interacts_with DB06779?
Antagonizing amyloid-β/calcium-sensing receptor signaling in human astrocytes and neurons : a key to halt Alzheimer 's disease progression ? Astrocytes ' roles in late-onset Alzheimer 's disease ( LOAD ) promotion are important , since they survive soluble or fibrillar amyloid-β peptides ( Aβs ) neurotoxic effects , undergo alterations of intracellular and intercellular Ca(2+) signaling and gliotransmitters release via the Aβ/α7-nAChR ( α7-nicotinic acetylcholine receptor ) signaling , and overproduce/oversecrete newly synthesized Aβ42 oligomers , NO , and P15692 via the Aβ/ P41180 ( calcium-sensing receptor ) signaling . Recently , it was suggested that the NMDAR ( N-methyl-D-aspartate receptor ) inhibitor nitromemantine would block the synapse-destroying effects of Aβ/α7-nAChR signaling . Yet , this and the progressive extracellular accrual and spreading of Aβ42 oligomers would be stopped well upstream by P0C0P6 2143 , an allosteric P41180 antagonist ( calcilytic ) . [ DB01257 in paroxysmal nocturnal hemoglobinuria ] . Paroxysmal nocturnal hemoglobinuria is a rare acquired clonal of the hematopoietic stem cell due to acquired mutation of the P37287 gene . This results in the lack of two P06744 -anchored membrane proteins involved in the inhibition of complement attack , thus explaining red cells hemolysis . The development of an anti- P01031 monoclonal antibody ( eculizumab ) had profoundly modified the treatment of the the hemolytic form of the disease . Comparative effects of azimilide and ambasilide on the human ether-a-go-go-related gene ( Q12809 ) potassium channel . OBJECTIVE : To evaluate the effects of azimilide and ambasilide on the biophysical properties of the human-ether-a-go-go-related ( Q12809 ) channel . METHODS : Q12809 was stably transfected into Chinese hamster ovary ( CHO- P04264 ) cells and currents were measured using a whole cell , voltage-clamp technique . RESULTS : DB04957 had a ' dual effect ' , inhibiting current at voltage steps above -40 mV and augmenting current at -40 and -50 mV . Tail current inhibition following a step to +30 mV did not vary with temperature ( IC(50) 610 nM at 22 degrees C and 560 nM at 37 degrees C ) . The agonist effect at -50 mV was concentration-dependent and correlated with a hyperpolarizing shift in the V(1/2) of activation ( r=0.98 , P < 0.05 ) . Time constants of inactivation were faster and there was a -10 mV shift in the V(1/2) of steady state inactivation suggestive of open and inactivated state binding . By comparison , ambasilide inhibited Q12809 channels with lower potency ( IC(50) 3.6 microM ) , in a voltage- and time-dependent but frequency-independent manner ( 0.03-1 Hz ) . Ambasilide had no effect on activation or inactivation gating but prolonged both fast and slow components of deactivation consistent with unbinding from the open state . The net effect of both drugs was similar during a voltage ramp which simulated a cardiac action potential . CONCLUSIONS : Inhibition of Q12809 channels by azimilide and ambasilide exhibits a similar time and voltage-dependence . While both exhibit affinity for the open state , azimilide also binds to inactivated channels . Treatment of peripapillary choroidal neovascularization with intravitreal bevacizumab . PURPOSE : Peripapillary choroidal neovascularization ( CNV ) is an uncommon condition and often shows a growth tendency towards the fovea during spontaneous progression that threatens visual acuity . Treatment of peripapillary CNV is difficult . The authors report results of intravitreal bevacizumab therapy for peripapillary CNV . METHODS : Four patients with CNV located in the temporal or superior peripapillary area received intravitreal bevacizumab injections . Ophthalmologic examinations including O75051 were performed at baseline and at 6-week intervals . DB00693 angiography was performed at baseline and depending on clinical and O75051 findings . The mean follow-up was 34+/-20 ( 22-69 ) weeks . RESULTS : The patients received an average of 3.5+/-3.1 ( 1-8 ) injections . In all patients fluorescein angiography showed inactivation of peripapillary CNV . No further increase in size was observed in any of the patients . The O75051 showed a decrease of intraretinal and subretinal fluid . No intraocular or systemic side effects were observed . CONCLUSIONS : In this series of patients , intravitreal bevacizumab appears to be efficacious . A progression of peripapillary CNV could be prevented in all patients and the lesion was successfully inactivated . Anti- P15692 treatment with bevacizumab represents a promising therapy option for peripapillary CNV . Pharmacology of the calcium sensing receptor . DB01373 sensing receptor ( P41180 ) is a G-protein couple receptor which plays a key role in calcium homeostasis in vertebrates . Its extracellular domain is sensitive to divalent cations , aminoacids and polyamines . In parathyroid glands , P41180 activation causes parathyroid hormone ( PTH ) reduction and subsequently a decrease in blood calcium concentration . In PTH-dependent disorders , e.g. primary and secondary hyperparathyroidism ( Q9HD23 ) , the need for therapeutic options other than surgery led to the synthesis of various allosteric P41180 agonists ( calcimimetics ) , such as cinacalcet . DB01012 is the only calcimimetic approved for Q9HD23 secondary to chronic kidney disease ( CDK ) , parathyroid carcinoma , and , in some countries , primary Q9HD23 . Clinical trials showed that cinacalcet reduced PTH and calcemia both in CDK and primary Q9HD23 , lowering the risk of bone fractures , surgery , and cardiovascular complications in the former patients . Long-term safety and pharmacoeconomics have to be fully tested yet . Few both in vitro and in vivo studies showed an association between Arg990Gly- P41180 polymorphism and cinacalcet sensitivity , though in patients with severe P41180 inactivating mutations the drug substantially retained its positive clinical effects . Recently , a new class of allosteric antagonists of P41180 , i.e. calcilytics , has been synthesized . Calcilytics are structurally similar to calcimimetics , but exert their effects acting on a different allosteric site . Infusion of calcilytics was followed by transient rise in PTH and calcium . One of these compounds , DB05255 , was able to increase femur BMD in post menopausal women , but with induction of mild hyperparathyroidism . In the future , calcilytics may contribute to the osteoporosis treatment choice . Effects of cytokines on P15692 expression and secretion by human first trimester trophoblast cell line . PROBLEM : The mechanism through which vascular endothelial growth factor ( P15692 ) regulation occurs at the feto-maternal interface is poorly understood . The aim of this study was to investigate the effects of various cytokines on P15692 expression and secretion by trophoblast cells . METHOD OF STUDY : We investigated the effects of cytokines on P15692 expression in human first trimester trophoblast cell line by analyzing P15692 messenger RNA ( mRNA ) by reverse transcription-polymerase chain reaction and P15692 protein secretion by enzyme linked immunosorbent assay . RESULTS : The trophoblast cells expressed P15692 mRNA constitutively and the main subtypes were identified as VEGF121 and VEGF165 . When cultured in the presence of interferon ( IFN ) -gamma , interleukin ( IL ) - 1beta , tumor necrosis factor ( P01375 ) -alpha , P60568 , or P22301 , P15692 mRNA expression was found to be significantly increased by IL-1beta , P01579 and P01375 but to be unaffected by P60568 and P22301 . Moreover , P15692 secretion was most significantly increased by P01579 treatment . CONCLUSION : These results suggest that IL-1beta , P01579 , and P01375 may regulate the production of P15692 in early gestational trophoblasts . Implantation of P15692 transfected preadipocytes improves vascularization of fibrin implants on the cylinder chorioallantoic membrane ( P62158 ) model . The successful substitution or augmentation of soft tissues by implantation of three dimensional cell constructs , consisting of human preadipocytes and fibrin glue as a carrier matrix , requires a rapid and homogeneous vascularization of the whole implant in order to provide a sufficient blood supply of centrally situated cells . Previous investigations have shown that under in vivo conditions primary human preadipocytes induce vascularization of fibrin matrices by secretion of several growth factors , such as P15692 and P09038 . The current study investigates whether vascularization of implants can be improved by transplantation of preadipocytes following transfection with a P15692 -vector . Transfection was performed by electroporation with an pCMX-GFP and pCMX-VEGF165 vector . Transfection efficiency ( GFP expression ) and P15692 expression were determined in vitro by FACS analysis and P15692 immunoassay , respectively . In vivo investigations to determine the vascularization of the implants were performed on the cylinder chorioallantoic membrane ( P62158 ) . Four million P15692 transfected cells were transferred within a fibrin matrix onto the P62158 on the 7(th) day of incubation and after 8 days the vascularization of the implant was histologically examined and evaluated by means of a computer-assisted image analysis program . Transfection of preadipocytes with the GFP vector by electroporation yielded transfection efficiencies between 12 % and 41 % of surviving cells . Results of the P15692 immunoassay demonstrated that P15692 expression was significantly higher following transfection . Investigations on the P62158 outlined a significantly higher rate of vascularization in the transfected vs. control population . Our investigations demonstrate that primary human preadipocytes can be successfully transfected by electroporation with a P15692 vector . The enhanced P15692 expression on transfected cells results in an increase of vascularization of the cell constructs on the P62158 . A novel strategy for the generation of angiostatic kringle regions from a precursor derived from plasminogen . In this study we have explored the feasibility of generating angiostatin by incorporating an endoproteolytic furin cleavage site into plasminogen to allow conversion of the precursor molecule into an angiostatic active P04264 -3 fragment . We show that secretable angiostatin can be successfully generated from cells infected with adenovirus carrying the furin-mutated plasminogen ( AdmuthPlgK3 ) . Supernatant from cells transduced with AdmuthPlagK3 inhibits tube formation and proliferation and migration of human umbilical vein endothelial cells with an efficiency similar to that of supernatant from cells infected with adenovirus expressing kringle 1-3 of plasminogen ( AdK1-3 ) . Administration of AdmuthPlgK3 and AdK1-3 in mice results in significantly decreased endothelial cell infiltration in P15692 -embedded Matrigel plugs . Treatment with AdmuthPlgK3 and AdK1-3 exerts strong antitumoral effect in models of hepatocellular carcinoma and Lewis lung cancer . This antitumor effect was associated with decreased microvessel density in the tumors . Taken together , our data demonstrate that angiostatin endowed with strong antiangiogenic and antitumor effects can be released from a furin-mutated plasminogen acting as a precursor . This strategy may have potential to develop angiostatic anti-cancer therapies . Pharmacology of recombinant low-voltage activated calcium channels . Several types of voltage- or ligand-activated calcium channels contribute to the excitability of neuronal cells . Low-voltage-activated ( LVA ) , T-type calcium channels are characterised by relatively negative threshold of activation and therefore they can generate low-threshold spikes , which are essential for burst firing . At least three different proteins form T-type calcium current in neurons : Ca(v)3.1 , Ca(v)3.2 and Q9P0X4 . Expression of these proteins in various brain regions is complementary . Individual channel types could be distinguished by different sensitivity towards inorganic cations . This inhibition can contribute to the toxicity of some heavy metals . Selective inhibition of T-type calcium channels by organic blockers may have clinical importance in some forms of epilepsy . DB01388 inhibits the expressed Ca(v2)3.1 , Ca(v)3.2 and Q9P0X4 channels in nanomolar concentrations with Q9P0X4 channel having lowest affinity . The sensitivity of the expressed Ca(v)3.1 channel to the antiepileptic drugs , valproate and ethosuximide , is low . Ca(v)3.1 channel is moderately sensitive to phenytoin . The Ca(v)3.2 channel is sensitive to ethosuximide , amlodipine and amiloride . All three LVA calcium channels are moderately sensitive to active metabolites of methosuximide , i.e. alpha-methyl-alpha-phenylsuccinimide . Several neuroleptics inhibit all three LVA channels in clinically relevant concentrations . All three channels are also inhibited by the endogenous cannabinoid anandamide . A high affinity peptide blocker for these Ca channels is the scorpion toxin kurtoxin which inhibits the Ca(v)3.1 and Ca(v)3.2 , but not the Q9P0X4 channel in nanomolar concentrations . DB06690 selectively inhibits the Ca(v)3.2 , but not the Ca(v)3.1 channel . The Ca(v)3.2 , but not the Ca(v)3.1 channel is potentiated by stimulation of Ca(2+)/ P62158 -dependent protein kinase . Isoenzyme-specific cyclooxygenase inhibitors : a whole cell assay system using the human erythroleukemic cell line HEL and the human monocytic cell line Mono Mac 6 . NSAIDs inhibit the conversion of arachidonic acid into DB03866 and Prostaglandin H2 which is catalyzed by the enzyme cyclooxygenase ( P36551 ) . Two genetically distinct isoforms have been discovered , P23219 and P35354 . While P23219 is thought to account for homeostatic amounts of eicosanoids , P35354 is induced during inflammation leading to pathologic amounts of eicosanoids . Since NSAIDs inhibit both P36551 isoforms , antiinflammatory drug research has refocused to discovering P35354 inhibitors that do not inhibit P23219 . For this purpose , we have developed a whole cell assay system using the human erythroleukemic cell line HEL as a source for P23219 and the human monocytic cell line Mono Mac 6 as a source for P35354 . Mono Mac 6 cells express high amounts of P35354 upon stimulation with lipopolysaccharide ( LPS ) in the absence of any detectable P23219 protein . On the other hand , we find HEL cells to naturally express P23219 protein , but not P35354 . Testing of a panel of NSAIDs as well as some P35354 specific inhibitors showed that this assay system is suitable for identifying compounds that selectively inhibit either P23219 or P35354 . This test system offers the advantage of assessing P23219 and P35354 inhibitors within the human species , within a similar test set-up , and circumvents the need for tedious purification of either platelets or peripheral blood monocytes . Vitamin D analogues . The plethora of actions attributed to 1,25(OH)2D3 throughout the body have suggested potential therapeutic applications for the treatment of hyperproliferative diseases , immune dysfunction , endocrine disorders , and metabolic bone disease . However , the potent calcemic activity of the natural vitamin D hormone has precluded its use in most cases . New vitamin D analogues are under development that display greater specificity , in most cases , by retaining the therapeutic properties of 1,25(OH)2D3 , but with lower calcemic activity . Two analogues have been approved for use in patients : calcipotriol ( DB02300 from Leo Pharmaceuticals , Copenhagen , Denmark ) for the treatment of psoriasis ; and 19-nor-1,25(OH)2D2 ( DB00910 from Abbott Laboratories , Abbott Park , IL ) for secondary hyperparathyroidism . Many others analogues are currently being tested in preclinical and clinical trials for the treatment of various types of cancer and osteoporosis , and for immunosuppression . The selectivity of the analogues can be attributed to the combined interactions with four proteins : the vitamin D receptor ( P11473 ) , the serum vitamin D binding protein ( DBP ) , the vitamin D-24-hydroxylase and to a newly described membrane receptor . Low DBP affinity has been shown to be responsible for the reduced calcemic actions of calcipotriol and 22-oxacalcitriol ( O75051 ) , which is being tested for secondary hyperparathyroidism . However , the low calcemic activity of other analogues , including 19-nor-1,25(OH)2D2 , involves other , as yet undefined , mechanisms . Understanding of the molecular basis for the selectivity of the vitamin D analogues will allow the design of more effective and safer vitamin D compounds for the treatment of a wide range of clinical disorders . DB06779 , a low-molecular-weight heparin , promotes angiogenesis mediated by heparin-binding P15692 in vivo . Tumors are angiogenesis dependent and vascular endothelial growth factor-A ( P15692 ) , a heparin-binding protein , is a key angiogenic factor . As chemotherapy and co-treatment with anticoagulant low-molecular-weight heparin ( LMWH ) are common in cancer patients , we investigated whether angiogenesis in vivo mediated by P15692 is modulated by metronomic-type treatment with : ( i ) the LMWH dalteparin ; ( ii ) low-dosage cytostatic epirubicin ; or ( iii ) a combination of these two drugs . Using the quantitative rat mesentery angiogenesis assay , in which angiogenesis was induced by intraperitoneal injection of very low doses of P15692 , dalteparin sodium ( Fragmin(®) ) and epirubicin ( Farmorubicin(®) ) were administered separately or in combination by continuous subcutaneous infusion at a constant rate for 14 consecutive days . DB06779 was administered at 27 , 80 , or 240 IU/kg/day , i.e. , doses that reflect the clinical usage of this drug , while epirubicin was given at the well-tolerated dosage of 0.4 mg/kg/day . While dalteparin significantly stimulated angiogenesis in an inversely dose-dependent manner , epirubicin did not significantly affect angiogenesis . However , concurrent treatment with dalteparin and epirubicin significantly inhibited angiogenesis . The effect of dalteparin is the first demonstration of a proangiogenic effect of any LMWH in vivo . The fact that co-treatment with dalteparin and epirubicin significantly inhibited angiogenesis suggests a complex drug effect . Growth factors expression in patients with erosive esophagitis . Although the pathogenesis and treatment of erosive esophagitis ( EE ) is well recognized , little is known about the cellular and molecular mechanisms of mucosal healing in EE patients . In this pilot study , we enrolled typical EE patients to evaluate what kinds of growth factors and their receptors were activated in their injured esophageal mucosa . Forty endoscopically proved EE patients were consecutively enrolled . Messenger RNA expressions , which includes keratinocyte growth factor ( KGF ) and its receptor ( P21802 ) , epidermal growth factor ( P01133 ) and its receptor ( P00533 ) , hepatocyte growth factor ( P14210 ) and its receptor ( HGFR ) , basic fibroblast growth factor ( P09038 ) , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase ( P36551 ) -1 and P35354 , were measured using real-time polymerase chain reaction ( PCR ) . Data were compared between the injured EE mucosa and their normal esophageal mucosa above EE . The mRNA expressions of P14210 , HGFR , P01133 , P15692 , and P35354 , but not P00533 , KGF , P21802 , P09038 , and P23219 , were significantly increased in the injured mucosa of EE patients compared with those of normal mucosa ( P < 0.05 ) . The study found that P14210 , HGFR , P01133 , P15692 , and , P35354 are activated in the injured mucosa of EE patients ; their activation might be involved in mucosal repair and ulcer healing of EE . Shear stress-mediated F1/FO DB00171 synthase-dependent CO2 gas excretion from human pulmonary arteriolar endothelial cells . We studied the physiological role of flow through pulmonary arterioles in CO(2) gas exchange . We established human pulmonary arteriolar endothelial cells ( HPAoEC ) . The cells demonstrated marked immunocytochemical staining of P16284 , P15692 R2 , P12821 -1 , and CA type IV on their cell surface . Ten seconds shear stress stimulation caused the co-release of H(+) and DB00171 via the activation of F(1)/F(O) DB00171 synthase on the HPAoEC . F(1)/F(O) DB00171 synthase was immunocytochemically observed on the cell surface of non-permeabilized HPAoEC . In the shear stress-loaded HPAoEC culture media supernatant , ATPase activity increased in a time-dependent manner . The HPAoEC were strongly stained for P49961 , which partially co-localized with purinergic P47900 . The purinergic P47900 receptor agonist UTP ( 10(-6) M ) significantly potentiated the shear stress-induced increase in ATPase activity in the culture medium supernatant . Ten seconds shear stress stimulation also produced stress strength-dependent CO(2) gas excretion from the HPAoEC , which was significantly reduced by the inhibition of F(1)/F(O) DB00171 synthase or CA IV on the endothelial cell ( EC ) surface . In conclusion , we have proposed a new concept of CO(2) exchange in the human lung , flow-mediated F(1)/F(O) DB00171 synthase-dependent H(+) secretion , resulting in the facilitation of a dehydration reaction involving HCO3(-) in plasma and the excretion of CO(2) gas from arteriolar ECs . ADP receptors -- targets for developing antithrombotic agents . Platelet P2 receptors -- P47900 , Q9H244 , and P51575 -- constitute the means by which adenine nucleotides can activate platelets . Coactivation of the Galphaq-coupled P47900 and Galphai2-coupled Q9H244 receptors is necessary for ADP-mediated platelet activation , which forms the basis of using P2 antagonists as antithrombotic drugs . P47900 receptor antagonists inhibit platelet activation , while P47900 knockout mice show longer bleeding times than normal mice but few other problems ; however , its ubiquitous expression in other tissues renders P47900 questionable as an antithrombotic target . The Q9H244 receptor is expressed nearly exclusively in platelets and brain , making it an attractive antithrombotic target . Antagonists for the Q9H244 receptor have been developed that either require metabolic activation to covalently inhibit Q9H244 and are irreversible , or simply are competitive in nature and thus reversible . DB00208 and clopidogrel are irreversible Q9H244 antagonists and have been repeatedly proven as clinical antithrombotic agents . In addition , a recently reported Q9H244 antagonist , CS-747 , shows promise as a future antithrombotic drug . The AR-C series of compounds represent reversible Q9H244 antagonists and have been used extensively to characterize the function of Q9H244 in platelets . Clinical studies show that AR-C69931MX is as effective as clopidogrel ; furthermore , the combination of AR-C69931MX ( cangrelor ) and clopidogrel confers greater antagonism of Q9H244 than either antagonist alone . The P51575 receptor is a calcium channel that functions to potentiate agonist-induced platelet shape change , and its inhibition or loss has little if any effect on hemostasis . A combination of P47900 and Q9H244 antagonists may represent an additional course of antithrombotic treatment . Angiogenic and inflammatory factor expressions in cutaneomeningospinal angiomatosis ( Cobb 's syndrome ) : case report . We report on a case of cervical cutaneomeningospinal angiomatosis ( Cobb 's syndrome ) , a rare somatic disorder , characterized by vascular abnormalities of the spinal cord , with a triad of associated vascular skin , muscle , bone , and dura involvement at the same somite . This case follows an 18-year-old male patient presenting with left extremity weakness and back cervical pain . Magnetic resonance imaging ( Q9BWK5 ) revealed a spinal cord arteriovenous malformation ( AVM ) at the P01024 - P01031 level . Cobb 's syndrome was diagnosed by coexistence of cutaneous naevi in a dermatomal pattern and neurological signs of a spinal cord lesion together with cervical Q9BWK5 and angiography . The patient underwent a combination of staged endovascular embolization and microsurgical resection . Multiple biopsies of the mass including the skin , muscle , dura , and spinal cord at the same somite revealed that the lesions had a similar pathology . Post-operative immunohistochemical characterizations on specimen included CD31 , smooth muscle actin ( SMA ) , vascular endothelial growth factor ( P15692 ) , and matrix metalloproteinase ( P14780 ) . The unique associations of somatic and spinal cord lesion as well as angiogenic and inflammatory factor expressions in all specimens are reported . Current and emerging biologics for ulcerative colitis . Conventional medical treatment for ulcerative colitis can have limited efficacy or severe adverse reactions requiring additional treatment or colectomy . Hence , different biological agents that target specific immunological pathways are be-ing investigated for treating ulcerative colitis . Anti-tumor necrosis factor ( P01375 ) agents were the first biologics to be used for treating inflammatory bowel disease . For example , infliximab and adalimumab , which are anti- P01375 agents , are be-ing used for treating ulcerative colitis . Recently , DB06674 , another anti- P01375 agent , and vedolizumab , an anti-adhesion therapy , have been approved for ulcerative colitis by the U.S . Food and Drug Administration . In addition , new medications such as tofacitinib , a Janus kinase inhibitor , and etrolizumab , another anti-adhesion therapy , are emerging as therapeutic agents . Therefore , there is a need for further studies to select appropriate patient groups for these biologics and to improve the outcomes of ulcerative colitis treatment through appropriate medical usage . DB09559 , a fully human IgG1 mAb directed against the P00533 for the potential treatment of cancer . DB09559 ( DB05774 ) , under development by ImClone Systems in collaboration with Bristol-Myers Squibb , is a fully human IgG1 mAb targeting the epidermal growth factor receptor ( P00533 ) , for the potential intravenous treatment of cancer , in particular NSCLC . In vitro studies demonstrate that necitumumab inhibits downstream targets in the P00533 pathway ( eg , MAPK ) , which are important for cellular proliferation , differentiation , invasion and metastasis . Furthermore , because necitumumab is an IgG1 construct , it has the potential to induce antibody-dependent cell-mediated cytotoxicity against tumor cells . Preclinical studies indicated that the antitumor activity of necitumumab is either comparable with or superior to that of ImClone 's chimeric anti- P00533 mAb cetuximab . In a phase I clinical trial in patients with advanced solid malignancies , necitumumab displayed nonlinear pharmacokinetic behavior . The toxicity profile of necitumumab is acceptable , with skin toxicity being the most frequently reported adverse event in the phase I and II clinical trials conducted to date . Preliminary data from a phase II clinical trial of necitumumab in combination with chemotherapy for the first-line treatment of advanced colon cancer are promising . Success in the ongoing phase III clinical trials in patients with advanced NSCLC would lead to necitumumab becoming a valuable addition to future therapeutic strategies in oncology .