal weights , only long-term hypothyroid rats showed changes in adrenal function with a significant decrease of DB01285 -induced corticosterone release from cultured adrenal cells . The data suggest that long-term hypothyroidism is associated with adrenal insufficiency with abnormalities in all three components of the Q9Y251 axis . Short-term hypothyroidism , on the other hand , is associated with increased pituitary corticotroph responsiveness to P06850 . P06850 enhances the invasiveness and migration of Ishikawa cells , possibly by increasing matrix metalloproteinase-2 and matrix metalloproteinase-9 . P06850 ( P06850 ) , synthesized in the hypothalamus , is also produced at several extrahypothalamic sites and in normal endometrial cells . P06850 exerts antiproliferative activity on oestrogen-dependent tumour cell lines ( Ishikawa cells and breast cancer cells ) via the P06850 receptor-1 . This study investigated the potential role of P06850 as a factor affecting endometrial migration and invasion in Ishikawa cells , and the possible mechanisms involved in this process . Increasing concentrations of P06850 ( 1 , 10 and 100 nM ) significantly reduced the proliferation of Ishikawa cells but increased the invasiveness these cells compared with the control group . All three concentrations of P06850 significantly increased matrix metalloproteinase ( MMP ) -2 and P14780 levels in Ishikawa cells . In conclusion , P06850 inhibited the growth of Ishikawa cells but enhanced their invasiveness , possibly by increasing P08253 and P14780 levels . These findings suggest that P06850 might induce invasion and migration by upregulating P08253 and P14780 in endometrial cancer . A new cell culture-based assay quantifies vitamin K 2,3-epoxide reductase complex subunit 1 function and reveals warfarin resistance phenotypes not shown by the dithiothreitol-driven Q9BQB6 assay . BACKGROUND : DB00682 directly inhibits the vitamin K 2,3-epoxide reductase complex subunit 1 ( Q9BQB6 ) enzyme to effect anticoagulation . Q9BQB6 function has historically been assessed in vitro using a dithiothreitol ( DTT ) -driven vitamin K 2,3-epoxide reductase ( Q9BQB6 ) assay . DB00682 inhibits wild-type Q9BQB6 function by the DTT- Q9BQB6 assay . However , Q9BQB6 variants with warfarin resistance-associated missense mutations often show low Q9BQB6 activities and warfarin sensitivity instead of resistance . OBJECTIVES : A cell culture-based , indirect Q9BQB6 assay was developed and characterized that accurately reports warfarin sensitivity or resistance for wild-type and variant Q9BQB6 proteins . METHODS : Human coagulation factor (F)IX and Q9BQB6 variants were coexpressed in P29320 293T cells under standardized conditions at various warfarin concentrations . Secreted FIX activity served as surrogate marker to report wild-type and variant Q9BQB6 inhibition by warfarin . RESULTS AND CONCLUSIONS : DB00682 dose-response curves fit to the secreted FIX activity data for coexpressed hVKORC1 wild-type , Val29Leu , Val45Ala and Leu128Arg variants . The corresponding calculated IC50 values were 24.7 , 136.4 , 152.0 and 1226.4 nm , respectively . Basal activities in the absence of warfarin for all Q9BQB6 variants were similar to that of wild-type Q9BQB6 . Ranked IC50 values from the cell culture-based assay accurately reflect elevated warfarin dosages for patients with Q9BQB6 missense mutation-associated warfarin resistance . DB05258 /beta promotes cell survival by activating nuclear factor kappa B through phosphatidylinositol 3-kinase and Akt . Interferons ( IFNs ) play critical roles in host defense by modulating gene expression via activation of signal transducer and activator of transcription ( P35610 ) factors . IFN-alpha/beta also activates another transcription factor , nuclear factor kappaB ( NF-kappaB ) , which protects cells against apoptotic stimuli . NF-kappaB activation requires the IFN-dependent association of P40763 with the P17181 chain of the IFN receptor . IFN-dependent NF-kappaB activation involves the sequential activation of a serine kinase cascade involving phosphatidylinositol 3-kinase ( PI-3K ) and Akt . Whereas constitutively active PI-3K and Akt induce NF-kappaB activation , Ly294002 ( a PI-3K inhibitor ) , dominant-negative PI-3K , and kinase-dead Akt block IFN-dependent NF-kappaB activation . Moreover , dominant-negative PI-3K blocks IFN-promoted degradation of kappaBox alpha . Ly294002 , a dominant-negative PI-3K construct , and kinase-dead Akt block IFN-promoted cell survival , enhancing apoptotic cell death . Therefore , P40763 , PI-3K , and Akt are components of an IFN signaling pathway that promotes cell survival through NF-kappaB activation . Binding affinities for sulfonamide inhibitors with matrix metalloproteinase-2 using a linear response method . Due to their involvement in many pathological conditions , matrix metalloproteinases ( MMPs ) , are very attractive therapeutic targets . Our study focuses on one of them , P08253 , which is involved in tumor progression and metastasis . Recently , the solution structure of the catalytic domain of P08253 complexed with a hydroxamic acid inhibitor ( DB01630 ) was published by Feng et al . Using the Hanessian group published binding affinity data and the structure published by Feng as a basis , we have built a binding affinity model by targeting the S(2) ' pocket of the enzyme with a set of nine alpha-N-sulfonylamino hydroxamic acid derivatives . Two binding geometries of each ligand have been generated corresponding to two binding modes denoted A and B , respectively , of which the first one is targeting the S(2) ' pocket and the second one the S(1) pocket . For the binding affinity model developed for mode A the computed activities show a rmsd of 0.583 kcal/mol as compared with the experimental data , and a correlation coefficient r(2) of 0.779 , while in the case of the binding mode B a rmsd of 0.834 kcal/mol and correlation coefficient r(2) of 0.500 , respectively , were obtained . In conclusion , our data suggest a higher probability for the DB00120 (76) gated S(2) ' open form pocket to accommodate the substituent alpha versus the wide solvent exposed S(1) subsite , probability which some research groups could have overlooked due to extensive use in their calculations of non revealing S(2) ' pocket open state crystallographic structures instead of NMR ones . The role of corticotropin-releasing hormone receptor 1 in the development of colitis-associated cancer in mouse model . Patients with ulcerative colitis are at a very high risk of developing colorectal cancer . DB01285 -releasing hormone ( P06850 ) family peptides and their receptors ( CRHRs ) are found to modulate inflammation and tumor cell growth . However , the role of P06850 family peptides and their receptors in the inflammation-related colon cancer is still unknown . The aim of this study was to investigate the functions of P34998 signaling on the development of colitis-associated cancer ( CAC ) . Crhr1-deficient ( Crhr1(-/-) ) mice were used to explore the role of P34998 in the development of azoxymethane ( AOM ) and dextran sodium sulfate ( DSS ) -induced CAC . WT ( Crhr1(+/+) ) littermates were set as control . We found that the expression of P34998 and its endogenous ligands : urocortin and P06850 were enhanced in the colon of Crhr1(+/+) mice during treatment with AOM and DSS . Tumorigenesis was significantly reduced in Crhr1(-/-) mice , determined by analysis of survival rate ( increased by 20 % ) , weight loss ( decreased by 10 % ) , tumor formation ( decreased by 60 % in tumor number ) , histological scores ( decreased by 58 % ) , and cytokine production . During early CAC tumorigenesis , Crhr1(-/-) mice exhibited much less tumorigenesis , accompanied by lower inflammatory response , including decreased IL1β , P05231 and TNFα expression and macrophage infiltration and increased P22301 expression . Moreover , Crhr1(-/-) mice displayed a reduced activation of NFκB and P40763 phosphorylation with decreased proliferating and enhanced apoptotic cells in the colon . In conclusion , P34998 has a proinflammatory and therefore a protumorigenesis effect in terms of CAC , which may be helpful to develop new therapeutic approaches for inflammation and cancer prevention and treatment . A novel spliced variant of the type 1 corticotropin-releasing hormone receptor with a deletion in the seventh transmembrane domain present in the human pregnant term myometrium and fetal membranes . P06850 exerts its actions via activation of specific G protein-coupled receptors , which exist in two types , P34998 and Q13324 , and arise from different genes with multiple spliced variants . RT-PCR amplification of P06850 receptor sequences from human myometrium and fetal membranes yielded cDNAs that encode a novel P06850 -R type 1 spliced variant . This variant ( P06850 -R1d ) is present in the human pregnant myometrium at term only , which suggests a physiologically important role at the end of human pregnancy and labor . The amino acid sequence of P06850 -R1d is identical to the P06850 -R1alpha receptor except that it contains an exon deletion resulting in the absence of 14 amino acids in the predicted seventh transmembrane domain . Binding studies in P29320 -293 cells stably expressing the P06850 -R1d or P06850 -R1alpha receptors revealed that the deletion does not change the binding characteristics of the variant receptor . In contrast , studies on the G protein activation demonstrated that P06850 -R1d is not well coupled to the four subtypes of G proteins ( G(s) , G(i) , G(o) , G(q) ) that P06850 -R1alpha can activate . These data suggest that although the deleted segment is not important for P06850 binding , it plays a crucial role in P06850 receptor signal transduction . Second messenger studies of the variant receptor showed that P06850 and P06850 -like peptides can stimulate the adenylate cyclase system , with reduced sensitivity and potency by 10-fold compared with the P06850 -R1alpha . Furthermore , P06850 failed to stimulate inositol trisphosphate production . Coexpression studies between the P06850 -R1d or P06850 -R1alpha showed that this receptor does not play a role as a dominant negative receptor for P06850 . Endocytosis of the vasopressin receptor by anterior pituitary cells is increased by DB05394 ( CRF ) . Endocytosis of certain receptors such as the transferrin receptor and the P01133 -receptor appears to be influenced by second messengers . If second messengers are involved in modulation of endocytosis , not only endocytosis of the stimulated receptor itself but also of receptors for other ligands on the cell surface may be influenced by receptor occupancy . P06850 ( CRF ) and vasopressin act synergistically on secretion of DB01285 from the anterior pituitary . The results presented here demonstrate that CRF increases retrieval of the vasopressin receptor in anterior pituitary cells in primary culture without influencing the surface binding of vasopressin . This is not a function of an increased membrane turnover since endocytosis of the transferrin receptor is not influenced by CRF .