interacts_with DB01427?
The immunological effects of electrolyzed reduced water on the Echinostoma hortense infection in C57BL/6 mice . Electrolyzed reduced water ( ERW ) is widely used for drinking by people in Asia . The purpose of this study was to examine the immunological effect of ERW on the immunity of animals by supplying ERW to C57BL/6 mice infected with Echinostoma hortense metacercariae . In the non-infected groups , interleukin ( IL ) -4 ( p < 0.001 ) , P05113 , P22301 , IL-1beta , tumor necrosis factor ( P01375 ) -alpha and immunoglobulin ( Ig ) A expression of the group fed ERW ( ERW group ) increased in small intestine compared with the normal control group . In the case of infected groups , the group fed ERW ( ERW+E. hortense group ) showed the result that P05112 , P05113 , P22301 and Ig A expression increased , but IL-1beta and P01375 ( p < 0.001 ) decreased , and the number of goblet cells ( p < 0.001 ) and helix pomatia agglutinin ( Q9Y251 ) positive cells increased compared with the group without feeding ERW . However , adult worm recovery rate was markedly increased ( p < 0.05 ) . On the other hand , the expression of all the cytokines except P22301 in spleen was mildly increased but not significant statistically , and there was no significant difference in the numerical changes of white blood cell ( WBC ) . These results indicate that feeding ERW may have influence on the local immune response ( Th-1 type cytokines such as IL-1beta , P01375 ) in the small intestine but not on the systemic immune response . Effect of the phosphodiesterase III inhibitor amrinone on cytokine and nitric oxide production in immunostimulated J774.1 macrophages . The level of intracellular cyclic nucleotides is a regulatory factor in a variety of immune processes . Increases in intracellular cyclic AMP ( DB02527 ) and/or cyclic GMP ( cGMP ) concentration by the inhibition of phosphodiesterase have been shown to modulate the inflammatory response . DB01427 is a clinically used positive inotropic agent which elevates intracellular DB02527 and cGMP levels by selective inhibition of the phosphodiesterase III isoenzyme . In the current study , we investigated the effect of various concentrations ( 1-300 microM ) of amrinone on lipopolysaccharide-induced production of pro- and anti-inflammatory cytokines and of nitric oxide ( NO ) in vitro . In cultured murine J774.1 macrophages , 1 ng/ml-10 microg/ml of lipopolysaccharide from Escherichia coli O55: P46977 induced production of tumor necrosis factor-alpha ( P01375 ) , interleukin-10 , and nitrite ( breakdown product of NO ) . Pretreatment of cells with amrinone caused a dose-dependent suppression of P01375 production in the concentration range of 1-100 microM . Furthermore , this drug suppressed NO production in the range of 30-300 microM . Similarly to the results in the J774.1 cells , amrinone also inhibited P01375 and NO production in the range of 10-100 microM in primary rat peritoneal macrophages . At 300 microM , but not at lower concentrations , amrinone inhibited interleukin-10 production in lipopolysaccharide-treated J774.1 macrophages . Pretreatment of the macrophages with 100 and 300 microM amrinone increased the lipopolysaccharide-elicited translocation of nuclear factor-kappa B . Taken together , our results indicate that the phosphodiesterase III inhibitor amrinone modulates the activation/production of many pro- and anti-inflammatory factors in endotoxin-stimulated cells . It remains to be further investigated how such immunomodulatory effects contribute to the clinical profile of the agent . Effects of the total saponins from Rosa laevigata Michx fruit against acetaminophen-induced liver damage in mice via induction of autophagy and suppression of inflammation and apoptosis . The effect of the total saponins from Rosa laevigata Michx fruit ( RLTS ) against acetaminophen ( DB00316 ) -induced liver damage in mice was evaluated in the present paper . The results showed that RLTS markedly improved the levels of liver SOD , CAT , DB00143 , DB00143 -Px , MDA , NO and P35228 , and the activities of serum ALT and Q9NRA2 caused by DB00316 . Further research confirmed that RLTS prevented fragmentation of DNA and mitochondrial ultrastructural alterations based on TdT-mediated dUTP nick end labeling ( TUNEL ) and transmission electron microscopy ( TEM ) assays . In addition , RLTS decreased the gene or protein expressions of cytochrome P450 ( P05181 ) , pro-inflammatory mediators ( IL-1β , P05112 , P05231 , P01375 -α , P35228 , Bax , HMGB-1 and P35354 ) , pro-inflammatory transcription factors ( NF-κB and AP-1 ) , pro-apoptotic proteins ( cytochrome C , p53 , caspase-3 , caspase-9 , p-JNK , p-p38 and p- P29323 ) , and increased the protein expressions of Bcl-2 and Bcl-xL . Moreover , the gene expression of P22301 , and the proteins including LC3 , Q14457 and Atg5 induced by DB00316 were even more augmented by the extract . These results demonstrate that RLTS has hepatoprotective effects through antioxidative action , induction of autophagy , and suppression of inflammation and apoptosis , and could be developed as a potential candidate to treat DB00316 -induced liver damage in the future . [ Functional characteristics of calcium-sensitive adenylyl cyclase of ciliate Tetrahymena pyriformis ] . DB01373 -sensitive forms of adenylyl cyclase ( AC ) were revealed in most vertebrates and invertebrates and also in some unicellular organisms , in particular ciliates . We have shown for the first time that calcium cations influence the AC activity of ciliate Tetrahymena pyriformis . These cations at the concentrations of 0.2-20 microM stimulated the enzyme activity , and maximum of catalytic effect was observed at 2 microM Ca2+ . DB01373 cations at a concentrations of 100 microM or higher inhibited the AC activity . P62158 antagonists W-5 and W-7 at the concentrations of 20-100 microM inhibited the catalytic effect induced by 5 microM Ca2+ and blocked the effect at higher concentrations of Ca2+ . DB00477 , another calmodulin antagonist , reduced Ca2+-stimulated AC activity only at the concentrations of 200-1000 microM . AC stimulating effects of serotonin , P01133 and DB02527 increased in the presence of 5 microM Ca2+ . AC stimulating effects of P01133 , DB02527 and insulin decreased in the presence of 100 microM Ca2+ , and AC stimulating effect of DB02527 decreased also in the presence of calmodulin antagonists ( 1 mM ) . At the same time , stimulating effect of D-glucose in the presence of Ca2+ and calmodulin antagonists did not change essentially . The data obtained speak in favor of the presence of calcium-sensitive forms of AC in ciliate T. pyriformis which mediate enzyme stimulation by P01133 , DB02527 , insulin , and serotonin . Modulation of cytokine release from human monocytes by drugs used in the therapy of inflammatory bowel diseases . BACKGROUND : Cytokines produced in the gut mucosa play an important role in the pathogenesis of inflammatory bowel diseases ( Q9UKU7 ) . To determine whether drugs used in the treatment of these diseases modulate cytokine synthesis , we investigated their effects on endotoxin-induced tumour necrosis factor ( P01375 ) -alpha , interleukin ( IL ) -1 beta and P05231 release by elutriation-purified human monocytes in vitro . METHODS : Drugs tested were dexamethasone , DB00244 , sulphapyridine and zileuton ( a P09917 inhibitor ) . Monocytes were isolated and stimulated with endotoxin , and P01375 , IL-1 and P05231 levels were determined using an enzyme-linked immunosorbent assay . RESULTS : Monocyte stimulation with endotoxin resulted in an average P01375 release of 2464 +/- 64 pg/10(6) cells , IL-1 release of 616 +/- 47 pg/10(6) cells and P05231 release of 2259 +/- 148 pg/10(6) cells . Addition of dexamethasone resulted in a reduction of P01375 , IL-1 and P05231 release to below background levels . DB00891 significantly reduced P01375 and induced IL-1 release in a dose-dependent fashion , but had no significant effect on P05231 release . 5- DB00233 did not modulate P05231 synthesis , but significantly reduced IL-1 and enhanced P01375 synthesis . Zileuton reduced P01375 and P05231 release , but enhanced IL-1 release . CONCLUSION : We conclude that these anti-inflammatory drugs are able to modulate cytokine release by human monocytes . Further studies are needed to determine whether these effects are related to their therapeutic efficacy in Q9UKU7 . Molecular and biologic characterization of a newly established Philadelphia-positive acute lymphoblastic leukemia cell line ( Z-33 ) with an autocrine response to GM- P04141 . We have recently established a new Philadelphia chromosome ( Ph1 ) -positive acute lymphoblastic leukemia ( ALL ) cell line , designated Z-33 . This line has Q401N2 morphology , ultrastructural characteristics of lymphoblasts and typical B lineage surface markers identical to those observed in the Ph1-positive ALL patient from whom the line was derived . In addition , a rearranged immunoglobulin heavy-chain gene ( JH ) band was found in Z-33 cells by Southern blot analysis , confirming B cell clonality . Cytogenetic analysis of the cell line revealed t(9;22)(q34;q11.2) . Polymerase chain reaction ( PCR ) -amplified cDNA from Z-33 cells demonstrated an e1-az P11274 - P00519 junction , and the p190BCR- P00519 protein was detected in them by the immune complex kinase assay . Z-33 cells produce interleukin ( IL ) -1 beta , P05231 , granulocyte colony-stimulating factor ( DB00099 ) , granulocyte-macrophage P04141 ( GM- P04141 ) , tumor necrosis factor ( P01375 ) -alpha , and transforming growth factor ( TGF ) -beta , Neither P01584 , DB00099 , P01375 , nor their corresponding antibodies affected the cell line 's growth . In contrast , anti-GM- P04141 neutralizing antibodies suppressed Z-33 colony formation , and GM- P04141 stimulated it in a dose-dependent fashion . In addition , receptor studies with biotinylated GM- P04141 demonstrated specific binding to Z-33 cells , indicating that the cells express GM- P04141 receptors . Taken together , our data suggest that the Ph1-positive Z-33 ALL cells produce GM- P04141 , express GM- P04141 receptors , and show an autocrine proliferative response to this cytokine . Nongenomic , glucocorticoid receptor-mediated regulation of serotonin transporter cell surface expression in embryonic stem cell derived serotonergic neurons . Depressive disorders have been linked to the combined dysregulation of the hypothalamus-pituitary-adrenal ( Q9Y251 ) -axis and the serotonergic system . The Q9Y251 -axis and serotonergic ( 5-HT ) neurons exert reciprocal regulatory actions . It has been reported that glucocorticoid-glucocorticoid receptor ( GR ) signaling influences serotonin transporter ( 5-HTT ) transcription but data also points to the fact that 5-HTT expression is regulated nongenomically via redistribution of 5-HTT from the cell surface into intracellular compartments . In order to analyze the acute effects of glucocorticoids on 5-HTT cell surface localization we differentiated serotonergic neurons from mouse embryonic stem ( ES ) cells derived from the C57BL/6N blastocysts . These postmitotic 5-HT neurons express all relevant serotonergic markers following the application of a growth factor-based differentiation protocol . Increasing concentrations of the GR agonist dexamethasone ( DB00514 ) resulted in enhanced , dose-dependent 5-HTT cell surface localization in the presence of the protein synthesis inhibitor cycloheximide already 1h after incubation . Inhibition of GR function by the specific GR-antagonist mifepristone abolished the increase in 5-HTT cell surface localization . Hence , our data account for a nongenomic upregulation of 5-HTT cell surface expression by glucocorticoid-GR interaction which likely constitutes a rapid physiological response to increased levels of glucocorticoids as seen during stress . Taken together , we provide a cellular model to analyze and dissect glucocorticoid- P31645 interactions on a molecular level that corresponds to in vivo animal models using C57BL/6N mice . DB00227 -stimulated superinduction of P16581 , P05362 and P19320 in P01375 activated human vascular endothelial cells . Inhibitors of P04035 ( statins ) reveal important pharmacological effects in addition to reducing the plasma LDL cholesterol level . In the pathogenesis of arteriosclerosis , transendothelial migration of various leukocytes including monocytes is a crucial step . We , therefore , investigated the expression of P16581 , intercellular cell adhesion molecule-1 ( P05362 ) and vascular cell adhesion molecule-1 ( P19320 ) in vascular endothelial cells as influenced by lovastatin . Human umbilical vein endothelial cells ( HUVECs ) express significant amounts of selectins and cell adhesion molecules ( CAMs ) within a few hours after stimulation with P01375 . This effect is potentiated by 100-200 % when the cells are pretreated with 0.1-2.5 microM lovastatin . The lovastatin-mediated increase in the cytoplasm and at the cell surface is dose-dependent and significant at lovastatin concentrations comparable to plasma levels in patients under lovastatin treatment . The lovastatin-potentiated increase of P16581 and CAMs is correlated with a corresponding increase of selectin- and P62158 -specific mRNA . We conclude that , in vivo , statin treatment could trigger an enhanced recruitment of macrophages that might support the cholesteryl ester efflux from the arteriosclerotic plaque . Cordycepin suppresses P01375 -α-induced NF-κB activation by reducing p65 transcriptional activity , inhibiting IκBα phosphorylation , and blocking IKKγ ubiquitination . Cordycepin is reported to participate in multiple pharmacological activities including anti-tumor and anti-inflammation , and is involved in the regulation of NF-κB signaling pathway . However , the detailed molecular mechanism of cordycepin in suppression of NF-κB signaling pathway remains ambiguous . In this study , we first analyzed the effect of cordycepin on NF-κB activity in P29320 -293T cells , and found that cordycepin resulted in a dose-dependent reduction in P01375 -α-induced NF-κB activation . Although cordycepin did not block P01375 -α-induced nuclear translocation of p65 , high concentration of cordycepin reduced the DNA-binding and transcriptional activities of NF-κB . Moreover , cordycepin also inhibited IκBα phosphorylation so as to suppress the degradation of IκBα . Further investigation revealed that cordycepin suppressed IKKs-mediated NF-κB activation and inhibited the ubiquitination of IKKγ . In conclusion , cordycepin effectively inhibits NF-κB signaling through suppressing the activities of NF-κB , IκB and IKK . Thus , cordycepin may provide some potential therapeutic application in inflammation-associated disorders and cancer . Anxiety-like behavior in the elevated-plus maze tests and enhanced IL-1β , P05231 , NADPH oxidase-1 , and P35228 mRNAs in the hippocampus during early stage of adjuvant arthritis in rats . We studied anxiety-like behavior in the elevated plus-maze ( EPM ) tests in male Lewis rats on days 2 and 4 of adjuvant arthritis ( AA ) . In plasma we analyzed P02741 ( CRP ) , albumin , DB01285 , corticosterone , in the hippocampus the mRNA expression of interleukin-1β ( IL-1β ) , interleukin-6 ( P05231 ) , corticotrophin releasing factor ( P06850 ) , NADPH oxidases Q9Y5S8 and P04839 , and inducible NO-synthase ( P35228 ) . EPM tests showed a higher anxiety index in AA rats on days 2 and 4 and reduction of total entries . On days 2 and 4 we found reduced plasma albumin , enhanced CRP , DB01285 and corticosterone , and in the hippocampus enhanced mRNA for Q9Y5S8 and IL-1β in AA rats , on day 4 we found enhanced mRNAs for P35228 and P05231 , and reduced mRNA for P06850 . The mRNA for P04839 did not change on any experimental day . These results suggest enhanced anxiety , as well as locomotor impairment during the early phase of AA that correlate with enhanced mRNA expressions of parameters of oxidative stress Q9Y5S8 , P35228 , and inflammatory cytokines IL-1β and P05231 in the hippocampus . DB04946 binding to human and rat dopamine and 5-HT receptors . DB04946 ( DB04946 ; 1- [ 4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy] -3- methoxyphenyl ] ethanone ) is a compound currently in clinical trials for the treatment of schizophrenia . DB04946 displays affinity for dopamine D2 receptors and for 5- Q13049 receptors and has a variety of in vivo activities suggestive of an atypical antipsychotic . Here we present an examination of the affinity of iloperidone to a variety of human and rat homologs of dopamine and 5-HT receptor subtypes . We employed receptor binding assays using membranes from cells stably expressing human dopamine D1 , D2S , D2L , D3 , D4 and D5 and 5- Q13049 and P28335 receptors and rat P50406 and P34969 receptors . DB04946 displayed higher affinity for the dopamine D3 receptor ( Ki = 7.1 nM ) than for the dopamine D4 receptor ( Ki = 25 nM ) . DB04946 displayed high affinity for the P50406 and P34969 receptors ( Ki = 42.7 and 21.6 nM , respectively ) , and was found to have higher affinity for the 5- Q13049 ( Ki = 5.6 nM ) than for the P28335 receptor ( Ki = 42.8 nM ) . The potential implications of this receptor binding profile are discussed in comparison with data for other antipsychotic compounds . Sexually dimorphic stress and pro-inflammatory cytokine responses to an intravenous corticotropin-releasing hormone challenge of Brahman cattle following transportation . This study was designed to characterize potential sexually dimorphic stress and immunological responses following a corticotropin-releasing hormone ( P06850 ) challenge in beef cattle . Six female ( heifers ) and six male ( bulls ) Brahman calves ( 264 ± 12 d of age ) were administered P06850 intravenously ( 0.5 µg of P06850 /kg body mass ) after which serum concentrations of cortisol increased from 0.5 h to 4 h . From 1 h to 4 h after P06850 administration , serum cortisol concentrations were greater in heifers than in bulls . In all cattle , increased serum concentrations of P01375 -α , P05231 and IFN-γ were observed from 2.5 h to 3 h after P06850 , with greater concentrations of IFN-γ and P05231 in heifers than bulls . Heifer total leukocyte counts decreased 1 h after P06850 administration , while bull leukocyte counts and percent neutrophils decreased 2 h after P06850 administration . Heifers had greater rectal temperatures than bulls , yet rectal temperatures did not change following administration of P06850 . There was no effect of P06850 administration on heart rate . However , bulls tended to have increased heart rate 2 h after P06850 administration than before P06850 . Heifer heart rate was greater than bulls throughout the study . These data demonstrate that acute P06850 administration can elicit a pro-inflammatory response , and cattle exhibit a sexually dimorphic pro-inflammatory cytokine and cortisol response to acute P06850 administration . Gating properties of Q14524 mutations and the response to mexiletine in long-QT syndrome type 3 patients . BACKGROUND : DB00379 ( Mex ) has been proposed as a gene-specific therapy for patients with long-QT syndrome type 3 ( LQT3 ) caused by mutations in the cardiac sodium channel gene ( Q14524 ) . The degree of QT shortening and the protection from arrhythmias vary among patients harboring different mutations . We tested whether the clinical response to Mex in LQT3 could be predicted by the biophysical properties of the different mutations . METHODS AND RESULTS : We identified 4 Q14524 mutations in 5 symptomatic LQT3 patients with different responses to Mex ( 6 to 8 mg . kg(-1) . d(-1) ) . We classified the mutations as sensitive to Mex ( P1332L , R1626P ; >/= 10 % of QTc shortening and QTc < 500 ms or no arrhythmias ) or insensitive to Mex ( S941N , M1652R ; negligible or no QTc shortening and sudden death ) . We measured Na(+) current from P29320 293 cells transfected with wild-type ( WT ) or mutant Nav1.5 . All mutations showed impaired inactivation of Na(+) current , but the mutations identified in patient responders to Mex ( P1332L , R1626P ) showed a hyperpolarizing shift of V(1/2) of steady-state inactivation . Furthermore , Mex produced use-dependent block with the order R1626P=P1332L > S941N=WT > M1652R , suggesting that Mex-sensitive mutants present prolonged recovery from Mex block . CONCLUSIONS : We propose that voltage dependence of channel availability and shifts of V(1/2) of steady-state inactivation correlate with the clinical response observed in LQT3 patients . This supports the view that the response to Mex is mutation specific and that in vitro testing may help to predict the response to therapy in LQT3 . Acute effects of sarpogrelate , a 5- Q13049 receptor antagonist on cytokine production in endotoxin shock model of rats . Serotonin ( 5-HT ) (2A) receptors are involved in cytokine production in infection or sepsis . Therefore , 5-HT(2A) receptor antagonist might be useful to treat sepsis . The present study investigates the effects of a 5-HT(2A) receptor antagonist , sarpogrelate on endotoxin shock . Catheters were inserted into the femoral artery and vein of Sprague-Dawley rats . First , sarpogrelate 0 ( control ) , 3 , or 10 mg/kg dissolved in 0.5 ml of distilled water has been given , followed by endotoxin 10 mg/kg in saline 0.5 ml 5 min later . Blood pressure , pulse rate and survival rate were monitored in 20 rats per dose . Blood gas and plasma cytokine concentrations were measured in 8 rats per dose . In four rats each of sarpogrelate 0 , 3 , or 10 mg/kg , and sham operation , the lung histology was examined . Zero , 15 , and 12 rats survived for 8 h in the control , 3 mg/kg , and 10 mg/kg groups , respectively . The control group had the lowest blood pressure , pulse rate , pH and arterial oxygen tension , and the highest arterial carbon dioxide tension and plasma IL-1beta concentration . The increase of P01375 was significantly lower in 3 mg/kg group than in the control group . Pathological changes of the lung were inhibited in 3 and 10 mg/kg groups . In conclusion , sarpogrelate might be effective to decrease production of pro-inflammatory cytokines , to keep hemodynamics , to inhibit lung damage , and to decrease mortality in endotoxin shock . Myocardial tumor necrosis factor-alpha secretion in hypertensive and heart failure-prone rats . Acute increases in blood pressure ( BP ) increase myocardial tumor necrosis factor ( P01375 ) -alpha production , but it is not known whether chronic hypertensive stress elevates myocardial P01375 production , possibly contributing to cardiac remodeling , decreased cardiac function , and faster progression to heart failure . BP , cardiac function , and size were evaluated in normotensive [ Sprague-Dawley ( SD ) ] , spontaneously hypertensive ( SHR ) , and spontaneously hypertensive heart failure-prone ( SHHF ) rats at 6 , 12 , 15 , and 18 mo of age and in failing SHHF . Left ventricular tissues were evaluated for secretion of bioactive P01375 and inhibition of P01375 secretion by phosphodiesterase inhibitors . All ventricles secreted bioactive and immunoreactive P01375 , but secretion decreased with age . SHR and SHHF rats secreted more P01375 than SD rats at 6 mo of age , but only failing SHHF rats secreted significantly more P01375 at 18 mo . DB01427 inhibited P01375 secretion in all rats and was less potent but more efficacious than RO-201724 in all strains . P01375 secretion correlated with BP and left ventricular mass in 6-mo-old rats , but this relationship disappeared with age . Results suggest that hypertension and/or cardiac remodeling is associated with elevated myocardial P01375 , and , although hypertension , per se , did not maintain elevated cardiac P01375 levels , SHHF rats increase P01375 production during the end stages of failure . Microglial activation , increased P01375 and P31645 expression in the prefrontal cortex define stress-altered behaviour in mice susceptible to anhedonia . A chronic stress paradigm comprising exposure to predation , tail suspension and restraint induces a depressive syndrome in C57BL/6J mice that occurs in some , but not all , animals . Here , we sought to extend our behavioural studies to investigate how susceptibility ( sucrose preference < 65 % ) or resilience ( sucrose preference > 65 % ) to stress-induced anhedonia affects the 5HT system and the expression of inflammation-related genes . All chronically stressed animals , displayed increased level of anxiety , but susceptible mice exhibited an increased propensity to float in the forced swim test and demonstrate hyperactivity under stressful lighting conditions . These changes were not present in resilient or acutely stressed animals . Compared to resilient animals , susceptible mice showed elevated expression of tumour necrosis factor alpha ( P01375 ) and the 5-HT transporter ( P31645 ) in the pre-frontal area . Enhanced expression of 5HT(2A) and P23219 in the pre-frontal area was observed in all stressed animals . In turn , indoleamine-2,3-dioxygenase ( P14902 ) was significantly unregulated in the raphe of susceptible animals . At the cellular level , increased numbers of Iba-1-positive microglial cells were also present in the prefrontal area of susceptible animals compared to resilient animals . Consequently , the susceptible animals display a unique molecular profile when compared to resilient , but anxious , animals . Unexpectedly , this altered profile provides a rationale for exploring anti-inflammatory , and possibly , P01375 -targeted therapy for major depression . DB00104 and the novel multireceptor ligand somatostatin receptor agonist pasireotide ( DB06663 ) block the adrenalectomy-induced increase in mitotic activity in male rat anterior pituitary . The novel somatostatin receptor agonist pasireotide binds with high affinity to somatostatin receptors P30872 , 2 , 3 , and 5 . Acting principally through the latter , it inhibits basal and P06850 -stimulated DB01285 secretion from the AtT20 corticotroph cell line and DB01285 release from a proportion of human corticotroph adenomas both in vitro and in vivo . Data supporting an additional antiproliferative effect has led to pasireotide being explored as a potential therapy for patients with Cushing 's disease . We have compared the effects of pasireotide and octreotide on adrenalectomy-induced mitotic and apoptotic activity in the male rat anterior pituitary . Adrenalectomized rats were treated with daily sc injections of vehicle , pasireotide , or octreotide . Changes in proliferation and apoptosis were determined 2-6 d postoperatively . DB06663 and octreotide had no effect on baseline pituitary cell turnover and no measurable effects on apoptosis . However , the wave of increased mitotic activity normally seen in the pituitary after adrenalectomy was completely abolished . Nevertheless , pasireotide and octreotide did not diminish the increase in DB01285 -immunopositive cell index after adrenalectomy , indicating that cell division and differentiation of hormonally null cells in the pituitary are under independent control . In conclusion , basal cell turnover in the pituitary is not inhibited by pasireotide or octreotide . Bilateral adrenalectomy stimulates differentiation of preexisting null cells into DB01285 -positive cells . Cell division after bilateral adrenalectomy occurs in a specific subpopulation of hormonally null cells that are equally sensitive to the antiproliferative effects of pasireotide and octreotide , implicating P30874 receptors in this antimitotic response . Acute renal failure from hemoglobinuric and interstitial nephritis secondary to iodine and mefenamic acid . DB00784 ingestion , usually in excess and over prolonged period is known to produce interstitial nephritis , or less commonly papillary necrosis , with acute renal failure . However , it is not dose-dependent for the induction of tubulointerstitial damage . Excess iodine ingestion is known to produce toxicity and possible death , but acute renal failure is rare . There is evidence from clinical and experimental data that iodine has toxic effect on tubular epithelial cells . Iodine has not been documented to produce red cell hemolysis and hemoglobinuria . We present a unique case of acute renal failure from hemoglobinuric and acute interstitial nephritis secondary to suicidal ingestion of potassium iodide solution and also ingestion of a few mefenamic acid tablets . These agents led to potentiation of the renal injury from hemoglobinuric tubulopathy , probably from the iodine , and renal dysfunction from alteration of renal perfusion by selective P23219 inhibition of prostaglandin production , and induction of acute interstitial nephritis from mefenamic acid , leading to acute renal failure which was reversible by hemodialysis and supportive therapy . DB01427 suppresses the synthesis of tumor necrosis factor-alpha in human mononuclear cells . P01375 -alpha ( P01375 ) exerts a wide spectrum of biological activities and contributes to the pathophysiology of septic shock . Elevated circulating levels of P01375 have also been reported in patients with severe chronic heart failure . We studied the effect of amrinone , a class III cyclic nucleotide phosphodiesterase inhibitor used in the treatment of acute heart failure , on the synthesis of P01375 in vitro . Peripheral blood mononuclear cells from healthy volunteers or cells of a permanent monoblast cell line were stimulated for 20 h with bacterial lipopolysaccharide and different doses of amrinone . P01375 production is suppressed in a dose-dependent manner to a minimum of 9 % of controls with 1000 microM of amrinone , reaching half-maximal inhibition at 80 microM amrinone . This effect appears to be mediated via DB02527 , which accumulated nearly twofold in the presence of amrinone . Suppression of P01375 synthesis by therapeutically administered phosphodiesterase inhibitors such as amrinone may contribute to their beneficial effect in the treatment of heart failure . Phosphodiesterase 4 inhibitor cilomilast inhibits fibroblast-mediated collagen gel degradation induced by tumor necrosis factor-alpha and neutrophil elastase . Tissue destruction , resulting in emphysema , can be a consequence of several pathologic processes . The current study evaluated the effects of the phosphodiesterase (PDE)4 inhibitor , cilomilast , and other PDE inhibitors on the ability of fibroblasts to degrade extracellular matrix . Using the three-dimensional collagen gel culture system , fibroblasts ( HFL-1 ) were cultured with tumor necrosis factor ( P01375 ) -alpha , known to induce matrix metalloproteinase ( MMP ) release , and/or neutrophil elastase ( NE ) , which can induce MMP activation . On Day 4 , gels containing P01375 and NE were significantly degraded ( 20.8 +/- 2.9 % of original collagen content ) . DB03849 ( 10 micro M ) inhibited this degradation ( 84.4 +/- 8.4 % ) . DB01427 , a PDE3 inhibitor , and zaprinast , a O76074 inhibitor , had no effect . Gelatin zymography and immunoblotting revealed that fibroblasts cultured with P01375 released increased amounts of latent P03956 and -9 . The addition of NE resulted in the conversion of P03956 and -9 to their active forms , indicative of collagen degradation . DB03849 inhibited the release of P03956 and -9 , as well as conversion of P03956 to its active form . Using real-time PCR analysis , cilomilast 's effect on P03956 release was not associated with the proteinase 's mRNA expression , suggesting that the inhibition of release is regulated at the post-transcriptional level . These results suggest that cilomilast may be a potentially effective therapeutic agent in diseases characterized by excessive tissue destruction , such as emphysema . Synergism between bosutinib ( DB06616 ) and the Chk1 inhibitor ( PF-00477736 ) in highly imatinib-resistant P11274 /ABL⁺ leukemia cells . Interactions between the dual P11274 / P00519 and Src inhibitor bosutinib and the Chk1 inhibitor PF-00477736 were examined in P11274 / P00519 (+) leukemia cells , particularly imatinib-resistant cells , including those with the T315I mutation . Bosutinib blocked PF-00477736-induced P27361 /2 activation and sharply increased apoptosis in association with Mcl-1 inhibition , p34(cdc2) dephosphorylation , BimEL up-regulation , and DNA damage in imatinib-resistant CML or Ph(+) ALL cell lines . Inhibition of Src or Q02750 by shRNA significantly enhanced PF-0047736 lethality . Bosutinib/PF-00477736 co-treatment also potentiated cell death in P28906 (+) CML patient samples , including dasatinib-resistant blast crisis cells exhibiting both T315I and E355G mutations , but was minimally toxic to normal P28906 (+) cells . Finally , combined in vivo treatment significantly suppressed BaF3/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 . DB01427 and theophylline differentially regulate cytokine and nitric oxide production in endotoxemic mice . Intracellular cyclic nucleotide levels play an important role in the regulation of several immunological processes . Since elevation of intracellular cyclic adenosine monophosphate and/or cyclic guanosine monophosphate concentration by inhibition of phosphodiesterase ( PDE ) is known to modulate the inflammatory response , we compared the effect of amrinone , an inhibitor of the PDE III isoenzyme , and of theophylline , a nonspecific PDE inhibitor , on the plasma tumor necrosis factor-alpha ( P01375 ) , interleukin-6 ( P05231 ) , interleukin-10 ( P22301 ) , and nitric oxide response in mice to intraperitoneal injection of bacterial lipopolysaccharide ( LPS ) . Intraperitoneal treatment of animals with amrinone ( 100 mg/kg ) 30 min before LPS administration decreased both plasma P05231 and P22301 concentrations in the first phase of the response , but enhanced plasma levels of these cytokines in the second part . In contrast , pretreatment of the animals with theophylline ( 100 mg/kg ) enhanced LPS-induced plasma P05231 and P22301 levels during the whole response . However , pretreatment with both PDE inhibitors resulted in a marked inhibition of LPS-evoked plasma concentrations of P01375 and nitrite/nitrate ( breakdown products of nitric oxide ) throughout the response . This study demonstrates for the first time that amrinone and theophylline possess differential , but primarily anti-inflammatory , properties during LPS-induced systemic inflammation in the mouse . Establishment of a double Philadelphia chromosome-positive acute lymphoblastic leukemia-derived cell line , TMD5 : effects of cytokines and differentiation inducers on growth of the cells . A double Philadelphia chromosome ( Ph ) -positive leukemia cell line with common-B cell phenotype , designated TMD5 , was established from the blast cells of a patient with double Ph-positive acute lymphoblastic leukemia . TMD5 cells expressed 190 kDa P11274 / P00519 chimeric protein and 145 kDa P00519 protein . The cells proliferated without added growth factors . Autocrine growth mechanism was not recognized . The addition of growth factors such as DB00099 , GM- P04141 , P08700 , P05231 , or Stem Cell Factor did not affect the growth . Herbimycin A suppressed the growth of TMD5 cells at the low concentration that did not affect Ph-negative cells . It suppressed tyrosine phosphorylation of intracellular proteins in TMD5 cells . Dexamethasone and dibutyryl cyclic AMP also suppressed the growth . They , however , did not affect the phosphorylation significantly . Neither all-trans retinoic acid nor interferon-alpha affected the growth . TMD5 cells , characterized minutely here and rare in that they have double Ph chromosomes , will be a useful tool for the study of Ph-positive leukemia . Pharmacological modulation of myocardial tumor necrosis factor alpha production by phosphodiesterase inhibitors . Phosphodiesterase ( PDE ) inhibitors are used as therapeutic agents for management of congestive heart failure . PDE inhibitors are potent inotropic and vasodilator drugs , which have also been shown to inhibit tumor necrosis factor alpha ( P01375 ) production . P01375 is a pleiotropic cytokine that has the ability to produce cardiac depressant and other cardiovascular effects in many disease conditions . P01375 levels are elevated in patients with chronic congestive heart failure , and it is possible that P01375 may play a role in this condition . The effects of PDE inhibitors on P01375 secretion from rat heart were evaluated in this study . Rat left ventricle was minced and incubated for 4 hr with various PDE inhibitors , and the amount of P01375 secretion was evaluated by cytotoxicity assay . Ro-20 , 1724 , etazolate , amrinone , milrinone and pentoxifylline inhibited unstimulated P01375 production , with IC50 values of 1.87 , 2.07 , 13.9 , 153 and 201 microM , respectively . Lipopolysaccharide-induced P01375 secretion from rat left ventricle was also evaluated in this study . DB01427 , milrinone and pentoxifylline inhibited lipopolysaccharide-induced P01375 secretion , with IC50 values of 14.8 , 81.6 and 748 microM , respectively , whereas Ro-2D , 1724 and etazolate had no effect on lipopolysaccharide-induced P01375 secretion . These results demonstrated that P01375 was secreted from rat left ventricle after 4 hr and different pharmacological manipulations were able to inhibit the secretion of P01375 from left ventricle . These initial pharmacological results may provide an important tool for further investigation into the beneficial effects of PDE inhibitors in congestive heart failure or other conditions where P01375 levels are elevated . The use of cytokine inhibitors . A new therapeutic insight into heart failure . Cytokines are being increasingly recognized as important factors in the pathogenesis and pathophysiology of heart failure . Elevated levels of circulating cytokines have been reported in patients with heart failure , and various cytokines have been shown to depress myocardial contractility in vitro and in vivo . We have recently compared the effects on cytokine production of drugs for therapy of heart failure that have different effects on survival . DB01427 , pimobendan and vesnarinone , phosphodiesterase III inhibitors that have been shown to have short term haemodynamic benefits , inhibited P01375 production . Differential modulation of the production of IL-1beta and P05231 was observed ; amrinone and pimobendan enhanced the production of IL-1beta , whereas vesnarinone did not . As inotropic agents differentially modulate cytokine production , these agents may interfere with induction of inducible nitric oxide ( NO ) synthase through an inhibition of cytokine formation . Although differential modulation of the production of NO by inotropic agents may explain their different effect in patients with heart failure , further study is necessary to reach this conclusion . We have shown that amlodipine increases the survival of mice with viral myocarditis and inhibits expression of inducible NO synthase and production of NO in vivo and in vitro . The therapeutic effect of amlodipine may in part result from inhibition of overproduction of NO . As we learn more about the pathophysiological and pathogenetic role of cytokines in heart failure , it should be possible to design better and more targeted pharmacological agents . Furthermore , the investigation of inotropic agents that are effective against the production of cytokines may help in the classification of these agents .