interacts_with DB00966?
Protective effect of treatment with low-dose gliclazide in a model of middle cerebral artery occlusion and reperfusion in rats . The aim of this study was to explore the expression of sulfonylurea receptor 1 ( Q09428 ) , the regulatory subunit of the NCCa- DB00171 channel , and to investigate the protective effects of gliclazide following middle cerebral artery occlusion ( MCAO ) /reperfusion in male Wistar rats . Adult rats underwent 2h of the left MCAO using the intraluminal thread technique before reperfusion . The core areas of the infarct at different reperfusion time points were examined for the mRNA level and protein expression of Q09428 using reverse transcription-polymerase chain reaction ( RT-PCR ) and western blotting respectively . DB01120 was administered intravenously into the right jugular vein for 12h simultaneously with the reperfusion . The number of apoptotic cells was determined using the TUNEL assay . The neurological functional deficits were evaluated using Bederson׳s test , and the cerebral infarction volume was visualized with TTC staining . We found up-regulation of Q09428 mRNA and protein levels in ischemic infarct tissues after reperfusion following MCAO , and Q09428 mRNA and protein were maximally upregulated 8-12h after a 2-hour ischemia . The treatment with low-dose of gliclazide reduced the total number of TUNEL-positive cells , the neurological functional deficits and the brain infarct volume . These results suggest that the Q09428 -regulated NCCa- DB00171 channel may be associated with MCAO/reperfusion injury and the infarct-reducing effects of intravenous treatment with gliclazide may be due , in part , to the blocked upregulation of Q09428 expression , the decreased infarct size and the reduced apoptosis in the ischemia-reperfusion brain . Potential utility of telmisartan , an angiotensin II type 1 receptor blocker with peroxisome proliferator-activated receptor-gamma ( P37231 ) -modulating activity for the treatment of cardiometabolic disorders . The metabolic syndrome is strongly associated with insulin resistance and consists of a constellation of factors such as hypertension and hyperlipidemia that raise the risk for cardiovascular diseases and diabetes mellitus . There is widespread agreement that the renin-angiotensin system ( DB01367 ) plays a pivotal role in the pathogenesis of insulin resistance and cardiovascular disease in diabetes . Indeed , large clinical trials have demonstrated substantial benefit of the blockade of this system for cardiovascular end-organ protection . Thus the blockade of the DB01367 may be a promising strategy for the treatment of the patients with the metabolic syndrome . Although several types of angiotensin II type 1 ( AT(1) ) receptor blockers ( ARBs ) are commercially available for the treatment of patients with hypertension , we have recently found that telmisartan ( DB00966 ) could have the strongest binding affinity to AT(1) receptor . Further , telmisartan is reported to act as a partial agonist of peroxisome proliferator-activated receptor-gamma ( P37231 ) . These observations suggest that , due to its unique P37231 -modulating activity , telmisartan may be one of the most promising sartans for the treatment of cardiometabolic disorders . In this paper , we reviewed the potential utility of telmisartan in insulin resistance and vascular complications in diabetes . 2(3H)-benzoxazolone and bioisosters as " privileged scaffold " in the design of pharmacological probes . The 2(3H)-benzoxazolone heterocycle and its bioisosteric surrogates ( such as 2(3H)-benzothiazolinone , benzoxazinone , etc. ) have received considerable attention from the medicinal chemists owing to their capacity to mimic a phenol or a catechol moiety in a metabolically stable template . These heterocycles and pyrocatechol have indeed similar pKa 's , electronic charge distribution , and chemical reactivity . Therapeutic applications of this template are very broad , and range from analgesic anti-inflammatory compounds ( including P37231 antagonists ) to antipsychotic and neuroprotective anticonvulsant compounds . High affinity ligands have been obtained also for dopaminergic ( D2 and D4 ) , serotoninergic ( P08908 and P28223 ) , sigma-1 and sigma-2 receptors . Owing to the high number of positive hits encountered with this heterocycle and its congeners , 2(3H)-benzoxazolone template certainly deserves the title of " privileged scaffold " in medicinal chemistry . Targeting other abnormal signaling pathways in sarcoma : P00533 in synovial sarcomas , P37231 in liposarcomas . Pathways targeted by antidiabetes drugs are enriched for multiple genes associated with type 2 diabetes risk . Genome-wide association studies ( GWAS ) have uncovered > 65 common variants associated with type 2 diabetes ( T2D ) ; however , their relevance for drug development is not yet clear . Of note , the first two T2D-associated loci ( P37231 and Q14654 / Q09428 ) encode known targets of antidiabetes medications . We therefore tested whether other genes/pathways targeted by antidiabetes drugs are associated with T2D . We compiled a list of 102 genes in pathways targeted by marketed antidiabetic medications and applied Gene Set Enrichment Analysis ( MAGENTA [ Meta-Analysis Gene-set Enrichment of variaNT Associations ] ) to this gene set , using available GWAS meta-analyses for T2D and seven quantitative glycemic traits . We detected a strong enrichment of drug target genes associated with T2D ( P = 2 × 10(-5) ; 14 potential new associations ) , primarily driven by insulin and thiazolidinedione ( TZD ) targets , which was replicated in an independent meta-analysis ( Metabochip ) . The glycemic traits yielded no enrichment . The T2D enrichment signal was largely due to multiple genes of modest effects ( P = 4 × 10(-4) , after removing known loci ) , highlighting new associations for follow-up ( P33121 , P19838 , P11168 , incretin targets ) . Furthermore , we found that TZD targets were enriched for LDL cholesterol associations , illustrating the utility of this approach in identifying potential side effects . These results highlight the potential biomedical relevance of genes revealed by GWAS and may provide new avenues for tailored therapy and T2D treatment design . P48061 and [N33A] P48061 in 5637 and HeLa cells : regulating P00533 phosphorylation via calmodulin/calcineurin . In the human neoplastic cell lines 5637 and HeLa , recombinant P48061 elicited , as expected , downstream signals via both G-protein-dependent and β-arrestin-dependent pathways responsible for inducing a rapid and a late wave , respectively , of P27361 /2 phosphorylation . In contrast , the structural variant [N33A] P48061 triggered no β-arrestin-dependent phosphorylation of P27361 /2 , and signaled via G protein-dependent pathways alone . Both P48061 and [N33A] P48061 , however , generated signals that transinhibited P00533 phosphorylation via intracellular pathways . 1 ) Prestimulation of P61073 / P00533 -positive 5637 or HeLa cells with P48061 modified the HB- P01133 -dependent activation of P00533 by delaying the peak phosphorylation of tyrosine 1068 or 1173 . 2 ) Prestimulation with the synthetic variant [N33A] P48061 , while preserving P61073 -related chemotaxis and P61073 internalization , abolished P00533 phosphorylation . 3 ) In cells knockdown of β-arrestin 2 , P48061 induced a full inhibition of P00533 like [N33A] P48061 in non-silenced cells . 4 ) P00533 phosphorylation was restored as usual by inhibiting PCK , calmodulin or calcineurin , whereas the inhibition of CaMKII had no discernable effect . We conclude that both recombinant P48061 and its structural variant [N33A] P48061 may transinhibit P00533 via G-proteins/calmodulin/calcineurin , but [N33A] P48061 does not activate β-arrestin-dependent P27361 /2 phosphorylation and retains a stronger inhibitory effect . Therefore , we demonstrated that P48061 may influence the magnitude and the persistence of signaling downstream of P00533 in turn involved in the proliferative potential of numerous epithelial cancer . In addition , we recognized that [N33A] P48061 activates preferentially G-protein-dependent pathways and is an inhibitor of P00533 . 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 . Telmisartan , its potential therapeutic implications in cardiometabolic disorders . There is a growing body of evidence that the renin-angiotensin system ( DB01367 ) plays a pivotal role in the pathogenesis of cardiovascular diseases . Indeed , large clinical trials have demonstrated substantial benefit of the blockade of this system for cardiovascular-organ protection . Although several types of angiotensin II type 1 ( AT(1) ) receptor blockers ( ARBs ) are commercially available for the treatment of patients with hypertension , we have recently found that telmisartan ( DB00966 ) could have the strongest binding affinity to AT(1) receptor . Telmisartan will be a promising cardiometabolic sartan due to its unique peroxisome proliferator-activated receptor-gamma ( P37231 ) -inducing properties as well . In this review , we focused on telmisartan , and discussed its potential therapeutic implications in cardiometabolic disorders . DB00452 -arginine conjugate , a novel HIV-1 Tat antagonist : synthesis and anti-HIV activities . HIV-1 transactivating protein Tat is essential for virus replication and progression of HIV disease . HIV-1 Tat stimulates transactivation by binding to HIV-1 transactivator responsive element ( TAR ) RNA , and while secreted extracellularly , it acts as an immunosuppressor , an activator of quiescent T-cells for productive HIV-1 infection , and by binding to CXC chemokine receptor type 4 ( P61073 ) as a chemokine analogue . Here we present a novel HIV-1 Tat antagonist , a neomycin B-hexaarginine conjugate ( NeoR ) , which inhibits Tat transactivation and antagonizes Tat extracellular activities , such as increased viral production , induction of P61073 expression , suppression of CD3-activated proliferation of lymphocytes , and upregulation of the CD8 receptor . Moreover , Tat inhibits binding of fluoresceine isothiocyanate ( FITC ) -labeled NeoR to human peripheral blood mononuclear cells ( PBMC ) , indicating that Tat and NeoR bind to the same cellular target . This is further substantiated by the finding that NeoR competes with the binding of monoclonal Abs to P61073 . Furthermore , NeoR suppresses HIV-1 binding to cells . Importantly , NeoR accumulates in the cell nuclei and inhibits the replication of M- and T-tropic HIV-1 laboratory isolates ( EC(50) = 0.8-5.3 microM ) . A putative model structure for the TAR-NeoR complex , which complies with available experimental data , is presented . We conclude that NeoR is a multitarget HIV-1 inhibitor ; the structure , and molecular modeling and dynamics , suggest its binding to TAR RNA . NeoR inhibits HIV-1 binding to cells , partially by blocking the P61073 HIV-1 coreceptor , and it antagonizes Tat functions . NeoR is therefore an attractive lead compound , capable of interfering with different stages of HIV infection and AIDS pathogenesis . Cross-talk between PKA-Cβ and p65 mediates synergistic induction of Q07343 by roflumilast and NTHi . Phosphodiesterase 4B ( Q07343 ) plays a key role in regulating inflammation . DB01656 , a phosphodiesterase (PDE)4-selective inhibitor , has recently been approved for treating severe chronic obstructive pulmonary disease ( P48444 ) patients with exacerbation . However , there is also clinical evidence suggesting the development of tachyphylaxis or tolerance on repeated dosing of roflumilast and the possible contribution of Q07343 up-regulation , which could be counterproductive for suppressing inflammation . Thus , understanding how Q07343 is up-regulated in the context of the complex pathogenesis and medications of P48444 may help improve the efficacy and possibly ameliorate the tolerance of roflumilast . Here we show that roflumilast synergizes with nontypeable Haemophilus influenzae ( NTHi ) , a major bacterial cause of P48444 exacerbation , to up-regulate PDE4B2 expression in human airway epithelial cells in vitro and in vivo . Up-regulated PDE4B2 contributes to the induction of certain important chemokines in both enzymatic activity-dependent and activity-independent manners . We also found that protein kinase A catalytic subunit β ( PKA-Cβ ) and nuclear factor-κB ( NF-κB ) p65 subunit were required for the synergistic induction of PDE4B2 . PKA-Cβ phosphorylates p65 in a DB02527 -dependent manner . Moreover , Ser276 of p65 is critical for mediating the PKA-Cβ-induced p65 phosphorylation and the synergistic induction of PDE4B2 . Collectively , our data unveil a previously unidentified mechanism underlying synergistic up-regulation of PDE4B2 via a cross-talk between PKA-Cβ and p65 and may help develop new therapeutic strategies to improve the efficacy of DB05876 inhibitor . Potential effects of peroxisome proliferator-activated receptor activator on LPS-induced lung injury in rats . Multiple factors contribute to the pathogenesis and prognosis of chronic obstructive pulmonary disease( P48444 ) , still requiring new therapeutic strategies and medications for the disease . The aim of the present study is to investigate the model of lipopolysaccharide ( LPS ) -induced chronic lung injury and hyperinflation and test therapeutic effects of peroxisome proliferator-activated receptor ( Q07869 ) -gamma agonist . Wister rats were challenged with intra-tracheal instillation of LPS at concentrations of 0.006 , 0.060 , 0.600 , and 6.000 mg/ml per kg , twice a week , for 1 , 2 , 4 and 6 weeks . Q07869 activator , 15-deoxy-Delta12,14-prostaglandin J2 ( 15D-PGJ2 ) , or vehicle ( PBS ) was administered orally and daily at the dose of 1 and 10 mg/ml per kg in animals challenged with LPS or PBS at the dose of 0.060 mg/ml per kg body weight twice a week for 4 weeks . We found that intra-tracheal exposure of LPS resulted in a dose-dependent pattern of chronic lung hyperinflation and hypertrophy , increased alveolar enlargement , reduced vascular endothelial growth factor ( P15692 ) and elevated tissue inhibitor of metalloproteinases ( P01033 ) -1 levels in bronchoalveolar lavage ( BAL ) fluid , and early changes of leukocyte influx and interferon ( IFN ) -gamma levels in bronchoalveolar lavage ( BAL ) fluid . P37231 agonist ameliorated these changes related with the dose used.LPS-induced lung disease model shows some similarities with human disease , and P37231 agonist maybe an alternative for P48444 therapy . 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 . Peroxisome-proliferator activator receptor-gamma activation decreases attachment of endometrial cells to peritoneal mesothelial cells in an in vitro model of the early endometriotic lesion . The aim of this study was to investigate whether peroxisome proliferator-activated receptor ( Q07869 ) -gamma activation has an effect on the attachment of endometrial cells to peritoneal mesothelial cells in a well-established in vitro model of the early endometriotic lesion . The endometrial epithelial cell line EM42 and mesothelial cell line LP9 were used for this study . EM42 cells , LP9 cells or both were treated with the P37231 agonist ciglitazone ( CTZ ) at varying concentrations ( 10 , 20 and 40 microM ) x 48 h with subsequent co-culture of EM42 and LP9 cells . The rate of EM42 attachment and invasion through LP9 cells was then assessed and compared with control ( EM42 and LP9 cells co-cultured without prior treatment with CTZ ) . Next , attachment of CTZ-treated and untreated EM42 cells to hyaluronic acid ( HA ) , a cell adhesion molecule ( P62158 ) on peritoneal mesothelial cells , were assessed . Although there was no difference in EM42 attachment when LP9 cells alone were treated with CTZ , treatment of EM42 cells with 40 microM CTZ decreased EM42 attachment to LP9 cells by 27 % ( P < 0.01 ) . Treatment of both EM42 and LP9 cells with 40 microM CTZ decreased EM42 attachment to LP9 by 37 % ( P < 0.01 ) . Treatment of EM42 cells with 40 microM CTZ decreased attachment to HA by 66 % ( P = 0.056 ) . CTZ did not decrease invasion of EM42 cells through the LP9 monolayer . CTZ may inhibit EM42 cell proliferation . In conclusion , CTZ significantly decreased EM42 attachment to LP9 cells and HA in an in vitro model of the early endometriotic lesion .