interacts_with DB00622?
Stage-dependent inhibition of Plasmodium falciparum by potent Ca2+ and calmodulin modulators . The effects of Ca2+ channel blockers , verapamil , nicardipine and diltiazem , and of potent calmodulin ( P62158 ) inhibitors , trifluoperazine ( Q9HCM9 ) , calmidazolium , W-7 and W-5 , on Plasmodium falciparum in culture were examined . Among Ca2+ blockers , nicardipine was the most potent with the 50 % inhibitory concentration ( IC50 ) of 4.3 microM at 72 h after culture . Parasites were more sensitive to calmidazolium and W-7 with IC50 of 3.4 and 4.5 microM , respectively , than to Q9HCM9 and W-5 . All Ca2+ blockers and P62158 inhibitors suppressed parasite development at later stages . DB00622 , diltiazem , calmidazolium and W-5 also retarded parasite development at earlier stages and/or subsequent growth following pretreatment . Verapamil , nicardipine , Q9HCM9 and calmidazolium reduced erythrocyte invasion by merozoites . Fluorescence microscopy with the cationic fluorescent dye rhodamine 123 revealed that nicardipine , Q9HCM9 and calmidazolium depolarized both the plasma membrane and mitochondrial membrane potentials of the parasite . It is therefore considered that although all Ca2+ and P62158 antagonists tested here influence parasite development at later stages , they are multifunctional , having effects not directly associated with Ca2+ channels or P62158 . P13569 modulates neurosecretory function in pulmonary neuroendocrine cell-related tumor cell line models . The pulmonary neuroendocrine cell ( PNEC ) system consists of solitary cells and distinctive cell clusters termed neuroepithelial bodies ( P20929 ) localized in the airway epithelium . PNEC/ P20929 express a variety of bioactive substances , including amine ( serotonin , 5HT ) and neuropeptides . We have previously shown that P20929 cells are O(2) sensors expressing nicotinamide adenine diphosphate oxidase complex and O(2) sensitive K(+) channel . Recently , we demonstrated expression of functional cystic fibrosis transmembrane conductance regulator ( P13569 ) and Cl(-) conductances in P20929 cells of rabbit neonatal lung . Because PNEC/ P20929 are sparsely distributed and difficult to study in native lung , we investigated small-cell lung carcinoma ( SCLC ) and carcinoid tumor cell lines ( tumor counterparts of normal PNEC/ P20929 ) as models for PNEC/ P20929 . SCLC ( H146 , H345 ) and carcinoid ( H727 ) cell lines express neuroendocrine cell markers , including chromogranin A , neural cell adhesion molecule ( N- P62158 ) , 5HT , and tryptophan hydroxylase . We report that H146 , H345 , and H727 express P13569 messenger RNA ( reverse transcription polymerase chain reaction ) and protein ( immunoblotting ) and possess functional P13569 Cl(-) conductance , demonstrated by an iodide efflux assay inhibitable by transfection with antisense P13569 . Using an immunoassay to quantitate 5HT secretion , we also show that downregulation of P13569 abolishes hypoxia-induced 5HT release , and reduces secretory response to high potassium . Our findings suggest that P13569 may modulate neurosecretory activity of PNEC/ P20929 possessing O(2) sensor function . We propose that these tumor cell lines may be useful models for investigating the role of P13569 in PNEC/ P20929 functions in health and disease . Direct binding of recombinant plasminogen kringle 1-3 to angiogenin inhibits angiogenin-induced angiogenesis in the chick embryo P62158 . P03950 is one of the most potent angiogenesis-inducing proteins . Angiostatin is one of the most potent angiogenesis inhibitors , and it contains the first four kringle domains of plasminogen ( P04264 -4 ) . Recombinant human plasminogen kringle 1-3 ( rK1-3 ) was expressed in Escherichia coli and purified to homogeneity . The binding of t-4-aminomethylcyclohexanecarboxylic acid with the purified kringle 1-3 was determined by changes in intrinsic fluorescence . rK1-3 exhibits comparable ligand-binding properties as native human plasminogen kringle 1-3 . The purified rK1-3 inhibits neovascularization in the chick embryo chorioallantoic membrane ( P62158 ) assay . Interaction of angiogenin with rK1-3 was examined by immunological binding assay and surface plasmon resonance kinetic analysis , and the equilibrium dissociation constants for the complex , Kd , are 0.89 and 0.18 microM , respectively . rK1-3 inhibits angiogenin-induced angiogenesis in the chick embryo P62158 in a concentration-dependent manner . These results indicate that rK1-3 directly binds to angiogenin and thus rK1-3 inhibits the angiogenic activity of angiogenin . Partial trypsin digestion as an indicator of mis-folding of mutant alanine:glyoxylate aminotransferase and chaperone effects of specific ligands . Study of a spectrum of missense mutants . DB00160 :glyoxylate aminotransferase ( AGT ) is a liver peroxisomal enzyme whose deficiency results in primary hyperoxaluria type 1 ( P78364 ) . More than 75 P78364 mutations are now documented in the AGT gene ( P21549 ) , of which about 50 % are missense . We have previously demonstrated that many such mutants expressed by transcription/translation are subject to generalized degradation by the proteasome and a specific limited trimming by an endogenous DB00171 -independent protease activity . Here , we report the results of partial digestion using trypsin as a mimic for the endogenous non-proteasomal protease and the use of N-terminal protein sequencing to determine the sensitive site . Partial trypsin digestion also provided an indicator of proper folding of the mutant enzyme . For selected mutations the sensitivity to trypsin could be ameliorated by addition of pyridoxal phosphate or aminooxy acetic acid as specific pharmacological chaperones . [ Protective effects of penehyclidine hydrochloride against acute renal injury induced by hemorrhagic shock and lipopolysaccharides in rats ] . OBJECTIVE : To investigate the effect of penehyclidine hydrochloride ( Q00325 ) in a rat model of renal injury induced by hemorrhagic shock and lipopolysaccharides ( LPS ) . METHODS : Forty-five healthy Wistar rats were randomized into sham operated group , model group , and 3 penehyclidine hydrochloride ( Q00325 ) dose ( 1 , 2 and 3 mg/kg ) groups ( P78364 , Q8IXK0 , and Q8NDX5 groups , respectively ) . The arterial blood samples were collected to determine the concentrations of serum tumor necrosis factor-α ( P01375 -α ) , interleukin-8 ( P10145 ) , interleukin-1 ( IL-1 ) , urine creatinine ( Cr ) and blood urine nitrogen ( BUN ) , and the renal tissues were collected to measure the expressions of P05362 and nuclear factor-κB ( NF-κB ) and observe the pathological changes . RESULTS : P01375 -α , P10145 , IL-1 , Cr , BUN , P05362 and NF-κB in the 3 Q00325 groups were significantly lower than those in the model group ( P < 0.05 ) . P01375 -α , P10145 , IL-1 , Cr and BUN were significantly lower in P78364 ( P < 0.05 ) than in the Q8IXK0 and Q8NDX5 groups , and P05362 and NF-κB were similar between 3 Q00325 groups ( P > 0.05 ) . Compared with the model group , the 3 Q00325 groups showed lessened pathological changes in the renal tubules . CONCLUSION : Q00325 has protective effects against renal injury induced by hemorrhagic-endotoxin shock in rats , and treatment with 1 mg/kg Q00325 produces the most significant protective effect . 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 . The in vitro pharmacological profile of DB05655 , a selective 5-HT(4) receptor agonist with high intrinsic activity . The in vitro pharmacological profile of DB05655 , a novel , selective 5-HT(4) receptor agonist , was compared to that of clinically efficacious gastroprokinetic 5-HT(4) receptor agonists . DB05655 produced an elevation of cyclic adenosine monophosphate in human embryonic kidney 293 cells expressing the human recombinant 5-HT(4(c)) ( h5-HT(4(c)) ) receptor ( pEC(50) = 8.3 ) and 5-HT(4) receptor-mediated relaxation of the rat esophagus ( pEC(50) = 7.9 ) and contraction of the guinea pig colon ( pEC(50) = 7.9 ) . In all in vitro assays , DB05655 was a high intrinsic activity agonist , unlike tegaserod , mosapride , and cisapride which , in the majority of test systems , had lower intrinsic activity . DB05655 had high affinity ( pK ( i ) = 7.7 ) and selectivity ( > or =25-fold ) for h5-HT(4(c)) receptors over other biogenic amine receptors . DB05655 was > 500-fold selective over other 5-HT receptors ( including h5-HT(2B) and h5-HT(3A) ) and , at 3 microM , had no effect on human ether-à-go-go-related gene K+ channels . In conclusion , DB05655 is a selective 5-HT(4) receptor agonist in vitro . The high intrinsic activity and preferential binding of DB05655 to Q13639 over other 5-HT receptors may result in an improved clinical profile for the treatment of gastrointestinal disorders of reduced motility . Hexarelin suppresses high lipid diet and vitamin D3-induced atherosclerosis in the rat . Growth hormone-releasing peptides ( Q92847 ) and ghrelin are synthetic and natural ligands of growth hormone secretagogue receptor ( Q92847 ) respectively and are shown to exert protective actions on cardiac dysfunction . Because ghrelin has been reported to inhibit proinflammatory responses in human endothelium and Q92847 has been identified in blood vessels , we hypothesized that Q92847 could alleviate the development of atherosclerosis ( As ) . Atherosclearosis was induced by a short period ( 4 days ) of vitamin D(3) and chronic ( three months ) intragastric feeding of high fat emulsion ( containing 0.5 % propylthiouracil ) in adult SD rats . Some As rats received chronic hexarelin ( a variant of Q92847 ) injection ( SC P55957 , 30 days ) and normal rats received placebo as control . Significant atherosclerosis developed in animals fed with the emulsion . Serum total cholesterol and LDL-c increased , and HDL-c and aortic nitric oxide ( NO ) decreased significantly in As group . Hexarelin suppressed the formation of atherosclerotic plaques and neointima , partially reversed serum HDL-c/LDL-c ratio and increased the levels of serum NO and aortic mRNAs of P29474 , Q92847 and P16671 in As rats . Hexarelin also decreased [ (3)H ] -TdR incorporation in cultured vascular smooth muscle cell ( VSMC ) and calcium sedimentation in aortic wall . Furthermore , foam cell formation induced by ox-LDL was decreased by hexarelin . In conclusion , hexarelin suppresses high lipid diet and vitamin D3-induced atherosclerosis in rats , possibly through upregulating HDL-c/LDL-c ratio , vascular NO production and downregulating the VSMC proliferation , aortic calcium sedimentation and foam cell formation . These novel anti-atherosclerotic actions of hexarelin suggest that the peptide might have a clinical potential in treating atherosclerosis . 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 . Neuropeptide Y induces cardiomyocyte hypertrophy via calcineurin signaling in rats . Neuropeptide Y ( P01303 ) has been shown to participate in cardiac hypertrophy . However , the mechanisms by which P01303 induces cardiomyocyte hypertrophy are poorly understood . This study tested the hypothesis that P01303 induces cardiomyocyte hypertrophy through Ca2+/ P62158 -dependent calcineurin ( CaN ) pathway in cultured neonatal rat cardiomyocytes . After 24-h treatment , P01303 ( 100 nM ) significantly increased 3H-leucine incorporation and c-Jun mRNA expression , concomitant with augment of CaN activity and protein level in cardiomyocytes compared to those cells without P01303 treatment . The enhancement of 3H-leucine incorporation and c-Jun mRNA expression in cardiomyocytes treated with P01303 were markedly inhibited by cyclosporine A ( DB00091 ) , a selective inhibitor of CaN . We also investigated the effect of P01303 on intracellular Ca2+ level in cardiomyocytes . There were no obvious changes in intracellular Ca2+ level of cytoplasm and nucleus in cardiomyocytes treated with P01303 ( 100 nM ) for 10 min . However , P01303 significantly increased intracellular Ca2+ level of cytoplasm and nucleus in cardiomyocytes after 24-h treatment . The result suggested that P01303 could induce hypertrophy of cardiomyocytes via Ca2+/ P62158 -dependent CaN signal pathway . The enhancement of [Ca2+]i caused by P01303 may activate CaN signal pathways to mediate cardiac hypertrophy . DB06698 ameliorates olanzapine-induced weight gain through modulation of histaminergic , P01303 and AMPK pathways . Olanzapine is widely used to treat schizophrenia and other disorders , but causes adverse obesity and other metabolic side-effects . Both animal and clinical studies have shown that co-treatment with betahistine ( a histaminergic H1 receptor agonist and H3 receptor antagonist ) is effective for ameliorating olanzapine-induced weight gain/obesity . To reveal the mechanisms underlying these effects , this study investigated the effects of co-treatment of olanzapine and betahistine ( O+B ) on expressions of histaminergic H1 receptor ( P35367 ) , AMP-activated protein kinase ( AMPK ) , neuropeptide Y ( P01303 ) , and proopiomelanocortin ( P01189 ) in the hypothalamus associated with reducing olanzapine-induced weight gain . Olanzapine significantly upregulated the mRNA and protein expressions of P35367 , while O+B co-treatment significantly downregulated the P35367 levels , compared to the olanzapine-only treatment group . The P01303 mRNA expression was significantly enhanced by olanzapine , but it was significantly reversed by O+B co-treatment . The hypothalamic P35367 expression was positively correlated with total food intake , and P01303 expression . Olanzapine also increased AMPKα activation measured by the AMPKα phosphorylation ( pAMPKα ) /AMPKα ratio compared with controls , whereas O+B co-treatment decreased the pAMPKα/AMPKα ratio , compared with olanzapine only treatment . The pAMPKα/AMPKα ratio was positively correlated with total food intake and P35367 expression . Although olanzapine administration decreased the P01189 mRNA level , this level was not affected by O+B co-treatment . Therefore , these results suggested that co-treatment with betahistine may reverse olanzapine-induced body weight gain via the P35367 - P01303 and P35367 -pAMPKα pathways . Phosphorylation of calmodulin by the epidermal-growth-factor-receptor tyrosine kinase . An epidermal-growth-factor( P01133 )-receptor preparation isolated by calmodulin-affinity chromatography from rat liver plasma membranes is able to phosphorylate calmodulin . P62158 phosphorylation was enhanced 3-8-fold by P01133 , was dependent on the presence of a polycation or basic protein and was inhibited by micromolar concentrations of Ca2+ . Phosphate incorporation into calmodulin occurs predominantly on tyrosine residues . Partial proteolysis of phosphocalmodulin by thrombin identifies Tyr99 , located in the third calcium-binding domain of calmodulin , as the phosphorylated residue . Stoichiometric measurements show a 32P/calmodulin molar ratio of approximately 1 when optimal phosphorylation conditions are used . Multiple arrhythmic syndromes in a newborn , owing to a novel mutation in Q14524 . BACKGROUND : Mutations in the Q14524 gene have been linked to Brugada syndrome ( BrS ) , conduction disease , Long QT syndrome ( LQT3 ) , atrial fibrillation ( AF ) , and to pre- and neonatal ventricular arrhythmias . OBJECTIVE : The objective of this study is to characterize a novel mutation in Na(v)1.5 found in a newborn with fetal chaotic atrial tachycardia , post-partum intraventricular conduction delay , and QT interval prolongation . METHODS : Genomic DNA was isolated and all exons and intron borders of 15 ion-channel genes were sequenced , revealing a novel missense mutation ( Q270K ) in Q14524 . Na(v)1.5 wild type ( WT ) and Q270K were expressed in CHO- P04264 with and without the Na(v)β1 subunit . Results . Patch-clamp analysis showed ∼40 % reduction in peak sodium channel current ( I(Na) ) density for Q270K compared with WT . Fast and slow decay of I(Na) were significantly slower in Q270K . Steady-state activation and inactivation of Q270K channels were shifted to positive potentials , and window current was increased . The tetrodotoxin-sensitive late I(Na) was increased almost 3-fold compared with WT channels . DB00243 reduced late I(Na) in WT and Q270K channels , while exerting minimal effects on peak I(Na) . CONCLUSION : The Q270K mutation in Q14524 reduces peak I(Na) while augmenting late I(Na) , and may thus underlie the development of atrial tachycardia , intraventricular conduction delay , and QT interval prolongation in an infant . Increase in intracellular Cl- concentration by DB02527 - and Ca2+-dependent stimulation of M1 collecting duct cells . In the lungs of cystic fibrosis ( CF ) patients , mutations of the cystic fibrosis transmembrane conductance regulator ( P13569 ) lead to defective Cl- secretion and hyperabsorption of electrolytes . This may be a an important cause for the defective mucociliary clearance in CF lungs . Previous studies have suggested that inhibition of ENaC during activation of P13569 or by purinergic stimulation could be related to an increase in the intracellular [Cl-]i . This was examined in the present study using cultured mouse M1 collecting duct cells transfected with the chloride-sensitive enhanced yellow fluorescent protein YFP(V163S) . Calibration experiments showed a linear decrease of YFP fluorescence intensity with increasing [Cl-]i ( 0-100 mM ) . Activation of P13569 by isobutyl-1-methylxanthine ( DB07954 , 100 microM ) and forskolin ( 2 microM ) increased [Cl-]i by 9.6+/-1.5 mM ( n=35 ) . Similarly , DB00171 ( 100 microM ) increased [Cl-]i transiently by 9.5+/-2.2 mM ( n=17 ) . The increase in [Cl-]i was reduced by the Na+/K+/2 Cl- -cortransporter-1 ( P55011 ) blocker azosemide ( 100 microM ) , the P13569 blocker DB04941 ( 50 microM ) , the blocker of Ca2+-activated Cl- channels DIDS ( 100 microM ) or the ENaC blocker amiloride ( 10 microM ) . Changes in YFP(V163S) fluorescence were not due to changes in cell volume or intracellular pH . The present data thus demonstrate an increase in [Cl-]i following stimulation with secretagogues , which could participate in the inhibition of ENaC . Phosphorylation of thymidylate synthase from various sources by human protein kinase CK2 and its catalytic subunits . P04818 ( TS ) was found to be a substrate for both catalytic subunits of human CK2 , with phosphorylation by CK2alpha and CK2alpha ' characterized by similar K(m) values , 4.6microM and 4.2microM , respectively , but different efficiencies , the apparent turnover number with CK2alpha being 10-fold higher . With both catalytic subunits , phosphorylation of human TS , like calmodulin and P55957 , was strongly inhibited in the presence of the regulatory subunit CK2beta , the holoenzyme being activated by polylysine . Phosphorylation of recombinant human , rat , mouse and Trichinella spiralis TSs proteins was compared , with the human enzyme being apparently a much better substrate than the others . Following hydrolysis and TLC , phosphoserine was detected in human and rat , and phosphotyrosine in T. spiralis , TS , used as substrates for CK2alpha . MALDI-TOF MS analysis led to identification of phosphorylated DB00133 (124) in human TS , within a sequence LGFS(124)TREEGD , atypical for a CK2 substrate recognition site . The phosphorylation site is located in a region considered important for the catalytic mechanism or regulation of human TS , corresponding to the loop 107-128 . Following phosphorylation by CK2alpha , resulting in incorporation of 0.4mol of phosphate per mol of dimeric TS , human TS exhibits unaltered K(m) values for DB03800 and N(5,10)-methylenetetrahydrofolate , but a 50 % lower turnover number , pointing to a strong influence of DB00133 (124) phosphorylation on its catalytic efficiency . DB04917 : a new drug for the treatment of constipation in the irritable bowel syndrome . DB04917 is a novel drug currently under clinical evaluation for the treatment of irritable bowel syndrome ( IBS ) . DB04917 is a mixed 5-hydroxytryptamine type 4 ( Q13639 ) agonist and 5- Q9H205 receptor antagonist that has a stimulatory effect on gastrointestinal motility and transit , as established by in vivo and in vitro studies . Its therapeutic efficacy , tolerability and safety have been evaluated in diabetic gastroparesis in a single study , as well as in IBS in a few other studies . Phase II studies indicated potential beneficial effects on symptoms and bowel habits in patients with constipation-predominant IBS and mixed-type IBS . The outcome of Phase III studies is currently under evaluation . DB00227 -stimulated superinduction of P16581 , P05362 and P19320 in P01375 activated human vascular endothelial cells . Inhibitors of P04035 ( statins ) reveal important pharmacological effects in addition to reducing the plasma LDL cholesterol level . In the pathogenesis of arteriosclerosis , transendothelial migration of various leukocytes including monocytes is a crucial step . We , therefore , investigated the expression of P16581 , intercellular cell adhesion molecule-1 ( P05362 ) and vascular cell adhesion molecule-1 ( P19320 ) in vascular endothelial cells as influenced by lovastatin . Human umbilical vein endothelial cells ( HUVECs ) express significant amounts of selectins and cell adhesion molecules ( CAMs ) within a few hours after stimulation with P01375 . This effect is potentiated by 100-200 % when the cells are pretreated with 0.1-2.5 microM lovastatin . The lovastatin-mediated increase in the cytoplasm and at the cell surface is dose-dependent and significant at lovastatin concentrations comparable to plasma levels in patients under lovastatin treatment . The lovastatin-potentiated increase of P16581 and CAMs is correlated with a corresponding increase of selectin- and P62158 -specific mRNA . We conclude that , in vivo , statin treatment could trigger an enhanced recruitment of macrophages that might support the cholesteryl ester efflux from the arteriosclerotic plaque . Ras-transfection up-regulated HaCaT cell migration : inhibition by Marimastat . Cell migration is an essential process in physiological and pathological conditions such as wound healing and tumor invasion . This phenomenon involves cell adhesion on the extracellular matrix mediated by integrins , and cell detachment promoted in part by metalloproteinases ( MMPs ) . In the present study , the migration of two HaCaT-ras clones ( metastatic or not ) , was compared with HaCaT cells , and normal human primary cultured keratinocytes . Using colloidal gold migration assay , the migration index on type I and type IV collagen was similar for primary cultured keratinocytes and HaCaT , whereas it was markedly higher for the HaCaT-ras clones . High motility of ras-transfected cells was confirmed from an in vitro wound healing assay . It was not correlated with changes in integrin expression or related to a different adhesion on extracellular matrix . The Marismastat ( DB00786 ) , a MMP inhibitor , inhibited in a dose-dependent effect the migration in both assays , demonstrating the important role of MMPs in the migration process . Under our experimental conditions , P03956 activity was not detected in HaCaT and P14780 activity was secreted by these cells only after their stimulation by P01133 . Here , P08253 was the major gelatinolytic activity secreted by all the cells and its secretion was markedly higher for HaCaT-nis clones compared with HaCaT . In addition , Western blotting results confirmed a higher expression of P08253 associated with a lower expression of P16035 in HaCaT-ras compared with HaCaT . These results suggest that Ha-ras oncogene could be a stimulating factor of migration and might modified the balance between P08253 and P16035 in keratinocyte cell lines . 5-hydroxytryptamine and its receptors in systemic vascular walls . 5-hydroxytryptamine ( 5-HT ) in the bloodstream is largely contained in platelets and circulates throughout the entire vascular system . 5-HT released from activated platelets dramatically changes the function of vascular smooth muscle cells ( VSMCs ) and endothelial cells ( ECs ) . In VSMCs , 5-HT induces proliferation and migration via 5- Q13049 receptors . These effects are further enhanced by vasoactive substances such as thromboxane A2 and angiotensin II . 5- Q13049 receptor activation in VSMCs also causes both enhancement of prostaglandin I2 production by inducing cyclooxygenase-2 and reduction of nitric oxide ( NO ) by suppressing inducible NO synthase . Evidence showing that 5-HT in ECs plays a principal role in angiogenesis now exists . Stimulation of 5-HT1 and/or 5-HT2 receptors has been implicated in the angiogenic effect of 5-HT . The extracellular signal-regulated kinase and endothelial NO synthase ( P29474 ) activation-dependent pathways are involved in the mechanisms . Moreover , Q13639 receptors in ECs have been shown to also regulate angiogenesis . Recent reports show sarpogrelate , a selective antagonist of the 5- Q13049 receptor , indirectly enhances the function of P28222 receptors in ECs via inhibition of 5- Q13049 receptors in VSMCs or platelets . This indirect action of P28222 receptors in ECs may increase NO production derived from P29474 and a vasodilator response . Furthermore , sarpogrelate and other 5- Q13049 receptor antagonists have been shown to reduce the constitutive activity of 5- Q13049 receptors . It is believed that increasing evidence on the role of 5-HT receptors will contribute to the expansion of the clinical application of existing therapeutic drugs such as sarpogrelate , and to the development of new 5-HT receptor-related drugs for treating cardiovascular diseases . Nitrergic response to cyclophosphamide treatment in blood and bone marrow . Daily intraperitoneal injection of cyclophosphamide ( P15085 ) ( 50 mgkg(-1) of body weight ) for 5 days resulted in reduced levels of marrow and blood cellularity , which was most pronounced in 18 days post-treatment ( pt ) . On day 18 after P15085 treatment the enhancedlevels of nitric oxide ( NO ) precursors and metabolites ( L-arginine , L-citrulline , reactive nitrogen species ( RNS ) ) of marrow and blood cells ( platelet , neutrophil , lymphocyte and monocyte ) resulted from up-regulation of Ca(II)/calmodulin( P62158 )-independent " inducible " NO synthase ( P35228 ) , with a lessercontribution of Ca(II)/ P62158 -dependent " constitutive " P29474 isoforms to systemic NO.Biphasic response to P15085 of marrow nitrergic system , i.e. both P35228 and P29474 showed significantly depressed activities , as well as diminished levels of NO metabolites on day 9 pt , suggested that signals in addition to NO might be involved in P15085 -induced inhibition of hematopoesis , while a gradual increase of neutrophil and platelet NOS activity appeared to be contributed to a P15085 -induced development of granulopenia , thrombocytopenia and hemorrhage .