interacts_with DB00501?
DB00131 cyclase 1 ( Q08828 ) mutations cause recessive hearing impairment in humans and defects in hair cell function and hearing in zebrafish . DB02527 ( DB02527 ) production , which is important for mechanotransduction within the inner ear , is catalyzed by adenylate cyclases ( AC ) . However , knowledge of the role of ACs in hearing is limited . Previously , a novel autosomal recessive non-syndromic hearing impairment locus DFNB44 was mapped to chromosome 7p14.1-q11.22 in a consanguineous family from Pakistan . Through whole-exome sequencing of DNA samples from hearing-impaired family members , a nonsense mutation c.3112C > T ( p.Arg1038* ) within adenylate cyclase 1 ( Q08828 ) was identified . This stop-gained mutation segregated with hearing impairment within the family and was not identified in ethnically matched controls or within variant databases . This mutation is predicted to cause the loss of 82 amino acids from the carboxyl tail , including highly conserved residues within the catalytic domain , plus a calmodulin-stimulation defect , both of which are expected to decrease enzymatic efficiency . Individuals who are homozygous for this mutation had symmetric , mild-to-moderate mixed hearing impairment . Zebrafish adcy1b morphants had no FM1-43 dye uptake and lacked startle response , indicating hair cell dysfunction and gross hearing impairment . In the mouse , Adcy1 expression was observed throughout inner ear development and maturation . Q08828 was localized to the cytoplasm of supporting cells and hair cells of the cochlea and vestibule and also to cochlear hair cell nuclei and stereocilia . Ex vivo studies in COS-7 cells suggest that the carboxyl tail of Q08828 is essential for localization to actin-based microvilli . These results demonstrate that Q08828 has an evolutionarily conserved role in hearing and that DB02527 signaling is important to hair cell function within the inner ear . [ Roles of P26718 in cytokine-induced killer ( CIK ) against hematological malignant cells lines ] . This study was purposed to investigate the CIK cell cytotoxicity to hematological malignant cell lines by interaction P26718 receptors and corresponding ligands . The CIK cells was expanded from healthy individual with interferon (IFN)γ , CD3 monoclonal antibodies ( mAb ) and interleukin-2 ( P60568 ) . The subset of lymphocyte and the expression of NK cell receptors on CIK cells was detected by flow cytometry ; P26718 ligand expression on hematological malignant cell lines was also analyzed by flow cytometry , the calcein acetoxymethyl ester ( P62158 ) was used for labeling target cells , then the cytotoxicity of CIK cells to hematological malignant cell lines was detected by flow cytometry . The results showed that most of CIK cells expressed CD3 ( 97.85 ± 1.95 % ) , CD3(+)CD8(+) cells and CD3(+)CD56(+) cells increased significantly as compared with un-cultured cells ( P < 0.001;P = 0.033 ) . About 86 % CIK cells expressed P26718 receptor but no other NK receptors such as CD158a , CD158b and NCR . Different levels of P26718 ligands were detected in hematological malignant cell lines U266 , K562 and Daudi . CIK cells showed high cytotoxicity to these three different cell lines , and this cytotoxicity was partially blocked by treating CIK cells with anti- P26718 antibody ( U266 52.67 ± 4.63 % vs 32.67 ± 4.81 % , P = 0.008;K562 71.67 ± 4.91 % vs 50.33 ± 4.91 % , P = 0.007;Daudi 68.67 ± 5.04 vs 52.67 ± 2.60 % , P = 0.024 ) . It is concluded that most of CIK cells express P26718 receptor , interaction of P26718 - P26718 ligands may be one of the mechanisms , by which CIK cells kill hematological malignant cells . P25021 overexpression induces U937 cell differentiation despite triggered mechanisms to attenuate DB02527 signalling . Knowing that cell-surface receptors that recognize and respond to extracellular stimuli are key components for the regular communication between individual cells required for the survival of any living organism , the aim of the present work was to investigate the effect of P25021 overexpression on the U937 signal transduction pathway and its consequences on cell proliferation and differentiation . The overexpression of P25021 led to an increase in DB02527 basal levels , a leftward shift of agonist concentration-response curves , and similar maximal response to agonist treatment , suggesting that overexpressed H2Rs act as functional spare receptors . In this system cells triggered several mechanisms tending to restore DB02527 basal levels to those of the naïve cells . P25021 overexpression induced PDE activity stimulation and P25098 overexpression . In spite of the onset of these regulatory mechanisms , H2 agonist and rolipram treatments induced the terminal differentiation of the P25021 overexpressed clone , conversely to the naïve cells . Present findings show that stably P25021 overexpression alters DB02527 signalling as the result of not only the amounts of second messenger generated but also the activation or upregulation of various components of signalling cascade , leading to an adapted biologically unique system . This adaptation may represent an advantage or a disadvantage , depending on the biological system , but in any case , the existence of compensatory mechanisms should be considered when a clinical treatment is designed . DB11320 reduces susceptibility to natural killer cells via down-regulation of P26718 ligands on human monocytic leukaemia THP-1 cells . Natural killer ( NK ) group 2D ( P26718 ) is a key activating receptor expressed on NK cells , whose interaction with ligands on target cells plays an important role in tumorigenesis . However , the effect of histamine on P26718 ligands on tumour cells is unclear . Here we showed that human monocytic leukaemia THP-1 cells constitutively express MHC class I-related chain A ( Q29983 ) and Q9BZM6 on their surface , and incubation with histamine reduced the expression in a dose-dependent and time-dependent manner as assessed by flow cytometry . Interferon-γ augmented the surface expression of the P26718 ligands , and this augmentation was significantly attenuated by histamine . The histamine H1 receptor ( P35367 ) agonist 2-pyridylethylamine and P25021 agonist dimaprit down-regulated the expression of P26718 ligands , and activation of P35367 and P25021 signalling by A23187 and forskolin , respectively , had the same effect , indicating that the histamine-induced down-regulation of P26718 ligands is mediated by P35367 and P25021 . Quantitative reverse transcription-PCR showed that mRNA levels of the P26718 ligands and relevant microRNAs were not significantly changed by histamine . DB11320 down-regulated the surface expression of endoplasmic reticulum protein 5 , and inhibition of matrix metalloproteinases did not impair this down-regulation , indicating that proteolytic shedding was not involved . Instead , pharmacological inhibition of protein transport and proteasome abrogated it , and histamine enhanced ubiquitination of Q29983 . Furthermore , histamine treatment significantly reduced susceptibility to NK cell-mediated cytotoxicity . These results suggest that histamine down-regulates P26718 ligands through the activation of an P35367 - and P25021 -mediated ubiquitin-proteasome pathway and consequently reduces susceptibility to NK cells . DB00501 enhances antigen-specific IgE and Th2 cytokine production . BACKGROUND : Treatment with anti-ulcer drugs has been shown to enhance IgE production against food antigens . However , little is known about the immunological effects of cimetidine , a histamine receptor type 2 ( P25021 ) antagonist that is widely used as an anti-ulcer drug , in allergy . Therefore , the present study investigated the role of cimetidine in Th2 immune responses in mice . METHODS : BALB/c mice were immunized intraperitoneally with ovalbumin ( OVA ) with and without cimetidine . The levels of cytokines in supernatants of spleen cells cultured in the presence of OVA for 4 days and the levels of total and OVA-specific IgG(1) , IgG(2a) and/or IgE in sera from these mice were determined by ELISA . RESULTS : Administration of cimetidine to OVA-sensitized BALB/c mice promoted Th2 cytokine secretion by OVA-stimulated spleen cells in vitro and increased serum levels of OVA-specific IgE , IgG(1) and IgG(2a) . CONCLUSIONS : These results indicate that cimetidine can enhance Th2 responses , suggesting that cimetidine may contribute to IgE production in allergies . RNA-seq reveals determinants of sensitivity to chemotherapy drugs in esophageal carcinoma cells . Chemotherapy remains the mainstay of treatment for patients with incurable disease of esophageal carcinoma . Most patients respond poorly to chemotherapy , it is necessary to figure out biomarkers for chemotherapy sensitivity or resistance to perform the individualized therapy . In present work , the sensitivities of two ESCC cell lines to 9 chemotherapy drugs were identified and the transcriptome of these two cell lines were investigated by RNA-seq , the correlation between the sensitivity to drugs and expression of some genes was attempted to construct . Eca-1 was more resistant to most of the chemotherapy drugs than Eca-109 cell line . RNA-seq results showed that there is dramatic difference in the basal expression between these two ESCC cell lines . Pathway analysis demonstrated that these differentially expressed genes were mainly enriched in Gαi signaling , calcium signaling , DB02527 -mediated signaling , G-protein coupled receptor signaling and actin cytoskeleton signaling pathways . The molecules in Gαi signaling ( Q08828 and P32745 ) and actin cytoskeleton signaling ( P13533 and P12883 ) were highly expressed in multidrug-resistant Eca-1 cells , which were validated by quantitative PCR . Activation of these two pathways results in the upregulation of downstream signaling , PKA signaling and Src- P40763 , and downregulation of RAF- P29323 signaling , which was validated by immunoblotting experiments . Our work proposed that activation of Gαi signaling or actin cytoskeleton signaling may confer ESCC cells resistance to most chemotherapy drugs . Our work might provide potential biomarkers and therapeutic targets for treatment of EC patients . DB11320 improves survival and protects against interleukin-2-induced pulmonary vascular leak syndrome in mice . The therapeutic efficacy in the treatment of metastatic cancer with high doses of interleukin-2 ( P60568 ) has been limited by the onset of vascular leak syndrome ( VLS ) and related toxicities . VLS is characterized by an increase in vascular permeability and severe hypotension resulting in interstitial edema and organ failure . This study explores the protective effects of DB05381 ( HDC ) against P60568 -induced toxicities in mice . Treatment with HDC administered before or after P60568 ( 1.25 x 10(6) IU , P55957 ) was shown to protect mice from VLS-related toxicities and mortality in a dose-dependent manner . Survival rates when HDC was added were 56 , 75 and 81 % at doses of 0.47 , 4.7 and 47.0 mg/kg , respectively , compared to 42 % survival with P60568 alone . HDC protected against P60568 -induced macroscopic pulmonary lesions , reduced edema ( up to 62 % reduction in lung wet/dry weight ratio ) and reduced capillary leakage into the lungs as measured by a reduction in Evans Blue dye content . In addition , the systemic effect on serum cytokine levels showed that HDC only moderately lowered P60568 induced P01579 , P05231 , P22301 , Q14116 and P01375 . Serum levels of IL-1beta , P05112 and IL-12 were not measurably induced by P60568 treatment . HDC modulates many cellular functions including regulating cytokines and blocking immune-suppression caused by reactive oxygen species ( ROS ) generated by the NADPH oxidase . However , the protective effect of HDC on alleviating P60568 -induced pulmonary edema was not related to ROS inhibition . Our data indicate that HDC treatment improves survival and protects against P60568 induced VLS independent of ROS regulation in mice . Oxyntomodulin differentially affects glucagon-like peptide-1 receptor beta-arrestin recruitment and signaling through Galpha(s) . The glucagon-like peptide ( GLP ) -1 receptor is a promising target for the treatment of type 2 diabetes and obesity , and there is great interest in characterizing the pharmacology of the P43220 and its ligands . In the present report , we have applied bioluminescence resonance energy transfer assays to measure agonist-induced recruitment of betaarrestins and G-protein-coupled receptor kinase ( GRK ) 2 to the P43220 in addition to traditional measurements of second messenger generation . The peptide hormone oxyntomodulin is described in the literature as a full agonist on the glucagon and P0C6A0 receptors . Surprisingly , despite being full agonists in P43220 -mediated DB02527 accumulation , oxyntomodulin and glucagon were observed to be partial agonists in recruiting betaarrestins and P25098 to the P43220 . We suggest that oxyntomodulin and glucagon are biased ligands on the P43220 . The design and development of pegfilgrastim ( PEG-rmetHuG- P04141 , Neulasta ) . Recombinant protein technology produces drugs for human therapy in unprecedented quantity and quality . Research is now focusing on the relationship between pharmacokinetic and pharmacodynamic properties of molecules , with the aim of engineering proteins that possess enhanced therapeutic characteristics in contrast to being used as simple replacements for the natural equivalent . The addition of a polyethylene glycol ( PEG ) moiety to filgrastim ( rmetHu- DB00099 , Neupogen ) resulted in the development of pegfilgrastim . DB00019 is a long-acting form of filgrastim that requires only once-per-cycle administration for the management of chemotherapy-induced neutropenia . The covalent attachment of PEG to the N-terminal amine group of the parent molecule was attained using site-directed reductive alkylation . Pegylation increases the size of filgrastim so that it becomes too large for renal clearance . Consequently , neutrophil-mediated clearance predominates in elimination of the drug . This extends the median serum half-life of pegfilgrastim to 42 hours , compared with between 3.5 and 3.8 hours for DB00099 , though in fact the half-life is variable , depending on the absolute neutrophil count , which in turn reflects of the ability of pegfilgrastim to sustain production of those same cells . The clearance of the molecule is thus dominated by a self-regulating mechanism . DB00019 retains the same biological activity as filgrastim , and binds to the same Q99062 , stimulating the proliferation , differentiation and activation of neutrophils . Once-per-chemotherapy cycle administration of pegfilgrastim reduces the duration of severe neutropenia as effectively as daily treatment with filgrastim . In clinical trials , patients receiving pegfilgrastim also had a lower observed incidence of febrile neutropenia than patients receiving filgrastim . Genetic mechanism of aspirin-induced urticaria/angioedema . PURPOSE OF REVIEW : DB00945 -induced urticaria/angioedema is a major aspirin-related hypersensitivity often associated with aspirin-intolerant asthma . Genetic studies on aspirin-intolerant asthma have shown chronic overproduction of cysteinyl leukotrienes . The genetic analysis of aspirin-induced urticaria/angioedema is limited , however . RECENT FINDINGS : A recent study on HLA genotypes has suggested that the HLA alleles DRB11302 and DQB10609 may be genetic markers for aspirin-induced urticaria/angioedema . A polymorphism study that examined nine single-nucleotide polymorphisms of five leukotriene-related genes [ P09917 ( encoding P09917 ) , P20292 ( P09917 -activating protein ) , P35354 ( cyclooxygenase 2 ) , Q16873 ( leukotriene C4 synthase ) , and Q9Y271 ( cysteinyl leukotriene receptor 1 ) ] found that promoter polymorphisms of P09917 ( -1708A > G ) and Q9Y271 ( -634C > T ) were significantly different between aspirin-intolerant asthma and aspirin-induced urticaria/angioedema , suggesting different contributions to the lipoxygenase pathway . A second polymorphism study , conducted on histamine-related genes , did not find any significant associations with aspirin-induced urticaria/angioedema for the genes P50135 ( encoding histamine N-methyltransferase ) , P35367 or P25021 ( encoding histamine receptor types 1 and 2 respectively ) , or the gene encoding high-affinity IgE receptor Ibeta ( FcepsilonRIbeta ) ; however , the FcepsilonRIalpha gene promoter polymorphism was significantly associated with aspirin-induced urticaria/angioedema . This finding has been supported by in vitro functional studies . SUMMARY : The HLA alleles DRB11302 and DQB10609 , and the P09917 and FcepsilonRIalpha promoter polymorphisms , may contribute to the pathogenesis of aspirin-induced urticaria/angioedema . Further investigation to identify candidate genetic markers would help to elucidate the pathogenic mechanism of this condition . Carboxyl-terminal parathyroid hormone fragments : role in parathyroid hormone physiopathology . PURPOSE OF REVIEW : Carboxyl-terminal parathyroid hormone ( C-PTH ) fragments constitute 80 % of circulating PTH . Since the first 34 amino acids of the PTH structure are sufficient to explain PTH classical biological effects on the type I PTH/ P12272 receptor and since C-PTH fragments do not bind to this receptor , they have long been considered inactive . Recent data suggest the existence of a C-PTH receptor through which C-PTH fragments exert biological effects opposite to those of human DB05829 on the type I PTH/ P12272 receptor . This is why a lot of attention has been paid to these fragments recently . RECENT FINDINGS : In vivo , synthetic C-PTH fragments are able to decrease calcium concentration , to antagonize the calcemic response to human PTH(1-34) and human DB05829 and to decrease the high bone turnover rate induced by human DB05829 . In vitro , they inhibit bone resorption , promote osteocyte apoptosis and exert a variety of effects on bone and cartilaginous cells . These effects are opposite to those of human DB05829 on the Q03431 . This suggests that the molecular forms of circulating PTH may control bone participation in calcium homeostasis via two different receptors . Clinically , the accumulation of C-PTH fragments in renal failure patients may cause PTH resistance and may be associated with adynamic bone disease . Rare parathyroid tumors , without a set point error , overproduce C-PTH fragments . The implication of C-PTH fragments in osteoporosis is still to be explored . SUMMARY : C-PTH fragments represent a new field of investigation in PTH biology . More studies are necessary to disclose their real importance in calcium and bone homeostasis in health and disease . Different responsiveness of endothelial cells to vascular endothelial growth factor and basic fibroblast growth factor added to culture media under gravity and simulated microgravity . When incubated under simulated microgravity ( s-microg ) , endothelial cells ( EC ) form tubular structures that resemble vascular intimas . This delayed formation of 3D EC structures begins between the 5th and 7th day of culturing EC under conditions of s-microg , when double-row cell assemblies become visible . With the aim of learning about this initial phase of tubular structure formation , we found that NFkappaBp65 protein content was similar in all cell populations , but gene and protein expression of phosphokinase A catalytic subunit , phosphokinase Calpha , and extracellular signal-regulated kinases 1 and 2 was altered in cells cultured under s-microg . Apoptosis remained below 30 % in all EC cultures . In contrast to controls , the 7-day-old s-microg cultures contained 3D aggregates with proliferating cells , enhanced numbers of necrotic cells , and osteopontin-negative EC as well as supernatants with reduced quantities of vascular endothelial growth factor ( P15692 ) , basic fibroblast growth factor ( P09038 ) , soluble P25942 , P29965 , intercellular adhesion molecule-1 , tumor necrosis factor receptor 2 , Q14116 , complement P01024 , and P04275 . P15692 and/or P09038 ( 10 ng/mL ) application influenced the accumulation of proteins in supernatants more profoundly under 1 g than under s-microg . These findings provide evidence that phosphokinase Calpha plays a key role in tube formation . Improving the interaction of P15692 and/or P09038 with EC under s-microg could enhance the engineering of vascular intimas . DB00501 induces interleukin-18 production through H2-agonist activity in monocytes . The present study demonstrates a possible mechanism for the improvement of gastrointestinal cancer patients ' prognosis by the histamine receptor type 2 ( P25021 ) antagonist cimetidine . This agent , but not the P25021 antagonists ranitidine and famotidine , induced the production of an antitumor cytokine , interleukin ( IL ) -18 , by human monocytes and dendritic cells ( DC ) . In fact , ranitidine and famotidine antagonized cimetidine-induced Q14116 production . DB00501 induced the activation of caspase-1 , which is reported to modify immature Q14116 to mature/active Q14116 , and the elevation of intracellular DB02527 , leading to the activation of protein kinase A ( PKA ) . The PKA inhibitor H89 abolished the Q14116 production induced by cimetidine . Moreover , the effects of cimetidine on Q14116 production were reproduced in peripheral blood mononuclear cells from wild-type mice , but not in those from P25021 knockout mice . In conclusion , cimetidine , a partial agonist for P25021 , has a pharmacological profile different from ranitidine and famotidine , possibly contributing to its antitumor activity on gastrointestinal cancers . Granulocyte macrophage-colony stimulating factor increases the expression of histamine and histamine receptors in monocytes/macrophages in relation to arteriosclerosis . OBJECTIVE : To study the effect of granulocyte macrophage-colony-stimulating factor ( GM- P04141 ) on histamine metabolism in arteriosclerosis , the expression of histidine decarboxylase ( HDC ; histamine-producing enzyme ) , histamine receptors 1 and 2 ( P35367 and P25021 ) , and GM- P04141 was investigated in human and mouse arteriosclerotic carotid arteries . Furthermore , the molecular mechanisms of GM- P04141 -induced HDC and P35367 expression in monocytic U937 cells were investigated . METHODS AND RESULTS : Immunohistochemistry showed that atherosclerotic human coronary and mouse ligated carotid arteries contained HDC-expressing macrophages . Gene expression of HDC , P35367 , P25021 , and GM- P04141 was also detected in the lesions . In U937 cells , GM- P04141 enhanced histamine secretion and gene expression of HDC and P35367 . A promoter assay showed that GM- P04141 enhanced gene transcription of HDC and P35367 but not P25021 . CONCLUSIONS : The present results indicate that HDC and HHR are expressed in arteriosclerotic lesion , and that GM- P04141 induces HDC and P35367 expression in monocytes . Locally produced histamine might participate in atherogenesis by affecting the expression of atherosclerosis-related genes in monocytes and smooth muscle cells . The presence of histamine-producing macrophages and gene expression of histamine receptors and GM- P04141 was demonstrated in arteriosclerotic lesions . In monocytic U937 cells , GM- P04141 upregulated the expression of histamine and P35367 . Coordinated expression of histamine and its receptors by GM- P04141 would participate in atherogenesis by affecting monocytic and SMC gene expression . [ DB09043 ( Eperzan ) : a new once-weekly agonist of glucagon-like peptide-1 receptors ] . DB09043 ( Eperzan ) is a new once-weekly agonist of Glucagon-Like Peptide-1 ( P0C6A0 ) receptors that is indicated in the treatment of type 2 diabetes . Two doses are available , 30 mg and 50 mg , to be injected subcutaneously once a week . It has been extensively evaluated in the HARMONY programme of eight large randomised controlled trials that were performed at different stages of type 2 diabetes , in comparison with placebo or an active comparator . The endocrine and metabolic effects of albiglutide are similar to those of other P43220 agonists : stimulation of insulin secretion ( incretin effect ) and inhibition of glucagon secretion , both in a glucose-dependent manner , retardation of gastric emptying and increase of satiety . These effects lead to a reduction in glycated haemoglobin ( HbA(1c) ) levels , combined with a weight reduction . The overall tolerance profile is good . DB09043 is currently reimbursed in Belgium after failure ( HbA(1c) > 7.5 % ) of and in combination with a dual therapy with metformin and a sulfonylurea as well as in combination with a basal insulin ( with or without oral antidiabetic drugs ) . To avoid hypoglycaemia , a reduction in the dose of sulfonylurea or insulin may be recommended . A once-weekly administration should increase patient 's acceptance of injectable therapy and improve compliance . Computational modeling of the direct hydride transfer mechanism for the MAO catalyzed oxidation of phenethylamine and benzylamine : ONIOM ( QM/QM ) calculations . Monoamine oxidases are two isozymic flavoenzymes which are the important targets for drugs used in the treatment of depression , Parkinson and Alzheimer 's diseases . The catalytic reaction taking place between the cofactor DB03147 and amine substrate is still not completely understood . Herein we employed quantum chemical methods on the recently proposed direct hydride transfer mechanism including full active site residues of MAO isoforms in the calculations . Activation free energy barriers of direct hydride transfer mechanism for P21397 and P27338 were calculated by ONIOM ( our own n-layered integrated molecular orbital + molecular mechanics ) method with QM/QM ( quantum mechanics:quantum mechanics ) approach employing several density functional theory functionals , B3LYP , WB97XD , P62158 -B3LYP and M06-2X , for the high layer . The formation of very recently proposed αC-flavin N5 adduct inside the enzyme has been investigated . ONIOM ( M06-2X/6-31+G(d,p):PM6 ) results revealed that such an adduct may form only in P27338 suggesting slightly different hydride transfer mechanisms for P21397 and P27338 . Neuromuscular therapeutics by RNA-targeted suppression of P22303 gene expression . RNA-targeted therapeutics offers inherent advantages over small molecule drugs wherever one out of several splice variant enzymes should be inhibited . Here , we report the use of Monarsen , a 20-mer acetylcholinesterase-targeted antisense agent with three 3'-2'o-methyl-protected nucleotides , for selectively attenuating the stress-induced accumulation of the normally rare , soluble " readthrough " acetylcholinesterase variant P22303 -R . DB03128 hydrolysis by P22303 -R may cause muscle fatigue and moreover , limit the cholinergic anti-inflammatory blockade , yielding inflammation-associated pathology . Specific P22303 -R targeting by Monarsen was achieved in cultured cells , experimental animals , and patient volunteers . In rats with experimental autoimmune myasthenia gravis , oral delivery of Monarsen improved muscle action potential in a lower dose regimen ( nanomolar versus micromolar ) , rapid and prolonged manner ( up to 72 h versus 2-4 h ) as compared with the currently used small molecule anticholinesterases . In central nervous system neurons of both rats and cynomolgus monkeys , systematic Monarsen treatment further suppressed the levels of the proinflammatory cytokines interleukin-1 ( IL-1 ) and P05231 . Toxicology testing and ongoing clinical trials support the notion that Monarsen treatment would offer considerable advantages over conventional cholinesterase inhibitors with respect to dosing , specificity , side effects profile , and duration of efficacy , while raising some open questions regarding its detailed mechanism of action . DB01064 inhibits fibroblast growth factor-2-induced growth of renal epithelial cells . The signal transduction pathways modulating P09038 effects in renal tubular epithelial cells ( RTEc ) are not completely understood . Since the DB02527 and the mitogen-activated protein kinase ( MAPK ) pathways can modulate the growth of RTEc , we studied whether two DB02527 elevating agents , isoproterenol and 8-bromo- DB02527 , would modulate basic fibroblast growth factor ( P09038 ) induction of MAPK activity ( P28482 ) and cell proliferation in human renal proximal tubular epithelial cells ( RPTEc ) and Madin-Darby canine kidney cells ( MDCK clone EI1 ) . DB01064 , but not P09038 , stimulated DB02527 production in RPTEc and MDCKEI1 cells . P09038 , isoproterenol , and 8-bromo- DB02527 alone increased P28482 activity in both cell types . However , isoproterenol and 8-bromo- DB02527 partially inhibited the P09038 induction of P28482 activity , but only isoproterenol inhibited the proliferation of both cell types . PD098059 ( 25 microM ) , an inhibitor of MAPK kinase ( Q02750 /2 ) , blocked the P09038 mitogenic effects , but did not affect the 8-bromo- DB02527 -induced mitogenic effects in MDCKEI1 cells . These findings suggest that activation of P28482 is required but not sufficient for mitogenesis in RTEc . We conclude that isoproterenol inhibits the growth-promoting effects of P09038 in RTEc via MEK-dependent and -independent pathways . FcεRI stimulation promotes the differentiation of histamine receptor 1-expressing inflammatory macrophages . BACKGROUND : Monocyte differentiation into dendritic cells or macrophages and recruitment to peripheral organs in chronic inflammatory diseases are directed by allergen challenge via FcεRI as well as the nature of soluble factors in the microenvironment . High-affinity receptor for IgE stimulation of effector cells results in the release of histamine , which acts on various histamine receptors ( HR ) 1-4 , expressed by immune cells . METHODS : We examined the effect of FcεRI stimulation of human monocytes on P35367 expression and function of differentiating cells . The mRNA levels of P35367 , P25021 and histidine decarboxylase of differentiating cells were detected by quantitative real-time PCR . Expression of CD1c , CD11c , P34810 and Q86VB7 was detected by flow cytometry . Amount of histamine , P05231 and IL-12p70 in the cell culture was measured with the help of cytometric bead arrays or ELISA assays . Numbers of P35367 -expressing macrophages were evaluated by immunofluorescence double staining of P34810 and P35367 on human skin sections . RESULTS : We demonstrated that FcεRI stimulation promotes the generation of P35367 -expressing macrophage-like cells with enhanced histamine biosynthesis and P35367 -mediated proinflammatory properties . Supporting our in vitro findings , high numbers of P35367 -expressing P34810 (pos) macrophages were detected in the dermis of atopic dermatitis ( AD ) skin lesions . CONCLUSION : Our observations point to a close histamine-/HR-mediated activation of dermal macrophages , leading to modified cell differentiation and responsiveness via P35367 , which might contribute to the aggravation of allergic skin inflammation in AD . Distinct signalling pathways of murine histamine H1- and H4-receptors expressed at comparable levels in HEK293 cells . DB11320 ( HA ) is recognized by its target cells via four G-protein-coupled receptors , referred to as histamine H1-receptor ( P35367 ) , P25021 , Q9Y5N1 , and Q9H3N8 . Both P35367 and Q9H3N8 exert pro-inflammatory functions . However , their signal transduction pathways have never been analyzed in a directly comparable manner side by side . Moreover , the analysis of pharmacological properties of the murine orthologs , representing the main targets of pre-clinical research , is very important . Therefore , we engineered recombinant HEK293 cells expressing either mouse (m) P35367 or mH4R at similar levels and analyzed HA-induced signalling in these cells . HA induced intracellular calcium mobilization via both mH1R and mH4R , with the mH1R being much more effective . Whereas DB02527 accumulation was potentiated via the mH1R , it was reduced via the mH4R . The regulation of both second messengers via the Q9H3N8 , but not the P35367 , was sensitive to pertussis toxin ( PTX ) . The mitogen-activated protein kinases ( MAPKs ) P29323 1/2 were massively activated downstream of both receptors and demonstrated a functional involvement in HA-induced P18146 gene expression . The p38 MAPK was moderately activated via both receptors as well , but was functionally involved in HA-induced P18146 gene expression only in Q9H3N8 -expressing cells . Surprisingly , in this system p38 MAPK activity reduced the HA-induced gene expression . In summary , using this system which allows a direct comparison of mH1R- and mH4R-induced signalling , qualitative and quantitative differences on the levels of second messenger generation and also in terms of p38 MAPK function became evident . A randomised , double-blind study comparing lumiracoxib with naproxen for acute musculoskeletal pain . BACKGROUND : Some selective cyclooxygenase-2 ( P35354 ) inhibitors have been shown to provide analgesic efficacy in patients with acute pain . AIM : To compare the efficacy and safety of the P35354 inhibitor lumiracoxib 400 mg once daily ( qd ) and naproxen 500 mg twice daily ( bid ) in patients with acute musculoskeletal pain caused by uncomplicated soft tissue injury . METHODS : This was a randomised , double-blind , parallel-group , non-inferiority study set in 39 primary care centres in the UK . Patients were randomised to lumiracoxib 400 mg qd or naproxen 500 mg bid and took the study medication for as long as they felt that it was needed , up to day 7 . The primary efficacy analysis was the sum of the pain intensity difference ( 0-100 mm visual analogue scale ) determined morning and evening over the first 5 days of treatment ( SPID-5 ) . RESULTS : The intention-to-treat population comprised 406 patients [ lumiracoxib 400 mg qd ( n = 207 ) ; naproxen 500 mg bid ( n = 199 ) ] . Both treatments were effective in reducing pain intensity over 5 days . The mean SPID-5 scores were 117.0 mm.day for lumiracoxib and 118.2 mm.day for naproxen [ the treatment difference based on adjusted means from the ANCOVA was -2.78 mm.day , 95 % confidence interval ( CI ) -17.4 , 11.9 ] . The lower margin of the 95 % CI was above the predetermined non-inferiority margin ( -50 mm.day ) for SPID-5 , indicating non-inferiority of lumiracoxib compared with naproxen . Both treatments were well tolerated . CONCLUSION : DB01283 400 mg qd is as effective as naproxen 500 mg bid for the management of moderate-to-severe acute musculoskeletal pain . NT-702 ( parogrelil hydrochloride , DB05505 ) , a novel and potent phosphodiesterase inhibitor , improves reduced walking distance and lowered hindlimb plantar surface temperature in a rat experimental intermittent claudication model . NT-702 ( parogrelil hydrochloride , DB05505 ) , 4-bromo-6-[3-(4-chlorophenyl)propoxy]-5-[(pyridin-3-ylmethyl)amino]pyridazin-3(2H)-one hydrochloride , a novel phosphodiesterase ( PDE ) inhibitor synthesized as a potent vasodilatory and antiplatelet agent , is being developed for the treatment of intermittent claudication ( IC ) in patients with peripheral arterial disease . We assessed the efficacy of NT-702 in an experimental IC model as compared with cilostazol and additionally investigated the pharmacological property in vitro and ex vivo . NT-702 selectively inhibited PDE3 ( IC(50)=0.179 and 0.260 nM for Q14432 and 3B ) more potently than cilostazol ( IC(50)=231 and 237 nM for Q14432 and 3B ) among recombinant human PDE1 to PDE6 . NT-702 inhibited in vitro human platelet aggregation induced by various agonists ( IC(50)=11 to 67 nM ) and phenylephrine-induced rat aortic contraction ( IC(50)=24 nM ) . Corresponding results for cilostazol were 4.1 to 17 microM and 1.0 microM , respectively . NT-702 ( 3 mg/kg or more ) significantly inhibited ex vivo rat platelet aggregation after a single oral dose . For cilostazol , 300 mg/kg was effective . In a rat femoral artery ligation model , NT-702 at 5 and 10 mg/kg repeated oral doses twice a day ( P55957 ) for 13 days significantly improved the reduced walking distance while the lowered plantar surface temperature was improved at 2.5 mg/kg and more . DB01166 also improved the walking distance and surface temperature at 300 mg/kg P55957 but significant difference was only observed for surface temperature on day 8 . These results suggest that NT-702 can be expected to have therapeutic advantage for IC . [ Blood cytokine levels as a clinical laboratory test ] . Cytokines have not been employed in clinical laboratory tests because of the many biological activities of individual cytokines and too complicated cytokine network . However , abnormal laboratory data and symptoms can be interpreted by blood cytokine levels . [ Cytokines attributable to abnormal data and symptoms ] For example , cytokines attributable to abnormal data and symptoms in rheumatoid arthritis are as follows : joint pain : TNFalpha , IL-1 , P05231 , and Q14116 ; general fatigue and appetite loss : TNFalpha and IL-1 ; leukocytosis : G- P04141 produced by IL-1-stimulated macrophages etc ; thrombocytosis : megakaryocyte potentiating activity of P05231 ; anemia : hepcidin up-regulated by P05231 , which inhibits iron absorption from the intestine , and IL-1 , which decreases the blood iron level and promotes ferritin synthesis . [ Differential diagnosis using blood cytokine levels ] Blood cytokine levels are useful and important in the differential diagnosis of inflammatory disorders such as neutrophilia , eosinophilia , and especially in distinguishing tumoral fever from infectious fever in malignant lymphomas . [ Disease/disorder-specific cytokines ] In recent years , disease- or disorder specific cytokines have been identified , making cytokines more important in clinical use . For example , Q14116 for adult-onset Still disease ; IFNgamma for hemophagocytic syndrome ; P05113 for allergic disorders ; thrombopoietin for immune thrombocytopenic purpura ; vascular endothelial growth factor for POEMS syndrome ; P12272 for malignancy associated hypercalcemia . [ Flow cytometric measurement of cytokines ] Recently , a flow cytometric method has been developed in addition to ELISA . With this method , 30 cytokine concentrations can be measured simultaneously within four hours with a wide range of detection limit and high cost performance . Cytokines will be included in laboratory tests with this method .