interacts_with DB01197?
Counteraction between angiotensin II and angiotensin-(1-7) via activating angiotensin type I and Mas receptor on rat renal mesangial cells . In the updated concept of renin-angiotensin system ( DB01367 ) , it contains the angiotensin converting enzyme ( P12821 ) -angiotensin ( Ang ) II-angtiogensin type 1 receptor ( AT1 ) axis and the angiotensin-converting enzyme-related carboxypeptidase ( Q9BYF1 ) -Ang-(1-7)-Mas axis . The former axis has been well demonstrated performing the vasoconstrictive , proliferative and pro-inflammatory functions by activation of AT1 receptors , while the later new identified axis is considered counterbalancing the effects of the former . The present study is aimed at observing the interaction between Ang-(1-7) and Ang II on cultured rat renal mesangial cells ( MCs ) . RT-PCR , Western blot and immunofluorescent staining and confocal microscopy results showed that both AT1 and Mas receptor were co-distributed in rat renal MCs . Ang-(1-7) showed similar effects on Ang II in cultured MCs that stimulated phosphorylated extracellular signal-regulated kinase ( P29323 )1/2 phosphorylation and transforms growth factor-β1 synthesis , and cell proliferation and extracellular matrix synthesis . Co-treatment of the cell with Ang-(1-7) and Ang II , Ang-(1-7) counteracted AngII-induced effects in a concentration dependent manner , but failed to alter the changes induced by endothelin-1 . The stimulating effect of Ang II was mediated by AT1 receptor while all the effects of Ang-(1-7) were blocked by Mas receptor antagonist A-779 , but not by AT1 receptor antagonist losartan or P50052 receptor antagonist PD123319 . These results suggest that Ang-(1-7) and Ang II specifically interact with each other on rat renal MCs via activation of their specific receptors , Mas and AT1 receptor respectively . 5-hydroxytryptamine2C receptor activation inhibits 5-hydroxytryptamine1B-like receptor function via arachidonic acid metabolism . We previously reported that in Chinese hamster ovary ( CHO ) cells , 5-hydroxytryptamine (5-HT)1B-like ( CHO/ P28222 ) receptor-mediated inhibition of forskolin-stimulated DB02527 accumulation is inhibited by activation of transfected human P28335 receptors but not 5- Q13049 receptors . In the current study , we investigated the mechanism involved in the regulation of receptor-mediated inhibition of adenylyl cyclase as a means to further elucidate differences between the signal transduction cascades of the 5- Q13049 and P28335 receptor subtypes . Activation of P28335 receptors with 5-HT or (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane increased release of arachidonic acid via a phospholipase A2 ( P04054 ) -dependent mechanism . Incubation with (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane ( 1 microM ) abolished 5-carboxamidotryptamine ( 5 nM ) -mediated inhibition of forskolin-stimulated DB02527 accumulation , which was blocked by the P04054 inhibitor mepacrine ( 100 microM ) and the cyclooxygenase inhibitor indomethacin ( 2 microM ) . Furthermore , purinergic receptor-mediated P04054 activation as well as direct activation of P04054 with melittin reduced CHO/ P28222 responsiveness . These data indicate that activation of the P04054 /arachidonic acid signaling cascade mediates P28335 receptor regulation of the CHO/ P28222 receptor pathway . Consistent with our previous report and in contrast to activation of P28335 or purinergic receptors , activation of 5- Q13049 receptors had no effect on CHO/ P28222 receptor function , although 5- Q13049 receptor-mediated activation of P04054 was measured . Interestingly , purinergic receptor-mediated inhibition of CHO/ P28222 receptor function was blocked when 5- Q13049 receptors were activated simultaneously . These data suggest that the lack of 5- Q13049 mediated regulation of CHO/ P28222 receptors may be due to activation of a third pathway ( in addition to P98160 and P04054 pathways ) , which results in the inhibition of the production or the actions of a cyclooxygenase-dependent arachidonic acid metabolite . DB01197 reduced plasminogen activator inhibitor activity in patients with acute myocardial infarction . Recent clinical trials have demonstrated that the administration of angiotensin-converting enzyme ( P12821 ) inhibitors to patients with myocardial infarction reduces the incidence of recurrent myocardial infarction . It has also been reported that an elevated level of plasminogen activator inhibitor ( P05121 ) appears to constitute a marker of the risk of recurrent coronary thrombosis . To determine whether the P12821 inhibitor captopril reduces plasma P05121 inhibitor activity , we measured changes in plasma P05121 activity ( IU/ml ) , tissue plasminogen activator ( t-PA ) antigen ( ng/ml ) , and serum P12821 activity ( IU/L ) in 14 survivors of myocardial infarction receiving captopril therapy ( 37.5 mg daily ) and compared them with the values in 15 placebo-treated patients chosen at random . Blood sampling was performed at 07.00 h . In the captopril-treated group , serum P12821 activity decreased significantly , from 14.0 +/- 0.8 to 11.5 +/- 1.2 IU/L 24 h after captopril therapy ( p < 0.01 ) , and those of P05121 activity and t-PA antigen also decreased significantly-from 11.9 +/- 2.8 to 5.5 +/- 2.2 IU/ml ( p < 0.02 ) and from 9.9 +/- 1.0 to 7.5 +/- 0.9 ng/ml ( p < 0.05 ) , respectively 48 h after captopril therapy . However , the levels of P12821 activity , P05121 activity , and t-PA antigen remained unchanged during the study period in the placebo group . Thus , our data indicate that the administration of captopril to patients with acute myocardial infarction may result in a reduced frequency of recurrent coronary thrombosis by increasing fibrinolytic capacity . Reduction of heart failure by pharmacological inhibition or gene deletion of protein tyrosine phosphatase 1B . Protein tyrosine phosphatase 1B ( P18031 ) regulates tyrosine kinase receptor-mediated responses , and especially negatively influences insulin sensitivity , thus P18031 inhibitors ( PTP1Bi ) are currently evaluated in the context of diabetes . We recently revealed another important target for PTP1Bi , consisting in endothelial protection . The present study was designed to test whether reduction of P18031 activity may be beneficial in chronic heart failure ( CHF ) . We evaluated the impact of either a 2 month pharmacological inhibition , or a gene deletion of P18031 ( P18031 (-/-) ) in CHF mice ( 2 months post-myocardial infarction ) . PTP1Bi and P18031 deficiency reduced adverse LV remodeling , and improved LV function , as shown by the increased LV fractional shortening and cardiac output ( measured by echocardiography ) , the increased LV end systolic pressure , and the decreased LV end diastolic pressure , at identical infarct sizes . This was accompanied by reduced cardiac fibrosis , myocyte hypertrophy and cardiac expression of P01160 . In vitro vascular studies performed in small mesenteric artery segments showed a restored endothelial function ( i.e. improved NO-dependent , flow-mediated dilatation , increased P29474 phosphorylation ) after either pharmacological inhibition or gene deletion . P18031 (-/-) CHF also displayed an improved insulin sensitivity ( assessed by euglycemic-hyperinsulinemic clamp studies ) , when compared to wild-type CHF associated with an increased insulin mediated mesenteric artery dilation . Thus , chronic pharmacological inhibition or gene deletion of P18031 improves cardiac dysfunction and cardiac remodeling in the absence of changes in infarct size . Thus this enzyme may be a new therapeutic target in CHF . Diabetic patients with cardiac complications may potentially benefit from P18031 inhibition via two different mechanisms , reduced diabetic complications , and reduced heart failure . DB08888 for vitreoretinal diseases . P02751 and laminin are clinically relevant plasmin receptors in the eye . Located at the vitreoretinal interface , they are cleaved by ocriplasmin ( DB05028 , ThromboGenics , Iselin , NJ ) , a novel ophthalmic medication . A series of clinical trials to study ocriplasmin for the treatment of vitreoretinal diseases such as vitreomacular traction , macular hole , and exudative age-related macular degeneration are underway . The results are promising and may impact patient care . No significant association between genetic variants in 7 candidate genes and response to methylphenidate treatment in adult patients with ADHD . Results from pharmacogenetic investigations of methylphenidate ( DB00422 ) response in patients with ADHD are still inconsistent , especially among adults . This study investigates the role of genetic variants ( P31645 , P28222 , Q8IWU9 , P09172 , P21917 , P21964 , and P60880 ) in the response to DB00422 in a sample of 164 adults . Genes were chosen owing to previous evidence for an influence in ADHD susceptibility . No significant differences in allele or genotype frequencies between DB00422 responders and nonresponders were detected . In conclusion , our findings do not support an effect of these genes in the pharmacogenetics of DB00422 among adults with ADHD . [ The effect of bunazosin vs captopril on hemodynamic and neurohumoral parameters in patients with congestive heart failure ] . The hemodynamic parameters ( right atrial pressure , mean pulmonary artery pressure , pulmonary capillary wedge pressure , cardiac index , heart rate , blood pressure ) and neurohumoral responses ( alpha- P01160 , plasma renin activity , aldosterone , angiotensin II ) of DB01197 , oral P12821 inhibitor , and Bunazosin , oral alpha 1-blocker , were investigated in 28 patients with congestive heart failure at rest and after exercise . These data were analysed in both acute and chronic phases . 1 ) Acute effect . DB01197 produced significant improvement of neurohumoral factors at rest and also after exercise . Bunazosin reduced alpha- P01160 , but other neurohumoral factors did not change . Bunazosin produced significant hemodynamic improvement both at rest and after exercise . 2 ) Chronic effect . DB01197 produced significant hemodynamic improvement both at rest and after exercise . Improvement of neurohumoral factors in acute phase was also preserved at chronic phase . On Bunazosin , improvement of hemodynamics at acute phase was also preserved at chronic phase without deterioration of neurohumoral factors . Role of microRNA 1207-5P and its host gene , the long non-coding RNA Pvt1 , as mediators of extracellular matrix accumulation in the kidney : implications for diabetic nephropathy . Diabetic nephropathy is the most common cause of chronic kidney failure and end-stage renal disease in the Western World . One of the major characteristics of this disease is the excessive accumulation of extracellular matrix ( Q13201 ) in the kidney glomeruli . While both environmental and genetic determinants are recognized for their role in the development of diabetic nephropathy , epigenetic factors , such as DNA methylation , long non-coding RNAs , and microRNAs , have also recently been found to underlie some of the biological mechanisms , including Q13201 accumulation , leading to the disease . We previously found that a long non-coding RNA , the plasmacytoma variant translocation 1 ( PVT1 ) , increases plasminogen activator inhibitor 1 ( P05121 ) and transforming growth factor beta 1 ( TGF-β1 ) in mesangial cells , the two main contributors to Q13201 accumulation in the glomeruli under hyperglycemic conditions , as well as fibronectin 1 ( P02751 ) , a major Q13201 component . Here , we report that miR-1207-5p , a PVT1-derived microRNA , is abundantly expressed in kidney cells , and is upregulated by glucose and TGF-β1 . We also found that like PVT1 , miR-1207-5p increases expression of TGF-β1 , P05121 , and P02751 but in a manner that is independent of its host gene . In addition , regulation of miR-1207-5p expression by glucose and TGFβ1 is independent of PVT1 . These results provide evidence supporting important roles for miR-1207-5p and its host gene in the complex pathogenesis of diabetic nephropathy . 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 . Antithymocyte globulins suppress dendritic cell function by multiple mechanisms . BACKGROUND : The polyclonal rabbit antithymocyte and anti-T-cell immunoglobulins ( ATGs ) DB00098 ( TG ) and DB05320 ( ATG-F ) have been widely used for the prevention and therapy of allograft rejection and graft versus host disease in transplantation . Although immunosuppressive mechanisms of ATGs on T cells are well studied , less is known about their impact on dendritic cells ( DCs ) . METHODS : Effects of TG and ATG-F on immune functions and signaling pathways of human monocyte-derived DCs were determined by flow cytometry , enzyme-linked immunosorbent assay , Western blot , apoptosis assays , endocytosis assays , and T cell stimulation assays . RESULTS : TG and ATG-F bind rapidly and with high affinity to CD11c , P33681 , P42081 , P25942 , P16671 , P28907 , CD206 , and human leukocyte antigen-DR on DCs . TG and , to a lesser extent , ATG-F induce apoptosis in immature and mature DCs . Macropinocytotic and receptor-mediated endocytotic antigen uptake in immature DCs is inhibited by TG and ATG-F due to their binding of the C-type lectins CD206 and Q9NNX6 . TG and ATG-F induce activation of the mitogen-activated protein kinases P27361 /2 and p38 that contributes to the induction of apoptosis . TG and ATG-F also induce cytoplasmic-nuclear translocation of the NF-kappaB/Rel transcription factors RelB , RelA , p50 , and p52 . Production of interleukin-12p70 in mature DCs is suppressed by TG and ATG-F . TG and ATG-F reduce the capacity of mature DCs to stimulate allogeneic and autologous T cells . CONCLUSIONS : ATGs interfere with basic DC functions , suggesting that DCs are relevant targets for the immunosuppressive action of ATGs in transplantation . DB06096 , a selective P29475 inhibitor and a P28222 /1D receptor agonist , inhibits P80511 release in preclinical migraine models . BACKGROUND : DB06096 is a combined neuronal nitric oxide synthase ( P29475 ) inhibitor and 5-hydroxytryptamine 1B/1D ( P28222 /1D ) receptor agonist . Using preclinical models , we evaluated whether these two unique therapeutic principles have a synergistic effect in attenuating stimulated calcitonin gene-related peptide ( P80511 ) release , a marker of trigeminal activation . METHODS : We examined the effect of DB06096 on : ( 1 ) DB00761 - , capsaicin- and resiniferatoxin ( RTX ) -induced immunoreactive P80511 ( iCGRP ) release from isolated preparation of rat dura mater , trigeminal ganglion ( TG ) and trigeminal nucleus caudalis ( P24821 ) ; and ( 2 ) capsaicin- and electrical stimulation ( ES ) -induced middle meningeal artery ( MMA ) dilation in a rat closed-cranial window . RESULTS : DB06096 inhibited : ( 1 ) DB00761 -stimulated iCGRP release from dura mater ( % decrease mean ± SEM , lowest effective concentration ) ( 35 ± 6 % , 30 µM ) , TG ( 24 ± 11 % , 10 µM ) and P24821 ( 40 ± 8 % , 10 µM ) ; ( 2 ) capsaicin- and RTX-induced iCGRP release from dura mater ; and ( 3 ) capsaicin- and ES-induced increase in dural artery diameter ( 32 ± 5 % , 3 mg kg(-1) intravenous ( i.v. ) and 36 ± 1 % , 10 mg kg(-1) i.v. ) . CONCLUSIONS : DB06096 inhibits P80511 release from migraine-relevant cephalic tissues . Its effect is most likely mediated via a combination of P29475 -inhibition and P28222 /1D receptor agonism in dura mater while the mechanisms of action for inhibition of P80511 release from TG and P24821 have to be investigated further . Oral administration of an angiotensin-converting enzyme 2 activator ameliorates diabetes-induced cardiac dysfunction . We evaluated the hypothesis that activation of endogenous angiotensin-converting enzyme ( P12821 ) 2 would improve cardiac dysfunction induced by diabetes . Ten days after diabetes induction ( streptozotocin , 50 mg/kg , i.v. ) , male Wistar rats were treated with the Q9BYF1 activator 1-[[2-(dimethylamino)ethyl]amino]-4-(hydroxymethyl)-7-[[(4-methylphenyl)sulfonyl]oxy]-9H-xanthen-9-one ( XNT , 1 mg/kg/day , gavage ) or saline ( control ) for 30 days . Echocardiography was performed to analyze the cardiac function and kinetic fluorogenic assays were used to determine cardiac P12821 and Q9BYF1 activities . Cardiac Q9BYF1 , P12821 , Mas receptor , AT(1) receptor , AT(2) receptor and collagen types I and III mRNA and Q9BYF1 , P12821 , Mas , AT(1) receptor , AT(2) receptor , P27361 /2 , Akt , AMPK-α and AMPK-β(1) protein were measured by qRT-PCR and western blotting techniques , respectively . Histological sections of hearts were analyzed to evaluate the presence of hypertrophy and fibrosis . Diabetic animals presented hyperglycemia and diastolic dysfunction along with cardiac hypertrophy and fibrosis . XNT treatment prevented further increase in glycemia and improved the cardiac function , as well as the hypertrophy and fibrosis . These effects were associated with increases in cardiac Q9BYF1 / P12821 ratios ( activity : ~26 % ; mRNA : ~113 % ; and protein : ~188 % ) and with a decrease in AT(1) receptor expression . Additionally , XNT inhibited P27361 /2 phosphorylation and prevented changes in AMPK-α and AMPK-β(1) expressions . XNT treatment did not induce any significant change in AT(2) receptor and Akt expression . These results indicate that activation of intrinsic cardiac Q9BYF1 by oral XNT treatment protects the heart against diabetes-induced dysfunction through mechanisms involving P12821 , Q9BYF1 , P27361 /2 , AMPK-α and AMPK-β(1) modulations . Serotonin skews human macrophage polarization through P41595 and P34969 . Besides its role as a neurotransmitter , serotonin ( 5-hydroxytryptamine , 5HT ) regulates inflammation and tissue repair via a set of receptors ( 5HT(1-7) ) whose pattern of expression varies among cell lineages . Considering the importance of macrophage polarization plasticity for inflammatory responses and tissue repair , we evaluated whether 5HT modulates human macrophage polarization . 5HT inhibited the LPS-induced release of proinflammatory cytokines without affecting P22301 production , upregulated the expression of M2 polarization-associated genes ( P05120 , P07996 , Q9NY15 , Q86Y22 ) , and reduced the expression of M1-associated genes ( P08476 , P41597 , P39900 , P05121 , P29016 , O94788 ) . Whereas only 5HT(7) mediated the inhibitory action of 5HT on the release of proinflammatory cytokines , both 5HT(2B) and 5HT(7) receptors mediated the pro-M2 skewing effect of 5HT . In fact , blockade of both receptors during in vitro monocyte-to-macrophage differentiation preferentially modulated the acquisition of M2 polarization markers . 5HT(2B) was found to be preferentially expressed by anti-inflammatory M2( P09603 ) macrophages and was detected in vivo in liver Kupffer cells and in tumor-associated macrophages . Therefore , 5HT modulates macrophage polarization and contributes to the maintenance of an anti-inflammatory state via 5HT(2B) and 5HT(7) , whose identification as functionally relevant markers for anti-inflammatory/homeostatic human M2 macrophages suggests their potential therapeutic value in inflammatory pathologies . DB00674 ameliorates the impairment of recognition memory in mice repeatedly treated with methamphetamine : involvement of allosteric potentiation of nicotinic acetylcholine receptors and dopaminergic- P27361 /2 systems . DB00674 , a drug used to treat Alzheimer 's disease , inhibits acetylcholinesterase ( P22303 ) and allosterically modulates nicotinic acetylcholine receptors ( nAChRs ) resulting in stimulation of catecholamine neurotransmission . In this study , we investigated whether galantamine exerts cognitive-improving effects through the allosteric modulation of nAChRs in an animal model of methamphetamine ( Meth ) psychosis . The mice treated with Meth ( 1 mg/kg.d ) for 7 d showed memory impairment in a novel object recognition test . DB00674 ( 3 mg/kg ) ameliorated the memory impairment , and it increased the extracellular dopamine release in the prefrontal cortex ( P27918 ) of Meth-treated mice . Donepezil , an P22303 inhibitor ( 1 mg/kg ) increased the extracellular ACh release in the P27918 , whereas it had no effect on the memory impairment in Meth-treated mice . The nAChR antagonist , mecamylamine , and dopamine D1 receptor antagonist , P35240 23390 , blocked the ameliorating effect of galantamine on Meth-induced memory impairment , whereas the muscarinic AChR antagonist , scopolamine , had no effect . The effects of galantamine on extracellular dopamine release were also antagonized by mecamylamine . DB00674 attenuated the defect of the novelty-induced activation of extracellular signal-regulated kinase 1/2 ( P27361 /2 ) . The ameliorating effect of galantamine on recognition memory in Meth-treated mice was negated by microinjection of an P29323 inhibitor , PD98059 , into the P27918 . These results suggest that the ameliorating effect of galantamine on Meth-induced memory impairment is associated with indirect activation of dopamine D1 receptor- P27361 /2 following augmentation with dopaminergic neurotransmission in the P27918 through the allosteric activation of nAChRs . DB00674 could be a useful therapeutic agent for treating cognitive deficits in schizophrenia/Meth psychosis , as well as Alzheimer 's disease . Pancreatic gene expression during the initiation of acute pancreatitis : identification of P18146 as a key regulator . We hypothesized that genes expressed in pancreatic acinar cells during the initiation of acute pancreatitis determine the severity of the disease . Therefore , we utilized microarrays to identify those genes commonly induced in rat pancreatic acinar cells within 1-4 h in two in vivo models , caerulein and taurocholate administration . This strategy yielded 51 known genes representing a complex array of molecules , including those that are likely to either reduce or increase the severity of the disease . Novel genes identified in the current study included P18847 , BRF1 , C/EBPbeta , P80511 , P18146 , ephrinA1 , villin2 , ferredoxin , latexin , lipocalin , P28562 , NGFI-B , RhoA , tissue factor ( TF ) , and syndecan . To validate these microarray results , the role of P18146 was further investigated using quantitative RT-PCR , Western blotting , and immunocytochemistry . P18146 expression occurred within acinar cells and correlated with the development of caerulein-induced acute pancreatitis in rats . Furthermore , the levels of the inflammation-related genes P13500 , P05121 , TF , P05231 , and P05362 and the extent of lung inflammation were reduced during the initiation of caerulein-induced acute pancreatitis in P18146 -deficient mice . Thus this study identified P18146 and several other novel genes likely to be important in the development and severity of acute pancreatitis . Mechanism of oral absorbent DB05269 in lipid abnormalities in experimental uremic rats . BACKGROUND : We have reported that oral sorbent DB05269 ( Q9NRA2 ) is effective in delaying the induction of dialysis in patients with chronic renal failure ( CRF ) because of its effect on lipid metabolism . To clarify the precise mechanism of Q9NRA2 in lipid abnormalities in CRF , we examined the effect of Q9NRA2 on plasma lipid profile , total bile acids ( TBA ) , and lipoprotein lipase ( P06858 ) activity in experimental uremic rats . METHODS : Uremic rats were prepared using male Wistar rats by ligating 5/6 of the renal artery . Uremic rats were randomly divided into two groups as follows : a control group in which rats were maintained on the standard diet and an Q9NRA2 group in which rats were maintained on a diet containing 5 g of Q9NRA2 per 100 g of standard diet for 10 weeks . Plasma P06858 activity was measured as free fatty acid ( FFA ) generation after intravenous administration of heparin . RESULTS : Plasma creatinine at 1.5 +/- 0.1 mg/dl was lower in the Q9NRA2 group than the 1.9 +/- 0.5 mg/ml level in the control group . Q9NRA2 significantly decreased plasma total cholesterol from 192 +/- 29 to 142 +/- 25 mg/dl , triglycerides from 198 +/- 71 to 99 +/- 38 mg/dl , and TBA from 19.6 +/- 2.6 mumol/liter to 8.8 +/- 3.5 mumol/ml . Plasma P06858 activity at 0.22 +/- 0.01 mumol FFA/min/hr was significantly higher in the Q9NRA2 group than 0.15 +/- 0.03 mumol FFA/min/hr in the control group . CONCLUSIONS : These results suggest that Q9NRA2 may improve plasma lipid abnormalities by binding to bile acids in the intestinal lumen and preventing their reabsorption and inhibiting the reduction of P06858 activity in experimental uremic rats . Synthesis of oleanolic acid derivatives : In vitro , in vivo and in silico studies for P18031 inhibition . Non-insulin dependent diabetes mellitus is a multifactorial disease that links different metabolic routes ; a point of convergence is the enzyme P18031 which turns off insulin and leptin receptors involved in glucose and lipid metabolism , respectively . Pentacyclic acid triterpenes such as oleanolic acid ( OA ) have proved to be excellent P18031 inhibitors , thus , the purpose of current work was to generate a series of derivatives that improve the pharmacological effect of OA . Our findings suggest that the presence of the carboxylic acid and/or its corresponding reduction product carbinol derivative ( H-bond donor ) in C-28 is required to maintain the inhibitory activity ; moreover , this is further enhanced by ester or ether formation on C-3 . The most active derivatives were cinnamoyl ester ( 6 ) and ethyl ether ( 10 ) . DB04088 showed potent in vitro inhibitory activity and significantly decrease of blood glucose levels on in vivo experiments . Meanwhile , 10 showed contrasting outcomes , since it was the compound with higher inhibitory activity and selectivity over P18031 and has improved interaction with site B , according with docking studies , the in vivo antidiabetic effect was similar to oleanolic acid . In conclusion , oleanolic acid derivatives have revealed an enhanced inhibitory effect over P18031 activity by increasing molecular interactions with either catalytic or allosteric sites and producing a hypoglycaemic effect on non insulin dependent diabetes mellitus rat model . Discovery of DB05130 , a Potent , Selective , and Orally Bioavailable hCCR2 Antagonist . We report the identification of 13 ( DB05130 ) as a potent human P41597 ( hCCR2 ) antagonist . DB05130 exhibited an IC50 of 3.7 nM in antagonism of monocyte chemoattractant protein-1 binding to hCCR2 , an IC50 of 4.7 nM in antagonism of chemotaxis activity , an IC50 of 84 μM in inhibition of the hERG potassium current , a free fraction of 58 % in protein binding , high selectivity over other chemokine receptors and G-protein-coupled receptors , and acceptable oral bioavailability in rodents and primates . In human clinical trials , DB05130 exhibited a pharmacokinetic profile suitable for once-a-day dosing ( T 1/2 = 15 h ) . Synergistic inhibition of angiogenesis by artesunate and captopril in vitro and in vivo . Inhibition of angiogenesis represents one major strategy of cancer chemotherapy . In the present investigation , we investigated the synergism of artesunate and captopril to inhibit angiogenesis . DB09274 is an antimalarial derivative of artemisinin from the Chinese medicinal plant , Artemisia annua L. , which also reveals profound anticancer activity in vitro and in vivo . DB01197 is an angiotensin I-converting ( P12821 ) inhibitor , which is well established in Western academic medicine . Both compounds inhibited migration of human umbilical vein endothelial cells ( HUVECs ) in vitro . The combination of both drugs resulted in synergistically inhibited migration . Whereas artesunate inhibited HUVEC growth in the XTT assay , captopril did not , indicating independent modes of action . We established a chorioallantoic membrane ( P62158 ) assay of quail embryos ( Coturnix coturnix L. ) and a computer-based evaluation routine for quantitative studies on vascularization processes in vivo . DB09274 and captopril inhibited blood vessel formation and growth . For the first time , we demonstrated that both drugs revealed synergistic effects when combined . These results may also have clinical impact , since cardiovascular diseases and cancer frequently occur together in older cancer patients . Therefore , comorbid patients may take advantage , if they take captopril to treat cardiovascular symptoms and artesunate to treat cancer . [ Quality of life and psychosocial factors during treatment with antihypertensive drugs. A comparison of captopril and quinapril in geriatric patients ] . BACKGROUND : There is an increasing prevalence of older adults ( > 65 years ) with hypertension and the need for antihypertensive medication . It is well established that elderly hypertensive patients benefit from drug treatment with regards to cardiovascular morbidity and mortality . Due to the comorbidity and reduced quality of life ( QOL ) in the elderly , drug-induced changes of well-being and QOL are especially important to maintain compliance and social abilities . Whereas in most studies different antihypertensive agents exerted similar influences on QOL , DB01197 was found to be superior to other antihypertensives in some trials . PATIENTS AND METHOD : In this controlled non-randomized study 100 elderly hypertensive patients ( mean age 75.4 +/- 7.2 years ; 56 % female ) were treated with DB01197 ( 25-50 mg twice daily ) or the newer P12821 -inhibitor Quinapril ( 5-20 mg per day ) . Blood pressure and QOL were recorded initially and after 6 months , assessment of QOL was based on a validated questionnaire ( P98160 ) . RESULTS : Blood pressure fell from 153/82 mm Hg to 142/80 mm Hg with DB01197 and 154/82 to 142/80 mm Hg [ corrected ] with Quinapril . An improvement of QOL was only seen with Quinapril , mainly due to better mood and lower depression scores . Analysis of underlying psychosocial factors on QOL found lack of social support , female sex and a current life event as additional significant negative influences on QOL . CONCLUSION : A favorable antidepressive effect of Quinapril in elderly hypertensive patients is concluded and should be studied in further investigations . [ The effect of blood pressure-reducing therapy with captopril on tubular marker excretion in type-1 diabetics with nephropathy ] . A prospective open clinical trial was carried out with 23 hypertensive type I diabetics ( 13 men , ten women , mean age 49 +/- 9.1 years , duration of diabetes 18 +/- 9.1 years ) with early nephropathy . Glomerular and tubular renal function and metabolic parameters were monitored during 8 months ' treatment with the angiotensin converting enzyme ( P12821 ) inhibitor , captopril , in addition to previous antihypertensive treatment with one or more drugs . Blood pressure control tended to improve on captopril ( systolic pressures 152 +/- 13 vs 140 +/- 13 mm Hg , P < 0.05 ; diastolic pressures 89 +/- 10 vs 87 +/- 10 mm Hg , not significant ) . Proteinuria ( > 0.5 g/24 hours ) fell into the microalbuminuria range ( albumin excretion 2-20 mg/mmol creatinine ) in four out of 13 patients , and microalbuminuria disappeared in four out of ten patients . Urinary levels of the brush border enzyme O60502 ( NAG ) , a marker of tubular dysfunction , were initially raised and fell significantly after 8 months ' treatment with captopril ( 20.3 +/- 14.4 vs 8.8 +/- 8.1 U/g creatinine ; P < 0.01 ) . DB01197 did not affect metabolic control ( HbA1 , total , HDL and LDL cholesterol , triglycerides , apolipoproteins A1 and B ) or the insulin dosage . These results show that long-term treatment with captopril may favourably influence both albumin excretion and NAG activity , a marker of tubular dysfunction , in type I diabetics with nephropathy . Genetic variants in pre-eclampsia : a meta-analysis . BACKGROUND Pre-eclampsia has a clear familial component , suggesting that the condition may be partly attributable to genetic susceptibility . The search for susceptibility genes has led to a drastic increase in the number of published studies associating genetic factors with pre-eclampsia . However , attempts to replicate these findings have yielded inconsistent results . This meta-analysis assessed the pooled effect of each genetic variant that is reproducibly associated with pre-eclampsia . METHODS Studies that assessed the association between genes and pre-eclampsia were searched in PubMed , Embase and Web of Science . We selected all genetic variants that were significantly associated with pre-eclampsia in an initial study and were subsequently independently reproduced in at least one additional study . All studies that assessed these reproduced variants were then included . The association between genetic variants and pre-eclampsia was calculated at the allele level , and the main measure of effect was a pooled odds ratio in a random-effects model . RESULTS The literature search yielded 2965 articles , of which 542 investigated genetic associations in pre-eclampsia . We identified 22 replicated genetic variants , of which 7 remained significantly associated with pre-eclampsia following meta-analysis . These variants were in or near the following genes : P12821 , P16410 , F2 , FV , P06858 and P05121 . CONCLUSIONS This meta-analysis identified seven genetic variants associated with pre-eclampsia . Importantly , many of these variants are also risk factors for developing cardiovascular disease , revealing that pre-eclampsia and cardiovascular disease have shared genetic risk factors . The contribution of the identified genetic variants in the pathogenesis of pre-eclampsia should be the focus of future studies .