MH_dev_288

P62158 - mediated effects of loperamide on chloride transport by brush border membrane vesicles from human ileum . We investigated whether the synthetic opiate loperamide-HCl is able to regulate specific transport systems for sodium and chloride in brush border membrane vesicles ( BBMVs ) from human ileum and whether such activities are mediated by calcium / calmodulin . In BBMVs we studied Na + / H + antiport , Cl + / OH - antiport , Na + / Cl - cotransport , and the Cl - conductive pathway . Brush border membrane vesicles were incubated with 10 microM loperamide over 4 h at 5 degrees C before the uptake experiments . In ileal BBMVs , loperamide stimulated intravesicular accumulation of Na + in the presence of Cl - and vice versa . After 1 min of incubation , the stimulatory effect was 35 % + / - 5 % ( p less than 0.005 ) of the control without loperamide . DB00836 MEN also stimulated Cl - / OH - antiport by 30 % + / - 5 % ( p less than 0.005 ) in BBMVs of ileum . In addition , we studied the role of Ca2 + / calmodulin in the action of loperamide on chloride transport by human BBMVs . In loperamide-pretreated BBMVs , calmodulin activity was significantly decreased ( 12 + / - 2 vs . 38 + / - 4 pmol / mg protein ) . When loperamide-pretreated vesicles were incubated with 2 microM calcium ( free concentration ) plus 5 microM calmodulin for 1 h at 5 degrees C , complete inhibition of the stimulatory effect of loperamide on Cl - / OH - antiport and Na + / Cl - cotransport was observed . Increasing the Ca2 + / calmodulin activity of loperamide-pretreated BBMVs with 2 microM calcium plus 5 microM calmodulin led to a significant inhibition of Cl - / OH - antiport and Na + / Cl - cotransport by 40 % + / - 5 % ( p less than 0.005 ) .

Inhibition of proliferation and migration of luminal and claudin-low breast cancer cells by P09619 REA inhibitors . BACKGROUND : Platelet-derived growth factors ( PDGFs ) bind to two receptors , PDGFRα and PDGFRβ to mediate cell proliferation , migration and survival . Although epithelial cells typically do not express high levels of PDGFRs , their expression has been reported to increase in breast cancer cells that have undergone epithelial to mesenchymal transition . METHODS : P09619 REA signaling was inhibited using DB01268 malate , Imatinib mesylate or DB08896 MEN in murine and human luminal-like and claudin-low mammary tumor cell lines or Masitinib in only the human cell lines . A scratch wound assay was used to assess tumor cell migration while immunofluorescence for phosphorylated histone H3 or cleaved caspase 3 was used to determine tumor cell proliferation and apoptosis , respectively . RESULTS : DB01268 and DB08896 MEN , but not Imatinib , were capable of significantly inhibiting the migration of both murine and human luminal-like and claudin-low breast cancer cells while Masitinib inhibited migration in both human breast cancer cell lines . DB01268 but not DB08896 MEN or Imatinib also significantly suppressed tumor cell proliferation in all four cell lines tested while Masitinib had no significant effect on human breast cancer cell proliferation . None of the P09619 REA inhibitors consistently regulated mammary tumor cell apoptosis . CONCLUSION : DB01268 , DB08896 MEN and Masitinib may prove clinically useful in inhibiting breast cancer cell migration and metastasis while only DB01268 ( and possibly DB08896 MEN in some breast cancer subtypes ) is effective at inhibiting both migration and proliferation of breast cancer cells .

Serotonin transporter interacts with the PDGFβ receptor in DB00102 - induced signaling and mitogenesis in pulmonary artery smooth muscle cells . The serotonin transporter ( P31645 REA ) and the platelet-derived growth factor receptor ( P09619 REA ) have been implicated in both clinical and experimental pulmonary hypertension ( PH ) and the facilitation of pulmonary artery smooth muscle cell ( PASMC ) growth . To gain a better understanding of the possible relationship of these two cell surface molecules we have explored interactions between P31645 REA and P09619 REA . We have previously demonstrated that P31645 REA transactivates PDGFRβ in serotonin-stimulated PASMC proliferation . We now provide evidence for a role for P31645 REA in DB00102 signaling and PASMC proliferation by using pharmacological inhibitors , genetic ablation , and construct overexpression of P31645 REA . The results show that four tested P31645 REA blockers dose dependently inhibit PDGF-stimulated human and bovine PASMC proliferation with comparable efficacy to that of P09619 REA inhibitors , whereas P28222 REA or 5 - Q13049 REA receptor inhibitors had no effect . Combinations of the P31645 REA and P09619 REA inhibitors led to synergistic / additive inhibition . Similarly , PDGF-induced PASMC proliferation was attenuated by small interfering RNA downregulation of P31645 REA . Inhibition of P31645 REA in PASMCs attenuated PDGF-induced phosphorylation of PDGFRβ , Akt , and p38 but not Erk . Overexpression of P31645 REA in HEK 293 cells led to enhanced Akt phosphorylation by PDGF , which was blunted by a P31645 REA PDZ motif mutant , indicating the mechanistic need for the PDZ motif of P31645 REA in PDGF signaling . Furthermore , coimmunoprecipitation experiments showed that P31645 REA and PDGFRβ become physically associated upon PDGF stimulation . In total , the data show for the first time an important interactive relationship between P31645 REA and the PDGFRβ in the production of PASMC proliferation triggered by PDGF that may be important in PH .

Effects of external calcium on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229-7 . DB01373 is a known signalling molecule in eukaryotic cells and plays a central role in the regulation of many cellular processes . In the following study , we report on the effect of external calcium treatments on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229-7 . We observed that the intracellular calcium content of P . bainier 229-7 mycelia was increased in response to exposure to high external Ca ( 2 + ) concentrations . Both ginsenoside Rd biotransformation and β-glucosidase activity were both found to be dependent on the external calcium concentration . At an optimal Ca ( 2 + ) concentration of 45 mM , maximal ginsenoside Rd bioconversion rate of 92.44 % was observed and maximal β-glucosidase activity of 0.1778 U was reached in a 72 - h biotransformation . The Ca ( 2 + ) channel blocker Verapamil blocked the trans-membrane influx of calcium and decreased ginsenoside Rd biotransformatiom . In addition , β-glucosidase activity and ginsenoside Rd content decreased by 36.0 and 29.2 % respectively after a 72 - h incubation in the presence of 0.05 mM P62158 ( P62158 ) antagonist DB00850 MENMAX DB00850 MEN . These results suggest that both Ca ( 2 + ) channels and P62158 are involved in ginsenoside Rd biotransformation via regulation of β-glucosidase activity . This is the first report regarding the effects of calcium signal transduction on biotransformation and enzyme activity in fungi .

Pulmonary arterial dysfunction in insulin resistant obese Zucker rats . BACKGROUND : P01308 REA resistance and obesity are strongly associated with systemic cardiovascular diseases . Recent reports have also suggested a link between insulin resistance with pulmonary arterial hypertension . The aim of this study was to analyze pulmonary vascular function in the insulin resistant obese Zucker rat . METHODS : Large and small pulmonary arteries from obese Zucker rat and their lean counterparts were mounted for isometric tension recording . mRNA and protein expression was measured by RT-PCR or Western blot , respectively . KV currents were recorded in isolated pulmonary artery smooth muscle cells using the patch clamp technique . RESULTS : Right ventricular wall thickness was similar in obese and lean Zucker rats . Lung Q13873 REA , KV1 . 5 and 5 - Q13049 REA receptor mRNA and protein expression and KV current density were also similar in the two rat strains . In conductance and resistance pulmonary arteries , the similar relaxant responses to acetylcholine and nitroprusside and unchanged lung P29474 REA expression revealed a preserved endothelial function . However , in resistance ( but not in conductance ) pulmonary arteries from obese rats a reduced response to several vasoconstrictor agents ( hypoxia , phenylephrine and 5 - HT ) was observed . The hyporesponsiveness to vasoconstrictors was reversed by L-NAME and prevented by the P35228 REA inhibitor 1400W . CONCLUSIONS : In contrast to rat models of type 1 diabetes or other mice models of insulin resistance , the obese Zucker rats did not show any of the characteristic features of pulmonary hypertension but rather a reduced vasoconstrictor response which could be prevented by inhibition of P35228 REA .

Role of presynaptic serotonergic receptors on the mechanism of action of P08908 REA and P28222 REA agonists on masculine sexual behaviour : physiological and pharmacological implications . In order to establish whether the P08908 REA or the 5HT1B agonists , 8 - OH-DPAT or TFMPP , produce their facilitatory or inhibitory actions on masculine sexual behaviour via a mechanism involving : ( a ) the serotonin synthesis or release ; ( b ) the stimulation of presynaptic receptors , or ( c ) the stimulation of somatodendritic receptors , three series of experiments were performed . The administration of the serotonin synthesis inhibitor , p-chlorophenylalanine ( p - P15085 , 300 mg / kg x 3 days ) , facilitated sexual behaviour but does not interfere neither with the inhibitory nor with the facilitatory effects of TFMPP ( 0.5 mg / kg ) or 8 - OH-DPAT ( 0.5 mg / kg ) , respectively . The icv or the intraraphé administration of the serotonergic neurotoxin , 5,7- dihydroxytryptamine ( 5,7- DB02901 ) , slightly stimulated masculine sexual behaviour and produced a decrease in serotonin and its metabolite levels . In lesioned animals TFMPP ( 0.5 mg / kg ) resulted in an inhibitory effect reflected as a prolongation of the ejaculation latency . The inhibitory effect of this drug on mounting behaviour was not observed in 5,7- DB02901 treated rats . In lesioned animals 8 - OH-DPAT ( 0.5 mg / kg ) produced the same facilitatory effect . Present data indicate that serotonergic postsynaptic receptors mediate both the inhibitory and the facilitatory actions of TFMPP or 8 - OH-DPAT in copulation . All data further support the idea that endogenous serotonin acts via the stimulation of P28222 REA receptors to induce its inhibitory effects on masculine sexual behaviour .

Anti - P04275 REA aptamer DB05202 MEN for refractory thrombotic thrombocytopenic purpura . BACKGROUND : Plasma exchange is the main therapy for thrombotic thrombocytopenic purpura ( TTP ) . No treatments other than plasma exchange have been documented to be effective nor are approved for treatment of TTP . The anti - P04275 REA ( P04275 REA ) aptamer DB05202 MEN effectively inhibits P04275 REA activity in plasma samples of TTP patients and thus shear-dependent platelet ( Q02083 REA ) function as measured by the Q02083 REA function analyzer PFA - 100 ( Dade Behring ) . It was hypothesized that DB05202 MEN would offer a potentially effective treatment option for a critically ill patient , refractory to standard care . CASE REPORT : A 39 - year-old male patient with idiopathic TTP , refractory to daily plasma exchange , rituximab , steroids , and splenectomy , was additionally treated with a continuous infusion of the anti - P04275 REA ( P04275 REA ) aptamer DB05202 MEN for 3 weeks . RESULTS : Plasma concentrations of approximately 10 microg / mL DB05202 MEN decreased P04275 REA activity by more than 96 % . Plasma exchange treatment acutely decreased the plasma concentrations of DB05202 MEN by a mean of 47 % ( range , 40 % - 61 % ) . Thus , additional minibolus infusions of DB05202 MEN were given after each plasma exchange to rapidly restore steady-state concentrations . DB05202 MEN resulted in an increase of Q02083 REA counts as long as DB05202 MEN was given . On three occasions the infusion was stopped , each accompanied by a decrease in Q02083 REA counts and worsening of microangiopathy . No serious adverse effects were observed during the treatment with DB05202 MEN . CONCLUSION : DB05202 MEN caused a clear and reproducible increase in Q02083 REA counts in an otherwise refractory TTP case . These clinical , pharmacokinetic , and pharmacodynamic data provide a rational basis for clinical trials with DB05202 MEN in TTP .

Cytokeratin immunoreactivity in gliomas . Monoclonal antibodies ( P02730 REA / 3 , P62158 5.2 and P03952 REA - 1 ) and polyclonal antisera against the cytokeratin proteins were reacted with a range of astrocytic tumours , oligodendrogliomas and ependymomas . Seven of 12 cases ( 58 % ) of glioblastoma multiforme , five of eight ( 63 % ) anaplastic astrocytomas and two of five ( 40 % ) well-differentiated astrocytomas were immunoreactive with P02730 REA / 3 but not with the other anti-cytokeratin antibodies . In oligodendrogliomas , P02730 REA / 3 stained isolated astrocyte-like cells as well as scattered neoplastic oligodendrocytes in four of eight cases ( 50 % ) cases . Four ependymomas were negative for all cytokeratin markers examined . The immunostaining of astrocytomas and oligodendrogliomas with P02730 REA / 3 might represent co-expression of cytokeratin with glial fibrillary acidic protein by gliomas and calls for caution in the use of these antibodies in the differential diagnosis between gliomas and carcinomas .

Ca2 + - calmodulin and janus kinase 2 are required for activation of sodium-proton exchange by the Gi-coupled 5 - hydroxytryptamine 1a receptor . The type 1 sodium-proton exchanger ( P19634 REA ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 REA remain incompletely defined . In this work , we present evidence that stimulation of the 5 - hydroxytryptamine 1A ( P08908 REA ) receptor results in the formation of a signaling complex that includes activated O60674 REA ( Jak 2 ) , Ca2 + / calmodulin ( P62158 ) , and P19634 REA , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist-induced association of P62158 and P19634 REA as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 REA is activated through this pathway : P08908 REA receptor --> G ( i2 ) alpha and / or G ( i3 ) alpha --> Jak 2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 REA --> induction of a conformational change in P19634 REA that unmasks an obscured proton-sensing and / or proton-transporting region of P19634 REA --> activation of P19634 REA . The G ( i / o ) - coupled P08908 REA receptor now joins a handful of Gq-coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2 + . We have also shown for the first time that the association of P62158 with P19634 REA in living cells is a dynamic process .

DB05311 MEN ( DX - 88 ) , a plasma kallikrein inhibitor for the treatment of hereditary angioedema and the prevention of blood loss in on-pump cardiothoracic surgery . BACKGROUND : P03952 REA plays a major role in the contact ( kallikrein-kinin ) cascade producing bradykinin . Bradykinin is a vasodilator , which increases vascular permeability , activates inflammation and produces pain . P03952 REA is also crosslinked to the coagulation system and the complement cascade . OBJECTIVE : DB05311 MEN ( DX - 88 ) is a potent and specific inhibitor of plasma kallikrein . DB05311 MEN is a recombinantly produced and engineered small protein based on the first Kunitz domain of human tissue factor pathway inhibitor . It was identified through phage display technology . METHODS : The search terms ' ecallantide ' , ' DX - 88 ' and ' hereditary angioedema ' were entered into Pubmed / Medline , ClinicalTrials and Google . RESULTS / CONCLUSION : At present , the drug is being studied for two major indications . First , the results for the treatment of hereditary angioedema are promising . Second , a prospective randomised multi-centre trial for the reduction of blood loss during on-pump cardiothoracic surgery will be terminated in October 2008 .

Aripiprazole : a novel atypical antipsychotic drug with a uniquely robust pharmacology . Aripiprazole ( DB01238 SUB ) is an atypical antipsychotic drug that has been recently introduced for clinical use in the treatment of schizophrenia . Aripiprazole has a unique pharmacologic profile that includes partial agonism at several G-protein coupled receptors ( GPCRs ) [ especially dopamine ( D2 ) and P08908 REA ] and antagonistic action at others ( especially 5 - Q13049 REA ) . Clinical trials indicate that aripiprazole is effective in treating the positive and negative symptoms of schizophrenia . In short-term studies rapid onset of action ( within one week ) has been demonstrated . Preliminary data indicate that aripiprazole may also be effective in the treatment of manic symptoms of bipolar disorder . At recommended doses , aripiprazole appears to be safe and well tolerated in most adult patients with schizophrenia and schizoaffective disorder . There is only limited information available on the use of aripiprazole in children and adolescents , and pilot data suggest that a revised dosing strategy , based on weight , is indicated in this population . In the long-term studies , the use of aripiprazole was associated with continued efficacy , good compliance and increased time-to-relapse . Aripiprazole represents the first functionally selective atypical antipsychotic drug .

Multifactor dimensionality reduction analysis of P42898 REA , P05121 REA , P12821 REA , P27169 REA , and P29474 REA gene polymorphisms in patients with early onset coronary artery disease . BACKGROUND : Association studies in the Turkish population have investigated the single locus effects of different gene polymorphisms on coronary artery disease ( CAD ) . CAD is a complex polygenic disease that involves complex interactions among multiple genetic and environmental conditions . DESIGN : We evaluated associations of five candidate genetic polymorphisms ( methylene DB00116 MEN reductase C677T , plasminogen activator inhibitor 4G / 5G , endothelial nitric oxide synthase ( P29474 REA ) 3-27 base pair repeat , insertion , or deletion of a 287 bp Alu repeat sequence polymorhism of angiotensin I converting enzyme , and paraoxonase Gln 192Arg P27169 REA polymorphisms ) with the presence and extent of early onset CAD . METHODS : DNA was isolated and amplified from 90 consecutive patients with angiographically proven early onset CAD ( ages 41 ± 5 for men , 49 ± 7 for women ) and also from 90 control subjects with no significant coronary obstruction angiographically ( ages 42 ± 5 for men , 48 ± 6 for women ) . Multifactor dimensionality reduction ( MDR ) analysis was performed to identify a model of CAD based on both genetic and conventional risk factors . RESULTS : MDR analysis detected a significant model with four genes ( prediction success ∼ 61 % , p = 0.03 ) . When the total number of the conventional risk factors is analysed with the candidate polymorphisms , a different model is identified that includes three of the four genes from the above model and achieves a similar prediction of CAD as the gene only model . CONCLUSION : These data indicate that gene-gene and gene-environmental risk interactions form significant models in predicting early onset CAD .

P50579 REA is required for P19526 REA initiation and proliferation . In a chemical screening , we tested the antiangiogenic effects of fumagillin derivatives and identified fumagillin as an inhibitor of definitive hematopoiesis in zebrafish embryos . DB02640 MEN is known to target methionine aminopeptidase II ( MetAP 2 ) , an enzyme whose function in hematopoiesis is unknown . We investigated the role of MetAP 2 in hematopoiesis by using zebrafish embryo and human umbilical cord blood models . Zebrafish metap 2 was expressed ubiquitously during early embryogenesis and later in the somitic region , the caudal hematopoietic tissue , and pronephric duct . metap 2 was inhibited by morpholino and fumagillin treatment , resulting in increased mpo expression at 18 hours postfertilization and reduced c-myb expression along the ventral wall of dorsal aorta at 36 hours postfertilization . It also disrupted intersegmental vessels in Tg ( fli 1 : gfp ) embryos without affecting development of major axial vasculatures . Inhibition of MetAP 2 in CB P28906 REA ( + ) cells by fumagillin had no effect on overall clonogenic activity but significantly reduced their engraftment into immunodeficient nonobese diabetes / severe combined immunodeficiency mice . metap 2 knock-down in zebrafish and inhibition by fumagillin in zebrafish and human CB P28906 REA ( + ) cells inhibited P62158 Kinase II activity and induced P29323 REA phosphorylation . This study demonstrated a hitherto-undescribed role of MetAP 2 in definitive hematopoiesis and a possible link to noncanonical Wnt and P29323 REA signaling .

Aripiprazole : a review of its use in the treatment of manic episodes in adolescents with bipolar I disorder . Aripiprazole ( DB01238 SUB ( ® ) ) is an atypical antipsychotic that is widely used in the treatment of psychiatric conditions . Unlike other currently available atypical antipsychotics that primarily have varying degrees of dopamine D2 receptor antagonism , aripiprazole is a partial agonist at D2 and serotonin P08908 REA receptors , which may explain differences in tolerability profiles . Recently in the EU , oral aripiprazole 10 mg once daily for 12 weeks was approved for the treatment of moderate to severe manic episodes in adolescents ( aged ≥ 13 years ) with bipolar I disorder . Approval was based on a phase 3 , 30 - week US trial in children and adolescents with bipolar I disorder experiencing manic or mixed episodes . Using trial data together with ancillary analyses , the European Medicines Agency concluded that aripiprazole 10 mg once daily for 12 weeks was effective in reducing symptoms of mania , but because of the high drop-out rate , efficacy over 30 weeks of treatment was not proven . Aripiprazole was generally well tolerated in the phase 3 trial . Ancillary analyses indicated that tolerability was less favourable in younger ( 10-12 years ) than in older ( ≥ 13 years ) subjects , and less favourable with the higher ( 30 mg / day ) than the lower dosage ( 10 mg / day ) . The drug is associated with sedation , weight gain and extrapyramidal symptoms ( EPS ) , although the incidence of EPS over 12 weeks was not significantly different between aripiprazole 10 mg / day and placebo . Data comparing the use of atypical antipsychotics in the treatment of mania in adolescents with bipolar I disorder are limited , but evidence shows that aripiprazole provides a valuable additional therapeutic option for use in this population .

Golimumab in patients affected by moderate to severe psoriatic arthritis : an open-label study in thirty-two patients previously treated with other biologics . BACKGROUND : Clinical trials have demonstrated the efficacy of DB06674 MEN ( GLB ) in improving the signs and symptoms of psoriatic arthritis ( PsA ) . OBJECTIVE : The aim of this study was to evaluate the efficacy of GLB in monotherapy in patients affected by PsA with cutaneous involvement unresponsive to other anti-tumor necrosis factor-α ( P01375 REA - α ) agents . METHODS : This study included 32 patients treated with GLB as monotherapy , at a dosage of 50 mg , subcutaneously , every 4 weeks . Patients were divided into 3 groups ( A , B , and C ) according to their number of previous anti - P01375 REA - α treatments ( 1 , 2 , or 3 ) . Clinical and laboratory evaluations were performed at weeks 0 , 12 , and 24 . RESULTS : All patients showed significant improvement of their clinical , inflammatory , and quality of life indexes . CONCLUSION : Data suggest that GLB can be successful and safe in patients affected by PsA with skin involvement previously treated with other anti - P01375 REA - α agents .

Stimulated secretion of endothelial P04275 REA is accompanied by rapid redistribution to the cell surface of the intracellular granule membrane protein P16109 REA . We have examined the cell activation-dependent redistribution of the intracellular granule membrane protein P16109 REA of human endothelial cells . By dual-label immunofluorescence , the distribution of P16109 REA within cultured human umbilical vein endothelial cells was found to coincide with the distribution of P04275 REA ( P04275 REA ) , suggesting that P16109 REA is located in the membranes of P04275 REA - containing storage granules . Stimulation of P04275 REA secretion resulted in an increase in P16109 REA on the cell surface , as detected by increased binding of the monoclonal antibody P28222 REA which recognizes the extracytoplasmic domain of P16109 REA . For each agonist tested ( histamine , thrombin , phorbol 12 - myristate 13 - acetate , and the calcium ionophore A23187 ) a dose-dependent redistribution of P16109 REA to the endothelial surface was observed which closely paralleled the dose-dependent secretion of P04275 REA into the cell supernatant . When cells were maximally stimulated by histamine in the presence of antibody P28222 REA , a 4 - fold increase in P28222 REA uptake by the cells was observed . This increase occurred rapidly and reached a plateau by 10 min . In contrast , when histamine-stimulated cells were first fixed with paraformaldehyde or chilled to 4 degrees C before addition of antibody P28222 REA , only a transient increase in cell surface P16109 REA was detected . Under these conditions of arrested membrane turnover during antibody binding , cell surface P16109 REA was maximal 3 min after histamine stimulation and then declined to control levels by 20 min . These data suggest that stimulated secretion of P04275 REA from endothelial cells entails fusion of P04275 REA - containing storage granules with the plasma membrane . Once inserted into the plasma membrane , P16109 REA is subsequently removed from the endothelial surface , most likely by an endocytic mechanism .

8 - OH-DPAT ( P08908 REA agonist ) Attenuates 6 - Hydroxy - dopamine-induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE ( S ) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8 - OH-DPAT on 6 - OHDA-induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 REA ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6 - OHDA ( 8 μg / 2 μl / rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar-test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8 - OH-DPAT ( P08908 REA receptor agonist ; 0.25 , 0.5 and 1mg / kg , IP for 10 days ) . P04141 REA samples were collected on the tenth day of 8 - OH-DPAT administration and analyzed by ELISA method to measure levels of P01375 REA - α , IL - 1β and P05231 REA . RESULTS : Chronic injection of 8 - OH-DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti-cataleptic effect was observed at the dose of 1 mg / kg of 8 - OH-DPAT . Levels of P01375 REA - α in P04141 REA increased three weeks after 6 - OHDA injection while there was a significant decrease in P01375 REA - α level of parkinsonian animals treated with 8 - OH-DPAT ( 1 mg / kg , IP for 10 days ) . IL - 1β and P05231 REA decreased and increased in parkinsonian rats and in 8 - OH-DPAT-treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8 - OH-DPAT improves catalepsy in 6 - OHDA-induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 REA receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines .

Single-prolonged stress induce changes of P62158 / CaMKIIα in the rats of dorsal raphe nucleus . Ca2 + / calmodulin-dependent protein kinase IIα ( CaMKIIα ) is identified as a Ca2 + - dependent kinase in brain involved in the activation of DB00150 hydroxylase ( P17752 REA ) acting through direct phosphorylation of P17752 REA , and playing key roles in the signaling pathways initiated by various G protein-coupled 5 - HT receptors . The goal of this study is to detect whether there are changes of P62158 and CaMKIIα in dorsal raphe nucleus in the rats exposed to single-prolonged stress ( P49903 ) , which is a model employed in post-traumatic stress disorder ( PTSD ) study extensively . A total of 90 male Wistar rats were randomly divided into a normal control group and P49903 groups of 7d , 14d . The changes of P62158 / CaMKIIα were detected by immunohistochemistry , reverse transcription-polymerase chain reaction and western blot . Our results demonstrate that both expressions of P62158 and CaMKIIα significantly increase ( P < 0.001 ) in the P49903 7d group than that in the control group , and then decreased dramatically ( P < 0.001 ) 14 days after P49903 . Our results confirm that P49903 induce changes of P62158 / CaMKIIα in the dorsal raphe nucleus . Changes of P62158 / CaMKIIα may be associated with the activation of P08908 REA receptor , and may contribute to the progress of molecular mechanism of PTSD .

Electrostatic steering at acetylcholine binding sites . The electrostatic environments near the acetylcholine binding sites on the nicotinic acetylcholine receptor ( nAChR ) and acetylcholinesterase were measured by diffusion-enhanced fluorescence energy transfer ( DEFET ) to determine the influence of long-range electrostatic interactions on ligand binding kinetics and net binding energy . Changes in DEFET from variously charged Tb3 + - chelates revealed net potentials of - 20 mV at the nAChR agonist sites and - 14 mV at the entrance to the P22303 REA active site , in physiological ionic strength conditions . The potential at the alphadelta-binding site of the nAChR was determined independently in the presence of DB01199 MEN to be - 14 mV ; the calculated potential at the alphagamma-site was approximately threefold stronger than at the alphadelta-site . By determining the local potential in increasing ionic strength , Debye-Hückel theory predicted that the potentials near the nAChR agonist binding sites are constituted by one to three charges in close proximity to the binding site . Examination of the binding kinetics of the fluorescent acetylcholine analog dansyl - P13671 REA - choline at ionic strengths from 12.5 to 400 mM revealed a twofold decrease in association rate . Debye-Hückel analysis of the kinetics revealed a similar charge distribution as seen by changes in the potentials . To determine whether the experimentally determined potentials are reflected by continuum electrostatics calculations , solutions to the nonlinear Poisson-Boltzmann equation were used to compute the potentials expected from DEFET measurements from high-resolution models of the nAChR and P22303 REA . These calculations are in good agreement with the DEFET measurements for P22303 REA and for the alphagamma-site of the nAChR . We conclude that long-range electrostatic interactions contribute -0.3 and - 1 kcal / mol to the binding energy at the nAChR alphadelta - and alphagamma-sites due to an increase in association rates .

Stimulation of cloned human serotonin P28221 REA beta receptor sites in stably transfected P13671 REA glial cells promotes cell growth . The involvement of serotonin P28221 REA beta receptor sites was investigated in the growth of rat P13671 REA glial cells permanently transfected with a gene encoding a human P28221 REA beta receptor . The 5 - HT receptor identity of control and transfected P13671 REA glial / P28221 REA beta cells was determined by reverse transcription-polymerase chain reaction using primers specific for rat P08908 REA , rat P28222 REA , rat P28221 REA alpha , human P28221 REA beta , and rat 5 - Q13049 REA receptor genes . Constitutive mRNA for 5 - Q13049 REA receptors was present in control and transfected P13671 REA glial / P28221 REA beta cells , whereas mRNA for P28221 REA beta receptor sites was only present in the transfected P13671 REA glial / P28221 REA beta cell line . 5 - HT inhibited forskolin-stimulated cyclic AMP formation and promoted cell growth , in contrast to the absence of any measurable effect in pcDNA 3 plasmid-transfected and nontransfected P13671 REA glial cells . The 5 - HT effects could be mimicked by sumatriptan ( EC50 = 44-76 nM ) and were totally and partially blocked by methiothepin ( IC50 = 9 nM ) and GR 127,935 ( 2 ' - methyl - 4 ' - ( 5 - methyl [ 1,2 , 4 ] oxadiazol - 3 - yl ) - biphenyl - 4 - carbox yli c acid [ 4 - methoxy - 3 - ( 4 - methylpiperazin - 1 - yl ) phenyl ] amide ; IC50 = 97 pM ) , respectively . No effect on cell growth was measured with the 5 - HT2 receptor agonist DOI [ 1 - ( 2,5- dimethoxy - 4 - iodophenyl ) - 2 - aminopropane ; 10 microM ] , suggesting that 5 - Q13049 REA receptors are not involved in the 5 - HT-stimulated P13671 REA glial / P28221 REA beta cell growth . Dibutyryl-cyclic AMP ( 0.3 mM ) - treated cultures did not show sumatriptan-promoted cell growth , indicating an inhibitory role for cyclic AMP in the cell growth mediated by P28221 REA beta receptor sites . ( ABSTRACT TRUNCATED AT 250 WORDS )