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Sample records for ace inhibitors improve

  1. [ACE inhibitors and the kidney].

    PubMed

    Hörl, W H

    1996-01-01

    Treatment with ACE inhibitors results in kidney protection due to reduction of systemic blood pressure, intraglomerular pressure, an antiproliferative effect, reduction of proteinuria and a lipid-lowering effect in proteinuric patients (secondary due to reduction of protein excretion). Elderly patients with diabetes melitus, coronary heart disease or peripheral vascular occlusion are at risk for deterioration of kidney function due to a high frequency of renal artery stenosis in these patients. In patients with renal insufficiency dose reduction of ACE inhibitors is necessary (exception: fosinopril) but more important is the risk for development of hyperkalemia. Patients at risk for renal artery stenosis and patients pretreated with diuretics should receive a low ACE inhibitor dosage initially ("start low - go slow"). For compliance reasons once daily ACE inhibitor dosage is recommended.

  2. Do ACE Inhibitors Improve the Response to Exercise Training in Functionally Impaired Older Adults? A Randomized Controlled Trial

    PubMed Central

    Band, Margaret; Miller, Suzanne; Cvoro, Vera; Witham, Miles; Struthers, Allan; McConnachie, Alex; Lloyd, Suzanne M.; McMurdo, Marion

    2014-01-01

    Background. Loss of muscle mass and strength with ageing is a major cause for falls, disability, and morbidity in older people. Previous studies have found that angiotensin-converting enzyme inhibitors (ACEi) may improve physical function in older people. It is unclear whether ACEi provide additional benefit when added to a standard exercise training program. We examined the effects of ACEi therapy on physical function in older people undergoing exercise training. Methods. Community-dwelling people aged ≥65 years with functional impairment were recruited through general (family) practices. All participants received progressive exercise training. Participants were randomized to receive either 4 mg perindopril or matching placebo daily for 20 weeks. The primary outcome was between-group change in 6-minute walk distance from baseline to 20 weeks. Secondary outcomes included changes in Short Physical Performance Battery, handgrip and quadriceps strength, self-reported quality of life using the EQ-5D, and functional impairment measured using the Functional Limitations Profile. Results. A total of 170 participants (n = 86 perindopril, n = 84 placebo) were randomized. Mean age was 75.7 (standard deviation [SD] 6.8) years. Baseline 6-minute walk distance was 306 m (SD 99). Both groups increased their walk distance (by 29.6 m perindopril, 36.4 m placebo group) at 20 weeks, but there was no statistically significant treatment effect between groups (−8.6m [95% confidence interval: −30.1, 12.9], p = .43). No statistically significant treatment effects were observed between groups for the secondary outcomes. Adverse events leading to withdrawal were few (n = 0 perindopril, n = 4 placebo). Interpretation. ACE inhibitors did not enhance the effect of exercise training on physical function in functionally impaired older people. PMID:24201696

  3. Angiotensin-converting enzyme (ACE) dimerization is the initial step in the ACE inhibitor-induced ACE signaling cascade in endothelial cells.

    PubMed

    Kohlstedt, Karin; Gershome, Cynthia; Friedrich, Matthias; Müller-Esterl, Werner; Alhenc-Gelas, François; Busse, Rudi; Fleming, Ingrid

    2006-05-01

    The binding of angiotensin-converting enzyme (ACE) inhibitors to ACE initiates a signaling cascade that involves the phosphorylation of the enzyme on Ser1270 as well as activation of the c-Jun NH2-terminal kinase (JNK) and leads to alterations in gene expression. To clarify how ACE inhibitors activate this pathway, we determined their effect on the ability of the enzyme to dimerize and the role of ACE dimerization in the initiation of the ACE signaling cascade. In endothelial cells, ACE was detected as a monomer as well as a dimer in native gel electrophoresis and dimerization/oligomerization was confirmed using the split-ubiquitin assay in yeast. ACE inhibitors elicited a rapid, concentration-dependent increase in the dimer/monomer ratio that correlated with that of the ACE inhibitorinduced phosphorylation of ACE. Cell treatment with galactose and glucose to prevent the putative lectin-mediated self-association of ACE or with specific antibodies shielding the N terminus of ACE failed to affect either the basal or the ACE inhibitor-induced dimerization of the enzyme. In ACE-expressing Chinese hamster ovary cells, ACE inhibitors elicited ACE dimerization and phosphorylation as well as the activation of JNK with similar kinetics to those observed in endothelial cells. However, these effects were prevented by the mutation of the essential Zn2+-complexing histidines in the C-terminal active site of the enzyme. Mutation of the N-terminal active site of ACE was without effect. Together, our data suggest that ACE inhibitors can initiate the ACE signaling pathway by inducing ACE dimerization, most probably via the C-terminal active site of the enzyme.

  4. Cromolyn sodium for ACE inhibitor-induced cough.

    PubMed

    Allen, T L; Gora-Harper, M L

    1997-06-01

    There are several theories on the cause of ACE inhibitor-induced cough, but the exact mechanism is not known. In many patients, if cough develops, the ACE inhibitor can be discontinued and a drug in another therapeutic class used in its place. However, in patients with CHF, diabetic nephropathy, and patients who have experienced a myocardial infarction, discontinuing the ACE inhibitor may not be in the best interest of the patient. In this patient population it would be reasonable to try cromolyn sodium to treat cough, while continuing the ACE inhibitor. Data are not available to support the efficacy of cromolyn sodium to treat cough in patients with diabetic nephropathy, but these patients clearly benefit from the use of an ACE inhibitor. Other factors not addressed in the case reports and the clinical trial such as patient adherence, cost, and quality of life should also play a role in the decision to use cromolyn sodium. Cromolyn sodium has been effective for the treatment of ACE inhibitor-induced cough in many case reports and has had mild success in one small clinical trial. Although none of the reports adequately assessed adverse effects, studies examining cromolyn for other indications have demonstrated a relatively benign adverse effect profile. It is difficult to recommend an exact dose to use because of the dosing variability in the case reports. The majority of the case reports and the one clinical trial used dosages similar to recommendations for bronchial asthma (i.e., 2 puffs [1.6 mg] 4 times daily via MDI or 20-mg capsules 4 times daily via breath-activated inhalation). At this time, the use of cromolyn sodium is a viable option, but more controlled studies are needed to fully elucidate its role in the treatment of ACE inhibitor-induced cough.

  5. Human intestine luminal ACE2 and amino acid transporter expression increased by ACE-inhibitors.

    PubMed

    Vuille-dit-Bille, Raphael N; Camargo, Simone M; Emmenegger, Luca; Sasse, Tom; Kummer, Eva; Jando, Julia; Hamie, Qeumars M; Meier, Chantal F; Hunziker, Schirin; Forras-Kaufmann, Zsofia; Kuyumcu, Sena; Fox, Mark; Schwizer, Werner; Fried, Michael; Lindenmeyer, Maja; Götze, Oliver; Verrey, François

    2015-04-01

    Sodium-dependent neutral amino acid transporter B(0)AT1 (SLC6A19) and imino acid (proline) transporter SIT1 (SLC6A20) are expressed at the luminal membrane of small intestine enterocytes and proximal tubule kidney cells where they exert key functions for amino acid (re)absorption as documented by their role in Hartnup disorder and iminoglycinuria, respectively. Expression of B(0)AT1 was shown in rodent intestine to depend on the presence of the carboxypeptidase angiotensin-converting enzyme 2 (ACE2). This enzyme belongs to the renin-angiotensin system and its expression is induced by treatment with ACE-inhibitors (ACEIs) or angiotensin II AT1 receptor blockers (ARBs) in many rodent tissues. We show here in the Xenopus laevis oocyte expression system that human ACE2 also functionally interacts with SIT1. To investigate in human intestine the potential effect of ACEIs or ARBs on ACE2, we analysed intestinal biopsies taken during routine gastroduodenoscopy and ileocolonoscopy from 46 patients of which 9 were under ACEI and 13 ARB treatment. Analysis of transcript expression by real-time PCR and of proteins by immunofluorescence showed a co-localization of SIT1 and B(0)AT1 with ACE2 in the brush-border membrane of human small intestine enterocytes and a distinct axial expression pattern of the tested gene products along the intestine. Patients treated with ACEIs displayed in comparison with untreated controls increased intestinal mRNA levels of ACE2, peptide transporter PEPT1 (SLC15A1) and AA transporters B(0)AT1 and PAT1 (SLC36A1). This study unravels in human intestine the localization and distribution of intestinal transporters involved in amino acid absorption and suggests that ACEIs impact on their expression.

  6. ACE

    NASA Technical Reports Server (NTRS)

    Lumia, R.

    1999-01-01

    This document describes the progress made during the fourth year of the Center for Autonomous Control Engineering (ACE). We currently support 30 graduate students, 52 undergraduate students, 9 faculty members, and 4 staff members. Progress will be divided into two categories. The first category explores progress for ACE in general. The second describes the results of each specific project supported within ACE.

  7. [ACE inhibitors from the viewpoint of the clinical pharmacologist].

    PubMed

    Hitzenberger, G

    1996-01-01

    For treatment of hypertension drugs are desirable which exert a 24 hours lasting blood pressure control. Among the ACE-inhibitors some drugs exist which have this action. The elimination pathway plays a minor role in this respect. Not only the inhibition of Angiotensin II generation but also the decreased inhibition of bradykinin-degeneration plays a crucial role with regard to several endothelial functions controlling the so called remodeling of the cardiovascular system.

  8. ACE Inhibitor-Induced Angioedema following Cervical Spine Surgery

    PubMed Central

    Sabbagh, Hussam

    2017-01-01

    Angioedema is a well-known side effect of angiotensin converting enzyme inhibitors (ACEi). However, ACE inhibitors induced angioedema after cervical surgery is a rare condition. They result in increased levels of circulating bradykinins. Rare cases of angioedema following local trauma in patients using ACE inhibitors have been published. We present such a case. A 54-year-old Caucasian female with a history significant for hypertension, controlled with lisinopril, was admitted for routine cervical spine surgery. She has severe degenerative cervical disc disease and was admitted to the hospital for an elective cervical diskectomy. The patient failed weaning off the ventilator on multiple attempts postoperatively. There were no observed symptoms of an allergic reaction. A CT scan of the neck showed extensive soft tissue edema at the level of the arytenoids. Dexamethasone was given to reduce the edema without successful resolution. On review of her medications, it was found that the patient was resumed on lisinopril following the procedure. It was subsequently discontinued. By the following day the patient had a positive leak around the ET tube cuff and patient was successfully extubated. PMID:28348897

  9. Structure of human ACE gives new insights into inhibitor binding and design.

    PubMed

    Brew, Keith

    2003-08-01

    Angiotensin-converting enzyme (ACE) is a primary target of drugs used for controlling hypertension. A new X-ray crystallographic structure of the key catalytic domain of ACE provides detailed information about the structure of its active site, located in a deep channel, and its interactions with an inhibitor. Such information might facilitate the rational design of ACE inhibitors that are more potent and more selective and therefore of clinical use.

  10. Targeting ACE and ECE with dual acting inhibitors.

    PubMed

    Hanessian, Stephen; Guesné, Sébastien; Riber, Ludivine; Marin, Julien; Benoist, Alain; Mennecier, Philippe; Rupin, Alain; Verbeuren, Tony J; De Nanteuil, Guillaume

    2008-02-01

    A series of urea analogues related to SA6817 and a GSK phosphonic acid with reported ACE inhibitory activity were prepared and tested for dual ACE and ECE activities. Although excellent ACE and NEP inhibition was achieved, only modest ECE inhibition was observed with one analogue.

  11. Angiotensin Converting Enzyme (ACE) Inhibitor Extends Caenorhabditis elegans Life Span.

    PubMed

    Kumar, Sandeep; Dietrich, Nicholas; Kornfeld, Kerry

    2016-02-01

    Animal aging is characterized by progressive, degenerative changes in many organ systems. Because age-related degeneration is a major contributor to disability and death in humans, treatments that delay age-related degeneration are desirable. However, no drugs that delay normal human aging are currently available. To identify drugs that delay age-related degeneration, we used the powerful Caenorhabditis elegans model system to screen for FDA-approved drugs that can extend the adult lifespan of worms. Here we show that captopril extended mean lifespan. Captopril is an angiotensin-converting enzyme (ACE) inhibitor used to treat high blood pressure in humans. To explore the mechanism of captopril, we analyzed the acn-1 gene that encodes the C. elegans homolog of ACE. Reducing the activity of acn-1 extended the mean life span. Furthermore, reducing the activity of acn-1 delayed age-related degenerative changes and increased stress resistance, indicating that acn-1 influences aging. Captopril could not further extend the lifespan of animals with reduced acn-1, suggesting they function in the same pathway; we propose that captopril inhibits acn-1 to extend lifespan. To define the relationship with previously characterized longevity pathways, we analyzed mutant animals. The lifespan extension caused by reducing the activity of acn-1 was additive with caloric restriction and mitochondrial insufficiency, and did not require sir-2.1, hsf-1 or rict-1, suggesting that acn-1 functions by a distinct mechanism. The interactions with the insulin/IGF-1 pathway were complex, since the lifespan extensions caused by captopril and reducing acn-1 activity were additive with daf-2 and age-1 but required daf-16. Captopril treatment and reducing acn-1 activity caused similar effects in a wide range of genetic backgrounds, consistent with the model that they act by the same mechanism. These results identify a new drug and a new gene that can extend the lifespan of worms and suggest new

  12. Angiotensin-I-Converting Enzyme (ACE) Inhibitors from Marine Resources: Prospects in the Pharmaceutical Industry

    PubMed Central

    Wijesekara, Isuru; Kim, Se-Kwon

    2010-01-01

    Hypertension or high blood pressure is one of the major independent risk factors for cardiovascular diseases. Angiotensin-I-converting enzyme (EC 3.4.15.1; ACE) plays an important physiological role in regulation of blood pressure by converting angiotensin I to angiotensin II, a potent vasoconstrictor. Therefore, the inhibition of ACE activity is a major target in the prevention of hypertension. Recently, the search for natural ACE inhibitors as alternatives to synthetic drugs is of great interest to prevent several side effects and a number of novel compounds such as bioactive peptides, chitooligosaccharide derivatives (COS) and phlorotannins have been derived from marine organisms as potential ACE inhibitors. These inhibitory derivatives can be developed as nutraceuticals and pharmaceuticals with potential to prevent hypertension. Hence, the aim of this review is to discuss the marine-derived ACE inhibitors and their future prospects as novel therapeutic drug candidates for treat hypertension. PMID:20479968

  13. Bradykinin-mediated cardiovascular protective actions of ACE inhibitors. A new dimension in anti-ischaemic therapy?

    PubMed

    Remme, W J

    1997-01-01

    In addition to being accepted therapy in hypertension and heart failure, ACE inhibitors may well offer a new dimension in anti-ischaemic therapy. Currently, anti-ischaemic properties have been demonstrated by ACE inhibitors in selected patient groups, including patients with left ventricular dysfunction with or without a direct temporal relationship with myocardial infarction. Anti-ischaemic effects of ACE inhibitors become apparent late after initiation of treatment and suggest a structural rather than a functional effect. Underlying mechanisms may include a reduction in ventricular dilatation and (abnormal) cardiac hypertrophy, leading to less myocardial oxygen demand and, possibly, improved subendocardial blood supply, and vasculoprotective effects, i.e. anti-atherosclerotic and antiremodelling properties, a beneficial effect on the fibrinolytic system and an improvement in abnormal endothelial vasodilator function. The latter aspect is most probably the pivotal mode of action where the anti-ischaemic profile of ACE inhibition is concerned. An improvement in endothelial dysfunction has been shown in patients with mild to moderate coronary artery disease [Trial on Reversing ENdothelial Dysfunction (TREND)]. It is of importance that, in both clinical experiments and human studies, the role of bradykinin appears central in the structural and functional cardiovascular effects of ACE inhibition. This is particularly true for the improvement of impaired endothelial function. Myocardial ischaemia evokes vasoconstrictor neurohormonal activation, which may lead to coronary vasoconstriction in diseased coronary segments. The subsequent abnormal endothelial function leads to diminished coronary flow and also increases systemic vasotone and afterload, thus unfavourably altering the myocardial oxygen supply/demand ratio. Under laboratory conditions, acute ACE inhibition counteracts this activation in humans. However, it is speculated that this anti-ischaemic mechanism may

  14. ACE inhibitors could be therapeutic for antisocial personality disorder.

    PubMed

    Hobgood, Donna K

    2013-11-01

    Antisocial personality traits are an important topic for research. The societal cost of these behaviors encourages efforts at a better understanding of central nervous system causes. Catecholamine genes are being studied to facilitate this understanding, and some tentative findings are being reached about several of these genes. It seems that many genes play a role to produce antisocial behaviors so complexity of elucidating each gene is obvious. One conclusion that could be drawn from the current research findings is that DA2 like receptors (DRD2, DRD3, DRD4) with alleles that decrease neurotransmission are facilitatory of antisocial behaviors. DA2 like receptors cause neuronal firing to inhibit many peripheral functions through adenylyl cyclase inhibition. When these receptors are less active by genetically decreased density, lower affinity, or by low dopamine levels as final common pathways then inhibition is released and a state of disinhibition can be said to describe this state. Peripheral metabolism is increased and behavioral activation is noted. Renin is disinhibited in this setting thus allowing sympathetic nervous system activation. The fight or flight behaviors thus produced, in the extreme, would be the setting of antisocial behavior. Research validates this hypothesis. Understanding this final common pathway toward antisocial behavior should lead to better treatment for individuals with this pattern of behavior before they have caused harm to themselves and others. ACE inhibitors are well tolerated drugs used in the treatment of hypertension and heart failure and would also treat antisocial behavior disorders.

  15. A prospective study of frequency and characteristics of cough during ACE inhibitor treatment.

    PubMed

    Sato, Atsuhisa; Fukuda, Seiichi

    2015-01-01

    Angiotensin converting enzyme (ACE) inhibitors are reportedly effective, and positively indicated in patients with chronic heart failure with decreased contractility, after myocardial infarction, after cerebrovascular disorders, and in those with chronic kidney disease. However, the biggest challenge to continuous use of ACE inhibitors is the adverse reaction of cough. Accordingly, in the present study, we investigated the present state and characteristics of ACE inhibitor-induced cough in patients with essential hypertension currently being treated with an ACE inhibitor for an average of 18 months, who could be regularly checked for cough. Subjects in this study were 176 patients overall (mean age 67 ± 11 years old), 90 men and 86 women. The adverse reaction of cough was observed in 20% of patients, and more frequently in women than in men. However, in 26 of the patients with cough, the cough either resolved naturally or completely disappeared while the treatment continued, after which patients could continue taking the medication. Specifically, ACE inhibitor treatment was eventually discontinued due to cough in 5.1% of patients. Cough occurred less frequently with concomitant calcium antagonists or diuretics than with ACE inhibitor monotherapy. Cough as an adverse reaction occurred at a low frequency when medication was taken at bedtime. We considered a number of measures to counteract cough, then in addition to starting the ACE inhibitor treatment as early as possible, it is important to devise ways for the ACE inhibitor treatment to be continued for as long as possible, through the adept use of these measures.

  16. Angiotensin converting enzyme (ACE) inhibitors from Jasminum azoricum and Jasminum grandiflorum.

    PubMed

    Somanadhan, B; Smitt, U W; George, V; Pushpangadan, P; Rajasekharan, S; Duus, J O; Nyman, U; Olsen, C E; Jaroszewski, J W

    1998-04-01

    Bioactivity-guided fractionation of extracts of the aerial parts of Jasminum azoricum var. travancorense, using an in vitro ACE inhibition assay, led to isolation of three oligomeric, iridoid-type compounds, which were named sambacein I-III. Their structures are based on spectroscopic and chemical evidence. Similarly, fractionation of extracts of aerial parts of J. grandiflorum resulted in the isolation of the previously reported ACE inhibitor, oleacein. The IC50 values of purified ACE inhibitors were 26-36 microM. Moreover, 2-(3,4-dihydroxyphenyl)-ethanol, isoquercitrin and ursolic acid were isolated from J. grandiflorum. Sambaceins and oleacein are formed from genuine iridoid glucosides during processing of the plant material. NMR spectroscopy was used to measure the level of the ACE inhibitors in the traditional medicines prepared in Kerala from these Jasminum species.

  17. Improved ACE-FTS observations of carbon tetrachloride (CCl4)

    NASA Astrophysics Data System (ADS)

    Harrison, Jeremy; Chipperfield, Martyn; Boone, Chris; Bernath, Peter

    2016-04-01

    The Atmospheric Chemistry Experiment Fourier transform spectrometer (ACE-FTS), on board the SCISAT satellite, has been recording solar occultation spectra through the Earth's atmosphere since 2004 and continues to take measurements with only minor loss in performance. ACE-FTS time series are available for a range of chlorine 'source' gases, including CCl3F (CFC-11), CCl2F2 (CFC-12), CHF2Cl (HCFC-22), CH3Cl and CCl4. Recently there has been much community interest in carbon tetrachloride (CCl4), a substance regulated by the Montreal Protocol because it leads to the catalytic destruction of stratospheric ozone. Estimated sources and sinks of CCl4 remain inconsistent with observations of its abundance. Satellite observations of CCl4 in the stratosphere are particularly useful in validating stratospheric loss (photolysis) rates; in fact the atmospheric loss of CCl4 is essentially all due to photolysis in the stratosphere. However, the latest ACE-FTS v3.5 CCl4 retrieval is biased high by ˜ 20-30%. A new ACE-FTS retrieval scheme utilising new laboratory spectroscopic measurements of CCl4 and improved microwindow selection has recently been developed. This improves upon the v3.5 retrieval and resolves the issue of the high bias; this new scheme will form the basis for the upcoming v4 processing version of ACE-FTS data. This presentation will outline the improvements made in the retrieval, and a subset of data will be compared with modelled CCl4 distributions from SLIMCAT, a state-of-the-art three-dimensional chemical transport model. The use of ACE-FTS data to evaluate the modelled stratospheric loss rate of CCl4 will also be discussed. The evaluated model, which also includes a treatment of surface soil and ocean sinks, will then be used to quantify current uncertainties in the global budget of CCl4.

  18. Angiotensin-converting enzyme (ACE) inhibitors modulate cellular retinol-binding protein 1 and adiponectin expression in adipocytes via the ACE-dependent signaling cascade.

    PubMed

    Kohlstedt, Karin; Gershome, Cynthia; Trouvain, Caroline; Hofmann, Wolf-Karsten; Fichtlscherer, Stephan; Fleming, Ingrid

    2009-03-01

    Inhibitors of the angiotensin-converting enzyme (ACE) decrease angiotensin II production and activate an intracellular signaling cascade that affects gene expression in endothelial cells. Because ACE inhibitors have been reported to delay the onset of type 2 diabetes, we determined ACE signaling-modulated gene expression in endothelial cells and adipocytes. Using differential gene expression analysis, several genes were identified that were 3-fold up- or down-regulated by ramiprilat in cells expressing wild-type ACE versus cells expressing a signaling-dead ACE mutant. One up-regulated gene was the cellular retinol-binding protein 1 (CRBP1). In adipocytes, the overexpression of CRBP1 enhanced (4- to 5-fold) the activity of promoters containing response elements for retinol-dependent nuclear receptors [retinoic acid receptor (RAR) and retinoid X receptor (RXR)] or peroxisome proliferator-activated receptors (PPAR). CRBP1 overexpression also enhanced the promoter activity (by 470 +/- 40%) and expression/release of the anti-inflammatory and antiatherogenic adipokine adiponectin (cellular adiponectin by 196 +/- 24%, soluble adiponectin by 228 +/- 74%). Significantly increased adiponectin secretion was also observed after ACE inhibitor treatment of human preadipocytes, an effect prevented by small interfering RNA against CRBP1. Furthermore, in ob/ob mice, ramipril markedly potentiated both the basal (approximately 2-fold) and rosiglitazonestimulated circulating levels of adiponectin. In patients with coronary artery disease or type 2 diabetes, ACE inhibition also significantly increased plasma adiponectin levels (1.6- or 2.1-fold, respectively). In summary, ACE inhibitors affect adipocyte homeostasis via CRBP1 through the activation of RAR/RXR-PPAR signaling and up-regulation of adiponectin. The latter may contribute to the beneficial effects of ACE inhibitors on the development of type 2 diabetes in patients with an activated renin-angiotensin system.

  19. Effects of ACE-inhibitors and beta-blockers on left ventricular remodeling in chronic heart failure.

    PubMed

    Khattar, R S

    2003-04-01

    In recent years, it has become increasingly recognised that a central feature of the disease progression associated with heart failure is the process of left ventricular remodeling. The remodeling process manifests as an increase in left ventricular volumes, leading to a rise in wall stress and a compensatory increase in myocardial mass. The left ventricle also gradually assumes a more spherical shape, resulting in functional mitral regurgitation leading to further haemodynamic overload, worsening myocardial function and an unfavourable clinical course. Accumulating clinical data support the hypothesis that the benefits in clinical outcome with ACE-inhibitors and beta-blockers may relate to modification of the remodeling process resulting in slowing of disease progression and preservation of contractile function. The general trend from a number of clinical studies indicates that whereas ACE-inhibitors seem to prevent progressive left ventricular dilatation, the third generation beta-blocker, carvedilol, may actually reverse the remodelling process by reducing left ventricular volumes and improving systolic function. Direct comparisons indicate that carvedilol has a similar safety and tolerability profile to ACE-inhibitors and thereby support the feasibility of administering this drug as first-line therapy in selected patients with mild to moderate chronic heart failure. Therefore, the decision to initiate treatment with carvedilol or an ACE-inhibitor might in future be tailored on an individual basis and followed thereafter by combination therapy at the earliest and safest opportunity. Finally, the possible development of treatment strategies addressing the cellular and molecular mechanisms responsible for the remodeling process and the recently published benefits of device therapies herald a combined, synergistic approach to the future management of heart failure.

  20. A novel aggregation-induced emission based fluorescent probe for an angiotensin converting enzyme (ACE) assay and inhibitor screening.

    PubMed

    Wang, Haibo; Huang, Yi; Zhao, Xiaoping; Gong, Wan; Wang, Yi; Cheng, Yiyu

    2014-12-11

    A 'turn-on' fluorescent probe based on aggregation-induced emission (AIE) has been developed. It exhibits excellent selectivity and sensitivity for monitoring angiotensin converting enzyme (ACE) activity both in solutions and in living cells as well as for screening ACE inhibitors in vitro.

  1. Evolution of diuretics and ACE inhibitors, their renal and antihypertensive actions—parallels and contrasts

    PubMed Central

    Lant, Ariel F.

    1987-01-01

    1 The emergence of diuretic drugs and angiotensin converting enzyme (ACE) inhibitors ranks amongst the major therapeutic advances of modern medicine. The discovery of these drug groups arose largely by chance, yet each has dramatically influenced the treatment of congestive cardiac failure and arterial hypertension. 2 The central role which diuretics have had in the management of both oedema and hypertension hinges on their ability to induce a net renal excretion of solute and water by selective interference with either active or passive ion transport processes in different segments of the nephron. Irrespective of sites of action, the continued antihypertensive action of diuretics is characterized by a reduction in plasma volume and extracellular fluid (ECF) volume that lasts for as long as the diuretic is given. The mechanism of this effect remains unclear but may involve autoregulatory reactions that leave cardiac output unaltered but maintain a sustained reduction in total peripheral resistance. 3 ACE inhibitors also lower blood pressure by decreasing total peripheral resistance, leaving cardiac output, plasma volume and ECF volume unchanged. The detailed way these haemodynamic changes are achieved remains unknown but inhibition of converting enzyme present not only in the kidney but also in many extrarenal tissue sites, appears important. In both hypertension and cardiac failure, however, the kidney acts as a key target organ for ACE inhibitors. The increased renal vascular resistance and inappropriate renal salt excretion are reversed with enhanced renal blood flow and saluresis. Both angiotensin II (AII) and vasopressin-mediated contraction of glomerular mesangial cells is inhibited, making glomerular filtration more efficient. Reduced aldosterone secondary to blockade of AII formation contributes to saluresis whilst encouraging positive potassium balance. ACE inhibition also impairs breakdown of kinins which may contribute to intrarenal and peripheral

  2. Occurrence and fate of ACE-inhibitor peptides in cheeses and in their digestates following in vitro static gastrointestinal digestion.

    PubMed

    Stuknytė, Milda; Cattaneo, Stefano; Masotti, Fabio; De Noni, Ivano

    2015-02-01

    The occurrence of the casein-derived angiotensin converting enzyme-inhibitor (ACE-I) peptides VPP, IPP, RYLGY, RYLG, AYFYPEL, AYFYPE, LHLPLP and HLPLP were investigated in 12 different cheese samples by Ultra Performance Liquid Chromatography/High-Resolution Mass Spectrometry. The total amount of ACE-I peptides was in the range 0.87-331mgkg(-1). VPP and IPP largely prevailed in almost all cheeses. Following in vitro static gastrointestinal digestion of Cheddar, Gorgonzola, Maasdam and Grana Padano cheeses, type and amount of ACE-I peptides changed, and only VPP, IPP, HLPLP and LHLPLP were detected in the intestinal digestates. The results evidenced that the degree of proteolysis itself cannot be regarded as a promoting or hindering factor for ACE-I peptide release during cheese digestion. Moreover, the data indicated that the ACE-I potential of cheeses cannot be inferred based on the type and amount of ACE-I peptides present in undigested samples.

  3. A role for the extracellular matrix component hyaluronan in kidney dysfunction during ACE-inhibitor fetopathy.

    PubMed

    Hansell, P; Palm, F

    2015-04-01

    Despite data showing that inhibitors of the renin-angiotensin system increase the risks of fetal morbidity and dysfunctionality later in life, their use during pregnancy has increased. The fetopathy induced by angiotensin converting enzyme (ACE) inhibitors is characterized by anuria, hypotension and growth restriction, but can also be associated with pulmonary hypoplasia. In the kidney, this fetopathy includes atrophy of the medulla, reduced number of glomeruli, developmental lesions of tubules and vessels, tubulointerstitial inflammation and extracellular matrix accumulation. Although angiotensin II (Ang II) inhibition during nephrogenesis interferes with normal growth and development, this review will focus on effects of the heavily accumulated matrix component hyaluronan (HA). An important mechanism of HA accumulation during nephrogenesis is disruption of its normal reduction as a consequence of lack of Ang II activation of hyaluronidase. Hyaluronan has very large water-attracting properties and is pro-inflammatory when fragmented. The ensuing inflammation and interstitial oedema affect kidney function. Hyaluronan is colocalized with CD44 overexpression and infiltrating immune cells. These properties make HA a plausible contributor to the observed structural and functional kidney defects associated with the fetopathy. Available data support an involvement of HA in kidney dysfunction of the foetus and during adulthood due to the physico-chemical characteristics of HA. No clinical treatment for HA accumulation exists. Treatment with the HA-degrading enzyme hyaluronidase and an HA synthesis inhibitor has been tested successfully in experimental models in the kidney, heart and pancreas. Reduced HA accumulation to reduce interstitial oedema and inflammation may improve organ function, but this concept needs to be tested in a controlled study before causal relationships can be established.

  4. Effects of ACE Inhibitors on Insulin Resistance and Lipid Profile in Children with Metabolic Syndrome

    PubMed Central

    Çelebi Bitkin, Eda; Boyraz, Mehmet; Taşkın, Necati; Akçay, Arzu; Ulucan, Korkut; Akyol, Mehmet Bedir; Akçay, Teoman

    2013-01-01

    Objective: The aim of this study was to evaluate the effects of using ACE inhibitors on insulin resistance, glucose metabolism, body fat composition, and lipid profile in children over 10 years of age with obesity-associated metabolic syndrome (MS). Methods: A total of 53 children with MS, who had been followed for at least one year were included in the study. The sample was divided into two groups: Group 1-30 obese children (13 female, 17 male) who were not using an ACE inhibitor and Group 2-23 obese children (13 female, 10 male) who were using an ACE inhibitor. Anthropometric and laboratory dataobtained at baseline and at the 3rd, 6th, and 12th months of follow-up were compared in the two groups. Results: Comparison of the data in the two groups at 3rd, 6th, and 12th months revealed no statistically significant differences in terms of weight standard deviation score (SDS), body mass index SDS, weight for height percentile, body fat percentage, and very low-density lipoprotein (VLDL)values. However, there were statistically significant differences in mean glucose and insulin levels, homeostasis model assessment for insulin resistance, LDL and high-density lipoprotein values, and highly significant differences in mean triglyceride values. Conclusions: The positive effects of ACE inhibitor drugs, particularly on hypertriglyceridemia and insulin resistance, might bring them forth as first-line drugs in the treatment of obese and hypertensive children. Randomized, controlled, double-blind, and long-term studies are needed for a definitive conclusion. Conflict of interest:None declared. PMID:24072084

  5. Investigation of interaction studies of cefpirome with ACE-inhibitors in various buffers

    NASA Astrophysics Data System (ADS)

    Nawaz, Muhammad; Arayne, Muhammad Saeed; Sultana, Najma; Abbas, Hira Fatima

    2015-02-01

    This work describes a RP-HPLC method for the determination and interaction studies of cefpirome with ACE-inhibitors (captopril, enalapril and lisinopril) in various buffers. The separation and interaction of cefpirome with ACE-inhibitors was achieved on a Purospher Star, C18 (5 μm, 250 × 4.6 mm) column. Mobile phase consisted of methanol: water (80:20, v/v, pH 3.3); however, for the separation of lisinopril, it was modified to methanol-water (40:60, v/v, pH 3.3) and pumped at a flow rate of 1 mL min-1. In all cases, UV detection was performed at 225 nm. Interactions were carried out in physiological pH i.e., pH 1 (simulated gastric juice), 4 (simulated full stomach), 7.4 (blood pH) and 9 (simulated GI), drug contents were analyzed by reverse phase high performance liquid chromatography. Method was found linear in the concentration range of 1.0-50.0 μg mL-1 with correlation coefficient (r2) of 0.999. Precision (RSD%) was less than 2.0%, indicating good precision of the method and accuracy was 98.0-100.0%. Furthermore, cefpirome-ACE-inhibitors' complexes were also synthesized and results were elucidated on the basis of FT-IR, and 1H NMR. The interaction results show that these interactions are pH dependent and for the co-administration of cefpirome and ACE-inhibitors, a proper interval should be given.

  6. Combination ACE inhibitor and angiotensin receptor blocker therapy - future considerations.

    PubMed

    Sica, Domenic A

    2007-01-01

    Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are regularly prescribed for the management of hypertension. Each of these drug classes has also been shown to provide survival benefits for patients with heart failure, proteinuric chronic kidney disease, and/or a high cardiac risk profile. The individual gains seen with each of these drug classes have led to speculation that their combination might offer additive if not synergistic outcome benefits. The foundation of this hypothesis, although biologically possible, has thus far not been sufficiently well proven to support the everyday use of these 2 drug classes in combination. Additional outcomes trials, which are currently proceeding to their conclusion, may provide the necessary proof to support an expanded use of these 2 drug classes in combination.

  7. Synthesis and evaluation of novel triazoles and mannich bases functionalized 1,4-dihydropyridine as angiotensin converting enzyme (ACE) inhibitors.

    PubMed

    Kumbhare, Ravindra M; Kosurkar, Umesh B; Bagul, Pankaj K; Kanwal, Abhinav; Appalanaidu, K; Dadmal, Tulshiram L; Banerjee, Sanjay Kumar

    2014-11-01

    A series of novel diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate embedded triazole and mannich bases were synthesized, and evaluated for their angiotensin converting enzyme (ACE) inhibitory activity. Screening of above synthesized compounds for ACE inhibition showed that triazoles functionalized compounds have better ACE inhibitory activity compared to that of mannich bases analogues. Among all triazoles we found 6 h, 6 i and 6 j to have good ACE inhibition activity with IC50 values 0.713 μM, 0.409 μM and 0.653 μM, respectively. Among mannich bases series compounds, only 7c resulted as most active ACE inhibitor with IC50 value of 0.928 μM.

  8. Binding of ACE-inhibitors to in vitro and patient-derived amyloid-β fibril models

    NASA Astrophysics Data System (ADS)

    Bhavaraju, Manikanthan; Phillips, Malachi; Bowman, Deborah; Aceves-Hernandez, Juan M.; Hansmann, Ulrich H. E.

    2016-01-01

    Currently, no drugs exist that can prevent or reverse Alzheimer's disease, a neurodegenerative disease associated with the presence, in the brain, of plaques that are composed of β-amyloid (Aβ) peptides. Recent studies suggest that angiotensin-converting enzyme (ACE) inhibitors, a set of drugs used to treat hypertension, may inhibit amyloid formation in vitro. In the present study, we investigate through computer simulations the binding of ACE inhibitors to patient-derived Aβ fibrils and contrast it with that of ACE inhibitors binding to in vitro generated fibrils. The binding affinities of the ACE inhibitors are compared with that of Congo red, a dye that is used to identify amyloid structures and that is known to be a weak inhibitor of Aβ aggregation. We find that ACE inhibitors have a lower binding affinity to the patient-derived fibrils than to in vitro generated ones. For patient-derived fibrils, their binding affinities are even lower than that of Congo red. Our observations raise doubts on the hypothesis that these drugs inhibit fibril formation in Alzheimer patients by interacting directly with the amyloids.

  9. ACE inhibitors in heart failure--switching from enalapril to perindopril.

    PubMed

    Masuell, Marcelo; Brusca, Gustavo; Pardo, Augusto; Piñeiro, Daniel; Checkerdhemian, Sergio; Forcada, Pedro

    2002-01-01

    Although ACE inhibitors have demonstrated their beneficial effects in heart failure, whether different agents may induce different benefits remains unclear. We designed an open, sequential, prospective study switching heart failure patients receiving enalapril to perindopril which has been reported to be longer acting and better tolerated. The objective of the study was to find out if clinical and functional status could be further improved by changing from enalapril 30 mg daily to a perindopril 4 mg daily. Assessments of clinical status, echocardiography and nuclear ventriculography were performed at baseline under enalapril (30 mg mean dose (b.i.d.)), then 6 and 12 months after the switch to perindopril (4 mg/day mean dose). Thirty-one patients were included (90% men, aged 56.5 +/- 11.8 years, mean radionuclide left ventricular (LV) ejection fraction 22.4 +/- 8.5 %). After 6 months of treatment, NYHA functional class was significantly improved; the percentage of patients in class I increased to 57% after perindopril versus 20% at baseline (p < 0.001), and 50% of the total study population gained at least one NYHA class. After 12 months of treatment, 80% of the patients were in NYHA class I. Blood pressure decreased significantly with a good tolerance at 6 months and then remained stable. After 12 months of treatment, significant reductions of LV end-diastolic diameter (61.4 +/- 5.3 vs. 64.5 +/- 6.5 mm; p = 0.001) and LV mass index (143.3 +/- 21.5 vs. 164.2 +/- 40.2 g/m2; p < 0.001) were observed, reflecting a positive effect on the LV remodelling process. Despite some limitations, because it is of an open-label design with a small number of patients, our study found significant differences in clinical and objective parameters in heart failure patients switched from enalapril to perindopril. The prognostic significance of these findings remains to be investigated.

  10. ACE inhibitors

    MedlinePlus

    ... In: Mann DL, Zipes DP, Libby P, Bonow RO, Braunwald E, eds. Braunwald's Heart Disease: A Textbook ... In: Mann DL, Zipes DP, Libby P, Bonow RO, Braunwald E, eds. Braunwald's Heart Disease: A Textbook ...

  11. Dual ACE and neutral endopeptidase inhibitors: novel therapy for patients with cardiovascular disorders.

    PubMed

    Tabrizchi, Reza

    2003-01-01

    Elevated blood pressure is a risk factor for a variety of cardiovascular disorders, including coronary heart disease, peripheral vascular disease, cardiac failure and cerebrovascular disease. The prevailing view is that an elevated systolic rather than diastolic blood pressure is the major contributor in mortality and morbidity attributed to cardiovascular disorders. Isolated high systolic blood pressure, especially in the elderly, is a major risk factor and should undoubtedly be a target for drug treatment. In the general population, systolic and diastolic blood pressure are highly correlated, and thus it is difficult to dissociate the effects of these two components of the blood pressure and specifically ascribe cardiovascular risk factors to just elevated systolic blood pressure. Therefore, the goal in therapy of an individual with hypertension must be to reduce elevated systolic and diastolic blood pressure in order to reduce mortality and morbidity. ACE and neutral peptidase inhibitors are a new class of drugs that may be beneficial in the treatment of patients with hypertension and heart failure. They may also be useful in the treatment of diabetic patients with hypertension and/or heart failure. Drugs of this class are dual inhibitors of ACE and neutral endopeptidase, and are capable of affecting vascular tone and fluid balance. They are capable of producing vasodilatation by virtue of inhibiting the production of angiotensin II, degradation of natriuretic peptides and bradykinin. They also appear to promote natriuresis and diuresis by amplifying the actions of natriuretic peptidase and reducing aldosterone effects. In addition, they should also attenuate trophogenic actions of the renin angiotensin system and the sympathetic nervous system. Omapatrilat is one drug that appears to be at the advanced stages of clinical development. This drug has been shown to be quite effective in the treatment of hypertension. Evidence also seems to indicate that treatment

  12. Radiation damage to the lung: mitigation by angiotensin converting enzyme (ACE) inhibitors

    PubMed Central

    Medhora, Meetha; Gao, Feng; Jacobs, Elizabeth R.; Moulder, John E.

    2011-01-01

    Concern regarding accidental overexposure to radiation has been raised after the devastating Tohuku earthquake and tsunami which initiated the Fukushima Daiichi nuclear disaster in Japan, in March 2011. Radiation exposure is toxic and can be fatal depending on the dose received. Injury to the lung is often reported as part of multi-organ failure in victims of accidental exposures. Doses of radiation >8 Gray to the chest can induce pneumonitis with right ventricular hypertrophy starting after ~2 months. Higher doses may be followed by pulmonary fibrosis that presents months to years after exposure. Though the exact mechanisms of radiation lung damage are not known, experimental animal models have been widely used to study this injury. Rodent models for pneumonitis and fibrosis exhibit vascular, parenchymal and pleural injuries to the lung. Inflammation is a part of the injuries suggesting involvement of the immune system. Researchers world-wide have tested a number of interventions to prevent or mitigate radiation lung injury. One of the first and most successful class of mitigators are inhibitors of angiotensin converting enzyme (ACE), an enzyme that is abundant in the lung. These results offer hope that lung injury from radiation accidents may be mitigated, since the ACE inhibitor captopril was effective when started up to one week after irradiation. PMID:22023053

  13. [The new drug is much more effective than ACE inhibitors in chronic heart failure].

    PubMed

    Sr, Jiří Widimský

    2015-02-01

    PARADIGM-HF study observed clinical outcomes after treatment by new drug LCZ696 or enalapril in patients with systolic chronic heart failure. It was randomized double-blind trial with LCZ696 (200 mg twice a day) and enalapril (10 mg twice a day). 8442 patients were enrolled with NYHA class II or III and left ventricular ejection fiction of 40% or less. Study drugs were added to other recommended medication. The trial was prematurely terminated after median follow-up of 27 months. The primary endpoint of the study was a combination of cardiovascular mortality and the first hospitalization for heart failure. LCZ696 drug, an inhibitor of angiotensin receptor and neprilysin (Arnie), has led to a reduction in the primary composite target by 20% (p <0.001). The treatment has decreased cardiovascular mortality by 20%, p <0.001 and hospitalization for worsening heart failure by 21%, p <0.001. LCZ696 has also decreased total mortality by 16%, p <0.001. The use of LCZ696 has been accompanied by frequent symptomatic hypotension and hypotension with a decrease in systolic blood pressure below 90 mm Hg, however, LCZ696 was less often associated with an increase in serum creatinine and serum potassium than enalapril. In addition, cough has occurred less frequently after LCZ696 than after enalapril. Discontinuation of therapy occurred in 746 patients (17.8%) treated with LCZ696 and in 833 patients (19.8%) treated with enalapril (19.8%) (p = 0.02). PARADIGM-HF study has also shown superiority of LCZ696 compared to ACE inhibitors in stable outpatients with chronic systolic heart failure NYHA stages II and III. Therefore, LCZ696 is more effective than ACE inhibitors (and angiotensin receptor blockers). Moreover, it is well tolerated. LCZ696 seems to replace the ACE inhibitors in mentioned patients. The authors also discuss the results of the first randomized study PARAMOUNT investigating LCZ696 efficacy in patients with chronic heart failure and good left ventricular ejection

  14. Effects of centrally acting ACE inhibitors on the rate of cognitive decline in dementia

    PubMed Central

    Gao, Yang; O'Caoimh, Rónán; Healy, Liam; Kerins, David M; Eustace, Joseph; Guyatt, Gordon; Sammon, David; Molloy, D William

    2013-01-01

    Objectives There is growing evidence that antihypertensive agents, particularly centrally acting ACE inhibitors (CACE-Is), which cross the blood–brain barrier, are associated with a reduced rate of cognitive decline. Given this, we compared the rates of cognitive decline in clinic patients with dementia receiving CACE-Is (CACE-I) with those not currently treated with CACE-Is (NoCACE-I), and with those who started CACE-Is, during their first 6 months of treatment (NewCACE-I). Design Observational case–control study. Setting 2 university hospital memory clinics. Participants 817 patients diagnosed with Alzheimer's disease, vascular or mixed dementia. Of these, 361 with valid cognitive scores were included for analysis, 85 CACE-I and 276 NoCACE-I. Measurements Patients were included if the baseline and end-point (standardised at 6 months apart) Standardised Mini-Mental State Examination (SMMSE) or Quick Mild Cognitive Impairment (Qmci) scores were available. Patients with comorbid depression or other dementia subtypes were excluded. The average 6-month rates of change in scores were compared between CACE-I, NoCACE-I and NewCACE-I patients. Results When the rate of decline was compared between groups, there was a significant difference in the median, 6-month rate of decline in Qmci scores between CACE-I (1.8 points) and NoCACE-I (2.1 points) patients (p=0.049), with similar, non-significant changes in SMMSE. Median SMMSE scores improved by 1.2 points in the first 6 months of CACE treatment (NewCACE-I), compared to a 0.8 point decline for the CACE-I (p=0.003) group and a 1 point decline for the NoCACE-I (p=0.001) group over the same period. Multivariate analysis, controlling for baseline characteristics, showed significant differences in the rates of decline, in SMMSE, between the three groups, p=0.002. Conclusions Cognitive scores may improve in the first 6 months after CACE-I treatment and use of CACE-Is is associated with a reduced rate of cognitive

  15. Are ACE-inhibitors or ARB's still needed for cardiovascular prevention in high risk patients? Insights from profess and transcend.

    PubMed

    Van Mieghem, W; Billiouw, J M; Brohet, C; Dupont, A G; Gazagnes, M D; Heller, F; Krzesinski, J M; Missault, L; Persu, A; Piérard, L; Rottiers, R; Vanhooren, G; Vervaet, P; Herman, A G

    2010-01-01

    The HOPE and EUROPA clinical studies have shown that treatment with the angiotensin-converting enzyme (ACE) inhibitors, ramipril and perindopril, may reduce the occurrence of major cardiovascular events in patients with proven atherosclerotic disease. The recently published results of the PRoFESS and TRANSCEND trials completed the much needed information concerning the use of an angiotensin receptor blocker for patients at high risk of cardiovascular events. PROFESS compared a therapy of telmisartan 80 mg daily with placebo in patients with a recent ischemic stroke. The difference in the primary outcome of first recurrent stroke was not statistically significant between telmisartan and placebo. The secondary outcome of major cardiovascular events showed a relative risk reduction (RRR) of 7% in favour of telmisartan. This tended to be significant (p = 0.06) despite a rather short follow-up period of only 28 months. In TRANSCEND 5926 patients at high risk for cardiovascular events were randomized to a treatment with telmisartan 80 mg daily or placebo for a mean duration of follow-up of 56 months. The primary composite outcome of cardiovascular death, myocardial infarction, stroke or hospitalization for heart failure showed a non-significant 8% RRR in favour of the telmisartan treated patients. The main secondary outcome of cardiovascular death and myocardial infarction or stroke as used in the HOPE trial showed a non-significant RRR of 13% in favour of telmisartan treated patients (p = 0.068 adjusted for multiplicity of comparisons). In comparing the Kaplan-Meier curves for the endpoint of major cardiovascular events used in HOPE, EUROPA, TRANSCEND and PRoFESS, the trends are similar. Results of most of the recently published trials have been neutral.This could partly be explained by major improvements in the optimal background therapy of the patients included. Nevertheless, the results of PRoFESS and TRANSCEND do not contradict the results from previous studies with

  16. Absence of Cardiac Benefit with Early Combination ACE Inhibitor and Beta Blocker Treatment in mdx Mice.

    PubMed

    Blain, Alison; Greally, Elizabeth; Laval, Steven H; Blamire, Andrew M; MacGowan, Guy A; Straub, Volker W

    2015-04-01

    Most patients with Duchenne muscular dystrophy (DMD) will develop cardiomyopathy; however, the evidence for prophylactic treatment of children with cardiac medications is limited. We have used the mdx mouse model of DMD to assess if early combination treatment with beta blocker (BB) and ACE inhibitor (AI) is superior to single treatment with either one of these drugs. Mice were assessed with cardiac MRI (ventricular structure and function, in vivo calcium influx (manganese-enhanced MRI)), pressure-volume loops, and histopathology. Combination treatment did not show benefits over treatment with AI or BB alone. Indeed, some beneficial aspects of BB and AI were lost when used in combination. None of the treatments impacted RV function. Combination treatment had no significant effect on sarcolemmal damage or histopathology. The study suggests that combined BB and AI may not confer an advantage at an early stage in DMD cardiomyopathy. However, limitations of the mdx model should be considered.

  17. Investigation of the biochemical effects of renin inhibition in normal volunteers treated by an ACE inhibitor.

    PubMed Central

    Chauveau, D; Guyenne, T T; Cumin, F; Chatellier, G; Corvol, P; Ménard, J

    1992-01-01

    1. In order to investigate accurately the biochemical effects of renin inhibition in man, we have developed a sensitive assay to measure angiotensin I (1-10) decapeptide. 2. Angiotensins were extracted from plasma by adsorption to phenylsilylsilica, and angiotensin I (Ang I) was quantified by radioimmunoassay. The detection limit was 0.77 fmol ml-1, and the extraction recovery of [125I]-Ang I added to albumin buffer was 83% at the inflection point (10 fmol ml-1) of the standard curve. The overall recovery was 98.5 +/- 3.5%. The intra- and inter-assay reproducibility was 10.4% and 9.7% respectively. Cross-reactivity of the antiserum used was low (less than 0.3%) with all angiotensin peptides tested except Ang (2-10) nonapeptide. 3. A human pharmacological model was subsequently used to assess in vivo the biochemical effects of the renin inhibitor CGP 38560A. Six healthy volunteers received 20 mg lisinopril, a long-acting ACE-inhibitor. During the following 24 h, the renin-angiotensin system was reset with typically elevated active plasma renin and Ang I, at respectively 275 and 429% of basal values. 4. In a randomized three-way cross-over protocol, the six volunteers received a 30 min infusion of the renin inhibitor CGP 38560A (125 or 250 micrograms kg-1) or 5% glucose. The fall in plasma Ang I was 92% and 97.5% after the lowest and highest dose of the renin inhibitor, respectively. A concomitant increase in active plasma renin was observed.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1315560

  18. Triple ACE-ECE-NEP inhibition in heart failure: a comparison with ACE and dual ECE-NEP inhibition.

    PubMed

    Mellin, Virginie; Jeng, Arco Y; Monteil, Christelle; Renet, Sylvanie; Henry, Jean Paul; Thuillez, Christian; Mulder, Paul

    2005-09-01

    Mortality remains high in chronic heart failure (CHF) because under ACE inhibitor treatment other neurohumoral systems remain/become (de)activated, such as the endothelin and atrial natriuretic peptide pathways. Dual endothelin-converting enzyme-neutral endopeptidase (ECE-NEP) inhibition exerts beneficial effects in experimental CHF, but whether "triple" ACE-ECE-NEP inhibition is superior to ACE or ECE-NEP inhibition is unknown. We compared, in rats with CHF, ACE-ECE-NEP to ACE or ECE-NEP inhibition in terms of left ventricular (LV) hemodynamics and remodeling. Benazepril (2 mg/kg/d) or the ECE-NEP inhibitor CGS26303 (10 mg/kg/d) were administered alone or in combination (subcutaneously for 28 days starting 7 days after coronary ligation). ACE-ECE-NEP inhibition reduced blood pressure more markedly than ACE or ECE-NEP inhibition. All treatments increased cardiac output to the same extent, but ACE-ECE-NEP inhibition reduced LV diameter and LV end-diastolic pressure more markedly than ACE or ECE-NEP inhibition. The reduction of LV weight and collagen accumulation in the "viable" myocardium was most pronounced after ACE-ECE-NEP inhibition. These results, obtained in experimental CHF, illustrate a further improvement of LV hemodynamics and structure after ACE-ECE-NEP inhibition compared with either ACE or ECE-NEP inhibition, but whether this is associated with a further improvement of exercise tolerance and/or survival remains to be determined.

  19. [ACE inhibitors and its usefulness in the prevention of aspiration pneumonia in chronic cerebrovascular disease patients with asymptomatic swallowing dysfunction].

    PubMed

    Shibuya, Seiji; Murahashi, Makoto; Inoue, Masahiko; Jimi, Takahiro; Wakayama, Yoshihiro

    2002-03-01

    The double contrast pharyngogram by use of computed radiography (DCP-CR) has been found to be useful in detection of asymptomatic swallowing dysfunction. Following the DCP-CR examination, we investigated the incidence of aspiration pneumonia in 143 patients with chronic cerebrovascular disease (CVD) for 3 years and the effects of ACE inhibitors on the prevention of pneumonia. Aspiration pneumonia occurred in 29 out of 143 patients, and more frequently in the elderly chronic CVD patients with multiple brain lesions. Aspiration pneumonia was confirmed in 26 out of 85 patients (30.6%) with abnormal barium adhesion to the pharyngeal wall on the double contrast pharyngogram image by DCP-CR; whereas pneumonia occurred in 3 out of 58 patients (5.2%) with normal findings of DCP-CR pharyngogram. Among chronic CVD patients with abnormal findings of DCP-CR pharyngogram, the incidence of aspiration pneumonia was significantly lower in the patients treated with ACE inhibitors than in those treated with other antihypertensive agents or without antihypertensive agents (chi 2 value = 7.163, p < 0.05). Accordingly, ACE inhibitors may prevent the aspiration pneumonia and reduce the incidence of aspiration pneumonia in the chronic CVD patients with abnormal DCP-CR pharyngogram images.

  20. Discovery of new angiotensin converting enzyme (ACE) inhibitors from medicinal plants to treat hypertension using an in vitro assay

    PubMed Central

    2013-01-01

    Background and purpose of the study Angiotensin converting enzyme (ACE) inhibitors plays a critical role in treating hypertension. The purpose of the present investigation was to evaluate ACE inhibition activity of 50 Iranian medicinal plants using an in vitro assay. Methods The ACE activity was evaluated by determining the hydrolysis rate of substrate, hippuryl-L-histidyl-L-leucine (HHL), using reverse phase high performance liquid chromatography (RP-HPLC). Total phenolic content and antioxidant activity were determined by Folin-Ciocalteu colorimetric method and DPPH radical scavenging assay respectively. Results Six extracts revealed > 50% ACE inhibition activity at 330 μg/ml concentration. They were Berberis integerrima Bunge. (Berberidaceae) (88.2 ± 1.7%), Crataegus microphylla C. Koch (Rosaceae) (80.9 ± 1.3%), Nymphaea alba L. (Nymphaeaceae) (66.3 ± 1.2%), Onopordon acanthium L. (Asteraceae) (80.2 ± 2.0%), Quercus infectoria G. Olivier. (Fagaceae) (93.9 ± 2.5%) and Rubus sp. (Rosaceae) (51.3 ± 1.0%). Q. infectoria possessed the highest total phenolic content with 7410 ± 101 mg gallic acid/100 g dry plant. Antioxidant activity of Q. infectoria (IC50 value 1.7 ± 0.03 μg/ml) was more than that of BHT (IC50 value of 10.3 ± 0.15 μg/ml) and Trolox (IC50 value of 3.2 ± 0.06 μg/ml) as the positive controls. Conclusions In this study, we introduced six medicinal plants with ACE inhibition activity. Despite the high ACE inhibition and antioxidant activity of Q. infectoria, due to its tannin content (tannins interfere in ACE activity), another plant, O. acanthium, which also had high ACE inhibition and antioxidant activity, but contained no tannin, could be utilized in further studies for isolation of active compounds. PMID:24359711

  1. Experiences with ACE inhibitors early after acute myocardial infarction. Rationale and design of the German Multicenter Study on the Effects of Captopril on Cardiopulmonary Exercise parameters post myocardial infarction (ECCE).

    PubMed

    Kleber, F X; Reindl, I; Wenzel, M; Rodewyk, P; Beil, S; Kosloswki, B; Doering, W; Sabin, G V; Hinzmann, S; Winter, U J

    1993-12-01

    Left ventricular damage by necrosis of myocardial tissue can lead to compromise of left ventricular function, to left ventricular volume increase and ultimately to development of heart failure. This sequence in the pathophysiology has been shown to be blunted by ACE inhibitors. Volume increase, however, can also be helpful in restoring stroke volume and ameliorate elevation of filling pressures. Furthermore, very early institution of ACE inhibition has failed to improve short-term mortality after myocardial infarction in one large trial. The aim of the ECCE trial therefore is, to investigate the early effects of the ACE inhibitor captopril on compromise of exercise capacity, thought to be a first measurable sign of developing heart failure. The ECCE trial is a randomized, seven-center investigation, studying the effects of ACE inhibition on oxygen uptake in a double blind, placebo controlled design in a group of 204 patients. Sample size was calculated on the basis of a pilot trial. The study design and first not unblinded data of 104 patients are presented. The population consists of predominantly male patients with mostly first myocardial infarction. They were admitted to hospital within five hours of onset of chest pain. End-diastolic volumes were normal, but ejection fraction was moderately compromised. ACE inhibition was started after the first day, but within 72 hours of onset of chest pain. After four and after twelve weeks, oxygen uptake was considerably below expected values and one third of the patients had severe compromise of exercise capacity.(ABSTRACT TRUNCATED AT 250 WORDS)

  2. Inequity of access to ACE inhibitors in Swedish heart failure patients: a register-based study

    PubMed Central

    Lindahl, Bertil; Hanning, Marianne; Westerling, Ragnar

    2016-01-01

    Background Several international studies suggest inequity in access to evidence-based heart failure (HF) care. Specifically, studies of ACE inhibitors (ACEIs) point to reduced ACEI access related to female sex, old age and socioeconomic position. Thus far, most studies have either been rather small, lacking diagnostic data, or lacking the possibility to account for several individual-based sociodemographic factors. Our aim was to investigate differences, which could reflect inequity in access to ACEIs based on sex, age, socioeconomic status or immigration status in Swedish patients with HF. Methods Individually linked register data for all Swedish adults hospitalised for HF in 2005–2010 (n=93 258) were analysed by multivariate regression models to assess the independent risk of female sex, high age, low employment status, low income level, low educational level or foreign country of birth, associated with lack of an ACEI dispensation within 1 year of hospitalisation. Adjustment for possible confounding was made for age, comorbidity, Angiotensin receptor blocker therapy, period and follow-up time. Results Analysis revealed an adjusted OR for no ACEI dispensation for women of 1.31 (95% CI 1.27 to 1.35); for the oldest patients of 2.71 (95% CI 2.53 to 2.91); and for unemployed patients of 1.59 (95% CI 1.46 to 1.73). Conclusions Access to ACEI treatment was reduced in women, older patients and unemployed patients. We conclude that access to ACEIs is inequitable among Swedish patients with HF. Future studies should include clinical data, as well as mortality outcomes in different groups. PMID:26261264

  3. Potential advantages of cell administration on the inflammatory response compared to standard ACE inhibitor treatment in experimental myocardial infarction

    PubMed Central

    Ciulla, Michele M; Montelatici, Elisa; Ferrero, Stefano; Braidotti, Paola; Paliotti, Roberta; Annoni, Giuseppe; De Camilli, Elisa; Busca, Giuseppe; Chiappa, Luisa; Rebulla, Paolo; Magrini, Fabio; Lazzari, Lorenza

    2008-01-01

    Background Bone Marrow (BM) progenitor cells can target the site of myocardial injury, contributing to tissue repair by neovascolarization and/or by a possible direct paracrine effect on the inflammatory cascade. Angiotensin Converting Enzyme inhibitors (ACE-I) are effective in reducing mortality and preventing left ventricular (LV) function deterioration after myocardial infarction. Methods We investigated the short term effects of BM mononuclear cells (BMMNCs) therapy on the pro-inflammatory cytokines (pro-CKs) and on LV remodelling and compared these effects over a standard ACE-I therapy in a rat model of myocardial cryodamage. Forty two adult inbread Fisher-F344 rats were randomized into three groups: untreated (UT; n = 12), pharmacological therapy (ACE-I; n = 14, receiving quinapril), and cellular therapy (BMMNCs; n = 16, receiving BMMNCs infusion). Rats underwent to a standard echocardiogram in the acute setting and 14 days after the damage, before the sacrifice. Pro-CKs analysis (interleukin (IL)1β, IL-6, tumor necrosis factor (TNF)α was performed (multiplex proteome arrays) on blood samples obtained by direct aorta puncture before the sacrifice; a control group of 6 rats was considered as reference. Results Concerning the extension of the infarcted area as well as the LV dimensions, no differences were observed among the animal groups; treated rats had lower left atrial diameters and higher indexes of LV function. Pro-Cks were increased in infarcted-UT rats if compared with controls, and significantly reduced by BMMNCs and ACE-I ; TNFα inversely correlated with LV fractional shortening. Conclusion After myocardial infarction, both BMMNCs and ACE-I reduce the pattern of pro-Ck response, probably contributing to prevent the deterioration of LV function observed in UT rats. PMID:18549470

  4. Effects of Small Molecule Calcium-Activated Chloride Channel Inhibitors on Structure and Function of Accessory Cholera Enterotoxin (Ace) of Vibrio cholerae

    PubMed Central

    Chatterjee, Tanaya; Sheikh, Irshad Ali; Chakravarty, Devlina; Chakrabarti, Pinak; Sarkar, Paramita; Saha, Tultul; Chakrabarti, Manoj K.; Hoque, Kazi Mirajul

    2015-01-01

    Cholera pathogenesis occurs due to synergistic pro-secretory effects of several toxins, such as cholera toxin (CTX) and Accessory cholera enterotoxin (Ace) secreted by Vibrio cholerae strains. Ace activates chloride channels stimulating chloride/bicarbonate transport that augments fluid secretion resulting in diarrhea. These channels have been targeted for drug development. However, lesser attention has been paid to the interaction of chloride channel modulators with bacterial toxins. Here we report the modulation of the structure/function of recombinant Ace by small molecule calcium-activated chloride channel (CaCC) inhibitors, namely CaCCinh-A01, digallic acid (DGA) and tannic acid. Biophysical studies indicate that the unfolding (induced by urea) free energy increases upon binding CaCCinh-A01 and DGA, compared to native Ace, whereas binding of tannic acid destabilizes the protein. Far-UV CD experiments revealed that the α-helical content of Ace-CaCCinh-A01 and Ace-DGA complexes increased relative to Ace. In contrast, binding to tannic acid had the opposite effect, indicating the loss of protein secondary structure. The modulation of Ace structure induced by CaCC inhibitors was also analyzed using docking and molecular dynamics (MD) simulation. Functional studies, performed using mouse ileal loops and Ussing chamber experiments, corroborate biophysical data, all pointing to the fact that tannic acid destabilizes Ace, inhibiting its function, whereas DGA stabilizes the toxin with enhanced fluid accumulation in mouse ileal loop. The efficacy of tannic acid in mouse model suggests that the targeted modulation of Ace structure may be of therapeutic benefit for gastrointestinal disorders. PMID:26540279

  5. Effects of Small Molecule Calcium-Activated Chloride Channel Inhibitors on Structure and Function of Accessory Cholera Enterotoxin (Ace) of Vibrio cholerae.

    PubMed

    Chatterjee, Tanaya; Sheikh, Irshad Ali; Chakravarty, Devlina; Chakrabarti, Pinak; Sarkar, Paramita; Saha, Tultul; Chakrabarti, Manoj K; Hoque, Kazi Mirajul

    2015-01-01

    Cholera pathogenesis occurs due to synergistic pro-secretory effects of several toxins, such as cholera toxin (CTX) and Accessory cholera enterotoxin (Ace) secreted by Vibrio cholerae strains. Ace activates chloride channels stimulating chloride/bicarbonate transport that augments fluid secretion resulting in diarrhea. These channels have been targeted for drug development. However, lesser attention has been paid to the interaction of chloride channel modulators with bacterial toxins. Here we report the modulation of the structure/function of recombinant Ace by small molecule calcium-activated chloride channel (CaCC) inhibitors, namely CaCCinh-A01, digallic acid (DGA) and tannic acid. Biophysical studies indicate that the unfolding (induced by urea) free energy increases upon binding CaCCinh-A01 and DGA, compared to native Ace, whereas binding of tannic acid destabilizes the protein. Far-UV CD experiments revealed that the α-helical content of Ace-CaCCinh-A01 and Ace-DGA complexes increased relative to Ace. In contrast, binding to tannic acid had the opposite effect, indicating the loss of protein secondary structure. The modulation of Ace structure induced by CaCC inhibitors was also analyzed using docking and molecular dynamics (MD) simulation. Functional studies, performed using mouse ileal loops and Ussing chamber experiments, corroborate biophysical data, all pointing to the fact that tannic acid destabilizes Ace, inhibiting its function, whereas DGA stabilizes the toxin with enhanced fluid accumulation in mouse ileal loop. The efficacy of tannic acid in mouse model suggests that the targeted modulation of Ace structure may be of therapeutic benefit for gastrointestinal disorders.

  6. ACE and platelet aggregation inhibitors from Tamarix hohenackeri Bunge (host plant of Herba Cistanches) growing in Xinjiang

    PubMed Central

    Xing, Yachao; Liao, Jing; Tang, Yingzhan; Zhang, Peng; Tan, Chengyu; Ni, Hui; Wu, Xueqin; Li, Ning; Jia, Xiaoguang

    2014-01-01

    Background: Tamarix hohenackeri Bunge is a salt cedar that grows widespread in the desert mountains in Xinjiang. T. hohenackeri has not been investigated earlier, although there are many reports of phytochemical work on other Tamarix species. Materials and Methods: To find out natural angiotensin-converting enzyme (ACE) inhibitor and platelet aggregation inhibitors, the bioactive extract (ethyl acetate [EtOAc] fraction) from the dried aerial parts of T. hohenackeri were investigated. The active fraction was purified by repeated column chromatography, including silica gel, Sephadex LH-20 column, medium-pressure liquid chromatography (MPLC) (polyamide column) and high-performance liquid chromatography (HPLC). The isolated major constituents were tested for their anti-platelet aggregation activity. Results: Bioassay-directed separation of the EtOAc fraction of the 70% ethanol extract from the air-dried aerial parts of T. hohenackeri led to the isolation of a new triterpenoid lactone (1), together with 13 known compounds (2-14). It was the first time to focus on screening bioactive constituents for this plant. The chemical structures were established on the basis of spectral data (ESI-MS and NMR). The results showed that the flavonoid compounds (7 and 8) and phenolic compounds (9, 10, 11, and 14) were potential ACE inhibitors. And the flavonoid compounds (5 and 7) showed significant anti-platelet aggregation activities. Conclusion: On the basis of the chemical and biological data, the material basis of ACE inhibitory activity for the active part was the phenolic constituents. However, the flavonoid compounds were responsible for the anti-platelet aggregation. The primary structure and activity relationship were also discussed respectively. PMID:24914275

  7. Prostacyclin: its pathogenic role in essential hypertension and the class effect of ACE inhibitors on prostaglandin metabolism.

    PubMed

    Rodríguez-García, J L; Villa, E; Serrano, M; Gallardo, J; García-Robles, R

    1999-01-01

    Angiotensin-converting enzyme inhibitors (ACEI) block degradation of bradykinin, and bradykinin stimulates prostacyclin synthesis. Therefore, we set out to determine whether the effects of ACE inhibitors on prostaglandin production in essential hypertensive patients are class effects or are dependent on ACE inhibitor structure. In addition, we studied whether hypertensives show an impaired capacity to synthesize vasodilator prostaglandins. To address these questions, we compared the effects of captopril (sulfhydryl-containing inhibitor), enalapril and ramipril (carboxyl-containing inhibitors) and fosinopril (phosphoryl-containing inhibitor) on blood pressure and urinary excretion of 6-keto-prostaglandin (PG) F1-alpha (the breakdown product of prostacyclin) in 44 mild-to-moderate essential hypertensive subjects before and 8 weeks after administration of an ACEI. We also studied prostacyclin excretion in 15 normotensive healthy controls. Levels of urinary 6-keto-PGF1-alpha (pg/ml) were measured by specific radioimmunoassay. Hypertensive subjects showed a lower excretion of 6-keto-PGF1-alpha than normotensive controls (212+/-147 vs 353+/-98 pg/ml, p < 0.001). All ACEI induced a significant decrease in MAP and increased the rate of excretion of the prostacyclin metabolite: C, 211+/-200 to 338+/-250 pg/ml, p < 0.05; E, 202+/-133 to 296+/-207 pg/ml, p < 0.05; R, 205+/-127 to 342+/-211 pg/ml, p < 0.05; F, 235+/-128 to 347+/-241 pg/ml, p < 0.05. In hypertensives (n = 44) the decrease in blood pressure correlated negatively with the rise in 6-keto-PGF1-alpha excretion (r = -0.51, p < 0.001). These data suggest that impaired prostacyclin biosynthesis in hypertensive patients could account for haemodynamic changes leading to the hypertensive state. Moreover, the hypotensive mechanisms of ACEI may be mediated by an increase in prostacyclin production; this effect seems to be class-dependent.

  8. ACE Inhibitor and ARB Medication Use among Medicaid Enrollees with Diabetes

    PubMed Central

    Lora, Claudia M.; Sokolovsky, Alexander W.; Touchette, Daniel R.; Jin, Jing; Xiaojing, Hu; Gao, Weihua; Gerber, Ben S.

    2013-01-01

    Objective To examine Ace-Inhibitor (ACEI)and Angiotensin Receptor Blockers (ARB) prescription and adherence patterns by race in diabetic Public Aid recipients. Design, Subjects, and Measures We analyzed prescription records of 27,529 adults age 18–64 with diabetes enrolled in the State of Illinois Public Aid program during 2007 who had at least one clinical indication for receiving an ACEI/ARB prescription. We calculated Proportion of Days Covered (PDC) to assess adherence. Multivariate models adjusted for age, gender, ACEI/ARB indication, and any significant interaction terms. Results Only 47.4% of individuals with at least one indication for ACEI/ARB had filled an ACEI/ARB prescription. African American men were more likely than Caucasian men to ever fill an ACEI/ARB prescription [Adjusted Odds Ratio, AOR (95% CI) 1.69 (1.55–1.83)]. Hispanic English and Spanish speaking men were also more likely than Caucasian men to ever fill an ACEI/ARB prescription [AOR (95% CI) 1.37 (1.16–1.62) and 1.27 (1.05–1.53), respectively]. Similarly, African American and Hispanic English and Spanish speaking women were more likely than Caucasian women to ever fill an ACEI/ARB prescription [AOR (95% CI) 1.70 (1.59–1.81)], 1.55 (1.36–1.76), and 1.98 (1.73–2.28), respectively]. However, African-Americans and Hispanics were less likely than Caucasians to achieve a PDC ≥ 80%. Compared to Caucasians, Hispanic Spanish speakers were the least likely to be adherent [AOR (95% CI) 0.49 (0.41–0.58)]. Furthermore, older individuals were more likely to achieve a PDC ≥ 80% than younger individuals. Conclusion African Americans and Hispanics with diabetes receiving public aid in Illinois were more likely than Caucasians to have filled at least one ACEI/ARB prescription. However, they were less adherent with these medications. Future studies should assess barriers to medication adherence in this population. PMID:23530300

  9. EARLY Treatment with azilsartan compared to ACE-inhibitors in anti-hypertensive therapy – rationale and design of the EARLY hypertension registry

    PubMed Central

    2013-01-01

    Background Arterial hypertension is highly prevalent but poorly controlled. Blood pressure (BP) reduction substantially reduces cardiovascular morbidity and mortality. Recent randomized, double-blind clinical trials demonstrated that azilsartan medoxomil (AZM) is more effective in reducing BP than the ubiquitary ACE inhibitor ramipril. Therefore, we aimed to test whether these can be verified under clinical practice conditions. Methods/Design The “Treatment with Azilsartan Compared to ACE-Inhibitors in Anti-Hypertensive Therapy” (EARLY) registry is a prospective, observational, national, multicenter registry with a follow-up of up to 12 months. It will include up to 5000 patients on AZM or ACE-inhibitor monotherapy in a ratio of 7 to 3. A subgroup of patients will undergo 24-hour BP monitoring. EARLY has two co-primary objectives: 1) Description of the safety profile of azilsartan and 2) achievement of BP targets based on recent national and international guidelines for patients treated with azilsartan in comparison to those treated with ACE-inhibitors. The most important secondary endpoints are the determination of persistence with treatment and the documentation of cardiovascular and renal events. Recruitment commenced in January 2012 and will be completed by February 2013. Conclusions The data obtained will supplement previous results from randomized controlled trials to document the potential value of utilizing azilsartan medoxomil in comparison to ACE-inhibitor treatment for target BP achievement in clinical practice. PMID:23819631

  10. Ace inhibitor therapy for heart failure in patients with impaired renal function: a review of the literature.

    PubMed

    Valika, Ali A; Gheorghiade, Mihai

    2013-03-01

    Heart failure syndromes are often associated with multi-organ dysfunction, and concomitant liver, renal, and neurologic involvement is very common. Neuro-hormonal antagonism plays a key role in the management of this syndrome, and angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are one of the cornerstones of therapy. Cardiorenal physiology is becoming more recognized in these patients with advanced heart failure, and the role of neuro-hormonal blockade in this setting is vaguely defined in the literature. Often, angiotensin-converting enzyme inhibitors are decreased or even withheld in these circumstances. The purpose of this article is to review the role and pathophysiology of ace inhibition and angiotensin receptor blockade in patients with acute and chronic heart failure syndromes and concomitant cardiorenal physiology.

  11. New and Improved Infrared Spectroscopy of Halogen-Containing Species for ACE-FTS Retrievals

    NASA Astrophysics Data System (ADS)

    Harrison, Jeremy J.

    2014-06-01

    The Atmospheric Chemistry Experiment Fourier transform spectrometer (ACE-FTS), onboard the SCISAT-1 satellite, is a high-resolution (0.02 cm-1) instrument covering the 750-4400 cm-1 spectral region in solar occultation mode. Launched in August 2003, the ACE-FTS has been taking atmospheric measurements for over ten years. With long atmospheric pathlengths (˜300 km) and the sun as a radiation source, the ACE-FTS provides a low detection threshold for trace species in the atmosphere. In fact, it measures the vertical profiles of more molecules in the atmosphere than any other satellite instrument.

    Fluorine- and chlorine-containing molecules in the atmosphere are very strong greenhouse gases, meaning that even small amounts of these gases contribute significantly to the radiative forcing of climate. Chlorofluorocarbons (CFCs) and hydrochlorofluorocarbons (HCFCs) are regulated by the 1987 Montreal Protocol because they deplete the ozone layer. Hydrofluorocarbons (HFCs), which do not deplete the ozone layer and are not regulated by the Montreal Protocol, have been introduced as replacements for CFCs and HCFCs. HFCs have global-warming potentials many times greater than carbon dioxide, and are increasing in the atmosphere at a very fast rate. The quantification of the atmospheric abundances of such molecules from measurements taken by the ACE-FTS and other satellite instruments crucially requires accurate quantitative infrared spectroscopy. HITRAN contains absorption cross section datasets for a number of these species, but many of them have minor deficiencies that introduce systematic errors into satellite retrievals. This talk will focus on new and improved laboratory measurements for a number of important halogenated species.

  12. Captopril improves postresuscitation hemodynamics protective against pulmonary embolism by activating the ACE2/Ang-(1-7)/Mas axis.

    PubMed

    Xiao, Hong-Li; Li, Chun-Sheng; Zhao, Lian-Xing; Yang, Jun; Tong, Nan; An, Le; Liu, Qi-Tong

    2016-11-01

    Acute pulmonary embolism (APE) has a very high mortality rate, especially at cardiac arrest and even after the return of spontaneous circulation (ROSC). This study investigated the protective effect of the angiotensin-converting enzyme (ACE) inhibitor captopril on postresuscitation hemodynamics, in a porcine model of cardiac arrest established by APE. Twenty-nine Beijing Landrace pigs were infused with an autologous thrombus leading to cardiac arrest and subjected to standard cardiopulmonary resuscitation and thrombolysis. Ten resuscitated pigs were randomly and equally apportioned to receive either captopril (22.22 mg/kg) infusion or the same volume saline, 30 min after ROSC. Hemodynamic changes and ACE-Ang II-angiotensin II type 1 receptor (AT1R) and ACE2/Ang-(1-7)/Mas receptor axis levels were determined. APE was associated with a decline in mean arterial pressure and a dramatic increase in pulmonary artery pressure and mean right ventricular pressure. After ROSC, captopril infusion was associated with significantly lower mean right ventricular pressure and systemic and pulmonary vascular resistance, faster heart rate, and higher Ang-(1-7) levels, ACE2/ACE, and Ang-(1-7)/Ang II, compared with the saline infusion. The ACE2/Ang-(1-7)/Mas pathway correlated negatively with external vascular lung water and pulmonary vascular permeability and positively with the right cardiac index. In conclusion, in a pig model of APE leading to cardiac arrest, captopril infusion was associated with less mean right ventricular pressure overload after resuscitation, compared with saline infusion. The reduction in systemic and pulmonary vascular resistance associated with captopril may be by inhibiting the ACE-Ang II-AT1R axis and activating the ACE2/Ang-(1-7)/Mas axis.

  13. A novel design of combining the angiotensin converting enzyme (ACE) inhibitor captopril with the angiotensin receptor blocker (ARB) losartan using homo coupling via PEG diacid linker.

    PubMed

    Hashemzadeh, Mehrnoosh; Park, Shery; Ju, Hee; Movahed, Mohammad R

    2013-12-01

    Cardiovascular disease is the leading cause of death in American adults. Furthermore, the incidence of congestive heart failure is on the rise as a major cause of hospitalization and mortality in this population. Angiotensin Converting Enzyme (ACE) inhibitors prevent the production of angiotensin II, which has been shown to reduce mortality in patients with congestive heart failure. Angiotensin II receptor blockers (ARB) were developed as a direct inhibitor of angiotensin II. ARBs have been shown to be effective in the treatment of patients with systolic heart failure but do not cause chronic coughing which is a common side effect of ACE inhibitors. In theory, a compound that has the combined effect of an ACE inhibitor and an ARB should be more effective in treating heart failure patients than either agents alone. Therefore, the purpose of this manuscript is to design and discuss the benefits of a new molecule, which combines captopril, an ACE inhibitor, with losartan, an ARB. In this experiment Captopril and Losartan were modified and synthesized separately and combined by homo or mono coupling. This was achieved by taking advantage of PEG (Polyethylene glycol) as a linker. It is expected that this molecule will have the combined modes of action of both ACEs and ARBs. Benefits from combination therapy include; increased efficacy, reduced adverse effects, convenience, compliance, and prolonged duration. Consequently, this combined molecule is expected to block the production of angiotensin II more efficiently and effectively. Although captopril and losartan work in the same system by blocking the effect of angiotensin II they have different action sites and mechanisms some patents are also discussed. Losartan blocks the AT1 receptor which is expressed on the cell surface, while captopril inhibits ACE, preventing production of angiotensin II, which is present in both the plasma and on the cell surface, especially on endothelial and smooth muscle cells.

  14. ACE inhibitors hypothesis generation for selective design, synthesis and biological evaluation of 3-mercapto-2-methyl-propanoyl-pyrrolidine-3-imine derivatives as antihypertensive agents.

    PubMed

    Ismail, Mohamed A H; Nabil Aboul-Enein, M; Abouzid, Khaled A M; Abou El Ella, Dalal A; Ismail, Nasser S M

    2009-05-15

    A series of new 3-mercapto-2-methyl-propanoyl-pyrrolidine derivatives (V, VIa-e) were designed. A new validated ACE inhibitors pharmacophore model (hypothesis) was generated for the first time in this research from the biologically active (frozen) conformation of Lisinopril-Human ACE complex that was downloaded from PDB, using stepwise technique of CATALYST modules. The molecular modeling compare-fit study of the designed molecules (V, VIa-e), with such ACE inhibitors hypothesis was fulfilled, and several compounds showed significant high simulation fit values. The compounds with high fit values were synthesized and biologically evaluated in vivo as hypotensive agents. It appears that the in vivo hypotensive activity of compounds V, VIa, VIb, and VIe was consistent with their molecular modeling results, and compound VIe showed the highest activity in comparison to Captopril.

  15. The effects of drug market regulation on pharmaceutical prices in Europe: overview and evidence from the market of ACE inhibitors.

    PubMed

    von der Schulenburg, Fritz; Vandoros, Sotiris; Kanavos, Panos

    2011-11-21

    This study provides an overview of policy measures targeting pharmaceutical expenditure in Europe and analyses their impact on originator pharmaceutical prices. Panel data methods are used to examine the market of ACE Inhibitors in six European countries (Denmark, France, Germany, Netherlands, Sweden, United Kingdom) over period 1991-2006. We find that although some measures are effective in reducing originator prices, others appear to have an insignificant effect. Results suggest that supply side measures such as mandatory generic substitution, regressive pharmacy mark-ups and claw-backs are effective in reducing pharmaceuticals prices. Results are not as strong for demand side measures. Profit controls and the use of cost-effectiveness analysis appear to have a negative effect on prices, while results on reference pricing are inconclusive. Findings also indicate that, although originator prices are not immediately affected by generic entry, they may be influenced by changes in generic prices post patent expiry.

  16. Refill Adherence in Relation to Substitution and the Use of Multiple Medications: A Nationwide Population Based Study on New ACE-Inhibitor Users

    PubMed Central

    Jönsson, Anna K.; Lesén, Eva; Mårdby, Ann-Charlotte; Sundell, Karolina Andersson

    2016-01-01

    Objective Generic substitution has contributed to economic savings but switching products may affect patient adherence, particularly among those using multiple medications. The aim was to analyse if use of multiple medications influenced the association between switching products and refill adherence to angiotensin-converting-enzyme (ACE) inhibitors in Sweden. Study Design and Setting New users of ACE-inhibitors, starting between 1 July 2006 and 30 June 2007, were identified in the Swedish Prescribed Drug Register. Refill adherence was assessed using the continuous measure of medication acquisition (CMA) and analysed with linear regression and analysis of covariance. Results The study population included 42735 individuals whereof 51.2% were exposed to switching ACE-inhibitor and 39.6% used multiple medications. Refill adherence was higher among those exposed to switching products than those not, but did not vary depending on the use of multiple medications or among those not. Refill adherence varied with age, educational level, household income, country of birth, previous hospitalisation and previous cardiovascular diagnosis. Conclusion The results indicate a positive association between refill adherence and switching products, mainly due to generic substitution, among new users of ACE-inhibitors in Sweden. This association was independent of use of multiple medications. PMID:27192203

  17. Screening of inhibitors of angiotensin-converting enzyme (ACE) employing high performance liquid chromatography-electrospray ionization triple quadrupole mass spectrometry (HPLC-ESI-QqQ-MS).

    PubMed

    Musharraf, Syed Ghulam; Bhatti, Muhammad Salman; Choudhary, Muhammad Iqbal; Rahman, Atta-Ur

    2017-04-01

    Angiotensin-converting enzyme (ACE) plays a key role in regulating blood pressure in the body by converting the angiotensin I (AI) into angiotensin II (AII). Angiotensin II is a potent vaso-active peptide that causes arterioles to constrict, resulting in increased blood pressure. A rapid and sensitive method for the identification of inhibitors of ACE was developed, and optimized employing HPLC-ESI-QqQ-MS. In this assay, angiotensin I substrate was converted into the product angiotensin II with the catalytic action of ACE. A calibration curve for depleting concentration of angiotensin I was developed and linearity of R(2)=0.999 with a remarkably low concentration of substrate range 20-200nM. The limit of detection and quantification of angiotensin I was found to be 1.93 and 5.84nM, respectively. The enzymatic reaction was optimized for incubation time, concentration, and volume of enzyme and substrate. All reactions were performed at 37°C at pH7.5 with standard incubation time of 20min. Two standard inhibitors, Captopril and Lisinopril, were checked through the newly developed method for their inhibitory potential, and their IC50 values were found to be 3.969 and 0.852μM, respectively. Reproducibility and precision analysis of different experiments showed <9.9% RSD. The developed method can be used for the identification of new ACE inhibitors.

  18. The ACE inhibitor ( sup 3 H)SQ29,852 identifies a high affinity recognition site located in the human temporal cortex

    SciTech Connect

    Barnes, N.M.; Costall, B.; Egli, P.; Horovitz, Z.P.; Ironside, J.W.; Naylor, R.J.; Williams, T.J. )

    1990-07-01

    The angiotensin converting enzyme (ACE) inhibitor ({sup 3}H)SQ29,852 identified a single high affinity recognition site (defined by 10.0 microM captopril) in the human temporal cortex (pKD 8.62 +/- 0.03; Bmax 248 +/- 24 fmol mg-1 protein, mean +/- S.E.M., n = 4). ACE inhibitors and thiorphan competed to a similar level for the ({sup 3}H)SQ29,852 binding site in the human temporal cortex with a rank order of affinity (pKi values mean +/- S.E.M., n = 3), lisinopril (9.49 +/- 0.02), captopril (9.16 +/- 0.08), SQ29,852 (8.58 +/- 0.04), epicaptopril (7.09 +/- 0.08), fosinopril (7.08 +/- 0.05) and thiorphan (6.40 +/- 0.04). Since this rank order of affinity is similar to the affinity of these compounds to inhibit brain ACE activity it is concluded that ({sup 3}H)SQ29,852 selectively labels the inhibitor recognition site of ACE in the human temporal cortex.

  19. Renal Expression of FGF23 in Progressive Renal Disease of Diabetes and the Effect of Ace Inhibitor

    PubMed Central

    Benigni, Ariela; Corna, Daniela; Tomasoni, Susanna; Rottoli, Daniela; Gaspari, Flavio; Remuzzi, Giuseppe; Zoja, Carlamaria

    2013-01-01

    Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone mainly produced by bone that acts in the kidney through FGF receptors and Klotho. Here we investigated whether the kidney was an additional source of FGF23 during renal disease using a model of type 2 diabetic nephropathy. Renal expression of FGF23 and Klotho was assessed in Zucker diabetic fatty (ZDF) and control lean rats at 2, 4, 6, 8 months of age. To evaluate whether the renoprotective effect of angiotensin converting enzyme (ACE) inhibitor in this model was associated with changes in FGF23 and Klotho, ZDF rats received ramipril from 4, when proteinuric, to 8 months of age. FGF23 mRNA was not detectable in the kidney of lean rats, nor of ZDF rats at 2 months of age. FGF23 became measurable in the kidney of diabetic rats at 4 months and significantly increased thereafter. FGF23 protein localized in proximal and distal tubules. Renal Klotho mRNA and protein decreased during time in ZDF rats. As renal disease progressed, serum phosphate levels increased in parallel with decline of fractional phosphorus excretion. Ramipril limited proteinuria and renal injury, attenuated renal FGF23 upregulation and ameliorated Klotho expression. Ramipril normalized serum phosphate levels and tended to increase fractional phosphorus excretion. These data indicate that during progressive renal disease the kidney is a site of FGF23 production which is limited by ACE inhibition. Interfering pharmacologically with the delicate balance of FGF23 and phosphorus in diabetes may have implications in clinics. PMID:23967103

  20. The ACE inhibitors enalapril and captopril modulate cytokine responses in Balb/c and C57Bl/6 normal mice and increase CD4(+)CD103(+)CD25(negative) splenic T cell numbers.

    PubMed

    Albuquerque, Deijanira; Nihei, Jorge; Cardillo, Fabíola; Singh, Ram

    2010-01-01

    Increasing evidence implies beneficial effects of angiotensin-converting enzyme (ACE) inhibitors beyond those of their original indications to control hypertension. One of the most attractive non-hemodynamic properties of ACE inhibitors is their ability to regulate cytokine production. The mechanism(s) underlying the role of ACE inhibitors on cytokine synthesis are not well understood but they have traditionally been attributed to the inhibition of angiotensin (Ang) II formation. In fact, it has been extensively demonstrated that ACE inhibitors decrease Ang II-induced production of proinflammatory cytokines and chemokines. However, it is not well described if inhibition of endogenous Ang II generation by ACE inhibitors modulates systemic cytokine production in mice. To verify that, in this work, we investigated the effects of treatment with the ACE inhibitors enalapril and captopril on cytokine synthesis in C57Bl/6 and Balb/c mice. Our results show that enalapril up regulates IL-10 produced by splenocytes from Balb/c and C57Bl/6 mice and captopril increased it only in Balb/c mice. Furthermore, CD4(+)CD103(+) presented increased IL-10 production after enalapril treatment. Enalapril as well as captopril short-term treatment enhanced IL-2 synthesis in Balb/c mice. Besides, enhanced IL-2 and IL-10 levels correlates with increased CD4(+)CD103(+)CD25(negative) T cells numbers in spleens from enalapril-treated mice.

  1. Renoprotective effects of combined SGLT2 and ACE inhibitor therapy in diabetic Dahl S rats

    PubMed Central

    Kojima, Naoki; Williams, Jan M; Slaughter, Tiffani N; Kato, Sota; Takahashi, Teisuke; Miyata, Noriyuki; Roman, Richard J

    2015-01-01

    This study examined whether control of hyperglycemia with a new SGLT2 inhibitor, luseogliflozin, given alone or in combination with lisinopril could prevent the development of renal injury in diabetic Dahl salt-sensitive (Dahl S) rats treated with streptozotocin (Dahl-STZ). Blood glucose levels increased from normoglycemic to hyperglycemic levels after treatment of STZ in Dahl S rats. Chronic treatment of Dahl-STZ rats with luseogliflozin (10 mg/kg/day) increased the fractional excretion of glucose and normalized blood glucose and HbA1c levels. Lisinopril (20 mg/kg/day) reduced blood pressure from 145 ± 9 to 120 ± 5 mmHg in Dahl-STZ rats, while luseogliflozin had no effect on blood pressure. Combination therapy reduced blood pressure more than that seen in the rats treated with luseogliflozin or lisinopril alone. Dahl-STZ rats exhibited hyperfiltration, mesangial matrix expansion, severe progressive proteinuria, focal glomerulosclerosis and interstitial fibrosis. Control of hyperglycemia with luseogliflozin reduced the degree of hyperfiltration and renal injury but had no effect on blood pressure or the development of proteinuria. Treatment with lisinopril reduced hyperfiltration, proteinuria and renal injury in Dahl-STZ rats. Combination therapy afforded greater renoprotection than administration of either drug alone. These results suggest that long-term control of hyperglycemia with luseogliflozin, especially in combination with lisinopril to lower blood pressure, attenuates the development of renal injury in this rat model of advanced diabetic nephropathy. PMID:26169541

  2. The sulphydryl containing ACE inhibitor Zofenoprilat protects coronary endothelium from Doxorubicin-induced apoptosis.

    PubMed

    Monti, Martina; Terzuoli, Erika; Ziche, Marina; Morbidelli, Lucia

    2013-10-01

    Pediatric and adult cancer patients, following the use of the antitumor drug Doxorubicin develop cardiotoxicity. Pharmacological protection of microvascular endothelium might produce a double benefit: (i) reduction of myocardial toxicity (the primary target of Doxorubicin action) and (ii) maintenance of the vascular functionality for the adequate delivery of chemotherapeutics to tumor cells. This study was aimed to evaluate the mechanisms responsible of the protective effects of the angiotensin converting enzyme inhibitor (ACEI) Zofenoprilat against the toxic effects exerted by Doxorubicin on coronary microvascular endothelium. We found that exposure of endothelial cells to Doxorubicin (0.1-1μM range) impaired cell survival by promoting their apoptosis. ERK1/2 related p53 activation, but not reactive oxygen species, was responsible for Doxorubicin induced caspase-3 cleavage. P53 mediated-apoptosis and impairment of survival were reverted by treatment with Zofenoprilat. The previously described PI-3K/eNOS/endogenous fibroblast growth factor signaling was not involved in the protective effect, which, instead, could be ascribed to cystathionine gamma lyase dependent availability of H2S from Zofenoprilat. Furthermore, considering the tumor environment, the treatment of endothelial/tumor co-cultures with Zofenoprilat did not affect the antitumor efficacy of Doxorubicin. In conclusion the ACEI Zofenoprilat exerts a protective effect on Doxorubicin induced endothelial damage, without affecting its antitumor efficacy. Thus, sulfhydryl containing ACEI may be a useful therapy for Doxorubicin-induced cardiotoxicity.

  3. ACE Inhibitor and Angiotensin Receptor Blocker Use and Mortality in Patients with Chronic Kidney Disease

    PubMed Central

    Molnar, Miklos Z; Kalantar-Zadeh, Kamyar; Lott, Evan H; Lu, Jun Ling; Malakauskas, Sandra M; Ma, Jennie Z; Quarles, Darryl L; Kovesdy, Csaba P

    2014-01-01

    Objective To assess the association between ACEI/ARB use and mortality in CKD patients. Background There is insufficient evidence about the association of angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARBs) with mortality in chronic kidney disease (CKD) patients. Methods A logistic regression analysis was used to calculate the propensity of ACEI/ARB initiation in 141,413 US veterans with non-dialysis CKD previously unexposed to ACEI/ARB treatment. We examined the association of ACEI/ARB administration with all-cause mortality in patients matched by propensity scores, using the Kaplan-Meier method and Cox models in “intention-to-treat” analyses, and in generalized linear models with binary outcomes and inverse probability treatment weighing (IPTW) in “as-treated” analyses. Results The mean±SD age of the patients at baseline was 75±10 years, 8% of patients were black, and 22% were diabetic. ACEI/ARB administration was associated with significantly lower risk of mortality both in the intention-to-treat analysis (HR=0.81; 95%CI: 0.78-0.84, p<0.001) and in the as-treated analysis with IPTW (OR=0.37; 95%CI: 0.34-0.41, p<0.001). The association of ACEI/ARB treatment with lower risk of mortality was present in all examined subgroups. Conclusions In this large contemporary cohort of non-dialysis dependent CKD patients, ACEI/ARB administration was associated with greater survival. PMID:24269363

  4. Sources of heterogeneity in case-control studies on associations between statins, ACE-inhibitors, and proton pump inhibitors and risk of pneumonia.

    PubMed

    de Groot, Mark C H; Klungel, Olaf H; Leufkens, Hubert G M; van Dijk, Liset; Grobbee, Diederick E; van de Garde, Ewoudt M W

    2014-10-01

    The heterogeneity in case-control studies on the associations between community-acquired pneumonia (CAP) and ACE-inhibitors (ACEi), statins, and proton pump inhibitors (PPI) hampers translation to clinical practice. Our objective is to explore sources of this heterogeneity by applying a common protocol in different data settings. We conducted ten case-control studies using data from five different health care databases. Databases varied on type of patients (hospitalised vs. GP), level of case validity, and mode of exposure ascertainment (prescription or dispensing based). Identified CAP patients and controls were matched on age, gender, and calendar year. Conditional logistic regression was used to calculate odds ratios (OR) for the associations between the drugs of interest and CAP. Associations were adjusted by a common set of potential confounders. Data of 38,742 cases and 118,019 controls were studied. Comparable patterns of variation between case-control studies were observed for ACEi, statins and PPI use and pneumonia risk with adjusted ORs varying from 1.04 to 1.49, 0.82 to 1.50 and 1.16 to 2.71, respectively. Overall, higher ORs were found for hospitalised CAP patients matched to population controls versus GP CAP patients matched to population controls. Prevalence of drug exposure was higher in dispensing data versus prescription data. We show that case-control selection and methods of exposure ascertainment induce bias that cannot be adjusted for and to a considerable extent explain the heterogeneity in results obtained in case-control studies on statins, ACEi and PPIs and CAP. The common protocol approach helps to better understand sources of variation in observational studies.

  5. Efficacy and Safety of Complete RAAS Blockade with ALISKIREN in Patients with Refractory Proteinuria Who were already on Combined ACE Inhibitor, ARB, and Aldosterone Antagonist

    PubMed Central

    Sreelatha, M

    2016-01-01

    Introduction Proteinuria is always associated with intrinsic kidney disese and is a strong predictor of later development of End Stage Renal Disease (ESRD). As Renin Angiotensin Aldosterone System (RAAS) has a role in mediating proteinuria, inhibitors of this system are renoprotective and patients with refractory proteinuria are put on a combination of these agents. The routinely employed triple blockade of RAAS with Angiotensin Converting Enzyme (ACE) inhibitor, ARB and Aldosterone antagonist has many limitations. Addition of Aliskiren to this combination suppresses the RAAS at the earliest stage and can offset many of these limitations. Aim This study was conducted to assess the safety and efficacy of complete RAAS blockade by the addition of Aliskiren in those patients with refractory proteinuria who were already on triple blockade with ACE inhibitor, ARB and Aldosterone antagonist. Settings This study was conducted in Nephrology Department, Calicut Medical College. Materials and Methods A total of 36 patients with refractory proteinuria who were already on ACE inhibitor, ARB and Aldosterone antagonist were divided in to two groups A and B. Group A received Aliskiren in addition to the above combination whereas group B continued the same treatment for 12 weeks. Efficacy of the treatment was assessed by recording 24hr urine protein and safety by S.Creatinine, S.Potassium every 2 weeks of the treatment period. Statistical Analysis Statistical analysis of the lab values was done using SPSS software. Unpaired t-test, Paired t-test and Chi-square test were done for data analysis. Results Statistical analysis revealed that addition of Aliskiren to the combination therapy with ACE inhibitor+ ARB+ Aldosterone antagonist offers no advantage. But mean reduction in proteinuria was more with Group A than Group B. There is no statistically significant change in S.Creatinine and S.Potassium at the end of treatment. Conclusion As proteinuria is a strong risk factor for

  6. ACED IT: A Tool for Improved Ethical and Moral Decision-Making

    ERIC Educational Resources Information Center

    Kreitler, Crystal Mata; Stenmark, Cheryl K.; Rodarte, Allen M.; Piñón DuMond, Rebecca

    2014-01-01

    Numerous examples of unethical organizational decision-making highlighted in the media have led many to question the general moral perception and ethical judgments of individuals. The present study examined two forms of a straightforward ethical decision-making (EDM) tool (ACED IT cognitive map) that could be a relatively simple instrument for…

  7. Antifibrotic medication using a combination of N-acetyl-L-cystein (NAC) and ACE inhibitors can prevent the recurrence of Dupuytren's disease.

    PubMed

    Knobloch, Karsten; Redeker, Joern; Vogt, Peter M

    2009-11-01

    Dupuytren's disease is a progress fibromatosis of unknown origin first described in 1831. Nonoperative treatment options have been suggested involving radiation therapy, vitamin E, local injection therapy suing calcium channel blockers, interferon, corticosteroids or collagenase. Transforming growth factor-beta1 (TGF-beta1) and its downstream Smad signalling system is well established as a key player during fibrogenesis. A number of in vitro experiments have been assessed the blockade of TGF-beta1 and TGF-beta 2. Clinically, a number of antifibrotic agents are available such as N-acetyl-L-cysteins (NAC) as well as angiotensin-converting enzyme (ACE) inhibitors or AT II antagonists. However, to date none of the well known substances has been tested clinically in fibromatosis such as Dupuytren's disease especially to prevent recurrences after surgical release. Antifibrotic medication using a combination of N-acetyl-L-cystein (NAC) and ACE inhibitor can prevent the recurrence of Dupyutren's disease. Given the fact that recurrence rate in Dupuytren's disease is high and unpredictable after surgical release, an antifibrotic intervention might be worthwhile to consider in the clinical setting. Antifibrotic agents inhibit TGF-beta1, which play a key role in fibromatosis. Thus, antifibrotic medication might reduce the recurrence rate in fibromatosis such as Dupuytren's disease in a clinical significant way.

  8. New and improved infra-red absorption cross sections and ACE-FTS retrievals of carbon tetrachloride (CCl4)

    NASA Astrophysics Data System (ADS)

    Harrison, Jeremy J.; Boone, Christopher D.; Bernath, Peter F.

    2017-01-01

    Carbon tetrachloride (CCl4) is one of the species regulated by the Montreal Protocol on account of its ability to deplete stratospheric ozone. As such, the inconsistency between observations of its abundance and estimated sources and sinks is an important problem requiring urgent attention (Carpenter et al., 2014) [5]. Satellite remote-sensing has a role to play, particularly limb sounders which can provide vertical profiles into the stratosphere and therefore validate stratospheric loss rates in atmospheric models. This work is in two parts. The first describes new and improved high-resolution infra-red absorption cross sections of carbon tetrachloride/dry synthetic air over the spectral range 700-860 cm-1 for a range of temperatures and pressures (7.5-760 Torr and 208-296 K) appropriate for atmospheric conditions. This new cross-section dataset improves upon the one currently available in the HITRAN and GEISA databases. The second describes a new, preliminary ACE-FTS carbon tetrachloride retrieval that improves upon the v3.0/v3.5 data products, which are biased high by up to 20-30% relative to ground measurements. Making use of the new spectroscopic data, this retrieval also improves the microwindow selection, contains additional interfering species, and utilises a new instrumental lineshape; it will form the basis for the upcoming v4.0 CCl4 data product.

  9. Renin-angiotensin-aldosterone system inhibition: overview of the therapeutic use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists, and direct renin inhibitors.

    PubMed

    Mercier, Kelly; Smith, Holly; Biederman, Jason

    2014-12-01

    Angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) therapy in hypertensive diabetic patients with macroalbuminuria, microalbuminuria, or normoalbuminuria has been repeatedly shown to improve cardiovascular mortality and reduce the decline in glomerular filtration rate. Renin-angiotensin-aldosterone system (RAAS) blockade in normotensive diabetic patients with normoalbuminuria or microalbuminuria cannot be advocated at present. Dual RAAS inhibition with ACE inhibitors plus ARBs or ACE inhibitors plus direct renin inhibitors has failed to improve cardiovascular or renal outcomes but has predisposed patients to serious adverse events.

  10. ACE inhibitors and angiotensin II receptor blockers in IgA nephropathy with mild proteinuria: the ACEARB study.

    PubMed

    Pozzi, Claudio; Del Vecchio, Lucia; Casartelli, Donatella; Pozzoni, Pietro; Andrulli, Simeone; Amore, Alessandro; Peruzzi, Licia; Coppo, Rosanna; Locatelli, Francesco

    2006-01-01

    Few studies have investigated IgA nephropathy patients presenting with 'favorable' clinical features at onset, such as normal renal function, proteinuria<1 g/24 hours and the absence of hypertension, and no controlled clinical trials have tested the effects of treatment in such patients who may nevertheless develop end-stage renal disease. It is therefore important to find a well-tolerated and economic therapy capable of decreasing their risk of high proteinuria and blood pressure levels. The aim of this multicenter open-label randomized clinical trial is to test whether blocking the renin-angiotensin system (RAS) decreases the risk of progression in patients aged 3-60 years with biopsy-proven benign IgA glomerulonephritis, proteinuria levels of 0.3-0.9 g/24 hours, and normal renal function and blood pressure. The RAS is blocked by first using a single drug class (angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker), and then combining the 2 classes as soon as the 1-drug blockade has become ineffective. We plan to enroll 378 patients over the next 3 years and randomize them to receive ramipril 5 mg/day (3 mg/m2 in children) (group A), irbesartan 300 mg/day (175 mg/m 2 in children) (group B) or supportive therapy (group C); if an increase in proteinuria of at least 50% from baseline is detected after 6 months of treatment, the other RAS inhibitor will be added. The observation period will be at least 5 years (except in the case of the development of the primary end point).

  11. ACE--Some Issues.

    ERIC Educational Resources Information Center

    Campbell, Annie, Ed.; Curtin, Penelope, Ed.

    This publication contains four papers that identify issues within the adult and community education (ACE) sector. "Overview" (Annie Campbell, Peter Thomson) considers what defines ACE; who offers ACE programs; who participates in ACE programs and who does not participate; what are the barriers to participation; who is responsible for…

  12. A genome-wide association study identifies variants in KCNIP4 associated with ACE inhibitor-induced cough.

    PubMed

    Mosley, J D; Shaffer, C M; Van Driest, S L; Weeke, P E; Wells, Q S; Karnes, J H; Velez Edwards, D R; Wei, W-Q; Teixeira, P L; Bastarache, L; Crawford, D C; Li, R; Manolio, T A; Bottinger, E P; McCarty, C A; Linneman, J G; Brilliant, M H; Pacheco, J A; Thompson, W; Chisholm, R L; Jarvik, G P; Crosslin, D R; Carrell, D S; Baldwin, E; Ralston, J; Larson, E B; Grafton, J; Scrol, A; Jouni, H; Kullo, I J; Tromp, G; Borthwick, K M; Kuivaniemi, H; Carey, D J; Ritchie, M D; Bradford, Y; Verma, S S; Chute, C G; Veluchamy, A; Siddiqui, M K; Palmer, C N A; Doney, A; MahmoudPour, S H; Maitland-van der Zee, A H; Morris, A D; Denny, J C; Roden, D M

    2016-06-01

    The most common side effect of angiotensin-converting enzyme inhibitor (ACEi) drugs is cough. We conducted a genome-wide association study (GWAS) of ACEi-induced cough among 7080 subjects of diverse ancestries in the Electronic Medical Records and Genomics (eMERGE) network. Cases were subjects diagnosed with ACEi-induced cough. Controls were subjects with at least 6 months of ACEi use and no cough. A GWAS (1595 cases and 5485 controls) identified associations on chromosome 4 in an intron of KCNIP4. The strongest association was at rs145489027 (minor allele frequency=0.33, odds ratio (OR)=1.3 (95% confidence interval (CI): 1.2-1.4), P=1.0 × 10(-8)). Replication for six single-nucleotide polymorphisms (SNPs) in KCNIP4 was tested in a second eMERGE population (n=926) and in the Genetics of Diabetes Audit and Research in Tayside, Scotland (GoDARTS) cohort (n=4309). Replication was observed at rs7675300 (OR=1.32 (1.01-1.70), P=0.04) in eMERGE and at rs16870989 and rs1495509 (OR=1.15 (1.01-1.30), P=0.03 for both) in GoDARTS. The combined association at rs1495509 was significant (OR=1.23 (1.15-1.32), P=1.9 × 10(-9)). These results indicate that SNPs in KCNIP4 may modulate ACEi-induced cough risk.

  13. ACE and ACE2 in kidney disease

    PubMed Central

    Mizuiri, Sonoo; Ohashi, Yasushi

    2015-01-01

    Renin angiotensin system (RAS) activation has a significant influence on renal disease progression. The classical angiotensin-converting enzyme (ACE)-angiotensin II (Ang II)-Ang II type 1 (AT1) axis is considered to control the effects of RAS activation on renal disease. However, since its discovery in 2000 ACE2 has also been demonstrated to have a significant impact on the RAS. The synthesis and catabolism of Ang II are regulated via a complex series of interactions, which involve ACE and ACE2. In the kidneys, ACE2 is expressed in the proximal tubules and less strongly in the glomeruli. The synthesis of inactive Ang 1-9 from Ang I and the catabolism of Ang II to produce Ang 1-7 are the main functions of ACE2. Ang 1-7 reduces vasoconstriction, water retention, salt intake, cell proliferation, and reactive oxygen stress, and also has a renoprotective effect. Thus, in the non-classical RAS the ACE2-Ang 1-7-Mas axis counteracts the ACE-Ang II-AT1 axis. This review examines recent human and animal studies about renal ACE and ACE2. PMID:25664248

  14. An additive effect of anti-PAI-1 antibody to ACE inhibitor on slowing the progression of diabetic kidney disease.

    PubMed

    Gu, Chunyan; Zhang, Jiandong; Noble, Nancy A; Peng, Xiao-Rong; Huang, Yufeng

    2016-11-01

    While angiotensin II blockade slows the progression of diabetic nephropathy, current data suggest that it alone cannot stop the disease process. New therapies or drug combinations will be required to further slow or halt disease progression. Inhibition of plasminogen activator inhibitor type 1 (PAI-1) aimed at enhancing ECM degradation has shown therapeutic potential in diabetic nephropathy. Here, using a mouse model of type diabetes, the maximally therapeutic dose of the PAI-1-neutralizing mouse monoclonal antibody (MEDI-579) was determined and compared with the maximally effective dose of enalapril. We then examined whether addition of MEDI-579 to enalapril would enhance the efficacy in slowing the progression of diabetic nephropathy. Untreated uninephrectomized diabetic db/db mice developed progressive albuminuria and glomerulosclerosis associated with increased expression of transforming growth factor (TGF)-β1, PAI-1, type IV collagen, and fibronectin from weeks 18 to 22, which were reduced by MEDI-579 at 3 mg/kg body wt, similar to enalapril given alone from weeks 12 to 22 Adding MEDI-579 to enalapril from weeks 18 to 22 resulted in further reduction in albuminuria and markers of renal fibrosis. Renal plasmin generation was dramatically reduced by 57% in diabetic mice, a decrease that was partially reversed by MEDI-579 or enalapril given alone but was further restored by these two treatments given in combination. Our results suggest that MEDI-579 is effective in slowing the progression of diabetic nephropathy in db/db mice and that the effect is additive to ACEI. While enalapril is renal protective, the add-on PAI-1 antibody may offer additional renoprotection in progressive diabetic nephropathy via enhancing ECM turnover.

  15. Adverse cardiac effects of exogenous angiotensin 1-7 in rats with subtotal nephrectomy are prevented by ACE inhibition

    PubMed Central

    Griggs, Karen; Patel, Sheila K.

    2017-01-01

    We previously reported that exogenous angiotensin (Ang) 1–7 has adverse cardiac effects in experimental kidney failure due to its action to increase cardiac angiotensin converting enzyme (ACE) activity. This study investigated if the addition of an ACE inhibitor (ACEi) to Ang 1–7 infusion would unmask any beneficial effects of Ang 1–7 on the heart in experimental kidney failure. Male Sprague–Dawley rats underwent subtotal nephrectomy (STNx) and were treated with vehicle, the ACEi ramipril (oral 1mg/kg/day), Ang 1–7 (subcutaneous 24 μg/kg/h) or dual therapy (all groups, n = 12). A control group (n = 10) of sham-operated rats were also studied. STNx led to hypertension, renal impairment, cardiac hypertrophy and fibrosis, and increased both left ventricular ACE2 activity and ACE binding. STNx was not associated with changes in plasma levels of ACE, ACE2 or angiotensin peptides. Ramipril reduced blood pressure, improved cardiac hypertrophy and fibrosis and inhibited cardiac ACE. Ang 1–7 infusion increased blood pressure, cardiac interstitial fibrosis and cardiac ACE binding compared to untreated STNx rats. Although in STNx rats, the addition of ACEi to Ang 1–7 prevented any deleterious cardiac effects of Ang 1–7, a limitation of the study is that the large increase in plasma Ang 1–7 with ramipril may have masked any effect of infused Ang 1–7. PMID:28192475

  16. Angiotensin-converting enzyme inhibitor (enalapril maleate) accelerates recovery of mouse skin from UVB-induced wrinkles

    SciTech Connect

    Matsuura-Hachiya, Yuko; Arai, Koji Y.; Ozeki, Rieko; Kikuta, Ayako; Nishiyama, Toshio

    2013-12-06

    Highlights: •Angiotensin converting enzyme (ACE) increases in UVB-irradiated skin. •Administration of an ACE inhibitor improved UVB-induced skin wrinkle. •ACE inhibitor improved UVB-induced epidermal hypertrophy. •ACE inhibitor improved transepidermal water loss in the UVB-irradiated skin. -- Abstract: Angiotensin-converting enzyme (ACE) activity and angiotensin II signaling regulate cell proliferation, differentiation, and tissue remodeling, as well as blood pressure, while in skin, angiotensin II signaling is involved in wound healing, inflammation, and pathological scar formation. Therefore, we hypothesized that angiotensin II is also involved in photoaging of skin. In this study, we examined the effect of enalapril maleate, an ACE inhibitor, on recovery of wrinkled skin of hairless mice exposed to long-term UVB irradiation. Immunohistochemical observation revealed that expression of ACE, angiotensin II, and angiotensin II type 1 (AT1) and type 2 (AT2) receptors in the skin was increased after UVB irradiation (3 times/week at increasing intensities for 8 weeks). Administration of enalapril maleate (5 times/week for 6 weeks, starting 1 week after 10-week irradiation) accelerated recovery from UVB-induced wrinkles, epidermal hyperplasia and epidermal barrier dysfunction, as compared with the vehicle control. Our results indicate that ACE and angiotensin II activity are involved in skin photoaging, and suggest that ACE inhibitor such as enalapril maleate may have potential for improvement of photoaged skin.

  17. Validated ligand mapping of ACE active site

    NASA Astrophysics Data System (ADS)

    Kuster, Daniel J.; Marshall, Garland R.

    2005-08-01

    Crystal structures of angiotensin-converting enzyme (ACE) complexed with three inhibitors (lisinopril, captopril, enalapril) provided experimental data for testing the validity of a prior active site model predicting the bound conformation of the inhibitors. The ACE active site model - predicted over 18 years ago using a series of potent ACE inhibitors of diverse chemical structure - was recreated using published data and commercial software. Comparison between the predicted structures of the three inhibitors bound to the active site of ACE and those determined experimentally yielded root mean square deviation (RMSD) values of 0.43-0.81 Å, among the distances defining the active site map. The bound conformations of the chemically relevant atoms were accurately deduced from the geometry of ligands, applying the assumption that the geometry of the active site groups responsible for binding and catalysis of amide hydrolysis was constrained. The mapping of bound inhibitors at the ACE active site was validated for known experimental compounds, so that the constrained conformational search methodology may be applied with confidence when no experimentally determined structure of the enzyme yet exists, but potent, diverse inhibitors are available.

  18. [Effect of Astragali Radix in improving early renal damage in metabolic syndrome rats through ACE2/Mas pathway].

    PubMed

    Wang, Qiong-ying; Liang, Wei; Jiang, Cheng; Li, Ning-yin; Xu, Han; Yang, Mi-na; Lin, Xin; Yu, Heng; Chang, Peng; Yu, Jing

    2015-11-01

    To study the expression of angiotensin converting enzyme 2 (ACE2) and angiotensin (Ang) 1-7 specific receptor Mas protain in renal blood vessels of metabolic syndrome ( MS) rats and its anti-oxidative effect. A total of 80 male SD rats were divided into four groups: the normal control group (NC, the same volume of normal saline), the MS group (high fat diet), the MS + Astragali Radix group (MS + HQ, 6 g x kg(-1) x d(-1) in gavage) and the MS + Valsartan group (MS + XST, 30 mg x kg(-1) x d(-1) in gavage). After four weeks of intervention, their general indexes, biochemical indexes and blood pressure were measured; plasma and renal tissue Ang II, malondialdehyde (MDA) and superoxide demutase (SOD) levels were measured with radioimmunoassay. The protein expressions of Mas receptor, AT1R, ACE and ACE2 were detected by western blot analysis. According to the result, compared with the NC group, the MS group and the MS + HQ group showed significant increases in systolic and diastolic pressures, body weight, fasting glucose, fasting insulin, triglycerides, free fatty acid and Ang II level of MS rats (P < 0.05). The MS + XST group showed notable decreases in systolic and diastolic pressures than that of the MS group. The MS group showed significant increases in the SOD activity and NO level and decrease in the MDA level after being intervened with Astragali Radix. ACE and AT1R protein expressions in renal tissues of the MS group were higher than that in the NC group, but with lower ACE2 and -Mas receptor expressions (all P < 0.05). Compared with the MS group, the MS + HQ group showed significant increase in Mas receptor expression in renal tissues, whereas the MS + XST group showed notable decrease in AT1R (all P < 0.05). In conclusion, Astragali Radix can increase the Mas receptor expressions in renal tissues, decrease ACE expression and change local Ang II, MDA, NO and SOD in kidneys, so as to protect early damages in renal tissues.

  19. Lysozyme and bilirubin bind to ACE and regulate its conformation and shedding

    PubMed Central

    Danilov, Sergei M.; Lünsdorf, Heinrich; Akinbi, Henry T.; Nesterovitch, Andrew B.; Epshtein, Yuliya; Letsiou, Eleftheria; Kryukova, Olga V.; Piegeler, Tobias; Golukhova, Elena Z.; Schwartz, David E.; Dull, Randal O.; Minshall, Richard D.; Kost, Olga A.; Garcia, Joe G. N.

    2016-01-01

    Angiotensin I-converting enzyme (ACE) hydrolyzes numerous peptides and is a critical participant in blood pressure regulation and vascular remodeling. Elevated tissue ACE levels are associated with increased risk for cardiovascular and respiratory disorders. Blood ACE concentrations are determined by proteolytic cleavage of ACE from the endothelial cell surface, a process that remains incompletely understood. In this study, we identified a novel ACE gene mutation (Arg532Trp substitution in the N domain of somatic ACE) that increases blood ACE activity 7-fold and interrogated the mechanism by which this mutation significantly increases blood ACE levels. We hypothesized that this ACE mutation disrupts the binding site for blood components which may stabilize ACE conformation and diminish ACE shedding. We identified the ACE-binding protein in the blood as lysozyme and also a Low Molecular Weight (LMW) ACE effector, bilirubin, which act in concert to regulate ACE conformation and thereby influence ACE shedding. These results provide mechanistic insight into the elevated blood level of ACE observed in patients on ACE inhibitor therapy and elevated blood lysozyme and ACE levels in sarcoidosis patients. PMID:27734897

  20. Comprehensive Database Service : ACE

    NASA Astrophysics Data System (ADS)

    Hiroki, Morio; Abe, Tetsuya

    The Data base, ACE commercialized by Chunichi Shimbun in Feb. 1986, aims at covering not only newspaper articles but also the other information which composes different data bases. This paper introduces newspaper articles, new material information and character information which are included in ACE. The content of ACE, how to use the online service, and future subjects are described.

  1. The Aerosol, Clouds and Ecosystem (ACE) Mission

    NASA Astrophysics Data System (ADS)

    Schoeberl, M.; Remer, L.; Kahn, R.; Starr, D.; Hildebrand, P.; Colarco, P.; Diner, D.; Vane, D.; Im, E.; Behrenfeld, M.; Stephens, G.; Maring, H.; Bontempi, P.; Martins, J. V.

    2008-12-01

    The Aerosol, Clouds and Ecosystem (ACE) Mission is a second tier Decadal Survey mission designed to characterize the role of aerosols in climate forcing, especially their impact on precipitation and cloud formation. ACE also includes ocean biosphere measurements (chlorophyll and dissolved organic materials) which will be greatly improved by simultaneous measurements of aerosols. The nominal ACE payload includes lidar and multiangle spectropolarimetric polarimetric measurements of aerosols, radar measurements of clouds and multi-band spectrometer for the measurement of ocean ecosystems. An enhancement to ACE payload under consideration includes µ-wave radiometer measurements of cloud ice and water outside the nadir path of the radar/lidar beams. This talk will cover ACE instrument and science options, updates on the science team definition activity and science potential.

  2. Improving cancer immunotherapy with DNA methyltransferase inhibitors.

    PubMed

    Saleh, Mohammad H; Wang, Lei; Goldberg, Michael S

    2016-07-01

    Immunotherapy confers durable clinical benefit to melanoma, lung, and kidney cancer patients. Challengingly, most other solid tumors, including ovarian carcinoma, are not particularly responsive to immunotherapy, so combination with a complementary therapy may be beneficial. Recent findings suggest that epigenetic modifying drugs can prime antitumor immunity by increasing expression of tumor-associated antigens, chemokines, and activating ligands by cancer cells as well as cytokines by immune cells. This review, drawing from both preclinical and clinical data, describes some of the mechanisms of action that enable DNA methyltransferase inhibitors to facilitate the establishment of antitumor immunity.

  3. Marketing ACE in Victoria.

    ERIC Educational Resources Information Center

    2001

    This publication presents options raised through various forums for marketing adult and community education (ACE) in Victoria, Australia, and suggested strategies. After an introduction (chapter 1), chapters 2 and 3 provide a broad view of the current situation for marketing ACE. Chapter 2 discusses general issues in the current position--ACE…

  4. Effects of a novel ACE inhibitor, 3-(3-thienyl)-l-alanyl-ornithyl-proline, on endothelial vasodilation and hepatotoxicity in l-NAME-induced hypertensive rats.

    PubMed

    Seth, Mahesh Kumar; Hussain, M Ejaz; Pasha, Santosh; Fahim, Mohammad

    2016-01-01

    Nitric oxide (NO) is a widespread biological mediator involved in many physiological and pathological processes, eg, in the regulation of vascular tone and hypertension. Chronic inhibition of NO synthase by N(G)-nitro-l-arginine methyl ester (l-NAME) hydrochloride results in the development of hypertension accompanied by an increase in vascular responsiveness to adrenergic stimuli. Recently, we developed a novel sulfur-containing angiotensin-converting enzyme inhibitor: 3-(3-thienyl)-l-alanyl-ornithyl-proline (TOP). Our previous studies indicated a superior nature of the molecule as an antihypertensive agent in spontaneously hypertensive rats (showing the involvement of renin-angiotensin-aldosterone system) in comparison to captopril. The aim of the present study was to investigate the effect of TOP on NO pathway in l-NAME-induced hypertensive rats, and captopril was included as the standard treatment group. Treatment with both TOP (20 mg/kg) and captopril (40 mg/kg) prevented the development of hypertension in l-NAME model, but TOP showed better restoration of NO and normal levels of angiotensin-converting enzyme. In addition, in vitro vasorelaxation assay showed an improvement in endothelium-dependent vasodilation in both the cases. Further, the biochemical (malondialdehyde, alanine aminotransferase, and aspartate aminotransferase) and the histopathological effects of TOP on rat liver tissues revealed a protective nature of TOP in comparison to captopril in the l-NAME model. In conclusion, TOP at 50% lesser dose than captopril was found to be better in the l-NAME model.

  5. Arctic Collaborative Environment (ACE)

    DTIC Science & Technology

    2012-08-01

    distribution is unlimited. Key Data Requirements • Sea Ice – Location: Area, Onset, Growth, Drift, and Decay – Characterization: % Coverage, Thickness...Cloud ACE Developmental Server hosted at UAHuntsville ACE User Community Public Internet Tailored Ice Product Generation (NIC) Arctic Research...distribution is unlimited. Arctic Map 26 July 2012 13 Multi-sensor Analyzed Sea Ice Extent; National Data Buoy Center DISTRIBUTION STATEMENT A

  6. Insulin treatment attenuates renal ADAM17 and ACE2 shedding in diabetic Akita mice.

    PubMed

    Salem, Esam S B; Grobe, Nadja; Elased, Khalid M

    2014-03-15

    Angiotensin-converting enzyme 2 (ACE2) is located in several tissues and is highly expressed in renal proximal tubules, where it degrades the vasoconstrictor angiotensin II (ANG II) to ANG-(1-7). Accumulating evidence supports protective roles of ACE2 in several disease states, including diabetic nephropathy. A disintegrin and metalloprotease (ADAM) 17 is involved in the shedding of several transmembrane proteins, including ACE2. Our previous studies showed increased renal ACE2, ADAM17 expression, and urinary ACE2 in type 2 diabetic mice (Chodavarapu H, Grobe N, Somineni HK, Salem ES, Madhu M, Elased KM. PLoS One 8: e62833, 2013). The aim of the present study was to determine the effect of insulin on ACE2 shedding and ADAM17 in type 1 diabetic Akita mice. Results demonstrate increased renal ACE2 and ADAM17 expression and increased urinary ACE2 fragments (≈70 kDa) and albumin excretion in diabetic Akita mice. Immunostaining revealed colocalization of ACE2 with ADAM17 in renal tubules. Renal proximal tubular cells treated with ADAM17 inhibitor showed reduced ACE2 shedding into the media, confirming ADAM17-mediated shedding of ACE2. Treatment of Akita mice with insulin implants for 20 wk normalized hyperglycemia and decreased urinary ACE2 and albumin excretion. Insulin also normalized renal ACE2 and ADAM17 but had no effect on tissue inhibitor of metalloproteinase 3 (TIMP3) protein expression. There was a positive linear correlation between urinary ACE2 and albuminuria, blood glucose, plasma creatinine, glucagon, and triglycerides. This is the first report showing an association between hyperglycemia, cardiovascular risk factors, and increased shedding of urinary ACE2 in diabetic Akita mice. Urinary ACE2 could be used as a biomarker for diabetic nephropathy and as an index of intrarenal ACE2 status.

  7. Angiotensin-converting enzyme-2 (ACE2): comparative modeling of the active site, specificity requirements, and chloride dependence.

    PubMed

    Guy, Jodie L; Jackson, Richard M; Acharya, K Ravi; Sturrock, Edward D; Hooper, Nigel M; Turner, Anthony J

    2003-11-18

    Angiotensin-converting enzyme 2 (ACE2), a homologue of ACE, represents a new and potentially important target in cardio-renal disease. A model of the active site of ACE2, based on the crystal structure of testicular ACE, has been developed and indicates that the catalytic mechanism of ACE2 resembles that of ACE. Structural differences exist between the active site of ACE (dipeptidyl carboxypeptidase) and ACE2 (carboxypeptidase) that are responsible for the differences in specificity. The main differences occur in the ligand-binding pockets, particularly at the S2' subsite and in the binding of the peptide carboxy-terminus. The model explains why the classical ACE inhibitor lisinopril is unable to bind to ACE2. On the basis of the ability of ACE2 to cleave a variety of biologically active peptides, a consensus sequence of Pro-X-Pro-hydrophobic/basic for the protease specificity of ACE2 has been defined that is supported by the ACE2 model. The dipeptide, Pro-Phe, completely inhibits ACE2 activity at 180 microM with angiotensin II as the substrate. As with ACE, the chloride dependence of ACE2 is substrate-specific such that the hydrolysis of angiotensin I and the synthetic peptide substrate, Mca-APK(Dnp), are activated in the presence of chloride ions, whereas the cleavage of angiotensin II is inhibited. The ACE2 model is also suggestive of a possible mechanism for chloride activation. The structural insights provided by these analyses for the differences in inhibition pattern and substrate specificity among ACE and its homologue ACE2 and for the chloride dependence of ACE/ACE2 activity are valuable in understanding the function and regulation of ACE2.

  8. Discovery of potent imidazole and cyanophenyl containing farnesyltransferase inhibitors with improved oral bioavailability.

    PubMed

    Tong, Yunsong; Lin, Nan-Horng; Wang, Le; Hasvold, Lisa; Wang, Weibo; Leonard, Nicholas; Li, Tongmei; Li, Qun; Cohen, Jerry; Gu, Wen-Zhen; Zhang, Haiying; Stoll, Vincent; Bauch, Joy; Marsh, Kennan; Rosenberg, Saul H; Sham, Hing L

    2003-05-05

    A pyridyl moiety was introduced into a previously developed series of farnesyltransferase inhibitors containing imidazole and cyanophenyl (such as 4), resulting in potent inhibitors with improved pharmacokinetics.

  9. The Aerosol/Cloud/Ecosystems Mission (ACE)

    NASA Technical Reports Server (NTRS)

    Schoeberl, Mark

    2008-01-01

    The goals and measurement strategy of the Aerosol/Cloud/Ecosystems Mission (ACE) are described. ACE will help to answer fundamental science questions associated with aerosols, clouds, air quality and global ocean ecosystems. Specifically, the goals of ACE are: 1) to quantify aerosol-cloud interactions and to assess the impact of aerosols on the hydrological cycle and 2) determine Ocean Carbon Cycling and other ocean biological processes. It is expected that ACE will: narrow the uncertainty in aerosol-cloud-precipitation interaction and quantify the role of aerosols in climate change; measure the ocean ecosystem changes and precisely quantify ocean carbon uptake; and, improve air quality forecasting by determining the height and type of aerosols being transported long distances. Overviews are provided of the aerosol-cloud community measurement strategy, aerosol and cloud observations over South Asia, and ocean biology research goals. Instruments used in the measurement strategy of the ACE mission are also highlighted, including: multi-beam lidar, multiwavelength high spectra resolution lidar, the ocean color instrument (ORCA)--a spectroradiometer for ocean remote sensing, dual frequency cloud radar and high- and low-frequency micron-wave radiometer. Future steps for the ACE mission include refining measurement requirements and carrying out additional instrument and payload studies.

  10. Difluoromethane, a new and improved inhibitor of methanotrophy

    USGS Publications Warehouse

    Miller, L.G.; Sasson, C.; Oremland, R.S.

    1998-01-01

    Difluoromethane (HFC-32; DFM) is compared to acetylene and methyl fluoride as an inhibitor of methanotrophy in cultures and soils. DFM was found to be a reversible inhibitor of CH4 oxidation by Methylococcus capsulatus (Bath). Consumption of CH4 in soil was blocked by additions of low levels of DFM (0.03 kPa), and this inhibition was reversed by DFM removal. Although a small quantity of DFM was consumed during these incubations, its remaining concentration was sufficiently elevated to sustain inhibition. Methanogenesis in anaerobic soil slurries, including acetoclastic methanogenesis, was unaffected by levels of DFM which inhibit methanotrophy. Low levels of DFM (0.03 kPa) also inhibited nitrification and N2O production by soils. DFM is proposed as an improved inhibitor of CH4 oxidation over acetylene and/or methyl fluoride on the basis of its reversibility, its efficacy at low concentrations, its lack of inhibition of methanogenesis, and its low cost.

  11. Regulation of urinary ACE2 in diabetic mice.

    PubMed

    Wysocki, Jan; Garcia-Halpin, Laura; Ye, Minghao; Maier, Christoph; Sowers, Kurt; Burns, Kevin D; Batlle, Daniel

    2013-08-15

    Angiotensin-converting enzyme-2 (ACE2) enhances the degradation of ANG II and its expression is altered in diabetic kidneys, but the regulation of this enzyme in the urine is unknown. Urinary ACE2 was studied in the db/db model of type 2 diabetes and stretozotocin (STZ)-induced type 1 diabetes during several physiological and pharmacological interventions. ACE2 activity in db/db mice was increased in the serum and to a much greater extent in the urine compared with db/m controls. Neither a specific ANG II blocker, telmisartan, nor an ACE inhibitor, captopril, altered the levels of urinary ACE2 in db/db or db/m control mice. High-salt diet (8%) increased whereas low-salt diet (0.1%) decreased urinary ACE2 activity in the urine of db/db mice. In STZ mice, urinary ACE2 was also increased, and insulin decreased it partly but significantly after several weeks of administration. The increase in urinary ACE2 activity in db/db mice reflected an increase in enzymatically active protein with two bands identified of molecular size at 110 and 75 kDa and was associated with an increase in kidney cortex ACE2 protein at 110 kDa but not at 75 kDa. ACE2 activity was increased in isolated tubular preparations but not in glomeruli from db/db mice. Administration of soluble recombinant ACE2 to db/m and db/db mice resulted in a marked increase in serum ACE2 activity, but no gain in ACE2 activity was detectable in the urine, further demonstrating that urinary ACE2 is of kidney origin. Increased urinary ACE2 was associated with more efficient degradation of exogenous ANG II (10(-9) M) in urine from db/db compared with that from db/m mice. Urinary ACE2 could be a potential biomarker of increased metabolism of ANG II in diabetic kidney disease.

  12. ACE and response to pulmonary rehabilitation in COPD: two observational studies

    PubMed Central

    Kon, Samantha S C; Jolley, Caroline J; Shrikrishna, Dinesh; Montgomery, Hugh E; Skipworth, James R A; Puthucheary, Zudin; Moxham, John; Polkey, Michael I; Man, William D-C

    2017-01-01

    Introduction Skeletal muscle impairment is an important feature of chronic obstructive pulmonary disease (COPD). Renin–angiotensin system activity influences muscle phenotype, so we wished to investigate whether it affects the response to pulmonary rehabilitation. Methods Two studies are described; in the first, the response of 168 COPD patients (mean forced expiratory volume in one second 51.9% predicted) to pulmonary rehabilitation was compared between different ACE insertion/deletion polymorphism genotypes. In a second, independent COPD cohort (n=373), baseline characteristics and response to pulmonary rehabilitation were compared between COPD patients who were or were not taking ACE inhibitors or angiotensin receptor antagonists (ARB). Results In study 1, the incremental shuttle walk distance improved to a similar extent in all three genotypes; DD/ID/II (n=48/91/29) 69(67)m, 61 (76)m and 78 (78)m, respectively, (p>0.05). In study 2, fat free mass index was higher in those on ACE-I/ARB (n=130) than those who were not (n=243), 17.8 (16.0, 19.8) kg m−2 vs 16.5 (14.9, 18.4) kg/m2 (p<0.001). However change in fat free mass, walking distance or quality of life in response to pulmonary rehabilitation did not differ between groups. Conclusions While these data support a positive association of ACE-I/ARB treatment and body composition in COPD, neither treatment to reduce ACE activity nor ACE (I/D) genotype influence response to pulmonary rehabilitation. PMID:28321311

  13. Diminazene aceturate enhances ACE2 activity and attenuates ischemia-induced cardiac pathophysiology

    PubMed Central

    Qi, YanFei; Zhang, Juan; Cole-Jeffrey, Colleen T; Shenoy, Vinayak; Espejo, Andrew; Hanna, Mina; Song, Chunjuan; Pepine, Carl J; Katovich, Michael J; Raizada, Mohan K

    2013-01-01

    Angiotensin-converting enzyme 2 (ACE2) plays a critical role against myocardial infarction (MI). We hypothesized that activation of intrinsic ACE2 would be protective against ischemia-induced cardiac pathophysiology. Diminazine aceturate (DIZE), a small molecule ACE2 activator has been used to evaluate this hypothesis. DIZE (15 mg/kg/day, s.c.) was injected two days prior to MI surgery and continued throughout the study-period. MI rats showed a 62% decrease in fractional shortening (FS,%) [control (Con): 51.1 ± 3.2; DIZE alone (D) : 52.1 ± 3.2; MI (M): 19.1± 3.0], a 55% decrease in contractility (dP/dtmax mmHg/s) (Con: 9480 ± 425.3; D: 9585 ± 597.4; M: 4251 ± 657.7), and a 27% increase in ventricular hypertrophy [VH, mg/mm (Con: 26.5 ± 1.5; D: 26.9 ± 1.4; M: 33.4± 1.1)]. DIZE attenuated the MI-induced decrease in FS by 89%, improved dP/dtmax by 92%, and reversed VH by 18%. MI also significantly increased ACE and angiotensin type 1 receptor levels while decreased ACE2 activity by 40% (Con: 246.2 ± 25.1; D: 254.2 ± 20.6; M: 148.9 ± 29.2, RFU/min), which was reversed by DIZE treatment. Thus, DIZE treatment decreased the infarct area, attenuated LV remodeling post-MI and restored normal balance of the cardiac renin angiotensin system. Additionally, DIZE treatment increased circulating endothelial progenitor cells, increased engraftment of cardiac progenitor cells and decreased inflammatory cells in peri-infarct cardiac regions. All of the beneficial effects associated with DIZE treatment were abolished by C-16, an ACE2 inhibitor. Collectively, DIZE and DIZE-like small molecules may represent promising new therapeutic agents for MI. PMID:23959549

  14. Novel Ferroptosis Inhibitors with Improved Potency and ADME Properties.

    PubMed

    Hofmans, Sam; Vanden Berghe, Tom; Devisscher, Lars; Hassannia, Behrouz; Lyssens, Sophie; Joossens, Jurgen; Van Der Veken, Pieter; Vandenabeele, Peter; Augustyns, Koen

    2016-03-10

    Ferroptosis is a nonapoptotic, iron-catalyzed form of regulated necrosis that is critically dependent on glutathione peroxidase 4 (GPX4). It has been shown to contribute to liver and kidney ischemia reperfusion injury in mice. A chemical inhibitor discovered by high-throughput screening displayed inhibition of ferroptosis with nanomolar activity and was dubbed ferrostatin-1 (fer-1). Ferrostatins inhibit oxidative lipid damage, but suffer from inherent stability problems due to the presence of an ester moiety. This limits the application of these molecules in vivo, due to rapid hydrolysis of the ester into the inactive carboxylic acid. Previous studies highlighted the importance of the ethyl ester and suggested steric modifications of the ester for generating improved molecules. In this study, we report the synthesis of novel ferroptosis inhibitors containing amide and sulfonamide moieties with improved stability, single digit nanomolar antiferroptotic activity, and good ADME properties suitable for application in in vivo disease models.

  15. ACES--Today and Tomorrow.

    ERIC Educational Resources Information Center

    Hackney, Harold

    1991-01-01

    Presents text of Presidential Address delivered March 24, 1991, at the Association for Counselor Education and Supervision (ACES) luncheon, part of the American Association for Counseling and Development Convention held in Reno, Nevada. Comments on past, present, and future of ACES, particularly on future challenges and role of ACES. (ABL)

  16. Calmodulin interacts with angiotensin-converting enzyme-2 (ACE2) and inhibits shedding of its ectodomain.

    PubMed

    Lambert, Daniel W; Clarke, Nicola E; Hooper, Nigel M; Turner, Anthony J

    2008-01-23

    Angiotensin-converting enzyme-2 (ACE2) is a regulatory protein of the renin-angiotensin system (RAS) and a receptor for the causative agent of severe-acute respiratory syndrome (SARS), the SARS-coronavirus. We have previously shown that ACE2 can be shed from the cell surface in response to phorbol esters by a process involving TNF-alpha converting enzyme (TACE; ADAM17). In this study, we demonstrate that inhibitors of calmodulin also stimulate shedding of the ACE2 ectodomain, a process at least partially mediated by a metalloproteinase. We also show that calmodulin associates with ACE2 and that this interaction is decreased by calmodulin inhibitors.

  17. Improving L-dopa therapy: the development of enzyme inhibitors.

    PubMed

    Gershanik, Oscar S

    2015-01-01

    The introduction of levodopa produced a monumental change in the treatment of Parkinson's disease (PD). Limitations in its bioavailability and tolerability led to the search for drugs that could improve its pharmacokinetics and safety profile. Dopa-decarboxylase inhibitors were the first such drugs that were developed, and their use in combination with L-dopa has become standard practice. Increasing knowledge on the metabolism of L-dopa allowed the identification of additional targets for intervention in an attempt to improve the symptomatic efficacy of L-dopa. Monoamineoxidase inhibitors, enhancing the central bioavailability of dopamine by blocking its metabolism, were the next step, and despite controversies regarding their efficacy, they have remained as valuable adjuncts to l-dopa in the treatment of PD. More recently, the introduction of potent, selective catechol-O-methyl transferase inhibitors have found their place in the therapeutic armamentarium of PD and are prescribed in combination with l-dopa to prolong the duration of its action.

  18. Aerobic and Cognitive Exercise (ACE) Pilot Study for Older Adults: Executive Function Improves with Cognitive Challenge While Exergaming.

    PubMed

    Barcelos, Nicole; Shah, Nikita; Cohen, Katherine; Hogan, Michael J; Mulkerrin, Eamon; Arciero, Paul J; Cohen, Brian D; Kramer, Arthur F; Anderson-Hanley, Cay

    2015-11-01

    Dementia cases are increasing worldwide; thus, investigators seek to identify interventions that might prevent or ameliorate cognitive decline in later life. Extensive research confirms the benefits of physical exercise for brain health, yet only a fraction of older adults exercise regularly. Interactive mental and physical exercise, as in aerobic exergaming, not only motivates, but has also been found to yield cognitive benefit above and beyond traditional exercise. This pilot study sought to investigate whether greater cognitive challenge while exergaming would yield differential outcomes in executive function and generalize to everyday functioning. Sixty-four community based older adults (mean age=82) were randomly assigned to pedal a stationary bike, while interactively engaging on-screen with: (1) a low cognitive demand task (bike tour), or (2) a high cognitive demand task (video game). Executive function (indices from Trails, Stroop and Digit Span) was assessed before and after a single-bout and 3-month exercise intervention. Significant group × time interactions were found after a single-bout (Color Trails) and after 3 months of exergaming (Stroop; among 20 adherents). Those in the high cognitive demand group performed better than those in the low cognitive dose condition. Everyday function improved across both exercise conditions. Pilot data indicate that for older adults, cognitive benefit while exergaming increased concomitantly with higher doses of interactive mental challenge.

  19. Human ACE gene polymorphism and distilled water induced cough

    PubMed Central

    Morice, A. H.; Turley, A. J.; Linton, T. K.

    1997-01-01

    BACKGROUND: Inhibitors of angiotensin converting enzyme (ACE) cause a non-productive cough. The insertion/deletion polymorphism of ACE was used as a genetic marker to investigate the relationship between ACE genotype and cough sensitivity. METHODS: A double blind cough challenge was performed in 66 normotensive subjects (34 men) of mean age 34.8 years (range 18-80) using aerosols of distilled water. The number of coughs during the one minute exposure to water was recorded. DNA samples from venous blood were amplified by the polymerase chain reaction and resolved on a 1% agarose gel. They were analysed for the presence of a polymorphism in intron 16 of the ACE gene consisting of an insertion (I) or deletion (D) of an Alu repetitive sequence 287 base pairs long. RESULTS: The distribution of genotypes was 20 II, 26 ID, and 20 DD. The cough response was significantly (p < 0.01) related to the ACE genotype, the mean number of coughs being 15.8, 11.3, and 9.6, respectively, in subjects with the II, ID, and DD genotypes. CONCLUSIONS: The observation that cough challenge is dependent on ACE genotype in normal subjects is evidence of a link between ACE activity and the cough reflex. 


 PMID:9059468

  20. Ace the Verbal on the SAT

    ERIC Educational Resources Information Center

    Meierding, Loren

    2005-01-01

    Many students are not accepted in to certain colleges and universities because of low SAT scores. Loren Meierding has written Ace the Verbal on the SAT to help students with minimal preparation do well by improving their vocabulary and use better techniques for finding the answers to the questions. This book provides strategies needed to score…

  1. Angiotensin-converting enzyme inhibition reduces food intake and weight gain and improves glucose tolerance in melanocortin-4 receptor deficient female rats.

    PubMed

    Mul, Joram D; Seeley, Randy J; Woods, Stephen C; Begg, Denovan P

    2013-09-10

    Functional loss of melanocortin-4 receptor (MC4R) activity leads to hyperphagia and an obese, glucose intolerant phenotype. We have previously established that inhibition of angiotensin-converting enzyme (ACE) reduces food intake, body weight and glucose homeostasis in diet-induced obesity. The current study assessed the effect of ACE inhibitor treatment in MC4R-deficient female rats on body weight, adiposity and glucose tolerance. Rats homozygous (HOM) for a loss of function Mc4r mutation had an obese phenotype relative to their wildtype (WT) littermates. Inhibition of ACE for 8weeks produced reductions in body weight gain in both HOM and WT rats; however, food intake was only reduced in HOM rats. Weight loss following ACE inhibitor treatment was specific to fat mass while lean mass was unaffected. HOM rats were severely glucose intolerant and insensitive to exogenous insulin injection, and treatment with an ACE inhibitor improved both glucose tolerance and insulin sensitivity in HOM rats although not fully to that of the level of WT rats. The current study indicates that HOM rats are sensitive to the anorectic effects of ACE inhibition, unlike their WT littermates. This resulted in a more rapid reduction in body weight gain and a more substantial loss of adipose mass in HOM animals, relative to WT animals, treated with an ACE inhibitor. Overall, these data demonstrate that MC4R signaling is not required for weight loss following treatment with an ACE inhibitor.

  2. ACEE composite structures technology

    NASA Technical Reports Server (NTRS)

    Klotzsche, M. (Compiler)

    1984-01-01

    The NASA Aircraft Energy Efficiency (ACEE) Composite Primary Aircraft Structures Program has made significant progress in the development of technology for advanced composites in commercial aircraft. Commercial airframe manufacturers have demonstrated technology readiness and cost effectiveness of advanced composites for secondary and medium primary components and have initiated a concerted program to develop the data base required for efficient application to safety-of-flight wing and fuselage structures. Oral presentations were compiled into five papers. Topics addressed include: damage tolerance and failsafe testing of composite vertical stabilizer; optimization of composite multi-row bolted joints; large wing joint demonstation components; and joints and cutouts in fuselage structure.

  3. ACES's Challenges: Past Presidents Comment.

    ERIC Educational Resources Information Center

    Sheeley, Vernon Lee

    1990-01-01

    Recognizes the golden anniversary of the Association for Counselor Education and Supervision (ACES) and presents the statements of 15 past presidents of the association. Presidential leaders briefly review the association's past and suggest opportunities to help create a promising future for ACES. Outlines nine challenges which confront members of…

  4. FIRE_ACE_SHIP_SSFR

    Atmospheric Science Data Center

    2015-10-28

    FIRE_ACE_SHIP_SSFR Project Title:  FIRE III ACE Discipline:  ... Level:  L3 Platform:  SHEBA Ship Instrument:  Solar Spectral Flux Radiometer ... Info:  Surface Heat Budget of the Arctic Ocean (SHEBA) Ship SCAR-B Block:  SCAR-B Products ...

  5. FIRE_ACE_UTRECHT_TOWER

    Atmospheric Science Data Center

    2015-10-28

    FIRE_ACE_UTRECHT_TOWER Project Title:  FIRE II ACE Discipline:  ... L3 Platform:  SHEBA Ship Site; Meteorological tower Instrument:  Eppley precision pyrgeometers Meteorological tower Spatial Coverage:  Fairbanks, Alaska and the surrounding ...

  6. New Perspectives in the Renin-Angiotensin-Aldosterone System (RAAS) II: Albumin Suppresses Angiotensin Converting Enzyme (ACE) Activity in Human

    PubMed Central

    Fagyas, Miklós; Úri, Katalin; Siket, Ivetta M.; Fülöp, Gábor Á.; Csató, Viktória; Daragó, Andrea; Boczán, Judit; Bányai, Emese; Szentkirályi, István Elek; Maros, Tamás Miklós; Szerafin, Tamás; Édes, István; Papp, Zoltán; Tóth, Attila

    2014-01-01

    About 8% of the adult population is taking angiotensin-converting enzyme (ACE) inhibitors to treat cardiovascular disease including hypertension, myocardial infarction and heart failure. These drugs decrease mortality by up to one-fifth in these patients. We and others have reported previously that endogenous inhibitory substances suppress serum ACE activity, in vivo, similarly to the ACE inhibitor drugs. Here we have made an effort to identify this endogenous ACE inhibitor substance. ACE was crosslinked with interacting proteins in human sera. The crosslinked products were immunoprecipitated and subjected to Western blot. One of the crosslinked products was recognized by both anti-ACE and anti-HSA (human serum albumin) antibodies. Direct ACE-HSA interaction was confirmed by binding assays using purified ACE and HSA. HSA inhibited human purified (circulating) and human recombinant ACE with potencies (IC50) of 5.7±0.7 and 9.5±1.1 mg/mL, respectively. Effects of HSA on the tissue bound native ACE were tested on human saphenous vein samples. Angiotensin I evoked vasoconstriction was inhibited by HSA in this vascular tissue (maximal force with HSA: 6.14±1.34 mN, without HSA: 13.54±2.63 mN), while HSA was without effects on angiotensin II mediated constrictions (maximal force with HSA: 18.73±2.17 mN, without HSA: 19.22±3.50 mN). The main finding of this study is that HSA was identified as a potent physiological inhibitor of the ACE. The enzymatic activity of ACE appears to be almost completely suppressed by HSA when it is present in its physiological concentration. These data suggest that angiotensin I conversion is limited by low physiological ACE activities, in vivo. PMID:24691203

  7. Phosphate May Promote CKD Progression and Attenuate Renoprotective Effect of ACE Inhibition

    PubMed Central

    Ruggenenti, Piero; Perna, Annalisa; Leonardis, Daniela; Tripepi, Rocco; Tripepi, Giovanni; Mallamaci, Francesca; Remuzzi, Giuseppe

    2011-01-01

    Phosphate may promote the onset and progression of chronic nephropathies. Here we evaluated the relationships between baseline serum phosphate levels, disease progression, and response to ACE inhibition in 331 patients with proteinuric nephropathies in the prospective Ramipril Efficacy In Nephropathy (REIN) trial. Independent of treatment, patients with phosphate levels in the highest two quartiles progressed significantly faster either to ESRD or to a composite endpoint of doubling of serum creatinine or ESRD compared with patients with phosphate levels below the median (P < 0.001). Results were similar when we analyzed phosphate as a continuous variable (P ≤ 0.004). The renoprotective effect of ramipril decreased as serum phosphate increased (P ≤ 0.008 for interaction); this modification of the treatment effect by phosphate persisted despite adjusting for potential confounders such as GFR and urinary protein. In summary, these data suggest that phosphate is an independent risk factor for progression of renal disease among patients with proteinuric CKD, and high levels of phosphate may even attenuate the renoprotective effect of ACE inhibitors. Future trials should test whether reducing serum phosphate improves renal outcomes and optimizes the renoprotective effect of ACE inhibition. PMID:21852581

  8. Influence of ACE I/D Polymorphism on Circulating Levels of Plasminogen Activator Inhibitor 1, D-Dimer, Ultrasensitive C-Reactive Protein and Transforming Growth Factor β1 in Patients Undergoing Hemodialysis

    PubMed Central

    de Carvalho, Sara Santos; Simões e Silva, Ana Cristina; Sabino, Adriano de Paula; Evangelista, Fernanda Cristina Gontijo; Gomes, Karina Braga; Dusse, Luci Maria SantAna; Rios, Danyelle Romana Alves

    2016-01-01

    Background There is substantial evidence that chronic renal and cardiovascular diseases are associated with coagulation disorders, endothelial dysfunction, inflammation and fibrosis. Angiotensin-Converting Enzyme Insertion/Deletion polymorphism (ACE I/D polymorphism) has also be linked to cardiovascular diseases. Therefore, this study aimed to compare plasma levels of ultrassensible C-reactive protein (usCRP), PAI-1, D-dimer and TGF-β1 in patients undergoing HD with different ACE I/D polymorphisms. Methods The study was performed in 138 patients at ESRD under hemodialysis therapy for more than six months. The patients were divided into three groups according to the genotype. Genomic DNA was extracted from blood cells (leukocytes). ACE I/D polymorphism was investigated by single polymerase chain reaction (PCR). Plasma levels of D-dimer, PAI-1 and TGF-β1 were measured by enzyme-linked immunosorbent assay (ELISA), and the determination of plasma levels of usCRP was performed by immunonephelometry. Data were analyzed by the software SigmaStat 2.03. Results Clinical characteristics were similar in patients with these three ACE I/D polymorphisms, except for interdialytic weight gain. I allele could be associated with higher interdialytic weight gain (P = 0.017). Patients genotyped as DD and as ID had significantly higher levels of PAI-1 than those with II genotype. Other laboratory parameters did not significantly differ among the three subgroups (P = 0.033). Despite not reaching statistical significance, plasma levels of usCRP were higher in patients carrying the D allele. Conclusion ACE I/D polymorphisms could be associated with changes in the regulation of sodium, fibrinolytic system, and possibly, inflammation. Our data showed that high levels of PAI-1 are detected when D allele is present, whereas greater interdialytic gain is associated with the presence of I allele. However, further studies with different experimental designs are necessary to elucidate the

  9. Atmospheric Constituent Explorer System (ACES)

    NASA Astrophysics Data System (ADS)

    Darrach, M. R.; Madzunkov, S.; Neidholdt, E.; Simcic, J.

    2016-10-01

    We report on the Atmospheric Constituent Explorer System (ACES), a mass spectrometer based instrument for atmospheric probe missions (e.g. Venus and ice giant) that can determine abundances and isotopic ratios of the noble-gases and trace species.

  10. ACE3 Draft Indicators: Health

    EPA Pesticide Factsheets

    The page information was provided by EPA in conjunction with the opportunity for public comment on the draft indicators for ACE3, which ran from March 8 – April 21, 2011. The public comment period is now closed.

  11. ACE3 Draft Indicators: Biomonitoring

    EPA Pesticide Factsheets

    The page information was provided by EPA in conjunction with the opportunity for public comment on the draft indicators for ACE3, which ran from March 8 – April 21, 2011. The public comment period is now closed.

  12. Dynamics of ADAM17-Mediated Shedding of ACE2 Applied to Pancreatic Islets of Male db/db Mice

    PubMed Central

    Pedersen, Kim Brint; Chodavarapu, Harshita; Porretta, Constance; Robinson, Leonie K.

    2015-01-01

    Angiotensin-converting enzyme 2 (ACE2) gene therapy aimed at counteracting pancreatic ACE2 depletion improves glucose regulation in two diabetic mouse models: db/db mice and angiotensin II-infused mice. A disintegrin and metalloproteinase 17 (ADAM17) can cause shedding of ACE2 from the cell membrane. The aim of our studies was to determine whether ADAM17 depletes ACE2 levels in pancreatic islets and β-cells. Dynamics of ADAM17-mediated ACE2 shedding were investigated in 832/13 insulinoma cells. Within a wide range of ACE2 expression levels, including the level observed in mouse pancreatic islets, overexpression of ADAM17 increases shed ACE2 and decreases cellular ACE2 levels. We provide a mathematical description of shed and cellular ACE2 activities as a function of the ADAM17 activity. The effect of ADAM17 on the cellular ACE2 content was relatively modest with an absolute control strength value less than 0.25 and approaching 0 at low ADAM17 activities. Although we found that ADAM17 and ACE2 are both expressed in pancreatic islets, the β-cell is not the major cell type expressing ACE2 in islets. During diabetes progression in 8-, 12-, and 15-week-old db/db mice, ACE2 mRNA and ACE2 activity levels in pancreatic islets were not decreased over time nor significantly decreased compared with nondiabetic db/m mice. Levels of ADAM17 mRNA and ADAM17 activity were also not significantly changed. Inhibiting basal ADAM17 activity in mouse islets failed to affect ACE2 levels. We conclude that whereas ADAM17 has the ability to shed ACE2, ADAM17 does not deplete ACE2 from pancreatic islets in diabetic db/db mice. PMID:26441236

  13. Improved prediction of inhibitor development in previously untreated patients with severe haemophilia A.

    PubMed

    Hashemi, S M; Fischer, K; Moons, K G M; van den Berg, H M

    2015-03-01

    Treatment of previously untreated patients (PUPs) with severe haemophilia A is complicated by the formation of inhibitors. Prediction of PUPs with high risk is important to allow altering treatment with the intention to reduce the occurrence of inhibitors. An unselected multicentre cohort of 825 PUPs with severe haemophilia A (FVIII<0.01 IU mL(-1) ) was used. Patients were followed until 50 exposure days (EDs) or inhibitor development. All predictors of the existing prediction model including three new potential predictors were studied using multivariable logistic regression. Model performance was quantified [area under the curve (AUC), calibration plot] and internal validation (bootstrapping) was performed. A nomogram for clinical application was developed. Of the 825 patients, 225 (28%) developed inhibitors. The predictors family history of inhibitors, F8 gene mutation and an interaction variable of dose and number of EDs of intensive treatment were independently associated with inhibitor development. Age and reason for first treatment were not associated with inhibitor development. The AUC was 0.69 (95% CI 0.65-0.72) and calibration was good. An improved prediction model for inhibitor development and a nomogram for clinical use were developed in a cohort of 825 PUPs with severe haemophilia A. Clinical applicability was improved by combining dose and duration of intensive treatment, allowing the assessment of the effects of treatment decisions on inhibitor risk and potentially modify treatment.

  14. Effect of phlorotannins isolated from Ecklonia cava on angiotensin I-converting enzyme (ACE) inhibitory activity

    PubMed Central

    Wijesinghe, W.A.J.P.; Ko, Seok-Chun

    2011-01-01

    Inhibition of angiotensin I-converting enzyme (ACE) activity is the most common mechanism underlying the lowering of blood pressure. In the present study, five organic extracts of a marine brown seaweed Ecklonia cava were prepared by using ethanol, ethyl acetate, chloroform, hexane, and diethyl ether as solvents, which were then tested for their potential ACE inhibitory activities. Ethanol extract showed the strongest ACE inhibitory activity with an IC50 value of 0.96 mg/ml. Five kinds of phlorotannins, phloroglucinol, triphlorethol-A, eckol, dieckol, and eckstolonol, were isolated from ethanol extract of E. cava, which exhibited potential ACE inhibition. Dieckol was the most potent ACE inhibitor and was found to be a non-competitive inhibitor against ACE according to Lineweaver-Burk plots. Dieckol had an inducible effect on the production of NO in EAhy926 cells without having cytotoxic effect. The results of this study indicate that E. cava could be a potential source of phlorotannins with ACE inhibitory activity for utilization in production of functional foods. PMID:21556221

  15. Effect of phlorotannins isolated from Ecklonia cava on angiotensin I-converting enzyme (ACE) inhibitory activity.

    PubMed

    Wijesinghe, W A J P; Ko, Seok-Chun; Jeon, You-Jin

    2011-04-01

    Inhibition of angiotensin I-converting enzyme (ACE) activity is the most common mechanism underlying the lowering of blood pressure. In the present study, five organic extracts of a marine brown seaweed Ecklonia cava were prepared by using ethanol, ethyl acetate, chloroform, hexane, and diethyl ether as solvents, which were then tested for their potential ACE inhibitory activities. Ethanol extract showed the strongest ACE inhibitory activity with an IC(50) value of 0.96 mg/ml. Five kinds of phlorotannins, phloroglucinol, triphlorethol-A, eckol, dieckol, and eckstolonol, were isolated from ethanol extract of E. cava, which exhibited potential ACE inhibition. Dieckol was the most potent ACE inhibitor and was found to be a non-competitive inhibitor against ACE according to Lineweaver-Burk plots. Dieckol had an inducible effect on the production of NO in EAhy926 cells without having cytotoxic effect. The results of this study indicate that E. cava could be a potential source of phlorotannins with ACE inhibitory activity for utilization in production of functional foods.

  16. Polymorphisms of ACE2 gene are associated with essential hypertension and antihypertensive effects of Captopril in women.

    PubMed

    Fan, X; Wang, Y; Sun, K; Zhang, W; Yang, X; Wang, S; Zhen, Y; Wang, J; Li, W; Han, Y; Liu, T; Wang, X; Chen, J; Wu, H; Hui, R

    2007-08-01

    ACE2 appears to counterbalance the vasopressor effect of angiotensin I converting enzyme (ACE) in the reninangiotensin system. We hypothesized that ACE2 polymorphisms could confer a high risk of hypertension and have an impact on the antihypertensive response to ACE inhibitors. The hypothesis was tested in two casecontrol studies and a clinical trial of 3,408 untreated hypertensive patients randomized to Atenolol, Hydrochlorothiazide, Captopril, or Nifedipine treatments for 4 weeks. ACE2 rs2106809 T allele was found to confer a 1.6-fold risk for hypertension in women (95% confidence interval (CI), 1.132.06), whereas when combined with the effect of the ACE DD genotype, the risk was 2.34-fold (95% CI, 1.754.85) in two independent samples. The adjusted diastolic blood pressure response to Captopril was 3.3 mm Hg lower in ACE2 T allele carriers than in CC genotype carriers (P=0.019) in women. We conclude that the ACE2 T allele confers a high risk for hypertension and reduced antihypertensive response to ACE inhibitors.

  17. The Atmospheric Chemistry Experiment (ACE)

    NASA Astrophysics Data System (ADS)

    Bernath, P. F.

    2017-01-01

    The Atmospheric Chemistry Experiment (ACE), also called SCISAT, is a Canadian-led small satellite mission for remote sensing of the Earth's atmosphere. ACE was launched into a low Earth circular orbit by NASA on August 12, 2003 and it continues to function nominally. The ACE instruments are a high spectral resolution (0.02 cm-1) Fourier Transform Spectrometer (FTS) operating from 2.2 to 13.3 μm (750-4400 cm-1), a spectrophotometer known as Measurement of Aerosol Extinction in the Stratosphere and Troposphere Retrieved by Occultation (MAESTRO) with wavelength coverage of 285-1020 nm and two filtered detector arrays to image the Sun at 0.525 and 1.02 μm. ACE operates in solar occultation mode to provide altitude profiles of temperature, pressure, atmospheric extinction and the volume mixing ratios (VMRs) for several dozen molecules and related isotopologues. This paper presents a mission overview and a summary of selected scientific results.

  18. Minocycline Improves the Efficacy of EGFR Inhibitor Therapy: A Hypothesis

    PubMed Central

    Venniyoor, Ajit; Al Bahrani, Bassim

    2016-01-01

    Skin rash is a side effect of drugs that inhibit epithelial growth factor receptor (EGFR) as a part of targeted therapy of cancer. Its appearance and severity correlates with survival. Minocycline, an oral tetracycline antibiotic, is recommended as treatment (and increasingly, for prevention) of the rash, though infection is seen in only one-third of the patients. Minocycline has additional anticancer properties such as poly(ADP-ribose) polymerase inhibition. It is proposed that such properties contribute to the efficacy of EGFR inhibitors and can also explain the positive correlation between grade of rash and survival as patients with higher grades of rash are more likely to receive minocycline. Early concurrent administration of minocycline is recommended in patients planned for EGFR therapy while awaiting trials proving this hypothesis. PMID:27833902

  19. Angiotensin-II mediates ACE2 Internalization and Degradation through an Angiotensin-II type I receptor-dependent mechanism

    PubMed Central

    Lazartigues, Eric; Filipeanu, Catalin M.

    2014-01-01

    Angiotensin Converting Enzyme type 2 (ACE2) is a pivotal component of the renin-angiotensin system, promoting the conversion of Angiotensin (Ang)-II to Ang-(1-7). We previously reported that decreased ACE2 expression and activity contribute to the development of Ang-II-mediated hypertension in mice. The present study aimed to investigate the mechanisms involved in ACE2 down-regulation during neurogenic hypertension. In ACE2-transfected Neuro-2A cells, Ang-II treatment resulted in a significant attenuation of ACE2 enzymatic activity. Examination of the subcellular localization of ACE2 revealed that Ang-II treatment leads to ACE2 internalization and degradation into lysosomes. These effects were prevented by both the Ang-II type 1 receptor (AT1R) blocker losartan and the lysosomal inhibitor leupeptin. In contrast, in HEK293T cells, which lack endogenous AT1R, Ang-II failed to promote ACE2 internalization. Moreover, this effect could be induced after AT1R transfection. Further, co-immunoprecipitation experiments demonstrated that AT1R and ACE2 form complexes and these interactions were decreased by Ang-II treatment, which also enhanced ACE2 ubiquitination. In contrast, ACE2 activity was not changed by transfection of AT2 or Mas receptors. In vivo, Ang-II-mediated hypertension was blunted by chronic infusion of leupeptin in wildtype C57Bl/6, but not in ACE2 knockout mice. Overall, this is the first demonstration that elevated Ang-II levels reduce ACE2 expression and activity by stimulation of lysosomal degradation through an AT1R-dependent mechanism. PMID:25225202

  20. Isolation, Purification and Molecular Mechanism of a Peanut Protein-Derived ACE-Inhibitory Peptide

    PubMed Central

    Shi, Aimin; Liu, Hongzhi; Liu, Li; Hu, Hui; Wang, Qiang; Adhikari, Benu

    2014-01-01

    Although a number of bioactive peptides are capable of angiotensin I-converting enzyme (ACE) inhibitory effects, little is known regarding the mechanism of peanut peptides using molecular simulation. The aim of this study was to obtain ACE inhibiting peptide from peanut protein and provide insight on the molecular mechanism of its ACE inhibiting action. Peanut peptides having ACE inhibitory activity were isolated through enzymatic hydrolysis and ultrafiltration. Further chromatographic fractionation was conducted to isolate a more potent peanut peptide and its antihypertensive activity was analyzed through in vitro ACE inhibitory tests and in vivo animal experiments. MALDI-TOF/TOF-MS was used to identify its amino acid sequence. Mechanism of ACE inhibition of P8 was analyzed using molecular docking and molecular dynamics simulation. A peanut peptide (P8) having Lys-Leu-Tyr-Met-Arg-Pro amino acid sequence was obtained which had the highest ACE inhibiting activity of 85.77% (half maximal inhibitory concentration (IC50): 0.0052 mg/ml). This peanut peptide is a competitive inhibitor and show significant short term (12 h) and long term (28 days) antihypertensive activity. Dynamic tests illustrated that P8 can be successfully docked into the active pocket of ACE and can be combined with several amino acid residues. Hydrogen bond, electrostatic bond and Pi-bond were found to be the three main interaction contributing to the structural stability of ACE-peptide complex. In addition, zinc atom could form metal-carboxylic coordination bond with Tyr, Met residues of P8, resulting into its high ACE inhibiting activity. Our finding indicated that the peanut peptide (P8) having a Lys-Leu-Tyr-Met-Arg-Pro amino acid sequence can be a promising candidate for functional foods and prescription drug aimed at control of hypertension. PMID:25347076

  1. Propulsion/ACEE

    NASA Technical Reports Server (NTRS)

    1981-01-01

    The research objectives of the NASA aircraft energy efficiency program are summarized. Engine component improvements for turbofan engines, diagnostics, the development of advanced turboprop engines, and propeller noise analysis are discussed.

  2. Mimosine Dipeptide Enantiomsers: Improved Inhibitors against Melanogenesis and Cyclooxygenase.

    PubMed

    Nguyen, Binh Cao Quan; Tawata, Shinkichi

    2015-08-06

    Melanogenesis plays an important role in the protection of skin against UV through production of melanin pigments, but abnormal accumulation of this pigment causes unaesthetic hyperpigmentation. Much effort is being made to develop effective depigmenting agents. Here, we show for the first time that a small library of mimosine dipeptide enantiomers (Mi-L/D-amino acid) inhibit the melanogenesis in B16F10 melanoma cells by down-regulating the cellular tyrosinase with little effect on their growth or viability. Two of them, Mi-D-Trp and Mi-D-Val, turned out to be the most potent inhibitors on melanin content and cellular tyrosinase in B16F10 melanoma cells. In addition, most of the mimosine dipeptides were more potent than mimosine for inhibiting cyclooxygenase 1 (COX-1) with IC50 of 18-26 μM. Among them, Mi-L-Val and Mi-L-Trp inhibited cyclooxygenase 2 (COX-2) more potently than indomethacin, with IC50 values of 22 and 19 μM, respectively. Taken together, our results suggest the possibility that mimosine dipeptides could be better candidates (than mimosine) for anti-melanogenic (skin hyperpigmentation treatment) and cyclooxygenase (COX) inhibition.

  3. Performance Enhancement of the Automated Concrete Evaluation System (ACES)

    SciTech Connect

    Baumgart,C.W.; Cave,S.P.; Linder,K.E.

    2002-02-14

    The objective of this proposed research is to improve and expand the detection and analysis capabilities of the automated, concrete evaluation (ACE) system. MoDOT and Honeywell jointly developed this system. The focus of this proposed research will be on the following: Coordination of concrete imaging efforts with other states, Validation and testing of the ACE system on a broad range of concrete samples, and Identification and development of software and hardware enhancements. These enhancements will meet the needs of diverse users in the field of concrete materials, construction, and research.

  4. Linkages between ACE Vocational Provision and Mainstream VET.

    ERIC Educational Resources Information Center

    Saunders, John

    A study investigated linkages between adult community education (ACE) and mainstream vocational education and training (VET) in Australia, which enable people to move between the two sectors in their pursuit of vocational learning, and the ways in which linkages might be improved or new ones developed. The data from the study were derived from 69…

  5. Applying computationally efficient schemes for biogeochemical cycles (ACES4BGC)

    SciTech Connect

    Vertenstein, Mariana

    2016-01-11

    NCAR contributed to the ACES4BGC project through software engineering work on aerosol model implementation, build system and script changes, coupler enhancements for biogeochemical tracers, improvements to the Community Land Model (CLM) code and testing infrastructure, and coordinating and integrating code changes from the various project participants.

  6. ACE2 is augmented in dystrophic skeletal muscle and plays a role in decreasing associated fibrosis.

    PubMed

    Riquelme, Cecilia; Acuña, María José; Torrejón, Javiera; Rebolledo, Daniela; Cabrera, Daniel; Santos, Robson A; Brandan, Enrique

    2014-01-01

    Duchenne muscular dystrophy (DMD) is the most common inherited neuromuscular disease and is characterized by absence of the cytoskeletal protein dystrophin, muscle wasting, and fibrosis. We previously demonstrated that systemic infusion or oral administration of angiotensin-(1-7) (Ang-(1-7)), a peptide with opposing effects to angiotensin II, normalized skeletal muscle architecture, decreased local fibrosis, and improved muscle function in mdx mice, a dystrophic model for DMD. In this study, we investigated the presence, activity, and localization of ACE2, the enzyme responsible for Ang-(1-7) production, in wild type (wt) and mdx skeletal muscle and in a model of induced chronic damage in wt mice. All dystrophic muscles studied showed higher ACE2 activity than wt muscle. Immunolocalization studies indicated that ACE2 was localized mainly at the sarcolemma and, to a lesser extent, associated with interstitial cells. Similar results were observed in the model of chronic damage in the tibialis anterior (TA) muscle. Furthermore, we evaluated the effect of ACE2 overexpression in mdx TA muscle using an adenovirus containing human ACE2 sequence and showed that expression of ACE2 reduced the fibrosis associated with TA dystrophic muscles. Moreover, we observed fewer inflammatory cells infiltrating the mdx muscle. Finally, mdx gastrocnemius muscles from mice infused with Ang-(1-7), which decreases fibrosis, contain less ACE2 associated with the muscle. This is the first evidence supporting ACE2 as an important therapeutic target to improve the dystrophic skeletal muscle phenotype.

  7. Advanced Collaborative Emissions Study (ACES)

    SciTech Connect

    Greenbaum, Daniel; Costantini, Maria; Van Erp, Annemoon; Shaikh, Rashid; Bailey, Brent; Tennant, Chris; Khalek, Imad; Mauderly, Joe; McDonald, Jacob; Zielinska, Barbara; Bemis, Jeffrey; Storey, John; Hallberg, Lance; Clark, Nigel

    2013-12-31

    The objective of the Advanced Collaborative Emissions Study (ACES) was to determine before widespread commercial deployment whether or not the new, energy-efficient, heavy duty diesel engines (2007 and 2010 EPA Emissions Standards Compliant) may generate anticipated toxic emissions that could adversely affect the environment and human health. ACES was planned to take place in three phases. In Phase 1, extensive emissions characterization of four production-intent prototype engine and control systems designed to meet 2007 standards for nitrogen oxides (NOx) and particulate matter (PM) was conducted at an existing emissions characterization facility: Southwest Research Institute (SwRI). One of the tested engines was selected (at random, after careful comparison of results) for health testing in Phase 3. In Phase 2, extensive emission characterization of three production-intent prototype engine and control systems meeting the 2010 standards (including more advanced NOx controls to meet the more stringent 2010 NOx standards) was conducted at the same test facility. In Phase 3, one engine/aftertreatment system selected from Phase 1 was further characterized during health effects studies (at an existing inhalation toxicology laboratory: Lovelace Respiratory Research Institute, [LRRI]) to form the basis of the ACES safety assessment. The Department of Energy (DOE) award provided funding for emissions characterization in Phases 1 and 2 as well as exposure characterization in Phase 3. The main health analyses in Phase 3 were funded separately and are not reported here.

  8. ACE: Detecting Volatile Organic Compounds from Orbit

    NASA Astrophysics Data System (ADS)

    Harrison, Jeremy J.; Allen, Nicholas D. C.; Bernath, Peter F.

    2010-12-01

    High-resolution infrared absorption cross sections for ethane, propane (both in the 3 μm region) and acetone (in the 3 μm and 5-8 μm regions) have been determined from spectra recorded using a high-resolution FTIR spectrometer (Bruker IFS 125/HR). Data are presented for mixtures with dry synthetic air at 0.015 cm-1 resolution (calculated as 0.9/MOPD using the Bruker definition of resolution), at a number of temperatures and pressures appropriate for atmospheric conditions. Intensities were calibrated using spectra taken from the Pacific Northwest National Laboratory (PNNL) IR database. Methane measurements are currently being performed in the 3 μm region in order to retrieve line mixing parameters, which will be used in an improved ACE forward model to minimize CH4 residuals in the retrievals of organic species. Preliminary retrievals of acetone from ACE spectra using a microwindow from 1364.7 to 1367.1 cm-1 have been performed.

  9. High-throughput screening of improved protease inhibitors using a yeast cell surface display system and a yeast cell chip.

    PubMed

    Aoki, Wataru; Yoshino, Yuichi; Morisaka, Hironobu; Tsunetomo, Keiji; Koyo, Hirotaka; Kamiya, Shinji; Kawata, Noriyuki; Kuroda, Kouichi; Ueda, Mitsuyoshi

    2011-01-01

    Protease-targeted inhibitors have been promising pharmaceuticals. Here, we combined a yeast cell surface display system with a yeast cell chip for the high-throughput screening of protease inhibitors, and succeeded in improving the activity of a protease inhibitor.

  10. ACE2 alterations in kidney disease

    PubMed Central

    Soler, María José; Wysocki, Jan; Batlle, Daniel

    2013-01-01

    Angiotensin-converting enzyme 2 (ACE2) is a monocarboxypeptidase that degrades angiotensin (Ang) II to Ang-(1–7). ACE2 is highly expressed within the kidneys, it is largely localized in tubular epithelial cells and less prominently in glomerular epithelial cells and in the renal vasculature. ACE2 activity has been shown to be altered in diabetic kidney disease, hypertensive renal disease and in different models of kidney injury. There is often a dissociation between tubular and glomerular ACE2 expression, particularly in diabetic kidney disease where ACE2 expression is increased at the tubular level but decreased at the glomerular level. In this review, we will discuss alterations in circulating and renal ACE2 recently described in different renal pathologies and disease models as well as their possible significance. PMID:23956234

  11. Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAFV600E melanoma

    PubMed Central

    Hu-Lieskovan, Siwen; Mok, Stephen; Moreno, Blanca Homet; Tsoi, Jennifer; Faja, Lidia Robert; Goedert, Lucas; Pinheiro, Elaine M.; Koya, Richard C.; Graeber, Thomas; Comin-Anduix, Begoña; Ribas, Antoni

    2016-01-01

    Combining immunotherapy and BRAF targeted therapy may result in improved antitumor activity with the high response rates of targeted therapy and the durability of responses with immunotherapy. However, the first clinical trial testing the combination of the BRAF inhibitor vemurafenib and the CTLA-4 antibody ipilimumab was terminated early due to substantial liver toxicities. MEK inhibitors can potentiate the MAPK inhibition in BRAF mutant cells, while potentially alleviating the unwanted paradoxical MAPK activation in BRAF wild type cells that lead to side effects when using BRAF inhibitors alone. However, there is the concern of MEK inhibitors being detrimental to T cell functionality. Using a mouse model of syngeneic BRAFV600E driven melanoma, we tested whether addition of the MEK inhibitor trametinib would enhance the antitumor activity of combined immunotherapy with the BRAF inhibitor dabrafenib. Combination of dabrafenib and trametinib with pmel-1 adoptive cell transfer (ACT) showed complete tumor regression, increased T cell infiltration into tumors and improved in vivo cytotoxicity. Single agent dabrafenib increased tumor-associated macrophages and T regulatory cells (Tregs) in tumors, which decreased with the addition of trametinib. The triple combination therapy resulted in increased melanosomal antigen and MHC expression, and global immune-related gene up-regulation. Given the up-regulation of PD-L1 seen with dabrafenib and/or trametinib combined with antigen-specific ACT, we tested combination of dabrafenib, trametinib with anti-PD1 therapy in SM1 tumors, and observed superior anti-tumor effect. Our findings support the testing of triple combination therapy of BRAF and MEK inhibitors with immunotherapy in patients with BRAFV600E mutant metastatic melanoma. PMID:25787767

  12. Structure-based parallel medicinal chemistry approach to improve metabolic stability of benzopyran COX-2 inhibitors.

    PubMed

    Xing, Li; Hamper, Bruce C; Fletcher, Theresa R; Wendling, Jay M; Carter, Jeffery; Gierse, James K; Liao, Subo

    2011-02-01

    Combination of the structure-based design and solid-phase parallel synthesis provided an integrated approach to rapidly develop the structure-activity relationship of benzopyran COX-2 inhibitors. Binding free energies predicted by free energy perturbation theory yielded good agreement with experimental results. New potent and selective lead compounds with improved metabolic properties were identified.

  13. Calpain inhibitors reduce retinal hypoxia in ischemic retinopathy by improving neovascular architecture and functional perfusion.

    PubMed

    Hoang, Mien V; Smith, Lois E H; Senger, Donald R

    2011-04-01

    In ischemic retinopathies, underlying hypoxia drives abnormal neovascularization that damages retina and causes blindness. The abnormal neovasculature is tortuous and leaky and fails to alleviate hypoxia, resulting in more pathological neovascularization and retinal damage. With an established model of ischemic retinopathy we found that calpain inhibitors, when administered in moderation, reduced architectural abnormalities, reduced vascular leakage, and most importantly reduced retinal hypoxia. Mechanistically, these calpain inhibitors improved stability and organization of the actin cytoskeleton in retinal endothelial cells undergoing capillary morphogenesis in vitro, and they similarly improved organization of actin cables within new blood vessels in vivo. Hypoxia induced calpain activity in retinal endothelial cells and severely disrupted the actin cytoskeleton, whereas calpain inhibitors preserved actin cables under hypoxic conditions. Collectively, these findings support the hypothesis that hyper-activation of calpains by hypoxia contributes to disruption of the retinal endothelial cell cytoskeleton, resulting in formation of neovessels that are defective both architecturally and functionally. Modest suppression of calpain activity with calpain inhibitors restores cytoskeletal architecture and promotes formation of a functional neovasculature, thereby reducing underlying hypoxia. In sharp contrast to "anti-angiogenesis" strategies that cannot restore normoxia and may aggravate hypoxia, the therapeutic strategy described here does not inhibit neovascularization. Instead, by improving the function of neovascularization to reduce underlying hypoxia, moderate calpain inhibition offers a method for alleviating retinal ischemia, thereby suggesting a new treatment paradigm based on improvement rather than inhibition of new blood vessel growth.

  14. Characterization of ACE and ACE2 Expression within Different Organs of the NOD Mouse.

    PubMed

    Roca-Ho, Heleia; Riera, Marta; Palau, Vanesa; Pascual, Julio; Soler, Maria Jose

    2017-03-05

    Renin angiotensin system (RAS) is known to play a key role in several diseases such as diabetes, and renal and cardiovascular pathologies. Its blockade has been demonstrated to delay chronic kidney disease progression and cardiovascular damage in diabetic patients. In this sense, since local RAS has been described, the aim of this study is to characterize angiotensin converting enzyme (ACE) and ACE2 activities, as well as protein expression, in several tissues of the non-obese diabetic (NOD) mice model. After 21 or 40 days of diabetes onset, mouse serums and tissues were analyzed for ACE and ACE2 enzyme activities and protein expression. ACE and ACE2 enzyme activities were detected in different tissues. Their expressions vary depending on the studied tissue. Thus, whereas ACE activity was highly expressed in lungs, ACE2 activity was highly expressed in pancreas among the studied tissues. Interestingly, we also observed that diabetes up-regulates ACE mainly in serum, lung, heart, and liver, and ACE2 mainly in serum, liver, and pancreas. In conclusion, we found a marked serum and pulmonary alteration in ACE activity of diabetic mice, suggesting a common regulation. The increase of ACE2 activity within the circulation in diabetic mice may be ascribed to a compensatory mechanism of RAS.

  15. Characterization of ACE and ACE2 Expression within Different Organs of the NOD Mouse

    PubMed Central

    Roca-Ho, Heleia; Riera, Marta; Palau, Vanesa; Pascual, Julio; Soler, Maria Jose

    2017-01-01

    Renin angiotensin system (RAS) is known to play a key role in several diseases such as diabetes, and renal and cardiovascular pathologies. Its blockade has been demonstrated to delay chronic kidney disease progression and cardiovascular damage in diabetic patients. In this sense, since local RAS has been described, the aim of this study is to characterize angiotensin converting enzyme (ACE) and ACE2 activities, as well as protein expression, in several tissues of the non-obese diabetic (NOD) mice model. After 21 or 40 days of diabetes onset, mouse serums and tissues were analyzed for ACE and ACE2 enzyme activities and protein expression. ACE and ACE2 enzyme activities were detected in different tissues. Their expressions vary depending on the studied tissue. Thus, whereas ACE activity was highly expressed in lungs, ACE2 activity was highly expressed in pancreas among the studied tissues. Interestingly, we also observed that diabetes up-regulates ACE mainly in serum, lung, heart, and liver, and ACE2 mainly in serum, liver, and pancreas. In conclusion, we found a marked serum and pulmonary alteration in ACE activity of diabetic mice, suggesting a common regulation. The increase of ACE2 activity within the circulation in diabetic mice may be ascribed to a compensatory mechanism of RAS. PMID:28273875

  16. ACE2 deficiency reduces β-cell mass and impairs β-cell proliferation in obese C57BL/6 mice

    PubMed Central

    Shoemaker, Robin; Yiannikouris, Frederique; Thatcher, Sean

    2015-01-01

    Drugs that inhibit the renin-angiotensin system (RAS) decrease the onset of type 2 diabetes (T2D). Pancreatic islets express RAS components, including angiotensin-converting enzyme 2 (ACE2), which cleaves angiotensin II (Ang II) to angiotensin-(1–7) [Ang-(1–7)]. Overexpression of ACE2 in pancreas of diabetic mice improved glucose homeostasis. The purpose of this study was to determine if deficiency of endogenous ACE2 contributes to islet dysfunction and T2D. We hypothesized that ACE2 deficiency potentiates the decline in β-cell function and augments the development of diet-induced T2D. Male Ace2+/y or Ace2−/y mice were fed a low-fat (LF) or high-fat (HF) diet for 1 or 4 mo. A subset of 1-mo HF-fed mice were infused with Sal (Sal), losartan (Los), or Ang-(1–7). At 4 mo, while both genotypes of HF-fed mice developed a similar level of insulin resistance, adaptive hyperinsulinemia was reduced in Ace2−/y vs. Ace2+/y mice. Similarly, in vivo glucose-stimulated insulin secretion (GSIS) was reduced in 1-mo HF-fed Ace2−/y compared with Ace2+/y mice, resulting in augmented hyperglycemia. The average islet area was significantly smaller in both LF- and HF-fed Ace2−/y vs. Ace2+/y mice. Additionally, β-cell mass and proliferation were reduced significantly in HF-fed Ace2−/y vs. Ace2+/y mice. Neither infusion of Los nor Ang-(1–7) was able to correct impaired in vivo GSIS of HF-fed ACE2-deficient mice. These results demonstrate a critical role for endogenous ACE2 in the adaptive β-cell hyperinsulinemic response to HF feeding through regulation of β-cell proliferation and growth. PMID:26389599

  17. The Atmospheric Chemistry Experiment (ACE): MLT Results

    NASA Astrophysics Data System (ADS)

    Bernath, Peter

    2010-05-01

    ACE (also known as SCISAT) is making a comprehensive set of simultaneous measurements of numerous trace gases, thin clouds, aerosols and temperature by solar occultation from a satellite in low earth orbit. A high inclination (74 degrees) low earth orbit (650 km) gives ACE coverage of tropical, mid-latitudes and polar regions. The primary instrument is a high-resolution (0.02 cm-1) infrared Fourier Transform Spectrometer (FTS) operating from 2 to 13 microns (750-4400 cm-1). ACE was launched by NASA on 12 August 2003 for a nominal 2-year mission; after 6 years on orbit the ACE-FTS performance is still excellent. The first results of ACE have been presented in a special issue of Geophysics Research Letters (http://www.agu.org/journals/ss/ACECHEM1/) in 2005 and recently a special issue on ACE validation has been prepared for Atmospheric Chemistry and Physics (http://www.atmos-chem-phys.net/special_issue114.html) by K. Walker and K. Strong; more information can be found at http://www.ace.uwaterloo.ca. The ACE mission goals were initially focussed mainly on polar ozone chemistry, and more recently have shifted more to the troposphere where organic pollutants such as methanol and formaldehyde have been detected. ACE makes limb observations from about 5 km (cloud free scenes) up to nearly 150 km in the lower thermosphere, where CO2 absorption is still weakly detectable. This talk will review ACE-FTS results in the mesosphere and lower thermosphere. Topics covered will include the mesospheric descent of NOx in the polar winter, spectra of polar mesospheric clouds, concentration profiles of CO2 (which do not match model predictions), and combined Odin-Osiris/ACE-FTS observations.

  18. Space clocks to test relativiy: ACES and SAGAS

    NASA Astrophysics Data System (ADS)

    Wolf, Peter; Salomon, Christophe; Reynaud, Serge

    2010-01-01

    Atomic clocks are an outstanding tool for the experimental verification of general relativity and more generally for fundamental astronomy (VLBI, pulsar timing, navigation, etc). Recent years have seen a rapid improvement in the performance of such clocks, promising new improved tests of relativity, in particular onboard terrestrial and interplanetary space missions. We present the scientific motivations of such tests taking the ACES Salomon et al. and SAGAS Wolf et al. (2009) projects as particular examples.

  19. Improved inhibitor tolerance in xylose-fermenting yeast Spathaspora passalidarum by mutagenesis and protoplast fusion.

    PubMed

    Hou, Xiaoru; Yao, Shuo

    2012-03-01

    The xylose-fermenting yeast Spathaspora passalidarum showed excellent fermentation performance utilizing glucose and xylose under anaerobic conditions. But this yeast is highly sensitive to the inhibitors such as furfural present in the pretreated lignocellulosic biomass. In order to improve the inhibitor tolerance of this yeast, a combination of UV mutagenesis and protoplast fusion was used to construct strains with improved performance. Firstly, UV-induced mutants were screened and selected for improved tolerance towards furfural. The most promised mutant, S. passalidarum M7, produced 50% more final ethanol than the wild-type strain in a synthetic xylose medium containing 2 g/l furfural. However, this mutant was unable to grow in a medium containing 75% liquid fraction of pretreated wheat straw (WSLQ), in which furfural and many other inhibitors were present. Hybrid yeast strains, obtained from fusion of the protoplasts of S. passalidarum M7 and a robust yeast, Saccharomyces cerevisiae ATCC 96581, were able to grow in 75% WSLQ and produce around 0.4 g ethanol/g consumed xylose. Among the selected hybrid strains, the hybrid FS22 showed the best fermentation capacity in 75% WSLQ. Phenotypic and partial molecular analysis indicated that S. passalidarum M7 was the dominant parental contributor to the hybrid. In summary, the hybrids are characterized by desired phenotypes derived from both parents, namely the ability to ferment xylose from S. passalidarum and an increased tolerance to inhibitors from S. cerevisiae ATCC 96581.

  20. ACE program/UNIX user manual

    SciTech Connect

    Feng-Berman, S.K.

    1993-01-12

    This report the following: How to use the ace program?; Introduction to the ace program; Online command; Define a macro file; Macro commands; Counters and MCA; Counters usage; Counters database; Feedback Counter Database; MCA functions and macro command; X window Interclient Communication; and How to get around in UNIX?

  1. ACE program/UNIX user manual

    SciTech Connect

    Feng-Berman, S.K.

    1993-01-12

    This report the following: How to use the ace program ; Introduction to the ace program; Online command; Define a macro file; Macro commands; Counters and MCA; Counters usage; Counters database; Feedback Counter Database; MCA functions and macro command; X window Interclient Communication; and How to get around in UNIX

  2. Discovery of MK-1832, a Kv1.5 inhibitor with improved selectivity and pharmacokinetics.

    PubMed

    Wolkenberg, Scott E; Nolt, M Brad; Bilodeau, Mark T; Trotter, B Wesley; Manley, Peter J; Kett, Nathan R; Nanda, Kausik K; Wu, Zhicai; Cato, Matthew J; Kane, Stefanie A; Kiss, Laszlo; Spencer, Robert H; Wang, Jixin; Lynch, Joseph J; Regan, Christopher P; Stump, Gary L; Li, Bing; White, Rebecca; Yeh, Suzie; Dinsmore, Christopher J; Lindsley, Craig W; Hartman, George D

    2017-02-15

    Selective inhibition of Kv1.5, which underlies the ultra-rapid delayed rectifier current, IKur, has been pursued as a treatment for atrial fibrillation. Here we describe the discovery of MK-1832, a Kv1.5 inhibitor with improved selectivity versus the off-target current IKs, whose inhibition has been associated with ventricular proarrhythmia. MK-1832 exhibits improved selectivity for IKur over IKs (>3000-fold versus 70-fold for MK-0448), consistent with an observed larger window between atrial and ventricular effects in vivo (>1800-fold versus 210-fold for MK-0448). MK-1832 also exhibits an improved preclinical pharmacokinetic profile consistent with projected once daily dosing in humans.

  3. Comparison of speech perception benefits with SPEAK and ACE coding strategies in pediatric Nucleus CI24M cochlear implant recipients.

    PubMed

    Pasanisi, Enrico; Bacciu, Andrea; Vincenti, Vincenzo; Guida, Maurizio; Berghenti, Maria Teresa; Barbot, Anna; Panu, Francesco; Bacciu, Salvatore

    2002-06-17

    Nine congenitally deaf children who received a Nucleus CI24M cochlear implant and who were fitted with the SPrint speech processor participated in this study. All subjects were initially programmed with the SPEAK coding strategy and then converted to the ACE strategy. Speech perception was evaluated before and after conversion to the new coding strategy using word and Common Phrase speech recognition tests in both the presence and absence of noise. In quiet conditions, the mean percent correct scores for words were 68.8% with SPEAK and 91% with ACE; for phrases the percentage was 66.6% with SPEAK and 85.5% with ACE. In the presence of noise (at +10 dB signal-to-noise ratio), the mean percent correct scores for words were 43.3% with SPEAK compared to 84.4% with ACE; for phrases the percentage was 41.1% with SPEAK and 82.2% with ACE. Statistical analysis revealed significant improvement in open-set speech recognition with ACE compared to SPEAK. Preliminary data suggest that converting children from SPEAK to the ACE strategy improves their performance. Subjects showed significant improvements for open-set word and sentence recognition in quiet as well as in noise when ACE was used in comparison with SPEAK. The greatest improvements were obtained when tests were presented in the presence of noise.

  4. Improvement of the linear polarization resistance method for testing steel corrosion inhibitors

    NASA Astrophysics Data System (ADS)

    Faritov, A. T.; Rozhdestvenskii, Yu. G.; Yamshchikova, S. A.; Minnikhanova, E. R.; Tyusenkov, A. S.

    2016-11-01

    The linear polarization resistance method is used to improve the technique of corrosion control in liquid conducting according to GOST 9.514-99 (General Corrosion and Aging Protection System. Corrosion Inhibitors for Metals in Water Systems. Electrochemical Method of Determining the Protective Ability). Corrosion monitoring is shown to be performed by electronic devices with real-time data transfer to industrial controllers and SCADA systems.

  5. Chronic Cognitive Dysfunction after Traumatic Brain Injury Is Improved with a Phosphodiesterase 4B Inhibitor

    PubMed Central

    Titus, David J.; Wilson, Nicole M.; Freund, Julie E.; Carballosa, Melissa M.; Sikah, Kevin E.; Furones, Concepcion; Dietrich, W. Dalton; Gurney, Mark E.

    2016-01-01

    Learning and memory impairments are common in traumatic brain injury (TBI) survivors. However, there are no effective treatments to improve TBI-induced learning and memory impairments. TBI results in decreased cAMP signaling and reduced cAMP-response-element binding protein (CREB) activation, a critical pathway involved in learning and memory. TBI also acutely upregulates phosphodiesterase 4B2 (PDE4B2), which terminates cAMP signaling by hydrolyzing cAMP. We hypothesized that a subtype-selective PDE4B inhibitor could reverse the learning deficits induced by TBI. To test this hypothesis, adult male Sprague-Dawley rats received sham surgery or moderate parasagittal fluid-percussion brain injury. At 3 months postsurgery, animals were administered a selective PDE4B inhibitor or vehicle before cue and contextual fear conditioning, water maze training and a spatial working memory task. Treatment with the PDE4B inhibitor significantly reversed the TBI-induced deficits in cue and contextual fear conditioning and water maze retention. To further understand the underlying mechanisms of these memory impairments, we examined hippocampal long-term potentiation (LTP). TBI resulted in a significant reduction in basal synaptic transmission and impaired expression of LTP. Treatment with the PDE4B inhibitor significantly reduced the deficits in basal synaptic transmission and rescued LTP expression. The PDE4B inhibitor reduced tumor necrosis factor-α levels and increased phosphorylated CREB levels after TBI, suggesting that this drug inhibited molecular pathways in the brain known to be regulated by PDE4B. These results suggest that a subtype-selective PDE4B inhibitor is a potential therapeutic to reverse chronic learning and memory dysfunction and deficits in hippocampal synaptic plasticity following TBI. SIGNIFICANCE STATEMENT Currently, there are an estimated 3.2–5.3 million individuals living with disabilities from traumatic brain injury (TBI) in the United States, and 8 of

  6. Bisubstrate analogue inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase: New design with improved properties

    SciTech Connect

    Shi, Genbin; Shaw, Gary; Liang, Yu-He; Subburaman, Priadarsini; Li, Yue; Wu, Yan; Yan, Honggao; Ji, Xinhua

    2012-07-11

    6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK), a key enzyme in the folate biosynthetic pathway, catalyzes the pyrophosphoryl transfer from ATP to 6-hydroxymethyl-7,8-dihydropterin. The enzyme is essential for microorganisms, is absent from humans, and is not the target for any existing antibiotics. Therefore, HPPK is an attractive target for developing novel antimicrobial agents. Previously, we characterized the reaction trajectory of HPPK-catalyzed pyrophosphoryl transfer and synthesized a series of bisubstrate analog inhibitors of the enzyme by linking 6-hydroxymethylpterin to adenosine through 2, 3, or 4 phosphate groups. Here, we report a new generation of bisubstrate analog inhibitors. To improve protein binding and linker properties of such inhibitors, we have replaced the pterin moiety with 7,7-dimethyl-7,8-dihydropterin and the phosphate bridge with a piperidine linked thioether. We have synthesized the new inhibitors, measured their K{sub d} and IC{sub 50} values, determined their crystal structures in complex with HPPK, and established their structure-activity relationship. 6-Carboxylic acid ethyl ester-7,7-dimethyl-7,8-dihydropterin, a novel intermediate that we developed recently for easy derivatization at position 6 of 7,7-dimethyl-7,8-dihydropterin, offers a much high yield for the synthesis of bisubstrate analogs than that of previously established procedure.

  7. Advanced control evaluation for structures (ACES) programs

    NASA Technical Reports Server (NTRS)

    Pearson, Jerome; Waites, Henry

    1988-01-01

    The ACES programs are a series of past, present, and future activities at the Marshall Space Flight Center (MSFC) Ground facility for Large Space Structure Control Verification (GF/LSSCV). The main objectives of the ACES programs are to implement control techniques on a series of complex dynamical systems, to determine the control/structure interaction for the control techniques, and to provide a national facility in which dynamics and control verification can be effected. The focus is on these objectives and how they are implemented under various engineering and economic constraints. Future plans that will be effected in upcoming ACES programs are considered.

  8. Hepatitis C virus NS3-4A serine protease inhibitors: SAR of P'2 moiety with improved potency.

    PubMed

    Arasappan, A; Njoroge, F G; Chan, T-Y; Bennett, F; Bogen, S L; Chen, K; Gu, H; Hong, L; Jao, E; Liu, Y-T; Lovey, R G; Parekh, T; Pike, R E; Pinto, P; Santhanam, B; Venkatraman, S; Vaccaro, H; Wang, H; Yang, X; Zhu, Z; Mckittrick, B; Saksena, A K; Girijavallabhan, V; Pichardo, J; Butkiewicz, N; Ingram, R; Malcolm, B; Prongay, A; Yao, N; Marten, B; Madison, V; Kemp, S; Levy, O; Lim-Wilby, M; Tamura, S; Ganguly, A K

    2005-10-01

    We have discovered that introduction of appropriate amino acid derivatives at P'2 position improved the binding potency of P3-capped alpha-ketoamide inhibitors of HCV NS3 serine protease. X-ray crystal structure of one of the inhibitors (43) bound to the protease revealed the importance of the P'2 moiety.

  9. Donor preconditioning with a calcineurin inhibitor improves outcome in rat syngeneic kidney transplantation.

    PubMed

    Shihab, Fuad S; Bennett, William M; Andoh, Takeshi F

    2009-02-15

    Ischemia-reperfusion injury (IRI) in the early posttransplant period affects immediate graft function and late allograft dysfunction. This study determines the influence of pharmacologic preconditioning with a calcineurin inhibitor on IRI in a syngeneic F344 rat kidney transplant model. Donor rats were pretreated with one dose of cyclosporine (10 mg/kg) or tacrolimus (1 mg/kg) administered at 24 hr or 7 days before being subjected to 2 hr of cold ischemia and then transplanted. Pharmacologic preconditioning significantly improved renal function, as assessed by serum creatinine and inulin clearance, and histologic score versus vehicle-treated rats. There were no differences between cyclosporine and tacrolimus in the measured outcomes. This renoprotective effect, although not complete, was seen with only one dose of calcineurin inhibitor, and the effect was sustained for at least 7 days before IRI. This approach may represent a viable pharmacologic intervention to decrease IRI at the time of organ transplantation.

  10. ACE infrared spectral atlases of the Earth's atmosphere

    NASA Astrophysics Data System (ADS)

    Hughes, Ryan; Bernath, Peter; Boone, Chris

    2014-11-01

    Five infrared atmospheric atlases are presented using solar occultation spectra from the Atmospheric Chemistry Experiment Fourier Transform Spectrometer (ACE-FTS) in low earth orbit. The spectral atlases were created for Arctic summer, Arctic winter, mid-latitude summer, mid-latitude winter and the tropics. Each covers the spectral range from 700 to 4400 cm-1 and consists of 31 spectra that span an altitude range of 6-126 km in 4-km altitude intervals. To improve the signal-to-noise ratio, each spectrum in the atlas is an average of at least several hundred individual ACE-FTS limb transmission spectra. Representative plots in pdf format at 10 km (troposphere), 30 km (stratosphere), 70 km (mesosphere), and 110 km (lower thermosphere) are also available.

  11. ACE3 Draft Indicators: Environments and Contaminants

    EPA Pesticide Factsheets

    The information on this page was provided by EPA in conjunction with the opportunity for public comment on the draft indicators for ACE3, which ran from March 8 – April 21, 2011. The public comment period is now closed.

  12. FIRE_ACE_ER2_MAS

    Atmospheric Science Data Center

    2015-10-28

    ... First ISCCP Regional Experiment (FIRE) Arctic Cloud Experiment (ACE) NASA ER-2 Moderate Resolution Imaging ... SSFR Location:  Northern Alaska Arctic Ocean Spatial Coverage:  Fairbanks, Alaska and the surrounding ...

  13. ACE3 Draft Indicators: Special Features

    EPA Pesticide Factsheets

    The page information was provided by EPA in conjunction with the opportunity for public comment on the draft indicators for ACE3, which ran from March 8 – April 21, 2011. The public comment period is now closed.

  14. ACE-FTS measurements of HCFC-22

    NASA Astrophysics Data System (ADS)

    Kolonjari, F.; Walker, K. A.; Boone, C. D.; Strahan, S.; McLinden, C. A.; Manney, G. L.; Daffer, W. H.; Bernath, P. F.

    2012-04-01

    In the 1980s scientists discovered an annual springtime minimum in stratospheric ozone over the Antarctic. It was determined that the decline in ozone concentration was primarily caused by catalytic reactions of ozone and chlorine. The emissions of anthropogenic chlorofluorocarbons (CFCs) were determined to be major sources of the chlorine. The Montreal Protocol on Substances that Deplete the Ozone Layer (with its subsequent amendments) restricts the emissions of ozone depleting substances. To fulfill the need for safe, stable replacements of CFCs, hydrochlorofluorocarbons (HCFCs) and hydrofluorocarbons (HFCs) were developed. The use of HCFC-22 as a replacement has led to an increase in its atmospheric abundance. This is of concern due to its ozone depletion potential and its global warming potential. The Atmospheric Chemistry Experiment (ACE) is a mission on-board the Canadian satellite SCISAT. The primary instrument on SCISAT is a high-resolution infrared Fourier Transform Spectrometer (ACE-FTS). With its wide spectral range, the ACE-FTS is capable of measuring an extensive range of gases including key CFC and HCFC species. The altitude distribution from the ACE-FTS profiles provides information that is complementary to the ground-based measurements that have been used to monitor these species. The global distribution of HCFC-22 has been computed from measurements by ACE-FTS. Both seasonal variations and an inter-hemispheric difference are observed. Additionally, a rapid increase in the global concentration of HCFC-22 has been observed since the start of the ACE mission in 2004. Comparisons to ground-based and air-borne measurements show good agreement with the ACE-FTS measurements. The global distributions of HCFC-22 have also been compared to a chemistry and transport model (CTM), the Global Modelling Initiative Combined Stratospheric-Tropospheric Model. There are distinct differences between the model results and ACE-FTS measurements. The causes and

  15. A chemical analog of curcumin as an improved inhibitor of amyloid Abeta oligomerization.

    PubMed

    Orlando, Robert A; Gonzales, Amanda M; Royer, Robert E; Deck, Lorraine M; Vander Jagt, David L

    2012-01-01

    Amyloid-like plaques are characteristic lesions defining the neuropathology of Alzheimer's disease (AD). The size and density of these plaques are closely associated with cognitive decline. To combat this disease, the few therapies that are available rely on drugs that increase neurotransmission; however, this approach has had limited success as it has simply slowed an imminent decline and failed to target the root cause of AD. Amyloid-like deposits result from aggregation of the Aβ peptide, and thus, reducing amyloid burden by preventing Aβ aggregation represents an attractive approach to improve the therapeutic arsenal for AD. Recent studies have shown that the natural product curcumin is capable of crossing the blood-brain barrier in the CNS in sufficient quantities so as to reduce amyloid plaque burden. Based upon this bioactivity, we hypothesized that curcumin presents molecular features that make it an excellent lead compound for the development of more effective inhibitors of Aβ aggregation. To explore this hypothesis, we screened a library of curcumin analogs and identified structural features that contribute to the anti-oligomerization activity of curcumin and its analogs. First, at least one enone group in the spacer between aryl rings is necessary for measureable anti-Aβ aggregation activity. Second, an unsaturated carbon spacer between aryl rings is essential for inhibitory activity, as none of the saturated carbon spacers showed any margin of improvement over that of native curcumin. Third, methoxyl and hydroxyl substitutions in the meta- and para-positions on the aryl rings appear necessary for some measure of improved inhibitory activity. The best lead inhibitors have either their meta- and para-substituted methoxyl and hydroxyl groups reversed from that of curcumin or methoxyl or hydroxyl groups placed in both positions. The simple substitution of the para-hydroxy group on curcumin with a methoxy substitution improved inhibitor function by 6

  16. Role of angiotensin-converting enzyme 2 (ACE2) in diabetic cardiovascular complications.

    PubMed

    Patel, Vaibhav B; Parajuli, Nirmal; Oudit, Gavin Y

    2014-04-01

    Diabetes mellitus results in severe cardiovascular complications, and heart disease and failure remain the major causes of death in patients with diabetes. Given the increasing global tide of obesity and diabetes, the clinical burden of diabetes-induced cardiovascular disease is reaching epidemic proportions. Therefore urgent actions are needed to stem the tide of diabetes which entails new prevention and treatment tools. Clinical and pharmacological studies have demonstrated that AngII (angiotensin II), the major effector peptide of the RAS (renin-angiotensin system), is a critical promoter of insulin resistance and diabetes mellitus. The role of RAS and AngII has been implicated in the progression of diabetic cardiovascular complications and AT1R (AngII type 1 receptor) blockers and ACE (angiotensin-converting enzyme) inhibitors have shown clinical benefits. ACE2, the recently discovered homologue of ACE, is a monocarboxypeptidase which converts AngII into Ang-(1-7) [angiotensin-(1-7)] which, by virtue of its actions on the MasR (Mas receptor), opposes the effects of AngII. In animal models of diabetes, an early increase in ACE2 expression and activity occurs, whereas ACE2 mRNA and protein levels have been found to decrease in older STZ (streptozotocin)-induced diabetic rats. Using the Akita mouse model of Type 1 diabetes, we have recently shown that loss of ACE2 disrupts the balance of the RAS in a diabetic state and leads to AngII/AT1R-dependent systolic dysfunction and impaired vascular function. In the present review, we will discuss the role of the RAS in the pathophysiology and treatment of diabetes and its complications with particular emphasis on potential benefits of the ACE2/Ang-(1-7)/MasR axis activation.

  17. Optimization of Amide-Based Inhibitors of Soluble Epoxide Hydrolase with Improved Water Solubility

    PubMed Central

    Kim, In-Hae; Heirtzler, Fenton R.; Morisseau, Christophe; Nishi, Kosuke; Tsai, Hsing-Ju; Hammock, Bruce D.

    2006-01-01

    Soluble epoxide hydrolase (sEH) plays an important role in the metabolism of endogenous chemical mediators involved in the regulation of blood pressure and inflammation. 1,3-Disubstituted ureas with a polar group located on the fifth atom from the carbonyl group of urea function are active inhibitors of sEH both in vitro and in vivo. However, their limited solubility in water and relatively high melting point lead to difficulties in formulating the compounds and poor in vivo efficacy. To improve these physical properties, the effect of structural modification of the urea pharmacophore on the inhibition potencies, water solubilities, octanol/water partition coefficients (log P), and melting points of a series of compounds was evaluated. For murine sEH, no loss of inhibition potency was observed when the urea pharmacophore was modified to an amide function, while for human sEH 2.5-fold decreased inhibition was obtained in the amide compounds. In addition, a NH group on the right side of carbonyl group of the amide pharmacophore substituted with an adamantyl group (such as compound 14) and a methylene carbon present between the adamantyl and amide groups were essential to produce potent inhibition of sEH. The resulting amide inhibitors have 10–30-fold better solubility and lower melting point than the corresponding urea compounds. These findings will facilitate synthesis of sEH inhibitors that are easier to formulate and more bioavailable. PMID:15887969

  18. Proteasome inhibitors, including curcumin, improve pancreatic β-cell function and insulin sensitivity in diabetic mice

    PubMed Central

    Weisberg, S; Leibel, R; Tortoriello, D V

    2016-01-01

    Background: Type 2 diabetes stems from obesity-associated insulin resistance, and in the genetically susceptible, concomitant pancreatic β-cell failure can occur, which further exacerbates hyperglycemia. Recent work by our group and others has shown that the natural polyphenol curcumin attenuates the development of insulin resistance and hyperglycemia in mouse models of hyperinsulinemic or compensated type 2 diabetes. Although several potential downstream molecular targets of curcumin exist, it is now recognized to be a direct inhibitor of proteasome activity. We now show that curcumin also prevents β-cell failure in a mouse model of uncompensated obesity-related insulin resistance (Leprdb/db on the Kaliss background). Results: In this instance, dietary supplementation with curcumin prevented hyperglycemia, increased insulin production and lean body mass, and prolonged lifespan. In addition, we show that short-term in vivo treatment with low dosages of two molecularly distinct proteasome inhibitors celastrol and epoxomicin reverse hyperglycemia in mice with β-cell failure by increasing insulin production and insulin sensitivity. Conclusions: These studies suggest that proteasome inhibitors may prove useful for patients with diabetes by improving both β-cell function and relieving insulin resistance. PMID:27110686

  19. Treatment with tumour necrosis factor inhibitor oxpentifylline does not improve corticosteroid dependent chronic active Crohn's disease.

    PubMed Central

    Bauditz, J; Haemling, J; Ortner, M; Lochs, H; Raedler, A; Schreiber, S

    1997-01-01

    BACKGROUND: In Crohn's disease, inflammation is presumably sustained by an increased production of proinflammatory cytokines, in particular tumour necrosis factor alpha (TNF alpha) and interleukin 1 beta (IL 1 beta). TNF alpha can induce a host of cellular effector events resulting in perpetuation of the inflammatory process. In vivo studies with anti-TNF alpha antibody treatment have led to impressive clinical results. AIMS: To investigate whether treatment with the TNF alpha inhibitor oxpentifylline results in clinical improvement in corticosteroid dependent chronic active Crohn's disease. METHODS: Sixteen Crohn's disease patients received oxpentifylline 400 mg four times a day in a four week open label study. RESULTS: Blockade of TNF alpha production in 16 patients with corticosteroid dependent Crohn's disease did not improve the clinical disease activity (CDAI mean (SEM) 188.75 (5.65) versus 185.13 (10.87) or the endoscopic degree of inflammation (CDEIS 14.9 (2.87) versus 14.8 (2.27) or laboratory parameters. CONCLUSIONS: In this study, use of the TNF alpha inhibitor oxpentifylline does not improve inflammation in Crohn's disease. This finding suggests that there may be more key mediators than only TNF alpha in the inflammatory process in Crohn's disease. PMID:9176073

  20. Flavonoids and polymer derivatives as CYP3A4 inhibitors for improved oral drug bioavailability.

    PubMed

    Fasinu, Pius; Choonara, Yahya E; Khan, Riaz A; Du Toit, Lisa C; Kumar, Pradeep; Ndesendo, Valence M K; Pillay, Viness

    2013-02-01

    Molecular modeling computations were utilized to generate pharmaceutical grade CYP3A4-enzyme inhibitors. In vitro metabolism of felodipine in human intestinal and liver microsomes (HLM and HIM) was optimized yielding a Michaelis-Menten plot from where the K(m) and V(max) values were estimated by nonlinear regression. The flavonoids, naringin, naringenin, and quercetin, were subsequently incubated with felodipine at the determined K(m) value in HLM. Comparing results obtained from a known CYP3A4 inhibitor, verapamil, the flavonoids inhibited felodipine metabolism. In-depth computational analysis of these flavonoids in terms of CYP3A4 binding, sequencing, and affinity, computational biomimetism was employed to validate the potential CYP3A4 inhibitors. The modeled compounds were comparatively evaluated by incubation with felodipine in both HLM and HIM. Results showed that the polymers 8-arm-PEG, o-(2-aminoethyl)-o-methyl-PEG, 4-arm-PEG (molecular weight = 10,000 g/mol and 20,000 g/mol, respectively), and poly(l-lysine) were able to inhibit the felodipine metabolism with the half maximal inhibitory concentration (IC(50)) values ranging from 7.22 to 30.0 μM (HLM) and 5.78 to 41.03 μM (HIM). Molecular docking confirmed drug-enzyme interactions by computing the free energies of binding (ΔE) and inhibition constants (K(i)) of the docked compounds utilizing a Lamarckian Genetic Algorithm. Comparative correlations between the computed and experimental K(i) values were obtained. Computational modeling of CYP3A4 inhibitors provided a suitable strategy to screen pharmaceutical grade compounds that may potentially inhibit presystemic CYP3A4-dependent drug metabolism with the prospect of improving oral drug bioavailability.

  1. Aerosol Characterization Data from the Asian Pacific Regional Aerosol Characterization Project (ACE-Asia)

    DOE Data Explorer

    The Aerosol Characterization Experiments (ACE) were designed to increase understanding of how atmospheric aerosol particles affect the Earth's climate system. These experiments integrated in-situ measurements, satellite observations, and models to reduce the uncertainty in calculations of the climate forcing due to aerosol particles and improve the ability of models to predict the influences of aerosols on the Earth's radiation balance. ACE-Asia was the fourth in a series of experiments organized by the International Global Atmospheric Chemistry (IGAC) Program (A Core Project of the International Geosphere Biosphere Program). The Intensive Field Phase for ACE-Asia took place during the spring of 2001 (mid-March through early May) off the coast of China, Japan and Korea. ACE-Asia pursued three specific objectives: 1) Determine the physical, chemical, and radiative properties of the major aerosol types in the Eastern Asia and Northwest Pacific region and investigate the relationships among these properties. 2) Quantify the physical and chemical processes controlling the evolution of the major aerosol types and in particular their physical, chemical, and radiative properties. 3) Develop procedures to extrapolate aerosol properties and processes from local to regional and global scales, and assess the regional direct and indirect radiative forcing by aerosols in the Eastern Asia and Northwest Pacific region [Edited and shortened version of summary at http://data.eol.ucar.edu/codiac/projs?ACE-ASIA]. The Ace-Asia collection contains 174 datasets.

  2. Racial differences in blood pressure response to angiotensin-converting enzyme inhibitors in children: a meta-analysis.

    PubMed

    Li, J S; Baker-Smith, C M; Smith, P B; Hasselblad, V; Murphy, M D; Califf, R M; Benjamin, D K

    2008-09-01

    Angiotensin-converting enzyme (ACE) inhibitors are frequently used to treat hypertension in children.(1) ACE inhibitors alter the balance between the vasoconstrictive, salt-retentive, and cardiac hypertrophic properties of angiotensin II and the vasodilatory and natriuretic properties of bradykinin; they also alter the metabolism of other vasoactive substances.(2) Through these mechanisms, ACE inhibitors decrease systemic vascular resistance and promote natriuresis without increasing heart rate. This study evaluated the results of six trials of ACE inhibitors in children, using meta-analytic techniques to estimate the effect of race on blood pressure response.

  3. A composite guanyl thiourea (GTU), dicyandiamide (DCD) inhibitor improves the efficacy of nitrification inhibition in soil.

    PubMed

    Duncan, Elliott G; O'Sullivan, Cathryn A; Simonsen, Anna K; Roper, Margaret M; Treble, Karen; Whisson, Kelley

    2016-11-01

    This study investigated whether applying dicyandiamide (DCD) and guanyl thiourea (GTU) in conjunction with urea improves the efficacy of nitrification inhibition relative to traditional fertiliser application of urea or urea + DCD. Urea at a rate of 100 mg N kg(-1) soil was applied to soil microcosms (high nutrient tenosol and low nutrient hydrosol) which were treated with either no inhibitor (urea-only); 15 mg DCD kg(-1) soil or 15 mg DCD kg(-1) soil plus 21 mg GTU kg soil(-1). Mineral N (NH4(+) & NO3(-)) concentrations, potential nitrification rates (PNR) and abundances of ammonia oxidising bacteria (AOB) were measured over time. After 100-days incubation, ∼73 mg N kg(-1) soil was found as NH4(+) when urea + DCD + GTU were applied to the tenosol. NH4(+) concentrations were lower (11-32 mg N kg(-1) soil) when urea or urea + DCD were applied. This suggests that the application of GTU in conjunction with DCD elongated the effects of nitrification inhibition. In both soils, PNRs were faster and AOB abundances (gene copies g(-1) soil) were higher when urea was applied without nitrification inhibitors. There were, however, no differences in PNR or AOB abundances in either soil type when 'urea + DCD' or 'urea + DCD + GTU' were applied. The results indicate that the application of GTU with DCD may extend nitrification inhibition in certain soil types. This finding has the potential to improve the efficacy of commercially available and widely used inhibitors such as DCD.

  4. [Job satisfaction among the professionals of AceS Baixo Vouga II].

    PubMed

    Santana, Silvina; Cerdeira, José

    2011-12-01

    Job satisfaction is a measure of quality of life at work and is related to emotional states. The interest for this theme is increasing and, in the last years, many studies have attempted to demonstrate its relation with professional performance. Primary care professionals are in the first line of the Serviço Nacional de Saúde (SNS). Therefore, it is necessary that they feel satisfaction with their jobs, in order to perform the tasks with the quality required. Several factors seem to have impact in the satisfaction of these professionals, such as payment, promotion, recognition from supervisors and peers, physical conditions at work and available resources, opportunities for personal development, among others. Insatisfaction may lead to absentism and in the limit to job quit. The main objective of this work is to study job satisfaction among the professionals working at the health centers of ACeS Baixo Vouga II, namely, the relationship between job characteristics and job satisfaction and between job characteristics and considering job quit as a serious option. All the professionals working in the four health centers were inquired. Results show that job characteristics are defined by six dimensions: leadership and supervision, task characteristics and autonomy, payment, personal and professional development and promotion, peers and relations inside the organization and work environment. Globally, payment and opportunities for personal and professional development and promotion are perceived at low level by all the professional groups. Results also show that there are differences by gender and professional groups regarding job satisfaction and the will to quit job. Considering the specificity of the tasks performed by these professionals, measures should be taken in order to improve job satisfaction in the Portuguese health centers.

  5. A novel 11β-HSD1 inhibitor improves diabesity and osteoblast differentiation.

    PubMed

    Park, Ji Seon; Bae, Su Jung; Choi, Sik-Won; Son, You Hwa; Park, Sung Bum; Rhee, Sang Dal; Kim, Hee Youn; Jung, Won Hoon; Kang, Seung Kyu; Ahn, Jin Hee; Kim, Seong Hwan; Kim, Ki Young

    2014-04-01

    Selective inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) have considerable potential as treatment for osteoporosis as well as metabolic syndrome including type 2 diabetes mellitus. Here, we investigated the anti-diabetic, anti-adipogenic, and anti-osteoporotic activity of KR-67500, as a novel selective 11β-HSD1 inhibitor. Cellular 11β-HSD1 activity was tested based on a homogeneous time-resolved fluorescence method. Oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) levels were measured in diet-induced obese (DIO)-C57BL/6 mice administered KR-67500 (50  mg/kg per day, p.o.) for 28 days and, additionally, its anti-diabetic effect was evaluated by OGTT and ITT. The in vitro anti-adipogenic effect of KR-67500 was determined by Oil Red O Staining. The in vitro anti-osteoporotic activity of KR-67500 was evaluated using bone morphogenetic protein 2 (BMP2)-induced osteoblast differentiation and receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation model systems. KR-67500 improved the in vivo glucose tolerance and insulin sensitivity in DIO-C57BL/6 mice. KR-67500 suppressed cortisone-induced differentiation of 3T3-L1 cells into adipocytes. KR-67500 enhanced BMP2-induced osteoblastogenesis in C2C12 cells and inhibited RANKL-induced osteoclastogenesis in mouse bone marrow-derived macrophages. KR-67500, a new selective 11β-HSD1 inhibitor, may provide a new therapeutic window in the prevention and/or treatment of type 2 diabetes, obesity, and/or osteoporosis.

  6. Cholinesterase inhibitors improve both memory and complex learning in aged beagle dogs.

    PubMed

    Araujo, Joseph A; Greig, Nigel H; Ingram, Donald K; Sandin, Johan; de Rivera, Christina; Milgram, Norton W

    2011-01-01

    Similar to patients with Alzheimer's disease (AD), dogs exhibit age-dependent cognitive decline, amyloid-β (Aβ) pathology, and evidence of cholinergic hypofunction. The present study sought to further investigate the role of cholinergic hypofunction in the canine model by examining the effect of the cholinesterase inhibitors phenserine and donepezil on performance of two tasks, a delayed non-matching-to-position task (DNMP) designed to assess working memory, and an oddity discrimination learning task designed to assess complex learning, in aged dogs. Phenserine (0.5 mg/kg; PO) significantly improved performance on the DNMP at the longest delay compared to wash-out and partially attenuated scopolamine-induced deficits (15 μg/kg; SC). Phenserine also improved learning on a difficult version of an oddity discrimination task compared to placebo, but had no effect on an easier version. We also examined the effects of three doses of donepezil (0.75, 1.5, and 6 mg/kg; PO) on performance of the DNMP. Similar to the results with phenserine, 1.5 mg/kg of donepezil improved performance at the longest delay compared to baseline and wash-out, indicative of memory enhancement. These results further extend the findings of cholinergic hypofunction in aged dogs and provide pharmacological validation of the canine model with a cholinesterase inhibitor approved for use in AD. Collectively, these studies support utilizing the aged dog in future screening of therapeutics for AD, as well as for investigating the links among cholinergic function, Aβ pathology, and cognitive decline.

  7. The PDE4 inhibitor roflumilast improves memory in rodents at non-emetic doses.

    PubMed

    Vanmierlo, Tim; Creemers, Pim; Akkerman, Sven; van Duinen, Marlies; Sambeth, Anke; De Vry, Jochen; Uz, Tolga; Blokland, Arjan; Prickaerts, Jos

    2016-04-15

    Enhancement of central availability of the second messenger cAMP is a promising approach to improve cognitive function. Pharmacological inhibition of phosphodiesterase type 4 (PDE4), a group of cAMP hydrolyzing enzymes in the brain, has been shown to improve cognitive performances in rodents and monkeys. However, inhibition of PDE4 is generally associated with severe emetic side-effects. Roflumilast, an FDA-approved PDE4 inhibitor for treatment of chronic obstructive pulmonary disease (COPD), is yielding only mild emetic side effects. In the present study we investigate the potential of roflumilast as a cognition enhancer and to determine the potential coinciding emetic response in comparison to rolipram, a classic PDE4 inhibitor with pronounced emetic effects. Cognition enhancement was evaluated in mice and it was found that both roflumilast and rolipram enhanced memory in an object location task (0.03mg/kg), whereas only roflumilast was effective in a spatial Y-maze (0.1mg/kg). Emetic potential was measured using competition of PDE4 inhibition for α2-adrenergic receptor antagonism in which recovery from xylazine/ketamine-mediated anesthesia is used as a surrogate marker. While rolipram displayed emetic properties at a dose 10 times the memory-enhancing dose, roflumilast only showed increased emetic-like properties at a dose 100 times the memory-enhancing dose. Moreover, combining sub-efficacious doses of the approved cognition-enhancer donepezil and roflumilast, which did not improve memory when given alone, fully restored object recognition memory deficit in rats induced by the muscarinic receptor antagonist scopolamine. These findings suggest that roflumilast offers a more favorable window for treatment of cognitive deficits compared to rolipram.

  8. Treatment with didemnin B, an elongation factor 1A inhibitor, improves hepatic lipotoxicity in obese mice.

    PubMed

    Hetherington, Alexandra M; Sawyez, Cynthia G; Sutherland, Brian G; Robson, Debra L; Arya, Rigya; Kelly, Karen; Jacobs, René L; Borradaile, Nica M

    2016-09-01

    Eukaryotic elongation factor EEF1A1 is induced by oxidative and ER stress, and contributes to subsequent cell death in many cell types, including hepatocytes. We recently showed that blocking the protein synthesis activity of EEF1A1 with the peptide inhibitor, didemnin B, decreases saturated fatty acid overload-induced cell death in HepG2 cells. In light of this and other recent work suggesting that limiting protein synthesis may be beneficial in treating ER stress-related disease, we hypothesized that acute intervention with didemnin B would decrease hepatic ER stress and lipotoxicity in obese mice with nonalcoholic fatty liver disease (NAFLD). Hyperphagic male ob/ob mice were fed semipurified diet for 4 weeks, and during week 5 received i.p. injections of didemnin B or vehicle on days 1, 4, and 7. Interestingly, we observed that administration of this compound modestly decreased food intake without evidence of illness or distress, and thus included an additional control group matched for food consumption with didemnin B-treated animals. Treatment with didemnin B improved several characteristics of hepatic lipotoxicity to a greater extent than the effects of caloric restriction alone, including hepatic steatosis, and some hepatic markers of ER stress and inflammation (GRP78, Xbp1s, and Mcp1). Plasma lipid and lipoprotein profiles and histopathological measures of NAFLD, including lobular inflammation, and total NAFLD activity score were also improved by didemnin B. These data indicate that acute intervention with the EEF1A inhibitor, didemnin B, improves hepatic lipotoxicity in obese mice with NAFLD through mechanisms not entirely dependent on decreased food intake, suggesting a potential therapeutic strategy for this ER stress-related disease.

  9. ACE2/Ang-(1-7)/Mas axis stimulates vascular repair-relevant functions of CD34+ cells.

    PubMed

    Singh, Neha; Joshi, Shrinidh; Guo, Lirong; Baker, Matthew B; Li, Yan; Castellano, Ronald K; Raizada, Mohan K; Jarajapu, Yagna P R

    2015-11-15

    CD34(+) stem/progenitor cells have been identified as a promising cell population for the autologous cell-based therapies in patients with cardiovascular disease. The counter-regulatory axes of renin angiotensin system, angiotensin converting enzyme (ACE)/Ang II/angiotensin type 1 (AT1) receptor and ACE2/Ang-(1-7)/Mas receptor, play an important role in the cardiovascular repair. This study evaluated the expression and vascular repair-relevant functions of these two pathways in human CD34(+) cells. CD34(+) cells were isolated from peripheral blood mononuclear cells (MNCs), obtained from healthy volunteers. Expression of ACE, ACE2, AT1, and angiotensin type 2 and Mas receptors were determined. Effects of Ang II, Ang-(1-7), Norleu(3)-Ang-(1-7), and ACE2 activators, xanthenone (XNT) and diminazene aceturate (DIZE) on proliferation, migration, and adhesion of CD34(+) cells were evaluated. ACE2 and Mas were relatively highly expressed in CD34(+) cells compared with MNCs. Ang-(1-7) or its analog, Norleu(3)-Ang-(1-7), stimulated proliferation of CD34(+) cells that was associated with decrease in phosphatase and tensin homologue deleted on chromosome 10 levels and was inhibited by triciribin, an AKT inhibitor. Migration of CD34(+) cells was enhanced by Ang-(1-7) or Norleu(3)-Ang-(1-7) that was decreased by a Rho-kinase inhibitor, Y-27632. In the presence of Ang II, XNT or DIZE enhanced proliferation and migration that were blocked by DX-600, an ACE2 inhibitor. Treatment of MNCs with Ang II, before the isolation of CD34(+) cells, attenuated the proliferation and migration to stromal derived factor-1α. This attenuation was reversed by apocynin, an NADPH oxidase inhibitor. Adhesion of MNCs or CD34(+) cells to fibronectin was enhanced by Ang II and was unaffected by Ang-(1-7). This study suggests that ACE2/Ang-(1-7)/Mas pathway stimulates functions of CD34(+) cells that are cardiovascular protective, whereas Ang II attenuates these functions by acting on MNCs. These findings

  10. New bifunctional metalloproteinase inhibitors: an integrated approach towards biological improvements and cancer therapy.

    PubMed

    Marques, Sérgio M; Abate, Claudia C; Chaves, Sílvia; Marques, Fernanda; Santos, Isabel; Nuti, Elisa; Rossello, Armando; Santos, M Amélia

    2013-10-01

    The key role of some matrix metalloproteinases (MMPs) on several pathological processes, including carcinogenesis and tumor growth, makes the development of MMP inhibitors (MMPIs) an attractive approach for cancer therapy. We present herein an integrated approach for the development of a new series of inhibitors of MMP2 and MMP14, two enzymes over-expressed by human ovarian cancer. As a first step, a new series of single model compounds bearing different zinc-binding groups (ZBGs), such as carboxylic, hydroxamic acid, hydrazide and sulfonylhydrazide groups, were studied and revealed reasonably good capacity for the Zn(II) chelation in solution and for the MMP inhibition. Aimed at further reinforcing the biological activity of these MMPIs as anti-cancer agents, a selection of those models was extra-functionalized with benzothiazole (BTA), a group with recognized antitumor activity. Analysis of the results obtained for these bifunctional compounds, in particular the inhibitory activity against MMP2 and MMP14 as well as the anti-proliferative activity on the A2780 ovarian cancer cell line, allowed to understand the activity dependence on the type of ZBG, as well as the relevance of the BTA moiety. Overall, the evidenced BTA-associated activity improvements on enzyme inhibition and cell antiproliferactivity, combined with the hydrolytic stability revealed by the hydrazide group, suggest that these new bifunctional BTA-hydrazide derivatives should be taken in consideration for the development of new generations of MMPIs with anti-cancer activity.

  11. Stiffening of the ACES deployable space boom

    NASA Technical Reports Server (NTRS)

    Sidwell, Vince

    1994-01-01

    The purpose of this design project was to design an active planar stiffening device for the existing ACES (Acoustic Containerless Experiment System) structure. the ACES structure was modeled using simple beam theory. Various concepts were generated about how the stiffening device should be configured in order to perform at an optimum level. The optimum configuration was selected to be a single set of spreaders located approximately 63% of the distance down the beam. Actuation was to be provided by a DC electric motor. From the test results, the design group was able to draw conclusions and make recommendations about the utility of further research into this area.

  12. Tumor necrosis factor-alpha convertase (ADAM17) mediates regulated ectodomain shedding of the severe-acute respiratory syndrome-coronavirus (SARS-CoV) receptor, angiotensin-converting enzyme-2 (ACE2).

    PubMed

    Lambert, Daniel W; Yarski, Mike; Warner, Fiona J; Thornhill, Paul; Parkin, Edward T; Smith, A Ian; Hooper, Nigel M; Turner, Anthony J

    2005-08-26

    Angiotensin-converting enzyme-2 (ACE2) is a critical regulator of heart function and a cellular receptor for the causative agent of severe-acute respiratory syndrome (SARS), SARS-CoV (coronavirus). ACE2 is a type I transmembrane protein, with an extracellular N-terminal domain containing the active site and a short intracellular C-terminal tail. A soluble form of ACE2, lacking its cytosolic and transmembrane domains, has been shown to block binding of the SARS-CoV spike protein to its receptor. In this study, we examined the ability of ACE2 to undergo proteolytic shedding and investigated the mechanisms responsible for this shedding event. We demonstrated that ACE2, heterologously expressed in HEK293 cells and endogenously expressed in Huh7 cells, undergoes metalloproteinase-mediated, phorbol ester-inducible ectodomain shedding. By using inhibitors with differing potency toward different members of the ADAM (a disintegrin and metalloproteinase) family of proteases, we identified ADAM17 as a candidate mediator of stimulated ACE2 shedding. Furthermore, ablation of ADAM17 expression using specific small interfering RNA duplexes reduced regulated ACE2 shedding, whereas overexpression of ADAM17 significantly increased shedding. Taken together, these data provided direct evidence for the involvement of ADAM17 in the regulated ectodomain shedding of ACE2. The identification of ADAM17 as the protease responsible for ACE2 shedding may provide new insight into the physiological roles of ACE2.

  13. The Atmospheric Chemistry Experiment (ACE): Mission Overview

    NASA Astrophysics Data System (ADS)

    Bernath, P. F.; Boone, C.; Walker, K.; McLeod, S.; Nassar, R.

    2003-12-01

    The ACE mission goals are: (1) to measure and to understand the chemical and dynamical processes that control the distribution of ozone in the upper troposphere and stratosphere, with a particular emphasis on the Arctic region; (2) to explore the relationship between atmospheric chemistry and climate change; (3) to study the effects of biomass burning in the free troposphere; (4) to measure aerosol number density, size distribution and composition in order to reduce the uncertainties in their effects on the global energy balance. ACE will make a comprehensive set of simultaneous measurements of trace gases, thin clouds, aerosols, and temperature by solar occultation from a satellite in low earth orbit. A high inclination (74 degrees) low earth orbit (650 km) gives ACE coverage of tropical, mid-latitudes and polar regions. The solar occultation advantages are high sensitivity and self-calibration. A high-resolution (0.02 cm-1) infrared Fourier Transform Spectrometer (FTS) operating from 2 to 13 microns (750-4100 cm-1) will measure the vertical distribution of trace gases, and the meteorological variables of temperature and pressure. The ACE concept is derived from the now-retired ATMOS FTS instrument, which flew on the Space Shuttle in 1985, 1992, 1993, 1994. Climate-chemistry coupling may lead to the formation of an Arctic ozone hole. ACE will provide high quality data to confront these model predictions and will monitor polar chemistry as chlorine levels decline. The ACE-FTS can measure water vapor and HDO in the tropical tropopause region to study dehydration and strat-trop exchange. The molecular signatures of massive forest fires will evident in the ACE infrared spectra. The CO2 in our spectra can be used to either retrieve atmospheric pressure or (if the instrument pointing knowledge proves to be satisfactory) for an independent retrieval of a CO2 profile for carbon cycle science. Aerosols and clouds will be monitored using the extinction of solar radiation at

  14. The Atmospheric Chemistry Experiment (ACE): Mission Overview

    NASA Astrophysics Data System (ADS)

    Bernath, P.

    2003-04-01

    The ACE mission goals are: (1) to measure and to understand the chemical and dynamical processes that control the distribution of ozone in the upper troposphere and stratosphere, with a particular emphasis on the Arctic region; (2) to explore the relationship between atmospheric chemistry and climate change; (3) to study the effects of biomass burning in the free troposphere; (4) to measure aerosol number density, size distribution and composition in order to reduce the uncertainties in their effects on the global energy balance. ACE will make a comprehensive set of simultaneous measurements of trace gases, thin clouds, aerosols, and temperature by solar occultation from a satellite in low earth orbit. A high inclination (74 degrees) low earth orbit (650 km) will give ACE coverage of tropical, mid-latitudes and polar regions. The solar occultation advantages are high sensitivity and self-calibration. A high-resolution (0.02 cm-1) infrared Fourier Transform Spectrometer (FTS) operating from 2 to 13 microns (750-4100 cm-1) will measure the vertical distribution of trace gases, and the meteorological variables of temperature and pressure. The ACE concept is derived from the now-retired ATMOS FTS instrument, which flew on the Space Shuttle in 1985, 1992, 1993, 1994. Climate-chemistry coupling may lead to the formation of an Arctic ozone hole. ACE will provide high quality data to confront these model predictions and will monitor polar chemistry as chlorine levels decline. The ACE-FTS can measure water vapor and HDO in the tropical tropopause region to study dehydration and strat-trop exchange. The molecular signatures of massive forest fires will evident in the ACE infrared spectra. The CO_2 in our spectra can be used to either retrieve atmospheric pressure or (if the instrument pointing knowledge proves to be satisfactory) for an independent retrieval of a CO_2 profile for carbon cycle science. Aerosols and clouds will be monitored using the extinction of solar

  15. A novel inhibitor of Rho GDP-dissociation inhibitor α improves the therapeutic efficacy of paclitaxel in Lewis lung carcinoma.

    PubMed

    Peng, Xing Chen; Chen, Xu Xia; Zhang, Y U; Wang, Hai Jun; Feng, You

    2015-07-01

    Molecular-targeted therapies are considered a promising strategy for the treatment of most types of human cancer. Rho GDP-dissociation inhibitor α (RhoGDIα), which functions mainly by controlling the cellular distribution and activity of Rho GTPases and is associated with tumor progression and poor prognosis of cancer patients, has become a new promising target for anticancer treatment. Recently, a specific RhoGDIα inhibitor (no. SKLB-163) was developed via computer-aided drug design and de novo synthesis. Previous studies have shown that SKLB-163 had extremely good antitumor activities against diverse cancer cell lines. In the present study, SKLB-163 was used in combination with paclitaxel in order to determine the synergistic effect of the antitumor activity. The findings showed that the combination therapy clearly inhibited cell proliferation and induced apoptosis of LL/2 in vitro. The LL/2 mice model also showed that the combination therapy inhibited tumor growth in vivo. Proliferative cell nuclear antigen (PCNA) immunohistochmeistry and terminal deoxynucleotidyl transferase dUTP nick end-labeling showed that combination therapy inhibited cell proliferation and increased apoptosis compared to the treatment with SKLB-163 or paclitaxel alone. The data suggests that the combination therapy exerted synergistic antitumor effects, providing a novel way to augment the antitumor efficacy of cytotoxic chemotherapy.

  16. Vascular dysfunction induced by hypochlorite is improved by the selective phosphodiesterase-5-inhibitor vardenafil.

    PubMed

    Radovits, Tamás; Arif, Rawa; Bömicke, Timo; Korkmaz, Sevil; Barnucz, Enikő; Karck, Matthias; Merkely, Béla; Szabó, Gábor

    2013-06-15

    Reactive oxygen species, such as hypochlorite induce oxidative stress, which impairs nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signalling and leads to vascular dysfunction. It has been proposed, that elevated cGMP-levels may contribute to an effective cytoprotection against oxidative stress. We investigated the effects of vardenafil, a selective inhibitor of the cGMP-degrading phosphodiesterase-5 enzyme on vascular dysfunction induced by hypochlorite. In organ bath experiments for isometric tension, we investigated the endothelium-dependent and endothelium-independent vasorelaxation of isolated rat aortic rings using cumulative concentrations of acetylcholine and sodium nitroprusside (SNP). Vascular dysfunction was induced by exposing rings to hypochlorite (100-400 µM). In the treatment groups, rats were pretreated with vardenafil (30 and 300 µg/kg i.v.). Immunohistochemical analysis was performed for the oxidative stress markers nitrotyrosine, poly(ADP-ribose) and for apoptosis inducing factor (AIF). Exposure to hypochlorite resulted in a marked impairment of acetylcholine-induced endothelium-dependent vasorelaxation of aortic rings. Pretreatment with vardenafil led to improved endothelial function as reflected by the higher maximal vasorelaxation (Rmax) to acetylcholine. Regarding endothelium-independent vasorelaxation, hypochlorite exposure led to a left-shift of SNP concentration-response curves in the vardenafil groups without any alterations of the Rmax. In the hypochlorite groups immunohistochemical analysis showed enhanced poly(ADP-ribose)-formation and nuclear translocation of AIF, which were prevented by vardenafil-pretreatment. Our results support the view that cytoprotective effects of PDE-5-inhibitors on the endothelium may underlie the improved endothelial function, however, a slight sensitisation of vascular smooth muscle to NO was also confirmed. PDE-5-inhibition may represent a potential therapy approach for treating vascular

  17. Inhibition of MAPK-mediated ACE expression by compound C66 prevents STZ-induced diabetic nephropathy.

    PubMed

    Pan, Yong; Huang, Yi; Wang, Zhe; Fang, Qilu; Sun, Yusheng; Tong, Chao; Peng, Kesong; Wang, Yangwei; Miao, Lining; Cai, Lu; Zhao, Yunjie; Liang, Guang

    2014-02-01

    A range of in vitro, experimental and clinical intervention studies have implicated an important role for hyperglycaemia-induced activation of the renin-angiotensin system (RAS) in the development and progression of diabetic nephropathy (DN). Blockade of RAS by angiotensin converting enzyme (ACE) inhibitors is an effective strategy in treating diabetic kidney diseases. However, few studies demonstrate the mechanism by which hyperglycaemia up-regulates the expression of ACE gene. Our previous studies have identified a novel curcumin analogue, (2E,6E)-2,6-bis(2-(trifluoromethyl)benzylidene)cyclohexanone (C66), which could inhibit the high glucose (HG)-induced phosphorylation of mitogen-activated protein kinases in mouse macrophages. In this study, we found that the renal protection of C66 in diabetic mice was associated with mitogen-activated protein kinase (MAPK) inactivation and ACE/angiotensin II (Ang II) down-regulation. Generally, MAPKs have been considered as a downstream signalling of Ang II and a mediator for Ang II-induced pathophysiological actions. However, using C66 and specific inhibitors as small molecule probes, in vitro experiments demonstrate that the MAPK signalling pathway regulates ACE expression under HG stimulation, which contributes to renal Ang II activation and the development of DN. This study indicates that C66 is a potential candidate of DN therapeutic agents, and more importantly, that reduction in ACE expression by MAPKs inhibition seems to be an alternative strategy for the treatment of DN.

  18. Translating the Adverse Childhood Experiences (ACE) Study into public policy: progress and possibility in Washington State.

    PubMed

    Kagi, Ruth; Regala, Debbie

    2012-01-01

    On June 15, 2011, Washington became the first state in the United States to enact legislation aimed at preventing adverse childhood experiences (ACE), reducing their prevalence, and mitigating their effects. House Bill 1965 (HB 1965) was established on the understanding among legislators and Washington communities of the need for policies aimed at preventing child abuse, promoting healthy development of children, and building community capacity to improve public health. Empirical examples of integrating ACE-related research with public policy and programmatic design are chronicled. The legislators who developed HB 1965 lay out questions that, if answered, would further improve policymakers' ability to craft public policy and programs that prevent ACE, reduce their effects, and promote a healthier, safer future.

  19. Developing Communities: Serving ACE through Tertiary Education

    ERIC Educational Resources Information Center

    Sofo, Francesco

    2011-01-01

    Purpose: The purpose of this paper is to review the focus and practice of Adult and Community Education (ACE) as well as its conceptualization and delivery and to suggest parameters for an approach based on excellence, a balanced scorecard and performance to meet community needs. Design/methodology/approach: The review examines key aspects of the…

  20. Advanced Colloids Experiment (ACE-T1)

    NASA Technical Reports Server (NTRS)

    Meyer, William V.; Sicker, Ron; Brown, Dan; Eustace, John

    2015-01-01

    Increment 45 - 46 Science Symposium presentation of Advanced Colloids Experiment (ACE-T1) to RPO. The purpose of this event is for Principal Investigators to present their science objectives, testing approach, and measurement methods to agency scientists, managers, and other investigators.

  1. Advanced Colloids Experiment (ACE-H-2)

    NASA Technical Reports Server (NTRS)

    Meyer, William V.; Sicker, Ron; Chmiel, Alan J.; Eustace, John; LaBarbera, Melissa

    2015-01-01

    Increment 43 - 44 Science Symposium presentation of Advanced Colloids Experiment (ACE-H-2) to RPO. The purpose of this event is for Principal Investigators to present their science objectives, testing approach, and measurement methods to agency scientists, managers, and other investigators.

  2. Growth Hormone With Aromatase Inhibitor May Improve Height in CYP11B1 Congenital Adrenal Hyperplasia.

    PubMed

    Hawton, Katherine; Walton-Betancourth, Sandra; Rumsby, Gill; Raine, Joseph; Dattani, Mehul

    2017-02-01

    With an estimated prevalence of 1 in 100 000 births, 11β-hydroxylase deficiency is the second most common form of congenital adrenal hyperplasia (CAH) and is caused by mutations in CYP11B1 Clinical features include virilization, early gonadotropin-independent precocious puberty, hypertension, and reduced stature. The current mainstay of management is with glucocorticoids to replace deficient steroids and to minimize adrenal sex hormone overproduction, thus preventing virilization and optimizing growth. We report a patient with CAH who had been suboptimally treated and presented to us at 6 years of age with precocious puberty, hypertension, tall stature, advanced bone age, and a predicted final height of 150 cm. Hormonal profiles and genetic analysis confirmed a diagnosis of 11β-hydroxylase deficiency. In addition to glucocorticoid replacement, the patient was commenced on growth hormone and a third-generation aromatase inhibitor, anastrozole, in an attempt to optimize his growth. After the initiation of this treatment, the patient's growth rate improved significantly and bone age advancement slowed. The patient reached a final height of 177.5 cm (0.81 SD score), 11.5 cm above his mid-parental height. This patient is only the second reported case of the use of an aromatase inhibitor in combination with growth hormone to optimize height in 11β-hydroxylase-deficient CAH. This novel treatment proved to be highly efficacious, with no adverse effects. It may therefore provide a promising option to promote growth in exceptional circumstances in individuals with 11β-hydroxylase deficiency presenting late with advanced skeletal maturation and consequent short stature.

  3. Adjunctive Phosphodiesterase-4 Inhibitor Therapy Improves Antibiotic Response to Pulmonary Tuberculosis in a Rabbit Model

    PubMed Central

    Subbian, Selvakumar; Tsenova, Liana; Holloway, Jennifer; Peixoto, Blas; O'Brien, Paul; Dartois, Véronique; Khetani, Vikram; Zeldis, Jerome B.; Kaplan, Gilla

    2016-01-01

    Objectives Adjunctive host-directed therapy is emerging as a new potential approach to improve the outcome of conventional antimicrobial treatment for tuberculosis (TB). We tested the ability of a phosphodiesterase-4 inhibitor (PDE4i) CC-11050, co-administered with the first-line anti-TB drug isoniazid (INH), to accelerate bacillary killing and reduce chronic inflammation in the lungs of rabbits with experimental Mycobacterium tuberculosis (Mtb) infection. Methods A rabbit model of pulmonary TB that recapitulates the pathologic manifestations seen in humans was used. Rabbits were infected with virulent Mtb by aerosol exposure and treated for eight weeks with INH with or without CC-11050, starting at four weeks post infection. The effect of CC-11050 treatment on disease severity, pathology, bacillary load, T cell proliferation and global lung transcriptome profiles were analyzed. Results Significant improvement in bacillary clearance and reduced lung pathology and fibrosis were noted in the rabbits treated for eight weeks with INH + CC-11050, compared to those treated with INH or CC-11050 only. In addition, expression of host genes associated with tissue remodeling, tumor necrosis factor alpha (TNF-α) regulation, macrophage activation and lung inflammation networks was dampened in CC-11050-treated, compared to the untreated rabbits. Conclusions Adjunctive CC-11050 therapy significantly improves the response of rabbits with experimental pulmonary TB to INH treatment. We propose that CC-11050 may be a promising candidate for host directed therapy of patients with pulmonary TB, reducing the duration and improving clinical outcome of antibiotic treatment. PMID:26981575

  4. Anoctamin 6 Contributes to Cl- Secretion in Accessory Cholera Enterotoxin (Ace)-stimulated Diarrhea: AN ESSENTIAL ROLE FOR PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE (PIP2) SIGNALING IN CHOLERA.

    PubMed

    Aoun, Joydeep; Hayashi, Mikio; Sheikh, Irshad Ali; Sarkar, Paramita; Saha, Tultul; Ghosh, Priyanka; Bhowmick, Rajsekhar; Ghosh, Dipanjan; Chatterjee, Tanaya; Chakrabarti, Pinak; Chakrabarti, Manoj K; Hoque, Kazi Mirajul

    2016-12-23

    Accessory cholera enterotoxin (Ace) of Vibrio cholerae has been shown to contribute to diarrhea. However, the signaling mechanism and specific type of Cl(-) channel activated by Ace are still unknown. We have shown here that the recombinant Ace protein induced ICl of apical plasma membrane, which was inhibited by classical CaCC blockers. Surprisingly, an Ace-elicited rise of current was neither affected by ANO1 (TMEM16A)-specific inhibitor T16A(inh)-AO1(TAO1) nor by the cystic fibrosis transmembrane conductance regulator (CFTR) blocker, CFTR inh-172. Ace stimulated whole-cell current in Caco-2 cells. However, the apical ICl was attenuated by knockdown of ANO6 (TMEM16F). This impaired phenotype was restored by re-expression of ANO6 in Caco-2 cells. Whole-cell patch clamp recordings of ANO currents in HEK293 cells transiently expressing mouse ANO1-mCherry or ANO6-GFP confirmed that Ace induced Cl(-) secretion. Application of Ace produced ANO6 but not the ANO1 currents. Ace was not able to induce a [Ca(2+)]i rise in Caco-2 cells, but cellular abundance of phosphatidylinositol 4,5-bisphosphate (PIP2) increased. Identification of the PIP2-binding motif at the N-terminal sequence among human and mouse ANO6 variants along with binding of PIP2 directly to ANO6 in HEK293 cells indicate likely PIP2 regulation of ANO6. The biophysical and pharmacological properties of Ace stimulated Cl(-) current along with intestinal fluid accumulation, and binding of PIP2 to the proximal KR motif of channel proteins, whose mutagenesis correlates with altered binding of PIP2, is comparable with ANO6 stimulation. We conclude that ANO6 is predominantly expressed in intestinal epithelia, where it contributes secretory diarrhea by Ace stimulation in a calcium-independent mechanism of RhoA-ROCK-PIP2 signaling.

  5. Polyamine metabolism and osmotic stress. II. Improvement of oat protoplasts by an inhibitor of arginine decarboxylase

    NASA Technical Reports Server (NTRS)

    Tiburcio, A. F.; Kaur-Sawhney, R.; Galston, A. W.

    1986-01-01

    We have attempted to improve the viability of cereal mesophyll protoplasts by pretreatment of leaves with DL-alpha-difluoromethylarginine (DFMA), a specific 'suicide' inhibitor of the enzyme (arginine decarboxylase) responsible for their osmotically induced putrescine accumulation. Leaf pretreatment with DFMA before a 6 hour osmotic shock caused a 45% decrease of putrescine and a 2-fold increase of spermine titer. After 136 hours of osmotic stress, putrescine titer in DFMA-pretreated leaves increased by only 50%, but spermidine and spermine titers increased dramatically by 3.2- and 6-fold, respectively. These increases in higher polyamines could account for the reduced chlorophyll loss and enhanced ability of pretreated leaves to incorporate tritiated thymidine, uridine, and leucine into macromolecules. Pretreatment with DFMA significantly improved the overall viability of the protoplasts isolated from these leaves. The results support the view that the osmotically induced rise in putrescine and blockage of its conversion to higher polyamines may contribute to the lack of sustained cell division in cereal mesophyll protoplasts, although other undefined factors must also play a major role.

  6. Next generation XPO1 inhibitor shows improved efficacy and in vivo tolerability in hematologic malignancies

    PubMed Central

    Hing, Zachary A.; Fung, Ho Yee Joyce; Ranganathan, Parvathi; Mitchell, Shaneice; El-Gamal, Dalia; Woyach, Jennifer A.; Williams, Katie; Goettl, Virginia M.; Smith, Jordan; Yu, Xueyan; Meng, Xiaomei; Sun, Qingxiang; Cagatay, Tolga; Lehman, Amy M.; Lucas, David M.; Baloglu, Erkan; Shacham, Sharon; Kauffman, Michael G.; Byrd, John C.; Chook, Yuh Min; Garzon, Ramiro; Lapalombella, Rosa

    2016-01-01

    The nuclear export receptor, Exportin 1 (XPO1), mediates transport of growth-regulatory proteins including tumor suppressors and is overactive in many cancers, including chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), and aggressive lymphomas. Oral Selective Inhibitor of Nuclear Export (SINE) compounds that block XPO1 function were recently identified and hold promise as a new therapeutic paradigm in many neoplasms. One of these compounds, KPT-330 (selinexor), has made progress in Phase I/II clinical trials, but systemic toxicities limit its administration to twice-per-week and requiring supportive care. We designed a new generation SINE compound, KPT-8602, with a similar mechanism of XPO1 inhibition and potency but considerably improved tolerability. Efficacy of KPT-8602 was evaluated in preclinical animal models of hematologic malignancies including CLL and AML. KPT-8602 shows similar in vitro potency compared to KPT-330 but lower central nervous system penetration which resulted in enhanced tolerability, even when dosed daily, and improved survival in CLL and AML murine models compared to KPT-330. KPT-8602 is a promising compound for further development in hematologic malignancies and other cancers in which upregulation of XPO1 is seen. The wider therapeutic window of KPT-8602 may also allow increased on-target efficacy leading to even more efficacious combinations with other targeted anticancer therapies. PMID:27323910

  7. Nanoparticle delivery of an AKT/PDK1 inhibitor improves the therapeutic effect in pancreatic cancer

    PubMed Central

    Lucero-Acuña, Armando; Jeffery, Justin J; Abril, Edward R; Nagle, Raymond B; Guzman, Roberto; Pagel, Mark D; Meuillet, Emmanuelle J

    2014-01-01

    The K-ras mutation in pancreatic cancer can inhibit drug delivery and increase drug resistance. This is exemplified by the therapeutic effect of PH-427, a small molecule inhibitor of AKT/PDK1, which has shown a good therapeutic effect against a BxPC3 pancreatic cancer model that has K-ras, but has a poor therapeutic effect against a MiaPaCa-2 pancreatic cancer model with mutant K-ras. To increase the therapeutic effect of PH-427 against the MiaPaCa-2 pancreatic cancer model with mutant K-ras, we encapsulated PH-427 into poly(lactic-co-glycolic acid) nanoparticles (PNP) to form drug-loaded PH-427-PNP. PH-427 showed a biphasic release from PH-427-PNP over 30 days during studies in sodium phosphate buffer, and in vitro studies revealed that the PNP was rapidly internalized into MiaPaCa-2 tumor cells, suggesting that PNP can improve PH-427 delivery into cells harboring mutant K-ras. In vivo studies of an orthotopic MiaPaCa-2 pancreatic cancer model showed reduced tumor load with PH-427-PNP as compared with treatment using PH-427 alone or with no treatment. Ex vivo studies confirmed the in vivo results, suggesting that PNP can improve drug delivery to pancreatic cancer harboring mutant K-ras. PMID:25516710

  8. Small Bowel Angioedema Secondary to Angiotensin-Converting Enzyme Inhibitors

    PubMed Central

    Hurairah, Abu

    2016-01-01

    Small bowel angioedema induced by angiotensin-converting enzyme (ACE) inhibitors is a rare clinicopathologic entity. It frequently poses a diagnostic challenge and is often not recognized before surgical exploration. The present study illustrates that clinical awareness for this condition and adequate use of radiologic investigations can help make the correct diagnosis of ACE inhibitor-associated angioedema, thus avoiding the cost and morbidity associated with unnecessary interventions. PMID:28133581

  9. Improving the Resistance Profile of Hepatitis C NS3/4A Inhibitors: Dynamic Substrate Envelope Guided Design

    PubMed Central

    Özen, Ayşegül; Sherman, Woody; Schiffer, Celia A.

    2014-01-01

    Drug resistance is a principal concern in the treatment of quickly evolving diseases. The viral protease NS3/4A is a primary drug target for the hepatitis C virus (HCV) and is known to evolve resistance mutations in response to drug therapy. At the molecular level, drug resistance reflects a subtle change in the balance of molecular recognition by NS3/4A; the drug resistant protease variants are no longer effectively inhibited by the competitive active site inhibitors but can still process the natural substrates with enough efficiency for viral survival. In previous works we have developed the “substrate envelope” hypothesis, which posits that inhibitors should be less susceptible to drug resistance if they better mimic the natural substrate molecular recognition features. In this work, we perform molecular dynamics simulations on four native substrates bound to NS3/4A and discover a clearly conserved dynamic substrate envelope. We show that the most severe drug resistance mutations in NS3/4A occur at residues that are outside the substrate envelope. Comparative analysis of three NS3/4A inhibitors reveals structural and dynamic characteristics of inhibitors that could lead to resistance. We also suggest inhibitor modifications to improve resistance profiles based on the dynamic substrate envelope. This study provides a general framework for guiding the development of novel inhibitors that will be more robust against resistance by mimicking the static and dynamic binding characteristics of natural substrates. PMID:24587770

  10. Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAF(V600E) melanoma.

    PubMed

    Hu-Lieskovan, Siwen; Mok, Stephen; Homet Moreno, Blanca; Tsoi, Jennifer; Robert, Lidia; Goedert, Lucas; Pinheiro, Elaine M; Koya, Richard C; Graeber, Thomas G; Comin-Anduix, Begoña; Ribas, Antoni

    2015-03-18

    Combining immunotherapy and BRAF targeted therapy may result in improved antitumor activity with the high response rates of targeted therapy and the durability of responses with immunotherapy. However, the first clinical trial testing the combination of the BRAF inhibitor vemurafenib and the CTLA4 antibody ipilimumab was terminated early because of substantial liver toxicities. MEK [MAPK (mitogen-activated protein kinase) kinase] inhibitors can potentiate the MAPK inhibition in BRAF mutant cells while potentially alleviating the unwanted paradoxical MAPK activation in BRAF wild-type cells that lead to side effects when using BRAF inhibitors alone. However, there is the concern of MEK inhibitors being detrimental to T cell functionality. Using a mouse model of syngeneic BRAF(V600E)-driven melanoma, SM1, we tested whether addition of the MEK inhibitor trametinib would enhance the antitumor activity of combined immunotherapy with the BRAF inhibitor dabrafenib. Combination of dabrafenib and trametinib with pmel-1 adoptive cell transfer (ACT) showed complete tumor regression, increased T cell infiltration into tumors, and improved in vivo cytotoxicity. Single-agent dabrafenib increased tumor-associated macrophages and T regulatory cells (Tregs) in tumors, which decreased with the addition of trametinib. The triple combination therapy resulted in increased melanosomal antigen and major histocompatibility complex (MHC) expression and global immune-related gene up-regulation. Given the up-regulation of PD-L1 seen with dabrafenib and/or trametinib combined with antigen-specific ACT, we tested the combination of dabrafenib, trametinib, and anti-PD1 therapy in SM1 tumors, and observed superior antitumor effect. Our findings support the testing of triple combination therapy of BRAF and MEK inhibitors with immunotherapy in patients with BRAF(V600E) mutant metastatic melanoma.

  11. Interaction of angiotensin-converting enzyme (ACE) with membrane-bound carboxypeptidase M (CPM) - a new function of ACE.

    PubMed

    Sun, Xiaoou; Wiesner, Burkhard; Lorenz, Dorothea; Papsdorf, Gisela; Pankow, Kristin; Wang, Po; Dietrich, Nils; Siems, Wolf-Eberhard; Maul, Björn

    2008-12-01

    Angiotensin-converting enzyme (ACE) demonstrates, besides its typical dipeptidyl-carboxypeptidase activity, several unusual functions. Here, we demonstrate with molecular, biochemical, and cellular techniques that the somatic wild-type murine ACE (mACE), stably transfected in Chinese Hamster Ovary (CHO) or Madin-Darby Canine Kidney (MDCK) cells, interacts with endogenous membranal co-localized carboxypeptidase M (CPM). CPM belongs to the group of glycosylphosphatidylinositol (GPI)-anchored proteins. Here we report that ACE, completely independent of its known dipeptidase activities, has GPI-targeted properties. Our results indicate that the spatial proximity between mACE and the endogenous CPM enables an ACE-evoked release of CPM. These results are discussed with respect to the recently proposed GPI-ase activity and function of sperm-bound ACE.

  12. Intravenous administration of piceatannol, an arginase inhibitor, improves endothelial dysfunction in aged mice

    PubMed Central

    Nguyen, Minh Cong

    2017-01-01

    Advanced age is one of the risk factors for vascular diseases that are mainly caused by impaired nitric oxide (NO) production. It has been demonstrated that endothelial arginase constrains the activity of endothelial nitric oxide synthase (eNOS) and limits NO generation. Hence, arginase inhibition is suggested to be vasoprotective in aging. In this study, we examined the effects of intravenous injection of Piceatannol, an arginase inhibitor, on aged mice. Our results show that Piceatannol administration reduced the blood pressure in aged mice by inhibiting arginase activity, which was associated with NO production and reactive oxygen species generation. In addition, Piceatannol administration recovered Ca2+/calmodulin-dependent protein kinase II phosphorylation, eNOS phosphorylation and eNOS dimer stability in the aged mice. The improved NO signaling was shown to be effective in attenuating the phenylephrine-dependent contractile response and in enhancing the acetylcholine-dependent vasorelaxation response in aortic rings from the aged mice. These data suggest Piceatannol as a potential treatment for vascular disease. PMID:28066144

  13. Sleep improvement in dogs after oral administration of mioflazine, a nucleoside transport inhibitor.

    PubMed

    Wauquier, A; Van Belle, H; Van den Broeck, W A; Janssen, P A

    1987-01-01

    Mioflazine, a nucleoside transport inhibitor, was given PO to dogs at doses of 0.04-10 mg/kg. Sixteen hour polygraphic sleep recordings were made and analysis and sleep stage classification was done by computer. Mioflazine decreased wakefulness and increased slow wave sleep, but did not affect the latencies of either REM sleep or slow wave sleep. This increased sleep was due to an increase in the number of light and deep slow wave sleep epochs. The effect lasted for about 8 h. The decreased wakefulness and increased slow wave sleep could be antagonized by the adenosine antagonist caffeine (2.5 and 10 mg/kg, PO); however, there was not a pure antagonistic effect. It might be that the enhancement of slow wave sleep is due to an activation of brain adenosine receptors. This is the first report of a drug acting on adenosine that given orally improves sleep. Mioflazine might be the prototype of substances worth considering for the treatment of a variety of sleep disorders.

  14. Synthesis and biological studies of highly concentrated lisinopril-capped gold nanoparticles for CT tracking of angiotensin converting enzyme (ACE)

    NASA Astrophysics Data System (ADS)

    Ghann, William E.; Aras, Omer; Fleiter, Thorsten; Daniel, Marie-Christine

    2011-05-01

    For patients with a history of heart attack or stroke, the prevention of another cardiovascular or cerebrovascular event is crucial. The development of cardiac and pulmonary fibrosis has been associated with overexpression of tissue angiotensin-converting enzyme (ACE). Recently, gold nanoparticles (GNPs) have shown great potential as X-ray computed tomography (CT) contrast agents. Since lisinopril is an ACE inhibitor, it has been used as coating on GNPs for targeted imaging of tissue ACE in prevention of fibrosis. Herein, lisinopril-capped gold nanoparticles (LIS-GNPs) were synthesized up to a concentration of 55 mgAu/mL. Their contrast was measured using CT and the results were compared to Omnipaque, a commonly used iodine-based contrast agent. The targeting ability of these LIS-GNPs was also assessed.

  15. Attenuation of myocardial fibrosis with curcumin is mediated by modulating expression of angiotensin II AT1/AT2 receptors and ACE2 in rats

    PubMed Central

    Pang, Xue-Fen; Zhang, Li-Hui; Bai, Feng; Wang, Ning-Ping; Garner, Ron E; McKallip, Robert J; Zhao, Zhi-Qing

    2015-01-01

    Curcumin is known to improve cardiac function by balancing degradation and synthesis of collagens after myocardial infarction. This study tested the hypothesis that inhibition of myocardial fibrosis by curcumin is associated with modulating expression of angiotensin II (Ang II) receptors and angiotensin-converting enzyme 2 (ACE2). Male Sprague Dawley rats were subjected to Ang II infusion (500 ng/kg/min) using osmotic minipumps for 2 and 4 weeks, respectively, and curcumin (150 mg/kg/day) was fed by gastric gavage during Ang II infusion. Compared to the animals with Ang II infusion, curcumin significantly decreased the mean arterial blood pressure during the course of the observation. The protein level of the Ang II type 1 (AT1) receptor was reduced, and the Ang II type 2 (AT2) receptor was up-regulated, evidenced by an increased ratio of the AT2 receptor over the AT1 receptor in the curcumin group (1.2±0.02%) vs in the Ang II group (0.7±0.03%, P<0.05). These changes were coincident with less locally expressed AT1 receptor and enhanced AT2 receptor in the intracardiac vessels and intermyocardium. Along with these modulations, curcumin significantly decreased the populations of macrophages and alpha smooth muscle actin-expressing myofibroblasts, which were accompanied by reduced expression of transforming growth factor beta 1 and phosphorylated-Smad2/3. Collagen I synthesis was inhibited, and tissue fibrosis was attenuated, as demonstrated by less extensive collagen-rich fibrosis. Furthermore, curcumin increased protein level of ACE2 and enhanced its expression in the intermyocardium relative to the Ang II group. These results suggest that curcumin could be considered as an add-on therapeutic agent in the treatment of fibrosis-derived heart failure patient who is intolerant of ACE inhibitor therapy. PMID:26648693

  16. Guidance and control/ACEE

    NASA Technical Reports Server (NTRS)

    1981-01-01

    Active controls improve airplane performance by stabilizing its flight, reducing departures from stable flight, and alleviating loads imposed by external forces such as gusts, turbulence, or maneuvers. Some uses for active control systems, the design of redundant and reliable stability augmentation systems, digital fly-by-wire, and NASA assessments of the technology of sensors and actuators are discussed. A series of trade-off studies to better define optimum flight control systems, and research by drone and full-scale models are described.

  17. Bicyclic-Capped Histone Deacetylase 6 Inhibitors with Improved Activity in a Model of Axonal Charcot-Marie-Tooth Disease.

    PubMed

    Shen, Sida; Benoy, Veronick; Bergman, Joel A; Kalin, Jay H; Frojuello, Mariana; Vistoli, Giulio; Haeck, Wanda; Van Den Bosch, Ludo; Kozikowski, Alan P

    2016-02-17

    Charcot-Marie-Tooth (CMT) disease is a disorder of the peripheral nervous system where progressive degeneration of motor and sensory nerves leads to motor problems and sensory loss and for which no pharmacological treatment is available. Recently, it has been shown in a model for the axonal form of CMT that histone deacetylase 6 (HDAC6) can serve as a target for the development of a pharmacological therapy. Therefore, we aimed at developing new selective and activity-specific HDAC6 inhibitors with improved biochemical properties. By utilizing a bicyclic cap as the structural scaffold from which to build upon, we developed several analogues that showed improved potency compared to tubastatin A while maintaining excellent selectivity compared to HDAC1. Further screening in N2a cells examining both the acetylation of α-tubulin and histones narrowed down the library of compounds to three potent and selective HDAC6 inhibitors. In mutant HSPB1-expressing DRG neurons, serving as an in vitro model for CMT2, these inhibitors were able to restore the mitochondrial axonal transport deficits. Combining structure-based development of HDAC6 inhibitors, screening in N2a cells and in a neuronal model for CMT2F, and preliminary ADMET and pharmacokinetic profiles, resulted in the selection of compound 23d that possesses improved biochemical, functional, and druglike properties compared to tubastatin A.

  18. Structural Basis of Resistance to Anti-Cytochrome bc1 Complex Inhibitors: Implication for Drug Improvement

    PubMed Central

    Esser, Lothar; Yu, Chang-An; Xia, Di

    2016-01-01

    The emergence of drug resistance has devastating economic and social consequences, a testimonial of which is the rise and fall of inhibitors against the respiratory component cytochrome bc1 complex, a time tested and highly effective target for disease control. Unfortunately, the mechanism of resistance is a multivariate problem, including primarily mutations in the gene of the cytochrome b subunit but also activation of alternative pathways of ubiquinol oxidation and pharmacokinetic effects. There is a considerable interest in designing new bc1 inhibitors with novel modes of binding and lower propensity to induce the development of resistance. The accumulation of crystallographic data of bc1 complexes with and without inhibitors bound provides the structural basis for rational drug design. In particular, the cytochrome b subunit offers two distinct active sites that can be targeted for inhibition - the quinol oxidation site and the quinone reduction site. This review brings together available structural information of inhibited bc1 by various quinol oxidation- and reduction-site inhibitors, the inhibitor binding modes, conformational changes upon inhibitor binding of side chains in the active site and large scale domain movements of the iron-sulfur protein subunit. Structural data analysis provides a clear understanding of where and why existing inhibitors fail and points towards promising alternatives. PMID:23688079

  19. Nh and CH in the Ace Satellite Solar Spectrumtitle of your Abstract

    NASA Astrophysics Data System (ADS)

    Bernath, P. F.; Ram, R. S.; Colin, R.

    2010-06-01

    The Canadian ACE (Atmospheric Chemistry Experiment) mission has a high resolution (0.02 cm-1) Fourier transform spectrometer (FTS) in low earth orbit. The primary ACE mission goal is the study ozone chemistry in the stratosphere although it is making a wide range of other measurements, for example, of organic molecules in the troposphere. In the normal operating mode, the ACE-FTS measures a sequence of atmospheric absorption spectra during sunrise and sunset (``solar occultation''). As part of the measurement sequence about 16 high sun exoatmospheric spectra are recorded for each occultation to serve as reference spectra. We have co-added 224782 pure solar spectra to produce the ACE solar atlas in the 750--4400 cm-1 spectral region [Hase et al., JQSRT 111, 521 (2010), see http://www.ace.uwaterloo.ca/solaratlas.html]. The ACE solar spectrum displays prominent vibration-rotation bands of CO, OH, NH and CH, and pure rotational lines of OH and NH. An improved spectroscopic analysis for OH has already been published [Bernath and Colin, JMS 257, 20 (2009)] and we now report on similar work for NH and CH. The vibration-rotation spectra of NH have been reinvestigated using laboratory spectra and infrared solar spectra recorded from orbit by the ACE and ATMOS instruments. In addition to identifying the previously unobserved 6-5 vibration-rotation band in the laboratory spectra, many additional high N rotational lines have been observed. By combining the new observations with the previously published data and recent far infrared data, an improved set of molecular constants and term values have been derived for the NH X^3Σ^- and A^3Π states. Vibration-rotation spectra of the CH X^2Π ground state have also been re-analyzed based on laboratory spectra, the ACE solar spectrum and published data. The previously unobserved 5-4 band has been measured and the other four bands (1-0 to 4-3) have been extended to higher J values. TEXT OF YOUR ABSTRACT

  20. Nicotianamine is a novel angiotensin-converting enzyme 2 inhibitor in soybean.

    PubMed

    Takahashi, Saori; Yoshiya, Taku; Yoshizawa-Kumagaye, Kumiko; Sugiyama, Toshihiro

    2015-01-01

    Angiotensin-converting enzyme 2 (ACE2) is a carboxypeptidase which is highly homologous to angiotensin-converting enzyme (ACE). ACE2 produces vasodilator peptides angiotensin 1-7 from angiotensin II. In the present study, we synthesized various internally quenched fluorogenic (IQF) substrates (fluorophore-Xaa-Pro-quencher) based on the cleavage site of angiotensin II introducing N-terminal fluorophore N-methylanthranilic acid (Nma) and C-terminal quencher N(ε)-2,4- dinitrophenyl-lysine [Lys(Dnp)]. The synthesized mixed substrates "Nma-Xaa-Pro-Lys(Dnp)" were hydrolyzed by recombinant human (rh) ACE2. The amount of each product was determined by liquid chromatography mass spectrometry (LC-MS) with fluorescence detection and it was found that Nma-His-Pro-Lys(Dnp) is the most suitable substrate for rhACE2. The K(m), k(cat), and k(cat)/K(m) values of Nma-His-Pro-Lys(Dnp) on rhACE2 were determined to be 23.3 μM, 167 s(-1), and 7.17 μM(-1) s(-1), respectively. Using the rhACE2 and the newly developed IQF substrate, we found rhACE2 inhibitory activity in soybean and isolated the active compound soybean ACE2 inhibitor (ACE2iSB). The physicochemical data on the isolated ACE2iSB were identical to those of nicotianamine. ACE2iSB strongly inhibited rhACE2 activity with an IC50 value of 84 nM. This is the first demonstration of an ACE2 inhibitor from foodstuffs.

  1. ACE inhibition with captopril retards the development of signs of neurodegeneration in an animal model of Alzheimer's disease.

    PubMed

    AbdAlla, Said; Langer, Andreas; Fu, Xuebin; Quitterer, Ursula

    2013-08-16

    Increased generation of reactive oxygen species (ROS) is a significant pathological feature in the brains of patients with Alzheimer's disease (AD). Experimental evidence indicates that inhibition of brain ROS could be beneficial in slowing the neurodegenerative process triggered by amyloid-beta (Abeta) aggregates. The angiotensin II AT1 receptor is a significant source of brain ROS, and AD patients have an increased brain angiotensin-converting enzyme (ACE) level, which could account for an excessive angiotensin-dependent AT1-induced ROS generation. Therefore, we analyzed the impact of ACE inhibition on signs of neurodegeneration of aged Tg2576 mice as a transgenic animal model of AD. Whole genome microarray gene expression profiling and biochemical analyses demonstrated that the centrally active ACE inhibitor captopril normalized the excessive hippocampal ACE activity of AD mice. Concomitantly, the development of signs of neurodegeneration was retarded by six months of captopril treatment. The neuroprotective profile triggered by captopril was accompanied by reduced amyloidogenic processing of the amyloid precursor protein (APP), and decreased hippocampal ROS, which is known to enhance Abeta generation by increased activation of beta- and gamma-secretases. Taken together, our data present strong evidence that ACE inhibition with a widely used cardiovascular drug could interfere with Abeta-dependent neurodegeneration.

  2. Angiotensin I-converting enzyme (ACE) activity and expression in rat central nervous system after sleep deprivation.

    PubMed

    Visniauskas, Bruna; Oliveira, Vitor; Carmona, Adriana K; D'Almeida, Vânia; de Melo, Robson L; Tufik, Sérgio; Chagas, Jair R

    2011-04-01

    Proteases are essential either for the release of neuropeptides from active or inactive proteins or for their inactivation. Neuropeptides have a fundamental role in sleep-wake cycle regulation and their actions are also likely to be regulated by proteolytic processing. Using fluorescence resonance energy transfer substrates, specific protease inhibitors and real-time PCR we demonstrate changes in angiotensin I-converting enzyme (ACE) expression and proteolytic activity in the central nervous system in an animal model of paradoxical sleep deprivation during 96 h (PSD). Male rats were distributed into five groups (PSD, 24 h, 48 h and 96 h of sleep recovery after PSD and control). ACE activity and mRNA levels were measured in hypothalamus, hippocampus, brainstem, cerebral cortex and striatum tissue extracts. In the hypothalamus, the significant decrease in activity and mRNA levels, after PSD, was only totally reversed after 96 h of sleep recovery. In the brainstem and hippocampus, although significant, changes in mRNA do not parallel changes in ACE specific activity. Changes in ACE activity could affect angiotensin II generation, angiotensin 1-7, bradykinin and opioid peptides metabolism. ACE expression and activity modifications are likely related to some of the physiological changes (cardiovascular, stress, cognition, metabolism function, water and energy balance) observed during and after sleep deprivation.

  3. Improved coagulation and hemostasis in hemophilia with inhibitors by combinations of superFactor Va and Factor VIIa

    PubMed Central

    Bhat, Vikas; von Drygalski, Annette; Gale, Andrew J.; Griffin, John H.; Mosnier, Laurent O.

    2015-01-01

    Bypassing inhibitors in hemophilia patients is limited to activated (a) Factor(F)VII products. We introduced “FVa activity augmentation” as another bypassing strategy and studied effects of an engineered FVa variant designated superFVa. Procoagulant and clot stabilizing properties of superFVa and recombinant human (rh)FVIa, either alone or in combination, were studied in thrombin generation and clot lysis assays in normal human plasma (NHP) with or without anti-FVIII inhibitors, in hemophilia plasma, and in FVIII-deficient mice or in wild-type mice with anti-FVIII inhibitors. superFVa was as effective as rhFVIIa to improve thrombin generation or clot lysis. Furthermore, procoagulant effects were significantly enhanced when these compounds were combined. RhFVIIa at 40 nM (a therapeutic concentration) improved thrombin generation mildly, but markedly improved thrombin generation when combined with a low concentration (e.g., 3 nM) of superFVa. In clot lysis studies, the concentration of rhFVIIa to normalize clot lysis times could be reduced by 100-fold (e.g., from 40 nM to 0.4 nM) when combined with a low concentration (0.37 nM) of superFVa. In hemostasis studies of FVIII-deficient mice, blood loss was dose-dependently reduced by either superFVa or rhFVIIa. SuperFVa (200 U/kg) corrected mean blood loss indistinguishably from rhFVIII. Blood loss correction by rhFVIIa was greatly improved when combined with superFVa. Similar blood loss correction results were observed for therapies in wild-type mice after infusion with anti-FVIII inhibitors. Thus, superFVa may be an effective procoagulant agent in the setting of hemophilia with inhibitors and it merits further evaluation for new bypassing strategies. PMID:26466980

  4. Second generation of BACE-1 inhibitors. Part 1: The need for improved pharmacokinetics.

    PubMed

    Charrier, Nicolas; Clarke, Brian; Cutler, Leanne; Demont, Emmanuel; Dingwall, Colin; Dunsdon, Rachel; Hawkins, Julie; Howes, Colin; Hubbard, Julia; Hussain, Ishrut; Maile, Graham; Matico, Rosalie; Mosley, Julie; Naylor, Alan; O'Brien, Alistair; Redshaw, Sally; Rowland, Paul; Soleil, Virginie; Smith, Kathrine J; Sweitzer, Sharon; Theobald, Pam; Vesey, David; Walter, Daryl S; Wayne, Gareth

    2009-07-01

    Inhibition of the aspartyl protease BACE-1 has the potential to deliver a disease-modifying therapy for Alzheimer's disease. We have recently disclosed a series of transition-state mimetic BACE-1 inhibitors showing nanomolar potency in cell-based assays. Amongst them, GSK188909 (compound 2) had favorable pharmacokinetics and was the first orally bioavailable inhibitor reported to demonstrate brain amyloid lowering in an animal model. In this Letter, we describe the reasons that led us to favor a second generation of inhibitors for further in vivo studies.

  5. Pioglitazone, a PPARγ agonist, provides comparable protection to angiotensin converting enzyme inhibitor ramipril against adriamycin nephropathy in rat.

    PubMed

    Ochodnicky, Peter; Mesarosova, Lucia; Cernecka, Hana; Klimas, Jan; Krenek, Peter; Goris, Maaike; van Dokkum, Richard P E; Henning, Robert H; Kyselovic, Jan

    2014-05-05

    Peroxisome proliferator-activated receptor γ (PPARγ) agonists have been shown to ameliorate diabetic nephropathy, but much less are known about their effects in non-diabetic nephropathies. In the present study, metabolic parameters, blood pressure, aortic endothelial function along with molecular and structural markers of glomerular and tubulointerstitial renal damage, were studied in a rat model of normotensive nephropathy induced by adriamycin and treated with PPARγ agonist pioglitazone (12mg/kg, po), angiotensin converting enzyme (ACE) inhibitor ramipril (1mg/kg, po) or their combination. Pioglitazone had no effect on systolic blood pressure, marginally reduced glycemia and improved aortic endothelium-dependent relaxation. In the kidney, pioglitazone prevented the development of proteinuria and focal glomerulosclerosis to the similar extent as blood-pressure lowering ramipril. Renoprotection provided by either treatment was associated with a reduction in the cortical expression of profibrotic plasminogen activator inhibitor-1 and microvascular damage-inducing endothelin-1, and a limitation of interstitial macrophage influx. Treatment with PPARγ agonist, as well as ACE inhibitor comparably affected renal expression of the renin-angiotensin system (RAS) components, normalizing increased renal expression of ACE and enhancing the expression of Mas receptor. Interestingly, combined pioglitazone and ramipril treatment did not provide any additional renoprotection. These results demonstrate that in a nondiabetic renal disease, such as adriamycin-induced nephropathy, PPARγ agonist pioglitazone provides renoprotection to a similar extent as an ACE inhibitor by interfering with the expression of local RAS components and attenuating related profibrotic and inflammatory mechanisms. The combination of the both agents, however, does not lead to any additional renal benefit.

  6. FV-162 is a novel, orally bioavailable, irreversible proteasome inhibitor with improved pharmacokinetics displaying preclinical efficacy with continuous daily dosing

    PubMed Central

    Wang, Z; Dove, P; Wang, X; Shamas-Din, A; Li, Z; Nachman, A; Oh, Y J; Hurren, R; Ruschak, A; Climie, S; Press, B; Griffin, C; Undzys, E; Aman, A; Al-awar, R; Kay, L E; O'Neill, D; Trudel, S; Slassi, M; Schimmer, A D

    2015-01-01

    Approved proteasome inhibitors have advanced the treatment of multiple myeloma but are associated with serious toxicities, poor pharmacokinetics, and most with the inconvenience of intravenous administration. We therefore sought to identify novel orally bioavailable proteasome inhibitors with a continuous daily dosing schedule and improved therapeutic window using a unique drug discovery platform. We employed a fluorine-based medicinal chemistry technology to synthesize 14 novel analogs of epoxyketone-based proteasome inhibitors and screened them for their stability, ability to inhibit the chymotrypsin-like proteasome, and antimyeloma activity in vitro. The tolerability, pharmacokinetics, pharmacodynamic activity, and antimyeloma efficacy of our lead candidate were examined in NOD/SCID mice. We identified a tripeptide epoxyketone, FV-162, as a metabolically stable, potent proteasome inhibitor cytotoxic to human myeloma cell lines and primary myeloma cells. FV-162 had limited toxicity and was well tolerated on a continuous daily dosing schedule. Compared with the benchmark oral irreversible proteasome inhibitor, ONX-0192, FV-162 had a lower peak plasma concentration and longer half-life, resulting in a larger area under the curve (AUC). Oral FV-162 treatment induced rapid, irreversible inhibition of chymotrypsin-like proteasome activity in murine red blood cells and inhibited tumor growth in a myeloma xenograft model. Our data suggest that oral FV-162 with continuous daily dosing schedule displays a favorable safety, efficacy, and pharmacokinetic profile in vivo, identifying it as a promising lead for clinical evaluation in myeloma therapy. PMID:26158521

  7. Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy.

    PubMed

    Leverson, Joel D; Phillips, Darren C; Mitten, Michael J; Boghaert, Erwin R; Diaz, Dolores; Tahir, Stephen K; Belmont, Lisa D; Nimmer, Paul; Xiao, Yu; Ma, Xiaoju Max; Lowes, Kym N; Kovar, Peter; Chen, Jun; Jin, Sha; Smith, Morey; Xue, John; Zhang, Haichao; Oleksijew, Anatol; Magoc, Terrance J; Vaidya, Kedar S; Albert, Daniel H; Tarrant, Jacqueline M; La, Nghi; Wang, Le; Tao, Zhi-Fu; Wendt, Michael D; Sampath, Deepak; Rosenberg, Saul H; Tse, Chris; Huang, David C S; Fairbrother, Wayne J; Elmore, Steven W; Souers, Andrew J

    2015-03-18

    The BCL-2/BCL-XL/BCL-W inhibitor ABT-263 (navitoclax) has shown promising clinical activity in lymphoid malignancies such as chronic lymphocytic leukemia. However, its efficacy in these settings is limited by thrombocytopenia caused by BCL-XL inhibition. This prompted the generation of the BCL-2-selective inhibitor venetoclax (ABT-199/GDC-0199), which demonstrates robust activity in these cancers but spares platelets. Navitoclax has also been shown to enhance the efficacy of docetaxel in preclinical models of solid tumors, but clinical use of this combination has been limited by neutropenia. We used venetoclax and the BCL-XL-selective inhibitors A-1155463 and A-1331852 to assess the relative contributions of inhibiting BCL-2 or BCL-XL to the efficacy and toxicity of the navitoclax-docetaxel combination. Selective BCL-2 inhibition suppressed granulopoiesis in vitro and in vivo, potentially accounting for the exacerbated neutropenia observed when navitoclax was combined with docetaxel clinically. By contrast, selectively inhibiting BCL-XL did not suppress granulopoiesis but was highly efficacious in combination with docetaxel when tested against a range of solid tumors. Therefore, BCL-XL-selective inhibitors have the potential to enhance the efficacy of docetaxel in solid tumors and avoid the exacerbation of neutropenia observed with navitoclax. These studies demonstrate the translational utility of this toolkit of selective BCL-2 family inhibitors and highlight their potential as improved cancer therapeutics.

  8. Effect of Angiotensin-Converting Enzyme Inhibitor, Lisinopril on Morphological and Biochemical Aspects of Fibrotic Liver Regeneration

    PubMed Central

    Ambreen, Aysha; Jahan, Sarwat; Malik, Satwat

    2016-01-01

    Background/Aims: Hepatic fibrosis results in defective liver regeneration following partial hepatectomy. Angiotensin converting enzyme (ACE) inhibitors can enhance liver regeneration and are also involved in the reduction of hepatic fibrosis. The present study has been conducted to evaluate the potential effect of an ACE inhibitor, lisinopril, on the morphological and biochemical aspects of fibrotic liver regeneration. Materials and Methods: Eight-week old female Sprague Dawley rats were made fibrotic by intragastric carbon tetrachloride treatment. Rats were given saline or lisinopril (1 mg/kg) orally for 1 week and were subjected to sham surgery or two-third partial hepatectomy. Liver regenerative and functional capacities were determined 48 hours post surgery. Results: Lisinopril administration did not affect the regeneration rate, proliferation cell nuclear antigen count, and hepatocellular area of fibrotic livers following partial hepatectomy. No statistically significant difference between treated and control rats regarding mitotic count, hepatocyte nuclear area, and binuclear hepatocyte frequency was observed. Serum biochemical analysis showed that lisinopril non-significantly decreased the partial hepatectomy induced elevated levels of alanine aminotransferase, aspartate transaminase, and alkaline phosphatase whereas lactate dehydrogenase and total bilirubin levels were significantly reduced. No marked reduction in hepatic collagen content and alpha smooth actin positive cells was observed by lisinopril treatment. Conclusion: ACE inhibitor lisinopril did not produce major histomorphological alterations in regenerating fibrotic liver following partial hepatectomy, however, it may improve its functional capability. PMID:27976638

  9. PAPR reduction in FBMC using an ACE-based linear programming optimization

    NASA Astrophysics Data System (ADS)

    van der Neut, Nuan; Maharaj, Bodhaswar TJ; de Lange, Frederick; González, Gustavo J.; Gregorio, Fernando; Cousseau, Juan

    2014-12-01

    This paper presents four novel techniques for peak-to-average power ratio (PAPR) reduction in filter bank multicarrier (FBMC) modulation systems. The approach extends on current PAPR reduction active constellation extension (ACE) methods, as used in orthogonal frequency division multiplexing (OFDM), to an FBMC implementation as the main contribution. The four techniques introduced can be split up into two: linear programming optimization ACE-based techniques and smart gradient-project (SGP) ACE techniques. The linear programming (LP)-based techniques compensate for the symbol overlaps by utilizing a frame-based approach and provide a theoretical upper bound on achievable performance for the overlapping ACE techniques. The overlapping ACE techniques on the other hand can handle symbol by symbol processing. Furthermore, as a result of FBMC properties, the proposed techniques do not require side information transmission. The PAPR performance of the techniques is shown to match, or in some cases improve, on current PAPR techniques for FBMC. Initial analysis of the computational complexity of the SGP techniques indicates that the complexity issues with PAPR reduction in FBMC implementations can be addressed. The out-of-band interference introduced by the techniques is investigated. As a result, it is shown that the interference can be compensated for, whilst still maintaining decent PAPR performance. Additional results are also provided by means of a study of the PAPR reduction of the proposed techniques at a fixed clipping probability. The bit error rate (BER) degradation is investigated to ensure that the trade-off in terms of BER degradation is not too severe. As illustrated by exhaustive simulations, the SGP ACE-based technique proposed are ideal candidates for practical implementation in systems employing the low-complexity polyphase implementation of FBMC modulators. The methods are shown to offer significant PAPR reduction and increase the feasibility of FBMC as

  10. Brain-targeted ACE2 overexpression attenuates neurogenic hypertension by inhibiting COX mediated inflammation

    PubMed Central

    Sriramula, Srinivas; Xia, Huijing; Xu, Ping; Lazartigues, Eric

    2014-01-01

    Overactivity of the renin angiotensin system (RAS), oxidative stress, and cyclooxygenases (COX) in the brain are implicated in the pathogenesis of hypertension. We previously reported that Angiotensin-Converting Enzyme 2 (ACE2) overexpression in the brain attenuates the development of DOCA-salt hypertension, a neurogenic hypertension model with enhanced brain RAS and sympathetic activity. To elucidate the mechanisms involved, we investigated whether oxidative stress, mitogen activated protein kinase signaling and cyclooxygenase (COX) activation in the brain are modulated by ACE2 in neurogenic hypertension. DOCA-salt hypertension significantly increased expression of Nox-2 (+61 ±5 %), Nox-4 (+50 ±13 %) and nitrotyrosine (+89 ±32 %) and reduced activity of the antioxidant enzymes, catalase (−29 ±4 %) and SOD (−31 ±7 %), indicating increased oxidative stress in the brain of non-transgenic mice. This increased oxidative stress was attenuated in transgenic mice overexpressing ACE2 in the brain. DOCA-salt-induced reduction of nNOS expression (−26 ±7 %) and phosphorylated eNOS/total eNOS (−30 ±3 %), and enhanced phosphorylation of Akt and ERK1/2 in the paraventricular nucleus (PVN), were reversed by ACE2 overexpression. In addition, ACE2 overexpression blunted the hypertension-mediated increase in gene and protein expression of COX-1 and COX-2 in the PVN. Furthermore, gene silencing of either COX-1 or COX-2 in the brain, reduced microglial activation and accompanied neuro-inflammation, ultimately attenuating DOCA-salt hypertension. Together, these data provide evidence that brain ACE2 overexpression reduces oxidative stress and COX-mediated neuro-inflammation, improves anti-oxidant and nitric oxide signaling, and thereby attenuates the development of neurogenic hypertension. PMID:25489058

  11. Lipid nanoparticle delivery of a microRNA-145 inhibitor improves experimental pulmonary hypertension.

    PubMed

    McLendon, Jared M; Joshi, Sachindra R; Sparks, Jeff; Matar, Majed; Fewell, Jason G; Abe, Kohtaro; Oka, Masahiko; McMurtry, Ivan F; Gerthoffer, William T

    2015-07-28

    pathology, and histopathology and did not detect significant off-target effects. AntimiR-145 reduced the degree of pulmonary arteriopathy, reduced the severity of pulmonary hypertension, and reduced the degree of cardiac dysfunction. The results establish effective and low toxicity of lung delivery of a miRNA-145 inhibitor using functionalized cationic lipopolyamine nanoparticles to repair pulmonary arteriopathy and improve cardiac function in rats with severe PAH.

  12. The Angiotensin-converting enzyme inhibitor captopril inhibits poly(adp-ribose) polymerase activation and exerts beneficial effects in an ovine model of burn and smoke injury.

    PubMed

    Asmussen, Sven; Bartha, Eva; Olah, Gabor; Sbrana, Elena; Rehberg, Sebastian W; Yamamoto, Yusuke; Enkhbaatar, Perenlei; Hawkins, Hal K; Ito, Hiroshi; Cox, Robert A; Traber, Lillian D; Traber, Daniel L; Szabo, Csaba

    2011-10-01

    We investigated the effect of the angiotensin-converting enzyme (ACE) inhibitor captopril in a clinically relevant ovine model of smoke and burn injury, with special reference to oxidative stress and activation of poly(ADP-ribose) polymerase, in the lung and in circulating leukocytes. Female, adult sheep (28-40 kg) were divided into three groups. After tracheostomy and under deep anesthesia, both vehicle-control-treated (n = 5) and captopril-treated (20 mg/kg per day, i.v., starting 0.5 h before the injury) (n = 5) groups were subjected to 2 × 20%, third-degree burn injury and were insufflated with 48 breaths of cotton smoke. A sham group not receiving burn/smoke was also studied (n = 5). Animals were mechanically ventilated and fluid resuscitated for 24 h in the awake state. Burn and smoke injury resulted in an upregulation of ACE in the lung, evidenced by immunohistochemical determination and Western blotting. Burn and smoke injury resulted in pulmonary dysfunction, as well as systemic hemodynamic alterations. Captopril treatment of burn and smoke animals improved PaO2/FiO2 ratio and pulmonary shunt fraction and reduced the degree of lung edema. There was a marked increase in PAR levels in circulating leukocytes after burn/smoke injury, which was significantly decreased by captopril. The pulmonary level of ACE and the elevated pulmonary levels of transforming growth factor β in response to burn and smoke injury were significantly decreased by captopril treatment. Our results suggest that the ACE inhibitor captopril exerts beneficial effects on the pulmonary function in burn/smoke injury. The effects of the ACE inhibitor may be related to the prevention of reactive oxygen species-induced poly(ADP-ribose)polymerase overactivation. Angiotensin-converting enzyme inhibition may also exert additional beneficial effects by inhibiting the expression of the profibrotic mediator transforming growth factor β.

  13. Augmenting serotonin reuptake inhibitors in obsessive-compulsive disorder: What moderates improvement?

    PubMed Central

    Wheaton, Michael G.; Rosenfield, David; Foa, Edna B.; Simpson, H. Blair

    2015-01-01

    Objective Patients with obsessive-compulsive disorder (OCD) often only partially respond to serotonin reuptake inhibitors (SRIs). In such cases, American Psychiatric Association practice guidelines suggest augmenting SRIs with cognitive behavioral therapy consisting of exposure and response prevention (EX/RP) or antipsychotic medication (i.e., risperidone). We examined moderators and predictors of these two augmentation strategies. Method Data came from a randomized controlled trial that compared adding EX/RP or risperidone to SRIs in adults with OCD. Patients entered the study on a stable SRI dosage and were randomized to EX/RP (N= 40), risperidone (N= 40) or placebo (N = 20). Data were analyzed using multilevel modeling. Results Pre-treatment OCD severity, age and depression were significant moderators. Although OCD severity was unrelated to EX/RP response, individuals with more severe OCD had poorer outcome and slower improvement with risperidone. Increasing age predicted better response to risperidone, but not EX/RP. Increased depression predicted poorer response to placebo, but not EX/RP or risperidone. Poorer functioning predicted worse outcome across all three conditions. Together, these moderators and predictor accounted for 33% of the variance in outcomes, above and beyond the 30.8% accounted for by treatment condition. Conclusions SRI augmentation with EX/RP was more effective than risperidone across all of the demographic and clinical variables tested. EX/RP’s superiority over risperidone increased with baseline OCD severity and with younger age. These data indicate that EX/RP should be the recommended SRI augmentation strategy, even for severe OCD. What determines the degree of EX/RP response in individual patients deserves further study. PMID:26009783

  14. Renin-angiotensin-aldosterone system inhibitors improve membrane stability and change gene-expression profiles in dystrophic skeletal muscles.

    PubMed

    Chadwick, Jessica A; Bhattacharya, Sayak; Lowe, Jeovanna; Weisleder, Noah; Rafael-Fortney, Jill A

    2017-02-01

    Angiotensin-converting enzyme inhibitors (ACEi) and mineralocorticoid receptor (MR) antagonists are FDA-approved drugs that inhibit the renin-angiotensin-aldosterone system (RAAS) and are used to treat heart failure. Combined treatment with the ACEi lisinopril and the nonspecific MR antagonist spironolactone surprisingly improves skeletal muscle, in addition to heart function and pathology in a Duchenne muscular dystrophy (DMD) mouse model. We recently demonstrated that MR is present in all limb and respiratory muscles and functions as a steroid hormone receptor in differentiated normal human skeletal muscle fibers. The goals of the current study were to begin to define cellular and molecular mechanisms mediating the skeletal muscle efficacy of RAAS inhibitor treatment. We also compared molecular changes resulting from RAAS inhibition with those resulting from the current DMD standard-of-care glucocorticoid treatment. Direct assessment of muscle membrane integrity demonstrated improvement in dystrophic mice treated with lisinopril and spironolactone compared with untreated mice. Short-term treatments of dystrophic mice with specific and nonspecific MR antagonists combined with lisinopril led to overlapping gene-expression profiles with beneficial regulation of metabolic processes and decreased inflammatory gene expression. Glucocorticoids increased apoptotic, proteolytic, and chemokine gene expression that was not changed by RAAS inhibitors in dystrophic mice. Microarray data identified potential genes that may underlie RAAS inhibitor treatment efficacy and the side effects of glucocorticoids. Direct effects of RAAS inhibitors on membrane integrity also contribute to improved pathology of dystrophic muscles. Together, these data will inform clinical development of MR antagonists for treating skeletal muscles in DMD.

  15. Improved kidney function in patients who switch their protease inhibitor from atazanavir or lopinavir to darunavir

    PubMed Central

    Jose, Sophie; Nelson, Mark; Phillips, Andrew; Chadwick, David; Trevelion, Roy; Jones, Rachael; Williams, Deborah I.; Hamzah, Lisa; Sabin, Caroline A.; Post, Frank A.

    2017-01-01

    Objective: Atazanavir (ATV) and lopinavir (LPV) have been associated with kidney disease progression in HIV positive patients, with no data reported for darunavir (DRV). We examined kidney function in patients who switched their protease inhibitor from ATV or LPV to DRV. Design: Cohort study. Methods: Data were from the UK CHIC study. We compared pre and post switch estimated glomerular filtration rate (eGFR) slopes (expressed in ml/min per 1.73 m2 per year) in all switchers and those with rapid eGFR decline (>5 ml/min per 1.73 m2 per year) on ATV or LPV. Mixed-effects models were adjusted for age, gender, ethnicity, eGFR at switch and time updated CD4+ cell count, HIV RNA and cumulative tenofovir (tenofovir disoproxil fumarate) exposure. Results: Data from 1430 patients were included. At the time of switching to DRV, median age was 45 years, 79% were men, 76% had an undetectable viral load, and median eGFR was 93 ml/min per 1.73 m2. Adjusted mean (95% confidence interval) pre and post switch eGFR slopes were −0.84 (−1.31, −0.36) and 1.23 (0.80, 1.66) for ATV (P < 0.001), and −0.57 (−1.09, −0.05) and 0.62 (0.28, 0.96) for LPV (P < 0.001). Stable or improved renal function was observed in patients with rapid eGFR decline on ATV or LPV who switched to DRV [−15.27 (−19.35, −11.19) and 3.72 (1.78, 5.66), P < 0.001 for ATV, −11.93 (−14.60, −9.26) and 0.87 (−0.54, 2.27), P < 0.001 for LPV]. Similar results were obtained if participants who discontinued tenofovir disoproxil fumarate at the time of switch were excluded. Conclusions: We report improved kidney function in patients who switched from ATV or LPV to DRV, suggesting that DRV may have a more favourable renal safety profile. PMID:28121667

  16. Structure based drug design of angiotensin-I converting enzyme inhibitors.

    PubMed

    Anthony, C S; Masuyer, G; Sturrock, E D; Acharya, K R

    2012-01-01

    Cardiovascular disease (CVD) is responsible for ∼27% of deaths worldwide, with 80% of these occuring in developing countries. Hypertension is one of the most important treatable factors in the prevention of CVD. Angiotensin-I converting enzyme (ACE) is a two-domain dipeptidylcarboxypeptidase that is a key regulator of blood pressure as a result of its critical role in the reninangiotensin- aldosterone and kallikrien-kinin systems. Consequently, ACE is an important drug target in the treatment of CVD. ACE is primarily known for its ability to cleave angiotensin-I to the vasoactive octapeptide angiotensin-II, but is also able to cleave a number of other substrates including the vasodilator bradykinin and N-acetyl-seryl-aspartyl-lysyl-proline (acetyl-SDKP), a physiological modulator of hematopoiesis. Numerous ACE inhibiors are available clinically, and these are generally effective in treating hypertension. However some adverse effects are associated with ACE inhibition, such as the persistent dry cough and the potentially fatal angioedema. The solution of ACE crystal structures over the last decade has facilitated rational drug design which has contributed to the development of domain-selective ACE inhibitors, the most notable of which include RXP407 (N-domain) and RXPA380 (C-domain), which in principle may herald new therapeutic approaches for ACE inhibition. Additionally, dual inhibitors to ACE and other targets such as neprilysin, endothelin converting enzyme and chymase have been developed. The success of ACE inhibitors has also led to the search for novel inhibitors in food and natural products and the structure guided screening of such libraries may well reveal a number of new ACE inhibitors.

  17. Tissue-Specific Expression of Transgenic Secreted ACE in Vasculature Can Restore Normal Kidney Functions, but Not Blood Pressure, of Ace-/- Mice

    PubMed Central

    Chattopadhyay, Saurabh; Kessler, Sean P.; Colucci, Juliana Almada; Yamashita, Michifumi; Senanayake, Preenie deS; Sen, Ganes C.

    2014-01-01

    Angiotensin-converting enzyme (ACE) regulates normal blood pressure and fluid homeostasis through its action in the renin-angiotensin-system (RAS). Ace-/- mice are smaller in size, have low blood pressure and defective kidney structure and functions. All of these defects are cured by transgenic expression of somatic ACE (sACE) in vascular endothelial cells of Ace-/- mice. sACE is expressed on the surface of vascular endothelial cells and undergoes a natural cleavage secretion process to generate a soluble form in the body fluids. Both the tissue-bound and the soluble forms of ACE are enzymatically active, and generate the vasoactive octapeptide Angiotensin II (Ang II) with equal efficiency. To assess the relative physiological roles of the secreted and the cell-bound forms of ACE, we expressed, in the vascular endothelial cells of Ace-/- mice, the ectodomain of sACE, which corresponded to only the secreted form of ACE. Our results demonstrated that the secreted form of ACE could normalize kidney functions and RAS integrity, growth and development of Ace-/- mice, but not their blood pressure. This study clearly demonstrates that the secreted form of ACE cannot replace the tissue-bound ACE for maintaining normal blood pressure; a suitable balance between the tissue-bound and the soluble forms of ACE is essential for maintaining all physiological functions of ACE. PMID:24475296

  18. Multiphysics Applications of ACE3P

    SciTech Connect

    K.H. Lee, C. Ko, Z. Li, C.-K. Ng, L. Xiao, G. Cheng, H. Wang

    2012-07-01

    The TEM3P module of ACE3P, a parallel finite-element electromagnetic code suite from SLAC, focuses on the multiphysics simulation capabilities, including thermal and mechanical analysis for accelerator applications. In this pa- per, thermal analysis of coupler feedthroughs to supercon- ducting rf (SRF) cavities will be presented. For the realistic simulation, internal boundary condition is implemented to capture RF heating effects on the surface shared by a di- electric and a conductor. The multiphysics simulation with TEM3P matched the measurement within 0.4%.

  19. Evaluation of Improved Glycogen Synthase Kinase-3α Inhibitors in Models of Acute Myeloid Leukemia

    PubMed Central

    Neumann, Theresa; Benajiba, Lina; Göring, Stefan; Stegmaier, Kimberly; Schmidt, Boris

    2016-01-01

    The challenge for Glycogen Synthase Kinase-3 (GSK-3) inhibitor design lies in achieving high selectivity for one isoform over the other. The therapy of certain diseases, such as acute myeloid leukemia (AML) may require α-isoform specific targeting. The scorpion shaped GSK-3 inhibitors developed by our group achieved the highest GSK-3α selectivity reported so far, but suffered from insufficient aqueous solubility. This work presents the solubility-driven optimization of our isoform-selective inhibitors using a scorpion shaped lead. Among 15 novel compounds, compound 27 showed high activity against GSK-3α/β with the highest GSK-3α selectivity reported to date. Compound 27 was profiled for bioavailability and toxicity in a zebrafish embryo phenotype assay. Selective GSK-3α targeting in AML cell lines was achieved with compound 27, resulting in a strong differentiation phenotype and colony formation impairment, confirming the potential of GSK-3α inhibition in AML therapy. PMID:26496242

  20. L-chicoric acid, an inhibitor of human immunodeficiency virus type 1 (HIV-1) integrase, improves on the in vitro anti-HIV-1 effect of Zidovudine plus a protease inhibitor (AG1350).

    PubMed

    Robinson, W E

    1998-08-01

    Combinations of anti-human immunodeficiency virus (HIV) drugs, including reverse transcriptase inhibitors and protease inhibitors, have proven immensely potent in the therapy of acquired immune deficiency syndrome (AIDS). To determine whether HIV integrase is a suitable target for combination therapy, the ability of an HIV integrase inhibitor, L-chicoric acid, to work in combination with a protease inhibitor and Zidovudine was tested in vitro. The addition of L-chicoric acid to either Zidovudine or protease inhibitor improved upon the observed anti-HIV activity of either compound alone. When all three drugs were combined, the anti-HIV activity was substantially better than either of the three compounds alone or any combination of two inhibitors. Doses of both Zidovudine and protease inhibitor could be reduced by more than 33% for an equivalent anti-HIV effect if L-chicoric acid was added. The improved anti-HIV activity was observed with a tissue culture adapted strain of HIV (HIV(LAI)) and with limited passage clinical isolates of HIV (HIV(R19) and HIV(R45)). These data demonstrate that a first generation HIV integrase inhibitor, L-chicoric acid, is at least additive in combination with existing multi-drug regimens and suggest that HIV integrase will be an excellent target for combination therapy of HIV infection.

  1. The ACES Mission: System Tests Results and Development Status

    NASA Astrophysics Data System (ADS)

    Cacciapuoti, Luigi

    Atomic Clock Ensemble in Space (ACES) is a mission of the European Space Agency (ESA) testing fundamental laws of physics with high-performance atomic clocks1 . Operated on-board the International Space Station, the ACES payload will distribute a clock signal with fractional frequency instability and inaccuracy of 1·10-16 . This frequency reference is resulting from the medium-term stability of an active hydrogen maser (SHM) and the long-term stability and accuracy of a primary standard based on samples of laser cooled Cs atoms (PHARAO). The ACES clocks are combined by two servo-loops, the first stabilizing the PHARAO local oscillator on SHM, the second controlling the long-term instabilities of SHM using the error signal generated by the PHARAO Cesium resonator. A link in the microwave domain (MWL) and an optical link (ELT) will make the ACES clock signal available to ground laboratories equipped with atomic clocks, connecting them in a worldwide network. Space-to-ground and ground-to-ground comparisons of atomic frequency standards will be used to test Einstein's theory of general relativity including a precision measurement of the gravitational red-shift, a search for time variations of fundamental constants, and Lorentz Invariance tests. Applications in geodesy, optical time transfer, and ranging will also be supported. The ACES main instruments and subsystems have now reached an advanced status of devel-opment, demonstrated by the completion and the successful test of their engineering models. In particular, a dedicated test campaign has recently verified the performance of the ACES system, where PHARAO and SHM, locked together via the ACES servo loops, are operated as a unique oscillator to generate the ACES frequency reference. The test campaign conducted 1 Luigi Cacciapuoti and Christophe Salomon, Space Clocks and Fundamental Tests: The ACES Experiment, EPJ Special topics 172, 57 (2009). at CNES premises in Toulouse between July and November 2009 concluded

  2. Active Control Evaluation for Spacecraft (ACES)

    NASA Technical Reports Server (NTRS)

    Pearson, J.; Yuen, W.

    1986-01-01

    The Air Force goal is to develop vibration control techniques for large flexible spacecraft by addressing sensor, actuator, and control hardware and dynamic testing. The Active Control Evaluation for Spacecraft (ACES) program will address the Air Force goal by looking at two leading control techniques and implementing them on a structural model of a flexible spacecraft under laboratory testing. The first phase in the ACES program is to review and to assess the High Authority Control/Low Authority Control (HAC/LAC) and Filter accomodated Model Error Sensitivity Suppression (FAMESS) control techniques for testing on the modified VCOSS structure. Appropriate sensors and actuators will be available for use with both techniques; locations will be the same for both techniques. The control actuators will be positioned at the midpoint and free end of the structure. The laser source for the optical sensor is mounted on the feed mast. The beam will be reflected from a mirror on the offset antenna onto the detectors mounted above the shaker table bay. The next phase is to develop an analysis simulation with the control algorithms implemented for dynamics verification. The third phase is to convert the control laws into high level computer language and test them in the NASA-MSFC facility. The final phase is to compile all analytical and test results for performance comparisons.

  3. ACE-I Inhibitory Activity from Phaseolus lunatus and Phaseolus vulgaris Peptide Fractions Obtained by Ultrafiltration.

    PubMed

    Betancur-Ancona, David; Dávila-Ortiz, Gloria; Chel-Guerrero, Luis Antonio; Torruco-Uco, Juan Gabriel

    2015-11-01

    The involvement of angiotensin-I-converting enzyme (ACE-I) as one of the mechanisms controlling blood pressure is being studied to find alternative means of control of hypertension on human beings. On the market there are synthetic drugs that can control it, but these can cause undesirable health side effects. In this work was assessed the fractionation by ultrafiltration of the Lima bean (Phaseolus lunatus) and Jamapa bean (Phaseolus vulgaris), protein hydrolysates obtained with Alcalase(®) and Flavourzyme(®) on ACE-I inhibitory activity. Four membranes of different molecular cutoffs (10, 5, 3, and 1 kDa) were used. Fractions that had a higher inhibitory activity in both legumes were denominated as E (<1 kDa) with IC50 of 30.3 and 51.8 μg/mL values for the P. lunatus with Alcalase and Flavourzyme, respectively, and for the Phaseolus vulgaris with Alcalase and Flavourzyme with about 63.8 and 65.8 μg/mL values, respectively. The amino acid composition of these fractions showed residues in essential amino acids, which make a good source of energy and amino acids. On the other hand, the presence of hydrophobic amino acids such as V and P is a determining factor in the ACE-I inhibitor effect. The results suggest the possibility of obtaining and utilizing these peptide fractions in the development and innovation of a functional product that helps with treatment and/or prevention of hypertension.

  4. Antidepressant-Like Properties of Novel HDAC6-Selective Inhibitors with Improved Brain Bioavailability

    PubMed Central

    Jochems, Jeanine; Boulden, Janette; Lee, Bridgin G; Blendy, Julie A; Jarpe, Matthew; Mazitschek, Ralph; Van Duzer, John H; Jones, Simon; Berton, Olivier

    2014-01-01

    HDAC inhibitors have been reported to produce antidepressant and pro-cognitive effects in animal models, however, poor brain bioavailability or lack of isoform selectivity of current probes has limited our understanding of their mode of action. We report the characterization of novel pyrimidine hydroxyl amide small molecule inhibitors of HDAC6, brain bioavailable upon systemic administration. We show that two compounds in this family, ACY-738 and ACY-775, inhibit HDAC6 with low nanomolar potency and a selectivity of 60- to 1500-fold over class I HDACs. In contrast to tubastatin A, a reference HDAC6 inhibitor with similar potency and peripheral activity, but more limited brain bioavailability, ACY-738 and ACY-775 induce dramatic increases in α-tubulin acetylation in brain and stimulate mouse exploratory behaviors in novel, but not familiar environments. Interestingly, despite a lack of detectable effect on histone acetylation, we show that ACY-738 and ACY-775 share the antidepressant-like properties of other HDAC inhibitors, such as SAHA and MS-275, in the tail suspension test and social defeat paradigm. These effects of ACY-738 and ACY-775 are directly attributable to the inhibition of HDAC6 expressed centrally, as they are fully abrogated in mice with a neural-specific loss of function of HDAC6. Furthermore, administered in combination, a behaviorally inactive dose of ACY-738 markedly potentiates the anti-immobility activity of a subactive dose of the selective serotonin reuptake inhibitor citalopram. Our results validate new isoform-selective probes for in vivo pharmacological studies of HDAC6 in the CNS and reinforce the viability of this HDAC isoform as a potential target for antidepressant development. PMID:23954848

  5. Abscinazole-E3M, a practical inhibitor of abscisic acid 8′-hydroxylase for improving drought tolerance

    PubMed Central

    Takeuchi, Jun; Okamoto, Masanori; Mega, Ryosuke; Kanno, Yuri; Ohnishi, Toshiyuki; Seo, Mitsunori; Todoroki, Yasushi

    2016-01-01

    Abscisic acid (ABA) is an essential phytohormone that regulates plant water use and drought tolerance. However, agricultural applications of ABA have been limited because of its rapid inactivation in plants, which involves hydroxylation of ABA by ABA 8′-hydroxylase (CYP707A). We previously developed a selective inhibitor of CYP707A, (−)-Abz-E2B, by structurally modifying S-uniconazole, which functions as an inhibitor of CYP707A and as a gibberellin biosynthetic enzyme. However, its synthetic yield is too low for practical applications. Therefore, we designed novel CYP707A inhibitors, Abz-T compounds, that have simpler structures in which the 1,2,3-triazolyl ring of (−)-Abz-E2B has been replaced with a triple bond. They were successfully synthesised in shorter steps, resulting in greater yields than that of (−)-Abz-E2B. In the enzymatic assays, one of the Abz-T compounds, (−)-Abz-E3M, acted as a strong and selective inhibitor of CYP707A, similar to (−)-Abz-E2B. Analysis of the biological effects in Arabidopsis revealed that (−)-Abz-E3M enhanced ABA’s effects more than (−)-Abz-E2B in seed germination and in the expression of ABA-responsive genes. Treatment with (−)-Abz-E3M induced stomatal closure and improved drought tolerance in Arabidopsis. Furthermore, (−)-Abz-E3M also increased the ABA response in rice and maize. Thus, (−)-Abz-E3M is a more practical and effective inhibitor of CYP707A than (−)-Abz-E2B. PMID:27841331

  6. ACE and AGTR1 polymorphisms in elite rhythmic gymnastics.

    PubMed

    Di Cagno, Alessandra; Sapere, Nadia; Piazza, Marina; Aquino, Giovanna; Iuliano, Enzo; Intrieri, Mariano; Calcagno, Giuseppe

    2013-02-01

    In the angiotensin-converting enzyme (ACE) gene, Alu deletion, in intron 16, is associated with higher concentrations of ACE serum activity and this may be associated with elite sprint and power performance. The Alu insertion is associated with lower ACE levels and this could lead to endurance performance. Moreover, recent studies have identified a single-nucleotide polymorphism of the angiotensin type 1 receptor gene AGTR1, which seems to be related to ACE activity. The aim of this study was to examine the involvement of the ACE and the AGTR1 gene polymorphisms in 28 Italian elite rhythmic gymnasts (age range 21 ± 7.6 years), and compare them to 23 middle level rhythmic gymnasts (age range 17 ± 10.9 years). The ACE D allele was significantly more frequent in elite athletes than in the control population (χ(2)=4.07, p=0.04). Comparisons between the middle level and elite athletes revealed significant differences (p<0.0001) for the ACE DD genotype (OR=6.48, 95% confidence interval=1.48-28.34), which was more frequent in elite athletes. There were no significant differences in the AGTR1 A/C genotype or allele distributions between the middle level and elite athletes. In conclusion, the ACE D allele genotype could be a contributing factor to high-performance rhythmic gymnastics that should be considered in athlete development and could help to identify which skills should be trained for talent promotion.

  7. Creating an antibacterial with in vivo efficacy: synthesis and characterization of potent inhibitors of the bacterial cell division protein FtsZ with improved pharmaceutical properties.

    PubMed

    Haydon, David J; Bennett, James M; Brown, David; Collins, Ian; Galbraith, Greta; Lancett, Paul; Macdonald, Rebecca; Stokes, Neil R; Chauhan, Pramod K; Sutariya, Jignesh K; Nayal, Narendra; Srivastava, Anil; Beanland, Joy; Hall, Robin; Henstock, Vincent; Noula, Caterina; Rockley, Chris; Czaplewski, Lloyd

    2010-05-27

    3-Methoxybenzamide (1) is a weak inhibitor of the essential bacterial cell division protein FtsZ. Alkyl derivatives of 1 are potent antistaphylococcal compounds with suboptimal drug-like properties. Exploration of the structure-activity relationships of analogues of these inhibitors led to the identification of potent antistaphylococcal compounds with improved pharmaceutical properties.

  8. Effects of prolonged angiotensin-converting enzyme inhibitor treatment on amyloid beta-protein metabolism in mouse models of Alzheimer disease.

    PubMed

    Hemming, Matthew L; Selkoe, Dennis J; Farris, Wesley

    2007-04-01

    Genetic and pathologic studies have associated angiotensin-converting enzyme (ACE) with Alzheimer disease. Previously, we and others have reported that ACE degrades in vitro the amyloid beta-protein (Abeta), a putative upstream initiator of Alzheimer disease. These studies support the hypothesis that deficiency in ACE-mediated Abeta proteolysis could increase Alzheimer disease risk and raise the question of whether ACE inhibitors, a commonly prescribed class of anti-hypertensive medications, can elevate Abeta levels in vivo. To test this hypothesis, we administered the ACE inhibitor captopril to two lines of APP transgenic mice harboring either low levels of Abeta or high levels of Abeta with associated plaque deposition. In both models, we show that captopril does not affect cerebral Abeta levels in either soluble or insoluble pools. Furthermore, we find no change in plaque deposition or in peripheral Abeta levels. Data from these Alzheimer models suggest that captopril and similar ACE inhibitors do not cause Abeta accumulation in vivo.

  9. Quantum chemistry calculation-aided structural optimization of combretastatin A-4-like tubulin polymerization inhibitors: improved stability and biological activity.

    PubMed

    Jiang, Junhang; Zheng, Canhui; Zhu, Kongkai; Liu, Jia; Sun, Nannan; Wang, Chongqing; Jiang, Hualiang; Zhu, Ju; Luo, Cheng; Zhou, Youjun

    2015-03-12

    A potent combretastatin A-4 (CA-4) like tubulin polymerization inhibitor 22b was found with strong antitumor activity previously. However, it easily undergoes cis-trans isomerization under natural light, and the resulting decrease in activity limits its further applications. In this study, we used quantum chemistry calculations to explore the molecular basis of its instability. Aided by the calculations, two rounds of structural optimization of 22b were conducted. Accelerated quantitative light stability testing confirmed that the stability of these designed compounds was significantly improved as predicted. Among them, compounds 1 and 3b displayed more potent inhibitory activity on tumor cell growth than 22b. In addition, the potent in vivo antitumor activity of compound 1 was confirmed. Quantum chemistry calculations were used in the optimization of stilbene-like molecules, providing new insight into stilbenoid optimization and important implications for the future development of novel CA-4-like tubulin polymerization inhibitors.

  10. Desert Dust Layers Over Polluted Marine Boundary Layers: ACE-2 Measurements and ACE-Asia Plans

    NASA Technical Reports Server (NTRS)

    Russell, Philip B.; Schmid, B.; Livingston, J. M.; Redemann, J.; Bergstrom, R. W.; Condon, Estelle P. (Technical Monitor)

    2000-01-01

    Aerosols in ACE-Asia are expected to have some commonalties with those in ACE-2, along with important differences. Among the commonalities are occurrences of desert dust layers over polluted marine boundary layers. Differences include the nature of the dust (yellowish in the East Asia desert outflow, vs. reddish-brown in the Sahara Outflow measured in ACE-2) and the composition of boundary-layer aerosols (e.g., more absorbing, soot and organic aerosol in-the Asian plume, caused by coal and biomass burning, with limited controls). In this paper we present ACE-2 measurements and analyses as a guide to our plans for ACE-2 Asia. The measurements include: (1) Vertical profiles of aerosol optical depth and extinction (380-1558 nm), and of water vapor column and concentration, from the surface through the elevated desert dust, measured by the 14-channel Ames Airborne Tracking Sunphotometer (AATS-14); (2) Comparisons of airborne and shipborne sunphotometer optical depths to satellite-retrieved values, with and without desert dust; (3) Comparisons between airborne Sunphotometer optical depth and extinction spectra and those derived from coincident airborne in situ measurements of aerosol size distribution, scattering and absorption; (4) Comparisons between size distributions measured in situ and retrieved from sunphotometer optical depth spectra; (5) Comparisons between aerosol single scattering albedo values obtained by several techniques, using various combinations of measurements of backscatter, extinction, size distribution, scattering, absorption, and radiative flux. We show how analyses of these data can be used to address questions important to ACE-Asia, such as: (1) How do dust and other absorbing aerosols affect the accuracy of satellite optical depth retrievals? How important are asphericity effects? (2) How important are supermicron dust and seasalt aerosols to overall aerosol optical depth and radiative forcing? How well are these aerosols sampled by aircraft

  11. The solar array is installed on ACE in SAEF-2

    NASA Technical Reports Server (NTRS)

    1997-01-01

    Applied Physics Laboratory engineers and technicians from Johns Hopkins University install solar array panels on the Advanced Composition Explorer (ACE) in KSC's Spacecraft Assembly and Encapsulation Facility-II. The panel on which they are working is identical to the panel (one of four) seen in the foreground on the ACE spacecraft. Scheduled for launch on a Delta II rocket from Cape Canaveral Air Station on Aug. 25, ACE will study low- energy particles of solar origin and high-energy galactic particles for a better understanding of the formation and evolution of the solar system as well as the astrophysical processes involved. The ACE observatory will be placed into an orbit almost a million miles (1.5 million kilometers) away from the Earth, about 1/100 the distance from the Earth to the Sun. The collecting power of instrumentation aboard ACE is at least 100 times more sensitive than anything previously flown to collect similar data by NASA.

  12. Use of Hydration Inhibitors to Improve Bond Durability of Aluminum Adhesive Joints

    NASA Technical Reports Server (NTRS)

    Davis, G. D.; Ahearn, J. S.; Matienzo, L. J.; Venables, J. D.

    1985-01-01

    An investigation is conducted of the mechanisms by which nitrilotris methylene phosphonic acid (NTMP) and related compounds are adsorbed onto oxidized aluminum surfaces to inhibit hydration and increase the durability of adhesive bonds formed with inhibitor-treated panels. P - O - Al bonds are identified as the basis of adsorption, and it is found that water initially adsorbed onto the etched aluminum surfaces is displaced by the NTMP. The hydration of the NTMP-treated surfaces occurs in three stages, namely the reverisble physisorption of water, the slow dissolution of NTMP followed by rapid hydration of the freshly exposed Al2O3 to AlOOH and further hydration of the surface to Al(OH)3. Five properties of an ideal inhibitor are identified.

  13. Discovery of bacterial NAD⁺-dependent DNA ligase inhibitors: improvements in clearance of adenosine series.

    PubMed

    Stokes, Suzanne S; Gowravaram, Madhusudhan; Huynh, Hoan; Lu, Min; Mullen, George B; Chen, Brendan; Albert, Robert; O'Shea, Thomas J; Rooney, Michael T; Hu, Haiqing; Newman, Joseph V; Mills, Scott D

    2012-01-01

    Optimization of clearance of adenosine inhibitors of bacterial NAD(+)-dependent DNA ligase is discussed. To reduce Cytochrome P-450-mediated metabolic clearance, many strategies were explored; however, most modifications resulted in compounds with reduced antibacterial activity and/or unchanged total clearance. The alkyl side chains of the 2-cycloalkoxyadenosines were fluorinated, and compounds with moderate antibacterial activity and favorable pharmacokinetic properties in rat and dog were identified.

  14. ACE2 and Microbiota: Emerging Targets for Cardiopulmonary Disease Therapy

    PubMed Central

    Cole-Jeffrey, Colleen T; Liu, Meng; Katovich, Michael J; Raizada, Mohan K; Shenoy, Vinayak

    2015-01-01

    The health of the cardiovascular and pulmonary systems is inextricably linked to the renin-angiotensin system (RAS). Physiologically speaking, a balance between the vasodeleterious (ACE/Ang II/AT1R) and vasoprotective (ACE2/Ang-(1–7)/MasR) components of the RAS is critical for cardiopulmonary homeostasis. Upregulation of the ACE/Ang II/AT1R axis shifts the system toward vasoconstriction, proliferation, hypertrophy, inflammation, and fibrosis, all factors that contribute to the development and progression of cardiopulmonary diseases. Conversely, stimulation of the vasoprotective ACE2/Ang-(1–7)/MasR axis produces a counter-regulatory response that promotes cardiovascular health. Current research is investigating novel strategies to augment actions of the vasoprotective RAS components, particularly ACE2, in order to treat various pathologies. While multiple approaches to increase the activity of ACE2 have displayed beneficial effects against experimental disease models, the mechanisms behind its protective actions remain incompletely understood. Recent work demonstrating a non-catalytic role for ACE2 in amino acid transport in the gut has led us to speculate that the therapeutic effects of ACE2 can be mediated, in part, by its actions on the gastrointestinal tract and/or gut microbiome. This is consistent with emerging data which suggests that dysbiosis of the gut and lung microbiomes is associated with cardiopulmonary disease. This review highlights new developments in the protective actions of ACE2 against cardiopulmonary disorders, discusses innovative approaches to targeting ACE2 for therapy, and explores an evolving role for gut and lung microbiota in cardiopulmonary health. PMID:26322922

  15. ACE2 and Microbiota: Emerging Targets for Cardiopulmonary Disease Therapy.

    PubMed

    Cole-Jeffrey, Colleen T; Liu, Meng; Katovich, Michael J; Raizada, Mohan K; Shenoy, Vinayak

    2015-12-01

    The health of the cardiovascular and pulmonary systems is inextricably linked to the renin-angiotensin system (RAS). Physiologically speaking, a balance between the vasodeleterious (Angiotensin-converting enzyme [ACE]/Angiotensin II [Ang II]/Ang II type 1 receptor [AT1R]) and vasoprotective (Angiotensin-converting enzyme 2 [ACE2]/Angiotensin-(1-7) [Ang-(1-7)]/Mas receptor [MasR]) components of the RAS is critical for cardiopulmonary homeostasis. Upregulation of the ACE/Ang II/AT1R axis shifts the system toward vasoconstriction, proliferation, hypertrophy, inflammation, and fibrosis, all factors that contribute to the development and progression of cardiopulmonary diseases. Conversely, stimulation of the vasoprotective ACE2/Ang-(1-7)/MasR axis produces a counter-regulatory response that promotes cardiovascular health. Current research is investigating novel strategies to augment actions of the vasoprotective RAS components, particularly ACE2, in order to treat various pathologies. Although multiple approaches to increase the activity of ACE2 have displayed beneficial effects against experimental disease models, the mechanisms behind its protective actions remain incompletely understood. Recent work demonstrating a non-catalytic role for ACE2 in amino acid transport in the gut has led us to speculate that the therapeutic effects of ACE2 can be mediated, in part, by its actions on the gastrointestinal tract and/or gut microbiome. This is consistent with emerging data which suggest that dysbiosis of the gut and lung microbiomes is associated with cardiopulmonary disease. This review highlights new developments in the protective actions of ACE2 against cardiopulmonary disorders, discusses innovative approaches to targeting ACE2 for therapy, and explores an evolving role for gut and lung microbiota in cardiopulmonary health.

  16. The toxicity of angiotensin converting enzyme inhibitors to larvae of the disease vectors Aedes aegypti and Anopheles gambiae

    PubMed Central

    Abu Hasan, Zatul-’Iffah; Williams, Helen; Ismail, Nur M.; Othman, Hidayatulfathi; Cozier, Gyles E.; Acharya, K. Ravi; Isaac, R. Elwyn

    2017-01-01

    The control of mosquitoes is threatened by the appearance of insecticide resistance and therefore new control chemicals are urgently required. Here we show that inhibitors of mosquito peptidyl dipeptidase, a peptidase related to mammalian angiotensin-converting enzyme (ACE), are insecticidal to larvae of the mosquitoes, Aedes aegypti and Anopheles gambiae. ACE inhibitors (captopril, fosinopril and fosinoprilat) and two peptides (trypsin-modulating oostatic factor/TMOF and a bradykinin-potentiating peptide, BPP-12b) were all inhibitors of the larval ACE activity of both mosquitoes. Two inhibitors, captopril and fosinopril (a pro-drug ester of fosinoprilat), were tested for larvicidal activity. Within 24 h captopril had killed >90% of the early instars of both species with 3rd instars showing greater resistance. Mortality was also high within 24 h of exposure of 1st, 2nd and 3rd instars of An. gambiae to fosinopril. Fosinopril was also toxic to Ae. aegypti larvae, although the 1st instars appeared to be less susceptible to this pro-drug even after 72 h exposure. Homology models of the larval An. gambiae ACE proteins (AnoACE2 and AnoACE3) reveal structural differences compared to human ACE, suggesting that structure-based drug design offers a fruitful approach to the development of selective inhibitors of mosquito ACE enzymes as novel larvicides. PMID:28345667

  17. The toxicity of angiotensin converting enzyme inhibitors to larvae of the disease vectors Aedes aegypti and Anopheles gambiae.

    PubMed

    Abu Hasan, Zatul-'Iffah; Williams, Helen; Ismail, Nur M; Othman, Hidayatulfathi; Cozier, Gyles E; Acharya, K Ravi; Isaac, R Elwyn

    2017-03-27

    The control of mosquitoes is threatened by the appearance of insecticide resistance and therefore new control chemicals are urgently required. Here we show that inhibitors of mosquito peptidyl dipeptidase, a peptidase related to mammalian angiotensin-converting enzyme (ACE), are insecticidal to larvae of the mosquitoes, Aedes aegypti and Anopheles gambiae. ACE inhibitors (captopril, fosinopril and fosinoprilat) and two peptides (trypsin-modulating oostatic factor/TMOF and a bradykinin-potentiating peptide, BPP-12b) were all inhibitors of the larval ACE activity of both mosquitoes. Two inhibitors, captopril and fosinopril (a pro-drug ester of fosinoprilat), were tested for larvicidal activity. Within 24 h captopril had killed >90% of the early instars of both species with 3(rd) instars showing greater resistance. Mortality was also high within 24 h of exposure of 1(st), 2(nd) and 3(rd) instars of An. gambiae to fosinopril. Fosinopril was also toxic to Ae. aegypti larvae, although the 1(st) instars appeared to be less susceptible to this pro-drug even after 72 h exposure. Homology models of the larval An. gambiae ACE proteins (AnoACE2 and AnoACE3) reveal structural differences compared to human ACE, suggesting that structure-based drug design offers a fruitful approach to the development of selective inhibitors of mosquito ACE enzymes as novel larvicides.

  18. Role of angiotensin converting enzyme and angiotensinogen gene polymorphisms in angiotensin converting enzyme inhibitor-mediated antiproteinuric action in type 2 diabetic nephropathy patients

    PubMed Central

    Aggarwal, Neerja; Kare, Pawan Kumar; Varshney, Parul; Kalra, Om Prakash; Madhu, Sri Venkata; Banerjee, Basu Dev; Yadav, Anil; Raizada, Alpana; Tripathi, Ashok Kumar

    2017-01-01

    AIM To investigate the role of genetic variants of angiotensin converting enzyme (ACE) and angiotensinogen (AGT) genes in the antiproteinuric efficacy of ACE inhibitor therapy in diabetic nephropathy (DN) patients. METHODS In the present study, 270 type 2 diabetes mellitus patients with nephropathy were enrolled and treated with ACE inhibitor (ramipril) and followed at 6 mo for renal function and albumin excretion by estimating serum creatinine, end stage renal disease, and albumin/creatinine ratio (ACR) in urine. Genotyping of ACE I/D and AGT M235T polymorphisms were performed by using primer specific polymerase chain reaction (PCR) and PCR-RFLP techniques, respectively. RESULTS Forty-eight percent of DN patients (responders) benefited with respect to proteinuria from ACE inhibitor therapy at 6 mo follow-up. A significant reduction in ACR was observed after 6 mo treatment with ACE inhibitor irrespective of whether DN patients were micro-albuminuric (≥ 30 and < 300 mg/g creatinine) or macro-albuminuric (≥ 300 mg/g creatinine) at the time of enrollment. However, macro-albuminuric patients (55%) showed better response to therapy. A reduction in urinary ACR was found independent of genotypes of ACE I/D and AGT M235T polymorphisms although macro-albuminuric patients having TT genotype showed statistically insignificant increased response (72%). CONCLUSION ACE inhibitor therapy reduced urinary ACR by ≥ 30% in 50% of DN patients and the response is independent of ACE I/D and AGT M235T polymorphisms. PMID:28344754

  19. Angiotensin 1-7 improves insulin sensitivity by increasing skeletal muscle glucose uptake in vivo.

    PubMed

    Echeverría-Rodríguez, Omar; Del Valle-Mondragón, Leonardo; Hong, Enrique

    2014-01-01

    The renin-angiotensin system (RAS) regulates skeletal muscle insulin sensitivity through different mechanisms. The overactivation of the ACE (angiotensin-converting enzyme)/Ang (angiotensin) II/AT1R (Ang II type 1 receptor) axis has been associated with the development of insulin resistance, whereas the stimulation of the ACE2/Ang 1-7/MasR (Mas receptor) axis improves insulin sensitivity. The in vivo mechanisms by which this axis enhances skeletal muscle insulin sensitivity are scarcely known. In this work, we investigated whether rat soleus muscle expresses the ACE2/Ang 1-7/MasR axis and determined the effect of Ang 1-7 on rat skeletal muscle glucose uptake in vivo. Western blot analysis revealed the expression of ACE2 and MasR, while Ang 1-7 levels were detected in rat soleus muscle by capillary zone electrophoresis. The euglycemic clamp exhibited that Ang 1-7 by itself did not promote glucose transport, but it increased insulin-stimulated glucose disposal in the rat. In a similar manner, captopril (an ACE inhibitor) enhanced insulin-induced glucose uptake and this effect was blocked by the MasR antagonist A-779. Our results show for the first time that rat soleus muscle expresses the ACE2/Ang 1-7/MasR axis of the RAS, and Ang 1-7 improves insulin sensitivity by enhancing insulin-stimulated glucose uptake in rat skeletal muscle in vivo. Thus, endogenous (systemic and/or local) Ang 1-7 could regulate insulin-mediated glucose transport in vivo.

  20. Active Control Technique Evaluation for Spacecraft (ACES)

    DTIC Science & Technology

    1988-06-16

    Due to Test Results 3-9 3.5 Representative Data 3-11 3.6 Control Model 3-21 4.0 Simulation 4-1 5.0 HAC/LAC 5-1 5.1 Theory 5-1...5.1.1 HAC Theory 5-1 5.1.2 LAC Theory 5-4 5.1.3 HAC/LAC Combined Control 5-6 5.1.4 HAC/LAC Applied to ACES 5-7 5.2 Model Selection and...5-39 5-50 6.0 Positivity 6-1 6-1 6-9 6-9 6-17 6-31 5.4 Observation 5.5 Test Results 5.6 Conclusions 6.1 Theory 6.2 Model

  1. Study on improvement of durability for reinforced concrete by surface-painting migrating corrosion inhibitor and engineering application

    NASA Astrophysics Data System (ADS)

    Song, Ning; WANG, Zixiao; LIU, Zhiyong; Zhou, Jiyuan; Zheng, Duo

    2017-01-01

    The corrosion currents of steel bar in concrete with three W/B and four chloride contents after surface-painting two migrating corrosion inhibitors (PCI-2015 and MCI-A) 14d to 150d in atmospheric condition were measured. The results showed that the corrosion current density (I corr) of steel bar reduced to 0.1 μA.cm-2 from the initial highest 3.833 μA.cm-2 (W/B=0.65, NaCl-1%) after surface-painting PCI-2015 14 d, and the I corr was still lower than 0.1 μA.cm-2 until 150d. The compressive strength and chloride migration coefficient of concrete specimens were tested. The possible reasons of the mechanisms of durability improvement for reinforced concrete by applying PCI-2015 inhibitor were PCI-2015 may be reacted with calcium hydroxide in cement concrete and lots of inhibitor particles may be adsorbed on the active sites first and then a stable protective layer may be formed. The I corr of steel bars in a hydraulic aqueduct concrete structure after painting PCI-2015, MCI-A (the United States) and MCI-B (Europe) during 6 months was monitored by Gecor 8 tester. The results showed that the average values of I corr of steel bars after painting the PCI-2015 150d fulfilled the specification requirements in “Design code for concrete structure strengthening (E.3) ”(GB 50367-2013).

  2. Improved Pharmacological and Structural Properties of HIV Fusion Inhibitor AP3 over Enfuvirtide: Highlighting Advantages of Artificial Peptide Strategy

    DOE PAGES

    Zhu, Xiaojie; Zhu, Yun; Ye, Sheng; ...

    2015-08-19

    Enfuvirtide (T20), is the first HIV fusion inhibitor approved for treatment of HIV/AIDS patients who fail to respond to the current antiretroviral drugs. However, its clinical application is limited because of short half-life, drug resistance and cross-reactivity with the preexisting antibodies in HIV-infected patients. Using an artificial peptide strategy, we designed a peptide with non-native protein sequence, AP3, which exhibited potent antiviral activity against a broad spectrum of HIV-1 strains, including those resistant to T20, and had remarkably longer in vivo half-life than T20. While the preexisting antibodies in HIV-infected patients significantly suppressed T20’s antiviral activity, these antibodies neither recognizedmore » AP3, nor attenuated its anti-HIV-1 activity. Structurally different from T20, AP3 could fold into single-helix and interact with gp41 NHR. The two residues, Met and Thr, at the N-terminus of AP3 form a hook-like structure to stabilize interaction between AP3 and NHR helices. Therefore, AP3 has potential for further development as a new HIV fusion inhibitor with improved antiviral efficacy, resistance profile and pharmacological properties over enfuvirtide. Meanwhile, this study highlighted the advantages of artificially designed peptides, and confirmed that this strategy could be used in developing artificial peptide-based viral fusion inhibitors against HIV and other enveloped viruses.« less

  3. A retrospective study of the effects of angiotensin receptor blockers and angiotensin converting enzyme inhibitors in diabetic nephropathy

    PubMed Central

    Pathak, Jahnavi V.; Dass, Ervilla E.

    2015-01-01

    Objective: Till date, several studies have compared angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in terms of delaying the progression of diabetic nephropathy. But the superiority of one drug class over the other remains unsettled. This study has retrospectively compared the effects of ACE inhibitors and ARBs in diabetic nephropathy. The study aims to compare ACE inhibitors and ARBs in terms of delaying or preventing the progression of diabetic nephropathy, association between blood pressure (B.P) and urinary albumin and also B.P and serum creatinine with ACE inhibitor and ARB, know the percentage of hyperkalemia in patients of diabetic nephropathy receiving ACE inhibitor or ARB. Settings and Design: A total of 134 patients diagnosed with diabetic nephropathy during the years 2001–2010 and having a complete follow-up were studied, out of which 99 were on ARB (63 patients of Losartan and 36 of Telmisartan) and 35 on ACE inhibitor (Ramipril). Subjects and Methods: There was at least 1-month of interval between each observation made and also between the date of treatment started and the first reading that is, the observation of the 1st month. In total, three readings were taken that is, of the 1st, 2nd and 3rd month after the treatment started. Comparison of the 1st and 3rd month after the treatment started was done. Mean ± standard deviation, Paired t-test, and Chi-square were used for the analysis of the data. Results: The results reflect that ARBs (Losartan and Telmisartan) when compared to ACE inhibitor (Ramipril) are more effective in terms of delaying the progression of diabetic nephropathy and also in providing renoprotection. Also, ARBs have the property of simultaneously decreasing the systolic B.P and albuminuria when compared to ACE inhibitor (Ramipril). Conclusions: Angiotensin receptor blockers are more renoprotective than ACE inhibitors and also provide better cardioprotection. PMID:25878372

  4. Cyclooxygenase-2-specific Inhibitor Improves Functional Outcomes, Provides Neuroprotection, and Reduces Inflammation in a Rat Model of Traumatic Brain Injury

    PubMed Central

    Gopez, Jonas J.; Yue, Hongfei; Vasudevan, Ram; Malik, Amir S.; Fogelsanger, Lester N.; Lewis, Shawn; Panikashvili, David; Shohami, Esther; Jansen, Susan A.; Narayan, Raj K.; Strauss, Kenneth I.

    2006-01-01

    OBJECTIVE Increases in brain cyclooxygenase-2 (COX2) are associated with the central inflammatory response and with delayed neuronal death, events that cause secondary insults after traumatic brain injury. A growing literature supports the benefit of COX2-specific inhibitors in treating brain injuries. METHODS DFU [5,5-dimethyl-3(3-fluorophenyl)-4(4-methylsulfonyl)phenyl-2(5H)-furanone] is a third-generation, highly specific COX2 enzyme inhibitor. DFU treatments (1 or 10 mg/kg intraperitoneally, twice daily for 3 d) were initiated either before or after traumatic brain injury in a lateral cortical contusion rat model. RESULTS DFU treatments initiated 10 minutes before injury or up to 6 hours after injury enhanced functional recovery at 3 days compared with vehicle-treated controls. Significant improvements in neurological reflexes and memory were observed. DFU initiated 10 minutes before injury improved histopathology and altered eicosanoid profiles in the brain. DFU 1 mg/kg reduced the rise in prostaglandin E2 in the brain at 24 hours after injury. DFU 10 mg/kg attenuated injury-induced COX2 immunoreactivity in the cortex (24 and 72 h) and hippocampus (6 and 72 h). This treatment also decreased the total number of activated caspase-3–immunoreactive cells in the injured cortex and hippocampus, significantly reducing the number of activated caspase-3–immunoreactive neurons at 72 hours after injury. DFU 1 mg/kg amplified potentially anti-inflammatory epoxyeicosatrienoic acid levels by more than fourfold in the injured brain. DFU 10 mg/kg protected the levels of 2-arachidonoyl glycerol, a neuro-protective endocannabinoid, in the injured brain. CONCLUSION These improvements, particularly when treatment began up to 6 hours after injury, suggest exciting neuroprotective potential for COX2 inhibitors in the treatment of traumatic brain injury and support the consideration of Phase I/II clinical trials. PMID:15730585

  5. Structure-based approach to improve a small-molecule inhibitor by the use of a competitive peptide ligand.

    PubMed

    Ono, Katsuki; Takeuchi, Koh; Ueda, Hiroshi; Morita, Yasuhiro; Tanimura, Ryuji; Shimada, Ichio; Takahashi, Hideo

    2014-03-03

    Structural information about the target-compound complex is invaluable in the early stage of drug discovery. In particular, it is important to know into which part of the initial compound additional interaction sites could be introduced to improve its affinity. Herein, we demonstrate that the affinity of a small-molecule inhibitor for its target protein could be successfully improved by the constructive introduction of the interaction mode of a competitive peptide. The strategy involved the discrimination of overlapping and non-overlapping peptide-compound pharmacophores by the use of a ligand-based NMR spectroscopic approach, INPHARMA. The obtained results enabled the design of a new compound with improved affinity for the platelet receptor glycoprotein VI (GPVI). The approach proposed herein efficiently combines the advantages of compounds and peptides for the development of higher-affinity druglike ligands.

  6. Chemoresistance to Valproate Treatment of Bovine Leukemia Virus-Infected Sheep; Identification of Improved HDAC Inhibitors

    PubMed Central

    Gillet, Nicolas; Vandermeers, Fabian; de Brogniez, Alix; Florins, Arnaud; Nigro, Annamaria; François, Carole; Bouzar, Amel-Baya; Verlaeten, Olivier; Stern, Eric; Lambert, Didier M.; Wouters, Johan; Willems, Luc

    2012-01-01

    We previously proved that a histone deacetylase inhibitor (valproate, VPA) decreases the number of leukemic cells in bovine leukemia virus (BLV)-infected sheep. Here, we characterize the mechanisms initiated upon interruption of treatment. We observed that VPA treatment is followed by a decrease of the B cell counts and proviral loads (copies per blood volume). However, all sheep eventually relapsed after different periods of time and became refractory to further VPA treatment. Sheep remained persistently infected with BLV. B lymphocytes isolated throughout treatment and relapse were responsive to VPA-induced apoptosis in cell culture. B cell proliferation is only marginally affected by VPA ex vivo. Interestingly, in four out of five sheep, ex vivo viral expression was nearly undetectable at the time of relapse. In two sheep, a new tumoral clone arose, most likely revealing a selection process exerted by VPA in vivo. We conclude that the interruption of VPA treatment leads to the resurgence of the leukemia in BLV-infected sheep and hypothesize that resistance to further treatment might be due to the failure of viral expression induction. The development of more potent HDAC inhibitors and/or the combination with other compounds can overcome chemoresistance. These observations in the BLV model may be important for therapies against the related Human T-lymphotropic virus type 1. PMID:25436765

  7. Targeting carbonic anhydrase IX improves the anti-cancer efficacy of mTOR inhibitors

    PubMed Central

    Faes, Seraina; Planche, Anne; Uldry, Emilie; Santoro, Tania; Pythoud, Catherine; Stehle, Jean-Christophe; Horlbeck, Janine; Letovanec, Igor; Riggi, Nicolo; Datta, Dipak; Demartines, Nicolas; Dormond, Olivier

    2016-01-01

    The inhibition of the mechanistic target of rapamycin complex 1 (mTORC1) by chemical inhibitors, such as rapamycin, has demonstrated anti-cancer activity in preclinical and clinical trials. Their efficacy is, however, limited and tumors eventually relapse through resistance formation. In this study, using two different cancer mouse models, we identify tumor hypoxia as a novel mechanism of resistance of cancer cells against mTORC1 inhibitors. Indeed, we show that the activity of mTORC1 is mainly restricted to the non-hypoxic tumor compartment, as evidenced by a mutually exclusive staining pattern of the mTORC1 activity marker pS6 and the hypoxia marker pimonidazole. Consequently, whereas rapamycin reduces cancer cell proliferation in non-hypoxic regions, it has no effect in hypoxic areas, suggesting that cancer cells proliferate independently of mTORC1 under hypoxia. Targeting the hypoxic tumor compartment by knockdown of carbonic anhydrase IX (CAIX) using short hairpin RNA or by chemical inhibition of CAIX with acetazolamide potentiates the anti-cancer activity of rapamycin. Taken together, these data emphasize that hypoxia impairs the anti-cancer efficacy of rapalogs. Therapeutic strategies targeting the hypoxic tumor compartment, such as the inhibition of CAIX, potentiate the efficacy of rapamycin and warrant further clinical evaluation. PMID:27153561

  8. Molecular Recognition of the Catalytic Zinc(II) Ion in MMP-13: Structure-Based Evolution of an Allosteric Inhibitor to Dual Binding Mode Inhibitors with Improved Lipophilic Ligand Efficiencies

    PubMed Central

    Fischer, Thomas; Riedl, Rainer

    2016-01-01

    Matrix metalloproteinases (MMPs) are a class of zinc dependent endopeptidases which play a crucial role in a multitude of severe diseases such as cancer and osteoarthritis. We employed MMP-13 as the target enzyme for the structure-based design and synthesis of inhibitors able to recognize the catalytic zinc ion in addition to an allosteric binding site in order to increase the affinity of the ligand. Guided by molecular modeling, we optimized an initial allosteric inhibitor by addition of linker fragments and weak zinc binders for recognition of the catalytic center. Furthermore we improved the lipophilic ligand efficiency (LLE) of the initial inhibitor by adding appropriate zinc binding fragments to lower the clogP values of the inhibitors, while maintaining their potency. All synthesized inhibitors showed elevated affinity compared to the initial hit, also most of the novel inhibitors displayed better LLE. Derivatives with carboxylic acids as the zinc binding fragments turned out to be the most potent inhibitors (compound 3 (ZHAWOC5077): IC50 = 134 nM) whereas acyl sulfonamides showed the best lipophilic ligand efficiencies (compound 18 (ZHAWOC5135): LLE = 2.91). PMID:26938528

  9. Molecular Recognition of the Catalytic Zinc(II) Ion in MMP-13: Structure-Based Evolution of an Allosteric Inhibitor to Dual Binding Mode Inhibitors with Improved Lipophilic Ligand Efficiencies.

    PubMed

    Fischer, Thomas; Riedl, Rainer

    2016-03-01

    Matrix metalloproteinases (MMPs) are a class of zinc dependent endopeptidases which play a crucial role in a multitude of severe diseases such as cancer and osteoarthritis. We employed MMP-13 as the target enzyme for the structure-based design and synthesis of inhibitors able to recognize the catalytic zinc ion in addition to an allosteric binding site in order to increase the affinity of the ligand. Guided by molecular modeling, we optimized an initial allosteric inhibitor by addition of linker fragments and weak zinc binders for recognition of the catalytic center. Furthermore we improved the lipophilic ligand efficiency (LLE) of the initial inhibitor by adding appropriate zinc binding fragments to lower the clogP values of the inhibitors, while maintaining their potency. All synthesized inhibitors showed elevated affinity compared to the initial hit, also most of the novel inhibitors displayed better LLE. Derivatives with carboxylic acids as the zinc binding fragments turned out to be the most potent inhibitors (compound 3 (ZHAWOC5077): IC50 = 134 nM) whereas acyl sulfonamides showed the best lipophilic ligand efficiencies (compound 18 (ZHAWOC5135): LLE = 2.91).

  10. AceCloud: Molecular Dynamics Simulations in the Cloud.

    PubMed

    Harvey, M J; De Fabritiis, G

    2015-05-26

    We present AceCloud, an on-demand service for molecular dynamics simulations. AceCloud is designed to facilitate the secure execution of large ensembles of simulations on an external cloud computing service (currently Amazon Web Services). The AceCloud client, integrated into the ACEMD molecular dynamics package, provides an easy-to-use interface that abstracts all aspects of interaction with the cloud services. This gives the user the experience that all simulations are running on their local machine, minimizing the learning curve typically associated with the transition to using high performance computing services.

  11. ACE--Alliance for Clinical Enhancement: a collaborative model.

    PubMed

    Poirrier, G P; Granger, M; Todaro, M

    1993-01-01

    This paper introduces an innovative collaborative model developed by nursing educators and practitioners, the Alliance for Clinical Enhancement Program (ACE), that combines components of traditional internship and extender programs. The goals of ACE are opportunities for role socialization, role transition, and role modeling for nursing students; enhancing clinical competence and provision of financial assistance to the students; increased recruitment of RN graduates by the involved hospital; and decreased RN time spent on non-nursing tasks by hospital RNs. The total development, implementation, and analysis of ACE Program is discussed.

  12. 1,3-Disubstituted Ureas Functionalized with Ether Groups are Potent Inhibitors of the Soluble Epoxide Hydrolase with Improved Pharmacokinetic Properties

    PubMed Central

    Kim, In-Hae; Tsai, Hsing-Ju; Nishi, Kosuke; Kasagami, Takeo; Morisseau, Christophe; Hammock, Bruce D.

    2008-01-01

    Soluble epoxide hydrolase (sEH) is a therapeutic target for treating hypertension and inflammation. 1,3-Disubstituted ureas functionalized with an ether group are potent sEH inhibitors. However, their relatively low metabolic stability leads to poor pharmacokinetic properties. To improve their bioavailability, we investigated the effect of incorporating various polar groups on the ether function on the inhibition potencies, physical properties, in vitro metabolic stability, and pharmacokinetic properties. The structure-activity relationship (SAR) studies showed that a hydrophobic linker between the urea group and the ether function is necessary to keep their potency. In addition, urea-ether inhibitors having a polar group such as diethylene glycol or morpholine significantly improved their physical properties and metabolic stability without any loss of inhibitory potency. Furthermore, improved pharmacokinetic properties in murine and canine models were obtained with the resulting inhibitors. These findings will facilitate the usage of sEH inhibitors in animal models of hypertension and inflammation. PMID:17894481

  13. Modification of triclosan scaffold in search of improved inhibitors for enoyl-acyl carrier protein (ACP) reductase in Toxoplasma gondii.

    PubMed

    Stec, Jozef; Fomovska, Alina; Afanador, Gustavo A; Muench, Stephen P; Zhou, Ying; Lai, Bo-Shiun; El Bissati, Kamal; Hickman, Mark R; Lee, Patty J; Leed, Susan E; Auschwitz, Jennifer M; Sommervile, Caroline; Woods, Stuart; Roberts, Craig W; Rice, David; Prigge, Sean T; McLeod, Rima; Kozikowski, Alan P

    2013-07-01

    Through our focused effort to discover new and effective agents against toxoplasmosis, a structure-based drug design approach was used to develop a series of potent inhibitors of the enoyl-acyl carrier protein (ACP) reductase (ENR) enzyme in Toxoplasma gondii (TgENR). Modifications to positions 5 and 4' of the well-known ENR inhibitor triclosan afforded a series of 29 new analogues. Among the resulting compounds, many showed high potency and improved physicochemical properties in comparison with the lead. The most potent compounds 16 a and 16 c have IC50 values of 250 nM against Toxoplasma gondii tachyzoites without apparent toxicity to the host cells. Their IC50 values against recombinant TgENR were found to be 43 and 26 nM, respectively. Additionally, 11 other analogues in this series had IC50 values ranging from 17 to 130 nM in the enzyme-based assay. With respect to their excellent in vitro activity as well as improved drug-like properties, the lead compounds 16 a and 16 c are deemed to be excellent starting points for the development of new medicines to effectively treat Toxoplasma gondii infections.

  14. Improving the bioavailability and anticancer effect of the PCA-1/ALKBH3 inhibitor HUHS015 using sodium salt.

    PubMed

    Mabuchi, Miyuki; Shimizu, Tadashi; Ueda, Masahiro; Sasakawa, Yuka; Nakao, Syuhei; Ueda, Yuko; Kawamura, Akio; Tsujikawa, Kazutake; Tanaka, Akito

    2015-01-01

    Prostate cancer antigen (PCA)-1/AlkB homologue 3 (ALKBH3) has been identified as a clinically significant factor and siRNA of PCA-1 inhibits DU145 proliferation both in vitro and in vivo. HUHS015 ( 1: ), a previous reported PCA-1 small-molecule inhibitor, was also effective without any obvious side-effects or toxicity. The potency of HUHS015, however, is not satisfying. We thought the reason is poor solubility of HUHS015 because insoluble material remained at the injection site after subcutaneous administration. To improve this inhibitor's solubility, we prepared various salts of HUHS015 and examined their solubility, which resulted in the selection of HUHS015 sodium salt ( 2: ) for further studies in vivo. Next, we compared the pharmacokinetics of 1: and 2: via several administration routes. We observed significant improvements in the pharmacokinetic parameters. For example, subcutaneous administration of 2: increased the area under the curve (AUC)0-24 by 8-fold compared to 1 and increased the suppressive effect on the proliferation of DU145 cells in a xenograft model.

  15. Modification of Triclosan Scaffold in Search of Improved Inhibitors for Enoyl-Acyl Carrier Protein (ACP) Reductase in Toxoplasma gondii

    PubMed Central

    Stec, Jozef; Fomovska, Alina; Afanador, Gustavo A.; Muench, Stephen P.; Zhou, Ying; Lai, Bo-Shiun; Bissati, Kamal El; Hickman, Mark R.; Lee, Patty J.; Leed, Susan E.; Auschwitz, Jennifer M.; Sommervile, Caroline; Woods, Stuart; Roberts, Craig W.; Rice, David; Prigge, Sean T.; McLeod, Rima; Kozikowski, Alan P.

    2013-01-01

    Through our focused effort to discover new and effective agents against toxoplasmosis, a structure-based drug design approach was utilized to develop a series of potent inhibitors of the enoyl-acyl carrier protein (ACP) reductase (ENR) enzyme in Toxoplasma gondii (TgENR). Modifications to positions 5 and 4′ of the well-known ENR inhibitor triclosan afforded a series of 29 new analogs. Among the resulting compounds, many showed high potency and improved physicochemical properties in comparison with the lead. The most potent compounds 16a and 16c have IC50 values of 250 nM against Toxoplasma gondii tachyzoites without apparent toxicity to the host cells. Their IC50 values against the recombinant TgENR were 43 and 26 nM, respectively. Additionally, 11 other analogs in this series had IC50 values ranging from 17 to 130 nM in the enzyme-based assay. With respect to their excellent in vitro activity as well as improved drug-like properties, the lead compounds 16a and 16c are deemed to be an excellent starting point for the development of new medicines to effectively treat Toxoplasma gondii infections. PMID:23776166

  16. ACE-Asia Chemical Transport Modeling Overview

    NASA Astrophysics Data System (ADS)

    UNO, I.; Chin, M.; Collins, W.; Ginoux, P.; Rasch, P.; Carmichael, G. R.; Yienger, J. J.

    2001-12-01

    ACE-Asia (Asia Pacific Regional Aerosol Characterization Experiment) was designed to increase our understanding of how atmospheric aerosol particles affect the Earth?s climate system. The intensive observation period was carried out during March to May, 2001, and more than 100 researchers from several countries (United States, Japan, Korea, China, and many other Asian countries) participated using aircraft, a research vessel, surface stations and numerical models. Aerosol transport forecast activities played an important role during the ACE-Asia intensive observation period. Three independent modeling groups operated chemical transport models in forecast mode and participated in flight planning activities at the operations center. These models were: MATCH (Model of Atmospheric Transport and Chemistry; Rasch and Collins); GOCART (Georgia Tech/Goddard Global Ozone Chemistry Aerosol Radiation and Transport model; Chin and Ginour) and CFORS (Research Institute for Applied Mechanics, Kyushu University + University of Iowa - Chemical weather FORecast System; Uno, Carmichael and Yienger). The MATCH model used in ACE-Asia was a transport model applied for the Asia region, driven by NCEP forecast meteorology. A unique feature of this model was that it assimilated satellite derived optical depths into its forecast algorithm. The GOCART model provided global aerosol forecast using forecast meteorological fields provided by the Goddard Earth Observing System Data Assimilation System (GEOS DAS). The CFORS model provided regional forecasts using a limited area transport model coupled with Regional Meteorological Modeling System (RAMS), initialized by NCEP and JMA forecasts. All models produced 3-d aerosol forecast products consisting of aerosol mass distributions and optical depths for sulfate, black carbon, organic carbon, sea salt, and dust. In the field these model products were made available to all participating scientists via the Web, and were also presented during the

  17. Preconception and pregnancy management of women with diabetic nephropathy on angiotensin converting enzyme inhibitors.

    PubMed

    Podymow, Tiina; Joseph, Geena

    2015-02-01

    Angiotensin converting enzyme (ACE) inhibitors are the mainstay of treatment for diabetic nephropathy to slow progression of disease. Diabetic women of childbearing age with nephropathy should be treated with ACE inhibitors as per guidelines in the pre-pregnancy period. ACE inhibitor use and exposure in the first trimester is controversial and requires counselling pre-pregnancy regarding the risks and benefits of use up to the first trimester, as well as the need to stop ACE inhibitors prior to the second trimester. Current evidence does not suggest that ACE inhibitors in the first trimester are associated with a greater risk of fetal malformations when compared to other antihypertensives. This topic is reviewed in depth, along with blood pressure targets in pregnant women with diabetic proteinuric disease, evidence for prevention of pre-eclampsia, self-monitoring of blood pressures at home in the latter half of pregnancy and the signs and symptoms of pre-eclampsia, proteinuria evolution in pregnancy, renal function prognosis, and restarting ACE inhibitors when breast feeding in the post-partum period.

  18. ACES: The ASCENDS CarbonHawk Experiment Simulator

    NASA Astrophysics Data System (ADS)

    Obland, M. D.; Prasad, N. S.; Harrison, F. W.; Browell, E. V.; Ismail, S.; Dobler, J. T.; Moore, B.; Zaccheo, T.; Campbell, J.; Chen, S.; Cleckner, C. S.; DiJoseph, M.; Little, A.; Notari, A.; Refaat, T. F.; Rosenbaum, D.; Vanek, M. D.; Bender, J.; Braun, M.; Chavez-Pirson, A.; Neal, M.; Rayner, P. J.; Rosiewicz, A.; Shure, M.; Welch, W.

    2012-12-01

    The ASCENDS CarbonHawk Experiment Simulator (ACES) is a NASA Langley Research Center project funded by NASA's Earth Science Technology Office (ESTO) Instrument Incubator Program (IIP) that seeks to advance technologies critical to measuring atmospheric column carbon dioxide (CO2) mixing ratios in support of the NASA Active Sensing of CO2 Emissions over Nights, Days, and Seasons (ASCENDS) mission. The technologies being advanced are: (1) a high bandwidth detector, (2) a multi-aperture telescope assembly, (3) advanced algorithms for cloud and aerosol discrimination, and (4) high-efficiency, multiple-amplifier CO2 and O2 laser transmitters. The instrument architecture will be developed to operate on a high-altitude aircraft and will be directly scalable to meet the ASCENDS mission requirements. These technologies are viewed as critical towards developing an airborne simulator and eventual spaceborne instrument with lower size, mass, and power consumption, and improved performance. The detector effort will improve the existing detector subsystem by increasing its bandwidth to a goal of 5 MHz, reducing its overall mass from 18 lbs to <10 lbs, and stretching the duration of autonomous, service-free operation periods from 4 hrs to >24 hrs. The development goals are to permit higher laser modulation rates, which provides greater flexibility for implementing thin-cloud discrimination algorithms as well as improving range resolution and error reduction, and to enable long flights on a high-altitude unmanned aerial vehicle (UAV). The telescope development consists of a three-telescope design built for the constraints of the Global Hawk aircraft. This task addresses the ability of multiple smaller telescopes to provide equal or greater collection efficiency compared with a single larger telescope with a reduced impact on launch mass and cost. The telescope assembly also integrates fiber-coupled transmit collimators for all of the laser transmitters and fiber-coupled optical

  19. Reversible linkage of two distinct small molecule inhibitors of Myc generates a dimeric inhibitor with improved potency that is active in myc over-expressing cancer cell lines.

    PubMed

    Wanner, Jutta; Romashko, Darlene; Werner, Douglas S; May, Earl W; Peng, Yue; Schulz, Ryan; Foreman, Kenneth W; Russo, Suzanne; Arnold, Lee D; Pingle, Maneesh; Bergstrom, Donald E; Barany, Francis; Thomson, Stuart

    2015-01-01

    We describe the successful application of a novel approach for generating dimeric Myc inhibitors by modifying and reversibly linking two previously described small molecules. We synthesized two directed libraries of monomers, each comprised of a ligand, a connector, and a bioorthogonal linker element, to identify the optimal dimer configuration required to inhibit Myc. We identified combinations of monomers, termed self-assembling dimeric inhibitors, which displayed synergistic inhibition of Myc-dependent cell growth. We confirmed that these dimeric inhibitors directly bind to Myc blocking its interaction with Max and affect transcription of MYC dependent genes. Control combinations that are unable to form a dimer do not show any synergistic effects in these assays. Collectively, these data validate our new approach to generate more potent and selective inhibitors of Myc by self-assembly from smaller, lower affinity components. This approach provides an opportunity for developing novel therapeutics against Myc and other challenging protein:protein interaction (PPI) target classes.

  20. Reversible Linkage of Two Distinct Small Molecule Inhibitors of Myc Generates a Dimeric Inhibitor with Improved Potency That Is Active in Myc Over-Expressing Cancer Cell Lines

    PubMed Central

    Wanner, Jutta; Romashko, Darlene; Werner, Douglas S.; May, Earl W.; Peng, Yue; Schulz, Ryan; Foreman, Kenneth W.; Russo, Suzanne; Arnold, Lee D.; Pingle, Maneesh; Bergstrom, Donald E.; Barany, Francis; Thomson, Stuart

    2015-01-01

    We describe the successful application of a novel approach for generating dimeric Myc inhibitors by modifying and reversibly linking two previously described small molecules. We synthesized two directed libraries of monomers, each comprised of a ligand, a connector, and a bioorthogonal linker element, to identify the optimal dimer configuration required to inhibit Myc. We identified combinations of monomers, termed self-assembling dimeric inhibitors, which displayed synergistic inhibition of Myc-dependent cell growth. We confirmed that these dimeric inhibitors directly bind to Myc blocking its interaction with Max and affect transcription of MYC dependent genes. Control combinations that are unable to form a dimer do not show any synergistic effects in these assays. Collectively, these data validate our new approach to generate more potent and selective inhibitors of Myc by self-assembly from smaller, lower affinity components. This approach provides an opportunity for developing novel therapeutics against Myc and other challenging protein:protein interaction (PPI) target classes. PMID:25875098

  1. The Canadian Arctic Atmospheric Chemistry Experiment (ACE) Validation Project: Overview and results from ten years of ACE operations

    NASA Astrophysics Data System (ADS)

    Walker, Kaley; Strong, Kimberly

    2014-05-01

    As of February 2014, the Canadian-led Atmospheric Chemistry Experiment (ACE) satellite mission has been making measurements of the Earth's atmosphere for ten years. As ACE operations have extended beyond the initial two-year mission, there is a continuing need to validate the trace gas data products from the ACE-Fourier Transform Spectrometer (ACE-FTS) and the Measurement of Aerosol Extinction in the Stratosphere and Troposphere Retrieved by Occultation (ACE-MAESTRO) instruments. Ground-based measurements provide critical data for the validation of satellite retrievals of trace gases and for the assessment of long-term stability of these measurements. In particular, validation comparisons are needed for ACE during Arctic springtime to understand better the measurements of species involved in stratospheric ozone chemistry. To this end, eleven Canadian Arctic Atmospheric Chemistry Experiment (ACE) Validation Campaigns have been conducted during the spring period (February - April in 2004 - 2014) at the Polar Environment Atmospheric Research Laboratory (PEARL) in Eureka, Nunavut (80°N, 86°W). This period coincides with the most chemically active time of year in the Arctic, as well as a significant number of satellite overpasses. A suite of as many as 12 ground-based instruments, as well as frequent balloon-borne ozonesonde and radiosonde launches, have been used in each campaign. These instruments include: a ground-based version of the ACE-FTS (PARIS - Portable Atmospheric Research Interferometric Spectrometer), a terrestrial version of the ACE-MAESTRO, a SunPhotoSpectrometer, two zenith-viewing UV-visible grating spectrometers, a Bomem DA8 Fourier transform spectrometer, a Bruker 125HR Fourier transform spectrometer, a Systeme d'Analyse par Observations Zenithales (SAOZ) instrument, and several Brewer spectrophotometers. In the past several years, these results have been used to validate the measurements by the ACE-FTS and ACE-MAESTRO instruments on SCISAT as well

  2. The solar array is installed on ACE in SAEF-2

    NASA Technical Reports Server (NTRS)

    1997-01-01

    Applied Physics Laboratory Engineer Cliff Willey (kneeling) and Engineering Assistant Jim Hutcheson from Johns Hopkins University install solar array panels on the Advanced Composition Explorer (ACE) in KSC's Spacecraft Assembly and Encapsulation Facility-II. Scheduled for launch on a Delta II rocket from Cape Canaveral Air Station on Aug. 25, ACE will study low-energy particles of solar origin and high-energy galactic particles for a better understanding of the formation and evolution of the solar system as well as the astrophysical processes involved. The ACE observatory will be placed into an orbit almost a million miles (1.5 million kilometers) away from the Earth, about 1/100 the distance from the Earth to the Sun. The collecting power of instrumentation aboard ACE is at least 100 times more sensitive than anything previously flown to collect similar data by NASA.

  3. The solar array is installed on ACE in SAEF-2

    NASA Technical Reports Server (NTRS)

    1997-01-01

    Applied Physics Laboratory engineers and technicians from Johns Hopkins University assist in guiding the Advanced Composition Explorer (ACE) as it is hoisted over a platform for solar array installation in KSC's Spacecraft Assembly and Encapsulation Facility-II. Scheduled for launch on a Delta II rocket from Cape Canaveral Air Station on Aug. 25, ACE will study low-energy particles of solar origin and high-energy galactic particles. The ACE observatory will contribute to the understanding of the formation and evolution of the solar system as well as the astrophysical processes involved. The collecting power of instruments aboard ACE is 10 to 1,000 times greater than anything previously flown to collect similar data by NASA.

  4. A novel angiotensin-І converting enzyme (ACE) inhibitory peptide from gastrointestinal protease hydrolysate of silkworm pupa (Bombyx mori) protein: Biochemical characterization and molecular docking study.

    PubMed

    Wu, Qiongying; Jia, Junqiang; Yan, Hui; Du, Jinjuan; Gui, Zhongzheng

    2015-06-01

    Silkworm pupa (Bombyx mori) protein was hydrolyzed using gastrointestinal endopeptidases (pepsin, trypsin and α-chymotrypsin). Then, the hydrolysate was purified sequentially by ultrafiltration, gel filtration chromatography and RP-HPLC. A novel ACE inhibitory peptide, Ala-Ser-Leu, with the IC50 value of 102.15μM, was identified by IT-MS/MS. This is the first report of Ala-Ser-Leu from natural protein. Lineweaver-Burk plots suggest that the peptide is a competitive inhibitor against ACE. The molecular docking studies revealed that the ACE inhibition of Ala-Ser-Leu is mainly attributed to forming very strong hydrogen bonds with the S1 pocket (Ala354) and the S2 pocket (Gln281 and His353). The results indicate that silkworm pupa (B. mori) protein or its gastrointestinal protease hydrolysate could be used as a functional ingredient in auxiliary therapeutic foods against hypertension.

  5. Aircraft Command in Emergency Situations (ACES). Phase 1. Concept. Development

    DTIC Science & Technology

    1991-04-01

    63 6-3 Schematic Layout of the York Fiber- Optic DTS System... optic thermal detection system. XS Federal Aviation Administration Aircraft Command in Emergency Situations (ACES) Final Report II N ’(0) 1 ( .i...fiber optic (York) 2.1 (OBECTIVES OF STUDY S;ivo n Imoli.0it ,moke, fire emergency: The oh1cctivc tf the ACES study was to develop two system concepts

  6. The Fatty Acid Synthase Inhibitor Platensimycin Improves Insulin Resistance without Inducing Liver Steatosis in Mice and Monkeys

    PubMed Central

    Nawrocki, Andrea R.; Zhou, Dan; Wu, Margaret; Previs, Stephen; Miller, Corey; Liu, Haiying; Hines, Catherine D. G.; Madeira, Maria; Cao, Jin; Herath, Kithsiri; Wang, Liangsu; Kelley, David E.; Li, Cai

    2016-01-01

    Objectives Platensimycin (PTM) is a natural antibiotic produced by Streptomyces platensis that selectively inhibits bacterial and mammalian fatty acid synthase (FAS) without affecting synthesis of other lipids. Recently, we reported that oral administration of PTM in mouse models (db/db and db/+) with high de novo lipogenesis (DNL) tone inhibited DNL and enhanced glucose oxidation, which in turn led to net reduction of liver triglycerides (TG), reduced ambient glucose, and improved insulin sensitivity. The present study was conducted to explore translatability and the therapeutic potential of FAS inhibition for the treatment of diabetes in humans. Methods We tested PTM in animal models with different DNL tones, i.e. intrinsic synthesis rates, which vary among species and are regulated by nutritional and disease states, and confirmed glucose-lowering efficacy of PTM in lean NHPs with quantitation of liver lipid by MRS imaging. To understand the direct effect of PTM on liver metabolism, we performed ex vivo liver perfusion study to compare FAS inhibitor and carnitine palmitoyltransferase 1 (CPT1) inhibitor. Results The efficacy of PTM is generally reproduced in preclinical models with DNL tones comparable to humans, including lean and established diet-induced obese (eDIO) mice as well as non-human primates (NHPs). Similar effects of PTM on DNL reduction were observed in lean and type 2 diabetic rhesus and lean cynomolgus monkeys after acute and chronic treatment of PTM. Mechanistically, PTM lowers plasma glucose in part by enhancing hepatic glucose uptake and glycolysis. Teglicar, a CPT1 inhibitor, has similar effects on glucose uptake and glycolysis. In sharp contrast, Teglicar but not PTM significantly increased hepatic TG production, thus caused liver steatosis in eDIO mice. Conclusions These findings demonstrate unique properties of PTM and provide proof-of-concept of FAS inhibition having potential utility for the treatment of diabetes and related metabolic

  7. New histone deacetylase inhibitors improve cisplatin antitumor properties against thoracic cancer cells.

    PubMed

    Gueugnon, Fabien; Cartron, Pierre-François; Charrier, Cedric; Bertrand, Philippe; Fonteneau, Jean-François; Gregoire, Marc; Blanquart, Christophe

    2014-06-30

    Histone deacetylase inhibitors (HDACi) have shown promising antitumor effects on numerous cancer cells including malignant pleural mesothelioma (MPM) and lung adenocarcinoma (ADCA) cells. However, clinical trials using these compounds alone have shown limited efficacy against solid tumors. Therefore, new molecules are being developed and combinations with classical chemotherapeutic drugs are being tested. Here, we have evaluated on three MPM and three lung ADCA cell lines the antitumor potential of four new HDACi compounds, either alone or in combination with cisplatin. These effects were compared with those of vorinostat, an HDACi approved for cancer treatments. First, we characterized the HDAC mRNA expression profiles of tumor cells and showed an increase of the classI/classII HDAC ratio. We then treated cancer cells with these new HDACi and observed a cell-death induction and an increase of HDACi target genes and proteins expression. This was particularly evident for NODH compound (pan-HDACi) which had similar effects at nanomolar concentrations as micromolar concentrations of vorinostat. Interestingly, we observed that the HDACi/cisplatin combination strongly increased cell-death and limited resistance-phenotype emergence as compared with results obtained when the drugs were used alone. These results could be exploited to develop MPM and lung ADCA treatments combining chemotherapeutic approaches.

  8. Improving allogeneic islet transplantation by suppressing Th17 and enhancing Treg with histone deacetylase inhibitors.

    PubMed

    Sugimoto, Koji; Itoh, Takeshi; Takita, Morihito; Shimoda, Masayuki; Chujo, Daisuke; SoRelle, Jeff A; Naziruddin, Bashoo; Levy, Marlon F; Shimada, Mitsuo; Matsumoto, Shinichi

    2014-04-01

    Islet transplantation is a new treatment for achieving insulin independence for patients with severe diabetes. However, major drawbacks of this treatment are the long graft survival, the necessity for immunosuppressive drugs, and the efficacy of transplantation. Donor-specific transfusion (DST) has been shown to reduce rejection after organ transplantation, potentially through enhanced regulatory T-cell (Treg) activity. However, recent findings have shown that activated Treg can be converted into Th17 cells. We focused on histone deacetylase inhibitors (HDACi) because it was reported that inhibition of HDAC activity prevented Treg differentiation into IL17-producing cells. We therefore sought to enhance Treg while suppressing Th17 cells using DST with HDACi to prolong graft survival. To stimulate Treg by DST, we used donor splenocytes. In DST with HDACi group, Foxp3 mRNA expression and Treg population increased in the thymus and spleen, whereas Th17 population decreased. qPCR analysis of lymphocyte mRNA indicated that Foxp3, IL-10, and TGF-b expression increased. However, interleukin 17a, Stat3 (Th17), and IFN-g expression decreased in DST + HDACi group, relative to DST alone. Moreover, DST treated with HDACi prolonged graft survival relative to controls in mice islet transplantation. DST with HDACi may therefore have utility in islet transplantation.

  9. The Louisiana ACES Student-built BalloonSat Program

    NASA Astrophysics Data System (ADS)

    Ellison, B.; Giammanco, J.; Guzik, T. G.; Johnson, K.; Wefel, J. P.

    The Aerospace Catalyst Experiences for Students (ACES) pilot project was funded at Louisiana State University by NASA's National Space Grant College and Fellowship program during the 2002-2003 academic year with the primary goal of giving students a true hands-on experience with project management, life-cycle, experiment construction, data collection, analysis and interpretation. In this project students design, build, fly and analyze the data returned from small payloads (typical dimensions 10 cm x 10 cm x 10 cm, typical weight ˜ 500 grams) carried up to ˜ 100,000 feet by a helium-filled latex sounding balloon. During the pilot project the 13 students that participated in the program, grouped in 4 teams, built payloads that included studies in atmospheric science, cosmic rays and remote sensing. These payloads were then launched from the NASA National Scientific Balloon Facility in Palestine, Texas on May 21, 2003. Most recently, the LaACES (Louisiana ACES) program has been selected for funding by NASA. During LaACES we will expand the pilot program to institutions across the state including developing student training materials, holding a workshop for institution representatives, awarding payload development grants to student teams, monitoring the progress of these teams and supporting the balloon flight of the completed payloads. Here we describe the ACES pilot, the outcomes, and plans for La ACES.

  10. Discovery of a highly selective PLD2 inhibitor (ML395): a new probe with improved physiochemical properties and broad-spectrum antiviral activity against influenza strains.

    PubMed

    O'Reilly, Matthew C; Oguin, Thomas H; Scott, Sarah A; Thomas, Paul G; Locuson, Charles W; Morrison, Ryan D; Daniels, J Scott; Brown, H Alex; Lindsley, Craig W

    2014-12-01

    Further chemical optimization of the halopemide-derived family of dual phospholipase D1/2 (PLD1/2) inhibitors afforded ML395 (VU0468809), a potent, >80-fold PLD2 selective allosteric inhibitor (cellular PLD1, IC50 >30,000 nM; cellular PLD2, IC50 =360 nM). Moreover, ML395 possesses an attractive in vitro DMPK profile, improved physiochemical properties, ancillary pharmacology (Eurofins Panel) cleaner than any other reported PLD inhibitor, and has been found to possess interesting activity as an antiviral agent in cellular assays against a range of influenza strains (H1, H3, H5 and H7).

  11. Secondary prophylaxis with recombinant activated factor VII improves health-related quality of life of haemophilia patients with inhibitors.

    PubMed

    Hoots, W K; Ebbesen, L S; Konkle, B A; Auerswald, G K-H; Roberts, H R; Weatherall, J; Ferran, J-M; Ljung, R C R

    2008-05-01

    Haemophilia patients with inhibitors characteristically have impaired joint function and reduced health-related quality of life (HRQoL). This analysis examined whether secondary prophylaxis with recombinant activated factor VII (rFVIIa) improves HRQoL vs. conventional on-demand therapy in patients with haemophilia with inhibitors and frequent bleeds. After a 3-month preprophylaxis period, 22 patients received daily rFVIIa prophylaxis (90 or 270 microg kg(-1)) for 3 months, followed by 3 months' postprophylaxis. Days of hospitalization, absence from school/work and mobility aids requirements were recorded. HRQoL was assessed by EuroQoL (EQ-5D) questionnaire, visual analogue scale (VAS), derived Time to Trade-Off (TTO) scores and Quality Adjusted Life Years (QALYs). rFVIIa prophylaxis significantly (P < 0.0001) reduced bleeding frequency vs. prior on-demand therapy. Hospitalization (5.9% vs. 13.5%; P = 0.0026) and absenteeism from school/work (16.7% vs. 38.7%; P = 0.0127) decreased during prophylaxis; these effects tended to be maintained during postprophylaxis. HRQoL (evaluated by EQ-5D) tended to improve during and after rFVIIa prophylaxis. Notably, pain decreased and mobility increased in 40.9% and 27.3% of patients, respectively, at the end of the postprophylaxis period vs. preprophylaxis. Median VAS score increased from 66 to 73 (P = 0.048), and TTO scores suggested better HRQoL (0.62 vs. 0.76; P = 0.054) during postprophylaxis than preprophylaxis. Small to moderate changes in effect sizes were reported for VAS and TTO scores. Median QALYs were 0.68 (VAS) and 0.73 (TTO). Reductions in bleeding frequency with secondary rFVIIa prophylaxis were associated with improved HRQoL vs. on-demand therapy.

  12. Dipeptidyl peptidase 4 inhibitor improves brain insulin sensitivity, but fails to prevent cognitive impairment in orchiectomy obese rats.

    PubMed

    Pintana, Hiranya; Pongkan, Wanpitak; Pratchayasakul, Wasana; Chattipakorn, Nipon; Chattipakorn, Siriporn C

    2015-08-01

    It is unclear whether the dipeptidyl peptidase 4 (DPP4) inhibitor can counteract brain insulin resistance, brain mitochondrial dysfunction, impairment of hippocampal synaptic plasticity and cognitive decline in testosterone-deprived obese rats. We hypothesized that DPP4 inhibitor vildagliptin improves cognitive function in testosterone-deprived obese rats by restoring brain insulin sensitivity, brain mitochondrial function and hippocampal synaptic plasticity. Thirty male Wistar rats received either a sham-operated (S, n=6) or bilateral orchiectomy (ORX, n=24). ORX rats were divided into two groups and fed with either a normal diet (ND (NDO)) or a high-fat diet (HFO) for 12 weeks. Then, ORX rats in each dietary group were divided into two subgroups (n=6/subgroup) to receive either a vehicle or vildagliptin (3 mg/kg per day, p.o.) for 4 weeks. After treatment, cognitive function, metabolic parameters, brain insulin sensitivity, hippocampal synaptic plasticity and brain mitochondrial function were determined in each rat. We found that HFO rats exhibited peripheral and brain insulin resistance, brain mitochondrial dysfunction, impaired hippocampal synaptic plasticity and cognitive decline. NDO rats did not develop peripheral and brain insulin resistance. However, impaired hippocampal synaptic plasticity and cognitive decline occurred. Vildagliptin significantly improved peripheral insulin sensitivity, restored brain insulin sensitivity and decreased brain mitochondrial reactive oxygen species production in HFO rats. However, vildagliptin did not restore hippocampal synaptic plasticity and cognitive function in both NDO and HFO rats. These findings suggest that vildagliptin could not counteract the impairment of hippocampal synaptic plasticity and cognitive decline in testosterone-deprived subjects, despite its effects on improved peripheral and brain insulin sensitivity as well as brain mitochondrial function.

  13. Molecular and recombinational mapping of mutations in the Ace locus of Drosophila melanogaster

    SciTech Connect

    Nagoshi, R.N.; Gelbart, W.M.

    1987-11-01

    The Ace locus in Drosophila melanogaster is known to be the structural gene for acetylcholinesterase. Ace is located in a region of chromosome arm 3R which has been subjected to intensive genetic and molecular analysis. Previous deletion mapping studies have identified a 40-kb region with which the Ace gene resides. This report focuses on the further localization of Ace within this 40-kb interval. Within this region, selective fine structure recombinational analysis was employed to localize three recessive Ace lethals relative to unselected restriction site variations. These three mutations fall into a segment of 7 kb within the Ace interval. Fine structure recombinational analysis was also used to confirm that the Ace/sup -/ phenotype of one deletion, Df(3R)Ace/sup HD1/, co-segregated with the molecular deletion. This deletion does not fully remove Ace activity, but it behaves as a recessive Ace lethal. Df(3R)Ace/sup HD1/ is the most distal Ace lesion identified and indicates that the Ace locus must extend at least 16 kb. Several poly(A)transcripts are detectable in the region defined by the Ace lesions. The position and extent of the Ace locus, as well as the types of transcripts found, is consistent with the recent findings which identified Torpedo-AChE homologous cDNA sequences in this region.

  14. Molecular and Recombinational Mapping of Mutations in the Ace Locus of Drosophila melanogaster

    PubMed Central

    Nagoshi, Rodney N.; Gelbart, William M.

    1987-01-01

    The Ace locus in Drosophila melanogaster is known to be the structural gene for acetylcholinesterase. Ace is located in a region of chromosome arm 3R which has been subjected to intensive genetic and molecular analysis. Previous deletion mapping studies have identified a 40-kb region within which the Ace gene resides. This report focuses on the further localization of Ace within this 40-kb interval. Within this region, selective fine structure recombinational analysis was employed to localize three recessive Ace lethals relative to unselected restriction site variations. These three mutations fall into a segment of 7 kb within the Ace interval. Fine structure recombinational analysis was also used to confirm that the Ace- phenotype of one deletion, Df(3R)AceHD1, co-segregated with the molecular deletion. This deletion does not fully remove Ace activity, but it behaves as a recessive Ace lethal. Df(3R)AceHD1 is the most distal Ace lesion identified and indicates that the Ace locus must extend at least 16 kb. Several poly(A)transcripts are detectable in the region defined by the Ace lesions. The position and extent of the Ace locus, as well as the types of transcripts found, is consistent with the recent findings which identified Torpedo-AChE homologous cDNA sequences in this region. PMID:2826288

  15. The Proton Pump Inhibitor Lansoprazole Improves the Skeletal Phenotype in Dystrophin Deficient mdx Mice

    PubMed Central

    Sali, Arpana; Many, Gina M.; Gordish-Dressman, Heather; van der Meulen, Jack H.; Phadke, Aditi; Spurney, Christopher F.; Cnaan, Avital; Hoffman, Eric P.; Nagaraju, Kanneboyina

    2013-01-01

    Background In Duchenne muscular dystrophy (DMD), loss of the membrane stabilizing protein dystrophin results in myofiber damage. Microinjury to dystrophic myofibers also causes secondary imbalances in sarcolemmic ion permeability and resting membrane potential, which modifies excitation-contraction coupling and increases proinflammatory/apoptotic signaling cascades. Although glucocorticoids remain the standard of care for the treatment of DMD, there is a need to investigate the efficacy of other pharmacological agents targeting the involvement of imbalances in ion flux on dystrophic pathology. Methodology/Principal Findings We designed a preclinical trial to investigate the effects of lansoprazole (LANZO) administration, a proton pump inhibitor, on the dystrophic muscle phenotype in dystrophin deficient (mdx) mice. Eight to ten week-old female mice were assigned to one of four treatment groups (n = 12 per group): (1) vehicle control; (2) 5 mg/kg/day LANZO; (3) 5 mg/kg/day prednisolone; and (4) combined treatment of 5 mg/kg/day prednisolone (PRED) and 5 mg/kg/day LANZO. Treatment was administered orally 5 d/wk for 3 months. At the end of the study, behavioral (Digiscan) and functional outcomes (grip strength and Rotarod) were assessed prior to sacrifice. After sacrifice, body, tissue and organ masses, muscle histology, in vitro muscle force, and creatine kinase levels were measured. Mice in the combined treatment groups displayed significant reductions in the number of degenerating muscle fibers and number of inflammatory foci per muscle field relative to vehicle control. Additionally, mice in the combined treatment group displayed less of a decline in normalized forelimb and hindlimb grip strength and declines in in vitro EDL force after repeated eccentric contractions. Conclusions/Significance Together our findings suggest that combined treatment of LANZO and prednisolone attenuates some components of dystrophic pathology in mdx mice. Our findings warrant

  16. Acetylcholinesterase inhibitors as a starting point towards improved Alzheimer's disease therapeutics.

    PubMed

    Recanatini, Maurizio; Valenti, Piero

    2004-01-01

    The knowledge about the pathogenesis and the development of the neurodegeneration associated with Alzheimer's disease (AD) has been organised throughout the years into two theories, namely the cholinergic and the amyloid hypotheses. The loss of cholinergic neurotransmission and the abnormal aggregation and deposition of the amyloid-beta peptide (A beta) in the brain are retained as the central events by the two theories, respectively. These phenomena and their pathological consequences are the main targets of the drug discovery strategies based on each hypothesis. However, the two paradigms share some common aspects as shown by several experimental evidences, such that they might even fit into a unifying scenario of neuropathology and neurodegeneration. In this context, in a perspective of drug discovery, the enzyme acetylcholinesterase (AChE) holds a key position, as it is a main target for cholinomimetic AD drugs being responsible for the breakdown of the neurotransmitter, and it is also involved in the aggregation of A beta and the formation of the neurotoxic fibrils. Following this view, in recent years, a drug design strategy has emerged, directed to finding molecules able to inhibit both of these actions exerted by AChE. In this review, we will briefly introduce the biological basis of this strategy, and then will account for the early results obtained in this field in our and in other laboratories. The main focus will be on potential lead compounds for which some experimental evidence exists supporting the hypothesis of their dual action, as AChE inhibitors and blockers of the AChE-induced A beta aggregation.

  17. Improved intervention of atherosclerosis and cardiac hypertrophy through biodegradable polymer-encapsulated delivery of glycosphingolipid inhibitor

    PubMed Central

    Foss, C.A.; Pomper, M.G.; Bhattacharya, R.; Yarema, K.J.; Chatterjee, S.

    2015-01-01

    D-Threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP), a glycosphingolipid synthesis inhibitor, holds promise for the treatment of atherosclerosis and cardiac hypertrophy but rapid in vivo clearance has severely hindered translation to the clinic. To overcome this impediment, we used a materials-based delivery strategy wherein D-PDMP was encapsulated within a biodegradable polymer composed of poly ethylene glycol (PEG) and sebacic acid (SA). PEG-SA was formulated into nanoparticles that were doped with 125I-labeled PEG to allow in vivo bio-distribution and release kinetics of D-PDMP to be determined by using γ-scintigraphy and subsequently, by mass spectrometry. Polymer-encapsulation increased the residence time of D-PDMP in the body of a treated mouse from less than one hour to at least four hours (and up to 48 h or longer). This substantially increased in vivo longevity provided by polymer encapsulation resulted in an order of magnitude gain in efficacy for interfering with atherosclerosis and cardiac hypertrophy in apoE−/− mice fed a high fat and high cholesterol (HFHC) diet. These results establish that D-PDMP encapsulated in a biodegradable polymer provides a superior mode of delivery compared to unconjugated D-PDMP by way of increased gastrointestinal absorption and increased residence time thus providing this otherwise rapidly cleared compound with therapeutic relevance in interfering with atherosclerosis, cardiac hypertrophy, and probably other diseases associated with the deleterious effects of abnormally high glycosphingolipid biosynthesis or deficient catabolism. PMID:26111596

  18. Multi-targeted organometallic ruthenium(II)-arene anticancer complexes bearing inhibitors of poly(ADP-ribose) polymerase-1: A strategy to improve cytotoxicity.

    PubMed

    Wang, Zhigang; Qian, Hui; Yiu, Shek-Man; Sun, Jianwei; Zhu, Guangyu

    2014-02-01

    Small-molecule inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1) have currently drawn much attention as promising chemotherapeutic drug candidates, and there is a need to develop more potent PARP inhibitors with improved bioavailability. Here we report a strategy to improve the cytotoxicity of PARP inhibitors by conjugation with organometallic ruthenium(II)-arene compounds. We also report a systematic study to reveal the mechanism of action of these ruthenium-PARP inhibitor conjugates. The complexes have been synthesized and characterized spectroscopically. The improved antiproliferative activity from the as-prepared complexes in four human cancer cell lines has indicated their potential for further development as antitumor drugs. Cellular uptake study reveals that the most active complex 3 easily entered into cells. Target validation assays show that the complexes inhibited PARP-1 slightly better than the original PARP inhibitors, that complex 3 strongly bound to DNA and inhibited transcription, and that this complex arrested the cell cycle at the G0/G1 stage. This type of information could shed light on the design of the next generation of more active ruthenium-PARP inhibitor conjugates.

  19. Spiro[chromane-2,4'-piperidine]-based histone deacetylase inhibitors with improved in vivo activity.

    PubMed

    Thaler, Florian; Varasi, Mario; Carenzi, Giacomo; Colombo, Andrea; Abate, Agnese; Bigogno, Chiara; Boggio, Roberto; Carrara, Simone; Cataudella, Tiziana; Dal Zuffo, Roberto; Reali, Veronica; Vultaggio, Stefania; Dondio, Giulio; Gagliardi, Stefania; Minucci, Saverio; Mercurio, Ciro

    2012-04-01

    A series of spiro[chromane-2,4'-piperidine] derivatives based on a previously published lead benzyl spirocycle 1 and bearing various N-aryl and N-alkylaryl substituents on the piperidine ring were prepared as novel histone deacetylase (HDAC) inhibitors. The compounds were evaluated for their abilities to inhibit nuclear HDACs, their in vitro antiproliferative activities, and in vitro ADME profiles. Based on these activities, 4-fluorobenzyl and 2-phenylethyl spirocycles were selected for further characterization. In vivo pharmacokinetic (PK) studies showed that both compounds exhibit an overall lower clearance rate, an increased half-life, and higher AUCs after intravenous and oral administration than spiropiperidine 1 under the conditions used. The improved PK behavior of these two compounds also correlated with superior in vivo antitumor activity in an HCT-116 xenograft model.

  20. Do matrix metalloproteinase inhibitors improve the bond durability of universal dental adhesives?

    PubMed

    Tekçe, Neslihan; Tuncer, Safa; Demirci, Mustafa; Balci, Sibel

    2016-11-01

    The aim of this study was to evaluate the effects of matrix metalloproteinases (MMPs) inhibitors on the microtensile bond strength (μTBS) and the adhesive-dentin interface of two universal dentin bonding agents, Single Bond Universal and All Bond Universal, after 12 months of water storage. Seventy extracted, caries-free, human third molars were used in this study. Of these, 50 were used for μTBS testing and 20 were used for scanning electron microscopy. The two bonding agents were applied to flat dentin surfaces in five different ways: self-etch mode, etch-and-rinse mode with 37% phosphoric acid, etch-and-rinse mode with phosphoric acid containing 1% benzalkonium chloride, etch-and-rinse mode with phosphoric acid and 2% chlorhexidine, and etch-and-rinse mode with 0.5 M ethylenediaminetetraacetic acid (EDTA) (n = 5 for each bonding agent in each group; N = 50). Half the specimens were subjected to μTBS tests at 24 h, while half were subjected to the tests after 12 months of water storage. For each bonding agent, inhibition, storage, and their interaction effects were tested by two-way analysis of variance and Bonferroni tests. For Single Bond Universal, the benzalkonium chloride (p = 0.024) and chlorhexidine groups (p = 0.033) exhibited significantly higher μTBS values at 24 h compared with the self-etch group. For All Bond Universal, all groups displayed similar bond strengths at 24 h (p > 0.05). After 12 months of water storage, the μTBS values decreased significantly in the benzalkonium chloride group for Single Bond Universal (p = 0.001) and the self-etch (p = 0.029), chlorhexidine (p = 0.046), and EDTA (p = 0.032) groups for All Bond Universal. These results suggest that the immediate dentin bond strength increases when universal bonding systems are applied in the etch-and-rinse mode, although the durability decreases. The use of chlorhexidine and EDTA can increase the bond durability of mild adhesives such as

  1. HMG-CoA reductase inhibitor rosuvastatin improves abnormal brain electrical activity via mechanisms involving eNOS.

    PubMed

    Seker, F B; Kilic, U; Caglayan, B; Ethemoglu, M S; Caglayan, A B; Ekimci, N; Demirci, S; Dogan, A; Oztezcan, S; Sahin, F; Yilmaz, B; Kilic, E

    2015-01-22

    Apart from its repressing effect on plasma lipid levels, 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors exert neuroprotective functions in animal models of neurodegenerative disorders. In view of these promising observations, we were interested in whether HMG-CoA reductase inhibition would affect epileptiform activity in the brain. To elucidate this issue, atorvastatin, simvastatin and rosuvastatin were administered orally at a dose of 20 mg/kg each for 3 days and their anti-epileptic activities were tested and compared in rats. Epileptiform activity in the brain was induced by an intracortical penicillin G injection. Among HMG-CoA reductase inhibitors, simvastatin-treatment was less effective in terms of spike frequency as compared with atorvastatin- and rosuvastatin-treated animals. Atorvastatin treatment reduced spike frequencies and amplitudes significantly throughout the experiment. However, the most pronounced anti-epileptic effect was observed in rosuvastatin-treated animals, which was associated with improved blood-brain barrier (BBB) integrity, increased expression of endothelial nitric oxide synthase (eNOS) mRNA and decreased expressions of pro-apoptotic p53, Bax and caspase-3 mRNAs. Inhibition of eNOS activity with L-NG-Nitroarginine Methyl Ester (L-NAME) reversed the anti-epileptic effect of rosuvastatin significantly. However, L-NAME did not alter the effect of rosuvastatin on the levels of p53, Bax and caspase-3 mRNA expression. Here, we provide evidence that among HMG-CoA reductase inhibitors, rosuvastatin was the most effective statin on the reduction of epileptiform activity, which was associated with improved BBB permeability, increased expression of eNOS and decreased expressions of pro-apoptotic p53, Bax and caspase-3. Our observation also revealed that the anti-epileptic effect of rosuvastatin was dependent on the increased expression level of eNOS. The robust anti-epileptic effect encourages proof-of-concept studies with

  2. Simultaneously improving xylose fermentation and tolerance to lignocellulosic inhibitors through evolutionary engineering of recombinant Saccharomyces cerevisiae harbouring xylose isomerase

    PubMed Central

    2014-01-01

    Background Yeasts tolerant to toxic inhibitors from steam-pretreated lignocellulose with xylose co-fermentation capability represent an appealing approach for 2nd generation ethanol production. Whereas rational engineering, mutagenesis and evolutionary engineering are established techniques for either improved xylose utilisation or enhancing yeast tolerance, this report focuses on the simultaneous enhancement of these attributes through mutagenesis and evolutionary engineering of Saccharomyces cerevisiae harbouring xylose isomerase in anoxic chemostat culture using non-detoxified pretreatment liquor from triticale straw. Results Following ethyl methanesulfonate (EMS) mutagenesis, Saccharomyces cerevisiae strain D5A+ (ATCC 200062 strain platform), harbouring the xylose isomerase (XI) gene for pentose co-fermentation was grown in anoxic chemostat culture for 100 generations at a dilution rate of 0.10 h-1 in a medium consisting of 60% (v/v) non-detoxified hydrolysate liquor from steam-pretreated triticale straw, supplemented with 20 g/L xylose as carbon source. In semi-aerobic batch cultures in the same medium, the isolated strain D5A+H exhibited a slightly lower maximum specific growth rate (μmax = 0.12 ± 0.01 h-1) than strain TMB3400, with no ethanol production observed by the latter strain. Strain D5A+H also exhibited a shorter lag phase (4 h vs. 30 h) and complete removal of HMF, furfural and acetic acid from the fermentation broth within 24 h, reaching an ethanol concentration of 1.54 g/L at a yield (Yp/s) of 0.06 g/g xylose and a specific productivity of 2.08 g/gh. Evolutionary engineering profoundly affected the yeast metabolism, given that parental strain D5A+ exhibited an oxidative metabolism on xylose prior to strain development. Conclusions Physiological adaptations confirm improvements in the resistance to and conversion of inhibitors from pretreatment liquor with simultaneous enhancement of xylose to ethanol fermentation. These data

  3. ACE2, angiotensin-(1-7) and Mas receptor axis in inflammation and fibrosis

    PubMed Central

    Simões e Silva, AC; Silveira, KD; Ferreira, AJ; Teixeira, MM

    2013-01-01

    Recent advances have improved our understanding of the renin-angiotensin system (RAS). These have included the recognition that angiotensin (Ang)-(1-7) is a biologically active product of the RAS cascade. The identification of the ACE homologue ACE2, which forms Ang-(1-7) from Ang II, and the GPCR Mas as an Ang-(1-7) receptor have provided the necessary biochemical and molecular background and tools to study the biological significance of Ang-(1-7). Most available evidence supports a counter-regulatory role for Ang-(1-7) by opposing many actions of Ang II on AT1 receptors, especially vasoconstriction and proliferation. Many studies have now shown that Ang-(1-7) by acting via Mas receptor exerts inhibitory effects on inflammation and on vascular and cellular growth mechanisms. Ang-(1-7) has also been shown to reduce key signalling pathways and molecules thought to be relevant for fibrogenesis. Here, we review recent findings related to the function of the ACE2/Ang-(1-7)/Mas axis and focus on the role of this axis in modifying processes associated with acute and chronic inflammation, including leukocyte influx, fibrogenesis and proliferation of certain cell types. More attention will be given to the involvement of the ACE2/Ang-(1-7)/Mas axis in the context of renal disease because of the known relevance of the RAS for the function of this organ and for the regulation of kidney inflammation and fibrosis. Taken together, this knowledge may help in paving the way for the development of novel treatments for chronic inflammatory and renal diseases. PMID:23488800

  4. North Atlantic Aerosol Properties and Direct Radiative Effects: Key Results from TARFOX and ACE-2

    NASA Technical Reports Server (NTRS)

    Russell, P. B.; Livingston, J. M.; Schmid, B.; Bergstrom, R. A.; Hignett, P.; Hobbs, P. V.; Durkee, P. A.; Condon, Estelle (Technical Monitor)

    1998-01-01

    Aerosol effects on atmospheric radiative fluxes provide a forcing function that can change the climate in potentially significant ways. This aerosol radiative Forcing is a major source of uncertainty in understanding the observed climate change of the past century and in predicting, future climate. To help reduce this uncertainty, the International Global Atmospheric Chemistry Project (IGAC) has endorsed a series of multiplatform aerosol field campaigns. The Tropospheric Aerosol Radiative Forcing Observational Experiment (TARFOX) and the second Aerosol Characterization Experiment (ACE-2) were the first IGAC campaigns to address the impact of anthropogenic aerosols. Both TARFOX and ACE-2 gathered extensive data sets on aerosol properties and radiative effects. TARFOX focused on the urban-industrial haze plume flowing from the eastern United States over the western Atlantic Ocean, whereas ACE-2 studied aerosols carried over the eastern Atlantic from both European urban/industrial and African mineral sources. These aerosols often have a marked influence on the top-of-atmosphere radiances measured by satellites, as illustrated in Figure 1. Shown there are contours of aerosol optical depth derived from radiances measured by the AVHRR sensor on the NOAA-11 satellite. The contours readily show that aerosols originating in North America, Europe, and Africa impact the radiative properties of air over the North Atlantic. However, the accurate derivation of flux chances, or radiative forcing, from the satellite-measured radiances or 'etrieved optical depths remains a difficult challenge. In this paper we summarize key Initial results from TARFOX and, to a lesser extent ACE-2, with a focus on those results that allow an improved assessment of the flux changes caused by North Atlantic aerosols at middle and high latitudes.

  5. North Atlantic Aerosol Properties and Direct Radiative Effects: Key Results from TARFOX and ACE-2

    NASA Technical Reports Server (NTRS)

    Russell, P. B.; Livingston, J. M.; Schmid, B.; Bergstrom, Robert A.; Hignett, P.; Hobbs, P. V.; Durkee, P. A.

    2000-01-01

    Aerosol effects on atmospheric radiative fluxes provide a forcing function that can change the climate In potentially significant ways. This aerosol radiative forcing is a major source of uncertainty in understanding the observed climate change of the past century and in predicting future climate. To help reduce this uncertainty, the International Global Atmospheric Chemistry Project (IGAC) has endorsed a series of multiplatform aerosol field campaigns. The Tropospheric Aerosol Radiative Forcing Observational Experiment (TARFOX) and the second Aerosol Characterization Experiment (ACE-2) were the first IGAC campaigns to address the impact of anthropogenic aerosols, Both TARFOX and ACE-2 gathered extensive data sets on aerosol properties and radiative effects, TARFOX focused on the urban-industrial haze plume flowing from the eastern United States over the western Atlantic Ocean, whereas ACE-2 studied aerosols carried over the eastern Atlantic from both European urban/industrial and African mineral sources. These aerosols often have a marked influence on the top-of-atmosphere radiances measured by satellites. Shown there are contours of aerosol optical depth derived from radiances measured by the AVHRR sensor on the NOAA-11 satellite. The contours readily show that aerosols originating in North America, Europe, and Africa impact the radiative properties of air over the North Atlantic. However, the accurate derivation of flux changes, or radiative forcing, from the satellite measured radiances or retrieved optical depths remains a difficult challenge. In this paper we summarize key initial results from TARFOX and, to a lesser extent, ACE-2, with a focus on those results that allow an improved assessment of the flux changes caused by North Atlantic aerosols at middle latitudes.

  6. Histone deacetylase inhibitor significantly improved the cloning efficiency of porcine somatic cell nuclear transfer embryos.

    PubMed

    Huang, Yongye; Tang, Xiaochun; Xie, Wanhua; Zhou, Yan; Li, Dong; Yao, Chaogang; Zhou, Yang; Zhu, Jianguo; Lai, Liangxue; Ouyang, Hongsheng; Pang, Daxin

    2011-12-01

    Valproic acid (VPA), a histone deacetylase inbibitor, has been shown to generate inducible pluripotent stem (iPS) cells from mouse and human fibroblasts with a significant higher efficiency. Because successful cloning by somatic cell nuclear transfer (SCNT) undergoes a full reprogramming process in which the epigenetic state of a differentiated donor nuclear is converted into an embryonic totipotent state, we speculated that VPA would be useful in promoting cloning efficiency. Therefore, in the present study, we examined whether VPA can promote the developmental competence of SCNT embryos by improving the reprogramming state of donor nucleus. Here we report that 1 mM VPA for 14 to 16 h following activation significantly increased the rate of blastocyst formation of porcine SCNT embryos constructed from Landrace fetal fibroblast cells compared to the control (31.8 vs. 11.4%). However, we found that the acetylation level of Histone H3 lysine 14 and Histone H4 lysine 5 and expression level of Oct4, Sox2, and Klf4 was not significantly changed between VPA-treated and -untreated groups at the blastocyst stage. The SCNT embryos were transferred to 38 surrogates, and the cloning efficiency in the treated group was significantly improved compared with the control group. Taken together, we have demonstrated that VPA can improve both in vitro and in vivo development competence of porcine SCNT embryos.

  7. Improving DNA double-strand repair inhibitor KU55933 therapeutic index in cancer radiotherapy using nanoparticle drug delivery.

    PubMed

    Tian, Xi; Lara, Haydee; Wagner, Kyle T; Saripalli, Srinivas; Hyder, Syed Nabeel; Foote, Michael; Sethi, Manish; Wang, Edina; Caster, Joseph M; Zhang, Longzhen; Wang, Andrew Z

    2015-12-21

    Radiotherapy is a key component of cancer treatment. Because of its importance, there has been high interest in developing agents and strategies to further improve the therapeutic index of radiotherapy. DNA double-strand repair inhibitors (DSBRIs) are among the most promising agents to improve radiotherapy. However, their clinical translation has been limited by their potential toxicity to normal tissue. Recent advances in nanomedicine offer an opportunity to overcome this limitation. In this study, we aim to demonstrate the proof of principle by developing and evaluating nanoparticle (NP) formulations of KU55933, a DSBRI. We engineered a NP formulation of KU55933 using nanoprecipitation method with different lipid polymer nanoparticle formulation. NP KU55933 using PLGA formulation has the best loading efficacy as well as prolonged drug release profile. We demonstrated that NP KU55933 is a potent radiosensitizer in vitro using clonogenic assay and is more effective as a radiosensitizer than free KU55933 in vivo using mouse xenograft models of non-small cell lung cancer (NSCLC). Western blots and immunofluorescence showed NP KU55933 exhibited more prolonged inhibition of DNA repair pathway. In addition, NP KU55933 leads to lower skin toxicity than KU55933. Our study supports further investigations using NP to deliver DSBRIs to improve cancer radiotherapy treatment.

  8. Improving DNA double-strand repair inhibitor KU55933 therapeutic index in cancer radiotherapy using nanoparticle drug delivery

    NASA Astrophysics Data System (ADS)

    Tian, Xi; Lara, Haydee; Wagner, Kyle T.; Saripalli, Srinivas; Hyder, Syed Nabeel; Foote, Michael; Sethi, Manish; Wang, Edina; Caster, Joseph M.; Zhang, Longzhen; Wang, Andrew Z.

    2015-11-01

    Radiotherapy is a key component of cancer treatment. Because of its importance, there has been high interest in developing agents and strategies to further improve the therapeutic index of radiotherapy. DNA double-strand repair inhibitors (DSBRIs) are among the most promising agents to improve radiotherapy. However, their clinical translation has been limited by their potential toxicity to normal tissue. Recent advances in nanomedicine offer an opportunity to overcome this limitation. In this study, we aim to demonstrate the proof of principle by developing and evaluating nanoparticle (NP) formulations of KU55933, a DSBRI. We engineered a NP formulation of KU55933 using nanoprecipitation method with different lipid polymer nanoparticle formulation. NP KU55933 using PLGA formulation has the best loading efficacy as well as prolonged drug release profile. We demonstrated that NP KU55933 is a potent radiosensitizer in vitro using clonogenic assay and is more effective as a radiosensitizer than free KU55933 in vivo using mouse xenograft models of non-small cell lung cancer (NSCLC). Western blots and immunofluorescence showed NP KU55933 exhibited more prolonged inhibition of DNA repair pathway. In addition, NP KU55933 leads to lower skin toxicity than KU55933. Our study supports further investigations using NP to deliver DSBRIs to improve cancer radiotherapy treatment.

  9. Heat shock protein 90 (HSP90) inhibitors activate the heat shock factor 1 (HSF1) stress response pathway and improve glucose regulation in diabetic mice.

    PubMed

    Lee, Jee-Hyung; Gao, Jiaping; Kosinski, Penelope A; Elliman, Stephen J; Hughes, Thomas E; Gromada, Jesper; Kemp, Daniel M

    2013-01-18

    The cytoprotective stress response factor HSF1 regulates the transcription of the chaperone HSP70, which exhibits anti-inflammatory effects and improves insulin sensitivity. We tested the therapeutic potential of this pathway in rodent models of diabetes using pharmacological tools. Activation of the HSF1 pathway was achieved using potent inhibitors of the upstream regulatory protein, HSP90. Treatment with AUY922, a selective HSP90 inhibitor led to robust inhibition of JNK1 phosphorylation, cytoprotection and improved insulin signaling in cells, consistent with effects observed with HSP70 treatment. Chronic dosing with HSP90 inhibitors reversed hyperglycemia in the diabetic db/db mouse model, and improved insulin sensitivity in the diet-induced obese mouse model of insulin resistance, further supporting the concept that the HSF1 pathway is a potentially viable anti-diabetes target.

  10. Investigating the selectivity of metalloenzyme inhibitors.

    PubMed

    Day, Joshua A; Cohen, Seth M

    2013-10-24

    The inhibitory activity of a broad group of known metalloenzyme inhibitors against a panel of metalloenzymes was evaluated. Clinically approved inhibitors were selected as well as several other reported metalloprotein inhibitors in order to represent a broad range of metal binding groups (MBGs), including hydroxamic acid, carboxylate, hydroxypyridinonate, thiol, and N-hydroxyurea functional groups. A panel of metalloenzymes, including carbonic anhydrase (hCAII), several matrix metalloproteinases (MMPs), angiotensin converting enzyme (ACE), histone deacetylase (HDAC-2), and tyrosinase (TY), was selected based on their clinical importance for a range of pathologies. In addition, each inhibitor was evaluated for its ability to remove Fe(3+) from holo-transferrin to gauge the ability of the inhibitors to access Fe(3+) from a primary transport protein. The results show that the metalloenzyme inhibitors are quite selective for their intended targets, suggesting that despite their ability to bind metal ions, metalloprotein inhibitors are not prone to widespread off-target enzyme inhibition activity.

  11. Phosphodiesterase Type 4 Inhibitor Rolipram Improves Survival of Spiral Ganglion Neurons In Vitro

    PubMed Central

    Kranz, Katharina; Warnecke, Athanasia; Lenarz, Thomas; Durisin, Martin; Scheper, Verena

    2014-01-01

    Sensorineural deafness is caused by damage of hair cells followed by degeneration of the spiral ganglion neurons and can be moderated by cochlear implants. However, the benefit of the cochlear implant depends on the excitability of the spiral ganglion neurons. Therefore, current research focuses on the identification of agents that will preserve their degeneration. In this project we investigated the neuroprotective effect of Rolipram as a promising agent to improve the viability of the auditory neurons. It is a pharmaceutical agent that acts by selective inhibition of the phosphodiesterase 4 leading to an increase in cyclic AMP. Different studies reported a neuroprotective effect of Rolipram. However, its significance for the survival of SGN has not been reported so far. Thus, we isolated spiral ganglion cells of neonatal rats for cultivation with different Rolipram concentrations and determined the neuronal survival rate. Furthermore, we examined immunocytologically distinct proteins that might be involved in the neuroprotective signalling pathway of Rolipram and determined endogenous BDNF by ELISA. When applied at a concentration of 0.1 nM, Rolipram improved the survival of SGN in vitro. According to previous studies, our immunocytological data showed that Rolipram application induces the phosphorylation and thereby activation of the transcription factor CREB. This activation can be mediated by the cAMP-PKA-signalling pathway as well as via ERK as a part of the MAP-kinase pathway. However, only in cultures pre-treated with BDNF, an endogenous increase of BDNF was detected. We conclude that Rolipram has the potential to improve the vitality of neonatal auditory nerve cells in vitro. Further investigations are necessary to prove the effect of Rolipram in vivo in the adult organism after lesion of the hair cells and insertion of cochlear implants. PMID:24642701

  12. Structural optimization of diphenylpyrimidine derivatives (DPPYs) as potent Bruton's tyrosine kinase (BTK) inhibitors with improved activity toward B leukemia cell lines.

    PubMed

    Zhao, Dan; Huang, Shanshan; Qu, Menghua; Wang, Changyuan; Liu, Zhihao; Li, Zhen; Peng, Jinyong; Liu, Kexin; Li, Yanxia; Ma, Xiaodong; Shu, Xiaohong

    2017-01-27

    A new series of diphenylpyrimidine derivatives (DPPYs) bearing various aniline side chains at the C-2 position of pyrimidine core were synthesized as potent BTK inhibitors. Most of these inhibitors displayed improved activity against B leukemia cell lines compared with lead compound spebrutinib. Subsequent studies showed that the peculiar inhibitor 7j, with IC50 values of 10.5 μM against Ramos cells and 19.1 μM against Raji cells, also displayed slightly higher inhibitory ability than the novel agent ibrutinib. Moreover, compound 7j is not sensitive to normal cells PBMC, indicating low cell cytotoxicity. In addition, flow cytometry analysis indicated that 7j significantly induced the apoptosis of Ramos cells, and arrested the cell cycle at the G0/G1 phase. These explorations provided new clues to discover pyrimidine scaffold as more effective BTK inhibitors.

  13. Outcomes of preoperative angiotensin-converting enzyme inhibitor therapy in patients undergoing isolated coronary artery bypass grafting.

    PubMed

    Bandeali, Salman J; Kayani, Waleed T; Lee, Vei-Vei; Pan, Wei; Elayda, Mac Arthur A; Nambi, Vijay; Jneid, Hani M; Alam, Mahboob; Wilson, James M; Birnbaum, Yochai; Ballantyne, Christie M; Virani, Salim S

    2012-10-01

    The association between preoperative use of angiotensin-converting enzyme (ACE) inhibitors and outcomes after coronary artery bypass grafting (CABG) remain controversial. Our aim was to study in-hospital outcomes after isolated CABG in patients on preoperative ACE inhibitors. A retrospective analysis of 8,889 patients who underwent isolated CABG from 2000 through 2011 was conducted. The primary outcome of interest was the incidence of major adverse events (MAEs) defined as a composite of mortality, postoperative renal dysfunction, myocardial infarction, stroke, and atrial fibrillation during index hospitalization. The secondary outcome was the incidence of individual outcomes included in MAEs. Logistic regression analyses were performed. Of 8,889 patients, 3,983 (45%) were on preoperative ACE inhibitors and 4,906 (55%) were not. Overall incidence of MAEs was 38.1% (n = 1,518) in the ACE inhibitor group compared to 33.6% (n = 1,649) in the no-ACE inhibitor group. Preoperative use of ACE inhibitors was independently associated with MAEs (odds ratio 1.13, 95% confidence interval 1.03 to 1.24), most of which was driven by a statistically significant increase in postoperative renal dysfunction (odds ratio 1.18, 95% confidence interval 1.03 to 1.36) and atrial fibrillation (odds ratio 1.15, 95% confidence interval 1.05 to 1.27). In-hospital mortality, postoperative myocardial infarction, and stroke were not significantly associated with preoperative ACE inhibitor use. Analyses performed after excluding patients with low ejection fractions yielded similar results. In conclusion, preoperative ACE inhibitor use was associated with an increased risk of MAEs after CABG, in particular postoperative renal dysfunction and atrial fibrillation.

  14. Contemplating Synergistic Algorithms for the NASA ACE Mission

    NASA Technical Reports Server (NTRS)

    Mace, Gerald G.; Starr, David O.; Marchand, Roger; Ackerman, Steven A.; Platnick, Steven E.; Fridlind, Ann; Cooper, Steven; Vane, Deborah G.; Stephens, Graeme L.

    2013-01-01

    ACE is a proposed Tier 2 NASA Decadal Survey mission that will focus on clouds, aerosols, and precipitation as well as ocean ecosystems. The primary objective of the clouds component of this mission is to advance our ability to predict changes to the Earth's hydrological cycle and energy balance in response to climate forcings by generating observational constraints on future science questions, especially those associated with the effects of aerosol on clouds and precipitation. ACE will continue and extend the measurement heritage that began with the A-Train and that will continue through Earthcare. ACE planning efforts have identified several data streams that can contribute significantly to characterizing the properties of clouds and precipitation and the physical processes that force these properties. These include dual frequency Doppler radar, high spectral resolution lidar, polarimetric visible imagers, passive microwave and submillimeter wave radiometry. While all these data streams are technologically feasible, their total cost is substantial and likely prohibitive. It is, therefore, necessary to critically evaluate their contributions to the ACE science goals. We have begun developing algorithms to explore this trade space. Specifically, we will describe our early exploratory algorithms that take as input the set of potential ACE-like data streams and evaluate critically to what extent each data stream influences the error in a specific cloud quantity retrieval.

  15. The absence of intrarenal ACE protects against hypertension

    PubMed Central

    Gonzalez-Villalobos, Romer A.; Janjoulia, Tea; Fletcher, Nicholas K.; Giani, Jorge F.; Nguyen, Mien T.X.; Riquier-Brison, Anne D.; Seth, Dale M.; Fuchs, Sebastien; Eladari, Dominique; Picard, Nicolas; Bachmann, Sebastian; Delpire, Eric; Peti-Peterdi, Janos; Navar, L. Gabriel; Bernstein, Kenneth E.; McDonough, Alicia A.

    2013-01-01

    Activation of the intrarenal renin-angiotensin system (RAS) can elicit hypertension independently from the systemic RAS. However, the precise mechanisms by which intrarenal Ang II increases blood pressure have never been identified. To this end, we studied the responses of mice specifically lacking kidney angiotensin-converting enzyme (ACE) to experimental hypertension. Here, we show that the absence of kidney ACE substantially blunts the hypertension induced by Ang II infusion (a model of high serum Ang II) or by nitric oxide synthesis inhibition (a model of low serum Ang II). Moreover, the renal responses to high serum Ang II observed in wild-type mice, including intrarenal Ang II accumulation, sodium and water retention, and activation of ion transporters in the loop of Henle (NKCC2) and distal nephron (NCC, ENaC, and pendrin) as well as the transporter activating kinases SPAK and OSR1, were effectively prevented in mice that lack kidney ACE. These findings demonstrate that ACE metabolism plays a fundamental role in the responses of the kidney to hypertensive stimuli. In particular, renal ACE activity is required to increase local Ang II, to stimulate sodium transport in loop of Henle and the distal nephron, and to induce hypertension. PMID:23619363

  16. The absence of intrarenal ACE protects against hypertension.

    PubMed

    Gonzalez-Villalobos, Romer A; Janjoulia, Tea; Fletcher, Nicholas K; Giani, Jorge F; Nguyen, Mien T X; Riquier-Brison, Anne D; Seth, Dale M; Fuchs, Sebastien; Eladari, Dominique; Picard, Nicolas; Bachmann, Sebastian; Delpire, Eric; Peti-Peterdi, Janos; Navar, L Gabriel; Bernstein, Kenneth E; McDonough, Alicia A

    2013-05-01

    Activation of the intrarenal renin-angiotensin system (RAS) can elicit hypertension independently from the systemic RAS. However, the precise mechanisms by which intrarenal Ang II increases blood pressure have never been identified. To this end, we studied the responses of mice specifically lacking kidney angiotensin-converting enzyme (ACE) to experimental hypertension. Here, we show that the absence of kidney ACE substantially blunts the hypertension induced by Ang II infusion (a model of high serum Ang II) or by nitric oxide synthesis inhibition (a model of low serum Ang II). Moreover, the renal responses to high serum Ang II observed in wild-type mice, including intrarenal Ang II accumulation, sodium and water retention, and activation of ion transporters in the loop of Henle (NKCC2) and distal nephron (NCC, ENaC, and pendrin) as well as the transporter activating kinases SPAK and OSR1, were effectively prevented in mice that lack kidney ACE. These findings demonstrate that ACE metabolism plays a fundamental role in the responses of the kidney to hypertensive stimuli. In particular, renal ACE activity is required to increase local Ang II, to stimulate sodium transport in loop of Henle and the distal nephron, and to induce hypertension.

  17. Multiple duplications of the rare ace-1 mutation F290V in Culex pipiens natural populations.

    PubMed

    Alout, Haoués; Labbé, Pierrick; Berthomieu, Arnaud; Pasteur, Nicole; Weill, Mylène

    2009-12-01

    Two amino acid substitutions in acetylcholinesterase 1 (AChE1), G119S and F290V, are responsible for resistance to organophosphate and carbamate insecticides in Culex pipiens mosquitoes. These mutations generate very different levels of insensitivity to insecticide inhibitors. We described here a biochemical method that rapidly identifies AChE1 variants (susceptible, G119S and F290V, named S, R and V, respectively) present in individual mosquitoes. We investigated the frequency of AChE1 phenotypes in 41 field samples collected around the Mediterranean Sea. F290V substitution was found only in 15 samples and at low frequency, whereas G119S was highly spread in all samples. However, seven V distinct alleles were identified whereas only one R allele was present. The [V] enzymatic phenotype was never observed alone, and the V allele was always found associated with the susceptible and/or G119S AChE1 ([VS], [VR] or [VRS] phenotypes). Furthermore, we showed the presence of duplicated alleles, associating a susceptible and a V copy of the ace-1 gene, in most individuals analyzed for its presence. Evolutionary forces driving the large number of F290V ace-1 alleles and their low frequency in Mediterranean countries are discussed.

  18. Anti-infective Activity of 2-Cyano-3-Acrylamide Inhibitors with Improved Drug-Like Properties against Two Intracellular Pathogens

    PubMed Central

    Passalacqua, Karla D.; Charbonneau, Marie-Eve; Donato, Nicholas J.; Showalter, Hollis D.; Sun, Duxin; Wen, Bo; He, Miao; Sun, Hanshi

    2016-01-01

    Due to the rise of antibiotic resistance and the small number of effective antiviral drugs, new approaches for treating infectious diseases are urgently needed. Identifying targets for host-based therapies represents an emerging strategy for drug discovery. The ubiquitin-proteasome system is a central mode of signaling in the eukaryotic cell and may be a promising target for therapies that bolster the host's ability to control infection. Deubiquitinase (DUB) enzymes are key regulators of the host inflammatory response, and we previously demonstrated that a selective DUB inhibitor and its derivative promote anti-infective activities in host cells. To find compounds with anti-infective efficacy but improved toxicity profiles, we tested a library of predominantly 2-cyano-3-acrylamide small-molecule DUB inhibitors for anti-infective activity in macrophages against two intracellular pathogens: murine norovirus (MNV) and Listeria monocytogenes. We identified compound C6, which inhibited DUB activity in human and murine cells and reduced intracellular replication of both pathogens with minimal toxicity in cell culture. Treatment with C6 did not significantly affect the ability of macrophages to internalize virus, suggesting that the anti-infective activity interferes with postentry stages of the MNV life cycle. Metabolic stability and pharmacokinetic assays showed that C6 has a half-life in mouse liver microsomes of ∼20 min and has a half-life of approximately 4 h in mice when administered intravenously. Our results provide a framework for targeting the host ubiquitin system in the development of host-based therapies for infectious disease. Compound C6 represents a promising tool with which to elucidate the role of DUBs in the macrophage response to infection. PMID:27139470

  19. Perioperative management of patients treated with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers: a quality improvement audit.

    PubMed

    Vijay, A; Grover, A; Coulson, T G; Myles, P S

    2016-05-01

    Previous studies have shown that patients continuing angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers on the day of surgery are more likely to have significant intraoperative hypotension, higher rates of postoperative acute kidney injury, and lower incidences of postoperative atrial fibrillation. However, many of these studies were prone to bias and confounding, and questions remain over the validity of these outcomes. This observational, before-and-after quality improvement audit aimed to assess the effect of withholding these medications on the morning of surgery. We recruited 323 participants, with 83 (26%) having their preoperative angiotensin-converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker (ARB) withheld on the day of surgery. There were only very small Spearman rank-order correlations between time since last dose of these medications (rho -0.12, P=0.057) and intraoperative and recovery room intravenous fluid administration (rho -0.11, P=0.042). There was no statistically significant difference between the continued or withheld groups in vasopressor (metaraminol use 3.5 [1.5-8.3] mg versus 3.5 [1.5-8.5] mg, P=0.67) or intravenous fluid administration (1000 ml [800-1500] ml versus 1000 [800-1500] ml, P=0.096), nor rates of postoperative acute kidney injury (13% vs 18%, P=0.25) or atrial fibrillation (15% versus 18%, P=0.71). This audit found no significant differences in measured outcomes between the continued or withheld ACEi/ARB groups. This finding should be interpreted with caution due to the possibility of confounding and an insufficient sample size. However, as the finding is in contrast to many previous studies, future prospective randomised clinical trials are required to answer this important question.

  20. Sarilumab improves patient-reported outcomes in rheumatoid arthritis patients with inadequate response/intolerance to tumour necrosis factor inhibitors

    PubMed Central

    Strand, Vibeke; Reaney, Matthew; Chen, Chieh-I; Proudfoot, Clare W J; Guillonneau, Sophie; Bauer, Deborah; Mangan, Erin; Graham, Neil M H; van Hoogstraten, Hubert; Lin, Yong; Pacheco-Tena, César; Fleischmann, Roy

    2017-01-01

    Objective To evaluate effects of the anti-interleukin-6 receptor monoclonal antibody sarilumab administered with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) on patient-reported outcomes (PROs) in the TARGET trial in patients with rheumatoid arthritis (RA) with inadequate response or intolerance to tumour necrosis factor inhibitors (TNF-IR). Methods 546 patients (81.9% female, mean age 52.9 years) were randomised to placebo, sarilumab 150 or 200 mg subcutaneously every 2 weeks + csDMARDs. PROs included patient global assessment (PtGA); pain and morning stiffness visual analogue scales; Health Assessment Questionnaire Disability Index (HAQ-DI); Short Form-36 Health Survey (SF-36); FACIT-Fatigue (FACIT-F); Work Productivity Survey-Rheumatoid Arthritis (WPS-RA) and Rheumatoid Arthritis Impact of Disease (RAID). Changes from baseline at weeks 12 and 24 were analysed using a mixed model for repeated measures; post hoc analyses included percentages of patients reporting improvements ≥ minimum clinically important differences (MCID) and scores ≥ normative values. Results Sarilumab + csDMARDs doses resulted in improvements from baseline at week 12 vs placebo + csDMARDs in PtGA, pain, HAQ-DI, SF-36 and FACIT-F that were maintained at week 24. Sarilumab improved morning stiffness and reduced the impact of RA on work, family, social/leisure activities participation (WPS-RA) and on patients' lives (RAID). Percentages of patients reporting improvements ≥MCID and ≥ normative scores were greater with sarilumab than placebo. Conclusions In patients with TNF-IR RA, 150 and 200 mg sarilumab + csDMARDs resulted in clinically meaningful patient-reported benefits on pain, fatigue, function, participation and health status at 12 and 24 weeks that exceeded placebo + csDMARDs, and were consistent with the clinical profile previously reported. Trial registration number NCT01709578; Results. PMID:28326189

  1. Advanced Colloids Experiment (ACE) Science Overview

    NASA Technical Reports Server (NTRS)

    Meyer, William V.; Sicker, Ronald J.; Chiaramonte, Francis P.; Luna, Unique J.; Chaiken, Paul M.; Hollingsworth, Andrew; Secanna, Stefano; Weitz, David; Lu, Peter; Yodh, Arjun; Yunker, Peter; Lohr, Matthew; Gratale, Matthew; Lynch, Matthew; Kodger, Thomas; Piazza, Roberto; Buzzaccaro, Stefano; Cipelletti, Luca; Schall, Peter; Veen, Sandra; Wegdam, Gerhard; Lee, Chand-Soo; Choi, Chang-Hyung; Paul, Anna-Lisa; Ferl, Robert J.; Cohen, Jacob

    2013-01-01

    accessible with the availability of the Light Microscopy Module (LMM) on ISS. To meet these goals, the ACE experiment is being built-up in stages, with the availability of confocal microscopy being the ultimate objective. Supported by NASAs Physical Sciences Research Program, ESAESTEC, and the authors respective governments.

  2. A Triazolopyrimidine-Based Dihydroorotate Dehydrogenase Inhibitor with Improved Drug-like Properties for Treatment and Prevention of Malaria.

    PubMed

    Phillips, Margaret A; White, Karen L; Kokkonda, Sreekanth; Deng, Xiaoyi; White, John; El Mazouni, Farah; Marsh, Kennan; Tomchick, Diana R; Manjalanagara, Krishne; Rudra, Kakali Rani; Wirjanata, Grennady; Noviyanti, Rintis; Price, Ric N; Marfurt, Jutta; Shackleford, David M; Chiu, Francis C K; Campbell, Michael; Jimenez-Diaz, Maria Belen; Bazaga, Santiago Ferrer; Angulo-Barturen, Iñigo; Martinez, Maria Santos; Lafuente-Monasterio, Maria; Kaminsky, Werner; Silue, Kigbafori; Zeeman, Anne-Marie; Kocken, Clemens; Leroy, Didier; Blasco, Benjamin; Rossignol, Emilie; Rueckle, Thomas; Matthews, Dave; Burrows, Jeremy N; Waterson, David; Palmer, Michael J; Rathod, Pradipsinh K; Charman, Susan A

    2016-12-09

    The emergence of drug-resistant malaria parasites continues to hamper efforts to control this lethal disease. Dihydroorotate dehydrogenase has recently been validated as a new target for the treatment of malaria, and a selective inhibitor (DSM265) of the Plasmodium enzyme is currently in clinical development. With the goal of identifying a backup compound to DSM265, we explored replacement of the SF5-aniline moiety of DSM265 with a series of CF3-pyridinyls while maintaining the core triazolopyrimidine scaffold. This effort led to the identification of DSM421, which has improved solubility, lower intrinsic clearance, and increased plasma exposure after oral dosing compared to DSM265, while maintaining a long predicted human half-life. Its improved physical and chemical properties will allow it to be formulated more readily than DSM265. DSM421 showed excellent efficacy in the SCID mouse model of P. falciparum malaria that supports the prediction of a low human dose (<200 mg). Importantly DSM421 showed equal activity against both P. falciparum and P. vivax field isolates, while DSM265 was more active on P. falciparum. DSM421 has the potential to be developed as a single-dose cure or once-weekly chemopreventative for both P. falciparum and P. vivax malaria, leading to its advancement as a preclinical development candidate.

  3. Novel inhibitors of neurotropic alphavirus replication that improve host survival in a mouse model of acute viral encephalitis.

    PubMed

    Sindac, Janice A; Yestrepsky, Bryan D; Barraza, Scott J; Bolduc, Kyle L; Blakely, Pennelope K; Keep, Richard F; Irani, David N; Miller, David J; Larsen, Scott D

    2012-04-12

    Arboviral encephalitis is a potentially devastating human disease with no approved therapies that target virus replication. We previously discovered a novel class of thieno[3,2-b]pyrrole-based inhibitors active against neurotropic alphaviruses such as western equine encephalitis virus (WEEV) in cultured cells. In this report, we describe initial development of these novel antiviral compounds, including bioisosteric replacement of the 4H-thieno[3,2-b]pyrrole core with indole to improve metabolic stability and the introduction of chirality to assess target enantioselectivity. Selected modifications enhanced antiviral activity while maintaining low cytotoxicity, increased stability to microsomal metabolism, and also revealed striking enantiospecific activity in cultured cells. Furthermore, we demonstrate improved outcomes (both symptoms and survival) following treatment with indole analogue 9h (CCG-203926) in an in vivo mouse model of alphaviral encephalitis that closely correlate with the enantiospecific in vitro antiviral activity. These results represent a substantial advancement in the early preclinical development of a promising class of novel antiviral drugs against virulent neurotropic alphaviruses.

  4. Inhibitors of angiotensin-converting enzyme modulate mitosis and gene expression in pancreatic cancer cells

    SciTech Connect

    Reddy, M.K.; Baskaran, K.; Molteni, A.

    1995-12-01

    The angiotensin-converting enzyme (ACE) inhibitor captopril inhibits mitosis in several cell types that contain ACE and renin activity. In the present study, we evaluated the effect of the ACE inhibitors captopril and CGS 13945 (10{sup {minus}8} to 10{sup {minus}2}M) on proliferation and gene expression in hamster pancreatic duct carcinoma cells in culture. These cells lack renin and ACE activity. Both ACE inhibitors produced a dose-dependent reduction in tumor cell proliferation within 24 hr. Captopril at a concentration of 0.36 mM and CGS 13945 at 150 {mu}M decreased cellular growth rate to approximately half that of the control. Neither drug influenced the viability or the cell cycle distribution of the tumor cells. Slot blot analysis of mRNA for four genes, proliferation associated cell nuclear antigen (PCNA), K-ras, protein kinase C-{Beta} (PKC-{Beta}) and carbonic anhydrase II (CA II) was performed. Both ACE inhibitors increased K-ras expression by a factor of 2, and had no effect on CA II mRNA levels. Captopril also lowered PCNA by 40% and CGS 13945 lowered PKC-{Beta} gene expression to 30% of the control level. The data demonstrate that ACE inhibitors exhibit antimitotic activity and differential gene modulation in hamster pancreatic duct carcinoma cells. The absence of renin and ACE activity in these cells suggests that the antimitotic action of captopril and CGS 13945 is independent of renin-angiotensin regulation. The growth inhibition may occur through downregulation of growth-related gene expression. 27 refs., 5 figs.

  5. Bioactive peptides: are there more antihypertensive mechanisms beyond ACE inhibition?

    PubMed

    Marques, Claudia; Amorim, Maria Manuela; Pereira, Joana Odila; Pintado, Manuela Estevez; Moura, Daniel; Calhau, Conceicao; Pinheiro, Helder

    2012-01-01

    Diet has a high relevance in health. Hypertension is a major risk factor for cardiovascular diseases and has an important impact on public health, and consequently on countries economy. Scientific research gathered strong evidence about the role of several dietary factors either in etiology or in treatment/prevention of these diseases. Peptides from different food matrices have been studied, and indicated as compounds with particular interest in the context of hypertension. The classical approach involves the identification of peptides with an in vitro ACE inhibitory activity and the assumption that the observed in vivo effects are due to this enzyme blockade. However, in some cases the potency of ACE blockade does not correlate with the antihypertensive activity in vivo. This paper reviews the current literature that identifies mechanisms of action, other than ACE inhibition, that might explain antihypertensive effects of biologically active peptides from different food sources.

  6. Improved Potency of Indole-Based NorA Efflux Pump Inhibitors: From Serendipity toward Rational Design and Development.

    PubMed

    Buonerba, Federica; Lepri, Susan; Goracci, Laura; Schindler, Bryan D; Seo, Susan M; Kaatz, Glenn W; Cruciani, Gabriele

    2017-01-12

    The NorA efflux pump is a potential drug target for reversal of resistance to selected antibacterial agents, and recently we described indole-based inhibitor candidates. Herein we report a second class of inhibitors derived from them but with significant differences in shape and size. In particular, compounds 13 and 14 are very potent inhibitors in that they demonstrated the lowest IC50 values (2 μM) ever observed among all indole-based compounds we have evaluated.

  7. North Atlantic Aerosol Properties for Radiative Impact Assessments. Derived from Column Closure Analyses in TARFOX and ACE-2

    NASA Technical Reports Server (NTRS)

    Russell, Philip A.; Bergstrom, Robert A.; Schmid, Beat; Livingston, John M.

    2000-01-01

    Aerosol effects on atmospheric radiative fluxes provide a forcing function that can change the climate in potentially significant ways. This aerosol radiative forcing is a major source of uncertainty in understanding the climate change of the past century and predicting future climate. To help reduce this uncertainty, the 1996 Tropospheric Aerosol Radiative Forcing Observational Experiment (TARFOX) and the 1997 Aerosol Characterization Experiment (ACE-2) measured the properties and radiative effects of aerosols over the Atlantic Ocean. Both experiments used remote and in situ measurements from aircraft and the surface, coordinated with overpasses by a variety of satellite radiometers. TARFOX focused on the urban-industrial haze plume flowing from the United States over the western Atlantic, whereas ACE-2 studied aerosols over the eastern Atlantic from both Europe and Africa. These aerosols often have a marked impact on satellite-measured radiances. However, accurate derivation of flux changes, or radiative forcing, from the satellite measured radiances or retrieved aerosol optical depths (AODs) remains a difficult challenge. Here we summarize key initial results from TARFOX and ACE-2, with a focus on closure analyses that yield aerosol microphysical models for use in improved assessments of flux changes. We show how one such model gives computed radiative flux sensitivities (dF/dAOD) that agree with values measured in TARFOX and preliminary values computed for the polluted marine boundary layer in ACE-2. A companion paper uses the model to compute aerosol-induced flux changes over the North Atlantic from AVHRR-derived AOD fields.

  8. Improved adipose tissue function with initiation of protease inhibitor-only ART

    PubMed Central

    Maughan, Robert T.; Feeney, Eoin R.; Capel, Emilie; Capeau, Jacqueline; Domingo, Pere; Giralt, Marta; Lange, Joep M. A.; Phanuphak, Praphan; Cooper, David A.; Reiss, Peter; Mallon, Patrick W. G.

    2016-01-01

    Objectives Use of ART containing HIV PIs has previously been associated with toxicity in subcutaneous adipose tissue (SAT), potentially contributing to the development of lipodystrophy and insulin resistance. However, the effect of PIs on SAT function in ART-naive patients independent of other ART classes is unknown. This study aimed to elucidate the effect of initiating PI-only ART on SAT function in ART-naive subjects. Methods In the HIVNAT-019 study, 48 HIV-infected, ART-naive Thai adults commencing PI-only ART comprising lopinavir/ritonavir/saquinavir for 24 weeks underwent assessments of fasting metabolic parameters and body composition. In a molecular substudy, 20 subjects underwent SAT biopsies at weeks 0, 2 and 24 for transcriptional, protein, mitochondrial DNA (mtDNA) and histological analyses. ClinicalTrials.gov registration number: NCT00400738. Results Over 24 weeks, limb fat increased (+416.4 g, P = 0.023), coinciding with larger adipocytes as indicated by decreased adipocyte density in biopsies (−32.3 cells/mm2, P = 0.047) and increased mRNA expression of adipogenesis regulator PPARG at week 2 (+58.1%, P = 0.003). Increases in mtDNA over 24 weeks (+600 copies/cell, P = 0.041), decreased NRF1 mRNA expression at week 2 (−33.7%, P < 0.001) and increased COX2/COX4 protein ratio at week 24 (+288%, P = 0.038) indicated improved mitochondrial function. Despite decreased AKT2 mRNA at week 2 (−28.6%, P = 0.002) and increased PTPN1 mRNA at week 24 (+50.3%, P = 0.016) suggesting insulin resistance, clinical insulin sensitivity [by homeostasis model assessment (HOMA-IR)] was unchanged. Conclusions Initiation of PI-only ART showed little evidence of SAT toxicity, the changes observed being consistent with a return to health rather than contributing to lipodystrophy. PMID:27516476

  9. Vascular Wall ACE is not required for Atherogenesis in ApoE-/- mice

    PubMed Central

    Weiss, Daiana; Bernstein, Kenneth E.; Fuchs, Sebastian; Adams, Jonathan; Synetos, Andreas; Taylor, W. Robert

    2009-01-01

    Background It has been proposed that elements of the renin angiotensin system expressed in the arterial wall are critical for the development of atherosclerosis. Angiotensin converting enzyme (ACE) is highly expressed by the endothelium and is responsible for a critical enzymatic step in the generation of angiotensin II. However, the functional contribution of ACE expression in the vascular wall in atherogenesis is unknown. Therefore, we made use of unique genetic models in which mice without expression of ACE in the vascular wall were crossed with apoE-/- mice in order to determine the contribution of tissue ACE expression to atherosclerotic lesion formation. Methods and Results Mice expressing either a soluble form of ACE (ACE 2/2) or mice with somatic ACE expression restricted to the liver and kidney (ACE 3/3) on an ApoE-/- background were placed on a standard chow or Western diet for 6 months. Atherosclerotic lesion area in the ACE 2/2 mice was significantly lower than that seen in the ACE 3/3 mice. However, these animals also had significantly lower blood pressure and reduced plasma ACE activity which precluded establishing a specific causal relationship between absent tissue ACE activity and decreased atherosclerotic lesion extent. Therefore, we studied the ACE 3/3 mice which are normotensive and lack vascular ACE expression. In the ACE 3/3 animals, atherosclerotic lesion area was no different from wild type controls despite reduced plasma ACE activity. Conclusions We concluded that under these experimental conditions, expression of ACE in the arterial wall is not required for atherosclerotic lesion formation. PMID:19880118

  10. Antiviral Activity of Bictegravir (GS-9883), a Novel Potent HIV-1 Integrase Strand Transfer Inhibitor with an Improved Resistance Profile

    PubMed Central

    Tsiang, Manuel; Jones, Gregg S.; Goldsmith, Joshua; Mulato, Andrew; Hansen, Derek; Kan, Elaine; Tsai, Luong; Bam, Rujuta A.; Stepan, George; Stray, Kirsten M.; Niedziela-Majka, Anita; Yant, Stephen R.; Yu, Helen; Kukolj, George; Cihlar, Tomas; Lazerwith, Scott E.; Jin, Haolun

    2016-01-01

    Bictegravir (BIC; GS-9883), a novel, potent, once-daily, unboosted inhibitor of HIV-1 integrase (IN), specifically targets IN strand transfer activity (50% inhibitory concentration [IC50] of 7.5 ± 0.3 nM) and HIV-1 integration in cells. BIC exhibits potent and selective in vitro antiretroviral activity in both T-cell lines and primary human T lymphocytes, with 50% effective concentrations ranging from 1.5 to 2.4 nM and selectivity indices up to 8,700 relative to cytotoxicity. BIC exhibits synergistic in vitro antiviral effects in pairwise combinations with tenofovir alafenamide, emtricitabine, or darunavir and maintains potent antiviral activity against HIV-1 variants resistant to other classes of antiretrovirals. BIC displayed an in vitro resistance profile that was markedly improved compared to the integrase strand transfer inhibitors (INSTIs) raltegravir (RAL) and elvitegravir (EVG), and comparable to that of dolutegravir (DTG), against nine INSTI-resistant site-directed HIV-1 mutants. BIC displayed statistically improved antiviral activity relative to EVG, RAL, and DTG against a panel of 47 patient-derived HIV-1 isolates with high-level INSTI resistance; 13 of 47 tested isolates exhibited >2-fold lower resistance to BIC than DTG. In dose-escalation experiments conducted in vitro, BIC and DTG exhibited higher barriers to resistance than EVG, selecting for HIV-1 variants with reduced phenotypic susceptibility at days 71, 87, and 20, respectively. A recombinant virus with the BIC-selected M50I/R263K dual mutations in IN exhibited only 2.8-fold reduced susceptibility to BIC compared to wild-type virus. All BIC-selected variants exhibited low to intermediate levels of cross-resistance to RAL, DTG, and EVG (<8-fold) but remained susceptible to other classes of antiretrovirals. A high barrier to in vitro resistance emergence for both BIC and DTG was also observed in viral breakthrough studies in the presence of constant clinically relevant drug concentrations. The

  11. Advanced Crew Escape Suits (ACES): Particle Impact Test

    NASA Technical Reports Server (NTRS)

    Rosales, Keisa R.; Stoltzfus, Joel M.

    2009-01-01

    NASA Johnson Space Center (JSC) requested NASA JSC White Sands Test Facility to assist in determining the effects of impaired anodization on aluminum parts in advanced crew escape suits (ACES). Initial investigation indicated poor anodization could lead to an increased risk of particle impact ignition, and a lack of data was prevalent for particle impact of bare (unanodized) aluminum; therefore, particle impact tests were performed. A total of 179 subsonic and 60 supersonic tests were performed with no ignition of the aluminum targets. Based on the resulting test data, WSTF found no increased particle impact hazard was present in the ACES equipment.

  12. Defective intestinal amino acid absorption in Ace2 null mice.

    PubMed

    Singer, Dustin; Camargo, Simone M R; Ramadan, Tamara; Schäfer, Matthias; Mariotta, Luca; Herzog, Brigitte; Huggel, Katja; Wolfer, David; Werner, Sabine; Penninger, Josef M; Verrey, François

    2012-09-15

    Mutations in the main intestinal and kidney luminal neutral amino acid transporter B(0)AT1 (Slc6a19) lead to Hartnup disorder, a condition that is characterized by neutral aminoaciduria and in some cases pellagra-like symptoms. These latter symptoms caused by low-niacin are thought to result from defective intestinal absorption of its precursor L-tryptophan. Since Ace2 is necessary for intestinal B(0)AT1 expression, we tested the impact of intestinal B(0)AT1 absence in ace2 null mice. Their weight gain following weaning was decreased, and Na(+)-dependent uptake of B(0)AT1 substrates measured in everted intestinal rings was defective. Additionally, high-affinity Na(+)-dependent transport of L-proline, presumably via SIT1 (Slc6a20), was absent, whereas glucose uptake via SGLT1 (Slc5a1) was not affected. Measurements of small intestine luminal amino acid content following gavage showed that more L-tryptophan than other B(0)AT1 substrates reach the ileum in wild-type mice, which is in line with its known lower apparent affinity. In ace2 null mice, the absorption defect was confirmed by a severalfold increase of L-tryptophan and of other neutral amino acids reaching the ileum lumen. Furthermore, plasma and muscle levels of glycine and L-tryptophan were significantly decreased in ace2 null mice, with other neutral amino acids displaying a similar trend. A low-protein/low-niacin diet challenge led to differential changes in plasma amino acid levels in both wild-type and ace2 null mice, but only in ace2 null mice to a stop in weight gain. Despite the combination of low-niacin with a low-protein diet, plasma niacin concentrations remained normal in ace2 null mice and no pellagra symptoms, such as photosensitive skin rash or ataxia, were observed. In summary, mice lacking Ace2-dependent intestinal amino acid transport display no total niacin deficiency nor clear pellagra symptoms, even under a low-protein and low-niacin diet, despite gross amino acid homeostasis alterations.

  13. ACE-Asia: Ground Stations Overview

    NASA Astrophysics Data System (ADS)

    Arimoto, R.; Sugimoto, N.; Shimizu, A.; Kim, J.; Oh, S.; Kang, C.; Asia Science Team; Murayama, T.; Delta Group; Zhang, X.; Kim, Y.; VMAP Group

    2001-12-01

    Observations of aerosol properties made at a network of ground stations were an integral part of ACE-Asia. During an intensive observation period (IOP, March - May 2001), high dust loadings were observed at many stations. At Zhenbeitai, China mass loadings well above average (260 μ g m-3) were observed during eleven dust storms, and ˜82% of the total particle mass at the site could be attributed to Asian dust. Daily bulk dust concentrations at Kosan, Korea ranged from 130 to 350 μ g m-3 from April 10 - 13. Important sub-micron dust signatures were obtained during this storm, coincident with highly absorbing ultra-fine (< 0.24 μ m) soot and other anthropogenic materials. PM2.5 aerosol concentrations at Kosan varied from 15.7 to 92.6 μ g m-3 during the IOP. Comparisons with prior data show some evidence for a decrease in the relative amount of nitrate vs. sulfate. An Asian dust storm with peak PM10 concentrations of about 200 μ g m-3 was observed over Taiwan on April 12 - 13. While most of the PM10 was dust, significant levels (up to about 30%) of pollutants also were found. Analysis of this and previous events indicates that the concentrations of pollutants over Taiwan during Asian dust storms are controlled more by long-range transport than local sources. Measurements of aerosols and associated species on four Japanese islands showed clear intermittent transport of continental aerosols, especially at Rishiri. A Mie and Raman lidar system with auxiliary instruments, including a sun photometer, operated at Tokyo during the IOP; some of these data were used for C-130 flight planning. From combined Raman lidar observations of dust at Tokyo, a typical extinction-to-backscatter ratio was found to be ˜40 sr, ranging from 30 and 70 sr and tending to increase with Angstrom exponent. A lidar intercomparison with C-130 flight observations on April 23 showed widely distributed dust and non-dust aerosols up to 8 km. A multi-channel backscatter lidar system operating at

  14. Angiotensin-converting enzyme (ACE and ACE2) imbalance correlates with the severity of cerulein-induced acute pancreatitis in mice.

    PubMed

    Liu, Ruixia; Qi, Haiyu; Wang, Jing; Wang, Yan; Cui, Lijian; Wen, Yan; Yin, Chenghong

    2014-04-01

    Angiotensin-converting enzyme (ACE) and its effector peptide angiotensin II (Ang II) have been implicated in the pathogenesis of pancreatitis. Angiotensin-converting enzyme 2 (ACE2) degrades Ang II to angiotensin-(1-7) [Ang-(1-7)] and has recently been described to have an antagonistic effect on ACE signalling. However, the specific underlying role of ACE2 in the pathogenesis of severe acute pancreatitis (SAP) is unclear. In the present study, the local imbalance of ACE and ACE2, as well as Ang II and Ang-(1-7) expression, was compared in wild-type (WT) and ACE2 knock-out (KO) or ACE2 transgenic (TG) mice subjected to cerulein-induced SAP. Serum amylase, tumour necrosis factor-α, interleukin (IL)-1β, IL-6 and IL-10 levels and histological morphometry were used to determine the severity of pancreatitis. In WT mice, pancreatic ACE and Ang II and serum Ang II expression increased (P < 0.05), while pancreatic ACE2 and Ang-(1-7) and serum Ang-(1-7) levels were also significantly elevated (P < 0.05) from 2 to 72 h after the onset of SAP. However, the ratio of pancreatic ACE2 to ACE expression was significantly reduced (from 1.46 ± 0.09 to 0.27 ± 0.05, P < 0.001) and paralleled the severity of pancreatitis. The Ace2 KO mice exhibited increased levels of tumour necrosis factor-α, IL-1β, IL-6, multifocal coagulative necrosis and inflammatory infiltrate, and lower levels of serum IL-10 and pancreatic Ang-(1-7) (4.70 ± 2.13 versus 10.87 ± 2.51, P < 0.001) compared with cerulein-treated WT mice at the same time point. Conversely, Ace2 TG mice with normal ACE expression were more resistant to SAP challenge as evidenced by a decreased inflammatory response, attenuated pathological changes and increased survival rates. These data suggest that the ACE2-ACE imbalance plays an important role in the pathogenesis of SAP and that pancreatic ACE2 is an important factor in determining the severity of SAP.

  15. 77 FR 48527 - National Customs Automation Program (NCAP) Test Concerning Automated Commercial Environment (ACE...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-08-14

    ... Automated Commercial Environment (ACE) Simplified Entry: Modification of Participant Selection Criteria and... (NCAP) test concerning the simplified entry functionality in the Automated Commercial Environment (ACE...) National Customs Automation Program (NCAP) test concerning Automated Commercial Environment...

  16. Jumping the nuclear envelop barrier: Improving polyplex-mediated gene transfection efficiency by a selective CDK1 inhibitor RO-3306.

    PubMed

    Zhou, Xuefei; Liu, Xiangrui; Zhao, Bingxiang; Liu, Xin; Zhu, Dingcheng; Qiu, Nasha; Zhou, Quan; Piao, Ying; Zhou, Zhuxian; Tang, Jianbin; Shen, Youqing

    2016-07-28

    Successful transfection of plasmid DNA (pDNA) requires intranuclear internalization of pDNA effectively and the nuclear envelope appears to be one of the critical intracellular barriers for polymer mediated pDNA delivery. Polyethylenimine (PEI), as the classic cationic polymer, compact the negatively charged pDNA tightly and make up stable polyplexes. The polyplexes are too large to enter the nuclear through nuclear pores and it is believed that the nuclear envelope breakdown in mitosis could facilitate the nuclear entry of polyplexes. To jump the nuclear envelope barrier, we used a selective and reversible CDK1 inhibitor RO-3306 to control the G2/M transition of the cell cycle and increased the proportion of mitotic cells which have disappeared nuclear envelope during transfection. Herein, we show that RO-3306 remarkably increases the transfection efficiency of PEI polyplexes through enhanced nuclear localization of PEI and pDNA. However, RO-3306 is less effective to the charge-reversal polymer poly[(2-acryloyl)ethyl(p-boronic acid benzyl)diethylammonium bromide] (B-PDEAEA) which responses to cellular stimuli and releases free pDNA in cytoplasm. Our findings not only offer new opportunities for improving non-viral based gene delivery but also provide theoretical support for the rational design of novel functional polymers for gene delivery. We also report current data showing that RO-3306 synergizes TRAIL gene induced apoptosis in cancer cells.

  17. Improvement of the Pharmacokinetics and In Vivo Antibacterial Efficacy of a Novel Type IIa Topoisomerase Inhibitor by Formulation in Liposomes

    PubMed Central

    Newman, Joseph; Goteti, Kosalaram; Beaudoin, Marie-Eve; Harrison, Rane; Hopkins, Sussie; Agrawal, Nikunj; Rivin, Olga

    2013-01-01

    Several useful properties of liposome-based formulations of various existing antibacterial drugs have been reported. These properties include lower MICs, improved pharmacokinetics, lower toxicity, selective distribution to infected tissues, and enhanced in vivo efficacy. Here we report in vivo studies of a liposomal formulation of a member of a novel class of antibacterial type II topoisomerase inhibitors, others of which have progressed to early phases of clinical trials. The free (i.e., nonliposomal) compound has broad-spectrum MICs but suboptimal pharmacokinetics in rats and mice, characterized by a high volume of distribution and rapid clearance. The liposomal formulation of the compound had essentially unchanged MICs but greatly reduced volume of distribution and clearance in rats and mice. In an in vivo mouse model of Staphylococcus aureus infection of one thigh, the liposomal compound localized preferentially to the infected thigh, whereas the free compound showed no preference for the infected versus the uninfected thigh. Most importantly, the liposomal compound had enhanced efficacy at clearing the infection compared with the free compound. Delivery of this class of compounds as liposomal formulations may offer clinical advantages compared with free compounds. PMID:23877679

  18. Polydopamine-Encapsulated Fe3O4 with an Adsorbed HSP70 Inhibitor for Improved Photothermal Inactivation of Bacteria.

    PubMed

    Liu, Dongdong; Ma, Liyi; Liu, Lidong; Wang, Lu; Liu, Yuxin; Jia, Qi; Guo, Quanwei; Zhang, Ge; Zhou, Jing

    2016-09-21

    Photothermal treatment, a new approach for inactivation of bacteria and pathogens that does not depend on traditional therapeutic approaches, has recently received much attention. In this study, a new type of nanoplatform (PDA@Fe3O4 + PES) was fabricated by using polydopamine (PDA, a photothermal conversion agent) to encapsulate Fe3O4 (a magnetic nanoparticle) and support 2-phenylethynesulfonamide (PES, an inhibitor of heat shock protein 70 (HSP70)). Upon near-infrared light irradiation, the increased temperature weakens π-π and hydrogen bonding interactions, and PES is released from the PDA@Fe3O4 + PES. The released PES inhibits the function of HSP70, reducing bacterial tolerance to photothermal therapy and improving the therapeutic effect against infectious bacterial pathogens. After treatment, PDA@Fe3O4 + PES can be recovered using the magnetic property of the Fe3O4 cores. Consequently, PDA@Fe3O4 + PES possesses the potential to be a recyclable photothermal agent for enhanced photothermal bacterial inactivation without causing secondary pollution.

  19. Ethacrynic acid improves the antitumor effects of irreversible epidermal growth factor receptor tyrosine kinase inhibitors in breast cancer

    PubMed Central

    Hu, YunLong; Chen, TingTing; Peng, BoYa; Gao, NingNing; Jin, ZhenChao; Jia, TieLiu; Zhang, Na; Wang, ZhuLin; Jin, GuangYi

    2016-01-01

    Prolonged treatment of breast cancer with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) often results in acquired resistance and a narrow therapeutic index. One strategy to improve the therapeutic effects of EGFR TKIs is to combine them with drugs used for other clinical indications. Ethacrynic acid (EA) is an FDA approved drug that may have antitumor effects and may enhance the cytotoxicity of chemotherapeutic agents by binding to glutathione and inhibiting WNT signaling. While the α,β-unsaturated-keto structure of EA is similar to that of irreversible TKIs, the mechanism of action of EA when combined with irreversible EGFR TKIs in breast cancer remains unknown. We therefore investigated the combination of irreversible EGFR TKIs and EA. We found that irreversible EGFR TKIs and EA synergistically inhibit breast cancer both in vitro and in vivo. The combination of EGFR TKIs and EA induces necrosis and cell cycle arrest and represses WNT/β-catenin signaling as well as MAPK-ERK1/2 signaling. We conclude that EA synergistically enhances the antitumor effects of irreversible EGFR TKIs in breast cancer. PMID:27487128

  20. Ethacrynic acid improves the antitumor effects of irreversible epidermal growth factor receptor tyrosine kinase inhibitors in breast cancer.

    PubMed

    Liu, Bing; Huang, XinPing; Hu, YunLong; Chen, TingTing; Peng, BoYa; Gao, NingNing; Jin, ZhenChao; Jia, TieLiu; Zhang, Na; Wang, ZhuLin; Jin, GuangYi

    2016-09-06

    Prolonged treatment of breast cancer with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) often results in acquired resistance and a narrow therapeutic index. One strategy to improve the therapeutic effects of EGFR TKIs is to combine them with drugs used for other clinical indications. Ethacrynic acid (EA) is an FDA approved drug that may have antitumor effects and may enhance the cytotoxicity of chemotherapeutic agents by binding to glutathione and inhibiting WNT signaling. While the α,β-unsaturated-keto structure of EA is similar to that of irreversible TKIs, the mechanism of action of EA when combined with irreversible EGFR TKIs in breast cancer remains unknown. We therefore investigated the combination of irreversible EGFR TKIs and EA. We found that irreversible EGFR TKIs and EA synergistically inhibit breast cancer both in vitro and in vivo. The combination of EGFR TKIs and EA induces necrosis and cell cycle arrest and represses WNT/β-catenin signaling as well as MAPK-ERK1/2 signaling. We conclude that EA synergistically enhances the antitumor effects of irreversible EGFR TKIs in breast cancer.

  1. Improvement of the pharmacokinetics and in vivo antibacterial efficacy of a novel type IIa topoisomerase inhibitor by formulation in liposomes.

    PubMed

    Shapiro, Adam B; Newman, Joseph; Goteti, Kosalaram; Beaudoin, Marie-Eve; Harrison, Rane; Hopkins, Sussie; Agrawal, Nikunj; Rivin, Olga

    2013-10-01

    Several useful properties of liposome-based formulations of various existing antibacterial drugs have been reported. These properties include lower MICs, improved pharmacokinetics, lower toxicity, selective distribution to infected tissues, and enhanced in vivo efficacy. Here we report in vivo studies of a liposomal formulation of a member of a novel class of antibacterial type II topoisomerase inhibitors, others of which have progressed to early phases of clinical trials. The free (i.e., nonliposomal) compound has broad-spectrum MICs but suboptimal pharmacokinetics in rats and mice, characterized by a high volume of distribution and rapid clearance. The liposomal formulation of the compound had essentially unchanged MICs but greatly reduced volume of distribution and clearance in rats and mice. In an in vivo mouse model of Staphylococcus aureus infection of one thigh, the liposomal compound localized preferentially to the infected thigh, whereas the free compound showed no preference for the infected versus the uninfected thigh. Most importantly, the liposomal compound had enhanced efficacy at clearing the infection compared with the free compound. Delivery of this class of compounds as liposomal formulations may offer clinical advantages compared with free compounds.

  2. Novel Improved Synthesis of HSP70 Inhibitor, Pifithrin-μ. In Vitro Synergy Quantification of Pifithrin-μ Combined with Pt Drugs in Prostate and Colorectal Cancer Cells.

    PubMed

    McKeon, Aoife M; Egan, Alan; Chandanshive, Jay; McMahon, Helena; Griffith, Darren M

    2016-07-21

    We describe a novel improved approach to the synthesis of the important and well-known heat shock protein 70 inhibitor (HSP70), pifithrin-μ, with corresponding and previously unreported characterisation. The first example of a combination study comprising HSP70 inhibitor pifithrin-μ and cisplatin or oxaliplatin is reported. We have determined, using the Chou-Talalay method, (i) moderate synergistic and synergistic effects in co-treating PC-3 prostate cancer cells with pifithrin-μ and cisplatin and (ii) significant synergistic effects including strong synergism in cotreating HT29 colorectal cancer cells with oxaliplatin and pifithrin-μ.

  3. 76 FR 69755 - National Customs Automation Program Test Concerning Automated Commercial Environment (ACE...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-09

    ... Commercial Environment (ACE) Simplified Entry AGENCY: U.S. Customs and Border Protection, Department of... Commercial Environment (ACE) entry capability. This new capability will include functionality specific to the... was on trade compliance and the development of the Automated Commercial Environment (ACE), the...

  4. ACE TECH: The Fourth Year of CTE and Academic Integration

    ERIC Educational Resources Information Center

    Knight, Eileen Quinn; Donahue, John; Knight, Patrick

    2008-01-01

    It only takes an hour or two of roaming the halls of Architecture, Construction and Engineering (ACE) Tech Charter High School to detect an enduring attitude of accomplishment from both the teachers and the students. This atmosphere is intentional. The school, located in Chicago, was created specifically to hone the skills of individuals choosing…

  5. Hyperspectral Detection and Discrimination Using the ACE Algorithm

    DTIC Science & Technology

    2011-08-08

    08-2011 Proceedings AUG 2011 - SEPT 2011 Hyperspectral Detection and Discrimination Using the ACE Algorithm FA8720-05-C-0002 M. L. Pieper , D...relative to the background. If an object spectrum has a close resemblance to its surroundings, it will Correspondence to M. L. Pieper E-mail: mpieper

  6. The history of inhibitors of angiotensin converting enzyme.

    PubMed

    Vane, J R

    1999-12-01

    This review paper by Sir John Vane, The Nobel Prize Laureate for the first time reveals the insides of discovery of inhibitors of angiotensin converting enzyme (ACE-1), presently known as important drugs for the treatment of hypertension, congestive heart failure and coronary artery disease.

  7. [Effect of calcium-independent phospholipase A(2) inhibitor in reducing hepatocyte lipoapoptosis and improving insulin resistance].

    PubMed

    Shi, H B; Fu, J F; Huang, Y; Liu, L R

    2017-01-20

    Objective: To investigate the effect of calcium-independent phospholipase A(2) (iPLA(2)) inhibitor in reducing hepatocyte lipoapoptosis and improving insulin resistance. Methods: A total of 28 male Sprague-Dawley rats were randomly divided into the following three groups: 12 rats in group I (normal control group) were given normal diet for 18 weeks; 8 rats in group II (non-alcoholic fatty liver disease model group) were given high-fat diet for 18 weeks; 8 rats in group III (iPLA(2) inhibitor group) were given high-fat diet for 18 weeks and intraperitoneal injection of the iPLA(2) inhibitor bromoenol lactone 150 μg/kg once every other day since week 15 (14 times of injection in total). All the rats were sacrificed at the same time, and body weight and liver weight were measured. Blood lipids, serum enzymes, fasting blood glucose, fasting insulin, free fatty acid, and serum iPLA(2) concentration were measured in each group, and liver pathological changes were evaluated. The terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling was used to measure the level of hepatocyte apoptosis and the apoptotic index was calculated. Quantitative PCR was used to measure the mRNA expression of iPLA(2). The Student-Newman-Keuls test and the chi-square test were used for comparison of parameters between groups I, II, and III. P < 0.05 was considered statistically significant. Results: Compared with group I, group II had significant increases in triglyceride (0.75±0.05 mmol/L vs 1.20±0.13 mmol/L, P < 0.05), cholesterol (1.50±0.12 mmol/L vs 2.94±0.34 mmol/L, P < 0.05), low-density lipoprotein (0.65±0.06 mmol/L vs 1.30±0.16 mmol/L, P < 0.05), free fatty acid (0.58±0.09 mEq/L vs 0.80±0.20 mEq/L, P < 0.05), fasting blood glucose (4.85±0.22 mmol/L vs 6.94±0.65 mmol/L, P < 0.05), and fasting insulin (0.89±0.52 mmol/L vs 1.29±0.52 mmol/L, P < 0.05), and a significant reduction in the insulin sensitivity index (0.52±0.21 vs 0.27±0.11, P < 0.05); group II also had

  8. AceDRG: a stereochemical description generator for ligands

    PubMed Central

    Emsley, Paul; Gražulis, Saulius; Merkys, Andrius; Vaitkus, Antanas

    2017-01-01

    The program AceDRG is designed for the derivation of stereochemical information about small molecules. It uses local chemical and topological environment-based atom typing to derive and organize bond lengths and angles from a small-molecule database: the Crystallography Open Database (COD). Information about the hybridization states of atoms, whether they belong to small rings (up to seven-membered rings), ring aromaticity and nearest-neighbour information is encoded in the atom types. All atoms from the COD have been classified according to the generated atom types. All bonds and angles have also been classified according to the atom types and, in a certain sense, bond types. Derived data are tabulated in a machine-readable form that is freely available from CCP4. AceDRG can also generate stereochemical information, provided that the basic bonding pattern of a ligand is known. The basic bonding pattern is perceived from one of the computational chemistry file formats, including SMILES, mmCIF, SDF MOL and SYBYL MOL2 files. Using the bonding chemistry, atom types, and bond and angle tables generated from the COD, AceDRG derives the ‘ideal’ bond lengths, angles, plane groups, aromatic rings and chirality information, and writes them to an mmCIF file that can be used by the refinement program REFMAC5 and the model-building program Coot. Other refinement and model-building programs such as PHENIX and BUSTER can also use these files. AceDRG also generates one or more coordinate sets corresponding to the most favourable conformation(s) of a given ligand. AceDRG employs RDKit for chemistry perception and for initial conformation generation, as well as for the interpretation of SMILES strings, SDF MOL and SYBYL MOL2 files. PMID:28177307

  9. AceDRG: a stereochemical description generator for ligands.

    PubMed

    Long, Fei; Nicholls, Robert A; Emsley, Paul; Graǽulis, Saulius; Merkys, Andrius; Vaitkus, Antanas; Murshudov, Garib N

    2017-02-01

    The program AceDRG is designed for the derivation of stereochemical information about small molecules. It uses local chemical and topological environment-based atom typing to derive and organize bond lengths and angles from a small-molecule database: the Crystallography Open Database (COD). Information about the hybridization states of atoms, whether they belong to small rings (up to seven-membered rings), ring aromaticity and nearest-neighbour information is encoded in the atom types. All atoms from the COD have been classified according to the generated atom types. All bonds and angles have also been classified according to the atom types and, in a certain sense, bond types. Derived data are tabulated in a machine-readable form that is freely available from CCP4. AceDRG can also generate stereochemical information, provided that the basic bonding pattern of a ligand is known. The basic bonding pattern is perceived from one of the computational chemistry file formats, including SMILES, mmCIF, SDF MOL and SYBYL MOL2 files. Using the bonding chemistry, atom types, and bond and angle tables generated from the COD, AceDRG derives the `ideal' bond lengths, angles, plane groups, aromatic rings and chirality information, and writes them to an mmCIF file that can be used by the refinement program REFMAC5 and the model-building program Coot. Other refinement and model-building programs such as PHENIX and BUSTER can also use these files. AceDRG also generates one or more coordinate sets corresponding to the most favourable conformation(s) of a given ligand. AceDRG employs RDKit for chemistry perception and for initial conformation generation, as well as for the interpretation of SMILES strings, SDF MOL and SYBYL MOL2 files.

  10. Association between ACE D allele and elite short distance swimming.

    PubMed

    Costa, Aldo Matos; Silva, António José; Garrido, Nuno Domingos; Louro, Hugo; de Oliveira, Ricardo Jacó; Breitenfeld, Luiza

    2009-08-01

    The influence of ACE gene on athletic performance has been widely explored, and most of the published data refers to an I/D polymorphism leading to the presence (I allele) or absence (D allele) of a 287-bp sequence in intron 16, determining ACE activity in serum and tissues. A higher I allele frequency has been reported among elite endurance athletes, while the D allele was more frequent among those engaged in more power-orientated sports. However, on competitive swimming, the reproducibility of such associations is controversial. We thus compared the ACE genotype of elite swimmers with that of non-elite swimming cohort and of healthy control subjects. We thus sought an association of the ACE genotype of elite swimmers with their competitive distance. 39 Portuguese Olympic swimming candidates were classified as: short (<200 m) and middle (400-1,500 m) distance swimmers, respectively. A group of 32 non-elite swimmers were studied and classified as well, and a control group (n = 100) was selected from the Portuguese population. Chelex 100 was used for DNA extraction and genotype was determined by PCR-RFLP methods. We found that ACE genotype distribution and allelic frequency differs significantly by event distance only among elite swimmers (P < or = 0.05). Moreover, the allelic frequency of the elite short distance swimmers differed significantly from that of the controls (P = 0.021). No associations were found between middle distance swimmers and controls. Our results seem to support an association between the D allele and elite short distance swimming.

  11. Selective serotonin reuptake inhibitor combined with dengzhanshengmai capsule improves the fatigue symptoms: a 12-week open-label pilot study

    PubMed Central

    Li, De-Qiang; Li, Zhong-Chun; Dai, Zhi-Yuan

    2015-01-01

    Objective: This study was to assess the efficacy and safety of selective serotonin reuptake inhibitor (SSRI) plus Dengzhanshengmai capsule in patients with chronic fatigue syndrome (CFS). Methods: SSRI at a moderate dose plus Dengzhanshengmai (n = 134) with SSRI alone (n = 134) were compared for the efficacy and safety in the treatment of CFS. The therapeutic efficacy and safety were evaluated. Results: As compared to monotherapy group, the efficacy in combined therapy group was better and characterized by the improvement of general fatigue (0.8±0.6 vs. 1.3±0.7), physical fatigue (0.6±0.3 vs. 1.0±0.4) and reduced activity (1.0±0.5 vs. 1.3±0.6) since the 2nd week (P<0.01) and in reduced motivation (2.1±0.8 vs. 2.4±1.0) since the 8th week (P<0.01) and the improvement continued thereafter. The mental fatigue score and HAD score were comparable between two groups (P>0.05). No significant difference was found in the drop-out rate between SSRI group (15.7%) and SSRI plus Dengzhanshengmai group (18.0%). The reasons for drop out were adverse events (7.5% vs. 9.7%), requests of the patients or career requirement (3.7% vs. 4.5%), loss to follow-up and others (2.2% vs. 3.0%) and lack of efficacy (2.2% vs. 0.7%). Although the patients in combined therapy group experienced a higher rate of hypertension than (5.8% vs. 1.5%), no significant difference was observed (P = 0.08). Conclusion: SSRI combined with Dengzhanshengmai capsule may significantly improve the general fatigue, physical fatigue, reduced activity and reduced motivation of CFS patients as compared to monotherapy with SSRI. Furthermore, this combined therapy is safe and tolerable. PMID:26380022

  12. Design, synthesis, and antihypertensive activity of curcumin-inspired compounds via ACE inhibition and vasodilation, along with a bioavailability study for possible benefit in cardiovascular diseases

    PubMed Central

    Zhuang, Xiao-dong; Liao, Li-zhen; Dong, Xiao-bian; Hu, Xun; Guo, Yue; Du, Zhi-min; Liao, Xin-xue; Wang, Li-chun

    2016-01-01

    This study describes the synthesis of a novel series of curcumin-inspired compounds via a facile synthetic route. The structures of these derivatives were ascertained using various spectroscopic and analytic techniques. The pharmacological effects of the target analogs were assessed by assaying their inhibition of angiotensin-converting enzyme (ACE). All of the synthesized derivatives exhibited considerable inhibition of ACE, with half-maximal inhibitory concentrations ranging from 1.23 to 120.32 μM. In a docking analysis with testicular ACE (tACE), the most promising inhibitor (4j) was efficiently accommodated in the deep cleft of the protein cavity, making close interatomic contacts with Glu162, His353, and Ala356, comparable with lisinopril. Compounds 4i, 4j, 4k, and 4l were further selected for determination of their vasodilator activity (cardiac output and stroke volume) on isolated rat hearts using the Langendorff technique. The bioavailability of compound 4j was determined in experimental mice. PMID:26792980

  13. Epitope mapping of mAbs to denatured human testicular ACE (CD143).

    PubMed

    Balyasnikova, I V; Metzger, R; Franke, F E; Conrad, N; Towbin, H; Schwartz, D E; Sturrock, E D; Danilov, S M

    2008-10-01

    Angiotensin I-converting enzyme (ACE; CD143) has two homologous enzymatically active domains (N and C) and plays a crucial role in blood pressure regulation and vascular remodeling. A wide spectrum of monoclonal antibodies (mAbs) to different epitopes on the N and C domains of human ACE have been used to study different aspects of ACE biology. In this study, we characterized a set of nine mAbs, developed against the C domain of human ACE, which recognize the denatured forms of ACE and thus are suitable for the detection and quantification of somatic ACE (sACE) and testicular ACE (tACE) using Western blotting and immunohistochemistry on paraffin-embedded human tissues. The epitopes for these mAbs were defined using species cross-reactivity, phage display library screening, Western blotting and ACE mutagenesis. Most of the mAbs recognized common/overlapping region(s) on both somatic and testicular forms of human ACE, whereas mAb 4E10 was relatively specific for the testicular isoform and mAb 5B9 mainly recognized the glycan attached to Asn 731. This set of mAbs is useful for identifying even subtle changes in human ACE conformation because of denaturation. These mAbs are also sensitive tools for the detection of human sACE and tACE in biological fluids and tissues using proteomic approaches. Their high reactivity in paraffin-embedded tissues provides opportunities to study changes in the pattern of ACE expression and glycosylation (particularly with mAb 5B9) in different tissues and cells.

  14. Histone deacetylase inhibitor pracinostat in doublet therapy: a unique strategy to improve therapeutic efficacy and to tackle herculean cancer chemoresistance.

    PubMed

    Ganai, Shabir Ahmad

    2016-09-01

    Context Histone deacetylase inhibitors (HDACi) have shown promising results in neurodegeneration and cancer. Hydroxamate HDACi, including vorinostat, have shown encouraging results in haematological malignancies, but the poor pharmacokinetic of these inhibitors leads to insufficient tumour concentration limiting their application against solid malignancies. Objective This article deals with novel HDAC inhibitor pracinostat (SB939) and delineates its therapeutic role in solid and haematological malignancies. The article provides rigorous details about the underlying molecular mechanisms modulated by pracinostat to exert cytotoxic effect. The article further highlights the doublet therapy that may be used to tackle monotonous cancer chemoresistance. Methods Both old and the latest literature on pracinostat was retrieved from diverse sources, such as PubMed, Science Direct, Springer Link, general Google search using both pracinostat and SB939 keywords in various ways: after thorough evaluation the topic which can fulfil the current gap was chosen. Results Pracinostat shows potent anticancer activity against both solid and haematological malignancies compared to the FDA-approved drug vorinostat. This marvellous inhibitor has better physicochemical, pharmaceutical and pharmacokinetic properties than the defined inhibitor vorinostat. Pracinostat has  >100-fold more affinity towards HDACs compared to other zinc-dependent metalloenzymes and shows maximum efficacy when used in doublet therapy. Conclusion Pracinostat shows potent anticancer activity even against therapeutically challenging cancers when used in doublet therapy. However, the triplet combination studies of the defined inhibitor that may prove even more beneficial are still undone, emphasizing the desperate need of further research in the defined gap.

  15. The DcpS inhibitor RG3039 improves survival, function and motor unit pathologies in two SMA mouse models.

    PubMed

    Gogliotti, Rocky G; Cardona, Herminio; Singh, Jasbir; Bail, Sophie; Emery, Carina; Kuntz, Nancy; Jorgensen, Michael; Durens, Madel; Xia, Bing; Barlow, Courtenay; Heier, Christopher R; Plasterer, Heather L; Jacques, Vincent; Kiledjian, Megerditch; Jarecki, Jill; Rusche, James; DiDonato, Christine J

    2013-10-15

    Spinal muscular atrophy (SMA) is caused by insufficient levels of the survival motor neuron (SMN) protein due to the functional loss of the SMN1 gene and the inability of its paralog, SMN2, to fully compensate due to reduced exon 7 splicing efficiency. Since SMA patients have at least one copy of SMN2, drug discovery campaigns have sought to identify SMN2 inducers. C5-substituted quinazolines increase SMN2 promoter activity in cell-based assays and a derivative, RG3039, has progressed to clinical testing. It is orally bioavailable, brain-penetrant and has been shown to be an inhibitor of the mRNA decapping enzyme, DcpS. Our pharmacological characterization of RG3039, reported here, demonstrates that RG3039 can extend survival and improve function in two SMA mouse models of varying disease severity (Taiwanese 5058 Hemi and 2B/- SMA mice), and positively impacts neuromuscular pathologies. In 2B/- SMA mice, RG3039 provided a >600% survival benefit (median 18 days to >112 days) when dosing began at P4, highlighting the importance of early intervention. We determined the minimum effective dose and the associated pharmacokinetic (PK) and exposure relationship of RG3039 and DcpS inhibition ex vivo. These data support the long PK half-life with extended pharmacodynamic outcome of RG3039 in 2B/- SMA mice. In motor neurons, RG3039 significantly increased both the average number of cells with gems and average number of gems per cell, which is used as an indirect measure of SMN levels. These studies contribute to dose selection and exposure estimates for the first studies with RG3039 in human subjects.

  16. The Phosphodiesterase 10A Selective Inhibitor TAK-063 Improves Cognitive Functions Associated with Schizophrenia in Rodent Models.

    PubMed

    Shiraishi, Eri; Suzuki, Kazunori; Harada, Akina; Suzuki, Noriko; Kimura, Haruhide

    2016-03-01

    Cognitive deficits in various domains, including recognition memory, attention, impulsivity, working memory, and executive function, substantially affect functional outcomes in patients with schizophrenia. TAK-063 [1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one] is a potent and selective phosphodiesterase 10A inhibitor that produces antipsychotic-like effects in rodent models of schizophrenia. We evaluated the effects of TAK-063 on multiple cognitive functions associated with schizophrenia using naïve and drug-perturbed rodents. TAK-063 at 0.1 and 0.3 mg/kg p.o. improved time-dependent memory decay in object recognition in naïve rats. TAK-063 at 0.1 and 0.3 mg/kg p.o. increased accuracy rate, and TAK-063 at 0.3 mg/kg p.o. reduced impulsivity in a five-choice serial reaction time task in naïve rats. N-methyl-d-aspartate receptor antagonists, such as phencyclidine and MK-801 [(5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine], were used to induce working memory deficits relevant to schizophrenia in animals. TAK-063 at 0.3 mg/kg p.o. attenuated both phencyclidine-induced working memory deficits in a Y-maze test in mice and MK-801-induced working memory deficits in an eight-arm radial maze task in rats. An attentional set-shifting task using subchronic phencyclidine-treated rats was used to assess the executive function. TAK-063 at 0.3 mg/kg p.o. reversed cognitive deficits in extradimensional shifts. These findings suggest that TAK-063 has a potential to ameliorate deficits in multiple cognitive domains impaired in schizophrenia.

  17. Enhancement of ACE and prolyl oligopeptidase inhibitory potency of protein hydrolysates from sardine and tuna by-products by simulated gastrointestinal digestion.

    PubMed

    Martínez-Alvarez, Oscar; Batista, Irineu; Ramos, Cristina; Montero, Pilar

    2016-04-01

    This work was focused on the study of the bioactive potential of three fish protein hydrolysates, one of them prepared from industrial sardine by-products (head and viscera) and the others from tuna by-products (head, and muscle and viscera). These protein hydrolysates exhibited moderate ability to inhibit Angiotensin Converting Enzyme or ACE (IC50 between 0.24-1.16 mg dry weight per ml) and prolyl oligopeptidase or PO (IC50 between 3.30-9.57 mg ml(-1)), those obtained from tuna by-products being the most effective. Overall, ACE- and PO-inhibiting activities were enhanced by sequential nanofiltration through 3 and 1 kDa MWCO membranes (IC50 between 0.02-0.16 mg ml(-1) (ACE) and 1.10-4.21 mg ml(-1) (PO)). The inhibitory properties of the hydrolysates were greatly improved by in vitro gastric digestion, and were barely affected by further intestinal digestion. The digested tuna hydrolysates, mainly that from heads, proved to be the best source of PO- and ACE- inhibiting molecules (IC50 = 0.16 mg ml(-1) (ACE) and 1.04 mg ml(-1) (PO)) and could be potential new ingredients in food with interest in the prevention or treatment of cardiovascular and neurological diseases.

  18. Modulation of the renal response to ACE inhibition by ACE insertion/deletion polymorphism during hyperglycemia in normotensive, normoalbuminuric type 1 diabetic patients.

    PubMed

    Weekers, Laurent; Bouhanick, Béatrice; Hadjadj, Samy; Gallois, Yves; Roussel, Ronen; Pean, Franck; Ankotche, Amos; Chatellier, Gilles; Alhenc-Gelas, François; Lefebvre, Pierre J; Marre, Michel

    2005-10-01

    ACE inhibition protects kidney function, but ACE insertion/deletion (I/D) polymorphism affects renal prognosis in type 1 diabetic patients. ACE genotype may influence the renal benefits of ACE inhibition. We studied the impact of ACE I/D polymorphism on the renal hemodynamic changes induced by ACE inhibition in type 1 diabetes. We studied renal hemodynamics (glomerular filtration rate [GFR], effective renal plasma flow [ERPF], filtration fraction [GFR/ERPF], mean arterial pressure [MAP], and total renal resistances [MAP/ERPF]) repeatedly during normoglycemia and then hyperglycemia in 12 normotensive, normoalbuminuric type 1 diabetes and the II genotype (associated with nephroprotection) versus 22 age- and sex-matched subjects with the ACE D allele after three randomly allocated 2- to 6-week periods on placebo, 1.25 mg/day ramipril, and 5 mg/day ramipril in a double-blind, cross-over study. During normoglycemia, the hemodynamic changes induced by ramipril were similar in both genotypes. During hyperglycemia, the changes induced by ramipril were accentuated in the II genotype group and attenuated dose dependently in the D allele group (treatment-genotype interaction P values for ERPF, 0.018; MAP, 0.018; and total renal resistances, 0.055). These results provide a basis to different renal responses to ACE inhibition according to ACE genotype in type 1 diabetes.

  19. A Discussion of Aerodynamic Control Effectors (ACEs) for Unmanned Air Vehicles (UAVs)

    NASA Technical Reports Server (NTRS)

    Wood, Richard M.

    2002-01-01

    A Reynolds number based, unmanned air vehicle classification structure has been developed which identifies four classes of unmanned air vehicle concepts. The four unmanned air vehicle (UAV) classes are; Micro UAV, Meso UAV, Macro UAV, and Mega UAV. In a similar fashion a labeling scheme for aerodynamic control effectors (ACE) was developed and eleven types of ACE concepts were identified. These eleven types of ACEs were laid out in a five (5) layer scheme. The final section of the paper correlated the various ACE concepts to the four UAV classes and ACE recommendations are offered for future design activities.

  20. ACE gene titration in mice uncovers a new mechanism for ACE on the control of body weight.

    PubMed

    Heimann, A S; Favarato, M H; Gozzo, F C; Rioli, V; Carreño, F R; Eberlin, M N; Ferro, E S; Krege, J H; Krieger, J E

    2005-01-20

    Mice harboring 1, 2, or 3 copies of the angiotensin-converting enzyme (ACE) gene were used to evaluate the quantitative role of the ACE locus on obesity. Three-copy mice fed with a high-fat diet had lower body weight and peri-epididymal adipose tissue than did 1- and 2-copy mice (P < 0.05). On regular diet, 3-copy mice had to eat more to maintain the same body weight; on a high-fat diet, they ate the same but weighed less than 1- and 2-copy mice (P < 0.05), indicating a higher metabolic rate in 3-copy mice that was not affected by ANG II AT(1) blocker treatment. A catalytically inactive form of thimet oligopeptidase (EC 3.4.24.15; EP24.15) was used to isolate ACE substrates from adipose tissue. Liquid chromatography electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) identified 162 peptide peaks; 16 peptides were present in both groups (1- and 3-copy mice fed with a high-fat diet), whereas 58 of the 72 unique peptides were found only in the 3-copy mice. Peptide size distribution was shifted to lower molecular weight in 3-copy mice. Two of the identified peptides, LVVYPWTQRY and VVYPWTQRY, which are ACE substrates, inhibited in vitro protein kinase C phosphorylation in a concentration-dependent manner. In addition, neurolysin (EC 3.4.24.16; EP24.16) activity was lower in fat tissue from 3- vs. 1-copy mice (P < 0.05). Taken together, these results provide evidence that ACE is associated with body weight and peri-epididymal fat accumulation. This response may involve the generation of oligopeptides that inhibit the activity of EP24.16 and other oligopeptidases within the adipose tissue.

  1. Advancements in the safe identification of explosives using a Raman handheld instrument (ACE-ID)

    NASA Astrophysics Data System (ADS)

    Arnó, Josep; Frunzi, Michael; Kittredge, Marina; Sparano, Brian

    2014-05-01

    Raman spectroscopy is the technology of choice to identify bulk solid and liquid phase unknown samples without the need to contact the substance. Materials can be identified through transparent and semi-translucent containers such as plastic and glass. ConOps in emergency response and military field applications require the redesign of conventional laboratory units for: field portability; shock, thermal and chemical attack resistance; easy and intuitive use in restrictive gear; reduced size, weight, and power. This article introduces a new handheld instrument (ACE-IDTM) designed to take Raman technology to the next level in terms of size, safety, speed, and analytical performance. ACE-ID is ruggedized for use in severe climates and terrains. It is lightweight and can be operated with just one hand. An intuitive software interface guides users through the entire identification process, making it easy-to-use by personnel of different skill levels including military explosive ordinance disposal technicians, civilian bomb squads and hazmat teams. Through the use of embedded advanced algorithms, the instrument is capable of providing fluorescence correction and analysis of binary mixtures. Instrument calibration is performed automatically upon startup without requiring user intervention. ACE-ID incorporates an optical rastering system that diffuses the laser energy over the sample. This important innovation significantly reduces the heat induced in dark samples and the probability of ignition of susceptible explosive materials. In this article, the explosives identification performance of the instrument will be provided in addition to a quantitative evaluation of the safety improvements derived from the reduced ignition probabilities.

  2. A Global Aerosol Model Forecast for the ACE-Asia Field Experiment

    NASA Technical Reports Server (NTRS)

    Chin, Mian; Ginoux, Paul; Lucchesi, Robert; Huebert, Barry; Weber, Rodney; Anderson, Tad; Masonis, Sarah; Blomquist, Byron; Bandy, Alan; Thornton, Donald

    2003-01-01

    We present the results of aerosol forecast during the Aerosol Characterization Experiment (ACE-Asia) field experiment in spring 2001, using the Georgia Tech/Goddard Global Ozone Chemistry Aerosol Radiation and Transport (GOCART) model and the meteorological forecast fields from the Goddard Earth Observing System Data Assimilation System (GEOS DAS). The aerosol model forecast provides direct information on aerosol optical thickness and concentrations, enabling effective flight planning, while feedbacks from measurements constantly evaluate the model, making successful model improvements. We verify the model forecast skill by comparing model predicted total aerosol extinction, dust, sulfate, and SO2 concentrations with those quantities measured by the C-130 aircraft during the ACE-Asia intensive operation period. The GEOS DAS meteorological forecast system shows excellent skills in predicting winds, relative humidity, and temperature for the ACE-Asia experiment area as well as for each individual flight, with skill scores usually above 0.7. The model is also skillful in forecast of pollution aerosols, with most scores above 0.5. The model correctly predicted the dust outbreak events and their trans-Pacific transport, but it constantly missed the high dust concentrations observed in the boundary layer. We attribute this missing dust source to the desertification regions in the Inner Mongolia Province in China, which have developed in recent years but were not included in the model during forecasting. After incorporating the desertification sources, the model is able to reproduce the observed high dust concentrations at low altitudes over the Yellow Sea. Two key elements for a successful aerosol model forecast are correct source locations that determine where the emissions take place, and realistic forecast winds and convection that determine where the aerosols are transported. We demonstrate that our global model can not only account for the large

  3. SARS coronavirus, but not human coronavirus NL63, utilizes cathepsin L to infect ACE2-expressing cells.

    PubMed

    Huang, I-Chueh; Bosch, Berend Jan; Li, Fang; Li, Wenhui; Lee, Kyoung Hoa; Ghiran, Sorina; Vasilieva, Natalya; Dermody, Terence S; Harrison, Stephen C; Dormitzer, Philip R; Farzan, Michael; Rottier, Peter J M; Choe, Hyeryun

    2006-02-10

    Viruses require specific cellular receptors to infect their target cells. Angiotensin-converting enzyme 2 (ACE2) is a cellular receptor for two divergent coronaviruses, SARS coronavirus (SARS-CoV) and human coronavirus NL63 (HCoV-NL63). In addition to hostcell receptors, lysosomal cysteine proteases are required for productive infection by some viruses. Here we show that SARS-CoV, but not HCoV-NL63, utilizes the enzymatic activity of the cysteine protease cathepsin L to infect ACE2-expressing cells. Inhibitors of cathepsin L blocked infection by SARS-CoV and by a retrovirus pseudotyped with the SARS-CoV spike (S) protein but not infection by HCoV-NL63 or a retrovirus pseudotyped with the HCoV-NL63 S protein. Expression of exogenous cathepsin L substantially enhanced infection mediated by the SARS-CoV S protein and by filovirus GP proteins but not by the HCoV-NL63 S protein or the vesicular stomatitis virus G protein. Finally, an inhibitor of endosomal acidification had substantially less effect on infection mediated by the HCoV-NL63 S protein than on that mediated by the SARS-CoV S protein. Our data indicate that two coronaviruses that utilize a common receptor nonetheless enter cells through distinct mechanisms.

  4. Adverse Childhood Experiences (ACEs) questionnaire and Adult Attachment Interview (AAI): implications for parent child relationships.

    PubMed

    Murphy, Anne; Steele, Miriam; Dube, Shanta Rishi; Bate, Jordan; Bonuck, Karen; Meissner, Paul; Goldman, Hannah; Steele, Howard

    2014-02-01

    Although Adverse Childhood Experiences (ACEs) are linked to increased health problems and risk behaviors in adulthood, there are no studies on the association between ACEs and adults' states of mind regarding their early childhood attachments, loss, and trauma experiences. To validate the ACEs questions, we analyzed the association between ACEs and emotional support indicators and Adult Attachment Interview (AAI) classifications in terms of unresolved mourning regarding past loss or trauma and discordant states of mind in cannot classify (U/CC) interviews. Seventy-five urban women (41 clinical and 34 community) completed a questionnaire on ACEs, which included 10 categories of abuse, neglect, and household dysfunction, in addition to emotional support. Internal psychological processes or states of mind concerning attachment were assessed using the AAI. ACE responses were internally consistent (Cronbach's α=.88). In the clinical sample, 84% reported≥4 ACEs compared to 27% among the community sample. AAIs judged U/CC occurred in 76% of the clinical sample compared to 9% in the community sample. When ACEs were≥4, 65% of AAIs were classified U/CC. Absence of emotional support in the ACEs questionnaire was associated with 72% of AAIs being classified U/CC. As the number of ACEs and the lack of emotional support increases so too does the probability of AAIs being classified as U/CC. Findings provide rationale for including ACEs questions in pediatric screening protocols to identify and offer treatment reducing the intergenerational transmission of risk associated with problematic parenting.

  5. Nitric Oxide Synthase Inhibitor Improves De Novo and Long-Term l-DOPA-Induced Dyskinesia in Hemiparkinsonian Rats

    PubMed Central

    Padovan-Neto, Fernando Eduardo; Echeverry, Marcela Bermúdez; Chiavegatto, Silvana; Del-Bel, Elaine

    2011-01-01

    Inhibitors of neuronal and endothelial nitric oxide synthase decrease l-3,4-dihidroxifenilalanine (l-DOPA)-induced dyskinesias in rodents. The mechanism of nitric oxide inhibitor action is unknown. The aims of the present study were to investigate the decrease of l-DOPA-induced abnormal involuntary movements (AIMs) in 6-hydroxydopamine (6-OHDA)-lesioned rats by nitric oxide inhibitors following either acute or chronic treatment. The primary findings of this study were that NG-nitro-l-Arginine, an inhibitor of endothelial and neuronal nitric oxide synthase, attenuated AIMs induced by chronic and acute l-DOPA. In contrast, rotational behavior was attenuated only after chronic l-DOPA. The 6-OHDA lesion and the l-DOPA treatment induced a bilateral increase (1.5 times) in the neuronal nitric oxide synthase (nNOS) protein and nNOS mRNA in the striatum and in the frontal cortex. There was a parallel increase, bilaterally, of the FosB/ΔFosB, primarily in the ipsilateral striatum. The exception was in the contralateral striatum and the ipsilateral frontal cortex, where chronic l-DOPA treatment induced an increase of approximately 10 times the nNOS mRNA. Our results provided further evidence of an anti-dyskinetic effect of NOS inhibitor. The effect appeared under l-DOPA acute and chronic treatment. The l-DOPA treatment also revealed an over-expression of the neuronal NOS in the frontal cortex and striatum. Our results corroborated findings that l-DOPA-induced rotation differs between acute and chronic treatment. The effect of the NOS inhibitor conceivably relied on the l-DOPA structural modifications in the Parkinsonian brain. Taken together, these data provided a rationale for further evaluation of NOS inhibitors in the treatment of l-DOPA-induced dyskinesia. PMID:21713068

  6. Carboxylesterase inhibitors

    PubMed Central

    Hatfield, M. Jason; Potter, Philip M.

    2011-01-01

    Introduction Carboxylesterases play major roles in the hydrolysis of numerous therapeutically active compounds. This is, in part, due to the prevalence of the ester moiety in these small molecules. However, the impact these enzymes may play on drug stability and pharmacokinetics is rarely considered prior to molecule development. Therefore, the application of selective inhibitors of this class of proteins may have utility in modulating the metabolism, distribution and toxicity of agents that are subjected to enzyme hydrolysis. Areas covered This review details the development of all such compounds dating back to 1986, but principally focuses on the very recent identification of selective human carboxylesterases inhibitors. Expert opinion The implementation of carboxylesterase inhibitors may significantly revolutionize drug discovery. Such molecules may allow for improved efficacy of compounds inactivated by this class of enzymes and/or reduce the toxicity of agents that are activated by these proteins. Furthermore, since lack of carboxylesterase activity appears to have no obvious biological consequence, these compounds could be applied in combination with virtually any esterified drug. Therefore, inhibitors of these proteins may have utility in altering drug hydrolysis and distribution in vivo. The characteristics, chemical and biological properties, and potential uses of such agents, are discussed here. PMID:21609191

  7. Aircraft Energy Efficiency (ACEE) status report

    NASA Technical Reports Server (NTRS)

    Nored, D. L.; Dugan, J. F., Jr.; Saunders, N. T.; Ziemianski, J. A.

    1979-01-01

    Fuel efficiency in aeronautics, for fuel conservation in general as well as for its effect on commercial aircraft operating economics is considered. Projects of the Aircraft Energy Efficiency Program related to propulsion are emphasized. These include: (1) engine component improvement, directed at performance improvement and engine diagnostics for prolonged service life; (2) energy efficient engine, directed at proving the technology base for the next generation of turbofan engines; and (3) advanced turboprop, directed at advancing the technology of turboprop powered aircraft to a point suitable for commercial airline service. Progress in these technology areas is reported.

  8. Complexes of Bacterial Nicotinate Mononucleotide Adenylyltransferase with Inhibitors: Implication for Structure-Based Drug Design and Improvement

    SciTech Connect

    Huang, Nian; Kolhatkar, Rohit; Eyobo, Yvonne; Sorci, Leonardo; Rodionova, Irina; Osterman, Andrei L.; MacKerell, Jr., Alexander D.; Zhang, Hong

    2010-12-07

    Bacterial nicotinate mononucleotide adenylyltransferase encoded by the essential gene nadD plays a central role in the synthesis of the redox cofactor NAD{sup +}. The NadD enzyme is conserved in the majority of bacterial species and has been recognized as a novel target for developing new and potentially broad-spectrum antibacterial therapeutics. Here we report the crystal structures of Bacillus anthracis NadD in complex with three NadD inhibitors, including two analogues synthesized in the present study. These structures revealed a common binding site shared by different classes of NadD inhibitors and explored the chemical environment surrounding this site. The structural data obtained here also showed that the subtle changes in ligand structure can lead to significant changes in the binding mode, information that will be useful for future structure-based optimization and design of high affinity inhibitors.

  9. Chronic Oral Administration of the Arginase Inhibitor 2(S)-amino-6-boronohexanoic Acid (ABH) Improves Erectile Function in Aged Rats

    PubMed Central

    Segal, Robert; Hannan, Johanna L.; Liu, Xiaopu; Kutlu, Omer; Burnett, Arthur L.; Champion, Hunter C.; Kim, Jae Hyung; Steppan, Jochen; Berkowitz, Dan E.; Bivalacqua, Trinity J.

    2014-01-01

    Arginase expression and activity have been noted to be heightened in conditions associated with erectile dysfunction, including aging. Previously, arginase inhibition by chronic administration of the arginase inhibitor 2-(S)-amino-6-boronohexanoic acid (ABH) has been shown to improve endothelial dysfunction in aged rats. The objective of this study was to assess whether chronic oral ABH administration affects cavernosal erectile function. Rats were divided into 4 groups: young control, young treated with arginase inhibitor, aged control, and aged treated with arginase inhibitor. Arginase activity was measured and presented as a proportion of young untreated rats. In vivo erectile responses to cavernous nerve stimulation were measured in all cohorts. The cavernous nerve was stimulated with a graded electrical stimulus, and the intracavernosal/ mean arterial pressure ratios and total intracavernosal pressure were recorded. Arginase activity was elevated in the aged rats compared with young controls; however, arginase activity was significantly decreased in aged rats treated with ABH. With the addition of ABH, erectile responses improved in the aged rats (P < .05). Oral inhibition of arginase with ABH results in improved erectile function in aged rats, resulting in erectile hemodynamics similar to young rats. This represents the first documentation of systemic arginase inhibition positively affecting corporal cavernosal function. PMID:22492840

  10. Chronic oral administration of the arginase inhibitor 2(S)-amino-6-boronohexanoic acid (ABH) improves erectile function in aged rats.

    PubMed

    Segal, Robert; Hannan, Johanna L; Liu, Xiaopu; Kutlu, Omer; Burnett, Arthur L; Champion, Hunter C; Kim, Jae Hyung; Steppan, Jochen; Berkowitz, Dan E; Bivalacqua, Trinity J

    2012-01-01

    Arginase expression and activity have been noted to be heightened in conditions associated with erectile dysfunction, including aging. Previously, arginase inhibition by chronic administration of the arginase inhibitor 2-(S)-amino-6-boronohexanoic acid (ABH) has been shown to improve endothelial dysfunction in aged rats. The objective of this study was to assess whether chronic oral ABH administration affects cavernosal erectile function. Rats were divided into 4 groups: young control, young treated with arginase inhibitor, aged control, and aged treated with arginase inhibitor. Arginase activity was measured and presented as a proportion of young untreated rats. In vivo erectile responses to cavernous nerve stimulation were measured in all cohorts. The cavernous nerve was stimulated with a graded electrical stimulus, and the intracavernosal/mean arterial pressure ratios and total intracavernosal pressure were recorded. Arginase activity was elevated in the aged rats compared with young controls; however, arginase activity was significantly decreased in aged rats treated with ABH. With the addition of ABH, erectile responses improved in the aged rats (P < .05). Oral inhibition of arginase with ABH results in improved erectile function in aged rats, resulting in erectile hemodynamics similar to young rats. This represents the first documentation of systemic arginase inhibition positively affecting corporal cavernosal function.

  11. Effect of angiotensin-converting enzyme (ACE) gene polymorphism on progression of renal disease and the influence of ACE inhibition in IDDM patients: findings from the EUCLID Randomized Controlled Trial. EURODIAB Controlled Trial of Lisinopril in IDDM.

    PubMed

    Penno, G; Chaturvedi, N; Talmud, P J; Cotroneo, P; Manto, A; Nannipieri, M; Luong, L A; Fuller, J H

    1998-09-01

    We examined whether the ACE gene insertion/deletion (I/D) polymorphism modulates renal disease progression in IDDM and how ACE inhibitors influence this relationship. The EURODIAB Controlled Trial of Lisinopril in IDDM is a multicenter randomized placebo-controlled trial in 530 nonhypertensive, mainly normoalbuminuric IDDM patients aged 20-59 years. Albumin excretion rate (AER) was measured every 6 months for 2 years. Genotype distribution was 15% II, 58% ID, and 27% DD. Between genotypes, there were no differences in baseline characteristics or in changes in blood pressure and glycemic control throughout the trial. There was a significant interaction between the II and DD genotype groups and treatment on change in AER (P = 0.05). Patients with the II genotype showed the fastest rate of AER progression on placebo but had an enhanced response to lisinopril. AER at 2 years (adjusted for baseline AER) was 51.3% lower on lisinopril than placebo in the II genotype patients (95% CI, 15.7 to 71.8; P = 0.01), 14.8% in the ID group (-7.8 to 32.7; P = 0.2), and 7.7% in the DD group (-36.6 to 37.6; P = 0.7). Absolute differences in AER between placebo and lisinopril at 2 years were 8.1, 1.7, and 0.8 microg/min in the II, ID, and DD groups, respectively. The significant beneficial effect of lisinopril on AER in the II group persisted when adjusted for center, blood pressure, and glycemic control, and also for diastolic blood pressure at 1 month into the study. Progression from normoalbuminuria to microalbuminuria (lisinopril versus placebo) was 0.27 (0.03-2.26; P = 0.2) in the II group, and 1.30 (0.33-5.17; P = 0.7) in the DD group (P = 0.6 for interaction). Knowledge of ACE genotype may be of value in determining the likely impact of ACE inhibitor treatment.

  12. Parallel Signal Processing and System Simulation using aCe

    NASA Technical Reports Server (NTRS)

    Dorband, John E.; Aburdene, Maurice F.

    2003-01-01

    Recently, networked and cluster computation have become very popular for both signal processing and system simulation. A new language is ideally suited for parallel signal processing applications and system simulation since it allows the programmer to explicitly express the computations that can be performed concurrently. In addition, the new C based parallel language (ace C) for architecture-adaptive programming allows programmers to implement algorithms and system simulation applications on parallel architectures by providing them with the assurance that future parallel architectures will be able to run their applications with a minimum of modification. In this paper, we will focus on some fundamental features of ace C and present a signal processing application (FFT).

  13. Apigenin: Selective CK2 inhibitor increases Ikaros expression and improves T cell homeostasis and function in murine pancreatic cancer

    PubMed Central

    Nelson, Nadine; Szekeres, Karoly; Iclozan, Cristina; Rivera, Ivannie Ortiz; McGill, Andrew; Johnson, Gbemisola; Nwogu, Onyekachi

    2017-01-01

    Pancreatic cancer (PC) evades immune destruction by favoring the development of regulatory T cells (Tregs) that inhibit effector T cells. The transcription factor Ikaros is critical for lymphocyte development, especially T cells. We have previously shown that downregulation of Ikaros occurs as a result of its protein degradation by the ubiquitin-proteasome system in our Panc02 tumor-bearing (TB) mouse model. Mechanistically, we observed a deregulation in the balance between Casein Kinase II (CK2) and protein phosphatase 1 (PP1), which suggested that increased CK2 activity is responsible for regulating Ikaros’ stability in our model. We also showed that this loss of Ikaros expression is associated with a significant decrease in CD4+ and CD8+ T cell percentages but increased CD4+CD25+ Tregs in TB mice. In this study, we evaluated the effects of the dietary flavonoid apigenin (API), on Ikaros expression and T cell immune responses. Treatment of splenocytes from naïve mice with (API) stabilized Ikaros expression and prevented Ikaros downregulation in the presence of murine Panc02 cells in vitro, similar to the proteasome inhibitor MG132. In vivo treatment of TB mice with apigenin (TB-API) improved survival, reduced tumor weights and prevented splenomegaly. API treatment also restored protein expression of some Ikaros isoforms, which may be attributed to its moderate inhibition of CK2 activity from splenocytes of TB-API mice. This partial restoration of Ikaros expression was accompanied by a significant increase in CD4+ and CD8+ T cell percentages and a reduction in Treg percentages in TB-API mice. In addition, CD8+ T cells from TB-API mice produced more IFN-γ and their splenocytes were better able to prime allogeneic CD8+ T cell responses compared to TB mice. These results provide further evidence that Ikaros is regulated by CK2 in our pancreatic cancer model. More importantly, our findings suggest that API may be a possible therapeutic agent for stabilizing Ikaros

  14. An overview of ACE-Asia: Strategies for quantifying the relationships between Asian aerosols and their climatic impacts

    NASA Astrophysics Data System (ADS)

    Huebert, Barry J.; Bates, Timothy; Russell, Philip B.; Shi, Guangyu; Kim, Young Joon; Kawamura, Kimitaka; Carmichael, Greg; Nakajima, Teruyuki

    2003-12-01

    The International Global Atmospheric Chemistry Program (IGAC) has conducted a series of Aerosol Characterization Experiments (ACE) that integrate in situ measurements, satellite observations, and models to reduce the uncertainty in calculations of the climate forcing due to aerosol particles. ACE-Asia, the fourth in this series of experiments, consisted of two focused components: (1) An intensive field study that sought to quantify the spatial and vertical distribution of aerosol concentrations and properties, the processes controlling their formation, evolution, and fate, and the column-integrated radiative effect of the aerosol (late March through May 2001). (2) A longer-term network of ground stations that used in situ and column-integrated measurements to quantify the chemical, physical, and optical properties of aerosols in the ACE-Asia study area and to assess their spatial and temporal (seasonal and interannual) variability (2000-2003). The approach of the ACE-Asia science team was to make simultaneous measurements of aerosol chemical, physical, and optical properties and their radiative impacts in a variety of air masses, often coordinated with satellite overpasses. Three aircraft, two research ships, a network of lidars, and many surface sites gathered data on Asian aerosols. Chemical transport models (CTMs) were integrated into the program from the start, being used in a forecast mode during the intensive observation period to identify promising areas for airborne and ship observations and then later as tools for integrating observations. The testing and improvement of a wide range of aerosol models (including microphysical, radiative transfer, CTM, and global climate models) was one important way in which we assessed our understanding of the properties and controlling processes of Asian aerosols. We describe here the scientific goals and objectives of the ACE-Asia experiment, its observational strategies, the types of observations made by the mobile

  15. ACES: An Enabling Technology for Next Generation Space Transportation

    NASA Astrophysics Data System (ADS)

    Crocker, Andrew M.; Wuerl, Adam M.; Andrews, Jason E.; Andrews, Dana G.

    2004-02-01

    Andrews Space has developed the ``Alchemist'' Air Collection and Enrichment System (ACES), a dual-mode propulsion system that enables safe, economical launch systems that take off and land horizontally. Alchemist generates liquid oxygen through separation of atmospheric air using the refrigeration capacity of liquid hydrogen. The key benefit of Alchemist is that it minimizes vehicle takeoff weight. All internal and NASA-funded activities have shown that ACES, previously proposed for hypersonic combined cycle RLVs, is a higher payoff, lower-risk technology if LOX generation is performed while the vehicle cruises subsonically. Andrews Space has developed the Alchemist concept from a small system study to viable Next Generation launch system technology, conducting not only feasibility studies but also related hardware tests, and it has planned a detailed risk reduction program which employs an experienced, proven contractor team. Andrews also has participated in preliminary studies of an evolvable Next Generation vehicle architecture-enabled by Alchemist ACES-which could meet civil, military, and commercial space requirements within two decades.

  16. The Louisiana ACES student-built BalloonSat program

    NASA Astrophysics Data System (ADS)

    Ellison, Brad; Giammanco, James; Guzik, T. Gregory; Johnson, Karen; Wefel, John P.

    2006-01-01

    A major concern of many aerospace industries and space agencies worldwide is the continuing decrease in undergraduate student enrollment and graduation from aerospace and closely related degree programs. With a decreasing number of new aerospace workforce candidates, expanding or sustaining our exploration of the universe over the coming decades could be at risk. In Louisiana, we have developed the Aerospace Catalyst Experiences for Students (ACES) program to address this issue by attracting new students to aerospace-related programs and providing interdisciplinary training on how to design, build, and manage aerospace payloads. Based upon the National Space Grant Student Satellite Program "Crawl, Walk, Run, Fly!" methodology, ACES closely ties cross-discipline content knowledge with extensive hands-on experiences to instill skills that are then applied by the students to design, document, build, test, and operate a small balloon-borne scientific payload. The ACES concept was initially piloted during 2002-2003 and now includes a semi-formal "Student Ballooning Course", five Louisiana institutions and serves ˜45 students.

  17. Targeting GRP75 improves HSP90 inhibitor efficacy by enhancing p53-mediated apoptosis in hepatocellular carcinoma.

    PubMed

    Guo, Weiwei; Yan, Lichong; Yang, Ling; Liu, Xiaoyu; E, Qiukai; Gao, Peiye; Ye, Xiaofei; Liu, Wen; Zuo, Ji

    2014-01-01

    Heat shock protein 90 (HSP90) inhibitors are potential drugs for cancer therapy. The inhibition of HSP90 on cancer cell growth largely through degrading client proteins, like Akt and p53, therefore, triggering cancer cell apoptosis. Here, we show that the HSP90 inhibitor 17-AAG can induce the expression of GRP75, a member of heat shock protein 70 (HSP70) family, which, in turn, attenuates the anti-growth effect of HSP90 inhibition on cancer cells. Additionally, 17-AAG enhanced binding of GRP75 and p53, resulting in the retention of p53 in the cytoplasm. Blocking GRP75 with its inhibitor MKT-077 potentiated the anti-tumor effects of 17-AAG by disrupting the formation of GRP75-p53 complexes, thereby facilitating translocation of p53 into the nuclei and leading to the induction of apoptosis-related genes. Finally, dual inhibition of HSP90 and GRP75 was found to significantly inhibit tumor growth in a liver cancer xenograft model. In conclusion, the GRP75 inhibitor MKT-077 enhances 17-AAG-induced apoptosis in HCCs and increases p53-mediated inhibition of tumor growth in vivo. Dual targeting of GRP75 and HSP90 may be a useful strategy for the treatment of HCCs.

  18. Computer-Aided Lead Optimization: Improved Small-Molecule Inhibitor of the Zinc Endopeptidase of Botulinum Neurotoxin Serotype A

    DTIC Science & Technology

    2007-08-01

    the yield of Friedel - Crafts acylation [29,30] for preparing 5 (Figure 3) was reduced to Figure 1. Chemical structures of inhibitors 1 and 2. doi...perform Friedel - Crafts acylation first and then Suzuki coupling (Figure 4); this scheme enables facile derivatization of the phenyl group substituted

  19. Influence of an oil soluble inhibitor on microbiologically influenced corrosion in a diesel transporting pipeline.

    PubMed

    Muthukumar, N; Maruthamuthu, S; Mohanan, S; Palaniswamy, N

    2007-01-01

    Microbial degradation of the oil soluble corrosion inhibitor (OSCI) Baker NC 351 contributed to a decrease in inhibitor efficiency. Corrosion inhibition efficiency was studied by the rotating cage and flow loop methods. The nature of the biodegradation of the corrosion inhibitor was also analysed using Fourier transform infrared spectroscopy, nuclear magnetic resonance spectroscopy and gas chromatography-mass spectrometry. The influence of bacterial activity on the degradation of the corrosion inhibitor and its influence on corrosion of API 5LX were evaluated using a weight loss technique and impedance studies. Serratia marcescens ACE2 and Bacillus cereus ACE4 can degrade aromatic and aliphatic hydrocarbons present in the corrosion inhibitor. The present study also discusses the demerits of the oil soluble corrosion inhibitors used in petroleum product pipeline.

  20. VO2 max is associated with ACE genotype in postmenopausal women.

    PubMed

    Hagberg, J M; Ferrell, R E; McCole, S D; Wilund, K R; Moore, G E

    1998-11-01

    Relationships have frequently been found between angiotensin-converting enzyme (ACE) genotype and various pathological and physiological cardiovascular outcomes and functions. Thus we sought to determine whether ACE genotype affected maximal O2 consumption (VO2 max) and maximal exercise hemodynamics in postmenopausal women with different habitual physical activity levels. Age, body composition, and habitual physical activity levels did not differ among ACE genotype groups. However, ACE insertion/insertion (II) genotype carriers had a 6.3 ml . kg-1 . min-1 higher VO2 max (P < 0.05) than the ACE deletion/deletion (DD) genotype group after accounting for the effect of physical activity levels. The ACE II genotype group also had a 3.3 ml . kg-1 . min-1 higher VO2 max (P < 0.05) than the ACE insertion/deletion (ID) genotype group. The ACE ID group tended to have a higher VO2 max than the DD genotype group, but the difference was not significant. ACE genotype accounted for 12% of the variation in VO2 max among women after accounting for the effect of habitual physical activity levels. The entire difference in VO2 max among ACE genotype groups was the result of differences in maximal arteriovenous O2 difference (a-vDO2). ACE genotype accounted for 17% of the variation in maximal a-vDO2 in these women. Maximal cardiac output index did not differ whatsoever among ACE genotype groups. Thus it appears that ACE genotype accounts for a significant portion of the interindividual differences in VO2 max among these women. However, this difference is the result of genotype-dependent differences in maximal a-vDO2 and not of maximal stroke volume and maximal cardiac output.

  1. Long-term treatment with a phosphodiesterase type 5 inhibitor improves pulmonary hypertension secondary to heart failure through enhancing the natriuretic peptides-cGMP pathway.

    PubMed

    Yamamoto, Takashi; Wada, Atsuyuki; Tsutamoto, Takayoshi; Ohnishi, Masato; Horie, Minoru

    2004-11-01

    In advanced heart failure (HF), the compensatory pulmonary vasodilation is attenuated due to the relative insufficiency of cGMP despite increased secretion of natriuretic peptides (NPs). Phosphodiesterase type 5 (PDE5) inhibitors prevent cGMP degradation, and thus may potentiate the effect of the NPs-cGMP pathway. We orally administered a specific PDE5 inhibitor, T-1032 (1 mg/kg; twice a day, n = 7) or placebo (n = 7) for 2 weeks in dogs with HF induced by rapid pacing (270 bpm, 3 weeks) and examined the plasma levels of atrial natriuretic peptide (ANP), cGMP, and hemodynamic parameters. We also examined the hemodynamic changes after injection of a specific NPs receptor antagonist, HS-142-1 (3 mg/kg), under treatment with T-1032. T-1032 significantly increased plasma cGMP levels compared with the vehicle group despite low plasma ANP levels associated with improvement in cardiopulmonary hemodynamics. HS-142-1 significantly decreased plasma cGMP levels in both groups, whereas it did not change all hemodynamic parameters in the vehicle group. In contrast, in the T-1032 group, HS-142-1 significantly increased pulmonary arterial pressure and pulmonary vascular resistance. These results indicated that long-term treatment with a PDE5 inhibitor improved pulmonary hypertension secondary to HF and the NPs-cGMP pathway contributed to this therapeutic effect.

  2. A new strategy for strain improvement of Aurantiochytrium sp. based on heavy-ions mutagenesis and synergistic effects of cold stress and inhibitors of enoyl-ACP reductase.

    PubMed

    Cheng, Yu-Rong; Sun, Zhi-Jie; Cui, Gu-Zhen; Song, Xiaojin; Cui, Qiu

    2016-11-01

    Developing a strain with high docosahexaenoic acid (DHA) yield and stable fermenting-performance is an imperative way to improve DHA production using Aurantiochytrium sp., a microorganism with two fatty acid synthesis pathways: polyketide synthase (PKS) pathway and Type I fatty acid synthase (FAS) pathway. This study investigated the growth and metabolism response of Aurantiochytrium sp. CGMCC 6208 to two inhibitors of enoyl-ACP reductase of Type II FAS pathway (isoniazid and triclosan), and proposed a method of screening high DHA yield Aurantiochytrium sp. strains with heavy ion mutagenesis and pre-selection by synergistic usage of cold stress (4°C) and FAS inhibitors (triclosan and isoniazid). Results showed that (1) isoniazid and triclosan have positive effects on improving DHA level of cells; (2) mutants from irradiation dosage of 120Gy yielded more DHA compared with cells from 40Gy, 80Gy treatment and wild type; (3) DHA contents of mutants pre-selected by inhibitors of enoyl-ACP reductase of Type II FAS pathway (isoniazid and triclosan)at 4°C, were significantly higher than that of wild type; (4) compared to the wild type, the DHA productivity and yield of a mutant (T-99) obtained from Aurantiochytrium sp. CGMCC 6208 by the proposed method increased by 50% from 0.18 to 0.27g/Lh and 30% from 21 to 27g/L, respectively. In conclusion, this study developed a feasible method to screen Aurantiochytrium sp. with high DHA yield by a combination of heavy-ion mutagenesis and mutant-preselection by FAS inhibitors and cold stress.

  3. Improvement of inhibitor identification for heat shock protein 90α by utilizing a red-shifted fluorescence polarization probe.

    PubMed

    Qian, Jie; Holskin, Beverly P; Theroff, Jay; Underiner, Ted; Meyer, Sheryl L; Angeles, Thelma S

    2012-08-01

    Heat shock protein-90 (HSP90) is an ATP-dependent molecular chaperone with intrinsic ATPase activity. HSP90 is required for the stability and function of client proteins, many of which are involved in oncogenesis. Thus, identification of HSP90 inhibitors would potentially lead to the discovery of cancer therapeutics. Here, we present a high-throughput screening campaign utilizing two geldanamycin (GM)-labeled probes in a fluorescence polarization (FP) assay. For the primary screen, a previously reported green BODIPY-labeled GM (GM-BODIPY) was used to evaluate a library collection of about 400,000 compounds. From this screen, 3058 compounds showed >30% inhibition. To distinguish true positives from compound interference, a confirmatory screen was deemed necessary. Accordingly, a red-shifted FP binding assay was developed using GM labeled with red BODIPY. This tool enabled reliable identification of promising HSP90α inhibitors.

  4. Identification of the major ACE-inhibitory peptides produced by enzymatic hydrolysis of a protein concentrate from cuttlefish wastewater.

    PubMed

    Amado, Isabel Rodríguez; Vázquez, José Antonio; González, Pilar; Esteban-Fernández, Diego; Carrera, Mónica; Piñeiro, Carmen

    2014-03-10

    The aim of this work was the purification and identification of the major angiotensin converting enzyme (ACE) inhibitory peptides produced by enzymatic hydrolysis of a protein concentrate recovered from a cuttlefish industrial manufacturing effluent. This process consisted on the ultrafiltration of cuttlefish softening wastewater, with a 10 kDa cut-off membrane, followed by the hydrolysis with alcalase of the retained fraction. Alcalase produced ACE inhibitors reaching the highest activity (IC₅₀ = 76.8 ± 15.2 μg mL⁻¹) after 8 h of proteolysis. Sequential ultrafiltration of the 8 h hydrolysate with molecular weight cut-off (MWCO) membranes of 10 and 1 kDa resulted in the increased activity of each permeate, with a final IC₅₀ value of 58.4 ± 4.6 μg mL⁻¹. Permeate containing peptides lower than 1 kDa was separated by reversed-phase high performance liquid chromatography (RP-HPLC). Four fractions (A-D) with potent ACE inhibitory activity were isolated and their main peptides identified using high performance liquid chromatography coupled to an electrospray ion trap Fourier transform ion cyclotron resonance-mass spectrometer (HPLC-ESI-IT-FTICR) followed by comparison with databases and de novo sequencing. The amino acid sequences of the identified peptides contained at least one hydrophobic and/or a proline together with positively charged residues in at least one of the three C-terminal positions. The IC₅₀ values of the fractions ranged from 1.92 to 8.83 μg mL⁻¹, however this study fails to identify which of these peptides are ultimately responsible for the potent antihypertensive activity of these fractions.

  5. Identification of the Major ACE-Inhibitory Peptides Produced by Enzymatic Hydrolysis of a Protein Concentrate from Cuttlefish Wastewater

    PubMed Central

    Rodríguez Amado, Isabel; Vázquez, José Antonio; González, Pilar; Esteban-Fernández, Diego; Carrera, Mónica; Piñeiro, Carmen

    2014-01-01

    The aim of this work was the purification and identification of the major angiotensin converting enzyme (ACE) inhibitory peptides produced by enzymatic hydrolysis of a protein concentrate recovered from a cuttlefish industrial manufacturing effluent. This process consisted on the ultrafiltration of cuttlefish softening wastewater, with a 10 kDa cut-off membrane, followed by the hydrolysis with alcalase of the retained fraction. Alcalase produced ACE inhibitors reaching the highest activity (IC50 = 76.8 ± 15.2 μg mL−1) after 8 h of proteolysis. Sequential ultrafiltration of the 8 h hydrolysate with molecular weight cut-off (MWCO) membranes of 10 and 1 kDa resulted in the increased activity of each permeate, with a final IC50 value of 58.4 ± 4.6 μg mL−1. Permeate containing peptides lower than 1 kDa was separated by reversed-phase high performance liquid chromatography (RP-HPLC). Four fractions (A–D) with potent ACE inhibitory activity were isolated and their main peptides identified using high performance liquid chromatography coupled to an electrospray ion trap Fourier transform ion cyclotron resonance-mass spectrometer (HPLC-ESI-IT-FTICR) followed by comparison with databases and de novo sequencing. The amino acid sequences of the identified peptides contained at least one hydrophobic and/or a proline together with positively charged residues in at least one of the three C-terminal positions. The IC50 values of the fractions ranged from 1.92 to 8.83 μg mL−1, however this study fails to identify which of these peptides are ultimately responsible for the potent antihypertensive activity of these fractions. PMID:24619242

  6. Technology advancement for the ASCENDS mission using the ASCENDS CarbonHawk Experiment Simulator (ACES)

    NASA Astrophysics Data System (ADS)

    Obland, M. D.; Antill, C.; Browell, E. V.; Campbell, J. F.; CHEN, S.; Cleckner, C.; Dijoseph, M. S.; Harrison, F. W.; Ismail, S.; Lin, B.; Meadows, B. L.; Mills, C.; Nehrir, A. R.; Notari, A.; Prasad, N. S.; Kooi, S. A.; Vitullo, N.; Dobler, J. T.; Bender, J.; Blume, N.; Braun, M.; Horney, S.; McGregor, D.; Neal, M.; Shure, M.; Zaccheo, T.; Moore, B.; Crowell, S.; Rayner, P. J.; Welch, W.

    2013-12-01

    The ASCENDS CarbonHawk Experiment Simulator (ACES) is a NASA Langley Research Center project funded by NASA's Earth Science Technology Office that seeks to advance technologies critical to measuring atmospheric column carbon dioxide (CO2) mixing ratios in support of the NASA Active Sensing of CO2 Emissions over Nights, Days, and Seasons (ASCENDS) mission. The technologies being advanced are: (1) multiple transmitter and telescope-aperture operations, (2) high-efficiency CO2 laser transmitters, (3) a high bandwidth detector and transimpedance amplifier (TIA), and (4) advanced algorithms for cloud and aerosol discrimination. The instrument architecture is being developed for ACES to operate on a high-altitude aircraft, and it will be directly scalable to meet the ASCENDS mission requirements. The above technologies are critical for developing an airborne simulator and spaceborne instrument with lower platform consumption of size, mass, and power, and with improved performance. This design employs several laser transmitters and telescope-apertures to demonstrate column CO2 retrievals with alignment of multiple laser beams in the far-field. ACES will transmit five laser beams: three from commercial lasers operating near 1.57-microns, and two from the Exelis atmospheric oxygen (O2) fiber laser amplifier system operating near 1.26-microns. The Master Oscillator Power Amplifier at 1.57-microns measures CO2 column concentrations using an Integrated-Path Differential Absorption (IPDA) lidar approach. O2 column amounts needed for calculating the CO2 mixing ratio will be retrieved using the Exelis laser system with a similar IPDA approach. The three aperture telescope design was built to meet the constraints of the Global Hawk high-altitude unmanned aerial vehicle (UAV). This assembly integrates fiber-coupled transmit collimators for all of the laser transmitters and fiber-coupled optical signals from the three telescopes to the aft optics and detector package. The detector

  7. The Role of Neprilysin Inhibitors in Cardiovascular Disease.

    PubMed

    Mills, Jared; Vardeny, Orly

    2015-12-01

    Heart failure affects over five million Americans each year and contributes to morbidity, mortality, and high health care costs. Despite the benefits of RAAS and SNS blockers, 5-year survival rates in patients with heart failure remain low, necessitating continued research and new drug targets. LCZ696 (sacubitril/valsartan) is an angiotensin-receptor neprilysin inhibitor recently approved for HFrEF, with dual actions that result in enhancement of natriuretic peptide levels and blockade of angiotensin II activities. This drug shows promise in further improving clinical outcomes in HFrEF and is being studied in patients with HFpEF. In the PARADIGM-HF study, LCZ696 (sacubitril/valsartan) was shown to reduce the composite of cardiovascular mortality and heart failure hospitalizations compared with enalapril in patients with HFrEF taking guideline-directed medical therapies and resulted in prolonged survival. In trials, hypotension occurred more frequently with LCZ696 (sacubitril/valsartan) compared to an ACE inhibitor, warranting careful dose titration. Further clinical experience with LCZ696 (sacubitril/valsartan) will provide additional information on tolerability in a broad range of patients of various demographics.

  8. Accessory cholera enterotoxin, Ace, from Vibrio cholerae: structure, unfolding, and virstatin binding.

    PubMed

    Chatterjee, Tanaya; Mukherjee, Debadrita; Dey, Sucharita; Pal, Aritrika; Hoque, Kazi Mirajul; Chakrabarti, Pinak

    2011-04-12

    Vibrio cholerae accessory cholera enterotoxin (Ace) is the third toxin, along with cholera toxin (CT) and zonula occludens toxin (Zot), that causes the endemic disease cholera. Structural characterization of Ace has been restricted because of the limited production of this toxic protein by V. cholerae. We have cloned, overexpressed, and purified Ace from V. cholerae strain O395 in Escherichia coli to homogeneity and determined its biological activity. The unfolding of the purified protein was investigated using circular dichroism and intrinsic tryptophan fluorescence. Because Ace is predominantly a hydrophobic protein, the degree of exposure of hydrophobic regions was identified from the spectral changes of the environment-sensitive fluorescent probe 4,4'-dianilino-1,1'-binaphthyl-5,5'-disulfonic acid (bis-ANS) that quenches the fluorescence of tryptophan residues of Ace in a concentration-dependent manner. Results showed that bis-ANS binds one monomeric unit of Ace with a 1:1 stoichiometry and a K' of 0.72 μM. Ace exists as a dimer, with higher oligomeric forms appearing upon glutaraldehyde cross-linking. This study also reports the binding of virstatin, a small molecule that inhibits virulence regulation in V. cholerae, to Ace. The binding constant (K=9×10(4) M(-1)) and the standard free energy change (ΔG°=-12 kcal mol(-1)) of Ace-virstatin interaction have been evaluated by the fluorescence quenching method. The binding does not affect the oligomeric status of Ace. A cell viability assay of the antibacterial activity of Ace has been performed using various microbial strains. A homology model of Ace, consistent with the experimental results, has been constructed.

  9. Brain ACE2 shedding contributes to the development of neurogenic hypertension

    PubMed Central

    Chhabra, Kavaljit H.; Lazartigues, Eric

    2015-01-01

    Rationale Over-activity of the brain Renin Angiotensin System (RAS) is a major contributor to neurogenic hypertension. While over-expression of Angiotensin-Converting Enzyme type 2 (ACE2) has been shown to be beneficial in reducing hypertension by transforming Angiotensin (Ang)-II into Ang-(1-7), several groups have reported decreased brain ACE2 expression and activity during the development of hypertension. Objective We hypothesized that ADAM17-mediated ACE2 shedding results in decreased membrane-bound ACE2 in the brain, thus promoting the development of neurogenic hypertension. Methods and Results To test this hypothesis, we used the DOCA-salt model of neurogenic hypertension in non-transgenic (NT) and syn-hACE2 mice over-expressing ACE2 in neurons. DOCA-salt treatment in NT mice led to significant increases in blood pressure, hypothalamic Ang-II levels, inflammation, impaired baroreflex sensitivity, autonomic dysfunction, as well as decreased hypothalamic ACE2 activity and expression, while these changes were blunted or prevented in syn-hACE2 mice. In addition, reduction of ACE2 expression and activity in the brain paralleled a rise in ACE2 activity in the cerebrospinal fluid of NT mice following DOCA-salt treatment and was accompanied by enhanced ADAM17 expression and activity in the hypothalamus. Chronic knockdown of ADAM17 in the brain blunted the development of hypertension and restored ACE2 activity and baroreflex function. Conclusions Our data provide the first evidence that ADAM17-mediated shedding impairs brain ACE2 compensatory activity, thus contributing to the development of neurogenic hypertension. PMID:24014829

  10. Extension of the ACE solar panels is tested in SAEF-II

    NASA Technical Reports Server (NTRS)

    1997-01-01

    Extension of the solar panels is tested on the Advanced Composition Explorer (ACE) spacecraft in KSC's Spacecraft Assembly and Encapsulation Facility-II (SAEF-II). Scheduled for launch on a Delta II rocket from Cape Canaveral Air Station on Aug. 25, ACE will study low-energy particles of solar origin and high-energy galactic particles. The collecting power of instruments aboard ACE is 10 to 1,000 times greater than anything previously flown to collect similar data by NASA.

  11. ACE2 orthologues in non-mammalian vertebrates (Danio, Gallus, Fugu, Tetraodon and Xenopus).

    PubMed

    Chou, Chih-Fong; Loh, Chay Boon; Foo, Yik Khoon; Shen, Shuo; Fielding, Burtram C; Tan, Timothy H P; Khan, Sehaam; Wang, Yue; Lim, Seng Gee; Hong, Wanjin; Tan, Yee-Joo; Fu, Jianlin

    2006-08-01

    Angiotensin-converting enzyme 2 (ACE2), a newly identified member in the renin-angiotensin system (RAS), acts as a negative regulator of ACE. It is mainly expressed in cardiac blood vessels and the tubular epithelia of kidneys and abnormal expression has been implicated in diabetes, hypertension and heart failure. The mechanism and physiological function of this zinc metallopeptidase in mammals are not yet fully understood. Non-mammalian vertebrate models offer attractive and simple alternatives that could facilitate the exploration of ACE2 function. In this paper we report the in silico analysis of Ace2 genes from the Gallus (chicken), Xenopus (frog), Fugu and Tetraodon (pufferfish) genome assembly databases, and from the Danio (zebrafish) cDNA library. Exon ambiguities of Danio and Xenopus Ace2s were resolved by RT-PCR and 3'RACE. Analyses of the exon-intron structures, alignment, phylogeny and hydrophilicity plots, together with the conserved synteny among these vertebrates, support the orthologous relationship between mammalian and non-mammalian ACE2s. The putative promoters of Ace2 from human, Tetraodon and Xenopus tropicalis drove the expression of enhanced green fluorescent protein (EGFP) specifically in the heart tissue of transgenic Xenopus thus making it a suitable model for future functional genomic studies. Additionally, the search for conserved cis-elements resulted in the discovery of WGATAR motifs in all the putative Ace2 promoters from 7 different animals, suggesting a possible role of GATA family transcriptional factors in regulating the expression of Ace2.

  12. CD36/Sirtuin 1 Axis Impairment Contributes to Hepatic Steatosis in ACE2-Deficient Mice

    PubMed Central

    Qadri, Fatimunnisa; Penninger, Josef M.; Santos, Robson Augusto S.; Bader, Michael

    2016-01-01

    Background and Aims. Angiotensin converting enzyme 2 (ACE2) is an important component of the renin-angiotensin system. Since angiotensin peptides have been shown to be involved in hepatic steatosis, we aimed to evaluate the hepatic lipid profile in ACE2-deficient (ACE2−/y) mice. Methods. Male C57BL/6 and ACE2−/y mice were analyzed at the age of 3 and 6 months for alterations in the lipid profiles of plasma, faeces, and liver and for hepatic steatosis. Results. ACE2−/y mice showed lower body weight and white adipose tissue at all ages investigated. Moreover, these mice had lower levels of cholesterol, triglycerides, and nonesterified fatty acids in plasma. Strikingly, ACE2−/y mice showed high deposition of lipids in the liver. Expression of CD36, a protein involved in the uptake of triglycerides in liver, was increased in ACE2−/y mice. Concurrently, these mice exhibited an increase in hepatic oxidative stress, evidenced by increased lipid peroxidation and expression of uncoupling protein 2, and downregulation of sirtuin 1. ACE2−/y mice also showed impairments in glucose metabolism and insulin signaling in the liver. Conclusions. Deletion of ACE2 causes CD36/sirtuin 1 axis impairment and thereby interferes with lipid homeostasis, leading to lipodystrophy and steatosis. PMID:28101297

  13. The Aspergillus fumigatus Transcription Factor Ace2 Governs Pigment Production, Conidiation and Virulence

    PubMed Central

    Ejzykowicz, Daniele E.; Cunha, Marcel M.; Rozental, Sonia; Solis, Norma V.; Gravelat, Fabrice N.; Sheppard, Donald C.; Filler, Scott G.

    2009-01-01

    Summary Aspergillus fumigatus causes serious and frequently fatal infections in immunocompromised patients. To investigate the regulation of virulence of this fungus, we constructed and analyzed an A. fumigatus mutant that lacked the transcription factor Ace2, which influences virulence in other fungi. The Δace2 mutant had dysmorphic conidiophores, reduced conidia production, and abnormal conidial cell wall architecture. This mutant produced an orange pigment when grown on solid media, although its conidia had normal pigmentation. Conidia of the Δace2 mutant were larger and had accelerated germination. The resulting germlings were resistant to hydrogen peroxide, but not other stressors. Non-neutropenic mice that were immunosuppressed with cortisone acetate and infected with the Δace2 mutant had accelerated mortality, greater pulmonary fungal burden, and increased pulmonary inflammatory responses compared to mice infected with the wild-type or Δace2∷ace2 complemented strains. The Δace2 mutant had reduced ppoC, ecm33, and ags3 mRNA expression. It is known that A. fumigatus mutants with absent or reduced expression of these genes have increased virulence in mice, as well as other phenotypic similarities to the Δace2 mutant. Therefore, reduced expression of these genes likely contributes to the increased virulence of the Δace2 mutant. PMID:19220748

  14. CD36/Sirtuin 1 Axis Impairment Contributes to Hepatic Steatosis in ACE2-Deficient Mice.

    PubMed

    Nunes-Souza, Valéria; Alenina, Natalia; Qadri, Fatimunnisa; Penninger, Josef M; Santos, Robson Augusto S; Bader, Michael; Rabelo, Luiza A

    2016-01-01

    Background and Aims. Angiotensin converting enzyme 2 (ACE2) is an important component of the renin-angiotensin system. Since angiotensin peptides have been shown to be involved in hepatic steatosis, we aimed to evaluate the hepatic lipid profile in ACE2-deficient (ACE2(-/y)) mice. Methods. Male C57BL/6 and ACE2(-/y) mice were analyzed at the age of 3 and 6 months for alterations in the lipid profiles of plasma, faeces, and liver and for hepatic steatosis. Results. ACE2(-/y) mice showed lower body weight and white adipose tissue at all ages investigated. Moreover, these mice had lower levels of cholesterol, triglycerides, and nonesterified fatty acids in plasma. Strikingly, ACE2(-/y) mice showed high deposition of lipids in the liver. Expression of CD36, a protein involved in the uptake of triglycerides in liver, was increased in ACE2(-/y) mice. Concurrently, these mice exhibited an increase in hepatic oxidative stress, evidenced by increased lipid peroxidation and expression of uncoupling protein 2, and downregulation of sirtuin 1. ACE2(-/y) mice also showed impairments in glucose metabolism and insulin signaling in the liver. Conclusions. Deletion of ACE2 causes CD36/sirtuin 1 axis impairment and thereby interferes with lipid homeostasis, leading to lipodystrophy and steatosis.

  15. Rediscovering ACE: Novel insights into the many roles of the angiotensin-converting enzyme

    PubMed Central

    Gonzalez-Villalobos, Romer A.; Shen, Xiao Z.; Bernstein, Ellen A.; Janjulia, Tea; Taylor, Brian; Giani, Jorge F.; Blackwell, Wendell-Lamar B.; Shah, Kandarp H.; Shi, Peng D.; Fuchs, Sebastien; Bernstein, Kenneth E.

    2013-01-01

    Angiotensin converting enzyme (ACE) is best known for the catalytic conversion of angiotensin I to angiotensin II. However, the use of gene-targeting techniques has led to mouse models highlighting many other biochemical properties and actions of this enzyme. This review discusses recent studies examining the functional significance of ACE tissue-specific expression and the presence in ACE of two independent catalytic sites with distinct substrates and biological effects. It is these features which explain why ACE makes important contributions to many different physiological processes including renal development, blood pressure control, inflammation and immunity. PMID:23686164

  16. RNAi of ace1 and ace2 in Blattella germanica reveals their differential contribution to acetylcholinesterase activity and sensitivity to insecticides.

    PubMed

    Revuelta, L; Piulachs, M D; Bellés, X; Castañera, P; Ortego, F; Díaz-Ruíz, J R; Hernández-Crespo, P; Tenllado, F

    2009-12-01

    Cyclorrhapha insect genomes contain a single acetylcholinesterase (AChE) gene while other insects contain at least two ace genes (ace1 and ace2). In this study we tested the hypothesis that the two ace paralogous from Blattella germanica have different contributions to AChE activity, using RNA interference (RNAi) to knockdown each one individually. Paralogous-specific depletion of Bgace transcripts was evident in ganglia of injected cockroaches, although the effects at the protein level were less pronounced. Using spectrophotometric and zymogram measurements, we obtained evidence that BgAChE1 represents 65-75% of the total AChE activity in nerve tissue demonstrating that ace1 encodes a predominant AChE. A significant increase in sensitivity of Bgace1-interfered cockroaches was observed after 48 h of exposure to chlorpyrifos. In contrast, Bgace2 knockdown had a negligible effect on mortality to this organophosphate. These results point out a key role, qualitative and/or quantitative, of AChE1 as target of organophosphate insecticides in this species. Silencing the expression of Bgace1 but not Bgace2 also produced an increased mortality in insects when synergized with lambda-cyhalothrin, a situation which resembles the synergistic effects observed between organophosphates and pyrethroids. Gene silencing of ace genes by RNAi offers an exciting approach for examining a possible functional differentiation in ace paralogous.

  17. Helium at Interplanetary Discontinuities: ACE STEREO Observations and Simulations

    NASA Astrophysics Data System (ADS)

    Moebius, E.; Kucharek, H.; Allegrini, F.; Desai, M.; Klecker, B.; Popecki, M.; Farrugia, C.; Galvin, A.; Bochsler, P.; Karrer, R.; Opitz, A.; Simunac, K.

    2007-12-01

    ACE/SEPICA observations showed that, on average, energetic He+ is after H+ and He2+ the third most abundant energetic particle species in the heliosphere. Depending on the type of the energetic population the He+/He2+ ratio can reach unusually high values in the energy range 250 - 800keV/n ratios up to unity. As a major source of energetic He+ interplanetary pickup ions have been identified that are preferentially accelerated at co-rotating interaction regions (CIRs), transient interaction regions (TIRs), and interplanetary traveling shocks. Most recent data from STEREO/PLASTIC in the energy range of 0.2-80keV/Q show clear evidence of abundant He+ at interplanetary discontinuities. Thus PLASTIC extends the energy range into injection region of the source. Furthermore, ACE/ULEIS and ACE/SEPICA measurements showed that very often 3He2+ and He+ are also accelerated simultaneously at CME-driven IP shocks. This is surprising because, these to species originate from different sources. However, this may indicate that the injection, or the acceleration efficiency of the accelerator for different source population may be similar. From observations, however, this cannot be differentiated easily. In numerical simulations this can be done because there is control over species and distribution functions. In a numerical study we applied test particle simulations and multi-dimensional hybrid simulations to address the contribution of source, injection and acceleration efficiency at shocks to the variability of the helium ratio. These, simulations with and without superimposed turbulence in the shock region will be compared with observations.

  18. A review of the preclinical cardiovascular pharmacology of cilazapril, a new angiotensin converting enzyme inhibitor

    PubMed Central

    Waterfall, J. F.

    1989-01-01

    1 Cilazapril is the monoethyl ester prodrug form of the di-acid cilazaprilat, a new angiotensin converting enzyme (ACE) inhibitor. Cilazaprilat has an IC50 of 1.9 nM as an inhibitor of rabbit lung ACE in vitro making it one of the most potent ACE inhibitors currently available. Studies on a wide range of other enzymes show that the inhibition is highly specific. 2 An oral dose of 0.1 mg kg-1 cilazapril evoked the same maximum degree of plasma ACE inhibition (∼76%) in the rat as 0.25 mg kg-1 enalapril. Cilazapril (0.25 mg kg-1 p.o.) inhibited plasma ACE by > 95%. The rate of recovery of ACE activity was slower with cilazapril (5-6% h-1) than with enalapril (10% h-1). 3 In anaesthetised rats cilazaprilat was equipotent with ramiprilat and slightly more potent (1.5×) than enalaprilat as an inhibitor of the angiotensin I pressor response. 4 Following oral administration to conscious rats and intravenous administration to anaesthetised dogs, cilazapril was 2-4.5× more potent than enalapril as an ACE inhibitor. 5 In cats cilazapril (0.1 and 0.3 mg kg-1 p.o.) dose dependently decreased plasma ACE activity and the angiotensin pressor response. Peak effects occurred at 2 h after dosing and plasma ACE inhibition was maintained at ≥ 50% for up to 18 h. Mean arterial pressure was also decreased dose dependently with a peak effect at 3-4 h. 6 Daily oral dosing of cilazapril (30 mg kg-1 p.o.) to spontaneously hypertensive rats evoked a progressive and prolonged (24 h) antihypertensive response with a maximum decrease in systolic blood pressure of 110 mm Hg. 7 Cilazapril (10 mg kg-1 p.o. twice daily for 3.5 days) progressively decreased blood pressure in volume depleted renal hypertensive dogs. The maximum fall in systolic pressure was 39 ± 6 mm Hg. 8 Haemodynamic studies in open chest anaesthetised dogs showed that the hypotensive response to intravenous cilazapril was accompanied by a reduction in total peripheral resistance. Small decreases in cardiac output and

  19. Use of buckwheat seed protease inhibitor gene for improvement of tobacco and potato plant resistance to biotic stress.

    PubMed

    Khadeeva, N V; Kochieva, E Z; Tcherednitchenko, M Yu; Yakovleva, E Yu; Sydoruk, K V; Bogush, V G; Dunaevsky, Y E; Belozersky, M A

    2009-03-01

    The possibility to use agrobacterial transformation of leaf discs to produce resistance to bacterial infections in tobacco and potato plants by introduction of a single gene encoding the serine proteinase inhibitor BWI-1a (ISP) from buckwheat seeds is shown. All studied PCR-positive transgenic plants exhibited antibacterial activity in biotests. It was shown that the presence of just a single gene of serine proteinase inhibitor provides sufficient protection at least against two bacterial phytopathogens, Pseudomonas syringae pv. tomato and Clavibacter michiganensis sbsp. michiganensis. The biotest including tobacco plant infection by the white wings butterfly in the green house has also demonstrated the existence of protective effect in transgenic tobacco plants. Significant genotypic variations in the protection efficiency were found between members of different genera of the same family (potato and tobacco) as well as between different lines of the same species. Northern blot analysis of four transgenic potato lines and three tobacco lines transformed by a vector plasmid containing the ISP gene of serine proteinases BWI-1a from buckwheat seeds has shown the presence of the expected size mRNA transcript.

  20. Photothermal therapy improves the efficacy of a MEK inhibitor in neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors

    NASA Astrophysics Data System (ADS)

    Sweeney, Elizabeth E.; Burga, Rachel A.; Li, Chaoyang; Zhu, Yuan; Fernandes, Rohan

    2016-11-01

    Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive tumors with low survival rates and the leading cause of death in neurofibromatosis type 1 (NF1) patients under 40 years old. Surgical resection is the standard of care for MPNSTs, but is often incomplete and can generate loss of function, necessitating the development of novel treatment methods for this patient population. Here, we describe a novel combination therapy comprising MEK inhibition and nanoparticle-based photothermal therapy (PTT) for MPNSTs. MEK inhibitors block activity driven by Ras, an oncogene constitutively activated in NF1-associated MPNSTs, while PTT serves as a minimally invasive method to ablate cancer cells. Our rationale for combining these seemingly disparate techniques for MPNSTs is based on several reports demonstrating the efficacy of systemic chemotherapy with local PTT. We combine the MEK inhibitor, PD-0325901 (PD901), with Prussian blue nanoparticles (PBNPs) as PTT agents, to block MEK activity and simultaneously ablate MPNSTs. Our data demonstrate the synergistic effect of combining PD901 with PBNP-based PTT, which converge through the Ras pathway to generate apoptosis, necrosis, and decreased proliferation, thereby mitigating tumor growth and increasing survival of MPNST-bearing animals. Our results suggest the potential of this novel local-systemic combination “nanochemotherapy” for treating patients with MPNSTs.

  1. Improvement of the Dimensional Stability of Powder Injection Molded Compacts by Adding Swelling Inhibitor into the Debinding Solvent

    NASA Astrophysics Data System (ADS)

    Fan, Yang-Liang; Hwang, Kuen-Shyang; Su, Shao-Chin

    2008-02-01

    Defects are frequently found in powder injection molded (PIM) compacts during solvent debinding due to the swelling of the binders. This problem can be alleviated by adjusting the composition of the debinding solvent. In this study, 10 vol pct swelling inhibitors were added into heptane, and the in-situ amounts of swelling and sagging of the specimen in the solvent were recorded using a noncontacting laser dilatometer. The results show that the addition of ethanol, 2-propanol, 1-butanol, and 1-pentanol reduced the amounts of swelling by 31, 21, 17, and 11 pct, respectively. This was because the small molecule alcohols, which do not dissolve paraffin wax (PW) or stearic acid (SA) in the binder system, could diffuse easily into the specimen and increased the portion of the swelling inhibitor inside. The amount of the extracted PW and SA also decreased, but only by 8.3, 6.1, 4.3, and 2.4 pct, respectively. The solubility parameters of 1-bromopropane (n-PB) and ethyl acetate (EA) are between those of heptane and alcohols, and they also yielded a slight reduction in the amounts of swelling by 6 and 11 pct, respectively. These results suggest that to reduce defects caused by binder swelling during solvent debinding, alcohols with high solubility parameters can be added into heptane without sacrificing significantly on the debinding rate.

  2. Photothermal therapy improves the efficacy of a MEK inhibitor in neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors

    PubMed Central

    Sweeney, Elizabeth E.; Burga, Rachel A.; Li, Chaoyang; Zhu, Yuan; Fernandes, Rohan

    2016-01-01

    Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive tumors with low survival rates and the leading cause of death in neurofibromatosis type 1 (NF1) patients under 40 years old. Surgical resection is the standard of care for MPNSTs, but is often incomplete and can generate loss of function, necessitating the development of novel treatment methods for this patient population. Here, we describe a novel combination therapy comprising MEK inhibition and nanoparticle-based photothermal therapy (PTT) for MPNSTs. MEK inhibitors block activity driven by Ras, an oncogene constitutively activated in NF1-associated MPNSTs, while PTT serves as a minimally invasive method to ablate cancer cells. Our rationale for combining these seemingly disparate techniques for MPNSTs is based on several reports demonstrating the efficacy of systemic chemotherapy with local PTT. We combine the MEK inhibitor, PD-0325901 (PD901), with Prussian blue nanoparticles (PBNPs) as PTT agents, to block MEK activity and simultaneously ablate MPNSTs. Our data demonstrate the synergistic effect of combining PD901 with PBNP-based PTT, which converge through the Ras pathway to generate apoptosis, necrosis, and decreased proliferation, thereby mitigating tumor growth and increasing survival of MPNST-bearing animals. Our results suggest the potential of this novel local-systemic combination “nanochemotherapy” for treating patients with MPNSTs. PMID:27833160

  3. Chelation: a fundamental mechanism of action of AGE inhibitors, AGE breakers, and other inhibitors of diabetes complications.

    PubMed

    Nagai, Ryoji; Murray, David B; Metz, Thomas O; Baynes, John W

    2012-03-01

    This article outlines evidence that advanced glycation end product (AGE) inhibitors and breakers act primarily as chelators, inhibiting metal-catalyzed oxidation reactions that catalyze AGE formation. We then present evidence that chelation is the most likely mechanism by which ACE inhibitors, angiotensin receptor blockers, and aldose reductase inhibitors inhibit AGE formation in diabetes. Finally, we note several recent studies demonstrating therapeutic benefits of chelators for diabetic cardiovascular and renal disease. We conclude that chronic, low-dose chelation therapy deserves serious consideration as a clinical tool for prevention and treatment of diabetes complications.

  4. Use of a small molecule cell cycle inhibitor to control cell growth and improve specific productivity and product quality of recombinant proteins in CHO cell cultures

    PubMed Central

    Du, Zhimei; Treiber, David; McCarter, John D; Fomina-Yadlin, Dina; Saleem, Ramsey A; McCoy, Rebecca E; Zhang, Yuling; Tharmalingam, Tharmala; Leith, Matthew; Follstad, Brian D; Dell, Brad; Grisim, Brent; Zupke, Craig; Heath, Carole; Morris, Arvia E; Reddy, Pranhitha

    2015-01-01

    The continued need to improve therapeutic recombinant protein productivity has led to ongoing assessment of appropriate strategies in the biopharmaceutical industry to establish robust processes with optimized critical variables, that is, viable cell density (VCD) and specific productivity (product per cell, qP). Even though high VCD is a positive factor for titer, uncontrolled proliferation beyond a certain cell mass is also undesirable. To enable efficient process development to achieve consistent and predictable growth arrest while maintaining VCD, as well as improving qP, without negative impacts on product quality from clone to clone, we identified an approach that directly targets the cell cycle G1-checkpoint by selectively inhibiting the function of cyclin dependent kinases (CDK) 4/6 with a small molecule compound. Results from studies on multiple recombinant Chinese hamster ovary (CHO) cell lines demonstrate that the selective inhibitor can mediate a complete and sustained G0/G1 arrest without impacting G2/M phase. Cell proliferation is consistently and rapidly controlled in all recombinant cell lines at one concentration of this inhibitor throughout the production processes with specific productivities increased up to 110 pg/cell/day. Additionally, the product quality attributes of the mAb, with regard to high molecular weight (HMW) and glycan profile, are not negatively impacted. In fact, high mannose is decreased after treatment, which is in contrast to other established growth control methods such as reducing culture temperature. Microarray analysis showed major differences in expression of regulatory genes of the glycosylation and cell cycle signaling pathways between these different growth control methods. Overall, our observations showed that cell cycle arrest by directly targeting CDK4/6 using selective inhibitor compound can be utilized consistently and rapidly to optimize process parameters, such as cell growth, qP, and glycosylation profile in

  5. HMG-CoA reductase inhibitor improves endothelial dysfunction in spontaneous hypertensive rats via down-regulation of caveolin-1 and activation of endothelial nitric oxide synthase.

    PubMed

    Suh, Jung-Won; Choi, Dong-Ju; Chang, Hyuk-Jae; Cho, Young-Seok; Youn, Tae-Jin; Chae, In-Ho; Kim, Kwang-Il; Kim, Cheol-Ho; Kim, Hyo-Soo; Oh, Buyng-Hee; Park, Young-Bae

    2010-01-01

    Hypertension is associated with endothelial dysfunction and increased cardiovascular risk. Caveolin-1 regulates nitric oxide (NO) signaling by modulating endothelial nitric oxide synthase (eNOS). The purpose of this study was to examine whether HMG-CoA reductase inhibitor improves impaired endothelial function of the aorta in spontaneous hypertensive rat (SHR) and to determine the underlying mechanisms involved. Eight-week-old male SHR were assigned to either a control group (CON, n=11) or a rosuvastatin group (ROS, n=12), rosuvastatin (10 mg/kg/day) administered for eight weeks. Abdominal aortic rings were prepared and responses to acetylcholine (10(-9)-10(-4) M) were determined in vitro. To evaluate the potential role of NO and caveolin-1, we examined the plasma activity of NOx, eNOS, phosphorylated-eNOS and expression of caveolin-1. The relaxation in response to acetylcholine was significantly enhanced in ROS compared to CON. Expression of eNOS RNA was unchanged, whereas NOx level and phosphorylated-eNOS at serine-1177 was increased accompanied with depressed level of caveolin-1 in ROS. We conclude that 3-Hydroxy-3-methylglutaryl Coenzyme-A (HMG-CoA) reductase inhibitor can improve impaired endothelial dysfunction in SHR, and its underlying mechanisms are associated with increased NO production. Furthermore, HMG-CoA reductase inhibitor can activate the eNOS by phosphorylation related to decreased caveolin-1 abundance. These results imply the therapeutic strategies for the high blood pressure-associated endothelial dysfunction through modifying caveolin status.

  6. Saturated- and n-6 polyunsaturated-fat diets each induce ceramide accumulation in mouse skeletal muscle: reversal and improvement of glucose tolerance by lipid metabolism inhibitors.

    PubMed

    Frangioudakis, G; Garrard, J; Raddatz, K; Nadler, J L; Mitchell, T W; Schmitz-Peiffer, C

    2010-09-01

    Lipid-induced insulin resistance is associated with intracellular accumulation of inhibitory intermediates depending on the prevalent fatty acid (FA) species. In cultured myotubes, ceramide and phosphatidic acid (PA) mediate the effects of the saturated FA palmitate and the unsaturated FA linoleate, respectively. We hypothesized that myriocin (MYR), an inhibitor of de novo ceramide synthesis, would protect against glucose intolerance in saturated fat-fed mice, while lisofylline (LSF), a functional inhibitor of PA synthesis, would protect unsaturated fat-fed mice. Mice were fed diets enriched in saturated fat, n-6 polyunsaturated fat, or chow for 6 wk. Saline, LSF (25 mg/kg x d), or MYR (0.3 mg/kg x d) were administered by mini-pumps in the final 4 wk. Glucose homeostasis was examined by glucose tolerance test. Muscle ceramide and PA were analyzed by mass spectrometry. Expression of LASS isoforms (ceramide synthases) was evaluated by immunoblotting. Both saturated and polyunsaturated fat diets increased muscle ceramide and induced glucose intolerance. MYR and LSF reduced ceramide levels in saturated and unsaturated fat-fed mice. Both inhibitors also improved glucose tolerance in unsaturated fat-fed mice, but only LSF was effective in saturated fat-fed mice. The discrepancy between ceramide and glucose tolerance suggests these improvements may not be related directly to changes in muscle ceramide and may involve other insulin-responsive tissues. Changes in the expression of LASS1 were, however, inversely correlated with alterations in glucose tolerance. The demonstration that LSF can ameliorate glucose intolerance in vivo independent of the dietary FA type indicates it may be a novel intervention for the treatment of insulin resistance.

  7. Use of a small molecule cell cycle inhibitor to control cell growth and improve specific productivity and product quality of recombinant proteins in CHO cell cultures.

    PubMed

    Du, Zhimei; Treiber, David; McCarter, John D; Fomina-Yadlin, Dina; Saleem, Ramsey A; McCoy, Rebecca E; Zhang, Yuling; Tharmalingam, Tharmala; Leith, Matthew; Follstad, Brian D; Dell, Brad; Grisim, Brent; Zupke, Craig; Heath, Carole; Morris, Arvia E; Reddy, Pranhitha

    2015-01-01

    The continued need to improve therapeutic recombinant protein productivity has led to ongoing assessment of appropriate strategies in the biopharmaceutical industry to establish robust processes with optimized critical variables, that is, viable cell density (VCD) and specific productivity (product per cell, qP). Even though high VCD is a positive factor for titer, uncontrolled proliferation beyond a certain cell mass is also undesirable. To enable efficient process development to achieve consistent and predictable growth arrest while maintaining VCD, as well as improving qP, without negative impacts on product quality from clone to clone, we identified an approach that directly targets the cell cycle G1-checkpoint by selectively inhibiting the function of cyclin dependent kinases (CDK) 4/6 with a small molecule compound. Results from studies on multiple recombinant Chinese hamster ovary (CHO) cell lines demonstrate that the selective inhibitor can mediate a complete and sustained G0/G1 arrest without impacting G2/M phase. Cell proliferation is consistently and rapidly controlled in all recombinant cell lines at one concentration of this inhibitor throughout the production processes with specific productivities increased up to 110 pg/cell/day. Additionally, the product quality attributes of the mAb, with regard to high molecular weight (HMW) and glycan profile, are not negatively impacted. In fact, high mannose is decreased after treatment, which is in contrast to other established growth control methods such as reducing culture temperature. Microarray analysis showed major differences in expression of regulatory genes of the glycosylation and cell cycle signaling pathways between these different growth control methods. Overall, our observations showed that cell cycle arrest by directly targeting CDK4/6 using selective inhibitor compound can be utilized consistently and rapidly to optimize process parameters, such as cell growth, qP, and glycosylation profile in

  8. ACE: A distributed system to manage large data archives

    NASA Technical Reports Server (NTRS)

    Daily, Mike I.; Allen, Frank W.

    1993-01-01

    Competitive pressures in the oil and gas industry are requiring a much tighter integration of technical data into E and P business processes. The development of new systems to accommodate this business need must comprehend the significant numbers of large, complex data objects which the industry generates. The life cycle of the data objects is a four phase progression from data acquisition, to data processing, through data interpretation, and ending finally with data archival. In order to implement a cost effect system which provides an efficient conversion from data to information and allows effective use of this information, an organization must consider the technical data management requirements in all four phases. A set of technical issues which may differ in each phase must be addressed to insure an overall successful development strategy. The technical issues include standardized data formats and media for data acquisition, data management during processing, plus networks, applications software, and GUI's for interpretation of the processed data. Mass storage hardware and software is required to provide cost effective storage and retrieval during the latter three stages as well as long term archival. Mobil Oil Corporation's Exploration and Producing Technical Center (MEPTEC) has addressed the technical and cost issues of designing, building, and implementing an Advanced Computing Environment (ACE) to support the petroleum E and P function, which is critical to the corporation's continued success. Mobile views ACE as a cost effective solution which can give Mobile a competitive edge as well as a viable technical solution.

  9. Combined use of crystalline salt forms and precipitation inhibitors to improve oral absorption of celecoxib from solid oral formulations.

    PubMed

    Guzmán, Héctor R; Tawa, Mark; Zhang, Zhong; Ratanabanangkoon, Pasut; Shaw, Paul; Gardner, Colin R; Chen, Hongming; Moreau, Jean-Pierre; Almarsson, Orn; Remenar, Julius F

    2007-10-01

    Biopharmaceutical evaluation of crystalline celecoxib salts in novel solid formulations, which were designed to simultaneously facilitate dissolution and inhibit precipitation in vitro, showed fast and complete absorption in beagle dogs at doses up to 7.5 mg/kg orally. In contrast, 5 mg/kg celecoxib in the form of Celebrex(R) showed approximately 40% absolute bioavailability in a cross-over experiment. An in vitro-in vivo correlation was observed in dog, and a threshold level of in vitro dissolution needed to maximize in vivo performance was highlighted. Oral bioavailability was limited in the absence of excipient combinations that delayed precipitation of celecoxib free acid as the salt neutralized in the GI fluid. Formulations of crystal forms having high energy (a 'spring'), thus transiently increasing solubility in aqueous solution relative to the free acid, combined with excipients functioning as precipitation inhibitors ('parachutes') were shown to provide both enhanced dissolution and high oral bioavailability.

  10. Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of the glycine transporter-1 inhibitor NFPS and D-serine.

    PubMed

    Hashimoto, Kenji; Fujita, Yuko; Ishima, Tamaki; Chaki, Shigeyuki; Iyo, Masaomi

    2008-06-01

    Accumulating evidence suggests that the glycine modulatory site on the NMDA receptor could be potential therapeutic target for cognitive deficits in schizophrenia. The present study was undertaken to examine the effects of the glycine transporter-1 (GlyT-1) inhibitor, (R)-(N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl])sarcosine (NFPS), on cognitive deficits in mice after repeated administration of the NMDA receptor antagonist phencyclidine (PCP). PCP (10 mg/kg/day for 10 days)-induced cognitive deficits were significantly improved by subsequent subchronic (2-week) administration of NFPS (1.0 and 3.0 mg/kg/day) or D-serine (600 mg/kg/day). However, PCP-induced cognitive deficits were not improved by a single administration of NFPS (3.0 mg/kg). Furthermore, Western blot analysis revealed that levels of GlyT-1 in the hippocampus, but not frontal cortex, of the PCP (10 mg/kg/day for 10 days)-treated mice were significantly higher than those of saline-treated mice. An in vivo microdialysis study revealed that repeated PCP administration significantly decreased the extracellular levels of glycine in the hippocampus, but not frontal cortex, of mice. These findings suggest that repeated PCP administration increased the density of GlyT-1 in the hippocampus of mouse brain, and that the GlyT-1 inhibitor NFPS could ameliorate cognitive deficits in mice after repeated administration of PCP.

  11. A novel phosphodiesterase-5 Inhibitor: Yonkenafil modulates neurogenesis, gliosis to improve cognitive function and ameliorates amyloid burden in an APP/PS1 transgenic mice model.

    PubMed

    Zhu, Lei; Yang, Jing-yu; Xue, Xue; Dong, Ying-xu; Liu, Yang; Miao, Feng-rong; Wang, Yong-feng; Xue, Hong; Wu, Chun-fu

    2015-09-01

    In Alzheimer's disease (AD), activated microglia invade and surround β-amyloid plaques, possibly contributing to the aggregation of amyloid β (Aβ), which affect the survival of neurons and lead to memory loss. Phosphodiesterase-5 (PDE-5) inhibitors have recently been shown a potential therapeutic effect on AD. In this study, the effects of yonkenafil (yonk), a novel PDE-5 inhibitor, on cognitive behaviors as well as the pathological features in transgenic AD mice were investigated. Seven-month-old APP/PS1 transgenic mice were treated with yonk (2, 6, or 18 mg/kg, intraperitoneal injection (i.p.)) or sildenafil (sild) (6 mg/kg, i.p.) daily for 3 months and then behavioral tests were performed. The results demonstrated that yonk improved nesting-building ability, ameliorated working memory deficits in the Y-maze tasks, and significantly improved learning and memory function in the Morris water maze (MWM) tasks. In addition, yonk reduced the area of Aβ plaques, and inhibited over-activation of microglia and astrocytes. Furthermore, yonk increased neurogenesis in the dentate granule brain region of APP/PS1 mice, indicated by increased BrdU(+)/NeuN(+) and BrdU(+)/DCX(+) cells compared to vehicle-treated transgenic mice. These results suggest that yonk could rescue cognitive deficits by ameliorated amyloid burden through regulating APP processing, inhibited the over-activation of microglia and astrocytes as well as restored neurogenesis.

  12. Improved bio-hydrogen production from glucose by adding a specific methane inhibitor to microbial electrolysis cells with a double anode arrangement.

    PubMed

    Zhang, Jingnan; Bai, Yanxia; Fan, Yaoting; Hou, Hongwei

    2016-10-01

    Improved hydrogen production from glucose was achieved by adding a specific methane inhibitor (such as chloroform) to repress the activity of methanogens in a single-chamber microbial electrolysis cells (MECs) with a double anode arrangement. A maximum hydrogen production of 8.4±0.2 mol H2/mol-G (G represents glucose), a hydrogen production rate of 2.39±0.3 m(3) H2/m3/d and a high energy efficiency (relative to the electrical input) of ηE=165±5% had been recorded from 1 g/L glucose at a low dosage of chloroform (5‰, v:v) and an applied voltage of 0.8 V. Almost all of the glucose was removed within 4 h, with 66% of the electrons in intermediates (mainly including acetate and ethanol), and methane gas was not detected in the MECs through 11 batch cycles. The experimental results confirmed that chloroform was an effective methane inhibitor that improved hydrogen production from glucose in the MECs. In addition, the cyclic voltammetry tests demonstrated that the electron transfer in the MECs was mainly due to the biofilm-bound redox compounds rather than soluble electron shuttles.

  13. Mixed inhibitors of angiotensin-converting enzyme and enkephalinase: Rational design, properties, and potential cardiovascular applications of glycopril and alatriopril

    SciTech Connect

    Gros, C.; Noel, N.; Souque, A.; Schwartz, J.C. ); Danvy, D.; Plaquevent, J.C.; Duhamel, L.; Duhamel, P. ); Lecomte, J.M. ); Bralet, J. )

    1991-05-15

    Angiotensin-converting enzyme (ACE) and enkephalinase, two cell surface metallopeptidases, are responsible for angiotensin II formation and atrial natriuretic factor (ANF) degradation, respectively, and thereby play a critical role in the metabolism of hormonal peptides exerting essentially opposite actions in cardiovascular regulations. To affect simultaneously both hormonal systems by a single molecular structure, the authors designed glycoprilat and alatrioprilat {l brace}(S)-N-(3-(3,4-methylenedioxyphenyl)-2-(mercaptomethyl)-1-oxopropyl)glycine and -alanine, respectively{r brace}. In vitro the two compounds inhibit both ACE and enkephalinase activities with similar, nanomolar potencies, and in vivo, glycopril and alatriopril, the corresponding diester prodrugs, occupy the two enzyme molecules in lung at similar low dosages. The high potency of these compounds is attributable to interaction of the methylenedioxy group with the S{sub 1} subsite of ACE and of the aromatic ring with the S{prime}{sub 1} subsite of enkephalinase. In rodents, low doses of these mixed inhibitors exert typical actions of ACE inhibitors--i.e., prevention of angiotensin I-induced hypertension-as well as of enkephalinase inhibitors--i.e., protection from {sup 125}I-ANF degradation or enhancement of diuresis and natriuresis following acute extracellular volume expansion. In view of the known counterbalanced physiological actions of the two hormonal peptides, whose metabolism is controlled by ACE and enkephalinase, mixed inhibitors of the two peptidases show promise for the treatment of various cardiovascular and salt-retention disorders.

  14. Angiotensin I-converting enzyme (ACE) inhibitory activity and ACE inhibitory peptides of salmon (Salmo salar) protein hydrolysates obtained by human and porcine gastrointestinal enzymes.

    PubMed

    Darewicz, Małgorzata; Borawska, Justyna; Vegarud, Gerd E; Minkiewicz, Piotr; Iwaniak, Anna

    2014-08-13

    The objectives of the present study were two-fold: first, to detect whether salmon protein fractions possess angiotensin I-converting enzyme (ACE) inhibitory properties and whether salmon proteins can release ACE inhibitory peptides during a sequential in vitro hydrolysis (with commercial porcine enzymes) and ex vivo digestion (with human gastrointestinal enzymes). Secondly, to evaluate the ACE inhibitory activity of generated hydrolysates. A two-step ex vivo and in vitro model digestion was performed to simulate the human digestion process. Salmon proteins were degraded more efficiently by porcine enzymes than by human gastrointestinal juices and sarcoplasmic proteins were digested/hydrolyzed more easily than myofibrillar proteins. The ex vivo digested myofibrillar and sarcoplasmic duodenal samples showed IC50 values (concentration required to decrease the ACE activity by 50%) of 1.06 and 2.16 mg/mL, respectively. The in vitro hydrolyzed myofibrillar and sarcoplasmic samples showed IC50 values of 0.91 and 1.04 mg/mL, respectively. Based on the results of in silico studies, it was possible to identify 9 peptides of the ex vivo hydrolysates and 7 peptides of the in vitro hydrolysates of salmon proteins of 11 selected peptides. In both types of salmon hydrolysates, ACE-inhibitory peptides IW, IY, TVY and VW were identified. In the in vitro salmon protein hydrolysates an ACE-inhibitory peptides VPW and VY were also detected, while ACE-inhibitory peptides ALPHA, IVY and IWHHT were identified in the hydrolysates generated with ex vivo digestion. In our studies, we documented ACE inhibitory in vitro effects of salmon protein hydrolysates obtained by human and as well as porcine gastrointestinal enzymes.

  15. A Consolidation of ACE Research, 1990-2000. Review of Research.

    ERIC Educational Resources Information Center

    Golding, Barry; Davies, Merryn; Volkoff, Veronica

    The volume and scope of research into adult and community education (ACE) in Australia have increased significantly over the past decade. Studies designed to map, reevaluate, showcase, and promote ACE have been funded by Australia's federal and state governments and by bodies such as Adult Learning Australia. Practitioner-generated research has…

  16. Preparing GMAT for Operational Maneuver Planning of the Advanced Composition Explorer (ACE)

    NASA Technical Reports Server (NTRS)

    Qureshi, Rizwan Hamid; Hughes, Steven P.

    2014-01-01

    The General Mission Analysis Tool (GMAT) is an open-source space mission design, analysis and trajectory optimization tool. GMAT is developed by a team of NASA, private industry, public and private contributors. GMAT is designed to model, optimize and estimate spacecraft trajectories in flight regimes ranging from low Earth orbit to lunar applications, interplanetary trajectories and other deep space missions. GMAT has also been flight qualified to support operational maneuver planning for the Advanced Composition Explorer (ACE) mission. ACE was launched in August, 1997 and is orbiting the Sun-Earth L1 libration point. The primary science objective of ACE is to study the composition of both the solar wind and the galactic cosmic rays. Operational orbit determination, maneuver operations and product generation for ACE are conducted by NASA Goddard Space Flight Center (GSFC) Flight Dynamics Facility (FDF). This paper discusses the entire engineering lifecycle and major operational certification milestones that GMAT successfully completed to obtain operational certification for the ACE mission. Operational certification milestones such as gathering of the requirements for ACE operational maneuver planning, gap analysis, test plans and procedures development, system design, pre-shadow operations, training to FDF ACE maneuver planners, shadow operations, Test Readiness Review (TRR) and finally Operational Readiness Review (ORR) are discussed. These efforts have demonstrated that GMAT is flight quality software ready to support ACE mission operations in the FDF.

  17. Screening for Adverse Childhood Experiences (ACEs) in an Integrated Pediatric Care Model

    ERIC Educational Resources Information Center

    Purewal, Sukhdip K.; Bucci, Monica; Wang, Lisa Gutiérrez; Koita, Kadiatou; Marques, Sara Silvério; Oh, Debora; Harris, Nadine Burke

    2016-01-01

    Adverse childhood experiences (ACEs) are stressful or traumatic events that place children at risk of negative health, mental health, and behavioral outcomes. The Center for Youth Wellness (CYW), working in partnership with the Bayview Child Health Center (BCHC), pioneered ACE screening for children and adolescents. This article describes the…

  18. 75 FR 64737 - Automated Commercial Environment (ACE): Announcement of a National Customs Automation Program...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-10-20

    ... SECURITY U.S. Customs and Border Protection Automated Commercial Environment (ACE): Announcement of a... required advance ocean and rail data through the Automated Commercial Environment (ACE). This notice... application period for participation, outlines the development and evaluation methodology to be used,...

  19. Isolation of angiotensin converting enzyme (ACE) inhibiting triterpenes from Schinus molle.

    PubMed

    Olafsson, K; Jaroszewski, J W; Smitt, U W; Nyman, U

    1997-08-01

    Bioactivity-guided fractionation of extracts of Schinus molle leaves, using an in vitro assay, led to the isolation of ACE-inhibitory steroidal triterpenes of the euphane type, identified by means of NMR spectroscopic methods. One of the triterpenes was isolated as an equilibrium mixture of epimeric aldehydes. The triterpenes showed moderate ACE-inhibitory activity (IC(50) about 250 microM).

  20. Formative Evaluation of ACES Program: Findings from Surveys and Interviews Year One, Grades 11 and 12

    ERIC Educational Resources Information Center

    Wolanin, Natalie; Modarresi, Shahpar

    2015-01-01

    The Office of Shared Accountability (OSA) in Montgomery County (Maryland) Public Schools (MCPS) is conducting a multiyear evaluation of the Achieving Collegiate Excellence and Success (ACES) program. The ACES program is a collaboration between MCPS, Montgomery College (MC), and the Universities at Shady Grove (USG) to create a seamless pathway…

  1. Communications, Navigation, and Surveillance Models in ACES: Design Implementation and Capabilities

    NASA Technical Reports Server (NTRS)

    Kubat, Greg; Vandrei, Don; Satapathy, Goutam; Kumar, Anil; Khanna, Manu

    2006-01-01

    Presentation objectives include: a) Overview of the ACES/CNS System Models Design and Integration; b) Configuration Capabilities available for Models and Simulations using ACES with CNS Modeling; c) Descriptions of recently added, Enhanced CNS Simulation Capabilities; and d) General Concepts Ideas that Utilize CNS Modeling to Enhance Concept Evaluations.

  2. The Evolution of the Automated Continuous Evaluation System (ACES) for Personnel Security

    DTIC Science & Technology

    2013-11-12

    recession, which reduced funding across the government for research and development of efficiencies like ACES, the obvious promise of ACES continues. The...Approved for Public Distribution: Distribution Unlimited Defense Personnel and Security Research Center Defense Manpower Data Center Technical... Research Center Defense Manpower Data Center Defense Personnel and Security Research Center Defense Manpower Data Center 400 Gigling

  3. ACE expression in monocytes is induced by cytokines, phorbol ester and steroid

    SciTech Connect

    Lazarus, D.; Lanzillo, J.; Fanburg, B. )

    1991-03-15

    Angiotensin converting enzyme (ACE) levels are elevated in the serum and peripheral blood monocytes (PBM) of patients with granulomatous diseases. However, the role of ACE in (Mo) physiology and the regulation of the inflammatory response is not well understood. Since Mo can be stimulated to form giant cells using phorbol esters, glucocorticoids or certain inflammatory cytokines, the authors examined production of ACE protein by normal PBM, a Mo-like cell line, THP-1, and a macrophage-like cell line, U937 following stimulation with these agents. Using a sensitive ELISA assay, they found that in U937 cells, expression of ACE protein increased by 3.4 fold with dexamethasone, 3.7. fold with phorbol 12-myristate acetate (PMA), and 5.8 fold with the two agents combined. The cytokines IL-4 and GM-CSF substantially increased ACE expression, by 7.6 and 7.7 fold respectively, with maximal effect at 0.01 U/ml, while IFN-{gamma} and TNF-{alpha} had little effect. Similar results were found with PBM and THP-1 cells. The combination of dexamethasone and PMA also induced homotypic cluster formation in PBM, suggesting a correlation between cell adhesion and ACE production. The authors conclude that ACE expression in monocytes and macrophages is stimulated by low concentration of glucocorticoids and certain inflammatory cytokines. ACE may participate in the initiation and propagation of granulomatous inflammatory processes.

  4. Airspace Concept Evaluation System (ACES), Concept Simulations using Communication, Navigation and Surveillance (CNS) System Models

    NASA Technical Reports Server (NTRS)

    Kubat, Greg; Vandrei, Don

    2006-01-01

    Project Objectives include: a) CNS Model Development; b Design/Integration of baseline set of CNS Models into ACES; c) Implement Enhanced Simulation Capabilities in ACES; d) Design and Integration of Enhanced (2nd set) CNS Models; and e) Continue with CNS Model Integration/Concept evaluations.

  5. Screening of Zulu medicinal plants for angiotensin converting enzyme (ACE) inhibitors.

    PubMed

    Duncan, A C; Jäger, A K; van Staden, J

    1999-12-15

    Twenty plants used by traditional healers in South Africa for the treatment of high blood pressure were investigated for their anti-hypertensive properties, utilizing the angiotensin converting enzyme assay. A hit rate of 65% was achieved, with the highest inhibition (97%) obtained by Adenopodia spicata leaves. A further seven plants exhibited an inhibition greater than 70% and five more over 50%. The leaves of the plants showed the greatest levels of inhibition. There was little difference in the overall hit rate between ethanolic and aqueous extracts, although in most cases there was a marked difference in activity between aqueous and ethanolic extracts from the same species. Plants exhibiting inhibition levels greater than 50% were further tested for the presence of tannins in order to eliminate possible false positives. Active plants that did not contain tannins were Agapanthus africanus, Agave americana, Clausena anisata, Dietes iridioides, Mesembruanthemum spp., Stangeria eriopus and Tulbaghia violacea.

  6. Combination of ACE inhibitor with nicorandil provides further protection in chronic kidney disease.

    PubMed

    Shiraishi, Takeshi; Tamura, Yoshifuru; Taniguchi, Kei; Higaki, Masato; Ueda, Shuko; Shima, Tomoko; Nagura, Michito; Nakagawa, Takahiko; Johnson, Richard J; Uchida, Shunya

    2014-12-15

    An inhibition in the renin-angiotensin system (RAS) is one of the most widely used therapies to treat chronic kidney disease. However, its effect is occasionally not sufficient and additional treatments may be required. Recently, we reported that nicorandil exhibited renoprotective effects in a mouse model of diabetic nephropathy. Here we examined if nicorandil can provide an additive protection on enalapril in chronic kidney disease. Single treatment with either enalapril or nicorandil significantly ameliorated glomerular and tubulointerstitial injury in the rat remnant kidney while the combination of these two compounds provided additive effects. In addition, an increase in oxidative stress in remnant kidney was also blocked by either enalapril or nicorandil while the combination of the drugs was more potent. A mechanism was likely due for nicorandil to preventing manganase superoxide dismutase (MnSOD) and sirtuin (Sirt)3 from being reduced in injured kidneys. A study with cultured podocytes indicated that the antioxidative effect could be mediated through sulfonylurea receptor (SUR) in the mitochondrial KATP channel since blocking SUR with glibenclamide reduced MnSOD and Sirt3 expression in podocytes. In conclusion, nicorandil may synergize with enalapril to provide superior protection in chronic kidney disease.

  7. An ace-1 gene duplication resorbs the fitness cost associated with resistance in Anopheles gambiae, the main malaria mosquito

    PubMed Central

    Assogba, Benoît S.; Djogbénou, Luc S.; Milesi, Pascal; Berthomieu, Arnaud; Perez, Julie; Ayala, Diego; Chandre, Fabrice; Makoutodé, Michel; Labbé, Pierrick; Weill, Mylène

    2015-01-01

    Widespread resistance to pyrethroids threatens malaria control in Africa. Consequently, several countries switched to carbamates and organophophates insecticides for indoor residual spraying. However, a mutation in the ace-1 gene conferring resistance to these compounds (ace-1R allele), is already present. Furthermore, a duplicated allele (ace-1D) recently appeared; characterizing its selective advantage is mandatory to evaluate the threat. Our data revealed that a unique duplication event, pairing a susceptible and a resistant copy of the ace-1 gene spread through West Africa. Further investigations revealed that, while ace-1D confers less resistance than ace-1R, the high fitness cost associated with ace-1R is almost completely suppressed by the duplication for all traits studied. ace-1 duplication thus represents a permanent heterozygote phenotype, selected, and thus spreading, due to the mosaic nature of mosquito control. It provides malaria mosquito with a new evolutionary path that could hamper resistance management. PMID:26434951

  8. Cyclo-oxygenase-2 inhibitors: when should they be used in the elderly?

    PubMed

    Savage, Ruth

    2005-01-01

    Chronic pain in the elderly is frequently a result of arthritic disorders, particularly osteoarthritis. The cyclo-oxygenase (COX)-2 inhibitors are as effective as standard NSAIDs for the relief of pain and for improving function in elderly patients with osteoarthritis and rheumatoid arthritis. COX-2 inhibitors increase the risk of serious gastroduodenal adverse reactions but there is evidence that they carry a lower risk for these adverse effects than standard NSAIDs, except when there is concurrent aspirin use. Since gastroduodenal disorders are the most frequently reported serious adverse effects of NSAIDs and these disorders occur more frequently in the elderly, COX-2 inhibitors offer an alternative to standard NSAIDs in this age group. However, they are not appropriate for many patients with cardiovascular and renal disease. The adverse reaction profile of the COX-2 inhibitors has confirmed the role of the COX-2 enzyme in renal function, salt and water homeostasis and the vascular endothelium. Thus, like standard NSAIDs, COX-2 inhibitors can cause renal failure, hypertension and exacerbation of cardiac failure. Of note is that these disorders are dose related. Thus, there are good reasons to avoid high doses of COX-2 inhibitors in the elderly. Clinical trials indicate that daily doses of rofecoxib 12.5 mg, celecoxib 100-200 mg, valdecoxib 10mg and etoricoxib 60 mg are the minimum effective doses of these agents. Data from the New Zealand Intensive Medicines Monitoring Programme indicate that celecoxib 200 mg/day and rofecoxib 25 mg/day are/were the most commonly prescribed doses and that 6% of patients had taken rofecoxib 50 mg/day for longer than recommended. Recent research indicates that COX-2 inhibitors have a thrombotic potential, especially in high doses and when use is prolonged, and this further limits the extent to which they can be used in the elderly. Important interactions with COX-2 inhibitors in the elderly include those with warfarin, which can

  9. ACE2 Inhibits Angiotensin II-Induced Abdominal Aortic Aneurysm in Mice.

    PubMed

    Hao, QingQing; Dong, XueFei; Chen, Xu; Yan, Feng; Wang, Xiaoyu; Shi, Haishui; Dong, Bo

    2017-01-31

    Recent study have demonstrated that ACE2 plays an important role in the pathogenesis of abdominal Aortic Aneurysm (AAA). But, little study was reported about the direct effect of ACE2 overexpression on the aneurysm. In this study, we hypothesize that overexpression of ACE2 may prevent the pathogenesis of aneurysm by decreasing RAS activation. Thirty-nine Mice were assigned to 3 groups randomly (n=13 in each group), ACE2 group, Ad.EGFP group and Control group. After 8-week treatment, abdominal aortas with AAA were obtained for HE staining, VVG, immunohistochemistry and Western blotting. The incidence and severity of AAA, macrophage infiltration and MMP protein expression were all detected. The results showed that ACE2 gene transfer significantly decreased the occurrence of AAA and inhibited AAA formation in ApoE-/- mice by inhibiting inflammatory response and MMP activation, the mechanisms may involve decreased ERK and AngII-NF-kB signaling pathways.

  10. Unique Kinase Catalytic Mechanism of AceK with a Single Magnesium Ion

    PubMed Central

    Li, Quanjie; Zheng, Jimin; Tan, Hongwei; Li, Xichen; Chen, Guangju; Jia, Zongchao

    2013-01-01

    Isocitrate dehydrogenase kinase/phosphatase (AceK) is the founding member of the protein phosphorylation system in prokaryotes. Based on the novel and unique structural characteristics of AceK recently uncovered, we sought to understand its kinase reaction mechanism, along with other features involved in the phosphotransfer process. Herein we report density functional theory QM calculations of the mechanism of the phosphotransfer reaction catalysed by AceK. The transition states located by the QM calculations indicate that the phosphorylation reaction, catalysed by AceK, follows a dissociative mechanism with Asp457 serving as the catalytic base to accept the proton delivered by the substrate. Our results also revealed that AceK prefers a single Mg2+-containing active site in the phosphotransfer reaction. The catalytic roles of conserved residues in the active site are discussed. PMID:23977203

  11. The effect of saturation of ACE binding sites on the pharmacokinetics of enalaprilat in man.

    PubMed Central

    Wade, J R; Meredith, P A; Hughes, D M; Elliott, H L

    1992-01-01

    1. Eight healthy male volunteers received oral enalapril, 10 mg, in the presence and absence of pretreatment with captopril, 50 mg, twice daily for 5 days. 2. Enalaprilat pharmacokinetics were characterised after both doses of enalapril to investigate the effect of saturating ACE binding sites by pretreatment with captopril. 3. The pharmacokinetics of enalaprilat were best described by a one compartment model with zero order input incorporating saturable binding to plasma and tissue ACE. 4. Values of AUC (0.72 h) for enalaprilat were 419 +/- 97 and 450 +/- 87 ng ml-1 h in the presence and absence of captopril, respectively. The difference was not statistically significant nor were there any other differences in model parameters. 5. Induction of ACE by captopril resulting in an increase in the number of ACE binding sites, may have obscured any effect of captopril on the occupancy of ACE binding sites by enalapril. PMID:1312853

  12. RF optimization and analysis of the 805-MHz cavity for the MuCool program using ACE3P

    NASA Astrophysics Data System (ADS)

    Li, Zenghai; Ge, Lixin; Adolphsen, Chris; Li, Derun; Bowring, Daniel

    2012-12-01

    An 805 MHz pillbox cavity tested at Fermilab's MTA facility showed significant degradation in gradient when operated in a several Tesla solenoidal magnetic field. We have used the advanced ACE3P simulation codes developed at SLAC to study the cavity dark current and multipacting characteristics to gain more insight into the gradient limitations. We also checked whether there is an optimal cavity length that minimizes the dark current impact energy. Finally, we have improved on the cavity design, significantly lowering the fields outside the beam area. These and other results are presented in this paper.

  13. RF optimization and analysis of the 805-MHz cavity for the MuCool program using ACE3P

    SciTech Connect

    Li Zenghai; Ge Lixin; Adolphsen, Chris; Li Derun; Bowring, Daniel

    2012-12-21

    An 805 MHz pillbox cavity tested at Fermilab's MTA facility showed significant degradation in gradient when operated in a several Tesla solenoidal magnetic field. We have used the advanced ACE3P simulation codes developed at SLAC to study the cavity dark current and multipacting characteristics to gain more insight into the gradient limitations. We also checked whether there is an optimal cavity length that minimizes the dark current impact energy. Finally, we have improved on the cavity design, significantly lowering the fields outside the beam area. These and other results are presented in this paper.

  14. End-organ protection in hypertension by the novel and selective Rho-kinase inhibitor, SAR407899

    PubMed Central

    Löhn, Matthias; Plettenburg, Oliver; Kannt, Aimo; Kohlmann, Markus; Hofmeister, Armin; Kadereit, Dieter; Monecke, Peter; Schiffer, Alexander; Schulte, Anke; Ruetten, Hartmut; Ivashchenko, Yuri

    2015-01-01

    AIM: To compare the therapeutic efficacy of SAR407899 with the current standard treatment for hypertension [an angiotensin converting enzyme (ACE)-inhibitor and a calcium channel blocker] and compare the frequency and severity of the hypertension-related end-organ damage. METHODS: Long-term pharmacological characte-rization of SAR407899 has been performed in two animal models of hypertension, of which one is sensitive to ACE-inhibition (LNAME) and the other is insensitive [deoxycorticosterone acetate (DOCA)]. SAR407899 efficiently lowered high blood pressure and significantly reduced late-stage end organ damage as indicated by improved heart, kidney and endothelial function and reduced heart and kidney fibrosis in both models of chronic hypertension. RESULTS: Long term treatment with SAR407899 has been well tolerated and dose-dependently reduced elevated blood pressure in both models with no signs of tachyphylaxia. Blood pressure lowering effects and protective effects on hypertension related end organ damage of SAR407899 were superior to ramipril and amlodipine in the DOCA rat. Typical end-organ damage was significantly reduced in the SAR407899-treated animals. Chronic administration of SAR407899 significantly reduced albuminuria in both models. The beneficial effect of SAR407899 was associated with a reduction in leukocyte/macrophage tissue infiltration. The overall protective effect of SAR407899 was superior or comparable to that of ACE-inhibition or calcium channel blockade. Chronic application of SAR407899 protects against hypertension and hypertension-induced end organ damage, regardless of the pathophysiological mechanism of hypertension. CONCLUSION: Rho-kinases-inhibition by the SAR407899 represents a new therapeutic option for the treatment of hypertension and its complications. PMID:25632317

  15. Poly(ADP-Ribose) Polymerase-1 (PARP-1) Inhibitors Reduce Reactive Gliosis and Improve Angiostatin Levels in Retina of Diabetic Rats.

    PubMed

    Guzyk, Mykhailo M; Tykhomyrov, Artem A; Nedzvetsky, Victor S; Prischepa, Irina V; Grinenko, Tatiana V; Yanitska, Lesya V; Kuchmerovska, Tamara M

    2016-10-01

    Diabetic retinopathy (DR) is a multifactorial disease characterized by reactive gliosis and disbalance of angiogenesis regulators, contributing to endothelial dysfunction and microvascular complications. This study was organized to elucidate whether poly(ADP-ribose) polymerase-1 (PARP-1) inhibition could attenuate diabetes-induced damage to macroglia and correct angiogenic disbalance in diabetic rat retina. After 8 weeks of streptozotocin (STZ)-induced diabetes, Wistar male rats were treated with PARP-1 inhibitors, nicotinamide (NAm) or 3-aminobenzamide (3-AB) (100 and 30 mg/kg/daily i.p., respectively), for 14 days. After the 10-weeks experiment period, retinas were undergone an immunohistochemical staining for glial fibrillary acidic protein (GFAP), while western blots were performed to evaluate effects of PAPR-1 inhibitors on the levels of PARP-1, poly(ADP-ribosyl)ated proteins (PARs), GFAP, and angiostatin isoforms. Diabetes induced significant up-regulation and activation of retinal PARP-1, reactive gliosis development, and GFAP overexpression compared to non-diabetic control. Moreover, extensive fragmentation of both PARP-1 and GFAP (hallmarks of apoptosis and macroglia reactivation, respectively) in diabetic retina was also observed. Levels of angiostatin isoforms were dramatically decreased in diabetic retina, sustaining aberrant pro-angiogenic condition. Both NAm and 3-AB markedly attenuated damage to macroglia, evidenced by down-regulation of PARP-1, PARs and total GFAP compared to diabetic non-treated group. PARP-1-inhibitory therapy prevented formation of PARP-1 and GFAP cleavage-derived products. In retinas of anti-PARP-treated diabetic animals, partial restoration of angiostatin's levels was shown. Therefore, PARP-1 inhibitors counteract diabetes-induced injuries and manifest retinoprotective effects, including attenuation of reactive gliosis and improvement of angiogenic status, thus, such agents could be considered as promising candidates for DR

  16. Improved Pharmacological and Structural Properties of HIV Fusion Inhibitor AP3 over Enfuvirtide: Highlighting Advantages of Artificial Peptide Strategy

    SciTech Connect

    Zhu, Xiaojie; Zhu, Yun; Ye, Sheng; Wang, Qian; Xu, Wei; Su, Shan; Sun, Zhiwu; Yu, Fei; Liu, Qi; Wang, Chao; Zhang, Tianhong; Zhang, Zhenqing; Zhang, Xiaoyan; Xu, Jianqing; Du, Lanying; Liu, Keliang; Lu, Lu; Zhang, Rongguang; Jiang, Shibo

    2015-08-19

    Enfuvirtide (T20), is the first HIV fusion inhibitor approved for treatment of HIV/AIDS patients who fail to respond to the current antiretroviral drugs. However, its clinical application is limited because of short half-life, drug resistance and cross-reactivity with the preexisting antibodies in HIV-infected patients. Using an artificial peptide strategy, we designed a peptide with non-native protein sequence, AP3, which exhibited potent antiviral activity against a broad spectrum of HIV-1 strains, including those resistant to T20, and had remarkably longer in vivo half-life than T20. While the preexisting antibodies in HIV-infected patients significantly suppressed T20’s antiviral activity, these antibodies neither recognized AP3, nor attenuated its anti-HIV-1 activity. Structurally different from T20, AP3 could fold into single-helix and interact with gp41 NHR. The two residues, Met and Thr, at the N-terminus of AP3 form a hook-like structure to stabilize interaction between AP3 and NHR helices. Therefore, AP3 has potential for further development as a new HIV fusion inhibitor with improved antiviral efficacy, resistance profile and pharmacological properties over enfuvirtide. Meanwhile, this study highlighted the advantages of artificially designed peptides, and confirmed that this strategy could be used in developing artificial peptide-based viral fusion inhibitors against HIV and other enveloped viruses.

  17. Effects of Angiotensin Converting Enzyme Inhibitors on Liver Fibrosis in HIV and Hepatitis C Coinfection.

    PubMed

    Reese, Lindsey J; Tider, Diane S; Stivala, Alicia C; Fishbein, Dawn A

    2012-01-01

    Background. Liver fibrosis is accelerated in HIV and hepatitis C coinfection, mediated by profibrotic effects of angiotensin. The objective of this study was to determine if angiotensin converting enzyme inhibitors (ACE-Is) attenuate liver fibrosis in coinfection. Methods. A retrospective review of 156 coinfected subjects was conducted to analyze the association between exposure to ACE-Is and liver fibrosis. Noninvasive indices of liver fibrosis (APRI, FIB-4, Forns indices) were compared between subjects who had taken ACE-Is and controls who had not taken them. Linear regression was used to evaluate ACE-I use as an independent predictor of fibrosis. Results. Subjects taking ACE-Is for three years were no different than controls on the APRI and the FIB-4 but had significantly higher scores than controls on the Forns index, indicating more advanced fibrosis. The use of ACE-Is for three years remained independently associated with an elevated Forns score when adjusted for age, race, and HIV viral load (P < 0.001). There were significant associations between all of the indices and significant fibrosis, as determined clinically and radiologically. Conclusions. There was not a protective association between angiotensin inhibition and liver fibrosis in coinfection. These noninvasive indices may be useful for ruling out significant fibrosis in coinfection.

  18. Improved nonclinical pharmacokinetics and biodistribution of a new PPAR pan-agonist and COX inhibitor in nanocapsule formulation.

    PubMed

    Garcia, Giani Martins; Oliveira, Líliam Teixeira; Pitta, Ivan da Rocha; de Lima, Maria do Carmo Alves; Vilela, José Mário Carneiro; Andrade, Margareth Spangler; Abdalla, Dulcinéia Saes Parra; Mosqueira, Vanessa Carla Furtado

    2015-07-10

    We report the in vitro release profile and comparative pharmacokinetics and biodistribution of a new peroxisome proliferator-activated receptor-γ agonist and cyclooxygenase inhibitor (Lyso-7) free or associated to poly(D,L-lactic acid) nanocapsules (NC) after intravenous administration in mice. Lyso-7 pertains to the class of insulin-sensitizing agents that shows potential beneficial effects in diabetes therapy. Monodispersed Lyso-7 NC with a mean diameter of 273 nm with high encapsulation efficiency (83%) were obtained. Lyso-7 dissolution rate was reduced (2.6-fold) upon loading in NC. The pharmacokinetic parameters were determined using a non-compartmental approach. In comparison with Lyso-7 in solution, the plasma-AUC increased 14-fold, the mean residence time 2.6-fold and the mean half-life (t1/2) 1.5-fold for Lyso-7-NC; the Lyso-7 plasma clearance, distribution volume and elimination rate were reduced 13, 10 and 1.4 fold, respectively, which indicates higher retention of encapsulated Lyso-7 in the blood compartment. Upon association with NC, organ exposure to Lyso-7 was higher in the heart (3.6-fold), lung (2.8-fold), spleen (2.3-fold), kidney (2-fold) and liver (1.8-fold) compared to Lyso-7 in solution. The analysis of whole data clearly indicates that body exposure to Lyso-7 was enhanced and the general toxicity reduced upon nanoencapsulation, allowing further evaluation of Lyso-7 in nonclinical and clinical studies.

  19. Single administration of soluble epoxide hydrolase inhibitor suppresses neuroinflammation and improves neuronal damage after cardiac arrest in mice.

    PubMed

    Taguchi, Noriko; Nakayama, Shin; Tanaka, Makoto

    2016-10-01

    Cardiac arrest (CA) causes ischemia-reperfusion injury in the whole body among victims. Especially in the brain, inflammation and neuronal cell death can lead to irreversible dysfunction. Our goal was to determine whether a single administration of soluble epoxide hydrolase inhibitor (AS2586144-CL) has a neuroprotective effect and decreases the inflammatory response after CA and cardiopulmonary resuscitation (CPR). Global cerebral ischemia was induced in male C57BL/6 mice with 8min of CA. Thirty minutes after recovery of spontaneous circulation, the mice were randomly assigned to three groups and administered AS2586144-CL: 1mg/kg (n=25), 10mg/kg (n=25), or 0mg/kg (vehicle, n=25). At 6 and 7 days after CA/CPR, behavioral tests were conducted and brains were removed for histological evaluation. Analysis of histological damage 7 days after CA/CPR revealed that 10mg/kg of AS2586144-CL protected neurons, and suppressed cytokine production and microglial migration into the hippocampus. Two hours after CA/CPR, 10mg/kg of AS2586144-CL suppressed serum tumor necrosis factor-α and hippocampal nuclear factor κB expression. Our data show that 10mg/kg of AS2586144-CL administered following CA/CPR suppresses inflammation and decreases neuronal damage.

  20. Exploiting conformational dynamics in drug discovery: design of C-terminal inhibitors of Hsp90 with improved activities

    PubMed Central

    Moroni, Elisabetta; Zhao, Huiping; Blagg, Brian S.J.; Colombo, Giorgio

    2014-01-01

    The interaction that occurs between molecules is a dynamic process that impacts both structural and conformational properties of the ligand and the ligand binding site. Herein, we investigate the dynamic cross-talk between a protein and the ligand as a source for new opportunities in ligand design. Analysis of the formation/disappearance of protein pockets produced in response to a first-generation inhibitor assisted in the identification of functional groups that could be introduced onto scaffolds to facilitate optimal binding, which allowed for increased binding with previously uncharacterized regions. MD simulations were used to elucidate primary changes that occur in the Hsp90 C-terminal binding pocket in the presence of first-generation ligands. This data was then used to design ligands that adapt to these receptor conformations, which provides access to an energy landscape that is not visible in a static model. The newly synthesized compounds demonstrated anti-proliferative activity at ~150 nanomolar concentration. The method identified herein may be used to design chemical probes that provide additional information on structural variations of Hsp90 C-terminal binding site. PMID:24397468

  1. The effect of ACE inhibition on the pulmonary vasculature in combined model of chronic hypoxia and pulmonary arterial banding in Sprague Dawley rats

    NASA Astrophysics Data System (ADS)

    Clarke, Shanelle; Baumgardt, Shelley; Molthen, Robert

    2010-03-01

    Microfocal CT was used to image the pulmonary arterial (PA) tree in rodent models of pulmonary hypertension (PH). CT images were used to measure the arterial tree diameter along the main arterial trunk at several hydrostatic intravascular pressures and calculate distensibility. High-resolution planar angiographic imaging was also used to examine distal PA microstructure. Data on pulmonary artery tree morphology improves our understanding of vascular remodeling and response to treatments. Angiotensin II (ATII) has been identified as a mediator of vasoconstriction and proliferative mitotic function. ATII has been shown to promote vascular smooth muscle cell hypertrophy and hyperplasia as well as stimulate synthesis of extracellular matrix proteins. Available ATII is targeted through angiotensin converting enzyme inhibitors (ACEIs), a method that has been used in animal models of PH to attenuate vascular remodeling and decrease pulmonary vascular resistance. In this study, we used rat models of chronic hypoxia to induce PH combined with partial left pulmonary artery occlusion (arterial banding, PLPAO) to evaluate effects of the ACEI, captopril, on pulmonary vascular hemodynamic and morphology. Male Sprague Dawley rats were placed in hypoxia (FiO2 0.1), with one group having underwent PLPAO three days prior to the chronic hypoxia. After the twenty-first day of hypoxia exposure, treatment was started with captopril (20 mg/kg/day) for an additional twenty-one days. At the endpoint, lungs were excised and isolated to examine: pulmonary vascular resistance, ACE activity, pulmonary vessel morphology and biomechanics. Hematocrit and RV/LV+septum ratio was also measured. CT planar images showed less vessel dropout in rats treated with captopril versus the non-treatment lungs. Distensibility data shows no change in rats treated with captopril in both chronic hypoxia (CH) and CH with PLPAO (CH+PLPAO) models. Hemodynamic measurements also show no change in the pulmonary vascular

  2. Autophagy inhibitors.

    PubMed

    Pasquier, Benoit

    2016-03-01

    Autophagy is a lysosome-dependent mechanism of intracellular degradation. The cellular and molecular mechanisms underlying this process are highly complex and involve multiple proteins, including the kinases ULK1 and Vps34. The main function of autophagy is the maintenance of cell survival when modifications occur in the cellular environment. During the past decade, extensive studies have greatly improved our knowledge and autophagy has exploded as a research field. This process is now widely implicated in pathophysiological processes such as cancer, metabolic, and neurodegenerative disorders, making it an attractive target for drug discovery. In this review, we will summarize the different types of inhibitors that affect the autophagy machinery and provide some potential therapeutic perspectives.

  3. The DPP-4 inhibitor linagliptin and the GLP-1 receptor agonist exendin-4 improve endothelium-dependent relaxation of rat mesenteric arteries in the presence of high glucose.

    PubMed

    Salheen, S M; Panchapakesan, U; Pollock, C A; Woodman, O L

    2015-04-01

    The aim of the study was to investigate the effects of the DPP-4 inhibitors and GLP-1R agonist, exendin-4 on the mechanism(s) of endothelium-dependent relaxation in rat mesenteric arteries exposed to high glucose concentration (40 mM). Organ bath techniques were employed to investigate vascular endothelial function in rat mesenteric arteries in the presence of normal (11 mM) or high (40 mM) glucose concentrations. Pharmacological tools (1μM TRAM-34, 1μM apamin, 100 nM Ibtx, 100 μM l-NNA, 10 μM ODQ) were used to distinguish between NO and EDHF-mediated relaxation. Superoxide anion levels were assessed by L-012 and lucigenin enhanced-chemiluminescence techniques. Incubation of mesenteric rings with high glucose for 2 h caused a significant increase in superoxide anion generation and a significant impairment of endothelium-dependent relaxation. Exendin-4 and DPP-4 inhibitor linagliptin, but not sitagliptin or vildagliptin, significantly reduced vascular superoxide and improved endothelium-dependent relaxation in the presence of high glucose. The beneficial actions of exendin-4, but not linagliptin, were attenuated by the GLP-1R antagonist exendin fragment (9-39). Further experiments demonstrated that the presence of high glucose impaired the contribution of both nitric oxide and endothelium-dependent hyperpolarisation to relaxation and that linagliptin improved both mechanisms involved in endothelium-dependent relaxation. These findings demonstrate that high glucose impaired endothelium-dependent relaxation can be improved by exendin-4 and linagliptin, likely due to their antioxidant activity and independently of any glucose lowering effect.

  4. SGLT2 inhibitor therapy improves blood glucose but does not prevent diabetic bone disease in diabetic DBA/2J male mice.

    PubMed

    Thrailkill, Kathryn M; Clay Bunn, R; Nyman, Jeffry S; Rettiganti, Mallikarjuna R; Cockrell, Gael E; Wahl, Elizabeth C; Uppuganti, Sasidhar; Lumpkin, Charles K; Fowlkes, John L

    2016-01-01

    Persons with type 1 and type 2 diabetes have increased fracture risk, attributed to deficits in the microarchitecture and strength of diabetic bone, thought to be mediated, in part, by the consequences of chronic hyperglycemia. Therefore, to examine the effects of a glucose-lowering SGLT2 inhibitor on blood glucose (BG) and bone homeostasis in a model of diabetic bone disease, male DBA/2J mice with or without streptozotocin (STZ)-induced hyperglycemia were fed chow containing the SGLT2 inhibitor, canagliflozin (CANA), or chow without drug, for 10weeks of therapy. Thereafter, serum bone biomarkers were measured, fracture resistance of cortical bone was assessed by μCT analysis and a three-point bending test of the femur, and vertebral bone strength was determined by compression testing. In the femur metaphysis and L6 vertebra, long-term diabetes (DM) induced deficits in trabecular bone microarchitecture. In the femur diaphysis, a decrease in cortical bone area, cortical thickness and minimal moment of inertia occurred in DM (p<0.0001, for all) while cortical porosity was increased (p<0.0001). These DM changes were associated with reduced fracture resistance (decreased material strength and toughness; decreased structural strength and rigidity; p<0.001 for all). Significant increases in PTH (p<0.0001), RatLAPs (p=0.0002), and urine calcium concentration (p<0.0001) were also seen in DM. Canagliflozin treatment improved BG in DM mice by ~35%, but did not improve microarchitectural parameters. Instead, in canagliflozin-treated diabetic mice, a further increase in RatLAPs was evident, possibly suggesting a drug-related intensification of bone resorption. Additionally, detrimental metaphyseal changes were noted in canagliflozin-treated control mice. Hence, diabetic bone disease was not favorably affected by canagliflozin treatment, perhaps due to insufficient glycemic improvement. Instead, in control mice, long-term exposure to SGLT2 inhibition was associated with

  5. Compressed images for affinity prediction-2 (CIFAP-2): an improved machine learning methodology on protein-ligand interactions based on a study on caspase 3 inhibitors.

    PubMed

    Erdas, Ozlem; Andac, Cenk A; Gurkan-Alp, A Selen; Alpaslan, Ferda Nur; Buyukbingol, Erdem

    2015-01-01

    The aim of this study is to propose an improved computational methodology, which is called Compressed Images for Affinity Prediction-2 (CIFAP-2) to predict binding affinities of structurally related protein-ligand complexes. CIFAP-2 method is established based on a protein-ligand model from which computational affinity information is obtained by utilizing 2D electrostatic potential images determined for the binding site of protein-ligand complexes. The quality of the prediction of the CIFAP-2 algorithm was tested using partial least squares regression (PLSR) as well as support vector regression (SVR) and adaptive neuro-fuzzy ınference system (ANFIS), which are highly promising prediction methods in drug design. CIFAP-2 was applied on a protein-ligand complex system involving Caspase 3 (CASP3) and its 35 inhibitors possessing a common isatin sulfonamide pharmacophore. As a result, PLSR affinity prediction for the CASP3-ligand complexes gave rise to the most consistent information with reported empirical binding affinities (pIC(50)) of the CASP3 inhibitors.

  6. A Rational Design of a Selective Inhibitor for Kv1.1 Channels Prevalent in Demyelinated Nerves That Improves Their Impaired Axonal Conduction.

    PubMed

    Al-Sabi, Ahmed; Daly, Declan; Hoefer, Patrick; Kinsella, Gemma K; Metais, Charles; Pickering, Mark; Herron, Caroline; Kaza, Seshu Kumar; Nolan, Kieran; Dolly, J Oliver

    2017-03-23

    K(+) channels containing Kv1.1 α subunits, which become prevalent at internodes in demyelinated axons, may underlie their dysfunctional conduction akin to muscle weakness in multiple sclerosis. Small inhibitors were sought with selectivity for the culpable hyper-polarizing K(+) currents. Modeling of interactions with the extracellular pore in a Kv1.1-deduced structure identified diaryldi(2-pyrrolyl)methane as a suitable scaffold with optimized alkyl ammonium side chains. The resultant synthesized candidate [2,2'-((5,5'(di-p-topyldiaryldi(2-pyrrolyl)methane)bis(2,2'carbonyl)bis(azanediyl)) diethaneamine·2HCl] (8) selectively blocked Kv1.1 channels (IC50 ≈ 15 μM) recombinantly expressed in mammalian cells, induced a positive shift in the voltage dependency of K(+) current activation, and slowed its kinetics. It preferentially inhibited channels containing two or more Kv1.1 subunits regardless of their positioning in concatenated tetramers. In slices of corpus callosum from mice subjected to a demyelination protocol, this novel inhibitor improved neuronal conduction, highlighting its potential for alleviating symptoms in multiple sclerosis.

  7. Improving potency and metabolic stability by introducing an alkenyl linker to pyridine-based histone deacetylase inhibitors for orally available RUNX3 modulators.

    PubMed

    Song, Doona; Lee, Chulho; Kook, Yoon Jeong; Oh, Soo Jin; Kang, Jong Soon; Kim, Hyun-Jung; Han, Gyoonhee

    2017-01-27

    RUNX3, a tumor suppressor, is suppressed in various cancers by abnormal epigenetic changes. Histone deacetylases (HDACs) can deacetylate the lysine residues of RUNX3, followed by degradation via a ubiquitin-mediated pathway. Inhibition of HDAC leads to functional restoration of the RUNX3 protein by epigenetic expression and RUNX3 protein stabilization. We previously reported a series of HDAC inhibitors that restored RUNX3 function. In the present study, we introduced an alkenyl linker group to pyridine-based HDAC inhibitors to improve their potencies and chemical properties. This alkenyl linker made the compounds more rigid, facilitating a better fit than alkyl moieties to the active site of HDAC proteins. Most compounds in this series exhibited potent RUNX activities, HDAC inhibitory activities, and inhibitory activities towards the growth of human cancer cell lines. Notably, one of these derivatives, (E)-3-(1-cinnamyl-2-oxo-1,2-dihydropyridin-3-yl)-N-hydroxyacrylamide (7k), showed excellent properties in a microsomal stability study, in a xenograft study, and in an in vivo pharmacokinetic evaluation. Modulation of RUNX3 therefore results in highly potent and orally available anticancer chemotherapeutic agents.

  8. Cosmic Ray Helium Intensities over the Solar Cycle from ACE

    NASA Technical Reports Server (NTRS)

    DeNolfo, G. A.; Yanasak, N. E.; Binns, W. R.; Cohen, C. M. S.; Cummings, A. C.; Davis, A. J.; George, J. S.; Hink. P. L.; Israel, M. H.; Lave, K.; Leske, R. A.; Mewaldt, R. A.; Moskalenko, I. V.; Ogliore, R.; Stone, E. C.; Von Rosenvinge, T. T.; Wiedenback, M. E.

    2007-01-01

    Observations of cosmic-ray helium energy spectra provide important constraints on cosmic ray origin and propagation. However, helium intensities measured at Earth are affected by solar modulation, especially below several GeV/nucleon. Observations of helium intensities over a solar cycle are important for understanding how solar modulation affects galactic cosmic ray intensities and for separating the contributions of anomalous and galactic cosmic rays. The Cosmic Ray Isotope Spectrometer (CRIS) on ACE has been measuring cosmic ray isotopes, including helium, since 1997 with high statistical precision. We present helium elemental intensities between approx. 10 to approx. 100 MeV/nucleon from the Solar Isotope Spectrometer (SIS) and CRIS observations over a solar cycle and compare these results with the observations from other satellite and balloon-borne instruments, and with GCR transport and solar modulation models.

  9. Angiotensin Converting Enzyme Inhibitors and Cognitive Decline in Older Adults with Hypertension: Results from the Cardiovascular Health Study

    PubMed Central

    Sink, Kaycee M.; Leng, Xiaoyan; Williamson, Jeff; Kritchevsky, Stephen B.; Yaffe, Kristine; Kuller, Lewis; Yasar, Sevil; Atkinson, Hal; Robbins, Mike; Psaty, Bruce; Goff, David C.

    2010-01-01

    Background Hypertension (HTN) is a risk factor for dementia and animal studies suggest that centrally active (cross the blood brain barrier) angiotensin converting enzyme (ACE) inhibitors may protect against dementia beyond HTN control. Methods Participants in the Cardiovascular Health Study cognition substudy (mean age 75 yrs) with treated HTN and no diagnosis of heart failure (n= 1054) were followed for a median of 6 years to determine whether cumulative exposure to ACE inhibitors (as a class and by central activity), compared to other antihypertensive agents, was associated with lower risk of incident dementia, cognitive decline (by the modified mini mental state exam, 3MSE), or incident disability in instrumental activities of daily living (IADL). Results Among 414 participants exposed to ACE inhibitors and 640 not, there were 158 cases of incident dementia. Compared to other anti-HTN drugs, there was no association between exposure to all ACE inhibitors and risk of dementia (HR 1.01, 95% CI 0.88–1.15), difference in 3MSE scores (−0.32 points/yr, p=0.15), or odds of IADL disability (OR (95% CI) 1.06 (0.99–1.14). Adjusted results were similar. However, centrally active ACE inhibitors were associated with 65% less decline in 3MSE scores per year of exposure (p= 0.01) and non-centrally active ACE inhibitors were associated with greater risk of incident dementia (adjusted HR 1.20 (1.00–1.43) per year of exposure) and greater odds of IADL disability (adjusted OR 1.16 (1.03–1.30) per year of exposure) compared to other anti-HTN drugs. Conclusions While ACE inhibitors as a class do not appear to be independently associated with dementia risk or cognitive decline in older hypertensive adults, there may be within class differences in regards to these outcomes. These results should be confirmed with an RCT of a centrally active ACE inhibitor in the prevention of cognitive decline and dementia. PMID:19597068

  10. The dipeptidyl peptidase-4 inhibitor linagliptin lowers postprandial glucose and improves measures of β-cell function in type 2 diabetes.

    PubMed

    Heise, T; Larbig, M; Patel, S; Seck, T; Hehnke, U; Woerle, H-J; Dugi, K

    2014-10-01

    Progressive deterioration of pancreatic β-cell function in patients with type 2 diabetes mellitus (T2DM) contributes to worsening of hyperglycaemia. To investigate the effects of the dipeptidyl peptidase-4 inhibitor linagliptin on β-cell function parameters, a pooled analysis of six randomized, 24-week, placebo-controlled, phase 3 trials of 5 mg of linagliptin daily was performed in 2701 patients with T2DM (linagliptin, n = 1905; placebo, n = 796). At week 24, observed improvements in HbA1c, fasting plasma glucose, and 2-h postprandial glucose were significantly greater for linagliptin than placebo (all p < 0.0001). Homeostasis model assessment (HOMA)-%β, as a surrogate marker of fasting β-cell function, was significantly improved with linagliptin, and did not change with placebo (placebo-adjusted mean ± s.e. change for linagliptin: 16.5 ± 4.6 (mU/l)/(mmol/l); p = 0.0003). Further study is required to determine if the significant improvement in HOMA-%β with linagliptin will translate into long-term improvements in β-cell function.

  11. The Solar Package on ISS: SOL-ACES

    NASA Astrophysics Data System (ADS)

    Wienhold, F. G.; Anders, J.; Galuska, B.; Klocke, U.; Knothe, M.; Neske, E.; Riedel, W. J.; Schmidtke, G.; Singler, R.; Ulmer, U.; Wolf, H.

    The "solar package" comprises the experiments SOLSPEC (UV/Vis to IR spectral range), SOVIM (total solar radiation) and SOL-ACES to be installed on a Coarse Pointing Device (CPD) of the International Space Station for a 1.5 year mission launched in 2003. The CPD allows for measuring periods of at least fifteen minutes per orbit totaling approximately 600 hours per year of solar observations. The Solar Auto Calibrating EUV/UV Spectrometers (SOL-ACES) are currently developed to measure the solar radiation (full disk) in the 17 nm to 220 nm spectral range with four grazing-incidence grating spectrometers. To obtain high radiometric accuracy of better than 10 %, a double ionization chamber is assigned to each of the spectrometers as a primary detector standard. Optical bandpass filters are mounted on a filter wheel to be placed at the entrance apertures of the spectrometers and ionization chambers and thereby will establish the radiometric link between these devices. The spectrometers are designed as scanning monochromators operating at fixed incidence angles. The deflected radiation is monitored by rotating an assembly containing a parabolic mirror, an exit slit and a channel electron multiplier around the grating center. The optical length of the ionization chamber of 0.5 m is divided into two identical electrode sections. In addition, the transmitted radiation is measured by a silicon diode detector located at the end of the absorption path. Detector and electrode signals are recorded as a function of the gas pressure in the chamber, which is increased from zero to a few hectopascal during a single measurement. These data permit the absolute quantification of the radiant solar flux in the wavelength interval transmitted by the bandpass filter and the correction for secondary effects, such as ionization caused by photoelectrons. With these measurements the spectrometer efficiencies at the filter bandpass wavelengths can be recalibrated as required during the mission.

  12. NADPH oxidase inhibitor, apocynin, improves renal glutathione status in Zucker diabetic fatty rats: a comparison with melatonin.

    PubMed

    Winiarska, Katarzyna; Focht, Dorota; Sierakowski, Bartosz; Lewandowski, Krystian; Orlowska, Marta; Usarek, Michal

    2014-07-25

    Apocynin (4'-hydroxy-3'-methoxyacetophenone) is the most commonly used NADPH oxidase (Nox) inhibitor. However, its application raises serious controversies, as the compound has been reported to reveal some prooxidative effects. The aim of this study was to elucidate apocynin action on glutathione, the main intracellular antioxidant, metabolism in kidneys of Zucker diabetic fatty (ZDF) rat, a well established model of diabetes type 2. Additionally, apocynin effects were compared with those of melatonin. The experiments were performed on five groups of animals: (1) untreated lean (?/+) ZDF rats, (2) ZDF ?/+ rats treated with apocynin (2 g/l) in drinking water, (3) untreated obese diabetic (fa/fa) ZDF rats, (4) ZDF fa/fa rats treated with apocynin (2 g/l) in drinking water, and (5) ZDF fa/fa rats treated with melatonin (20 mg/l) in drinking water. After 8weeks of the treatment, the following parameters were measured in kidneys: NADPH oxidase activity, the rate of hydroxyl free radicals (HFR) production, GSH and GSSG content and the activities of the enzymes of glutathione metabolism: γ-glutamylcysteine synthetase (GCS), glutathione reductase (GR) and glutathione peroxidase (GPx). Compared to ?/+ controls, ZDF fa/fa rats exhibited increased Nox activity, accelerated HFR generation and dramatically lowered GSH/GSSG ratio accompanied by increased GPx and diminished GCS activities. In case of diabetic animals, apocynin treatment resulted in attenuation of both Nox activity and HFR production, restoration of control GSH/GSSG ratio (due to both an increase in GSH and a decline in GSSG content), normalization of GPx activity and a slight increase in GCS activity. Similar observations were made upon melatonin application to ZDF fa/fa rats. Thus, it is concluded that, in the diabetic model studied, apocynin extends a beneficial effect on renal glutathione homeostasis. The mechanism of this phenomenon involves attenuation of glutathione peroxidase activity, which is

  13. Patients With Newly Diagnosed Hypertension Treated With the Renin Angiotensin Receptor Blocker Azilsartan Medoxomil vs Angiotensin-Converting Enzyme Inhibitors: The Prospective EARLY Registry.

    PubMed

    Schmieder, Roland E; Potthoff, Sebastian A; Bramlage, Peter; Baumgart, Peter; Mahfoud, Felix; Buhck, Hartmut; Ouarrak, Taoufik; Ehmen, Martina; Senges, Jochen; Gitt, Anselm K

    2015-12-01

    For patients with newly diagnosed hypertension, angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) are usually the first-line therapies. There is, however, no real-life data regarding the relative clinical effectiveness and tolerability of either drug class. The prospective registry, Treatment With Azilsartan Compared to ACE Inhibitors in Antihypertensive Therapy (EARLY), was conducted to evaluate the effectiveness of the ARB azilsartan medoxomil (AZL-M) vs ACE inhibitors in real-world patients. Of the 1153 patients with newly diagnosed hypertension who were included in the registry, 789 were prescribed AZL-M and 364 were prescribed an ACE inhibitor. After multivariate adjustment, AZL-M was found to provide superior blood pressure reduction and better target blood pressure (<140/90 mm Hg) achievement. The proportion of patients with adverse events was not statistically different between groups. The authors conclude that in newly diagnosed hypertensive patients, AZL-M provides superior blood pressure control with a similar safety profile compared with ACE inhibitors.

  14. Biodegradation of corrosion inhibitors and their influence on petroleum product pipeline.

    PubMed

    Rajasekar, Aruliah; Maruthamuthu, Sundaram; Palaniswamy, Narayanan; Rajendran, Annamalai

    2007-01-01

    The present study enlightens the role of Bacillus cereus ACE4 on biodegradation of commercial corrosion inhibitors (CCI) and the corrosion process on API 5LX steel. Bacillus cereus ACE4, a dominant facultative aerobic species was identified by 16S rDNA sequence analysis, which was isolated from the corrosion products of refined diesel-transporting pipeline in North West India. The effect of CCI on the growth of bacterium and its corrosion inhibition efficiency were investigated. Corrosion inhibition efficiency was studied by rotating cage test and the nature of biodegradation of corrosion inhibitors was also analyzed. This isolate has the capacity to degrade the aromatic and aliphatic hydrocarbon present in the corrosion inhibitors. The degraded products of corrosion inhibitors and bacterial activity determine the electrochemical behavior of API 5LX steel.

  15. Nine novel angiotensin I-converting enzyme (ACE) inhibitory peptides from cuttlefish (Sepia officinalis) muscle protein hydrolysates and antihypertensive effect of the potent active peptide in spontaneously hypertensive rats.

    PubMed

    Balti, Rafik; Bougatef, Ali; Sila, Assaâd; Guillochon, Didier; Dhulster, Pascal; Nedjar-Arroume, Naima

    2015-03-01

    This study aimed to identify novel ACE inhibitory peptides from the muscle of cuttlefish. Proteins were hydrolyzed and the hydrolysates were then subjected to various types of chromatography to isolate the active peptides. Nine ACE inhibitory peptides were isolated and their molecular masses and amino acid sequences were determined using ESI-MS and ESI-MS/MS, respectively. The structures of the most potent peptides were identified as Val-Glu-Leu-Tyr-Pro, Ala-Phe-Val-Gly-Tyr-Val-Leu-Pro and Glu-Lys-Ser-Tyr-Glu-Leu-Pro. The first peptide displayed the highest ACE inhibitory activity with an IC50 of 5.22μM. Lineweaver-Burk plots suggest that Val-Glu-Leu-Tyr-Pro acts as a non-competitive inhibitor against ACE. Furthermore, antihypertensive effects in spontaneously hypertensive rats (SHR) also revealed that oral administration of Val-Glu-Leu-Tyr-Pro can decrease systolic blood pressure significantly (p<0.01). These results suggest that the Val-Glu-Leu-Tyr-Pro would be a beneficial ingredient for nutraceuticals and pharmaceuticals acting against hypertension and its related diseases.

  16. A novel HSP90 inhibitor with reduced hepatotoxicity synergizes with radiotherapy to induce apoptosis, abrogate clonogenic survival, and improve tumor control in models of colorectal cancer

    PubMed Central

    Albrecht, Valerie; Hennel, Roman; Brix, Nikko; Frey, Benjamin; Gaipl, Udo S.; Zuchtriegel, Gabriele; Reichel, Christoph A.; Blutke, Andreas; Schilling, Daniela; Multhoff, Gabriele; Li, Minglun; Niyazi, Maximilian; Friedl, Anna A.; Winssinger, Nicolas; Belka, Claus; Lauber, Kirsten

    2016-01-01

    The chaperone heat shock protein 90 (HSP90) crucially supports the maturation, folding, and stability of a variety of client proteins which are of pivotal importance for the survival and proliferation of cancer cells. Consequently, targeting of HSP90 has emerged as an attractive strategy of anti-cancer therapy, and it appears to be particularly effective in the context of molecular sensitization towards radiotherapy as has been proven in preclinical models of different cancer entities. However, so far the clinical translation has largely been hampered by suboptimal pharmacological properties and serious hepatotoxicity of first- and second-generation HSP90 inhibitors. Here, we report on NW457, a novel radicicol-derived member of the pochoxime family with reduced hepatotoxicity, how it inhibits the DNA damage response and how it synergizes with ionizing irradiation to induce apoptosis, abrogate clonogenic survival, and improve tumor control in models of colorectal cancer in vitro and in vivo. PMID:27259245

  17. Is there an ACE ID - ACTN3 R577X polymorphisms interaction that influences sprint performance?

    PubMed

    Eynon, N; Alves, A J; Yamin, C; Sagiv, M; Duarte, J A; Oliveira, J; Ayalon, M; Goldhammer, E; Sagiv, M; Meckel, Y

    2009-12-01

    Functional R577X (rs.1815739) and ID (rs.5186) polymorphisms in the alpha-actinin-3 ( ACTN3) and the angiotensin converting enzyme (ACE) genes, respectively, have been associated with sprint performance. The aim of this study was to determine their effect on sprint performance among 81 Israeli sprinters and 240 healthy controls. Results revealed that the ACE II genotype+ ACTN3 R allele (P=0.003 for sprinters vs. controls), and the ACTN3 RR genotype +ACE I allele (P=0.001 for sprinters vs. controls) might be the genotype for sprinters. In the whole cohort the probability of ACTN3 RR genotype+ ACE I allele being a sprinter (odds ratio 2.67, 95% confidence interval 1.45-4.93) and of ACE II genotype+ ACTN3 R allele being a sprinter (odds ratio 3.57, 95% confidence interval 1.78-7.15) was significantly higher than that in the controls. In conclusion, the above data suggest that ACE ID/ ACTN3 R577X genotype combination is associated with sprint ability. However, ACE ID/ ACTN3 R577X genotype combination is not related to the level of performance.

  18. ACE I/D Polymorphism in Hypertensive Patients of Kashmiri Population

    PubMed Central

    Sameer, A. Syed; Syeed, Nidda; Tak, Shahid A.; Bashir, Samina; Nissar, Saniya; Siddiqi, Mushtaq A.

    2010-01-01

    Background The angiotensin-converting enzyme (ACE) gene in humans has an insertion-deletion (I/D) polymorphic state in intron 16 on chromosome 17q23. This polymorphism has been widely investigated in different diseases. In this study we aimed to investigate the ACE I/D genotype frequency in hypertensive cases in Kashmiri population. Materials and Methods We designed a case control study, where 52 hypertensive cases were studied for ACE I/D polymorphism against 150 age/sex matched controls taken from general population. The polymorphisms of ACE gene were investigated using polymerase chain reaction for detection of ACE I/D genotype. Fisher’s Chi square test was used for calculation of P value and OR. Results We found the frequency of ACE DD genotype to be 46.15% (24/52), II 23.07% (12/52) and DI 30.77% (16/52) in 52 hypertensive cases. Conclusions The ACE I/D genotype is positively associated with hypertension in our population.

  19. Switch from unboosted protease inhibitor to a single-tablet regimen containing rilpivirine improves cholesterol and triglycerides.

    PubMed

    Di Biagio, Antonio; Riccardi, Niccolò; Taramasso, Lucia; Capetti, Amedeo; Cenderello, Giovanni; Signori, Alessio; Vitiello, Paola; Guerra, Michele; de Socio, Giuseppe Vittorio; Cassola, Giovanni; Quirino, Tiziano; Viscoli, Claudio

    2016-11-01

    This study aimed to evaluate the efficacy, tolerability and potential savings of combined antiretroviral therapy (cART) simplification from an unboosted protease inhibitor (PI) regimen with atazanavir or fosamprenavir to a single-tablet regimen (STR) based on rilpivirine/emtricitabine/tenofovir disoproxil fumarate (RPV/FTC/TDF) among HIV-1-infected patients with HIV-1 RNA <50 copies/mL. This was a retrospective, multicentre, open-label, 12-week trial. Plasma HIV-1-RNA levels, CD4+ cell counts, cholesterol, triglycerides, bilirubin, glycaemia, creatinine and physical examination were performed at baseline and at scheduled follow-up. All patient costs were calculated and were estimated for 52 weeks of therapy. Fifty-one patients were enrolled [28 male (54.9%)]. At baseline, 30 patients (58.8%) were treated with FTC/TDF, 20 (39.2%) with abacavir/lamivudine and 1 (2.0%) with lamivudine/zidovudine. Thirty-three patients (64.7%) received atazanavir. All patients maintained HIV-RNA <50 copies/mL; the median CD4+ cell count remained stable. Mean triglycerides decreased from 124 mg/dL (range, 39-625) at enrolment to 108.7 mg/dL (range, 39-561) at study end (P = 0.25). At baseline, mean cholesterol was 172.8 ± 38.1 mg/dL and decreased to 161.9 ± 38.6 mg/dL (P = 0.038); likewise, median total bilirubin decreased from 1.07 mg/dL (range, 0.2-4.7) to 0.6 mg/dL (range, 0.13-3.1) (P <0.001). cART-related annual cost reduction with a STR was €3155.47 per patient (-24%). Non-cART patient management expenses were €402.68 vs. €299.10 for atazanavir or fosamprenavir and STR regimens, respectively. Switching to RPV/FTC/TDF from an unboosted PI in virologically suppressed HIV-infected patients is safe and is associated with a reduction in triglycerides, cholesterol and cART-related costs.

  20. Dst Prediction from CIR Events During 2008 Using Synthesized Signals Derived From SOHO, STEREO, and ACE Observations

    NASA Astrophysics Data System (ADS)

    Spencer, E. A.; Andriyas, T.; Mays, M. L.; Sojka, J. J.

    2011-12-01

    Observations from SOHO, STEREO, and ACE during the declining phase of the deep solar minimum in 2008 are analyzed in order to synthesize signals of the IMF Bz, solar wind velocity vx, and solar wind proton density Np at 1 AU. These synthesized signals are used as a substitute for ACE measurements to represent solar wind forcing due to coronal hole driven CIR events occuring during multiple Bartel rotations (BR 2381 - BR 2393). The signals drive a low order physics based model of the magnetosphere called WINDMI, one of whose outputs is the ground based measurement of the Dst index. Estimating the arrival of CIR events for future rotations using ACE and SOHO data during BR 2381 produced what we referred to as an uncalibrated yearly prediction. We proceeded to generate a video calibrated (VC) estimate of the arrival times of CIR events in addition to information from BR 2381 using SOHO and STEREO images of the Sun in order to produce a simulated 3.5 day ahead prediction of possible geomagnetic activity. The time of arrival of CIR events is taken to be the travel time of compressions as seen in a non-inertial frame according to a radial solar wind speed of 500 km/s and a distance of 1 AU. We found that we were able to predict the timing of CIR induced geomagnetic activity quite accurately by using the expected recurrence of the events through multiple Bartel rotations, and further improve it through SOHO and STEREO coronal hole sightings made 3.5 days before every event. The uncertainty in the IMF Bz led to predictions of levels of geomagnetic activity on an ensemble basis, yielding a distribution of different possible Dst signatures.

  1. New Tools to Prepare ACE Cross-section Files for MCNP Analytic Test Problems

    SciTech Connect

    Brown, Forrest B.

    2016-06-17

    Monte Carlo calculations using one-group cross sections, multigroup cross sections, or simple continuous energy cross sections are often used to: (1) verify production codes against known analytical solutions, (2) verify new methods and algorithms that do not involve detailed collision physics, (3) compare Monte Carlo calculation methods with deterministic methods, and (4) teach fundamentals to students. In this work we describe 2 new tools for preparing the ACE cross-section files to be used by MCNP® for these analytic test problems, simple_ace.pl and simple_ace_mg.pl.

  2. Progress on the Multiphysics Capabilities of the Parallel Electromagnetic ACE3P Simulation Suite

    SciTech Connect

    Kononenko, Oleksiy

    2015-03-26

    ACE3P is a 3D parallel simulation suite that is being developed at SLAC National Accelerator Laboratory. Effectively utilizing supercomputer resources, ACE3P has become a key tool for the coupled electromagnetic, thermal and mechanical research and design of particle accelerators. Based on the existing finite-element infrastructure, a massively parallel eigensolver is developed for modal analysis of mechanical structures. It complements a set of the multiphysics tools in ACE3P and, in particular, can be used for the comprehensive study of microphonics in accelerating cavities ensuring the operational reliability of a particle accelerator.

  3. Interaction of diabetes and ACE2 in the pathogenesis of cardiovascular disease in experimental diabetes.

    PubMed

    Tikellis, Chris; Pickering, Raelene; Tsorotes, Despina; Du, Xiao-Jun; Kiriazis, Helen; Nguyen-Huu, Thu-Phuc; Head, Geoffrey A; Cooper, Mark E; Thomas, Merlin C

    2012-10-01

    Local and systemic AngII (angiotensin II) levels are regulated by ACE2 (angiotensin-converting enzyme 2), which is reduced in diabetic tissues. In the present study, we examine the effect of ACE2 deficiency on the early cardiac and vascular changes associated with experimental diabetes. Streptozotocin diabetes was induced in male C57BL6 mice and Ace2-KO (knockout) mice, and markers of RAS (renin-angiotensin system) activity, cardiac function and injury were assessed after 10 weeks. In a second protocol, diabetes was induced in male ApoE (apolipoprotein E)-KO mice and ApoE/Ace2-double-KO mice, and plaque accumulation and markers of atherogenesis assessed after 20 weeks. The induction of diabetes in wild-type mice led to reduced ACE2 expression and activity in the heart, elevated circulating AngII levels and reduced cardiac Ang-(1-7) [angiotensin-(1-7)] levels. This was associated structurally with thinning of the LV (left ventricular) wall and mild ventricular dilatation, and histologically with increased cardiomyocyte apoptosis on TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling) staining and compensatory hypertrophy denoted by an increased cardiomyocyte cross-sectional area. By contrast Ace2-KO mice failed to increase circulating AngII concentration, experienced a paradoxical fall in cardiac AngII levels and no change in Ang-(1-7) following the onset of diabetes. At the same time the major phenotypic differences between Ace2-deficient and Ace2-replete mice with respect to BP (blood pressure) and cardiac hypertrophy were eliminated following the induction of diabetes. Consistent with findings in the heart, the accelerated atherosclerosis that was observed in diabetic ApoE-KO mice was not seen in diabetic ApoE/Ace2-KO mice, which experienced no further increase in plaque accumulation or expression in key adhesion molecules beyond that seen in ApoE/Ace2-KO mice. These results point to the potential role of ACE2 deficiency in regulating

  4. APL workers install CRIS on the Advanced Composition Explorer (ACE) in SAEF-2

    NASA Technical Reports Server (NTRS)

    1997-01-01

    Workers from the Johns Hopkins University's Applied Physics Laboratory (APL) install the Cosmic Ray Isotope Spectrometer (CRIS) on the Advanced Composition Explorer (ACE) spacecraft in KSC's Spacecraft Assembly and Encapsulation Facility-2 (SAEF-2). From left, are Al Sadilek, Marcos Gonzalez and Cliff Willey. CRIS is one of nine instruments on ACE, which will investigate the origin and evolution of solar phenomenon, the formation of the solar corona, solar flares and the acceleration of the solar wind. ACE was developed for NASA by the APL. The spacecraft is scheduled to be launched Aug. 21 aboard a two-stage Delta II 7920-8 rocket from Space Launch Complex 17, Pad A.

  5. The first stage of the Delta II for ACE is erected at LC 17A, CCAS

    NASA Technical Reports Server (NTRS)

    1997-01-01

    The first stage of the Delta II rocket which will to be used to launch the Advanced Composition Explorer (ACE) spacecraft is erected at Launch Complex 17A at Cape Canaveral Air Station. Scheduled for launch on Aug. 25, ACE will study low-energy particles of solar origin and high-energy galactic particles. The ACE observatory will be placed into an orbit almost a million miles (1.5 million kilometers) away from the Earth, about 1/100 the distance from the Earth to the Sun.

  6. Differential regulation of the cellulase transcription factors XYR1, ACE2, and ACE1 in Trichoderma reesei strains producing high and low levels of cellulase.

    PubMed

    Portnoy, Thomas; Margeot, Antoine; Seidl-Seiboth, Verena; Le Crom, Stéphane; Ben Chaabane, Fadhel; Linke, Rita; Seiboth, Bernhard; Kubicek, Christian P

    2011-02-01

    Due to its capacity to produce large amounts of cellulases, Trichoderma reesei is increasingly being investigated for second-generation biofuel production from lignocellulosic biomass. The induction mechanisms of T. reesei cellulases have been described recently, but the regulation of the genes involved in their transcription has not been studied thoroughly. Here we report the regulation of expression of the two activator genes xyr1 and ace2, and the corepressor gene ace1, during the induction of cellulase biosynthesis by the inducer lactose in T. reesei QM 9414, a strain producing low levels of cellulase (low producer). We show that all three genes are induced by lactose. xyr1 was also induced by d-galactose, but this induction was independent of d-galactose metabolism. Moreover, ace1 was carbon catabolite repressed, whereas full induction of xyr1 and ace2 in fact required CRE1. Significant differences in these regulatory patterns were observed in the high-producer strain RUT C30 and the hyperproducer strain T. reesei CL847. These observations suggest that a strongly elevated basal transcription level of xyr1 and reduced upregulation of ace1 by lactose may have been important for generating the hyperproducer strain and that thus, these genes are major control elements of cellulase production.

  7. Effect of extrusion process on antioxidant and ACE inhibition properties from bovine haemoglobin concentrate hydrolysates incorporated into expanded maize products.

    PubMed

    Cian, Raúl E; Luggren, Pablo; Drago, Silvina R

    2011-11-01

    Extrusion process has been widely used for the development of many functional foods. The aim of this study was to assess the effect of extrusion process on antioxidant and angiotensin-converting enzyme (ACE) inhibition properties from bovine haemoglobin concentrate (BHC) hydrolysates (P, FC, PF and FCF). Extrusion was carried out with a Brabender single screw extruder. The ACE inhibition and the antioxidant capacity (AC) were estimated by the inhibition of the ACE and ABTS+√ radical cation expressed as Trolox equivalent antioxidant capacity (TEAC), respectively. The ACE inhibition and TEAC values from hydrolysates were significantly higher than that from BHC. The highest ACE inhibition corresponded to P hydrolysate and the highest TEAC corresponded to PF and FCF hydrolysates. The ACE inhibition and AC from extruded products with added hydrolysates were higher than that from maize control; however, the extrusion process modified both ACE inhibition and AC formerly present in hydrolysates.

  8. Differential downregulation of ACE2 by the spike proteins of severe acute respiratory syndrome coronavirus and human coronavirus NL63.

    PubMed

    Glowacka, Ilona; Bertram, Stephanie; Herzog, Petra; Pfefferle, Susanne; Steffen, Imke; Muench, Marcus O; Simmons, Graham; Hofmann, Heike; Kuri, Thomas; Weber, Friedemann; Eichler, Jutta; Drosten, Christian; Pöhlmann, Stefan

    2010-01-01

    The human coronaviruses (CoVs) severe acute respiratory syndrome (SARS)-CoV and NL63 employ angiotensin-converting enzyme 2 (ACE2) for cell entry. It was shown that recombinant SARS-CoV spike protein (SARS-S) downregulates ACE2 expression and thereby promotes lung injury. Whether NL63-S exerts a similar activity is yet unknown. We found that recombinant SARS-S bound to ACE2 and induced ACE2 shedding with higher efficiency than NL63-S. Shedding most likely accounted for the previously observed ACE2 downregulation but was dispensable for viral replication. Finally, SARS-CoV but not NL63 replicated efficiently in ACE2-positive Vero cells and reduced ACE2 expression, indicating robust receptor interference in the context of SARS-CoV but not NL63 infection.

  9. One-year treatment of Alzheimer's disease with acetylcholinesterase inhibitors: improvement on ADAS-cog and TMT A, no change or worsening on other tests.

    PubMed

    Borkowska, Alina; Ziolkowska-Kochan, Marzena; Rybakowski, Janusz K

    2005-08-01

    The aim of this study was to assess cognitive functioning measured by selected psychometric and neuropsychological tools in patients with Alzheimer's disease (AD) after 1-year treatment with acetylcholinesterase inhibitors. Seventy-six patients (22 male and 54 female) with a mild to moderate stage of AD, aged 56-86 (mean 68) years, were treated. Forty-seven received donepezil (mean dose 9.3 mg/d) and 29 rivastigmine (mean dose 8.5 mg/d). Cognitive measurements included: the mini mental state examination (MMSE), the Alzheimer disease assessment scale-cognitive (ADAS- cog), the trail making test (TMT) and the Stroop color word interference test. The assessments were made before and after 3, 6 and 12 months of treatment. A significant improvement in ADAS-cog (p < 0.001, 83% of patients improved) and a worsening in MMSE (84% of patients worsened, p < 0.01 after 6 and 12 months) was noted after the 1 year treatment. A majority of patients (57%) improved in the TMT-A (p < 0.001), measuring psychomotor speed and worsened in the TMT-B (p < 0.01, after 12 months), and Stroop B test (p < 0.001), measuring working memory and executive functions, 53% and 61%, respectively. Most patients (83%) did not change their performance in the Stroop A (improvement after 3 months, p < 0.001, worsening after 6 and 12 months p < 0.01) test measuring verbal abilities, after 1 year treatment. The results obtained suggest that the treatment with cholinergic drugs may improve global cognitive functioning (ADAS-cog) and psychomotor speed (TMT A), however, such treatment is unable to prevent the deterioration of working memory and executive functions.

  10. Small-Molecule Inhibitors of Cytokine-Mediated STAT1 Signal Transduction In β-Cells With Improved Aqueous Solubility

    PubMed Central

    Scully, Stephen S.; Tang, Alicia J.; Lundh, Morten; Mosher, Carrie M.; Perkins, Kedar M.; Wagner, Bridget K.

    2013-01-01

    We previously reported the discovery of BRD0476 (1), a small molecule generated by diversity-oriented synthesis that suppresses cytokine-induced β-cell apoptosis. Herein, we report the synthesis and biological evaluation of 1 and analogs with improved aqueous solubility. By replacing naphthyl with quinoline moieties, we prepared active analogs with up to a 1400-fold increase in solubility from 1. In addition, we demonstrated that compound 1 and analogs inhibit STAT1 signal transduction induced by IFN-γ. PMID:23617753

  11. Beneficial effects and improved survival in rodent models of septic shock with S-methylisothiourea sulfate, a potent and selective inhibitor of inducible nitric oxide synthase.

    PubMed Central

    Szabó, C; Southan, G J; Thiemermann, C

    1994-01-01

    Enhanced formation of nitric oxide (NO) by both the constitutive and the inducible isoforms of NO synthase (NOS) has been implicated in the pathophysiology of a variety of diseases, including circulatory shock. Non-isoform-selective inhibition of NO formation, however, may lead to side effects by inhibiting the constitutive isoform of NOS and, thus, the various physiological actions of NO. S-Methylisothiourea sulfate (SMT) is at least 10- to 30-fold more potent as an inhibitor of inducible NOS (iNOS) in immunostimulated cultured macrophages (EC50, 6 microM) and vascular smooth muscle cells (EC50, 2 microM) than NG-methyl-L-arginine (MeArg) or any other NOS inhibitor yet known. The effect of SMT on iNOS activity can be reversed by excess L-arginine in a concentration-dependent manner. SMT (up to 1 mM) does not inhibit the activity of xanthine oxidase, diaphorase, lactate dehydrogenase, monoamine oxidase, catalase, cytochrome P450, or superoxide dismutase. SMT is equipotent with MeArg in inhibiting the endothelial, constitutive isoform of NOS in vitro and causes increases in blood pressure similar to those produced by MeArg in normal rats. SMT, however, dose-dependently reverses (0.01-3 mg/kg) the hypotension and the vascular hyporeactivity to vasoconstrictor agents caused by endotoxin [bacterial lipopolysaccharide (LPS), 10 mg/kg, i.v.] in anesthetized rats. Moreover, therapeutic administration of SMT (5 mg/kg, i.p., given 2 hr after LPS, 10 mg/kg, i.p.) attenuates the rises in plasma alanine and aspartate aminotransferases, bilirubin, and creatinine and also prevents hypocalcaemia when measured 6 hr after administration of LPS. SMT (1 mg/kg, i.p.) improves 24-hr survival of mice treated with a high dose of LPS (60 mg/kg, i.p.). Thus, SMT is a potent and selective inhibitor of iNOS and exerts beneficial effects in rodent models of septic shock. SMT, therefore, may have considerable value in the therapy of circulatory shock of various etiologies and other

  12. Statins, HMG-CoA Reductase Inhibitors, Improve Neovascularization by Increasing the Expression Density of CXCR4 in Endothelial Progenitor Cells.

    PubMed

    Chiang, Kuang-Hsing; Cheng, Wan-Li; Shih, Chun-Ming; Lin, Yi-Wen; Tsao, Nai-Wen; Kao, Yung-Ta; Lin, Chih-Ting; Wu, Shinn-Chih; Huang, Chun-Yao; Lin, Feng-Yen

    2015-01-01

    Statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, are used to reduce cholesterol biosynthesis in the liver. Accordingly, statins regulate nitric oxide (NO) and glutamate metabolism, inflammation, angiogenesis, immunity and endothelial progenitor cells (EPCs) functions. The function of EPCs are regulated by stromal cell-derived factor 1 (SDF-1), vascular endothelial growth factor (VEGF), and transforming growth factor β (TGF-β), etc. Even though the pharmacologic mechanisms by which statins affect the neovasculogenesis of circulating EPCs, it is still unknown whether statins affect the EPCs function through the regulation of CXCR4, a SDF-1 receptor expression. Therefore, we desired to explore the effects of statins on CXCR4 expression in EPC-mediated neovascularization by in vitro and in vivo analyses. In animal studies, we analyzed the effects of atorvastatin or rosuvastatin treatments in recovery of capillary density and blood flow, the expression of vWF and CXCR4 at ischemia sites in hindlimb ischemia ICR mice. Additionally, we analyzed whether the atorvastatin or rosuvastatin treatments increased the mobilization, homing, and CXCR4 expression of EPCs in hindlimb ischemia ICR mice that underwent bone marrow transplantation. The results indicated that statins treatment led to significantly more CXCR4-positive endothelial progenitor cells incorporated into ischemic sites and in the blood compared with control mice. In vivo, we isolated human EPCs and analyzed the effect of statins treatment on the vasculogenic ability of EPCs and the expression of CXCR4. Compared with the control groups, the neovascularization ability of EPCs was significantly improved in the atorvastatin or rosuvastatin group; this improvement was dependent on CXCR4 up-regulation. The efficacy of statins on improving EPC neovascularization was related to the SDF-1α/CXCR4 axis and might be regulated by the NO. In conclusion, atorvastatin and rosuvastatin improved

  13. Effects of bradykinin B2 receptor antagonism on the hypotensive effects of ACE inhibition.

    PubMed Central

    Bouaziz, H; Joulin, Y; Safar, M; Benetos, A

    1994-01-01

    1. The aim of this study was to determine the participation of endogenous bradykinin (BK) in the antihypertensive effects of the angiotensin converting enzyme inhibitor (ACEI), perindoprilat, in the spontaneously hypertensive rat (SHR) on different salt diets. 2. Conscious SHRs receiving either a low or a high NaCl diet were used in order to evaluate the respective roles of angiotensin II suppression and bradykinin stimulation in the acute hypotensive effects of perindoprilat. Two different B2 receptor antagonists (B 4146 and Hoe 140) were used after bolus administration of 7 mg kg-1 of the ACEI, perindoprilat. In separate animals, Hoe 140 was administered before the injection of perindoprilat. In other experiments, the effects of Hoe 140 on the hypotensive effects of the calcium antagonist, nicardipine, were tested. 3. The different NaCl diets had no effect on baseline blood pressure. Hoe 140 injection before ACE inhibition did not modify blood pressure. Perindoprilat caused more marked hypotension in the low salt-fed rats than in the high salt animals (P < 0.01). Administration of Hoe 140 or B4146 after perindoprilat significantly reduced the antihypertensive effects of perindoprilat in the different groups, but this effect was more pronounced in high salt-fed rats. However, in SHRs receiving Hoe 140 before perindoprilat, the antihypertensive effect of perindoprilat was completely abolished in both high or low salt diet rats. In separate experiments we confirmed that Hoe 140 did not affect the hypotensive efficacy of the calcium antagonist, nicardipine. 4. Our study shows that inhibition of endogenous bradykinin degradation participates in the acute antihypertensive effects of perindoprilat in SHRs. The role of bradykinin is more pronounced following exposure to a high salt diet i.e., when the renin-angiotensin system is suppressed.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7858859

  14. ACE2: Angiotensin II/Angiotensin-(1-7) balance in cardiorenal injury

    PubMed Central

    Varagic, Jasmina; Ahmad, Sarfaraz; Nagata, Sayaka; Ferrario, Carlos M.

    2014-01-01

    Our current recognition of the renin-angiotensin system is more convoluted than originally thought due to the discovery of multiple novel enzymes, peptides, and receptors inherent to this interactive biochemical cascade. Over the last decade angiotensin converting enzyme 2 (ACE2) has emerged as a key player in the pathophysiology of hypertension and cardiovascular and renal disease due to its pivotal role in metabolizing vasoconstrictive/hypertrophic/proliferative angiotensin II into favorable angiotensin-(1-7). This review addresses a considerable advancement in research on the role of tissue ACE2 in development and progression of hypertension and cardiorenal injury. We also summarize the results from recent clinical and experimental studies suggesting that serum or urine soluble ACE2 may serve as a novel biomarker or independent risk factor relevant for diagnosis and prognosis of cardiorenal disease. Recent proceedings on novel therapeutic approaches to enhance ACE2/angiotensin-(1-7) axis are also reviewed. PMID:24510672

  15. Atmospheric Chemistry Experiment (ACE) Measurements of Tropospheric and Stratospheric Chemistry and Long-Term Trends

    NASA Technical Reports Server (NTRS)

    Rinsland, Curtis P.; Bernath, Peter; Boone, Chris; Nassar, Ray

    2007-01-01

    We highlight chemistry and trend measurement results from the Atmospheric Chemistry Experiment (ACE) which is providing precise middle troposphere to the lower thermosphere measurements with a 0.02/cm resolution Fourier transform spectrometer covering 750-4400/cm

  16. MicroRNA-324-3p Promotes Renal Fibrosis and Is a Target of ACE Inhibition

    PubMed Central

    Tomasoni, Susanna; Romagnani, Paola; Trionfini, Piera; Sangalli, Fabio; Mazzinghi, Benedetta; Rizzo, Paola; Lazzeri, Elena; Abbate, Mauro; Remuzzi, Giuseppe; Benigni, Ariela

    2012-01-01

    The contribution of microRNA (miRNA) to the pathogenesis of renal fibrosis is not well understood. Here, we investigated whether miRNA modulates the fibrotic process in Munich Wistar Fromter (MWF) rats, which develop spontaneous progressive nephropathy. We analyzed the expression profile of miRNA in microdissected glomeruli and found that miR-324-3p was the most upregulated. In situ hybridization localized miR-324-3p to glomerular podocytes, parietal cells of Bowman’s capsule, and most abundantly, cortical tubules. A predicted target of miR-324-3p is prolyl endopeptidase (Prep), a serine peptidase involved in the metabolism of angiotensins and the synthesis of the antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP). In cultured tubular cells, transient transfection with a miR-324-3p mimic reduced Prep protein and activity, validating Prep as a target of this miRNA. In MWF rats, upregulation of miR-324-3p associated with markedly reduced expression of Prep in both glomeruli and tubules, low urine Ac-SDKP, and increased deposition of collagen. ACE inhibition downregulated glomerular and tubular miR-324-3p, promoted renal Prep expression, increased plasma and urine Ac-SDKP, and attenuated renal fibrosis. In summary, these results suggest that dysregulation of the miR-324-3p/Prep pathway contributes to the development of fibrosis in progressive nephropathy. The renoprotective effects of ACE inhibitors may result, in part, from modulation of this pathway, suggesting that it may hold other potential therapeutic targets. PMID:22822076

  17. The dipeptidyl peptidase-4 inhibitor teneligliptin improved endothelial dysfunction and insulin resistance in the SHR/NDmcr-cp rat model of metabolic syndrome.

    PubMed

    Nakagami, Hironori; Pang, Zhengda; Shimosato, Takashi; Moritani, Toshinori; Kurinami, Hitomi; Koriyama, Hiroshi; Tenma, Akiko; Shimamura, Munehisa; Morishita, Ryuichi

    2014-07-01

    Diabetes mellitus, hypertension and metabolic syndrome are major risk factors for the occurrence of cardiovascular events. In this study, we used spontaneous hypertensive rat (SHR)/NDmcr-cp (cp/cp) (SHRcp) rats as a model for metabolic syndrome to examine the effects of dipeptidyl peptidase (DPP)-4 inhibition on hypertension, glucose metabolism and endothelial dysfunction. First, we confirmed that SHRcp rats showed very severe obesity, hypertension and endothelial dysfunction phenotypes from 14 to 54 weeks of age. Next, we examined whether the DPP-4 inhibitor teneligliptin (10 mg kg(-1) per day per os for 12 weeks) could modify any of these phenotypes. Treatment with teneligliptin significantly improved hyperglycemia and insulin resistance, as evidenced by an oral glucose tolerance test and homeostasis model assessment for insulin resistance, respectively. Teneligliptin showed no effects on systolic blood pressure or heart rate. In regard to endothelial function, the vasodilator response to acetylcholine was significantly impaired in SHRcp rats when compared with WKY rats. Long-term treatment with teneligliptin significantly attenuated endothelial dysfunction through the upregulation of endothelium-derived nitric oxide synthase mRNA. These results demonstrate that long-term treatment with teneligliptin significantly improved endothelial dysfunction and glucose metabolism in a rat model of metabolic syndrome, suggesting that teneligliptin treatment might be beneficial for patients with hypertension and/or diabetes.

  18. A triazolopyrimidine-based dihydroorotate dehydrogenase inhibitor (DSM421) with improved drug-like properties for treatment and prevention of malaria

    PubMed Central

    Phillips, Margaret A.; White, Karen L.; Kokkonda, Sreekanth; Deng, Xiaoyi; White, John; Mazouni, Farah El; Marsh, Kennan; Tomchick, Diana R.; Manjalanagara, Krishne; Rudra, Kakali Rani; Wirjanata, Grennady; Noviyanti, Rintis; Price, Ric N; Marfurt, Jutta; Shackleford, David M.; Chiu, Francis C.K.; Campbell, Michael; Jimenez-Diaz, Maria Belen; Bazaga, Santiago Ferrer; Angulo-Barturen, Iñigo; Martinez, Maria Santos; Lafuente-Monasterio, Maria; Kaminsky, Werner; Silue, Kigbafori; Zeeman, Anne-Marie; Kocken, Clemens; Leroy, Didier; Blasco, Benjamin; Rossignol, Emilie; Rueckle, Thomas; Matthews, Dave; Burrows, Jeremy N.; Waterson, David; Palmer, Michael J.; Rathod, Pradipsinh K.; Charman, Susan A.

    2016-01-01

    The emergence of drug resistant malaria parasites continues to hamper efforts to control this lethal disease. Dihydroorotate dehydrogenase has recently been validated as a new target for the treatment of malaria and a selective inhibitor (DSM265) of the Plasmodium enzyme is currently in clinical development. With the goal of identifying a backup compound to DSM265, we explored replacement of the SF5-aniline moiety of DSM265 with a series of CF3-pyridinyls, while maintaining the core triazolopyrimidine scaffold. This effort led to the identification of DSM421, which has improved solubility, lower intrinsic clearance and increased plasma exposure after oral dosing compared to DSM265, while maintaining a long predicted human half-life. Its improved physical and chemical properties will allow it to be formulated more readily than DSM265. DSM421 showed excellent efficacy in the SCID mouse model of P. falciparum malaria that supports the prediction of a low human dose (<200 mg). Importantly DSM421 showed equal activity against both P. falciparum and P. vivax field isolates, while DSM265 was more active on P. falciparum. DSM421 has the potential to be developed as a single dose cure or once-weekly chemopreventative for both P. falciparum and P. vivax malaria leading to its advancement as a preclinical development candidate. PMID:27641613

  19. DPP4-inhibitor improves neuronal insulin receptor function, brain mitochondrial function and cognitive function in rats with insulin resistance induced by high-fat diet consumption.

    PubMed

    Pipatpiboon, Noppamas; Pintana, Hiranya; Pratchayasakul, Wasana; Chattipakorn, Nipon; Chattipakorn, Siriporn C

    2013-03-01

    High-fat diet (HFD) consumption has been demonstrated to cause peripheral and neuronal insulin resistance, and brain mitochondrial dysfunction in rats. Although the dipeptidyl peptidase-4 inhibitor, vildagliptin, is known to improve peripheral insulin sensitivity, its effects on neuronal insulin resistance and brain mitochondrial dysfunction caused by a HFD are unknown. We tested the hypothesis that vildagliptin prevents neuronal insulin resistance, brain mitochondrial dysfunction, learning and memory deficit caused by HFD. Male rats were divided into two groups to receive either a HFD or normal diet (ND) for 12 weeks, after which rats in each group were fed with either vildagliptin (3 mg/kg/day) or vehicle for 21 days. The cognitive function was tested by the Morris Water Maze prior to brain removal for studying neuronal insulin receptor (IR) and brain mitochondrial function. In HFD rats, neuronal insulin resistance and brain mitochondrial dysfunction were demonstrated, with impaired learning and memory. Vildagliptin prevented neuronal insulin resistance by restoring insulin-induced long-term depression and neuronal IR phosphorylation, IRS-1 phosphorylation and Akt/PKB-ser phosphorylation. It also improved brain mitochondrial dysfunction and cognitive function. Vildagliptin effectively restored neuronal IR function, increased glucagon-like-peptide 1 levels and prevented brain mitochondrial dysfunction, thus attenuating the impaired cognitive function caused by HFD.

  20. Phosphodiesterase type 5 inhibitor administered immediately after radical prostatectomy temporarily increases the need for incontinence pads, but improves final continence status

    PubMed Central

    Yamashita, Shinichi; Ito, Akihiro; Kawasaki, Yoshihide; Izumi, Hideaki; Kawamorita, Naoki; Adachi, Hisanobu; Mitsuzuka, Koji; Arai, Yoichi

    2016-01-01

    Purpose To evaluate the effects of phosphodiesterase type 5 inhibitor (PDE5i) on urinary continence recovery after bilateral nerve-sparing radical prostatectomy (BNSRP). Materials and Methods Between 2002 and 2012, 137 of 154 consecutive patients who underwent BNSRP in our institution retrospectively divided into 3 groups that included patients taking PDE5i immediately after surgery (immediate PDE5i group, n=41), patients