interacts_with DB04817?
A comparative study of the antipyretic effects of indomethacin and dipyrone in rats . OBJECTIVE : Compare the antipyretic effects of dipyrone and indomethacin . MATERIALS AND METHODS : Fever was induced in rats by i. v. LPS or i . c . v. interleukins ( IL ) , prostaglandins ( PG ) , arachidonic acid ( AA ) , pre-formed pyrogenic factor ( PFPF ) , tumour necrosis factor-alpha ( P01375 ) or corticotrophin releasing hormone ( P06850 ) . DB04817 and indomethacin were administered i.p. , arginine vasopressin V1-receptor antagonist , d(CH2)5 DB00135 (Me)AVP , into the ventral septal area . Cyclooxygenase ( P23219 /-2 ) blocking activity was assessed in transfected COS-7 cells . P06850 release from isolated hypothalami was determined by ELISA . RESULTS : Indomethacin or dipyrone reduced LPS , IL-1beta , P05231 or P01375 induced fever and P06850 release from rat hypothalamus . Only dipyrone inhibited P10145 , PFPF or PGF2alpha fever . Only indomethacin inhibited fever induced by AA or IL-1beta , plus AA . Neither antipyretic affected fever caused by DB00917 or P06850 . d(CH2)5Tyr(Me)AVP only blocked antipyresis induced by indomethacin . DB04817 at a very high concentration ( 10 mM ) inhibited only P23219 , while indomethacin ( 0.1 microM ) blocked P23219 and P35354 in COS-7 cells . CONCLUSION : The antipyretic effect of dipyrone differs from that of indomethacin in that it does not depend on AVP release or inhibition of PG synthesis . Suppression of androgen receptor-mediated gene expression by a sequence-specific DNA-binding polyamide . P10275 ( AR ) is essential for the growth and progression of prostate cancer in both hormone-sensitive and hormone-refractory disease . A DNA-binding polyamide that targets the consensus androgen response element binds the prostate-specific antigen ( PSA ) promoter androgen response element , inhibits androgen-induced expression of PSA and several other AR-regulated genes in cultured prostate cancer cells , and reduces AR occupancy at the PSA promoter and enhancer . Down-regulation of PSA by this polyamide was comparable to that produced by the synthetic antiandrogen bicalutamide ( DB01128 ) at the same concentration . Genome-wide expression analysis reveals that a similar number of transcripts are affected by treatment with the polyamide and with bicalutamide . Direct inhibition of the AR-DNA interface by sequence-specific DNA binding small molecules could offer an alternative approach to antagonizing AR activity . Cannabinoid receptor activation induces apoptosis through tumor necrosis factor alpha-mediated ceramide de novo synthesis in colon cancer cells . PURPOSE : Cannabinoids have been recently proposed as a new family of potential antitumor agents . The present study was undertaken to investigate the expression of the two cannabinoid receptors , P21554 and CB2 , in colorectal cancer and to provide new insight into the molecular pathways underlying the apoptotic activity induced by their activation . EXPERIMENTAL DESIGN : Cannabinoid receptor expression was investigated in both human cancer specimens and in the DLD-1 and HT29 colon cancer cell lines . The effects of the P21554 agonist arachinodyl-2'-chloroethylamide and the CB2 agonist N-cyclopentyl-7-methyl-1-(2-morpholin-4-ylethyl)-1,8-naphthyridin-4(1H)-on-3-carboxamide ( CB13 ) on tumor cell apoptosis and ceramide and tumor necrosis factor ( P01375 ) -alpha production were evaluated . The knockdown of P01375 mRNA was obtained with the use of selective small interfering RNA . RESULTS : We show that the P21554 receptor was mainly expressed in human normal colonic epithelium whereas tumor tissue was strongly positive for the CB2 receptor . The activation of the P21554 and , more efficiently , of the CB2 receptors induced apoptosis and increased ceramide levels in the DLD-1 and HT29 cells . Apoptosis was prevented by the pharmacologic inhibition of ceramide de novo synthesis . The CB2 agonist CB13 also reduced the growth of DLD-1 cells in a mouse model of colon cancer . The knockdown of P01375 mRNA abrogated the ceramide increase and , therefore , the apoptotic effect induced by cannabinoid receptor activation . CONCLUSIONS : The present study shows that either P21554 or CB2 receptor activation induces apoptosis through ceramide de novo synthesis in colon cancer cells . Our data unveiled , for the first time , that P01375 acts as a link between cannabinoid receptor activation and ceramide production . Growth factors expression in patients with erosive esophagitis . Although the pathogenesis and treatment of erosive esophagitis ( EE ) is well recognized , little is known about the cellular and molecular mechanisms of mucosal healing in EE patients . In this pilot study , we enrolled typical EE patients to evaluate what kinds of growth factors and their receptors were activated in their injured esophageal mucosa . Forty endoscopically proved EE patients were consecutively enrolled . Messenger RNA expressions , which includes keratinocyte growth factor ( KGF ) and its receptor ( P21802 ) , epidermal growth factor ( P01133 ) and its receptor ( P00533 ) , hepatocyte growth factor ( P14210 ) and its receptor ( HGFR ) , basic fibroblast growth factor ( P09038 ) , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase ( P36551 ) -1 and P35354 , were measured using real-time polymerase chain reaction ( PCR ) . Data were compared between the injured EE mucosa and their normal esophageal mucosa above EE . The mRNA expressions of P14210 , HGFR , P01133 , P15692 , and P35354 , but not P00533 , KGF , P21802 , P09038 , and P23219 , were significantly increased in the injured mucosa of EE patients compared with those of normal mucosa ( P < 0.05 ) . The study found that P14210 , HGFR , P01133 , P15692 , and , P35354 are activated in the injured mucosa of EE patients ; their activation might be involved in mucosal repair and ulcer healing of EE . Gene expression by PBMC in primary sclerosing cholangitis : evidence for dysregulation of immune mediated genes . Primary sclerosing cholangitis ( PSC ) is a chronic disease of the bile ducts characterized by an inflammatory infiltrate and obliterative fibrosis . The precise role of the immune system in the pathogenesis of PSC remains unknown . We used RNA microarray analysis to identify immune-related genes and pathways that are differentially expressed in PSC . Messenger RNA ( mRNA ) from peripheral blood mononuclear cells ( PBMC ) was isolated from both patients with PSC and age and sex matched healthy controls . Samples from 5 PSC patients and 5 controls were analyzed by microarray and based upon rigorous statistical analysis of the data , relevant genes were chosen for confirmation by RT-PCR in 10 PSC patients and 10 controls . Using unsupervised hierarchical clustering , gene expression in PSC was statistically different from our control population . Interestingly , genes within the P60568 receptor beta , P05231 and Q96HU1 Kinase pathways were found to be differently expressed in patients with PSC compared to controls . Further , individual genes , P01375 induced protein 6 ( TNFaip6 ) and membrane-spanning 4-domains , subfamily A ( ms4a ) were found to be upregulated in PSC while similar to Q99717 ( Q99717 ) was downregulated . In conclusion , several immune-related pathways and genes were differentially expressed in PSC compared to control patients , giving further evidence that this disease is systemic and immune-mediated . Role of the androgen receptor axis in prostate cancer . P10275 ( AR ) is expressed in nearly all prostate cancers , including treatment-refractory disease . The role of this receptor in the molecular endocrinology of prostate cancer has become increasingly clear in recent years . The AR is now known to participate in tumor progression through 3 mechanisms : expression ( activation and upregulation of receptor activity ) , point mutations , and ligand-independent activation . With regard to the latter mechanism , interleukin-6 ( P05231 ) is among the most important nonsteroidal regulators of AR activity . In the absence of androgen , P05231 causes activation of AR that is approximately 50 % of the maximal activity induced by androgen . At low concentrations of androgen , P05231 and androgen synergistically activate AR . Nonsteroidal antiandrogens usually antagonize this activation , but they switch to an agonist effect in the presence of oncostatin M , an P05231 -related cytokine . The growth of parental LNCaP cells is initially inhibited by exposure to P05231 , but long-term treatment renders the cells resistant to such inhibition and confers a growth advantage . Both P05231 and oncostatin M stimulate AR activity , but only oncostatin M is associated with strong acquisition of the agonist properties of nonsteroidal antiandrogens . It is hoped that continuing research on AR expression and function in prostate cancer will pave the way for new therapeutic strategies . Q99572 receptor-dependent intestinal afferent hypersensitivity in a mouse model of postinfectious irritable bowel syndrome . The DB00171 -gated P2X(7) receptor ( P2X(7)R ) was shown to be an important mediator of inflammation and inflammatory pain through its regulation of IL-1β processing and release . Trichinella spiralis-infected mice develop a postinflammatory visceral hypersensitivity that is reminiscent of the clinical features associated with postinfectious irritable bowel syndrome . In this study , we used P2X(7)R knockout mice ( P2X(7)R(-/-) ) to investigate the role of P2X(7)R activation in the in vivo production of IL-1β and the development of postinflammatory visceral hypersensitivity in the T. spiralis-infected mouse . During acute nematode infection , IL-1β-containing cells and P2X(7)R expression were increased in the jejunum of wild-type ( WT ) mice . Peritoneal and serum IL-1β levels were also increased , which was indicative of elevated IL-1β release . However , in the P2X(7)R(-/-) animals , we found that infection had no effect upon intracellular , plasma , or peritoneal IL-1β levels . Conversely , infection augmented peritoneal P01375 -α levels in both WT and P2X(7)R(-/-) animals . Infection was also associated with a P2X(7)R-dependent increase in extracellular peritoneal lactate dehydrogenase , and it triggered immunological changes in both strains . Jejunal afferent fiber mechanosensitivity was assessed in uninfected and postinfected WT and P2X(7)R(-/-) animals . Postinfected WT animals developed an augmented afferent fiber response to mechanical stimuli ; however , this did not develop in postinfected P2X(7)R(-/-) animals . Therefore , our results demonstrated that P2X(7)Rs play a pivotal role in intestinal inflammation and are a trigger for the development of visceral hypersensitivity . DB01032 reduces infection and inflammation in acute Pseudomonas aeruginosa pneumonia . The activation of inflammasome signaling mediates pathology of acute Pseudomonas aeruginosa pneumonia . This suggests that the inflammasome might represent a target to limit the pathological consequences of acute P. aeruginosa lung infection . Q96RD7 ( Px1 ) channels mediate the activation of caspase-1 and release of IL-1β induced by Q99572 receptor activation . The approved drug probenecid is an inhibitor of Px1 and DB00171 release . In this study , we demonstrate that probenecid reduces infection and inflammation in acute P. aeruginosa pneumonia . Treatment of mice prior to infection with P. aeruginosa resulted in an enhanced clearance of P. aeruginosa and reduced levels of inflammatory mediators , such as IL-1β . In addition , probenecid inhibited the release of inflammatory mediators in murine alveolar macrophages and human U937 cell-derived macrophages upon bacterial infection but not in human bronchial epithelial cells . Thus , Px1 blockade via probenecid treatment may be a therapeutic option in P. aeruginosa pneumonia by improving bacterial clearance and reducing negative consequences of inflammation . Anti-inflammatory activity of Taraxacum officinale . Taraxacum officinale has been widely used as a folkloric medicine for the treatment of diverse diseases . The dried plant was extracted with 70 % ethanol to generate its ethanol extract ( TEE ) . For some experiments , ethyl acetate ( EA ) , n-butanol ( BuOH ) and aqueous ( Aq ) fractions were prepared in succession from TEE . TEE showed a scavenging activity in the 1,1-diphenyl-2-picrylhydrazyl ( DPPH ) assay , a diminishing effect on intracellular reactive oxygen species ( ROS ) level , and an anti-angiogenic activity in the chicken chorioallantoic ( P62158 ) assay . In the carrageenan-induced air pouch model , TEE inhibited production of exudate , and significantly diminished nitric oxide ( NO ) and leukocyte levels in the exudate . It also possessed an inhibitory effect on acetic acid-induced vascular permeability and caused a dose-dependent inhibition on acetic acid-induced abdominal writhing in mice . Suppressive effects of TEE on the production of NO and expression of inducible nitric oxide synthase ( P35228 ) and cyclooxygenase-2 ( P35354 ) in lipopolysaccharide ( LPS ) -stimulated macrophages were also assessed . Among the fractions , the n-butanol fraction ( BuOH ) was identified to be most effective in the P62158 assay . Collectively , Taraxacum officinale contains anti-angiogenic , anti-inflammatory and anti-nociceptive activities through its inhibition of NO production and P35354 expression and/or its antioxidative activity . 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 . DB00316 -inhibitable P35354 . Although paracetamol potently reduces pain and fever , its mechanism of action has so far not been satisfactorily explained . It inhibits both P23219 and P35354 weakly in vitro , but reduces prostaglandin synthesis markedly in vivo . In mouse macrophage J774.2 cells , P35354 induced for 48 hr with high concentrations of NSAIDs is more sensitive to inhibition with paracetamol than endotoxin-induced P35354 . In the rat pleurisy model of inflammation , a second peak of P35354 protein appears 48 hr after administration of the inflammatory stimulus , during the resolution phase of the inflammatory process . Inhibition of the activity of this late-appearing P35354 with indomethacin or a selective P35354 inhibitor , delays resolution and the inflammation is prolonged . Cultured lung fibroblasts also express P35354 activity after stimulation with IL-1beta which is highly sensitive to inhibition with paracetamol . Thus , evidence is accumulating for the existence of a P35354 variant or a new P36551 enzyme which can be inhibited with paracetamol . Novel agents that potentially inhibit irinotecan-induced diarrhea . DB00762 ( CPT-11 , 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin ) has exhibited clinical activities against a broad spectrum of carcinomas by inhibiting P11387 ( Topo I ) . However , severe and unpredictable dosing-limiting toxicities ( mainly myelosuppression and severe diarrhea ) hinder its clinical use . The latter consists of early and late-onset diarrhea , occurring within 24 hr or > or = 24 hr after CPT-11 administration , respectively . This review highlights novel agents potentially inhibiting CPT-11-induced diarrhea , which are designed and tested under guidance of disposition pathways and potential toxicity mechanisms . Early-onset diarrhea is observed immediately after CPT-11 infusion and probably due to the inhibition of acetylcholinesterase activity , which can be eliminated by administration of atropine . Late-onset diarrhea appears to be associated with intestinal exposure to SN-38 ( 7-ethyl-10-hydroxycamptothecin ) , the major active metabolite of CPT-11 , which may bind to Topo I and induce apoptosis of intestinal epithelia , leading to the disturbance in the absorptive and secretory functions of mucosa . CPT-11 and SN-38 may also stimulate the production of pro-inflammatory cytokines and prostaglandins ( PGs ) , thus inducing the secretion of Na(+) and Cl(-) . Early treatment of severe late-onset diarrhea with oral high-dose loperamide has decreased patient morbidity . Extensive studies have been conducted to identify other potential agents to ameliorate diarrhea in preclinical and clinical models . These include intestinal alkalizing agents , oral antibiotics , enzyme inducers , P-glycoprotein ( PgP ) inhibitors , cyclooxygenase-2 ( P35354 ) inhibitors , tumor necrosis factor-alpha ( P01375 ) inhibitors , or blockers of biliary excretion of SN-38 . Further studies are needed to identify the molecular targets associated with CPT-11 toxicity and safe and effective agents for alleviating CPT-11-induced diarrhea . [ DB01373 signaling mediated by nicotine receptors in neurons ] . DB00184 has many acute and chronic pharmacological effects . DB00184 treatment activates neuronal nicotinic acetylcholine receptors ( nAChR ) in peripheral and central nervous systems leading to depolarization and elevation of intracellular calcium levels , which are considered to cause stimulation of neurotransmitter release , synaptic transmission , intracellular signal transduction and gene expression . Multiple subtypes of nAChRs display different sensitivity to nicotinic agonists and antagonists . Each of these subtypes has a unique distribution in peripheral and central nervous systems . Although presynaptic nAChRs have been extensively studied to modulate the release of neurotransmitters , the functional importance of nAChRs in somata is not sufficiently characterized . To clarify the mechanisms of calcium signaling and its stimulation of gene expression via nAChRs in somata , we have investigated nAChR-mediating calcium signaling mechanisms including phosphorylation of Q8NFH3 /44 Q96HU1 kinase ( P29323 ) , CREB and Akt in PC12h cells . DB00184 transiently activates phosphorylation of P29323 - , CREB and Akt . DB00184 induces the activation of both P19957 kinase/Act and P29323 /CREB pathways via common pathways including non-alpha 7-nAChRs , L-type VSCC , P62158 kinase and P00533 in PC12h cells , but Src family tyrosine kinases only participate in the pathway to activate Akt . Based on these results , we discuss nAChR signaling mechanisms in neurons . 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 . Novel bioactive metabolites of dipyrone ( metamizol ) . DB04817 is a common antipyretic drug and the most popular non-opioid analgesic in many countries . In spite of its long and widespread use , molecular details of its fate in the body are not fully known . We administered dipyrone orally to mice . Two unknown metabolites were found , viz. the arachidonoyl amides of the known major dipyrone metabolites , 4-methylaminoantipyrine ( 2 ) and 4-aminoantipyrine ( 3 ) . They were identified by P19957 -LC-MS/MS after extraction from the CNS , and comparison with reference substances prepared synthetically . The arachidonoyl amides were positively tested for cannabis receptor binding ( CB(1) and CB(2) ) and cyclooxygenase inhibition ( P23219 and P35354 in tissues and as isolated enzymes ) , suggesting that the endogenous cannabinoid system may play a role in the effects of dipyrone against pain . Involvement of the Q99572 purinergic receptor and c-Jun N-terminal and extracellular signal-regulated kinases in cyclooxygenase-2 and prostaglandin E2 induction by LL-37 . Periodontal disease is caused by microorganisms and host-derived inflammation involving increased cyclooxygenase-2 ( P35354 ) expression and prostaglandin E(2) ( PGE(2) ) production . We previously demonstrated that human β-defensin-3 induces P35354 and PGE(2) in human gingival fibroblasts ( HGFs ) . We , therefore , aimed to examine the inducible effects of LL-37 , the only cathelicidin expressed in humans , on P35354 expression and PGE(2) synthesis in HGFs and to elucidate the relevant signaling pathways . The P35354 expression was upregulated by LL-37 in dose- and time-dependent manners . Accordingly , the synthesis of PGE(2) in cell-free culture supernatants was raised by LL-37 ( p < 0.01 ) and blocked by NS-398 , a specific P35354 inhibitor ( p < 0.01 ) . P2X inhibitors and a neutralizing antibody against P2X(7) purinergic receptor significantly abrogated P35354 induction and PGE(2) production by LL-37 ( p < 0.01 ) . LL-37 upregulated P35354 expression and PGE(2) synthesis via activation of extracellular signal-regulated kinase ( P29323 ) and Q9BY77 c-Jun N-terminal kinase ( JNK ) , while interleukin-1β did so via nuclear factor-ĸB and all three mitogen-activated protein kinases . In summary , LL-37 can control arachidonic acid metabolism by induction of P35354 expression and PGE(2) synthesis via the P2X(7) receptor , P29323 , and Q9BY77 JNK . The pro-inflammatory effects of LL-37 may be essential for initiating oral mucosal inflammation in periodontal disease . Inhibition of cyclooxygenase-2 elicits a P21554 -mediated decrease of excitatory transmission in rat P00915 hippocampus . Cannabinoid receptor ( P21554 ) ligands decrease excitatory and inhibitory transmission in the hippocampus , but the influence of endogenously formed cannabinoids ( eCBs ) on basal excitatory transmission remains uncertain . Here , we investigated the influence of eCBs on synaptic transmission in P00915 hippocampus using the slice preparation . Blockade of P21554 with the selective receptor antagonists SR141716 ( rimonabant ) or AM251 augmented synaptic responses evoked upon stimulation of the Schaffer collaterals . This effect persisted in the presence of bicuculline or CGP55845 to block GABA(A) or GABA(B) receptors , revealing a tonic eCB influence on excitatory transmission . Selective inhibition of cyclooxygenase-2 ( P35354 ) with meloxicam or NS-398 decreased excitatory responses partly in a P21554 -dependent manner , independently of GABA(A) transmission . Paired-pulse paradigms suggested a presynaptic P21554 mechanism to decrease glutamate release . Inhibition of P23219 or other routes of eCB degradation did not affect synaptic transmission . We conclude that P35354 regulates the formation of P21554 ligands that decrease hippocampal excitatory transmission . Immunohistochemical analysis of carcinomatous and sarcomatous components in the uterine carcinosarcoma : a case report . Uterine carcinosarcoma ( malignant mixed Mullerian tumor ) is an uncommon female genital tract neoplasm characterized by an admixture of epithelial and stromal malignant cells . We report a case of 50-year-old peri-menopausal woman diagnosed to have early-stage ( IB due to FIGO ) uterine carcinosarcoma of the homologous type with superficial ( 3mm ) myo-invasion . The patient showed no clinical symptoms of the disease and had no family history of female genital tract malignancies . Positive immunostaining for steroid receptors ( estrogen-alpha and progesterone receptors ) , cytokeratin , and P00533 was detected only in the carcinomatous area , whereas beta-catenin , BCL-2 , P35354 , p16(INK4a) , P60484 , Q8IUH3 , and vimentin were immunoreactive in both components . P10275 , CD10 , desmin , HER-2/neu , and P04637 were found to be negative either in the carcinomatous or in the sarcomatous area . Tumor proliferative activity was higher in the carcinomatous ( 25 % ) than in the sarcomatous ( 2 % ) component . Based on these findings , immunohistochemical evaluation of multiple receptor status in the carcinomatous and sarcomatous areas of carcinosarcoma may provide a clue to the pathogenesis and hormonal receptor status of this uncommon uterine malignancy . Neuroprotective and anti-inflammatory activities of atorvastatin in a rat chronic constriction injury model . DB01076 is an P04035 inhibitor used to treat hypercholesterolemic conditions associated with hypertension . This study aims to investigate the anti-inflammatory and neuroprotective effects of atorvastatin on peripheral neuropathic pain . Peripheral neuropathic pain was induced by chronic constriction injury ( CCI ) in Sprague-Dawley rats . Rats were divided into 3 groups including sham-operated , CCI , and atorvastatin-treated . DB01076 ( 10 mg/kg ) or phosphate-buffered saline was orally administered for 2 weeks . All animals were assessed by neurobehavioral tests before surgery and at days 3 , 7 , 14 after surgery . Inflammatory and neuroprotective factors were evaluated by Western blot analysis . P29474 , P35354 and P35228 in the sciatic nerve were also studied using immunohistochemistry . DB01076 attenuated CCI-induced nociceptive sensitization and thermal hyperalgesia in a time-dependent manner . DB01076 improved CCI-induced neurobehavioral/inflammatory activity by inhibition of TGF-beta , pIkB/IkB , NFkB , P35354 , P35228 , EP1 and EP4 in the sciatic nerve . DB01076 was also found to increase neuroprotection factors pAkt/Akt , P29474 and P15692 . Taken together , these data indicate that atorvastatin could protect the sciatic nerve against CCI-induced neuroinflammation and nociception . Evaluation of the endogenous cannabinoid system in mediating the behavioral effects of dipyrone ( metamizol ) in mice . DB04817 is a common nonopioid analgesic and antipyretic , which , in many countries , is available over the counter and is more widely used than paracetamol or aspirin . However , the exact mechanisms by which dipyrone acts remain inconclusive . Two novel arachidonoyl-conjugated metabolites are formed in mice following the administration of dipyrone that are dependent on the activity of fatty acid amide hydrolase ( FAAH ) , which also represents the major catabolic enzyme of the endogenous cannabinoid ligand anandamide . These arachidonoyl metabolites not only inhibit cyclooxygenase ( P23219 / P35354 ) but also bind to cannabinoid receptors at low micromolar concentrations . The relative contributions of cannabinoid receptors and FAAH in the overall behavioral response to dipyrone remain untested . Accordingly , the two primary objectives of the present study were to determine whether the behavioral effects of dipyrone would ( a ) be blocked by cannabinoid receptor antagonists and ( b ) occur in FAAH mice . Here , we report that thermal antinociceptive , hypothermic , and locomotor suppressive actions of dipyrone are mediated by a noncannabinoid receptor mechanism of action and occurred after acute or repeated administration irrespective of FAAH . These findings indicate that FAAH-dependent arachidonoyl metabolites and cannabinoid receptors are not requisites by which dipyrone exerts these pharmacological effects under noninflammatory conditions . The role of atorvastatin in regulating the immune response leading to vascular damage in a model of Kawasaki disease . Superantigens have been implicated in a number of diseases including Kawasaki disease ( KD ) , a multi-system vasculitis resulting in coronary artery aneurysms . We have characterized a murine disease model in which coronary arteritis is induced by a novel superantigen found in Lactobacillus casei cell wall extract ( LCWE ) . Using this animal model of KD , we have identified three pathogenic steps leading to coronary artery aneurysm formation . These steps include T cell activation and proliferation , production of the proinflammatory cytokine tumour necrosis factor ( P01375 ) -α and up-regulation of matrix metalloproteinase 9 ( P14780 ) , an elastolytic protease . In addition to their cholesterol-lowering effects , 3-hydroxy-3-methylglutaryl ( HMG ) coenzyme A ( DB01992 ) reductase inhibitors ( statins ) have pleotropic immunomodulatory properties . Thus , we examined the effect of atorvastatin in modulating each of these three critical pathogenic processes leading to aneurysm formation in the disease model . DB01076 inhibited lymphocyte proliferation in response to superantigen stimulation in a dose-dependent manner . This inhibition was also observed for production of soluble mediators of inflammation including interleukin ( IL ) -2 and P01375 -α . The inhibitory effect on proliferation was rescued completely by mevalonic acid , confirming that the mechanism responsible for this inhibitory activity on immune activation was inhibition of P04035 . Similarly , P01375 -α-induced P14780 production was reduced in a dose-dependent manner in response to atorvastatin . Inhibition of extracellular-regulated kinase ( P29323 ) phosphorylation appears to be the mechanism responsible for inhibition of P14780 production . In conclusion , atorvastatin is able to inhibit critical steps known to be important in the development of coronary aneurysms , suggesting that statins may have therapeutic benefit in patients with KD . 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 . [ 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 . AM2389 , a high-affinity , in vivo potent P21554 -receptor-selective cannabinergic ligand as evidenced by drug discrimination in rats and hypothermia testing in mice . RATIONALE : The endocannabinoid signaling system ( ECS ) has been targeted for developing novel therapeutics since ECS dysfunction has been implicated in various pathologies . Current focus is on chemical modifications of the hexahydrocannabinol ( HHC ) nabilone ( DB00486 (®) ) . OBJECTIVE : To characterize the novel , high-affinity cannabinoid receptor 1 ( CB(1)R ) HHC-ligand AM2389 [ 9β-hydroxy-3-(1-hexyl-cyclobut-1-yl)-hexahydrocannabinol in two rodent pre-clinical assays . MATERIALS AND METHODS : CB(1)R mediation of AM2389-induced hypothermia in mice was evaluated with AM251 , a CB(1)R-selective antagonist/inverse agonist . Additionally , two groups of rats discriminated the full cannabinergic aminoalkylindole AM5983 ( 0.18 and 0.56 mg/kg ) from vehicle 20 min post-injection in a two-choice operant conditioning task motivated by 0.1 % saccharin/water . Generalization/substitution tests were conducted with AM2389 , AM5983 , and Δ(9)-tetrahydrocannabinol ( Δ(9)-THC ) . RESULTS : Δ(9)-THC (30 mg/kg)-induced hypothermia exhibited a faster onset and shorter duration of action compared with AM2389 ( 0.1 and 0.3 mg/kg ) . AM251 ( 3 and 10 mg/kg ) attenuated/blocked hypothermia induced by 0.3 mg/kg AM2389 . In drug discrimination , the order of potency was AM2389 > AM5983 > Δ(9)-THC with ED(50) values of 0.0025 , 0.0571 , and 0.2635 mg/kg , respectively , in the low-dose condition . The corresponding ED(50) values in the high-dose condition were 0.0069 , 0.1246 , and 0.8438 mg/kg , respectively . Onset of the effects of AM2389 was slow with a protracted time-course ; the functional , perceptual in vivo half-life was approximately 17 h . CONCLUSIONS : This potent cannabinergic HHC exhibited a slow onset of action with a protracted time-course . The AM2389 chemotype appears well suited for further drug development , and AM2389 currently is used to probe behavioral consequences of sustained ECS activation .