MH_dev_173

Quantification of raf antisense oligonucleotide ( rafAON ) in biological matrices by LC-MS / MS to support pharmacokinetics of a liposome-entrapped rafAON formulation . An LC-MS / MS method was developed to quantify an antisense oligonucleotide against P04049 expression ( rafAON ) in monkey and mouse plasma and in mouse tissue homogenates from animals dosed with a liposome-entrapped rafAON easy-to-use formulation ( DB04973 MEN - ETU ) intended for use as an antineoplastic agent . RafAON was extracted from mouse and monkey plasma using solid-phase extraction . Tissues were homogenized and sample cleanup was achieved by protein precipitation . RafAON and the internal standard ( IS ) were separated on a Hamilton PRP - 1 column and quantified by tandem mass spectrometry using an electrospray source in negative ion mode . The total run time was 4.0 min . The peak areas of two rafAON transitions were summed and plotted against the peak area of an IS transition to generate the standard curve . In monkey plasma the linear range was 50-10 , 000 ng / mL , and in mouse plasma it was 25-5000 ng / mL . The lower limit of quantification was 500 ng / mL ( 10 microg / g tissue ) in heart , kidney , liver , lung and spleen homogenates , and the standard curve was linear up to 10,000 ng / mL . Accuracy , precision and stability were evaluated and found to be acceptable in all three matrices . The assay was used to support pharmacokinetics and tissue distribution studies of DB04973 MEN - ETU in mice and monkeys .

Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ) . tPA has not been replaced by third generation plasminogen activators , e . g . DB00015 SUB ( Ret ) and DB00031 ( TNK ) that circulate with longer life-spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility .

DB11320 inhibits differentiation of skin fibroblasts into myofibroblasts . DB11320 and TGF-β , major mediators secreted by mast cells , are involved in skin inflammation and play critical roles in the pathogenesis of systemic sclerosis . However , the roles of signaling mechanisms in the development of skin fibrosis remain largely unclear . Here we show that histamine suppressed the expression of α smooth muscle actin ( αSMA ) , a marker of myofibroblasts , induced by TGF-β 1 in skin fibroblasts . DB11320 H1 - receptor ( P35367 ) , but not H2 - receptor ( P25021 ) or H4 - receptor ( Q9H3N8 ) , was expressed on skin fibroblasts at both mRNA and protein levels . Interestingly , an P35367 antagonist , but not P25021 or Q9H3N8 antagonists , antagonized the histamine-mediated suppression of αSMA expression by TGF-β 1 . Correspondingly , phosphorylated Q15796 was detected after treatment with TGF-β 1 , whereas the addition of histamine inhibited this phosphorylation . Taken together , histamine - P35367 decreased TGF-β 1 - mediated Q15796 phosphorylation and inhibited differentiation of skin fibroblasts into myofibroblasts .

DB02342 causes functional repression of transforming growth factor β3 signaling by ameliorating Smad and non-Smad signaling pathways in immortalized uterine fibroid cells . OBJECTIVE : To investigate the effects and the mechanism of action of 2 - methoxyestradiol ( 2ME ( 2 ) ) on transforming growth factor ( TGF ) β3 - induced profibrotic response in immortalized human uterine fibroid smooth muscle ( huLM ) cells . DESIGN : Laboratory study . SETTING : University research laboratory . PATIENTS ( S ) : Not applicable . INTERVENTIONS ( S ) : Not applicable . MAIN OUTCOME MEASURE ( S ) : huLM cells were treated with TGF-β 3 ( 5 ηg / mL ) in the presence or absence of specific P8 4022 inhibitor SIS 3 ( 1 μmol / L ) , inhibitor of the PI3K / Akt ( LY294002 , 10 μmol / L ) , or 2ME ( 2 ) ( 0.5 μmol / L ) , and the expression of collagen ( Col ) type I ( αI ) , Col III ( αI ) , plasminogen activator inhibitor ( P05121 ) 1 , connective tissue growth factor ( P29279 ) , and α-smooth muscle actin ( α-SMA ) were determined by real-time reverse-transcription polymerase chain reaction and immunoblotting . The effect of 2ME ( 2 ) on Smad-microtubule binding was evaluated by coimmunoprecipitation . RESULT ( S ) : Our data revealed that TGF-β 3 - induced fibrogenic response in huLM is mediated by both Smad-dependent and Smad-independent PI3K / Akt / P42345 signaling pathways . 2ME ( 2 ) abrogates TGF-β 3 - induced expression of Col I ( αI ) , Col III ( αI ) , P05121 , P29279 , and α-SMA . Molecularly , 2ME ( 2 ) ameliorates TGF-β 3 - induced Q15796 / 3 phosphorylation and nuclear translocation . In addition , 2ME ( 2 ) inhibits TGF-β 3 - induced activation of the PI3K / Akt / P42345 pathway . CONCLUSION ( S ) : TGF-β 3 - induced profibrotic response in fibroid cells is mediated by Smad-dependent and Smad-independent PI3K / Akt / P42345 pathways . 2ME ( 2 ) inhibits TGF-β 3 profibrotic effects in huLM cells by ameliorating both Smad-dependent and Smad-independent signaling pathways .

DB00183 MEN infusions in patients with panic disorder . II . Neuroendocrinology . Cholecystokinin ( CCK ) has well-documented anxiogenic effects in animals and normal people , and panicogenic effects in patients with panic disorder , but little is known about its neuroendocrine profile . We examined neuroendocrine responses to intravenous infusions of pentagastrin , a selective P32239 agonist , in 10 patients with panic disorder and 10 normal control subjects . DB00183 MEN potently activated the hypothalamic-pituitary-adrenal ( Q9Y251 ) axis , but did not release growth hormone or any of several vasoactive peptides ( neurokinin A , DB05875 , vasoactive intestinal peptide ) . The Q9Y251 axis response was unrelated to increases in symptoms . Panic patients did not differ from controls in neuroendocrine responses to the CCK agonist . Differential sensitivity to novelty stress accounted for the only patient-control differences in neuroendocrine profiles . The data suggest that CCK may help modulate normal Q9Y251 axis activity , but its anxiogenic effects are unrelated to its stimulatory effects on the Q9Y251 axis . DB00183 MEN provides a safe and readily available probe for further study of CCK receptor systems in humans .

The role of cycloxygenase - 2 in the rodent kidney following ischaemia / reperfusion injury in vivo . The role of cyclooxygenase - 2 ( P35354 ) in the pathophysiology of renal ischaemia / reperfusion injury is still not fully understood . In order to elucidate the role of P35354 in ischaemia / reperfusion injury of the kidney , we have evaluated the effects of ischaemia / reperfusion on renal dysfunction and injury in ( i ) rats treated with either vehicle or the selective P35354 inhibitor parecoxib , and ( ii ) wild-type mice or mice in which the gene for P35354 has been deleted ( P35354 knock-out mice or P35354 ( - / - ) ) . Rats were subjected to bilateral renal ischaemia ( 45 min ) and reperfusion ( 6 h ) , and received parecoxib ( 20 mg / kg , i . v . ) 30 min prior to ischaemia and 3 h after the commencement of reperfusion . Serum urea , serum creatinine , serum aspartate aminotransferase , creatinine clearance and fractional excretion of sodium were all used as indicators of renal dysfunction and injury . Mice ( wild-type and P35354 ( - / - ) ) were subjected to bilateral renal ischaemia ( 30 min ) and reperfusion ( 24 h ) after which renal dysfunction ( serum urea and creatinine ) and renal injury was assessed by histological analysis . DB08439 MEN significantly augmented the degree of renal dysfunction and injury caused by ischaemia / reperfusion in the rat . In addition , the degree of renal injury and dysfunction caused by ischaemia / reperfusion was also significantly augmented in P35354 ( - / - ) mice when compared to their wild-type littermates . These findings support the view that metabolites of P35354 protect the kidney against ischaemia / reperfusion injury , and ( ii ) that selective inhibitors of P35354 may worsen renal dysfunction and injury in conditions associated with renal ischaemia .

[ Proteolytic processing by dipeptidyl aminopeptidase IV generates receptor selectivity for peptide YY ( P10082 ) ] . Two receptor subtypes , Q03519 and P28062 , are known to mediate P10082 biological activity . P10082 1-36 binds to Q03519 and P28062 receptors with equal affinity , whereas the second endogenous form of P10082 , DB05004 MEN , selectively binds to P28062 receptors . Dipeptidyl cleavage thus transforms an unselective Y agonist into a highly selective P28062 agonist , DB05004 MEN . The enzyme responsible for this processing is unknown . Since P10082 has a proline in the penultimate position it is protected from the attack of most unspecific exopeptidases . Only a few exopeptidases are theoretically capable of generating DB05004 MEN from P10082 1-36 . Of the enzymes tested only the dipeptidyl aminopeptidase IV ( P27487 , E . C . 3.4 . 14.5 ) cleaved DB00135 - Pro from P10082 1-36 with high activity . Since P27487 is found on the endothelial surface and brush border membranes it can be considered a candidate enzyme for generating DB05004 MEN in vivo , thereby regulating the ratio of Q03519 / P49146 stimulation by P10082 .

P19957 kinase / AKT pathway as a therapeutic target in multiple myeloma . The development of novel therapies for multiple myeloma depends on a comprehensive understanding of the events leading to cellular proliferation and survival . Controlling pathways that regulate growth signals is an emerging and complementary approach to myeloma treatment . The PI3K / Akt pathway is a central gatekeeper for crucial cellular functions including adhesion , angiogenesis , migration and development of drug resistance . Established proteins and genes such as P42345 , p53 , NF-kappaB and Q92934 are all regulated through PI3K and Akt activation , making them attractive targets for broad downstream effects . Direct PI3K inhibition has demonstrated impressive tumor inhibition and regression in cell-line and animal models , and multiple agents including DB05210 MEN are currently in clinical trials . Drugs such as perifosine that are specific for Akt are also in development . Combinations of these agents with existing therapies are rational approaches on the path to improving myeloma treatment .

[ Effects of chronic fluoxetine treatment on catalepsy and immune response in mice genetically predisposed to freezing reaction : the role of P08908 and 5 - Q13049 receptors and tph 2 and P31645 genes ] . ASC / Icg ( Antidepressant Sensitive Catalepsy ) mouse strain selected for high predisposition to pinch-induced catalepsy is characterized by depressive-like behavior and impaired immune response . Chronic treatment with SSRI fluoxetine attenuated catalepsy manifestation and normalized a decreased number of rosette-forming cells ( P41440 ) in spleen in ASC mice . Chronic fluoxetine administration had no effect on catalepsy and P41440 number in mice of parental cataleptic CBA / Lac strain . DB00472 MENMAX DB00472 MEN failed to alter P08908 receptor functional activity in mice of both strains and diminished 5 - Q13049 receptor functional activity in CBA but not in ASC mice . No effect on cortical P08908 and 5 - Q13049 receptor mRNA levels and on P08908 receptor , tph 2 ( tryptophan hydroxylase - 2 ) and P31645 ( serotonin transporter ) mesencephalic gene expression was observed in ASC mice . Other possible serotonergic mechanisms of fluoxetine effect on catalepsy and immune response in mice with depressive-like state are discussed .

Antagonism of Q9GZP0 by human antibody DB05139 MEN prevents renal scarring in experimental glomerulonephritis . Glomerular mesangial cell proliferation and / or matrix accumulation characterizes many progressive renal diseases . Q9GZP0 was identified recently as a novel mediator of mesangial cell proliferation in vitro and in vivo . This study investigated the long-term consequences of Q9GZP0 inhibition in vivo . Rats with progressive mesangioproliferative glomerulonephritis ( uninephrectomy plus anti-Thy -1.1 antibody ) received the Q9GZP0 - neutralizing , fully human mAb DB05139 MEN on days 3 , 10 , and 17 after disease induction . Glomerular mesangioproliferative changes on day 10 were significantly reduced by anti - Q9GZP0 treatment as compared with control antibody . Eight weeks after disease induction , anti - Q9GZP0 therapy significantly ameliorated focal segmental glomerulosclerosis , podocyte damage ( de novo desmin expression ) , tubulointerstitial damage , and fibrosis as well as the accumulation of renal interstitial matrix including type III collagen and fibronectin . Treatment with anti - Q9GZP0 also reduced the cortical infiltration of monocytes / macrophages on day 56 , possibly related to lower renal cortical complement activation ( C5b - 9 deposition ) and / or reduced epithelial-to-mesenchymal transition ( preserved cortical expression of P12830 and reduced expression of vimentin and alpha-smooth muscle actin ) . In conclusion , these data provide evidence for a causal role of Q9GZP0 in the pathogenesis of renal scarring and point to a new therapeutic approach to progressive mesangioproliferative renal disease .

Serotonin induces the expression of tissue factor and plasminogen activator inhibitor - 1 in cultured rat aortic endothelial cells . Serotonin ( 5 - hydroxytryptamine , or 5 - HT ) , released from activated platelets , not only accelerates aggregation of platelets but also is known to promote mitosis , migration , and contraction of vascular smooth muscle cells ( VSMCs ) . These effects are considered to contribute to thrombus formation and atherosclerosis . The aim of this study was to investigate the effects of 5 - HT on the expressions of coagulative and fibrinolytic factors in rat aortic endothelial cells . Endothelial cells were stimulated with various concentrations of 5 - HT ( 0.1 approximately 10 microM ) , and the expressions of tissue factor ( TF ) , tissue factor pathway inhibitor ( P10646 ) , plasminogen activator inhibitor - 1 ( P05121 ) , and tissue-type plasminogen activator ( TPA ) messenger RNAs ( mRNAs ) were evaluated by Northern blot analysis . The activities of TF and P05121 were also measured . TF and P05121 mRNA were increased significantly in a concentration - and time-dependent manner . However , P10646 and TPA mRNA expression did not change . The inductions of TF and P05121 mRNAs were inhibited by a 5 - HT1 / 5 - HT2 receptor antagonist ( methiothepin ) and a selective 5 - Q13049 receptor antagonist ( D6RGH6 - 9042 ) . These results indicate that 5 - HT increases procoagulant activity and reduces fibrinolytic activities of endothelial cells through the 5 - Q13049 receptor . It was concluded that the modulation of procoagulant and hypofibrinolytic activities of endothelial cells by 5 - HT synergistically promotes thrombus formation at the site of vessel injury with the platelet aggregation , VSMC contraction , and VSMC proliferation .

Suppression of P05121 expression through inhibition of the P00533 - mediated signaling cascade in rat kidney fibroblast by ascofuranone . Fibrosis in glomerulosclerosis causes progressive loss of renal function . Transforming growth factor ( TGF ) - beta , one of the major profibrotic cytokines , induces the synthesis of plasminogen activator inhibitor ( P05121 ) - 1 , a factor that plays a crucial role in the development of fibrosis . Here , we found that an isoprenoid antibiotic , ascofuranone , suppresses expression of profibrotic factors including matrix proteins and P05121 induced by TGF-beta in renal fibroblasts . Ascofuranone selectively inhibits phosphorylation of epidermal growth factor receptor ( P00533 ) , and downstream kinases such as P04049 , MEK -1/2 , and P27361 / 2 . P05121 transcription also is suppressed by treatment with kinase inhibitors for MEK -1/2 or P00533 , and with small interfering RNA for P00533 . Ascofuranone inhibits cellular metalloproteinase activity , and an inhibitor of metalloproteinases suppresses P00533 phosphorylation and P05121 transcription . These results suggest that ascofuranone suppresses expression of profibrotic factors through the inhibition of an P00533 - dependent signal transduction pathway activated by metalloproteinases .

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 BaCl 2 and also inhibited the contractile effect of carbachol . DB08805 MEN 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 .

P8 4022 linker phosphorylation attenuates P8 4022 transcriptional activity and TGF-β 1 / P8 4022 - induced epithelial-mesenchymal transition in renal epithelial cells . Transforming growth factor-β 1 ( TGF-β 1 ) has a distinct role in renal fibrosis associated with epithelial-mesenchymal transition ( EMT ) of the renal tubules and synthesis of extracellular matrix . P8 4022 plays an essential role in fibrosis initiated by EMT . Phosphorylation of P8 4022 in the C-terminal SSXS motif by type I TGF-β receptor kinase is essential for mediating TGF-β response . P8 4022 activity is also regulated by phosphorylation in the linker region . However , the functional role of P8 4022 linker phosphorylation is not well characterized . We now show that P8 4022 EPSM mutant , which mutated the four phosphorylation sites in the linker region , markedly enhanced TGF-β 1 - induced EMT of P8 4022 - deficient primary renal tubular epithelial cells , whereas P8 4022 3S - A mutant , which mutated the C-terminal phosphorylation sites , was unable to induce EMT in response to TGF-β 1 . Furthermore , immunoblotting and RT-PCR analysis showed a marked induction of fibrogenic gene expression with a significant reduction in P12830 in P52789 human renal epithelial cells expressing P8 4022 EPSM . TGF-β 1 could not induce the expression of α-SMA , vimentin , fibronectin and P05121 or reduce the expression of P12830 in P52789 cells expressing P8 4022 3S - A in response to TGF-β 1 . Our results suggest that P8 4022 linker phosphorylation has a negative regulatory role on P8 4022 transcriptional activity and TGF-β 1 / P8 4022 - induced renal EMT . Elucidation of mechanism regulating the P8 4022 linker phosphorylation can provide a new strategy to control renal fibrosis .

Differential functional activity of 5 - hydroxytryptamine receptor ligands and beta adrenergic receptor antagonists at 5 - hydroxytryptamine 1B receptor sites in Chinese hamster lung fibroblasts and opossum renal epithelial cells . Functional activity of 5 - hydroxytryptamine ( 5 - HT ) receptor ligands and beta adrenergic receptor antagonists was studied at P28222 receptor sites in Chinese hamster lung ( CHL ) fibroblasts by measuring two cellular responses : inhibition of forskolin-stimulated cyclic AMP formation and potentiation of basic fibroblast growth ( BFGF ) induced mitogenesis . A good correlation was found between the potency of agonists to inhibit forskolin-induced cyclic AMP formation and their potency to potentiate P09038 - induced thymidine incorporation in CHL fibroblasts . Potent agonist activity was measured with 5 - methoxy -3,1 , 2,3 , 6 - tetrahydro - 4 - pyidinyl - 1H - indole ( RU 24,969 ) , 5 - carboxamidotryptamine ( 5 - CT ) , 3 - ( 1,2 , 5,6 ) - tetrahydro - 4 - pyridyl - 5 - pyrrolo ( 3,2- b ) pyril - 5 - one ( CP 93,129 ) and 5 - HT , whereas sumatriptan displayed weak agonist activity at concentrations different from its binding affinity for P28222 binding sites . In contrast to the observed P28222 receptor-mediated agonist activity in opossum kidney cells for metergoline and the beta adrenergic receptor antagonists : cyanopindolol , 4 - ( 3 - tert-butyl-amino - 2 - hydroxypropoxy ) - indole - 2 carbonic acid isopropyl ester ( SDZ 21,009 ) , isamoltane , ( - ) - propranolol and ( - ) - pindolol , antagonist activity at P28222 receptor sites was yielded in CHL fibroblasts in accordance with the reported observations at rat brain P28222 receptors . Methiothepin was the only compound that antagonized both the opossum kidney cell and CHL fibroblast P28222 receptor-mediated responses although the antagonist effect was more pronounced in CHL fibroblasts . ( ABSTRACT TRUNCATED AT 250 WORDS )

The pulse wave analysis of normal pregnancy : investigating the gestational effects on photoplethysmographic signals . OBJECTIVE : Normal pregnancy is associated with profound alterations in the maternal cardiovascular system and PPG represents a sensitive and convenient technique capable of tracking changes in the pulsatile function of arteries . The aim of this study was to investigate the effects of maternal cardiovascular alterations on the finger tip photoplethysmography ( PPG ) during normal gestation . METHODS : Thirty five healthy pregnant women were studied at each trimester of pregnancy and again on gestational age using PPG signals , peripheral blood pressure ( BP ) and heart rate ( HR ) . RESULTS : Comparing with nonpregnant controls , several characteristic differences in PPG derived parameters and morphologies occurred in the pregnant . P05121 , RI , PTT as well as AUC 1 and Q03519 of bcAUC 1 were different and significant difference had been found in second and third trimester , despite little change in the peripheral blood pressure . The mean heart rate increased linearly with gestational age . CONCLUSION : This study has confirmed that normal pregnancy is associated with profound alterations in PPG signals occurred principally as a result of maternal cardiovascular adaptation and PPG-based noninvasive assessment of cardiovascular activities is feasible throughout pregnancy . Using this technique we demonstrated a delay in wave reflection within the arterial tree and a reduction in magnitude of arterial wave reflections in normal pregnancy which is consistent with previous observations and the known cardiovascular changes of pregnancy .

Normal and perturbed endothelial cells from canine femoral arteries and femoral veins exhibit heterogeneity in hemostatic properties and growth characteristics . BACKGROUND : We sought to examine the heterogeneity of endothelial cells from the same anatomic site but different vascular systems and described P04275 ( P04275 ) release and morphological change in response to injury-associated factor in femoral vessels from canine in vitro . METHODS : Levels of hemostatic factors ( P04275 , plasminogen activator inhibitor type 1 ( P05121 ) , antithrombin III ( P01008 ) , in tissue sections and cultured endothelial cells of canine femoral arteries and canine femoral veins were compared by the immunohistochemistry technique . In addition to comparing cell growth density and cell protein contents , cultured femoral arterial endothelial cells ( FAECs ) and cultured femoral venous endothelial cells ( FVECs ) were incubated with a series concentration of basic fibroblast factor ( P09038 ) ( 1 , 10 , 100 ng / ml ) for up to 48 hours to test the amount of P04275 secretion and morphological change . RESULTS : Both in tissue sections and cultured cells , the levels of P04275 are higher in FVECs than in FAECs . We were unable to differentiate the level of P05121 and P01008 difference between FAECs and FVECs . P09038 ( 10 ng / ml ) significantly increased P04275 secretion from cultured FAECs but not from FVECs . The size of cultured FAECs is smaller than of FVECs ; however , FAECs have higher amounts of protein contents than FVECs . CONCLUSIONS : These comparative studies provide evidence indicating that the characteristics of FVECs differ from those of FAECs . These differences may be indicated heterogeneity with either inherited or acquired thrombotic disease .

Role of TGFbeta / Smad signaling in gremlin induction of human trabecular meshwork extracellular matrix proteins . PURPOSE : The bone morphogenic protein ( BMP ) antagonist gremlin is elevated in glaucomatous trabecular meshwork ( TM ) cells and tissues and elevates intraocular pressure ( IOP ) . Gremlin also blocks P12644 inhibition of transforming growth factor ( TGF ) - β2 induction of TM extracellular matrix ( Q13201 ) proteins . The purpose of this study was to determine whether Gremlin regulates Q13201 proteins in cultured human TM cells . METHODS : Human TM cells were treated with recombinant gremlin to determine the effects on Q13201 gene and protein expression . Expression of the Q13201 genes FN , COL 1 , P05121 , and P15502 was examined in cultured human TM cells by quantitative RT-PCR and Western immunoblot analysis . TM cells were pretreated with TGFBR inhibitors ( LY364947 , SB431542 or P36897 / P61812 siRNAs ) , inhibitors of the Smad signaling pathway ( SIS 3 or Q15796 / 3/4 siRNAs ) , or P29279 siRNA to identify the signaling pathway ( s ) involved in gremlin induction of Q13201 gene and protein expression . RESULTS : All Q13201 genes analyzed ( FN , COL 1 , P05121 , and P15502 ) were induced by gremlin . This gremlin induction of Q13201 genes and protein expression was blocked by inhibitors of TGFBR and the canonical Q15796 / 3/4 and P29279 signaling pathways . CONCLUSIONS : Gremlin employs canonical TGFβ 2 / Smad signaling to induce Q13201 genes and proteins in cultured human TM cells . Gremlin also induces both TGFβ 2 and P29279 , which can act downstream to mediate some of these Q13201 changes in TM cells .

Amelioration of nephropathy with apoA - 1 mimetic peptide in apoE-deficient mice . BACKGROUND : There is mounting evidence that dyslipidaemia may contribute to development and progression of renal disease . For instance , hyperlipidaemia in apolipoprotein E-deficient ( apoE ( - / - ) ) mice is associated with glomerular inflammation , mesangial expansion and foam cell formation . ApoA - 1 mimetic peptides are potent antioxidant and anti-inflammatory compounds which are highly effective in ameliorating atherosclerosis and inflammation in experimental animals . Given the central role of oxidative stress and inflammation in progression of renal disease , we hypothesized that apoA - 1 mimetic peptide , D - 4F , may attenuate renal lesions in apoE ( - / - ) mice . METHODS : Twenty-five-month-old female apoE ( - / - ) mice were treated with D - 4F ( 300 µg / mL in drinking water ) or placebo for 6 weeks . Kidneys were harvested and examined for histological and biochemical characteristics . RESULTS : Compared with the control mice , apoE ( - / - ) mice showed significant proteinuria , tubulo-interstitial inflammation , mesangial expansion , foam cell formation and up-regulation of oxidative [ NAD ( P ) H oxidase subunits ] and inflammatory [ NF-κB , P13500 , P05121 and P35354 ] pathways . D - 4F administration lowered proteinuria , improved renal histology and reversed up-regulation of inflammatory and oxidative pathways with only minimal changes in plasma lipid levels . CONCLUSIONS : The apoE ( - / - ) mice develop proteinuria and glomerular and tubulo-interstitial injury which are associated with up-regulation of oxidative and inflammatory mediators in the kidney and are ameliorated by the administration of apoA - 1 mimetic peptide . These observations point to the role of oxidative stress and inflammation in the pathogenesis of renal disease in hyperlipidaemic animals and perhaps humans .

DB00952 MEN : a review . Even though naratriptan and sumatriptan are both P28222 / P28221 receptor agonists , the biological and pharmacokinetic profile of naratriptan differs significantly from that of sumatriptan . With a plasma half-life of 6 h , very high oral bioavailability of 63-74 % and higher lipophilicity than sumatriptan , naratriptan exhibits a distinct clinical therapeutic profile . The similar tolerability to placebo , prolonged efficacy for 24 h or more and very low headache recurrence rate make naratriptan an attractive option in the treatment of acute migraine .

A prospective case-control study analyzes 12 thrombophilic gene mutations in Turkish couples with recurrent pregnancy loss . PROBLEM : Recurrent pregnancy loss ( RPL ) is a heterogeneous disorder . The contribution of specific thrombophilic genes to the pathophysiology of RPL has remained controversial . We evaluated the prevalences of 12 thrombophilic gene mutations among homogenous Caucasian couples with RPL and fertiles . METHOD : of study This was a prospective case-control study evaluating 272 women with RPL and 152 of their male partners , and a control group of 56 fertile couples . We investigated mutations including FV Leiden , factor V H1299R , factor II prothrombin G20210A , F XIII V34L , beta-fibrinogen - 455G > A , plasminogen activator inhibitor - 1 , P05106 L33P ( Q9Y251 - 1 a / b L33P ) , P42898 C677T , P42898 A1298C , P12821 I / D , Apo B R3500Q , and Apo E . RESULTS : Overall , heterozygous mutations of FV Leiden , FXIII V34L , P05106 L33P , Apo E4 , and prothrombin G20210A and homozygous mutations of P05121 - 1and P42898 C677T were associated with RPL . There was no meaningful association between RPL and other studied genes . CONCLUSION : In contrast to the other mutations and polymorphisms , FV Leiden , FXIII V34L , P05106 L33P , Apo E , prothrombin G20210A , P05121 and P42898 C677T gene mutations may help to identify the couples at risk for recurrent pregnancy loss .