interacts_with DB06273?
Glucocorticoid-independent repression of tumor necrosis factor ( P01375 ) alpha-stimulated interleukin ( IL ) -6 expression by the glucocorticoid receptor : a potential mechanism for protection against an excessive inflammatory response . TNFα signaling and cytokine levels play a crucial role in cervical immunity and the host response to infections . We investigated the role of liganded and unliganded glucocorticoid receptor ( GR ) in P05231 and P10145 gene regulation in response to TNFα in the End1/E6E7 immortalized human endocervical epithelial cell line . In the absence of glucocorticoids , both decreasing GR protein levels by an siRNA strategy and results with the GR antagonist DB00834 suggest a role for the unliganded GR in reduction of TNFα-induced P05231 and P10145 mRNA levels in End1/E6E7 cells . Moreover , GR-dependent repression of endogenous P05231 mRNA as well as a minimal P05231 promoter-reporter gene is also demonstrated in COS-1 cells in the absence of GR ligand , suggesting a transcriptional mechanism that is not cell-specific . TNFα induced recruitment of both the unliganded GR and GR-interacting protein type 1 ( Q9Y3R0 ) to the P05231 promoter . This , together with Q9Y3R0 overexpression studies , suggests a function for Q9Y3R0 as a GR co-repressor in this context . TNFα was shown to induce phosphorylation of the unliganded human GR at DB00133 -226 but not DB00133 -211 , unlike dexamethasone , which induced hyperphosphorylation at both serine residues . DB00133 -226 is shown to be required for the ligand-independent GR-mediated repression of P05231 in response to TNFα . Taken together , these results support a model whereby the unliganded GR attenuates TNFα-stimulated P05231 transcription by a mechanism involving selective phosphorylation and recruitment of the unliganded GR and Q9Y3R0 to the P05231 promoter . These findings suggest the presence of a novel autoregulatory mechanism that may prevent overproduction of P05231 in the endocervix , possibly protecting against negative effects of excessive inflammation . 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 . DB06273 infusion therapy normalizes inflammation in sporadic P35858 patients . Patients with sporadic amyotrophic lateral sclerosis ( sALS ) show inflammation in the spinal cord and peripheral blood . The inflammation is driven by stimulation of macrophages by aggregated superoxide dismutase 1 ( P00441 ) through caspase1 , interleukin 1 ( IL1 ) , P05231 and chemokine signaling . Inflammatory gene activation is inhibited in vitro by tocilizumab , a humanized antibody to P05231 receptor ( P08887 ) . DB06273 inhibits global interleukin-6 ( P05231 ) signaling , a key mechanism in chronic rheumatoid disorders . Here we studied in vivo baseline inflammatory gene transcription in peripheral blood mononuclear cells ( PBMCs ) of 10 sALS patients , and the effects of tocilizumab ( Actemra(R) ) infusions . At baseline , one half of P35858 subjects had strong inflammatory activation ( Group 1 ) ( 8 genes up regulated > 4-fold , P < 0.05 vs. controls ) and the other half ( Group 2 ) had weak activation . All patients showed greater than four-fold up regulation of P03956 , P80098 , Q99616 and O00175 . DB06273 infusions in the Group 1 patients resulted in down regulation of inflammatory genes ( in particular IL1β ) , whereas in the Group 2 patients in up regulation of inflammatory genes . Post-infusion serum and P04141 concentrations of tocilizumab inhibited caspase1 activation in vitro . Three of 5 patients receiving tocilizumab infusions showed time-limited attenuation of clinical progression . In conclusion , inflammation of sALS patients at baseline is up- or down-regulated in comparison to controls , but is partially normalized by tocilizumab infusions . Successful thrombolysis of a stroke with a pulmonary embolism in a young woman . BACKGROUND : Paradoxical embolism is a rare event , accounting for < 2 % of all arterial emboli . The diagnosis is often difficult , and consequences for the patient can be severe . CASE REPORT : We describe the case of a 35-year-old female physician who presented to our Emergency Department ( ED ) in severe hemodynamic compromise , with an altered level of consciousness and major expressive aphasia 1 day after undergoing a leg varicosal stripping procedure under regional anesthesia . She was successfully thrombolyzed with 0.9 mg/kg of Recombinant Tissue P00747 Activator ( rtPA , DB00009 ) and had a full recovery . CONCLUSION : To our knowledge , this is the first description of a case of massive pulmonary embolism associated with a paradoxical stroke related to patent foramen ovale that was thrombolyzed for both conditions with a " neurological dose " of rtPA . Although thrombolysis was completely successful in this case , indications and contraindications should be thoroughly respected . A more conservative approach with anticoagulation , or a more aggressive approach with surgical thrombectomy , can each potentially have a place in particular cases . Intra-arterial catheter-directed thrombolysis and percutaneous embolectomy are additional options to be considered when available , especially if there are contraindications for systemic thrombolysis . Effects of external calcium on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229-7 . DB01373 is a known signalling molecule in eukaryotic cells and plays a central role in the regulation of many cellular processes . In the following study , we report on the effect of external calcium treatments on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229-7 . We observed that the intracellular calcium content of P. bainier 229-7 mycelia was increased in response to exposure to high external Ca(2+) concentrations . Both ginsenoside Rd biotransformation and β-glucosidase activity were both found to be dependent on the external calcium concentration . At an optimal Ca(2+) concentration of 45 mM , maximal ginsenoside Rd bioconversion rate of 92.44 % was observed and maximal β-glucosidase activity of 0.1778 U was reached in a 72-h biotransformation . The Ca(2+) channel blocker Verapamil blocked the trans-membrane influx of calcium and decreased ginsenoside Rd biotransformatiom . In addition , β-glucosidase activity and ginsenoside Rd content decreased by 36.0 and 29.2 % respectively after a 72-h incubation in the presence of 0.05 mM P62158 ( P62158 ) antagonist DB00850 . These results suggest that both Ca(2+) channels and P62158 are involved in ginsenoside Rd biotransformation via regulation of β-glucosidase activity . This is the first report regarding the effects of calcium signal transduction on biotransformation and enzyme activity in fungi . Clinical endocannabinoid deficiency ( CECD ) : can this concept explain therapeutic benefits of cannabis in migraine , fibromyalgia , irritable bowel syndrome and other treatment-resistant conditions ? OBJECTIVES : This study examines the concept of clinical endocannabinoid deficiency ( CECD ) , and the prospect that it could underlie the pathophysiology of migraine , fibromyalgia , irritable bowel syndrome , and other functional conditions alleviated by clinical cannabis . METHODS : Available literature was reviewed , and literature searches pursued via the National Library of Medicine database and other resources . RESULTS : Migraine has numerous relationships to endocannabinoid function . Anandamide ( AEA ) potentiates P08908 and inhibits 5- Q13049 receptors supporting therapeutic efficacy in acute and preventive migraine treatment . Cannabinoids also demonstrate dopamine-blocking and anti-inflammatory effects . AEA is tonically active in the periaqueductal gray matter , a migraine generator . THC modulates glutamatergic neurotransmission via DB01221 receptors . Fibromyalgia is now conceived as a central sensitization state with secondary hyperalgesia . Cannabinoids have similarly demonstrated the ability to block spinal , peripheral and gastrointestinal mechanisms that promote pain in headache , fibromyalgia , IBS and related disorders . The past and potential clinical utility of cannabis-based medicines in their treatment is discussed , as are further suggestions for experimental investigation of CECD via P04141 examination and neuro-imaging . CONCLUSION : Migraine , fibromyalgia , IBS and related conditions display common clinical , biochemical and pathophysiological patterns that suggest an underlying clinical endocannabinoid deficiency that may be suitably treated with cannabinoid medicines . Anti-interleukin 6 receptor antibody treatment in rheumatic disease . Interleukin 6 ( P05231 ) is a pleiotropic cytokine with a wide range of biological activities . P05231 transgene into mice gives rise to the abnormalities such as hypergammaglobulinaemia , thrombocytosis , infiltration of inflammatory cells into the tissues , mesangial cell proliferation of the kidney as well as splenomegaly and lymphadenopathy , which are predictable by the biological functions of P05231 shown in vitro . Continuous overproduction of P05231 is observed in patients with some immune-inflammatory diseases such as Castleman 's disease and rheumatoid arthritis that are frequently associated with similar abnormalities to those of P05231 transgenic mice , strongly suggesting the involvement of P05231 in the human diseases . Successful treatment of the model animals for immune-inflammatory diseases with anti- P05231 receptor ( P08887 ) antibody thus indicates the possible application of P05231 blocking agents to treat the P05231 related immune-inflammatory diseases of humans . In this review , the new therapeutic strategy for Castleman 's disease and RA using humanized antibody to human P05231 receptor , DB06273 , is discussed . Ca2+-calmodulin and janus kinase 2 are required for activation of sodium-proton exchange by the Gi-coupled 5-hydroxytryptamine 1a receptor . The type 1 sodium-proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5-hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2+/calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist-induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G(i2)alpha and/or G(i3)alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton-sensing and/or proton-transporting region of P19634 --> activation of P19634 . The G(i/o)-coupled P08908 receptor now joins a handful of Gq-coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2+ . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process . DB00619 inhibition effect on KITAsn822Lys-mediated signal transduction cascade . OBJECTIVE : Alterations in growth factor signaling pathways may be a frequent collaborating event in Q01196 - Q06455 -mediated leukemogenesis . Gain-of-function P10721 receptor mutations have been reported in adult AML patients , especially those with core binding factor leukemia ( CBFL ) . We have previously reported a new gain-of-function P10721 (Asn822Lys) mutation that is constitutively expressed in the Kasumi-1 CBFL cell line , and has recently been described in two childhood AML patients . To explore the molecular basis of the effects of this mutation in the appropriate context of hemopoietic dysregulation , we investigated P10721 downstream signaling in the Kasumi-1 cell line by means of DB00619 ( Imatinib , Gleevec ) pharmacological inhibition . MATERIALS AND METHODS : We investigated P10721 (Asn822Lys) mutant-initiated signaling in Kasumi-1 cell line , and characterized the inhibitory effect of the DB00619 protein tyrosine kinase inhibitor on downstream signaling . RESULTS : The use of DB00619 -mediated inhibition impaired the tyrosine phosphorylation of P10721 (Asn822Lys) and its association with the p85 subunit of phosphatidylinositol 3'-kinase ( p85PI3K ) . The downstream constitutive phosphorylation of P45983 /2 and P40763 was also significantly inhibited , but DB00619 had no effect on the constitutive activation of Akt , thus suggesting that it is due to other signaling in Kasumi-1 cells . DB00619 inhibited the P10721 -mediated proliferation of Kasumi-1 cells in a dose-dependent manner . CONCLUSIONS : These findings show the role of PI3K in P10721 (Asn822Lys)-mediated constitutive activation through the Akt-independent downstream signaling pathway of JNK , and also demonstrate the mutant 's susceptibility to DB00619 , which may therefore have therapeutic potential in CBFL patients with susceptible P10721 mutations . P05231 -receptor polymorphisms rs12083537 , rs2228145 , and rs4329505 as predictors of response to tocilizumab in rheumatoid arthritis . DB06273 ( TCZ ) , a monoclonal antibody targeting the human interleukin-6-receptor ( IL-6R ) , is indicated for the treatment of rheumatoid arthritis ( RA ) . We examined whether three P08887 single-nucleotide polymorphisms rs12083537 , rs2228145 ( formerly rs8192284 ) , and rs4329505 with previously reported functional effects were associated with clinical response to TCZ in a retrospective study cohort consisting of 79 RA patients . Three months after initiation of TCZ therapy , changes in swollen joint count ( SJC ) and , subordinately , tender joint count ( TJC ) , serum-CRP , DAS28-CRP , and EULAR-response were tested for association with the P08887 -haplotype or genotype . The major allele ( A ) of rs12083537 and the minor allele ( C ) of rs4329505 were associated with a poor SJC response ( P=0.02 and 0.02 , respectively ) . Moreover , the AAC-haplotype ( for rs12083537 , rs2228145 , and rs4329505 , respectively ) was associated with a poor SJC response ( P=0.00004 ) and , with borderline significance , EULAR-response ( P=0.05 ) . These data suggest that genetic variation in P08887 may aid in predicting TCZ therapy outcome in RA patients . Effect of canagliflozin on renal threshold for glucose , glycemia , and body weight in normal and diabetic animal models . BACKGROUND : DB08907 is a sodium glucose co-transporter ( SGLT ) 2 inhibitor in clinical development for the treatment of type 2 diabetes mellitus ( T2DM ) . METHODS : (14)C-alpha-methylglucoside uptake in Chinese hamster ovary-K cells expressing human , rat , or mouse SGLT2 or P13866 ; (3)H-2-deoxy-d-glucose uptake in Q9BTT4 myoblasts ; and 2-electrode voltage clamp recording of oocytes expressing human SGLT3 were analyzed . Graded glucose infusions were performed to determine rate of urinary glucose excretion ( UGE ) at different blood glucose ( BG ) concentrations and the renal threshold for glucose excretion ( RT(G) ) in vehicle or canagliflozin-treated Zucker diabetic fatty ( ZDF ) rats . This study aimed to characterize the pharmacodynamic effects of canagliflozin in vitro and in preclinical models of T2DM and obesity . RESULTS : Treatment with canagliflozin 1 mg/kg lowered RT(G) from 415±12 mg/dl to 94±10 mg/dl in ZDF rats while maintaining a threshold relationship between BG and UGE with virtually no UGE observed when BG was below RT(G) . DB08907 dose-dependently decreased BG concentrations in db/db mice treated acutely . In ZDF rats treated for 4 weeks , canagliflozin decreased glycated hemoglobin ( HbA1c ) and improved measures of insulin secretion . In obese animal models , canagliflozin increased UGE and decreased BG , body weight gain , epididymal fat , liver weight , and the respiratory exchange ratio . CONCLUSIONS : DB08907 lowered RT(G) and increased UGE , improved glycemic control and beta-cell function in rodent models of T2DM , and reduced body weight gain in rodent models of obesity . Anti- P05231 -receptor-alpha ( tocilizumab ) does not inhibit human monocyte-derived dendritic cell maturation or alloreactive T-cell responses . Significant comorbidites and lethality complicate GVHD and its treatment . Targeting the cytokine milieu may improve GVHD control ; and P05231 is an attractive candidate , given its role in dendritic cell activation and T-cell differentiation . DB06273 is a humanized mAb to P05231 -receptor-α ( P08887 -α ) , which is Food and Drug Administration-approved for treatment of rheumatoid arthritis . Mouse transplant models have demonstrated that P05231 blockade also improves GVHD scores and survival . Definitive immunologic effects of P05231 inhibition have not emerged given inconsistent alterations in regulatory T cells ( Tregs ) and suppression of T-cell proliferation . Despite on-target suppression of P08887 -α signaling in human monocyte-derived dendritic cells ( moDCs ) and T cells , our data show no effect on moDC maturation/activation , alloreactive T-cell proliferation , Treg expansion , or allogeneic Th1/Th17 responses in vitro . These findings merit attention in any clinical trials of tocilizumab for GVHD prevention or treatment and provide a rationale for evaluating more specific inhibitors of downstream O60674 / P40763 signaling as well . DB06273 in pediatric rheumatology : the clinical experience . During the last two decades , clinical use of novel biological therapy has led to increased mechanistic understanding of complex rheumatological diseases . Conversely , basic and translational studies have led to development of new and varied therapeutic agents . These new medications which " target " specific steps in one or more immune pathways have the potential to control disease symptoms , improve quality of life and long-term prognosis , and perhaps in some , restore immunological tolerance . Use of these agents in clinical trials , combined with post-marketing surveillance , has revealed both the benefits and the undesirable side-effects of biological disease-modifying anti-rheumatic drugs ( DMARDs ) . In this review we focus on the use of tocilizumab , a monoclonal antibody directed against the P05231 receptor ( P08887 ) , which potently inhibits P05231 / P08887 signaling . Mutation of the calmodulin binding motif IQ of the L-type Ca(v)1.2 Ca2+ channel to EQ induces dilated cardiomyopathy and death . Cardiac excitation-contraction coupling ( EC coupling ) links the electrical excitation of the cell membrane to the mechanical contractile machinery of the heart . DB01373 channels are major players of EC coupling and are regulated by voltage and Ca(2+)/calmodulin ( P62158 ) . P62158 binds to the IQ motif located in the C terminus of the Ca(v)1.2 channel and induces Ca(2+)-dependent inactivation ( CDI ) and facilitation ( P05231 ) . Mutation of DB00167 to DB00142 ( Ile1624Glu ) in the IQ motif abolished regulation of the channel by CDI and P05231 . Here , we addressed the physiological consequences of such a mutation in the heart . Murine hearts expressing the Ca(v)1.2(I1624E) mutation were generated in adult heterozygous mice through inactivation of the floxed WT Ca(v)1.2( Q401N2 ) allele by tamoxifen-induced cardiac-specific activation of the MerCreMer Cre recombinase . Within 10 days after the first tamoxifen injection these mice developed dilated cardiomyopathy ( DCM ) accompanied by apoptosis of cardiac myocytes ( CM ) and fibrosis . In Ca(v)1.2(I1624E) hearts , the activity of phospho- P62158 kinase II and phospho-MAPK was increased . CMs expressed reduced levels of Ca(v)1.2(I1624E) channel protein and I(Ca) . The Ca(v)1.2(I1624E) channel showed " CDI " kinetics . Despite a lower sarcoplasmic reticulum Ca(2+) content , cellular contractility and global Ca(2+) transients remained unchanged because the EC coupling gain was up-regulated by an increased neuroendocrine activity . Treatment of mice with metoprolol and captopril reduced DCM in Ca(v)1.2(I1624E) hearts at day 10 . We conclude that mutation of the IQ motif to IE leads to dilated cardiomyopathy and death . Increase in proinflammatory cytokines in peripheral blood without haemostatic changes after LPS inhalation . INTRODUCTION : Bronchoalveolar fibrin deposition is a characteristic of various lung disorders including acute lung injury , acute respiratory distress syndrome and sepsis . It is secondary to the activation of coagulation and inhibition of fibrinolysis in the alveolar space , and can be stimulated by lipopolysaccharide ( LPS ) inhalation . The aim of this study was to determine the relation between compartmental stress in the lung and systemic response after LPS inhalation by measuring haemostatic parameters . PATIENTS AND METHODS : 12 healthy subjects underwent a bronchial challenge test with LPS ; sequential dosages were performed for 5 biological markers ( P05231 ( P05231 ) , C-Reactive Protein ( CRP ) , P00734 Fragments 1 and 2 ( F 1+2 ) , cortisol and P00747 Activator Inhibitor 1 ( P05121 ) before endotoxin inhalation and 2 , 4 , 6 , 8 and 24 hours afterwards . RESULTS : P05231 and CRP levels in the peripheral blood were higher after LPS inhalation ; there was no activation of coagulation and no increase in P05121 level . CONCLUSION : This study confirms that despite systemic release of proinflammatory cytokines , LPS inhalation does not induce systemic haemostatic response to LPS challenge . Topical glucocorticoids downregulate P23219 positive cells in nasal polyps . BACKGROUND : Influx of inflammatory cells is one of the hallmarks of nasal polyposis . As glucocorticoids ( GC ) are known to exhibit strong anti-inflammatory effects , these drugs are frequently used in the treatment of the disease . Part of the anti-inflammatory effects of GC is attributed to their interference with prostanoid synthesis . As cyclooxygenases ( P36551 ) are key enzymes in the synthesis of both pro- ( P23219 , P35354 ) and anti-inflammatory prostanoids ( P35354 ) , we investigated the role of topical GC on P23219 , P35354 and inflammatory markers in nasal polyps ( NP ) . METHODS : Immunohistochemical analysis of inflammatory markers ( P34810 , CD117 , MBP , elastase , IgE , BB-1 , P05112 , P05113 and P05231 ) , P23219 and P35354 was performed on normal nasal mucosa ( NM ) ( n = 18 ) , non-GC treated NP ( n = 27 ) and topical GC treated NP ( n = 12 ) . NP groups were matched for allergy , asthma and ASA intolerance . RESULTS : Increased numbers of eosinophils , P05113 + cells and IgE+ cells and decreased numbers of mastcells are striking features of NP inflammation ( P < 0.05 ) . In addition , increased numbers of P23219 + cells are observed in NP epithelium compared to NM ( P < 0.05 ) . CONCLUSION : Topical GC significantly reduce the number of P23219 + NP cells ( P < 0.05 ) , but have no significant effect on P35354 + NP cells . No significant reduction in the number of eosinophils is observed for GC treated NP . The number of P05113 + cells is however increased significantly upon GC treatment ( P < 0.05 ) . [ Signal transduction inhibitor -- STI571 -- a new treatment for chronic myeloid leukemia ( CML ) , which opens a new targeted approach to cancer therapy ] . Chronic myeloid leukemia ( CML ) , in most of the cases , is the molecular consequence of the t(9,22) translocation , resulting in the Philadelphia ( Ph ) chromosome and the creation of the fusion gene P11274 - P00519 . The fusion gene is translated to the protooncogen P11274 - P00519 , a constitutively activated tyrosine kinase that is linked to the malignant transformation . Thus , this tyrosine kinase became an attractive target for drug design . The development of the novel investigational drug DB00619 is based on its potent and selective ability to inhibit this fusion tyrosine kinase . In preclinical studies , DB00619 selectively inhibited the growth of CML cells that carry the Ph chromosome . In this review we discuss the drug development and design , its mechanism of action , the preclinical studies and the results of phase I and II clinical trials . Identification of Reverb(alpha) as a novel ROR(alpha) target gene . The nuclear receptor superfamily comprises a large number of ligand-activated transcription factors that are involved in numerous biological processes such as cell proliferation , differentiation , and homeostasis . ROR(alpha) ( P35398 ) and Reverb(alpha) ( P20393 ) are two members of this family whose biological functions are largely unknown . In addition , no ligand has been yet identified for these two receptors ; therefore , they are referred as orphan receptors . Here , we show that ROR(alpha) and Reverb(alpha) are expressed with a similar tissue distribution and are both induced during the differentiation of rat Q9BTT4 myoblastic cells . Ectopic expression of ROR(alpha)1 in Q9BTT4 cells significantly induces Reverb(alpha) expression as demonstrated by Northern blot analysis . Using reverse transcription-PCR to analyze Reverb(alpha) gene expression from staggerer mice , we found that there was a significant reduction of Reverb(alpha) mRNA in the skeletal muscle comparing it with the wild-type mice , which suggests that ROR(alpha) is involved in the regulation of Reverb(alpha) gene expression . Transient transfection assays using the Reverb(alpha) promoter demonstrate that ROR(alpha) regulates the Reverb(alpha) gene at the transcriptional level . Furthermore , mutagenesis experiments indicate that ROR(alpha) regulates Reverb(alpha) transcription via a monomeric ROR response element located in the Reverb(alpha) gene promoter . Electrophoretic mobility shift assays show that ROR(alpha) binds strongly to this site in a specific-manner . Finally , overexpression of Q9Y3R0 / Q06418 -2 , but not Q15788 , potentiates ROR(alpha)-stimulated Reverb(alpha) promoter activity in transient transfection experiments . Together , our results identify Reverb(alpha) as a novel target gene for ROR(alpha) . 8-OH-DPAT ( P08908 agonist ) Attenuates 6-Hydroxy- dopamine-induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE(S) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8-OH-DPAT on 6-OHDA-induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6-OHDA ( 8 μg/2 μl/rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar-test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8-OH-DPAT ( P08908 receptor agonist ; 0.25 , 0.5 and 1mg/kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8-OH-DPAT administration and analyzed by ELISA method to measure levels of P01375 -α , IL-1β and P05231 . RESULTS : Chronic injection of 8-OH-DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti-cataleptic effect was observed at the dose of 1 mg/kg of 8-OH-DPAT . Levels of P01375 -α in P04141 increased three weeks after 6-OHDA injection while there was a significant decrease in P01375 -α level of parkinsonian animals treated with 8-OH-DPAT ( 1 mg/kg , IP for 10 days ) . IL-1β and P05231 decreased and increased in parkinsonian rats and in 8-OH-DPAT-treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8-OH-DPAT improves catalepsy in 6-OHDA-induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines . Mobilization of Ph chromosome-negative peripheral blood stem cells in chronic myeloid leukaemia patients with imatinib mesylate-induced complete cytogenetic remission . Imatinib mesylate ( IM , DB00619 , Glivec ) can induce a high rate of complete cytogenetic response ( CCR ) in chronic myeloid leukaemia ( CML ) patients , although to date the majority of patients continue to have detectable disease by sensitive reverse transcription polymerase chain reaction ( RT-PCR ) . It is therefore possible that these patients may ultimately relapse and require treatment such as autologous peripheral blood stem cell transplant ( APBSCT ) . We attempted mobilization of haemopoietic progenitor cells from 58 patients in CCR using recombinant human granulocyte colony-stimulating factor [ rHu- DB00099 ; 10 micro g/kg/d subcutaneously ( s.c. ) for at least 4 d ] alone , while continuing IM treatment . The median d 5 ( peak ) P28906 + count was 11.5/ microl ( range 0-108/ microl ) , and 43/58 ( 74 % ) patients underwent a median of two ( range 1-3 ) apheresis procedures . A median dose of 2.1 x 10(6)/kg P28906 + cells ( range 0.1-6.5 x 10(6)/kg ) was collected . Some 84 % of 31 collections analysed were negative for the Philadelphia ( Ph ) chromosome or breakpoint cluster region and Abelson murine leukaemia viral oncogene homologue ( P11274 - P00519 ) translocation by cytogenetics or fluorescent in situ hybridization respectively . No toxicity was reported with the regimen . Overall , the target P28906 + dose ( 2 x 10(6)/kg P28906 + ) was attained in 23/58 ( 40 % ) patients who entered the study . In summary , we have demonstrated that successful mobilization of Ph- P28906 + cells from IM-treated patients in CCR is possible using rHu-G- P04141 alone . 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 . Augmentation by citalopram of risperidone-induced monoamine release in rat prefrontal cortex . RATIONALE : A typical antipsychotics ( APDs ) , e.g. olanzapine and risperidone , have been reported to be effective adjunctive treatment for depression if selective serotonin ( 5-HT ) reuptake inhibitors ( SSRIs ) alone are ineffective . OBJECTIVES AND METHODS : We utilized microdialysis in awake , freely moving rats to study the effect of risperidone in combination with citalopram , an SSRI , on extracellular 5-HT , dopamine ( DA ) , and norepinephrine ( NE ) efflux in rat medial prefrontal cortex ( mPFC ) . RESULTS : DB00734 ( 1.0 mg/kg , s.c. ) , given alone , significantly increased 5-HT , DA , and NE concentrations in the mPFC . DB00215 ( 10 mg/kg , s.c. ) , by itself , produced a significant increase in 5-HT levels only . The combination of risperidone and citalopram produced significantly greater increases in efflux of both DA and NE than risperidone alone . However , the effect of this combination on extracellular 5-HT concentrations was not significantly different than that of citalopram alone . The augmentation of DA and NE efflux induced by risperidone plus citalopram could be partially blocked by the selective P08908 antagonist , WAY 100635 ( 0.2 mg/kg , s.c. ) . CONCLUSIONS : The results suggest that the ability of atypical APDs to augment the therapeutic efficacy of SSRIs in major depression and treatment-resistant depression may be due , at least in part , to potentiation of SSRI-induced increases in cortical DA and NE . The contributions of P08908 receptor stimulation and 5- Q13049 and alpha2 adrenergic receptor antagonism to this augmentation are discussed .