interacts_with DB00814?
Effects of systemic injections of vilazodone , a selective serotonin reuptake inhibitor and serotonin 1A receptor agonist , on anxiety induced by predator stress in rats . We examined the effect of DB06684 , a selective serotonin reuptake inhibitor ( SSRI ) and serotonin 1A ( 5-HT(1A) ) receptor agonist [ Bartoszyk , G.D. , Hegenbart , R. , Ziegler , H. , 1997. P50402 68843 , a serotonin reuptake inhibitor with selective presynaptic P08908 receptor agonistic properties. Eur. J. Pharmacol. 322 , 147-153. ] , on change in affect following predator stress . DB06684 and vehicle injection ( intraperitoneal ) occurred either 10 min after predator stress ( prophylactic testing ) , or 90 min prior to behavioral testing for the effects of predator stress ( therapeutic testing ) . Predator stress involved unprotected exposure of rats to a domestic cat . Behavioral effects of stress were evaluated with hole board , plus-maze , and acoustic startle tests 1 week after stress . Predator stress increased anxiety-like behavior in the plus-maze and elevated response to acoustic startle . In prophylactic testing , DB06684 affected stress potentiation of startle at doses above 5 mg/kg . DB06684 increased stress elevation of startle at 10 mg/kg . Higher doses of DB06684 ( 20 and 40 mg/kg ) blocked stress potentiation of startle . In contrast , DB06684 had no effect on stress potentiation of anxiety in the plus-maze . In therapeutic testing , DB06684 increased stress elevation of startle at all doses . In contrast , therapeutic DB06684 had no effect on stress potentiation of anxiety in the plus-maze . Taken together , the data suggest a prophylactic potential for DB06684 in the treatment of changes in hypervigilance following severe stress . 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 . Some studies on spontaneous Hymenolepis diminuta infection in laboratory rats . Hymenolepis diminuta is a tapeworm that occurs worldwide . It is known to be found commonly in areas where large amounts of food grains or other dry feed products , which are the favorite foods for rats . Transmission of disease to human is uncommon ; however , it may be a serious threat for population who are living in rural areas which are suffering from excessive rodents . Here , this study had done on spontaneous H. diminuta infection in laboratory rats as a model . Out of thirty five adult laboratory rats investigated for parasitic diseases only nine ( 25.71 % ) were diagnosed positive for spontaneous H. diminuta infection . Four of them ( 44.44 % ) were found losing of weight and lacking of motility , while the others were normal . On microscopic examination , H. diminuta eggs had been found in their stool . On autopsy , small intestines were found to contain from 5-6 multi-segmented tapeworms in each rat . Histopathologically , intestinal lumen showed varying sections of H. diminuta segments with serrated borders . H. diminuta infection caused multiple mucosal ulcers with absence of intestinal villi from the surface epithelium and excessive mucin . Moreover , inflammatory cells infiltration in the connective tissue core of the villi . Furthermore , the Toluidine blue stain showed that there are Mastiocytosis . Additionally , there were goblet cells hyperplasia on using DB00233 . Moreover , there were high expression of cyclooxygenase 2 ( P35354 ) , tumor necrosis factor-α ( P01375 -α ) and inducible Nitric-Oxide Synthase ( iNOs ) . This implicate , strong correlation between P35354 , P01375 -α and iNOs expression and inflammation induced by H. diminuta . Meloxicam . Meloxicam ( DB00814 trade mark , Boehringer Ingelheim ) is a relatively new oral non-steroidal anti-inflammatory drug ( NSAID ) approved for the treatment of osteoarthritis in the US . It has also been evaluated for the treatment of rheumatoid arthritis , ankylosing spondylitis and acute ' rheumatic ' pain . Meloxicam has been shown to be P35354 preferential , particularly at its lowest therapeutic dose , and is anti-inflammatory by inhibiting prostanoid synthesis in inflammatory cells . Since it is P35354 preferential , it would be expected to have less gastrointestinal toxicity than non-selective NSAIDs . In clinical trials of meloxicam in osteoarthritis , it was found to be as effective as piroxicam , diclofenac and naproxen with less clinical gastrointestinal symptoms and less perforations , obstructions and bleeds by meta-analysis . Adverse events , including peripheral oedema and hypertension , occurred at a similar rate as with traditional NSAIDs . Expression profile of genes associated with the dopamine pathway in vitiligo skin biopsies and blood sera . BACKGROUND : Dopamine has been proven to be toxic for melanocytes . In vitiligo patients the level of dopamine is increased and the functioning of several enzymes participating in the dopamine pathway is changed . METHODS : With the use of quantitative real-time polymerase chain reaction and ELISA the expression of genes connected to the dopamine pathway ( PAH , P61457 , TH , DDC , P09172 , PNMT , P07203 , P21397 , P27338 , P21964 , P21728 - P21918 , P54219 and Q05940 ) was observed in vitiligo patients ' and control subjects ' skin and blood . RESULTS : The mRNA expression of P07203 , DDC , P21397 , P21728 and P21918 differs in vitiligo skin and the protein level of DDC , P21397 , P27338 , P21728 and P21918 is changed in vitiligo patients ' skin and/or blood sera . CONCLUSIONS : The dopamine pathway probably influences melanogenesis directly or through the melanocortin pathway . We provide new data about changes of expression profile of the dopamine-synthesizing enzyme DDC , the dopamine-degrading enzymes P21397 and P27338 and the D1-like family dopamine receptors in vitiligo skin and blood sera . P35354 promotes early atherosclerotic lesion formation in P01130 -deficient mice . BACKGROUND : Atherosclerosis has features of an inflammatory disease . Because cyclooxygenase ( P36551 ) -2 is expressed in atherosclerotic lesions and promotes inflammation , we tested the hypotheses that selective P35354 inhibition would reduce early lesion formation in P01130 -deficient ( P01130 -/- ) mice and that macrophage P35354 expression contributes to atherogenesis in P01130 -/- mice . METHODS AND RESULTS : Treatment of male P01130 -/- mice fed the Western diet with rofecoxib or indomethacin for 6 weeks resulted in significant reductions in atherosclerosis in the proximal aorta ( 25 % and 37 % ) and in the aorta en face ( 58 % and 57 % ) , respectively . DB00533 treatment did not inhibit platelet thromboxane production , a P23219 -mediated process , but it significantly reduced the urinary prostacyclin metabolite 2,3-dinor-6-keto-PGF1alpha . Fetal liver cell transplantation was used to generate P01130 -/- mice null for expression of the P35354 gene by macrophages . After 8 weeks on the Western diet , P35354 -/- --> P01130 -/- mice developed significantly less ( 33 % to 39 % ) atherosclerosis than control P35354 +/+ --> P01130 -/- mice . In both the inhibitor studies and the transplant studies , serum lipids did not differ significantly between groups . CONCLUSIONS : The present studies provide strong pharmacological and genetic evidence that P35354 promotes early atherosclerotic lesion formation in P01130 -/- mice in vivo . These results support the potential of anti-inflammatory approaches to the prevention of atherosclerosis . Bioassay-guided isolation of an alkaloid with antiangiogenic and antitumor activities from the extract of Fissistigma cavaleriei root . Fissistigma cavaleriei ( Levl ) Rehd ( Annonaceae ) is used as a folklore medicine for treatment of inflammation , arthritis , and tuberculosis by Miao people in China . In the present study , the antiangiogenic activity of F. cavaleriei was investigated . The chorioallantoic membrane of the fertilized hen 's egg ( P62158 assay ) was used to determine antiangiogenic activity of the plant extract . Compound ( 1 ) , a compound with antiangiogenic activity , was isolated by bioassay-guided fractionation from F. cavaleriei for the first time . The structure of compound ( 1 ) was elucidated on the basis of spectroscopic methods . Colorimetric P36551 ( ovine ) inhibitor screening assay was used to determine its inhibitory effect on P23219 and P35354 . MTT and Sulforhodamine B assays were used to investigate its cytotoxic effects on tumor cell lines . As a result , compound ( 1 ) showed a selectively inhibiting effect on P35354 and could inhibit the growth of tumor cells in vitro . The antitumor activity of compound ( 1 ) was further confirmed by the observation that compound ( 1 ) administration significantly inhibited the growth of S-180 cells in mice . Moreover , compound ( 1 ) was able to enhance the antitumor activity of doxorubicin in the mice bearing with S-180 cells while combined with doxorubicin . In conclusion , compound ( 1 ) is a multi-target molecule and further experimental investigations are needed to determine whether it can be used as a lead molecule for tumor treatment . Antiinflammatory and neurological activity of pyrithione and related sulfur-containing pyridine N-oxides from Persian shallot ( Allium stipitatum ) . ETHNOPHARMACOLOGICAL RELEVANCE : Persian shallot ( Allium stipitatum ) is a bulbous plant native to Turkey , Iran and Central Asia . It is frequently used in folk medicine for the treatment of a variety of disorders , including inflammation and stress . Antiinflammatory and neurological activities of pyrithione and four related sulfur-containing pyridine N-oxides which are prominent constituents of Allium stipitatum were tested . METHODS : The antiinflammatory activity was tested by the ability of the compounds to inhibit cyclooxygenase ( P23219 and P35354 ) , whereas the neurological activities were evaluated by assessing the compounds ability to inhibit monoamine oxidase-A ( P21397 ) and acetylcholinesterase ( P22303 ) . The compounds׳ affinity for the serotonin transport protein ( P31645 ) and the GABAA-benzodiazepine receptor were also investigated . RESULTS : 2-[(Methylthio)methyldithio]pyridine N-oxide showed very high antiinflammatory effects which are comparable with those of common pharmaceuticals ( IC₅₀ of 7.8 and 15.4 µM for P23219 and P35354 , respectively ) . On the other hand , neurological activities of the compounds were rather modest . Some compounds moderately inhibited P22303 ( IC₅₀ of 104-1041 µM ) and P21397 ( IC₅₀ of 98-241 µM ) and exhibited an affinity for the P31645 and GABAA-benzodiazepine receptor . CONCLUSIONS : Our findings may help to rationalize the wide use of Persian shallot for the treatment of inflammatory disorders . Effect of active smoking on the human bronchial epithelium transcriptome . BACKGROUND : Lung cancer is the most common cause of cancer-related deaths . Tobacco smoke exposure is the strongest aetiological factor associated with lung cancer . In this study , using serial analysis of gene expression ( Q9NXZ1 ) , we comprehensively examined the effect of active smoking by comparing the transcriptomes of clinical specimens obtained from current , former and never smokers , and identified genes showing both reversible and irreversible expression changes upon smoking cessation . RESULTS : Twenty-four Q9NXZ1 profiles of the bronchial epithelium of eight current , twelve former and four never smokers were generated and analyzed . In total , 3,111,471 Q9NXZ1 tags representing over 110 thousand potentially unique transcripts were generated , comprising the largest human Q9NXZ1 study to date . We identified 1,733 constitutively expressed genes in current , former and never smoker transcriptomes . We have also identified both reversible and irreversible gene expression changes upon cessation of smoking ; reversible changes were frequently associated with either xenobiotic metabolism , nucleotide metabolism or mucus secretion . Increased expression of Q07654 , O75952 , and Q5MY95 were found to be reversible upon smoking cessation . Expression of P49841 , which regulates P35354 expression , was irreversibly decreased . P98088 expression was only partially reversed . Validation of select genes was performed using quantitative RT-PCR on a secondary cohort of nine current smokers , seven former smokers and six never smokers . CONCLUSION : Expression levels of some of the genes related to tobacco smoking return to levels similar to never smokers upon cessation of smoking , while expression of others appears to be permanently altered despite prolonged smoking cessation . These irreversible changes may account for the persistent lung cancer risk despite smoking cessation . Celecoxib with chemotherapy in colorectal cancer . P35354 ( P35354 ) is the enzyme that normally synthesizes prostaglandins during an inflammatory response . Many primary and metastatic cancers express P35354 , and its presence is correlated with tumor angiogenesis , more invasive tumor phenotype , resistance to apoptosis , and systemic immunosuppression . The expression of P35354 is associated with a worse prognosis . Inhibition of prostaglandin synthesis may be beneficial in human malignancy . Regular consumption of nonsteroidal anti-inflammatory drugs ( NSAIDs ) decreases the incidence of , and mortality rate resulting from , a number of types of gastrointestinal cancers . Premalignant colonic lesions regress following the administration of nonspecific P36551 inhibitors , such as sulindac ( DB00605 ) . Advanced solid tumor patients treated with indomethacin ( DB00328 ) survive twice as long as do such patients who receive supportive care alone . The U.S . Food and Drug Administration has approved specific P35354 inhibitors for the treatment of arthritis , pain , and familial adenomatous polyposis . Preclinical studies show that these drugs block angiogenesis , suppress solid tumor metastases , and slow the growth of implanted gastrointestinal cancer cell lines . The P35354 inhibitors have safely and effectively been combined with chemotherapeutic agents in experimental studies . Ongoing clinical trials are currently assessing the potential therapeutic role of P35354 inhibitors in both prevention and treatment of a diverse range of human cancers . Signaling pathways mediating induction of the early response genes prostaglandin G/H synthase-2 and egr-1 by serotonin via 5- Q13049 receptors . Signaling pathways responsible for serotonin ( 5-HT ) -mediated induction of early response genes prostaglandin G/H synthase-2 ( P35354 , cyclooxygenase-2 ) and egr-1 were investigated in rat mesangial cells . Gene induction by 5-HT was dependent on 5- Q13049 receptors that were pertussis toxin insensitive indicating coupling to a G-protein of the Gq family . Binding of 5-HT to this receptor activates phosphatidylinositol-specific phospholipase C ( P98160 ) and release of Ca2+ from internal stores , but this activation was not related to P35354 mRNA expression . Similarly , P19957 kinase was not involved in 5-HT signaling . Instead , inhibition of phosphatidylcholine-specific P98160 interfered with P35354 and egr-1 mRNA induction , suggesting this enzyme as a link between 5- Q13049 receptors and protein kinase C , an essential part of 5-HT-mediated signaling . The Q96HU1 kinase pathway was identified as common signaling pathway of 5-HT or phorbol ester-induced gene expression . Increase of intracellular DB02527 by forskolin or dibutyryl DB02527 did not induce P35354 or egr-1 mRNA expression by itself , but strongly inhibited 5-HT-mediated mRNA induction . P35354 mRNA and protein induction by 5-HT was also abolished by chelation of Ca2+ ions by EGTA , suggesting involvement of Ca2+-dependent enzymes . In contrast , egr-1 mRNA expression was superinduced in the presence of EGTA . Induction of Egr-1 protein was not changed by EGTA hinting to Ca2+-sensitive posttranscriptional steps . Activation of the Gq-coupled 5- Q13049 receptor thus leads to the expression of the early response genes P35354 and egr-1 , using common as well as differing signaling elements that allow differential regulation of the expression of these genes that are functionally related to renal hemodynamics and proliferation of mesangial cells , respectively . DB01356 inhibits glycogen synthase kinase-3 activity and mimics wingless signalling in intact cells . BACKGROUND : Exposing eukaryotic cells to lithium ions ( Li+ ) during development has marked effects on cell fate and organization . The phenotypic consequences of Li+ treatment on Xenopus embryos and sporulating Dictyostelium are similar to the effects of inhibition or disruption , respectively , of a highly conserved protein serine/threonine kinase , glycogen synthase kinase-3 ( GSK-3 ) . In Drosophila , the GSK-3 homologue is encoded by zw3sgg , a segment-polarity gene involved in embryogenesis that acts downstream of wg . In higher eukaryotes , GSK-3 has been implicated in signal transduction pathways downstream of phosphoinositide 3-kinase and mitogen-activated protein kinases . RESULTS : We investigated the effect of Li+ on the activity of the GSK-3 family . At physiological doses , Li+ inhibits the activity of human P49841 and Drosophila Zw3Sgg , but has no effect on other protein kinases . The effect of Li+ on GSK-3 is reversible in vitro . Treatment of cells with Li+ inhibits GSK-3-dependent phosphorylation of the microtubule-associated protein Tau . Li+ treatment of Drosophila S2 cells and rat PC12 cells induces accumulation of cytoplasmic Armadillo/beta-catenin , demonstrating that Li+ can mimic Wingless signalling in intact cells , consistent with its inhibition of GSK-3 . CONCLUSIONS : Li+ acts as a specific inhibitor of the GSK-3 family of protein kinases in vitro and in intact cells , and mimics Wingless signalling . This reveals a possible molecular mechanism of Li+ action on development and differentiation . DB01037 transdermal system : in the treatment of major depressive disorder . The monamine oxidase ( MAO ) inhibitor selegiline is selective for P27338 at the low oral dosages used in the treatment of Parkinson 's disease . However , P21397 is also inhibited at the high oral dosages needed to effectively treat depression ( not an approved indication ) , necessitating a tyramine-restricted diet . The selegiline transdermal system was designed to deliver antidepressant drug concentrations to the CNS , without substantially impairing small intestine P21397 activity . At the target dose of 6 mg/24 hours , tyramine dietary restrictions are not needed . Short-term treatment with fixed ( 6 mg/24 hours ) or flexible ( 6 , 9 or 12 mg/24 hours ) doses of selegiline transdermal system was superior to placebo on most measures of antidepressant activity in 6- or 8-week , randomised , double-blind , multicentre studies in adult outpatients with major depressive disorder ( MDD ) . Likewise , long-term treatment with a fixed dose of selegiline transdermal system 6 mg/24 hours was superior to placebo as maintenance therapy in a 52-week , randomised , double-blind , multicentre , relapse-prevention trial in patients with MDD . DB01037 transdermal system therapy was generally well tolerated in placebo-controlled studies ; application site reactions , mostly of mild to moderate severity , were the most commonly reported adverse events . The incidence of sexual adverse effects and weight gain was low and similar to that with placebo . [ Meloxicam ( DB00814 ) : a review of its pharmacological and clinical profile ] . Meloxicam ( DB00814 ) is a new nonsteroidal anti-inflammatory drug ( NSAID ) derived from enolic acid , exhibiting selectivity for cyclooxygenase ( P36551 ) -2 over P23219 . Meloxicam has shown potent anti-inflammatory and analgesic activity together with low gastrointestinal toxicity in animal models . It is a potent inhibitor not only of acute exudation in adjuvant arthritis in the rat , but also of bone and cartilage destruction . The therapeutic range of meloxicam in the rat , with regard to inhibition of adjuvant arthritis , was several times greater than that of other NSAIDs . Meloxicam in therapeutic doses was found to have no effect on bleeding time or platelet aggregation in healthy volunteers . In clinical studies , meloxicam has shown reliable efficacy against rheumatoid arthritis , osteoarthritis , lumbago ( low back pain ) , scapulohumeral periarthritis , and neck-shoulder-arm syndrome with low gastrointestinal toxicity . DB00175 -induced changes in receptor-mediated metabolism of low density lipoprotein in guinea pigs . The effect of pravastatin , an inhibitor of P04035 , on the metabolism of human low density lipoprotein ( LDL ) was examined in guinea pigs . DB00175 treatment significantly reduced plasma levels of total cholesterol and LDL-cholesterol by 15.6 mg/dl ( 38.8 % ) and 12.7 mg/dl ( 42.9 % ) , respectively . We investigated the metabolism of LDL in pravastatin-treated and untreated guinea pigs using the simultaneous intravenous injection of 131I-labeled LDL and 125I-labeled , galactose-treated LDL to quantify the P01130 pathway . DB00175 increased the fractional catabolic rate ( FCR ) of the P01130 -dependent pathway . The treatment with pravastatin did not alter the FCR of the P01130 -independent pathway . The FCR of the P01130 -dependent pathway was higher for LDL isolated from pravastatin-treated subjects than for LDL isolated from control subjects . These findings suggest that pravastatin mainly reduced plasma cholesterol levels by accelerated FCR of the P01130 -mediated pathway . Genotype frequencies of 50 polymorphisms for 241 Japanese non-cancer patients . This paper lists the genotype frequencies of 50 polymorphisms of 37 genes ( P05091 , P07550 , P13945 , P21964 , P16671 , P25025 , P24385 , P35354 , P11509 , P05093 , P11511 , IGF1 , IL-1A , IL-1B , IL-1RN , IL-1R1 , P05231 , P10145 , P22301 , P41159 , Le , L-myc , P05164 , Q99707 , P42898 , P21397 , P15559 , O15527 , p53 , p73 , Se , P31213 , TGF-B , P01375 -A , P01375 -B , P18074 , and P18887 ) and 6 sets of combined genotype frequencies for 241 non-cancer Japanese outpatients . Though the genotype frequencies of 25 polymorphisms have already been reported in our previous papers , 15 polymorphisms ( P16671 A52C , P25025 C785T , P24385 G870A , IGF1 C/T at intron 2 and G2502T , IL-1A 46-bp VNTR , IL-1R1 C-116T , P05231 Ins/Del 17C , P10145 A-278T and C74T , IL- 10 T-819C , P41159 A-2548G , P31213 2-bp VNTR , P18074 Lys751Gln , and P18887 Arg399Gln ) and six sets of combined genotype frequencies ( IL-1B C-31T and IL-1A C-889T , IL-1B C-31T and IL-1RN 86-bp VNTR , IL-1B C-31T and IL-1R1 C-116T , P01375 -A G-308A and P01375 -B A252G , P31213 Val89Leu and 2-bp VNTR , and P18887 Arg399Gln and P18074 Lys751Gln ) were reported in this paper for the first time for Japanese . Although microarray technology will produce this kind of information in near future , this is the first document that reports the genotype/allele frequencies among Japanese for an archival purpose . Investigation of the binding of isoform-selective inhibitors to prostaglandin endoperoxide synthases using fluorescence spectroscopy . Prostaglandin endoperoxide synthase ( PGHS ) is a heme protein that catalyzes the committed step in prostaglandin and thromboxane biosynthesis . Two isoforms of PGHS exist , a constitutive form termed P23219 and an inducible form termed P35354 . We report here fluorescence resonance energy transfer analysis of isoform-selective inhibitors interacting with P23219 and P35354 . By measuring fluorescence quenching due to the energy transfer of the inhibitor fluorescence to the heme prosthetic group of PGHS , we determined these inhibitors bind in the arachidonic acid substrate access channel with an R0 of 35 A for P23219 with the P23219 inhibitor and an R0 of 21 A for P35354 with the P35354 inhibitor . The observed fluorescence quenching is completely dynamic and dominated by quenching by the heme . Time-resolved results combined with molecular modeling determine the distance from the inhibitor to the heme moiety to be 20 A in P23219 and 18 A in P35354 . Preliminary stopped-flow kinetic studies reveal that the rate of quenching is limited by a first-order protein transition , which is slow , and that bound inhibitor undergoes rapid exchange . Aripiprazole : pharmacodynamics of a dopamine partial agonist for the treatment of schizophrenia . Aripiprazole is the first approved atypical antipsychotic with a mechanism of action that exerts a partial agonism with high affinity at DB00988 D2- and Serotonin- P08908 -receptors as well as an antagonism at Serotonin-5- Q13049 -receptors . Aripiprazole provides good clinical effectiveness and a favorable profile of safety and tolerability . The special pharmacodynamics of aripiprazole are described herein . Correcting human mitochondrial mutations with targeted RNA import . Mutations in the human mitochondrial genome are implicated in neuromuscular diseases , metabolic defects , and aging . An efficient and simple mechanism for neutralizing deleterious mitochondrial DNA ( mtDNA ) alterations has unfortunately remained elusive . Here , we report that a 20-ribonucleotide stem-loop sequence from the H1 RNA , the RNA component of the human RNase P enzyme , appended to a nonimported RNA directs the import of the resultant RNA fusion transcript into human mitochondria . The methodology is effective for both noncoding RNAs , such as tRNAs , and mRNAs . The RNA import component , polynucleotide phosphorylase ( Q8TCS8 ) , facilitates transfer of this hybrid RNA into the mitochondrial matrix . In addition , nucleus-encoded mRNAs for mitochondrial proteins , such as the mRNA of human mitochondrial ribosomal protein P28222 ( O15235 ) , contain regulatory sequences in their 3'-untranslated region ( UTR ) that confers localization to the mitochondrial outer membrane , which is postulated to aid in protein translocation after translation . We show that for some mitochondrial-encoded transcripts , such as P35354 , a 3'-UTR localization sequence is not required for mRNA import , whereas for corrective mitochondrial-encoded tRNAs , appending the 3'-UTR localization sequence was essential for efficient fusion-transcript translocation into mitochondria . In vivo , functional defects in mitochondrial RNA ( mtRNA ) translation and cell respiration were reversed in two human disease lines . Thus , this study indicates that a wide range of RNAs can be targeted to mitochondria by appending a targeting sequence that interacts with Q8TCS8 , with or without a mitochondrial localization sequence , providing an exciting , general approach for overcoming mitochondrial genetic disorders . Dehydration activates an NF-kappaB-driven , P35354 -dependent survival mechanism in renal medullary interstitial cells . Renal prostaglandin ( PG ) synthesis is mediated by cyclooxygenase-1 and -2 ( P23219 and P35354 ) . After dehydration , the maintenance of normal renal function becomes particularly dependent upon PG synthesis . The present studies were designed to examine the potential link between medullary P23219 and P35354 expression in hypertonic stress . In response to water deprivation , P35354 , but not P23219 , mRNA levels increase significantly in the renal medulla , specifically in renal medullary interstitial cells ( RMICs ) . DB09145 deprivation also increases renal NF-kappaB-driven reporter expression in transgenic mice . NF-kappaB activity and P35354 expression could be induced in cultured RMICs with hypertonic sodium chloride and mannitol , but not urea . RMIC P35354 expression was also induced by driving NF-kappaB activation with a constitutively active O15111 alpha ( IKKalpha ) . Conversely , introduction of a dominant-negative IkappaB mutant reduced P35354 expression after hypertonicity or IKKalpha induction . RMICs failed to survive hypertonicity when P35354 was downregulated using a P35354 -selective antisense or blocked with the selective nonsteroidal anti-inflammatory drug ( NSAID ) SC58236 , reagents that did not affect cell survival in isotonic media . In rabbits treated with SC58236 , water deprivation induced apoptosis of medullary interstitial cells in the renal papilla . These results demonstrate that water deprivation and hypertonicity activate NF-kappaB . The consequent increase in P35354 expression favors RMIC survival in hypertonic conditions . Inhibition of RMIC P35354 could contribute to NSAID-induced papillary injury . [ DB00988 -beta-hydroxylaseaktivität im Plasma von Dialysepatienten ( author 's transl ) ] . Plasma dopamin-b-hydroxylase ( P09172 ) was studied in 70 healthy control persons and in 37 hemodialysed patients . Basal P09172 in controls corresponded to 50.0 +/- 29.3 IU . There was was no significant difference between males ( 53.9 +/1 33.8 IU ) and females ( 47.4 +/- 25 IU ) ; no correlation could be found between age and plasma P09172 . In hemodialysed patients basal P09172 levels were significantly ( p less than 0.01 ) decreased ( 32.5 % /- 17.6 IU ) , suggesting lowered sympathetic activity and/or abnormalities in release , distribution space , or metabolism of P09172 . During hemodialysis plasma P09172 activity rose during ultrafiltration . This finding indicates a directionally appropriate sympathetic reflex response to volume depletion in dialysed patients . [ Measurement of rifampicin and clarithromycin in serum by high-performance liquid chromatography with electrochemical detection ] . DB01045 ( RFP ) induces hepatic drug-metabolizing enzymes , making drug interactions a very important clinical problem . DB01211 ( P62158 ) metabolism is reportedly enhanced by induction of hepatic drug-metabolizing enzymes ( P08684 ) by RFP , so that the blood lend of P62158 decreases when RFP is administered concurrently . We connected an electrochemical detector to a high-performance liquid chromatograph ( HPLC ) for simple , rapid , easy measurement of blood concentrations of RFP and P62158 . Using samples of patient serum , normal serum , and reference standards , we compared HPLC by an external laboratory and the results of LC/MS/MS analysis with those of this new assay . A strong correlation was seen between our HPLC results and those of the external laboratory in RFP levels ( r=0.975 , p < 0.01 ) . A strong correlation was also seen between results we obtained for P62158 with the electrochemical detector in this assay and values measured by LC/MS/MS analysis ( r=0.995 , p < 0.01 ) . Our method enabled simple , rapid measurement of RFP and P62158 by connecting the HPLC and electrochemical detector in tandem . This system was used to modulate dosage during combined therapy with RFP and P62158 . The therapeutic effect for nontuberculous mycobacteriosis is expected to improve , and our HPLC is expected to be useful for simple , rapid , easy measurement of blood concentrations . Suppression of NF-kappaB activity by sulfasalazine is mediated by direct inhibition of IkappaB kinases alpha and beta . BACKGROUND & AIMS : Activation of NF-kappaB/Rel has been implicated in the pathogenesis of inflammatory bowel disease ( Q9UKU7 ) . Various drugs used in the treatment of Q9UKU7 , such as glucocorticoids , DB00244 , and sulfasalazine , interfere with NF-kappaB/Rel signaling . The aim of this study was to define the molecular mechanism by which sulfasalazine inhibits NF-kappaB activation . METHODS : The effects of sulfasalazine and its moieties on NF-kappaB signaling were evaluated using electromobility shift , transfection , and immune complex kinase assays . The direct effect of sulfasalazine on O15111 ( IKK ) activity was investigated using purified recombinant O15111 and -beta proteins . RESULTS : NF-kappaB/Rel activity induced by tumor necrosis factor alpha , 12-O-tetradecanoylphorbol-13-acetate , or overexpression of NF-kappaB-inducing kinase , O15111 , O14920 , or constitutively active O15111 and O14920 mutants was inhibited dose dependently by sulfasalazine . Sulfasalazine inhibited tumor necrosis factor alpha-induced activation of endogenous IKK in Jurkat T cells and SW620 colon cells , as well as the catalytic activity of purified O15111 and O14920 in vitro . In contrast , the moieties of sulfasalazine , DB00244 , and sulfapyridine or DB00233 had no effect . Activation of extracellular signal-related kinase ( P29323 ) 1 and 2 , c-Jun-N-terminal kinase ( JNK ) 1 , and p38 was unaffected by sulfasalazine . The decrease in substrate phosphorylation by O15111 and -beta is associated with a decrease in autophosphorylation of IKKs and can be antagonized by excess adenosine triphosphate . CONCLUSIONS : These data identify sulfasalazine as a direct inhibitor of O15111 and -beta by antagonizing adenosine triphosphate binding . The suppression of NF-kappaB activation by inhibition of the IKKs contributes to the well-known anti-inflammatory and immunosuppressive effects of sulfasalazine . P35354 promotes early atherosclerotic lesion formation in ApoE-deficient and C57BL/6 mice . Cyclooxygenase ( P36551 ) 2 is expressed in atherosclerotic lesions . We have previously reported that selective inhibition of P35354 reduces early atherosclerosis in P01130 deficient mice . To examine the role of P35354 in atherosclerosis in other mouse models , we studied the effects of selective P35354 inhibition ( by rofecoxib and NS-398 ) and nonselective P36551 inhibition ( by indomethacin ) on early atherosclerotic lesion formation in apolipoprotein E-deficient ( apoE(-/-) ) mice . Selective P35354 and nonselective P36551 inhibition reduced atherosclerosis in female apoE(-/-) mice by 35-38 % and 38-51 % in the proximal and en face aortas , respectively . Next we investigated the role of macrophage P35354 by transplanting P35354 (-/-) fetal liver cells into C57BL/6 mice and challenging the mice with an atherogenic diet . Genetic deletion of P35354 from hematopoietic cells reduced atherosclerosis by 51 % . In addition , LPS activated P35354 (-/-) macrophages had decreased expression of monocyte chemoattractant protein-1 ( P13500 ) and tumor necrosis factor-alpha ( TNFalpha ) . The results demonstrate that selective inhibition of P35354 and elimination of P35354 from macrophages significantly reduces early atherosclerotic lesion formation in apoE-deficient and C57BL/6 mice . These results are compatible with P35354 expression by macrophages having a proatherogenic role , and support the potential of anti-inflammatory therapeutic approaches for atherosclerosis . Role of presynaptic serotonergic receptors on the mechanism of action of P08908 and P28222 agonists on masculine sexual behaviour : physiological and pharmacological implications . In order to establish whether the P08908 or the 5HT1B agonists , 8-OH-DPAT or TFMPP , produce their facilitatory or inhibitory actions on masculine sexual behaviour via a mechanism involving : ( a ) the serotonin synthesis or release ; ( b ) the stimulation of presynaptic receptors , or ( c ) the stimulation of somatodendritic receptors , three series of experiments were performed . The administration of the serotonin synthesis inhibitor , p-chlorophenylalanine ( p- P15085 , 300 mg/kg x 3 days ) , facilitated sexual behaviour but does not interfere neither with the inhibitory nor with the facilitatory effects of TFMPP ( 0.5 mg/kg ) or 8-OH-DPAT ( 0.5 mg/kg ) , respectively . The icv or the intraraphé administration of the serotonergic neurotoxin , 5,7-dihydroxytryptamine ( 5,7- DB02901 ) , slightly stimulated masculine sexual behaviour and produced a decrease in serotonin and its metabolite levels . In lesioned animals TFMPP ( 0.5 mg/kg ) resulted in an inhibitory effect reflected as a prolongation of the ejaculation latency . The inhibitory effect of this drug on mounting behaviour was not observed in 5,7- DB02901 treated rats . In lesioned animals 8-OH-DPAT ( 0.5 mg/kg ) produced the same facilitatory effect . Present data indicate that serotonergic postsynaptic receptors mediate both the inhibitory and the facilitatory actions of TFMPP or 8-OH-DPAT in copulation . All data further support the idea that endogenous serotonin acts via the stimulation of P28222 receptors to induce its inhibitory effects on masculine sexual behaviour . A real time quantitative PCR analysis and correlation of P23219 and P35354 enzymes in inflamed dental pulps following administration of three different NSAIDs . Dental pain is encountered daily by clinicians . Nonsteroidal anti-inflammatory drugs ( NSAIDs ) commonly used for pain management are traditionally cyclooxygenase-1 ( P23219 ) and cyclooxygenase-2 ( P35354 ) inhibitors , and more recently selective P35354 inhibitors . This study was designed to identify and quantify P23219 and P35354 gene expression level in inflamed rat molar pulps after administration of three NSAIDs : DB00482 , Vioxx , and DB01050 . Fifty male Wistar rats had their first and second molar pulps exposed and sealed with Cavit for 4 days . Rats were randomly divided into the three drug groups and two control groups . RNA was isolated from the rat pulps . Real Time Quantitative Reverse Transcriptase-Polymerase Chain Reaction assay , a relatively new PCR technique , was used to quantify P23219 and P35354 mRNA . Statistical analysis demonstrated no significant differences in P23219 and P35354 levels among the drug groups . However , Vioxx and DB01050 significantly reduced P35354 expression levels compared to inflamed ( positive control ) pulps ( p < 0.05 ) . 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 . Human mesenchymal stem cell proliferation is regulated by DB00917 through differential activation of DB02527 -dependent protein kinase isoforms . The conditions used for in vitro differentiation of hMSCs contain substances that affect the activity and expression of cyclooxygenase enzymes ( P23219 / P35354 ) and thereby the synthesis of prostanoids . hMSC constitutively produce DB00917 when cultivated in vitro . In this study we have investigated effects of DB00917 on proliferation of hMSC . We here demonstrate that one of the main control molecules in the Wnt pathway , P49841 , is phosphorylated at the negative regulatory site ser-9 after treating the cells with DB00917 . This phosphorylation is mediated by elevation of DB02527 and subsequent activation of PKA . Furthermore , DB00917 treatment leads to enhanced nuclear translocation of beta-catenin , thus influencing cell proliferation . The presence of two PKA isoforms , types I and II , prompted us to investigate their individual contribution in DB00917 -mediated regulation of proliferation . Specific activation of PKA type II with synthetic DB02527 analogues , resulted in enhancement of proliferation . On the other side , we found that treatment of hMSC with high concentrations of DB00917 inhibited cell proliferation by arresting the cells in G0/ P55008 phase , an effect we found to be mediated by PKA I . Hence , the two different PKA isoforms seem to have opposing functions in the regulation of proliferation and differentiation in these cells . [ P35354 inhibitor non-steroidal anti-inflammatory drugs , myth or reality ? ] . The discovery of two isoforms of cyclooxygenase , Cox-1 constitutive and Cox-2 inducible , has prompted the development of new molecules with high Cox-2 selectivity . These new NSAIDs belong to the coxib class and have theoretically a better digestive tolerability than classical NSAID have . In Belgium , rofecoxib ( ( Vioxx ) and celecoxib ( DB00482 ) are commercialized . DB00533 is indicated in the symptomatic treatment of osteoarthritis ( 12.5 to 25 mg/d ) and celecoxib is indicated in osteoarthritis ( 200 mg/d ) and in rheumatoid arthritis ( 200 to 400 mg/d ) . Several studies have demonstrated their efficacy , similarly to classical NSAID as diclofenac ( Voltaren ) , naproxen ( Naprosyne ) , ibuprofen ( DB01050 ) and their superiority compared to placebo . Their safety profile for gastrointestinal events is proven in patients without ulcer history compared to classical NSAID . However , the concomitant use of aspirin decreases the benefit as demonstrated for celecoxib at 400 mg/d but not investigated for rofecoxib . The selective inhibition of Cox-2 with no effect on Cox-1 favors cardiovascular events in patients at risk . Other side effects are similar to classical NSAID . Thus Cox-2 inhibitors NSAID are interesting molecules for their sparing gastrointestinal activity . They must be used with caution in patients with ulcer history , in the elderly and in patients requiring aspirin for cardiovascular prophylaxis .