interacts_with DB00227?
The efficacy of activated protein C in murine endotoxemia is dependent on integrin CD11b . DB00055 ( P25054 ) , the only FDA-approved biotherapeutic drug for sepsis , possesses anticoagulant , antiinflammatory , and barrier-protective activities . However , the mechanisms underlying its anti-inflammatory functions are not well defined . Here , we report that the antiinflammatory activity of P25054 on macrophages is dependent on integrin CD11b/ P05107 , but not on endothelial protein C receptor ( Q9UNN8 ) . We showed that CD11b/ P05107 bound P25054 within specialized membrane microdomains/lipid rafts and facilitated P25054 cleavage and activation of protease-activated receptor-1 ( PAR1 ) , leading to enhanced production of sphingosine-1-phosphate ( Q14703 ) and suppression of the proinflammatory response of activated macrophages . Deletion of the gamma-carboxyglutamic acid domain of P25054 , a region critical for its anticoagulant activity and Q9UNN8 -dependent barrier protection , had no effect on its antiinflammatory function . Genetic inactivation of CD11b , PAR1 , or sphingosine kinase-1 , but not Q9UNN8 , abolished the ability of P25054 to suppress the macrophage inflammatory response in vitro . Using an LPS-induced mouse model of lethal endotoxemia , we showed that P25054 administration reduced the mortality of wild-type mice , but not CD11b-deficient mice . These data establish what we believe to be a novel mechanism underlying the antiinflammatory activity of P25054 in the setting of endotoxemia and provide clear evidence that the antiinflammatory function of P25054 is distinct from its barrier-protective function and anticoagulant activities . Involvement of sphingosine kinase in P01375 -stimulated tetrahydrobiopterin biosynthesis in P13671 glioma cells . In P13671 glioma cells , the sphingolipid second messenger ceramide potentiates expression of inducible nitric-oxide synthase ( P35228 ) induced by tumor necrosis factor alpha ( P01375 ) without affecting P30793 ( GTPCH ) , the rate-limiting enzyme in the biosynthesis of 6(R)- DB00360 ( BH(4) ) , a cofactor required for P35228 activity . P01375 also stimulates sphingosine kinase , the enzyme that phosphorylates sphingosine to form sphingosine-1-phosphate ( Q8TCT9 ) , a further metabolite of ceramide . Several clones of P13671 cells , expressing widely varying levels of sphingosine kinase , were used to examine the role of Q8TCT9 in regulation of GTPCH and BH(4) biosynthesis . Overexpression of sphingosine kinase , with concomitant increased endogenous Q8TCT9 levels , potentiated the effect of P01375 on GTPCH expression and activity and BH(4) biosynthesis . In contrast , enforced expression of sphingosine kinase had no effect on P35228 expression or NO formation . Furthermore , N,N-dimethylsphingosine , a potent sphingosine kinase inhibitor , completely eliminated the increased GTPCH activity and expression induced by P01375 . Surprisingly , we found that , although P13671 cells can secrete Q8TCT9 , which is enhanced by P01375 , treatment of P13671 cells with exogenous Q8TCT9 or dihydro- Q8TCT9 had no affect on BH(4) biosynthesis . However , both Q8TCT9 and dihydro- Q8TCT9 markedly stimulated P29323 1/2 in P13671 cells , which express cell surface Q8TCT9 receptors . Interestingly , although this P29323 activation was blocked by PD98059 , which also reduced cellular proliferation induced by enforced expression of sphingosine kinase , PD98059 had no effect on GTPCH activity . Collectively , these results suggest that only intracellularly generated Q8TCT9 plays a role in regulation of GTPCH and BH(4) levels . Somatostatin preserved blood brain barrier against cytokine induced alterations : possible role in multiple sclerosis . Multiple sclerosis ( MS ) is an inflammatory neurological disorder associated with demyelination , impaired blood brain barrier ( BBB ) , axonal damage and neuronal loss . In the present study , we measured somatostatin ( P61278 ) and tumor necrosis factor-α ( P01375 -α ) like immunoreactivity in P04141 samples from MS and non-MS patients . We also examined the role of P61278 in cytokines and lipopolysaccharide ( LPS ) -induced damage to the BBB using human brain endothelial cells in culture . Most of the cerebrospinal fluid ( P04141 ) samples studied from definite MS patients exhibited lower somatostatin ( P61278 ) -like immunoreactivity and higher expression of P01375 -α in comparison to non-MS patients . Treatment of cells with cytokines and LPS blocked P61278 secretion and decreased P61278 expression . Human brain endothelial cells expressed all five somatostatin receptors ( SSTRs ) with increased expression of P30874 and 4 upon treatment with cytokines and LPS . Cytokines and LPS-induced disruption of the tight junction proteins Zonula occludens ( ZO-1 ) organization was restored in presence of P61278 , P30874 or P31391 selective agonists . Furthermore , inflammation induced changes in extracellular signal-regulated kinases ( P27361 /2 and Q13164 ) signaling and altered expression of endothelial and inducible nitric oxide synthase are modulated in presence of P61278 . These data indicate that decreased levels of P61278 contribute to failure of the BBB in MS . Glutamate modulators as potential therapeutic drugs in schizophrenia and affective disorders . Severe psychiatric disorders such as schizophrenia are related to cognitive and negative symptoms , which often are resistant to current treatment approaches . The glutamatergic system has been implicated in the pathophysiology of schizophrenia and affective disorders . A key component is the dysfunction of the glutamatergic N-methyl-D-aspartate ( DB01221 ) receptor . Substances regulating activation/inhibition of the DB01221 receptor have been investigated in schizophrenia and major depression and are promising in therapeutic approaches of negative symptoms , cognition , and mood . In schizophrenia , add-on treatments with glycine , D-serine , D-alanine , D-cycloserine , D-amino acid oxidase inhibitors , glycine transporter-1 ( P48067 ) inhibitors ( e.g. , sarcosine , bitopertin ) and agonists ( e.g. , DB05096 ) or positive allosteric modulator ( e.g. , ADX71149 ) of group II metabotropic glutamate receptors ( mGluRs ) have been studied . In major depression , the DB01221 receptor antagonists ( e.g. , ketamine , AZD6765 ) , Q13224 subtype antagonists ( e.g. , traxoprodil , MK-0657 ) , and partial agonists ( e.g. , D-cycloserine , GLYX-13 ) at the glycine site of the DB01221 receptor have been proven to be effective in animal studies and first clinical trials . In addition , clinical studies of Q14416 /3 antagonist BCI-838 ( a prodrug of BCI-632 ( MGS0039 ) ) , Q14416 /3-negative allosteric modulators ( NMAs ) ( e.g. , RO499819 , RO4432717 ) , and P41594 NAMs ( e.g. , AZD2066 , RO4917523 ) are in progress . Future investigations should include effects on brain structure and activation to elucidate neural mechanisms underlying efficacy of these drugs . Activation of spinal alpha-7 nicotinic acetylcholine receptor attenuates remifentanil-induced postoperative hyperalgesia . The activation of alpha-7 nicotinic acetylcholine receptors ( α7-nAchRs ) are currently being considered as novel therapeutic approaches for managing hyperalgesia in inflammation and chronic neuropathic pain , but the role of a7-nAChRs on opioids induced hyperalgesia remain unknown . The present study investigated the effects of α7-nAChRs selective agonists PHA-543613 and type II positive allosteric modulators ( PAMs ) PNU-120596 in remifentanil induced postoperative hyperalgesia . As the results shown , intrathecal treatment with both α7-nAChRs agonists and type II PAMs could attenuate remifentanil induced hyperalgesia by increasing paw withdrawal mechanical threshold ( PWMT ) and paw withdrawal thermal latency ( PWTL ) . Furthermore , we also investigated the protein level of proinflammatory cytokines and phosphorylation N-methyl-d-aspartate receptor 2B subunit ( p- Q13224 ) in the spinal cord . Our data indicated that activation of α7-nAchRs decreased the proinflammatory cytokines ( P01375 -α , P05231 ) and p- Q13224 protein level in the spinal cord . The depression of the increased levels of proinflammatory cytokines and p- Q13224 after remifentanil treatment may contribute to the anti-hyperalgesia effects of PHA-543613and PNU-120596 via α7-nAChRs . Therefore , our findings demonstrated that α7-nAChRs may be potential candidates for treating opioids induced hyperalgesia . Novel synthesis of various orthogonally protected Cα-methyllysine analogues and biological evaluation of a vapreotide analogue containing ( S ) -α-methyllysine . Prochiral malonic diesters containing a quaternary carbon center have been successfully transformed into a diverse set of (t)Boc-Fmoc-α(2,2)-methyllysine-OH analogues through chiral malonic half-ester intermediates obtained via enzymatic ( Pig Liver Esterase , PLE ) hydrolysis . The variety of chiral half-ester intermediates , which vary from 1 to 6 methylene units in the side chain , are achieved in moderate to high optical purity and in good yields . The PLE hydrolysis of malonic diesters with various side chain lengths appears to obey the Jones 's PLE model according to the stereochemical configurations of the resulting chiral half-esters . The established synthetic strategy allows the construction of both enantiomers of α(2,2)-methyllysine analogues , and a ( S ) -β(2,2)-methyllysine analogue from a common synthon by straightforward manipulation of protecting groups . Two different straightforward and cost effective synthetic strategies are described for the synthesis of α(2,2)-methyllysine analogues . The described strategies should find significant usefulness in preparing novel peptide libraries with unnatural lysine analogues . A DB04894 analogue incorporating ( S ) -α(2,2)-methyllysine was prepared . However , the DB04894 analogue with ( S ) -α-methyl-α-lysine is found to lose its specific binding to somatostatin receptor subtype 2 ( P30874 ) . [ 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 . Differential interleukin-10 ( P22301 ) and IL-23 production by human blood monocytes and dendritic cells in response to commensal enteric bacteria . Human peripheral blood contains antigen-presenting cells ( P25054 ) , including dendritic cells ( DC ) and monocytes , that may encounter microbes that have translocated from the intestine to the periphery in disease states like HIV-1 infection and inflammatory bowel disease . We investigated the response of DC and monocytes in peripheral blood mononuclear cells ( PBMC ) to a panel of representative commensal enteric bacteria , including Escherichia coli , Enterococcus sp. , and Bacteroides fragilis . All three bacteria induced significant upregulation of the maturation and activation markers P25942 and Q01151 on myeloid dendritic cells ( mDC ) and plasmacytoid dendritic cells ( pDC ) . However , only mDC produced cytokines , including interleukin-10 ( P22301 ) , IL-12p40/70 , and tumor necrosis factor alpha ( P01375 -α ) , in response to bacterial stimulation . Cytokine profiles in whole PBMC differed depending on the stimulating bacterial species : B. fragilis induced production of IL-23 , IL-12p70 , and P22301 , whereas E. coli and Enterococcus induced an P22301 -predominant response . mDC and monocyte depletion experiments indicated that these cell types differentially produced P22301 and IL-23 in response to E. coli and B. fragilis . Bacteroides thetaiotaomicron did not induce levels of IL-23 similar to those of B. fragilis , suggesting that B. fragilis may have unique proinflammatory properties among Bacteroides species . The addition of recombinant human P22301 to PBMC cultures stimulated with commensal bacteria abrogated the IL-23 response , whereas blocking P22301 significantly enhanced IL-23 production , suggesting that P22301 controls the levels of IL-23 produced . These results indicate that blood mDC and monocytes respond differentially to innate stimulation with whole commensal bacteria and that P22301 may play a role in controlling the proinflammatory response to translocated microbes . P30047 -dependent and -independent inhibitors of P30793 . P30047 ( P30047 ) mediates the feedback inhibition of P30793 activity by ( 6R ) -L-erythro- DB00360 ( BH4 ) through protein complex formation . Since guanine and BH4 have a common pyrimidine ring structure , we examined the inhibitory effect of guanine and its analogs on the enzyme activity . DB02377 , 8-hydroxyguanine , 8-methylguanine , and 8-bromoguanine inhibited the enzyme activity in a P30047 -dependent and pH-dependent manner and induced complex formation between P30793 and P30047 . The type of inhibition by this group is a mixed type . All these properties were shared with BH4 . In striking contrast , inhibition by DB01667 and 8-mercaptoguanine was P30047 -independent and pH-independent . The type of inhibition by DB01667 and 8-mercaptoguanine was a competitive type . The two compounds did not induce complex formation between the enzyme and P30047 . These results demonstrate that guanine compounds of the first group bind to the BH4-binding site of the P30793 / P30047 complex , whereas DB01667 and 8-mercaptoguanine bind to the active site of the enzyme . Finally , the possible implications in Lesch-Nyhan syndrome and Parkinson diseases of the inhibition of P30793 by guanine and 8-hydroxyguanine are discussed . Expression of human all-trans-retinoic acid receptor beta and its ligand-binding domain in Escherichia coli . DB00755 , one of the hormonally active derivatives of vitamin A , occurs physiologically in plasma at a concentration below 10 nmol/l . The methods currently used for its quantification are based on HPLC , need about 1 ml of serum , are relatively laborious and thus not well suited for mass analysis . The affinity and specificity of retinoic acid receptors for all-trans-retinoic acid encouraged us to express both the entire human retinoic acid receptor beta ( P10826 ) and two versions of its retinoic acid-binding domain in Escherichia coli in the hope that these recombinant proteins might be used as binders in a ligand-binding assay for all-trans-retinoic acid . The recombinant receptors , the whole receptor [ P10826 -( Q93033 -Q448) ] , corresponding to domains A-F , and the ligand-binding domain [ P10826 -(E149-Q448) ] , corresponding to domains D-F , were expressed in the vector pET 3d/BL21 ( DE3 ) as inclusion bodies , solubilized with guanidinium chloride , renatured and purified by ion-exchange chromatography . P10826 -(P193-Q448) , corresponding to domains E-F , was expressed in the vector pET 3d/BL21(DE3)pLysS , and purified by reversed-phase chromatography . Under non-denaturing conditions , the expressed whole receptor [ P10826 -( Q93033 -Q448) ] and the D-F construct ( P10826 -(E149-Q448) ] behaved chromatographically as monomeric proteins whereas the E-F construct [ P10826 -(P193-Q448) ] had a strong tendency to aggregate . P10826 -( Q93033 -Q448) and P10826 -(E149-Q448) had similar Kd values for all-trans-retinoic acid ( 1.4 and 0.6 nmol/l respectively ) whereas P10826 -(P193-Q448) bound all-trans-retinoic acid less avidly ( Kd 9.6 nmol/l ) . DB00523 bound to P10826 -(E149-Q448) and P10826 -( Q93033 -Q448) as avidly as all-trans-retinoic acid . Competition experiments showed weak or no binding of 4-oxo-all-trans-retinoic acid , 4-oxo-13-cis-retinoic acid , 13-cis-retinoic acid , acitretin and retinol by P10826 -(E149-Q448) . Molecular systematics of armadillos ( Xenarthra , Dasypodidae ) : contribution of maximum likelihood and Bayesian analyses of mitochondrial and nuclear genes . The 30 living species of armadillos , anteaters , and sloths ( Mammalia : Xenarthra ) represent one of the three major clades of placentals . Armadillos ( Cingulata : Dasypodidae ) are the earliest and most speciose xenarthran lineage with 21 described species . The question of their tricky phylogeny was here studied by adding two mitochondrial genes ( P03886 [ P03886 ] and 12S ribosomal RNA [ 12S rRNA ] ) to the three protein-coding nuclear genes ( alpha2B adrenergic receptor [ P18089 ] , breast cancer susceptibility exon 11 [ P38398 ] , and P04275 exon 28 [ P04275 ] ) yielding a total of 6869 aligned nucleotide sites for thirteen xenarthran species . The two mitochondrial genes were characterized by marked excesses of transitions over transversions-with a strong bias toward CT transitions for the 12S rRNA-and exhibited two- to fivefold faster evolutionary rates than the fastest nuclear gene ( P18089 ) . Maximum likelihood and Bayesian phylogenetic analyses supported the monophyly of Dasypodinae , Tolypeutinae , and Euphractinae , with the latter two armadillo subfamilies strongly clustering together . Conflicting branching points between individual genes involved relationships within the subfamilies Tolypeutinae and Euphractinae . Owing to a greater number of informative sites , the overall concatenation favored the mitochondrial topology with the classical grouping of Cabassous and Priodontes within Tolypeutinae , and a close relationship between Euphractus and Chaetophractus within Euphractinae . However , low statistical support values associated with almost equal distributions of apomorphies among alternatives suggested that two parallel events of rapid speciation occurred within these two armadillo subfamilies . The Retinoic Acid Receptor-alpha mediates human T-cell activation and Th2 cytokine and chemokine production . BACKGROUND : We have recently demonstrated that all-trans-retinoic acid ( DB00755 ) and 9-cis-retinoic acid ( 9-cis RA ) promote P05112 , P05113 and P35225 synthesis , while decreasing P01579 and P01375 expression by activated human T cells and reduces the synthesis of IL-12p70 from accessory cells . Here , we have demonstrated that the observed effects using DB00755 and 9-cis RA are shared with the clinically useful RAR ligand , 13-cis retinoic acid ( 13-cis RA ) , and the retinoic acid receptor-alpha ( P10276 ) -selective agonist , AM580 but not with the P10826 /gamma ligand , 4-hydroxyphenylretinamide ( DB05076 ) . RESULTS : The increase in type 2 cytokine production by these retinoids correlated with the expression of the T cell activation markers , Q07108 and P28907 . The P10276 -selective agonist , AM580 recapitulated all of the T cell activation and type 2 cytokine-inducing effects of DB00755 and 9- DB00982 , while the P10276 -selective antagonist , RO 41-5253 , inhibited these effects . CONCLUSION : These results strongly support a role for P10276 engagement in the regulation of genes and proteins involved with human T cell activation and type 2 cytokine production . P18089 genotype differentially modulates stress-induced neural activity in the amygdala and hippocampus during emotional memory retrieval . RATIONALE : DB00368 interacts with stress hormones in the amygdala and hippocampus to enhance emotional memory consolidation , but the noradrenergic-glucocorticoid interaction at retrieval , where stress impairs memory , is less understood . OBJECTIVES : We used a genetic neuroimaging approach to investigate whether a genetic variation of the noradrenergic system impacts stress-induced neural activity in amygdala and hippocampus during recognition of emotional memory . METHODS : This study is based on genotype-dependent reanalysis of data from our previous publication ( Li et al. Brain Imaging Behav 2014 ) . Twenty-two healthy male volunteers were genotyped for the P18089 gene encoding the α2B-adrenergic receptor . Ten deletion carriers and 12 noncarriers performed an emotional face recognition task , while their brain activity was measured with fMRI . During encoding , 50 fearful and 50 neutral faces were presented . One hour later , they underwent either an acute stress ( Trier Social Stress Test ) or a control procedure which was followed immediately by the retrieval session , where participants had to discriminate between 100 old and 50 new faces . RESULTS : A genotype-dependent modulation of neural activity at retrieval was found in the bilateral amygdala and right hippocampus . Deletion carriers showed decreased neural activity in the amygdala when recognizing emotional faces in control condition and increased amygdala activity under stress . Noncarriers showed no differences in emotional modulated amygdala activation under stress or control . Instead , stress-induced increases during recognition of emotional faces were present in the right hippocampus . CONCLUSION : The genotype-dependent effects of acute stress on neural activity in amygdala and hippocampus provide evidence for noradrenergic-glucocorticoid interaction in emotional memory retrieval . DB00227 , a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor , induces apoptosis and differentiation in human anaplastic thyroid carcinoma cells . Although only 1 % of differentiated thyroid cancers transform into anaplastic thyroid cancer , this disease is always fatal . Differentiation therapy may provide a new therapeutic approach to increasing the survival rate in such patients . 3-Hydroxy-3-methylglutaryl coenzyme A ( HMG- DB01992 ) reductase inhibitors are reported to promote cellular apoptosis and differentiation in many cancer cells ; these effects are unrelated to lipid reduction . Recently , we found that TNFalpha induces cytomorphological differentiation in anaplastic thyroid cancer cells and increases thyroglobulin expression ; however , P01375 is cytotoxic for normal human tissue . The aim of this study was to determine whether lovastatin , an P04035 inhibitor , could induce apoptosis and differentiation in anaplastic thyroid cancer cells . Anaplastic thyroid cancer cells were treated with lovastatin , then examined for cellular apoptosis and cytomorphological differentiation by DNA fragmentation , phosphatidylserine externalization/flow cytometry , and electron microscopy . Thyroglobulin levels in the culture medium were also measured . Our results showed that at a higher dose ( 50 micro M ) , lovastatin induced apoptosis of anaplastic thyroid cancer cells , whereas at a lower dose ( 25 micro M ) , it promoted 3-dimensional cytomorphological differentiation . It also induced increased secretion of thyroglobulin by anaplastic cancer cells . Our results show that lovastatin not only induces apoptosis , but also promotes redifferentiation in anaplastic thyroid cancer cells , and suggest that it and other P04035 inhibitors merit further investigation as differentiation therapy for the treatment of anaplastic thyroid cancer . The role of selectins and P05107 in leukotriene B4-mediated white blood cell emigration in human skin grafts transplanted on SCID mice . The purpose of this study was to examine the role of selectins and P05107 cell adhesion molecules ( CAMs ) in inflammation induced by injection of leukotriene B4 ( LTB4 ) into human skin . To accomplish this , the expression of CAMs and the ability of specific antibodies against CAMs to block white blood cell ( WBC ) transmigration were studied in an in vivo model consisting of human skin transplanted onto mice with the severe combined immune deficiency ( SCID ) mutation . The results indicate that LTB4-induced WBC transmigration in the human/SCID model is rapid and pronounced ; however , it is not accompanied by a significant upregulation of the baseline expression of endothelial P16109 , P16581 , P05362 or P19320 . An anti-murine P05107 mAb markedly inhibited white cell infiltration ( 89 % inhibition ) confirming the importance of beta 2 integrins in the process . The role of selectins was also examined . P61006 -14 , a bioactive antibody against murine P14151 inhibited transmigration by 66 % . A significant , but smaller , effect ( 39 % inhibition ) was observed by blocking P16581 function . These results indicate that LTB4-induced inflammation does not require upregulation of endothelial P62158 expression and , in contrast to P01375 alpha-induced transmigration , is only partially blocked by anti- P16581 antibodies . P05231 , P01579 and P01375 production by liver-associated T cells and acute liver injury in rats administered concanavalin A . The relationship between the development of acute hepatitis and the production of P01375 P01579 and P05231 by liver-associated T lymphocytes following intravenous injection of concanavalin A ( Con A ) was studied in rats . Following a single injection of Con A , there was a dose and time-dependent correlation in the serum levels of serum alanine aminotransferase ( ALT ) , P05231 , P01579 and P01375 . These increases correlated with an increase in the numbers of P01730 + , CD8+ and CD25+ T cells in blood and P01730 + and CD25+ T cells in the liver perfusate , but not with CD8+ T cells in liver perfusate . Increased levels of P05231 , P01579 and P01375 were constitutively produced by liver-associated P01730 + T cells when cultured . In Con A-stimulated cultures , liver-associated P01730 + T cells secreted increasing levels of P01375 in a time-dependent manner following Con A injection , but P01375 production by peripheral blood lymphocytes was transient with peak levels detected at 1 h which then declined over 24 h . Histological examination of the liver revealed fatty change , hepatocyte degeneration and necrosis , with an associated cell infiltrate of neutrophils and P01730 + T cells both in the portal areas and around the central veins . These results support the hypothesis that Con A-induced liver damage is mediated by P01730 + T cells acting within the liver , at least in part through the secretion of P01375 , P01579 and P05231 . Changes in circulating lymphocyte subpopulations following administration of the leucocyte function-associated antigen-3 ( LFA-3 ) /IgG1 fusion protein alefacept . DB00092 , a recombinant leucocyte function-associated antigen-3 ( LFA-3 ) /IgG1 fusion protein approved for the treatment of psoriasis , is reported to reduce selectively the numbers of circulating P01730 (+) CD45RO(+) and CD8(+) CD45RO(+) T cells , while sparing the naive cells . The purpose of the present study was to elucidate further the effect of alefacept on various circulating lymphocyte subsets . Sixteen patients , 12 with chronic plaque psoriasis and four with pustular psoriasis , received alefacept 7.5 mg once weekly for 12 weeks . Blood samples collected at study entry and after 12 weeks of treatment were analysed by four-colour flow cytometry . There were statistically significant reductions in the total number of conventional memory ( CD45RA(-) P26842 (+) ) and effector ( CD45RA(-) P26842 (-) or CD45RA(+) P26842 (-) ) T cells , including P01730 (+) and CD8(+) T cells expressing CD161 and CD8(+) T cells expressing cutaneous lymphocyte-associated antigen ( DB01211 ) . Natural killer ( NK ) T cells were also reduced significantly , while no statistically significant changes were seen in NK cells and P01730 (+) CD25(high) cells . The affected subpopulations were all characterized by a high expression of P06729 . However , P01730 (+) CD25(low) , and P01730 (+) DB01211 (+) cells , which also expressed relative high levels of P06729 , were not reduced significantly . Our results suggest a heterogeneous effect of alefacept on the circulating memory T cell population , indicating that high expression of P06729 may not , by itself , be sufficient to explain the reduction in cell count for a specific subpopulation . Genetic dissection of atypical antipsychotic-induced weight gain : novel preliminary data on the pharmacogenetic puzzle . Atypical antipsychotics such as clozapine represent a significant improvement over typical antipsychotics in the treatment of schizophrenia , particularly regarding extrapyramidal symptoms . Despite their benefits , use is limited by the occurrence of adverse reactions such as sedation and weight gain . This article provides a comprehensive review and discussion of obesity-related pathways and integrates these with the known mechanisms of atypical antipsychotic action to identify candidate molecules that may be disrupted during antipsychotic treatment . Novel preliminary data are presented to genetically dissect these obesity pathways and elucidate the genetic contribution of these candidate molecules to clozapine-induced weight gain . There is considerable variability among individuals with respect to the ability of clozapine to induce weight gain . Genetic predisposition to clozapine-induced weight gain has been suggested . Therefore , genetic variation in these candidate molecules may predict patient susceptibility to clozapine-induced weight gain . This hypothesis was tested for 10 genetic polymorphisms across 9 candidate genes , including the serotonin 2C , 2A , and 1A receptor genes ( P28335 /2A/1A ) ; the histamine H1 and H2 receptor genes ( P35367 / P25021 ) ; the cytochrome P450 1A2 gene ( P05177 ) ; the beta3 and alpha,alpha-adrenergic receptor genes ( P13945 /ADRAIA ) ; and tumor necrosis factor alpha ( P01375 ) . Prospective weight gain data were obtained for 80 patients with schizophrenia who completed a structured clozapine trial . Trends were observed for P13945 , ADRA1A , P01375 , and P28335 ; however , replication in larger , independent samples is required . Although in its infancy , psychiatric pharmacogenetics will in the future aid clinical practice in the prediction of response and side effects , such as antipsychotic-induced weight gain , and minimize the current " trial and error " approach to prescribing . P25021 mediated relaxation of buffalo ( Bubalus bubalus ) ureter . On the buffalo ureter , histamine did not elicit any direct effect . However , it caused concentration-dependent relaxation of the tissues precontracted by carbachol , phenylephrine , norepinephrine , KCI or BaCl2 and also inhibited the contractile effect of carbachol . DB08805 selectively antagonised the relaxation and inhibition of contractile response but mepyramine did not show this effect . Isoprenaline , dobutamine , salbutamol , verapamil and papaverine neither produced any direct effect nor relaxed the carbachol-contracted tissues ; norepinephrine and epinephrine had contractile effects . Hence , the histamine-induced relaxation was mediated through the activation of H2 receptors and not through adrenergic mechanisms or blockade of Ca(2+)-channels or inhibition of cyclic nucleotide phosphodiesterase . In vivo imaging visualizes discoid platelet aggregations without endothelium disruption and implicates contribution of inflammatory cytokine and integrin signaling . The mechanism by which thrombotic vessel occlusion occurs independently of plaque development or endothelial cell ( EC ) disruption remains unclear , largely because of an inability to visualize the formation of thrombus , especially at the single-platelet level in real time . Here we demonstrate that rapidly developing thrombi composed of discoid platelets can be induced in the mesenteric capillaries , arterioles , and large-sized arteries of living mice , enabling characterization of the kinetics of thrombosis initiation and the multicellular interrelationships during thrombus development . Platelet aggregation without EC disruption was triggered by reactive oxygen species ( ROS ) photochemically induced by moderate power laser irradiation . The inflammatory cytokines P01375 -α and IL-1 could be key components of the EC response , acting through regulation of P04275 mobilization to the cell surface . Thrombus formation was then initiated by the binding of platelet GPIbα to endothelial P04275 in our model , and this effect was inhibited by the ROS scavenger DB06151 . Actin linker talin-dependent activation of alphaIIb-beta3 integrin or Rac1 in platelets was required for late-phase thrombus stability . Our novel imaging technology illustrates the molecular mechanism underlying inflammation-based thrombus formation by discoid platelets on undisrupted ECs and suggests control of ROS could be a useful therapeutic target for the prevention of thrombotic diseases . The P04035 inhibitors , simvastatin , lovastatin and mevastatin inhibit proliferation and invasion of melanoma cells . BACKGROUND : A number of recent studies have suggested that cancer incidence rates may be lower in patients receiving statin treatment for hypercholesterolemia . We examined the effects of statin drugs on in vitro proliferation , migration and invasion of melanoma cells . METHODS : The ability of lovastatin , mevastatin and simvastatin to inhibit the melanoma cell proliferation was examined using cytotoxicity and apoptosis assays . Effects on cell migration and invasion were assessed using transwell invasion and migration chambers . Hypothesis testing was performed using 1-way Q9UNW9 , and Student 's t-test . RESULTS : DB00227 , mevastatin and simvastatin inhibited the growth , cell migration and invasion of HT144 , M14 and SK- P61006 -28 melanoma cells . The concentrations required to inhibit proliferation of melanoma cells ( 0.8-2.1 microave previously been achieved in a phase I clinical trial of lovastatin in patients with solid tumours , ( 45 mg/kg/day resulted in peak plasma concentrations of approximately 3.9 micro CONCLUSION : Our results suggest that statin treatment is unlikely to prevent melanoma development at standard doses . However , higher doses of statins may have a role to play in adjuvant therapy by inhibiting growth and invasion of melanoma cells .